Analytical sensor, sharp part for delivering therapeutic agent in extremely close proximity to the analytical sensor, and method thereof.

Abstract

The present disclosure provides therapeutic compositions and methods for delivering therapeutic agents in close proximity to an analyte sensor. In certain embodiments, the present disclosure provides an analyte sensor comprising one or more therapeutic agents, e.g., a covalently attached therapeutic agent. In certain embodiments, the present disclosure further provides therapeutic release compositions and methods for delivering such therapeutic release compositions.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 132,737, filed December 31, 2020, the entirety of which is incorporated herein by reference. The subject matter described herein relates to compositions and methods for delivering therapeutic agents in extremely close proximity to implanted analyte sensors. [Background technology]

[0002] Because deviations from normal analyte levels may indicate a physiological condition, detecting various analytes within an individual can be important for monitoring their health. For example, monitoring glucose levels allows individuals with diabetes to take appropriate corrective measures, such as administering medication or consuming certain foods or beverages, to avoid serious physiological harm. Other analytes may be desirable to monitor other physiological conditions. In certain cases, particularly when a person suffers from a comorbidity that causes simultaneous dysregulation of two or more analytes in combination, it may be desirable to monitor two or more analytes to monitor multiple physiological conditions. Analyte monitoring in individuals can be performed periodically or continuously over a set period. Periodic analyte monitoring can be performed by collecting bodily fluid samples, such as blood or urine, at set time intervals and analyzing them ex vivo. Periodic ex vivo analyte monitoring may be sufficient to determine the physiological state of many individuals. However, ex vivo analyte monitoring can be inconvenient or painful in some cases. Furthermore, if analyte measurements are not taken at the appropriate time, there is no way to recover the lost data. Continuous analyte monitoring can be performed using one or more sensors that remain at least partially implanted in the individual's tissue, such as in the skin, subcutaneously, or intravenously, so that analysis can be performed in vivo. The implanted sensors can collect analyte data on demand, on a set schedule, or continuously, depending on the individual's specific health needs and / or previously measured analyte levels. Analyte monitoring with in vivo implanted sensors may be a more desirable approach for individuals with severe analyte dysregulation and / or rapid fluctuations in analyte levels, but it may be equally beneficial for other individuals.

[0003] However, implantable sensors may have a short lifespan when implanted in vivo. For example, the loss of in vivo sensor function observed in implantable sensors is likely to be largely a result of certain responses occurring in the surrounding tissue, including immune responses, inflammation, fibrosis, and vascular regression. These tissue reactions may result from tissue trauma caused by the insertion of the sensor into the skin, or from tissue reacting to the sensor as a foreign body. While the tissue response at the sensor implantation site is histopathologically similar to other forms of tissue inflammation, the ability of anti-inflammatory agents (e.g., glucocorticoids and nonsteroidal anti-inflammatory drugs) to directly suppress sensor-induced tissue trauma is limited. Therefore, there is a need in the art to develop compositions of anti-inflammatory agents and methods for delivering such therapeutic compositions near analyte sensors. [Overview of the project]

[0004] The objectives and merits of the disclosed subject matter are set forth in the following description and will become apparent from the following description, as well as will be known by practicing the disclosed subject matter. Additional merits of the disclosed subject matter will be realized and achieved in the written description and claims of this specification, and by the devices specifically indicated in the accompanying drawings. To achieve these and other advantages, the subject matter of the disclosure includes an analytic sensor comprising a therapeutic agent, as embodied and extensively described in accordance with the objectives of the subject matter of the disclosure. For example, but not limited to, the analytic sensor of the disclosure comprises (i) a sensor tail comprising at least a first working electrode; (ii) an active region disposed on the surface of the first working electrode for detecting an analytic agent; (iii) a mass transport limiting membrane permeable to the analytic agent, overcoating at least the active region; and (iv) a therapeutic agent. In certain embodiments, the analytic agent is glucose. In certain embodiments, the sensor tail may further comprise a counter electrode / reference electrode.

[0005] In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent may be one or more of triamsilolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, or derivatives or salts thereof. In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt thereof. In certain embodiments, a derivative of dexamethasone is dexamethasone acetate. In certain embodiments, a derivative of dexamethasone is dexamethasone sodium phosphate. In certain embodiments, the analyte sensor comprises a polymer composition containing a therapeutic agent and at least one polymer. In certain embodiments, the therapeutic agent is covalently bonded to the polymer. In certain embodiments, the therapeutic agent is covalently bonded to the polymer via hydrolyzable bonds, such as ester bonds, amide bonds, or hydrazone-based bonds. In certain embodiments, the therapeutic agent is not covalently bonded to the polymer. In certain embodiments, the polymer may be a polyvinylpyridine-based polymer, polyvinylimidazole, polyacrylate, polyurethane, polyether urethane, silicone or derivative, or a combination thereof. In certain embodiments, the polymer may be polyvinylpyridine, a copolymer of vinylpyridine and styrene, or a derivative thereof. In certain embodiments, the polymer may include a block polymer.

[0006] In a particular embodiment, the polymer composition is placed on the counter electrode / reference electrode. In certain embodiments, the therapeutic agent is covalently bonded to the polymer of the substance transport restriction membrane. This disclosure further provides a method for delivering a therapeutic agent in very close proximity to an analyte sensor at an in vivo site. In certain embodiments, this method may include providing an analyte sensor as disclosed herein and implanting the analyte sensor at an in vivo site. In certain embodiments, a method for delivering a therapeutic agent in close proximity to an analyte sensor at an in vivo site may include the steps of (i) providing a sharp portion containing an analyte sensor and a therapeutic release composition comprising the therapeutic agent; (ii) penetrating a target tissue with the sharp portion; (iii) inserting the therapeutic release composition and the analyte sensor into the target tissue; and (iv) withdrawing the sharp portion from the target tissue. In certain embodiments, the analyte sensor is located within a channel of the sharp portion, and the therapeutic release composition is located distal to the analyte sensor within the channel of the sharp portion.

[0007] This disclosure further provides a sharp part for delivering a therapeutic release composition, for example, a pre-loaded sharp part. In certain embodiments, the sharp part includes an analyte sensor and a therapeutic release composition. In certain embodiments, the analyte sensor is located within a channel of the sharp part, and the therapeutic release composition is located distal to the analyte sensor within the channel of the sharp part. In certain embodiments, the therapeutic agent present in the therapeutic release composition is an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent may be triamsilolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, or derivatives or salts thereof. In certain embodiments, the therapeutic release composition may contain two or more therapeutic agents. In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt thereof. In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt thereof. In certain embodiments, a derivative of dexamethasone is dexamethasone acetate. In certain embodiments, a derivative of dexamethasone is dexamethasone sodium phosphate.

[0008] In certain embodiments, the therapeutic release composition further comprises a polymer. In certain embodiments, the polymer is a bioabsorbable polymer and / or a biodegradable polymer. In certain embodiments, the polymer contains, for example, one or more hydrolyzable bonds in its main chain. Non-limiting examples of such polymers include polyethylene glycol-based polymers. In a particular embodiment, the analyte sensor is configured to detect glucose. [Brief explanation of the drawing]

[0009] The following figures are included to illustrate certain aspects of the Disclosure and should not be considered exclusive embodiments. The disclosed subject matter can be substantially modified, altered, combined, and made equivalent in form and function without departing from the scope of the Disclosure. [Figure 1A] This is a system overview of the sensor applicator, reader device, monitoring system, network, and remote system. [Figure 1B] This diagram illustrates the operating environment of an exemplary analyte monitoring system for use with the technology described herein. [Figure 2A] This is a block diagram illustrating an exemplary embodiment of a reader device. [Figure 2B] A block diagram shows an exemplary data receiving device for communicating with a sensor, according to an exemplary embodiment of the disclosed subject matter. [Figure 2C-2D] This is a block diagram illustrating an exemplary embodiment of a sensor control device. [Figure 2E] A block diagram showing an exemplary analyte sensor according to an exemplary embodiment of the disclosed subject. [Figure 3A] This is a close perspective view showing an exemplary embodiment in which the user prepares the assembly tray. [Figure 3B] This is a side view illustrating an exemplary embodiment in which a user prepares an applicator device for assembly. [Figure 3C] This is a close perspective view showing an exemplary embodiment in which a user inserts an applicator device into a tray during assembly. [Figure 3D] This is a close perspective view showing an exemplary embodiment in which a user removes the applicator device from the tray during assembly. [Figure 3E] This is a proximal perspective view showing an exemplary embodiment of a patient to whom a sensor is applied using an applicator device. [Figure 3F] This is a proximal perspective view showing an exemplary embodiment of a patient with the applied sensor and the applicator device used. [Figure 4A]A side view showing an exemplary embodiment of an applicator device coupled to a cap. [Figure 4B] A side perspective view showing an exemplary embodiment of a decoupled applicator device and cap. [Figure 4C] A perspective view showing an exemplary embodiment of a distal end of an applicator device and an electronic device housing. [Figure 4D] A top perspective view of an exemplary applicator device according to the disclosed subject matter. [Figure 4E] A bottom perspective view of the applicator device of FIG. 4D. [Figure 4F] An exploded view of the applicator device of FIG. 4D. [Figure 4G] A side cross-sectional view of the applicator device of FIG. 4D. [Figure 5] A proximal perspective view showing an exemplary embodiment of a tray with a sterilization lid attached [Figure 6A] A proximal perspective cross-sectional view showing an exemplary embodiment of a tray with a sensor delivery component. [Figure 6B] A proximal perspective view showing a sensor delivery component. [Figures 7A-7B] Isometric exploded top and bottom views, respectively, of an exemplary sensor control device. [Figures 8A-8C] An assembly and cross-sectional view of a body-worn device including an integral connector for sensor assembly. [Figure 9A-9B] Side and side cross-sectional views, respectively, of an exemplary embodiment of the sensor applicator of FIG. 1A with the cap of FIG. 2C attached. [Figure 10A-10B] Isometric and side views, respectively, of another exemplary sensor control device. [Figure 11A-11C] A step-by-step cross-sectional side view showing the assembly of a sensor applicator with the sensor control device of FIGS. 10A - 10B. [Figure 12A-12C] A step-by-step cross-sectional side view showing the assembly and disassembly of an exemplary embodiment of a sensor applicator with the sensor control device of FIGS. 10A - 10B. [Figures 13A-13F] A cross-sectional view is shown illustrating an exemplary embodiment of the applicator during the deployment phase. [Figure 14] This graph shows an example of the in vitro sensitivity of an analyte sensor. [Figure 15] This figure shows an example of exemplary operating states of a sensor according to an exemplary embodiment of the disclosed subject matter. [Figure 16] This figure shows exemplary operation and data flow for wireless programming of a sensor according to the disclosed subject. [Figure 17] This figure shows an example of a data flow for securely exchanging data between two devices based on the disclosed subject. [Figures 18A-18C] A cross-sectional view of an analyte sensor containing a single active region is shown. [Figures 19A-19C] A cross-sectional view of the analyte sensor, including two active regions, is shown. [Figure 20] A cross-sectional view of the analyte sensor, including two active regions, is shown. [Figure 21A-21C] A perspective view of an analyte sensor containing two active regions on separate working electrodes is shown. [Figure 22A] The NMR spectrum of compound intermediate 17 is provided. [Figure 22B] The NMR spectrum of compound 18 is provided. [Figure 22C] The HPLC analysis of compound 18 is provided. [Figure 22D] An exemplary partition of compound 18 is shown. [Figure 23A] An exemplary trace of a glucose sensor showing LSA is shown. [Figure 23B] A typical schematic diagram of the counter electrode of the sensor tail, which has a dexamethasone acetate (DEXA) / TIMB non-conjugate polymer matrix placed on the counter electrode, is shown. [Figure 23C] A typical schematic sensor tail of an analyte sensor, including a counter electrode with a DEXA / TIMB non-conjugate polymer matrix positioned on the counter electrode, is shown. [Figure 24]The release profile of the DEXA / TIMB non-conjugate polymer matrix is ​​shown. [Figure 25] This shows the sensitivity of a glucose sensor including a counter electrode coated with a DEXA / TIMB non-conjugate polymer matrix. [Figures 26A-26C] Exemplary traces of glucose sensors, including counter electrodes coated with or uncoated with a DEXA / TIMB non-conjugate polymer matrix, are shown. [Figure 27] This provides an exemplary trace of a glucose sensor exhibiting LSA, featuring a counter electrode coated with a DEXA / TIMB non-conjugate polymer matrix. [Figures 28A-28B] A graph is provided showing the LSA of a control sensor and a sensor including a counter electrode coated with a DEXA / TIMB non-conjugate polymer matrix. [Figures 29A-29B] A graph is provided showing the ESA of a control sensor and a sensor including a counter electrode coated with a DEXA / TIMB non-conjugate polymer matrix. [Figures 30A-30B] Exemplary traces of glucose sensors, including counter electrodes coated with or uncoated with a DEXA / TIMB non-conjugate polymer matrix, are shown. [Figure 31] This provides an exemplary trace of a glucose sensor exhibiting LSA, featuring a counter electrode coated with a DEXA / TIMB non-conjugate polymer matrix. [Figure 32] A graph is provided showing the LSA of a control sensor and a sensor including a counter electrode coated with a DEXA / TIMB non-conjugate polymer matrix. [Figure 33] A graph is provided showing the LSA of a control sensor and a sensor including a counter electrode coated with a DEXA / TIMB non-conjugate polymer matrix. [Figure 34]This provides a graph showing the hydrolysis rate from dexamethasone acetate (DEXA) to dexamethasone in a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 35] The release profiles of dexamethasone in a DEXA / 10Q5 non-conjugated polymer matrix are shown compared to those of dexamethasone in a DEXA / TIMB non-conjugated polymer matrix. [Figure 36] This provides an exemplary strategy for distributing a DEXA / 10Q5 non-conjugate polymer matrix onto the counter electrode of the sensor tail. [Figure 37] This shows the in vitro kinetic analysis of dexamethasone in a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 38] A graph is provided showing the LSA of a control sensor and a sensor including a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 39A-39B] A graph is provided showing the ESA of a control sensor and a sensor including a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 40] A graph is provided showing the LSA of a control sensor and a sensor including a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 41A-41B] Exemplary traces of glucose sensors, including counter electrodes coated with or uncoated with a DEXA / 10Q5 non-conjugate polymer matrix, are shown. [Figures 41C-41E] This provides an exemplary trace of a glucose sensor exhibiting LSA, featuring a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 42] A graph is provided showing the LSA of a control sensor and a sensor including a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 43]A graph is provided showing the MRD of the sensor, including a control sensor and a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 44] A graph is provided showing the MRD of the sensor, including a control sensor and a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 45] A graph is provided showing the MRD of the sensor, including a control sensor and a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 46] A graph is provided showing the MRD of the sensor, including a control sensor and a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 47] A graph is provided showing the ESA of a control sensor and a sensor including a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix. [Figure 48] The present invention provides a graph showing the LSA of a control sensor and a sensor including a counter electrode, coated with a DEXA / 10Q5 non-conjugate polymer matrix, when inserted into the arm of a subject. [Figure 49] The present invention provides a graph showing the LSA of a sensor including a control sensor and a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix, which is inserted into the arm or abdomen of a subject. [Figure 50] This provides a comparison of the reduction in LSA of a control sensor and a sensor including a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix, both inserted into the abdomen of a subject. [Figures 51A-51B] A graph is provided showing the MRD of a sensor, including a control sensor and a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix, inserted into the arm (Figure 51A) or abdomen (Figure 51B). [Figure 51C] A graph showing the MRD of a control sensor inserted into the arm or abdomen is provided. [Figure 51D]The present invention provides a graph showing the MRD of a sensor, which includes a control sensor and a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix, inserted into the arm or abdomen. [Figure 52] The present invention provides a graph showing the LSA of a sensor including a control sensor and a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix, when inserted into the arm of a subject. [Figure 53] This provides a comparison of the reduction in LSA of sensors, including a control sensor and a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix, both inserted into the arm of a subject. [Figure 54] A graph is provided showing the ESA of a sensor, including a control sensor and a counter electrode coated with a DEXA / 10Q5 non-conjugate polymer matrix, inserted into the arm or abdomen. [Figure 55] This provides a representative image of the analyte sensor tail, including the counter electrode to which the PVP-dexamethasone polymer conjugate is distributed. [Figure 56] This shows the in vitro kinetic analysis of dexamethasone from PVP-dexamethasone polymer conjugates. [Figure 57] This shows the in vitro kinetic analysis of dexamethasone from a PVP-dexamethasone polymer conjugate coated with a membrane. [Figure 58] This paper compares the in vitro release dynamics of three types of sensors (DEX-1: DEXA / TIMB non-conjugate polymer matrix; DEX-2: DEXA / 10Q5 non-conjugate polymer matrix; and DEX-3: PVP-dexamethasone polymer conjugate). [Figure 59] An exemplary trace of a glucose sensor, including a counter electrode coated with or uncoated with a PVP-dexamethasone polymer conjugate, is shown. [Figure 60]The present invention provides a graph showing the LSA of a sensor including a control sensor and a counter electrode coated with a PVP-dexamethasone polymer conjugate, which is inserted into the arm or abdomen of a subject. [Figure 61] This provides a comparison of the reduction in LSA of a control sensor and a sensor including a counter electrode coated with a PVP-dexamethasone polymer conjugate, both inserted into the abdomen or arm of a subject. [Figures 62A-62B] A graph is provided showing the MRD of a sensor, including a control sensor and a counter electrode coated with a PVP-dexamethasone polymer conjugate, inserted into the arm (Figure 62A) or abdomen (Figure 62B). [Figures 63A-63B] A cross-sectional view of the sharp end is shown, which has a channel for loading a therapeutic release composition in front of the analyte sensor at the distal end of the sharp end. [Modes for carrying out the invention]

[0010] As described herein, the implantation of an analyte sensor may induce several physiological responses that could adversely affect the sensor's function. For example, inflammation or immune responses at the site of tissue injury induced by the analyte sensor and its implantation may lead to loss of sensor function and sensitivity in vivo.

[0011] To address the aforementioned needs, this disclosure provides an analytic sensor comprising a therapeutic agent incorporated into the analytic sensor to treat the tissue surrounding the implanted analytic sensor. For example, but not limited to, this disclosure provides an analytic sensor comprising a therapeutic agent covalently bonded to a polymer matrix within the analytic sensor, such as an anti-inflammatory agent. In certain embodiments, the therapeutic agent may be covalently bonded to the polymer matrix via hydrolyzable bonds, thereby enabling sustained release of the therapeutic agent when the analytic sensor is implanted in vivo. Alternatively or additionally, the therapeutic agent may be incorporated into the polymer matrix without forming covalent bonds. In certain embodiments, the therapeutic agent may be covalently bonded to the polymer matrix via hydrolyzable bonds, and the therapeutic agent may also be incorporated into the polymer matrix without forming covalent bonds. Alternatively or additionally, this disclosure provides a therapeutic composition that can be placed near the analytic sensor in vivo, thereby enabling sustained release of the therapeutic agent over a long period of time.

[0012] In certain embodiments, sustained release of a therapeutic agent, such as an anti-inflammatory agent, in close proximity to the analyte sensor can result in the prevention and / or reduction of inflammation or immune responses in the tissue surrounding the implantation site. For example, but not limited to, the lifespan of the implanted analyte sensor can be extended by preventing and / or reducing inflammation in the tissue surrounding the implantation site. In certain embodiments, the lifespan of the implanted analyte sensor can be extended by preventing and / or reducing immune responses to the analyte sensor. For example, but not limited to, the lifespan of analyte sensors disclosed herein can be extended by about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, or about 20 days.

[0013] For clarity, but not limited to, a detailed description of the subject matter disclosed herein is divided into the following subsections: I. Definition; II. Analytical substance sensors; 1. General structure of an analyte sensor system; 2. Enzymes; 3. Polymer backbone; 4. Redox mediators; 5. Substance transport limiting membrane; and 6. Interference domain; III. Therapeutic compositions and their delivery; and IV. Exemplary Embodiments

[0014] I. Definition The terms used herein generally have the ordinary meanings in the art within the context of this disclosure and in the specific context in which each term is used. Certain terms are considered below or elsewhere in the specification to provide additional guidance to practitioners when describing the compositions and methods of this disclosure, as well as their preparation and use. As used herein, the use of the words "a" or "an," when used in combination with the term "including" in the claims and / or specification, may mean "one," but also coincide with the meanings of "one or more," "at least one," and "one or more than one."

[0015] The terms “comprise,” “include,” “having,” “has,” “can,” and “contain,” as used herein, and their variations thereof, are intended to be non-restrictive transitional phrases, terms, or words that do not preclude additional acts or structures. This disclosure also contemplates other embodiments that “comprising,” “consisting of,” and “consisting essentially of” the embodiments or elements presented herein, whether expressly described herein or otherwise.

[0016] The terms “approximately” or “about” mean within a range of tolerance for a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined, i.e., on the limitations of the measuring system. For example, “approximately” may mean within or greater than three standard deviations, according to convention in the art. Alternatively, “approximately” may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Or, particularly with respect to biological systems or processes, the term may mean within a number of orders of magnitude of the value, preferably up to five times, and more preferably up to two times.

[0017] As used herein, “analyte sensor” or “sensor” may refer to any device capable of receiving sensor information from a user, and for illustrative purposes only, but are not limited to, a body temperature sensor, a blood pressure sensor, a pulse or heart rate sensor, a glucose level sensor, an analyte sensor, a physical activity sensor, a movement sensor, or any other sensor for collecting physical or biological information. Analytes measured by an analyte sensor may include, but are not limited to, glutamate, glucose, ketones, lactate, oxygen, hemoglobin A1C, albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartate, asparagine, magnesium, pH, phosphorus, potassium, sodium, total protein, uric acid, and others.

[0018] As used herein, the term “biological fluid” refers to any body fluid or derivative of body fluid on which an analyte can be measured. Non-limiting examples of biological fluids include dermal fluid, interstitial fluid, plasma, blood, lymph, synovial fluid, cerebrospinal fluid, saliva, bronchoalveolar lavage fluid, amniotic fluid, sweat, and tears. In certain embodiments, the biological fluid is dermal fluid or interstitial fluid. In certain embodiments, the biological fluid is interstitial fluid. As used herein, the term “redox mediator” refers to an electron transfer agent for transporting electrons between an analyte or analyte reductase or analyte oxidase and an electrode, either directly or via one or more additional electron transfer agents. In certain embodiments, a redox mediator comprising a polymer backbone may also be referred to as a “redox polymer.”

[0019] As used herein, the term “reference electrode” may refer to either a reference electrode or an electrode that functions as both a reference electrode and a counter electrode. Similarly, as used herein, the term “counter electrode” may refer to both a counter electrode and a counter electrode that also functions as a reference electrode. In certain embodiments, the term “counter electrode / reference electrode” may refer to both a counter electrode and a counter electrode that also functions as a reference electrode. As used herein, the term "hydrolysis" refers to a chemical reaction in which a nucleophile, such as water, breaks one or more chemical bonds. As used herein, the term “hydrolyzable bond” refers to a chemical bond that undergoes hydrolysis in the presence of a nucleophile. Non-exclusive examples of hydrolyzable bonds include ester bonds and amide bonds. In certain embodiments, the nucleophile is water. For example, but not limited to, hydrolyzable bonds undergo hydrolysis in vivo in the presence of water. As used herein, the term “covalent bond” refers to a chemical bond that involves the sharing of electron pairs between atoms. Similarly, “covalent bond” refers to a chemical bond that involves the sharing of electron pairs between atoms. As used herein, the term "non-covalent bond" refers to a chemical interaction that does not involve the sharing of electrons, but rather involves a more dispersed change in intermolecular or intramolecular electromagnetic interactions.

[0020] As used herein, the term “reactive group” refers to a molecular functional group that can react with another compound to link at least a portion of the other compound to the molecule. Non-limiting examples of reactive groups include carboxyl groups, reactive ester groups, halogenated sulfonyl groups, sulfonic acid ester groups, isocyanate groups, isothiocyanate groups, epoxide groups, aziridine groups, halide groups, aldehyde groups, ketone groups, amine groups, acrylamide groups, thiol groups, acyl azide groups, halogenated acyl groups, hydrazine groups, hydroxylamine groups, halogenated alkyl groups, imidazole groups, pyridine groups, phenol groups, alkyl sulfonate groups, halotriazine groups, imide ester groups, maleimide groups, hydrazide groups, hydroxyl groups, and photoreactive azidoaryl groups. Activated esters used herein and understood in the art include, but are not limited to, esters of succinimidyl, benzotriazolyl, or aryl esters substituted with electron-withdrawing groups such as sulfo, nitro, cyano, or halo groups; or carboxylic acids activated by carbodiimide.

[0021] As used herein, the term "multicomponent membrane" refers to a membrane comprising two or more membrane polymers. As used herein, the term "single-component membrane" refers to a membrane comprising one type of membrane polymer. As used herein, the term "polyvinylpyridine polymer" refers to a polymer (e.g., copolymer) comprising polyvinylpyridine (e.g., poly(2-vinylpyridine) or poly(4-vinylpyridine)) or its derivatives.

[0022] II. Analytical Sensors 1. General structure of the analyte sensor system Before describing the subject matter of the present invention in detail, it should be understood that this disclosure is not limited to the specific embodiments described and may, of course, be modified. Furthermore, since the scope of this disclosure is limited only by the appended claims, it should be understood that the terminology used herein is intended solely to describe specific embodiments and is not intended to limit them. The publications discussed herein are provided solely for their disclosure prior to the filing date of this application. Nothing in this specification should be construed as acknowledging that this disclosure is not granted prior rights over such publications simply because they are prior disclosures. Furthermore, the dates of the publications provided may differ from the actual publication dates, which may need to be independently verified.

[0023] Generally, embodiments of this disclosure include systems, devices, and methods for using an analytic sensor insertion applicator for use with an in vivo analytic analytic monitoring system. The applicator may be provided to the user in a sterile package containing an electronic component housing for a sensor control device. According to some embodiments, a separate structure from the applicator, such as a container, may also be provided to the user as a sterile package containing a sensor module and a sharp part module. The user can connect the sensor module to the electronic component housing and the sharp part to the applicator by an assembly process involving insertion of the applicator into the container in a specified manner. In other embodiments, the applicator, sensor control device, sensor module, and sharp part module may be provided in a single package. The applicator can be used to position the sensor control device on the human body so that the sensor comes into contact with the wearer's bodily fluids. Embodiments provided herein are improvements to reduce the possibility of the sensor being improperly inserted or damaged or inducing adverse physiological responses. Other improvements and advantages are also provided. Various configurations of these devices will be described in detail by embodiments that are merely examples.

[0024] Furthermore, many embodiments include in vivo analyte sensors that are positioned, or structurally configured to allow, at least a portion of the sensor to be positioned within a user's body in order to acquire information about at least one analyte in the body. However, it should be noted that the embodiments disclosed herein can be used with in vivo analyte monitoring systems that incorporate in vitro capabilities, as well as with purely in vitro or ex vivo analyte monitoring systems, such as systems that are completely non-invasive.

[0025] Furthermore, for any embodiment of the methods disclosed herein, systems and devices capable of performing each of those embodiments are included within the scope of this disclosure. For example, embodiments of sensor control devices are disclosed, which may include one or more sensors, an analyte monitoring circuit (e.g., an analog circuit), a memory (e.g., for storing instructions), a power supply, a communication circuit, a transmitter, a receiver, a processor and / or controller (e.g., for executing instructions) capable of performing any method step or facilitating the performance of any method step. These embodiments of sensor control devices may be used to implement the steps performed by the sensor control device from any method described herein.

[0026] Furthermore, the systems and methods presented herein can be used to operate sensors used in analyte monitoring systems for any purpose involving the sensing of analytes over time, including but not limited to health, fitness, diet, research, information, or any other purpose involving the sensing of analytes over time. Where used herein, “analyte sensor” or “sensor” can refer to any device capable of receiving sensor information from a user, and for illustrative purposes only, but not limited to, a body temperature sensor, a blood pressure sensor, a pulse or heart rate sensor, a glucose level sensor, an analyte sensor, a physical activity sensor, a motion sensor, or any other sensor for collecting physical or biological information. In certain embodiments, the analyte sensor of this disclosure can further measure analytes including, but not limited to, glucose, ketones, lactate, oxygen, hemoglobin A1C, albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, lactate, magnesium, pH, phosphorus, potassium, sodium, total protein, uric acid, and the like.

[0027] As mentioned herein, several embodiments of systems, devices, and methods providing improved assembly and use of skin sensor insertion devices for use in in vivo analyte monitoring systems are described herein. In particular, some embodiments of the present disclosure are designed to improve sensor insertion methods with respect to in vivo analyte monitoring systems, in particular to prevent premature withdrawal of the insertion sharpener during the sensor insertion process. For example, some embodiments include a skin sensor insertion mechanism that increases the firing rate and delays the withdrawal of the sharpener. In other embodiments, the sharpener withdrawal mechanism can be activated by motion sensing so that the sharpener is not withdrawn until the user pulls the applicator away from the skin. Thus, to name some advantages, these embodiments can reduce the possibility of premature withdrawal of the insertion sharpener during the sensor insertion process; reduce the possibility of improper sensor insertion; and reduce the possibility of sensor damage during the sensor insertion process. Some embodiments of the present disclosure also provide improved insertion sharpener modules considering small skin sensors and relatively shallow insertion paths located in the dermis layer of the target. In addition, some embodiments of the present disclosure are designed to prevent undesirable axial and / or rotational movements of the applicator components during sensor insertion. Therefore, to name a few advantages, these embodiments can reduce the possibility of instability of the placed skin sensor, inflammation at the insertion site, damage to surrounding tissue, and rupture of capillaries that could lead to blood contamination of skin fluids. Furthermore, to mitigate inaccurate sensor readings that may be caused by trauma to the insertion site, some embodiments of the present disclosure can reduce the needle's tip depth penetration into the sensor tip during insertion.

[0028] However, before describing these aspects of the embodiments in detail, it is desirable to first describe, for example, examples of devices that may be present in an in vivo analyte monitoring system and examples of their operation, all of which can be used in conjunction with the embodiments described herein.

[0029] Various types of in vivo analyte monitoring systems exist. For example, a "continuous analyte monitoring" system (or "continuous glucose monitoring" system) can continuously transmit data from a sensor control device to a reading device automatically, for example, according to a schedule, without prompting. Another example is a "flash analyte monitoring" system (or "flash glucose monitoring" system, or simply a "flash" system) which can transfer data from a sensor control device in response to a scan or request for data by a reading device, for example, using a Near Field Communication (NFC) or Radio Frequency Identification (RFID) protocol. In vivo analyte monitoring systems can also operate without requiring fingerstick calibration. In vivo analyte monitoring systems can be distinguished from “in vitro” systems, which typically involve measuring devices with ports for receiving analyte test strips carrying the user’s bodily fluids, and which come into contact with and can analyze an extra vivo (or “ex vivo”) biological sample to determine the user’s blood analyte levels.

[0030] An in vivo monitoring system may include sensors that come into contact with the user's bodily fluids while in vivo and sense the levels of analytes contained therein. The sensors may be part of a sensor control device that resides on the user's body and includes electronic components and a power supply that enable and control the sensing of analytes. Sensor control devices and their variations may also be referred to, to some extent, as "sensor control units," "body-worn electronic component" devices or units, "body-worn" devices or units, or "sensor data communication" devices or units. In vivo monitoring systems may also include devices that receive analyte data sensed from sensor control devices, process that sensed analyte data, and / or display it to the user in any number of formats. These devices and their variations may be referred to, to some extent, as “handheld reading devices,” “reading devices” (or simply “readers”), “handheld electronic components” (or simply “handheld”), “portable data processing” devices or units, “data receivers,” “receiver” devices or units (or simply “receiver”), or “remote” devices or units. Other devices, such as personal computers, may also be used with or incorporated into in vivo and in vitro monitoring systems.

[0031] A. Exemplary in vivo analyte monitoring system Figure 1 is a conceptual diagram showing an exemplary embodiment of an analyte monitoring system 100, which includes a sensor applicator 150, a sensor control device 102, and a reader device 120. Here, the sensor applicator 150 can be used to deliver the sensor control device 102 to a monitoring location on the user's skin, where the sensor 104 is held in place for a period of time by an adhesive patch 105. The sensor control device 102 is further described in Figures 2B and 2C, and can communicate with the reader device 120 via a communication path or link 140 using wired or wireless, unidirectional or bidirectional, and encrypted or unencrypted techniques. Examples of wireless protocols include Bluetooth, Bluetooth Low Energy (BLE, BTLE, Bluetooth SMART, etc.), and Near Field Communication (NFC). The user can monitor applications installed in the memory of the reader device 120 using the display 122 and input 121, and the device battery can be charged using the power port 123. Further details regarding the reader device 120 are described below in relation to Figure 2A. According to a particular embodiment, the reader device 120 can constitute an output medium for viewing analyte concentrations and alarms or notifications determined by the sensor 104 or an associated processor, and can also allow one or more user inputs. The reader device 120 may be a multipurpose smartphone or a dedicated electronic reader device. Although only one reader device 120 is shown, in a particular example, there may be multiple reader devices 120.

[0032] The reader device 120 can communicate with the local computer system 170 via a communication path 141, which may be wired or wireless, one-way or two-way, and encrypted or unencrypted. The local computer system 170 may be one or more of the following: laptop, desktop, tablet, phablet, smartphone, set-top box, video game console, remote terminal, or other computing device, and the wireless communication may be one of many applicable wireless networking protocols, including Bluetooth, Bluetooth Low Energy (BTLE), and Wi-Fi. The local computer system 170 can communicate with the network 190 via a communication path 143, similar to how the reader device 120 can communicate with the network 190 via a communication path 142 using the wired or wireless technology described above. The network 190 may be one of many networks, such as private networks and public networks, local area networks, or wide area networks. The highly reliable computer system 180 may include a server, which may provide authentication services and secure data storage, and may communicate with the network 190 via a communication path 144 using wired or wireless technology. The local computer system 170 and / or the highly reliable computer system 180 may, according to certain embodiments, be accessible to individuals other than the primary user who are interested in the user's analysis level. The reader device 120 may include a display 122 and an optional input component 121. According to certain embodiments, the display 122 may include a touchscreen interface.

[0033] The sensor control device 102 includes a sensor housing 103 that can house the circuit configuration and power supply for operating the sensor 104. Optionally, the power supply and / or active circuit configuration can be omitted. A processor (not shown) can be communicatively connected to the sensor 104, and the processor is physically located within the sensor housing 103 or the reader device 120. According to a particular embodiment, the sensor 104 protrudes from the underside of the sensor housing 103, extends through an adhesive layer 105, and is adapted to adhere the sensor housing 103 to a tissue surface such as skin.

[0034] Figure 1B shows the operating environment of an analyte monitoring system 100a that can embody the technology described herein. The analyte monitoring system 100a may include a system of components designed to provide monitoring of parameters such as analyte levels in a human or animal body, or may provide other operations based on the configuration of various components. As embodied herein, the system may include a low-power analyte sensor 110, or simply a “sensor” worn by a user or attached to the body from which information is collected. As embodied herein, the analyte sensor 110 may be a sealed, disposable device having a predetermined effective service life (e.g., 1 day, 14 days, 30 days, etc.). The sensor 110 may be applied to the skin of a user’s body and remain adhered for the duration of the sensor’s service life, or may be designed to remain functional even after selective removal and reapplication. The low-power analyte monitoring system 100a may further include a data reading device 120 or a multipurpose data receiving device 130 configured as described herein to facilitate the acquisition and distribution of data, including analyte data from the analyte sensor 110.

[0035] As embodied herein, the analyte monitoring system 100a may be provided to a third party, for example via a remote application server 150 or an application storefront server 160, and may include software or firmware libraries or applications that are embedded in a multipurpose hardware device 130, for example, a mobile phone, tablet, personal computing device, or other similar computing device that can communicate with the analyte sensor 110 via a communication link. The multipurpose hardware may further include, but is not limited to, an implantable device having an implantable library configured to communicate with the analyte sensor 110, including an insulin pump or insulin pen. While illustrated embodiments of the analyte monitoring system 100a include only one of each illustrated device, this disclosure intends for the analyte monitoring system 100a to incorporate multiple of each of the multiple components that interact as a whole system. For example, but not limited to, as embodied herein, the data reading device 120 and / or multipurpose data receiving device 130 may include multiple of each. As embodied herein, multiple data receiving devices 130 may communicate directly with the sensor 110 as described herein. Additionally or alternatively, the data receiving device 130 may communicate with the secondary data receiving device 130 to provide the analyte data, or a visualization or analysis of the data, for secondary display to the user or other authorized party.

[0036] The sensor 104 in Figure 1A is adapted to be at least partially inserted into a target tissue, such as within the dermis or subcutaneous layer of the skin. The sensor 104 may include a sensor tail of sufficient length to be inserted to a desired depth within a given tissue. The sensor tail may include at least one working electrode. A counter electrode may be present in combination with at least one working electrode. Specific electrode configurations on the sensor tail are described in further detail below. Also, as described in further detail below, one or more mass transport limiting membranes may overcoat the active region.

[0037] In certain configurations, the sensor tail may include an active region for detecting an analyte. The active region may be configured to detect a specific analyte. In certain embodiments, the active region may be configured to detect two or more analytes. For example, but not limited to, analytes include glutamate, glucose, ketones, lactate, oxygen, hemoglobin A1C, albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, magnesium, pH, asparagine, aspartate, phosphorus, potassium, sodium, total protein, uric acid, and the like. In certain embodiments, analytes for detection using the disclosed analyte sensor include ketones, creatinine, glucose, alcohol, and lactate. In certain embodiments, the active region of the sensor of this disclosure is configured to detect glucose. In certain embodiments, the active region of the sensor of this disclosure is configured to detect lactate. In certain embodiments, the active region of the sensor of the disclosure is configured to detect ketones. In certain embodiments, the active region of the sensor of the disclosure is configured to detect creatinine. In certain embodiments, the active region of the sensor of the disclosure is configured to detect alcohol, such as ethanol. In certain embodiments, the active region of the sensor of the disclosure is configured to detect glutamate. In certain embodiments, the active region of the sensor of the disclosure is configured to detect aspartate. In certain embodiments, the active region of the sensor of the disclosure is configured to detect asparagine.

[0038] In certain embodiments of the present disclosure, one or more analytes can be monitored in any biological fluid of interest, such as dermal fluid, interstitial fluid, plasma, blood, lymph, synovial fluid, cerebrospinal fluid, saliva, bronchoalveolar lavage fluid, amniotic fluid, etc. In certain embodiments, the analyte sensor of the present disclosure can be adapted to assay dermal fluid or interstitial fluid in vivo to determine the concentration of one or more analytes. In certain embodiments, the biological fluid is interstitial fluid.

[0039] An introducer may be present temporarily to facilitate the introduction of the sensor 104 into the tissue. In certain exemplary embodiments, the introducer may include a needle or similar sharp part. As will be readily apparent to those skilled in the art, in alternative embodiments, other types of introducers may be present, such as a sheath or blade. More specifically, the needle or other introducer may be present temporarily near the sensor 104 before insertion into the tissue and then withdrawn. While the needle or other introducer is present, it can facilitate the insertion of the sensor 104 into the tissue by opening an access path for the sensor 104 to follow. For example, according to one or more embodiments, but not limited to these, the needle may facilitate penetration into the epidermis as an access path to the dermis, thereby enabling the implantation of the sensor 104. Since the needle or other introducer can be withdrawn after opening the access path, there is no risk of sharpness. In certain embodiments, a preferred needle may be solid or hollow, chamfered or unchamfered, and / or have a circular or non-circular cross-section. In certain specific embodiments, a suitable needle may be comparable to an acupuncture needle having a cross-sectional diameter of approximately 250 microns in terms of its cross-sectional diameter and / or tip design. However, as required for certain specific applications, a suitable needle may have a larger or smaller cross-sectional diameter.

[0040] In certain embodiments, the tip of the needle (while present) can be angled over the end of the sensor 104 so that the needle first penetrates the tissue and opens an access path for the sensor 104. In certain embodiments, the sensor 104 can be located within the lumen or groove of the needle, and the needle similarly opens an access path for the sensor 104. In either case, the needle is withdrawn after facilitating the insertion of the sensor.

[0041] B. Exemplary Reader Devices Figure 2A is a block diagram showing an exemplary embodiment of a reader device configured as a smartphone. Here, the reader device 120 may include a display 122, an input component 121, and a processing core 206 including a communication processor 222 coupled to memory 223 and an application processor 224 coupled to memory 225. It may also include a separate memory 230, an RF transceiver 228 with an antenna 229, and a power supply 226 with a power management module 238. Furthermore, it may include a multifunction transceiver 232 that can communicate via Wi-Fi, NFC, Bluetooth, BTLE, and GPS using an antenna 234. As will be understood by those skilled in the art, these components are electrically and communicatively coupled in a manner that creates a functional device.

[0042] C. Exemplary Data Receiving Device Architecture For illustrative purposes only, and not limiting, an exemplary embodiment of the data receiving device 120 used in the disclosed subject is shown in Figure 2B. The data receiving device 120 and the associated multipurpose data receiving device 130 include, and may include, components related to the analysis of the analyte sensor 110 and its operation. In certain embodiments, the data receiving device 120 and the multipurpose data receiving device 130 may include, or may include, components provided by a third party, and are not necessarily limited to including devices manufactured by the same manufacturer as the sensor 110.

[0043] As shown in Figure 2B, the data receiving device 120 includes a microcontroller 4010, memory 4020, and storage 4030, and includes an ASIC 4000 that is communicatively coupled to a communication module 4040. Power for the components of the data receiving device 120 can be supplied by a power module 4050, which may include a rechargeable battery, as embodied herein. The data receiving device 120 may further include a display 4070 to facilitate the review of analyte data received from the analyte sensor 110 or other devices (e.g., a user device 140 or a remote application server 150). The data receiving device 120 may include separate user interface components (e.g., physical keys, optical sensors, microphones, etc.).

[0044] The communication module 4040 may include a BLE module 4041 and an NFC module 4042. The data receiving device 120 can be configured to wirelessly connect with the analyte sensor 110, send commands to the analyte sensor 110, and receive data from the analyte sensor 110. As embodied herein, the data receiving device 120 can be configured to operate as an NFC scanner and BLE endpoint with respect to the analyte sensor 110 described herein, via a specific module of the communication module 4040 (e.g., BLE module 4042 or NFC module 4043). For example, the data receiving device 120 may use a first module of the communication module 4040 to issue commands to the analyte sensor 110 (e.g., a command to activate the sensor's data broadcast mode; a pairing command to identify the data receiving device 120), and use a second module of the communication module 4040 to receive data from and send data to the analyte sensor 110. The data receiving device 120 can be configured to communicate with the user device 140 via the universal serial bus (USB) module 4045 of the communication module 4040.

[0045] As another example, the communication module 4040 may include, for example, a cellular radio module 4044. The cellular radio module 4044 may include, but is not limited to, one or more radio transceivers for communication using a broadband cellular network, including third-generation (3G), fourth-generation (4G), and fifth-generation (5G) networks. Furthermore, the communication module 4040 of the data receiving device 120 may include a Wi-Fi radio module 4043 for communication using a wireless local area network according to one or more of the IEEE 802.11 standards (e.g., 802.11a, 802.11b, 802.11g, 802.11n (also known as Wi-Fi 4), 802.11ac (also known as Wi-Fi 5), 802.11ax (also known as Wi-Fi 6)). Using a cellular wireless module 4044 or a Wi-Fi wireless module 4043, the data receiving device 120 can communicate with a remote application server 150 to receive analyte data or provide updates or inputs received from a user (e.g., via one or more user interfaces). Although not shown, the communication module 5040 of the analyte sensor 120 may also include a cellular wireless module or a Wi-Fi wireless module.

[0046] As embodied herein, the onboard storage 4030 of the data receiving device 120 can store analytic data received from the analytic sensor 110. Furthermore, the data receiving device 120, the multipurpose data receiving device 130, or the user device 140 can be configured to communicate with a remote application server 150 via a wide area network. As embodied herein, the analytic sensor 110 can provide data to the data receiving device 120 or the multipurpose data receiving device 130. The data receiving device 120 can transmit the data to the user computing device 140. The user computing device 140 (or the multipurpose data receiving device 130) can then transmit the data to the remote application server 150 for processing and analysis.

[0047] As embodied herein, the data receiving device 120 may further include sensing hardware 4060 similar to, or an extension thereof, the sensing hardware 5060 of the analyte sensor 110. In certain embodiments, the data receiving device 120 may be configured to work in conjunction with the analyte sensor 110 and operate based on analyte data received from the analyte sensor 110. For example, if the analyte sensor 110 is a glucose sensor, the data receiving device 120 may be, or include, an insulin pump or an insulin injection pen. In conjunction, the compatible device 130 can adjust the user's insulin dosage based on the glucose value received from the analyte sensor.

[0048] D. Examples of sensor-controlled devices Figures 2C and 2D are block diagrams illustrating exemplary embodiments of the sensor control device 102, which comprises an analyte sensor 104 and sensor electronic components 160 (including an analyte monitoring circuit configuration), which can have most of the processing power for rendering final result data suitable for display to the user. In Figure 2C, a single semiconductor chip 161 is shown, which can be a custom application-specific integrated circuit (ASIC). Shown within the ASIC 161 is a specific higher-order functional unit including an analog front-end (AFE) 162, a power management (or control) circuit configuration 164, a processor 166, and a communication circuit configuration 168 (which can be implemented as a transmitter, receiver, transceiver, passive circuit, or otherwise, depending on the communication protocol). In this embodiment, both the AFE 162 and the processor 166 are used as the analyte monitoring circuit configuration, but in other embodiments, the analyte monitoring function can be performed by either circuit. The processor 166 may include one or more processors, microprocessors, controllers, and / or microcontrollers, each of which may be a discrete chip or distributed across (and as part of) a number of different chips.

[0049] Memory 163 is also included in the ASIC 161 and can be shared by various functional units present within the ASIC 161, or distributed among two or more of these units. Memory 163 may be a separate chip. Memory 163 can be volatile and / or non-volatile memory. In this embodiment, the ASIC 161 is connected to a power supply 170, which may be a coin cell battery. The AFE 162 interfaces with the in vivo analyte sensor 104, receives measurement data from it, and outputs the data in digital format to the processor 166, which then processes this data to obtain discrete and trend values ​​of glucose as the final result. This data can then be supplied to a communication circuit configuration 168 via the antenna 171 to send it to, for example, a reader device 120 (not shown), where minimal further processing by a resident software application is required to display the data.

[0050] Figure 2D is similar to Figure 2C, but includes two discrete semiconductor chips 162 and 174, which may be packaged together or separately. Here, the AFE 162 resides on the ASIC 161. The processor 166 is integrated on chip 174 together with a power management circuit configuration 164 and a communication circuit configuration 168. The AFE 162 includes memory 163, and chip 174 includes memory 165, which may be internally isolated or distributed. In one exemplary embodiment, the AFE 162 is combined with the power management circuit configuration 164 and the processor 166 on a single chip, while the communication circuit configuration 168 is on a separate chip. In another exemplary embodiment, both the AFE 162 and the communication circuit configuration 168 are on a single chip, while the processor 166 and the power management circuit configuration 164 are on separate chips. It should be noted that other combinations of chips are also possible, including three or more chips, each performing a separate function as described above, or sharing one or more functions for fail-safe redundancy.

[0051] For illustrative purposes only, and not limiting, an exemplary embodiment of the analyte sensor 110 used in the disclosed subject is shown in Figure 2E. Figure 2E shows a block diagram of the exemplary analyte sensor 110 according to an exemplary embodiment compatible with the security architecture and communication scheme described herein.

[0052] As embodied herein, the analyte sensor 110 may include an application-specific integrated circuit ("ASIC") 5000 communicably coupled to a communication module 5040. The ASIC 5000 may include a microcontroller core 5010, onboard memory 5020, and storage memory 5030. The storage memory 5030 may store data used in authentication and cryptographic security architectures. The storage memory 5030 may store programming instructions for the sensor 110. As embodied herein, a specific communication chipset (e.g., an NFC transceiver 5025) may be embedded within the ASIC 5000. The ASIC 5000 may receive power from a power module 5050, such as an onboard battery, or from NFC pulses. The storage memory 5030 of the ASIC 5000 may be programmed to contain information such as an identifier for the sensor 110 for identification and tracking purposes. The storage memory 5030 may also be programmed with configuration parameters or calibration parameters used by the sensor 110 and its various components. The storage memory 5030 may include rewritable memory or one-time programming (OTP) memory. The storage memory 5030 can be updated using the techniques described herein to extend the usefulness of the sensor 110.

[0053] As embodied herein, the communication module 5040 of the sensor 100 may be one or more modules supporting the analyte sensor 110 for communication with other devices of the analyte monitoring system 100, or may include such modules. For illustrative purposes only, and not limited to, an exemplary communication module 5040 may include a Bluetooth Low-Energy ("BLE") module 5041. As used throughout this disclosure, Bluetooth Low Energy ("BLE") refers to a short-range communication protocol optimized for easy pairing of Bluetooth devices for end users. The communication module 5040 can send and receive data and commands through interaction with a similarly functioning communication module of a data receiving device 120 or a user device 140. The communication module 5040 may include additional or alternative chipsets for use with similar short-range communication schemes such as personal area networks using the IEEE 802.15 protocol, the IEEE 802.11 protocol, or infrared communication using Infrared Data Association standards (IrDA). To perform that function, the sensor 100 may further include appropriate sensing hardware 5060 suitable for that function. As embodied herein, the sensing hardware 5060 may include an analyte sensor placed transcutaneously or subcutaneously in contact with the body fluid of interest. The analyte sensor can generate sensor data containing values ​​corresponding to the levels of one or more analytes in the body fluid.

[0054] E. Exemplary assembly process for sensor-controlled devices The components of the sensor control device 102 can be obtained by the user in multiple packages that require final assembly by the user before delivery to the appropriate user site. Figures 3A-3D show exemplary embodiments of the user assembly process for the sensor control device 102, which includes preparing separate components before linking them together in preparation for sensor delivery. Figures 3E-3F show exemplary embodiments of delivery of the sensor control device 102 to the appropriate user site by selecting the appropriate delivery site and applying the device 102 to that site.

[0055] Figure 3A is a proximal perspective view showing an exemplary embodiment of a user preparing a container 810 (which is configured here as a tray, although other packages may also be used) for the assembly process. The user can achieve this preparation by removing the lid 812 from the tray 810 to expose the platform 808, for example by peeling the non-adhesive portion of the lid 812 from the tray 810 and removing the adhesive portion of the lid 812. Removal of the lid 812 may be appropriate in various embodiments, as long as the platform 808 is adequately exposed within the tray 810. The lid 812 can then be set aside.

[0056] Figure 3B is a side view showing an exemplary embodiment in which a user prepares the applicator device 150 for assembly. The applicator device 150 can be supplied in a sterile package sealed by a cap 708. Preparation of the applicator device 150 may include removing the housing 702 from the cap 708 to expose the sheath 704 (Figure 3C). This can be achieved by unscrewing (or otherwise disconnecting) the cap 708 from the housing 702. The cap 708 can then be set aside.

[0057] Figure 3C is a proximal perspective view showing an exemplary embodiment in which a user inserts the applicator device 150 into the tray 810 during assembly. First, the user can insert the sheath 704 into the platform 808 in the tray 810 after aligning the housing orientation feature portion 1302 (or slot or recess) and the tray orientation feature portion 924 (contact portion or detent). Inserting the sheath 704 into the platform 808 temporarily unlocks the sheath 704 from the housing 702 and also temporarily unlocks the platform 808 from the tray 810. At this stage, removing the applicator device 150 from the tray 810 would return it to the same state as before the applicator device 150 was first inserted into the tray 810 (i.e., the process could be reversed or stopped at this point and then repeated without producing any results). The sheath 704 can maintain its position within the platform 808 relative to the housing 702 while the housing 702 advances distally and engages with the platform 808, causing the platform 808 to advance distally relative to the tray 810. This step unlocks the platform 808, causing it to fold within the tray 810. The sheath 704 can disengage by contacting a locking feature (not shown) within the tray 810, which unlocks the sheath 704 relative to the housing 702, preventing the sheath 704 from moving (relatively) while the housing 702 continues to advance distally towards the platform 808. At the end of the advancement of the housing 702 and the platform 808, the sheath 704 is permanently unlocked relative to the housing 702. Sharp parts and sensors (not shown) within the tray 810 can engage with electronic component housings (not shown) within the housing 702 at the end of the distal advancement of the housing 702. The operation and interaction of the applicator device 150 and tray 810 will be described further below.

[0058] Figure 3D is a proximal perspective view showing an exemplary embodiment in which a user removes the applicator device 150 from the tray 810 during assembly. The user can remove the applicator 150 from the tray 810 by advancing the housing 702 proximal to the tray 810, or by other actions having the same final effect of discouplering the applicator 150 from the tray 810. The applicator device 150 is removed with a fully assembled sensor control device 102 (not shown) positioned for delivery (sharp parts, sensors, electronic components).

[0059] Figure 3E is a proximal perspective view showing an exemplary embodiment in which a patient applies the sensor control device 102 to a target area of ​​skin, such as the abdomen or another suitable site, using the applicator device 150. As the housing 702 is advanced, the sheath 704 within the housing 702 folds distally, applying the sensor to the target site so that the adhesive layer on the bottom surface of the sensor control device 102 adheres to the skin. When the housing 702 is fully advanced, the sharp part is automatically withdrawn, but the sensor (not shown) remains in place at the site for measuring the analyte level.

[0060] Figure 3F is a proximal perspective view showing an exemplary embodiment of a patient with the sensor control device 102 at the application site. The user can then remove the applicator 150 from the application site. The system 100 described in Figures 3A-3F and elsewhere in this specification can reduce or eliminate the opportunity for accidental breakage, permanent deformation, or improper assembly of applicator components compared to systems of the prior art. The applicator housing 702 engages directly with the platform 808 rather than indirectly through the sheath 704 while the sheath 704 is unlocked, and the relative angle between the sheath 704 and the housing 702 does not result in breakage or permanent deformation of the arm or other components. The possibility of relatively large forces being generated during assembly (as in conventional devices) is reduced, thereby reducing the opportunity for user failure in assembly.

[0061] F. Exemplary Sensor Applicator Device Figure 4A is a side view showing an exemplary embodiment of the applicator device 150 coupled with the screw cap 708. This is an example of how the applicator 150 is shipped to and received by the user before being assembled with the sensor by the user. Figure 4B is a side perspective view showing the applicator 150 and cap 708 after uncoupling. Figure 4C is a perspective view of an exemplary embodiment of the distal end of the applicator device 150, where the electronic component housing 706 and adhesive patch 105 are removed from their positions where they would be held within the sensor carrier 710 of the sheath 704 when the cap 708 is in place. Referring to 4D-G for illustrative purposes rather than limitation, the applicator device 20150 can be provided to the user as a single, integrated assembly. Figures 4D and 4E provide a top and bottom perspective view of the applicator device 20150, respectively; Figure 4F provides an exploded view of the applicator device 20150; and Figure 4G provides a side cutaway view. The perspective views show how the applicator 20150 is shipped and received by the user. The exploded view and cutaway view show the components of the applicator device 20150. The applicator device 20150 may include a housing 20702, a gasket 20701, a sheath 20704, a sharpness carrier 201102, a spring 205612, a sensor carrier 20710 (also called the "pack carrier"), a sharpness hub 205014, a sensor control device (also called the "pack") 20102, an adhesive patch 20105, a desiccant 20502, a cap 20708, a serial label 20709, and a tamper-evident feature portion 20712. When the user receives the device, only the housing 20702, cap 20708, tamper-evident feature portion 20712, and label 20709 will be visible. The tamper-evident feature portion 20712 may be, for example, a sticker attached to the housing 20702 and the cap 20708, and the tamper-evident feature portion 20712 may be irreparably damaged by, for example, unbinding the housing 20702 and the cap 20708, thereby indicating to the user that the housing 20702 and the cap 20708 have never been unbinding before. These feature portions are described in more detail below.

[0062] G. Exemplary tray and sensor module assembly Figure 5 is a proximal perspective view showing an exemplary embodiment of a tray 810 with a detachably connected sterile lid 812, which can illustrate how the package is shipped before assembly and how it is received by the user.

[0063] Figure 6A is a proximal cutaway perspective view showing the sensor delivery components within tray 810. The platform 808 is slidably connected within tray 810. The desiccant 502 is stationary relative to tray 810. The sensor module 504 is mounted within tray 810.

[0064] Figure 6B is a close perspective view showing the sensor module 504 in more detail. Here, the retaining arm extension 1834 of the platform 808 securely fixes the sensor module 504 in place. Module 2200 is connected to a connector 2300, a sharp part module 2500, and a sensor (not shown), and these can be removed together as the sensor module 504 during assembly.

[0065] H. Exemplary Applicators and Sensor Control Devices for Single-Component Architecture Referring again briefly to Figures 1A and 3A-3G, in the case of a two-component architecture system, the sensor tray 202 and the sensor applicator 102 are provided to the user as separate packages, so the user needs to open each package and finally assemble the system. In some applications, the separate sealed packages allow the sensor tray 202 and the sensor applicator 102 to be sterilized in separate sterilization processes specific to the contents of each package, or not compatible with the contents of other packages. More specifically, the sensor tray 202, including the sensor 110 and the plug assembly 207 including the sharp part 220, can be sterilized using radiation sterilization such as electron beam (or "e-beam") irradiation. Suitable radiation sterilization processes include, but are not limited to, electron beam (e-beam) irradiation, gamma ray irradiation, X-ray irradiation, or any combination thereof. However, radiation sterilization may damage the electrical components located within the electronic component housing of the sensor control device 102. Therefore, if the sensor applicator 102, which houses the electronic component housing of the sensor control device 102, needs to be sterilized, it can be sterilized by another method, such as gas sterilization using ethylene oxide. However, gas sterilization may damage enzymes or other chemicals and biological agents contained in the sensor 110. Due to this sterilization incompatibility, the sensor tray 202 and the sensor applicator 102 are usually sterilized in separate sterilization processes and then packaged separately so that the user can finally assemble the components for use.

[0066] Figures 7A and 7B are exploded top and bottom views, respectively, of a sensor control device 3702 according to one or more embodiments. The shell 3706 and mount 3708 act as opposing clamshell halves that house, or otherwise substantially encapsulate, various electronic components of the sensor control device 3702. As shown, the sensor control device 3702 may also include a printed circuit board assembly (PCBA) 3802, which includes a printed circuit board (PCB) 3804 to which a plurality of electronic modules 3806 are linked. Examples of electronic modules 3806 include, but are not limited to, resistors, transistors, capacitors, inductors, diodes, and switches. Conventional sensor control devices typically stack PCB components on only one side of the PCB. In contrast, the PCB components 3806 in the sensor control device 3702 can be distributed around the surface areas of both sides (i.e., the top and bottom) of the PCB 3804. In addition to the electronic module 3806, PCBA3802 may also include a data processing unit 3808 mounted on PCB3804. The data processing unit 3808 may comprise an application-specific integrated circuit (ASIC) configured to implement, for example, one or more functions or routines related to the operation of the sensor control device 3702. More specifically, the data processing unit 3808 can be configured to perform data processing functions, such as, but not limited to, filtering and coding of data signals, each of which corresponds to the user's sampled analyte level. The data processing unit 3808 also includes, or can communicate with, an antenna for communicating with the reader device 106 (Figure 1A).

[0067] The battery opening 3810 may be sized to receive and mount a battery 3812 defined within the PCB 3804 and configured to power the sensor control device 3702. Axial battery contacts 3814a and radial battery contacts 3814b may be connected to the PCB 3804 and extend within the battery opening 3810 to facilitate the transmission of power from the battery 3812 to the PCB 3804. As their names suggest, the axial battery contact 3814a may be configured to provide an axial contact to the battery 3812, while the radial battery contact 3814b may provide a radial contact to the battery 3812. Placing the battery 3812 within the battery opening 3810 with battery contacts 3814a,b helps reduce the height H of the sensor control device 3702, thereby allowing the PCB 3804 to be centrally positioned and its components distributed to both sides (i.e., the top and bottom). This also helps to facilitate the chamfering 3718 provided on the electronic component housing 3704.

[0068] The sensor 3716 is centrally positioned relative to the PCB 3804 and may include a tail 3816, a flag 3818, and a neck 3820 interconnecting the tail 3816 and the flag 3818. The tail 3816 may extend through the central opening 3720 of the mount 3708 and be configured to be received percutaneously under the user's skin. Furthermore, the tail 3816 may have enzymes or other chemicals included to help facilitate the monitoring of the analyte.

[0069] The flag 3818 may include a substantially flat surface having one or more sensor contacts 3822 (three shown in Figure 7B) positioned thereon. The sensor contacts 3822 may be configured to align and engage with one or more corresponding circuit contacts 3824 (three shown in Figure 7A) provided on the PCB 3804. In some embodiments, the sensor contacts 3822 may include a carbon-impregnated polymer printed or otherwise digitally applied to the flag 3818. Conventional sensor control devices typically include a silicone rubber connector that encapsulates one or more compatible carbon-impregnated polymer modules that function as conductive contacts between the sensor and the PCB. In contrast, the sensor contacts 3822 disclosed herein provide a direct connection between the sensor 3716 and the PCB 3804 connection, thereby eliminating the need for a conventional connector and advantageously reducing the height H. Furthermore, by eliminating compatible carbon-impregnated polymer modules, circuit resistance is significantly reduced, resulting in improved circuit conductivity.

[0070] The sensor control device 3702 may further include a conforming member 3826 that can be positioned between the flag 3818 and the inner surface of the shell 3706. More specifically, when the shell 3706 and the mount 3708 are assembled relative to each other, the conforming member 3826 may be configured to provide a passive biasing load to the flag 3818, causing the sensor contact 3822 to engage in sequence with the corresponding circuit configuration contact 3824. In the illustrated embodiment, the conforming member 3826 is an elastomer O-ring, but any other type of biasing device or mechanism, such as a compression spring, may be provided instead without departing from the scope of the present disclosure.

[0071] The sensor control device 3702 may further include one or more electromagnetic shields, indicated as a first shield 3828a and a second shield. The shell 3706 may provide or otherwise define a first clock receptacle 3830a (Figure 7B) and a second clock receptacle 3830b (Figure 7B), and the mount 3708 may provide or otherwise define a first clock post 3832a (Figure 7A) and a second clock post 3832b (Figure 7A). When the first and second clock receptacles 3830a and b are mated with the first and second clock posts 3832a and b, respectively, the shell 3706 is properly aligned with the mount 3708.

[0072] Referring particularly to Figure 7A, the inner surface of the mount 3708 can provide or otherwise define a plurality of pockets or recesses configured to accommodate various components of the sensor control device 3702 when the shell 3706 is fitted onto the mount 3708. For example, the inner surface of the mount 3708 can define a battery locator 3834 configured to accommodate a portion of the battery 3812 when the sensor control device 3702 is assembled. Adjacent contact pockets 3836 can be configured to accommodate a portion of the axial contacts 3814a. Furthermore, multiple module pockets 3838 can be defined on the inner surface of the mount 3708 to accommodate various electronic modules 3806 located at the bottom of the PCB 3804. Additionally, a shield locator 3840 can be defined on the inner surface of the mount 3708 to accommodate at least a portion of the second shield 3828b when the sensor control device 3702 is assembled. The battery locator 3834, contact pocket 3836, module pockets 3838, and shield locator 3840 all extend only short distances within the inner surface of the mount 3708, resulting in a reduction in the overall height H of the sensor control device 3702 compared to conventional sensor control devices. The module pockets 3838 may also help minimize the diameter of the PCB 3804 by allowing PCB components to be placed on both sides (i.e., the top and bottom surfaces).

[0073] Referring further to Figure 7A, the mount 3708 may further include a plurality of carrier grip feature portions 3842 (two are shown) defined around the outer periphery of the mount 3708. The carrier grip feature portions 3842 are axially offset from the bottom 3844 of the mount 3708, allowing for the application of transfer adhesive (not shown) during assembly. In contrast to conventional sensor control devices that generally include conical carrier grip feature portions intersecting the bottom of the mount, the carrier grip feature portions 3842 disclosed herein are offset from the plane (i.e., the bottom 3844) to which the transfer adhesive is applied. This may prove advantageous in that it helps ensure that the delivery system does not accidentally stick to the transfer adhesive during assembly. Furthermore, the carrier grip feature portions 3842 disclosed herein eliminate the need for corrugated transfer adhesive, thereby simplifying the manufacture of the transfer adhesive and eliminating the need to precisely align (clock) the transfer adhesive relative to the mount 3708. This also increases the bonding area and therefore the bonding strength.

[0074] Referring to Figure 7B, the bottom 3844 of the mount 3708 can provide or define a number of grooves 3846, which may be defined on or near the outer circumference of the mount 3708 and positioned equidistant from one another. A transfer adhesive (not shown) can be bonded to the bottom 3844, and the grooves 3846 may be configured to help carry (transfer) moisture from the sensor control device 3702 toward the periphery of the mount 3708 during use. In some embodiments, the spacing of the grooves 3846 may sandwich a module pocket 3838 (Figure 7A) defined on the opposite side (inner surface) of the mount 3708. As understood, alternating the positions of the grooves 3846 and the module pocket 3838 ensures that opposing feature portions on either side of the mount 3708 do not penetrate each other. This helps to maximize the material utilization of the mount 3708, which may help to maintain the minimum height H of the sensor control device 3702. The module pocket 3838 can also significantly reduce mold sinking and improve the flatness of the bottom 3844 to which the transfer adhesive adheres.

[0075] Referring further to Figure 7B, the inner surface of the shell 3706 can also provide or otherwise define a number of pockets or recesses configured to accommodate various components of the sensor control device 3702 when the shell 3706 is fitted onto the mount 3708. For example, the inner surface of the shell 3706 can be positioned on the opposite side of the battery locator 3834 (Figure 7A) of the mount 3708, and a counter-battery locator 3848 can be defined, configured to accommodate a portion of the battery 3812 when the sensor control device 3702 is assembled. The counter-battery locator 3848 extends only a short distance into the inner surface of the shell 3706, which helps to reduce the overall height H of the sensor control device 3702. The sharp portion and sensor locator 3852 can also be provided by the inner surface of the shell 3706 or otherwise defined on the inner surface of the shell 3706. The sharp portion and sensor locator 3852 can be configured to accept both the sharp portion (not shown) and a portion of the sensor 3716. Furthermore, the sharp portion and sensor locator 3852 can be configured to align and / or mate with a corresponding sharp portion and sensor locator 2054 (Figure 7A) provided on the inner surface of the mount 3708.

[0076] According to embodiments of the present disclosure, alternative sensor assembly / electronic component assembly connection approaches are shown in Figures 8A–8C. As shown, the sensor assembly 14702 includes a sensor 14704, a connector support 14706, and a sharp portion 14708. In particular, a recess or receptacle 14710 can be defined at the bottom of the mount of the electronic component assembly 14712, providing a place where the sensor assembly 14702 can be received and coupled to the electronic assembly 14712, thereby allowing the sensor control device to be fully assembled. The profile of the sensor assembly 14702 can be formed to match or complement the receptacle 14710, which includes an elastomer sealing member 14714 (containing a conductive material coupled to the circuit board and aligned with the electrical contacts of the sensor 14704). Therefore, when the sensor assembly 14702 is snap-fitted or bonded to the electronic assembly 14712 by pushing it into the recess 14710 integrally formed in the electronic assembly 14712, the body-worn device 14714 shown in Figure 8C is formed. This embodiment provides an integrated connector for the sensor assembly 14702 within the electronic component assembly 14712.

[0077] Additional information relating to the sensor assembly is provided in U.S. Publication No. 2013 / 0150691 and U.S. Publication No. 2021 / 0204841, both of which are incorporated herein by reference in their entirety. According to embodiments of this disclosure, the sensor control device 102 can be modified to provide a single-component architecture to which sterilization techniques specifically designed for single-component architecture sensor control devices can be applied. The single-component architecture allows the sensor applicator 150 and the sensor control device 102 to be shipped to the user in a single sealed package, eliminating the need for a final user assembly step. Rather, the user only needs to open one package and then deliver the sensor control device 102 to the target monitoring site. The single-component system architecture described herein may prove advantageous in that it eliminates components, various manufacturing process steps, and user assembly steps. As a result, packaging and waste are reduced, and the possibility of user error or contamination of the system is mitigated.

[0078] Figures 9A and 9B are side and side cross-sectional views, respectively, of exemplary embodiments of a sensor applicator 102 with an applicator cap 210 attached. More specifically, Figure 9A shows how the sensor applicator 102 is shipped to and received by the user, and Figure 9B shows a sensor control device 4402 located inside the sensor applicator 102. Thus, a fully assembled sensor control device 4402 can be assembled and installed inside the sensor applicator 102 before being delivered to the user, thus eliminating the need for additional assembly steps that the user would otherwise have to perform.

[0079] The fully assembled sensor control device 4402 may be loaded into the sensor applicator 102, after which the applicator cap 210 may be coupled to the sensor applicator 102. In some embodiments, the applicator cap 210 may be screwed into the housing 208 and may include a tampering ring 4702. Rotating the applicator cap 210 relative to the housing 208 (e.g., loosening the screw) will break the tampering ring 4702, thereby releasing the applicator cap 210 from the sensor applicator 102.

[0080] According to this disclosure, while loaded in the sensor applicator 102, the sensor control device 4402 can undergo gaseous chemical sterilization 4704 configured to sterilize the electronic component housing 4404 and any other exposed parts of the sensor control device housing 4402. To achieve this, a chemical may be injected into a sterilization chamber 4706 defined in cooperation with the sensor applicator 102 and the interconnected cap 210. In some applications, the chemical may be injected into the sterilization chamber 4706 through one or more vents 4708 defined at the proximal end 610 of the applicator cap 210. Examples of chemicals that may be used in gaseous chemical sterilization 4704 include, but are not limited to, ethylene oxide, vaporized hydrogen peroxide, nitrogen oxides (e.g., nitrous oxide, nitrogen dioxide, etc.), and vapors. Since the distal portions of the sensor 4410 and the sharp part 4412 are sealed within the sensor cap 4416, the chemicals used during the gaseous chemical sterilization process do not interact with the enzymes, chemicals, and biologics supplied to the tail 4524 and other sensor components, such as the membrane coating that regulates the inflow of analytes. Once the desired level of sterilization assurance is achieved within the sterilization chamber 4706, the gaseous solution is removed and the sterilization chamber 4706 is ventilated. Ventilation can be achieved by circulating a series of vacuums and subsequent gases (e.g., nitrogen) or filtered air through the sterilization chamber 4706. Once the sterilization chamber 4706 is properly ventilated, the vent holes 4708 can be sealed with seals 4712 (indicated by dashed lines).

[0081] In some embodiments, the seal 4712 may comprise two or more layers of different materials. The first layer can be made from a synthetic material such as Tyvek®, available from DuPont® (e.g., flash-spun high-density polyethylene fiber). Tyvek® is durable, puncture-resistant, and vapor-permeable. The Tyvek® layer can be applied before the gaseous chemical sterilization process, and after the gaseous chemical sterilization process, a foil or other vapor-resistant and moisture-resistant material layer can be sealed (e.g., heat-sealed) over the Tyvek® layer to prevent contaminants and moisture from entering the sterilization chamber 4706. In other embodiments, the seal 4712 may comprise only a single protective layer applied to the applicator cap 210. In such embodiments, the single layer may be gas-permeable to the sterilization process but may also protect from moisture and other harmful elements once the sterilization process is complete. With the seal 4712 in place, the applicator cap 210 provides a barrier against external contamination, thereby maintaining a sterile environment for the assembled sensor control device 4402 until the user removes the applicator cap 210 (by loosening the screw). The applicator cap 210 also creates a dust-free environment, preventing the adhesive patch 4714 from becoming contaminated during shipping and storage.

[0082] Figures 10A and 10B are isometric and side views, respectively, of another exemplary sensor control device 5002 according to one or more embodiments of the present disclosure. The sensor control device 5002 may be similar in some respects to the sensor control device 102 of Figure 1A, and therefore it would be best understood by referring to it. Furthermore, the sensor control device 5002 can replace the sensor control device 102 of Figure 1A and can therefore be used in combination with the sensor applicator 102 of Figure 1A, thereby enabling the sensor control device 5002 to be delivered to a target monitoring site on the user's skin.

[0083] However, unlike the sensor control device 102 in Figure 1A, the sensor control device 5002 can have a single-component system architecture that does not require the user to open multiple packages and finally assemble the sensor control device 5002 before application. Rather, the sensor control device 5002 is already fully assembled and properly positioned within the sensor applicator 150 when the user receives it (Figure 1A). To use the sensor control device 5002, the user only needs to open one barrier (e.g., the applicator cap 708 in Figure 3B) before promptly delivering the sensor control device 5002 to the target monitoring site for use.

[0084] As illustrated, the sensor control device 5002 is substantially disc-shaped and includes an electronic component housing 5004 which may have a circular cross-section. However, in other embodiments, the electronic component housing 5004 may have other cross-sectional shapes, such as oval or polygonal, without departing from the scope of the present disclosure. The electronic component housing 5004 may be configured to house, or otherwise include, various electrical components used to operate the sensor control device 5002. In at least one embodiment, an adhesive patch (not shown) may be placed at the bottom of the electronic component housing 5004. The adhesive patch may be similar to the adhesive patch 105 in Figure 1A and thus may be useful for adhering the sensor control device 5002 to the user's skin for use. As illustrated, the sensor control device 5002 includes an electronic component housing 5004 which includes a shell 5006 and a mount 5008 matable with the shell 5006. The shell 5006 can be secured to the mount 5008 by a variety of methods such as snap-fit ​​engagement, crimp-fit, ultrasonic welding, one or more mechanical fasteners (e.g., screws), gaskets, adhesives, or any combination thereof. In some cases, the shell 5006 may be secured to the mount 5008 such that a sealed interface is created between them.

[0085] The sensor control device 5002 may further include a sensor 5010 (partially visible) and a sharp portion 5012 (partially visible) used to help deliver the sensor 5010 percutaneously under the user's skin during application of the sensor control device 5002. As shown, the corresponding portions of the sensor 5010 and the sharp portion 5012 extend distally from the bottom of the electronic component housing 5004 (e.g., mount 5008). The sharp portion 5012 may include a sharp portion hub 5014 configured to fix and support the sharp portion 5012. As best shown in Figure 10B, the sharp portion hub 5014 may include a mating member 5016, or the mating member 5016 may be defined otherwise. To connect the sharp portion 5012 to the sensor control device 5002, the sharp portion 5012 can advance axially through the electronic component housing 5004 until the sharp portion hub 5014 engages with the upper surface of the shell 5006 and the mating member 5016 extends distally from the bottom of the mount 5008. Once the sharp portion 5012 has penetrated the electronic component housing 5004, the exposed portion of the sensor 5010 can be received within the hollow or recessed (bow-shaped) portion of the sharp portion 5012. The remaining portion of the sensor 5010 is located inside the electronic component housing 5004.

[0086] The sensor control device 5002 may further include a sensor cap 5018, shown in Figures 10A-10B disassembled from the electronic component housing 5004 or removed from the electronic equipment housing 5004. The sensor cap 5016 can be removably coupled to the sensor control device 5002 (e.g., the electronic component housing 5004) at or near the bottom of the mount 5008. The sensor cap 5018 can help provide a sealed barrier that surrounds the sensor 5010 and the exposed portion of the sharp part 5012, protecting them from gaseous chemical sterilization. As shown, the sensor cap 5018 may comprise a substantially cylindrical body having a first end 5020a and a second end 5020b opposite the first end 5020a. The first end 5020a may be open to provide access to an internal chamber 5022 defined within the body. In contrast, the second end 5020b may be closed, providing or otherwise defining an engagement feature portion 5024. As described herein, the engagement feature portion 5024 can help to fit the sensor cap 5018 onto the cap of a sensor applicator (e.g., the sensor applicator 150 in Figures 1A and 3A-3G) (e.g., the applicator cap 708 in Figure 3B), and this can help to remove the sensor cap 5018 from the sensor control device 5002 when removing the cap from the sensor applicator.

[0087] The sensor cap 5018 can be removably coupled to the electronic component housing 5004 at or near the bottom of the mount 5008. More specifically, the sensor cap 5018 can be removably coupled to a fitting member 5016 extending distally from the bottom of the mount 5008. In at least one embodiment, for example, the fitting member 5016 may define a pair of male threads 5026a (Figure 10B) that can mate with a pair of female threads 5026b (Figure 10A) defined by the sensor cap 5018. In some embodiments, the male threads 5026a and female threads 5026b may have a flat thread design (e.g., lack of helical curvature) which may prove advantageous when forming the part. Alternatively, the male threads 5026a and female threads 5026b may include helical threading. Therefore, the sensor cap 5018 can be screwed to the sensor control device 5002 at the mating member 5016 of the sharp hub 5014. In other embodiments, the sensor cap 5018 can be removably coupled to the mating member 5016 via other types of engagement, including but not limited to press-fit or friction-fit, or to a fragile member or material that may break with minimal separating force (e.g., axial or rotational force).

[0088] In some embodiments, the sensor cap 5018 may have a monolithic (single) structure extending between a first end 5020a and a second end 5020b. However, in other embodiments, the sensor cap 5018 may include two or more components. In the illustrated embodiment, for example, the sensor cap 5018 may include a seal ring 5028 located at the first end 5020a and a desiccant cap 5030 located at the second end 5020b. The seal ring 5028 may be configured to help seal the inner chamber 5022, as will be described in more detail below. In at least one embodiment, the seal ring 5028 may include an elastomer O-ring. The desiccant cap 5030 may contain or include a desiccant that helps maintain a preferred humidity level within the inner chamber 5022. The desiccant cap 5030 may define or otherwise provide the engagement feature portion 5024 of the sensor cap 5018.

[0089] Figures 11A–11C are stepwise cross-sectional side views showing the assembly of a sensor applicator 102 with a sensor control device 5002 according to one or more embodiments. Once the sensor control device 5002 is fully assembled, it can be loaded into the sensor applicator 102. Referring to Figure 11A, the sharp part hub 5014 includes, or can be otherwise defined, a hub snap-fitting claw 5302 configured to help connect the sensor control device 5002 to the sensor applicator 102. More specifically, the sensor control device 5002 can advance into the sensor applicator 102, and the hub snap-fitting claw 5302 can be received by the corresponding arm 5304 of a sharp part carrier 5306 located inside the sensor applicator 102.

[0090] Figure 11B shows that the sensor control device 5002 is received by the sharp part carrier 5306 and thus secured within the sensor applicator 102. Once the sensor control device 5002 is loaded into the sensor applicator 102, the applicator cap 210 may be coupled to the sensor applicator 102. In some embodiments, the applicator cap 210 and the housing 208 may have opposing mating thread sets 5308 that allow the applicator cap 210 to be screwed into the housing 208 in a clockwise (or counterclockwise) direction, thereby securing the applicator cap 210 to the sensor applicator 102. As shown in the illustration, the sheath 212 is also located within the sensor applicator 102, and the sensor applicator 102 may include a sheath lock mechanism 5310 configured to ensure that the sheath 212 does not collapse prematurely during an impact event. In the illustrated embodiment, the sheath lock mechanism 5310 may include a screw engagement between the applicator cap 210 and the sheath 212. More specifically, one or more female threads 5312a may be defined on or otherwise provided on the inner surface of the applicator cap 210, and one or more male threads 5312b may be defined on or otherwise provided on the sheath 212. The female threads 5312a and male threads 5312b may be configured to screw together when the applicator cap 210 is screwed into the sensor applicator 102 with the threads 5308. The female thread 5312a and the male thread 5312b may have the same thread pitch as the thread 5308, which allows the applicator cap 210 to be screwed into the housing 208.

[0091] Figure 11C shows the applicator cap 210 fully screwed (connected) into the housing 208. As shown, the applicator cap 210 may further have, or be otherwise defined, a cap post 5314 located in the center of the applicator cap 210 and extending proximal from its bottom. The cap post 5314 may be configured to receive at least a portion of the sensor cap 5018 when the applicator cap 210 is screwed into the housing 208. With the sensor control device 5002 loaded into the sensor applicator 102 and the applicator cap 210 properly secured, the sensor control device 5002 can undergo gaseous chemical sterilization configured to sterilize the electronic component housing 5004 and any other exposed parts of the sensor control device 5002. Since the distal portions of the sensor 5010 and the sharp part 5012 are sealed within the sensor cap 5018, the chemicals used during the gaseous chemical sterilization process cannot interact with the enzymes, chemicals, and bioagents supplied to the tail 5104 and other sensor components, such as the membrane coating that regulates the inflow of analytes.

[0092] Figures 12A to 12C are stepwise cross-sectional side views showing the assembly and disassembly of alternative embodiments of the sensor applicator 102 with a sensor control device 5002, according to one or more additional embodiments. The fully assembled sensor control device 5002 can be loaded into the sensor applicator 102 by connecting the hub snap fitting claws 5302 to the arms 5304 of the sharp part carrier 5306 located inside the sensor applicator 102, as generally described above. In the illustrated embodiment, the sheath arm 5604 of the sheath 212 can be configured to interact with a first detent 5702a and a second detent 5702b defined inside the housing 208. The first detent 5702a is sometimes called the “lock” detent, and the second detent 5702b is sometimes called the “firing” detent. When the sensor control device 5002 is first installed inside the sensor applicator 102, the sheath arm 5604 can be received into the first detent 5702a. As will be discussed below, the sheath 212 can be actuated to move the sheath arm 5604 to the second detent 5702b, thereby positioning the sensor applicator 102 in the firing position.

[0093] In Figure 12B, the applicator cap 210 is aligned with the housing 208 and advances toward the housing 208 so that the sheath 212 is received within the applicator cap 210. Instead of rotating the applicator cap 210 relative to the housing 208, the applicator cap 210 may be connected to the housing 208 by fitting the threads of the applicator cap 210 into the corresponding threads of the housing 208. An axial notch or slot 5703 (one is shown) defined within the applicator cap 210 may allow the portion of the applicator cap 210 near its threads to bend outward, enabling a snap-fit ​​engagement with the threads of the housing 208. Once the applicator cap 210 is snap-fitted into the housing 208, the sensor cap 5018 can be correspondingly snap-fitted into the cap post 5314.

[0094] Similar to the embodiments shown in Figures 11A-11C, the sensor applicator 102 may include a sheath lock mechanism configured to ensure that the sheath 212 does not collapse prematurely during an impact event. In the illustrated embodiment, the sheath lock mechanism includes one or more ribs 5704 (one shown) defined near the base of the sheath 212 and configured to interact with one or more ribs 5706 (two shown) and shoulders 5708 defined near the base of the applicator cap 210. The ribs 5704 may be configured to interlock between the ribs 5706 and shoulders 5708 when the applicator cap 210 is mounted to the housing 208. More specifically, once the applicator cap 210 is snapped into the housing 208, the applicator cap 210 can be rotated (for example, clockwise), which positions the rib 5704 of the sheath 212 between the rib 5706 and shoulder 5708 of the applicator cap 210, thereby "locking" the applicator cap 210 in place until the user rotates it in the reverse direction to remove it for use. The engagement of the rib 5704 between the rib 5706 and shoulder 5708 of the applicator cap 210 also prevents the sheath 212 from collapsing prematurely.

[0095] In Figure 12C, the applicator cap 210 is removed from the housing 208. Similar to the embodiments in Figures 12A to 12C, the applicator cap 210 is removed by rotating it in the opposite direction, as generally described above, and the cap post 5314 rotates in the same direction in response, which allows the sensor cap 5018 to be removed by loosening the screw from the fitting member 5016. Furthermore, when the sensor cap 5018 is removed from the sensor control device 5002, the sensor 5010 and the distal portion of the sharp part 5012 are exposed.

[0096] When the applicator cap 210 is unscrewed from the housing 208, the rib 5704 defined on the sheath 212 can slide-engage with the upper part of the rib 5706 defined on the applicator cap 210. The upper part of the rib 5706 may provide a corresponding inclined surface that displaces the sheath 212 upward as the applicator cap 210 rotates, and as the sheath 212 moves upward, the sheath arm 5604 bends, disengaging from the first detent 5702a and being received into the second detent 5702b. As the sheath 212 moves into the second detent 5702b, the radial shoulder 5614 disengages radially from the carrier arm 5608, thereby allowing the passive spring force of the spring 5612 to push the sharp part carrier 5306 upward and disengage the carrier arm 5608 from the groove 5610. As the sharp part carrier 5306 moves upward within the housing 208, the mating member 5016 may be withdrawn in response until it is flush, substantially flush, or nearly flush with the bottom of the sensor control device 5002. At this point, the sensor applicator 102 is in the firing position. Therefore, in this embodiment, when the applicator cap 210 is removed, the mating member 5016 is withdrawn in response.

[0097] I. Exemplary firing mechanisms of single-part and two-part applicators Figures 13A–13F show detailed examples of embodiments of an internal device mechanism that “launches” the applicator 216 to apply the sensor control device 222 to the user and safely retracts the sharp portion 1030 into the used applicator 216. In summary, these drawings represent a series of examples in which the sharp portion 1030 (supporting the sensor connected to the sensor control device 222) is driven into the user’s skin, the sharp portion is withdrawn while the sensor remains in operative contact with the user’s interstitial fluid, and the sensor control device is adhesively bonded to the user’s skin. Modifications of such operation for use with alternative applicator assembly embodiments and components will be understood by those skilled in the art by reference to similar examples. Furthermore, the applicator 216 may be a sensor applicator having a single-part architecture or a two-part architecture, as disclosed herein.

[0098] Referring here to Figure 13A, the sensor 1102 is supported within the sharp portion 1030 just above the user's skin 1104. Rails 1106 (optionally three of them) of the upper guide section 1108 can be provided to control the movement of the applicator 216 relative to the sheath 318. The sheath 318 is held by the detent feature portion 1110 within the applicator 216, so that the resistance provided by the detent feature portion 1110 is overcome by a suitable downward force along the longitudinal axis of the applicator 216, and as a result, the sharp portion 1030 and the sensor control device 222 can be translated along the longitudinal axis within (and on) the user's skin 1104. In addition, the catch arm 1112 of the sensor carrier 1022 engages with the sharp portion withdrawal assembly 1024 to maintain the sharp portion 1030 in a certain position relative to the sensor control device 222.

[0099] In Figure 13B, user force is applied to overcome or disable the detent feature portion 1110, causing the sheath 318 to fold into the housing 314 and drive the sensor control device 222 (with associated components) to translate downward along the longitudinal axis as indicated by arrow L. The inner diameter of the upper guide section 1108 of the sheath 318 constrains the position of the carrier arm 1112 throughout the entire stroke of the sensor / sharp insertion process. The position of the member is maintained with the return spring 1118 fully biased by holding the stop surface 1114 of the carrier arm 1112 against the complementary surface 1116 of the sharp part extraction assembly 1024. According to one embodiment, instead of using user force to drive the sensor control device 222 to translate downward along the longitudinal axis as indicated by arrow L, the housing 314 may include a button (e.g., a push button) that acts as a drive spring (e.g., a coil spring, but not limited to) to drive the sensor control device 222.

[0100] In Figure 13C, the sensor 1102 and the sharp part 1030 have reached their full insertion depth. In doing so, the carrier arm 1112 exceeds the inner diameter of the upper guide section 1108. Next, the compressive force of the coil return spring 1118 drives the angled stop surface 1114 radially outward, releasing the force driving the sharp part carrier 1102 of the sharp part withdrawal assembly 1024, and pulling the sharp part 1030 (slotted or otherwise configured) away from the user and away from the sensor 1102, as indicated by arrow R in Figure 13D.

[0101] As shown in Figure 13E, once the sharp portion 1030 is completely withdrawn, the upper guide section 1108 of the sheath 318 is secured by the final locking feature portion 1120. As shown in Figure 13F, the used applicator assembly 216 is removed from its insertion site, leaving the sensor control device 222 and the sharp portion 1030 securely fixed inside the applicator assembly 216. At this point, the used applicator assembly 216 is ready for disposal. The operation of the applicator 216 when the sensor control device 222 is applied is designed to give the user the sensation that both the insertion and withdrawal of the sharp part 1030 are performed automatically by the internal mechanism of the applicator 216. In other words, the present invention avoids the user experiencing the sensation of manually striking the sharp part 1030 into their skin. Thus, when the user applies sufficient force to overcome the resistance from the detent feature portion of the applicator 216, the resulting operation of the applicator 216 is perceived as an automatic response to the applicator being "triggered". Despite all driving force being provided by the user and no additional biasing / driving means being used to insert the sharp part 1030, the user does not perceive that they are providing additional force to drive the sharp part 1030 to penetrate the skin. Withdrawal of the sharp part 1030 is automated by the coil return spring 1118 of the applicator 216, as described in detail above in Figure 13C.

[0102] Those skilled in the art will understand that any embodiment of the applicator described herein, and any of its components, for example, embodiments of the sharpening portion, sharpening portion module, and sensor module, for example, embodiments of the sharpening portion, sharpening portion module, and sensor module, can be sized and configured for use with a sensor configured to sense the level of analyte in the bodily fluids of the epidermis, dermis, or subcutaneous tissue of a subject. In some embodiments, for example, both the sharpening portion and distal portion of the analyte sensor disclosed herein can be sized and configured to position at a specific end depth (i.e., the furthest point of penetration of the tissue or layer of the body of the subject, such as the epidermis, dermis, or subcutaneous tissue). With respect to some embodiments of the applicator, those skilled in the art will understand that certain embodiments of the sharpening portion can be sized and configured to position at different end depths within the body of the subject relative to the final end depth of the analyte sensor. In some embodiments, for example, the sharpening portion can be positioned at a first end depth in the epidermis of the subject before withdrawal, while the distal portion of the analyte sensor can be positioned at a second end depth in the dermis of the subject. In another embodiment, the sharp portion can be positioned at a first end depth in the dermis of the target before withdrawal, while the distal portion of the analyte sensor can be positioned at a second end depth in the subcutaneous tissue of the target. In yet another embodiment, the sharp portion can be positioned at the first end depth and the analyte sensor at the second end depth, both of which are located within the same layer or tissue of the target body.

[0103] Furthermore, with respect to any embodiment of the applicator described herein, those skilled in the art will understand that one or more structural components, including but not limited to an analyte sensor and one or more spring mechanisms coupled to the analyte sensor, can be positioned within the applicator at an off-center position with respect to one or more axes of the applicator. In some embodiments of the applicator, for example, the analyte sensor and spring mechanism can be positioned on a first side of the applicator, at a first off-center position with respect to the axis of the applicator, and the sensor electronic components can be positioned on a second side of the applicator, at a second off-center position with respect to the axis of the applicator. In other embodiments of the applicator, the analyte sensor, spring mechanism, and sensor electronic components can be positioned on the same side, at an off-center position with respect to the axis of the applicator. Those skilled in the art will understand that other permutations and configurations are possible and are entirely within the scope of this disclosure, in which any or all of the applicator's analyte sensor, spring mechanism, sensor electronic components, and other components are positioned centrally or off-center with respect to one or more axes of the applicator.

[0104] Further details regarding suitable devices, systems, methods, components and their operation, along with relevant feature sections, are described in International Publication No. WO2018 / 136898 by Rao et al., International Publication No. WO2019 / 236850 by Thomas et al., International Publication No. WO2019 / 236859 by Thomas et al., International Publication No. WO2019 / 236876 by Thomas et al., and U.S. Patent Publication No. 2020 / 0196919 filed June 6, 2019, each of which is incorporated herein by reference in its entirety. Further details regarding embodiments of applicators, their components and their variations, are described in U.S. Patent Publication Nos. 2013 / 0150691, 2016 / 0331283, and 2018 / 0235520, all of which are incorporated herein by reference in their entirety for any purpose. Further details relating to the sharp parts modules, sharp parts, their components, and embodiments of their modified forms are described in U.S. Patent Application Publication No. 2014 / 0171771, which is incorporated herein by reference in whole for all purposes.

[0105] J. Exemplary method for calibrating an analyte sensor Biochemical sensors can be described by one or more sensing characteristics. A common sensing characteristic, called the sensitivity of a biochemical sensor, is a measure of the sensor's responsiveness to the concentration of the chemical or composition it is designed to detect. In the case of electrochemical sensors, this response can be in the form of electric current (current measurement) or electric charge (coulometry). For other types of sensors, the response can take different forms, such as photonic intensity (e.g., optical light). The sensitivity of a biochemical analyte sensor can vary depending on several factors, including whether the sensor is in vitro or in vivo.

[0106] Figure 14 is a graph showing the in vitro sensitivity of a current-measuring analyte sensor. In vitro sensitivity can be obtained by in vitro testing the sensor at various analyte concentrations and 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 substantially linear and can be modeled according to the equation y = mx + b, where y is the electrical output current of the sensor, 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 usually corresponds to a background signal (e.g., noise). For sensors with a linear or substantially linear response, 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 resulting from the sensor's output current, and those skilled in the art are familiar with methods for modeling nonlinear sensitivity. In certain embodiments of an in vivo sensor, the in vitro sensitivity may be the same as the in vivo sensitivity, but in other embodiments, a transfer (or conversion) function is used to convert the in vitro sensitivity to an in vivo sensitivity applicable to the sensor's intended in vivo use.

[0107] Calibration is a technique for improving or maintaining accuracy by adjusting the measured output of a sensor to reduce the difference between the measured output and the expected output. One or more parameters describing the sensor's sensing characteristics, such as sensitivity, are established for use in the calibration adjustment.

[0108] In certain in vivo analyte monitoring systems, calibration is required either through user interaction or an automated method by the system itself after the sensor is implanted in the user or patient. For example, if user interaction is required, the user performs an in vitro measurement (e.g., blood glucose (BG) measurement using a finger stick and in vitro test strip) while the analyte sensor is implanted and inputs this into the system. 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 an algorithmic process to convert the data collected by the sensor into a value indicating the user's analyte level. This process and other processes that require user action to perform calibration are called "user calibration." The system may require user calibration because the sensor sensitivity is unstable, such as drifting or changing over time. Therefore, multiple user calibrations may be required (e.g., on a regular (e.g., daily) schedule, according to a variable schedule, or as needed) to maintain accuracy. While embodiments described herein may incorporate some degree of user calibration for specific implementations, this is generally undesirable as it may require the user to perform painful or otherwise cumbersome BG measurements, potentially leading to user error.

[0109] Some in vivo analyte monitoring systems can periodically adjust calibration parameters using automated measurements of sensor characteristics performed by the system itself (e.g., processing circuits running software). The repeated adjustment of sensor sensitivity based on variables measured by the system (rather than by the user) is generally referred to as "system" (or automated) calibration and can be performed with or without user calibration, such as initial BG measurements. As with repeated user calibration, repeated system calibration is usually necessary because sensor sensitivity drifts over time. Therefore, the embodiments described herein can be used with some degree of automated system calibration, but preferably the sensor sensitivity is relatively stable over time so that post-implantation calibration is not required.

[0110] Some in vivo analytes monitoring systems operate with factory-calibrated sensors. Factory calibration refers to determining or estimating one or more calibration parameters before distribution to the user or healthcare professional (HCP). These calibration parameters may be determined by the sensor manufacturer (or, if the two entities are different, the manufacturers of other components of the sensor control device). Many in vivo sensor manufacturing processes produce sensors in groups or batches referred to as production lots, manufacturing stage lots, or simply lots. A single lot may contain thousands of sensors.

[0111] The sensor may include calibration codes or parameters, for example, as barcodes, laser tags, RFID tags, or other machine-readable information provided on the sensor, which can be derived or determined during the manufacturing process of one or more types of sensors, coded or programmed within a data processing device of the analyte monitoring system as part of the manufacturing process, or provided to the sensor itself. If the codes are provided to a receiver (or other data processing device), user calibration during in vivo use of the sensor can be omitted, or the frequency of in vivo calibration while the sensor is installed can be reduced. In embodiments where the calibration codes or parameters are provided to the sensor itself, the calibration codes or parameters can be automatically transmitted or provided to a data processing device in the analyte monitoring system before or at the start of use of the sensor.

[0112] Some in vivo analytes monitoring systems operate with sensors that may be one or more of the following: factory calibrated, system calibrated, and / or user calibrated. For example, a calibration code or parameters can be provided to the sensor to enable factory calibration. If information is provided to the receiver (e.g., entered by the user), the sensor can operate as a factory calibrated sensor. If no information is provided to the receiver, the sensor can operate as a user-calibrated sensor and / or a system-calibrated sensor. In a further embodiment, the data processing device and / or receiver / controller unit of the analyte monitoring system may be provided with or store programmable or executable instructions in order to provide a time-varying adjustment algorithm to the in vivo sensor during use. For example, based on retrospective statistical analysis of the analyte sensor used in vivo and corresponding glucose level feedback, a predetermined time-based curve or analysis curve or database may be generated, which are configured to provide additional adjustments to one or more in vivo sensor parameters to compensate for potential sensor drift in the stability profile or other factors.

[0113] According to the disclosed subject matter, an analyte monitoring system can be configured to compensate for or adjust sensor sensitivity based on a sensor drift profile. A time-varying parameter β(t) can be defined or determined based on an analysis of the sensor behavior in vivo during use, and can determine the time-varying drift profile. In certain embodiments, the compensation or adjustment of sensor sensitivity can be programmed within the receiver unit, controller, or data processor of the analyte monitoring system so that compensation or adjustment, or both, can be performed automatically and / or iteratively upon receiving sensor data from the analyte sensor. According to the disclosed subject matter, the adjustment or compensation algorithm can be initiated or executed by the user (rather than self-initiated or executed) so that the adjustment or compensation of the analyte sensor sensitivity profile is performed or executed when the user initiates or starts the corresponding function or routine, or when the user enters a sensor calibration code.

[0114] According to the disclosed subject matter, each sensor in a sensor lot (and possibly not including the sample sensor used for in vitro testing) can be non-destructively inspected to determine or measure properties such as film thickness at one or more points on the sensor, and other properties including physical properties such as the surface area / volume of the active region. Such measurements or determinations can be performed in an automated manner, for example, using an optical scanner or other suitable measuring device or system, and the sensor properties determined for each sensor in the sensor lot are compared to the corresponding average value based on the sample sensor in relation to the possibility of correction of the calibration parameter or code assigned to each sensor. For example, in the case of a calibration parameter defined as the sensitivity of a sensor, the sensitivity is approximately inversely proportional to the film thickness, and therefore, for example, if the measured film thickness of a sensor is approximately 4% thicker than the average film thickness of a sample sensor from the same sensor lot as that sensor, in one embodiment, the sensitivity assigned to that sensor is the average sensitivity determined from the sample sensor divided by 1.04. Similarly, since sensitivity is roughly proportional to the sensor's active area, if the measurable active area of ​​a sensor is approximately 3% smaller than the average active area of ​​sampled sensors from the same sensor lot, the sensitivity assigned to that sensor is the average sensitivity multiplied by 0.97. The assigned sensitivity can be determined from the average sensitivity from sampled sensors by adjusting it multiple times consecutively for each sensor inspection or measurement. In certain embodiments, the inspection or measurement of each sensor may further include measuring the viscosity or texture of the film in addition to the film thickness and / or surface area or volume of the active sensing area.

[0115] Additional information regarding sensor calibration is provided in U.S. Patent Application Publication No. 2010 / 00230285 and U.S. Patent Application Publication No. 2019 / 0274598, each of which is incorporated herein by reference in its entirety.

[0116] K. Exemplary Bluetooth communication protocol The storage memory 5030 of the sensor 110 may include software blocks related to the communication protocol of the communication module. For example, the storage memory 5030 may include a BLE service software block that provides an interface that the BLE module 5041 can use with the computing hardware of the sensor 110. These software functions may include a BLE logical interface and an interface parser. BLE services provided by the communication module 5040 may include a general access profile service, a general attribute service, a general access service, a device information service, a data transmission service, and a security service. The data transmission service may be the primary service used to transmit data such as sensor control data, sensor status data, analyte measurement data (historical and current), and event log data. Sensor status data may include error data, the current active time, and software status. Analyte measurement data may include current and past raw measurements, current and past values ​​after processing using an appropriate algorithm or model, predictions and trends in measurement levels, comparisons with other values ​​and patient-specific mean values, algorithms or models, and information such as calls to action determined by other similar types of data.

[0117] According to aspects of the disclosed subject matter, as embodied herein, the sensor 110 can be configured to communicate simultaneously with multiple devices by adapting the hardware and feature portions of the wirelessly supported communication protocol or medium of the sensor 110. For example, the BLE module 5041 of the communication module 5040 may be provided with software or firmware that enables multiple simultaneous connections between the sensor 110 as a central device and other devices as peripheral devices, or as peripheral devices to which another device is connected.

[0118] A connection between two devices using a communication protocol such as BLE, and a subsequent communication session, can be characterized by similar physical channels operating between the two devices (e.g., sensor 110 and data receiving device 120). The physical channels may include a single channel or a set of channels, and may include, for example, the use of an agreed-upon set of channels determined by a common clock and a channel-hopping sequence or frequency-hopping sequence, but are not limited to these. Communication sessions may use similar amounts of available communication spectrum, and multiple such communication sessions may exist in close proximity. In a particular embodiment, each group of devices within a communication session may use different physical channels or sets of channels to manage interference between devices in the same proximity range.

[0119] For illustrative, not limiting, purposes, exemplary embodiments of procedures for connecting a sensor and a receiver for use in the disclosed subject matter are referenced. First, the sensor 110 repeatedly advertises its own connection information to its environment in search of the data receiving device 120. The sensor 110 may repeat the advertisement periodically until a connection is established. The data receiving device 120 detects the advertised packets and scans and filters the sensor 120 to connect to via the data provided in the advertised packets. Next, the data receiving device 120 sends a scan request command, and the sensor 110 responds with a scan response packet providing additional details. Next, the data receiving device 120 sends a connection request using the Bluetooth device address associated with the data receiving device 120. The data receiving device 120 may also continuously request to establish a connection to a sensor 110 having a specific Bluetooth device address. Next, the devices establish an initial connection, which allows them to begin data exchange. The devices initiate a process to initialize the data exchange service and perform a mutual authentication procedure.

[0120] During the initial connection between sensor 110 and data receiving device 120, data receiving device 120 can initialize a service, characteristic, and attribute discovery procedure. Data receiving device 120 can evaluate these characteristic parts of sensor 110 and store them for use during subsequent connections. The device then enables notification of customized security services used for mutual authentication between sensor 110 and data receiving device 120. The mutual authentication procedure can be automated and does not require user intervention. After the mutual authentication procedure is successfully completed, sensor 110 sends a connection parameter update requesting data receiving device 120 to use connection parameter settings configured to prioritize sensor 110 and maximize its lifespan.

[0121] Next, the data receiving device 120 executes a sensor control procedure to backfill historical data, current data, event logs, and factory default data. For example, for each type of data, the data receiving device 120 sends a request to initiate the backfill process. The request may specify, as appropriate, a range of records defined based on, for example, a measurement, a timestamp, or something similar. Sensor 110 responds with request data until all previously unsent data in sensor 110's memory has been delivered to the data receiving device 120. Sensor 110 can respond to a backfill request from data receiving device 120 indicating that all data has already been sent. Once backfilling is complete, data receiving device 120 can notify sensor 110 that it is ready to receive periodic measurements. Sensor 110 may repeatedly send measurements across multiple notification results. As embodied herein, multiple notifications may be redundant to ensure that data is transmitted correctly. Alternatively, multiple notifications may constitute a single payload.

[0122] For illustrative purposes only, not limiting, an exemplary embodiment of the procedure for sending a shutdown command to sensor 110 is referenced. The shutdown operation is performed, for example, if sensor 110 is in an error state, an insertion failure state, or a sensor timeout state. If sensor 110 is not in any of these states, sensor 110 logs the command and can perform a shutdown when sensor 110 transitions to an error state or a sensor timeout state. The data receiving device 120 sends a properly formatted shutdown command to sensor 110. If sensor 110 is actively processing another command, sensor 110 will respond with a standard error response indicating that sensor 110 is busy. Otherwise, sensor 110 sends a response when the command is received. In addition, sensor 110 sends a success notification through the sensor control characteristics to confirm that sensor 110 has received the command. Sensor 110 registers the shutdown command. At the next appropriate opportunity (for example, depending on the current sensor state as described herein), sensor 110 shuts down.

[0123] L. Exemplary sensor status and startup For illustrative purposes only, not limitation, an exemplary embodiment of the state machine representation 6000, a high-level description of the actions that can be performed by the sensor 110, is referred to, as shown in Figure 15. After initialization, the sensor enters a state 6005 related to the manufacturing of the sensor 110. In the manufacturing state 6005, the sensor 110 can be configured to operate, for example, by writing to the storage memory 5030. At various points while in state 6005, the sensor 110 checks for incoming commands to transition to the storage state 6015. Upon entering the storage state 6015, the sensor performs a software integrity check. While in the storage state 6015, the sensor may also receive an activation request command before proceeding to the insertion detection state 6025.

[0124] Upon entering state 6025, the sensor 110 can either store information about the authenticated device for communicating with the sensor, as configured during startup, or initialize algorithms related to performing and interpreting measurements from the sensing hardware 5060. The sensor 110 can also initialize a lifecycle timer responsible for maintaining an active count of the sensor 110's operating time and initiate communication with the authenticated device for transmitting recorded data. While in insertion detection state 6025, the sensor can enter state 6030, where the sensor 110 checks whether the operating time is equal to a predetermined threshold. This operating time threshold can correspond to a timeout function for determining whether insertion was successful. If the operating time reaches the threshold, the sensor 110 proceeds to state 6035, where the sensor 110 checks whether the average data reading is greater than a threshold amount corresponding to the expected data reading to trigger insertion success detection. If the data reading is lower than the threshold while in state 6035, the sensor proceeds to state 6040, which corresponds to insertion failure. If the data reading meets the threshold, the sensor proceeds to active pair state 6055.

[0125] The active pair state 6055 of sensor 110 reflects the state while sensor 110 is operating normally by recording, processing, and reporting measurement values ​​as appropriate. While in the active pair state 6055, sensor 110 attempts to transmit measurement results or establish a connection with the receiving device 120. Sensor 110 also increments its operating time. When sensor 110 reaches a predetermined operating threshold time (for example, when the operating time reaches a predetermined threshold), sensor 110 transitions to the active timeout state 6065. The active timeout state 6065 of sensor 110 reflects the state while sensor 110 is operating for a predetermined maximum time.

[0126] While in the active timeout state 6065, the sensor 110 can generally perform actions related to the termination of operation and ensuring that collected measurements have been securely transmitted to a receiving device as needed. For example, while in the active timeout state 6065, the sensor 110 can transmit collected data and, if no connection is available, can intensify attempts to find a nearby authenticated device and establish a connection with it. While in the active timeout state 6065, the sensor 110 can receive a shutdown command in state 6070. If no shutdown command is received, the sensor 110 can also check in state 6075 whether the operating time has exceeded the final operating threshold. The final operating threshold can be based on the battery life of the sensor 110. The normal termination state 6080 corresponds to the final operation of the sensor 110 and the final shutdown of the sensor 110.

[0127] Before the sensor becomes active, the ASIC5000 is in a low-power storage mode state. The startup process can be initiated, for example, when the voltage of the power supply to the ASIC5000 is driven above a reset threshold by an input RF electromagnetic field (e.g., an NFC electromagnetic field), thereby causing the sensor 110 to enter a wake-up state. While in the wake-up state, the ASIC5000 enters a startup sequence state. Next, the ASIC5000 starts up the communication module 5040. The communication module 5040 is initialized, and a power-on self-test is triggered. The power-on self-test may include the ASIC5000 communicating with the communication module 5040 using a predetermined sequence of data reads and writes to verify that the memory and one-time programmable memory are not corrupted.

[0128] When the ASIC5000 first enters measurement mode, it performs an insertion detection sequence to verify that the sensor 110 is properly attached to the patient's body before performing appropriate measurements. First, the sensor 110 interprets a command to initiate the measurement setup process, causing the ASIC5000 to enter measurement command mode. Next, the sensor 110 temporarily enters a measurement lifecycle state and performs a number of consecutive measurements to test whether the insertion was successful. The communication module 5040 or the ASIC5000 evaluates the measurement results to determine whether the insertion was successful. If the insertion is deemed successful, the sensor 110 enters a measurement state, in which case the sensor 110 uses the sensing hardware 5060 to begin periodic measurements. If the sensor 110 determines that the insertion was unsuccessful, the sensor 110 is triggered into insertion failure mode, the ASIC5000 is instructed to return to storage mode, and the communication module 5040 is disabled.

[0129] M. Exemplary Wireless Update Figure 1B further illustrates an exemplary operating environment for providing over-the-air ("OTA") updates for use with the technologies described herein. An operator of the analyte monitoring system 100 can provide updates for the data receiving device 120 or sensor 110 together with updates for applications running on the multipurpose data receiving device 130. Using the available communication channels between the data receiving device 120, the multipurpose data receiving device 130, and the sensor 110, the multipurpose data receiving device 130 can receive periodic updates for the data receiving device 120 or sensor 110 and initiate the installation of the updates to the data receiving device 120 or sensor 110. Since the applications that enable the multipurpose data receiving device 130 to communicate with the analyte sensor 110, the data receiving device 120, and / or the remote application server 150 can update the software or firmware on the data receiving device 120 or sensor 110 without using wide-area network capabilities, the multipurpose data receiving device 130 functions as an installation or update platform for the data receiving device 120 or sensor 110.

[0130] As embodied herein, a remote application server 150 operated by the manufacturer of the analyte sensor 110 and / or the operator of the analyte monitoring system 100 can provide software and firmware updates to the devices of the analyte monitoring system 100. In certain embodiments, the remote application server 150 can provide the updated software and firmware to the user device 140 or directly to the multipurpose data receiving device. As embodied herein, the remote application server 150 can also provide application software updates to the application storefront server 160 using an interface provided by the application storefront. The multipurpose data receiving device 130 can periodically contact the application storefront server 160 to download and install the updates.

[0131] After the multipurpose data receiving device 130 downloads an application update, including a firmware or software update for the data receiving device 120 or sensor 110, the data receiving device 120 or sensor 110 and the multipurpose data receiving device 130 establish a connection. The multipurpose data receiving device 130 determines that the firmware or software update is available to the data receiving device 120 or sensor 110. The multipurpose data receiving device 130 can prepare the software or firmware update for distribution to the data receiving device 120 or sensor 110. For example, the multipurpose data receiving device 130 can compress or segment the data related to the software or firmware update, encrypt or decrypt the firmware or software update, or perform an integrity check on the firmware or software update. The multipurpose data receiving device 130 transmits the data for the firmware or software update to the data receiving device 120 or sensor 110. The multipurpose data receiving device 130 can also send a command to the data receiving device 120 or sensor 110 to initiate the update. Additionally or alternatively, the multipurpose data receiving device 130 may provide a notification to its user, which may include instructions for use to facilitate updates, such as instructions to keep the data receiving device 120 and the multipurpose data receiving device 130 connected to a power source and in very close proximity until the update is complete.

[0132] The data receiving device 120 or sensor 110 receives update data and a command to start the update from the multipurpose data receiving device 130. The data receiving device 120 can then install the firmware or software update. To install the update, the data receiving device 120 or sensor 110 can either place itself into a so-called "safe" mode with limited functionality or restart. Once the update is complete, the data receiving device 120 or sensor 110 returns to standard operating mode or is reset to standard operating mode. The data receiving device 120 or sensor 110 can perform one or more self-tests to determine that the firmware or software update has been successfully installed. The multipurpose data receiving device 130 can receive notification of the update's success. The multipurpose data receiving device 130 can then report the confirmation of the successful update to the remote application server 150.

[0133] In certain embodiments, the storage memory 5030 of the sensor 110 includes one-time programmable (OTP) memory. The term OTP memory can refer to memory that includes access restrictions and security that facilitate a predetermined number of writes to a specific address or segment within the memory. The memory 5030 can be pre-configured into a plurality of pre-allocated memory blocks or containers. The containers are pre-allocated to a fixed size. If the storage memory 5030 is one-time programmable memory, the containers can be considered to be in a non-programmable state. Additional containers that have not yet been written to can be made programmable or writable. Containerizing the storage memory 5030 in this manner can improve the portability of code and data written to the storage memory 5030. Software updates of a device stored in OTP memory (e.g., the sensor device described herein) can be performed by replacing only the code in a specific one or more previously written container with updated code written to a new one or more containers, rather than replacing the entire code in the memory. In a second embodiment, the memory is not pre-configured. Instead, the space allocated for data is dynamically allocated or determined as needed. Because you can define containers of various sizes where updates are expected, you can provide incremental updates.

[0134] Figure 16 is a diagram illustrating exemplary operation and data flow for over-the-air (OTA) programming of storage memory 5030 in sensor device 100, and for the use of memory after OTA programming in the execution of a process by sensor device 110, according to the disclosed subject matter. In the example of OTA programming 500 shown in Figure 5, a request is sent from an external device (e.g., data receiving device 130) to initiate OTA programming (or reprogramming). At 511, the communication module 5040 of sensor device 110 receives the OTA programming command. The communication module 5040 sends the OTA programming command to the microcontroller 5010 of sensor device 110.

[0135] In step 531, after receiving an OTA programming command, the microcontroller 5010 verifies the OTA programming command. The microcontroller 5010 can, for example, determine whether the OTA programming command is signed with an appropriate digital signature token. If the OTA programming command is determined to be valid, the microcontroller 5010 can set the sensor device to OTA programming mode. In step 532, the microcontroller 5010 can verify the OTA programming data. In step 533, the microcontroller 5010 can reset the sensor device 110 to reinitialize it into a programming state. Once the sensor device 110 has transitioned to the OTA programming state, the microcontroller 5010 can, in step 534, begin writing data to the rewritable memory 540 (e.g., memory 5020) of the sensor device, and in step 535, begin writing data to the OTP memory 550 (e.g., storage memory 5030) of the sensor device. The data written by the microcontroller 5010 can be based on the verified OTA programming data. The microcontroller 5010 can write data to one or more programming blocks or areas in the OTP memory 550 to mark them as invalid or inaccessible. The invalid or inaccessible programming blocks in the OTP memory 550 can be replaced with the data written to the free or unused portion of the OTP memory. After the microcontroller 5010 has written data to the respective memories in 534 and 535, the microcontroller 5010 can perform one or more software integrity checks to confirm that no errors were introduced into the programming blocks during the writing process. Once the microcontroller 5010 determines that the data was written without errors, the microcontroller 5010 can resume the standard operation of the sensor device.

[0136] In execution mode, at 536, the microcontroller 5010 can retrieve a programming manifest or profile from the rewritable memory 540. The programming manifest or profile may contain a list of valid software programming blocks and may include guidance for programming the sensor 110. By following the programming manifest or profile, the microcontroller 5010 can determine which memory blocks in the OTP memory 550 are suitable for execution, thereby avoiding the execution of expired or invalid programming blocks or references to expired data. At 537, the microcontroller 5010 can selectively retrieve memory blocks from the OTP memory 550. At 538, the microcontroller 5010 can use the retrieved memory blocks by executing the stored programming code or by using variables stored in memory.

[0137] N. Exemplary security and other architectural features As embodied herein, the first layer of security for communication between the analyte sensor 110 and other devices is specified by the communication protocol used for communication and can be established based on a security protocol integrated into the communication protocol. Another layer of security may be based on a communication protocol that requires the communicating devices to be in very close proximity. Furthermore, certain packets and / or certain data contained within packets may be encrypted, while other packets and / or data within packets may be encrypted or not encrypted in a different manner. Additionally or alternatively, application layer encryption can be used with one or more block ciphers or stream ciphers to establish mutual authentication and communication encryption with other devices in the analyte monitoring system 100.

[0138] The ASIC 5000 of the analyte sensor 110 can be configured to dynamically generate authentication and encryption keys using data held in the storage memory 5030. The storage memory 5030 can also be pre-programmed with a set of valid authentication and encryption keys for use with a specific class of devices. The ASIC 5000 can further be configured to perform authentication procedures with other devices using received data and to apply the generated keys to sensitive data before transmitting the sensitive data. The generated keys may be specific to the analyte sensor 110, specific to a pair of devices, specific to a communication session between the analyte sensor 110 and other devices, specific to a message transmitted during the communication session, or specific to a block of data contained within a message.

[0139] Both the sensor 110 and the data receiving device 120 can, for example, issue commands or receive data, after ensuring the authentication of the other party in the communication session. In certain embodiments, identity authentication can be performed through two feature parts. First, the party claiming its identity provides a verified certificate signed by the device manufacturer or the operator of the analyte monitoring system 100. Second, authentication can be performed through the use of a public key and a private key, and a shared secret derived therefrom, established by the device of the analyte monitoring system 100 or by the operator of the analyte monitoring system 100. To verify the identity of the other party, the other party can provide evidence that they are in control of the private key.

[0140] The manufacturer of the analyte sensor 110, the data receiving device 120, or the provider of the application for the multipurpose data receiving device 130 can provide the information and programming necessary for the devices to communicate securely through secure programming and updates. For example, the manufacturer can provide information that can be used to generate encryption keys for each device, including a secure root key for the analyte sensor 110 and for the data receiving device 120, which can optionally be used in combination with device-specific information and, as needed, operational data (e.g., entropy-based random values) to generate encryption values ​​specific to the device, session, or data transmission. The analyte data associated with a user is confidential, at least in part, as it may be used for a variety of purposes, including monitoring health status and determining medication. In addition to user data, the analyte monitoring system 100 can implement enhanced security against attempts at reverse engineering by external parties. Communication connections can be encrypted using device-specific or session-specific encryption keys. Encrypted or unencrypted communications between any two devices can be verified using transmission integrity checks built into the communications. The operation of the analyte sensor 110 can be protected from tampering by restricting access to read and write functions to memory 5020 via the communication interface. The sensor can be configured to allow access only to known devices or "high-reliability" devices provided on a "whitelist," or only to devices that can provide a predetermined code associated with a manufacturer or otherwise authenticated user. The whitelist can represent an exclusive range meaning that connection identifiers other than those included in the whitelist will not be used, or a priority range where the whitelist is searched first, but other devices can still be used. Furthermore, the sensor 110 can reject the connection request and shut down if the requester fails to complete the login procedure via the communication interface within a predetermined time (e.g., within 4 seconds). These characteristics protect against certain denial-of-service attacks, particularly those against the BLE interface.

[0141] As embodied herein, the analyte monitoring system 100 may employ periodic key rotation to further reduce the potential for key security breaches and exploits. The key rotation strategy employed by the analyte monitoring system 100 may be designed to support backward compatibility of field-deployed or distributed devices. As an example, the analyte monitoring system 100 may employ keys for downstream devices (e.g., field-deployed devices or devices for which updates cannot be pragmatically provided) that are designed to be compatible with multiple generations of keys used by upstream devices.

[0142] For illustrative purposes only, and not limiting, an exemplary embodiment of the message sequence diagram 600 for use in the disclosed subject matter will be shown, as in Figure 17, illustrating an example of data exchange between a pair of devices, in particular a sensor 110 and a data receiving device 120. The data receiving device 120 may be a data receiving device 120 or a multipurpose data receiving device 130, as embodied herein. In step 605, the data receiving device 120 may send a sensor activation command 605 to the sensor 110, for example, via a short-range communication protocol. The sensor 110 may be in a dormant state prior to step 605 and may conserve its battery until a full activation is required. After activation in step 610, the sensor 110 may collect data or perform other appropriate operations on the sensing hardware 5060 of the sensor 110. In step 615, the data receiving device 120 may initiate an authentication request command 615. In response to the authentication request command 615, both the sensor 110 and the data receiving device 120 may participate in a mutual authentication process 620. The mutual authentication process 620 may involve the transfer of data, including a challenge parameter that enables the sensor 110 and the data receiving device 120 to ensure that the other device can adequately comply with the agreed security framework described herein. Mutual authentication can verify the establishment of a secret key via challenge / response, based on a mechanism for mutually authenticating two or more entities, with or without an online highly trusted third party. Mutual authentication can be performed using two, three, four, or five authentications, or similar versions thereof.

[0143] After the mutual authentication process 620 is successful, in step 625, the sensor 110 can provide the data receiving device 120 with a sensor secret 625. The sensor secret may include a sensor-specific value, which may be derived from a random value generated during manufacturing. The sensor secret may be encrypted before or during transmission to prevent third parties from accessing the secret. The sensor secret 625 may be encrypted via one or more keys generated by or in response to the mutual authentication process 620. In step 630, the data receiving device 120 may derive a sensor-specific encryption key from the sensor secret. The sensor-specific encryption key may also be session-specific. Thus, the sensor-specific encryption key can be determined by each device without being transmitted between the sensor 110 and the data receiving device 120. In step 635, the sensor 110 may encrypt the data contained in the payload. In step 640, the sensor 110 can transmit the encrypted payload 640 to the data receiving device 120 using the communication link established between the sensor 110 and the appropriate communication model of the data receiving device 120. In step 645, the data receiving device 120 can decrypt the payload using the sensor-specific encryption key derived during step 630. Following step 645, the sensor 110 can deliver additional data (including newly collected data), and the data receiving device 120 can process the received data appropriately.

[0144] As discussed herein, sensor 110 may be a device with limited processing power, battery supply, and storage. The encryption technology used by sensor 110 (e.g., the choice of cryptographic algorithm or implementation of the algorithm) can be selected at least in part on the basis of these limitations. Data receiving device 120 may be a more powerful device with fewer of these constraints. Therefore, data receiving device 120 can employ more sophisticated, computationally intensive encryption technologies, such as cryptographic algorithms and implementations.

[0145] O. Exemplary payload / communication frequency The analyte sensor 110 can be configured to modify its discoverability behavior in an attempt to increase the probability that a receiving device will receive appropriate data packets and / or provide an acknowledgment signal, or otherwise mitigate limitations that may prevent the reception of an acknowledgment signal. Modifications to the discoverability behavior of the analyte sensor 110 include, but are not limited to, changing how often data packets contain connection data, changing how often data packets are transmitted in general and extending or shortening the broadcast window of data packets, changing the time the analyte sensor 110 listens for an acknowledgment or scan signal after a broadcast, for example, to one or more devices that have previously communicated with the analyte sensor 110 and / or to one or more devices on a whitelist (e.g., through one or more transmission attempts), changing the transmission power associated with the communication module when broadcasting data packets (e.g., to extend the broadcast range or to reduce energy consumption and extend the battery life of the analyte sensor), changing the rate of data packet preparation and broadcasting, or one or more other modifications in combination. Additionally or alternatively, a receiving device can similarly adjust parameters related to its listening behavior to increase the likelihood of receiving data packets containing connection data.

[0146] As embodied herein, the analyte sensor 110 can be configured to broadcast data packets using two types of windows. The first window refers to the rate at which the analyte sensor 110 is configured to operate the communication hardware. The second window refers to the rate at which the analyte sensor 110 is configured to actively transmit (e.g., broadcast) data packets. As an example, the first window may indicate that the analyte sensor 110 operates the communication hardware to transmit and / or receive data packets (including connection data) during the first two seconds of each 60-second period. The second window may indicate that during each two-second window, the analyte sensor 110 transmits data packets every 60 milliseconds. The remainder of the two-second period is spent by the analyte sensor 110 scanning. The analyte sensor 110 can modify the discoverability behavior of the analyte sensor 110 by extending or shortening either window.

[0147] In certain embodiments, the discoverability behavior of the analyte sensor can be stored in a discoverability profile, and modifications can be made based on one or more factors, such as the status of the analyte sensor 110, and / or by applying rules based on the status of the analyte sensor 110. For example, if the battery level of the analyte sensor 110 falls below a certain level, the rules can cause the analyte sensor 110 to reduce the power consumed by the broadcast process. As another example, configuration settings related to broadcasting or otherwise transmitting packets can be adjusted based on ambient temperature, the temperature of the analyte sensor 110, or the temperature of a specific component of the communication hardware of the analyte sensor 110. In addition to modifying the transmit power, other parameters related to the transmit capability or process of the communication hardware of the analyte sensor 110, such as, but not limited to, transmit speed, frequency, and timing, can be modified. As yet another example, if the analyte data indicates that the subject is experiencing or is experiencing a negative health event, the rules can increase the discoverability of the analyte sensor 110 to alert the receiving device of the negative health event.

[0148] P. Exemplary Sensor Sensitivity Initialization / Adjustment Feature Section As embodied herein, certain calibration feature portions of the sensing hardware 5060 of the analyte sensor 110 can be adjusted based on an external environment feature portion or an interval environment feature portion, and to compensate for degradation of the sensing hardware 5060 during periods of non-use (e.g., a “storage period” before use). The calibration feature portions of the sensing hardware 5060 can be adjusted autonomously by the sensor 110 (e.g., by the operation of the ASIC 5000 to modify feature portions in memory 5020 or storage 5030), or by other devices of the analyte monitoring system 100.

[0149] As an example, the sensor sensitivity of the sensing hardware 5060 can be adjusted based on external temperature data or time since manufacture. If the external temperature is monitored during storage of the sensor, the subject of disclosure is that the compensation for sensor sensitivity can be adaptively changed over time as the device encounters changes in storage conditions. For illustrative purposes rather than limitation, adaptive sensitivity adjustment can be performed in an "active" storage mode in which the analyte sensor 110 wakes up periodically to measure temperature. These feature parts can conserve the battery of the analyte device and extend the life of the analyte sensor. In each temperature measurement, the analyte sensor 110 can calculate the sensitivity adjustment for that period based on the measured temperature. The temperature weighted adjustments can then be accumulated over the active storage mode period to calculate the total sensor sensitivity adjustment value at the end of the active storage mode (e.g., at insertion). Similarly, upon insertion, the sensor 110 can determine the time difference between the manufacturing of the sensor 110 (which can be written to the storage 5030 of the ASIC 5000) or the sensing hardware 5060, and modify the sensor sensitivity or other calibration feature portion according to one or more known attenuation rates or formulas.

[0150] Furthermore, for illustrative purposes rather than limitation, as embodied herein, sensor sensitivity adjustments may take into account other sensor conditions, such as sensor drift. Sensor sensitivity adjustments may be hardcoded into the sensor 110 during manufacturing, for example, based on an estimate of how much the average sensor drifts, in the case of sensor drift. The sensor 110 may use a calibration function having time-varying functions of sensor offset and gain that can account for drift over the sensor's wear period. Thus, the sensor 110 may utilize a device-dependent function that describes the drift of the sensor 110 over time, utilizing a function used to convert interstitial current to interstitial glucose, which can represent sensor sensitivity and, in combination with a baseline of glucose profiles, can be device-specific. Such a function that takes into account sensor sensitivity and drift can improve the accuracy of the sensor 110 over its wear period without requiring user calibration.

[0151] Q. Exemplary model-based analyte measurement Sensor 110 detects raw measurement values ​​from sensing hardware 5060. Processing on the sensor can be performed by one or more models trained to interpret the raw measurement values. The models may be machine learning models trained off-device to detect, predict, or interpret the raw measurement values ​​to detect, predict, or interpret the levels of one or more analytes. Additional trained models can operate on the output of machine learning models trained to interact with raw measurement values. As an example, the models can be used to detect, predict, or recommend events based on the raw measurement values ​​and analyte types detected by sensing hardware 5060. Events include the start or end of physical activity, meals, medical procedures or drug applications, urgent health events, and other events of a similar nature.

[0152] The model may be installed on the sensor 110, the data receiving device 120, or the multipurpose data receiving device 130 during manufacturing or firmware or software updates. The model may be periodically improved by the manufacturer of the sensor 110 or the operator of the analyte monitoring system 100, etc., based on data received from the sensor 110 and, collectively, from the data receiving devices of individual users or multiple users. In certain embodiments, the sensor 110 includes sufficient computational components to support further training or improvement of the machine learning model, such as based on the unique feature portion of the user to whom the sensor 110 is attached. Examples of machine learning models, but not limited to, include models trained using decision tree analysis, gradient boosting, ADA boosting, artificial neural networks or their variations, linear discriminant analysis, nearest neighbor analysis, support vector machines, supervised or unsupervised classification, or models including these. In addition to machine learning models, models may also include algorithmic models or rule-based models. Model-based processing may be performed by other devices, including the data receiving device 120 or the multipurpose data receiving device 130, upon receiving data from the sensor 110 (or other downstream devices).

[0153] R. Exemplary alarm feature portion The data transmitted between the sensor 110 and the data receiving device 120 may include unprocessed or processed measurements. The data transmitted between the sensor 110 and the data receiving device 120 may further include alarms or notifications for display to the user. The data receiving device 120 may display or otherwise communicate notifications to the user based on the unprocessed or processed measurements, or may display alarms when received from the sensor 110. Alarms triggered for display to the user include alarms based directly on the value of the analyte (e.g., if a single reading exceeds or falls below a threshold value), trends in analyte values ​​(e.g., whether the average reading over a period of time exceeds or falls below a threshold; slope), predictions of analyte values ​​(e.g., if an algorithmic calculation based on the analyte value exceeds or falls below a threshold), sensor warnings (e.g., a suspected malfunction has been detected), communication warnings (e.g., no communication between sensor 110 and data receiving device 120 for a threshold period; an unknown device attempting to start a communication session with sensor 110 or failing to start one), reminders (e.g., a reminder to charge data receiving device 120; a reminder to take medication or perform other activities), and other alerts of a similar nature. For illustrative purposes only, not limiting, the alarm parameters described herein, as embodied herein, may be configurable by the user, fixed during manufacturing, or a combination of user-configurable and non-user-configurable parameters.

[0154] S. Exemplary configuration Sensor configurations featuring a single active region configured for the detection of a corresponding single analyte can employ two-electrode or three-electrode detection motifs, as will be further described herein with reference to Figures 18A-18C. Sensor configurations featuring two different active regions for detecting the same or different analytes, either on separate working electrodes or on the same working electrode, will be described separately thereafter with reference to Figures 19A-21C. Sensor configurations with multiple working electrodes are particularly advantageous when incorporating two different active regions within the same sensor tail, as the signal contribution from each active region can be more easily determined. When a single working electrode is present within the analyte sensor, a three-electrode sensor configuration includes a working electrode, a counter electrode, and a reference electrode. A related two-electrode sensor configuration may include a working electrode and a second electrode, the second electrode may function as both a counter electrode and a reference electrode (i.e., a counter / reference electrode). The various electrodes may be at least partially stacked on top of each other (layered) and / or spaced laterally from each other on the sensor tail. Preferred sensor configurations may be substantially flat, substantially cylindrical, or any other preferred shape. In any of the sensor configurations disclosed herein, the various electrodes may be electrically insulated from each other by a dielectric material or similar insulator. Similarly, an analyte sensor featuring multiple working electrodes may include at least one additional electrode. If there is one additional electrode, it can function as a counter / reference electrode for each of the multiple working electrodes. If there are two additional electrodes, one of the additional electrodes can function as a counter electrode for each of the multiple working electrodes, and the other additional electrode can function as a reference electrode for each of the multiple working electrodes.

[0155] Figure 18A shows an exemplary two-electrode analyte sensor configuration suitable for use in the disclosure herein. As shown, the analyte sensor 200 includes a substrate 30212 positioned between a working electrode 214 and a counter electrode / reference electrode 30216. Alternatively, the working electrode 214 and the counter electrode / reference electrode 30216 may be positioned on the same side of the substrate 30212 with a dielectric material in between (configuration not shown). An active region 218 is positioned as at least one layer on at least a portion of the working electrode 214. The active region 218 may include multiple spots or a single spot configured for analyte detection, as further discussed herein.

[0156] Referring further to Figure 18A, the film 220 overcoats at least the active region 218. In certain embodiments, the film 220 may also overcoat part or all of the working electrode 214 and / or the counter electrode / reference electrode 30216, or the entire analyte sensor 200. One or both sides of the analyte sensor 200 may be overcoated with the film 220. The film 220 may include one or more polymer film materials having the ability to restrict the flux of analyte to the active region 218 (i.e., the film 220 is a material transport restriction film having some degree of permeability to the analyte of interest). According to the disclosure herein, the film 220 may be crosslinked using a branched-chain crosslinking agent in certain sensor configurations. The composition and thickness of the film 220 may be varied to facilitate the flux of a desired analyte to the active region 218, thereby providing a desired signal intensity and stability. The analyte sensor 200 may be capable of assaying the analyte by any of the following electrochemical detection techniques: coulometry, amperometry, voltammetry, or potentiometric analysis.

[0157] Figures 18B and 18C show diagrams of exemplary three-electrode analyte sensor configurations, which are also suitable for use in the disclosure herein. The three-electrode analyte sensor configuration may be similar to that shown for analyte sensor 200 in Figure 18A (Figures 18B and 18C), except that an additional electrode 217 is included for analyte sensors 201 and 202. With the additional electrode 217, the counter electrode / reference electrode 30216 can function as either the counter electrode or the reference electrode, and the additional electrode 217 performs other electrode functions not otherwise considered. The working electrode 214 continues to perform its original function. The additional electrode 217 can be placed on either the working electrode 214 or electrode 30216, with a dielectric material separator layer in between. For example, but not limited to, as shown in Figure 18B, dielectric layers 219a, 219b, and 219c separate electrodes 214, 30216, and 217 from each other and provide electrical insulation. Alternatively, as shown in Figure 18C, at least one of electrodes 214, 30216, and 217 can be placed on the opposing surface of the substrate 30212. Thus, in certain embodiments, electrode 214 (working electrode) and electrode 30216 (counter electrode) can be placed on the opposing surface of the substrate 30212, and electrode 217 (reference electrode) can be placed on either electrode 214 or 30216 and separated from them by a dielectric material. A reference material layer 230 (e.g., Ag / AgCl) can be present on electrode 217, but the location of the reference material layer 230 is not limited to the locations shown in Figures 18B and 18C. Similar to the sensor 200 shown in Figure 18A, the active region 218 of the analyte sensors 201 and 202 can include multiple spots or a single spot. Furthermore, the analyte sensors 201 and 202 may be operable to assay the analyte by any of the electrochemical detection techniques, such as coulometry, amperometry, voltammetry, or potentiometric analysis.

[0158] Similar to the analyte sensor 200, the film 220 can also overcoat the active region 218 and other sensor components of the analyte sensors 201 and 202, thereby functioning as a material transport limiting film. In certain embodiments, an additional electrode 217 can be overcoated with film 220. In Figures 18B and 18C, electrodes 214, 30216, and 217 are shown to be overcoated with film 220, but it should be noted that in certain embodiments, only the working electrode 214 is overcoated. Furthermore, the thickness of film 220 on each of electrodes 214, 30216, and 217 may be the same or different. Similar to the two-electrode analyte sensor configuration (Figure 18A), in the sensor configurations of Figures 18B and 18C, one or both sides of the analyte sensors 201 and 202 can be overcoated with film 220, or the entire analyte sensors 201 and 202 can be overcoated. Therefore, the three-electrode sensor configuration shown in Figures 18B and 18C is not intended to limit the embodiments disclosed herein, and alternative electrode and / or layer configurations should be understood to be within the scope of this disclosure.

[0159] Figure 19A shows an exemplary configuration of a sensor 203 having a single working electrode on which two different active regions are positioned. Figure 19A is similar to Figure 18 except for the presence of two active regions on the working electrode 214: a first active region 218a and a second active region 218b, which respond to different analytes and are spaced laterally apart from each other on the surface of the working electrode 214. The active regions 218a and 218b may include multiple spots or a single spot configured for the detection of each analyte. The composition of the film 220 may be different in the active regions 218a and 218b, or they may be compositionally the same. The first active region 218a and the second active region 218b may be configured to detect the corresponding analytes at different working electrode potentials, as will be further discussed below.

[0160] Figures 19B and 19C show cross-sectional views of exemplary three-electrode sensor configurations of sensors 204 and 205, each featuring a single working electrode with a first active region 218a and a second active region 218b, respectively. Figures 19B and 19C are otherwise similar to Figures 18B and 18C and can be better understood by referring to them. As with Figure 19A, the composition of the film 220 can be varied or compositionally the same in the active regions 218a and 218b.

[0161] Exemplary sensor configurations having multiple working electrodes, specifically two working electrodes, will be described in more detail with reference to Figures 20-21C. While the following description primarily focuses on sensor configurations with two working electrodes, it should be understood that three or more working electrodes can be incorporated through extensions of the disclosure herein. Additional working electrodes can be used to provide the analyte sensor with additional detection capabilities beyond the first and second analytes, for example, to detect a third and / or fourth analyte.

[0162] Figure 20 shows a cross-sectional view of an exemplary analyte sensor configuration having two working electrodes, a reference electrode, and a counter electrode, suitable for use in the disclosure herein. As shown, the analyte sensor 300 includes working electrodes 304 and 306 disposed on opposing surfaces of a substrate 302. A first active region 310a is located on the surface of the working electrode 304, and a second active region 310b is located on the surface of the working electrode 306. The counter electrode 320 is electrically insulated from the working electrode 304 by a dielectric layer 322, and the reference electrode 321 is electrically insulated from the working electrode 306 by a dielectric layer 323. Outer dielectric layers 30230 and 332 are located on the reference electrode 321 and the counter electrode 320, respectively. The film 340 can overcoat at least the active regions 310a and 310b according to various embodiments, and other components of the analyte sensor 300 or the entire analyte sensor 300 may also be optionally overcoated with the film 340.

[0163] In certain embodiments, the film 340 may be continuous, but may have different compositions on the active region 310a and / or active region 310b to provide different permeability values ​​for differential control of the analytical flux at each site. For example, different film formulations can be sprayed and / or printed onto the opposing surface of the analyte sensor 300. Dip coating techniques may also be particularly suitable for depositing at least a portion of a bilayer film on one of the active regions 310a and 310b. In certain embodiments, the film 340 may be the same or have different compositions in the active regions 310a and 310b. For example, the film 340 may be homogeneous when overcoating active region 310a and heterogeneous when overcoating active region 310b. In certain embodiments, the film 340 may include a bilayer overcoat active region 310a and a homogeneous film overcoat active region 310b, or the film 340 may include a bilayer overcoat active region 310b and a homogeneous film overcoat active region 310a. In certain embodiments, according to certain embodiments of the present disclosure, one of the first film portion 340a and the second film portion 340b may include a bilayer film, and the other of the first film portion 340a and the second film portion 340b may include a single film polymer. In certain embodiments, the analyte sensor may include two or more films 340, for example, two or more films. For example, but not limited to, the analyte sensor may include a film that overcoats one or more active regions, for example, 310a and 310b, and an additional film that overcoats the entire sensor, as shown in Figure 20. In such a configuration, the bilayer film may be formed on one or more active regions, for example, 310a and 310b. Similar to analyte sensors 200, 201, and 202, analyte sensor 300 may be operable to assay ketones (and / or a second analyte) by any of the electrochemical detection techniques of coulometry, amperometry, voltammetry, or potentiometric analysis.

[0164] Alternative sensor configurations having multiple working electrodes, different from the configuration shown in Figure 20, may feature counter electrodes / reference electrodes instead of separate counter electrodes and reference electrodes 320, 321, and / or feature different characteristic layers and / or film configurations than those explicitly shown. For example, but not limited to, the positioning of counter electrodes 320 and reference electrodes 321 may be reversed from that shown in Figure 20. Furthermore, working electrodes 304 and 306 do not necessarily have to be located on the opposing surface of the substrate 302 in the manner shown in Figure 20.

[0165] While a preferred sensor configuration may feature electrodes having substantially planar characteristics, it should be understood that sensor configurations featuring non-planar electrodes may be advantageous and particularly suitable for use in the disclosure herein. In particular, substantially cylindrical electrodes arranged concentrically with respect to each other can facilitate the deposition of a material transport limiting film, as described below. For example, but not limited to, concentric working electrodes spaced along the length of the sensor tail can facilitate film deposition through a continuous dip-coating operation in a manner similar to that described above for substantially planar sensor configurations. Figures 21A-21C show perspective views of an analyte sensor featuring two working electrodes arranged concentrically with respect to each other. It should be understood that sensor configurations having a concentric electrode arrangement but lacking a second working electrode are also possible in this disclosure.

[0166] Figure 21A shows a perspective view of an exemplary sensor configuration in which multiple electrodes are substantially cylindrical and arranged concentrically around a central substrate. As shown, the analyte sensor 400 includes a central substrate 402, around which all electrodes and dielectric layers are arranged concentrically. In particular, the working electrode 410 is located on the surface of the central substrate 402, and the dielectric layer 412 is located on the distal portion of the working electrode 410 on the sensor chip 404. The working electrode 420 is located on the dielectric layer 412, and the dielectric layer 422 is located on the distal portion of the working electrode 420 on the sensor chip 404. The counter electrode 430 is located on the dielectric layer 422, and the dielectric layer 432 is located on the distal portion of the counter electrode 430 on the sensor chip 404. The reference electrode 440 is located on the dielectric layer 432, and the dielectric layer 442 is located on the distal portion of the reference electrode 440 on the sensor chip 404. Therefore, the exposed surfaces of the working electrode 410, the working electrode 420, the counter electrode 430, and the reference electrode 440 are spaced apart from each other along the longitudinal axis B of the analyte sensor 400.

[0167] Referring further to Figure 21A, a first active region 414a and a second active region 414b, which respond to different or the same analytes, are located on the exposed surfaces of the working electrodes 410 and 420, respectively, thereby enabling contact with the fluid for sensing. Although the active regions 414a and 414b are shown as three separate spots in Figure 21A, it should be understood that in alternative sensor configurations, there may be fewer or more spots, including a continuous layer of active regions. As shown in Figure 21A, the sensor 400 is partially coated with a film 450 over the working electrodes 410 and 420 and the active regions 414a and 414b located thereon. Figure 21B shows an alternative sensor configuration in which substantially the entire sensor 401 is overcoated with film 450. The film 450 may be the same or have different compositions over the active regions 414a and 414b. For example, film 450 may include a bilayer overcoating the active region 414a and a homogeneous film overcoating the active region 414b.

[0168] Furthermore, it should be understood that the positioning of the various electrodes in Figures 21A and 21B may differ from those explicitly shown. For example, the positioning of the counter electrode 430 and the reference electrode 440 may be reversed from the configuration shown in Figures 21A and 21B. Similarly, the positioning of the working electrodes 410 and 420 is not limited to the positions explicitly shown in Figures 21A and 21B. Figure 21C shows an alternative sensor configuration to the sensor configuration shown in Figure 21B, where the sensor 405 includes the counter electrode 430 and the reference electrode 440 positioned more proximal to the sensor chip 404, and the working electrodes 410 and 420 positioned more distal to the sensor chip 404. The sensor configuration in which the working electrodes 410 and 420 are positioned more distal to the sensor chip 404 is advantageous by providing a larger surface area for the deposition of the active regions 414a and 414b (five distinct sensing spots illustrated in Figure 21C), thereby potentially promoting an increase in signal intensity. Similarly, in any concentric sensor configuration disclosed herein, the central substrate 402 can be omitted, and instead the innermost electrode can support a layer to which a subsequent layer is deposited.

[0169] In certain embodiments, one or more electrodes of the analyte sensor described herein are wire electrodes, such as permeable wire electrodes. In certain embodiments, the sensor tail comprises a working electrode and a reference electrode helically wound around the working electrode. In certain embodiments, an insulator is placed between the working electrode and the reference electrode. In certain embodiments, a portion of the electrode is exposed to allow the reaction of the analyte on the electrode with one or more enzymes. In certain embodiments, each electrode is formed from a fine wire having a diameter of about 0.001 inches or less to about 0.010 inches or more. In certain embodiments, the working electrode has a diameter of about 0.001 inches or less to about 0.010 inches or more, for example, about 0.002 inches to about 0.008 inches, or about 0.004 inches to about 0.005 inches. In certain embodiments, the electrodes are formed from a plated insulator, plated wire, or bulk conductive material. In certain embodiments, the working electrode includes a wire formed from a conductive material such as platinum, platinum-iridium, palladium, graphite, gold, carbon, conductive polymer, or alloy. In certain embodiments, the conductive material is a permeable conductive material. In certain embodiments, the electrode can be formed by various manufacturing techniques (e.g., bulk metal treatment, metal deposition on a substrate), and the electrode can be formed from plated wire (e.g., platinum on steel wire) or bulk metal (e.g., platinum wire). In certain embodiments, the electrode is formed from, for example, a tantalum wire coated with platinum.

[0170] In certain embodiments, the reference electrode can function as a reference electrode alone or as a dual reference electrode and counter electrode, and is formed from silver, silver / silver chloride, etc. In certain embodiments, the reference electrode is positioned alongside the working electrode and / or twisted together with or around the working electrode. In certain embodiments, the reference electrode is spirally wound around the working electrode. In certain embodiments, the wire assembly can be coated or bonded with insulating material to provide an insulated mounting. In certain embodiments, additional electrodes may be included in the sensor tail. For example, but not limited to, a three-electrode system (working electrode, reference electrode, and counter electrode) and / or an additional working electrode (e.g., an electrode for detecting a second analyte). In certain embodiments where the sensor has two working electrodes, the two working electrodes may be juxtaposed around the reference electrode where it is located (e.g., spirally wound around two or more working electrodes). In certain embodiments, two or more working electrodes may extend parallel to each other. In certain embodiments, the reference electrode is coiled around the working electrode and extends toward the distal end (i.e., the in vivo end) of the sensor tail. In certain embodiments, the reference electrode extends (e.g., spirally) to the exposed area of ​​the working electrode.

[0171] In certain embodiments, one or more working electrodes are spirally wound around a reference electrode. In certain embodiments where two or more working electrodes are provided, the working electrodes may be formed in a double, triple, quadruple, or more spiral structure along the length of the sensor tail (e.g., surrounding the reference electrode, insulating rod, or other support structure). In certain embodiments, electrodes, for example, two or more working electrodes, are formed coaxially. For example, but not limited to these, all electrodes share the same central axis.

[0172] In certain embodiments, the working electrode includes a tube with a reference electrode disposed inside or coiled, with an insulator in between. Alternatively, the reference electrode includes a tube with a working electrode disposed inside or coiled, with an insulator in between. In certain embodiments, a polymer (e.g., insulating) rod is provided on which one or more electrodes (e.g., one or more electrode layers) are disposed (e.g., by electroplating). In certain embodiments, a metal (e.g., steel or tantalum) rod or wire coated with an insulating material (as described herein) is provided on which one or more working electrodes and reference electrodes are disposed. For example, but not limited to, the Disclosure provides a sensor comprising one or more tantalum wires, e.g., a sensor tail, where a conductive material is disposed on a portion of one or more tantalum wires and functions as a working electrode. In certain embodiments, a platinum-clad tantalum wire is covered with an insulating material, the insulating material is partially covered with a silver / silver chloride composition and functions as a reference electrode and / or counter electrode.

[0173] In certain embodiments where the insulator is placed on the working electrode (e.g., on the platinum surface of the electrode), a portion of the insulator can be peeled off or otherwise removed to expose the electroactive surface of the working electrode. For example, but not limited to, a portion of the insulator can be removed by manual work, excimer laser irradiation, chemical etching, laser ablation, grit blasting, etc. Alternatively, a portion of the electrode can be masked before depositing the insulator to maintain the exposed electroactive surface area. In certain embodiments, the portion of the insulator to be peeled and / or removed may be about 0.1 mm or less to about 2 mm or more in length, for example, about 0.5 mm to about 0.75 mm in length. In certain embodiments, the insulator is a non-conductive polymer. In certain embodiments, the insulator includes parylene, fluorinated polymers, polyethylene terephthalate, polyvinylpyrrolidone, polyurethane, polyimide, and other non-conductive polymers. In certain embodiments, glass or ceramic materials can also be used for the insulator layer. In certain embodiments, the insulator includes parylene. In certain embodiments, the insulator includes polyurethane. In certain embodiments, the insulator comprises polyurethane and polyvinylpyrrolidone. Some parts of the sensor will be explained further below.

[0174] 2. Enzymes The analytic sensors of this disclosure include one or more enzymes for detecting one or more analytics. Enzymes suitable for use in the sensors of this disclosure include, but are not limited to, enzymes for use in detecting glutamate, glucose, ketones, lactate, oxygen, hemoglobin A1C, albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartic acid, asparagine, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, and uric acid. In certain embodiments, enzymes for use in detecting glucose, lactate, ketone, creatinine, alcohol, such as ethanol, may be included in the active region of the analytic sensors disclosed herein. In certain embodiments, one or more enzymes may include a group of enzymes, such as an enzyme system, that respond collectively to the analytics.

[0175] In certain embodiments, one or more active sites of the analytic sensor of the Disclosure may include one or more enzymes that can be used to detect glucose. For example, but not limited to, the analytic sensor of the Disclosure may include a first active region comprising one or more enzymes for detecting glucose. In certain embodiments, the analytic sensor may include an active site comprising glucose oxidase and / or glucose dehydrogenase for detecting glucose. In certain embodiments, the analytic sensor may include an active site comprising glucose oxidase.

[0176] In certain embodiments, one or more active sites of the analytic sensor of the Disclosure may include one or more enzymes that can be used to detect ketones. For example, but not limited to, the analytic sensor of the Disclosure may include a first active region comprising one or more enzymes, e.g., an enzyme system, for detecting ketones. In certain embodiments, the analytic sensor may include an active site comprising β-hydroxybutyrate dehydrogenase. In certain embodiments, the analytic sensor may include an active site comprising β-hydroxybutyrate dehydrogenase and diaphorase for detecting ketones.

[0177] In certain embodiments, one or more active sites of the analytic sensor of the Disclosure may include one or more enzymes that can be used to detect lactate. For example, but not limited to, the analytic sensor of the Disclosure may include a first active region comprising one or more enzymes, e.g., an enzyme system, for detecting lactate. In certain embodiments, the analytic sensor may include an active site comprising lactate dehydrogenase. In certain embodiments, the analytic sensor may include an active site comprising lactate oxidase.

[0178] In certain embodiments, the analytic sensor disclosed herein may include two or more active sites, each active site including at least one enzyme for detecting an analytic. In certain embodiments, each active site may be configured to detect the same analytic or different analytics. For example, but not limited to, the analytic sensor disclosed herein may include a first active site including a first enzyme (or enzyme system) for detecting a first analytic, and a second active site including a second enzyme (or second enzyme system) for detecting a second analytic. Alternatively, the first and second active sites may be used to detect the same analytic, wherein the first and second active sites may include different enzymes (or enzyme systems) or the same enzyme (or enzyme system) for detecting the analytic. In certain embodiments, the analyte sensor disclosed herein may include a sensor tail comprising at least one working electrode and one or more analyte-responsive active regions disposed on the surface of the working electrode. In certain embodiments, the analyte sensor may include two working electrodes, for example, a first active region located on a first working electrode and a second active region located on a second working electrode. In certain embodiments, if the sensor is configured to detect two or more analytes, the detection of each analyte may include applying a potential separately to each working electrode so that distinct signals are obtained from each analyte. The signals obtained from each analyte can then be correlated with the analyte concentration by using a calibration curve or function, or by employing a lookup table. In certain embodiments, the correlation between the analyte signal and the analyte concentration can be achieved through the use of a processor. In certain embodiments, the analyte sensor of this disclosure is configured to detect glucose and ketones.

[0179] In certain other analyte sensor configurations, a first active region and a second active region can be placed on a single working electrode. The first signal can be acquired, for example, from the first active region at a low potential, and the second signal, which includes signal contributions from both active regions, can be acquired at a higher potential. By subtracting the first signal from the second signal, the signal contribution from the second analyte can be determined. The signal contribution from each analyte can then be correlated with the analyte concentration in a manner similar to that described for sensor configurations with multiple working electrodes.

[0180] It should also be understood that the sensitivity (output current) of the analyte sensor to each analyte may vary by changing the scope (area or size) of the active region, the area ratio of the active regions to each other, and the identity, thickness, and / or composition of the mass transport limiting film overcoating the active region. These parameter changes are readily available to those skilled in the art, provided they benefit from the disclosures herein.

[0181] In certain embodiments, the analyte response active region of this disclosure may contain one or more enzymes disclosed herein in amounts of about 10% to about 80% by mass, for example, about 15% to about 75% by mass, about 20% to about 70% by mass, about 25% to about 65% by mass, about 30% to about 60% by mass, or about 20% to about 50% by mass. In certain embodiments, the analyte response active region may contain one or more enzymes disclosed herein in amounts of about 20% to about 70% by mass. In certain embodiments, the analyte response active region may contain one or more enzymes disclosed herein in amounts of about 30% to about 60% by mass. In certain embodiments, the analyte response active region may contain one or more enzymes disclosed herein in amounts of about 30% to about 50% by mass. In certain embodiments, the analyte response active region may contain one or more enzymes disclosed herein in amounts of about 20% to about 50% by mass. In certain embodiments, the analyte response activity region may contain about 20% to about 40% by mass of one or more enzymes disclosed herein.

[0182] In certain embodiments, the analyte response activity region may further include, for example, a stabilizer for stabilizing one or more enzymes. For example, but not limited to, the stabilizer may be albumin, such as serum albumin. Non-limiting examples of serum albumin include bovine serum albumin and human serum albumin. In certain embodiments, the stabilizer is human serum albumin. In certain embodiments, the stabilizer is bovine serum albumin. In certain embodiments, the analyte response activity range of the Disclosure is approximately 100:1 to approximately 1:100, for example, approximately 95:1 to approximately 1:95, approximately 90:1 to approximately 1:90, approximately 85:1 to approximately 1:85, approximately 80:1 to approximately 1:80, approximately 75:1 to approximately 1:75, approximately 60:1 to approximately 1:60, approximately 55:1 to approximately 1:55, approximately 50:1 to approximately 1:50, approximately 45:1 to approximately 1:45, approximately 40:1 to approximately 1:40, approximately 35:1 to approximately 1:35, approximately 30:1 to approximately 1 The analyte-responsive active region may include ratios of a stabilizer, such as serum albumin, to one or more enzymes present in the active region, such as 30, approximately 25:1 to 1:25, approximately 20:1 to 1:20, approximately 15:1 to 1:15, approximately 10:1 to 1:10, approximately 9:1 to 1:9, approximately 8:1 to 1:8, approximately 7:1 to 1:7, approximately 6:1 to 1:6, approximately 5:1 to 1:5, approximately 4:1 to 1:4, approximately 3:1 to 1:3, or approximately 2:1 to 1:2. In certain embodiments, the analyte-responsive active region may include ratios of a stabilizer to one or more enzymes present in the active region, such as approximately 50:1 to 1:50. In certain embodiments, the analyte-responsive active region may include ratios of a stabilizer to one or more enzymes present in the active region, such as approximately 10:1 to 1:10. In certain embodiments, the analyte-responsive active region may include a ratio of stabilizer to one or more enzymes present in the active region, approximately 7:1 to approximately 1:7. In certain embodiments, the analyte-responsive active region may include a ratio of stabilizer to one or more enzymes present in the active region, approximately 6:1 to approximately 1:6. In certain embodiments, the analyte-responsive active region may include a ratio of stabilizer to one or more enzymes present in the active region, approximately 5:1 to approximately 1:5.In certain embodiments, the analyte-responsive active region may include a ratio of stabilizer to one or more enzymes present in the active region, approximately 4:1 to approximately 1:4. In certain embodiments, the analyte-responsive active region may include a ratio of stabilizer to one or more enzymes present in the active region, approximately 3:1 to approximately 1:3. In certain embodiments, the analyte-responsive active region may include a ratio of stabilizer to one or more enzymes present in the active region, approximately 2:1 to approximately 1:2. In certain embodiments, the analyte-responsive active region may include a ratio of stabilizer to one or more enzymes present in the active region, approximately 1:1. In certain embodiments, the analyte-responsive active region may include a stabilizer in an amount of approximately 5% to approximately 50% by mass, for example, approximately 10% to approximately 50% by mass, approximately 15% to approximately 45% by mass, approximately 20% to approximately 40% by mass, approximately 20% to approximately 35% by mass, or approximately 20% to approximately 30% by mass. In certain embodiments, the analyte-responsive active region may contain about 5% to about 40% by mass of stabilizer. In certain embodiments, the analyte-responsive active region may contain about 5% to about 35% by mass of stabilizer. In certain embodiments, the analyte-responsive active region may contain about 5% to about 30% by mass of stabilizer. In certain embodiments, the analyte-responsive active region may contain about 10% to about 30% by mass of stabilizer. In certain embodiments, the analyte-responsive active region may contain about 15% to about 35% by mass of stabilizer.

[0183] In certain embodiments, the analyte response active region, for example, the analyte response active region may further include one or more enzyme cofactors or coenzymes present in the analyte response active region. In certain embodiments, the cofactor is nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) (collectively referred to herein as "NAD(P)"). In certain embodiments, the coenzyme is FAD. In certain embodiments, the analyte response activity region may include cofactor-to-enzyme ratios such as approximately 40:1 to approximately 1:40, for example, approximately 35:1 to approximately 1:35, approximately 30:1 to approximately 1:30, approximately 25:1 to approximately 1:25, approximately 20:1 to approximately 1:20, approximately 15:1 to approximately 1:15, approximately 10:1 to approximately 1:10, approximately 9:1 to approximately 1:9, approximately 8:1 to approximately 1:8, approximately 7:1 to approximately 1:7, approximately 6:1 to approximately 1:6, approximately 5:1 to approximately 1:5, approximately 4:1 to approximately 1:4, approximately 3:1 to approximately 1:3, approximately 2:1 to approximately 1:2, or approximately 1:1. In certain embodiments, the analyte response activity region may include cofactor-to-enzyme ratios such as approximately 5:1 to approximately 1:5. In certain embodiments, the analyte response-active region may include a cofactor-to-enzyme ratio of approximately 4:1 to approximately 1:4. In certain embodiments, the analyte response-active region may include a cofactor-to-enzyme ratio of approximately 3:1 to approximately 1:3. In certain embodiments, the analyte response-active region may include a cofactor-to-enzyme ratio of approximately 2:1 to approximately 1:2. In certain embodiments, the analyte response-active region may include a cofactor-to-enzyme ratio of approximately 1:1. In certain embodiments, the analyte response-active region may include a cofactor-to-enzyme ratio of approximately 10% to approximately 50% by mass, for example, approximately 15% to approximately 45% by mass, approximately 20% to approximately 40% by mass, approximately 20% to approximately 35% by mass, or approximately 20% to approximately 30% by mass of cofactors. In certain embodiments, the analyte response-active region may include a cofactor-to-enzyme ratio of approximately 20% to approximately 40% by mass. In certain embodiments, the analyte response-active region may contain about 20% to 30% by mass of cofactors. In certain embodiments, the analyte response-active region may contain about 15% to 35% by mass of cofactors. In certain embodiments, cofactors, such as NAD(P), can be physically retained within the analyte response-active region.For example, but not limited to, a film overcoating the analyte response-active region may help retain cofactors within the analyte response-active region, while still allowing sufficient internal diffusion of the analyte, thus enabling its detection. In a particular embodiment, the analyte response activity region is approximately 0.01 mm 2 ~approximately 2.0 mm 2 For example, about 0.1 mm 2 ~approximately 1.0 mm 2 Or approximately 0.2 mm 2 ~about 0.5mm 2 It has an area of ​​.

[0184] 3. Oxidation-reduction mediators In certain embodiments, the analyte sensors disclosed herein may include electron transfer agents. For example, but not limited to, one or more active sites of the analyte sensor may include electron transfer agents. In certain embodiments, the analyte sensor may include one active site containing an electron transfer agent and a second active site not containing an electron transfer agent. Alternatively, the analyte sensor may include two active sites, both of which contain electron transfer agents. In certain embodiments, the presence of electron transfer agents in the active region may depend on the composition of the enzyme or enzyme system and / or working electrode used to detect the analyte.

[0185] The electron transfer agents disclosed herein, suitable for use in analyte sensors, can facilitate the transfer of electrons to an adjacent working electrode after the analyte has undergone an enzymatic redox reaction within its corresponding active region, thereby generating a current that indicates the presence of a specific analyte. The amount of current generated is proportional to the amount of analyte present.

[0186] In certain embodiments, suitable electron transfer agents may include electroreducible and electrooxidizing ions, complexes, or molecules (e.g., quinones) having redox potentials several hundred millivolts above or below the redox potential of a standard calomel electrode (SCE). In certain embodiments, redox mediators may include osmium complexes and other transition metal complexes, such as those described in U.S. Patents 6,134,461 and 6,605,200, which are incorporated herein by reference in their entirety. Additional examples of suitable redox mediators include those described in U.S. Patents 6,736,957, 7,501,053, and 7,754,093, the entirety of which is also incorporated herein by reference. Other examples of suitable redox mediators include, for example, metal compounds or complexes of ruthenium, osmium, iron (e.g., polyvinylferrocene or hexacyanoferate), or cobalt, including their metallocene compounds. Suitable ligands for metal complexes may include, for example, bidentate or higher-dentate ligands such as bipyridine, biimidazole, phenanthroline, or pyridyl(imidazole). Other suitable bidentate ligands include, for example, amino acids, oxalic acid, acetylacetone, diaminoalkanes, or o-diaminoarenes. Any combination of monodentate, bidentate, tridentate, tetradentate, or higher-dentate ligands can be present in metal complexes, such as osmium complexes, to achieve a complete coordination sphere. In certain embodiments, the electron transfer agent is an osmium complex. In certain embodiments, the electron transfer agent is osmium complexed with a bidentate ligand.

[0187] In certain embodiments, the electron transfer agents disclosed herein may include suitable functional groups that promote covalent bonding to a polymer (also referred to herein as a polymer backbone) within an active region, as will be further discussed below. For example, but not limited to, electron transfer agents used in this disclosure include polymer-bonded electron transfer agents. Suitable non-limiting examples of polymer-bonded electron transfer agents are those described in U.S. Patents 8,444,834, 8,268,143 and 6,605,201, the entirety of which is incorporated herein by reference. In certain embodiments, a polymer-bonded redox mediator shown in Figure 3 of U.S. Patent 8,444,834 may be used in the sensor of this disclosure.

[0188] In certain embodiments, the analytes of the present disclosure may include: (i) a sensor tail comprising at least a first working electrode; (ii) a first active region disposed on the surface of the first working electrode and responding to the first analyte; and (iii) a mass transport restriction membrane permeable to the first analyte, overcoating at least the first active region. In certain embodiments, the first active region comprises a first redox mediator and at least one enzyme responding to the first analyte. In certain embodiments, the first active region comprises a first polymer, a first redox mediator covalently bonded to the first polymer, and at least one enzyme responding to the first analyte covalently bonded to the first polymer. In certain embodiments, the at least one enzyme responding to the first analyte may include an enzyme system comprising multiple enzymes that respond collectively to the first analyte.

[0189] In certain embodiments, the analyte sensor of the Disclosure may be further configured to analyze a second or subsequent analyte in addition to the analyte detectable in the first active region. To facilitate the detection of the second analyte, the analyte sensor of the Disclosure may further include (iv) a second working electrode, and (v) a second active region disposed on the surface of the second working electrode and responding to a second analyte different from the first analyte. In certain embodiments, the second active region includes a second redox mediator different from the first redox mediator, and at least one enzyme that responds to the second analyte. Alternatively, the second active region includes a second redox mediator which is the same as the first redox mediator. In certain embodiments, the second active region includes a second polymer, a second redox mediator covalently bonded to the second polymer different from the first redox mediator, and at least one enzyme that responds to the second analyte covalently bonded to the second polymer. In certain embodiments, the enzyme system comprising at least one enzyme responding to the second analyte may include a plurality of enzymes that respond collectively to the second analyte. In certain embodiments, the second portion of the mass transport restriction membrane may overcoat the second active region. Alternatively or additionally, the second mass transport restriction membrane may overcoat the second active region, or the second mass transport restriction membrane may overcoat both the second and first active regions. In certain embodiments, the second mass transport restriction membrane comprises a different polymer than the first mass transport restriction membrane. In certain embodiments, the second mass transport restriction membrane comprises the same polymer as the first mass transport restriction membrane, but comprises a different crosslinking agent.

[0190] In certain embodiments, the analyte response activity range of the Disclosure is approximately 100:1 to approximately 1:100, for example, approximately 95:1 to approximately 1:95, approximately 90:1 to approximately 1:90, approximately 85:1 to approximately 1:85, approximately 80:1 to approximately 1:80, approximately 75:1 to approximately 1:75, approximately 60:1 to approximately 1:60, approximately 55:1 to approximately 1:55, approximately 50:1 to approximately 1:50, approximately 45:1 to approximately 1:45, approximately 40:1 to approximately 1:40, approximately 35:1 to approximately 1: The enzyme-to-oxidation-reduction mediator ratios can include 35, approximately 30:1 to 1:30, approximately 25:1 to 1:25, approximately 20:1 to 1:20, approximately 15:1 to 1:15, approximately 10:1 to 1:10, approximately 9:1 to 1:9, approximately 8:1 to 1:8, approximately 7:1 to 1:7, approximately 6:1 to 1:6, approximately 5:1 to 1:5, approximately 4:1 to 1:4, approximately 3:1 to 1:3, or approximately 2:1 to 1:2. In certain embodiments, the analyte response activity region can include enzyme-to-oxidation-reduction mediator ratios of approximately 10:1 to 1:10. In certain embodiments, the analyte response activity region can include enzyme-to-oxidation-reduction mediator ratios of approximately 9:1 to 1:9. In certain embodiments, the analyte response-active region may include an enzyme-to-oxidation-reduction mediator ratio of approximately 8:1 to approximately 1:8. In certain embodiments, the analyte response-active region may include an enzyme-to-oxidation-reduction mediator ratio of approximately 7:1 to approximately 1:7. In certain embodiments, the analyte response-active region may include an enzyme-to-oxidation-reduction mediator ratio of approximately 6:1 to approximately 1:6. In certain embodiments, the analyte response-active region may include an enzyme-to-oxidation-reduction mediator ratio of approximately 5:1 to approximately 1:5. In certain embodiments, the analyte response-active region may include an enzyme-to-oxidation-reduction mediator ratio of approximately 4:1 to approximately 1:4. In certain embodiments, the analyte response-active region may include an enzyme-to-oxidation-reduction mediator ratio of approximately 3:1 to approximately 1:3. In certain embodiments, the analyte response-active region may include an enzyme ratio of approximately 2:1 to approximately 1:2. In certain embodiments, the analyte response activity region may include an enzyme-to-redox mediator ratio of approximately 1:1.

[0191] In certain embodiments, the analyte-responsive region of the disclosed herein may contain about 10% to about 50% by mass of redox mediators, for example, about 15% to about 45% by mass, about 20% to about 40% by mass, about 20% to about 35% by mass, or about 20% to about 30% by mass of redox mediators. In certain embodiments, the analyte-responsive region may contain about 5% to about 35% by mass of redox mediators. In certain embodiments, the analyte-responsive region may contain about 10% to about 35% by mass of redox mediators. In certain embodiments, the analyte-responsive region may contain about 10% to about 30% by mass of redox mediators. In certain embodiments, the analyte-responsive region may contain about 15% to about 35% by mass of redox mediators.

[0192] 4. Polymer backbone In certain embodiments, one or more active sites for facilitating analyte detection may include polymers to which enzymes and / or redox mediators are covalently bonded. Any suitable polymer backbone can be present in the active region to facilitate analyte detection via covalent bonding of enzymes and / or redox mediators. Non-limiting examples of suitable polymers in the active region include polyvinylpyridine, e.g., poly(4-vinylpyridine) or poly(2-vinylpyridine), and polyvinylimidazole, e.g., poly(N-vinylimidazole) and poly(1-vinylimidazole), or copolymers thereof, where, for example, quaternized pyridine groups function as binding sites for redox mediators or enzymes. Examples of suitable copolymers to be included in the active region include those containing monomer units such as styrene, acrylamide, methacrylamide, or acrylonitrile. In certain embodiments, polymers that may be present in the active region include, but are not limited to, those described in U.S. Patent No. 6,605,200, which are incorporated herein by reference in whole, poly(acrylic acid), styrene / maleic anhydride copolymer, methyl vinyl ether / maleic anhydride copolymer (GANTREZ polymer), poly(vinyl benzyl chloride), poly(allylamine), polylysine, poly(4-vinylpyridine) quaternized with carboxypentyl groups, and poly(4-sodium styrenesulfonate). In certain embodiments in which the analyte sensor includes two active sites, the polymers in each active region may be the same or different.

[0193] In certain embodiments, if an enzyme system containing multiple enzymes is present in a given active region, all of the multiple enzymes can be covalently bonded to the polymer. In certain other embodiments, only a subset of the multiple enzymes are covalently bonded to the polymer. For example, but not limited to, one or more enzymes in the enzyme system can be covalently bonded to the polymer, and at least one enzyme can be non-covalently bonded to the polymer, so that the non-covalently bonded enzyme is physically retained within the polymer.

[0194] In certain embodiments, covalent bonding of one or more enzymes and / or redox mediators to a polymer in a given active region may occur via crosslinking introduced by a crosslinking agent. In certain embodiments, crosslinking of the polymer with one or more enzymes and / or redox mediators can reduce the occurrence of delamination of the enzyme composition from the electrode. Suitable crosslinking agents for reactions with free amino groups in enzymes (e.g., reactions with free side-chain amines in lysine) include, for example, polyethylene glycol diglycidyl ether (PEGDGE) or other polyepoxides, cyanuryl chloride, N-hydroxysuccinimide, imide esters, epichlorohydrin, or derivatives thereof. Suitable crosslinking agents for reactions with free carboxylic acid groups in enzymes include, for example, carbodiimide. In certain embodiments, the crosslinking of the enzyme to the polymer is generally intermolecular. In certain embodiments, the crosslinking of the enzyme to the polymer is generally intramolecular.

[0195] 5. Material transport limiting membrane In certain embodiments, the analyte sensor disclosed herein further includes a film that overcoats at least one active region of the analyte sensor, e.g., a first active region and / or a second active region. In certain embodiments, the film is permeable to the analyte detected in the active region. In certain embodiments, the film overcoats each of the active regions of the analyte sensor. Alternatively, the first film overcoats one of the active regions, and the second film overcoats the second active region. In certain embodiments, the first film overcoats one or both of the active regions, and then the second film overcoats both the first and second active regions.

[0196] In certain embodiments, a film overcoating the analyte-responsive active region can function as a mass transport restriction film and / or to improve biocompatibility. The mass transport restriction film can act as a diffusion-restricting barrier that reduces the mass transport rate of analytes such as glucose, alcohol, ketones, or lactates when the sensor is in use. For example, but not limited to, using a mass transport restriction film to restrict access of an analyte, such as a ketone, to the analyte-responsive active region helps avoid sensor overload (saturation), thereby improving detection performance and accuracy. In certain embodiments, the mass transport restriction layer restricts the flux of analyte to the electrodes in an electrochemical sensor, resulting in a linear response of the sensor over a wide range of analyte concentrations.

[0197] In certain embodiments, the mass transport restriction membrane may be homogeneous and single-component (containing a single membrane polymer). Alternatively, the mass transport restriction membrane may be multi-component (containing two or more different membrane polymers). In certain embodiments, the multi-component membrane may exist as a two-layer membrane or as a homogeneous mixture of two or more membrane polymers. The homogeneous mixture can be deposited by combining two or more membrane polymers in a solution and then depositing the solution onto the working electrode, for example, by dip coating.

[0198] In certain embodiments, the material transport restriction membrane may include two or more layers, for example, a two-layer or three-layer membrane. In certain embodiments, each layer may include a different polymer or the same polymer in different concentrations or thicknesses. In certain embodiments, the first analyte-responsive active region may be covered with a multilayer membrane, for example, a two-layer membrane, and the second analyte-responsive active region may be covered with a single membrane. In certain embodiments, the first analyte-responsive active region may be covered with a multilayer membrane, for example, a two-layer membrane, and the second analyte-responsive active region may be covered with a multilayer membrane, for example, a two-layer membrane. In certain embodiments, the first analyte-responsive active region may be covered with a single membrane, and the second analyte-responsive active region may be covered with a multilayer membrane, for example, a two-layer membrane can be covered with a single membrane. In certain embodiments, the first analyte-responsive active region may be covered with a single membrane, and the second analyte-responsive active region may be covered with a single membrane.

[0199] In certain embodiments, the substance transport restriction membrane may include a polymer containing heterocyclic nitrogen groups. In certain embodiments, the substance transport restriction membrane may include a polyvinylpyridine-based polymer. Non-limiting examples of polyvinylpyridine polymers are disclosed in U.S. Patent Application Publication 2003 / 0042137 (e.g., Formula 2b), the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the polyvinylpyridine polymer has a molecular weight of about 50 Da to about 500 kDa, for example, about 50 to about 200 kDa.

[0200] In certain embodiments, the material transport restriction membrane can be polyvinylpyridine (e.g., poly(4-vinylpyridine) or poly(4-vinylpyridine)), polyvinylimidazole, polyvinylpyridine copolymer (e.g., copolymer of vinylpyridine and styrene), polyacrylate, polyurethane, polyether urethane, silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, polyurethane homopolymers, copolymers or terpolymers, polypropylene, polyvinyl chloride, polyvinylidene difluoride, polybutylene terephthalate, polymethyl methacrylate, polyether ether ketone, cellulosonic polymers, polysulfones and their block copolymers, for example, diblock copolymers, triblock copolymers, alternating copolymers, random copolymers and graft copolymers, or chemically related materials.

[0201] In certain embodiments, a film for use in the Disclosure, for example, a single-component film, may be polyvinylpyridine (e.g., poly(4-vinylpyridine) and / or poly(2-vinylpyridine)). In certain embodiments, a film for use in the Disclosure, for example, a single-component film, may be poly(4-vinylpyridine). In certain embodiments, a film for use in the Disclosure, for example, a single-component film, may be a copolymer of vinylpyridine and styrene. In certain embodiments, a film may be a polyvinylpyridine-co-styrene copolymer. For example, but not limited to, a polyvinylpyridine-co-styrene copolymer for use in the Disclosure may be a polyvinylpyridine-co-styrene copolymer in which some of the pyridine nitrogen atoms are functionalized with non-crosslinked polyethylene glycol tails and some of the pyridine nitrogen atoms are functionalized with alkyl sulfonic acid, for example, propyl sulfonic acid groups. In certain embodiments, a derivatized polyvinylpyridine-co-styrene copolymer for use as a film polymer may be the 10Q5 polymer described in U.S. Patent No. 8,761,857, the entire contents of which are incorporated herein by reference.

[0202] Suitable copolymers of vinylpyridine and styrene may have a styrene content ranging from about 0.01% to about 50% mole percent, or about 0.05% to about 45% mole percent, or about 0.1% to about 40% mole percent, or about 0.5% to about 35% mole percent, or about 1% to about 30% mole percent, or about 2% to about 25% mole percent, or about 5% to about 20% mole percent. In certain embodiments, the vinylpyridine and styrene copolymers used in this disclosure contain a styrene content ranging from about 2% to about 25% mole percent. Substituted styrenes can be used in similar amounts. Suitable copolymers of vinylpyridine and styrene may have molecular weights of 5 kDa or more, or about 10 kDa or more, or about 15 kDa or more, or about 20 kDa or more, or about 25 kDa or more, or about 30 kDa or more, or about 40 kDa or more, or about 50 kDa or more, or about 75 kDa or more, or about 90 kDa or more, or about 100 kDa or more, or about 110 kDa or more. In non-limiting examples, suitable copolymers of vinylpyridine and styrene may have molecular weights in the range of about 5 kDa to about 150 kDa, or about 10 kDa to about 125 kDa, or about 15 kDa to about 100 kDa, or about 20 kDa to about 80 kDa, or about 25 kDa to about 75 kDa, or about 30 kDa to about 60 kDa. In certain embodiments, the vinylpyridine-styrene copolymer used in this disclosure may have a molecular weight in the range of about 10 kDa to about 125 kDa.

[0203] In certain embodiments, the membrane includes a polyurethane membrane containing both hydrophilic and hydrophobic regions. In certain embodiments, the hydrophobic polymer component is polyurethane, polyurethane urea, or poly(ether-urethane-urea). In certain embodiments, the polyurethane is a polymer produced by a condensation reaction between a diisocyanate and a bifunctional hydroxyl-containing material. In certain embodiments, the polyurethane urea is a polymer produced by a condensation reaction between a diisocyanate and a bifunctional amine-containing material. In certain embodiments, the diisocyanates for use herein include, for example, aliphatic diisocyanates containing about 4 to about 8 methylene units, or diisocyanates containing alicyclic moieties. Additional non-limiting examples of polymers that can be used to produce the membranes of the sensors of this disclosure include vinyl polymers, polyethers, polyesters, polyamides, inorganic polymers (e.g., polysiloxanes and polycarbosiloxanes), natural polymers (e.g., cellulose and protein-based materials), and mixtures (e.g., admixtures or layered structures), or combinations thereof. In certain embodiments, the hydrophilic polymer component is polyethylene oxide and / or polyethylene glycol. In certain embodiments, the hydrophilic polymer component is a polyurethane copolymer. For example, but not limited to, hydrophobic-hydrophilic copolymer components for use in this disclosure are polyurethane polymers containing about 10% to about 50%, for example, about 20% hydrophilic polyethylene oxide.

[0204] In certain embodiments, the membrane comprises a hydrophobic-hydrophilic polymer or a blend of a silicone polymer / hydrophobic-hydrophilic polymer. In certain embodiments, hydrophobic-hydrophilic polymers for use in the membrane can include, but are not limited to, polyvinylpyrrolidone, polyhydroxyethyl methacrylate, polyvinyl alcohol, polyacrylic acid, polyethers such as polyethylene glycol or polypropylene oxide, and copolymers thereof, such as diblock copolymers, triblock copolymers, alternating copolymers, random copolymers, comb copolymers, star copolymers, dendritic copolymers, and graft copolymers and any suitable hydrophobic-hydrophilic polymers. In certain embodiments, the hydrophobic-hydrophilic polymer is a copolymer of polyethylene oxide (PEO) and polypropylene oxide (PPO). Non-limiting examples of PEO and PPO copolymers include PEO-PPO diblock copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblock copolymers, alternating block copolymers of PEO-PPO, random copolymers of ethylene oxide and propylene oxide, and blends thereof. In certain embodiments, the copolymer can be substituted with hydroxy substituents. In certain embodiments, membranes for use in the present disclosure can include PPO-PEO-PPO triblock copolymers. In certain embodiments, membranes for use in the present disclosure can include PEO-PPO-PEO triblock copolymers.

[0205] In certain embodiments, hydrophilic or hydrophobic modifiers can be used to “fine-tune” the permeability of the resulting membrane to the target analyte. In certain embodiments, hydrophilic modifiers such as poly(ethylene) glycol, hydroxyl or polyhydroxyl modifiers, and any combinations thereof can be used to enhance the biocompatibility of the polymer or resulting membrane.

[0206] In certain embodiments, the mass transport limiting membrane can include a membrane polymer such as a homopolymer or copolymer of polyvinylpyridine or polyvinylimidazole, which can be further crosslinked with a suitable crosslinking agent. In certain specific embodiments, the membrane polymer can include, for example, a copolymer of vinylpyridine and styrene that has been further crosslinked with a suitable crosslinking agent.

[0207] In certain embodiments, the mass transport limiting membrane can include a membrane polymer crosslinked with a crosslinking agent disclosed herein and in Section 4 above. In certain embodiments where two mass transport limiting membranes are present, e.g., a first mass transport limiting membrane and a second mass transport limiting membrane, each membrane can be crosslinked with a different crosslinking agent. For example, without limitation, the crosslinking agent can result in a membrane that more restricts the diffusion of a particular compound, e.g., an analyte within the membrane, or a membrane where the restriction of diffusion of a particular compound is less, e.g., by affecting the pore size within the membrane.

[0208] In certain embodiments, crosslinking agents for use in the present disclosure include polyepoxides, carbodiimides, cyanuryl chloride, triglycidylglycerol (Gly3), N-hydroxysuccinimide, imide esters, epichlorohydrins, or derivatives thereof. In certain embodiments, a membrane polymer overcoating one or more active regions can be crosslinked with a branched-chain crosslinking agent that can, for example, reduce the amount of extract obtained from a material transport restriction membrane. Non-limiting examples of branched-chain crosslinking agents include branched-chain glycidyl ether crosslinking agents, such as branched-chain glycidyl ether crosslinking agents containing two or more crosslinkable groups. In certain embodiments, the branched-chain crosslinking agent may contain two or more crosslinkable groups, such as polyethylene glycol diglycidyl ether. In certain embodiments, the branched-chain crosslinking agent may contain three or more crosslinkable groups, such as polyethylene glycol tetraglycidyl ether. In certain embodiments, the substance transport restriction membrane may include polyvinylpyridine crosslinked with a branched glycidyl ether crosslinking agent containing two or three crosslinkable groups, such as polyethylene glycol tetraglycidyl ether or polyethylene glycol diglycidyl ether, or a copolymer of vinylpyridine and styrene. In certain embodiments, the epoxide groups of a polyepoxide, such as polyethylene glycol tetraglycidyl ether or polyethylene glycol diglycidyl ether, can form covalent bonds with pyridine or imidazole via epoxide ring-opening, resulting in the hydroxyalkyl group crosslinking the crosslinking agent body with the heterocycle of the membrane polymer. In a particular embodiment, the crosslinking agent is Gly3. In certain embodiments, the crosslinking agent is polyethylene glycol diglycidyl ether (PEGDGE). In certain embodiments, PEGDGE used to facilitate crosslinking (e.g., intermolecular crosslinking) between two or more membrane polymer backchains can exhibit a wide range of suitable molecular weights. In certain embodiments, the molecular weight of PEGDGE may range from about 100 g / mol to about 5,000 g / mol. The number of ethylene glycol repeating units in each arm of PEGDGE may be the same or different, and may vary over a certain range within a given sample, usually to obtain an average molecular weight. In certain embodiments, PEGDGE for use in this disclosure has an average molecular weight of about 200 to 1,000, for example, about 400 (M n ) has. In a particular embodiment, the crosslinking agent is PEGDGE400.

[0209] In certain embodiments, polydimethylsiloxane (PDMS) can be incorporated into any of the material transport limiting membranes disclosed herein.

[0210] In certain embodiments, the analyte sensor described herein may include at least a first working electrode, a first active region disposed on the surface of the first working electrode, and a sensor tail comprising a mass transport limiting membrane permeable to a first analyte that overcoats at least the first active region. In certain embodiments, the first active region comprises a first polymer and at least one enzyme (which may be covalently bonded to the first polymer) that responds to the first analyte. In certain embodiments, the first active region may further include an electron transfer agent (which may be covalently bonded to the first polymer).

[0211] In certain embodiments, the analyte sensor of the present disclosure may include a second active region, e.g., a second analyte response region, configured to detect the same or a different analyte as the first active region. In certain embodiments, the second active region may include a second polymer and at least one enzyme (which may be covalently bonded to the second polymer) that responds to the first or second analyte. In certain embodiments, the second active region may further include an electron transfer agent (which may be covalently bonded to the second polymer). In certain embodiments, at least a portion of the mass transport restriction membrane overcoating the first active region may overcoat the second active region. Alternatively or additionally, the second mass transport restriction membrane may be used to overcoat the second active region. In certain embodiments, at least a portion of the second mass transport restriction membrane overcoating the second active region may overcoat the first active region. In a particular embodiment, the mass transport restriction film overcoating the first active region has a different composition from the second mass transport restriction film.

[0212] In certain embodiments, the composition of the mass transport restriction film disposed on an analyte sensor having two active regions may be the same or different when the mass transport restriction film overcoats each active region. For example, but not limited to, the portion of the mass transport restriction film overcoating the first active region may be multi-component, and / or the portion of the mass transport restriction film overcoating the second active region may be single-component. Alternatively, the portion of the mass transport restriction film overcoating the first active region may be single-component, and / or the portion of the mass transport restriction film overcoating the second active region may be multi-component.

[0213] In certain embodiments of the present disclosure, the first active region may be overcoated with a film containing polyvinylpyridine-co-styrene copolymer, and the second active region may be overcoated with a multicomponent film containing polyvinylpyridine and polyvinylpyridine-co-styrene copolymer. Alternatively, the first active region may be overcoated with a multicomponent film containing polyvinylpyridine and polyvinylpyridine-co-styrene copolymer, either as a two-layer film or a homogeneous mixture, and the second active region may be overcoated with a film containing polyvinylpyridine-co-styrene copolymer. In a particular embodiment, the substance transport restriction membrane comprises a membrane polymer crosslinked with a branched-chain glycidyl ether crosslinking agent containing two or more or three or more crosslinkable groups.

[0214] In certain embodiments, when a first active region and a second active region configured to assay different analytes are placed on separate working electrodes, the mass transport restriction membrane may have different transmittance values ​​for the first and second analytes. While the sensitivity for each analyte can be equalized by varying the membrane thickness and / or the size of the active region on each working electrode, this approach can significantly complicate the manufacture of the analyte sensor. As a solution, the mass transport restriction membrane overcoating at least one of the active regions may include a mixture of the first and second membrane polymers, or a bilayer of the first and second membrane polymers. A homogeneous membrane can overcoat active regions not overcoated by the mixture or bilayer, and the homogeneous membrane may contain only one of the first or second membrane polymers. Advantageously, the analyte sensor architecture disclosed herein facilitates the creation of a continuous film having a homogeneous film portion located on a first active region of the analyte sensor and a multi-component film portion located on a second active region, thereby simultaneously leveling the permeability values ​​of each analyte and improving sensitivity and detection accuracy. Continuous film deposition can be carried out by a continuous dip coating operation in certain embodiments.

[0215] Generally, the thickness of the membrane is controlled by the concentration of the membrane solution, the number of drops of the membrane solution applied, the number of times the sensor is immersed in or sprayed with the membrane solution, the amount of membrane solution sprayed onto the sensor, and any combination of these factors. In certain embodiments, the membranes described herein may have thicknesses ranging from about 0.1 μm to about 1,000 μm, for example, about 1 μm to about 500 μm, about 10 μm to about 100 μm, or about 10 μm to about 100 μm. In certain embodiments, the sensor may be immersed in the membrane solution multiple times. For example, but not limited to, the sensor (or working electrode) of this disclosure may be immersed in the membrane solution at least two, at least three, at least four, or at least five times to obtain a desired film thickness.

[0216] 6. Interference Domain In certain embodiments, the sensor of the Disclosure, for example, the sensor tail, may further include interference domains. In certain embodiments, the interference domains may include polymer domains that restrict the flow of one or more interfering substances to the surface of the working electrode, for example. In certain embodiments, the interference domains may function as molecular sieves that allow the analyte and other substances measured by the working electrode to pass through, while blocking the passage of other substances, such as interfering substances. In certain embodiments, the interfering substances may affect the signal obtained at the working electrode. Non-limiting examples of interfering substances include acetaminophen, ascorbate, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, trazamide, tolbutamide, triglycerides, urea, and uric acid.

[0217] In certain embodiments, the interference domain is positioned between the working electrode and one or more active regions. In certain embodiments, non-limiting examples of polymers that can be used in the interference domain include polyurethanes, polymers having pendant ionic groups, and polymers having controlled pore sizes. In certain embodiments, the interference domain is formed from one or more cellulose derivatives. Non-limiting examples of cellulose derivatives include polymers such as cellulose acetate, cellulose acetate butyrate, 2-hydroxyethylcellulose, cellulose acetate phthalate, cellulose acetate propionate, and cellulose acetate trimellitate. In certain embodiments, the interference domain is part of the mass transport restriction membrane and not a separate membrane. In certain embodiments, the interference domain is located between one or more active regions and the mass transport restriction membrane. In certain embodiments, the interference domain comprises a thin hydrophobic film that is non-swelling and restricts the diffusion of high molecular weight species. For example, but not limited to, the interference domain can be permeable to relatively low molecular weight substances such as hydrogen peroxide while restricting the passage of high molecular weight substances such as ketones, glucose, acetaminophen, and / or ascorbic acid.

[0218] In certain embodiments, the interference domains can be deposited directly onto the working electrode, for example, on the surface of a permeable working electrode. In certain embodiments, the interference domains have a thickness in the range of about 0.1 μm to about 1,000 μm, for example, about 1 μm to about 500 μm, about 10 μm to about 100 μm, or about 10 μm to about 100 μm, for example, a dry thickness. In certain embodiments, the interference domains can have a thickness of about 0.1 μm to about 10 μm, for example, about 0.5 μm to about 10 μm, about 1 μm to about 10 μm, about 1 μm to about 5 μm, or about 0.1 μm to about 5 μm. In certain embodiments, the sensor can be immersed in the interference domain solution multiple times. For example, but not limited to, the sensor (or working electrode) of the Disclosure can be immersed in the interference domain solution at least two, at least three, at least four, or at least five times to obtain a desired interference domain thickness.

[0219] III. Therapeutic Compositions and Their Delivery This disclosure further provides compositions for releasing one or more therapeutic agents in vivo in close proximity to an analyte sensor. In certain embodiments, this disclosure provides an analyte sensor incorporating a therapeutic agent coupled to a polymer. In certain embodiments, this disclosure provides an analyte sensor incorporating a polymer composition containing a therapeutic agent. Alternatively or additionally, this disclosure provides therapeutic compositions containing therapeutic agents and methods for delivering such compositions. Incorporating the therapeutic agent within the analyte sensor itself, or delivering the therapeutic composition in close proximity to the sensor in vivo, enables targeted delivery of the therapeutic agent to the implantation site and the surrounding tissue of the analyte sensor.

[0220] In certain embodiments, the therapeutic agent delivered in accordance with the present disclosure can be a therapeutic agent effective to reduce, minimize, prevent, and / or inhibit the tissue response to implantation of an analyte sensor. In certain embodiments, the therapeutic agent is an anti-inflammatory agent, an antiplatelet agent, an anticoagulant, a coagulant, and / or an antiglycolytic agent. For example, without limitation, the therapeutic agent delivered in accordance with the present disclosure can be a therapeutic agent effective to reduce, minimize, prevent, and / or inhibit inflammation within the tissue. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent is a non-steroidal anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent is a steroidal anti-inflammatory agent, such as a corticosteroid. Non-limiting examples of anti-inflammatory agents include triamcinolone, betamethasone, dexamethasone, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid or derivatives thereof, analogs thereof, salts thereof, or prodrugs thereof. Non-limiting forms of salts include pharmaceutically acceptable salts including acetate and phosphate salts. In certain embodiments, the anti-inflammatory agent is a salt of dexamethasone.

[0221] In certain embodiments, the anti-inflammatory agent is a derivative of dexamethasone. In certain embodiments, the dexamethasone derivative is dexamethasone acetate. In certain embodiments, the dexamethasone derivative is sodium dexamethasone phosphate. In certain embodiments, the therapeutic agent is the glucocorticoid steroid dexamethasone shown in Formula I below, or a prodrug thereof.

Chemical formula

[0222] In certain embodiments, the therapeutic agent is a derivative of the glucocorticoid steroid dexamethasone shown in Formula IA below, or a prodrug thereof.

Chemical formula

[0223] 1. Integrating therapeutic agents into analyte sensors This disclosure provides analyte sensors according to this specification, further comprising one or more therapeutic agents, for example, anti-inflammatory agents. In certain embodiments, the analyte sensors of this disclosure may include one or more anti-inflammatory glucocorticoid steroids. In certain embodiments, the analyte sensors of this disclosure may include dexamethasone, its derivatives, or its prodrugs (for example, as shown in formulas I and IA and scheme XII). In certain embodiments, the analyte sensors of this disclosure may include dexamethasone, dexamethasone sodium phosphate, or dexamethasone acetate. As discussed herein, incorporating therapeutic agents into analyte sensors enables targeted release of the therapeutic agent into the surrounding tissue and the insertion site of the analyte sensor. In certain embodiments, the release of an anti-inflammatory agent from the analyte sensor into the surrounding tissue can result in reduction, prevention, and / or elimination of inflammation in such tissue. In certain embodiments, the release of an anti-inflammatory agent from the analyte sensor into the surrounding tissue can result in reduction, prevention, and / or elimination of the immune response to the analyte sensor in such tissue.

[0224] In certain embodiments, the therapeutic agent can be incorporated into the polymer matrix of the analyte sensor. For example, but not limited to, the therapeutic agent can be covalently bonded to the polymers of the polymer matrix. In certain embodiments, the therapeutic agent is covalently bonded directly or via a linker to one or more polymers of the polymer matrix. In certain embodiments, the therapeutic agent is covalently bonded to one or more polymers of the polymer matrix via hydrolyzable bonds, thereby enabling delayed release of the therapeutic agent after insertion of the analyte sensor in vivo. In certain embodiments, the hydrolyzable bond may be an ester bond, an amide bond, or a hydrazone-based bond. As shown in Scheme I, esters are readily hydrolyzed, thereby producing alcohols and carboxylic acids. Similarly, amides can be hydrolyzed as shown in Scheme II. As shown in Scheme III, hydrazone-based bonds can be hydrolyzed under acidic conditions.

[0225] [ka] Scheme I [ka] Scheme II [ka] Scheme III

[0226] In certain embodiments, the therapeutic agent may contain one or more functional groups that enable covalent bonding with one or more polymers in a polymer matrix. Non-limiting examples of such functional groups include alcohol groups, primary amine groups, secondary amine groups, chloroacetate groups, and carboxylic acid groups. In certain embodiments, such functional groups can form ester or amide bonds when covalently bonded to one or more polymers in a polymer matrix. In certain embodiments, the therapeutic agent may be functionalized to include such functional groups, as shown in Example 1 and Schemes IV, V, and VI, for example, alcohol groups, primary amine groups, secondary amine groups, chloroacetate groups, carboxylic acid groups, ketone groups, aldehyde groups, or hydrazide groups. For example, but not limited to, dexamethasone can be functionalized to include alcohol groups, primary amine groups, secondary amine groups, or carboxylic acid groups when covalently bonded to one or more polymers in a polymer matrix to form ester or amide bonds. In certain embodiments, therapeutic agents having an alcohol functional group (R-OH), a primary amine functional group (R-NH2), or a secondary amine group (R-NHR') can form hydrolyzable bonds, for example, ester bonds or amide bonds with polymers having carboxylic acid functional groups, as shown in Scheme IV.

[0227] [ka] Scheme IV In certain embodiments, therapeutic agents having a ketone or aldehyde functional group can form hydrolyzable bonds, such as hydrazone-based bonds, with polymers having a hydrazide functional group, as shown in Scheme V.

[0228] [ka] Scheme V In certain embodiments, a therapeutic agent having a hydrazide functional group can form a hydrolyzable bond, such as a hydrazone-based bond, with a polymer having an aldehyde or ketone functional group, as shown in Scheme VI.

[0229] [ka] Scheme VI In certain embodiments, one or more polymers in the polymer matrix can be functionalized with one or more functional groups to form a covalent bond, such as a hydrolyzable bond, with a therapeutic agent. Non-limiting examples of such functional groups include alcohol groups, primary amine groups, secondary amine groups, chloroacetate groups, carboxylic acid groups, ketone groups, aldehyde groups, or hydrazide groups. In certain embodiments, polymers having such functional groups can form a hydrolyzable bond with a therapeutic agent containing a carboxylic acid functional group, as shown in Scheme VII.

[0230] [ka] Scheme VII In certain embodiments, the therapeutic agent can be linked to the polymer via a hydrolyzable bond. In such embodiments, the linker has a first functional group capable of forming a hydrolyzable bond with the polymer and a second functional group capable of forming a hydrolyzable bond with the therapeutic agent. In certain embodiments, the hydrolyzable bond is selected from the group consisting of ester bonds, amide bonds, or hydrazone-based bonds. In certain embodiments, the first and second functional groups are the same. In certain other embodiments, the first and second functional groups are different. For example, but not limited to, the first and second functional groups may independently be an alcohol group, a primary amine group, a secondary amine group, a chloroacetate group, or a carboxylic acid group, a ketone group, an aldehyde group, or a hydrazide group. In certain embodiments, if the therapeutic agent is dexamethasone, it can be linked to the polymer via a hydrazone-based bond, as shown in Formula II below.

[0231] [ka] Formula II In certain embodiments, if the therapeutic agent is dexamethasone, it can be linked to the polymer via a hydrazone / amide linker, as shown in Formula III below.

[0232] [ka] Formula III

[0233] In certain embodiments, the polymer matrix may include at least one polymer having a pyridine group. In certain embodiments, the pyridine group of the polymer is functionalized to have a carboxylic acid moiety for linking with a therapeutic agent, for example, a therapeutic agent having an alcohol group and / or functionalized to have an alcohol group. For example, but not limited to, a polymer having a pyridine group with a carboxylic acid moiety can form a hydrolyzable bond, such as an ester bond, with dexamethasone, as shown in schemes VIII and IX.

[0234] [ka] Scheme VIII [ka] Scheme IX

[0235] In certain embodiments, the polymer matrix may include at least one polymer having a primary amine group. In certain embodiments, the primary amine group of the polymer is functionalized to have a carboxylic acid moiety for linking with a therapeutic agent, for example, a therapeutic agent having an alcohol group and / or functionalized to have an alcohol group. For example, but not limited to, a polymer having a primary amine group functionalized with a carboxylic acid moiety can form a hydrolyzable bond with dexamethasone, as shown in schemes X and XI.

[0236] [ka] Scheme X [ka] Scheme XI

[0237] As shown in Scheme XII and Formula I, dexamethasone contains a primary hydroxyl group at the 21-position and can form an ester bond with a carboxylic acid, such as the carboxylic acid moiety of a polymer, to form a dexamethasone "prodrug." This dexamethasone prodrug is hydrolyzed to release free dexamethasone, as shown in Scheme XII below.

[0238] [ka] Scheme XII

[0239] In certain embodiments, the R group in Scheme XIII is a polymer functionalized with a carboxylic acid group, as shown in Schemes VIII-XI. Non-limiting examples of polymers that can be functionalized with a carboxylic acid group include polyvinylpyridine (PVP), copolymers of vinylpyridine and styrene, or derivatives thereof. Examples of copolymers include polyvinylpyridine-polystyrene sulfonate, polyvinylpyridine-co-aminomethylstyrene, polyvinylpyridine-co-carboxystyrene, polyvinylimidazole, e.g., poly(N-vinylimidazole) and poly(1-vinylimidazole), or copolymers thereof. Examples of copolymers include PVP copolymers with acrylic acid and its homologues. Scheme XIII provides non-limiting examples of therapeutic agents functionalized with a chloroacetate group. For example, but not limited to, dexamethasone can be functionalized with a chloroacetate group, as shown in Scheme XIII. This group can facilitate the coupling reaction between dexamethasone and polymers functionalized with a nucleophilic group. In certain embodiments, the nucleophile may be an amine or a pyridine, as shown in Scheme XIII. As further shown in Scheme XIII, the resulting ester bond can be hydrolyzed in vivo to release free dexamethasone.

[0240] [ka] Scheme XIII

[0241] In certain embodiments, as shown in Scheme XIV, dexamethasone can be functionalized with a chloroacetate group and coupled with a polymer functionalized with a primary amine. In certain embodiments, the polymer is conjugated with a linker containing a primary amine. As shown in Scheme XIV, the ester bond formed between the functionalized polymer and dexamethasone can be hydrolyzed in vivo to release free dexamethasone.

[0242] [ka] Scheme XIV

[0243] In certain embodiments, the therapeutic agent can be coupled to a polymer or polymer matrix by a linker. The selection of the linker and the specific functional group may depend on the desired release rate of the therapeutic agent. In certain embodiments, the rate can be controlled by the specific functional group selected for the linker and the hydrolysis rate of the covalent bond formed between the linker and the therapeutic agent and / or the covalent bond formed between the linker and the polymer of the polymer matrix. Non-limiting examples of such functional groups include alcohol groups, primary amine groups, secondary amine groups, carboxylic acid groups, acyl halides, hydroxyl groups, alkynyl groups, aldehyde groups, ketone groups, carboxylate groups, or amino groups. In certain embodiments, the linker includes at least one functional group that is reactive to a primary amine or pyridine.

[0244] In certain embodiments, the linker may include at least one functional group capable of forming a covalent bond, such as a hydrolyzable covalent bond, with at least one therapeutic agent. In certain embodiments, the linker may include at least one functional group capable of forming a covalent bond, such as a hydrolyzable covalent bond, with the polymer of the polymer matrix. In certain embodiments, the linker may include at least one functional group capable of forming a covalent bond, such as a hydrolyzable covalent bond, with at least one therapeutic agent, and at least one functional group capable of forming a covalent bond, such as a hydrolyzable covalent bond, with the polymer of the polymer matrix. In certain other embodiments, the linker may include at least one functional group capable of forming a non-hydrolyzable covalent bond with at least one therapeutic agent, and at least one functional group capable of forming a hydrolyzable covalent bond with the polymer of the polymer matrix. In certain other embodiments, the linker may include at least one functional group capable of forming a hydrolyzable covalent bond with at least one therapeutic agent, and at least one functional group capable of forming a non-hydrolyzable covalent bond with the polymer of the polymer matrix. For example, but not limited to, the linker may include a first functional group that can form hydrolyzable bonds with the therapeutic agent, such as an alcohol group, primary amine group, secondary amine group, carboxylic acid group, acyl halide, hydroxyl group, alkynyl group, aldehyde group, carboxylate group, or amino group, and an epoxide that can form non-hydrolyzable covalent bonds with the polymer in the polymer matrix.

[0245] In certain embodiments, the linker may contain one or more internally hydrolyzable covalent bonds. In certain embodiments, the linker may form non-hydrolyzable covalent bonds with the therapeutic agent and / or polymer, and the release of the therapeutic agent in vivo may result from the hydrolysis of one or more internally hydrolyzable covalent bonds of the linker. In certain embodiments, the linker may contain two, three, four or more carboxylic acid groups. In certain embodiments, the linker may be a dicarboxylic acid, for example, but not limited to, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, salts thereof, and halides thereof. In certain embodiments, the dicarboxylic acid, salts thereof, and halides thereof may contain 2 to 20 carbon atoms in the chain. For the purposes of this disclosure, the two carboxylate groups in the carboxyl linker are referred to as the first and second carboxylate groups.

[0246] In certain embodiments, the dicarboxylic acid linker can be coupled to a therapeutic agent via a first carboxylate group and to a polymer via a second carboxylate group. In certain embodiments, the dicarboxylic acid linker can first be coupled to a therapeutic agent via a first carboxylate group, and then the second carboxylate group can be converted to a different functional group for coupling to a polymer. In certain embodiments, the second carboxylate group can be converted to an acyl halogen, as shown in scheme XV.

[0247] [ka] Scheme XV In certain embodiments, the therapeutic agent can then be coupled to the polymer of the polymer matrix using an acyl halogenate in the same manner as described above, the method shown in Example 1, and the methods shown in Scheme XIII and Scheme XIV. In certain embodiments, therapeutic agents can be incorporated into a polymer matrix by derivatizing them with a polymerizable group and incorporating them as monomers during the synthesis of the polymer matrix. For example, but not limited to, therapeutic agents having polymerizable groups can be incorporated as monomers during the synthesis of parts of an analyte sensor, such as the active layer and / or the film. In certain embodiments, the polymerizable group may be methacrylate, methyl methacrylate, benzyl acrylate, n-butyl acrylate, isobutyl methacrylate, n-butyl methacrylate, tert-butyl acrylate, 2-methoxyethyl acrylate, neopentyl methacrylate, phenyl acrylate, stearyl acrylate, stearyl methacrylate, n-propyl acrylate, or n-propyl methacrylate. In certain embodiments, the polymerizable group may be acrylamide, for example, N-hydroxyethylacrylamide or N-(2-hydroxypropyl)methacrylamide, represented by formulas IVA and IVB, respectively, but not limited to these examples.

[0248] [ka] In certain embodiments, if the polymerizable group has an oxidizing group such as an alcohol or aldehyde (but is not limited), the polymerizable group can first be oxidized to a carboxylic acid before forming a hydrolyzable covalent bond with the therapeutic agent. Scheme XVI provides an unrestricted example of such a reaction, in which the hydroxyl group of N-hydroxyethylacrylamide can first be oxidized to a carboxylic acid group, and then the carboxylic acid group can react with the hydroxyl group on dexamethasone to form an ester bond. In certain embodiments, if the therapeutic agent contains a primary or secondary amine, an amide bond can be formed.

[0249] [ka] Scheme XVI In certain alternative embodiments, the therapeutic agent is derivatized with a methacrylate group, and formula V:

[0250] [ka] Formula V Compounds like those shown can be formed. In certain embodiments, the therapeutic agent can be bonded to a polymerizable group, such as an acrylamide group, via a hydrazone bond, as shown in formula VI.

[0251] [ka] Equation VI

[0252] In certain embodiments, a therapeutic agent derivatized with a polymerizable group can be incorporated into the polymer's main chain by forming a copolymer with the polymer. In certain embodiments, a therapeutic agent derivatized with a polymerizable group, such as a methacrylate group, can be copolymerized with one or more of the following to form a polymer matrix: 4-vinylpyridine, N-vinylimidazole, 1-vinylimidazole, styrene, styrene / maleic anhydride, methyl vinyl ether / maleic anhydride, vinyl benzyl chloride, allylamine, lysine, or sodium 4-styrenesulfonate.

[0253] In certain embodiments, one or more catalysts can be used to catalyze the coupling of a therapeutic agent to a polymer. The type of catalyst used may vary depending on the conditions of the chemical reaction. In certain embodiments, the coupling catalyst may be 4-dimethylaminopyridine (DMAP), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboxymido)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU), and O-(1,2-dihydro-2-oxo-1-pyridyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), or carbonyldiimidazole (CDI). In certain embodiments, the polymer that can be coupled to the therapeutic agent may be any polymer that contains a functional group for forming a hydrolyzable bond with the therapeutic agent, or any polymer derivatized with such a functional group.

[0254] In certain embodiments, polymers that can be coupled to or mixed with therapeutic agents may be polymers disclosed in Section II.5 above. For example, but not limited to, polymers for use in material transport restriction membranes described herein may be coupled to or mixed with therapeutic agents to form, for example, therapeutic agent elution compositions. In certain embodiments, the polymer may be a polyvinylpyridine-based polymer. For example, but not limited to, the polymer may include polyvinylpyridine, e.g., poly(4-vinylpyridine), or derivatives thereof.

[0255] In certain embodiments, a polymer that can be coupled to or mixed with a therapeutic agent may be a copolymer. In certain embodiments, the polymer may be a linear copolymer or a branched copolymer. In certain embodiments, the polymer may be a copolymer of polyvinylpyridine, for example, a copolymer of vinylpyridine and styrene, or a derivative thereof. In certain embodiments, the polymer may include polyvinylpyridine-co-styrene copolymer or a derivative thereof. In certain embodiments, the polymer may be a polyvinylpyridine-co-styrene copolymer in which some of the pyridine nitrogen atoms are functionalized with non-crosslinked polyethylene glycol tails, and some of the pyridine nitrogen atoms are functionalized with alkyl sulfonic acid groups, for example, propyl sulfonic acid groups.

[0256] In certain embodiments, the polymer may be a biodegradable or bioabsorbable polymer, for example, polycaprolactone (PCL) or poly(D,L-lactide-co-glycolide), without limitation. In certain embodiments, the polymer may be a polylactide, polyglycolide, or polyethylene glycol polymer. In certain embodiments, the polymer may be a blend of two or three of these functional groups as a block copolymer, for example, a diblock copolymer or a triblock copolymer. Non-limiting embodiments of such block copolymers include poly(D,L-lactic acid-co-glycolic acid) (PLGA) and the triblock copolymer polylactide-block-poly(ethylene glycol)-block-polylactide (PLA-PEG-PLA). Further non-limiting examples of block copolymers include PEO and PPO copolymers, e.g., PEO-PPO diblock copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblock copolymers, alternating PEO-PPO block copolymers, random copolymers of ethylene oxide and propylene oxide, and blends thereof. In certain embodiments, the polymer is TIMB. Additional polymers that can be included in compositions containing therapeutic agents, for example, that can be coupled to therapeutic agents, are disclosed in Section III.2 below and Section II.5 above, as considered in relation to material transport restriction membrane polymers.

[0257] In certain embodiments, the polymer may include block polymers, such as PPO-PEO-PPO triblock copolymers and polyvinylpyridine-co-styrene copolymers. In certain embodiments, the block polymers and polyvinylpyridine-co-styrene copolymers are crosslinked. In certain embodiments, the polymer may be a polyvinylpyridine-based polymer, such as a polyvinylpyridine-co-styrene copolymer, derivatized with a block polymer, such as a PPO-PEO-PPO triblock copolymer.

[0258] In certain embodiments, the polymers used in the Disclosure may have a molecular weight of 5 kDa or more, or about 10 kDa or more, or about 15 kDa or more, or about 20 kDa or more, or about 25 kDa or more, or about 30 kDa or more, or about 40 kDa or more, or about 50 kDa or more, or about 75 kDa or more, or about 90 kDa or more, about 100 kDa or more, about 150 kDa or more, about 200 kDa or more, about 250 kDa or more, about 300 kDa or more, about 350 kDa or more, about 400 kDa or more, about 450 kDa or more, or about 500 kDa or more. In non-limiting examples, polymers used in this disclosure may have molecular weights in the range of about 5 kDa to about 500 kDa, or about 10 kDa to about 450 kDa, or about 15 kDa to about 400 kDa, or about 20 kDa to about 350 kDa, about 25 kDa to about 300 kDa, about 30 kDa to about 250 kDa, about 30 kDa to about 200 kDa, about 30 kDa to about 200 kDa, or about 30 kDa to about 175 kDa. In certain embodiments, polymers for use in this disclosure may have molecular weights of about 30 kDa to about 175 kDa. In certain embodiments, polymers for use in this disclosure may have molecular weights of about 50 kDa to about 150 kDa. In certain embodiments, the therapeutic agent is mixed with a polymer matrix containing one or more polymers disclosed herein without forming chemical bonds, as shown in Example 4. For example, but not limited to, the therapeutic agent can be mixed with a polymer matrix and placed on an analyte sensor. Alternatively, the therapeutic agent may be covalently bonded to the polymer matrix, or it may not be covalently bonded to the polymer matrix.

[0259] In certain embodiments, the polymer matrix may include a first therapeutic agent that conjugates to one or more polymers of the polymer matrix, and a second therapeutic agent that is mixed with the polymer matrix but is not covalently bonded to the polymer matrix. In certain embodiments, the first and second therapeutic agents are the same. In certain embodiments, the first and second therapeutic agents are different. For example, but not limited to these, one of the therapeutic agents may be dexamethasone (or a derivative or salt thereof), and the other therapeutic agents may be different anti-inflammatory agents.

[0260] In certain embodiments, the polymer may be a polymer present in any one of the components of the analyte sensor disclosed herein, and / or a polymer incorporated into any one of the components of the analyte sensor. In certain embodiments, the polymer may be a polymer of a mass transport limiting membrane. Alternatively or additionally, the polymer may be a polymer of the active region of the sensor. In certain embodiments, the therapeutic agent can be incorporated into the material transport restriction membrane. For example, but not limited to, the therapeutic agent can be conjugated to the polymer of the material transport restriction membrane and / or mixed with the material transport restriction membrane. In certain embodiments, the therapeutic agent can be incorporated into the membrane 220, for example, by covalent bonding to the polymer of the membrane 220. Alternatively, the therapeutic agent can be incorporated into the material transport restriction membrane as a mixture or by covalent bonding to a polymer.

[0261] In certain embodiments, a therapeutic agent, such as a derivatized therapeutic agent described herein, can be included in the membrane immersion solution. In certain embodiments, the reactive groups of the therapeutic agent, such as dexamethasone, can react with the functional groups of the polymer in the membrane immersion solution, such as pyridine groups. Alternatively, the therapeutic agent, such as a derivatized therapeutic agent described herein, can be partitioned onto the membrane and reacted with the functional groups of the polymer in the membrane, such as pyridine groups. In certain embodiments, the therapeutic agent can be mixed with the membrane polymer without covalent bonding, for example, in the membrane immersion solution, and then partitioned onto the sensor.

[0262] In certain embodiments, the therapeutic agent can be placed within one or more active regions positioned on the working electrode of an analyte sensor. In certain embodiments, the active regions may include a polymer, for example, a polymer backbone as described herein, and the therapeutic agent can be conjugated to or mixed with the polymer within the active region. In certain embodiments, the polymer present in the active region can be bound to an oxidation-reduction mediator, and the therapeutic agent can be conjugated to such a polymer within the active region. In certain embodiments, the therapeutic agent can be placed on the surface of an electrode. For example, the electrode may be a working electrode, for example. In certain embodiments, the electrode may be a counter electrode / reference electrode. In certain embodiments, the therapeutic agent and polymer can be placed on the surface of an electrode. In certain embodiments, the therapeutic agent is conjugated to the polymer, or the therapeutic agent is mixed with the polymer and is not covalently bonded to the polymer.

[0263] In certain embodiments, a polymer matrix incorporating the therapeutic agent can be placed on or incorporated into the membrane 220. In certain embodiments, a polymer matrix incorporating the therapeutic agent can be placed on the substrate 30212 of the analyte sensor. In certain embodiments, a polymer matrix incorporating the therapeutic agent can be placed on the working electrode 214. In certain embodiments, a polymer matrix incorporating the therapeutic agent can be placed on the counter electrode / reference electrode 30216 or 217. In certain embodiments, a polymer matrix incorporating the therapeutic agent can be placed on an active region, for example, 218. In certain embodiments, a polymer matrix incorporating the therapeutic agent can be placed on the counter electrode. For example, but not limited to, a polymer matrix incorporating the therapeutic agent can be placed on the counter electrode 30216, 217, or 320.

[0264] In certain embodiments, the polymer matrix contains an amount of a therapeutic agent, such as dexamethasone, effective in reducing, minimizing, preventing, and / or inhibiting inflammation in the tissue surrounding the insertion site of the analyte sensor. In certain embodiments, the polymer matrix contains an amount of a therapeutic agent, such as dexamethasone, effective in reducing, minimizing, preventing, and / or inhibiting the immune response to the analyte sensor. For example, but not limited to, the polymer matrix may contain an amount of a therapeutic agent effective in reducing, minimizing, preventing, and / or inhibiting inflammation in the tissue surrounding the insertion site of the analyte sensor for a duration of up to about 14 days, up to about 15 days, up to about 16 days, up to about 17 days, up to about 18 days, up to about 19 days, up to about 20 days, up to about 25 days, or up to about 30 days. In certain embodiments, the polymer matrix contains an amount of a therapeutic agent, such as dexamethasone, effective in reducing, minimizing, preventing and / or inhibiting the immune response to the analyte sensor for a duration of up to approximately 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 25 days, or 30 days or longer. In certain embodiments, the polymer matrix may contain an effective amount of therapeutic agent to reduce late sensitivity attenuation (LSA). In certain embodiments, the polymer matrix may contain an effective amount of therapeutic agent, such as dexamethasone, to reduce late sensitivity attenuation (LSA) compared to an analyte sensor without the therapeutic agent, such as dexamethasone. For example, but not limited to, the polymer matrix may contain an effective amount of therapeutic agent to reduce LSA by more than twofold. In certain embodiments, the polymer matrix may contain an effective amount of therapeutic agent to reduce LSA by more than threefold. In certain embodiments, the polymer matrix may contain an effective amount of therapeutic agent to reduce LSA by more than fourfold. In certain embodiments, the polymer matrix may contain an effective amount of therapeutic agent to reduce LSA by more than fivefold. In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in reducing LSA by about 5%, 10%, 20%, 30%, 40%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 95%, 96%, 97%, 98%, or 99%. In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in reducing LSA by about 20%. In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in reducing LSA by about 30%. In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in reducing LSA by about 40%. In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in reducing LSA by about 50%. In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in reducing LSA by more than approximately 60%. In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in reducing LSA by more than approximately 70%.In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in reducing LSA by more than approximately 75%.

[0265] In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in extending the lifespan of the analyte sensor. For example, but not limited to, the polymer matrix may contain an amount of therapeutic agent effective in extending the lifespan of the analyte sensor by approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days or more. In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in extending the lifespan of the analyte sensor by approximately 5 days. In certain embodiments, the polymer matrix may contain an amount of therapeutic agent effective in extending the lifespan of the analyte sensor by approximately 10 days.

[0266] In certain embodiments, the analyte sensor of the Disclosure containing dexamethasone has a lifespan of about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days or more. In certain embodiments, the analyte sensor of the Disclosure containing dexamethasone has a lifespan of about 14 days or more. In certain embodiments, the analyte sensor of the Disclosure containing dexamethasone has a lifespan of about 15 days or more. In certain embodiments, the analyte sensor of the Disclosure containing dexamethasone has a lifespan of about 20 days or more. In certain embodiments, the analyte sensor of the Disclosure containing dexamethasone has a lifespan of about 25 days or more. In certain embodiments, the analyte sensor of the present disclosure, which contains dexamethasone, has a lifespan of about 30 days or more.

[0267] In certain embodiments, the polymer matrix may contain a therapeutic agent in a value of about 0.0005 mg to about 0.2 mg, or any value in between, such as dexamethasone. In certain embodiments, the polymer matrix may contain a therapeutic agent in a value of about 0.0005 mg, about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, or about 0.2 mg, such as dexamethasone. In certain embodiments, the polymer matrix may contain a therapeutic agent in a value of about 0.1 μg to about 20 μg.In a particular embodiment, the polymer matrix contains approximately 1 μg to approximately 100 μg of therapeutic agent, for example, approximately 1 μg to approximately 95 μg, approximately 1 μg to approximately 90 μg, approximately 1 μg to approximately 85 μg, approximately 1 μg to approximately 80 μg, approximately 1 μg to approximately 75 μg, approximately 1 μg to approximately 70 μg, approximately 1 μg to approximately 65 μg, approximately 1 μg to approximately 60 μg, approximately 1 μg to approximately 55 μg, approximately 1 μg to approximately 50 μg, approximately 1 μg to approximately 45 μg, approximately 1 μg to approximately 40 μg, approximately 1 μg to approximately 35 μg, approximately 1 μg to approximately 30 μg μg, about 1 μg to about 25 μg, about 1 μg to about 20 μg, about 1 μg to about 15 μg, about 1 μg to about 14 μg, about 1 μg to about 13 μg, about 1 μg to about 12 μg, about 1 μg to about 11 μg, about 1 μg to about 10 μg, about 1 μg to about 9 μg, approximately 2μg to approximately 100μg, approximately 3μg to approximately 100μg, approximately 4μg to approximately 100μg, approximately 5μg to approximately 100μg, approximately 6μg to approximately 100μg, approximately 7μg to approximately 100μg, approximately 8μg to approximately 100μg, approximately 9μg to approximately 100μg , about 10 μg to about 100 μg, about 11 μg to about 100 μg, about 12 μg to about 100 μg, about 13 μg to about 100 μg, about 14 μg to about 100 μg, about 15 μg to about 100 μg, about 16 μg to about 100 μg, about 20 μg Approximately 100μg, approximately 25μg to approximately 100μg, approximately 30μg to approximately 100μg, approximately 35μg to approximately 100μg, approximately 40μg to approximately 100μg, approximately 45μg to approximately 100μg, approximately 50μg to approximately 100μg, approximately 55μg to approximately 100μg, The polymer matrix may contain approximately 60 μg to 100 μg, 65 μg to 100 μg, 70 μg to 100 μg, 75 μg to 100 μg, 80 μg to 100 μg, 85 μg to 100 μg, 90 μg to 100 μg, 95 μg to 100 μg, 5 μg to 50 μg, 5 μg to 45 μg, 5 μg to 40 μg, 5 μg to 35 μg, 5 μg to 30 μg, 5 μg to 25 μg, or approximately 5 μg to 20 μg of the therapeutic agent. In certain embodiments, the polymer matrix may contain approximately 1 μg to 20 μg of the therapeutic agent. In certain embodiments, the polymer matrix may contain approximately 5 μg to 20 μg of the therapeutic agent. In certain embodiments, the polymer matrix may contain about 1 μg to about 30 μg of the therapeutic agent. In certain embodiments, the polymer matrix may contain about 5 μg to about 30 μg of the therapeutic agent.

[0268] In certain embodiments, the polymer matrix contains about 10% to about 70% by mass of a therapeutic agent, such as dexamethasone. In certain embodiments, the polymer matrix contains about 15% to about 65% by mass, about 20% to about 50% by mass, or about 25% to about 40% by mass of a therapeutic agent, such as dexamethasone. In certain embodiments, the polymer matrix contains about 20% to about 50% by mass of a therapeutic agent, such as dexamethasone. In certain embodiments, the polymer matrix contains about 30% to about 60% by mass of a therapeutic agent, such as dexamethasone. In certain embodiments, the polymer composition containing the therapeutic agent described herein may have a thickness in the range of about 0.1 μm to about 1,000 μm, for example, about 1 μm to about 500 μm, about 10 μm to about 500 μm, about 10 μm to about 400 μm, about 10 μm to about 300 μm, about 10 μm to about 200 μm, about 10 μm to about 100 μm, or about 10 μm to about 100 μm, for example, a dry thickness. In certain embodiments, the polymer composition containing the therapeutic agent described herein may have a thickness in the range of about 1 μm to about 500 μm, for example, a dry thickness. In certain embodiments, the polymer composition containing the therapeutic agent described herein may have a thickness in the range of about 1 μm to about 400 μm, for example, a dry thickness. In certain embodiments, the polymer composition containing the therapeutic agent described herein may have a thickness in the range of about 1 μm to about 300 μm, for example, a dry thickness. In certain embodiments, the polymer composition containing the therapeutic agent described herein may have a thickness in the range of about 1 μm to about 200 μm, for example, a dry thickness. In certain embodiments, the polymer composition containing the therapeutic agent described herein may have a thickness in the range of about 10 μm to about 200 μm, for example, a dry thickness. In certain embodiments, the polymer composition containing the therapeutic agent described herein may have a thickness in the range of about 10 μm to about 300 μm, for example, a dry thickness. In certain embodiments, the polymer composition containing the therapeutic agent described herein may have a thickness in the range of about 50 μm to about 300 μm, for example, a dry thickness.

[0269] In certain embodiments, the polymer composition comprising a therapeutic agent can be dispensed multiple times onto an analyte sensor, such as onto a counter electrode of the analyte sensor. For example, without limitation, the polymer composition comprising a therapeutic agent can be dispensed at least 2 times, at least 3 times, at least 4 times, at least 5 times or at least 6 times onto an analyte sensor, such as onto a counter electrode of the analyte sensor, to obtain a desired thickness. In certain embodiments, the polymer composition on the analyte sensor is about 0.01 mm 2 to about 3.0 mm 2 , for example, 0.01 mm 2 to about 2.0 mm 2 , 0.1 mm 2 to about 3.0 mm 2 , 0.1 mm 2 to about 2.0 mm 2 , about 0.1 mm 2 to about 1.0 mm 2 or about 0.2 mm 2 to about 0.5 mm 2 in area.

[0270] In certain embodiments, the polymer composition on the analyte sensor has a length of about 0.1 mm to about 10.0 mm, such as 0.1 mm to about 10.0 mm, 0.1 mm to about 9.0 mm, 0.1 mm to about 8.0 mm, 0.1 mm to about 7.0 mm, 0.1 mm to about 6.0 mm, 0.1 mm to about 5.0 mm, 0.1 mm to about 4.0 mm, 0.1 mm to about 3.0 mm, 0.1 mm to about 2.0 mm, 0.5 mm to about 3.0 mm, 0.5 mm to about 2.0 mm, or 1.0 mm to about 2.0 mm. In certain embodiments, the polymer composition on the analyte sensor has a length of about 0.1 mm to about 3.0 mm. In certain embodiments, the analyte sensor of the present disclosure may include at least a first working electrode, a first active region disposed on the surface of the first working electrode, and a sensor tail comprising a substance transport limiting membrane permeable to a first analyte that overcoats at least the first active region, and a therapeutic agent disposed on the counter electrode. In certain embodiments, the therapeutic agent is present in a polymer composition and is conjugated to polymers in the polymer composition via hydrolyzable bonds.

[0271] 2. Delivery of therapeutic release compositions In certain embodiments, the therapeutic agent can be delivered in vivo to very close proximity to the sensor without altering the structure and / or composition of the analyte sensor. For example, but not limited to, the therapeutic agent can be delivered to very close proximity to the sensor by inserting a therapeutic composition containing the therapeutic agent (referred to herein as the “therapeutic release composition”) near the analyte sensor. In certain embodiments, the therapeutic release composition can be delivered into tissue, for example, inserted, and then release the therapeutic agent over time, for example, by sustained release of the therapeutic agent.

[0272] In certain embodiments, the therapeutic release composition comprises one or more polymers and one or more therapeutic agents. As disclosed herein, the therapeutic agent may be an agent effective in reducing, minimizing, preventing and / or inhibiting the immune response to inflammation and / or analyte sensors. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the therapeutic release composition of the Disclosure may contain one or more anti-inflammatory glucocorticoid steroids. In certain embodiments, the therapeutic release composition of the Disclosure may contain dexamethasone or its derivatives or salts. In certain embodiments, one or more polymers in the therapeutic release composition are bioabsorbable and / or biodegradable when implanted in vivo. In certain embodiments, the main chain of one or more polymers in the therapeutic release composition contains hydrolyzable bonds. For example, but not limited to, the main chain of one or more polymers present in the therapeutic release composition includes ester bonds, amide bonds, and / or ether bonds. In certain embodiments, the main chain of one or more polymers contains ester bonds. In certain embodiments, the main chain of one or more polymers contains amide bonds. In certain embodiments, the main chain of one or more polymers contains ether bonds.

[0273] In certain embodiments, the polymer of the therapeutic release composition may be a polymer disclosed in Section II.5 or Section III.1. In certain embodiments, the polymer of the therapeutic release composition may be a polylactide, polyglycolide, or polyethylene glycol. In certain embodiments, the polymer may be a copolymer. In certain embodiments, the polymer may be a linear copolymer or a branched copolymer. In certain embodiments, the polymer may be a blend of two or three of these functional groups as a block copolymer, for example, a diblock copolymer or a triblock copolymer. Non-limiting embodiments of such block copolymers include poly(D,L-lactic acid-co-glycolic acid) (PLGA) and the triblock copolymer polylactide-block-poly(ethylene glycol)-block-polylactide (PLA-PEG-PLA). In certain embodiments, the therapeutic release composition may include a therapeutic agent, such as dexamethasone, covalently bonded to a polymer, for example, via hydrolyzable bonds, as described herein.

[0274] In certain embodiments, the therapeutic composition comprises an amount of therapeutic agent, such as dexamethasone, effective in reducing, minimizing, preventing, and / or inhibiting inflammation in the tissue surrounding the insertion site of the analyte sensor. For example, but not limited to, the therapeutic composition may contain an amount of therapeutic agent effective in reducing, minimizing, preventing, and / or inhibiting inflammation in the tissue surrounding the insertion site of the analyte sensor for a duration of up to approximately 14, 15, 16, 17, 18, 19, 20, 25, or 30 days or longer. In certain embodiments, the therapeutic composition comprises an amount of a therapeutic agent, such as dexamethasone, effective in reducing, minimizing, preventing, and / or inhibiting the immune response to the analyte sensor. For example, but not limited to, the therapeutic composition may contain an amount of a therapeutic agent effective in reducing, minimizing, preventing, and / or inhibiting the immune response to the analyte sensor for a duration of up to about 14, 15, 16, 17, 18, 19, 20, 25, or 30 days or longer.

[0275] In certain embodiments, the therapeutic release composition may contain about 0.005 mg to about 0.2 mg of a therapeutic agent, such as dexamethasone. In certain embodiments, the polymer matrix may contain about 0.0005 mg, about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, or about 0.2 mg of a therapeutic agent, such as dexamethasone. In certain embodiments, the therapeutic release composition may contain about 0.1 μg to about 20 μg of a therapeutic agent. In a particular embodiment, the therapeutic release composition is approximately 1 μg to approximately 100 μg of the therapeutic agent, for example, approximately 1 μg to approximately 95 μg, approximately 1 μg to approximately 90 μg, approximately 1 μg to approximately 85 μg, approximately 1 μg to approximately 80 μg, approximately 1 μg to approximately 75 μg, approximately 1 μg to approximately 70 μg, approximately 1 μg to approximately 65 μg, approximately 1 μg to approximately 60 μg, approximately 1 μg to approximately 55 μg, approximately 1 μg to approximately 50 μg, approximately 1 μg to approximately 45 μg, approximately 1 μg to approximately 40 μg, approximately 1 μg to approximately 35 μg, approximately 1 μg to approximately 30 μg , about 1 μg to about 25 μg, about 1 μg to about 20 μg, about 1 μg to about 15 μg, about 1 μg to about 14 μg, about 1 μg to about 13 μg, about 1 μg to about 12 μg, about 1 μg to about 11 μg, about 1 μg to about 10 μg, about 1 μg to about 9 μg g, about 2 μg to about 100 μg, about 3 μg to about 100 μg, about 4 μg to about 100 μg, about 5 μg to about 100 μg, about 6 μg to about 100 μg, about 7 μg to about 100 μg, about 8 μg to about 100 μg, about 9 μg to about 100 μg, Approximately 10μg to approximately 100μg, approximately 11μg to approximately 100μg, approximately 12μg to approximately 100μg, approximately 13μg to approximately 100μg, approximately 14μg to approximately 100μg, approximately 15μg to approximately 100μg, approximately 16μg to approximately 100μg, approximately 20μg Approximately 100μg, approximately 25μg to approximately 100μg, approximately 30μg to approximately 100μg, approximately 35μg to approximately 100μg, approximately 40μg to approximately 100μg, approximately 45μg to approximately 100μg, approximately 50μg to approximately 100μg, approximately 55μg to approximately 100μg, The formulation may include approximately 60 μg to 100 μg, 65 μg to 100 μg, 70 μg to 100 μg, 75 μg to 100 μg, 80 μg to 100 μg, 85 μg to 100 μg, 90 μg to 100 μg, 95 μg to 100 μg, 5 μg to 50 μg, 5 μg to 45 μg, 5 μg to 40 μg, 5 μg to 35 μg, 5 μg to 30 μg, 5 μg to 25 μg, or 5 μg to 20 μg of therapeutic agent.In certain embodiments, the therapeutic release composition may contain about 1 μg to about 20 μg of the therapeutic agent. In certain embodiments, the therapeutic release composition may contain about 5 μg to about 20 μg of the therapeutic agent. In certain embodiments, the therapeutic release composition may contain about 1 μg to about 30 μg of the therapeutic agent. In certain embodiments, the therapeutic release composition may contain about 5 μg to about 30 μg of the therapeutic agent.

[0276] In certain embodiments, the therapeutic release composition contains about 10% to about 70% by mass of a therapeutic agent, such as dexamethasone. In certain embodiments, the polymer matrix contains about 15% to about 65% by mass, about 20% to about 50% by mass, or about 25% to about 40% by mass of a therapeutic agent, such as dexamethasone. In certain embodiments, the therapeutic release composition contains about 20% to about 50% by mass of a therapeutic agent, such as dexamethasone. In certain embodiments, the therapeutic release composition contains about 30% to about 60% by mass of a therapeutic agent, such as dexamethasone.

[0277] In certain embodiments, the therapeutic release composition is shaped to fit within the dimensions of a device used to deliver the therapeutic release composition. In certain embodiments, the therapeutic release composition has a shape that allows it to fit securely into the lumen, channel, or groove of a delivery device, for example, a sharp part, during delivery, but also allows for the release of the therapeutic release composition from the delivery device into the tissue. For example, but not limited to, the therapeutic release composition may have a cubic, rectangular, cylindrical, spherical, diamond, or irregular shape. In certain embodiments, the delivery unit may be able to split into multiple parts upon contact with the tissue. In certain embodiments, the therapeutic release composition is shaped and / or sized to fit within the dimensions of a sharp object (i.e., an insertion needle) used to deliver the therapeutic release composition very close to the analyte sensor. For example, but not limited to, the therapeutic release composition is shaped to correspond to the lumen, channel, or groove of the sharp object. As shown in Figure 63A, the therapeutic release composition 502 may have a shape that fits within the U-shaped chan...

Claims

1. (i) Sensor tail portion including at least a first working electrode and a counter electrode / reference electrode; (ii) an active region located on the surface of the first working electrode for detecting the analyte; (iii) A substance transport limiting film that is permeable to the analyte and overcoats at least the active region; and (iv) A polymer composition comprising a therapeutic agent comprising dexamethasone, a derivative thereof or a salt form thereof, and at least one polymer, wherein the therapeutic agent is covalently bonded to the at least one polymer via a hydrolyzable bond, and the hydrolyzable bond is an ester bond, an amide bond, or a hydrazone-based bond. Analytical sensor including

2. The analyte sensor according to claim 1, wherein the therapeutic agent is an anti-inflammatory agent.

3. The analyte sensor according to claim 1 or 2, wherein the polymer composition is disposed on the counter electrode / reference electrode.

4. The analyte sensor according to any one of claims 1 to 3, wherein the at least one polymer is selected from the group consisting of polyvinylpyridine-based polymers, polyvinylimidazole, polyacrylate, polyurethane, polyether urethane, silicone, or derivatives or combinations thereof.

5. The analyte sensor according to any one of claims 1 to 4, wherein the analyte is glucose.

6. An analyte sensor for use in a method of delivering a therapeutic agent in very close proximity to the analyte sensor at an in vivo position, The aforementioned analyte sensor, (a) Sensor tail portion including at least a first working electrode; (b) an active region located on the surface of the first working electrode for detecting the analyte; (c) A substance transport limiting film that is permeable to the analyte and overcoats at least the active region; and (d) A polymer composition comprising a therapeutic agent comprising dexamethasone, a derivative thereof or a salt form thereof, and at least one polymer, wherein the therapeutic agent is covalently bonded to the at least one polymer via a hydrolyzable bond, and the hydrolyzable bond is an ester bond, an amide bond, or a hydrazone-based bond; Includes, The method described above is (i) the step of providing the analyte sensor, (ii) The step of embedding the analyte sensor at the in vivo position Includes an analyte sensor.

7. The analyte sensor according to claim 6, wherein the therapeutic agent is an anti-inflammatory agent.

8. The analyte sensor according to claim 6 or 7, wherein the polymer composition is disposed on the counter electrode / reference electrode located on the sensor tail.

9. The analyte sensor according to any one of claims 6 to 8, wherein the at least one polymer is selected from the group consisting of polyvinylpyridine-based polymers, polyvinylimidazole, polyacrylate, polyurethane, polyether urethane, silicone, or derivatives or combinations thereof.

10. The analyte sensor according to any one of claims 6 to 9, wherein the analyte is glucose.

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