JP2022509742A - Measurement of elevated levels of circulating ketone bodies in physiological fluids - Google Patents

Abstract

Ketoacidosis is a medical emergency that requires immediate intervention to avoid life-threatening sequelae. It is configured to measure the level of a ketone compound circulating in the wearer's physiological fluid and is to generate a warning to the wearer if the level of the circulating ketone compound exceeds a given level or rate of change. Possible body-worn sensors (50) are disclosed herein. The sensor (50) is preferably an electrochemical sensor, an optical sensor, a galvanic sensor, a voltanmetric sensor, an amperometric sensor, a potentiality sensor, an impedance sensor, a resistance sensor, a capacitance sensor, an ultrasonic sensor, and a radio frequency. Includes at least one of a sensor, or a microwave sensor.
[Selection diagram] Fig. 1

Description

The techniques described herein provide a device and method for generating viable warnings to the user by measurement using a skin-worn analyte selective sensor for circulating ketone body levels in the user's physiological fluid. include.

Ketone bodies, which are water-soluble molecules produced by the liver during the overconsumption of fatty acids, are normal by-products of energy metabolism in gluconeogenesis, the production of glucose (the body's major energy source) from non-carbohydrate sources. In healthy individuals, circulating ketone levels are typically low, but hepatic glycogen stores are depleted during low food intake (fasting), low carbohydrate consumption, starvation, prolonged strenuous exercise, or high alcohol intake. The level of ketone bodies may increase with this. This is commonly referred to as ketosis and is relatively harmless, and a series of recent studies suggest that a ketogenic lifestyle with diet and exercise may be beneficial. However, in individuals with type 1 diabetes, elevated ketone levels often resulting from insulin deficiency can induce fatty acid synthesis, resulting in a sharp rise in circulating ketone body levels. This metabolic pathway can lead to a life-threatening condition known as diabetic ketoacidosis (DKA). DKA is often present in first-time diabetic patients and is the leading cause of death. In diagnosed type 1 diabetic patients, DKA is acute insulin deficiency due to either inadvertent omission of insulin administration, blockage of the insulin pump set, or long-term administration of insulin suspension by an automated insulin delivery system. Can also arise from. Complications can also contribute to the development of DKA. The manifestation of DKA symptoms is not fully apparent until severe conditions, at which point avoiding DKA complications, often including excessive dehydration, tachycardia, hypotension, cerebral edema, and coma. Therefore, hospitalization is required. DKA is a major cause of hospitalization, morbidity and death in children with type 1 diabetes.

Prior art solutions have been for temporally discrete or transient measurements of ketone bodies in urine or capillary blood, either by colorimetric detection or electrochemical detection, respectively. The colorimetric method is non-invasive but mostly qualitative, and the relative range of ketone bodies present in the sample, typically urine, is compared to the color chart of the specimen. It is necessary to judge. On the other hand, the electrochemical method is somewhat invasive and requires a finger puncture capillary blood sample, although it is quantitative when combined with a handheld measuring instrument. A newer method of breath analysis of ketone bodies (typically highly volatile acetone) is made possible by an analyte-selective gas sensor or a handheld device with a built-in fuel cell. While these systems are simple to operate and can provide quantitative readings of ketone levels in exhaled breath, they are prone to many sources of error, including interference from food intake and oral hygiene. More comprehensively, current methods of measuring ketones are purely transient measurements at a single point in time that require user action to isolate the sample. Therefore, such systems cannot generate warnings because they cannot use these platforms for persistent, semi-persistent, or online monitoring. In other words, prior art requires the user to be aware of the risk of ketoacidosis and proactively make measurements in an available manner. Under many circumstances, this approach is impractical and cannot provide users with sufficiently timely measurements to eliminate the need for doctor visits, emergency room transport or hospitalization. Passive and automated methods of detecting ketones are preferred, especially if the symptoms associated with DKA are not readily apparent.

The products of the prior art include: Colorimetric test strips for urinary ketone measurements (Fig. 3): Ketostics® Regent Strips for Urinarysis (Leverkusen, German Bayer Healthcare); for capillary blood ketone measurements. Electrochemical test strips for: Precision Xtra® Blood Glucose & Ketone Monotoring System (Illinolitha), which is intended to be used in combination with Precision Xtra® Blood Ketone Test Strips®. ); StatStrip (registered trademark) Glucose / Ketone Conductivity Meter (Nova Biomedical in Waltham, Massachusetts), which is intended to be used in combination with StatStep Ketone Test Strips. Trademark) Plus Blood Glucose Monumenting System (Nova Diabetes Care, Villelica, Massachusetts); StatStrip Ketone Ketone TestStrip (StatStrip KetoneBest) Registered for use in combination with StandardStem ); Ketone-mojo (registered trademark) Ketone Meter (Ketone-mojo, Napa, California), which is intended to be used in combination with Ketone-mojo Ketone Test Strips; FORA 6 (registered trademark) Connect Blood β-Ketone Tes. FORA 6® Connect Blood Glucose and β-Ketone Monotering System (ForaCare Inc, Mopark, California), intended for use in combination with Strips; STAT-Site® M β-HB Test STAT-Site® M Beta-Hydroxybutyrate (BHB) Analyzer (EKF Diagnostics, UK Cardiff), intended for use in combination with ips; Ketoneix® Breath Konezer (Ketoneix AB, Stockholm, Sweden) (FIG. 5); LEVLhome® or LEVLpro® device (Mediamotor LLC, Seattle, Washington).

The prior art patent is Patent Document 1 by Gerber et al., entitled "Systems And Methods For Multiple Analyte Analysis", and discloses a system and a method for analyzing a plurality of analysts. In one embodiment, the method comprises measuring the concentration of the first and second analytes in the sample. The first and second analytes may be, for example, glucose and hydroxybutyrate. In this form, an indication of the measured hydroxybutyrate concentration is provided in response to the determination that the hydroxybutyrate concentration exceeds a predetermined value. In a further aspect of this form, a quantitative representation of the measured glucose concentration is automatically provided regardless of the value of the measured glucose concentration. In another embodiment, the system comprises a measuring instrument configured to interact with the test element to evaluate the first and second analytes in the sample. Further embodiments, embodiments, objectives, features, advantages, embodiments, and advantages are apparent from the description and drawings.

Another prior art patent document is "Deveice For Determining Fat Expenditure From Ketone Bodies That Have Passed The Skin And Methods For Determining The 1 Disclosed is a detection device having a first semipermeable membrane having a first surface and a second surface, a second semipermeable membrane having third and fourth surfaces, a ketone body sensor, and a void. ing. The first opening is juxtaposed on the first surface and the second opening is juxtaposed on the third surface. The space between the first opening and the second opening is a void, and the ketone body sensor is arranged in the void. The gas can penetrate the void through the first opening and come into contact with the sensor and exit the void through the second opening.

Another prior art patent document is "Methods for Analyte Manufacturing Management And Analyte Data Management, and Arts of Analyte Management, and Articles of Analyte Management, and" The product is generally disclosed. The method includes receiving the analytical material measurement data and analyzing the analytical material measurement data for health-related parameters. Based on the analysis, recommendations for creating or modifying the treatment program are determined and provided within the user interface that allows the user to create or modify the treatment program. In addition, methods for managing analytical material measurement data and related manufactured products are generally provided. The method comprises receiving analytical material measurement data representing the data collected over a period of time and analyzing the analytical material measurement data for the analytical material episode within that period. Threshold-based episodes and / or rate-based episodes may be measured.

Another prior art patent document is Patent Document 4 by Ahmad, entitled "Ketone Measurement System and Related Method with Accuracy and Reporting Enhancement Features", wherein the portable ketone solution measuring device is a user of a portable ketone liquid measuring device. It discloses that a ketone level is measured and the ketone measurement is transmitted to an application running on a user's smartphone or other mobile device. The application can communicate with the remote server and report the measurements to the remote server. One or more components of the system (eg, a portable ketone meter, a mobile application, and / or a server) may adjust the ketone measurements as needed, eg, the age of the user, the medical condition of the user. , Missing medication events, or interrupted sleep events can compensate for ketone variability. In some scenarios, the application may suspend the display of ketone measurements to the user until authentication is received from the server.

Another prior art patent document is Patent Document 5 entitled "Systems, Devices, and Methods for Wellness and Nutrition Monitoring and Management Analyte Data", which uses analysis data from an in vivo analyte sensor and uses analysis data from an in vivo analyzer sensor. And discloses systems, devices and methods for monitoring and managing nutrition. Generally, a sensor control device is provided for attachment to the body. The sensor control device includes an in vivo analyte sensor for measuring the level of the analyte in the body fluid, an accelerometer for measuring the level of physical activity of the subject, and a communication circuit for wirelessly transmitting data to the reader device. Can be included. In addition, this specification displays analytical material metrics on a reader device, compares the analytical material responses of various foods and / or diets, and is based on daily analytical material metrics and physical activity level measurements. Various graphical user interfaces for changing nutritional recommendations as well as other embodiments of the features described herein are disclosed. In addition, the embodiments disclosed herein can be used to monitor various types of analytes.

The techniques described herein are devices for generating viable warnings to the user by continuous measurement using a skin-worn analyte selective sensor for circulating ketone body levels in the user's physiological fluid. And methods are included.

One aspect of the invention is configured to measure the level of a ketone compound circulating in the wearer's physiological fluid, the wearer when the level of the circulating ketone compound exceeds a predetermined level or rate of change. It is a body-worn sensor capable of generating a warning to.

Another aspect of the invention is configured to measure the level of a ketone compound circulating in the wearer's physiological fluid, which is persistent or quasi-persistent. It is a body-worn sensor that can display various readings to this wearer.

Yet another aspect of the invention is a method of generating a warning to the wearer of a body-worn sensor, which warning indicates an increased metabolic state of the ketone compound.

Yet another aspect of the invention is a method of measuring elevated levels of circulating ketone bodies in a physiological fluid. This method includes electrochemical sensors, optical sensors, galvanic sensors, voltanmetric sensors, amperometric sensors, potentiometric sensors, impedance sensors, resistance sensors, capacitive sensors, ultrasonic sensors, radio frequency sensors, and microwaves. Includes measuring the concentration of ketone compounds circulating in the physiological fluid of the wearer of a body-worn sensor device, including one of the sensors. The method also involves storing the measurements in the memory of the body-worn device. The method also comprises determining whether the concentration level exceeds a predetermined level, threshold, or rate of change from a previous measurement. The method also includes generating a warning if the concentration level exceeds a predetermined level, threshold, or rate of change from a previous measurement.

The sensors are preferably electrochemical sensors, optical sensors, galvanic sensors, voltanmetric sensors, amperometric sensors, potentiometric sensors, impedance sensors, resistance sensors, capacitive sensors, ultrasonic sensors, high frequency sensors, and micros. Includes at least one of the wave sensors.

Yet another aspect of the invention comprises incorporating a biometric element, such as an enzyme, into the sensor to convert the presence of the ketone compound into a physically quantifiable signal.

Illustration of an exemplary body-worn sensor configured to measure the level of ketone compounds circulating in the wearer's physiological fluid, configured to receive radio readouts from this body-worn sensor. The wearer's smartphone is displaying a warning to the wearer.

FIG. 6 is a schematic diagram of a fatty acid synthesis metabolic pathway illustrating three ketone body products, namely acetone, acetoacetic acid salt and D-β-hydroxybutyrate.

It illustrates the detection of ketone bodies in urine by means of a conventional disposable colorimetric test strip.

It illustrates the prior art quantification of ketone bodies in finger puncture capillaries blood samples by means of disposable electrochemical test strips.

It illustrates the quantification of ketone bodies in exhaled breath by a prior art handheld spirometer.

FIG. 3 is a block diagram showing key components involved in the functionalization of skin-penetrating electrochemical sensors to facilitate chemical or biochemical quantification of various analytes in physiological fluids.

FIG. 3 is a process flow diagram showing key components involved in the generation of warnings to the wearer of a body-worn sensor based on the reading of one or more ketone compounds circulating in a physiological fluid.

Shown is an electronic circuit contained in a prototype wearable device enclosure designed to interface directly with a microneedle-based biosensor device.

Another figure of an electronic circuit contained in a prototype wearable device enclosure designed to interface directly with a microneedle-based biosensor device is shown.

Shown is an electronic circuit housed in a sealed housing that accesses the microneedle device via a gold-plated pressure connector located on the visible surface of the housing.

Demonstrating a skin-penetrating hollow microneedle array containing multiple protrusions with a vertical range of about 1000 μm, each element of the microneedle array is functionalized to impart selective biosensing capability.

Shown is a hollow, non-functionalized microneedle array.

Demonstrates a hollow "filled" functionalized microneedle array with selective biosensing capability.

Illustrated all functional components including a microneedle biosensor and a printed circuit board containing the electronic circuits required to convert biochemical signals into digital data that can be wirelessly transmitted to external devices via the built-in wireless transceiver. The exploded view rendering of the complete microneedle biosensing system is shown.

FIG. 13 is a separation and enlargement view of the microneedle biosensor component of FIG.

Another figure of a wearable microneedle biosensing system containing an electronic backbone and an adhesive patch is shown, where the microneedles are located behind the adhesive patch (not shown).

FIG. 3 shows a rear view of a skin-mounted adhesive patch containing an electronic component housing component of a microneedle-based biosensing system and a microneedle array.

A detailed block / process flow diagram showing the key functional components of a microneedle-based biosensing system and support electronic system is shown.

It is a circuit diagram of a stand-alone potentiometer integrated circuit.

It is a circuit diagram of a multi-component potentiometer.

It is a block diagram of a differential amplifier.

It is a signal flow chart of this invention.

It is a circuit diagram of an integrated analog front end and a sensor interface.

It is a circuit diagram of a mirror type differential amplifier and filtering.

It is a circuit diagram of a fixed mirror type instrumentation amplifier.

It is a circuit diagram of the digital potentiometer adjustment type mirror type instrumentation amplifier.

It is a figure of the handheld analyzer of a large form factor.

It is a figure of a handheld analyzer of a small form factor.

It is a block diagram of a sample algorithm.

It is a figure of a handheld analyzer of a small form factor.

In healthy individuals, circulating ketone levels are typically well below 0.5 mmol (“ mM”). A slight increase in ketone levels (ie, 0.5-1 mM) is usually the result of the liver removing its fat reserves to convert it into energy, typically upon fasting or a low-carbohydrate diet. It is a sign of ketosis that occurs in. It is very rare for healthy individuals to face the risk of ketoacidosis (above 1 mM, which causes blood acidification due to extreme elevations in ketone body levels). When insulin is deficient, which allows glucose to enter the cell and supply energy to the cell, the body removes energy from free fatty acids in the liver, resulting in excessive production of ketone bodies and subsequent acidification of the blood. Causes and destroys acid / base homeostasis. The mortality rate of diabetic ketoacidosis (DKA) is 2-10%, which is a life-threatening metabolic complication of diabetes. DKA is usually manifested by long-term hyperglycemic conditions and overall poor glycemic control, including inadequate administration of insulin, inadequate carbohydrate intake and response to administered insulin. The risk of diabetic ketoacidosis is increased by complications. For example, gastroenteritis is a common precursor to DKA in patients with insulin-dependent diabetes mellitus, but among its multiple causes, insulin intake should be reduced or eliminated if the illness makes it impossible to eat. There is a false belief by some patients that it is. Early detection of elevated blood ketone levels allows patients to take various measures at home to prevent the onset of acute illness and the need for emergency medical services and / or hospitalization, such as increased insulin delivery and increased hydration. It is widely understood in clinical practice that by allowing it to be taken, it can help avoid DKA.

The solution of the present invention provides a body-worn sensor device and method for selectively quantifying ketone body analysts in a wearer's physiological fluid in an automated and sustained manner. When ketone bodies exceed a given threshold or rate of change, warnings are generated so that behavior can be triggered in a timely manner, thereby avoiding the development of potentially life-threatening ketoacidosis.

Ketoacidosis is most often the result of insulin deficiency in undiagnosed type 1 diabetes (type 1 diabetes mellitus: T1D) or diagnosed T1D and requires immediate intervention to avoid life-threatening sequelae. It is a medical emergency. Signs of diabetic ketoacidosis (DKA) can be difficult to discern physical manifestations in the acute phase, often only when circulating ketone bodies reach dangerous levels. In fact, individuals with T1D are trained to test ketone bodies in a temporary manner that is available only when the onset of symptoms becomes apparent, and in such scenarios, hospitalization. Often too late to avoid. In most cases, orthodontic treatment is not easy and often requires a visit to the emergency department of the hospital. It is clear that early identification of potential episodes of DKA in the acute phase (and subsequent rapid corrective action) can reduce the need for hospitalization or visits to the community's emergency / emergency department. A promising class of drugs (sodium-glucose lowering transporter-2 (SGLT2) inhibitors) substantially lower blood glucose by allowing the kidneys to excrete circulating sugar via urine. Helps individuals with T1D achieve normal blood glucose levels (normal blood glucose, 70-180 mg / dL plasma glucose) by providing a generous capacity, which may be considered beneficial for T1D patients. However, these drugs have been observed to increase the risk of normoglycemic diabetic ketoacidosis (DKA) in the absence of persistent hyperglycemia. In such circumstances, these drugs should be used. Individuals taking it may not be aware of dangerously elevated circulating ketone levels because blood glucose appears to be well controlled. Current methods for ketone analysis are blood, urine or Evaluated by any of the exhaled breath samplings, but does not allow a sustained and passive assessment of circulating ketones in these physiological compartments. Rather, the user actively samples the physiological fluid or plasma. Precautionary measures must be taken to test the blood glucose by. In this case, the detection of the blood glucose is sporadic (not persistent) and the presentation of the warning can only occur after the action by the user. Such a scenario. In, sampling during sleep or activity is not feasible due to the often delayed symptoms of DKA, and the user may be able to identify fluctuations in blood glucose levels during the acute phase (ie, immediately after elevation of circulating ketones). In addition, warnings generated by rate of change, differential values, or trend analysis require the implementation of memory functionality, so at least one past value information must be obtained to make a determination. In many cases, past assays have been performed days, weeks, or months ago, which is beyond the reach of an individual's recollection and makes it difficult to obtain historical values. The ability of the body provides a device and method for alerting the wearer of a body-worn sensor in an automated and sustained manner when circulating ketone levels exceed a predetermined threshold or rate of change. Wearable sensors can rapidly control glucose levels to avoid DKA by identifying potentially dangerous deviations in glycemic levels through sustained online quantification of circulating ketones in physiological fluids. A series of The wearer can be warned to take action. Such interventions are likely to improve outcomes and reduce DKA morbidity and mortality. This new, innovative and clinically useful capability will help improve current standard treatments in the field of diabetes, thus burdening patients, healthcare providers, and healthcare reimbursement infrastructure. It is expected to be reduced.

The apparatus disclosed herein addresses the above challenges by automatically generating warnings about an increase in absolute ketone levels above a threshold or an increase in ketone levels above a specified rate of change. It includes physiological fluid compartments (ie, blood, serum, plasma, interstitial fluid, intracellular interstitial fluid) for the presence of one or more circulating ketone bodies (acetoacetic acid, acetone, D-β-hydroxybutyrate). , Extracellular fluid, intracellular fluid, cerebrospinal fluid). Sensors take samples subcutaneously, transdermally, through the skin, intradermally or on the surface of the skin, and use electrical or optical stimuli to make electrical, optical, or chemical changes. Promote the occurrence of. Subsequently, voltage, current, charge, resistance or impedance characteristics are measured to estimate the concentration of a single or multiple ketone bodies circulating in the physiological fluid compartment. The programmable memory element included in the body-worn sensor includes a pre-programmed threshold, which here refers to the absolute value of a single ketone body or multiple ketone bodies. In addition, the device also retains past readings and makes comparative evaluations for calculating gradients, rates of change, derivatives, or trends. When the value measured by this body-worn sensor exceeds a predetermined value or threshold, the wearer (and optionally the wearer's support network, such as family, health care providers, friends, etc.) is alerted. .. This warning is in multiple forms of visual, audible, tactile, and textual notifications to the wearer's smartphone, smartwatch, wearable device, tablet, eyewear, earphones, or directly to the wearer's body-worn device. Can be taken. Trend / pattern analysis can be used to predict future ketone variability, as well as machine learning to identify scenarios that expose wearers of body-worn devices to the risk of DKA. Is. This ability to generate ketone warnings can also be combined with other detection modality, such as a sustained glucose monitor. The method of the present disclosure is a body-worn sensor when the absolute level or rate of change of a single ketone body (acetoacetic acid salt, acetone, D-β-hydroxybutyrate) or multiple ketone bodies exceeds a predetermined threshold. Facilitates the presentation of warnings to the wearer of the device. The method comprises detection of these ketone bodies in the wearer's physiological fluid compartment (ie, blood, serum, plasma, interstitial fluid, skin interstitial fluid, extracellular fluid, intracellular fluid, cerebrospinal fluid). .. The method is configured to promote the occurrence of electrical, optical, or chemical changes using electrical or optical stimuli, subcutaneous, transdermal, skin permeation, intradermal or skin surface. Regarding detection using a body-worn sensor. Subsequently, voltage, current, charge, resistance or impedance characteristics are measured to estimate the concentration of a single or multiple ketone bodies circulating in the physiological fluid compartment. The programmable memory element included in this body-worn sensor includes a pre-programmed threshold, which here refers to the absolute value of a single ketone body or multiple ketone bodies. In addition, the device also retains past readings and makes comparative evaluations for gradient, rate of change, derivative, or trend calculations. When the value measured by this body-worn sensor exceeds a predetermined value or threshold, a warning is issued.

Commercially available products can be utilized in practicing the present invention with respect to presenting a warning to the wearer of a body-worn sensor. Such commercial products include smartphones (ie, Apple iPhone®, Samsung Galaxy phone), smart watches (ie, Apple Watch, Fitbit versa), wearable devices (ie, Fitbit Blaze, Garmin Forerunner), tablets. That is, Apple iPad®, Samsung Galaxy tabs, eyewear (ie, Google Glass, Oclus Lift), earphones (ie, Apple Earpods, Bose SoundSport Free), laptops (ie, Apple) Computer (ie, Apple). (Ie, Apple iMac, Lenovo ThinkCenter), or body-worn devices (ie, iRhythm Zio), but not limited to these.

FIG. 1 is a diagram of an exemplary body-worn sensor 50 worn on the arm 256 of the wearer 250 and configured to measure the level of ketone compounds circulating in the wearer's physiological fluid. The wearer's smartphone 1208 configured to receive the wireless readout from the body-worn sensor 50 displays a warning to the wearer 250. The body-worn sensor 50 is preferably subjected to an electrical or optical stimulus to accelerate the oxidation-reduction reaction, the voltage, current, charge, resistance or impedance characteristics are measured and the physiological fluid compartment in which the sensor is located. A subcutaneous, transdermal, skin permeation, intradermal or skin surface sensor that estimates the concentration of specific ketone bodies (acetoacetic acid, acetone, D-β-hydroxybutyrate) present within. The body-worn sensor 50 is preferably configured to include a built-in memory for storing past measurements. The body-worn sensor 50 is preferably configured to include a radio communicator, transmitter, or transceiver for relaying measurements to a paired radio-enabled device.

FIG. 2 is a schematic diagram of a fatty acid synthesis metabolic pathway illustrating three ketone body products, namely acetone, acetoacetic acid salt and D-β-hydroxybutyrate. FIG. 3 illustrates the detection of ketone bodies in urine by means 300 of the conventional disposable colorimetric test strip 301. FIG. 4 illustrates the quantification of ketone bodies in finger puncture capillary blood samples by means 400 of a prior art disposable electrochemical test strip 401. FIG. 5 illustrates the quantification of ketone bodies in exhaled breath by conventional handheld spirometers 501 and 502.

FIG. 6 is a block diagram showing key components involved in the functionalization of skin-penetrating electrochemical sensors to facilitate chemical or biochemical quantification of various analytes in physiological fluids. At block 601 the body-worn sensor determines if the ketone compound exceeds a predetermined level, threshold, or rate of change from a previous measurement. At block 602, the body-worn sensor produces a warning to the wearer of the body-worn sensor indicating that a predetermined ketone value, threshold, or rate of change has been exceeded.

As shown in FIG. 7, a method of measuring elevated levels of circulating ketone bodies in a physiological fluid is, in block 701, a body-worn sensor of the level or concentration of ketone bodies circulating in the wearer's physiological fluid. It involves making measurements or readings and then storing the measurements or readings in the memory of the body-worn sensor. This sensor converts the concentration of circulating ketone compounds in the wearer's physiological fluid into quantitative or qualitative values. The previous concentration may be stored in the memory element to determine the rate of change, derivative, or gradient.

At block 702, the body-worn sensor determines whether the ketone compound exceeds a predetermined level, threshold, or rate of change from a previous measurement. A comparative evaluation is performed between this measurement or reading and a predetermined level, threshold, or rate of change from a previous measurement input from block 705.

In block 703, if the result of the action in block 702 is affirmative, the body-worn sensor indicates to the wearer of the body-worn sensor that the predetermined ketone value, threshold, or rate of change has been exceeded. Generate a warning. If the result of the comparative evaluation is affirmative, a warning is generated to the wearer of the body-worn sensor device indicating that the ketone level has increased or the rate of change in ketone has increased.

In block 704, if the result of the action in block 702 is negative, the body-worn sensor is given a predetermined or (based on absolute ketone level or rate of change of this ketone level) prior to the next measurement or reading cycle. Wait for a variable amount of time. The body-worn sensor device identifies and subsequently warns the wearer when the ketone compound circulating in the wearer's physiological fluid exceeds a predetermined level, threshold, or rate of change from previous measurements. It works continuously like.

The input is a ketone compound that circulates in the wearer's physiological fluid. The ketone compound can include at least one of acetone, acetone, acetoacetic acid and β-hydroxybutyric acid. Physiological fluids can include blood, serum, plasma, interstitial fluid, skin interstitial fluid, extracellular fluid, intracellular fluid, and cerebrospinal fluid.

A given threshold, level, rate of change, derivative, gradient, or trend. A quantified reference value that can be used as a reference for the evaluation of current measurements of circulating ketone compounds. A warning is generated when the current measurement exceeds this reference value.

The output is a warning. The warning preferably includes at least one of visual, audible, tactile, and textual notifications. The warning preferably indicates that at least one of a predetermined threshold, level, rate of change, derivative, or gradient value has been exceeded. Warnings are preferably, but are not limited to, presented to the wearer by a smartphone, smartwatch, wearable device, tablet, eyewear, earphones, laptop, computer, or body-worn device. Warnings are preferably issued to induce behavior or purely for informational purposes. Warnings may be communicated to an individual or a group of individuals using a communication network or internet connection in addition to the wearer.

A microneedle-based biosensor is preferably a physical for facilitating transdermal analysis of relevant biochemical analytes from biophysiological media (interstitial fluid, blood) that occupy layers of the epidermis and dermis. Mounted as a transducer / electrode. The electrochemical analog front end performs one (or more) of several electroanalytical techniques such as voltammetry, amperometry, potentiometry, conductance measurement, couometry, impedance measurement, and polarography, and is microneedle-based. Facilitates control and readout of electrochemical reactions that occur in biosensors. Optionally, the electrical signal generated at the output of the electrochemical analog front end is sent into an amplifier circuit to increase the signal strength to line level. Following this, the output is optionally sent to a lowpass or bandpass filter to extract the signal of interest and remove unwanted noise. As a further optional step, the signal is then analog-to-digital converted to convert the analog signal to a digital bitstream. Finally, the signal is a radio transmitter or transceiver to send the signal (depending on the level of the biochemical analyzer) to a mobile or wearable device for further information processing, interpretation, display, storage and trend analysis. (Bluetooth®, WiFi, RFID / NFC, Zigbee, Ant +).

FIG. 8 shows an electronic circuit contained in a wearable device enclosure 20 designed to directly interface with a microneedle-based biosensor device. The electronic circuit of the device includes a wireless transceiver (preferably BLUETOOTH® LOW ENERGY), a microcontroller with an integrated analog-to-digital converter 21, and a high amplifier circuit 22. FIG. 9 shows another diagram of an electronic circuit contained in a prototype wearable device enclosure 20 designed to directly interface with a microneedle-based biosensor device. The electronic circuit comprises a high sensitivity electrochemical analog front end 23 and a filtering circuit 24.

FIG. 10 shows an electronic circuit housed in a wearable device enclosure 20 that accesses a microneedle device via a gold-plated pressure connector 27 disposed on a visible surface of the wearable device enclosure 20. Connection port 25 is also shown.

FIG. 11 shows a skin-penetrating hollow microneedle array 30 containing a plurality of protrusions having a vertical range of about 1000 μm, each element of the microneedle array being functionalized to impart selective biosensing capability. FIG. 12A shows a hollow, non-functionalized microneedle array 30a. FIG. 12B shows a hollow “filled” functionalized microneedle array 30b with selective biosensing capability.

13 and 13A include a housing member 125, a microneedle biosensor 130, and a print that includes the electronic circuits required to convert the biochemical signal into digital data that is wirelessly transmitted to an external device via the built-in wireless transceiver. An exploded view rendering of the complete microneedle biosensing system 120 illustrating the functional components including the circuit board 127 and.

FIG. 14 shows a top perspective view of a wearable microneedle biosensing system 120 that includes an electronic backbone and an adhesive patch. The microneedles are located on the back surface of the adhesive patch (not shown).

FIG. 15 shows a rear view of a skin-worn adhesive patch comprising an electronic component housing component 130 and a microneedle array 127 of a microneedle-based biosensing system 120.

FIG. 16 shows a detailed block / process flow diagram 1200 showing the key functional components of a microneedle-based biosensing system and a supporting electronic system. At block 1201, a microneedle array is utilized to obtain transdermal biochemical analyzes from biophysiological media (interstitial fluid, blood) that occupy the epidermis and dermis layers of the user of the microneedle-based biosensing system. To. At block 1202, the electrochemical analog front end performs one (or more) of several electroanalytical techniques such as voltammetry, amperometry, potentiometry, conductance measurement, impedance measurement, and polarography. Facilitates control and readout of electrochemical reactions that occur in needle-based biosensing systems. At block 1203, the electrical signal generated at the output of the electrochemical analog front end is sent to an amplifier circuit to increase the signal strength to line level. At block 1204, the output from the amplifier circuit is sent to a low pass filter or band pass filter to extract the signal of interest and remove unwanted noise. At block 1205, the signal is then analog-digital converted at the ADC to convert the analog signal to a digital bitstream. At block 1206, the signal is a radio transmitter or a radio transmitter to transmit the signal (depending on the level of the biochemical analyzer) to the mobile communication device 1208 for further information processing, interpretation, display, storage and trend analysis. It is routed to a transceiver (BLUETOOTH®, WiFi, RFID / NFC, Zigbee, Ant +) 1207.

The electrochemical analog front end is preferably a Texas Instruments LMP91000 sensor AFE system, which is a configurable AFE potential for low power chemical detection applications; Texas Instruments LMP91200, which is a configurable AFE for low power chemical detection applications; or , Texas-M3 and a meter-on-chip with connectivity, Analog Devices ADuCM350 16-Bit Precision. The wireless transceiver is preferably BLUEGIGA BLE-113A BLUETOOTH® Smart Module, or Texas Instruments CC2540 SimpleLink BLUETOOTH® Smart Wireless Bluetooth USB. The relevant mobile device is preferably an ANDROID® or iOS® based smartphone, Samsung GALAXY GEAR or APPLE WATCH®.

Microneedle array electrochemical biosensors convert biochemical signals from interstitial fluid into useful electrical signals.

The electrochemical analog front end preferably applies a fixed potential or a time-varying potential to the microneedle array to induce an electrochemical reaction, thereby causing a current flow, to the microneedle array a fixed current or time. Applying a changing current to induce an electrochemical reaction to generate a potential, measuring the time-varying open circuit potential generated by an electrochemical reaction or ion gradient, electrochemical with a microneedle transducer. At least one of measuring the frequency-dependent impedance generated by a reaction or bioaffinity reaction and measuring the specific resistance or conductance generated by an electrochemical reaction or biocompatibility reaction with a microneedle transducer. Do the above.

The electrochemical analog front end is preferably dynamically configured to achieve any one of the above embodiments. Similarly, the inputs are preferably arranged to operate sequentially or in parallel to extend the sensing capabilities of the system.

The wireless transceiver uses any one of several standardized wireless transmission protocols (Bluetooth®, WiFi, NFC, RFID, Zigbee, Ant +) for the electrical signals generated by the electrochemical analog front end. And wirelessly relay to a mobile or wearable device. Optionally, the electrical signal generated by the analog front end can undergo amplification, filtering, and / or analog-to-digital conversion and further signal processing before being relayed by the radio transceiver.

The mobile or wearable device displays the sensor readings to the user in an easy-to-understand format and performs any further signal processing required.

The method of transmitting an electrical signal generated by a microneedle array-based electrochemical biosensor preferably comprises the following steps. Application of an electrical probe signal to induce an electrochemical reaction or to measure changes in the electrical properties of the biosensor surface. Conversion of a biochemical signal to an electrical signal converts the biochemical signal into an electrical signal of magnitude or phase that is a function of the concentration of the sensed biochemical signal, amperometry, voltammetry, potentialometry, impedance measurement, couometry. Alternatively, it is performed using electrochemical techniques such as conductance measurement. Biochemical signals from microneedle array-based electrochemical biosensors are preferably ketone compounds, metabolites, electrolytes, hormones, vitamins, minerals, nerves found in interstitial fluid, blood or other physiological media. Includes mediators and other analytes. The (relative or absolute) concentration or level is displayed to the user on the associated mobile device (telephone, tablet) or wearable device (smartwatch, fitness band).

A method of transmitting electrical signals generated by a microneedle array-based electrochemical biosensor. This method pairs a skin-penetrating microneedle array with an electrochemical analog front end to provide the appropriate potential or current probe required for inducing an electrochemical reaction or measuring changes in electrical properties of the biosensor surface. Including applying to. The skin-penetrating microneedle array contains multiple protrusions with a longitudinal length of 20-2000 μm. All or a subset of the projections are functionalized to confer selective electrochemical biosensing capability. The method also comprises measuring an electrical signal based on voltage, current, frequency, phase, or conductance generated in response to an electrical probe. The method also comprises processing an electrical signal measured by an electrochemical analog front end. The method also includes routing the converted electrical signal to a wireless transceiver following the processing operation. The method also includes broadcasting an electrical signal to an external radio-enabled readout device using a standardized radio transmission format.

Processing involves at least one of amplification, filtering, and analog-to-digital conversion of the signal produced by the electrochemical analog front end.

The potential or current probe preferably embodies steady-state or time-varying properties.

One embodiment is a system for transmitting electrical signals generated by a microneedle array-based electrochemical biosensor. The system includes microneedle array electrochemical biosensors, electrochemical analog front ends, wireless transceivers, and wearable or mobile devices. The microneedle array electrochemical biosensor converts the biochemical signal from the user's interstitial fluid into multiple electrical signals. The wireless transceiver wirelessly relays each of the multiple electrical signals generated by the electrochemical analog front end to a mobile or wearable device using a standardized wireless transmission protocol.

The electrochemical analog front end preferably applies a fixed current or a time-varying current to the microneedle array to induce an electrochemical reaction, thereby generating an electric potential.

Alternatively, the electrochemical analog front end applies a fixed or time-varying potential to the microneedle array to induce an electrochemical reaction, thereby generating an electric current.

The electrochemical analog front end preferably measures the time-varying open-circuit potential generated by an electrochemical reaction or ion gradient.

Alternatively, the electrochemical analog front end measures the frequency-dependent impedance produced by an electrochemical or bioaffinity reaction in a microneedle transducer.

Alternatively, the electrochemical analog front end measures the resistivity or conductance produced by an electrochemical or bioaffinity reaction in a microneedle transducer.

The mobile or wearable device preferably displays the sensor readings in a user-friendly format.

The microneedle array electrochemical biosensor preferably comprises a plurality of projections having a longitudinal length of 20-2000 μm. All or a subset of the projections are functionalized to confer selective electrochemical biosensing capability.

The standardized wireless transmission format is preferably one of Bluetooth®, WiFi, NFC, RFID, Zigbee, Ant +, or 4G LTE.

The external radio-enabled readout device is preferably a smartwatch, fitness tracker, smartphone, mobile phone, tablet computer, or notebook computer.

The present invention uses a precision integrator and a pair of high input impedance and high (adjustable) gain differential amplifiers to construct a scalable linear output potentiostat system with a sensitivity of less than 1 nA (operating range 100 pA to 700 uA). Can be used with a high precision and high input impedance analog front end (consisting of a stand-alone IC or a series of high input impedance operational amplifiers) cascaded. This range can be adjusted via external gain control. High resolution analog-to-digital converters are utilized to improve signal resolution to femtoampere or attoampere levels.

The high input impedance analog front end is paired with an adjustable precision integrator and a pair of mirrored differential amplifiers or any of a variety of such differential amplifiers. By using a mirrored amplifier and a subtraction algorithm, it is possible to reduce noise and eliminate the problem of floating ground or ground drift and fluctuations caused by the inflow of external signals. The complex system makes it possible to detect very low currents without the use of offboard shielding elements (such as Faraday cages). Time-averaged hardware filtering and sampling algorithms also help stabilize readings by removing disturbing signal harmonics. High resolution analog-to-digital converters can be utilized to improve signal resolution to femtoampere or attoampere levels to achieve sensitivities close to single molecule sensitivity.

As shown in FIG. 17, the adjustable bias analog front end / potential stat 29 is a high input impedance operational amplifier and digital-to-analog converter, or a stand-alone analog front end (“analog front end: AFE”) or analog. Consists of an interface integrated circuit package.

An adjustable low noise transimpedance amplifier (“transimpedance amplifier: TIA”) converts the current flow into a proportional voltage signal, which is either adjustable or adjustable by manual component selection. It is electronically controlled and configured for linear gain (TIA) or integrator (integrator) through the implementation of bypass capacitors.

A mirrored (inverting input) high input impedance and high (adjustable) gain differential amplifier is a physical resistor (a set of components-multiplexers, relays, and other signal paths-or physically adjustable potentiometers). Alternatively, it is adjustable via an electronically controlled resistor (digital potentiometer) and is configured as a base differential amplifier or any of a variety of such amplifiers, including instrumentation amplifiers. Depending on the voltage polarity of the combination of AFE and TIA, one amplifier represents the signal and the second amplifier represents any existing ground interference or bias.

Signal filtering eliminates signal ripple due to electromagnetic interference (“electromagnetic interference: EMI”) after differential amplifiers, by active or passive lowpass, highpass, bandpass, or any combination thereof. Will be implemented.

High resolution analog-to-digital converters are used to convert filtered analog signals to accurately quantified values and to improve signal resolution to femtoampere or attoampere levels. ..

Sampling algorithms include time average sampling plus offsets. Opposed differential amplifiers are used to subtract the ground offset caused by the EMI and eliminate the need for an external shield cage or true ground connection.

FIG. 18 is a circuit diagram of a multi-component potentiostat 330 having an electrochemical cell 31.

Method of potentiostat operation The steps are as follows.

Analog front end / potentiostat operation. The potentiostat / AFE unit consists of two (FIG. 17) or three (FIG. 18) precision instrumentation operational amplifiers (A1 / OA1, OA2, TIA / OA3) configured as follows: Control. Amplifiers A1 / OA1 amplify the differential voltage (V _x in FIG. 9) measured between variable (programmable) bias and ground (gain A) and supply current through the counter electrode (CE). Upon sensing the voltage generated by the reference electrode (RE), the A1 / OA1 draws sufficient current to maintain its output voltage at the input (V _RE ) value. The RE is then adjusted and the output potential / current of the A1 / OA2 (buffer or unity gain amplifier) is changed accordingly. Therefore, the control amplifier functions as a voltage control current source that keeps the reference electrode at a constant potential and supplies sufficient current to arbitrate the electrochemical reaction. When performing negative feedback, it is essential that A1 / OA2 can fluctuate to extreme potentials to allow for the full voltage compliance required for chemical synthesis. Furthermore, it is important that the OA2 has a very high input impedance in order to draw a negligible current. Otherwise, the reference electrode may deviate from its intended action potential. In practice, the use of precision amplifiers with an input bias current of 20 fA (or less) allows unlimited operation up to subpicoamperage levels suitable for almost any electrochemical study. The TIA / OA3 receives a current supplied through a working electrode (WE) and is proportional to the amount of current passing through the electrode WE by a voltage (resistor / capacitor network R _TIA / C ₅ + R ₄ ). To be converted) is output.

Analog front end and applied reference / operating bias. In the systems shown in FIGS. 17 and 18, the reference voltage (V _RE / RE) is held constant at the inverting and non-inverting inputs of the operational amplifiers A1 / OA2, respectively, while the operating voltage is the voltage divider and resistor. It produces an operational bias that is modified and applied to the connected sensor via the network or other means. The current flowing from CE to WE is a non-inverted variable gain transimpedance amplifier that converts the current into a voltage output scaled (at C2 and / or VOUT / Vo) according to the VOUT / Vo = -i _cell R _{4 / TIA} relationship. Sent to input.

The differential amplifier stage 35 is shown in FIG. The differential amplifier is configured to receive an applied reference voltage (RE or C1 in the internal IC diagram) and an output (with or without a buffer stage) from the transimpedance amplifier. The inputs are juxtaposed between the two amplifiers, i.e. the reference input is to the positive terminal of one amplifier (for negative applied voltage / current) and the negative terminal of the other amplifier (for positive applied voltage / current). It is connected. The VOUT is connected to the opposite amplifier input. The input of an unused amplifier (with the opposite polarity to the applied current / voltage) is driven to zero, but still has a ground bias if present in the system. The gain of the differential amplifier can be configured in real time by manufacturing or according to the amount of voltage / current read by AFE.

Filtering step. The output generated from the differential amplifier pair is subsequently applied to a filtering circuit to remove external noise. Signal vibrations or random fluctuations can be present for several reasons, including ground bias, RF interference, commercial power vibrations, input impedance mismatches (from 3-electrode sensors), or those from other sources.

Analog-to-digital converter step. The filtered signal is finally placed in an external integrated circuit (“integrated circuit: IC”) or co-located in a microcontroller or other IC (“analog to digital converter”). : ADC ") and converted into a typical digital signal. The sampling resolution may be improved in order to further improve the sensitivity and minimize the quantification error.

Collection algorithm step. To further reduce noise, time averages of both positive and negative bias lines are collected and calculated by the microcontroller / microprocessor over a period of seconds (following digitization by the ADC). The active bias amplifier (applied voltage / current) subtracts the value of the inactive bias amplifier (ground offset) to remove the bias present in the appliance. This process eliminates the need for shielding cages to bring sensitivity to pico amp levels. Inactive bias amplifiers, time average data acquisition, and filtering schemes always provide a stable and scalable output to the microcontroller / processor.

The input of the electrochemical cell or sensor or the analyte is measured by a constant potential method (amperometry, voltammetry, etc.). The output of the detection system consisting of the measured voltage and the calculated current value (measurement of the current flowing through the working electrode and counter electrode of the electrochemical cell or sensor) corresponds to the concentration of the analyte in the sample.

FIG. 20 is a signal flow chart for detecting a current flowing through an electrochemical cell. The current signal from the electrochemical cell 26 is sent to the adjustable bias analog front end 41. The signal is sent to the transimpedance amplifier 42. The signal is sent from both the adjustable bias analog front end 41 and the transimpedance amplifier 42 to the mirrored differential amplifier 44. The output generated from the mirror type differential amplifier 44 is subsequently applied to the filtering circuits 46 and 47 to remove external noise. Signal vibrations or random fluctuations can be present for several reasons, including ground bias, RF interference, commercial power vibrations, input impedance mismatches (from 3-electrode sensors), or those from other sources. In the acquisition algorithm 48, in order to further reduce noise, the time averages of both positive and negative bias lines are microcontroller / Collected and calculated by the microprocessor. The active bias amplifier (applied voltage / current) subtracts the value of the inactive bias amplifier (ground offset) to remove the bias present in the appliance. This process eliminates the need for shielding cages to bring sensitivity to pico amp levels. Inactive bias amplifiers, time average data acquisition, and filtering schemes always provide a stable and scalable output to the microcontroller / processor / ADC.

FIG. 21 is a detailed circuit diagram of the integrated analog front end 550 and the sensor interface. It communicates with the central microcontroller / microprocessor unit (SCL and SDA lines) and connects the electrochemical sensor via the CE (opposite electrode) line, WE (working electrode) line, and RE (reference electrode) line. It is a circuit diagram of an integrated AFE that is controlled and available from the manufacturer. Constructable circuit components for a transimpedance amplifier (TIA) exist across 9 and 10 to form an integrator as configured in the figure.

FIG. 22 is a detailed circuit diagram of the mirror type differential amplifier 44'and filtering. Here, a set of mirrored differential amplifiers utilizing individual op amp components (left side) and a low pass filter for the output (right side) is shown. AMORP and AMORN are positive and negative differential signals, and AMOUTN and AMOUTP are filtered differential signals. The output gain is controlled by a passive resistor connected to the amplifier.

FIG. 23 is a detailed circuit diagram of the fixed mirror type instrumentation amplifiers 44a and 44b. Here, a set of mirrored differential amplifiers using a pair of integrated instrumentation amplifiers is shown. The output gain is controlled by a single resistor connected to the RG terminal.

FIG. 24 is a detailed circuit diagram of the digital potentiometer adjustable mirror type instrumentation amplifier 44c. This is similar to FIG. 23, except that it utilizes a programmable / digitally selectable gain resistor integrated circuit (IC3) rather than a passive component.

FIG. 25 is a diagram of a handheld analyzer 220 with a large form factor. FIG. 26 is a diagram of a handheld analyzer 220a with a small form factor. FIG. 28 is a diagram of a small form factor handheld analyzer 220b.

Sampling and measurement algorithms are designed to minimize sources of noise that are not compensated or removed using circuit hardware. Block of FIG. 27 As shown in FIG. 60, each "sample" relates to reading both positive and negative differential outputs and subtracting one from the other. Multiple samples can be collected and analyzed by statistical calculations to obtain measurements. The simplest form is to calculate the mean and variance / standard deviation from the set of individual samples. The sampling period must be selected to minimize the possibility of noise from other power sources.

The main sources of noise are floating ground and ground drift, commercial power, and high frequency interference.

Floating ground and ground drift are compensated by various means. Floating ground (DC noise) is compensated for by the presence of paired differential amplifiers. Ground drift is compensated by averaging multiple samples. When measuring positive bias / current, the negative output is equal to floating ground. Subtracting the negative output from the positive output removes the noise caused by ground drift. The reverse can be done when measuring negative bias / current. The subtraction step should be performed on a sample-by-sample basis, rather than using the average of multiple readings.

Commercial power is also compensated in various ways. Noise caused by commercial power when connected to an AC power line or induced by proximity to equipment powered by another AC power line is compensated by the choice of algorithm sampling period. Sampling should be performed with the same delay as the line power cycle period (16 ms or 20 ms for 60 Hz and 50 Hz power systems, respectively) or any multiple thereof (ie, 32-40 ms for multiples of 2). is not it. If the sampling delay is less than a line power cycle (16-20 ms), then at least one cycle (50-60 Hz) must be captured by multiple samples. For proper statistical analysis, sufficient samples must be collected to properly estimate the standard deviation and mitigate the power line harmonics. For a 95% confidence interval for type 1 (false positive) and type 2 (false negative) errors, for example, at least 13 samples must be measured. This is for specific applications, but a minimum of 10 samples is recommended. The maximum sample size depends on the application (for example, it can fluctuate suddenly due to external factors such as movement in the case of a body-worn sensor).

High frequency interference, noise from radio transmission and other high frequency signals are completely removed by hardware filtering, especially low pass filtering.

In one embodiment of the apparatus, an enzyme such as D-β-hydroxybutyric acid dehydrogenase and a cofactor such as nicotinamide adenine dinucleotide are immobilized on the sensor surface and in the presence of a ketone compound, eg, D-β-hydroxybutyrate. It is an enzyme electrochemical sensor that reduces the oxidation state of nicotinamide adenine dinucleotide, which is a chemically equivalent cofactor. This reduced cofactor (reduced nicotinamide adenine dinucleotide) is then converted to an oxidized form by application of a bias potential, current, DC signal, AC signal, waveform, optical or acoustic signal. Following quantification, the magnitude, phase, or other physical quantity of this signal is evaluated to determine if it exceeds a predetermined level, threshold, or rate of change required to generate a warning. ..

In yet another embodiment of the apparatus, a catalyst such as a metal or metal oxide is placed on the surface of the sensor or electrode and the compound is sensored or in the presence of a ketone compound, eg, D-β-hydroxybutyrate. A non-enzymatic electrochemical sensor that converts into an electroactive product that can be directly oxidized or reduced on the surface of the electrode. When a bias potential, current, DC signal, AC signal, waveform, light, or acoustic signal is applied to this sensor / electrode, the magnitude, phase, or other physical quantity of this signal is evaluated to generate a warning. It is determined whether or not the required predetermined level, threshold, or rate of change is exceeded.

In yet another embodiment of the apparatus, a catalyst such as a metal or metal oxide is placed on the surface of the sensor or electrode and directly oxidizes this compound in the presence of a ketone compound, eg, D-β-hydroxybutyrate. Or a non-enzymatic electrochemical sensor that reduces. When a bias potential, current, DC signal, AC signal, waveform, light, or acoustic signal is applied to this sensor / electrode, the magnitude, phase, or other physical quantity of this signal is evaluated to generate a warning. It is determined whether or not the required predetermined level, threshold, or rate of change is exceeded.

In yet another embodiment of the apparatus, at least one of the anode and cathode contains an enzyme such as D-β-hydroxybutyric acid dehydrogenase, on which a cofactor such as nicotinamide adenine dinucleotide or a redox mediator is immobilized. It is also an enzyme biofuel cell. The presence of a ketone compound, such as D-β-hydroxybutyrate, causes a stoichiometrically equal amount of cofactor, namely nicotinamide adenine dinucleotide or mediator, to change (reduce or increase) its oxidative state. Due to the oxidation reaction at this anode and the reduction reaction at this cathode, along with the oxidation or reduction reaction at the accompanying counter electrode (anode or cathode), the voltage (electromotive force) between these anodes and cathode. ) Occurs. This electromotive force then generates a current proportional to the magnitude of the redox reaction. Following quantification, the magnitude or other physical quantity of this signal is evaluated to determine if it exceeds a predetermined level, threshold, or rate of change required to generate a warning.

In yet another embodiment of the apparatus, at least one of the anode and cathode contains an enzyme such as D-β-hydroxybutyric acid dehydrogenase, on which a cofactor such as nicotinamide adenine dinucleotide or a redox mediator is immobilized. It is also a non-enzyme fuel cell. The presence of a ketone compound, such as D-β-hydroxybutyrate, causes a stoichiometrically equal amount of cofactor, namely nicotinamide adenine dinucleotide or mediator, to change (reduce or increase) its oxidative state. Due to the oxidation reaction at this anode and the reduction reaction at this cathode, along with the oxidation or reduction reaction at the accompanying counter electrode (anode or cathode), the voltage (electromotive force) between these anodes and cathode. ) Occurs. This electromotive force then generates a current proportional to the magnitude of the redox reaction. Following quantification, the magnitude or other physical quantity of this signal is evaluated to determine if it exceeds a predetermined level, threshold, or rate of change required to generate a warning.

Yet another embodiment of the device is a colorimetric sensor (any dye) that undergoes color change or color intensity modulation when exposed to a ketone compound, eg, D-β-hydroxybutyrate. The magnitude of this change or modulation is evaluated to determine if it exceeds a predetermined level, threshold, or rate of change required to generate a warning.

Yet another embodiment of the device is an optical sensor optionally comprising a fluorophore or an optically active intermediate. Exposure to ketone compounds, such as D-β-hydroxybutyrate, results in changes in absorbance or emission wavelength. The magnitude of this change is evaluated to determine if it exceeds a predetermined level, threshold, or rate of change required to generate a warning.

A further embodiment is to generate a user prompt warning, alarm, or notification in a scenario where the level of the ketone compound or plurality of ketone compounds in the physiological fluid is greater than or equal to 0.6 mmol / L.

A further embodiment is that glucose in the user's blood (or stroma) as measured by a continuous glucose monitor exceeds a predetermined value (eg, 300 mg / dL) and is a ketone in a physiological fluid. By generating a user prompt warning, alarm, or notification in a scenario where the level of a compound or multiple ketone compounds is increasing from a baseline of 0.4 mmol / L to a predetermined level associated with an increase in ketone level. be.

In a further embodiment, the user is receiving intravenous, subcutaneous, intramuscular, intradermal, or oral treatment such as a sodium-glucose cotransporter-1 / 2 inhibitor, and the ketone is in a physiological fluid. To generate a warning, alarm, or notification of a user prompt in a scenario where the level of a compound or multiple ketone compounds is increasing from a baseline of 0.4 mmol / L.

A further embodiment is a user prompt warning, alarm, in a scenario where the user is receiving automatic insulin delivery and the levels of the ketone compound or plurality of ketone compounds in the physiological fluid are gradually increasing. Or to generate a notification.

Yet another embodiment is a warning, alarm, prompt or notification that is essentially visual, auditory, or tactile, or a combination thereof.

Yet another embodiment is to generate a warning, alarm, prompt or notification based on the rate of change in the level of a ketone compound or a plurality of ketone compounds in a physiological fluid.

Yet another embodiment is to generate warnings, alarms, prompts or notifications based on exceeding the threshold of the level of a ketone compound or a plurality of ketone compounds in a physiological fluid.

Yet another embodiment is to generate a warning, alarm, prompt or notification based on an individualized or comprehensive risk stratification of a ketone compound or a plurality of ketone compounds in a physiological fluid.

Yet another embodiment is to generate a layered warning level in scenarios where the ketone compound or multiple ketone compounds in the physiological fluid is within the following range: normal: 0.6 mmol / L. Less than; moderate ketosis / nutritional ketosis: 0.6 mmol / L to 1.5 mmol / L; DKA risk: 1.5 mmol / L to 3.0 mmol / L; possible DKA: more than 3.0 mmol / L ..

Yet another embodiment is to present a unique color on the user's display device in scenarios where the ketone compound or plurality of ketone compounds in the physiological fluid is within the following range: green: 0. Less than 6 mmol / L; Yellow: 0.6-1.5 mmol / L; Red: Over 1.5 mmol / L.

Yet another embodiment is to present an icon, color, or shape that represents various risk stratifications associated with a particular level of a ketone compound or a plurality of ketone compounds.

Yet another embodiment is to generate a unique vibration or tactile pattern that represents various stratifications of risk associated with a particular level of a ketone compound or a plurality of ketone compounds.

Yet another embodiment is to generate a report describing when an increase in the level of a ketone compound or a plurality of ketone compounds has been measured, or when such an increase in the rate of change of a ketone has been measured.

Yet another embodiment is titrating automated or user-driven delivery of therapeutic compounds as a result of measuring the levels of a ketone compound or plurality of ketone compounds in a physiological fluid.

Yet another embodiment encourages the user to take steps to prevent or treat the onset of DKA based on the measured levels or rates of change of the ketone compound or multiple ketone compounds in the physiological fluid. Is.

Yet another embodiment is to present the user with a unified glucose-ketone quantification value, which is derived from a mathematical relationship and indicates the degree of control of the user's blood glucose status.

Yet another embodiment is to present a metabolic system activated to meet a user's energy needs based on measured levels of a ketone compound or a plurality of ketone compounds in a physiological fluid. Optionally, this measurement may include the level of glucose in the physiological fluid.

Yet another embodiment is to present the user's calorie consumption based on the measured levels of the ketone compound or the plurality of ketone compounds in the physiological fluid. Optionally, this measurement may include the level of glucose in the physiological fluid.

Yet another embodiment is physical activity, with readings from an inertial measurement unit placed on the user, such as a smartphone or smartwatch, along with measurements of the level of the ketone compound or multiple ketone compounds in the physiological fluid. Is to incorporate to advise on.

Yet another embodiment provides measurements of the level of a ketone compound or multiple ketone compounds in a physiological fluid to a user's support network, health care provider, emergency responder, or other related party. Sending data for evaluation.

Yet another embodiment is to issue warnings, alarms, prompts or notifications of the user based on the absolute level of the ketone compound or plurality of ketone compounds in a physiological fluid or the rate of change of this level, or exceeding the threshold level thereof. Sending data for evaluation to support networks, healthcare providers, emergency responders, or other relevant parties.

Yet another embodiment is a user's connected mobile device (ie, a smartphone) that exceeds the absolute level of the ketone compound or plurality of ketone compounds in a physiological fluid or the rate of change of this level, or a threshold level thereof. Alternatively, data is transmitted to a wearable device (that is, a smart watch).

Yet another embodiment is a user's connected mobile device for warnings, alarms, prompts or notifications based on the absolute level of the ketone compound in the physiological fluid or the rate of change of this level, or exceeding its threshold level. To transmit data to (ie, a smartphone) or a wearable device (ie, a smartwatch).

Yet another embodiment is the ability of the user to enable and disable persistent data display, warnings, and / or notifications.

Yet another embodiment is to present the user with a time-series trace of both the glucose level in the physiological fluid and the level of the ketone compound or the plurality of ketone compounds in the physiological fluid on the display device.

Yet another embodiment sets the threshold level of a ketone compound or multiple ketone compounds in a physiological fluid for a user identified as low risk (ie, normal CGM reading, no SGLT-2 treatment). Dynamic or adaptive notifications in which warnings, alerts, prompts or notifications are presented only if they are exceeded.

Yet another embodiment is to generate audible or tactile warnings and notifications specific to the glucose level in the physiological fluid and the level of the ketone compound or the plurality of ketone compounds in the physiological fluid, respectively.

Yet another embodiment is to present semi-persistent measurements of a ketone compound or a plurality of ketone compounds in a physiological fluid.

Yet another embodiment is when the user is (1) using an insulin pump and therefore presents with a higher risk hypoinsulinemia due to dysfunction of the insulin pump or infusion set; (2) If you are taking a therapeutic agent such as an SGLT-2 inhibitor and have higher basal circulating ketone body levels even in a normal blood glucose state; (3) you are taking insulin for that purpose. , If it is likely that basal insulin will only cover a certain amount of time; (4) if you are distracted and therefore ignore insulin administration; or (5) carbohydrate restriction or intake To generate a risk stratified warning, alert or notification when a defined time zone follows an existing diurnal pattern.

Yet another embodiment is to generate a warning if the measured level of the ketone compound or plurality of ketone compounds in the physiological fluid is above 0.6 mmol / L.

Yet another embodiment is to generate a warning, alarm or notification when the measured level of the ketone compound or the plurality of ketone compounds in the physiological fluid exceeds 0.6 mmol / L.

Yet another embodiment is based on which the measured level of glucose in the physiological fluid exceeds 240 mg / dL and the level of the ketone compound or plurality of ketone compounds in the physiological fluid is 0.4 mmol / L. To generate a warning, alarm or notification when increasing from the line level.

In yet another embodiment, the user is receiving an oral therapeutic agent (ie, an SGLT-2 inhibitor) and the level of the ketone compound or plurality of ketone compounds in the physiological fluid is 0.4 mmol /. Is it to generate a warning, alarm or notification regardless of the measured glucose level when increasing from the baseline level of L.

Yet another embodiment is when the user is receiving insulin infusion therapy and the level of the ketone compound or multiple ketone compounds in the physiological fluid is increased from the baseline level of 0.4 mmol / L. Is to generate a warning, alarm or notification regardless of the measured glucose level.

Yet another embodiment is to mount the electrochemical sensor in a microneedle array configured to perform ketone quantification in the biological epidermis or dermis.

Yet another embodiment is to mount two electrochemical sensors in a microneedle array configured to quantify glucose and ketones in the epidermis or dermis.

Yet another embodiment is to mount a plurality of electrochemical sensors in a microneedle array configured to quantify ketones and analytes in the epidermis or dermis.

Yet another embodiment mounts an electrochemical ketone sensor on one microneedle array for the purpose of quantifying ketones and glucose in the epidermis or dermis, respectively, as well as a second separate microneedle array. It is to mount an electrochemical glucose sensor on top.

Yet another embodiment is to implement an electrochemical sensor within a subcutaneous sensor configured to perform ketone quantification within the adipose tissue of the subcutaneous tissue.

Yet another embodiment is to implement two electrochemical sensors within a subcutaneous sensor configured to quantify glucose and ketones within the adipose tissue of the subcutaneous tissue.

Yet another embodiment is to mount multiple electrochemical sensors within a subcutaneous sensor configured to quantify ketones and analytes within the adipose tissue of the subcutaneous tissue.

U.S. Pat. No. 9,95409. U.S. Patent Application Publication No. 20150071994 U.S. Patent Application Publication No. 2015475094 U.S. Patent Publication No. 2015136629 PCT International Patent Application Publication No. WO2018164886

Claims (35)

It is configured to measure the level of a ketone compound circulating in the wearer's physiological fluid and produces a warning to the wearer if the level of the circulating ketone compound exceeds a predetermined level or rate of change. It is possible to wear a body-mounted sensor. The sensor may be an electrochemical sensor, an optical sensor, a galvanic sensor, a voltanmetric sensor, an amperometric sensor, a potentiality sensor, an impedance sensor, a resistance sensor, a capacitance sensor, an ultrasonic sensor, a radio frequency sensor, or a microwave. The device of claim 1, comprising at least one of the sensors. The apparatus according to claim 1, wherein the ketone compound contains at least one of acetone, acetoacetic acid, or β-hydroxybutyric acid. The apparatus according to claim 1, wherein the physiological fluid comprises at least one of blood, serum, plasma, interstitial fluid, skin interstitial fluid, extracellular fluid, intracellular fluid, or cerebrospinal fluid. The device of claim 1, wherein the sensor is further configured to measure glucose circulating in the wearer's physiological fluid. The device of claim 1, wherein the warning is at least one of visual, audible, tactile, or textual notifications. The predetermined level is a threshold value, a value indicating clinical ketosis, a value indicating clinical ketosis, a value indicating metabolic ketosis, a value indicating diabetic ketoacidosis, a value indicating metabolic ketosis, or a nutritional ketosis. The apparatus according to claim 1, comprising a value indicating. The apparatus according to claim 1, wherein the rate of change includes a derivative value or a gradient value. It is configured to measure the level of the ketone compound circulating in the wearer's physiological fluid and displays to the wearer a persistent or semi-persistent reading of the ketone compound circulating in the physiological fluid. A body-worn sensor that can be used. The sensor may be an electrochemical sensor, an optical sensor, a galvanic sensor, a voltanmetric sensor, an amperometric sensor, a potentiality sensor, an impedance sensor, a resistance sensor, a capacitance sensor, an ultrasonic sensor, a radio frequency sensor, or a microwave. 9. The apparatus of claim 9, comprising at least one of the sensors. The apparatus according to claim 9, wherein the ketone compound contains at least one of acetone, acetoacetic acid, and β-hydroxybutyric acid. 9. The apparatus of claim 9, wherein the physiological fluid comprises at least one of blood, serum, plasma, interstitial fluid, skin interstitial fluid, extracellular fluid, intracellular fluid, or cerebrospinal fluid. The device of claim 9, wherein the sensor is further configured to measure glucose circulating in the wearer's physiological fluid. The device of claim 9, wherein the reading is at least one of a numerical value, a textual notification, and a symbolic notification. A method of generating a warning to the wearer of a body-worn sensor, wherein the warning indicates an increased metabolic state of the ketone compound. 15. The method of claim 15, wherein the warning is at least one of visual, audible, tactile, or textual notifications. 15. The method of claim 15, wherein the wearable device comprises at least one of a skin permeation sensor, a transdermal sensor, an internal skin sensor, an intradermal sensor, a direct skin sensor, or a subcutaneous sensor. 15. The method of claim 15, wherein the sensor operates by optical, electrical, or electrochemical means. 15. The method of claim 15, wherein the metabolic state comprises a baseline health state, a normal health state, a ketosis state, or a ketoacidosis state. 15. The method of claim 15, wherein the ketone compound comprises at least one of acetone, acetoacetic acid, or β-hydroxybutyric acid. A method for measuring elevated levels of circulating ketone bodies in physiological fluids.
Among electrochemical sensors, optical sensors, galvanic sensors, voltanmetric sensors, amperometric sensors, potentiometric sensors, impedance sensors, resistance sensors, capacitance sensors, ultrasonic sensors, radio frequency sensors, or microwave sensors. Measuring the concentration of ketone compounds circulating in the physiological fluid of the wearer of a body-worn sensor device, including one, and
The measurement is stored in the memory of the body-worn device, and it is determined whether or not the concentration level exceeds a predetermined level, a threshold value, or a rate of change from a previous measurement value.
A method comprising generating a warning if the concentration level exceeds a predetermined level, threshold, or rate of change from a previous measurement. 21. The method of claim 21, wherein the physiological fluid comprises at least one of blood, serum, plasma, interstitial fluid, skin interstitial fluid, extracellular fluid, intracellular fluid and cerebrospinal fluid. 21. The method of claim 21, wherein the body-worn sensor device further comprises a processor. 23. The method of claim 23, wherein the processor of the body-worn sensor device is further configured to measure glucose circulating in the wearer's physiological fluid. 21. The method of claim 21, wherein the body-worn sensor device is configured to generate the warning. 25. The method of claim 25, wherein the warning is at least one of visual, audible, tactile, or textual notifications. 21. The method of claim 21, wherein the body-worn sensor device further comprises a wireless transceiver. 21. The method of claim 21, wherein the body-worn sensor device further comprises a graphical user display. 21. The method of claim 21, wherein the body-worn sensor device further comprises at least one of a skin permeation sensor, a transdermal sensor, an internal skin sensor, an intradermal sensor, a direct skin sensor, or a subcutaneous sensor. 25. The method of claim 25, wherein the warning indicates an increased metabolic state of the ketone compound. Alerts to persons with diabetes to inform them of elevated and / or increased risk of elevated ketone levels and to warn them of the need for treatment to prevent progression to diabetic ketoacidosis. It ’s a way to generate
Utilizing a sensor for the sustained and autonomous detection of ketone levels in a person's physiological fluid, the sensor primarily intended for the sustained measurement of another analyte. It's built into the body-worn element,
A method comprising generating a warning when the ketone level exceeds a predetermined threshold. 31. The method of claim 31, wherein the simultaneous measurements of ketones and glucose are from the body-worn element within the subcutaneous adipose tissue sensor. 31. The method of claim 31, wherein the simultaneous measurements of ketones and glucose are from the body-worn element within the intradermal sensor. Each of the plurality of glucose readings is continuously updated to the display to the person and each of the plurality of ketone readings is continuously monitored, but as requested by the user or the value is predetermined. 31. The method of claim 31, which is displayed only when the threshold value of is exceeded. 31. The method of claim 31, wherein the warning is an audible or tactile warning, or the warning is transmitted to a designated caregiver using remote monitoring, including a plurality of cloud-based notifications.

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