Continuous glucose, analyte monitoring systems and methods, manufacturing methods and kits

Abstract

Continuous glucose, analyte monitoring systems and methods, manufacturing methods, and kits are provided herein in the form of example embodiments. The medical devices can be sensors adapted to sense a biochemical property. Embodiments can be used to determine calibration information specific to an individual medical device. Embodiments can determine calibration information by reference to one or more parameters obtained during manufacture of the medical device. Embodiments can also determine calibration information by reference to in vitro testing of the medical device. Embodiments are also adapted for use in systems of those medical devices incorporated in their field of use. Embodiments are also described that modify the surface of a sensor substrate, such as by applying radiation and / or creating wells, to aid in placement of sensor elements on the substrate and / or to adjust the size of the sensor elements.

Description

[0001] This application is a divisional application of the Chinese national phase application of PCT application No. PCT / IB2018 / 056223, filed on August 17, 2018, entitled "Systems, apparatus and methods related to individualized calibration and / or manufacturing of medical devices", the entire contents of which are incorporated herein by reference.

[0002] Cross-reference to related applications

[0003] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 547,635, filed August 18, 2017, the entire contents of which are incorporated herein by reference and for all purposes. Technical Field

[0004] The topics described herein generally relate to the identification or utilization of calibration information specific to individual medical devices such as physiological sensors, and / or systems, apparatus, and methods for manufacturing physiological sensors. Background Technology

[0005] There is a huge and growing market for monitoring the health and condition of humans and other living animals. Information describing a human body or physiological condition can be used in countless ways to help and improve quality of life, as well as to diagnose and treat adverse human conditions.

[0006] Common devices used to collect this information are physiological sensors, such as biochemical sensors, or devices capable of sensing the chemical properties of a biological entity. Biochemical sensors come in various forms and can be used to sense the properties of fluids, tissues, or gases that are part of or produced by a biological entity, such as a human. These biochemical sensors can be used on or inside the body, or they can be used on biological material that has been removed from the body.

[0007] The performance of biochemical sensors can be characterized in many ways, and a particularly important characteristic is the accuracy of the biochemical sensor, or the degree to which the biochemical sensor correctly measures the concentration or content of the analyte. The accuracy of the biochemical sensor, or the degree to which the measured value is accurate or precise, is also important.

[0008] Although biochemical sensors typically have complex and well-studied designs, they are still susceptible to variations in performance. This can be caused by a number of factors, including variations in the manufacturing process and the constituent materials used to manufacture the sensor. These variations can lead to measurable differences in the performance of sensors with the same design and manufacturing process. For these and other reasons, there is a need to improve the performance of manufactured biochemical sensors. Summary of the Invention

[0009] This document provides numerous example embodiments that can be used to improve the performance of medical devices such as biochemical sensors, and devices and systems utilizing these sensors. These example embodiments relate to improved techniques for evaluating and predicting the performance of biochemical sensors when used by patients, healthcare professionals (HCPs), or other users. Many of these example embodiments relate to determining calibration information based on parameters measured, recorded, or otherwise obtained during manufacturing. These parameters may be individualized or specific to a discrete sensor, and the calibration information determined thereby may also be individualized or specific to that discrete sensor.

[0010] In many example embodiments, calibration information is also determined by referencing actual tests of the sensing capabilities or characteristics of certain sensors. The data obtained from those tests can be used with one or more parameters acquired during manufacturing to determine, estimate, speculate, or otherwise predict the performance of the sensor once it is distributed to a user. Tests used to evaluate sensing characteristics (e.g., in vitro tests) are often destructive, contaminating, or otherwise detrimental to the sensor being tested, rendering it unsuitable for distribution to a user. In many embodiments, tests are performed on one or more sensors, and the results are used with manufacturing parameters of different untested sensors to predict the performance of that untested sensor. In this way, the performance of a particular sensor can be predicted without in vitro testing of the sensor.

[0011] Information representing the predictive performance of a sensor can be embodied in calibration information, which can be provided to any device attempting to determine the final result of a measurement (e.g., the concentration or content of a sensed substance) using sensing signals or data generated by a biochemical sensor. While applicable on a smaller scale, the embodiments described herein are particularly useful when applied to high-volume manufacturing processes. For example, the embodiments described herein can be applied to groups or batches of sensors manufactured simultaneously. For example, in some embodiments, a subset of one or more sensors from the group or batch is tested in vitro, and the resulting test data is used with one or more manufacturing parameters obtained from different subsets of sensors from the same group or batch to predict the performance of those different subsets of sensors when assigned to a user. Other exemplary embodiments combining one or more aspects described herein, as well as other exemplary embodiments different from those described herein, are also described.

[0012] This document also provides several example embodiments of systems, apparatuses, and methods for modifying the surface of a sensor substrate to aid in the placement and / or sizing of sensor elements. In some of these embodiments, surface regions of the sensor substrate may be modified using electromagnetic radiation to create modified regions. The modified regions may have altered surface properties such that the mobility of a liquid applied to the substrate surface increases or decreases through the modified regions. A liquid may be applied to the surface of the sensor substrate such that the liquid remains in a target region on the surface, wherein the target region is determined at least in part by the location of the modified regions. The electromagnetic radiation may take various forms, such as laser radiation. In these and other embodiments, surface modification may be the creation of wells in which sensing elements may be placed. Wells may be formed in various ways, such as by applying mechanical force. Example embodiments of sensors manufactured using modified regions and / or wells are within the scope of this disclosure, as are apparatuses, systems, and kits including them.

[0013] Other systems, apparatuses, methods, features, and advantages of the subject matter described herein will be or will become apparent to those skilled in the art upon reading the following figures and detailed description. It is intended that all such additional systems, methods, features, and advantages are included in this specification, within the scope of the subject matter described herein, and protected by the appended claims. Where these features are not expressly stated in the claims, the features of the exemplary embodiments should in no way be construed as limiting the appended claims. Attached Figure Description

[0014] By studying the accompanying drawings, the details of the subject matter described herein, both in terms of its structure and operation, become readily apparent, with the same reference numerals indicating the same parts. The components in the drawings are not necessarily drawn to scale, but rather to emphasize the principles of the subject matter. Furthermore, all illustrations are intended to convey concepts, where relative dimensions, shapes, and other detailed attributes are shown schematically rather than literally or precisely.

[0015] Figure 1 This is a block diagram illustrating an example embodiment of an in vivo analyte monitoring system.

[0016] Figure 2 This is a block diagram illustrating an example embodiment of the data processing unit.

[0017] Figure 3 This is a block diagram illustrating an example embodiment of a display device.

[0018] Figure 4 This is a schematic diagram illustrating an example embodiment of an analyte sensor.

[0019] Figure 5AThis is a perspective view illustrating an example embodiment of an analyte sensor that penetrates the skin.

[0020] Figure 5B It is shown Figure 5A A cross-sectional view of a portion of the analyte sensor.

[0021] Figures 6 to 9 This is a cross-sectional view illustrating an example embodiment of the analyte sensor.

[0022] Figure 10A This is a cross-sectional view illustrating an example embodiment of the analyte sensor.

[0023] Figures 10B to 10C It shows from Figure 10A A cross-sectional view of an example embodiment of the analyte sensor obtained by line AA observation.

[0024] Figure 11 This is a conceptual diagram illustrating an example embodiment of an analyte monitoring system.

[0025] Figure 12 This is a block diagram illustrating an example embodiment of an on-body electronic device.

[0026] Figure 13 This is a block diagram illustrating an example embodiment of a display device.

[0027] Figure 14 This is a flowchart illustrating an example embodiment of information exchange within an analyte monitoring system.

[0028] Figure 15A , Figure 15B as well as Figure 16 This is a top view illustrating an example embodiment of an in vitro analyte sensor.

[0029] Figure 17 This is an exploded view illustrating an example embodiment of an in vitro analyte sensor.

[0030] Figure 18A This is a perspective view showing an example embodiment of an in vitro analyte measuring instrument.

[0031] Figure 18B This is a front view showing an example embodiment of an in vitro analyte measuring instrument.

[0032] Figure 19A This is a graph illustrating an example of the in vitro sensitivity of the analyte sensor.

[0033] Figure 19B This is a graph showing examples of different sensitivities of the analyte sensor.

[0034] Figures 20A to 20CThis is a flowchart illustrating an example embodiment of a method for calibrating a medical device capable of sensing biomedical properties.

[0035] Figure 21A This is a top view showing a portion of an example embodiment of the analyte sensor.

[0036] Figures 21B to 21C It shows along Figure 21A A cross-sectional view of a portion of an example embodiment of the analyte sensor obtained by observation along line 21BC-21BC.

[0037] Figure 22A This is a top view showing a portion of an example embodiment of the analyte sensor.

[0038] Figures 22B to 22C It shows along Figure 22A A cross-sectional view of an exemplary embodiment of a portion of the analyte sensor obtained by observation along line 22BC-22BC.

[0039] Figure 23A This is a perspective view showing a portion of an example embodiment of an analyte sensor.

[0040] Figure 23B It shows along Figure 23A A cross-sectional view of an exemplary embodiment of the analyte sensor, taken from line 23B-23B.

[0041] Figure 24 This is a cross-sectional view illustrating an example embodiment of an in vivo sensor.

[0042] Figure 25A This is a perspective view illustrating an example embodiment of the analyte sensor.

[0043] Figure 25B It shows along Figure 25A A cross-sectional view of an example embodiment of the analyte sensor, taken from lines 25B-25B.

[0044] Figure 26A This is an example graph of in vitro test data.

[0045] Figure 26B It corresponds to Figure 26A Example curves showing the sensitivity of in vitro test data.

[0046] Figures 27A to 27F This is a flowchart illustrating an example embodiment of a method for determining individualized calibration information.

[0047] Figures 28A to 28B This is a flowchart illustrating an additional example embodiment of a method related to determining individualized calibration information.

[0048] Figure 29A This is a block diagram illustrating an example embodiment of a computer system that can be used to implement the calibration embodiments described herein.

[0049] Figures 29B to 29D This is a block diagram illustrating the conceptual process and information flow for manufacturing biochemical sensors.

[0050] Figures 30A to 30B The graph shows an example dataset that demonstrates a statistically significant association between in vivo sensitivity and certain manufacturing parameters.

[0051] Figures 31A to 31B This is a graph showing a sample dataset used to evaluate certain example embodiments.

[0052] Figures 32A to 32F This is a schematic diagram illustrating example embodiments of sensor substrates at various stages of manufacturing.

[0053] Figures 33A to 33B This is a top view photograph showing an example embodiment of the sensor substrate.

[0054] Figures 34A to 34B This is a top view photograph showing an example embodiment of a sensing element formed on a sensor substrate.

[0055] Figures 35A to 35D This is a schematic diagram illustrating an example embodiment of a modified region on a sensor substrate.

[0056] Figures 36A to 36B This is a flowchart illustrating an example embodiment of a method for manufacturing one or more sensing elements.

[0057] Figures 37A to 37B This is a schematic diagram illustrating example embodiments of sensor substrates at various stages of manufacturing.

[0058] Figure 37C It is along Figure 37B The cross-section taken from line 37C-37C.

[0059] Figures 37D to 37F This is a cross-section of an additional example embodiment of the sensor substrate.

[0060] Figure 37G This is a top view schematic diagram of an example embodiment of a sensor substrate.

[0061] Figure 37H It is along Figure 37G The cross-section taken from line 37H-37H.

[0062] Figures 38A to 38D This is a cross-section of an example embodiment of a sensor substrate on which electrochemical reagents are deposited.

[0063] Figures 39A to 39B This is a photograph illustrating an exemplary embodiment of the tamping instrument.

[0064] Figures 40A to 40B This is a photograph illustrating an example embodiment of a sensor substrate having a well.

[0065] Figure 41A and Figure 41B This is a top view photograph showing an example embodiment of a well in a sensor substrate before and after reagent dispersion.

[0066] Figure 42A and Figure 42B This is a top view photograph showing an example embodiment of a well in a sensor substrate before and after reagent dispersion.

[0067] Figure 43 These are a series of top-view photographs showing various examples of reagent dispersion on sensor substrates with and without wells.

[0068] Figures 44A to 44B This is a flowchart illustrating an example embodiment of a method for manufacturing one or more sensing elements. Detailed Implementation

[0069] The subject matter has been described in detail with reference to exemplary embodiments. These exemplary embodiments are set forth for illustrative purposes to assist those skilled in the art in understanding and appreciating the full scope of the subject matter. These exemplary embodiments do not constitute an exhaustive description of all ways in which the subject matter can be implemented, as such an exhaustive description would be both redundant and unnecessary given the explicitly set forth exemplary embodiments. Therefore, the breadth of the subject matter extends beyond the specific embodiments explicitly set forth herein.

[0070] The subject matter described herein generally relates to advances in techniques for calibrating medical devices capable of sensing one or more biochemical properties, and to systems and apparatuses for performing these calibration techniques. In many embodiments, these techniques allow for the determination of individualized calibration information that varies between individual medical devices and is specific to each individual device, in contrast to a single calibration value determined for a group of medical devices as a whole. Many types of medical devices can sense biochemical properties, and therefore many applications can utilize this subject matter. Several of these categories of medical devices will be described herein, but these are merely examples and do not constitute an exhaustive list of all categories of medical devices that have found useful to this subject matter.

[0071] Medical devices capable of sensing or monitoring chemical levels in bodily fluids can generally be categorized as either in vivo systems or as part of an extracorporeal system. In vivo systems comprise one or more medical devices that typically sense one or more biochemical properties of bodily fluids by partially or wholly implanting a medical device (e.g., a sensor) within the body. A common example is an in vivo analyte sensor used to monitor analyte levels in the body. These analyte sensors can be designed to detect glucose or other analytes that are particularly relevant to monitoring diabetes.

[0072] An in vitro system includes one or more medical devices that sense one or more biochemical properties of bodily fluids, such as blood, plasma, urine, etc., taken from the human body, or other substances, such as homogenized biopsy samples. In vitro systems can also be called ex vivo systems. A common example is an in vitro analyte sensor, such as a test strip. In vitro test strips can also be designed to detect and measure glucose or other analytes that are particularly relevant to monitoring diabetes conditions.

[0073] Systems and devices that combine or utilize data from in vivo or extracorporeal medical devices are broadly referred to herein as biochemical monitoring systems and biochemical monitoring devices, respectively. Systems and devices that combine or utilize data from medical devices are referred to herein as analyte monitoring systems and analyte monitoring devices, respectively, and these systems and devices are designed to sense the level of an analyte (e.g., glucose).

[0074] Exemplary embodiments related to these calibration techniques will be presented by reference to their application in in vivo and in vitro medical devices. Most embodiments are described with respect to in vivo medical devices, particularly in vivo analyte sensors. This is merely for the purpose of illustrating the various features and aspects of these exemplary embodiments, and not to limit these calibration techniques to in vivo analyte sensors. In fact, as already noted, this subject matter is broadly applicable to other types of medical devices, many of which will also be explicitly described.

[0075] Certain example embodiments associated with these calibration techniques allow for the determination of individualized calibration information specific to an individual sensor, and, if necessary, this individualized calibration information is subsequently used to calibrate the output of the individual sensor. In many embodiments, the individualized calibration information is specific to each individual medical device in a co-manufacturing group or batch, and can vary between each individual medical device in the co-manufacturing group. These embodiments contrast with methods that determine a single calibration value for a group or many medical devices as a whole, such that each medical device in the co-manufacturing group has the same calibration value.

[0076] In some example embodiments, sensing characteristics of a first subset of medical devices (e.g., a sample or baseline subset) are determined. For analyte sensors, this sensing characteristic may be, for example, the sensor's sensitivity to the analyte. Sensing characteristics can be determined by in vitro (or in vivo) testing of the first subset of medical devices. Examples of such testing will be described in more detail herein. One or more individualized manufacturing parameters can be measured from each medical device in different second subsets of medical devices (e.g., a distribution subset intended to be distributed from the manufacturer to third-party users). In some example embodiments, the baseline subset and the distribution subset are taken from the same production batch. Measurements of individualized manufacturing parameters can be performed by, for example, the manufacturer during or after the manufacturing process. Individualized manufacturing parameters can be directly or indirectly associated with the sensing characteristics of the medical devices, and numerous examples of such individualized manufacturing parameters are described herein.

[0077] Then, individualized calibration information is independently determined for each medical device in the distribution subset, using at least the individualized manufacturing parameters of each device in the distribution subset and the sensing characteristics of the baseline subset. This allows calibration information specific to each medical device in the distribution subset to vary across medical devices as individualized manufacturing parameters change. In some embodiments, two or more individualized manufacturing parameters may be used to determine calibration information. In some embodiments, one or more qualitative manufacturing parameters may be used alone or in combination with quantitative individualized manufacturing parameters.

[0078] As will be discussed in further detail herein, research has confirmed that embodiments of this subject matter provide a tangible improvement in the accuracy of biochemical sensing measurements performed by medical devices. This translates to improvements in the operation of calibrating the medical devices themselves, which in turn improves the operation of monitoring systems and / or monitoring devices that incorporate these medical devices, as well as the operation of computing devices that process or otherwise utilize the improved accuracy data generated by calibrating the medical devices. Improvements have also been confirmed through reduced variability between medical devices, and increased production yields in the manufacture of medical devices.

[0079] Before describing in detail the embodiments related to personalized calibration techniques, it is necessary to first describe example embodiments of in vivo and in vitro analyte monitoring systems, as well as operational examples of them, all of which can be used with these calibration technique embodiments.

[0080] Example embodiments of in vivo analyte monitoring systems

[0081] Various types of analyte monitoring systems can be used with in vivo sensors. For example, a "continuous analyte monitoring" system (e.g., a "continuous glucose monitoring" system) is an in vivo system that can repeatedly or continuously transmit data from a sensor control device to a reader device without prompting, such as automatically according to a schedule. Another example is a "flash analyte monitoring" system (e.g., a "flash glucose monitoring" system, or simply a "flash" system), which is an in vivo system that can transmit data from a sensor control device in response to a reader device, such as by scanning or requesting data using near field communication (NFC) or radio frequency identification (RFID) protocols.

[0082] An in vivo analyte sensor can be partially or completely implanted in the human body, allowing it to come into contact with bodily fluids and sense analyte levels. The in vivo sensor can be part of a sensor control device located on the user's body and includes electronics and a power source capable of sensing and controlling the analyte sensing. The sensor control device and its variations may also be referred to as a "sensor control unit," an "on-body electronics" device or unit, an "on-body" device or unit, a "sensor data communication" device or unit, or a transmitter device or unit, etc. The term "on-body" or "on-body" refers to any device located directly on or near the body, such as wearable devices (e.g., glasses, armbands, wristbands or bracelets, neckbands or necklaces, etc.).

[0083] The in vivo monitoring system may also include one or more reader devices that receive sensed analyte data from a sensor control device. These reader devices can process, retransmit, and / or display the sensed analyte data in any form. These devices and variations thereof may be referred to as “handheld reader devices,” “reader devices” (or simply “readers”), “display devices,” “handheld electronics” (or handheld devices), “portable data processing” devices or units, “data receivers,” “receiver” devices or units (or simply “receivers”), “relay” devices or units, “remote” devices or units, “accompanying” devices or units, “human-machine interface” devices or units, and so on. Computing devices such as personal computers can be used as reader devices.

[0084] In vivo analyte monitoring systems can also be used in external medical devices. For example, a reader device can be combined with or coupled to a port for receiving an in vitro test strip carrying the user's bodily fluids, which can be analyzed to determine the user's analyte levels.

[0085] In-body sensors

[0086] In vivo sensors can be formed on a substrate, such as a generally planar substrate or a non-planar circular or cylindrical substrate. In many embodiments, the sensor includes at least one conductive structure, such as an electrode. Sensor embodiments can be single-electrode embodiments (e.g., having no more than one electrode) or multi-electrode embodiments (e.g., having exactly two, exactly three, or more electrodes). Sensor embodiments will generally include a working electrode and may also include at least one counter electrode (or anti / reference electrode) and / or at least one reference electrode (or at the reference / counter electrode). Electrodes can be arranged as discrete regions electrically isolated by insulating regions and can be electrically connected to circuitry for receiving (and optionally for regulating and / or processing) electrical signals generated by the electrodes. Electrodes can have planar (e.g., relatively flat) surfaces or non-planar (e.g., relatively curved or circular, such as hemispherical, cylindrical, or irregular surfaces and combinations thereof). Electrodes can be arranged in layers or concentrically or otherwise.

[0087] Therefore, embodiments include analyte monitoring devices and systems, such devices and systems including analyte sensors, at least a portion of which is positioned beneath the user's skin surface for detecting analytes, including glucose, lactate, etc., in bodily fluids within the body. Embodiments include fully implantable analyte sensors and analyte sensors with only a portion of the sensor located beneath and a portion of the sensor located above the skin, for example, for contact with sensor control devices (which may include a transmitter), receiver / display unit, transceiver, processor, etc. For example, the sensor can be positioned via the user's external skin surface for continuous or periodic monitoring (based on periodic intervals, irregular intervals, schedules, frequent repetitions, etc.) of the user's bodily fluids (e.g., interstitial fluid, subcutaneous fluid, dermal fluid, blood, or other fluids of interest). For the purposes of this description, unless otherwise stated, continuous monitoring and periodic monitoring will be used alternately. Sensor responses can be correlated and / or translated into analyte levels in blood or other fluids. In some embodiments, the analyte sensor may be positioned to contact interstitial fluid to detect glucose levels, wherein the detected glucose can be used to infer glucose levels in the user's blood. The analyte sensor can be inserted into a vein, artery, or other part of the body that contains fluid. Embodiments of the analyte sensor can be configured to monitor analyte levels over time periods ranging from seconds, minutes, hours, days, weeks, months, or longer.

[0088] In some embodiments, analyte sensors, such as glucose sensors, are capable of detecting analytes in vivo for one hour or longer, such as several hours or longer, such as several days or longer, such as three days or longer, such as five days or longer, such as seven days or longer, such as several weeks or longer, or even one month or longer. Future analyte levels can be predicted based on obtained information, such as the current analyte level at time t0, the rate of change of the analyte, etc. Predictive alerts can notify the user of potentially concerning predicted analyte levels before the user's analyte level reaches a future predicted analyte level. This provides the user with an opportunity to take corrective action.

[0089] In electrochemical embodiments, the sensor is placed, for example, percutaneously in a subcutaneous site, such that the subcutaneous fluid at that site contacts the sensor. In other in vivo embodiments, at least a portion of the sensor may be placed in a blood vessel. The sensor is used to electrolyze an analyte of interest in subcutaneous fluid or blood, thereby generating a current between a working electrode and a counter electrode. The current value associated with the working electrode is determined. If multiple working electrodes are used, the current value from each working electrode can be determined. A microprocessor can be used to collect these periodically determined current values ​​or to further process these values.

[0090] If the analyte concentration is successfully determined, it can be displayed, stored, transmitted, and / or otherwise processed to provide useful information. For example, the raw signal or analyte concentration can be used as a basis for determining the rate of change of the analyte concentration, which should not exceed the rate of change of a predetermined threshold amount. If the rate of change of the analyte concentration exceeds the predetermined threshold, an indication can be displayed or otherwise transmitted to indicate this fact. In some embodiments, if the rate of change of the analyte concentration exceeds the predetermined threshold, an alarm is activated to warn the user.

[0091] As shown herein, this embodiment can be used in conjunction with devices for measuring or monitoring analytes (e.g., glucose), such as any such device described herein. The embodiments described herein can be used to monitor and / or process information about any number of one or more different analytes. Monitorable analytes include, but are not limited to, acetylcholine, amylase, bilirubin, carbon dioxide, cholesterol, human chorionic gonadotropin (hCG), glycated hemoglobin (HbA1c), creatine kinase (e.g., CK-MB), creatine, creatine anhydride, deoxyribonucleic acid (DNA), fructosamine, glucose, glucose derivatives, glutamine, growth hormone, hormones, ketones, ketone bodies, lactate, oxygen, peroxides, prostate-specific antigen, proteins, prothrombin, ribonucleic acid (RNA), thyroid-stimulating hormone (TSH), troponin, and any combination thereof. In addition to analytes or substituted analytes, the concentration of drugs such as antibiotics (e.g., gentamicin, vancomycin, etc.), digoxin, drugs of abuse, theophylline, and warfarin can be monitored. In embodiments monitoring more than one analyte, the analytes can be monitored at the same or different times. These methods can also be used in conjunction with devices for measuring or monitoring another analyte (e.g., ketones, ketone bodies, HbA1c, etc.), which includes, for example, oxygen, carbon dioxide, proteins, drugs, or other components of interest, or any combination thereof, found in body fluids (e.g., subcutaneous fluid, dermal fluid, interstitial fluid, or other body fluids of interest, or any combination thereof). Generally, the device maintains good contact with the body fluid, such as thorough and substantially continuous contact.

[0092] According to embodiments of this disclosure, the measuring sensor is suitable for electrochemically measuring the concentration of an analyte, such as glucose, in bodily fluids. In these embodiments, the measuring sensor includes at least a working electrode and a counter electrode. Other embodiments may also include a reference electrode. The working electrode is typically associated with a glucose-reacting enzyme. A mediator may also be included. In some embodiments, hydrogen peroxide, which may be referred to as a mediator, is generated by the reaction of the sensor and can be used to infer the glucose concentration. In some embodiments, the mediator is added to the sensor by the manufacturer, for example, the mediator is contained in the sensor prior to use. A redox mediator may be positioned relative to the working electrode and is capable of transferring electrons directly or indirectly between the compound and the working electrode. The redox mediator may, for example, be immobilized on the working electrode, e.g., trapped on a surface or chemically bonded to a surface.

[0093] The embodiments disclosed in this subject matter include in vivo analyte monitoring devices, systems, kits, and processes for monitoring and manufacturing analyte monitoring devices, systems, and kits. Including on-the-body (e.g., at least a portion of the device, system, or a component thereof is held on or near a user's body to monitor analytes), physiological monitoring devices are configured to measure / monitor desired analyte levels (e.g., glucose levels) in real time over one or more predetermined time periods (e.g., one or more predetermined monitoring time periods). Embodiments include transdermal analyte sensors electrically coupled to electronics disposed in a housing designed to adhere to the user's body, e.g., to the user's skin surface, for the duration of the analyte sensor's lifespan or the predetermined monitoring time periods. For example, on-the-body electronics include electronics operatively coupled to the analyte sensor and disposed in the housing for placement on the user's body.

[0094] Such devices and systems with analyte sensors provide continuous or periodic monitoring of analyte levels, which is performed automatically or semi-automatically by programmed or programmable control logic or routines within the monitoring device or system. As used herein, continuous, automatic, and / or periodic monitoring refers to in vivo monitoring or detection of analyte levels using a transdermal analyte sensor.

[0095] In some embodiments, the results of in vivo analyte level monitoring are automatically transmitted from the electronic unit to another device or component of the system. That is, when the results are available, for example, according to a fixed or dynamic data communication schedule executed by the system, the results are automatically transmitted to the system's display device (or other user interaction device). In other embodiments, the results of in vivo analyte level monitoring are not automatically transmitted, transferred, or output to one or more devices or components of the system. In such embodiments, the results are provided only in response to system queries. That is, the results are transmitted to system components or devices only in response to queries or requests for such results. In some embodiments, the results of in vivo monitoring may be recorded or stored in the system's memory and transmitted or transferred to another device or component of the system only after one or more predetermined monitoring periods.

[0096] The embodiments include software and / or hardware for converting any one of a device, component, or system into any other device, component, or system, wherein such conversion can be configured by the user after manufacturing. A conversion module, including hardware and / or software for performing this conversion, can be matched to a given system to convert it.

[0097] The embodiments include electronics connected to an analyte sensor that provides the functionality to operate the analyte sensor for monitoring analyte levels over a predetermined monitoring period, such as about 30 days (or longer in some embodiments), about 14 days, about 10 days, about 5 days, about 1 day, or less than 1 day. In some embodiments, the lifespan of each analyte sensor may be the same as or different from the predetermined monitoring period. In some embodiments, the electronics providing the functionality to operate the analyte sensor include control logic or a microprocessor coupled to a power source, such as a battery, to drive the in vivo analyte sensor to perform an electrochemical reaction, thereby generating a signal corresponding to the monitored analyte level.

[0098] The electronic device may also include other components, such as one or more data storage units or memories (volatile and / or non-volatile), and communication components, to automatically or selectively transmit information corresponding to the monitored analyte level to the display device when information is available or in response to a request for information on the monitored analyte level. In some embodiments, data communication between the display device and the electronics coupled to the sensor is implemented serially (e.g., data transmission between them is not performed simultaneously) or in parallel. For example, in some embodiments, the display device is configured to send signals or data packets to the electronics coupled to the sensor, and upon receiving the sent signals or data packets, the electronics coupled to the sensor reconnects to the display device. In some embodiments, the display device may be configured to continuously provide radio frequency (RF) power and data / signals, and when the RF power is within a predetermined RF power range from the display device, detect or receive one or more return data packets or signals from the electronics coupled to the sensor. In some embodiments, the display device and the electronics coupled to the sensor may be configured to simultaneously send one or more data packets.

[0099] The embodiments also include electronics programmed to store or record in one or more data storage units or to store or record memory data associated with the monitored analyte level during the sensor's lifespan or during a monitoring period. Information corresponding to the monitored analyte level may be stored during the monitoring period, but is not displayed or output during the sensor's lifespan, and the stored data can be retrieved from the memory at the end of the sensor's lifespan or after the predetermined monitoring period has expired, for example, for clinical analysis, treatment management, etc.

[0100] In some embodiments, the predetermined monitoring period is the same as the sensor's lifespan, such that the predetermined monitoring period ends when the analyte sensor reaches the end of its lifespan (and is therefore no longer used for monitoring in vivo analyte levels). In some embodiments, the predetermined monitoring period may include multiple sensor lifespans, such that when the analyte sensor reaches the end of its lifespan, the predetermined monitoring period has not yet ended, and the expired analyte sensor is replaced by another analyte sensor within the same predetermined monitoring period. In some embodiments, the predetermined monitoring period includes replacing multiple analyte sensors to be used.

[0101] In some embodiments, analyte level trend information is generated or constructed based on stored analyte level information spanning time periods (e.g., corresponding to temperature time periods or others) and is transmitted to a display device. In some embodiments, the trend information is output graphically and / or audibly and / or tactilely, and / or presented digitally and / or otherwise on the user interface of the display device to provide an indication of changes in analyte levels during that time period.

[0102] Examples include wirelessly transmitting analyte level information from a bulk electronics device to a second device, such as a display device. Examples of communication protocols between the bulk electronics device and the display device may include radio frequency identification (RFID) protocols or RF communication protocols. Example RFID protocols include, but are not limited to, near field communication protocols (NFC), which include short communication ranges (e.g., about 12 inches or less, or about 6 inches or less, or about 3 inches or less, or about 2 inches or less), high-frequency wireless communication protocols, and far-field communication protocols (e.g., using ultra-high frequency (UHF) communication systems) for providing signals or data from the bulk electronics device to the display device.

[0103] In some embodiments, the communication protocol uses a 433 MHz frequency, a 13.56 MHz frequency, a 2.45 GHz frequency, or other suitable frequencies for wireless communication between bulk electronics, including electronics coupled to an analyte sensor, and one or more display devices and / or other devices such as a personal computer. While certain data transmission frequencies and / or data communication ranges have been described above, other suitable data transmission frequencies and / or data communication ranges may be used between various devices in an analyte monitoring system within the scope of this disclosure.

[0104] The embodiments include a data management system comprising, for example, a data network and / or a personal computer and / or a server terminal and / or one or more remote computers, configured to receive collected or stored data from a display device for presenting analyte information and / or for further processing in conjunction with physiological monitoring for health management. For example, the display device may include one or more communication ports (wired or wireless) for connecting to the data network or computer terminal to transfer collected or stored analyte-related data to another device and / or location. In some embodiments, analyte-related data is transmitted directly from electronics coupled to analyte sensors to a personal computer, server terminal, and / or remote computer via a data network.

[0105] In some embodiments, even if the in vivo analyte sensor automatically and / or continuously monitors in vivo analyte levels—for example, the sensor automatically monitors analytes such as glucose at predetermined time intervals during its lifespan—analyte information is only provided to or visible to the user when needed (provided at a user interface device). For example, the analyte sensor may be located in the body and coupled to in vivo electronics over a given sensing period, such as approximately 14 days, approximately 21 days, or approximately 30 days or longer. In some embodiments, analyte information derived from the sensor is automatically transmitted from the sensor electronics to a remote monitoring or display device for output to the user throughout the 14-day period according to a schedule programmed on the in vivo electronics (e.g., approximately every 1 minute, approximately every 5 minutes, or approximately every 10 minutes, etc.). In some embodiments, analyte information derived from the sensor is transmitted from the sensor electronics to the remote monitoring or display device only at times determined by the user, such as whenever the user decides to check the analyte information. In this case, a communication system is activated, and then the sensor-derived information is sent from the in vivo electronics to the remote device or display device. For example, in one embodiment, using RFID communication, a user places the display device close to the on-body electronics coupled to the analyte sensor and receives real-time (and / or historical) analyte level information (hereinafter referred to as “on-demand” readings) from the on-body electronics.

[0106] In another embodiment, when analyte information is available, the information can be automatically and / or continuously transmitted from the first device to the second device, and the second device stores or records the received information without presenting or outputting it to a user. In this embodiment, the second device receives information from the first device when it becomes available (e.g., when a sensor detects an analyte level according to a schedule). However, the received information is initially stored in the second device and is only output to a user interface or an output component of the second device (e.g., a display) when a request for information on the second device is detected.

[0107] Therefore, in some embodiments, once the sensor electronics are placed on the body such that at least a portion of the in vivo sensor is in contact with bodily fluids and the sensor is electrically coupled to the electronic unit, the analyte information derived by the sensor can be transmitted on demand from the on-body electronics to the display device by turning on the display device (or it can be continuously powered) and executing software algorithms stored in and accessed from the display device's memory, thereby generating one or more request commands, control signals, or data packets to be sent to the on-body electronics. The software algorithm, executed under the control of, for example, the display device's microprocessor or application-specific integrated circuit (ASIC), may include routines for detecting the position of the on-body electronics relative to the display device to initiate the transmission of the generated request commands, control signals, and / or data packets.

[0108] The display device may also include programs stored in memory for execution by one or more microprocessors and / or ASICs to generate and send one or more request commands, control signals, or data packets in response to user activation of an input mechanism on the display device, such as pressing a button on the display device, triggering a soft button associated with a data communication function, etc., to a body electronics device. The input mechanism may optionally or additionally be disposed on or within the body electronics device, which may be configured for user activation. In some embodiments, voice commands or auditory signals may be used to prompt or instruct the microprocessor or ASIC to execute software routines stored in memory to generate and send one or more request commands, control signals, or data packets to the body electronics device. In embodiments activated by voice or in response to voice commands or auditory signals, the body electronics device and / or display device include a microphone, a speaker, and processing routines stored in the corresponding memory of the body electronics device and / or display device to process the voice commands and / or auditory signals. In some embodiments, positioning the body device and the display device within a predetermined distance (e.g., very close) can activate one or more software routines stored in the memory of the display device to generate and send request commands, control signals, or data packets.

[0109] For each on-demand read, different types and / or forms and / or quantities of information may be sent, including but not limited to one or more of the following: current analyte level information (e.g., real-time or recently acquired analyte level information corresponding to the start time of the read), the rate of change of the analyte over a predetermined time period, the rate of change of the analyte (the rate of increase of the rate of change), and historical analyte information corresponding to analyte information acquired and stored in the component memory prior to a given read. For a given read, some or all of the real-time, historical, rate of change, and rate of change (e.g., acceleration or deceleration) information may be sent to the display device. In some embodiments, the type and / or form and / or quantity of information sent to the display device may be pre-programmed and / or immutable (e.g., preset at manufacturing), or may not be pre-programmed and / or mutable, thus allowing selection and / or modification once or multiple times on-site (e.g., by activating a system switch, etc.).

[0110] Therefore, in some embodiments, for each on-demand read, the display device will output the current (real-time) analyte value derived by the sensor (e.g., in digital format), the current rate of analyte change (e.g., in the form of an analyte rate indicator, such as an arrow pointing in the direction of the current rate), and historical analyte trend data (e.g., in the form of a graphical trajectory), which is based on sensor readings acquired by the on-body electronics and stored in the memory of the on-body electronics. Furthermore, the skin or sensor temperature readings or measurements associated with each on-demand read can be transmitted from the on-body electronics to the display device. However, the temperature readings or measurements may not be output or displayed on the display device, but may be used in conjunction with software routines executed by the display device to correct or compensate for the analyte measurements output to the user on the display device.

[0111] As described above, embodiments include in vivo analyte sensors and on-body electronics, which together provide a wearable sensor electronics assembly for the body. In some embodiments, the in vivo analyte sensor and the on-body electronics are fully integrated (fixed during manufacturing), while in other embodiments they are separate but connectable after manufacturing (e.g., before, during, or after the sensor is inserted into the body). The on-body electronics may include an in vivo glucose sensor, electronics, a battery, and an antenna (other than the sensor portion for in-body positioning) encapsulated in a waterproof housing, the waterproof housing including or being attachable to an adhesive pad. In some embodiments, the housing withstands immersion in approximately one meter of water for at least 30 minutes. In some embodiments, the housing withstands continuous underwater contact, for example, for more than approximately 30 minutes, and continues to function normally according to its intended use, for example, without water damage to the housing electronics if the housing is suitable for immersion.

[0112] The embodiments include a sensor insertion device, which may also be referred to herein as a sensor delivery unit, etc. The insertion device may be entirely held on an on-body electronics component within an internal compartment; for example, the insertion device may be “pre-installed” on the on-body electronics component during manufacturing (e.g., the on-body electronics may be encapsulated in a sterile internal compartment of the insertion device). In such embodiments, the insertion device may form a sensor assembly package (including a sterile package) for a pre-used or new on-body electronics component, and the insertion device is configured to apply the on-body electronics component to the recipient's body.

[0113] Embodiments include portable handheld display devices, which are separate devices and isolated from onboard electronics, collecting information from the components and providing the user with sensor-derived analyte readings. Such devices may be referenced in the various ways already described. Some embodiments may include an integrated in vitro analyte measuring instrument. In some embodiments, the display device includes one or more wired or wireless communication ports, such as USB, serial, parallel, etc., configured to establish communication between the display device and another unit (e.g., onboard electronics, a power supply unit for charging a battery, a personal computer, etc.). For example, the display device communication port may charge the display device battery using its respective charging cable and / or data exchange between the display device and its compatible informatics software.

[0114] For example, in some embodiments, the compatible informatics software includes, but is not limited to, standalone or network-connected data management software programs that reside on or run on, for example, a display device, a personal computer, or a server terminal, to perform data analysis, mapping, data storage, data archiving, data communication, and data synchronization. In some embodiments, the informatics software may also include software for performing field-upgradeable functions to upgrade the firmware on the display device and / or the body-on-electronics unit, thereby upgrading the resident software on the display device and / or the body-on-electronics unit, for example, a firmware version including additional features and / or including fixes for software vulnerabilities or bugs.

[0115] Examples include programs embedded in computer-readable media, such as computer-based application software (also referred to herein as informatics software or programs) that processes analyte information and / or user-reported data obtained from the system. The application software can be installed on a host computer via a display device or on-device electronic unit, such as a mobile phone, personal computer, or internet-enabled human-machine interface device, such as an internet-enabled telephone or personal digital assistant. Informatics programming can transform data collected and stored on the display device or on-device unit for user use.

[0116] As described in detail below, embodiments include apparatus, systems, kits, and / or methods for monitoring one or more physiological parameters, such as but not limited to analyte levels, temperature levels, heart rate, and user activity levels, over a predetermined monitoring period. Methods of manufacturing are also provided. The predetermined monitoring period may be less than about 1 hour, or may include about 1 hour or longer, such as about several hours or longer, such as about several days or longer, such as about 3 days or longer, such as about 5 days or longer, such as about 7 days or longer, such as about 10 days or longer, such as about 14 days or longer, such as about several weeks, such as about 1 month or longer. In some embodiments, after the predetermined monitoring period has elapsed, one or more features of the system may be automatically deactivated or disabled at the on-body electronic components and / or display device.

[0117] For example, the predetermined monitoring period may begin with positioning the sensor inside the body and bringing it into contact with bodily fluids (e.g., interstitial fluid), and / or with activating (or powering on to full operating mode) the on-body electronics. Initialization of the on-body electronics may be achieved by a display device responding to activation of a switch and / or by generating and sending a command by positioning the display device within a predetermined distance (e.g., very close) of the on-body electronics, or by the user manually activating a switch on the on-body electronics (e.g., pressing a button), or such activation may be caused by an insertion device, for example, as described in U.S. Patent Publication No. 2011 / 0213225A1, the entire disclosure of which is incorporated herein by reference.

[0118] When initialized in response to a command received from the display device, the bulk electronics retrieves and executes its memory software routines to fully power its components. Upon receiving an activation command from the display device, it effectively places the bulk electronics into a fully operational mode. For example, before receiving a command from the display device, some components of the bulk electronics may be powered by their internal power source (e.g., a battery), while other components may be in a power-off or low-power state, including no-power, inactive modes, or all components may be in an inactive, power-off mode. Once a command is received, the remaining (or all) components of the bulk electronics are switched to the active, fully operational mode.

[0119] Embodiments of on-body electronics may include one or more printed circuit boards incorporating electronics, wherein the electronics include control logic implemented in an ASIC, microprocessor, memory, etc., and a transdermal analyte sensor forming a single component. The on-body electronics may be configured to provide one or more signals or data packets associated with the monitored analyte level when the display device of the analyte monitoring system is detected within a predetermined proximity for a period of time (e.g., about 2 minutes, or 1 minute or less, or about 30 seconds or less, or about 10 seconds or less, or about 5 seconds or less, or about 2 seconds or less) and / or until the display device outputs confirmation (e.g., auditory and / or visual and / or tactile (e.g., vibration) notification) indicating successful acquisition of analyte-related signals from the on-body electronics. In some embodiments, differentiated notifications may also be output for unsuccessful acquisition.

[0120] In some embodiments, the monitored analyte levels can be correlated with and / or converted into glucose levels in blood or other bodily fluids. This conversion can be accomplished using on-body electronics, but in other embodiments, it will be accomplished using display device electronics.

[0121] Now for reference Figure 1 The analyte monitoring system 100 includes an analyte sensor 101, a data processing unit 102 coupled to the sensor 101, and a main receiver unit or main display device 104. In some cases, the main display device 104 is configured to communicate with the data processing unit 102 via a communication link 103. In some embodiments, the main display device 104 may also be configured to send data to a data processing terminal 105 to evaluate or otherwise process or format the data received by the main display device 104. The data processing terminal 105 may be configured to receive data directly from the data processing unit 102 via a communication link 107, which may optionally be configured for bidirectional communication. Furthermore, the data processing unit 102 may include electronics and a transmitter or transceiver to send data to and / or receive data from the main display device 104 and / or the data processing terminal 105 and / or an optional secondary receiver unit or secondary display device 106.

[0122] Figure 1An optional secondary display device 106 is also shown, operatively coupled to the communication link 103 and configured to receive data transmitted from the data processing unit 102. The secondary display device 106 may be configured to communicate with the main display device 104 and the data processing terminal 105. In some embodiments, the secondary display device 106 may be configured for bidirectional wireless communication with each of the main display device 104 and the data processing terminal 105. As discussed in further detail below, in some cases, the secondary display device 106 may be a de-featured receiver compared to the main display device 104; for example, the secondary display device 106 may include a limited or minimal number of functions and features compared to the main display device 104. Thus, the secondary display device 106 may include a smaller (in one or more dimensions, including all dimensions), compact housing, or be contained in devices including, for example, watches, armbands, handheld computers (PDAs), MP3 players, mobile phones, etc. Optionally, the secondary display device 106 may be configured with the same or substantially similar functions and features as the main display device 104. The secondary display device 106 may include a docking portion and / or a two-way communication device, the docking portion being configured to fit snugly with a docking bracket unit for placement, for example, at a bedside for nighttime monitoring. The docking bracket can recharge its power supply.

[0123] exist Figure 1 In the illustrated embodiment of the analyte monitoring system 100, only one analyte sensor 101, data processing unit 102, and data processing terminal 105 are shown. However, those skilled in the art will understand that the analyte monitoring system 100 may include more than one sensor 101 and / or more than one data processing unit 102 and / or more than one data processing terminal 105. Multiple sensors can be positioned within the user's body for analyte monitoring at the same or different times. In some embodiments, analyte information obtained by a first sensor positioned within the user's body is compared with analyte information obtained by a second sensor. This can help confirm or verify analyte information obtained from one or both sensors. This redundancy can be useful if analyte information is considered in critical treatment-related decisions. In some embodiments, the first sensor can be used to calibrate the second sensor.

[0124] In a multi-component environment, each component can be configured to be uniquely identified by one or more other components in the system, making it easy to resolve communication conflicts between various components within the analyte monitoring system 100. For example, unique identifiers, communication channels, etc., can be used.

[0125] In some embodiments, sensor 101 is physically located within or on the user's body where the analyte level is being monitored. Sensor 101 may be configured to sample the user's analyte level at least periodically and convert the sampled analyte level into a corresponding signal for transmission by data processing unit 102. Data processing unit 102 may be coupled to sensor 101 such that both devices are located within or on the user's body, wherein at least a portion of analyte sensor 101 is percutaneously positioned. Data processing unit 102 may include a securing element, such as an adhesive, to secure it to the user's body. A base (not shown) that can be attached to the user and mated with data processing unit 102 may be used. For example, the base may include an adhesive surface. Data processing unit 102 performs data processing functions, which may include, but are not limited to, filtering and encoding data signals, each corresponding to the user's sampled analyte level, for transmission to main display device 104 via communication link 103. In some embodiments, sensor 101 or data processing unit 102 or a combination of sensor / data processing unit may be completely implanted under the user's skin surface.

[0126] In some embodiments, the main display device 104 may include an analog interface portion and a data processing portion. The analog interface portion includes an RF receiver and an antenna configured to communicate with the data processing unit 102 via a communication link 103. The data processing portion is used to process data received from the data processing unit 102, including data decoding, error detection and correction, data clock generation, data bit recovery, or any combination thereof.

[0127] In operation, in some embodiments, the main display device 104 is configured to synchronize with the data processing unit 102 to uniquely identify the data processing unit 102 based on, for example, identification information of the data processing unit 102, and thereafter periodically receive signals from the data processing unit 102 related to the level of the monitoring analyte monitored by the sensor 101.

[0128] Refer to Figure 1 The data processing terminal 105 may include a personal computer, a portable computer including a laptop or handheld device (e.g., a PDA), or a telephone including a mobile phone (e.g., including...). Android phones or similar multimedia mobile phones that support the internet), MP3 players (e.g., iPods) TM The data processing terminal 105 may also be coupled to a data network (not shown) for storing, retrieving, updating, and / or analyzing data corresponding to the detected user analyte level. This includes devices such as pagers, infusion devices, etc., and / or medication delivery devices (e.g., infusion devices), each of which may be configured to communicate data with the display device via a wired or wireless connection.

[0129] The data processing terminal 105 may include a drug delivery device (e.g., an infusion device), such as an insulin infusion pump, configured to administer a drug (e.g., insulin) to a user, and configured to communicate with the main display device 104 to receive measured analyte levels, etc. Optionally, the main display device 104 may be configured to integrate the infusion device, such that the main display device 104 is configured to administer an appropriate drug (e.g., insulin) to the user, for example, to manage and modify baseline data, and to determine an appropriate dose based on detected analyte levels, etc., received from the data processing unit 102. The infusion device may be an external or internal device, such as a device that is fully implantable within the user's body.

[0130] In some embodiments, the data processing terminal 105, including an infusion device (e.g., an insulin pump), may be configured to receive analyte signals from the data processing unit 102, and thus incorporate the functions of the main display device 104, including data processing for managing the user's insulin therapy and analyte monitoring. In some embodiments, the communication link 103 and... Figure 1 One or more other communication interfaces shown may use one or more wireless communication protocols, such as, but not limited to, RF communication protocols, infrared communication protocols, Bluetooth enabled communication protocols, 802.11x wireless communication protocols, or equivalent wireless communication protocols, which will allow secure wireless communication between multiple units (e.g., as required by the Health Insurance Portability and Accountability Act (HIPPA)) while avoiding potential data conflicts and interference.

[0131] Figure 2 It is shown Figure 1 The diagram illustrates a block diagram of an embodiment of the data processing unit 102 of the analyte monitoring system. It may include user input and / or interface components, or the data processing unit may not have user input and / or interface components. In some embodiments, one or more application-specific integrated circuits (ASICs) (e.g., processing circuitry and non-transitory memory having processing circuitry for storing software instructions executed by processing circuitry) may be used to implement one or more functions or routines related to the operation of the data processing unit (and / or display device) using, for example, one or more state machines and buffers.

[0132] like Figure 2 As shown in the embodiment, the analyzer sensor 101 ( Figure 1The device includes four contacts, three of which are electrodes: a working electrode (W) 210, a reference electrode (R) 212, and a counter electrode (C) 213, each operatively coupled to the analog interface 201 of the data processing unit 102. This embodiment also illustrates an optional protection contact (G) 211. Fewer or more electrodes can be used. For example, the counter electrode and reference electrode functions can be provided by a single counter electrode / reference electrode. In some cases, there can be more than one working electrode and / or reference electrode and / or counter electrode, etc.

[0133] Figure 3 Is it like this? Figure 1 This is a block diagram of an embodiment of the receiver / monitoring unit of the main display device 104 of the illustrated analyte monitoring system. The main display device 104 includes one or more of the following: a test strip interface 301, an RF receiver 302, a user input 303, an optional temperature detection section 304, and a clock 305, each operatively coupled to a processing and storage section 307 (which may include processing circuitry and a non-transitory memory storing software instructions executed by the processing circuitry). The main display device 104 also includes a power supply 306, operatively coupled to a power conversion and monitoring section 308. Additionally, the power conversion and monitoring section 308 is also coupled to the processing and storage section 307. Furthermore, a receiver serial communication section 309 and an output 310 are shown, each operatively coupled to the processing and storage section 307. The main display device 104 may include user input and / or interface components, or may not include user input and / or interface components.

[0134] In some embodiments, the test strip interface 301 includes an analyte testing portion (e.g., a glucose level testing portion) to receive information about analyte testing or related to blood (or other bodily fluid samples). For example, the test strip interface 301 may include a test strip port to receive a test strip (e.g., a glucose test strip). The device can determine the analyte level of the test strip and optionally display (or otherwise notify) the analyte level on the output 310 of the main display device 104. Any suitable test strip can be used, for example, requiring only a very small amount of sample (e.g., 3 μL or less, e.g., 1 μL or less, e.g., 0.5 μL or less, e.g., 0.1 μL or less) applied to the test strip to obtain accurate glucose information. The glucose information obtained by the in vitro glucose testing device can be used for various purposes, calculations, etc. For example, this information can be used to calibrate sensor 101 ( Figure 1 (e.g., when the information obtained by sensor 101 is used for treatment-related decisions, etc.)

[0135] In a further embodiment, the data processing unit 102 and / or the main display device 104 and / or the secondary display device 106 and / or the data processing terminal / infusion device 105 may be configured to wirelessly receive analyte values ​​from, for example, a blood glucose meter via a communication link. In a further embodiment, a user operating or using the analyte monitoring system 100 may manually input analyte values ​​using a user interface (e.g., keyboard, keypad, voice commands, etc.) incorporated in one or more of the data processing unit 102, main display device 104, secondary display device 106, or data processing terminal / infusion device 105.

[0136] Figure 4 An embodiment of an analyte sensor 400 according to an embodiment of the present disclosure is illustrated schematically. This sensor embodiment includes electrodes 401, 402, and 403 on a base 404. The electrodes (and / or other features) can be applied or processed using any suitable technique, such as chemical vapor deposition (CVD), physical vapor deposition, sputtering, reactive sputtering, printing, coating, ablation (e.g., laser ablation), spraying, dip coating, etching, etc. Materials include, but are not limited to, any one or more of aluminum, carbon (including graphite), cobalt, copper, gallium, gold, indium, iridium, iron, lead, magnesium, mercury (as an amalgam), nickel, niobium, osmium, palladium, platinum, rhenium, rhodium, selenium, silicon (e.g., doped polycrystalline silicon), silver, tantalum, tin, titanium, tungsten, uranium, vanadium, zinc, zirconium, mixtures thereof, and alloys, oxides, or metallic compounds of these elements.

[0137] The analyte sensor 400 can be fully implanted in the user's body, or it can be configured such that only a portion is located inside the user's body (internal), while another portion is located outside the user's body (external). For example, the sensor 400 may include a first portion located above the skin surface 410 and a second portion located below the skin surface. In such an embodiment, the external portion may include contacts (connected via traces to corresponding electrodes of the second portion) for connection to another device external to the user, such as a sensor control device. Although Figure 4 The embodiment shows three electrodes side by side on the same surface of the base 404, but other configurations are also conceivable, such as fewer or more electrodes, some or all electrodes on different surfaces of the base or some or all electrodes present on another base, some or all electrodes stacked together, electrodes of different materials and sizes, etc.

[0138] Figure 5AA perspective view of an embodiment of an analyte sensor 500 is shown, having a first portion (characterized as the primary portion in this embodiment) positionable above a skin surface 510, and a second portion (characterized as the secondary portion in this embodiment) including an insertion tip 530 positionable below the skin surface, the insertion tip 530 penetrating the skin and entering, for example, a subcutaneous space 520, in contact with a user's biofluid, such as interstitial fluid. The contact portions of a working electrode 511, a reference electrode 512, and a counter electrode 513 are located on the first portion of the sensor 500 above the skin surface 510. The working electrode 501, the reference electrode 502, and the counter electrode 503 are shown in the second portion of the sensor 500, particularly at the insertion tip 530. Figure 5A As shown, traces can be provided from the electrode at tip 530 to the contact. It should be understood that more or fewer electrodes can be provided on the sensor. For example, the sensor may include more than one working electrode and / or counter electrode, and the reference electrode may be a single counter / reference electrode, etc.

[0139] Figure 5B It shows Figure 5A A cross-sectional view of a portion of sensor 500. Electrodes 501, 509 / 502, and 503 of sensor 500, as well as the substrate and dielectric layer, are provided in a layered configuration or structure. For example, as... Figure 5B As shown, in one embodiment, sensor 500 (e.g. Figure 1 The analyte sensor 101 includes a substrate layer 504 and a first conductive layer 501 (e.g., carbon, gold, etc.). The first conductive layer 501 is disposed on at least a portion of the substrate layer 504 and can provide a working electrode. A sensing region 508 is also shown disposed on at least a portion of the first conductive layer 501.

[0140] A first insulating layer 505, such as a first dielectric layer in some embodiments, is disposed or stacked on at least a portion of the first conductive layer 501, and furthermore, a second conductive layer 509 may be disposed or stacked on top of at least a portion of the first insulating layer (or dielectric layer) 505. Figure 5B As shown, the second conductive layer 509, combined with the second conductive material 502, such as a silver / silver chloride (Ag / AgCl) layer, can provide a reference electrode.

[0141] A second insulating layer 506, such as a second dielectric layer in some embodiments, may be disposed on or stacked on at least a portion of the second conductive layer 509. Furthermore, a third conductive layer 503 may be disposed on at least a portion of the second insulating layer 506 and may provide a counter electrode 503. Finally, a third insulating layer 507 may be disposed on or stacked on at least a portion of the third conductive layer 503. In this way, the sensor 500 can be layered such that at least a portion of each conductive layer is separated by a corresponding insulating layer (e.g., a dielectric layer). Figure 5A and Figure 5B The embodiments illustrate layers with different lengths. In some cases, some or all layers may have the same or different lengths and / or widths.

[0142] In some embodiments, in the layered structure described above, some or all of the electrodes 501, 502, and 503 may be disposed on the same side of the substrate 504, or alternatively, they may be disposed in a coplanar manner, such that two or more electrodes may be located on the same plane on the substrate 504 (e.g., side-by-side (e.g., parallel) or at an angle relative to each other). For example, suitable spacing may be included between the coplanar electrodes and / or dielectric or insulating material disposed between the conductive layer / electrode.

[0143] Furthermore, in some embodiments, one or more of electrodes 501, 502, and 503 may be disposed on opposite sides of substrate 504. In such embodiments, the contacts may be on the same side or different sides of the substrate. For example, the electrodes may be on a first side, and their corresponding contacts may be on a second side; for example, traces connecting the electrodes and contacts may pass through the substrate.

[0144] The following reference Figures 6 to 8 The description may be combined with embodiments of the double-sided stacked sensor configuration used in this disclosure. Figure 6 A cross-sectional view of the distal portion of a bifacial analyte sensor 600 is shown. The analyte sensor 600 includes an insulating substrate 601 that is at least generally flat, for example, a dielectric substrate having a first conductive layer 602 that substantially covers the entire first surface region (e.g., the top surface region) of the insulating substrate 601. For example, the conductive layer extends substantially the entire length of the substrate to the distal edge and from the side edges to across the entire width of the substrate. A second conductive layer 603 substantially covers the entire second surface of the insulating substrate 601, for example, the bottom side. However, one or both of the conductive layers may terminate proximally at the distal edge and / or may have a width less than that of the insulating substrate 601, wherein the width terminates at a selected distance from the side edges of the substrate, which may be equidistant from or different from each side edge.

[0145] One of the first and second conductive layers, such as the first conductive layer 602, may be configured to include the working electrode of the sensor. The opposing conductive layer, referred to herein as the second conductive layer 603, may be configured to include a reference electrode and / or a counter electrode. When the conductive layer 603 serves as either a reference electrode or a counter electrode, but not both simultaneously, a third electrode may optionally be disposed on a surface region of the proximal portion of the sensor (not shown), on a separate substrate, or as an additional conductive layer above or below the conductive layers 602 or 603 and separated from these layers by an insulating layer. For example, in some embodiments, when the analyte sensor 600 is configured for partial implantation, the conductive layer 603 may be configured to include a reference electrode and a third electrode (not shown), and the third electrode (not shown), present only on the non-implanted proximal portion of the sensor, may be configured to include the counter electrode of the sensor.

[0146] A first insulating layer 604 covers at least a portion of the conductive layer 602, and a second insulating layer 605 covers at least a portion of the conductive layer 603. In one embodiment, at least one of the first insulating layer 604 and the second insulating layer 605 does not extend to the distal end of the analyte sensor 600, leaving an exposed area of ​​the conductive layer.

[0147] Figure 7 A cross-sectional view of the distal portion of a bifacial analyte sensor 700 is shown. The bifacial analyte sensor 700 includes an insulating substrate 701 that is at least generally flat, such as a dielectric substrate. The dielectric substrate has a first conductive layer 702 that substantially covers the entire first surface region of the insulating substrate 701, such as the top surface region of the insulating substrate 701. For example, the conductive layer extends substantially the entire length of the substrate to the distal edge and from the side edges to the entire width of the substrate. A second conductive layer 703 substantially covers the entire second surface of the insulating substrate 701, such as the bottom side. However, one or both of the conductive layers may terminate proximally at the distal edge and / or may have a width less than that of the insulating substrate 701, wherein the width terminates at a selected distance from the side edges of the substrate, which may be equidistant from or different from each side edge.

[0148] exist Figure 7 In one embodiment, as shown in the figure, the conductive layer 702 is configured to include a working electrode, which includes a sensing region 702A disposed on at least a portion of the first conductive layer 702, as discussed in more detail below. Although a single sensing region 702A is shown, it should be noted that in other embodiments, multiple spatially separated sensing elements may be used.

[0149] exist Figure 7In one embodiment, the conductive layer 703 is configured to include a reference electrode, which includes a sublayer of conductive material 703A disposed on a distal portion of the conductive layer 703, such as silver / silver chloride.

[0150] A first insulating layer 704 covers a portion of the conductive layer 702, and a second insulating layer 705 covers a portion of the conductive layer 703. The first insulating layer 704 does not extend to the distal end of the analyte sensor 700, leaving an exposed area of ​​the conductive layer where the sensing area 702A is located. The insulating layer 705 on the bottom / reference electrode side of the sensor can extend to any suitable length of the distal portion of the sensor; for example, it can extend the entire length or a portion of the length of both the primary and secondary conductive layers. For example, as... Figure 7 As shown, the bottom insulating layer 705 extends over the entire bottom surface area of ​​the secondary conductive material 703A, but terminates near the distal end of the length of the conductive layer 703. It should be noted that at least the ends of the secondary conductive material 703A extending along the side edges of the substrate 701 are not covered by the insulating layer 705, and are therefore exposed to the environment during operation and use.

[0151] In alternative embodiments, such as Figure 8 As shown, the analyte sensor 800 has an insulating layer 804 on the working electrode side of the insulating substrate 801. The insulating layer 804 can be provided before the sensing region 802A, whereby the insulating layer 804 has at least two spaced-apart portions on the conductive layer 802. The sensing region 802A is then provided in the gap between the two portions. More than two spaced portions can be provided, for example, when multiple sensing elements or layers are required. The length of the bottom insulating layer 805 terminates near the proximal end of the secondary conductive layer 803A on the bottom main conductive layer 803. As described above, additional conductive and dielectric layers can be provided on either side or both sides of the sensor.

[0152] Although Figures 6 to 8 The ability to configure the working electrode and reference electrode in a specific layered configuration has been described or discussed; however, it should be noted that the relative positioning of these layers can be modified. For example, the counter electrode layer can be disposed on one side of the insulating substrate, while the working electrode layer and reference electrode layer are disposed on opposite sides of the insulating substrate in a stacked configuration. Furthermore, different configurations can be achieved by adjusting the number of conductive and insulating layers. Figures 6 to 8 The number of electrodes shown. For example, three or four electrode sensors can be set.

[0153] As will be discussed in more detail below, one or more membranes, which may be used as one or more of an analyte flow conditioning layer and / or an interference elimination layer and / or a biocompatibility layer, may be included in, on, or around the sensor, for example as one or more outermost layers. Those skilled in the art will readily recognize that membranes can take many forms. A membrane may comprise only one component or include multiple components. A membrane may have a spherical shape, for example, if it surrounds the end region of the sensor (e.g., sides and ends). A membrane may have a generally flat structure and may be characterized as a layer. A planar membrane may be smooth or may have minute surface (topological) variations. Membranes may also be configured as other non-planar structures. For example, a membrane may have a cylindrical or partially cylindrical shape, a hemispherical shape or other partially spherical shape, an irregular shape, or other circular or curved shape.

[0154] In some embodiments, such as Figure 7 As shown, the first membrane layer 706 can be disposed only on the sensing region 702A on the working electrode 702 to regulate the rate or flux of analyte diffusion into the sensing region. For embodiments where the membrane layer is disposed on a single component / material, it is suitable to do so using the same striping configuration and method as used for other materials / components. Here, the membrane material 706 preferably has a width greater than that of the sensing component 702A. Since its function is to limit the flux of analyte to the effective region of the sensor, and thus contribute to the sensor's sensitivity, controlling the thickness of the membrane 706 is important. Providing the membrane 706 in the form of stripes / bands facilitates control of its thickness. The second membrane layer 707 covering the remaining surface area of ​​the sensor tail can also provide a biocompatible conformal coating and provide smooth edges across the entire sensor. In other sensor embodiments, such as... Figure 8 As shown, a single homogeneous membrane 806 can cover the entire sensor surface area, or at least both sides of the distal tail. Note that in order to coat the distal and side edges of the sensor, the membrane material must be applied after the sensor precursor is segmented. In some embodiments, the analyte sensor is dip-coated after segmentation to apply one or more membranes. Alternatively, the analyte sensor can be mold-coated, wherein each side of the analyte sensor is individually coated.

[0155] Figure 9A cross-sectional view of the distal portion of an exemplary bifacial analyte sensor 900 according to an embodiment of the present disclosure is shown, wherein the bifacial analyte sensor includes an insulating substrate 901 having at least a generally planar surface, such as a dielectric substrate having at least a generally flat surface, including a first conductive layer 902. A second conductive layer 903 is located on a first side of the insulating substrate 901, such as the bottom side. Although shown extending to the distal edge of the sensor, one or both of the conductive layers may terminate near the distal edge and / or may have a width less than that of the insulating substrate 901, wherein the width terminates at a selected distance from the side edge of the substrate, which may be equidistant from or different from each side edge. For example, see the analyte sensor assembly 900 discussed in more detail below, in which a first conductive layer and a second conductive layer defining electrodes are provided, including, for example, electrode traces having a width less than that of the insulating substrate.

[0156] exist Figure 9 In some embodiments, the conductive layer 903 is configured to include a working electrode comprising a sensing region 908 disposed on at least a portion of the conductive layer 903, which will be discussed in more detail below. It should be noted that multiple spatially separated sensing elements or layers may be used to form the working electrode; for example, one or more sensing “points” or regions may be disposed on the conductive layer 903, as shown herein, or a single sensing element (not shown) may be used.

[0157] exist Figure 9 In one embodiment, the conductive layer 906 is configured to include a reference electrode comprising a sublayer of a conductive material 906A, such as silver / silver chloride, disposed on a distal portion of the conductive layer 906. Like conductive layers 902 and 903, the conductive layer 906 may terminate at a proximal end of its distal edge and / or may have a width smaller than that of the insulating substrate 901, wherein this width terminates at a selected distance from a side edge of the substrate, which may be equidistant from or different from each side edge, as referenced below. Figures 10A to 10C To be discussed in more detail.

[0158] exist Figure 9 In the illustrated embodiment, conductive layer 906 is configured to include a counter electrode. A first insulating layer 904 covers a portion of conductive layer 902, and a second insulating layer 905 covers a portion of conductive layer 903. The first insulating layer 904 does not extend to the distal end of the analyte sensor 900, leaving an exposed area of ​​conductive layer 902 as the counter electrode. Insulating layer 905 covers a portion of conductive layer 903, leaving an exposed area of ​​conductive layer 903 where sensing area 908 is located. As described above, in some embodiments, multiple spatially separated sensing elements or layers (as shown) may be provided, while in other embodiments, a single sensing area may be provided. The first side (e.g., the bottom side of the sensor) Figure 9The insulating layer 907 in the provided view can extend to any suitable length of the distal portion of the sensor; for example, it can extend the entire length or a portion of both conductive layers 906 and 906A. For example, as... Figure 9 As shown, the bottom insulating layer 907 extends over the entire bottom surface area of ​​the secondary conductive material 906A and terminates at the distal end of the length of the conductive layer 906. Note that at least the ends of the secondary conductive material 906A extending along the side edges of the substrate 901 are not covered by the insulating layer 907 and are therefore exposed to the environment during operation.

[0159] like Figure 9 As shown, the homogeneous membrane 909 can cover the entire sensor surface area, or at least both sides of the distal tail. Note that in order to coat the distal and side edges of the sensor, the membrane material must be applied after the sensor precursor is segmented. In some embodiments, the analyte sensor is dip-coated after segmentation to apply one or more membranes (or a membrane is applied at different stages). Optionally, the analyte sensor can be mold-coated, wherein each side of the analyte sensor is individually coated. Membrane 909 in Figure 9 It is shown as a square shape that matches the surface variations below, but it can also have a more spherical or amorphous shape.

[0160] When manufacturing layered sensors, it is desirable to use relatively thin insulating layers to reduce the overall sensor width. For example, refer to... Figure 9 The insulating layers 904, 905, and 907 can be relatively thin compared to the insulating substrate layer 901. For example, the insulating layers 904, 905, and 907 can have a thickness in the range of 20 to 25 micrometers, while the substrate layer 901 has a thickness in the range of 0.1 to 0.15 millimeters. However, during the sensor segmentation process, where such segmentation is achieved by cutting two or more conductive layers separated by these thin insulating layers, a short circuit may occur between these two conductive layers.

[0161] One approach to address this potential problem is to provide one of the conductive layers, such as an electrode layer, at least in part as a relatively narrow electrode, including, for example, a relatively narrow conductive trace, such that during the slicing process, the sensor is cut on either side of the narrow electrode, such that an electrode is cut without cutting the narrow electrode.

[0162] For example, refer to Figures 10A to 10CThe image illustrates a sensor 1000 comprising insulating layers 1003 and 1005. Insulating layers 1003 and 1005 can be thinner relative to a generally flat insulating substrate layer 1001, and vice versa. For example, insulating layers 1003 and 1005 can have a thickness in the range of 15 to 30 micrometers, while substrate layer 1001 has a thickness in the range of 0.1 to 0.15 millimeters. This sensor can be fabricated as a sheet, wherein a single sheet comprises multiple sensors. However, this process typically requires dicing the sensor before use. When this dicing requires cutting two or more conductive layers separated by insulating layers, a short circuit can occur between the two conductive layers, especially if the insulating layers are thin. To avoid this short circuit, not all conductive layers can be cut during the dicing process. For example, at least one conductive layer may be at least partially configured as an electrode, such as including conductive traces having a narrow width relative to one or more other conductive layers, such that during the dicing process, only the first conductive layer separated from the second conductive layer by a thin insulating layer (e.g., an insulating layer with a thickness in the range of 15 to 30 micrometers) is cut, while the second conductive layer is not cut.

[0163] For example, refer to Figure 10A and Figure 10C The sensor 1000 includes at least a generally flat insulating substrate 1001. A first conductive layer 1002 is located on the generally flat insulating substrate 1001. A first relatively thin insulating layer 1003, for example having an insulating layer with a thickness in the range of 15 to 30 micrometers, is located on the first conductive layer 1002, and a second conductive layer 1004 is located on the relatively thin insulating layer 1003. Finally, a second relatively thin insulating layer 1005, for example having an insulating layer with a thickness in the range of 15 to 30 micrometers, is located on the second conductive layer 1004.

[0164] like Figure 10B As shown, the first conductive layer 1002 may be an electrode with a narrow width relative to the conductive layer 1004, such as... Figure 10B The cross-section taken along line AA is shown. Optionally, the second conductive layer 1004 may be a conductive electrode having a narrow width relative to the conductive layer 1002, such as... Figure 10C The cross-section taken along line AA is shown. The dividing line 1006 is at... Figure 10B and Figure 10C As shown in the image. Figure 10B and Figure 10C As shown, the sensor can be segmented, for example, by cutting to either side of a relatively narrow conductive electrode, such as in region 1007. (Refer to...) Figure 10B The cutting along the dividing line 1006 results in a cut that penetrates the conductive layer 1004 instead of the conductive layer 1002. (See reference...) Figure 10CThe cutting along the dividing line 1006 results in a cut that passes through the conductive layer 1002 instead of the conductive layer 1004.

[0165] An embodiment of the sensing area can be described as being in Figure 5B Zhong 508 and Figure 9 The area schematically shown in 908. As described above, the sensing area can be set as follows: Figure 5B 508 Figure 7 702A and Figure 8 A single sensing component as shown in 802A, or configured as follows Figure 9 Multiple sensing components are shown in 908. Multiple sensing components or sensing “points” are described in U.S. Patent Application Publication No. 2012 / 0150005, the entire contents of which are incorporated herein by reference.

[0166] The term "sensing region" is a broad term that can describe the active chemical region of a biosensor. Those skilled in the art will readily recognize that the sensing region can take many forms. The sensing region may include only one component or multiple components (e.g., such as...). Figure 9 (The sensing area 908). For example, in Figure 5B In some embodiments, the sensing region is a generally flat structure and can be characterized as a layer. The planar sensing region can be smooth or have minute surface (topological) variations. The sensing region can also be a non-planar structure. For example, the sensing region can have a cylindrical or partially cylindrical shape, a hemispherical or other partially spherical shape, an irregular shape, or other circular or curved shape.

[0167] The sensing region formulation, which may include a glucose transducer, may include, for example, a redox mediator, such as hydrogen peroxide, or a transition metal complex, such as a ruthenium-containing complex or an osmium-containing complex, and an analyte-responsive enzyme, such as a glucose-responsive enzyme (e.g., glucose oxidase, glucose dehydrogenase, etc.) or a lactate-responsive enzyme (e.g., lactate oxidase). In some embodiments, the sensing region includes glucose oxidase. The sensing region may also include other optional components, such as polymers and bifunctional short-chain epoxide crosslinking agents, such as polyethylene glycol (PEG).

[0168] In some cases, the analyte-responsive enzyme is distributed throughout the sensing region. For example, the analyte-responsive enzyme may be uniformly distributed throughout the sensing region, such that the concentration of the analyte-responsive enzyme is approximately the same throughout the sensing region. In some cases, the sensing region may have a uniform distribution of the analyte-responsive enzyme. In some embodiments, a redox mediator is distributed throughout the sensing region. For example, a redox mediator may be uniformly distributed throughout the sensing region, such that the concentration of the redox mediator is approximately the same throughout the sensing region. In some cases, the sensing region may have a uniform distribution of the redox mediator. In some embodiments, as described above, both the analyte-responsive enzyme and the redox mediator are uniformly distributed throughout the sensing region.

[0169] As described above, analyte sensors may include analyte-responsive enzymes to provide sensing elements or sensing regions. Some analytes, such as oxygen, can be directly electro-oxidized or electro-reduced on the sensor, and more specifically, at least on the working electrode of the sensor. Other analytes, such as glucose and lactate, require the presence of at least one electron transfer agent and / or at least one catalyst to facilitate the electro-oxidation or electro-reduction of the analyte. Catalysts may also be used for those analytes that can be directly electro-oxidized or electro-reduced on the working electrode, such as oxygen. For these analytes, each working electrode includes a sensing region proximate to or located on the surface of the working electrode (e.g., see...). Figure 5B (Sensing area 508). In many embodiments, the sensing area is formed near or on only a small portion of at least one working electrode.

[0170] The sensing region may include one or more components configured to facilitate the electrochemical oxidation or reduction of the analyte. For example, the sensing region may include a catalyst that catalyzes the reaction of the analyte and generates a response at the working electrode, an electron transfer agent that transfers electrons between the analyte and the working electrode (or other components), or both.

[0171] A variety of different sensing region configurations can be used. The sensing region is typically located in contact with or near an electrode (e.g., a working electrode). In some embodiments, the sensing region is deposited on a conductive material of the working electrode. The sensing region extends beyond the conductive material of the working electrode. In some cases, the sensing region may also extend onto other electrodes, such as on a counter electrode and / or a reference electrode (or if a counter electrode / reference electrode is provided).

[0172] The sensing region in direct contact with the working electrode may contain an electron transfer agent that directly or indirectly transfers electrons between the analyte and the working electrode, and / or a catalyst that promotes the reaction of the analyte. For example, a glucose, lactate, or oxygen electrode may be formed with a sensing region containing a catalyst and an electron transfer agent, the catalyst comprising glucose oxidase, glucose dehydrogenase, lactate oxidase, or laccase, which promotes the electro-oxidation of glucose, lactate, or oxygen.

[0173] In other embodiments, the sensing region is not deposited directly on the working electrode. Instead, the sensing region 508 (FIG. 5) may be spaced apart from the working electrode, for example, and may be separated from the working electrode by a separation layer. The separation layer may include one or more membranes or thin films or physical distances. In addition to separating the working electrode from the sensing region, the separation layer may also serve as a mass transfer confinement layer and / or an interference cancellation layer and / or a biocompatibility layer.

[0174] In some embodiments that include more than one working electrode, one or more working electrodes may not have a corresponding sensing region, or may have a sensing region that does not contain one or more components required for electrolytic analyte (e.g., electron transfer agents and / or catalysts). Therefore, the signal at this working electrode may correspond to a background signal, which can be removed from the analyte signal obtained from one or more other working electrodes associated with the full-function sensing region, for example, by subtracting the signal.

[0175] In some embodiments, the sensing region includes one or more electron transfer agents. The electron transfer agents that can be used are electroreducible and electrooxidizable ions or molecules with a redox potential several hundred millivolts higher or lower than the redox potential of a saturated calomel electrode (SCE). The electron transfer agents can be organic, organometallic, or inorganic. Examples of organic redox substances are quinones and species with quinone structures in their oxidized states, such as Nile blue and indophenol. Examples of organometallic redox substances are metallocenes including ferrocene. Examples of organic redox substances are hexacyanoferrate(III), hexaamineruthenium, etc. Further examples include those described in U.S. Patents 6,736,957, 7,501,053, and 7,754,093, the entire disclosure of each of which is incorporated herein by reference.

[0176] In some embodiments, the electron transfer agent has a structure or charge that prevents or significantly reduces electron transfer agent diffusion loss during sample analysis. For example, the electron transfer agent includes, but is not limited to, redox substances, such as those bound to a polymer, which may then be disposed on or near the working electrode. The bond between the redox substance and the polymer can be a covalent bond, a coordinate bond, or an ionic bond. While any organic, organometallic, or inorganic redox substance can be bound to the polymer and used as an electron transfer agent, in some embodiments, the redox substance is a transition metal compound or complex, such as osmium, ruthenium, iron, and cobalt compounds or complexes. It will be appreciated that many of the redox substances described for use with polymer components can also be used without the polymer component.

[0177] Embodiments of polymeric electron transfer agents may include redox substances covalently bound to the polymeric composition. An example of this type of mediator is poly(vinylferrocene). Another type of electron transfer agent comprises ionically bound redox substances. Such mediators may comprise charged polymers coupled to redox substances with opposite charges. Examples of such mediators include negatively charged polymers coupled to positively charged redox substances (e.g., osmium or ruthenium polypyridine cations). Another example of ionically bound mediators is positively charged polymers, including quaternized poly(4-vinylpyridine) or poly(1-vinylimidazole) coupled to negatively charged redox substances such as ferrocyanide or ferricyanide. In other embodiments, the electron transfer agent comprises redox substances coordinated to the polymer. For example, the mediator may be formed by coordination of osmium or cobalt 2,2'-bipyridine complexes with poly(1-vinylimidazole) or poly(4-vinylpyridine).

[0178] Suitable electron transfer agents are osmium transition metal complexes having one or more ligands, each ligand having a nitrogen-containing heterocycle, such as 2,2'-bipyridine, 1,10-phenanthroline, 1-methyl, 2-pyridylbiimidazole, or derivatives thereof. Electron transfer agents may also have one or more ligands covalently bonded to a polymer, each ligand having at least one nitrogen-containing heterocycle, such as pyridine, imidazole, or derivatives thereof. An example of an electron transfer agent includes (a) a polymer or copolymer having a pyridine or imidazole functional group and (b) an osmium cation complexed with two ligands, each ligand comprising 2,2'-bipyridine, 1,10-phenanthroline, or derivatives thereof, the two ligands need not be identical. Derivatives of 2,2'-bipyridine used for complexing with osmium cations include, but are not limited to, 4,4'-dimethyl-1,2'-bipyridine and mono-, di-, and polyalkoxy-2,2'-bipyridine, including 4,4'-dimethoxy-2,2'-bipyridine. Derivatives of 1,10-phenanthroline used for complexing with osmium cations include, but are not limited to, 4,7-dimethyl-1,10-phenanthroline and mono-, di-, and polyalkoxy-1,10-phenanthroline, such as 4,7-dimethoxy-1,10-phenanthroline. Polymers used for complexing with osmium cations include, but are not limited to, polymers and copolymers of poly(1-vinylimidazolium) (referred to as "polyvinylpyrrolidone") and poly(4-vinylpyridine) (referred to as "polyvinylpyrrolidone"). Suitable copolymer substituents for poly(l-vinylimidazole) include acrylonitrile, acrylamide, and substituted or quaternized N-vinylimidazole, such as electron transfer agents complexed with osmium onto polymers or copolymers of poly(l-vinylimidazole).

[0179] Compared to a saturated calomel electrode (SCE), the embodiments can use electron transfer agents with redox potentials in the range of about -200 mV to about +200 mV. The sensing region may also include a catalyst capable of catalyzing the reaction of the analyte. In some embodiments, the catalyst may also act as an electron transfer agent. An example of a suitable catalyst is an enzyme that catalyzes the reaction of the analyte. For example, when the analyte of interest is glucose, catalysts including glucose oxidase, glucose dehydrogenase (e.g., pyrrolidone (PQQ), flavin-dependent adenine dinucleotide (FAD)-dependent glucose dehydrogenase, or nicotinamide adenine dinucleotide (NAD)-dependent glucose dehydrogenase) can be used. When the analyte of interest is lactate, lactate oxidase or lactate dehydrogenase can be used. When the analyte of interest is oxygen, or when oxygen is generated or consumed in response to the reaction of the analyte, laccase can be used.

[0180] In some embodiments, the catalyst may be attached to a polymer, allowing the catalyst to crosslink with another electron transfer agent, which, as described above, may be a polymer. A second catalyst may also be used in some embodiments. This second catalyst can be used to catalyze the reaction of a product compound produced by the catalytic reaction of the analyte. The second catalyst can operate in conjunction with the electron transfer agent to electrolyze the product compound, thereby generating a signal at the working electrode. Optionally, a second catalyst may be provided in the interference elimination layer to catalyze the reaction to remove interferences.

[0181] In some embodiments, the sensor operates at a low oxidation potential, for example, approximately +40 mV relative to silver / silver chloride. The sensing region uses, for example, an osmium (Os)-based mediator constructed for low-potential operation. Thus, in some embodiments, the sensing element is a redox-active component comprising (1) an osmium-based mediator molecule including a (dual-coordinate) ligand, and (2) a glucose oxidase molecule. These two components are combined in the sensing region of the sensor.

[0182] The sensor may include a mass transfer limiting layer (not shown), such as an analyte flux regulating layer, to act as a diffusion limiting barrier, thereby reducing the mass transfer rate of an analyte (e.g., glucose or lactate) to the region surrounding the working electrode. The mass transfer limiting layer can be used to restrict the flux of the analyte to the working electrode in an electrochemical sensor, enabling the sensor to respond linearly over a wide range of analyte concentrations and facilitating calibration. The mass transfer limiting layer may include a polymer and may be biocompatible. The mass transfer limiting layer can provide numerous functionalities, such as biocompatibility and / or interference removal capabilities.

[0183] In some embodiments, the mass transfer confinement layer is a membrane composed of a cross-linked polymer containing heterocyclic nitrogen groups, such as a polymer of polyvinylpyridine and polyvinylimidazole. Embodiments also include membranes made of polyurethane or polyether polyurethane or chemically related materials, or membranes made of silicone resin, etc.

[0184] The membrane can be formed by in-situ crosslinking in an alcohol buffer solution with a zwitterionic moiety, a non-pyridine copolymer component, and optionally another portion modified with hydrophilic or hydrophobic properties and / or other desired properties. The modified polymer can be made from a precursor polymer containing heterocyclic nitrogen groups. For example, the precursor polymer can be polyvinylpyridine or polyvinylimidazole. Optionally, hydrophilic or hydrophobic modifiers can be used to "fine-tune" the permeability of the resulting membrane to the analyte of interest. Optional hydrophilic modifiers, such as poly(ethylene glycol), hydroxyl, or polyhydroxyl modifiers, can be used to enhance the biocompatibility of the polymer or the resulting membrane.

[0185] The membrane can be formed in situ by applying an alcohol buffer solution of a crosslinking agent and a modified polymer to the enzyme-containing sensing region and allowing the solution to solidify for approximately 1 to 2 days or other suitable time periods. The crosslinking agent polymer solution can be applied to the sensing region by placing one or more drops of the membrane solution onto the sensor, by immersing the sensor in the membrane solution, by spraying the membrane solution onto the sensor, etc. Typically, the membrane thickness is controlled by the concentration of the membrane solution, the number of droplets of membrane solution applied, the number of times the sensor is immersed in the membrane solution, the volume of the membrane solution sprayed onto the sensor, or any combination of these factors. The membrane applied in this manner can have any combination of the following functions: (1) mass transfer restriction, e.g., a reduction in the analyte flux reaching the sensing region, (2) enhanced biocompatibility, or (3) reduction of interfering substances.

[0186] In some cases, the membrane can form one or more bonds with the sensing region. A bond refers to any type of interaction between atoms or molecules that allows compounds to associate with each other, such as, but not limited to, covalent bonds, ionic bonds, dipole-dipole interactions, hydrogen bonds, London dispersion forces, etc. For example, in-situ polymerization of the membrane can form crosslinks between the polymer in the membrane and the polymer in the sensing region. In some embodiments, crosslinking of the membrane with the sensing region helps reduce the occurrence of membrane delamination from the sensing region.

[0187] In some embodiments, the sensing system detects hydrogen peroxide to infer glucose levels. For example, a hydrogen peroxide detection sensor can be constructed in which the sensing region includes an enzyme, such as glucose oxidase, glucose dehydrogenase, etc., and the sensor is positioned close to the working electrode. The sensing region can be covered by one or more layers, such as a glucose-selectively permeable membrane. Once glucose passes through the membrane, it is oxidized by the enzyme, and then the reduced glucose oxidase can be oxidized again by reacting with molecular oxygen to produce hydrogen peroxide.

[0188] Some embodiments include a hydrogen peroxide detection sensor comprising sensing regions prepared by combining elements together, such as: (1) a redox mediator having a transition metal complex, including an osmium polypyridine complex with an oxidation potential of approximately +200 mV relative to the SCE, and (2) an aromatic amine peroxidase (HRP) for periodate oxidation. This sensor operates in a reduction mode; the working electrode is controlled at a potential opposite to that of the osmium complex, resulting in the mediated reduction of hydrogen peroxide via the HRP catalyst.

[0189] In another example, the potential sensor can be constructed as follows. The glucose sensing region is constructed by combining the following two elements: (1) a redox mediator with a transition metal complex comprising an osmium polypyridine complex with an oxidation potential of approximately -200 mV to +200 mV relative to the SCE, and (2) glucose oxidase. The sensor can then be used in potential mode by exposing the sensor to a glucose-containing solution under zero-current conditions and allowing the osmium reduction / oxidation ratio to reach equilibrium. The osmium reduction / oxidation ratio varies with glucose concentration in a reproducible manner, causing the electrode potential to vary in a similar manner.

[0190] The substrate can be formed using a variety of non-conductive materials, including, for example, polymeric or plastic materials and ceramic materials. The appropriate material for a particular sensor can be determined, at least in part, based on the sensor's intended use and the material's properties.

[0191] In some embodiments, the substrate is flexible. For example, if the sensor is configured for implantation in a user's body, the sensor can be made flexible (although rigid sensors can also be used for implantable sensors) to reduce user pain and tissue damage caused by sensor implantation and / or wear. Flexible substrates can generally increase user comfort and allow for a wider range of motion. Suitable materials for flexible substrates include, for example, non-conductive plastics or polymers, as well as other non-conductive, flexible, deformable materials. Examples of useful plastics or polymers include thermoplastics such as polycarbonate, polyesters (e.g., Mylar), etc. TM And copolymers of polyethylene terephthalate (PET), polyvinyl chloride (PVC), polyurethane, polyether, polyamide, polyimide, or these thermoplastics, such as PETG (ethylene glycol-modified polyethylene terephthalate).

[0192] In other embodiments, the sensor is made using a relatively rigid substrate, thereby providing structural support, for example, against bending or fracture. Examples of rigid materials that can be used as substrates include ceramics with poor electrical conductivity, such as alumina and silicon dioxide. Implantable sensors with rigid substrates can have sharp points and / or sharp edges to facilitate sensor implantation without additional insertion devices.

[0193] It will be understood that both rigid and flexible sensors can function adequately for many sensors and sensor applications. The flexibility of a sensor can also be controlled by changing, for example, the composition and / or thickness of the substrate, and varies along a continuum.

[0194] In addition to considerations of flexibility, it is generally desirable for implantable sensors to have a physiologically harmless substrate, such as a substrate approved by regulatory or private institutions for use in vivo.

[0195] The sensor may include optional features to facilitate insertion of the implantable sensor. For example, the sensor may be pointed to a tip for easy insertion. Additionally, the sensor may include barbs that help anchor the sensor within the user's tissue during operation. However, the barbs are typically small enough to cause minimal damage to the subcutaneous tissue when the sensor is removed for replacement.

[0196] Implantable sensors may optionally have an anticoagulant placed on the substrate portion implanted in the user's body. This anticoagulant can reduce or eliminate clotting of blood or other bodily fluids around the sensor, especially after sensor insertion. Blood clots can clog the sensor or non-renewably reduce the amount of analyte diffused into the sensor. Examples of useful anticoagulants include heparin and tissue plasminogen activator (TPA), as well as other known anticoagulants.

[0197] An anticoagulant may be applied to at least a portion of the area to which the sensor will be implanted. The anticoagulant may be applied, for example, by water bath, spray, brushing, or immersion. The anticoagulant is allowed to dry on the sensor. The anticoagulant may be fixed to the surface of the sensor, or it may be allowed to diffuse away from the sensor surface. The amount of anticoagulant applied to the sensor may be less than that typically used to treat medical conditions involving blood clots, and therefore has only a limited local effect.

[0198] Figure 11 An example of an in vivo analyte monitoring system 1100 according to certain embodiments of the present disclosure is shown. As shown, the analyte monitoring system 1100 includes an in vivo electronics device 1110 that is electrically connected to an in vivo analyte sensor 1101 (its proximal portion as shown in the figure). Figure 11 (As shown in the figure) and attached to an adhesive layer 1140 for attachment to the skin surface of a user's body. Body electronics 1110 includes a body housing 1119 defining an internal compartment. Figure 11 The diagram also shows an insertion device 1150, which, in operation, transdermally positions a portion of the analyte sensor 1101 through the skin surface and comes into contact with bodily fluids, and is positioned on the skin surface over on-body electronics 1110 and adhesive layer 1140. In some embodiments, the on-body electronics 1110, the analyte sensor 1101, and the adhesive layer 1140 are sealed within a housing of the insertion device 1150 before use, and in other embodiments, the adhesive layer 1140 is also sealed within the housing or provides a terminal seal for the insertion device 1150 itself.

[0199] Back Figure 11The analyte monitoring system 1100 includes a display device 1120, which includes a display 1122 for outputting information to a user and input components 1121 for inputting data or commands to the display device 1120 or otherwise controlling its operation, such as buttons, actuators, touch switches, capacitive switches, pressure-sensitive switches, scroll wheels, etc. Note that some embodiments may include displayless devices or devices without any user interface components. These devices may be functionalized to store data as data loggers and / or provide conduits for transferring data from bulk electronics and / or displayless devices to another device and / or location. For illustrative purposes, embodiments herein will be described as display devices, and these display devices are in no way intended to limit the embodiments of this disclosure. Obviously, displayless devices may also be used in some embodiments.

[0200] In some embodiments, the on-body electronics 1110 may be configured to store and maintain some or all of the monitored analyte-related data received from the analyte sensor 1101 in memory during a monitoring period until the end of the monitoring period. In such an embodiment, the stored data is retrieved from the on-body electronics 1110 at the end of the monitoring period, for example, after the analyte sensor 1101 is removed from the user by detaching the on-body electronics 1110 from the skin surface on which it was located during the monitoring period. In this data recording configuration, the analyte level detected in real time is not transmitted to the display device 1120 or otherwise transmitted from the on-body electronics 1110 during the monitoring period, but is retrieved from the on-body electronics 1110 after the monitoring period.

[0201] In some embodiments, the input component 1121 of the display device 1120 may include a microphone, and the display device 1120 may include software configured to analyze audio input received from the microphone, such that the function and operation of the display device 1120 can be controlled by voice commands. In some embodiments, the output component of the display device 1120 includes a speaker for outputting information as an auditory signal. Similar voice response components, such as speakers, microphones, and software routines, are used to generate, process, and store voice-driven signals, which can be provided to the bulk electronics 1110.

[0202] In some embodiments, the display 1122 and the input component 1121 may be integrated into a single component, such as a display capable of detecting the presence and location of physical touches on the display, like a touchscreen user interface. In such embodiments, a user can control the operation of the display device 1120 by utilizing a set of pre-programmed motion commands, including but not limited to, clicking or double-clicking the display, dragging a finger or tool on the display, moving multiple fingers or tools toward each other, moving multiple fingers or tools away from each other, etc. In some embodiments, the display includes a touchscreen having pixel areas with single- or dual-function capacitive elements serving as LCD elements and touch sensors.

[0203] Display device 1120 also includes a data communication port 1123 for wired data communication with an external device, such as a remote terminal (personal computer) 1170. Example embodiments of the data communication port 1123 include a USB port, mini-USB port, RS-232 port, Ethernet port, FireWire port, or other similar data communication port configured to connect to a compatible data cable. Display device 1120 may also include an integrated in vitro blood glucose meter, including an in vitro test strip port 1124 for receiving in vitro blood glucose test strips for performing in vitro blood glucose measurements.

[0204] Still refer to Figure 11 In some embodiments, display 1122 is configured to display various information, some or all of which may be displayed on display 1122 at the same or different times. In some embodiments, the information displayed is user-selectable, allowing the user to customize the information displayed on a given screen. Display 1122 may include, but is not limited to, a graphical display 1138, for example, providing graphical output of glucose values ​​over a monitoring period (which may show important markers such as diet, exercise, sleep, heart rate, blood pressure, etc.), a digital display 1132 (e.g., providing monitored glucose values ​​(acquired or received in response to a request for information)), and an arrow display 1131 (indicating the trend or direction of the analyte change rate and / or the rate of change of the analyte).

[0205] like Figure 11As further shown, the display 1122 also includes: a date display 1135 providing, for example, date information to the user; a time information display 1139 providing the user with time information throughout the day; a battery level indicator display 1133 graphically showing the status of the battery (rechargeable or disposable) of the display device 1120; a sensor calibration status icon display 1134, for example, in a monitoring system requiring periodic, routine, or predetermined number of user calibration events, notifying the user that analyte sensor calibration is necessary; an audio / vibration setting icon display 1136 for displaying the status of audio / vibration output or alarm status; and a wireless connectivity status icon display 1137 providing an indication of wireless communication connectivity with other devices such as body electronics, data processing module 1167, and / or remote terminal 1170. Figure 11 As also shown, the display 1122 may further include analog touchscreen buttons 1140, 1141 for accessing menus, changing display graphics output configurations, or controlling the operation of the display device 1120.

[0206] Back Figure 11 In some embodiments, the display 1122 of the display device 1120 may additionally, or in place of a visual display, be configured to output alarm notifications, such as alarms and / or warnings, glucose levels, etc., which may be auditory, tactile, or any combination thereof. In one aspect, in addition to the visual output indications provided on the display 1122, the display device 1120 may include other output components, such as speakers, vibration output components, etc., for providing auditory and / or vibration output indications to the user.

[0207] After positioning the on-body electronics 1110 on the skin surface and within the analyte sensor 1101 to establish fluid contact with the interstitial fluid (or other suitable body fluid), in some embodiments, the on-body electronics 1110 is configured to wirelessly transmit analyte-related data (e.g., data corresponding to monitored analyte levels and / or monitored temperature data and / or stored historical analyte-related data) when it receives a command or request signal from the display device 1120. In some embodiments, the on-body electronics 1110 may be configured to broadcast, at least periodically, real-time data related to the monitored analyte levels received by the display device when the display device 1120 is within communication range of data broadcast from the on-body electronics 1110, for example, without requiring a command or request from the display device to send the information.

[0208] For example, display device 1120 may be configured to send one or more commands to body electronics 1110 to initiate data transmission, and in response, body electronics 1110 may be configured to wirelessly transmit stored analyte-related data collected during the monitoring period to display device 1120. Display device 1120 may then be connected to remote terminal 1170, such as a personal computer, and act as a data conduit to transmit stored analyte level information from body electronics 1110 to remote terminal 1170. In some embodiments, data received from body electronics 1110 may be stored (permanently or temporarily) in one or more memories of display device 1120. In some other embodiments, display device 1120 is configured as a data conduit to transfer data received from body electronics 1110 to remote terminal 1170 connected to display device 1120.

[0209] Still refer to Figure 11 The analyte monitoring system 1100 also includes a data processing module 1160 and a remote terminal 1170. The remote terminal 1170 may include a personal computer, server terminal, laptop computer, or other suitable data processing device, including software for data management and analysis and communication with components in the analyte monitoring system 1100. For example, the remote terminal 1170 may be connected to a local area network (LAN), wide area network (WAN), or other data network for one-way or two-way data communication between the remote terminal 1170 and the display device 1120 and / or the data processing module 1160.

[0210] In some embodiments, remote terminal 1170 may include one or more computer terminals located in a doctor's office or hospital. For example, remote terminal 1170 may be located in a different location than display device 1120. Remote terminal 1170 and display device 1120 may be in different rooms or different buildings. Remote terminal 1170 and display device 1120 may be at least about 1 mile apart, for example, at least about 10 miles apart, for example, at least about 1100 miles apart. For example, remote terminal 1170 may be in the same city as display device 1120, in a different city than display device 1120, in the same state as display device 1120, in a different state than display device 1120, in the same country as display device 1120, or in a different country than display device 1120.

[0211] In some embodiments, a separate, optional data communication / processing device, such as a data processing module 1160, may be provided within the analyte detection system 1100. The data processing module 1160 may include components that communicate using one or more wireless communication protocols (e.g., but not limited to, infrared (IR), Bluetooth, Zigbee, and 802.11 wireless LAN protocols). Further description of communication protocols, including those based on Bluetooth and / or Zigbee, can be found in U.S. Patent Publication No. 2006 / 0193375, the entire contents of which are incorporated herein by reference for all purposes. The data processing module 1160 may also include communication ports, drivers, or connectors to establish wired communication with one or more of the display device 1120, bulk electronics 1110, or remote terminal 1170, for example, including but not limited to USB connectors and / or USB ports, Ethernet connectors and / or ports, FireWire connectors and / or ports, or RS-232 ports and / or connectors.

[0212] In some embodiments, the data processing module 1160 is programmed to send polling or query signals to the body electronics 1110 at predetermined time intervals (e.g., once per minute, once every five minutes, etc.) and, in response, receive monitored analyte level information from the body electronics 1110. The data processing module 1160 stores the received analyte level information in its memory and / or relays or retransmits the received information to another device, such as the display device 1120. More specifically, in some embodiments, the data processing module 1160 may be configured as a data relay device to retransmit or transfer analyte level data received from the body electronics 1110 to the display device 1120 or a remote terminal (e.g., via a data network such as a cellular network or a WiFi data network) or both.

[0213] In some embodiments, the body electronics 1110 and the data processing module 1160 may be positioned on the user's skin surface within a predetermined distance from each other (e.g., about 1 to 12 inches, or about 1 to 10 inches, or about 1 to 7 inches, or about 1 to 5 inches) to maintain periodic communication between the body electronics 1110 and the data processing module 1160. Alternatively, the data processing module 1160 may be worn on the user's belt or clothing to maintain a desired distance for data communication between the body electronics 1110 and the data processing module 1160. On the other hand, the housing of the data processing module 1160 may be configured to connect to or engage with the body electronics 1110, such that the two devices are combined or integrated into a single component and positioned on the skin surface. In other embodiments, the data processing module 1160 may be detachably engaged or connected to the body electronics 1110, thereby providing additional modularity so that the data processing module 1160 can be optionally removed or reconnected as needed.

[0214] Refer to Figure 11 In some embodiments, the data processing module 1160 is programmed to send commands or signals to the in vivo electronics 1110 at predetermined time intervals, such as once every 1 minute, or once every 5 minutes, or once every 30 minutes, or any other suitable or desired programmable time interval, to request analyte-related data from the in vivo electronics 1110. When the data processing module 1160 receives the requested analyte-related data, it stores the received data. In this way, the analyte monitoring system 1100 can be configured to continuously receive monitored analyte-related information at programmed or programmable time intervals, which is stored and / or displayed to the user. The data stored in the data processing module 1160 is then provided or transmitted to a display device 1120, a remote terminal 1170, etc., for subsequent data analysis, such as identifying the frequency of blood glucose level fluctuations during the monitoring period, or the frequency of alarm events occurring during the monitoring period, to improve treatment-related decisions. Using this information, doctors, healthcare providers, or users can adjust or suggest modifications to diet, daily habits, and daily activities such as exercise.

[0215] In another embodiment, the data processing module 1160, in response to user activation of a switch provided on the data processing module 1160 or receiving a user-initiated command from the display device 1120, sends a command or signal to the body electronics 1110 to receive analyte-related data. In other embodiments, the data processing module is configured to send a command or signal to the body electronics 1110 only after a predetermined time interval has elapsed, in response to receiving a user-initiated command. For example, in some embodiments, if the user has not initiated communication within a programmed time period, such as approximately 5 hours (or 10 hours, or 24 hours) since the last communication, the data processing module 1160 may be programmed to automatically send a request command or signal to the body electronics 1110. Optionally, the data processing module 1160 may be programmed to activate an alarm to notify the user that a predetermined time period has elapsed since the last communication between the data processing module 1160 and the body electronics 1110. In this way, users or healthcare providers can program or configure the data processing module 1160 to provide a degree of compliance with the analyte monitoring protocol, enabling users to maintain or perform frequent determinations of analyte levels.

[0216] In some embodiments, when a programmed or programmable alarm condition is detected (e.g., a glucose level monitored by analyte sensor 1101 is outside a predetermined acceptable range, indicating a physiological condition requiring attention or intervention for medical or analytical purposes (e.g., hypoglycemia, hyperglycemia, impending hyperglycemia, or impending hypoglycemia), one or more output indications may be generated by the control logic or processor of the body electronics 1110 and output to the user on the user interface of the body electronics 1110, thereby enabling timely corrective action. Additionally or optionally, if the display device 1120 is within communication range, the output indication or alarm data may be transmitted to the display device 1120, and the processor of the display device 1120, upon detecting the receipt of alarm data, controls the display 1122 to output one or more notifications.

[0217] In some embodiments, the control logic or processor of the body electronics 1110 can execute software programs stored in memory to determine future or expected analyte levels based on information acquired from the analyte sensor 1101, such as the current analyte level, the rate of change of the analyte level, the acceleration of the change in the analyte level, and / or analyte trend information determined based on stored monitored analyte data, which provides historical trends or directions of analyte level fluctuations over a monitoring period as a function of time. Predictive alarm parameters can be programmed or programmable in the display device 1120 or the body electronics 1110, or both, and output to the user before the predicted analyte level reaches a future level. This provides the user with an opportunity to take timely corrective action.

[0218] For example, information such as changes or fluctuations in monitored analyte levels as a function of time during a monitoring period providing analyte trend information can be determined by one or more control logics or processors of display device 1120, data processing module 1160, and / or remote terminal 1170 and / or on-board electronics 1110. This information can be displayed, for example, graphically (e.g., a graph) to indicate to the user the current and / or historical and / or predicted future analyte levels measured and predicted by analyte monitoring system 1100. This information can also be displayed as directional arrows (e.g., see trend or directional arrow display 1131) or other icons, for example, whose position on the screen relative to a reference point indicates whether the analyte level is increasing or decreasing, and whether the increase or decrease is accelerating or decelerating. The user can use this information to determine any necessary corrective actions to ensure that the analyte level remains within acceptable and / or clinically safe ranges. Other visual indicators, including color, flashes, fading, etc., and audio indicators, including changes in pitch, volume, or tone of audio output and / or vibration or other tactile indicators, may also be incorporated into the display of trend data as a means of informing the user of the current level and / or direction and / or rate of change of the monitored analyte level. For example, based on a determined rate of glucose change, a programmed clinically significant glucose threshold level (e.g., hyperglycemia and / or hypoglycemia), and the current analyte level derived from an in vivo analyte sensor, system 1100 may include an algorithm stored on a computer-readable medium to determine the time required to reach a clinically significant level and to output a notification before reaching the clinically significant level, for example, 30 minutes, and / or 20 minutes, and / or 10 minutes, and / or 5 minutes, and / or 3 minutes, and / or 1 minute, etc., as the output intensity increases.

[0219] Refer to Figure 11In some embodiments, the software algorithms executed by the data processing module 1160 may be stored in an external storage device, such as an SD card, microSD card, flash memory card, XD card, Memory Stick card, Memory Stick Duo card, or USB memory stick / device, including executable programs stored in these devices for execution when connected to one or more physical electronic devices 1110, remote terminals 1170, or display devices 1120. In another aspect, the software algorithms for execution by the data processing module 1160 may be provided to communication devices such as mobile phones, for example, smartphones or handheld computers (PDAs) supporting WiFi or the Internet, as downloadable applications executed by the downloading communication device.

[0220] Examples of smartphones include those based on Android™ operating system, WebOSTM, System or Mobile phones with operating systems have data network connectivity capabilities for data communication via the Internet and / or a local area network (LAN). PDAs as described above include, for example, portable electronic devices comprising one or more processors and data communication capabilities with a user interface (e.g., display / output unit and / or input unit), and configured to perform data processing, data uploading / downloading, for example, via the Internet. In such embodiments, remote terminal 1170 may be configured to provide executable application software to one or more of these communication devices when communication is established between remote terminal 1170 and the aforementioned one or more communication devices.

[0221] On-body electronic devices

[0222] In some embodiments, on-body electronics (or sensor control devices) 1110 ( Figure 11 This includes at least a portion of the electronic components that operate the sensor and display device. The electronic components of the body electronics typically include a power supply for operating the body electronics and sensor, sensor circuitry for acquiring signals from and operating the sensor, measurement circuitry for converting the sensor signals into a desired format, and processing circuitry (or processing lines) for acquiring signals from at least the sensor circuitry and / or the measurement circuitry and providing those signals to the optional body electronics. In some embodiments, the processing circuitry also partially or completely evaluates the signals from the sensor and transmits the resulting data to the optional body electronics and / or activates an optional alarm system if the analyte level exceeds a threshold. The processing circuitry typically includes digital logic circuitry.

[0223] The body electronics may optionally include electronics for transmitting sensor signals or processed data from the processing circuitry to the receiver / display unit; a data storage unit for temporarily or permanently storing data from the processing circuitry; a temperature probe circuit for receiving signals from the temperature probe and operating the temperature probe; a reference voltage generator for providing a reference voltage for comparison with the signal generated by the sensor; and / or a watchdog circuit for monitoring the operation of the electronic components in the body electronics.

[0224] Furthermore, bulk electronics also include digital and / or analog components utilizing semiconductor devices, including transistors. To operate these semiconductor devices, bulk electronics may include other components, including, for example, bias control generators for properly biasing analog and digital semiconductor devices, oscillators for providing clock signals, and digital logic and timing components for providing timing signals and logic operations to the digital components of the circuit.

[0225] As an example of the operation of these components, the sensor circuitry and optional temperature probe circuitry provide raw signals from the sensor to the measurement circuitry. The measurement circuitry converts the raw signal into a desired format using, for example, a current-to-voltage converter, a current-to-frequency converter, and / or a binary counter, or other indicators that generate a signal proportional to the absolute value of the raw signal. This can, for example, be used to convert the raw signal into a format that can be used by digital logic circuitry. The processing circuitry can then optionally evaluate the data and provide commands to operate the electronics.

[0226] Figure 12 In some embodiments, the bulk electronic device 1110 ( Figure 11 The diagram is shown below. (Refer to...) Figure 12 In some embodiments, the on-body electronics 1110 includes a control unit 1210 (e.g., but not limited to, one or more processors (or processing circuits) and / or application-specific integrated circuits (ASICs) with processing circuits) operatively coupled to the analog front-end circuitry 1270 to process signals, such as raw current signals received from the analyte sensor 1101. Figure 12 The diagram also shows a memory 1220 operatively coupled to a control unit 1210 for storing data and / or software routines executed by the control unit 1210. In some embodiments, the memory 1220 may include an electrically erasable programmable read-only memory (EEPROM), an erasable programmable read-only memory (EPROM), random access memory (RAM), read-only memory (ROM), flash memory, or one or more combinations thereof.

[0227] In some embodiments, in addition to retrieving one or more stored software routines for execution, the control unit 1210 accesses data or software routines stored in the memory 1220 to update, store, or replace data or information stored in the memory 1220. Figure 12 The diagram also shows a power supply 1260, which in some embodiments provides power to some or all of the components of the bulk electronics 1110. For example, in some embodiments, the power supply 1260 is configured to provide power to components of the bulk electronics 1110 other than the communication module 1240. In such embodiments, the bulk electronics 1110 is configured to operate the analyte sensor 1101 to detect and monitor analyte levels at predetermined or programmed (or programmable) time intervals, and to generate and store, for example, signals or data corresponding to the detected analyte levels.

[0228] In some embodiments, the power supply 1260 in the bulk electronics can switch between its internal power supply (e.g., a battery) and RF power received from the display device 1120. For example, in some embodiments, the bulk electronics 1110 may include a diode or switch disposed in the internal power connection path of the bulk electronics 1110, such that when the bulk electronics 1110 detects a predetermined level of RF power, the diode or switch is triggered to disable the internal power connection (e.g., form an open circuit at the power connection path), and components of the bulk electronics are powered by the received RF power. The open circuit at the power connection path prevents the internal power supply from being depleted or dissipated, as when it is used to power the bulk electronics 1110.

[0229] When the RF power from the display device 1120 drops below a predetermined level, a diode or switch is triggered to establish a connection between the internal power supply and other components of the bulk electronics 1110, thereby powering the bulk electronics 1110 using the internal power supply. In this way, in some embodiments, the switching between the internal power supply and the RF power from the display device 1120 can be configured to extend or prolong the lifespan of the internal power supply.

[0230] However, the stored analyte-related data will not be transmitted or otherwise transferred to another device (e.g., display device 1120) until the communication module 1240 is powered on independently. Figure 11 For example, the RF power from display device 1120 is located within a predetermined distance from the onboard electronics 1110. In such an embodiment, as described above, the analyte level is sampled based on predetermined or programmed time intervals and stored in memory 1220. When, for example, based on data from display device 1120 (…), the analyte level is sampled based on data from display device 1120 (…). Figure 11When another device receives a request or sends a command to request analysis level information using RF power from the display device, the communication module 1240 of the bulk electronics 1110 initiates data transmission to the display device 1120.

[0231] Back Figure 12 An optional output unit 1250 is provided to the body electronics 1110. In some embodiments, the output unit 1250 may include, for example, an LED indicator to warn the user of one or more predetermined conditions related to the operation of the body electronics 1110 and / or the determined analyte level. As a non-limiting example, when a signal received from the analyte sensor 1101 (based on one or more sampled sensor data points) indicates that it exceeds a programmed acceptable range, the body electronics 1110 may be programmed to use an LED indicator or other indicator on the body electronics 1110 to issue a notification that potentially indicates a health risk condition, such as hyperglycemia or hypoglycemia, or the onset or likelihood of such a condition. With such a prompt or indication, the user can be promptly informed of such a potential condition and, using the display device 1120, obtain glucose level information from the body electronics 1110 to confirm the existence of such a condition, thereby enabling timely corrective action.

[0232] Refer to Figure 12 Antenna 1230 and communication module 1240, operably coupled to control unit 1210, can be configured such that when onboard electronics 1110 are located at display device 1120 providing or radiating RF power ( Figure 11 When the RF power is near a predetermined location, it is detected and processed. Furthermore, the bulk electronics 1110 can provide analyte level information and optional analyte trend or historical information to the display device 1120 based on stored analyte level data. In some aspects, the trend information may include multiple analyte level information over a predetermined time period, stored in the memory 1220 of the bulk electronics 1110, and provided to the display device 1120 along with real-time analyte level information. For example, the trend information may include analyte level data over a series of time intervals within a period since the last transmission of analyte level information to the display device 1120. Optionally, the trend information may include analyte level data stored in the memory 1220 and retrieved under the control of the control unit 1210 for the previous 30 minutes or 1 hour to be transmitted to the display device 1120.

[0233] In some embodiments, the on-body electronics 1110 is configured to store analyte level data in a first first-in-first-out (FIFO) buffer and a second first-in-first-out (FIFO) buffer, which are part of a memory 1220. The first FIFO buffer stores 16 (or 10, or 20) recent analyte level data at one-minute intervals. The second FIFO buffer stores analyte level data at 10-minute (or 15-minute, or 20-minute) intervals from the most recent 8 hours (or 10 hours, or 3 hours). In response to a request received from the display unit 1120, the stored analyte level data is transferred from the on-body electronics 1110 to the display unit 1120. The display unit 1120 uses the analyte level data from the first FIFO buffer to estimate the rate of change in glucose and uses the analyte level data from the second FIFO buffer to determine historical graphs or trend information.

[0234] In some embodiments, for the configuration of the bulk electronics including a power supply, the bulk electronics may be configured to detect RF control commands (ping signals) from the display device 1120. More specifically, an on / off (OOK) detector may be disposed in the bulk electronics, which is turned on and powered by the power supply of the bulk electronics to detect RF control commands or ping signals from the display device 1120. Additional details of the OOK detector are provided in U.S. Patent Publication No. 2008 / 0278333, the entire disclosure of which is incorporated herein by reference for all purposes. In some aspects, when an RF control command is detected, the bulk electronics determines what response packet is necessary and generates a response packet to transmit back to the display device 1120. In this embodiment, the analyte sensor 1101 continuously receives power from the power supply of the bulk electronics or a battery and continuously monitors the analyte level during use. However, the sampling signal from the analyte sensor 1101 may not be provided to the display device 1120 until the bulk electronics receives RF power (from the display device 1120) to initiate data transmission to the display device 1120. In one embodiment, the power source for the bulk electronics may include a rechargeable battery that charges when the bulk electronics receives RF power (e.g., from the display device 1120).

[0235] Back Figure 11In some embodiments, the body electronics 1110 and the display device 1120 may be configured to communicate using a radio frequency identification (RFID) protocol. More specifically, in some embodiments, the display device 1120 is configured to interrogate the body electronics 1110 (associated with an RFID tag) via an RF communication link, and in response to an RF interrogation signal from the display device 1120, the body electronics 1110 provides an RF response signal including, for example, data related to the level of sampled analyte from the sensor 1101. Additional information regarding the operation of RFID communication can be found in U.S. Patent Nos. 7,545,272, 12 / 698,624, 12 / 699,653, 12 / 761,387, and U.S. Patent Publication No. 2009 / 0108992, the entire disclosures of which are incorporated herein by reference for all purposes.

[0236] For example, in one embodiment, the display device 1120 may include a backscatter RFID reader configured to provide an RF field such that when the bulk electronics 1110 is within the RF field emitted by the RFID reader, the antenna of the bulk electronics 1110 is tuned, thereby providing a reflected or response signal (e.g., a backscatter signal) to the display device 1120. The reflected or response signal may include sampled analyte level data from the analyte sensor 1101.

[0237] In some embodiments, when the display device 1120 is positioned within a predetermined range of the body electronics 1110 and receives a response signal from the body electronics 1110, the display device 1120 is configured to output an indication (auditory, visual, or other) to confirm the acquisition of the analyte level measurement. That is, during the 5 to 10 days of wearing the body electronics 1110, the user can position the display device 1120 at any time within a predetermined distance (e.g., approximately 1 to 5 inches, or approximately 1 to 10 inches, or approximately 1 to 12 inches) from the body electronics 1110, and after waiting for a sample acquisition period of several seconds, output an audible indication to confirm the receipt of real-time analyte level information. The received analyte information can be output to the display 1122 of the display device 1120. Figure 11 (This is used to present information to the user.)

[0238] Display device

[0239] Figure 13 In some embodiments, such as Figure 11A block diagram of the display device 1120 is shown. Although the term "display device" is used, the device can be configured to read data without displaying it, and can provide data without a display, such as in the case of a relay or other device that receives signals according to the same or different transmission protocols (e.g., NFC to Bluetooth or Bluetooth Low Energy). See also... Figure 13 Display device 1120 ( Figure 11 The display device 1120 includes a control unit 1310, such as one or more processors (or processing circuitry) operatively connected to the display 1122, and an input component (e.g., a user interface) 1121. The display device 1120 may also include one or more data communication ports, such as a USB port (or connector) 1123 or an RS-232 port 1330 (or any other wired communication port), for communication with the processing module 1160. Figure 11 ), Remote terminal 1170 ( Figure 11 It can communicate data with other handheld data processing devices such as personal computers, servers, mobile computing devices, mobile phones, pagers, or mobile phones including smartphones with Internet connectivity, and has data communication and processing capabilities including data storage and output.

[0240] Back Figure 13 The display device 1120 may include a test strip port 1124 configured to receive an in vitro test strip, the test strip port 1124 being coupled to a control unit 1310, and further wherein the control unit 1310 includes components programmed to process the sample received on the in vitro test strip in the test strip port 1124. Any suitable in vitro test strip can be used, for example, a test strip requiring only a very small amount of sample applied to the test strip (e.g., 1 μL or less, e.g., about 0.5 μL or less, e.g., about 0.1 μL or less) to obtain accurate glucose information. The display device with an integrated in vitro monitor and test strip port can be configured to perform in vitro analyte monitoring without user calibration of the in vitro test strip (e.g., no human intervention calibration).

[0241] In some embodiments, the integrated in vitro measuring instrument can accept and process various types of test strips (e.g., test strips that require user calibration and test strips that do not require user calibration), some of which can use different technologies (test strips that operate using current measurement technology and test strips that operate using coulomb technology), etc. U.S. Patent Nos. 6,377,894, 6,616,819, 7,749,740, and 7,418,285; U.S. Patent Publications Nos. 2004 / 0118704, 2006 / 0096006, 2008 / 0066305, 2008 / 0267823, 2010 / 0094610, 2010 / 0094111, and 2010 / 0094112; and U.S. Application No. 12 / 695,947 provide detailed descriptions of such test strips and devices for in vitro analyte monitoring, all of which are incorporated herein by reference in their entirety for all purposes.

[0242] Glucose information obtained from an in vitro glucose testing device can be used for a variety of purposes. For example, if the sensor requires in vivo calibration, this information can be used to calibrate the analyte sensor 1101. Figure 11 The results from the analyte sensor 1101 are confirmed to increase confidence in the monitored analyte levels indicated by the sensor 1101 (e.g., in cases where information obtained from the sensor 1101 is used for treatment-related decisions). In some embodiments, the analyte sensor does not require manual calibration during its lifespan. However, in other embodiments, the system may be programmed to self-detect problems and take action, such as shutting down and / or notifying the user. For example, the analyte monitoring system may be configured to detect system malfunctions, or potential degradation of sensor stability or potential adverse conditions related to the operation of the analyte sensor, and the system may use, for example, a display device 1120 (…). Figure 11 The system can notify the user to perform analyte sensor calibration or compare the results received from the analyte sensor corresponding to the monitored analyte level with a reference value (e.g., the result of an in vitro blood glucose measurement).

[0243] In some embodiments, when potential adverse conditions related to sensor operation and / or potential sensor stability degradation are detected, the system may be configured to shut down (automatically shut down without notifying the user, or shut down after notifying the user) or disable the output or display of analyte level monitoring information received by the on-body electronics. In some embodiments, the analyte monitoring system may be temporarily shut down or disabled to provide the user with an opportunity to correct any detected adverse conditions or sensor instability. In some other embodiments, the analyte monitoring system may be permanently disabled when adverse sensor operating conditions or sensor instability are detected.

[0244] Still refer to Figure 13 It also provides a power source 1320 (e.g., one or more rechargeable or disposable batteries) and is operatively coupled to the control unit 1310, and is configured to output power to the display device 1120. Figure 11 The display device 1120 may provide the power required for operation. Additionally, the display device 1120 may include an antenna 1351, such as a 433MHz (or other equivalent) loop antenna, a 13.56MHz antenna, or a 2.45GHz antenna, coupled to the receiver processor 1350 (e.g., which may include a 433MHz, 13.56MHz, or 2.45GHz transceiver chip), for communication with the body electronics 1110 (…). Figure 11 Wireless communication is performed. Optionally, an inductive loop antenna 1341 is provided and coupled to a square wave driver 1340, which is operatively coupled to a control unit 1310.

[0245] In some embodiments, data packets received from the on-body electronics and in response to a request from the display device include, for example, one or more of the following: the current glucose level from the analyte sensor, the currently estimated rate of change in blood glucose, and a glucose trend history based on automatically acquired readings stored in the memory of the on-body electronics. For example, the current glucose level may be output as a numerical value on the display 1122 of the display device 1120, and the currently estimated rate of change in blood glucose may be displayed as a directional arrow 1131. Figure 11 The data is output on display 1122, and the glucose trend history based on the stored monitoring values ​​can be displayed as a graphical trajectory 1138. Figure 11 The information is output on the display 1122. In some embodiments, the processor (processing circuitry) of the display device 1120 can be programmed to output more or less information on the display 1122, and furthermore, the type and amount of information output on the display 1122 can be programmed by the user or can be programmable.

[0246] Data communication and processing routines

[0247] Now refer to Figure 14This illustrates the data and / or command exchange between body electronics 1110 and display device 1120 during initialization and pairing routines, whereby display device 1120 provides an initial signal 1421 to body electronics 1110. When the received initial signal 1421 includes RF energy exceeding a predetermined threshold level 1403, an envelope detector 1404 of body electronics 1110 is triggered, one or more oscillators of body electronics 1110 are turned on, and the control logic or processor of body electronics 1110 is temporarily locked to retrieve and execute one or more software routines to extract a data stream from envelope detector 1404. If the data stream from envelope detector returns a valid query 1405, a response signal 1422 is sent to display device 1120. The response signal 1422 from body electronics 1110 includes an identification code, such as the serial number of body electronics 1110. After this, the body electronics 1110 returns to the idle mode (shelf mode) when inactive.

[0248] On the other hand, if the data stream from the envelope detector does not return a valid query from the display device 1120, the bulk electronics 1110 will not send a response signal to the display device 1120, nor will it provide the display device 1120 with its serial number. Thereafter, the bulk electronics 1110 returns to idle mode 1403 and remains powered off until it detects a subsequent initial signal 1421 from the display device 1120.

[0249] When display device 1120 receives a data packet containing identification information or a serial number from body electronics 1110, it extracts that information from data packet 1412. Using the extracted serial number on body electronics 1110, display device 1120 determines whether body electronics 1110 associated with the received serial number is configured. If body electronics 1110 associated with the received serial number has already been configured, for example, by another display device, display device 1120 returns to the beginning of the routine to send another initial signal 1411 in an attempt to initialize another body electronics that has not yet been configured. In this way, in some embodiments, display device 1120 is configured to pair with body electronics that have not yet been paired or configured with another display device.

[0250] Back Figure 14If the on-device electronics 1110 associated with the extracted serial number is not configured 1413, the display device 1120 is configured to send a wake-up signal including a configuration command to the on-device electronics 1110. In some embodiments, the wake-up command from the display device 1120 includes the serial number of the on-device electronics 1110, such that only on-device electronics with the same serial number included in the wake-up command are detected and exit the inactive idle mode to enter the active mode. More specifically, when the on-device electronics 1110 receives a wake-up command including the serial number, the control logic of the on-device electronics 1110 or one or more processors (or processing circuits) executes routines 1403, 1404, and 1405 to temporarily exit the idle mode if the RF energy received along with the wake-up signal (including the configuration command) exceeds a threshold level, and to determine that it is not a valid query (because the determination was made previously, and its serial number was sent to the display device 1120). Subsequently, the on-device electronics 1110 determines whether the received serial number (received via a wake-up command) matches its stored serial number 1406. If the two serial numbers do not match, the routine returns to the beginning, and the on-device electronics 1110 is again placed in an inactive idle mode 1402. On the other hand, if the on-device electronics 1110 determines that the received serial number matches its stored serial number 1406, the control logic of the on-device electronics 1110 or one or more processors is permanently locked 1407, and the oscillator is turned on to activate the on-device electronics 1110. Furthermore, returning to... Figure 14 When the on-body electronic device 1110 determines that the received serial number matches its own serial number 1406, the display device 1120 and the on-body electronic device 1110 are successfully paired 1416.

[0251] In this manner, by using wireless signals to turn on and initialize the bulk electronics 1110, the idle period of the bulk electronics 1110 can be extended because very little current is drawn from or dissipated from the power supply of the bulk electronics 1110 during the inactive, idle period prior to operation. In some embodiments, the bulk electronics 1110 has minimal operation (if any) requiring extremely low current during the inactive idle mode. The RF envelope detector of the bulk electronics 1110 can operate in two modes: a desensitized mode, which responds to received signals less than about 1 inch; and a normal operating mode, which has normal signal sensitivity such that it responds to received signals at a distance of about 3 to 12 inches.

[0252] During the initial pairing between display device 1120 and body electronics 1110, in some embodiments, display device 1120 sends its identification information, such as a 4-byte display device ID, which may include its serial number. Body electronics 1110 stores the received display device ID in one or more storage units or storage components, and subsequently includes the stored display device ID data in a response packet or data provided to display device 1120. In this way, display device 1120 can distinguish detected data packets from body electronics 1110 to determine whether the received or detected data packets originate from pairing or correct data packets on body electronics 1110. In some embodiments, the pairing routine based on display device ID avoids potential conflicts between multiple devices, especially when body electronics 1110 does not selectively provide analyte-related data to specific display devices, but rather provides it to any display device within range and / or broadcasts it to any display device within communication range.

[0253] In some embodiments, the payload size from the display device 1120 to the bulk electronics 1110 is 12 bytes, including a 4-byte display device ID, a 4-byte bulk electronics ID, a 1-byte command data, a 1-byte spare data space, and a 2-byte CRC (Cyclic Redundancy Check) for error detection.

[0254] In some embodiments, after pairing is complete, when the display device 1120 queries the on-body electronics 1110 for real-time monitored analyte information and / or recorded or stored analyte data, the response data packet transmitted to the display device 1120 includes a total of 418 bytes, comprising 34 bytes of status information, time information, and calibration data, 96 bytes of the most recent 16 1-minute glucose data points, and 288 bytes of glucose data at the most recent 15-minute intervals within a 12-hour period. Depending on the size or capacity of the memory or storage unit of the on-body electronics 1110, the data stored and subsequently provided to the display device 1120 may have different time resolutions and / or span longer or shorter time periods. For example, using a larger data buffer, the glucose-related data provided to the display device 1120 may include glucose data sampled at 15-minute, 10-minute, 5-minute, or 1-minute sampling intervals within a 24-hour time period. Furthermore, the changes in the monitored analyte levels that indicate historical trends in the monitored analyte levels can be processed and / or determined by the on-body electronics 1110, or alternatively or additionally, the stored data can be provided to the display device 1120, which can then determine trend information of the monitored analyte levels based on the received data packets.

[0255] The size of the data packets provided from the bulk electronics 1110 to the display device 1120 can also vary depending on the communication protocol and / or the underlying data transmission frequency: whether 433MHz, 13.56MHz or 2.45GHz is used, as well as other parameters, such as the presence of data processing devices in the bulk electronics 1110, such as processors or processing circuits (e.g., central processing units, CPUs), in addition to the size of the ASIC state machine, data buffers and / or memory.

[0256] In some embodiments, after successfully activating the on-body electronics 1110 and pairing it with the display device 1120, the control unit of the display device 1120 can be programmed to generate and output one or more visual, auditory, and / or tactile notifications to the user on the display 1122 or on the user interface of the display device 1120. In some embodiments, only one display device may be paired with one on-body electronics at a time. Optionally, in some embodiments, a display device may be configured to pair with multiple on-body electronics simultaneously.

[0257] Once paired, the display 1122 of the display device 1120, for example under the control of the processor of the display device 1120, outputs the remaining working life of the analyte sensor 1101 in the user's body. Furthermore, as the sensor's lifespan nears its end, the display device can be configured to output a notification to warn the user of the approaching end of the sensor's lifespan. The timing of this notification can be programmed by the user or is programmable and executed by the processor of the display device.

[0258] Back Figure 11 In some embodiments, the analyte monitoring system 1100 may store historical analyte data, along with date and / or timestamps and / or concurrent temperature measurements, in a memory, such as the memory of a data logger configured as described above. In some embodiments, the analyte data is stored at a frequency of approximately once per minute, or approximately once every ten minutes, or approximately once per hour, etc. Data logger embodiments may store historical analyte data for predetermined time periods, such as a duration specified by a physician, for example, from about 1 day to about 1 month or longer, for example, about 3 days or longer, for example, about 5 days or longer, for example, about 7 days or longer, for example, about 2 weeks or longer, for example, about 1 month or longer.

[0259] Depending on the clinical significance of the observed data, other durations may be appropriate. The analyte monitoring system 1100 can display analyte readings to the subject during monitoring. In some embodiments, no data is displayed to the subject. Optionally, the data logger can transmit historical analyte data to a receiving device located adjacent to, for example, immediately after, the data logger. For example, the receiving device can be configured to communicate with the data logger using a transmission protocol that operates at low power at a distance of a fraction of an inch to approximately a few feet. Such short-range protocols include, for example but not limited to, certified wireless USB. TM TransferJet TM , (IEEE 802.15.1), WiFi TM (IEEE 802.11) (IEEE 802.15.4-2006), Wibree TM wait.

[0260] The analyte data parameters can be calculated by a processor or processing circuit that executes a program stored in memory. In some embodiments, the processor executing the program stored in memory is located in the data processing module 1160. Figure 11 In some embodiments, the processor executing the program stored in memory is located in the data processing module 1120. An example technique for analyzing the data is applied dynamic glucose profile (AGP) analysis. Additional detailed descriptions are provided in U.S. Patent Nos. 5,262,035, 5,264,104, 5,262,305, 5,320,715, 5,593,852, 6,175,752, 6,650,471, 6,746,582, 6,284,478, and 7,299,082, and U.S. Patent Application Nos. 10 / 745,878 and 11 / 060,365, the entire contents of which are incorporated herein by reference for all purposes.

[0261] As described above, in certain aspects of this disclosure, discrete glucose measurement data can be acquired on demand or upon request from a display device, wherein glucose measurement is obtained from an in vivo glucose sensor percutaneously positioned under the user's skin layer, and further, a portion of the sensor is kept in contact with subcutaneous bodily fluids. Therefore, in various aspects of this disclosure, users of the analyte monitoring system can conveniently determine real-time glucose information at any time using the RFID communication protocol described above.

[0262] On one hand, the integrated assembly, including the on-body electronics and the insertion device, can be sterilized and packaged as a single device and provided to the user. Furthermore, during manufacturing, the insertion device assembly can be terminally packaged, saving costs and avoiding the use of expensive thermoformed trays or foil seals. Additionally, the insertion device can include end caps rotatably coupled to the insertion device body, providing a safe and sterile environment for the sensor housed within the insertion device along with the integrated assembly (and avoiding the use of desiccants on the sensor). Moreover, the end-cap-sealed insertion device can be configured to retain the sensor within the housing during transport, preventing significant movement and maintaining the sensor's position relative to the integrated assembly and insertion device from manufacturing, assembly, and transportation until the device is ready for user use.

[0263] Drug delivery system

[0264] The in-body device and / or display device may also include a drug delivery device (e.g., insulin, etc.) or may be integrated into a system such that they, for example, share a common housing. In other embodiments, the in-body device, display device, and drug delivery device may each be a separate and independent device, for example, each having its own housing. The drug delivery device may deliver medication in response to signals from sensors on the in-body device to counteract high or low levels of the analyte, or the system may monitor drug concentration to ensure that the medication remains within the desired therapeutic range. Examples of such drug delivery devices may include a drug pump with a cannula that remains in the body to allow infusion over multiple hours or days (e.g., a wearable pump for delivering basal insulin and bolus insulin). When combined with a drug pump, the in-body device or display device may include a reservoir for storing the medication, a pump that can be connected to a delivery tubing, and an infusion cannula. The pump may force the medication from the reservoir through a catheter and through the cannula inserted therein into the diabetic patient. Other examples of drug delivery devices that may be included in (or integrated with) a display device include portable injection devices that puncture the skin only for each delivery and are subsequently removed (e.g., an insulin pen). A display device, when combined with a portable injection device, may include an injection needle, a reservoir for carrying the drug, an interface for controlling the amount of drug to be delivered, and an actuator for causing the injection. The device can be reused until the drug is depleted, at which point the assembly can be discarded, or the reservoir can be replaced with a new reservoir, allowing for repeated reuse of the assembly. The needle can be replaced after each injection.

[0265] In vivo devices integrated with drug delivery devices, or display devices integrated with drug delivery devices, can be part of closed-loop systems (e.g., artificial pancreas systems that do not require user intervention) or semi-closed-loop systems (e.g., insulin loop systems that require little user intervention, such as confirming dose changes). For example, an in vivo device can repeatedly and automatically monitor the analyte levels of a diabetic patient. The in vivo device can then transmit the monitored analyte levels to a display device and can automatically determine the appropriate drug dose to control the analyte levels in the diabetic patient, subsequently delivering the drug into the patient's body (e.g., via a display device integrated with the drug delivery device, or by transmitting the dose from the display device to a separate drug delivery device). Software instructions for controlling the pump and insulin delivery volume can be stored in the memory of the display device and executed by the display device's processing circuitry. These instructions can also calculate the drug delivery volume and duration (e.g., pill infusion and / or basal infusion curves) based on analyte level measurements obtained directly or indirectly from the in vivo device. In some embodiments, the in vivo device can determine the drug dose and transmit it to the display device.

[0266] Example embodiments of in vitro analyte monitoring systems

[0267] In vitro analyte monitoring systems typically use in vitro analyte sensors in the form of test strips. These strips have an area adapted for contact with a sample of bodily fluids (e.g., blood) that has been removed from the organism, usually by pricking the skin with a sharp needle to allow one or a few drops of blood to flow. Such in vitro devices can be referred to as test strip-based in vitro devices. In vitro analyte sensors can be configured to sense the same analytes as previously described with respect to in vivo analyte sensors. Many embodiments of the in vitro sensor can be formed on a substrate, such as a generally flat substrate. In some embodiments, the in vitro sensor includes a working electrode. Working ink can be disposed on at least a portion of the working electrode. The in vitro sensor may also include at least one counter electrode (or counter / reference electrode) and / or at least one reference electrode or at least one reference / counter electrode.

[0268] In some embodiments, the external sensor may include, for example, Figure 15A and Figure 15B , Figure 16 and Figure 17 The first electrode, second electrode, and third electrode are shown. For example, as shown... Figure 15A As shown in the in vitro sensor 1510, the first electrode 1511 is closest to the sample application location 111, followed by the second electrode 1512 and the third electrode 1513. Figure 15AThe in vitro sensor shown is illustrated as having a first substrate 1530 on which electrodes are disposed, and also having an insulating layer 1531 having a cutout in a sample chamber 1532 disposed on the electrodes, the cutout exposing the electrodes in the sample chamber while covering other portions of the electrodes. Thus, within the sample chamber, the electrodes are arranged such that a sample applied to the sensor tip at application position 111 first contacts the first electrode 1511, then the second electrode 1512, and then the third electrode 1513. The conductive trace portions of the electrodes connecting to the measuring instrument are covered by the insulating layer. These in vitro sensors may have additional layers, such as a second substrate disposed on the insulating layer. The cutout in the insulating layer and the first and second substrates define the sample chamber. In some embodiments, the first electrode 1511 may be a counter electrode or a reference electrode / counter electrode, the second electrode 1512 may be a working electrode, and the third electrode 1513 may be a trigger electrode indicating the presence of a sufficient sample volume in the sample chamber for accurate analyte measurement.

[0269] In other embodiments, at least two electrodes may be configured facing each other. For example, the first electrode may be on a first substrate of the in vitro sensor, while the second and / or third electrode may be on a second substrate of the sensor, wherein the arrangement of the electrodes relative to the sample application location may be as described above.

[0270] In other embodiments, the external sensor can be as follows: Figure 15B As shown. In Figure 15B In the sensor 1520, a first electrode 1521 is mounted on a first substrate 1525; two second electrodes 1522 and 1523 are used to detect the full filling of the sample chamber; and a third electrode 1524 is mounted on a second substrate 1526. In the assembled sensor, the first electrode 1521 faces electrodes 1522, 1523, and 1524. Figure 15B In the sensor, the sample can be filled from the side inlet 112 or 113. Spacer layers 1510 and 1510', together with two substrates 1525 and 1526, define the sample chamber. Figure 15B The sensor includes two side inlets 112 and 113, either of which can be used to fill the sensor with a sample. In these embodiments, when the sample enters through inlet 112, the sample can simultaneously contact the first electrode (1521) and the second electrode (1522) before contacting the third electrode 1524. In other embodiments, the sample enters through inlet 113 and simultaneously contacts electrodes 1521 and 1523 before contacting electrode 1522. In some embodiments, the second electrode acts as a trigger electrode, indicating the presence of a sufficient sample volume in the sample chamber for accurate analyte measurement. In some embodiments, the third electrode 1524 can be a working electrode, and the first electrode 1521 can be a counter electrode or a reference / counter electrode.

[0271] In another embodiment, the external sensor can be as follows: Figure 16 As shown in the diagram. In this embodiment, all electrodes are disposed on a single surface of the same substrate 1630. These coplanar electrodes include counter electrodes or counter / reference electrodes 1631 disposed in a wound configuration relative to the working electrode 1632. A trigger electrode 1633 is disposed downstream of electrodes 1631 and 1632 such that a sample applied to application position 123 contacts the trigger electrode 1633 after contacting electrodes 1631 and 1632.

[0272] Figure 17 An embodiment of an in vitro analyte sensor with configured electrodes is shown, illustrated in an exploded view. The in vitro sensor includes a working electrode 17112 disposed on a substrate 17124. Electrodes 17118, 17120, and 17122 are disposed on a substrate 17128. A spacer layer 17126 (e.g., an adhesive) separates the working electrode 17112 from electrodes 17118, 17120, and 17122. 17118 and 17122 are trigger electrodes, and 17120 may be a counter / reference electrode of a silver / silver chloride combination. The substrates 17128 and 17124, together with the spacer 17126, define a sample chamber 17114. The sample chamber 17114 includes two inlets on a sensor-side edge, labeled with reference numerals 17114a and 17114b. 17110 illustrates a sample filled into the sample chamber 17114. The sample chamber 17114 includes a working electrode 17112. The trigger electrode closest to the side where the sample is applied indicates when the sample begins to fill the sample chamber, while the trigger electrode on the opposite side of the sample chamber indicates when the sample chamber has been filled with the sample.

[0273] As used herein, the terms “working electrode,” “counter electrode,” “reference electrode,” and “counter / reference electrode” refer to portions or portions of a conductive trace configured to function as a working electrode, counter electrode, reference electrode, or counter / reference electrode, respectively. In other words, a working electrode is the portion of a conductive trace that serves as the working electrode as described herein, for example, a portion of the conductive trace exposed to an environment containing one or more analytes to be measured and not covered by an insulating layer (e.g., a separator, tape, or covering), and in some cases, the conductive trace has been modified with one or more of the sensing layers described herein. Similarly, a reference electrode is the portion of a conductive trace that serves as the reference electrode as described herein, for example, a portion of the conductive trace exposed to an environment containing one or more analytes to be measured and not covered by an insulating layer, and in some cases, this portion includes a secondary conductive layer, such as a silver / silver chloride layer. A counter electrode is the portion of a conductive trace configured to function as the counter electrode as described herein, for example, a portion of the conductive trace exposed to an environment containing one or more analytes to be measured and not covered by an insulating layer. As described above, in some embodiments, a portion of the conductive trace may be used as one or both of the counter electrode and the reference electrode.

[0274] In some embodiments, a working ink containing an analyte-responsive enzyme may be disposed in the sample chamber of an in vitro sensor. In some embodiments, the sample chamber is defined by a first substrate, a second substrate, and a spacer layer disposed between the first and second substrates. The spacer layer may be shorter than the first and second substrates, or may include a cutout defining the space between the first and second substrates. The sample chamber includes at least a portion of a working electrode and a counter electrode or counter / reference electrode. In some embodiments, the working ink may be disposed on the working electrode (e.g., in a sensor having an electrode-facing configuration), or may be disposed on the working electrode and the counter electrode or counter / reference electrode (e.g., in a sensor having a coplanar electrode configuration). The portion of the working electrode exposed in the sample chamber, for example, not covered by the spacer layer, defines a working area that can be used to measure analyte-related signals from a sample present in the sample chamber. In some embodiments, the working area is a working pad covered with the working ink. In some embodiments, the working ink may contain a redox mediator in addition to the analyte-responsive enzyme. The area of ​​the working sheet can depend on the area of ​​the working electrode and the area of ​​the working electrode not covered by the spacer layer, which holds the first and second substrates apart. The thickness of the working sheet can be suitable for measuring the analyte and can be controlled during manufacturing.

[0275] In some embodiments, the electrodes are connected to a contact plate via traces. The contact plate facilitates connection of the electrodes to a measuring instrument or other device that detects electrochemical signals generated by the interaction of analytes and analyte-specific enzymes in a sample. Generally, in the assembled sensor, at least a portion of the electrodes and contact plate is not covered by a spacer layer or other insulating layer when the traces are covered by a spacer layer or another insulating layer. In some embodiments, the traces may be made of the same material as the electrodes and contact plate. The resistance of the traces depends on the trace area and the trace material.

[0276] The in vitro sensor can be configured for top filling, tip filling, corner filling, and / or side filling. In some embodiments, the in vitro sensor includes one or more optional filling aids, such as one or more notches, cuts, gaps, and / or protrusions, which facilitate the collection of fluid samples. For example, the in vitro sensor can be configured such that the proximal end of the in vitro sensor is narrower than the distal end of the sensor. In one such embodiment, the analyte sensor includes a tapered tip at the proximal end of the in vitro sensor, for example, at the end of the in vitro sensor that engages with the measuring instrument.

[0277] The in vitro analyte sensor can be configured to include one or more protrusions that facilitate sensor filling. One or more protrusions may extend from a first substrate or a second substrate, or both. In some embodiments, the in vitro analyte sensor includes one or more spacers positioned relative to the protrusions such that they provide structural support for the protrusions. Additional filling aid structures are described in U.S. Patent Publication No. 2008 / 0267823 and U.S. Patent Application No. 11 / 461,725, filed August 1, 2006, the entire disclosures of which are incorporated herein by reference for all purposes.

[0278] The configuration and operation of in vitro measuring instruments are well known in the field. Figure 18A This is a perspective view illustrating an example embodiment of an in vitro analyte measuring instrument 18100. In this embodiment, the measuring instrument 18100 includes a test strip slot or port 18102, a display 18104, and one or more operating buttons 18106. Although in Figure 18A As not shown, the measuring instrument 18100 may include component circuitry for receiving signals based on the analyte level of a liquid applied to a test strip in insertion slot 18102, and for determining the analyte level based on the received signals. This component circuitry may include processing circuitry communicatively coupled to a non-transitory memory. The non-transitory memory may include one or more software instructions that, when executed by the processing circuitry, cause the processing circuitry to calculate the analyte level based on the signals received from the test strip, and cause the processing circuitry to display the analyte level to a user. Figure 18BThis is a front view of an analyte measuring instrument 18200, which has a display 18104 and operation buttons 18106, and also has a glucose test strip 18202 inserted into a slot 18102 for testing bodily fluid samples (e.g., blood) applied to the test strip 18202.

[0279] Example of calibration

[0280] Biochemical sensors can be described by one or more sensing characteristics. A common sensing characteristic is called the sensitivity of a biochemical sensor, which is a measure of how well the sensor responds to the concentration of a chemical substance or component it is designed to detect. For electrochemical sensors, this response can be in the form of current (amperes) or charge (coulombs). For other types of sensors, the response can be in different forms, such as photon intensity (e.g., light). The sensitivity of biochemical analyte sensors can vary based on many factors, including whether the sensor is in vitro or in vivo.

[0281] Figure 19A This is a graph illustrating the in vitro sensitivity of an amperometric analyte sensor. In vitro sensitivity can be obtained by testing the sensor in vitro at various analyte concentrations and then performing regression (e.g., linear or nonlinear) or other curve fitting on the resulting data. In this example, the sensitivity of the analyte sensor is linear, or approximately linear, and can be modeled according to the equation y = mx + b, where y is the sensor's electrical output current, x is the analyte level (or concentration), m is the slope of the sensitivity, and b is the intercept of the sensitivity, where the intercept typically corresponds to the background signal (e.g., noise). For sensors with linear or approximately linear responses, the analyte level corresponding to a given current can be determined from the slope and intercept of the sensitivity. Sensors with nonlinear sensitivity require additional information to determine the analyte level generated by the sensor's output current, and those skilled in the art are familiar with ways of modeling nonlinear sensitivity. In some embodiments of in vivo sensors, the in vitro sensitivity may be the same as the in vivo sensitivity; however, in other embodiments, a transfer (or conversion) function is used to convert the in vitro sensitivity into an in vivo sensitivity suitable for the intended in vivo use of the sensor.

[0282] Due to differences in manufacturing processes and materials used in manufacturing, biochemical sensors of the same design that undergo the same manufacturing process can have different in vitro sensitivities (and in vivo sensitivities, if applicable). Figure 19BExamples of different sensitivities 1901-1904 for different analyte sensors with the same mechanical and electrochemical design are described. For ease of illustration, the sensitivities 1901-1904 in this example are linear, but may be nonlinear in other examples. Here, the first sensitivity 1901 has the same intercept as the second sensitivity 1902, but a larger slope. The third sensitivity 1903 typically has the same slope as sensitivity 1902, but a larger intercept. The fourth sensitivity 1904 has an even larger slope and intercept than sensitivities 1901-1903.

[0283] To compensate for these variations, sensors can be calibrated. Calibration is a technique that improves or maintains accuracy by adjusting the sensor's measurement output to reduce discrepancies from the sensor's expected output. One or more parameters describing the sensor's sensing characteristics (such as sensitivity) are established for calibration adjustments. However, in vitro testing of sensors can damage, degrade, contaminate, or otherwise render them unsuitable for distribution from the manufacturer's property to the user's property (e.g., for clinical testing, commercial use, etc.), and therefore, in vitro testing of each sensor before distribution is not a viable option.

[0284] In vivo calibration example

[0285] After obtaining raw measurement signals from a user's body using an in vivo sensor, the in vivo electronics can apply analog signal conditioning to the raw signals and convert them into a digital form of the conditioned raw signals. For example, the raw digital data can be a count converted from a raw analog signal (e.g., voltage or ampere) by an A / D converter. In some embodiments, this conditioned raw digital data can be encoded for transmission to another device, such as the display device described herein, which then algorithmically processes the raw digital data into a processed result representing the user's analyte level (e.g., a result easily suitable for display to the user). This algorithmic processing utilizes calibration information from the sensor to obtain the processed result and may utilize one or more other variables depending on the implementation. The algorithmic processing of converting raw digital data into a processed result using calibration information is within the skill of those skilled in the art. The result of this algorithmic processing can then be digitally formatted or graphically processed for digital display to the user. In other embodiments, the in vivo electronics itself can algorithmically process the raw digital data into a processed result representing the user's measured analyte level and then encode and wirelessly transmit the data to a display device, which can then format or graphically process the received data for digital display to the user. In some such embodiments, the on-body electronics may further graphically process the data to prepare it for display, and then display the data on the on-body electronics' display or transfer the data to a display device. In some embodiments, the processed analyte data results (before graphical processing) are used by the system (e.g., incorporated into a diabetes monitoring protocol) without further processing for display to the user. In some embodiments, the on-body electronics and / or display device transfer raw digital data to another computer system for algorithmic processing and display.

[0286] Some embodiments of in vivo analyte monitoring systems require calibration, either through user interaction or automatically by the system itself, after the sensor is implanted in the user or patient. For example, when user interaction is required, the user performs an in vitro measurement (e.g., a blood glucose (BG) measurement using a finger stick and an in vitro test strip) and inputs it into the system simultaneously with the implantation of the analyte sensor. The system then compares the in vitro measurement with the in vivo signal and uses the difference to determine an estimate of the sensor's in vivo sensitivity. The in vivo sensitivity can then be used in algorithmic processing to convert the data collected by the sensor into a value indicating the user's analyte level. This process, along with other processes requiring user intervention to perform calibration, is referred to as "user calibration." Due to the instability of sensor sensitivity, the system may require user calibration, and therefore the sensitivity may shift or change over time. Therefore, multiple user calibrations may be required (e.g., according to a periodic (e.g., daily) schedule or as needed) to maintain accuracy. While the embodiments described herein may incorporate a particular implementation with some degree of user calibration, this is generally not preferred as it requires the user to perform painful or strenuous BG measurements and introduces user error.

[0287] Several embodiments of in vivo analyte monitoring systems have been proposed that periodically adjust calibration parameters using automated measurements of sensor characteristics performed by the system itself (e.g., processing circuitry executing software). A system that repeatedly measures the impedance of a sensor and uses it to update sensitivity is described in U.S. Patent Publication No. 2012 / 0265037, the entire contents of which are incorporated herein by reference for all purposes. Repeatedly adjusting sensor sensitivity based on variables measured by the system (rather than the user) is generally referred to as “system” (or automated) calibration and can be performed by user calibration (e.g., early BG measurements) or without user calibration. As with repeated user calibration, shifts in sensor sensitivity over time typically require repeated system calibration. Therefore, while the embodiments described herein can be used with a degree of automated system calibration, preferably, the sensor sensitivity becomes relatively stable over time, thus eliminating the need for post-implantation calibration.

[0288] Some embodiments of in vivo analyte monitoring systems operate using factory-calibrated sensors. Factory calibration refers to the determination or estimation of one or more calibration parameters before distribution to users or healthcare professionals (HCPs). Calibration parameters can be determined by the sensor manufacturer (or, if the two objects differ, by the manufacturer of other components of the sensor control unit). Many in vivo sensor manufacturing processes produce sensors in groups or batches (referred to as production batches, manufacturing stage batches, or simple batches). A single batch can include thousands of sensors.

[0289] Production batches are typically individually numbered or coded to provide traceability throughout the manufacturing process. In some examples of factory calibration, one or a subset of sensors from each individual batch are tested, and one or more nominal calibration parameters are determined. These sensors are then applied to the remaining untested sensors in that particular batch that are designated for field distribution (e.g., for commercial use, clinical testing, etc.). Thus, each sensor distributed from that batch is assigned the same nominal calibration parameters. This can be referred to as “batch-level” calibration, and depending on the results of batch testing, the sensors in the first batch may have calibration parameters different from those in the second batch.

[0290] One or more calibration parameters can be stored in the memory of the corresponding sensor control device, so that the required calibration parameters are readily available when the user initiates operation of the sensor control device. Embodiments of factory-calibrated sensors with relatively unstable sensitivity can be used in conjunction with one or more user calibration steps and / or one or more system calibration steps.

[0291] Factory-calibrated sensors with stable or substantially stable sensitivity can operate without user and system calibration. For example, in all embodiments described herein, in vivo sensors can be calibrated by the manufacturer and then provided to the user, who can then use such sensors to accurately monitor their in vivo analyte levels for the duration of their lifespan without requiring user or system calibration steps. Such systems and methods determine clinically accurate analyte concentrations at least within a predetermined sensing period of the analyte sensor system without obtaining one or more independent analyte measurements (e.g., without the use of in vitro test strips or other reference devices) for calibrating analyte-related signals generated from the analyte sensor during the sensor's lifespan (e.g., post-manufacturing). In other words, once the analyte sensor is positioned within the user's body, the control logic or microprocessor in the electronic device, or the microprocessor in the display device, includes one or more algorithms or programs to precisely convert or correlate signals associated with the sensed analyte (e.g., in nanoamps (nA), counts, or other suitable units) to the corresponding analyte level (e.g., in milligrams per deciliter (mg / dL) or other suitable units) without providing a reference value to the system. Thus, sensor calibration is "invisible" to the user, allowing the system to perform analyte sensor calibration without any human intervention.

[0292] External calibration example

[0293] Like in vivo analyte monitoring systems, in vitro analyte monitoring systems can also benefit from calibration. In vitro test strips are typically used only once, and any calibration information associated with the in vitro sensor is determined by the manufacturer, not the user. In some examples, calibration parameters or codes may be printed on the packaging containing the in vitro sensor set. Each time a user uses one of the in vitro sensors, the user inputs the calibration parameters into the measuring instrument so that the instrument can adjust the results appropriately. The algorithmic processing performed by the in vitro system is similar to that described for the in vivo system, where the raw measurement signal may undergo analog conditioning and be converted into a digital form of the conditioned raw signal, which is then processed by the algorithm to represent the user's analyte level (e.g., results that are easily adapted for display to the user). This algorithmic processing utilizes the calibration information of the in vitro sensor to obtain the processing result and may utilize one or more other variables depending on the implementation. As with factory-calibrated in vivo sensors, calibration codes are determined for a production batch (or multiple production batches) of in vitro sensors, with each in vitro sensor in that batch assigned the same calibration code.

[0294] Example embodiments related to individualized calibration of medical devices

[0295] Many medical device manufacturing processes produce medical devices in batches. In vivo analyte sensors and in vitro analyte sensors (e.g., test strips) are just a few examples of medical devices that can be mass-produced. The example embodiments described herein allow for the independent determination or estimation of individualized calibration parameters for each medical device within a batch. Thus, instead of batch-level calibration, the embodiments allow for separate “device-level” calibration (e.g., “sensor-level” calibration). The terms “individualized calibration information” and “individualized calibration parameters” as used herein refer to calibration information or calibration parameters that have been determined using at least (or based on or represent) a characteristic, measurement, or aspect specific to an individual medical device within a group (e.g., a production batch) and can vary among medical devices in that group. While “individualized calibration information” and “individualized calibration parameters” can also be determined using characteristics, measurements, or aspects not specific to an individual medical device but shared by medical devices within a group, these terms still distinguish them from batch-level calibration information and batch-level calibration parameters. Individualized calibration parameters can be determined for a particular medical device without requiring in vitro testing of that particular medical device, as such testing would render the device unsuitable for distribution to third-party users as described above.

[0296] Figure 20AThis is a flowchart illustrating an example embodiment of a method 2000 for individually calibrating a medical device capable of sensing biomedical properties. At 2008, sensing characteristics of the first medical device are determined. For an analyte sensor, this sensing characteristic may be, for example, the sensitivity of the analyte. The sensing characteristics can be determined by in vitro (or in vivo) testing that makes the first medical device suitable for dispensing. At 2009, calibration information for the second medical device can be determined using at least a representation of manufacturing parameters of the second medical device and a representation of the sensing characteristics of the first medical device. The representation of manufacturing parameters may be a measured value of the manufacturing parameter, a value calculated based on the manufacturing parameter (e.g., the relative difference between the manufacturing parameter and a reference value (nominal value or central tendency of the manufacturing parameter)), an aspect of the manufacturing parameter, or others. As will be further described below, the representation of the sensing characteristic may be a value of the sensing characteristic itself, a value calculated based on the sensing characteristic (e.g., the relative difference between the sensing characteristic and a reference value (nominal value or central tendency of the sensing characteristic)), an aspect of the sensing characteristic, or others. The first and second medical devices preferably have the same structure, chemical configuration, and design.

[0297] In many cases, manufacturing parameters are specific to the second medical device. For example, manufacturing parameters of the second device can be measured directly or indirectly from the second device during or after manufacturing. Examples of manufacturing parameters are described in more detail herein. The manufacturing parameters of the second device can be used together with the sensing characteristics of the first device to determine, estimate, calculate, or infer calibration information for the second device. In this way, calibration information specific to the second device can be determined using the characteristics of the second device obtained in a manner free from degradation, damage, or contamination, while also utilizing the actual sensing characteristics measured from the first medical device.

[0298] Descriptions for two individual medical devices (first and second) Figure 20A This is one approach, but the topic can be expanded to a larger scale. Figure 20B This is a flowchart illustrating another example embodiment of method 2010, used to individually calibrate a batch of medical devices (e.g., in vivo or in vitro analyte sensors) capable of sensing biochemical properties. At 2018, sensing characteristics of a first subset of the medical devices are determined. This first subset may be referred to herein as a sample subset or a baseline subset, and the sensing characteristics obtained from the first subset may be referred to herein as sample sensing characteristics or baseline sensing characteristics. For analyte sensors, this sensing characteristic may be, for example, the sensitivity of the analyte. The sensing characteristics can be determined by in vitro (or in vivo, if applicable) testing of the first subset of medical devices, such testing renders the first subset of medical devices unsuitable for distribution. Examples of such testing will be described in more detail herein.

[0299] At 2019, using at least a representation of the individualized manufacturing parameters of each device within the second subset and a representation of the sensing characteristics of the medical devices in the first subset, calibration information for each medical device within the second subset can be determined independently. In other words, for example, if the second subset comprises 100 individual medical devices, then 100 independent calibration information determinations are required (e.g., by executing software instructions via processing circuitry). These 100 independent determinations can be performed as 100 discrete mathematical steps, or in a single mathematical step, for example, by using a digital array. The second subset of medical devices corresponds to a subset intended for distribution to users such as patients and / or healthcare professionals, and may be referred to herein as the distribution subset.

[0300] The medical devices in the baseline subset undergoing in vitro testing differ from those in the distribution subset. In some embodiments, the baseline and distribution subset are part of a large batch of medical devices that have undergone one or more manufacturing steps together as a common group or batch. For example, a larger batch of medical devices may be a production batch that has undergone all or almost all of the manufacturing steps together. The baseline subset of medical devices can be obtained from the production batch and used to derive baseline sensing characteristics, which are then used in part to determine individualized calibration information for each sensor within the distribution subset. The baseline subset and distribution subset need not be considered for every medical device in the production batch, as some medical devices in the batch may be removed (e.g., because they failed online inspection) or used for other purposes (e.g., quality control).

[0301] It is desirable to take the baseline subset and distribution subset from the same batch, as this inherently accounts for numerous manufacturing variations, especially those that occur uniformly throughout the batch but may vary between batches. However, for manufacturing processes with more limited significant intra- and inter-batch variations, the medical devices in the baseline subset and distribution subset may not be taken from the same batch, although care should be taken not to significantly reduce the applicability of baseline test results to the distribution subset. For example, in some embodiments, the medical devices in the baseline subset may be taken from two or more different production batches, and the distribution subset may be taken from the same production batch as one or more medical devices in the baseline subset (e.g., the baseline subset represents a cross-section of many production batches for which baseline sensing characteristics are subsequently applied). In other embodiments, the medical devices in the baseline subset may be taken from one production batch, and the medical devices in the distribution subset may be taken from a second different production batch. In yet another embodiment, the baseline subset may be taken from two or more different production batches, and the distribution subset may be taken from one production batch from which no sensors are included in the baseline subset. In the embodiments just described, the concept of whether the baseline subset and the distribution subset come from the same or different production batches is viewed in relation to whether the apparatus is processed together during one or more manufacturing stages.

[0302] Generally, the more medical devices in the baseline subset, the more accurate the in vitro sensing characteristics obtained. However, because in vitro testing is often destructive, medical devices in the baseline subset are typically unsuitable for distribution. Therefore, the number of devices in the baseline subset can be determined by balancing the ability to obtain accurate and representative results with the reduction in yield (and the resulting costs). The number of devices in the baseline subset can also be related to the number of devices in a production batch (or average production batch). For example, the baseline subset can be approximately 0.01% to 10% of the medical devices in a production batch (e.g., approximately 0.01%, approximately 0.1%, approximately 0.5%, approximately 1.0%, approximately 5%, or approximately 10%). Similarly, the number of medical devices in the baseline subset can be approximately 0.01% to 10% of the number of medical devices in the distribution subset (e.g., approximately 0.01%, approximately 0.1%, approximately 0.5%, approximately 1.0%, approximately 5%, or approximately 10%). Percentages outside these ranges are also within the scope of this disclosure.

[0303] Figure 20C This shows method 2010 ( Figure 20BThe flowchart below shows another example embodiment of the procedure, where additional steps may be included as appropriate. At 2012, at least partially, a batch (a production batch or a portion thereof) of medical devices is manufactured, wherein the batch includes a baseline subset and a distribution subset. At 2014, individualized manufacturing parameters for each medical device in the batch are measured. In some embodiments, the individualized manufacturing parameters are measured only for those medical devices in the distribution subset. The measurement steps may be performed concurrently with the manufacture of the batch of medical devices in step 2012, for example, during or after each stage of manufacturing. Measurements may be performed after the medical device manufacturing is complete, for example, for those manufacturing parameters that are measurable at that stage. If the medical devices are subsequently assembled with other components into a larger device, measurements may be performed after assembly if those manufacturing parameters remain measurable. At 2016, the medical devices within the baseline subset are tested in vitro to obtain in vitro test data. In vitro testing may be performed after the sensor manufacturing has reached a stage that allows for accurate in vitro testing (e.g., after membrane application and post-processing, but before the sensor is assembled with its associated electrical components). Figure 20B Similar to the previous implementation, at 2018, the sensing characteristics of the baseline subset of medical devices are determined, and then at 2019, the calibration information of each medical device in the distribution subset can be determined independently using at least a representation of the individualized manufacturing parameters of each medical device in the distribution subset and a representation of the sensing characteristics of the baseline subset of medical devices.

[0304] In 2020, calibration information can be associated with each individual medical device. This paper describes various techniques for achieving this in more detail. For example, for in vivo devices, this can be achieved by storing personalized calibration information in a non-transitory memory of an electronic device assigned to the individual in vivo device, or by storing personalized calibration information in a non-transitory memory associated with a server, allowing the calibration information to be transmitted to a field device (e.g., a read / write device) working with the individual in vivo sensor. For in vitro devices, this can be achieved by recording calibration information on a medium located on or with each in vitro device. In some examples where the in vitro device is a test strip, the test strip can be packaged with other test strips having the same individually defined calibration information, which can be printed on the packaging.

[0305] Manufacturing parameter examples

[0306] The term "manufacturing parameters" is a broad term intended to encompass any aspect of a medical device that is measurable (directly or indirectly) during or after the manufacturing process, or any descriptor of the manner in which a particular medical device (or group of medical devices) is manufactured. Manufacturing parameters are preferably specific to an individual medical device, such that they can vary between medical devices in the same group or batch; in this case, it is referred to herein as individualized manufacturing parameters. This contrasts with manufacturing parameters that are not specific to an individual medical device, which are referred to herein as "group" manufacturing parameters or "batch" manufacturing parameters. Examples may include environmental parameters present when a batch of medical devices is processed simultaneously (e.g., in a public room), or identifiers of devices used to manufacture a production batch.

[0307] The medical device is preferably traceable throughout the manufacturing process, allowing the identification of the medical device at each manufacturing stage to be tracked. Individualized manufacturing parameters can be stored as data in a manner that associates them with the corresponding individual medical device from which they were obtained. When manufacturing parameters for a particular medical device are obtained, the newly obtained manufacturing parameters can be stored along with any and all other manufacturing parameters measured for the same medical device. Thus, each individual medical device can have one or more manufacturing parameters associated with it, for example, in data or log files.

[0308] Examples of manufacturing parameters may include measurements of the dimensions or dimensions of an individual medical device. Dimensional measurements can be any dimension in three-dimensional space. Dimensional measurements can be one-dimensional, such as length, width, height, thickness, radius, diameter, chord, or others. Dimensional measurements can represent two-dimensional (2D) space, such as the area of ​​a plane or the size of its perimeter, an arc, or others. Dimensional measurements can represent three-dimensional (3D) space, such as the area, volume, or others of a non-planar surface (e.g., a cylinder, hemisphere, irregular shape, or a portion thereof). Dimensional measurements can be obtained directly or indirectly. For example, 2D or 3D measurements are obtained by measuring various individual dimensions and then calculating or estimating the 2D or 3D dimensions. In some examples, dimensions such as the height or thickness of a particular structure may be difficult to measure directly but can be estimated by measuring other comparable structures that can serve as substitutes (e.g., works of art). Dimensional measurements can be obtained using inspection devices such as optical sensors.

[0309] In the case of in vivo analyte sensors, all of the aforementioned dimensions can be measured from any of its components, such as any and all electrodes, sensing areas, membranes, contacts, insulating components, substrates, traces, etc. In many embodiments, as will be described herein, the size or dimensional characteristics of the sensing area and / or membrane of the in vivo analyte sensor are particularly important in determining accurate calibration information for the sensor, although the embodiments described herein are not limited to these examples. As a non-limiting example, the size of the sensing area can represent at least one of the following: the width of the sensing area, the length of the sensing area, the thickness of the sensing area, the perimeter of the sensing area, the area of ​​the sensing area, or the volume of the sensing area. As a non-limiting example, the size of the membrane can represent at least one of the following: the width of the membrane, the length of the membrane, the thickness of the membrane, the perimeter of the membrane, the area of ​​the membrane, or the volume of the membrane.

[0310] In the case of in vitro analyte sensors (such as test strips), all of the aforementioned dimensions can be measured from any of its components, such as any and all electrodes, workpieces, working inks, insulating components, substrates, spacers, traces, cutouts, etc. In some embodiments, the dimensions of the workpiece (e.g., length, width, area, thickness or height, perimeter, volume, etc.) are particularly important in determining accurate calibration information, although the embodiments described herein are not limited thereto.

[0311] Examples of manufacturing parameters may include the chemical composition or concentration of any part or component of a medical device. The chemical composition or concentration can be any structure described herein or known in the art. In the case of an in vivo analyte sensor, the chemical composition can be the chemical composition of any and all electrodes, sensing areas and their components, membranes, contacts, substrates, insulating layers, traces, etc. In the case of an in vitro sensor (such as a test strip), the chemical composition can be the chemical composition of any and all electrodes, working sheets, working inks, insulating components, substrates, separators, traces, etc. Many chemical aspects of medical devices are described herein, and these will not be repeated except to note that manufacturing parameters can be related to the composition and / or concentration of each described chemical aspect. Furthermore, chemical composition or concentration can represent the level of impurities within the medical device. Examples of manufacturing parameters may also include material properties such as porosity, surface roughness or smoothness, density, brittleness, catheter width, catheter length, etc.

[0312] Examples of manufacturing parameters can include electrical characteristics such as resistance, impedance, capacitance, leakage, etc. In the case of in vivo analyte sensors, electrical characteristics can be measured from any of their components, such as any and all electrodes, conductive components (e.g., wires, connecting lines, traces, or contacts), insulating components (e.g., resistance, impedance, leakage), sensing areas, membranes, substrates, etc. In the case of in vitro sensors (e.g., strips), electrical characteristics can be measured from any of their components, such as any and all electrodes, conductive components (e.g., wires, connecting lines, traces, or contacts), insulating components, substrates, working sheets, working ink, spacers, etc. In some embodiments, trace resistance is particularly important in determining accurate calibration information, although the embodiments described herein are not limited thereto.

[0313] Examples of manufacturing parameters, which can be individualized parameters (e.g., using a single-unit process, where individual medical devices are acted upon individually by a manufacturing apparatus at a specific stage) or non-individualized parameters (e.g., using batch processing), can include environmental conditions. One example could be the temperature or the amount of temperature change observed during a specific manufacturing stage (e.g., annealing). Another example could be the ambient pressure or the amount of pressure change observed during a specific manufacturing stage (e.g., vapor deposition). The amount of time a specific medical device (or batch, or production batch) spends at a specific manufacturing stage, or the time spent between manufacturing stages (if relevant), can also be considered a manufacturing parameter.

[0314] Manufacturing parameters can also be qualitative. The identification of a specific device used on a medical device during manufacturing can be a qualitative manufacturing parameter, as can the processing order of the medical devices. For example, the position of a particular medical device (or a batch of medical devices) within a sequence of medical devices acted upon by a specific device can be a qualitative manufacturing parameter. In some embodiments, in vitro test strips can be made from printed cards, which are then divided into individual test strips, and the position of the test strip in each row is particularly important for determining accurate calibration information, although the embodiments described herein are not limited thereto. Similarly, reprocessing of the medical device at any stage of the manufacturing process, for example, due to exceeding specifications, can be a qualitative manufacturing parameter.

[0315] Returning to the measurement of the sensing area of ​​the example sensor, Figure 21A This is a top view of an example embodiment of the surface of a substrate 2102 having a sensing region, which includes three sensing elements 2103-1, 2103-2, and 2103-3 with diameter indicators, and the area of ​​the sensing region can be the sum of the areas of each of the three sensing elements. Figures 21B to 21C This is a cross-sectional view taken along line 21BC-21BC, where electrodes and other components are omitted for simplicity. Figure 21B In this configuration, each of the three sensing elements 2103 has a planar surface. Figure 21C In this, each of the three sensing elements 2103 is a dome or circular surface, the area of ​​which can be approximated as the area of ​​a two-dimensional circle or calculated as a three-dimensional structure. Figure 22A This is a top view showing an example embodiment of the surface of substrate 2202, which has a sensing region including a sensing layer 2203, the area of ​​which can be determined as the product of length 2204 and width 2205. Figures 22B to 22C This is a cross-sectional view taken along line 22BC-22BC, where electrodes and other components are omitted for simplicity. Figure 22B In the middle, the sensing layer 2203 is disposed above the substrate 2202, while Figure 22C In this process, the sensing layer 2203 is embedded or disposed within a well created within the substrate 2202. Figure 23A This is a perspective view of an example embodiment of a sensor 2301 within a cylindrical or generally cylindrical body, the sensor 2301 having a sensing region 2303 located between insulating (or non-sensing) portions 2302. Figure 23B It is along Figure 23A The diagram shows a cross-sectional view taken along lines 23B-23B, and illustrates a sensing region 2303 surrounding a core region 2305, where the core region 2305 may be made of a conductive material. In this embodiment, the area of ​​the sensing region 2303 can be calculated as the area of ​​a cylinder having a length 2304 and a diameter 2306.

[0316] Returning to the measurement of film thickness, Figure 24This is a cross-sectional view illustrating an example embodiment of an in vivo sensor 2401, which has a substrate 2402, a sensing region 2403, and a membrane 2404 surrounding the ends of the substrate 2402 and the sensing region 2403. The thickness of the membrane 2404 can be determined by performing one or more measurements 2406 between the outer surface 2407 of the membrane 2404 and the surface 2408 of the substrate 2402. Arrows 2406-1 to 2406-4 illustrate examples of different measurement locations, which may be aligned with or coincide with the sensing region 2403 (locations 2406-2 and 2406-3), or located outside the sensing region 2403 (locations 2406-1 and 2406-4). If the membrane thickness is measured multiple times, the value used as an individualized manufacturing parameter can be the central tendency of these measurements (e.g., median, average). In some cases, it may be difficult to measure the film thickness directly. In such cases, the thickness of the film 2404 in the region between surfaces 2407 and 2408 can be estimated by measuring the total thickness or diameter 2409 of the film 2404 between surfaces 2407 and 2410 (if measured multiple times with a central tendency) and the known, nominal, or estimated thickness 2411 of the substrate 2402 (or the substrate 2402 and the sensing region 2403), and then halving (or separating appropriately). Figure 25A It is similar to Figure 23A A perspective view of an example embodiment of sensor 2501, but showing the outer membrane 2504. Figure 25B It is along Figure 25A The cross-sectional view taken by lines 25B-25B shows the core region 2305, in which the sensing region 2303 is located on the core region 2305, and the membrane 2504 is located on the sensing region 2503. The thickness of the membrane 2504 is indicated by 2506.

[0317] Example of exported sensing characteristics from the test

[0318] As described above, one or more medical devices within a baseline subset can be tested to empirically determine the sensing characteristics of that subset. In many embodiments, the testing is capable of generating data that verifiable represents the medical device's ability to sense biochemical properties. In many in vivo and in vitro analyte sensor (e.g., test strip) embodiments, the sensing characteristics may be the sensitivity of the analyte sensor to the presence of an analyte. Typically, this testing will be performed in vitro, resulting in the collection of in vitro test data. The sensing characteristics derived from or otherwise obtained from the in vitro test data of the baseline subset may be referred to as in vitro sensing characteristics (e.g., in vitro sensitivity).

[0319] Figure 26AThis is an example graph of in vitro test data obtained from an in vitro test current-based in vivo glucose sensor constituting a baseline subset. In this example, the baseline subset includes five sensors, and the in vitro test datasets corresponding to each of these five sensors are labeled 2602-1 to 2602-5. The baseline subset may include quantities beyond five without departing from the scope of this topic. The in vitro test datasets were obtained by applying different glucose solutions to each analyte sensor and monitoring the resulting current, which can be on the order of nanoamps, picoamps, or other orders of magnitude depending on the sensor design. From time t0 to t1, no solution is applied to the sensor (or a solution with no glucose concentration is applied). At time t1, a first glucose solution with a first relatively low concentration (e.g., 1 mmol / L) is applied to the in vivo sensor, and the resulting response is recorded. At time t2, a second glucose solution with a relatively higher concentration than the first solution is applied to the in vivo sensor, and the resulting response is again recorded. This process can be iterated at t3, thereafter increasing the glucose solution concentration to obtain empirical data representing the sensitivity of the in vivo glucose sensor over a wide range of glucose concentrations. As can be seen, these embodiments of the glucose sensor respond differently to the presence of glucose solution, and these differences become more pronounced as the concentration of glucose solution increases. Note that the x-axis represents time, not glucose concentration; therefore, although the in vitro test data may appear somewhat non-linear, the sensitivity derived from the in vitro test data remains linear.

[0320] Figure 26B It corresponds to Figure 26A Example curves for the sensitivities 2604-1 to 2604-5 of the in vitro test datasets 2602-1 to 2602-5 are provided. The sensitivities 2604-1 to 2604-5 can be determined by independently performing regressions (e.g., linear or nonlinear) on each corresponding in vitro test dataset 2602-1 to 2602-5. In some embodiments, such as for nonlinear sensitivity, the in vitro datasets can be divided into separate response regions, where each response region is modeled with linear sensitivity to approximate a nonlinear curve, such that the resulting calibration information will vary based on the measured degree of response (e.g., current).

[0321] exist Figure 26BIn the examples, the various sensitivities 2604 are linear or substantially linear. The in vitro sensitivity (or other sensing characteristic) of the baseline subset can be determined in any desired manner. In some embodiments, the baseline in vitro sensitivity can be the central tendency of sensitivities 2604-1 to 2604-5, such as the mean or median of sensitivities 2604-1 to 2604-5. In this example, the median is sensitivity 2604-3. In some embodiments, the baseline in vitro sensitivity can be the central tendency (e.g., mean or median) of an aspect or characteristic of sensitivities 2604-1 to 2604-5, such as the central tendency of the slope of sensitivities 2604-1 to 2604-5 or the central tendency of the intercept of sensitivities 2604-1 to 2604-5. Other aspects of sensitivity can also be used as the in vitro sensitivity of the baseline subset. In some embodiments, instead of deriving individual sensitivities 2604-1 to 2604-5 from each of the in vitro test datasets 2602-1 to 2602-5, a single regression can be performed on all in vitro test data from a baseline subset, and this single regression, or one aspect thereof, can be used as the baseline in vitro sensitivity. In all these embodiments, the in vitro test dataset or the in vitro sensing characteristics determined therefrom (e.g., Figure 26B Those shown can be filtered to remove one or more values ​​(e.g., values ​​below the minimum threshold, values ​​above the maximum threshold, values ​​within the threshold, atypical values, etc.) before determining the baseline in vitro sensitivity.

[0322] Additional example implementations related to individualized plant calibration

[0323] Returning to the exemplary embodiment for individualized calibration, Figure 27A , Figure 27B as well as Figure 27C These are flowcharts describing example embodiments of methods 2700, 2710, and 2720 for determining individualized calibration information, respectively. For example, they can be... Figure 20A Step 2009 of the embodiment or Figure 20B and Figure 20CThe steps in step 2019 of the embodiments are performed. In many embodiments, methods 2700, 2710, and 2720 are performed independently for each medical device in the distribution subset. These methods relate to a “corresponding” medical device, which, in this and other embodiments described herein, is a specific medical device in a subset (e.g., a distribution or baseline) that changes each time the method is executed. Here, the “corresponding” medical device is the first medical device in the distribution subset when method 2700 is executed for the first time, then becomes the second medical device when method 2700 is executed for the second time, and so on, until method 2700 has been executed independently on all medical devices in the distribution subset. This also applies to methods 2710 and 2720. Methods 2700, 2710, and 2720 are described in relation to representations of individualized manufacturing parameters, but can also be applied in conjunction with non-individualized (e.g., environmental) manufacturing parameters. Similarly, methods 2700, 2710 and 2720 are described in relation to the representation of in vitro sensing characteristics, but they can also be applied in conjunction with other sensing characteristics (or their representations).

[0324] Now go to Figure 27A At 2702, at least the representation of the individualized manufacturing parameters of the corresponding medical device and the representation of the in vitro sensing characteristics of the baseline subset are used to determine the in vitro sensing characteristics (or their representation) of the corresponding medical device in the distribution subset. At 2705, individualized calibration information of the corresponding medical device corresponding to the representation of the in vitro sensing characteristics of the corresponding medical device is determined. This individualized calibration information can be determined directly from the in vitro sensing characteristics of 2702, or the in vitro sensing characteristics can be modified or converted to another value in one or more steps, and the resulting modified or converted value can then be used to determine the individualized calibration information.

[0325] Figure 27B Method 2710 is illustrated, which can be particularly applicable to in vivo medical devices. Here, at 2712, the in vitro sensing characteristics (or their representations) of the corresponding medical device in the distributed subset can be determined using at least a representation of the individualized manufacturing parameters of the corresponding medical device and a representation of the in vitro sensing characteristics of a baseline subset. This can be performed by applying at least the representation of the individualized manufacturing parameters and the representation of the baseline in vitro sensing characteristics to the model or equation, such that the in vitro sensing characteristics (or their representations) of the corresponding medical device are generated by the model. At 2714, the representation of the in vivo sensing characteristics of the corresponding medical device can be determined using at least the representation of the in vitro sensing characteristics of the corresponding medical device. At 2715, individualized calibration information is determined for the corresponding medical device corresponding to the representation of the in vivo sensing characteristics of the corresponding medical device.

[0326] Figure 27CMethod 2720 is illustrated, which can be particularly applied to in vitro medical devices, wherein in vitro sensing characteristics are modified before determining individualized calibration information. Here, at 2722, a first in vitro sensing characteristic (or its representation) of the corresponding medical device in the distribution subset can be determined using at least a representation of the individualized manufacturing parameters of the corresponding medical device and a representation of the in vitro sensing characteristics of a baseline subset. As in the previous example, this can be performed by inputting at least the representation of the individualized manufacturing parameters and the representation of the baseline in vitro sensing characteristics into a model or equation that outputs the first in vitro sensing characteristic (or its representation) of the corresponding medical device. At 2724, a second in vivo sensing characteristic (or its representation) of the corresponding medical device can be determined using at least the representation of the in vitro sensing characteristics of the corresponding medical device. At 2725, individualized calibration information is determined for the corresponding medical device corresponding to the representation of the second in vitro sensing characteristic of the corresponding medical device. An example application of method 2720 is an in vitro test strip, wherein a first in vitro sensing characteristic corresponds to a test result obtained by performing an in vitro test with a glucose solution, and then the test result is modified (e.g., using a transfer function described in more detail herein) to a second in vitro sensing characteristic that corresponds to a sensing characteristic in the presence of a sampled bodily fluid (e.g., blood).

[0327] For embodiments where the manufacturing parameter is a quantitative value or measurement, the representation of the manufacturing parameter (or individualized manufacturing parameter) may be the actual measured value of the manufacturing parameter, a relative indication of the measured manufacturing parameter, or other information calculated or derived from the actual measured value. In some example embodiments, it is desirable to use the relative difference between the quantitatively measured manufacturing parameter and the central tendency (e.g., mean, median) of the quantitatively measured manufacturing parameter for a larger group (e.g., the entire batch or the entire subset of allocations, etc.). For example, a manufacturing parameter may be the area of ​​the sensing region of a medical device. Instead of using the actual measured value of the sensing region area (or the measured length and width of the sensing region) to determine calibration information, it is desirable to use the relative difference between the measured sensing area and the central tendency of the sensing area for a larger group. For a quantitative manufacturing parameter (MP) that varies among individual medical devices, the relative representation of the manufacturing parameter may be determined according to (1) below:

[0328]

[0329] As previously mentioned, other manufacturing parameters of various devices, such as film thickness, working sheet area, and working ink resistance, can be used in conjunction with or in place of the sensing area. Similarly, the representation of baseline in vitro sensing characteristics can be an actual in vitro sensing characteristic determined for a baseline subset, a relative indication of the degree of variation of that in vitro sensing characteristic with another sensing characteristic (e.g., a reference), or other methods. Likewise, the representation of in vivo sensing characteristics can be an estimated in vivo sensing characteristic, a relative indication of the degree of variation of that in vivo sensing characteristic with another sensing characteristic (e.g., a reference), or other methods.

[0330] Steps 2702, 2712, and 2722 of methods 2700, 2710, and 2720 can be performed, respectively, by inputting at least the representations of individualized manufacturing parameters and baseline in vitro sensing characteristics into a model (or equation) representing the in vitro sensing characteristics of the output individual medical device. Many different models (or equations) can be used, including but not limited to linear regression models; multivariate regression models, random forest models, nonlinear models, Bayesian regression models, neural networks, machine learning models, non-random decision trees, or discriminant analysis models, etc. Examples of models incorporating or determined by multivariate regression analysis are described below, while examples of these other models will be further discussed in the appendix.

[0331] Many of the example embodiments described herein determine the sensing characteristics of an individual medical device by utilizing manufacturing parameters of that individual medical device centered on empirically determined baseline sensing characteristics. In some embodiments, individualized calibration information is determined directly from individualized manufacturing parameters without reference to baseline sensing characteristics. However, incorporating empirically determined baseline sensing characteristics into the model, particularly when the representation of manufacturing parameters differs relatively from the whole group, can minimize the effects of group-to-group (or batch-to-batch) variations. The following (2), (3) are examples of multivariate regression-based models that can be used with the embodiments described herein:

[0332] (2)SC MD =SC B +α+(βRMP A )

[0333] (3)SC MD =SC B +(1+0.1(α+(βRMP A )))

[0334] Among them, SC MD It refers to the in vitro sensing characteristics of individual medical devices, modeled or calculated. B It represents the in vitro properties of a baseline subset, where α is an optional adjustment factor (zero or non-zero), RMP. AThis represents the manufacturing parameters, and β is RMP. A The coefficients. β and α can be empirically determined constants (positive or negative), for example, by comparing the estimated in vitro sensing characteristics of a medical device with the empirically observed characteristics of the same medical device. In these examples (2), (3) and other examples in models (4) through (7) below, RMP is a quantitative measurement rather than a qualitative descriptor, such as an identifier of the manufacturing device or an indication of whether the device has been reprocessed. Above, Equation 3 takes a more relatively corrected form than Equation 2. Constant values ​​other than 0.1 can be used in Equation (3), and in Equations (5) and (7) below.

[0335] In some embodiments, the model may include higher-order exponential terms to account for nonlinearities in the manufacturing parameter data. The following (4), (5) are examples of models with higher-order terms that can be used with all embodiments described herein, where δ may be another empirically determined RMP. A Coefficient of the squared term:

[0336] (4)

[0337] (5)

[0338] In some embodiments, the model may utilize multiple different manufacturing parameters, with or without higher-order terms. The following (6) and (7) are two examples of models utilizing two different manufacturing parameters, which can be used with all embodiments described herein:

[0339] (6)

[0340] (7)

[0341] RMP A It is the first manufacturing parameter, RMP B It is the second manufacturing parameter, γ is RMP. B The coefficient, ε is the RMP B The coefficients of the exponent, and ρ is RMP A and RMP B The coefficients of the product. Each of these coefficients can also be determined empirically, can be a constant, and can be positive or negative. These coefficients can be determined and then applied to all production batches. In other embodiments, these coefficients can be determined batch-by-batch, such that the coefficients are constant for all devices in a batch (or other group), but different for all devices in different batches (or groups). The coefficients can also be determined individually. RMP A and RMP BHigher-order products help capture the interactions between these manufacturing parameters. For example, when RMP B The value is relatively high (compared to RMP). B When compared to the nominal value, RMP A The value is relatively low (compared to RMP). A The impact of the nominal value may be greater than that of the model. Those skilled in the art can extend and implement these models with three or more different manufacturing parameters. Any and all coefficients described in (2) through (7) can be weighted, for example, to indicate the confidence level.

[0342] Back Figure 27B At 2714, the external sensing characteristics of the corresponding medical device (e.g., external SC) are used. MD The representation of ) determines the in vivo sensing characteristics of the corresponding medical device, and returns to Figure 27C At 2724, the first external sensing characteristic of the corresponding medical device (e.g., external SC) is used. MD The representation of 2714 (or 2724 (the first in vitro sensing characteristic)) is used to determine the second in vitro sensing characteristic of the corresponding medical device. These and similar determinations described herein can be made by applying the representation of the in vitro sensing characteristic of 2714 (or the first in vitro sensing characteristic of 2724) to the transfer function. Transfer functions used to convert in vitro sensing characteristics to in vivo sensing characteristics and to convert between in vitro sensing characteristics are within the scope of the art of those skilled in the art. Transfer functions can be determined analytically. For example, a transfer function used to convert from in vitro sensing characteristics to in vivo sensing characteristics can take into account factors that differ between in vitro and in vivo states, such as absolute glucose concentration, temperature, oxygen, and interfering substances. Furthermore, transfer functions used to convert between in vitro sensing characteristics, such as transfer functions for analyte test solutions and transfer functions for body fluids, can also take into account, for example, hematocrit percentage. Transfer functions can also be determined empirically, for example, by conducting clinical studies and comparing in vivo responses with in vitro data, or by comparing in vitro responses to different substances. If this relationship is in the form of an offset, then the transfer function can be implemented by adding or subtracting a constant value. More complex transfer functions may include multiplying by a constant value, multiplying by a variable value (e.g., the variable depends on the magnitude of the in vitro sensing characteristic), or others.

[0343] In all embodiments herein, the representation of sensing characteristics (e.g., SC) MD SC BThe sense characteristic (e.g., sensitivity itself (e.g., slope and intercept)) can be the sense characteristic itself, an aspect of the sense characteristic (e.g., only the slope of the sensitivity or only the intercept of the sensitivity), the relative change of the sense characteristic relative to a reference value (e.g., nominal value, average value, average value, etc.), the relative change of an aspect of the sense characteristic (e.g., relative slope, relative intercept, etc.) relative to a reference value (e.g., nominal value, average value, average value, etc.), or others. Returning to methods 2700, 2710, and 2720, personalized calibration information can be determined from the in vitro sense characteristics of the individual medical device (step 2705 of method 2700), the in vivo sense characteristics of the individual medical device (step 2715 of method 2710), or a second in vitro sense characteristic (step 2725 of method 2720). The personalized calibration information can capture the sense characteristic in the form of a factor or code, which can be recorded or stored in a manner that allows processing circuitry that processes raw or conditioned data collected by the individual medical device to access the factor or code. Many different techniques exist to enable calibration information to be accessed by appropriate processing circuitry, and the techniques employed typically depend on the type of medical device and the specific requirements of the implementation. Several embodiments of apparatuses and techniques for recording individualized calibration information and enabling that information to be accessed by processing circuitry will be described in more detail below.

[0344] Figure 27D This is a flowchart illustrating another example embodiment of method 2750 for determining individualized calibration information for an individual medical device. Method 2750 incorporates many aspects of the embodiments discussed above. At 2752, one or more manufacturing parameters are obtained for N medical devices, where N = X devices of a baseline subset + Y devices of a distribution subset. In some embodiments, one or more manufacturing parameters are obtained only for the Y devices of the distribution subset. Manufacturing parameters can be individualized manufacturing parameters or non-individualized manufacturing parameters (e.g., environmental factors, device identification, etc.), although the resulting calibration information would not be individualized if only non-individualized manufacturing parameters are measured. Manufacturing parameters can be obtained at various different stages of the manufacturing process. For example, in an example embodiment where the medical device is an in vivo analyte sensor, at least two different individualized manufacturing parameters are measured: the size of the sensing region after manufacturing the sensing region, and the size of the membrane after applying the membrane. If N = 1000, then after manufacturing and measuring the sensing regions for N sensors, 1000 different measurements of the sensing region size will be obtained. After placing (e.g., depositing) the membrane onto N sensors and measuring it, 1000 different membrane size measurements, or a total of 2000 measurements, will be obtained. Depending on the number and type of measuring devices, the 1000 different sensing area measurements can be obtained serially, in parallel, or in a combination thereof, and this also applies to the measurement of membrane size or any other manufacturing parameter.

[0345] At point 2753, in vitro testing was performed on X medical devices within the baseline subset to obtain in vitro testing data. In vitro testing can be performed in a manner similar to... Figure 26A The described method of execution results in data that is an empirical representation of the in vitro sensing characteristics of each of the X devices. Each of the X devices can be tested individually to generate an individual in vitro test dataset. When X is greater than 1, the X devices can be tested in vitro in a serial, parallel, or combined manner, depending on the number and type of in vitro test devices. If each of the X devices is tested individually, then the execution of step 2753 will generate X individual in vitro test datasets. For example only, when N = 1000, X can be a relatively small fraction of N, such as 5, 10, or 20 medical devices, where Y is much larger, such as 995, 990, or 980. Other values ​​of N, X, and Y are also within the scope of this disclosure.

[0346] At position 2754, the in vitro sensing characteristics of the baseline subset are determined. In some example embodiments, this can be achieved by first converting X individual in vitro test datasets into X individual in vitro sensing characteristics (one for each of the X devices), and then determining the entire baseline subset from these X in vitro sensing characteristics (e.g., SC). B This can be achieved using a single in vitro sensing characteristic. For example, the baseline in vitro sensing characteristic could be the central tendency (e.g., mean or median) of the in vitro sensing characteristics of X individuals. In another embodiment, the baseline in vitro sensing characteristic can be determined by performing a regression analysis on a dataset of X individual in vitro tests. Similarly, the in vitro sensing characteristic can be sensitivity or one aspect thereof (e.g., slope or intercept).

[0347] At position 2755, individualized calibration information for the Y medical devices in the distributed subset is determined. In this embodiment, it is similar to... Figure 27A Method 2700 determines individualized calibration information for each specific medical device within a distribution subset in the manner described.

[0348] When i=1, at position 2756, determine the external sensing characteristics (e.g., SC) of the i-th device among the Y devices. MD The estimation of the calibration information is performed, for example, using a model as described herein. Then, at 2758, individualized calibration information for the i-th medical device is determined based on the in vitro sensing characteristics. At 2759, it is determined whether i = Y. If not, i is incremented by 1 (e.g., i = i + 1), and method 2750 returns to step 2756. This process is repeated until i = Y, in which case individualized calibration information is determined independently, one for each of the Y medical devices.

[0349] Figure 27EThis is a flowchart illustrating another example embodiment of method 2760 for determining personalized calibration information for an individual medical device. Method 2760 incorporates many aspects of the previously discussed embodiments, and steps 2752 to 2756 are similar to... Figure 27D An example of this implementation. At 2755, individualized calibration information for the Y medical devices in the distributed subset is determined. In this embodiment, it is similar to... Figure 27B Method 2710 determines individualized calibration information for each specific medical device within a distribution subset, and this individualized calibration information is particularly applicable to in vivo devices.

[0350] At position 2756, with i=1, determine the external sensing characteristics (e.g., SC) of the i-th device among the Y devices. MD The estimation of SC can be performed using a model such as that described herein. In an example embodiment where the medical device is an in vivo analyte sensor and the manufacturing parameters are the size of the sensing area and the size of the membrane, the SC can be determined according to equation (6) or (7). MD RMP A It is the size (e.g., area) of the sensing region, and RMP B This refers to the membrane's dimensions (e.g., thickness). Then, at 2764, the in vivo sensing characteristics of the i-th medical device are determined. This can be achieved, for example, by using a transfer function. Then, at 2765, individualized calibration information for the i-th medical device is determined based on the in vivo sensing characteristics. At 2759, it is determined whether i = Y. If not, i is incremented by 1 (e.g., i = i + 1), and method 2760 returns to step 2756. This process is repeated until i = Y, in which case individualized calibration information is determined independently, one for each of the Y medical devices.

[0351] Figure 27F This is a flowchart illustrating another example embodiment of method 2770 for determining personalized calibration information for an individual medical device. Method 2770 also incorporates many aspects of the previously discussed embodiments, and steps 2752 to 2756 are similar to... Figure 27D An example of this implementation. At 2755, individualized calibration information for the Y medical devices in the distributed subset is determined. In this embodiment, it is similar to... Figure 27C Method 2720 determines individualized calibration information for each specific medical device within a distribution subset, and this individualized calibration information is particularly applicable to in vitro devices.

[0352] At position 2756, with i=1, determine the external sensing characteristics (e.g., SC) of the i-th device among the Y devices. MDThe first estimate is then made. This estimate can also be accomplished using a model such as that described herein. Then, at 2774, the second in vitro sensing characteristic of the i-th medical device is determined. This can be achieved, for example, by using a transfer function. Then, at 2775, individualized calibration information for the i-th medical device can be determined based on the second in vitro sensing characteristic. At 2759, it is determined whether i = Y. If not, i is incremented by 1 (e.g., i = i + 1), and method 2760 returns to step 2756. This process is repeated until i = Y, in which case individualized calibration information is determined independently, one for each of the Y medical devices.

[0353] exist Figures 27D to 27F In an example embodiment, the sub-steps within 2755 are executed once sequentially for a single medical device before those sub-steps are executed again for the next individual medical device. In other embodiments, each sub-step may be executed Y times before proceeding to the next sub-step. For example, regarding Figure 27F Before performing step 2774 or 2775, step 2756 can be performed Y times on all Y medical devices. For example, step 2756 can be performed Y times, then step 2774 can be performed Y times, and then step 2775 can be performed Y times. In many embodiments, the sub-steps of 2755 (e.g., 2756, 2774, and 2775) will be performed by processing circuitry that executes software instructions, and those skilled in the art will recognize that these steps can be implemented by those instructions in a variety of different ways without departing from the scope of the subject matter described herein.

[0354] Figure 28A and Figure 28B The flowchart illustrates additional example embodiments of methods related to the determination of individualized calibration information. These methods utilize direct analysis of clinical data to determine or derive baseline sensing characteristics of all or most medical devices produced by the manufacturing process, thereby minimizing or eliminating the need for periodic in vitro testing of a subset of baselines for each production batch (or multiple batches).

[0355] Figure 28AA method 2800 for determining baseline sensing characteristics from clinical data is illustrated. At 2802, one or more individualized manufacturing parameters are measured (or otherwise obtained) from each medical device in a first batch of medical devices. The resulting manufacturing parameter data is stored or archived for later use. Then, at 2804, the medical devices from the first batch are used for clinical testing, and the clinical test data obtained therefrom is also stored or archived. At 2806, baseline sensing characteristics are determined based on the clinical test data. As with other embodiments described herein, baseline sensing characteristics can be used for in vivo or in vitro states of the medical device and can be, for example, the sensitivity of the medical device or an aspect of its sensitivity.

[0356] For example, clinical trials are preferably conducted on a substantial number of participants to obtain a robust dataset. Traceability between each participant and the specific medical device used by that participant is preferably maintained. In this way, the medical device used by each participant can be tracked, and manufacturing parameters measured from that medical device can be correlated with the resulting clinical data produced by that medical device (or the resulting clinical data collected during clinical trials). Statistical and / or other analyses can then be performed to determine baseline sensing characteristics from that clinical data. In some examples, the baseline sensing characteristic may be the central tendency of the clinical data, such as the mean or median. The baseline sensing characteristics preferably represent the medical device produced throughout the entire manufacturing process. The manner and extent to which measured manufacturing parameters affect sensing characteristics can be determined by referencing and analyzing archived manufacturing parameters and clinical trial data.

[0357] Figure 28B A method 2810 for determining individualized sensing characteristics from at least baseline sensing characteristics (or representations thereof) is illustrated, such as that determined in method 2800. At 2812, one or more manufacturing parameters are measured or otherwise obtained from each medical device in a second batch of medical devices. At 2814, individualized sensing characteristics are determined from at least one or more manufacturing parameters obtained in step 2812 and, for example, from baseline sensing characteristics determined from the first batch of medical devices. This can be performed, for example, using models such as those described herein, and using manufacturing parameters identified as potentially influencing the baseline sensing characteristics. Then, at 2816, individualized calibration information for each individual medical device can be determined at least based on the individualized sensing characteristics determined for the respective medical device. This individualized calibration information can then be associated with the respective medical device, as described elsewhere herein.

[0358] The second batch of medical devices can be part of a production batch or an entire production batch, and in some embodiments, it can be multiple production batches. Furthermore, in many embodiments, production batches can be manufactured and released for distribution to users without requiring routine in vitro or other tests on a baseline subset from the production line, making those devices in the baseline subset unsuitable for distribution to users. Alternatively, if such testing is not completely eliminated, the amount of testing required per or multiple production batches can be significantly reduced compared to technologies where baseline sensing characteristics are not directly determined from clinical data. In both cases, yield increases accordingly because such testing is reduced or eliminated. (Refer to...) Figure 28A and Figure 28B The described embodiments can be implemented using any in vivo or external medical device described herein.

[0359] Figure 29A This is a block diagram illustrating an example embodiment of a computer system 2900 that can be used to implement the calibration embodiments described herein. The computer system 2900 is shown herein as a single system, but can also be implemented in a distributed manner. System 2900 may include an input port 2902, processing circuitry 2904, non-transitory memory 2906, and an output port 2908. Input port 2902 may be communicatively coupled to processing circuitry 2904 and memory 2906. Examples of data that may be provided to input port 2902 include: a representation of manufacturing parameters 2910 collected during or after the medical device manufacturing process, in vitro test data 2912 collected during in vitro testing of a baseline subset of the medical device. Other examples, not shown, may include data identifying individual medical devices, data logs tracking the flow of each medical device through the manufacturing process and the current location of the medical device, identification of the production batch to which each medical device belongs, data identifying the electronic devices to be used with the medical device, allocation of a specific medical device to associated electronic devices, and data logs tracking the flow of each electronic device unit through the manufacturing process and the current location of the unit, etc. The input data can be stored in memory 2906 and read by processing circuitry 2904 via internal bus 2914. Memory 2906 can also store software instructions that, when executed by processing circuitry 2904, cause processing circuitry 2904 to perform various steps, including determining, estimating, calculating, using a model, using a transfer function, causing data storage, receiving data, and causing the data output described herein. For example, processing circuitry 2904 can perform any and all of the following steps: Figure 20A Steps 2008 and 2009; Figure 20B Steps 2018 and 2019; Figure 20C Steps in 2018, 2019, and 2020; Figure 27ASteps 2702 and 2705; Figure 27B Steps 2712, 2714, and 2715; Figure 27C Steps 2722, 2724, and 2725; Figure 27D Steps 2753, 2754, 2755, 2756, 2758, and 2759; Figure 27E Steps 2753, 2754, 2755, 2756, 2764, 2765, and 2759; Figure 27F Steps 2753, 2754, 2755, 2756, 2774, 2775, and 2759; Figure 28A Step 2806; and Figure 28B Steps 2814 and 2816.

[0360] Processing circuitry 2904 can determine calibration information based on appropriate sensing characteristics in a variety of ways. In some embodiments, one of a plurality of predetermined codes that most closely approximates or best matches the sensing characteristics is identified, such that a relatively large number of potential sensing characteristic values ​​can be reduced to a more limited number of options without sacrificing significant performance. The predetermined code can be in the form of the sensing characteristic set itself; for example, the number 5 can be used as calibration information if a slope of 5 is to be indicated. In other embodiments, the predetermined code is an alphanumeric value or string that does not indicate calibration information itself, but is set by system 2900 so that it can be used by devices (e.g., reader devices, measuring instruments, sensor control devices, etc.) to look up the corresponding calibration information, for example, by referencing a transformation matrix. In some embodiments, the in vivo sensor and the on-body electronics having in vivo sensor calibration information stored in its memory can be housed in separate packages, in which case both the package for the in vivo sensor and the package for the on-body electronics can have calibration information or some other code printed thereon, so that, in the case of separation, a user can identify which sensor is used with which on-body electronics.

[0361] Processing circuitry 2904 can also cause determined calibration information (e.g., calibration code) 2914 to be output from output port 2908. Processing circuitry 2904 can be implemented as a single discrete processor device or distributed as processing circuitry shared among multiple devices. Similarly, memory 2906 can be implemented as a single discrete memory or multiple memories, or as a single database or multiple databases, or a combination thereof. Memory 2906 can reside on the same chip or device as other functional circuitry, including processing circuitry 2904. Memory 2906 can be partially located within computer system 2900 or distributed in other locations accessible through the manufacturer's network (e.g., separate databases).

[0362] Individual medical devices are traceable throughout the manufacturing process, thus maintaining the relevance of manufacturing parameters to the individual medical devices collected from them. In some embodiments, each individual medical device can be uniquely identified by an identifier associated with it physically. In some examples of in vitro test strips, the test strips are manufactured on a printed card or substrate and then separated into individual test strips, and an identifier can be associated with that card or substrate. Each test strip can then be uniquely tracked using the card's identifier and data indicating the relative position of the test strips on the card.

[0363] The identifier may be in the form of a barcode, a printed two-dimensional (QR) code, optical character recognition (OCR) text (e.g., an alphanumeric string), a resistive code (e.g., as described in U.S. Publication No. 2014 / 0200917, the full text of which is incorporated herein by reference for all purposes), a radio frequency (RF) readable device (e.g., an RFID element or a near field communication (NFC) element), etc. The identifier (or a second identifier) ​​may also identify the production batch associated with the medical device. The identifier is read each time the medical device undergoes a specific manufacturing stage and / or each time manufacturing parameter data is obtained, and a log may be created (or an existing log may be retrieved and appended) containing an indication of the current date and time, an identifier of the manufacturing stage, an identifier of the manufacturing apparatus used to process the medical device, the length of time the medical device spends in the manufacturing stage, and / or any manufacturing parameters obtained in that specific manufacturing stage related to the processing of the medical device.

[0364] Figures 29B to 29D This is a block diagram describing the conceptual process and information flow for the manufacture of biochemical sensors. While not limited to this, Figure 29B Especially suitable for in vivo sensors. First refer to... Figure 29B Section 2920 typically describes the manufacturing stages and the collection of manufacturing parameter data. At 2922, a group of medical devices (e.g., a production batch) is processed through a first manufacturing stage, and then at 2924, manufacturing parameters of that group of medical devices are measured or otherwise obtained. Depending on the type of manufacturing parameters collected, step 2924 may occur simultaneously with or after manufacturing stage 2922. The group of medical devices then proceeds to a second manufacturing stage 2926, and manufacturing parameter data may be collected again at 2928, either simultaneously with or after the end of stage 2926. This process may continue through all manufacturing stages until, at 2930, the construction of the medical devices is completed, or completed to the point where in vitro testing data can be obtained. When manufacturing parameter data is collected, for example, at 2924 or 2928, the manufacturing parameter data may be output to computer system 2900 for storage, as shown in information paths 2925 and 2929, respectively. Testing or monitoring devices that obtain the manufacturing data may be coupled or linked to computer system 2900 via the manufacturer's data network communication.

[0365] In vitro testing of a baseline subset of the medical device is performed at point 2932, and the resulting in vitro test data can be output to computer system 2900 via information path 2931. Similarly, the device recording the in vitro test results can be communicatively coupled to computer system 2900 via a data network. In alternative embodiments where in vitro testing is not performed (or only minimally performed and does not rely on determining individualized calibration information) (e.g., regarding...), Figures 28A to 28B In the embodiments described, communication of in vitro test data at 2932 or via path 2931 can be performed. Figures 29B to 29D (Omitted). Furthermore, the baseline subset can be completely eliminated, and the distributed subset can be the entire production batch.

[0366] Computer system 2900 can then acquire manufacturing parameter data and in vitro test data, and determine individualized calibration information for each medical device in the distribution subset. Computer system 2900 can assign each medical device in the distribution subset to a specific electronic unit (e.g., 1110). Optionally, this assignment can be performed manually or automatically at another location within the manufacturing assembly line via manufacturing equipment. The identifier of the electronic unit assigned to each medical device can be transmitted to computer system 2900.

[0367] In some embodiments, personalized calibration information is stored in the non-transitory memory of an electronic unit (e.g., the memory of the on-body electronics 1110), which is a single sub-unit to which the personalized medical device is assigned. As shown at 2933, the personalized calibration information can be provided by computer system 2900 to a means responsible for writing data into the non-transitory memory of the electronic unit. This data can then be written into the electronic unit at 2934 (e.g., at the release point stage), for example, via wireless transmission to the electronic unit or via a wired access port (e.g., a Universal Serial Bus (USB) port, if available, or an internal data port such as a Serial Boundary Scan port). The personalized medical device can then be packaged with the associated electronic unit to maintain a physical assignment relationship (this step can also be performed before the data is written into the electronic unit). Then, at stage 2940, the final component can be distributed to the user.

[0368] These devices may be distributed to users in the form of kits or packages containing one or more sensors. For example, in vivo devices may be distributed (e.g., sold) to users in a common package comprising multiple (two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more) in vivo sensors and their associated electronic units (e.g., sensor control units). Each electronic unit may have non-transitory memory where individualized calibration information is stored, the memory being at least based on individualized manufacturing parameters measured by the associated in vivo sensor and specific to the associated in vivo sensor. In some embodiments, the in vivo sensor may be packaged separately from the associated electronic unit, or the electronic unit may be packaged separately, both within a common package. In these embodiments, some user assembly may be performed before or simultaneously with use.

[0369] Figure 29C The diagram illustrates a process where personalized calibration information is output from system 2900 at 2943 and directly associated with the medical device itself at 2944, and is particularly suitable for medical devices such as in vitro test strips that do not have an associated electronic unit. Numerous methods can be used. In some embodiments, personalized calibration information can be determined and printed directly onto the medical device before leaving the manufacturing process, for example, in the form of a printed alphanumeric code, a printed 2D barcode, or a 3D QR or data matrix code. Resistance codes (as described in merged U.S. Publication No. 2014 / 0200917) can be placed on the medical device and read by the circuitry of a measuring instrument. In other embodiments, personalized calibration information can be associated with the medical device by attaching an RF tag (e.g., RFID or NFC) in which calibration information is stored. Furthermore, a ROM calibrator can be used, such as a personalized calibrator programmed to correspond to an individual sensor.

[0370] As already described, in some embodiments, in vitro test strips can be separated and grouped according to their individualized calibration codes, and groups with the same calibration code can then be packaged and sold as a unit. In these embodiments, individualized calibration information can be associated directly with each individual test strip or with the packaging of the test strip group, for example using any of the printed, RF, or ROM calibration methods described above.

[0371] To program the code in the measuring instrument or other processing device, the printed alphanumeric code can be entered by the user, selected from a list of options provided to the user, or read by an OCR camera on the measuring instrument or test strip port (so that it can be automatically read when the test strip is inserted). Similar camera-based or barcode-based methods can be used for QR codes, printed barcodes, or data matrix codes. If an RF tag (e.g., RFID or NFC) is used, the measuring instrument or processing device will include an RF tag reader, which can be included in the test strip port for automatic reading when the test strip is inserted. One such method is described in U.S. Patent No. 8,115,635, the entire contents of which are incorporated herein by reference for all purposes. In other examples, a ROM calibrator can be used. In some examples, a computing device such as a mobile phone can use one of the aforementioned technologies (e.g., optical scanning, NFC, or RFID communication, etc.) to obtain calibration information, and the measuring instrument can include Bluetooth communication circuitry and establish a Bluetooth link with the computing device. The obtained calibration information can be transmitted from the computing device to the measuring instrument via the Bluetooth link. In another example, if the computing device has an identifier for an external medical device (which can also be obtained through one of the aforementioned technologies), then a computing device such as a mobile phone can obtain calibration information from a server (via the cloud, as discussed below). Figure 29D The device transmits the calibration information to the server, and then, after receiving the calibration information, the computing device can transmit it to the measuring instrument via a Bluetooth link.

[0372] Figure 29D An example embodiment is shown in which calibration information can be provided to a field processing device 2949 for processing biochemical data collected by the individual medical device after distribution. For example, a reader device, measuring instrument, or other processing device can obtain the identifier of the individual medical device. If the individual medical device has an associated electronic unit, the identifier can be requested from or provided by the electronic unit (e.g., 1110). Otherwise, the identifier can be obtained directly from the medical device, for example, by a user manually reading the identifier from the medical device or its packaging and inputting it into the processing device 2949, or the processing device 2949 can read the identifier from the medical device or packaging in one of the aforementioned ways. At 2950, ​​the processing device 2949 can transmit the identifier to a computer system 2900 (or a trusted server) via the Internet or cloud network 2942. The computer system 2900 can read the identifier, select the appropriate individualized calibration information, and output the calibration information back to the processing device 2949 at 2954. The processing device 2949 can then process the data collected by the medical device using algorithms and present it to the user via a display (or output it to another device).

[0373] Improvements related to calibration

[0374] Studies have confirmed that the calibration embodiments described herein significantly improve the accuracy of biochemical sensing measurements performed by medical devices. This translates to improvements in the operation of the calibrated medical devices themselves, and further improvements in the operation of monitoring systems and / or monitoring devices incorporating these medical devices, as well as improvements in the operation of computing devices that process or otherwise utilize the improved accuracy data generated by calibrating the medical devices. Improvements have also been confirmed through reduced variability between medical devices, and increased manufacturing yields for medical devices. These and other improvements form the basis for patentability of this subject matter, for example, under 35 U.S.C. 101 and similar claims in other jurisdictions.

[0375] For example, studies were conducted on in vivo analyte sensors that explored the relationship between the in vivo glucose sensitivity of sensors obtained through clinical studies and various manufacturing parameters collected during the fabrication of those same sensors. Subjects in the clinical studies were asked to perform in vivo measurements using an implanted in vivo sensor immediately after a blood glucose (BG) reference test using a finger stick and test strip. The relative deviation between the BG reference test and the subsequent in vivo sensor readings was modeled based on various manufacturing parameters of the in vivo sensor. The correlation (traceability) between clinical and manufacturing data was maintained using batch reports, unique identifiers for the in vivo sensor, and unique identifiers for the in vivo system containing the sensor.

[0376] Various statistically significant associations were identified. Figures 30A to 30B The graph shows an example dataset that demonstrates a statistically significant association between in vivo results and manufacturing parameters. Figure 30A The y-axis shows the relative deviation between in vivo readings and corresponding in vitro blood glucose (BG) measurements, relative to the sensing area (e.g., mm²) of each sensor studied on the x-axis. 2 The x-axis represents the relative area difference between individual sensors, as well as the central tendency of the production batch in which the sensors are produced. Figure 30A This indicates a positive correlation between sensing area and in vivo sensitivity, such that a relatively large sensing area is associated with a relatively high in vivo sensitivity, while a relatively small sensing area is associated with a relatively low in vivo sensitivity.

[0377] Figure 30BThe relative deviation between in vivo readings and corresponding in vitro blood glucose (BG) measurements is shown on the y-axis, expressed relative to the membrane thickness (e.g., μm) of each sensor studied on the x-axis. In this example, the total lateral thickness of the sensor is measured at and near the sensing area, and an average value is determined. The average value is then subtracted from the average value to obtain the average membrane thickness for each particular sensor, which is then used as a representation of the membrane thickness. Figure 30B This indicates a negative correlation between membrane thickness and in vivo sensitivity, meaning that relatively large membrane thickness is associated with relatively low in vivo sensitivity, while relatively small membrane thickness is associated with relatively high in vivo sensitivity.

[0378] Using both sensing area and film thickness as manufacturing parameters, individualized calibration information (sensitivity slope in this example) was determined for the sensors used in clinical studies. The clinical studies were reanalyzed using this individualized calibration information for each sensor, rather than batch-level calibration codes. The reanalysis showed a significant improvement in the mean absolute relative difference (MARD) using the individualized calibration information. The reanalysis also showed an improvement in the total standard deviation of the relative difference between sensors using the individualized calibration information. Furthermore, the mean relative difference (MRD), or accuracy performance, was also improved.

[0379] Further studies were conducted using sensors from individual batches divided into three groups: group one, where individualized calibration information represented relatively high predicted in vivo sensitivity; group two, where individualized calibration information represented relatively low predicted in vivo sensitivity; and group three, where individualized calibration information represented intermediate or moderate predicted in vivo sensitivity between groups one and two. In this study, subjects used sensors from all three groups, the accuracy of the obtained data was analyzed, and it was compared with data from factory-calibrated batch sensors. Figures 31A to 31B This is a graph showing the sample dataset used in the study, with MRD on the y-axis and glucose levels (mg / dL) on the x-axis. Figure 31A The MRD for each of the three groups is shown when batch-level calibration information is used, while Figure 31B The MARD for each of the three groups is shown when individualized sensor-level calibration information is used. This demonstrates that the use of individualized calibration information minimizes performance variations across the entire production batch, while also resulting in an improvement in MARD.

[0380] The use of personalized calibration information improved yield. It was found that by significantly reducing the use of personalized calibration information, and thus allowing more medical devices to pass sensitivity accuracy testing, improvements were made in sensor-to-sensor variability (e.g., sensor-to-sensor variability) within a production batch. Examples utilizing personalized calibration information achieved greater than 20% improvement in accuracy performance.

[0381] Other statistically significant associations are possible and may depend on the design details of the medical device and the associated manufacturing process. Some embodiments of the medical devices within the scope of this disclosure may have a sensing area different from that described herein, and may have a membrane different from that described herein, or may have no membrane at all. Because this subject matter is not limited to any one design or manufacturing process, it is likely and indeed expected that other statistically significant associations may exist for different designs and processes. Those skilled in the art will readily recognize that this subject matter is not limited to using only the size of the sensing area and / or the size of the membrane to determine individualized calibration information.

[0382] Furthermore, the models used in the example embodiments herein can be continuously refined to capture variability not explained by the model. This is especially relevant when in vivo or in vitro sensors are tested in vitro and their predicted in vitro sensing characteristics are determined (e.g., SC). MD When ), the remaining sensing characteristics can be calculated. In some embodiments, the remaining sensing characteristics can be determined according to (5):

[0383] SC R = (actual in vitro SC - SC) MD )+ Batch-grade in vitro SC

[0384] Here, the batch-level in vitro sensing characteristic (SC) can be a central tendency and can be a subset of the baseline, such as the baseline sensing characteristic SC. B As previously mentioned, the sensing characteristic being evaluated can be sensitivity or one aspect thereof (e.g., slope or intercept). Residual sensing characteristics examine the differences between the sensing characteristics observed from the model and the predicted sensing characteristics, and reveal the level of variability in the model that cannot be explained by manufacturing parameters. These differences can be assessed as the variability of batch-level in vitro sensing characteristics, and thus indicate how much unexplained variation exists in the model.

[0385] While many embodiments have been described for sensors with biochemical properties, these embodiments can also be applied to sensors with other physiological properties. Similarly, although many embodiments have been described for identifying or utilizing calibration information, these embodiments can also be applied to identifying or utilizing other types of information characterizing medical devices.

[0386] Example embodiments of sensor substrate surface modification

[0387] This document also describes embodiments involving surface modification of a sensor substrate to aid in the positioning of a sensing element (or a portion thereof) on the sensor surface. While not limited thereto, these embodiments are particularly useful when a liquid is applied to the sensor surface to form a sensing element. Electromagnetic radiation and / or mechanical forces can be applied to the surface to modify a specific area or location. This modified area affects the dispersion or aggregation of the liquid on the surface. When used in the manufacture of sensors, this technique can allow for more accurate and precise dimensions (e.g., area and / or depth) and positioning of the sensing elements produced during the manufacturing process. It also reduces the variability in the size and position of each sensing element compared to one or more other sensing elements on the same sensor and / or sensing elements of other sensors. This, in turn, can lead to a reduction in the variation in sensitivity between sensors, and thus provide users with more accurate, precise, and consistent analyte measurements.

[0388] Figures 32A to 32F This is a schematic diagram illustrating various example embodiments of a portion of a sensor substrate 3202 at different stages during the manufacturing of the sensing element. The substrate 3202 may be, for example, in reference... Figure 5A The described embodiment of sensor 500 is inserted at the tip 530, or may be part of any other embodiment of the in vivo and in vitro sensors described herein (e.g., see reference ). Figure 4 , Figure 5B , Figures 6 to 10C , Figures 15A to 17 as well as Figures 21A to 25B (Described embodiments).

[0389] A liquid or liquid reagent is applied to a substrate to form a sensing element. This liquid reagent may have electrochemical properties that detect or aid in the detection of an analyte (e.g., glucose) and may be referred to as an electrochemical reagent. The electrochemical reagent may be a solution, such as water-based or others. Embodiments of surface modification techniques may also be used in conjunction with other reagents, such as reagents for forming sensor films, treatment agents, additives, secondary electrochemical reagents, fixatives (e.g., crosslinking agents), or other reagents. Figure 32A The substrate 3202 before modification is shown. The substrate 3202 can be any part of the sensor where the sensing element needs to be placed, such as a substrate, a coating or layer on the substrate, electrodes, etc.

[0390] Figure 32BThe substrate 3202 is shown after region 3204 has been modified by applying electromagnetic radiation. The application of electromagnetic radiation can cause a change in the visible appearance of the substrate 3202, although this is not always the case. In this example, region 3204 has an annular shape formed by an inner boundary 3205 and an outer boundary 3206, which in this embodiment are concentric circles separated by a distance 3207. Other shapes may also be used (as further described below). The inner boundary 3205 defines an unmodified interior 3208 of region 3204, which is the target area for placing a sensing element. The area of ​​substrate 3202 extending beyond the outer boundary 3206 is also unmodified.

[0391] The application of electromagnetic radiation modifies the surface properties of the substrate in region 3204 compared to adjacent regions not exposed to electromagnetic radiation. Surface properties can affect liquid flowability in various ways. For example, modified surface properties can be such that liquid is attracted to the modified region even when it is not in direct contact with it (e.g., liquid on the surface but not in contact with the modified region can move toward the modified region). Such modified surface properties can also induce or increase attraction between the liquid and the modified region in direct contact compared to the unmodified region (e.g., hydrophilic properties, which facilitate liquid diffusion on the modified region). Although modified and unmodified surface features cause liquid to move toward the modified region, the liquid may only advance to the boundary of the modified region without moving along the modified region itself (e.g., see [reference needed]). Figure 32D If the magnitude of the surface properties increases, for example by applying relatively high power (an example of one of the various factors that can control the properties), then in such an embodiment, the liquid can move toward and across the modified region (e.g., see...). Figure 32E ).

[0392] In other examples, the modified surface properties can be such that the liquid is repelled by the modified region even when the liquid is not in direct contact with it (e.g., a liquid placed in a location not in contact with the modified region can be kept away from the modified region; see example...). Figure 32F Compared to unmodified regions, this property can also cause or increase repulsion (or reduce attraction) between the liquid and the modified region when in direct contact (e.g., hydrophobic properties that cause liquid beading or hinder liquid diffusion on the modified region). Furthermore, combinations of these techniques can be used. For example, multiple modified regions with opposite properties can be created to allow liquid to move from a first modified region to a second modified region (which also serves as the target region).

[0393] Figure 32CThe substrate 3202 is shown at the instant after liquid 3209 is applied. Here, liquid 3209 has been applied to a region smaller than the area defined by the inner boundary 3205 within region 3204. The shape of the liquid applied at this time can be irregular and off-center. Figure 32D The diagram shows the substrate 3202 after liquid 3209 has been dispersed on its surface. In this embodiment, modification of region 3204 attracts liquid 3209, causing it to disperse or diffuse throughout the unmodified interior 3208 until dispersion stops at the interior boundary 3205. The boundary of the dispersed liquid 3209 is typically aligned with the interior boundary 3205. The liquid 3209 then dries, forming a relatively uniform sensing element on the interior region 3208 of the sensor.

[0394] Figure 32E It shows that when applying such Figure 32C Another exemplary embodiment of the substrate 3202 following the liquid 3209 is shown. In this embodiment, the modification of region 3204 attracts the liquid 3209 and causes the liquid 3209 to diffuse throughout the entire interior 3208 of region 3204 (e.g., Figure 32D (As shown), but also extends through the inner boundary 3205 to the outer boundary 3206, where the dispersion stops. The boundary of the dispersed liquid 3209 is generally aligned with the outer boundary 3206. The liquid 3209 then dries, forming a relatively uniform sensing element on the inner region 3208 and the modified region 3204.

[0395] Figure 32F It shows that when applying such Figure 32C Another exemplary embodiment of the substrate 3202 following the liquid 3209 is shown. In this embodiment, the modification of region 3204 repels the liquid 3209, causing the liquid 3209 to move to the center of the interior 3208, where it forms beads or accumulates. In this embodiment, the target region is the area where the liquid 3209 is present, which is close to the modified region 3204, but neither on nor adjacent to (i.e., bordering) the modified region 3204. The liquid 3209 then dries, and a sensing element is formed in this central region.

[0396] The type of electromagnetic radiation used for surface modification can vary, as can the surface composition itself. Figure 33A and Figure 33B The photograph illustrates an example embodiment of substrate 3202, which has a series of annular surface modifications 3204-1, 3204-2, and 3204-3 formed by applying laser radiation. Various frequencies of laser radiation, such as ultraviolet, visible, and infrared light, can be used to perform the surface modification. Figure 33AThis is a photograph of laser modification performed on an empty polyethylene terephthalate (PET) substrate 3202. Figure 33B This is a photograph of the laser modification of carbon-printed PET substrate 3202, where the outline of the central region 3204-2 has been annotated for easier observation. Substrates such as ultraviolet (UV)-curable dielectrics (and others) can also be used.

[0397] exist Figures 33A to 33B In both examples, surface modification of an annular region 3204 is performed by guiding a laser beam onto a substrate through five adjacent circles of progressively increasing diameter. Each adjacent circle is generated by pulsed laser light at discrete points arranged in a circular pattern, although adjacent circles (or the entire annular region itself) may or may not be generated by cont...

Claims

1. An analyte monitoring system, comprising: Sensor control device, including: In vivo analyte sensors; and Electronic devices communicatively coupled to the in vivo analyte sensor, the electronic devices including non-transitory memory, wherein individualized calibration information is stored in the memory, wherein the individualized calibration information is based on manufacturing parameters measured by the in vivo analyte sensor and is specific to the in vivo sensor. The manufacturing parameter being measured is the size of the sensing region of the in vivo analyte sensor, wherein the sensing region includes a sensing element located in a well of the sensor substrate and / or located on or adjacent to a modified region of the sensor substrate, the modified region having liquid migration characteristics different from those of the adjacent region of the sensor substrate.

2. The analyte monitoring system according to claim 1, wherein, The electronic device further includes a wireless communication circuit and a processing circuit, wherein the non-transitory memory has a plurality of instructions stored thereon, which, when executed by the processing circuit, cause the processing circuit to: The analyte level is determined based on raw data measured by the in vivo analyte sensor and the individualized calibration information; and The determined analyte level is output to a wireless communication circuit for transmission.

3. The analyte monitoring system according to claim 1, wherein, The electronic device further includes wireless communication circuitry and processing circuitry, wherein the non-transitory memory includes a plurality of instructions stored thereon, which, when executed by the processing circuitry, cause the processing circuitry to: The individualized calibration information is output to a wireless communication circuit for transmission; and The raw analyte data collected by the in vivo analyte sensor is output to the wireless communication circuit for transmission.

4. The analyte monitoring system according to claim 1, wherein, The sensor control device has a service life and can be used within that service life without user calibration.

5. The analyte monitoring system according to claim 1, wherein, The sensor control device has a service life and can be used within that service life without user calibration or system calibration.

6. The analyte monitoring system according to claim 1, further comprising: A reader device includes processing circuitry, wireless communication circuitry, and a non-transitory memory containing a plurality of instructions, which, when executed by the processing circuitry, cause the processing circuitry to determine an analyte level based on raw data measured by the analyte sensor and individualized calibration information received from the sensor control device, the raw analyte data, and individualized communication information.

7. A method for monitoring an analyte, the method comprising: The raw analyte data collected using the analyte sensor is processed using individualized calibration information to determine the user's analyte level. This individualized calibration information is based on and specific to the analyte sensor and is measured manufacturing parameters of the analyte sensor. The measured manufacturing parameters are the dimensions of the sensing region of the analyte sensor, which includes a sensing element located in a well of the sensor substrate and / or on or adjacent to a modified region of the sensor substrate, the modified region having liquid migration characteristics different from those of the adjacent region of the sensor substrate.

8. The method according to claim 7, wherein, The analyte sensor is an in vivo analyte sensor, which is a component of a sensor control device. The sensor control device further includes a processing circuit, wherein the processing circuit of the sensor control device processes the raw analyte data using individualized calibration information to determine the user's analyte level.

9. The method according to claim 8, further comprising: The individualized calibration information is wirelessly transmitted to the reader device; as well as The collected raw analyte data is wirelessly transmitted to the reader device.

10. The method according to claim 9, wherein, The reader device includes processing circuitry, wherein the processing circuitry of the reader device processes the raw analyte data using individualized calibration information to determine the user's analyte level.

11. The method according to claim 8, wherein, The in vivo analyte sensor has a lifespan, and the method further includes using the in vivo analyte sensor during the lifespan without performing user calibration.

12. The method according to claim 8, wherein, The in vivo analyte sensor has a lifespan, and the method further includes using the in vivo analyte sensor during the lifespan without performing user calibration and without performing system calibration.

13. The method according to claim 7, wherein, The analyte sensor is an in vitro analyte sensor.

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