Systems and methods for fructosamine sensing

Abstract

A device for measurement of a concentration of glycated serum protein is disclosed, the device comprising: an analyte sensing portion configured to generate a signal associated with a concentration of a glycated serum protein, the analyte sensing portion comprising a flavin adenine dinucleotide (FAD)-dependent enzyme or an adenosine triphosphate (ATP)- dependent enzyme; a working electrode (WE); and a counter electrode (CE) and / or a reference electrode (RE). Methods of monitoring kidney disease in a subject using the device are also disclosed.

Description

Attorney Docket No. 0981-PCT01SYSTEMS AND METHODS FOR FRUCTOSAMINE SENSINGCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Application No.63 / 739,877, filed December 30, 2024, U.S. Provisional Application No. 63 / 739,877, filed February 20, 2025, and U.S. Provisional Patent Application No. 63 / 776,906, filed March 24, 2025. Each of the aforementioned applications is incorporated by reference herein in its entirety, and each is hereby expressly made a part of this specification.BACKGROUND

[0002] The kidney is responsible for many critical functions within the human body, including filtering waste and excess fluids that are thereafter excreted in urine, and removing acid that is produced by the cells of the body, in order to maintain a healthy balance of water, salts, and minerals (e.g., such as sodium, calcium, phosphorus, and potassium) in the blood. In other words, the kidney plays a major role in homeostasis by renal mechanisms that transport and regulate water, salt, and mineral secretion, reabsorption, and excretion.

[0003] Kidney disease is generally classified as either acute or chronic based on the duration of the disease and / or whether the disease is caused by a specific event (e.g., dehydration or surgery) or develops over time in response to a long-term disease. Chronic kidney disease (CKD) is irreversible damage that can develop over time in response to a longterm disease such as high blood pressure or diabetes, for example, which slowly damages the kidneys and reduce their function over time. Symptoms of CKD can develop slowly and may not be apparent until very little kidney function remains.

[0004] Hosts with diabetes are among the most likely to develop kidney disease, having nearly 2-fold higher odds of developing CKD than those without diabetes. Diabetes mellitus (DM) is the leading cause of CKD and end-stage kidney disease (ESKD) worldwide.

[0005] Hosts with diabetes often experience diminished glycemic control, which is associated with worse cardiovascular and kidney outcomes in diabetic hosts. Glycemic control refers to the maintenance of blood glucose levels within a desirable range to prevent both hypoglycemia and hyperglycemia.

[0006] Measuring glycated hemoglobin (HbAlc) has long been the standard for assessing glycemic control in diabetic hosts, and therefore, preventing worse cardiovascular and kidney outcomes. In red blood cells, HbAlc is hemoglobin that has glucose attached to the N-terminalAttorney Docket No. 0981-PCT01valine of the beta chain and is reported as the proportion of total hemoglobin. Current guidelines recommend a target HbAlc of approximately 7% for preventing or delaying microvascular complications, including diabetic kidney disease.SUMMARY

[0007] In examples, a device for measurement of a concentration of glycated serum protein is provided, the device comprising: an analyte sensing portion configured to generate a signal associated with a concentration of a glycated albumin, the analyte sensing portion comprising a flavin adenine dinucleotide (FAD)-dependent enzyme or an adenosine triphosphate (ATP)-dependent enzyme; a working electrode (WE); and a counter electrode (CE) and / or a reference electrode (RE).

[0008] In aspects, the device comprises a transcutaneous glycated protein sensor. In aspects, alone or in combination with any of the previous aspects, the device comprises a subcutaneous glycated protein sensor. In aspects, alone or in combination with any of the previous aspects, the device comprises a continuous glycated protein sensor.

[0009] In aspects, alone or in combination with any of the previous aspects, the glycated serum protein is glycated hemoglobin Ale. In aspects, alone or in combination with any of the previous aspects, the glycated serum protein is glycated albumin. In aspects, alone or in combination with any of the previous aspects, the glycated serum protein is fructosamine.

[0010] In aspects, alone or in combination with any of the previous aspects, the working electrode comprises metal, metal alloy, carbon, graphite, carbon fiber, carbon nanotubes, conductive polymer, a doped conductive polymer, or combinations thereof. In aspects, alone or in combination with any of the previous aspects, the working electrode is configured as a wire or present on a planar substrate. In aspects, alone or in combination with any of the previous aspects, the reference electrode is external from the analyte sensing portion upon implantation.

[0011] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a first working electrode and a second working electrode. In aspects, alone or in combination with any of the previous aspects, the first working electrode is configured to generate a first signal associated with a first analyte. In aspects, alone or in combination with any of the previous aspects, the second working electrode is configured toAttorney Docket No. 0981-PCT01generate a signal associated with a second analyte, the second analyte being chemically different from the first analyte. In aspects, alone or in combination with any of the previous aspects, the second working electrode is configured to operate at a potential different from the first working electrode.

[0012] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a polymer layer adjacent the working electrode. In aspects, alone or in combination with any of the previous aspects, the working electrode comprises fructosyl-amino acid oxidase (FAOx) adjacent thereto. In aspects, alone or in combination with any of the previous aspects, the working electrode comprises a fructosamine 6-kinase, a pyruvate kinase, a pyruvate oxidase or combinations thereof adjacent the working electrode.

[0013] In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a first polymer layer adjacent the working electrode and a second polymer layer adjacent the first polymer layer. In aspects, alone or in combination with any of the previous aspects, the working electrode comprises a first working electrode and a second working electrode, the first and the second electrodes being the same or different composition.

[0014] In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a first polymer layer adjacent the first working electrode and a second polymer layer adjacent the second working electrode, the first and the second polymer layers being the same or different.

[0015] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a flavin adenine dinucleotide (FAD)-dependent enzyme. In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a first flavin adenine dinucleotide (FAD)-dependent enzyme and a second flavin adenine dinucleotide (FAD)-dependent enzyme, the first and the second flavin adenine dinucleotide (FAD)-dependent enzymes being different.

[0016] In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a single polymer layer, the first flavin adenine dinucleotide (FAD)-dependent enzyme and the second flavin adenine dinucleotide (FAD)-dependent enzyme being present in the single polymer layer. In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a first polymer layer and a second polymer layer adjacent the first polymer layer, the first flavin adenine dinucleotide (FAD)-dependent enzyme is present in the first polymer layer and the second flavin adenine dinucleotide (FAD)-dependent enzyme areAttorney Docket No. 0981-PCT01present in the second polymer layer, the first and the second polymer layers being the same or different.

[0017] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a first working electrode and a second working electrode, a first polymer layer adjacent the first working electrode, and a second polymer layer adjacent the second working electrode, wherein the first flavin adenine dinucleotide (FAD)-dependent enzyme is present in the first polymer layer and the second flavin adenine dinucleotide (FAD)-dependent enzyme is present in the second polymer layer, the first and the second polymer layers being the same or different.

[0018] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a first working electrode and a second working electrode, a first polymer layer adjacent the first working electrode, and a second polymer layer adjacent the second polymer layer, wherein the first flavin adenine dinucleotide (FAD)-dependent enzyme is present in the first polymer layer and the second flavin adenine dinucleotide (FAD)-dependent enzyme is present in the second polymer layer, the first and the second polymer layers being the same or different.

[0019] In aspects, alone or in combination with any of the previous aspects, the first flavin adenine dinucleotide (FAD)-dependent enzyme is fructosyl-amino acid oxidase (FAOx) and the second flavin adenine dinucleotide (FAD)-dependent enzyme is glucose oxidase (GOx), lactate oxidase, or combinations thereof. In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a flavin adenine dinucleotide (FAD)-dependent enzyme and a NAD(P)+-dependent dehydrogenase enzyme. In aspects, alone or in combination with any of the previous aspects, the NAD(P)+-dependent dehydrogenase enzyme is hydroxysteroid dehydrogenase enzyme or glucose dehydrogenase. In aspects, alone or in combination with any of the previous aspects, the NAD(P)+-dependent dehydrogenase enzyme is glucose dehydrogenase, alcohol dehydrogenase, D-3-hydroxybutyrate dehydrogenase, or combinations thereof. In aspects, alone or in combination with any of the previous aspects, the flavin adenine dinucleotide (FAD)-dependent enzyme is fructosyl-amino acid oxidase (FAOx) and the NAD(P)+-dependent dehydrogenase enzyme is glucose dehydrogenase, alcohol dehydrogenase, D-3-hydroxybutyrate dehydrogenase, or combinations thereof.

[0020] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a first working electrode and a second working electrode, a firstAttorney Docket No. 0981-PCT01polymer layer adjacent the first working electrode, and a second polymer layer adjacent the second electrode, wherein the first polymer layer comprises the at least one flavin adenine dinucleotide (FAD)-dependent enzyme and the second polymer layer comprises the at least one NAD(P)+-dependent dehydrogenase enzyme.

[0021] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a first working electrode and a second working electrode, a first polymer layer adjacent the first working electrode, and a second polymer layer adjacent the second polymer layer, wherein the first polymer layer comprises the at least one flavin adenine dinucleotide (FAD)-dependent enzyme and the second polymer layer comprises the at least one NAD(P)+-dependent dehydrogenase enzyme.

[0022] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a flavin adenine dinucleotide (FAD)-dependent enzyme and a glucose responsive enzyme, a 1,5-anydroglucitol (1,5-AG) responsive enzyme, a potassium sensor, or combinations thereof. In aspects, alone or in combination with any of the previous aspects, the flavin adenine dinucleotide (FAD)-dependent enzyme is a thermally stable mutant fructo syl- amino acid oxidase enzyme with an amino acid substitution at T60A, A188G, M244L, N257S, L261M and combinations thereof.

[0023] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises at least one ATP-dependent enzyme. In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises at least two different ATP-dependent enzymes and a flavin adenine dinucleotide (FAD)-dependent enzyme.

[0024] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises at least two different ATP-dependent enzymes, a flavin adenine dinucleotide (FAD)-dependent enzyme, and a glucose responsive enzyme, a 1,5-anydroglucitol (1,5-AG) responsive enzyme, a potassium sensor, or combinations thereof.

[0025] In aspects, alone or in combination with any of the previous aspects, the at least two different ATP-dependent enzymes comprise fructosamine 6-kinase and pyruvate kinase. In aspects, alone or in combination with any of the previous aspects, the flavin adenine dinucleotide (FAD)-dependent enzyme is pyruvate oxidase. In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises fructosamine 6-kinase, pyruvate kinase, and pyruvate oxidase. In aspects, alone or in combination with any of theAttorney Docket No. 0981-PCT01previous aspects, the analyte sensing portion comprises fructosamine 6-kinase, pyruvate kinase, pyruvate oxidase and glucose oxidase enzyme.

[0026] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises fructosamine 6-kinase, pyruvate kinase, pyruvate oxidase and a NAD(P)+-dependent dehydrogenase enzyme. In aspects, alone or in combination with any of the previous aspects, the NAD(P)+-dependent dehydrogenase enzyme is glucose dehydrogenase, alcohol dehydrogenase, D-3-hydroxybutyrate dehydrogenase, or combinations thereof. In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises fructosamine 6-kinase, pyruvate kinase, pyruvate oxidase, and a glucose responsive enzyme, a 1,5-anydroglucitol (1,5-AG) responsive enzyme, a potassium sensor, or combinations thereof.

[0027] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion further comprises adenosine triphosphate (ATP), phosphoenolpyruvate, or combinations thereof. In aspects, alone or in combination with any of the previous aspects, the adenosine triphosphate (ATP), the phosphoenolpyruvate, or combinations thereof are immobilized.

[0028] In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a first polymer layer and a second polymer layer adjacent the first polymer layer, the first polymer layer comprising fructosamine 6-kinase and adenosine triphosphate (ATP), the second polymer layer comprising pyruvate kinase or pyruvate oxidase and the phosphoenolpyruvate.

[0029] In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a first polymer layer adjacent a first electrode and a second polymer layer adjacent the first polymer layer, the first polymer layer comprising fructosamine 6-kinase and adenosine triphosphate (ATP), the second polymer layer comprising pyruvate kinase or pyruvate oxidase and the phosphoenolpyruvate, and a third polymer layer adjacent a second working electrode, the third polymer layer comprising glucose oxidase, a NAD(P)+-dependent dehydrogenase enzyme, or combination thereof.

[0030] In aspects, alone or in combination with any of the previous aspects, the NAD(P)+-dependent dehydrogenase enzyme is glucose dehydrogenase, alcohol dehydrogenase, D-3-hydroxybutyrate dehydrogenase, or combinations thereof. In aspects, alone or in combinationAttorney Docket No. 0981-PCT01with any of the previous aspects, the polymer layer comprises a waterborne polyurethane polymer or copolymer.

[0031] In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a zwitterionic functional group. In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a waterborne polyurethane polymer or copolymer comprising zwitterionic functional groups. In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a polymer chain having polyurethane segments and / or polyurea segments. In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a polymer chain having both hydrophilic and hydrophobic regions. In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a polymer backbone having one or more zwitterionic compounds.

[0032] In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a polymer with a heterocyclic group. In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a polymer chain having poly(l -vinyl imidazole), poly(4-vinyl pyridine), poly(2-vinyl pyridine), acrylonitrile, acrylamide, and / or copolymers and / or quaternized forms thereof. In aspects, alone or in combination with any of the previous aspects, the polymer layer comprises a copolymer including styrene.

[0033] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion further comprises a mediator or an electron transfer agent. In aspects, alone or in combination with any of the previous aspects, the at least one mediator or electron transfer agent comprise at least one transition metal or at least one transition metal complex. In aspects, alone or in combination with any of the previous aspects, the mediator or the electron transfer agent comprises ruthenium, osmium, rhodium, cobalt, iron, or alloys thereof.

[0034] In aspects, alone or in combination with any of the previous aspects, the mediator or the electron transfer agent comprises a ruthenium complex, an osmium complex, a rhodium complex, a cobalt complex, an iron complex, or combinations thereof. In aspects, alone or in combination with any of the previous aspects, the ruthenium complex, the osmium complex, the rhodium complex, the cobalt complex, or the iron complex independently comprises monodentate, bidentate, tridentate, tetradentate, or higher denticity ligands.

[0035] In aspects, alone or in combination with any of the previous aspects, the monodentate, bidentate, tridentate, tetradentate, or higher denticity ligands comprise one or more of bipyridine, biimidazole, phenanthroline, or pyridyl(imidazole). In aspects, alone or inAttorney Docket No. 0981-PCT01combination with any of the previous aspects, the mediator or the electron transfer agent is covalently coupled to a polymer. In aspects, alone or in combination with any of the previous aspects, the polymer comprises poly(4-vinylpyridine), poly(2-vinylpyridine), polyvinylimidazoles, or copolymer thereof.

[0036] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion further comprising at least one globular protein. In aspects, alone or in combination with any of the previous aspects, the at least one globular protein comprises albumin. In aspects, alone or in combination with any of the previous aspects, the albumin is serum albumin.

[0037] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion further comprising one or more functional polymer membranes selected from a resistance layer, a blocking layer, an electrode layer, a biointerface layer, and combinations thereof.

[0038] In aspects, alone or in combination with any of the previous aspects, the biointerface layer comprises an anti-inflammatory agent or tissue response modifying agent. In aspects, alone or in combination with any of the previous aspects, the biointerface layer comprises a polymer chain having polyurethane segments and / or polyurea segments. In aspects, alone or in combination with any of the previous aspects, the biointerface layer comprises a polymer chain having both hydrophilic and hydrophobic regions. In aspects, alone or in combination with any of the previous aspects, the biointerface layer comprises a polymer chain having one or more zwitterionic compounds.

[0039] In aspects, alone or in combination with any of the previous aspects, the method further comprises an analyte sensor circuit electrically coupled to the analyte sensing portion. In aspects, alone or in combination with any of the previous aspects, the analyte sensor circuit is configured for coulometric, amperometric, voltametric, or potentiometric electrochemical detection. In aspects, alone or in combination with any of the previous aspects, the analyte sensor circuit is configured for gated amperometric electrochemical detection.

[0040] In examples, a method of monitoring kidney disease in a subject is provided, the method comprising operating an analyte sensor the configured for detecting glycated protein in a fluid as defined in any of the previous aspects, the method comprising: applying a potential to the working electrode at or above an oxidation-reduction potential of the analyte sensingAttorney Docket No. 0981-PCT01portion to generate a signal corresponding to a glycated protein concentration; and correlating the glycated protein concentration to kidney disease in the subject.

[0041] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion is configured for introduction to a space between an epidermis and muscle tissue.

[0042] In aspects, alone or in combination with any of the previous aspects, the method further comprises correlating glycated protein concentration with glomerular filtration rate (eGFR) alone or in combination with glucose and / or 1,5-anhydroglucitol (1,5-AG), and / or potassium.

[0043] In aspects, alone or in combination with any of the previous aspects, the method further comprises determining at least one other analyte concentration selected from glucose, ketone, alcohol, potassium, lactate and combinations thereof. In aspects, alone or in combination with any of the previous aspects, the method further comprises correlating the glycated protein concentration and the at least one other analyte concentration.

[0044] In examples, a method of operating an analyte sensor for detecting glycated protein in a fluid is provided, the analyte sensor as defined in any of the previous aspects, the analyte sensing portion capable of at least facilitating detection of the glycated protein; the method comprising: applying a potential to the working electrode at or above an oxidation-reduction potential of the analyte sensing portion to generate a signal corresponding to a glycated protein concentration in the space; and correlating the signal to the glycated protein concentration.

[0045] In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion is configured for introduction to a space between an epidermis and muscle tissue. In aspects, alone or in combination with any of the previous aspects, the glycated serum protein is glycated albumin. In aspects, alone or in combination with any of the previous aspects, the glycated serum protein is glycated hemoglobin Ale. In aspects, alone or in combination with any of the previous aspects, the glycated serum protein is fructosamine.

[0046] In aspects, alone or in combination with any of the previous aspects, the reference electrode is external from the analyte sensing portion upon implantation.

[0047] In aspects, alone or in combination with any of the previous aspects, the working electrode is configured as a wire or present on a planar substrate. In aspects, alone or in combination with any of the previous aspects, the analyte sensing portion comprises a firstAttorney Docket No. 0981-PCT01working electrode and a second working electrode. In aspects, alone or in combination with any of the previous aspects, the first working electrode is configured to generate a first signal associated with a first analyte.

[0048] In aspects, alone or in combination with any of the previous aspects, the second working electrode is configured to operate at a potential different from the first working electrode. In aspects, alone or in combination with any of the previous aspects, the second working electrode is configured to generate a signal associated with a second analyte, the second analyte being chemically different from the first analyte. In aspects, alone or in combination with any of the previous aspects, the second analyte is glucose, ketone, alcohol, potassium or lactate.BRIEF DESCRIPTION OF THE DRAWINGS

[0049] So that the manner in which the above-recited features of the present disclosure can be understood in detail, a more particular description, briefly summarized above, may be had by reference to aspects, some of which are illustrated in the drawings. It is to be noted, however, that the appended drawings illustrate only certain typical aspects of this disclosure and are therefore not to be considered limiting of its scope, for the description may admit to other equally effective aspects.

[0050] FIG. 1 illustrates aspects of an example therapy management system used in connection with implementing embodiments of the present disclosure.

[0051] FIG. 2 is a diagram conceptually illustrating an example continuous analyte monitoring system including example continuous analyte sensor(s) with sensor electronics, according to certain embodiments of the present disclosure.

[0052] FIG. 3 illustrates example inputs and example metrics that are calculated based on the inputs for use by the therapy management system of FIG. 1, according to certain embodiments of the present disclosure.

[0053] FIG. 4 is a flow diagram of an example method for providing therapy management support related to the risk, presence, and / or progression of kidney dysfunction using a continuous analyte monitoring system configured to continuously measure at least fructosamine and glucose data, according to certain embodiments of the present disclosure.

[0054] FIG. 5 is a flow diagram depicting a method for training machine learning models to determine a risk, presence, and / or progression of kidney dysfunction of a host, and / orAttorney Docket No. 0981-PCT01provide therapy management guidance to the host based on the determination, according to certain embodiments of the present disclosure.

[0055] FIG. 6 is a block diagram depicting a computing device configured to perform the operations of FIG. 4, according to certain embodiments of the present disclosure.

[0056] FIG. 7A is an illustration of an example wearable analyte sensor system.

[0057] FIG. 7B is an enlarged view of an example analyte sensor portion of the wearable analyte sensor system shown in FIG. 7A.

[0058] FIG. 7C is a cross-sectional view of the analyte sensor of FIG. 7B, depicting an exemplary enzyme domain configuration for a continuous analyte sensor as disclosed and described herein.

[0059] FIG. 7D is an illustration of an example planar analyte sensor with sensing membranes, according to certain examples of the present disclosure.

[0060] FIGS. 8A-8E illustrate a double-sided, co-planar un-connected analyte sensor, according to certain embodiments of the present disclosure.

[0061] FIGS. 9A-9E illustrate a double-sided, co-planar connected analyte sensor, according to certain embodiments of the present disclosure.

[0062] FIG. 10A is a schematic illustration of various example electronic components that may be part of exemplary gated amperometry based analyte sensor system.

[0063] FIG. 10B depicts idealized current plotted against fructosamine concentration for a sensor measured using gated amperometry and normal (non-gated) amperometry across a range of fructosamine concentrations.

[0064] FIGs. 11A and 11B depict exemplary one-enzyme cascades with and without mediator, respectively, as disclosed and described herein.

[0065] FIGs. 12 A, 12B depict example membrane configurations representative of continuous one-enzyme glycated protein sensors as disclosed and described herein.

[0066] FIG. 13 depict example one-enzyme cascades representative of continuous analyte sensors as disclosed and described herein.

[0067] FIGs. 14A, 14B depict example membrane configurations representative of continuous multi-enzyme glycated protein sensors as disclosed and described herein.Attorney Docket No. 0981-PCT01

[0068] To facilitate understanding, identical reference numerals have been used, where possible, to designate identical elements that are common to the figures. It is contemplated that elements disclosed in one aspect may be beneficially utilized on other aspects without specific recitation.DETAILED DESCRIPTION

[0069] Aspects of the present disclosure relate to systems and methods for continuously monitoring fructosamine data, glucose data, and / or other analyte and / or non-analyte data of a host to determine a risk, presence, and / or progression of kidney dysfunction, and provide accurate therapy management to a host for treatment and / or management of kidney dysfunction.

[0070] Currently, HbAlc is the standard for monitoring glycemic control. However, HbAlc may not be the most effective indicator of glycemic control and thus, may not be a good predictor of kidney disease in healthy and diabetic hosts. Further, because the lifespan of red blood cells is approximately 120 days, HbAlc reflects the average glycemia over the past approximately three months. Although this allows for standardization across hosts and settings, HbAlc measurements have limited interpretability in the setting of altered red blood cell lifespan, and do not accurately reflect recent glycemic control or large variances that might otherwise converge to a nominal average value.

[0071] While HbAlc is the preferred test for monitoring glycemic control, laboratory tests also exist to monitor fructosamine levels to assist hosts with the management of their diabetes. Fructosamines are compounds that result from glycation reactions between a sugar, such as glucose, and a primary amine, such as those found on the surface of nearly all proteins. Therefore, fructosamine levels of a host can be directly correlated to a host’s glucose levels. Given this correlation, fructosamine levels can be valuable for monitoring glycemic control. However, fructosamine laboratory tests are rarely used in clinical practice today.

[0072] Even further, in humans, fructosamines primarily bind to albumins, given their preponderance in most physiological fluids. Because albumin has a half-life of approximately 20 days, the plasma fructosamine concentration reflects relatively recent (e.g., 1-2 week) changes in blood glucose levels. Also, because fructosamines have a shorter half-life than HbAlc (e.g., 1-2 weeks versus 2-3 months), fructosamines reflect recent glycemic control more accurately than HbAlc. Further, fructosamines can be more useful in monitoring diabetic ESKD hosts, as changes in red blood cell turnover affect percent glycation, making it difficultAttorney Docket No. 0981-PCT01to interpret HbAlc in ESKD dialysis hosts. Even further, fructosamines can indicate glomerular functionality of the kidneys, which may better capture some types of nephropathies as compared to GFR, etc.

[0073] Since fructosamines primarily bind to albumins, abnormal fructosamine levels can cause a host to experience albuminuria (generalized herein as proteinuria). Proteinuria is toxic, and may demonstrate kidney dysfunction, specifically glomerular dysfunction, early enough to allow for accurate treatment and management of kidney dysfunction before it progresses to kidney disease.

[0074] Accordingly, existing techniques for detecting a risk, presence, and / or progression of kidney dysfunction prior to a diagnosis of kidney disease lack the ability to provide realtime guidance and recommendations to the host to treat and / or manage kidney dysfunction and prevent the development of kidney disease.

[0075] Currently, no technology exists to dynamically provide real-time determinations of a risk, presence, and / or progression of kidney dysfunction. More particularly, current techniques for tracking a host’s kidney function involves point-in-time measurements of HbAlc in a clinic, which may not demonstrate kidney dysfunction until up to three months after hosts begin experiencing kidney dysfunction.

[0076] Consequently, there is a need in the art for an accurate, continuous therapy management system to continuously monitor a host’s analyte concentration levels to determine a risk, presence, and / or progression of kidney dysfunction, and provide accurate therapy management to a host for treatment and / or management of kidney dysfunction. In particular, continuous monitoring of a host’s analyte concentration levels allows for more immediate diagnosis and monitoring of kidney dysfunction, which in turn enables the therapy management system provide accurate recommendations to the host for treatment and / or management of kidney dysfunction. Based on the host’s kidney dysfunction, the therapy management system may recommend the host seek medical intervention, provide medication recommendations, and / or suggest lifestyle changes (e.g., consume specific foods) to treat, improve, or manage kidney dysfunction. Accordingly, the present disclosure addresses the above needs and deficiencies, and more.

[0077] In particular, certain embodiments provided herein are directed to a therapy management system that monitors at least fructosamine data and glucose data of a host via a continuous analyte monitoring system, as well as non-analyte data associated with the host, toAttorney Docket No. 0981-PCT01determine whether the host is at risk of kidney dysfunction, experiencing kidney dysfunction, or experiencing progressing kidney dysfunction. In such embodiments, the host can be a healthy host, a healthy host with a known risk of kidney dysfunction or a comorbid condition with a risk of kidney dysfunction, and / or a diabetic host.

[0078] In certain embodiments, based on the determination of a risk, presence, and / or progression of kidney dysfunction, the therapy management system provides real-time identification and notification of a risk, presence, and / or progression of kidney dysfunction, as well as recommendations to treat or manage kidney dysfunction.

[0079] For example, the therapy management system can provide a recommendation for the host to seek medical intervention to treat kidney dysfunction and / or potential kidney disease. In another example, the therapy management system can provide medication recommendations and / or lifestyle changes in order to prevent a worsening of the kidney dysfunction and / or improve kidney function.

[0080] As described above, because fructosamines result from glycation reactions between a sugar, such as glucose, and a primary amine, fructosamine concentration levels of a host can be directly correlated to a host’s glucose concentration levels. In light of the relationship between fructosamines and glucose, the therapy management system can monitor both glucose and fructosamine concentration levels to determine the risk, presence, and / or progression of kidney dysfunction well before current techniques would be able to detect kidney dysfunction. Specifically, glucose concentration levels alone are not necessarily indicative of kidney health, but, as described herein, can be utilized to determine the fructosamine concentration levels a host with healthy kidney function would be expected to have based on their glucose levels.

[0081] As described herein, the therapy management system can derive measured glucose values and measured fructosamine values based on the fructosamine concentration levels and the glucose concentration levels. The measured glucose values and measured fructosamine values can be stored in a host profile, for example, as measured glucose data and measured fructosamine data, respectively. In addition, one or more fructosamine metrics and glucose metrics can be derived from the fructosamine concentration levels and glucose concentration levels, as described in reference to FIG. 3, and can also be stored in the host profile as glucose data and fructosamine data.

[0082] Therefore, the therapy management system described herein can monitor glucose data and fructosamine data to determine when a measured real-time fructosamine valueAttorney Docket No. 0981-PCT01(“measured fructosamine value”) of a host is abnormal as compared to a fructosamine value that a host with healthy kidney function would be expected to have (“expected fructosamine value”) based on the host’s glucose data. Given the shorter half-life of fructosamine and the relationship between glucose and fructosamine levels, changes in real-time measured fructosamine values over time as compared to expected fructosamine values can demonstrate changes in kidney function and / or progression of kidney dysfunction to CKD and / or other severe kidney diseases.

[0083] For example, in certain embodiments, the therapy management system monitors the host’s glucose data to determine an expected fructosamine value based on the glucose data. As an example, the therapy management system derives a mean glucose level from the monitored glucose data and then determines the expected fructosamine value using the following equation: Fructosamine {micromol (pmol) / liter (L)} = 1.9391 * (Mean Glucose {milligram (mg) / deciliter (dL)} + 20). Therapy management system then derives a measured fructosamine value from the measured fructosamine concentration levels and compares the expected fructosamine value with the measured fructosamine value to determine a fructosamine delta.

[0084] When the host’s fructosamine delta is at or near zero, the therapy management system determines that the host is at low risk of experiencing kidney dysfunction. Accordingly, where the therapy management system determines that the host is at low risk of experiencing kidney dysfunction, the therapy management system continues monitoring the host’s fructosamine levels, and, therefore, kidney function over time to monitor any deviations from the host’s normal kidney function.

[0085] Conversely, when the host’s fructosamine delta is high (e.g., the measured fructosamine level of the host is much different than their expected fructosamine level derived based on glucose data), the therapy management system determines that the host is experiencing kidney dysfunction, which may further indicate nephropathy, proteinuria, glomerular issues, etc. In such examples, the therapy management system can provide notification / recommendations to the host suggesting the host seek medical intervention, begin a medication regimen, and / or implement lifestyle changes to improve or maintain kidney function. In some examples, the degree or magnitude of the delta can further be correlated to a risk level or progression of kidney dysfunction.

[0086] As used herein, the term “continuous” analyte monitoring refers to monitoring one or more analytes in a fully continuous, semi-continuous, periodic manner, which results in aAttorney Docket No. 0981-PCT01data stream of analyte values over time. A data stream of analyte values over time is what allows for meaningful data and insight to be derived using the algorithms described herein for monitoring a host’s glucose and fructosamine data to manage and / or diagnose kidney disease or kidney dysfunction. In other words, single point- in-time measurements collected as a result of a host visiting their health care professional every few months results in sporadic data points (e.g., that are, at best, months apart in timing) that cannot form the basis of any meaningful data or insight to be derived. As such, without the continuous analyte monitoring system of the embodiments herein, it is simply impossible to continuously monitor a host’s glucose and fructosamine data over time to manage and / or diagnose kidney disease or kidney dysfunction.

[0087] Further, the data stream of analyte values collected over time, with the continuous analyte monitoring system presented herein, include real-time analyte values, which allows for deriving meaningful data and insight in real-time using the systems and algorithms described herein. The derived real-time data and insight in turn allows for monitoring of a host’s kidney function in real-time, managing the host’s kidney dysfunction in real-time, providing therapy management guidance based on known or possible kidney dysfunction in real-time, etc.

[0088] Real time analyte values herein refer to analyte values that become available and actionable within seconds or minutes of being produced as a result of at least one sensor electronics module of the continuous analyte monitoring system (1) converting sensor current(s) (i.e., analog electrical signals) generated by the continuous analyte sensor(s) into sensor count values, (2) calibrating the count values to generate at least glucose, fructosamine, and / or other analyte concentration values using calibration techniques described herein to account for the sensitivity of the continuous analyte sensor(s), and (3) transmitting measured fructosamine, glucose, and / or other analyte concentration values, to a display device via wireless connection.

[0089] For example, the at least one sensor electronics module may be configured to sample the analog electrical signals at a particular sampling period (or rate), such as every 1 second (1 Hz), 5 seconds, 10 seconds, 30 seconds, 1 minute, 3 minutes, 5 minutes, etc., and to transmit the measured glucose, fructosamine, and / or other analyte concentration data to a display device at a particular transmission period (or rate), which may be the same as (or longer than) the sampling period, such as every 1 minute (0.16 Hz), 5 minutes, 10 minutes, etc.

[0090] The real-time analyte data that is continuously generated by the continuous analyte monitoring system described herein, therefore, allows the therapy management system hereinAttorney Docket No. 0981-PCT01to monitor of a host’s kidney function in real-time, manage the host’s kidney function in realtime, provide therapy management guidance based on kidney function in real-time, etc., which is technically impossible to perform using existing or conventional techniques or systems. Further, because of the real-time nature of this data, it is also humanly impossible to continuously process a real-time data stream of analyte values over time to derive meaningful data and insight using the algorithms and systems described herein to monitor a host’s kidney function in real-time, manage the host’s kidney function in real-time, provide therapy management guidance based on kidney function in real-time. In other words, deriving meaningful data and insight from a stream of real-time data that is continuously generated, processed, calibrated, and analyzed, using the algorithms and systems described herein, is not a task that can be mentally performed. For example, executing the algorithms described in relation to FIG. 4 in real-time and on a continuous basis, which would involve using a stream of real-time data that is continuously generated by a host’s continuous analyte monitoring system and / or significantly large amount of population data (e.g., hundreds or thousands of data points for each one of thousands or millions of hosts in the host population) is not a task that can be mentally performed, especially in real-time.

[0091] Further, certain embodiments herein are directed to a technical solution to a technical problem associated with analyte sensor systems. In particular, each analyte sensor system that is manufactured by a sensor manufacturer might perform slightly different. As such, there might be inconsistencies between sensors and the measurements they generate once in use. Accordingly, certain embodiments herein are directed to determining the performance of an analyte sensor system during a manufacturing calibration process (in vitro), which includes quantifying certain sensor operating parameters, such as a calibration slope (also known as calibration sensitivity), a calibration baseline, etc.

[0092] Generally, calibration sensitivity refers to the amount of electrical current produced by an analyte sensor of an analyte sensor system when immersed in a predetermined amount of a measured analyte. The amount of electrical current may be expressed in units of picoAmps (pA) or counts. The amount of measured analyte may be expressed as a concentration level in units of milligrams per deciliter (mg / dL), and the calibration sensitivity may be expressed in units of pA / (mg / dL) or counts / (mg / dL). The calibration baseline refers to the amount of electrical current produced by the analyte sensor when no analyte is detected, and may be expressed in units of pA or counts.Attorney Docket No. 0981-PCT01

[0093] The calibration sensitivity, calibration baseline, and other information related to the sensitivity profile for the analyte sensor system may be programmed into the sensor electronics module of the analyte sensor system during the manufacturing process, and then used to convert the analyte sensor electrical signals into measured analyte concentration levels. For example, the calibration slope (calibration sensitivity) may be used to predict an initial in vivo sensitivity (Mo) and a final in vivo sensitivity (Mf), which are programmed into the sensor electronics module and used to convert the analyte sensor electrical signals into measured analyte concentration levels.

[0094] In certain embodiments, during in vivo use, the sensor electronics module of an analyte sensor system samples the analog electrical signals produced by the analyte sensor to generate analyte sensor count values, and then determines the measured analyte concentration levels based on the analyte sensor count values, the initial in vivo sensitivity (Mo), and the final in vivo sensitivity (Mf). For example, measured analyte concentration levels may be determined using a sensitivity function M(t) that is based on the initial in vivo sensitivity (Mo) and the final in vivo sensitivity (Mf). The sensitivity function M(t) may expressed in several different ways, such as a simple correction factor that is not dependent on elapsed time (ti) of in vivo use, a linear relationship between sensitivity and time (ti), an exponential relationship between sensitivity and time (ti), etc. Equation 1 presents one technique for determining a measured analyte concentration level (ACL) from an analyte sensor count value (count) at a time ft:ACL = count / M(ti) Eq. 1 A calibration baseline (baseline) may also be used to determine a measured analyte concentration level (ACL) from an analyte sensor count value (count) at a time ti, and Equation 2 presents one technique:ACL = (count - baseline) / M(ti) Eq. 2 Example Therapy Management System Including an Example Continuous Analyte Sensor

[0095] FIG. 1 illustrates an example therapy management system 100 for (1) managing or determining a risk, presence, and / or progression of kidney dysfunction for host(s) 102 (individually referred to herein as a host and collectively referred to herein as hosts), (2) notifying host(s) 102 of a risk or presence of kidney dysfunction for host(s) 102, and / or (3) providing personalized therapy management guidance to treat and / or manage kidney dysfunction of host(s) 102, using a continuous analyte monitoring system 104 configured to continuously measure, at least, glucose levels and fructosamine levels. A host, in certainAttorney Docket No. 0981-PCT01embodiments, is a host or, in some cases, the host’s caregiver. A host, in certain embodiments, is a host suffering from kidney dysfunction, a host at risk of developing kidney dysfunction, a host with diabetes, or any other comorbid disease state that is at risk of developing kidney dysfunction.

[0096] In certain embodiments, therapy management system 100 includes continuous analyte monitoring system 104, including, at least, a continuous glucose monitor (CGM) and a continuous fructosamine monitor, a display device 107 that executes application 106, a host database 110, a historical records database 112, a training server system 140, and a therapy management engine 114, each of which is described in more detail below.

[0097] The term “analyte” as used herein is a broad term used in its ordinary sense, including, without limitation, to refer to a substance or chemical constituent in a biological fluid (for example, blood, interstitial fluid, cerebral spinal fluid, lymph fluid or urine) that can be analyzed. Analytes can include naturally occurring substances, artificial substances, metabolites, and / or reaction products. Analytes for measurement by the devices and methods may include, but may not be limited to, potassium, glucose, endogenous insulin, acarboxyprothrombin; acylcarnitine; endogenous insulin; adenine phosphoribosyl transferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle), histidine / urocanic acid, homocysteine, phenylalanine / tyrosine, tryptophan); androstenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactive protein; calcium, carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-P hydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcohol dehydrogenase, alpha 1 -antitrypsin, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, hepatitis B virus, HCMV, HIV-1, HTLV-1, MCAD, RNA, PKU, Plasmodium vivax, 21 -deoxycortisol); desbutylhalofantrine; dihydropteridine reductase; diptheria / tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids / acylglycines; free P-human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine (FT3); fumarylacetoacetase; galactose / gal-1-phosphate; galactose- 1 -phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione perioxidase; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyteAttorney Docket No. 0981-PCT01carbonic anhydrase I; 17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase; immunoreactive trypsin; lactate; lead; lipoproteins ((a), B / A-l, ); lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin; phytanic / pristanic acid; progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3); selenium; serum pancreatic lipase; sisomicin; somatomedin C; specific antibodies recognizing any one or more of the following that may include (adenovirus, anti-nuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's disease virus, dengue virus, Dracunculus medinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, leptospira, measles / mumps / rubella, Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa, respiratory syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosoma cruzi / rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin.

[0098] Salts, sugar, protein, fat, vitamins, and hormones (e.g., insulin) naturally occurring in blood or interstitial fluids can also constitute analytes in certain implementations. The analyte can be naturally present in the biological fluid, for example, a metabolic product, a hormone, an antigen, an antibody, and the like. Alternatively, the analyte can be introduced into the body or exogenous, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to insulin; glucagon, ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants (barbiturates, methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine, amphetamines, methamphetamines, and phencyclidine, for example, Ecstasy);Attorney Docket No. 0981-PCT01anabolic steroids; and nicotine. The metabolic products of drugs and pharmaceutical compositions are also contemplated analytes. Analytes such as neurochemicals and other chemicals generated within the body can also be analyzed, such as, for example, ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC), Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and 5-Hydroxyindoleacetic acid (FHIAA), and intermediaries in the Citric Acid Cycle.

[0099] While the analytes that are measured and analyzed by the devices and methods described herein include fructosamine and glucose, and in some cases, potassium, 1,5 AG, creatinine, etc., in some cases, other analytes listed above, and / or other analytes, may also be considered and measured by, for example, continuous analyte monitoring system 104.

[0100] In certain embodiments, continuous analyte monitoring system 104 is configured to continuously measure one or more analytes. The analyte measurements (either in raw for, or a processed form that represent the measurements) can be transmitted via the analyte monitoring system 104 or the display device 107 to an electronic medical records (EMR) system (not shown in FIG. 1). An EMR system is a software platform which allows for the electronic entry, storage, and maintenance of digital medical data. An EMR system is generally used throughout hospitals and / or other caregiver facilities to document clinical information on hosts over long periods. EMR systems organize and present data in ways that assist clinicians with, for example, interpreting health conditions and providing ongoing care, scheduling, billing, and follow up. Data contained in an EMR system may also be used to create reports for clinical care and / or disease management for a host. In certain embodiments, the EMR may be in communication with therapy management engine 114 (e.g., via a network) for performing the techniques described herein. In particular, as described herein, therapy management engine 114 may obtain data associated with a host, use the obtained data as input into one or more trained model(s), and output a prediction. In some cases, the EMR may provide the data to therapy management engine 114 to be used as input into the one or more models. Further, in some cases, therapy management engine 114, after making a prediction, may provide the output prediction to the EMR.

[0101] In certain embodiments, continuous analyte monitoring system 104 is configured to continuously measure one or more analytes and transmit the analyte measurements to display device 107 for use by application 106. In certain embodiments, continuous analyte monitoring system 104 transmits the analyte measurements to display device 107 through a wireless connection (e.g., Bluetooth connection). In certain embodiments, display device 107 is a smartAttorney Docket No. 0981-PCT01phone. However, in certain other embodiments, display device 107 may instead be any other type of computing device such as a laptop computer, a smart watch, a smart band, smart glasses, a tablet, a phablet, or any other computing device capable of executing application 106. Continuous analyte monitoring system 104 is described in more detail with respect to FIG. 2.

[0102] Application 106 is a mobile health application that is configured to receive and analyze analyte measurements from continuous analyte monitoring system 104. For example, application 106 stores information about a host, including the host’s analyte measurements, in a host profile 118 of the host for processing and analysis as well as for use by the therapy management engine 114 to provide therapy management support recommendations or guidance to the host.

[0103] Therapy management engine 114 refers to a set of software instructions with one or more software modules, including data analysis module (DAM) 116. In certain embodiments, therapy management engine 114 executes entirely on one or more computing devices in a private or a public cloud. In such embodiments, application 106 communicate with therapy management engine 114 over a network (e.g., Internet). In certain other embodiments, therapy management engine 114 executes partially on one or more local devices, such as display device 107, and partially on one or more computing devices in a private or a public cloud. In certain other embodiments, therapy management engine 114 executes entirely on one or more local devices, such as display device 107. As discussed in more detail herein, therapy management engine 114, may provide therapy management support recommendations to the host via application 106. Therapy management engine 114 provides therapy management support recommendations based on information included in host profile 118.

[0104] Host profile 118 may include information collected about the host from application 106. For example, application 106 provides a set of inputs 130, including the analyte measurements associated with one or more analytes received from continuous analyte monitoring system 104 that are stored in host profile 118. In certain embodiments, inputs 130 provided by application 106 include other data in addition to analyte measurements. For example, application 106 may obtain additional inputs 130 through manual host input, one or more other non-analyte sensors or devices, other applications executing on display device 107, etc. Non-analyte sensors and devices include one or more of, but are not limited to, an insulin pump, respiratory sensor, sensors or devices provided by display device 107 (e.g., accelerometer, camera, global positioning system (GPS), heart rate monitor, electrocardiogram (ECG), etc.) or other host accessories (e.g., a smart watch, a continuous positive airwayAttorney Docket No. 0981-PCT01pressure (CPAP) machine, or a fitness tracker), or any other sensors or devices that provide relevant information about the host. Inputs 130 of host profile 118 provided by application 106 are described in further detail below with respect to FIG. 3.

[0105] DAM 116 of therapy management engine 114 is configured to process the set of inputs 130 to determine one or more metrics 132. Metrics 132, discussed in more detail below with respect to FIG. 3, may, at least in some cases, be generally indicative of the health or state of a host, such as one or more of the physiological state of a host, trends associated with the health or state of a host, etc. In certain embodiments, metrics 132 may then be used by therapy management engine 114 as input for providing guidance to a host. As shown, metrics 132 are also stored in host profile 118.

[0106] Host profile 118 also includes demographic information 120, anthropometric information 122, disease information 124, and / or medication information 126. In certain embodiments, such information may be provided through host input or obtained from certain data stores (e.g., electronic medical records (EMRs), etc.). In certain embodiments, demographic information 120 may include one or more of the host’s age, ethnicity, gender, etc. In certain embodiments, anthropometric information 122 may include one or more of the host’s height, weight, and / or body mass index (BMI). In certain embodiments, disease information 124 may include information about one or more diseases of a host, including relevant information pertaining to the host’s kidney disease, CKD, acute kidney failure, acquired cystic kidney disease, kidney stones, multicystic dysplastic kidney, nephrotic syndrome, polycystic kidney disease (PKD), kidney dysfunction, acute kidney injury, diabetes, liver disease, albumin-to-creatinine ratio (ACR) tests, glomerular filtration rate (GFR) tests, blood tests for monitoring potassium levels historical host kidney metabolic panels, and / or other health conditions, syndromes, or diseases. In certain embodiments, disease information 124 may also include the length of time since diagnosis, disease progression information, the level of disease control, level of compliance with disease management therapy, other types of diagnoses (e.g., obesity, hormone imbalances, hyperkalemia or hypokalemia, etc.), and the like. In certain embodiments, disease information 124 may include hospitalizations and / or surgical history. In certain embodiments, disease information 124 may include other measures of health (e.g., heart rate, heart rhythm, blood pressure, stress, sleep, etc.) or fitness (e.g., cardiovascular endurance, metabolic state, muscular endurance, and other measures of fitness), and / or the like.

[0107] In certain embodiments, medication information 126 may include information about the amount, frequency, and / or type of a medication taken by a host. In certainAttorney Docket No. 0981-PCT01embodiments, the amount, frequency, and type of a medication taken by a host is time-stamped and correlated with the host’s analyte levels, thereby, indicating the impact the amount, frequency, and type of the medication had on the host’s analyte levels. In certain embodiments, medication information 126 may include information about the consumption of one or more drugs, including medications that may alter the host’s analyte levels and / or metrics (e.g., SGLT-2 inhibitors), diuretics (which may be used to treat excessive fluid accumulation caused by, for example, nephritic syndrome, HF, and / or liver failure) such as loop diuretics, thiazide and thiazide-like diuretics, and potassium-sparing diuretics, antibiotics such as amoxicillin / clavulanate, clindamycin, erythromycin, nitrofurantoin, rifampin, sulfonamides, tetracyclines, trimethoprim / sulfamethoxazole, and drugs used to treat tuberculosis (isoniazid and pyrazinamide), anticonvulsants such as tarbamazepine, thenobarbital, phenytoin, and valproate, antidepressants such as bupropion, fluoxetine, mirtazapine, paroxetine, sertraline, trazodone, and tricyclic antidepressants such as amitriptyline, antifungal drugs such as ketoconazole and terbinafine, antihypertensive drugs (e.g., drugs used to treat high blood pressure or sometimes kidney or heart disorder) such as captopril, enalapril, irbesartan, lisinopril, losartan, and verapamil, antipsychotic drugs such as phenothiazines (e.g., such as chlorpromazine) and risperidone, hormone regulation drugs such as anabolic steroids, birth control pills (oral contraceptives), and estrogens, pain relievers such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), and other drugs such as acarbose (e.g., used to treat diabetes), allopurinol (e.g., used to treat gout), antiretroviral therapy (ART) drugs (e.g., used to treat human immunodeficiency virus (HIV) infection), baclofen (e.g., a muscle relaxant), cyproheptadine (e.g., an antihistamine), azathioprine (e.g., used to prevent rejection of an organ transplant), methotrexate (e.g., used to treat cancer), omeprazole (e.g., used to treat gastroesophageal reflux), PD-1 / PD-L1 inhibitors (e.g., anticancer drugs), statins (e.g., used to treat high cholesterol levels), ademetionine, avatrombopag, dehydroemetine, entecavir, glecaprevir and pibrentasvir, lamivudine, metadoxine, methionine, sofosbuvir, velpatasvir, and voxilaprevir, telbivudine, tenofovir, trientine, ursodeoxycholic acid, and many types of chemotherapies, including immune checkpoint inhibitors, and the like.

[0108] In certain embodiments, host profile 118 is dynamic because at least part of the information that is stored in host profile 118 may be revised or updated over time and / or new information may be added to host profile 118 by therapy management engine 114 and / or application 106. Accordingly, information in host profile 118 stored in host database 110 provides an up-to-date repository of information related to the host.Attorney Docket No. 0981-PCT01

[0109] Host database 110, in certain embodiments, refers to a storage server that operates, for example, in a public or private cloud. Host database 110 may be implemented as any type of datastore, such as relational databases, non-relational databases, key-value datastores, file systems including hierarchical file systems, and the like. In some exemplary implementations, host database 110 is distributed. For example, host database 110 may comprise a plurality of persistent storage devices, which are distributed. Furthermore, host database 110 may be replicated so that the storage devices are geographically dispersed.

[0110] Host database 110 includes host profiles 118 associated with a plurality of hosts, including hosts who similarly interact or have interacted in the past with application 106 on their own devices. Host profiles stored in host database 110 are accessible to not only application 106, but therapy management engine 114 as well. Host profiles in host database 110 may be accessible to application 106 and / or therapy management engine 114 over one or more networks (not shown), such as one or more wireless networks. As described above, therapy management engine 114, and more specifically data analysis module (DAM) 116 of therapy management engine 114, can fetch inputs 130 from a host’s profile 118 stored in host database 110 and compute one or more metrics 132 which can then be stored as application data 126 in the host’s profile 118.

[0111] In certain embodiments, host profiles 118 stored in host database 110 may also be stored in historical records database 112. Host profiles 118 stored in historical records database 112 may provide a repository of up-to-date information and historical information for each host of application 106. Thus, historical records database 112 essentially provides all data related to each host of application 106, where data is stored using timestamps. The timestamp associated with any piece of information stored in historical records database 112 may identify, for example, when the piece of information was obtained and / or updated.

[0112] Further, historical records database 112 may include data collected for one or more hosts over a period of time, includes hosts who are hosts of continuous analyte monitoring system 104 and / or application 106, as well as hosts who are not hosts of continuous analyte monitoring system 104 and / or application 106. For example, historical records database 112 may include information (e.g., host profile(s)) related to one or more hosts analyzed by, for example, a healthcare physician (or other known method), and not previously diagnosed with kidney dysfunction, and / or other indications, as well as information (e.g., host profile(s)) related to one or more hosts who were analyzed by, for example, a healthcare physician (orAttorney Docket No. 0981-PCT01other known method) and were previously diagnosed with (varying types and stages of) kidney disease, kidney dysfunction, and / or other indications.

[0113] Data stored in historical records database 112 may be referred to herein as population data, which could include hundreds or thousands of data points for each one of thousands or millions of hosts in the host population. In other words, data stored in historical records database 112 and used in certain embodiments described herein could include gigabytes, terabytes, petabytes, exabytes, etc. of data.

[0114] Data related to each host stored in historical records database 112 may provide time series data collected over the lifetime of the host, a period of the lifetime of the host, and / or a disease lifetime of the host. For example, the data may include information about the host prior to being diagnosed with kidney disease, kidney dysfunction, and / or other indications, and information associated with the host during the lifetime of the disease, including information related to each stage of the disease as it progressed and / or regressed in the host, as well as information related to other diseases, such as diabetes, liver disease, or similar diseases that are co-morbid in relation thereto. The data may also include physiological information (e.g., height and weight), as well as non-analyte sensor data (e.g., heart rate, respiratory rate, etc.). Such data may indicate physiological states of the host, glucose levels of the host, fructosamine levels of the host, lactate levels of the host, potassium levels of the host, creatinine levels of host, HbAlC levels of the host, 1,5-anhydroglucitol (1,5 AG) levels of the host, habits of the host (e.g., activity levels, food consumption, etc.), medication prescribed throughout the lifetime of the disease, as well as progress of outcomes such as weight loss and kidney health over time, etc. Though HbAlc levels are mentioned herein, note that HbAlc cannot be measured in interstitial fluid, but HbAlc levels can be estimated based on measured fructosamine levels using the following equation: HbAlc (%) = 0.17 * conc[Fructosamine] + 1.61.

[0115] Although depicted as separate databases for conceptual clarity, in certain embodiments, host database 110 and historical records database 112 may operate as a single database. That is, historical and current data related to hosts of continuous analyte monitoring system 104 and application 106, as well as historical data related to hosts that were not previously hosts of continuous analyte monitoring system 104 and application 106 and / or application 111, may be stored in a single database. The single database may be a storage server that operates in a public or private cloud.Attorney Docket No. 0981-PCT01

[0116] As mentioned previously, therapy management system 100 is configured to diagnose and manage kidney dysfunction, as well as provide therapy management guidance to (1) hosts at risk of developing kidney dysfunction (e.g., a host with diabetes) and (2) hosts with kidney dysfunction to improve or maintain kidney function, using continuous analyte monitoring system 104, including, at least, a continuous glucose sensor and a continuous fructosamine sensor. In certain embodiments, therapy management engine 114 is configured to (1) provide a determination of a risk, presence, and / or progression of kidney dysfunction, and (2) provide real-time and or non-real-time therapy management guidance (e.g., guidance) to the host and / or others, including but not limited, to healthcare providers, family members of the host, caregivers of the host, etc. Therapy management guidance may be intended to manage and improve kidney function (e.g., prevent development and / or progression of kidney disease and / or improve kidney function).

[0117] In particular, therapy management engine 114 can be used to collect information associated with a host in host profile 118 stored in host database 110, to perform analytics thereon to diagnose and manage kidney dysfunction, as well as provide therapy management guidance. Host profile 118 may be accessible to therapy management engine 114 over one or more networks (not shown) for performing such analytics.

[0118] In certain embodiments, therapy management engine 114 utilizes one or more rules-based algorithms or trained machine learning models capable of performing analytics on information that therapy management engine 114 has collected / received from host profile 118.

[0119] In embodiments where the therapy management engine 114 provides therapy management guidance using a rules-based algorithm, various rules can be defined around a set of parameters, including the host’s glucose and fructosamine data, other analyte data, nonanalyte data, host input data, as well as other parameters.

[0120] In one particular example of a rules-based model, a rule dictates that if the delta between a host’s measured fructosamine value and the expected fructosamine value derived from the host’s glucose data (also referred to herein as “fructosamine delta”) is higher than a defined threshold, then the therapy management engine 114 will determine that the host may be experiencing kidney dysfunction. The determination may then be provided in the form of an output 144.

[0121] In another example, a rule dictates that if the fructosamine delta described above is increasing over time, then the therapy management engine 114 will determine that the host isAttorney Docket No. 0981-PCT01likely experiencing worsening kidney dysfunction and recommend to the host to seek medical intervention for kidney dysfunction, kidney disease, and / or a potential kidney injury.

[0122] In another example of a rules-based model, a rule dictates that if a host is taking a RAASi medication or other medication affecting urine protein levels, and the host is experiencing a consistently low fructosamine delta over time, then the therapy management engine 114 will determine that the RAASi medication is preserving kidney function. Following this determination, the therapy management engine 114 can recommend the host maintain their current medication regimen to maintain kidney function. An example rules-based model is described below in reference to FIG. 4.

[0123] In certain other embodiments, therapy management engine 114 utilizes one or more trained machine learning models capable of performing analytics on information that therapy management engine 114 has collected / received from host profile 118 to (1) provide a determination of a risk, presence, and / or progression of kidney dysfunction, and (2) provide real-time and or non-real-time therapy management guidance.

[0124] For example, the illustrated embodiment of FIG. 1 , therapy management engine 114 may utilize trained machine learning model(s) provided by a training server system 140. Although depicted as a separate server for conceptual clarity, in certain embodiments, training server system 140 and therapy management engine 114 may operate as a single server or system. That is, the model may be trained and used by a single server, or may be trained by one or more servers and deployed for use on one or more other servers or systems. In certain embodiments, the model may be trained on one or many virtual machines (VMs) running, at least partially, on one or many physical services in relational and or non-relational database formats.

[0125] Training server system 140 is configured to train the machine learning model(s) using training data, which may include data (e.g., from host profiles) associated one or more hosts (e.g., hosts or non-hosts of continuous analyte monitoring system 104 and / or application 106) previously diagnosed with, for example, varying stages of kidney disease, varying levels of kidney dysfunction, varying stages of diabetes, as well as hosts not previously diagnosed with kidney disease, kidney dysfunction, or diabetes. The training data may be stored in historical records database 112 and may be accessible to training server system 140 over one or more networks (not shown) for training the machine learning model(s).Attorney Docket No. 0981-PCT01

[0126] The training data refers to a dataset that has been featurized and labeled. For example, the dataset may include a plurality of data records, each including information corresponding to a different host profile stored in host database 110, where each data record is featurized and labeled. In machine learning and pattern recognition, a feature is an individual measurable property or characteristic. Generally, the features that best characterize the patterns in the data are selected to create predictive machine learning models. Data labeling is the process of adding one or more meaningful and informative labels to provide context to the data for learning by the machine learning model.

[0127] As an illustrative example, each relevant characteristic of a host, which is reflected in a corresponding data record, may be a feature used in training the machine learning model.

[0128] Such features may include demographic information (e.g., age, gender, ethnicity, etc.), analyte information (e.g., glucose data, measured fructosamine data (e.g., a measured fructosamine value), expected fructosamine data (e.g., an expected fructosamine value), fructosamine delta, 1,5 AG data, creatinine data, lactate data, HbAlc data, etc.)), non-analyte sensor information (e.g., heart rate, temperature, etc.), kidney health information (e.g., kidney disease diagnoses and staging), comorbidities (e.g., diabetes), and / or any other information relevant to diagnosing or managing kidney dysfunction. In addition, the data record is labeled with information the corresponding model is being trained to predict. In one example, if a model is being trained to output a determination of kidney function, then the data records in the training dataset are labeled with one or more of such parameters. In certain embodiments, the determination of kidney function is specific to the type of dysfunction (e.g., glomerular dysfunction, proximal tubule dysfunction, filtration dysfunction, etc.).

[0129] Note that, in one example, such a model may be a multi-input single-output (MISO) model, configured to predict only a determination of kidney dysfunction, in which case additional MISO models may be trained for each predicting other aspects of kidney dysfunction (e.g., risk or progression of kidney dysfunction, etc.). In another example, such a model may be a multi-input multi-output (MIMO) model, configured to predict various therapy management guidance (e.g., recommend the host seek medical intervention, provide medication recommendations, and / or suggest lifestyle changes (e.g., consume specific foods), etc.).

[0130] The model(s) are then trained by training server system 140 using the featurized and labeled training data. In particular, the features of each data record may be used as inputAttorney Docket No. 0981-PCT01into the machine learning model(s), and the generated output may be compared to label(s) associated with the corresponding data record. The model(s) may compute a loss based on the difference between the generated output and the provided label(s). This loss is then used to modify the internal parameters or weights of the model. By iteratively processing each data record corresponding to each historical host, the model(s) may be iteratively refined to generate accurate determinations of a risk, presence, and / or progression of kidney dysfunction of a host, and / or optimized therapy management guidance to treat and / or manage a host’s kidney dysfunction, etc.

[0131] As illustrated in FIG. 1, training server system 140 deploys these trained model(s) to therapy management engine 114 for use during runtime. For example, therapy management engine 114 may obtain host profile 118 associated with a host and stored in host database 110, use information in host profile 118 as input into the trained model(s), and output a determination indicative of a risk, presence, and / or progression of kidney dysfunction, and / or optimized therapy management guidance to treat and / or manage a host’s kidney dysfunction (e.g., shown as output 144 in FIG. 1).

[0132] Output 144 generated by therapy management engine 114, whether as a result of executing a rules-based or a machine learning model, may also indicate improvement in the host’s kidney function over time. Further, whether as a result of executing a rules-based or a machine learning model, output 144 may be provided to the host (e.g., through application 106), to a caretaker of the host (e.g., a parent, a relative, a guardian, a teacher, a physical therapist, a fitness trainer, a nurse, etc.), to a physician or healthcare provider of the host, or any other individual that has an interest in the wellbeing of the host for purposes of improving the health of the host, such as, in some cases by effectuating recommended therapy management guidance. Output 144 generated by therapy management engine 114 is stored in host database 110 and can be utilized to train or re-train the trained model(s).

[0133] In certain embodiments, whether as a result of executing a rules-based or a machine learning model, output 144 generated by therapy management engine 114 may be stored in host profile 118. Also, output 144 stored in host profile 118 may be continuously updated by therapy management engine 114. Accordingly, for example, previous kidney function determinations and / or therapy management recommendations, originally stored as outputs 144 in host profile 118 in host database 110 and then passed to historical records database 112, may provide an indication of the progression or management of the kidney dysfunction of a hostAttorney Docket No. 0981-PCT01over time, as well as provide an indication as to the effectiveness of different recommendations to improve or manage kidney function.

[0134] In certain embodiments, a host’s own historical data may be used by training server system 140 to train a personalized model for the host that provides therapy management support and insight around the host’s kidney function. For example, in certain embodiments, a model trained based on population data may be used to provide optimized therapy management guidance to the host. However, after collecting personalized information (e.g., analyte sensor information, non-analyte sensor information, etc.) associated with the host following one or more therapy management guidance, the personalized information may be used for further personalizing the model. For example, information obtained following prior therapy management guidance to the host may be used to optimize therapy management guidance in the future.

[0135] In certain embodiments, a model may be trained to provide food, lifestyle, medication, and other types of therapy management support recommendations to help the host improve or maintain kidney function based on the host’s historical data, including how different types of medications and / or activities impacted the host’s kidney function in the past. In certain embodiments, a model is trained to predict the underlying cause of certain improvements or deteriorations in the host’s kidney function. For example, application 106 can display a user interface with a graph that shows the kidney function (e.g., based on glucose data, fructosamine data, and fructosamine delta) with trend lines and indicate, e.g., retrospectively, how kidney function was affected at certain points in time.

[0136] FIG. 2 is a diagram 200 conceptually illustrating an example continuous analyte monitoring system 104 including example continuous analyte sensor(s) with sensor electronics, in accordance with certain aspects of the present disclosure. For example, continuous analyte monitoring system 104 is configured to continuously monitor one or more analytes of a hosts, in accordance with certain aspects of the present disclosure.

[0137] Continuous analyte monitoring system 104 in the illustrated embodiment includes sensor electronics module 204 and one or more continuous analyte sensor(s) 202 (individually referred to herein as continuous analyte sensor 202 and collectively referred to herein as continuous analyte sensors 202) associated with sensor electronics module 204. Sensor electronics module 204 can be in wireless communication (e.g., directly or indirectly) with one or more of display devices 210, 220, 230, and 240. In certain embodiments, sensor electronicsAttorney Docket No. 0981-PCT01module 204 is also in wireless communication (e.g., directly or indirectly) with one or more medical devices, such as medical devices 208 (individually referred to herein as medical device 208 and collectively referred to herein as medical devices 208), and / or one or more other nonanalyte sensors 206 (individually referred to herein as non-analyte sensor 206 and collectively referred to herein as non-analyte sensor 206).

[0138] In certain embodiments, a continuous analyte sensor 202 comprises one or more sensors for detecting and / or measuring analyte(s). The continuous analyte sensor 202 can be a multi-analyte sensor configured to continuously measure two or more analytes or a single analyte sensor configured to continuously measure a single analyte as a non-invasive device, a subcutaneous device, a transcutaneous device, a transdermal device, and / or an intravascular device. In certain embodiments, the continuous analyte sensor 202 is configured to continuously measure analyte levels of a host using one or more techniques, such as enzymatic techniques, chemical techniques, physical techniques, electrochemical techniques, spectrophotometric techniques, polarimetric techniques, potentiometric techniques, calorimetric techniques, iontophoretic techniques, radiometric techniques, immunochemical techniques, and the like. The term “continuous,” as used herein, can mean fully continuous, semi-continuous, periodic, etc. In certain aspects, the continuous analyte sensor 202 provides a data stream indicative of the concentration of one or more analytes in the host. The data stream can include raw data signals, which are then converted into a calibrated and / or filtered data stream used to provide estimated analyte value(s) to the host.

[0139] In certain embodiments, the continuous analyte sensor 202 is a multi-analyte sensor, configured to continuously measure multiple analytes in a host’s body. For example, in certain embodiments, the continuous multi-analyte sensor is a single sensor configured to measure glucose, fructosamine, creatinine, 1,5 AG, lactate, potassium, and / or HbAlc in the host’s body.

[0140] In certain embodiments, one or more multi-analyte sensors can be used in combination with one or more single analyte sensors. As an illustrative example, a multianalyte sensor can be configured to continuously measure fructosamine, glucose, and / or creatinine, and can, in some cases, be used in combination with an analyte sensor configured to measure only 1,5 AG, lactate, HbAlc, or another analyte. Information from each of the multi-analyte sensor(s) and single analyte sensor(s) can be combined to provide therapy management support using methods described herein. In further embodiments, other noncontact and or periodic or semi-continuous, but temporally limited, measurements for physiological information is integrated into the system such as by including weight scaleAttorney Docket No. 0981-PCT01information or non-contact heart rate monitoring from a sensor pad under the host while in a chair or bed, through an infra-red camera detecting temperature and / or blood flow patterns of the host, and / or through a visual camera with machine vision for height, weight, or other parameter estimation without physical contact.

[0141] In certain embodiments, the continuous analyte sensor(s) 202 comprises a percutaneous wire that has a proximal portion coupled to the sensor electronics module 204 and a distal portion with several electrodes, such as a measurement electrode and a reference electrode. The measurement (or working) electrode is coated, covered, treated, embedded, etc., with one or more chemical molecules that react with a particular analyte, and the reference electrode provides a reference electrical voltage. The measurement electrode generates the analog electrical signal, which is conveyed along a conductor that extends from the measurement electrode to the proximal portion of the percutaneous wire that is coupled to the sensor electronics module 204. After the continuous analyte monitoring system 104 has been applied to epidermis of the host, continuous analyte sensor(s) 202 penetrates the epidermis, and the distal portion extends into the dermis and / or subcutaneous tissue under epidermis. Other configurations of continuous analyte sensor(s) 202 can also be used, such as a multi-analyte sensor that includes multiple measurement electrodes, each generating an analog electrical signal that represents the concentration levels of a particular analyte.

[0142] In certain embodiments, the continuous analyte sensor(s) 202 comprises a planar substrate that has a proximal portion coupled to the sensor electronics module 204 and a distal portion with several electrodes, such as a measurement electrode and a reference electrode, as described in reference to FIGs. 7-9. The measurement (or working) electrode is coated, covered, treated, embedded, etc., with one or more chemical molecules that react with a particular analyte, and the reference electrode provides a reference electrical voltage. The measurement electrode generates the analog electrical signal, which is conveyed along a conductor that extends from the measurement electrode to the proximal portion of the planar substrate that is coupled to the sensor electronics module 204. After the continuous analyte monitoring system 104 has been applied to epidermis of the host, continuous analyte sensor(s) 202 penetrates the epidermis, and the distal portion extends into the dermis and / or subcutaneous tissue under epidermis. Other configurations of continuous analyte sensor(s) 202 can also be used, such as a multi-analyte sensor that includes multiple measurement electrodes, each generating an analog electrical signal that represents the concentration levels of a particular analyte.Attorney Docket No. 0981-PCT01

[0143] Generally, a single-analyte sensor generates an analog electrical signal that is proportional to the concentration level of a particular analyte. Similarly, each multi-analyte sensor generates multiple analog electrical signals, and each analog electrical signal is proportional to the concentration level of a particular analyte. As an illustrative example, continuous analyte sensor 202 includes a single-analyte sensor configured to measure fructosamine concentration levels, and another single-analyte sensor configured to measure glucose or creatinine concentration levels of the host. As another illustrative example, continuous analyte sensor(s) 202 includes a single-analyte sensor configured to measure potassium concentration levels, and one or more multi-analyte sensors configured to measure 1,5 AG concentration levels, lactate concentration levels, potassium concentration levels, etc. As yet another illustrative example, continuous analyte sensor(s) 202 includes a multi-analyte sensor configured to measure fructosamine concentration levels, glucose concentration levels, lactate concentration levels, creatinine concentration levels, 1,5 AG concentration levels, potassium levels, potassium concentration levels, etc.

[0144] Accordingly, continuous analyte sensor(s) 202 is configured to generate at least one analog electrical signal that is proportional to the concentration level of a particular analyte, and sensor electronics module 204 is configured to convert the analog electrical signal into an analyte sensor count values, calibrate the analyte sensor count values based on the sensitivity profile of the continuous analyte sensor(s) 202 to generate measured analyte concentration levels, and transmit the measured analyte concentration level data, including the measured analyte concentration levels, to a display device, such as display devices 210, 220, and / or 230, via a wireless connection. For example, sensor electronics module 204 is configured to sample the analog electrical signal at a particular sampling period (or rate), such as every 1 second (1 Hz), 5 seconds, 10 seconds, 30 seconds, 1 minute, 3 minutes, 5 minutes, etc., and to transmit the measured analyte concentration data to the display device at a particular transmission period (or rate), which can be the same as (or longer than) the sampling period, such as every 1 minute (0.16 Hz), 5 minutes, 10 minutes, 30 minutes, at the conclusion of the wear period, etc. In certain embodiments, the sampling period can be less frequent, such as one time per continuous analyte monitoring system wear period of the host (e.g., one time every two weeks). Depending on the sampling and transmission periods, the measured analyte concentration data transmitted to the display device include at least one measured analyte concentration level having an associated time tag, sequence number, etc.Attorney Docket No. 0981-PCT01

[0145] In certain embodiments, continuous analyte sensor(s) 202 incorporates a thermocouple within, or alongside, the percutaneous wire to provide an analog temperature signal to the sensor electronics module 204, which is used to correct the analog electrical signal or the measured analyte data for temperature. In other embodiments, the thermocouple is incorporated into the sensor electronics module 204 above the adhesive pad, or, alternatively, the thermocouple contacts the epidermis of the host through openings in the adhesive pad.

[0146] In certain embodiments, the sensor electronics module 204 includes, inter alia, processor 233, storage element or memory 234, wireless transmitter / receiver (transceiver) 236, one or more antennas coupled to wireless transceiver 236, analog electrical signal processing circuitry, analog to-digital (A / D) signal processing circuitry, digital signal processing circuitry, a power source for continuous analyte sensor(s) 202 (such as a potentiostat), etc.

[0147] Processor 233 can be a general-purpose or application-specific microprocessor, an application-specific integrated circuit (ASIC), a field programmable gate array (FPGA), etc., that executes instructions to perform control, computation, input / output, etc. functions for the sensor electronics module 204. Processor 233 can include a single integrated circuit, such as a micro processing device, or multiple integrated circuit devices and / or circuit boards working in cooperation to accomplish the appropriate functionality. In certain embodiments, processor 233, memory 234, wireless transceiver 236, the A / D signal processing circuitry, and the digital signal processing circuitry can be combined into a system-on-chip (SoC).

[0148] Generally, processor 233 can be configured to sample the analog electrical signal using the A / D signal processing circuitry at regular intervals (such as the sampling period) to generate analyte sensor count values based on the analog electrical signals produced by the continuous analyte sensor(s) 202, calibrate the analyte sensor count values based on the sensitivity profile of the continuous analyte sensor(s) 202 to generate measured analyte concentration levels, and generate measured analyte data from the measured analyte concentration levels, generate sensor data packages that include, inter alia, the measured analyte concentration level data. Processor 233 can store the measured analyte concentration level data in memory 234, and generate the sensor data packages at regular intervals (such as the transmission period) for transmission by wireless transceiver 236 to a display device, such as display devices 210, 220, 230, and / or 240. Processor 233 can also add additional data to the sensor data packages, such as supplemental sensor information that includes a sensor identifier, a sensor status, temperatures that correspond to the measured analyte data, etc. The sensor data packages are then wirelessly transmitted over a wireless connection to the display device. InAttorney Docket No. 0981-PCT01certain embodiments, the wireless connection is a Bluetooth or Bluetooth Low Energy (BLE) connection. In such embodiments, the sensor data packages are transmitted in the form of Bluetooth or BLE data packets to the display device

[0149] In various embodiments, memory 234 can include volatile and nonvolatile medium. For example, memory 234 can include combinations of random access memory (RAM), dynamic RAM (DRAM), static RAM (SRAM), read only memory (ROM), flash memory, cache memory, and / or any other type of non-transitory computer-readable medium. Memory 234 can store one or more analyte sensor system applications, modules, instruction sets, etc. for execution by processor 233, such as instructions to generate measured analyte data from the analyte sensor count values, etc.

[0150] Memory 234 can also store certain sensor operating parameters 235, such as a calibration slope (or calibration sensitivity), a calibration baseline, etc. In particular, the calibration sensitivity, calibration baseline, and other information related to the sensitivity profile for the sensor electronics module 204 can be programmed into the sensor electronics module 204 during the manufacturing process, and then used to convert the analyte sensor electrical signals into measured analyte concentration levels. For example, as discussed above, the calibration slope can be used to predict an initial in vivo sensitivity (Mo) and a final in vivo sensitivity (Mf), which are stored in memory 234 and used to convert the analyte sensor electrical signals into measured analyte concentration levels. In certain embodiments, calibration sensitivity (Mcc) 246 and / or calibration baseline 247 can be stored in memory 234.

[0151] In certain embodiments, the initial in vivo sensitivity (Mo) and the final in vivo sensitivity (Mf) of a current continuous analyte sensor 202 can be based on an initial in vivo sensitivity (Mo) and a final in vivo sensitivity (Mf) of a previous continuous analyte sensor 202 of continuous analyte monitoring system 104 worn by a host. For example, the initial in vivo sensitivity (Mo) and the final in vivo sensitivity (Mf) of the previous continuous analyte sensor worn by the host can be used to predict an initial in vivo sensitivity (Mo) and a final in vivo sensitivity (Mf) of the current continuous analyte sensor worn by the host. Utilizing the sensitivities of the previous continuous analyte sensor to determine sensitivities of the current continuous analyte sensor can ensure continuous analyte sensors worn by the host over time are performing similarly to one another.

[0152] In certain embodiments, sensor electronics module 204 includes electronic circuitry associated with measuring and processing the continuous analyte sensor data, includingAttorney Docket No. 0981-PCT01prospective algorithms associated with processing and calibration of the sensor data. Sensor electronics module 204 can be physically connected to continuous analyte sensor(s) 202 and can be integral with (non-releasably attached to) or releasably attachable to continuous analyte sensor(s) 202. Sensor electronics module 204 can include hardware, firmware, and / or software that enable measurement of levels of analyte(s) via continuous analyte sensor(s) 202. For example, sensor electronics module 204 can include a potentiostat, a power source for providing power to the sensor, other components useful for signal processing and data storage, and a telemetry module for transmitting data from the sensor electronics module to, e.g., one or more display devices. Electronics can be affixed to a printed circuit board (PCB), or the like, and can take a variety of forms. For example, the electronics can take the form of an integrated circuit (IC), such as an Application- Specific Integrated Circuit (ASIC), a microcontroller, and / or a processor.

[0153] Display devices 210, 220, 230, and / or 240 are configured for displaying displayable sensor data, including analyte data, which can be transmitted by sensor electronics module 204. Each of display devices 210, 220, 230, or 240 can include a display such as a touchscreen display 212, 222, 232, and / or 242 for displaying sensor data to a host and / or for receiving inputs from the host. For example, a graphical user interface (GUI) can be presented to the host for such purposes. In certain embodiments, the display devices can include other types of user interfaces such as a voice user interface instead of, or in addition to, a touchscreen display for communicating sensor data to the host of the display device and / or for receiving host inputs. Display devices 210, 220, 230, and 240 can be examples of display device 107 illustrated in FIG. 1 used to display sensor data to a host of the system of FIG. 1 and / or to receive input from the host.

[0154] In certain embodiments, one, some, or all of the display devices are configured to display or otherwise communicate (e.g., verbalize) the sensor data as it is communicated from the sensor electronics module (e.g., in a customized data package that is transmitted to display devices based on their respective preferences), without any additional prospective processing required for calibration and real-time display of the sensor data.

[0155] The plurality of display devices can include a custom display device specially designed for displaying certain types of displayable sensor data associated with analyte data received from sensor electronics module. In certain embodiments, the plurality of display devices can be configured for providing alerts / alarms based on the displayable sensor data. Display device 210 is an example of such a custom device. In certain embodiments, one of theAttorney Docket No. 0981-PCT01plurality of display devices is a smartphone, such as display device 220 which represents a mobile phone, using a commercially available operating system (OS), and configured to display a graphical representation of the continuous sensor data (e.g., including current and historic data). Other display devices can include other hand-held devices, such as display device 230 which represents a tablet or phablet, display device 240 which represents a smart watch or fitness tracker, medical device 208 (e.g., a medication administration device or a blood glucose meter), and / or a desktop or laptop computer (not shown).

[0156] Because different display devices provide different user interfaces, content of the data packages (e.g., amount, format, and / or type of data to be displayed, alarms, and the like) can be customized (e.g., programmed differently by the manufacture and / or by an end host) for each particular display device. Accordingly, in certain embodiments, a plurality of different display devices can be in direct wireless communication with a sensor electronics module (e.g., such as an on-skin sensor electronics module 204 that is physically connected to continuous analyte sensor(s) 202) during a sensor session to enable a plurality of different types and / or levels of display and / or functionality associated with the display able sensor data.

[0157] As mentioned, sensor electronics module 204 can be in communication with a medical device 208. Medical device 208 can be a passive device in some example embodiments of the disclosure. For example, medical device 208 can be a medication pump for administering one or more medications to a host, such as one or more medications for treating diabetes. For a variety of reasons, it is desirable for such a medication pump to receive and track glucose, lactate, creatinine, potassium, 1,5 AG, and / or other analytes transmitted from continuous analyte monitoring systems 104, where continuous analyte sensor 202 is configured to measure glucose, fructosamine, potassium, lactate, creatinine, 1,5 AG, HbAlc, and / or other analytes. In certain embodiments, medical device 208 can include an insulin pump.

[0158] Further, as mentioned, sensor electronics module 204 can also be in communication with other non-analyte sensors 206. Non-analyte sensors 206 can include, but are not limited to, an altimeter sensor, an accelerometer sensor, a global positioning system (GPS) sensor, a temperature sensor, a respiration rate sensor, etc. Non-analyte sensors 206 can also include monitors such as heart rate monitors, blood pressure monitors, pulse oximeters, caloric intake monitors, indirect calorimetry devices and medicament administration / delivery devices. One or more of these non-analyte sensors 206 can provide data to therapy management engine 114Attorney Docket No. 0981-PCT01described further below. In some aspects, a host can manually provide some of the data for processing by training server system 140 and / or therapy management engine 114 of FIG. 1.

[0159] In certain embodiments, non-analyte sensors 206 can further include sensors for measuring skin temperature, core temperature, sweat rate, and / or sweat composition.

[0160] In certain embodiments, the non-analyte sensors 206 can be combined in any other configuration, such as, for example, combined with one or more continuous analyte sensors 202. As an illustrative example, a non-analyte sensor, e.g., a temperature sensor, can be combined with a continuous glucose sensor 202 to form a glucose / temperature sensor used to transmit sensor data to the sensor electronics module 204 using common communication circuitry. As another illustrative example, a non-analyte sensor, e.g., a temperature sensor, can be combined with a multi-analyte sensor configured to measure glucose, fructosamine, creatinine, and / or lactate to form a glucose / fructosamine / creatinine / lactate / temperature sensor used to transmit sensor data to the sensor electronics module 204 using common communication circuitry.

[0161] In certain embodiments, a wireless access point (WAP) can be used to couple one or more of continuous analyte monitoring system 104, the plurality of display devices, medical device(s) 208, and / or non-analyte sensor(s) 206 to one another. For example, WAP 138 can provide Wi-Fi and / or cellular connectivity among these devices. Near Field Communication (NFC) and or Bluetooth can also be used among devices depicted in diagram 200 of FIG. 2.

[0162] FIG. 3 illustrates example inputs and example metrics that are calculated based on the inputs for use by the therapy management system of FIG. 1, according to some embodiments disclosed herein. In particular, FIG. 3 provides a more detailed illustration of example inputs and example metrics introduced in FIG. 1.

[0163] FIG. 3 illustrates example inputs 130 on the left, application 106 and DAM 116 in the middle, and metrics 132 on the right. In certain embodiments, each one of metrics 132 can correspond to one or more values, e.g., discrete numerical values, ranges, or qualitative values (high / medium / low, stable / unstable, etc.). Application 106 obtains inputs 130 through one or more channels (e.g., manual host input, sensors, other applications executing on display device 107, an EMR system, etc.). As mentioned previously, in certain embodiments, inputs 130 can be processed by DAM 116 to output a plurality of metrics, such as metrics 132. Inputs 130 and metrics 132 can be used by training server system 140 and therapy management engine 114 to both train and deploy one or more machine learning models for determining a risk,Attorney Docket No. 0981-PCT01presence, and / or progression of kidney dysfunction, providing accurate therapy management to for treatment and / or management of kidney dysfunction, and other functionalities described herein.

[0164] In certain embodiments, starting with inputs 130, host statistics, such as one or more of age, height, weight, BMI, body composition (e.g., % body fat or % muscle from a computed tomography (CT) scan, a magnetic resonance imaging (MRI) scan, dual-energy X-ray absorptiometry (DEXA) scan, etc.), stature, build, or other information can also be provided as an input. In certain embodiments, host statistics are provided through a user interface, by interfacing with an electronic source such as an electronic medical record, and / or from measurement devices. In certain embodiments, the measurement devices include one or more wireless devices, e.g., Bluetooth-enabled, weight scale and / or camera, which can, for example, communicate with the display device 107 to provide host data.

[0165] In certain embodiments, medication / treatment information is also provided as an input. Medication information can include information about the type, dose, and / or timing of when one or more medications are to be taken by the host. As mentioned elsewhere herein, the medication information can include information about one or more medications prescribed to the host for treating one or more symptoms of kidney dysfunction, kidney disease, diabetes, and / or other conditions. Treatment information can further include information regarding different lifestyle habits, surgical procedures, and / or other non-invasive procedures recommended by the host’s physician. For example, the host’s physician can recommend a certain diet for the host, or exercise for a minimum of thirty minutes a day following meals, etc. In certain embodiments, medication / treatment information can be provided through manual host input.

[0166] In certain embodiments, analyte sensor data can also be provided as input, for example, through continuous analyte monitoring system 104. In certain embodiments, analyte sensor data includes glucose data (e.g., a host’s glucose values) derived from measured glucose levels by at least a glucose sensor (or multi-analyte sensor) in continuous analyte monitoring system 104. In certain embodiments, analyte sensor data includes fructosamine data derived from measured fructosamine levels by at least a fructosamine sensor (or multi-analyte sensor) in continuous analyte monitoring system 104. In certain embodiments, analyte sensor data includes lactate data (e.g., a host’s lactate values) measured by at least a lactate sensor (or multi-analyte sensor) in continuous analyte monitoring system 104. In certain embodiments, analyte sensor data includes other analyte data, such as creatinine data, 1,5 AG data, potassiumAttorney Docket No. 0981-PCT01data, or HbAlc data, measured by a sensor (or multi-analyte sensor) in continuous analyte monitoring system 104.

[0167] In certain embodiments, input can also be received from one or more non-analyte sensors, such as non-analyte sensors 206 described with respect to FIG. 2. Input from such non-analyte sensors 206 includes information related to heart rate, heart rate variability, electrocardiogram data, respiration rate, oxygen saturation, blood pressure, accelerometer data, or a body temperature (e.g. to detect illness, physical activity, etc.) of a host. In certain embodiments, electromagnetic sensors also detect low-power radio frequency (RF) fields emitted from objects or tools touching or near the object, which provides information about host activity or location.

[0168] In certain embodiments, input received from non-analyte sensors can include input relating to a host’s medication administration / delivery. In particular, input related to the host’s medication administration can be received, via a wireless connection on a smart pen, via host input, and / or from a medication pump or other device. Medication administration information can include one or more of medication volume, time of delivery, etc. Other parameters, such as medication action time or duration of medication action, can also be received as inputs.

[0169] In certain embodiments, inputs 130 can also include food consumption information, including information about one or more of meals, snacks, and / or beverages, such as one or more of the size, content (carbohydrate, fat, protein, etc.), sequence of consumption, and time of consumption. In certain embodiments, food consumption can be provided by a host through manual entry, by providing a photograph through an application that is configured to recognize food types and quantities, and / or by scanning a bar code or menu. In various examples, meal size can be manually entered as one or more of calories, quantity (“three cookies”), menu items (“Royale with Cheese”), and / or food exchanges (1 fruit, 1 dairy). In some examples, meal information can be received via a convenient user interface provided by application 106 and / or application 111.

[0170] In certain embodiments, food consumption information (the type of food (e.g., liquid or solid, snack or meal, etc.) and / or the composition of the food (e.g., carbohydrate, fat, protein, etc.) can be determined automatically based on information provided by one or more sensors. Some example sensors can include body sound sensors (e.g., abdominal sounds can be used to detect the types of meal, e.g., liquid / solid food, snack / meal, etc.), radio-frequency sensors, cameras, hyperspectral cameras, and / or analyte (e.g., fructosamine, glucose,Attorney Docket No. 0981-PCT01potassium, lactate, 1,5 AG, creatinine, etc.) sensors to determine the type and / or composition of the food.

[0171] In certain embodiments, medical history and / or disease diagnoses (e.g., kidney disease, diabetes, liver disease, cardiovascular disease, hypertension, etc.) is provided as an input. For example, the host can have an existing diagnosis of diabetes and this diagnosis can be provided through manual host input. In certain embodiments, disease diagnoses are also provided by interfacing with an electronic source such as an EMR. In certain embodiments, medical history can include prior test results such as albumin-to-creatinine ratio (ACR) tests, glomular filtration rate (GFR) tests, blood tests for monitoring potassium levels, historical host kidney metabolic panels, etc.

[0172] In certain embodiments, exercise information is also provided as an input. Exercise information can be any information surrounding activities requiring physical exertion by the host. For example, exercise information can range from information related to low intensity (e.g., walking a few steps) and high intensity (e.g., five mile run) physical exertion. In certain embodiments, the exercise information can comprise information related to HIIT, resistance training, or Zone 2 training. In certain embodiments, exercise information can also be provided through manual host input suggesting the host will begin a specific exercise type and / or with certain exercise parameters. In certain embodiments, exercise information can be provided or determined based on information provided, for example, by non-analyte sensors 206 (e.g., a temperature sensor, a heart rate monitor, a wearable blood pressure monitor, an accelerometer sensor on a wearable device such as a watch, fitness tracker, and / or patch, etc.). In certain embodiments, exercise information can be provided or determined based on information provided, for example, by continuous analyte monitoring system 104 (e.g., it can be deduced that the host engaged in exercise based on their potassium, glucose, and / or lactate data). The exercise information provided by analyte and non-analyte sensors can be used as input into a model trained for predicting whether the host is engaging in exercise and / or predicting the types and / or parameters of such exercise.

[0173] In certain embodiments, time can also be provided as an input, such as time of day or time from a real-time clock. For example, in certain embodiments, input analyte data can be timestamped to indicate a date and time when the analyte measurement was taken for the host.Attorney Docket No. 0981-PCT01

[0174] Host input of any of the above-mentioned inputs 130 can be provided through continuous analyte monitoring system 104, non-analyte sensors 206, and / or a user interface, such a user interface of display device 107 of FIG. 1. As described above, in certain embodiments, DAM 116 determines or computes the host’s metrics 132 based on inputs 130. An example list of metrics 132 is shown in FIG. 3.

[0175] In certain embodiments, glucose metrics can be calculated by DAM 116 based on inputs 130. Glucose metrics can include glucose levels, glucose baselines, maximum and minimum glucose levels, mean glucose levels, glucose rates of change, glucose baseline rates of change, glucose clearance rates, and / or glucose trends. In certain embodiments, the mean glucose level can be a weighted average of filtered (e.g., for noise and compression) glucose levels measured in 5-minute intervals. In some examples, the mean glucose level can be determined over a one to two week time period, corresponding to the half-life of fructosamines, as discussed herein.

[0176] In certain embodiments, fructosamine metrics can be calculated by DAM 116 based on inputs 130. Fructosamine metrics can include measured fructosamine levels, a measured fructosamine value, measured fructosamine baselines, measured maximum and minimum fructosamine levels, measured fructosamine rates of change, measured fructosamine baseline rates of change, measured fructosamine clearance rates, measured fructosamine trends, and / or an expected fructosamine value.

[0177] Specifically, the measured fructosamine metrics (e.g., measured fructosamine levels, measured fructosamine value, measured fructosamine baselines, etc.) can be derived from real-time fructosamine concentration levels from a continuous fructosamine monitor of continuous analyte monitoring system 104. The expected fructosamine value can be calculated from a mean glucose value derived from measured glucose data using the following equation: Fructosamine {pmol / L} = 1.9391 * (Mean Glucose {mg / dL} + 20).

[0178] In certain embodiments, fructosamine delta can be calculated by DAM 116 based on inputs 130 and fructosamine and glucose metrics. As described herein, fructosamine delta is calculated based on the difference between an expected fructosamine value (e.g., derived based on glucose data) as compared to a measured fructosamine value based on the measured fructosamine concentration levels. The fructosamine delta can be calculated and updated continuously based on updated fructosamine data (e.g., a measured fructosamine value and an expected fructosamine value).Attorney Docket No. 0981-PCT01

[0179] In certain embodiments, the host’s metrics 132 can further include metrics for other analytes. For example, in certain embodiments, metrics 132 can include potassium data, potassium baselines, maximum and minimum potassium levels, potassium rates of change, potassium baseline rates of change, potassium clearance rates, potassium trends, lactate data, lactate baselines, maximum and minimum lactate levels, lactate rates of change, lactate baseline rates of change, lactate clearance rates, lactate trends, 1,5 AG data, 1,5 AG baselines, maximum and minimum 1,5 AG levels, 1,5 AG rates of change, 1,5 AG baseline rates of change, 1,5 AG clearance rates, 1,5 AG trends, 1,5 AG glucose renal threshold (e.g., the level of a patient’s blood glucose where glucose begins to outcompete 1,5 AG for reabsorption and 1,5 AG levels begin to decrease), HbAlc data, HbAlc baselines, maximum and minimum HbAlc levels, HbAlc rates of change, HbAlc baseline rates of change, HbAlc clearance rates, HbAlc trends, creatinine levels, creatinine baselines, maximum and minimum creatinine levels, creatinine rates of change, creatinine baseline rates of change, creatinine clearance rates, creatinine trends, and / or levels, baselines, maximum and minimum levels, rates of change, baseline rates of change, clearance rates, and / or trends of one or more other analytes of the host.

[0180] In certain embodiments, health and sickness metrics can be determined, for example, based on one or more of host input (e.g., pregnancy information or known sickness information), from physiologic sensors (e.g., temperature), activity sensors, or a combination thereof. In certain embodiments, based on the values of the health and sickness metrics, for example, a host’s state can be defined as being one or more of healthy, ill, rested, or exhausted.

[0181] In certain embodiments, medication habit metrics are based on the host’s prescribed medications and a determination of whether the prescribed medications can have an effect on the host’s analyte data. For example, by analyzing a host’s medication habits, DAM 116 can determine whether the host’s medications can impact the host’s analyte measurements at a particular time. Based on the host’s medication habits, DAM 116 can determine whether the host’s analyte data are a result of medication consumption or another cause, such as worsening organ (e.g., liver or kidney) function, for example. Medication habit metrics can be time-stamped so that they can be correlated with the host’s analyte data at the same time.

[0182] In certain embodiments, medication adherence is measured by one or more metrics that are indicative of how committed the host is towards their medication regimen. In certain embodiments, medication adherence metrics are calculated based on one or more of the timing of when the host takes medication (e.g., whether the host is on time or on schedule), the typeAttorney Docket No. 0981-PCT01of medication (e.g., is the host taking the right type of medication), and the dosage of the medication (e.g., is the host taking the right dose).

[0183] In certain embodiments, the activity level metric can indicate the host’s level of activity. In certain embodiments, the activity level metric be determined, for example based on input from an activity sensor or other physiologic sensors, such as non-analyte sensors 206. In certain embodiments, the activity level metric can be calculated by DAM 116 based on one or more of inputs 130, such as one or more of exercise information, non-analyte sensor data (e.g., accelerometer data), time, host input, etc. In certain embodiments, the activity level can be expressed as a step rate of the host. Activity level metrics can be time-stamped so that they can be correlated with the host’s fructosamine data and / or glucose data at the same time.

[0184] In certain embodiments, body temperature metrics can be calculated by DAM 116 based on inputs 130, and more specifically, non-analyte sensor data from a temperature sensor. In certain embodiments, heart rate metrics (e.g., including heart rate and heart rate variability) can be calculated by DAM 116 based on inputs 130, and more specifically, non-analyte sensor data from a heart rate sensor. In certain embodiments, respiratory metrics can be calculated by DAM 116 based on inputs 130, and more specifically, non-analyte sensor data from a respiratory rate sensor.

[0185] FIG. 4 is a flow diagram depicting an example workflow 400 for determining a risk, presence, and / or progression of kidney dysfunction, as well as providing therapy management guidance, according to certain embodiments of the present disclosure. Generally, workflow 400 is performed, at least in part, by therapy management system 100, including therapy management engine 114. In certain embodiments, therapy management system 100 provides guidance via the workflow 400 using at least a continuous fructosamine monitor and a CGM, as described with reference to FIGs. 1 and 2.

[0186] Turning to FIG. 4, workflow 400 begins at block 402 by therapy management engine 114 monitoring at least fructosamine concentration levels and glucose concentration levels of the host during a time period using at least a CGM and a continuous fructosamine monitor of the continuous analyte monitoring system 104. As described above, the measured fructosamine concentration levels and the measured glucose concentration levels can be stored as measured fructosamine data and measured glucose data in host profile 118, for example. The measured fructosamine data and measured glucose data are provided as input to the therapy management engine 114.Attorney Docket No. 0981-PCT01

[0187] At block 404, the therapy management engine 114 determines, based on the measured glucose concentration levels of the host during the time period, a glucose metric of the host. In certain embodiments, the glucose metric includes at least a mean glucose value as described in reference to FIG. 3. As described above, the measured glucose data can include measured glucose values obtained every few seconds or minutes (e.g., every 5 minutes) over a certain time period, such as the most recent two weeks. The mean glucose value is calculated as the mean of the measured glucose values over the time period.

[0188] At block 406, the therapy management engine 114 determines an expected fructosamine value based on the glucose metric, such as the mean glucose value. The expected fructosamine value can be calculated from the mean glucose value using the following equation: Fructosamine { mol / L} = 1.9391 * (Mean Glucose {mg / dL} + 20).

[0189] At block 408, the therapy management engine 114 compares the expected fructosamine value determined at block 406 with the measured fructosamine value based on the host’s measured fructosamine concentration levels to obtain a fructosamine delta, as described in reference to FIG. 3. Following the comparison, the therapy management engine 114 can proceed to block 410.

[0190] At block 410, the therapy management engine 114 provides a determination of risk, presence, and / or progression of kidney dysfunction and provides personalized therapy management guidance to the host based on the comparison at block 408. The determination of a risk, presence, and / or progression of kidney dysfunction for the host can include a determination of a risk, presence, and / or progression of proteinuria.

[0191] If the therapy management engine 114 determines that host’s fructosamine delta is below a specified threshold or zero, the therapy management engine 114 determines that the host is at low risk of experiencing kidney dysfunction. In such an example, the therapy management engine 114 can provide therapy management guidance to the host suggesting that the host is at low risk of experiencing kidney dysfunction. In certain embodiments, the specified threshold can be I Op mol. In one example, therapy management engine 114 provides therapy management guidance as an output to the host, such as a risk score or risk indication, at the display device of the host, such as display device 107. In one example, the risk score or risk indication can be provided in a report or in real time to the host’s healthcare provider.

[0192] A low risk of kidney dysfunction based on glucose and fructosamine data can demonstrate that the host is not experiencing glomerular dysfunction, however, withoutAttorney Docket No. 0981-PCT01additional analyte data, a low risk of kidney dysfunction does not necessarily confirm healthy kidney function. In certain embodiments, additional analyte data can be used to further refine the therapy management engine 114 and provide a more complete view of kidney function and kidney health. For example, 1,5 AG data and / or medication information can be utilized in addition to glucose and fructosamine data to determine that the host is not experiencing a proximal tubule issue, in addition to the absence of glomerular dysfunction as determined by glucose and fructosamine data. In such an example, the therapy management engine 114 can notify the host of a low risk of kidney dysfunction, including a low risk of a proximal tubule issue, and recommend the host continue following medical guidance for preventing and / or identifying kidney dysfunction, including completing an annual urine test to monitor the host’s kidney function.

[0193] If the therapy management engine 114 determines that host’s fructosamine delta is above the specified threshold, the therapy management engine 114, determines the host is at risk of experiencing kidney dysfunction. In such an example, the therapy management engine 114 can provide therapy management guidance to the host suggesting that the host is experiencing or at risk of experiencing kidney dysfunction. Therapy management guidance can include an alarm or alert, or other form of notification provided as an output at the host display device, such as display device 107. The output can be a visual, audible, and / or tactile signal. In one example, the output can include information regarding the level of risk such as a risk indicator or a risk score. In addition to the output provided to the host, a report can be generated, in real time or retrospectively, and provided to the host or the host’s healthcare provider.

[0194] In certain embodiments, the degree of magnitude of the fructosamine delta can be correlated to a risk level or progression of kidney dysfunction. For example, the larger the fructosamine delta, the higher the risk of progression of kidney dysfunction. Further, if the host’s fructosamine delta is increasing over time, the therapy management engine 114 determines the host is experiencing worsening kidney dysfunction.

[0195] In addition to providing therapy management guidance related to the risk, presence, or progression of kidney dysfunction, the therapy management engine 114 can provide therapy management guidance related to medication compliance and / or medication recommendations. In such an example, therapy management engine 114 can monitor host input (e.g., treatment / medication information) to determine when the host is taking various medications that are known to improve kidney dysfunction. If a host is prescribed a medication to improveAttorney Docket No. 0981-PCT01kidney function (e.g., renin-angiotensin-aldosterone system inhibitors (RAASi) or SGLT-2) and the host’s fructosamine delta continues to increase over time, the therapy management engine 114 can suggest that the host take the medication more regularly or suggest that the host begin an alternative medication regimen to improve kidney function.

[0196] In certain embodiments, the therapy management guidance can also include feedback based on the success of one or more medications the host is taking to improve kidney function, and / or feedback on various medications that can improve the host’s kidney function. For example, if the host is taking a medication to improve kidney function but the host’s fructosamine delta is worsening over time, the therapy management engine 114 can recommend the host adjust the dosage of the medication or begin taking an alternative medication. In another example, the therapy management guidance can include a recommendation to seek medical intervention for further testing and / or kidney disease diagnosis if the medication recommendations described above do not improve kidney function.

[0197] In certain embodiments, the therapy management guidance provided to the host may be based on whether the host has liver disease and / or liver dysfunction. Liver disease and / or liver dysfunction, especially late stage liver disease (e.g., cirrhosis), can affect albumin production, which can cause the host’s measured fructosamine value to differ from the expected fructosamine value derived from the host’s mean glucose value. In such cases, if therapy management engine 114 determines the host has liver disease, an increase of fructosamine delta of the host over time can be determined to be indicative of the host’s liver disease instead of kidney dysfunction. Liver disease and / or liver dysfunction can be confirmed based on correlations with elevated lactate data of the host, in addition to medical history and / or known liver disease diagnoses. A confirmation of liver disease and / or liver dysfunction can inform the feedback provided by the therapy management engine 114 to improve liver function.

[0198] While the use of fructosamine data is described herein relative to determining kidney dysfunction, the therapy management engine 114 can also provide therapy management guidance for the host to seek medical intervention for inflammation, chronic inflammatory disease, cancer, viral infection or chronic viral illness, HIV, AIDS, amlyoidosis, bone marrow malignancies, etc. If the therapy management engine 114 determines the host’s fructosamine delta is below a specified threshold or zero and the host’s other analyte data indicate normal kidney function (e.g., 1,5 AG, creatinine, potassium etc.), the therapy management engine 114 can recommend the host seek medical intervention for one of the above mentioned diseases.Attorney Docket No. 0981-PCT01

[0199] Upon performance of block 410, the therapy management engine 114 returns to block 402 to continue monitoring the host’s glucose and fructosamine data. As the therapy management engine 114 continues monitoring the host’s glucose data, fructosamine data, and / or fructosamine delta over time, the therapy management engine 114 can provide therapy management guidance based on trends and / or patterns in the analyte data over time.

[0200] Additionally, therapy management engine 114 can further provide therapy management guidance based on the host’s measured fructosamine levels as compared to the host’s previous measured fructosamine levels over time. For example, therapy management engine 114 can utilize changes in measured fructosamine levels of the host over time and / or calculate a percent change of fructosamine levels of the host over time to provide personalized therapy management guidance to the host.

[0201] FIG. 5 is a flow diagram depicting a method 500 for training machine learning models to determine a risk, presence, and / or progression of kidney dysfunction of a host, and / or provide therapy management guidance to the host based on the determination. In certain embodiments, the method 500 is used to train models to provide an early diagnosis of kidney dysfunction and / or prevent the progression of kidney dysfunction.

[0202] Method 500 begins, at block 502, by a training server system, such as training server system 140 illustrated in FIG. 1, retrieving data from a historical records database, such as historical records database 112 illustrated in FIG. 1. As mentioned herein, historical records database 112 can provide a repository of up-to-date information and historical information for hosts of a continuous analyte monitoring system and connected mobile health application, such as hosts of continuous analyte monitoring system 104 and application 106 illustrated in FIG.1, as well as data for one or more hosts who are not, or were not previously, hosts of continuous analyte monitoring system 104 and / or application 106.

[0203] Retrieval of data from historical records database 112 by training server system 140, at block 502, can include the retrieval of all, or any subset of, information maintained by historical records database 112. For example, where historical records database 112 stores information for 100,000 hosts (e.g., non-hosts and hosts of continuous analyte monitoring system 104 and application 106), data retrieved by training server system 140 to train one or more machine learning models can include information for all 100,000 hosts or only a subset of the data for those hosts, e.g., data associated with only 50,000 hosts or only data from the last ten years.Attorney Docket No. 0981-PCT01

[0204] As an illustrative example, integrating with on premises or cloud based medical record databases through Fast Healthcare Interoperability Resources (FHIR), web application programming interfaces (APIs), Health Level 7 (HL7), and or other computer interface language can enable aggregation of healthcare historical records for baseline assessment in addition to the aggregation of de-identifiable host data from a cloud based repository. Similarly, when integrating into the medical record databases, the integration can be accomplished by directly interfacing with the electronic medical record (EMR) system or through one or more intermediary systems (e.g., an interface engine, etc.).

[0205] As an illustrative example, at block 502, training server system 140 can retrieve information for 100,000 hosts with various diseases or conditions, and / or prescribed medications and / or other therapies, stored in historical records database 112 to train a model to determine a risk, presence, and / or progression of kidney dysfunction, and provide therapy management guidance based on the determination. Each of the 100,000 hosts can have a corresponding data record (e.g., based on their corresponding host profile)), stored in historical records database 112. Each host profile 118 can include information, such as information discussed with respect to FIG. 3.

[0206] The training server system 140 then uses information in each of the records to train an artificial intelligence or ML model (for simplicity referred to as “ML model” herein). Examples of types of information included in a host’s host profile were provided above. The information in each of these records can be featurized (e.g., manually or by training server system 140), resulting in features that can be used as input features for training the ML model. For example, a host record can include or be used to generate features related to the host’s demographic information (e.g., an age of a host, a gender of the host, etc.), analyte information, such as glucose data and fructosamine data, and / or any other data points in the host record (e.g., inputs 130, metrics 132, etc.). Features used to train the machine learning model(s) can vary in different embodiments.

[0207] In certain embodiments, each historical host record retrieved from historical records database 112 is further associated with a label indicating a risk of kidney dysfunction, a level of kidney dysfunction, atherapy management guidance based on the kidney dysfunction, etc. What the record is labeled with would depend on what the model is being trained to predict.

[0208] At block 504, method 500 continues by training server system 140 training one or more machine learning models based on the features and labels associated with the historicalAttorney Docket No. 0981-PCT01host records. In some embodiments, the training server does so by providing the features as input into a model. This model can be a new model initialized with random weights and parameters, or can be partially or fully pre-trained (e.g., based on prior training rounds). Based on the input features, the model-in-training generates some output. In certain embodiments, the output can include an indication of a host’s risk, presence, and / or progression of kidney dysfunction, and / or therapy management guidance based on the determination, or similar outputs. Note that the output could be in the form of a notification, a recommendation, and / or other types of output.

[0209] In certain embodiments, training server system 140 compares this generated output with the actual label associated with the corresponding historical host record to compute a loss based on the difference between the actual result and the generated result. This loss is then used to refine one or more internal weights and parameters of the model (e.g., via backpropagation) such that the model learns to provide feedback to the host more accurately based on their determined kidney dysfunction.

[0210] One of a variety of machine learning algorithms can be used for training the model(s) described above. For example, one of a supervised learning algorithm, a neural network algorithm, a deep neural network algorithm, a deep learning algorithm, etc. can be used.

[0211] At block 506, training server system 140 deploys the trained model(s) to make predictions associated with a host’s kidney dysfunction and provide therapy management guidance to the host during runtime. In some embodiments, this includes transmitting some indication of the trained model(s) (e.g., a weights vector) that can be used to instantiate the model(s) on another device. For example, training server system 140 can transmit the weights of the trained model(s) to therapy management engine 114, which could execute on display device 107, etc. The model(s) can then be used to determine, in real-time, treatment parameters to optimize therapy of a host using application 106, and / or make other types of recommendations discussed above. In certain embodiments, the training server system 140 can continue to train the model(s) in an “online” manner by using input features and labels associated with new host records.

[0212] Further, similar methods for training illustrated in FIG. 5 using historical host records can also be used to train models using host-specific records to create more personalized models for making predictions associated with optimized therapy management guidance forAttorney Docket No. 0981-PCT01the host. For example, a model trained using historical host records that is deployed for a particular host, can be further re-trained after deployment. For example, the model can be retrained after the model is deployed for a specific host to create a more personalized model for the host. The more personalized model can be able to more accurately provide therapy management guidance to the host based on the host’s own data (as opposed to only historical host record data), including the host’s own inputs 130 and metrics 132.

[0213] FIG. 6 is a block diagram depicting a computing device 600 configured to execute a therapy management engine (e.g., therapy management engine 114), according to certain embodiments disclosed herein. Although depicted as a single physical device, in embodiments, computing device 600 can be implemented using virtual device(s), and / or across a number of devices, such as in a cloud environment. As illustrated, computing device 600 includes a processor 605, memory 610, storage 615, a network interface 625, and one or more VO interfaces 620. In the illustrated embodiment, processor 605 retrieves and executes programming instructions stored in memory 610, as well as stores and retrieves application data residing in storage 615. Processor 605 is generally representative of a single CPU and / or GPU, multiple CPUs and / or GPUs, a single CPU and / or GPU having multiple processing cores, and the like. Memory 610 is generally included to be representative of a random-access memory. Storage 615 can be any combination of disk drives, flash-based storage devices, and the like, and can include fixed and / or removable storage devices, such as fixed disk drives, removable memory cards, caches, optical storage, network attached storage (NAS), or storage area networks (SAN).

[0214] In some embodiments, input and output (VO) devices 635 (such as keyboards, monitors, etc.) can be connected via the VO interface(s) 620. Further, via network interface 625, computing device 600 can be communicatively coupled with one or more other devices and components, such as host database 110. In certain embodiments, computing device 600 is communicatively coupled with other devices via a network, which can include the Internet, local network(s), and the like. The network can include wired connections, wireless connections, or a combination of wired and wireless connections. As illustrated, processor 605, memory 610, storage 615, network interface(s) 625, and VO interface(s) 620 are communicatively coupled by one or more interconnects 630. In certain embodiments, computing device 600 is representative of display device 107 associated with the host. In certain embodiments, as discussed above, the display device 107 can include the host’s laptop,Attorney Docket No. 0981-PCT01computer, smartphone, and the like. In another embodiment, computing device 600 is a server executing in a cloud environment.

[0215] In the illustrated embodiment, storage 615 includes host profile 118. Memory 610 includes therapy management engine 114, which itself includes DAM 116.

[0216] As described above, continuous analyte monitoring system 104, described in relation to FIG. 1, can be a multi-analyte sensor system including a multi-analyte sensor. In certain other embodiments, continuous analyte monitoring system 104 can be a single analyte sensor system, such as a fructosamine sensor system.

[0217] FIG. 7A is a side view of an exemplary continuous glycated protein sensor system, illustrating an analyte sensor 34 implanted into a host. A mounting unit 14 may be adhered to the host's skin using an adhesive pad 8. The adhesive pad 8 may be formed from an extensible material, which may be removably attached to the skin using an adhesive. The sensor electronics 18 may mechanically couple to the adhesive pad 8. In examples, adhesive pad 8 includes and / or functions as an external reference electrode. In other examples, the sensor electronics and mounting unit are combined in a single device. In examples, the sensor electronics and mounting unit are integral or of a unitary construction. In examples, the sensor electronics are disposed in a housing, with the analyte sensor being preconnected prior to insertion into a host.

[0218] FIG. 7B is an enlarged view of a distal portion of the analyte sensor 34. The analyte sensor 34 may be adapted for insertion under the host's skin and may be mechanically coupled to the mounting unit 14 and electrically coupled to the sensor electronics 18. The example analyte sensor 34 shown in FIG. 7B includes an elongated conductive body 41. The elongated conductive body 41 can include a wire or planar core (hereinafter “core”) with various layers positioned thereon. A first layer 38 that at least partially surrounds the core and includes a working electrode, for example located in window 39). In some examples, the core and the first layer 38 are made of a single material (such as, for example, platinum). In some examples, the elongated conductive body 41 is a composite of two conductive materials, or a composite of at least one conductive material and at least one non-conductive material. A membrane system 32 is located over the working electrode and may cover other layers and / or electrodes of the sensor 34, as described herein.

[0219] The first layer 38 may be formed of a conductive material. The working electrode (at window 39) is an exposed portion of the surface of the first layer 38. Accordingly, the firstAttorney Docket No. 0981-PCT01layer 38 is formed of a material configured to provide a suitable electroactive surface for the working electrode. Examples of suitable materials include, but are not limited to, platinum, dealloyed platinum with another metal, platinum-iridium, gold, palladium, iridium, graphite, carbon, carbon fiber, carbon nanotubes, a conductive polymer, an alloy, and / or the like.

[0220] A second layer 40 surrounds at least a portion of the first layer 38, thereby defining boundaries of the working electrode. In some examples, the second layer 40 serves as an insulator and is formed of an insulating material, such as polyimide, polyurethane, parylene, or any other suitable insulating materials or materials. In some examples, the second layer 40 is configured such that the working electrode (of the layer 38) is exposed via the window 39.

[0221] In some examples, the sensor 34 further includes a third layer 43 comprising a conductive material. The third layer 43 may comprise a reference electrode. In some examples, the third layer 43, including the reference electrode, is formed of a silver-containing material that is applied onto the second layer 40 (e.g., an insulator). The silver-containing material may include various materials and be in various forms such as, for example, Ag / AgCl-polymer pastes, paints, polymer-based conducting mixtures, inks, etc.

[0222] The analyte sensor 34 may include two (or more) electrodes, e.g., a working electrode at the layer 38 and exposed at window 39 and at least one additional electrode, such as a reference electrode of the layer 43. In the example arrangement of FIG. 7B, the reference electrode also functions as a counter electrode, although other arrangements can include a separate counter electrode. While the analyte sensor 34 may be used with a mounting unit in some examples, in other examples, the analyte sensor 34 may be used with other types of sensor systems. For example, the analyte sensor 34 may be part of a system that includes a battery and sensor in a single package, and may optionally include, for example, a near-field communication (NFC) circuit. In examples, electrochemical detection is analog in electrical communication with a digital processor and / or memory. In examples, electrochemical detection is analog in electrical communication with a digital processor and / or memory, the processor in electrical communication with a wireless radio (e.g., Bluetooth Eow Energy, WiFi, cellular) transmitter configured to send a signal to a receiver.

[0223] FIG. 7C is a cross-sectional view through the sensor 34 of FIG. 7B on plane 2-2 illustrating a membrane system 32. The membrane system 32 may include a number of domains (e.g., layers). In an example, the membrane system 32 may include an enzyme domain 42, a diffusion resistance domain 44, and a biointerface domain 46 located around the workingAttorney Docket No. 0981-PCT01electrode. In some examples, a unitary diffusion resistance domain and biointerface domain may be included in the membrane system 32 (e.g., wherein the functionality of both the diffusion resistance domain and biointerface domain are incorporated into one domain).

[0224] The membrane system 32, in some examples, also includes an electrode layer 47. The electrode layer 47 may be arranged to provide an environment between the surfaces of the working electrode and the reference electrode that facilitates the electrochemical reaction between the electrodes. For example, the electrode layer 47 may include a coating that maintains a layer of water at the electrochemically reactive surfaces of the sensor 34.

[0225] In some examples, the sensor 34 may be configured for short-term implantation (e.g., from about 1 to 30 days). However, it is understood that the membrane system 32 can be modified for use in other devices, for example, by including only one or more of the domains, or additional domains. For example, a membrane system may include a plurality of resistance layers, or a plurality of enzyme layers. In some example, the resistance domain 44 may include a plurality of resistance layers, or the enzyme domain 42 may include a plurality of enzyme layers.

[0226] The diffusion resistance domain 44 may include a semipermeable membrane that controls the flux of oxygen and glycated protein to the underlying enzyme domain 42. As a result, the upper limit of linearity of glycated protein measurement is extended to a much higher value than that which is achieved without the diffusion resistance domain 44.

[0227] In some examples, the membrane system 32 may include a biointerface domain 46, also referred to as a domain or biointerface domain, comprising a base polymer as described in more detail elsewhere herein. However, the membrane system 32 of some examples can also include a plurality of domains or layers including, for example, an electrode domain, an interference domain, or a cell disruptive domain, such as described in more detail elsewhere herein and in U.S. Pat. Nos. 7,494,465, 8,682,408, and 9,44,199, which are incorporated herein by reference in their entirety.

[0228] It is to be understood that sensing membranes modified for other sensors, for example, may include fewer or additional layers. For example, in some examples, the membrane system 32 may comprise one electrode layer, one enzyme layer, and two bioprotective layers, but in other examples, the membrane system 32 may comprise one electrode layer, two enzyme layers, and one biointerface layer. In some examples, theAttorney Docket No. 0981-PCT01biointerface layer may be configured to function as the diffusion resistance domain 44 and control the flux of the analyte (e.g., glycated protein) to the underlying membrane layers.

[0229] In some examples, the sensing membrane can be deposited on the electroactive surfaces of the electrode material using known thin or thick film techniques (for example, slot die coating, contact dispensing, spraying, microfluidic spraying, electro-depositing, dipping, or the like). The sensing membrane located over the working electrode does not have to have the same structure as the sensing membrane located over the reference electrode 30; for example, the enzyme domain 42 deposited over the working electrode does not necessarily need to be deposited over the reference or counter electrodes.

[0230] Although the examples illustrated in FIGS. 7B-7C involve circumferentially extending membrane systems, the membranes described herein may be applied to any planar or non-planar surface, for example, the substrate-based sensor structure of U.S. Pat. No.6,565,509 to Say et al., which is incorporated by reference, and discussed further below. In examples, one or more membranes can be deposited on one or both sides of planar surface and the membranes can be geometrically confined to a certain region within the planar surface, for example, at discrete working electrode regions or on discrete working electodes.

[0231] In the membrane configurations depicted in FIG. 7C, production of an electrochemically active species in the enzyme domain diffuses to the WE surface and transduces a signal that corresponds directly or indirectly to an analyte concentration. In some examples, the electrochemically active species comprises hydrogen peroxide. For sensor configurations that include a cofactor, the cofactor from the first layer can diffuse to the enzyme domain to extend sensor life, for example, by regenerating the cofactor. For other sensor configurations, the cofactor can be optionally included to improve performance attributes, such as stability. For example, a continuous glycated protein sensor can comprise NAD(P)H. One or more resistance domains (“RL”) can be positioned adjacent the second membrane (or can be between the layers). The RL can be configured to block diffusion of cofactor from the second membrane and / or interferents from reaching the WE surface. Other configurations can be used in the aforementioned configuration, such as electrode, resistance, bio-interfacing, and drug releasing membranes, layers or domains. In other examples, continuous analyte sensors including one or more cofactors that contribute to sensor performance.

[0232] FIG. 7D is an illustration of an example planar analyte sensor with sensing membranes, according to certain embodiments of the present disclosure. The planar analyteAttorney Docket No. 0981-PCT01sensor can include electrode 780 with a sensing membrane with multiple layers or domains. For example, the planar version can include an interference domain 782, an enzyme domain 784, and resistance domain 786, in addition to other variations of domains. As shown, the planar analyte sensor includes sensing membrane surrounding the electrically conductive material or electrode 780, however, the electrically conductive material or electrode 780 can be on one side thereof in other examples.

[0233] FIGS. 8A to 8B depict an exemplary planar sensor assembly 800, showing top-down drawings of a first side 802 and a second side 804 opposite the first side, in addition to a first end 812 and a second end 814. FIGS. 8C to 8E depict schematic cross-section drawings of the full sensor assembly 800. The sensor assembly 800 can include substrate 810, conductive traces 820, 821, connector pads 822, 823 working electrodes 824, 825, counter electrode 826, insulating layers 830, 832, and reference electrode 840. In sensor assembly 800, a double-sided planar configuration is used. In the sensor assembly 800, a multiple-electrode sensor is shown, with two working electrodes (WE) 824, 825, a counter electrode (CE) 826 and a reference electrode (RE) 840. In sensor assembly 800, the electrodes are co-planar. The sensor assembly 800 is an unconnected variation. In examples, working electrodes (WE) 824, 825 are coated with the sensing membrane with multiple layers or domains as disclosed herein.

[0234] In sensor assembly 800, structures can be formed on both sides 802, 804, of the substrate 810. For example, the connector pads 822, 823, can be formed, respectively, on opposing sides 802, 804. This can allow for connection to the sensing electronics from both sides of the sensor assembly 800. Similarly, the conductive traces 820, 821, can be formed on both sides 802, 804, of the sensor assembly 800. On each individual side 802, 804 the conductive traces 820, 821, can be co-planar with each other.

[0235] The insulating layers 830, 832, such as a solder mask or other insulating material, can be deposited over the conductive layers including the conductive traces 820, 821. Openings can be formed in the insulating layers 830, 832, to form the working electrodes 824, 825, and the counter electrode 826. An opening can be left for the reference electrode 840. A reference electrode material, such as silver / silver chloride, can be deposited on the designated sensing surface for the reference electrode 840. The insulating material can include epoxy, polyimide, polyurethane, polyethylene, or other materials or combinations of materials.

[0236] As illustrated in FIGS. 8A and 8B, the double-sided sensor assembly 800 can include a first working electrode 824, a second working electrode 825, a counter electrode 826,Attorney Docket No. 0981-PCT01and a reference electrode 840. In some cases, such a double-sided sensor can contain more or less electrodes. For example, a double-sided sensor can include a single working electrode and a reference electrode or two working electrodes and a single reference electrode.

[0237] FIGS. 8C to 8E depict cross-sections of the sensor assembly 800. Shown in FIG.8C is a cross section along line C-C, where the substrate 810 is situated between the two insulating layers 830, 832. The substrate 810 can be, for example, about 50 microns thick. Conductive traces 820, 821, can be seen. On the first side 802, three conductive traces 820 extend along the length of the sensor assembly 800, each connecting to a connector pad 822. The conductive traces 821 on the second side 804 can connect to the connector pad 823.

[0238] In FIG. 8D, the cross-section is taken along line D-D. The reference electrode 840 can be seen at this point. In FIG. 8E, the cross-section is taken along line E-E, both working electrodes 824, 825, can be seen on opposing sides 802, 804, of the sensor assembly 800.

[0239] FIGS. 9A-9B illustrate a double-sided co-planar connected analyte sensor assembly 900, in accordance with an example. The sensor assembly 900 can include similar components to those of assembly 800 discussed above, except where otherwise noted.

[0240] FIGS. 9A to 9B depict schematic top-down drawings of opposing sides of the assembly 900. FIGS. 9C to 9E depict schematic cross-section drawings along cross-sections taken along C-C, D-D, and E-E, respectively, of the full sensor assembly 900. In some cases, the sensor assembly 900 can include a chamfer end, a rounded end, a flat end, or other appropriate shape. In some cases, the sensor assembly 900 can include a chamfer end, a rounded end, a flat end, or other appropriate shape.

[0241] The sensor assembly 900 can have a first side 902 and a second side 904 opposite the first side, in addition to a first end 912 and a second end 914. The sensor assembly 900 can include substrate 910, conductive traces 920, 921, connector pads 922, working electrodes 924, 925, counter electrode 926, insulating layers 930, 932, and reference electrode 940. In sensor assembly 900, a double-sided planar configuration is used. In the sensor assembly 900, a multiple-electrode sensor is shown, with two working electrodes (WE) 924, 925, a counter electrode (CE) 926 and a reference electrode (RE) 940. In sensor assembly 900, the electrodes are co-planar. The assembly 900 is a co-planar, connected variation.

[0242] In sensor assembly 900, the substrate 910 is situated between two sides 902, 904, which can each host several co-planar components. For example, co-planar conductive traces 920 can be on the first side 902, and second conductive traces 921 can be on the second sideAttorney Docket No. 0981-PCT01904. Each side 902, 904, can be covered by an insulating layer 930, 932. The insulating layers 930, 932, can define electrodes 924, 925, 926, and an area for the reference electrode 940.

[0243] The assembly 900 can also include a via, which can provide for an electrical connection between both sides 902, 904 of the sensor assembly 900. A via can also be used within the substrate to connect buried conductive traces occupying differing layers of the assembly. Including vias can allow for connection to the sensing electronics through the connector pads 922 on a single side 902 of the sensor, as well as routing traces to new locations, allowing flexible geometries to be used. The vias can be formed from various conductive materials discussed herein, including gold, carbon, graphitic carbon, Pt, Pd, Ni, Cu, or combinations including Pt and C, Au and C. In some examples, the conductive material forming the vias between sides 902, 904 of the assembly or other assemblies as discussed herein may or may not further include conductive nanoparticles.

[0244] Shown in FIGS. 9A to 9E, the assembly 900 can include four connector pads 922 can be on a first side 902, electrically coupled to the electrodes 925, 940, on the second side 904 by vias and traces. In some cases, a WE, RE, and CE can be placed on the opposite side of the sensor assembly 900 to the connector pads 922. In some cases, as shown in assembly 900, a first working electrode 924 and counter electrode 926 can be located on the first side 902 of the sensor, while a second working electrode 925 and a reference electrode 940 can be located on the other side 904 of the sensor. Vias can be used to establish electrical contact between traces and pads on both sides 902, 904 of the sensor assembly 900, since the connector pads 922 for connecting to the sensing electronics, in some examples, are located only on one side. In examples, working electrodes (WE) 924, 925 are coated with the sensing membrane with multiple layers or domains as disclosed herein.Electrodes

[0245] Examples of electrodes suitable for use in the devices and methods disclosed herein include, for example, platinum and its binary and tertiary alloys, palladium and its binary and tertiary alloys, gold and its binary and tertiary alloys, silver and its binary and tertiary alloys, iridium or indium and its binary and tertiary alloys, rhodium, ruthenium, nitinol, indium tin oxide, bismuth molybdate (Bi2Mo06), tin sulfide metal oxide (SnS2), boron doped diamond, platinum coated boron doped diamond, conductive graphite and inks therefrom, gold, platinum, pallidum or iridium coated silicon wafers, doped polyaniline, doped poly(3,4-ethylenedioxythio-phene) polystyrene sulfonate (PEDOT:PSS), doped polypyrrole (Ppy),Attorney Docket No. 0981-PCT01amorphous carbon, carbon, graphite, carbon fiber, carbon nanotubes, graphene metallic nanoparticles, and / or ternary metal oxide composites. The electrode may be roughened, via electrochemical or other physical or chemical etching means. Roughening the electrode augments the electroactive surface area available for a reaction of interest to occur, thereby augmenting detected signal level.Sensor / Sensor System

[0246] Exemplary sensors are described previously herein. In some examples, the core and first layer can be of a single material (e.g., platinum). In some examples, the elongated conductive body is a composite of at least two materials, such as a composite of two conductive materials, or a composite of at least one conductive material and at least one non-conductive material. In some examples, the elongated conductive body comprises a plurality of layers. In certain examples, there are at least two concentric (e.g., annular) layers, such as a core formed of a first material and a first layer formed of a second material. However, additional layers can be included in some examples. In some examples, the layers are coaxial.

[0247] The elongated conductive body may be long and thin, yet flexible and strong. For example, in some examples, the smallest dimension of the elongated conductive body is less than about 0.1 inches, 0.75 inches, 0.5 inches, 0.25 inches, 0.01 inches, 0.004 inches, or 0.002 inches. While the elongated conductive body is shown as having a circular or substantially circular cross-section in some examples, in other examples the cross-section of the elongated conductive body is ovoid, rectangular, triangular, polyhedral, star-shaped, C-shaped, T-shaped, X-shaped, Y-Shaped, irregular, or the like. In examples, a conductive wire electrode is employed as a core. To such a clad electrode, two additional conducting layers may be added (e.g., with intervening insulating layers provided for electrical isolation). The conductive layers can be comprised of any suitable material. In certain examples, it can be desirable to employ a conductive layer comprising conductive particles (i.e., particles of a conductive material) in a polymer or other binder. In other examples, the conductive body can be configured in a linear or planar arrangement, e.g., on a generally flat surface or substrate.

[0248] In addition to providing structural support, resiliency and flexibility, in some examples, the core (or a component thereof) provides electrical conduction for an electrical signal from the working electrode to sensor electronics (not shown), which are described elsewhere herein. In some examples, the core comprises a conductive material, such as titanium, stainless steel, tantalum, nitinol, a conductive polymer, and / or the like. However, inAttorney Docket No. 0981-PCT01other examples, the core is formed from a non-conductive material, such as a non-conductive polymer. In yet other examples, the core comprises a plurality of layers of materials. For example, in examples the core includes an inner core and an outer core. In a further example, the inner core is formed of a first conductive material and the outer core is formed of a second conductive material. For example, in some examples, the first conductive material is stainless steel, titanium, tantalum, platinum, a platinum-iridium alloy, a conductive polymer, an alloy, and / or the like, and the second conductive material is conductive material selected to provide electrical conduction between the core and the first layer, and / or to attach the first layer to the core (e.g., if the first layer is formed of a material that does not attach well to the core material). In another example, the core is formed of a non-conductive material (e.g., a non-conductive metal and / or a non-conductive polymer) and the first layer is a conductive material, such as titanium, stainless steel, tantalum, nitinol, a conductive polymer, and / or the like. The core and the first layer can be of a single (or same) material, e.g., platinum. One skilled in the art appreciates that additional configurations are possible.

[0249] In some examples, the first layer is formed of a conductive material. The working electrode is an exposed portion of the surface of the first layer. Accordingly, the first layer is formed of a material configured to provide a suitable electroactive surface for the working electrode, a material such as but not limited to platinum, platinum-iridium, gold, palladium, iridium, nitinol, graphite, a ternary metal oxide composite, carbon, a conductive polymer, an alloy and / or the like.

[0250] In some example, second layer surrounds a least a portion of the first layer, thereby defining the boundaries of the working electrode. In some examples, the second layer serves as an insulator and is formed of an insulating material, such as polyimide, polyurethane, parylene, or any other known insulating materials, for example, fluorinated polymers, polyethylene terephthalate, polyurethane, polyimide, liquid crystal polymer, other nonconducting polymers, or the like. Glass or ceramic materials can also be employed. Other materials suitable for use include surface energy modified coating systems such as are marketed under the trade names AMC18, AMC148, AMC141, and AMC321 by Advanced Materials Components Express of Bellafonte, Pa. In some alternative examples, however, the working electrode does not require a coating of insulator.

[0251] In some examples, the second layer is disposed on the first layer and configured such that the working electrode is exposed via window. In another example, an elongated conductive body, including the core, the first layer and the second layer, is provided, and theAttorney Docket No. 0981-PCT01working electrode is exposed (i.e., formed) by removing a portion of the second layer, thereby forming the window through which the electroactive surface of the working electrode (e.g., the exposed surface of the first layer) is exposed. In some examples, the working electrode is exposed by (e.g., window is formed by) removing a portion of the second and (optionally) third layers. Removal of coating materials from one or more layers of elongated conductive body (e.g., to expose the electroactive surface of the working electrode) can be performed by hand, excimer lasing, chemical etching, laser ablation, grit-blasting, or the like.

[0252] In some examples, the sensor further comprises a third layer comprising a conductive material. In further examples, the third layer comprises a reference electrode, which is formed of a silver-containing material that is applied onto the second layer (e.g., an insulator). The silver-containing material can include any of a variety of materials and be in various forms, such as, Ag / AgCl-polymer pastes, paints, polymer-based conducting mixture, and / or inks that are commercially available, for example. The third layer can be processed using a pasting / dipping / coating step, for example, using a die-metered dip coating process. In one exemplary example, an Ag / AgCl polymer paste is applied to an elongated body by dipcoating the body (e.g., using a meniscus coating technique) and then drawing the body through a die to meter the coating to a precise thickness. In some examples, multiple coating steps are used to build up the coating to a predetermined thickness.

[0253] In some examples, the silver grain in the Ag / AgCl solution or paste can have an average particle size corresponding to a maximum particle dimension that is less than about 100 microns, or less than about 50 microns, or less than about 30 microns, or less than about 20 microns, or less than about 10 microns, or less than about 5 microns. The silver chloride grain in the Ag / AgCl solution or paste can have an average particle size corresponding to a maximum particle dimension that is less than about 100 microns, or less than about 80 microns, or less than about 60 microns, or less than about 50 microns, or less than about 20 microns, or less than about 10 microns. The silver grain and the silver chloride grain can be incorporated at a ratio of the silver chloride graimsilver grain of from about 0.01:1 to 2:1 by weight, or from about 0.1 : 1 to 1:1. The silver grains and the silver chloride grains are then mixed with a carrier (e.g., a polyurethane) to form a solution or paste. In certain examples, the Ag / AgCl component form from about 10% to about 65% by weight of the total Ag / AgCl solution or paste, or from about 20% to about 50%, or from about 23% to about 37%. In some examples, the Ag / AgCl solution or paste has a viscosity (under ambient conditions) that is from about 1 to about 500 centipoise, or from about 10 to about 300 centipoise, of from about 50 to about 150 centipoise.Attorney Docket No. 0981-PCT01

[0254] In examples, the above-exemplified sensor has an overall diameter of not more than about 0.20 inches (about 0.51 mm), more preferably not more than about 0.18 inches (about 0.46 mm), and most preferably not more than about 0.16 inches (0.41 mm). In some examples, the working electrode has a diameter of from about 0.001 inches or less to about 0.10 inches or more, preferably from about 0.002 inches to about 0.008 inches, and more preferably from about 0.004 inches to about 0.005 inches. The length of the window can be from about 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.78 inches) or more, and preferably from about 0.5 mm (about 0.2 inches) to about 0.75 mm (0.3 inches). In such examples, the exposed surface area of the working electrode is preferably from about 0.000013 in2 (0.0000839 cm2) or less to about 0.0025 in2(0.016129 cm2) or more (assuming a diameter of from about 0.001 inches to about 0.10 inches and a length of from about 0.004 inches to about 0.78 inches). The exposed surface area of the working electrode is selected to produce an analyte signal with a current in the femtoampere range, picoampere range, the nanoampere range, the or the microampere range such as is described in more detail elsewhere herein. However, a current in the picoampere range or less can be dependent upon a variety of factors, for example the electronic circuitry design (e.g., sample rate, current draw, A / D converter bit resolution, etc.), the membrane system (e.g., permeability of the analyte through the membrane system), and the exposed surface area of the working electrode. Accordingly, the exposed electroactive working electrode surface area can be selected to have a value greater than or less than the abovedescribed ranges taking into consideration alterations in the membrane system and / or electronic circuitry. In examples of a fructosamine sensor, it can be advantageous to minimize the surface area of the working electrode while maximizing the diffusivity of fructosamine in order to optimize the signal-to-noise ratio while maintaining sensor performance in both high and low fructosamine concentration ranges.

[0255] In some alternative examples, the exposed surface area of the working (and / or other) electrode can be increased by altering the cross-section of the electrode itself. For example, in some examples the cross-section of the working electrode can be defined by a cross, star, cloverleaf, ribbed, dimpled, ridged, irregular, or other non-circular configuration; thus, for any predetermined length of electrode, a specific increased surface area can be achieved (as compared to the area achieved by a circular cross-section). Increasing the surface area of the working electrode can be advantageous in providing an increased signal responsive to the concentration of an analyte, which in turn can be helpful in improving the signal-to-noise ratio, for example.Attorney Docket No. 0981-PCT01

[0256] In some examples, the elongated conductive body further comprises one or more intermediate layers located between the core and the first layer. For example, in some examples, the intermediate layer is an insulator, a conductor, a polymer, and / or an adhesive.

[0257] In certain example, the core comprises a non-conductive polymer and the first layer comprises a conductive material. Such a sensor configuration can sometimes provide reduced material costs, in that it replaces a typically expensive material with an inexpensive material. For example, in some examples, the core is formed of a non-conductive polymer, such as, a nylon or polyester filament, string or cord, which can be coated and / or plated with a conductive material, such as platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, a conductive polymer, and allows or combinations thereof.Membrane Systems

[0258] In some examples, the sensor also includes a membrane covering at least a portion of the working electrode. Membranes are discussed in detail in greater detail elsewhere herein.

[0259] Exemplary sensor configurations can be applied to any planar or non-planar surface, for example. In another example, the sensor system has additional electrodes arranged as one or more concentric substantially ring-shaped electrodes, or rows or arrays of electrodes on a planar or substantially planar substrate.

[0260] As discussed herein, in some examples, the membrane system includes a bioprotective domain, also referred to as a cell-impermeable domain or biointerface domain, comprising a surface-modified base polymer as described in more detail elsewhere herein. In some examples, a unitary diffusion resistance domain and bioprotective domain can be included in the membrane system (e.g., wherein the functionality of both domains is incorporated into one domain, i.e., the bioprotective domain). In some examples, the sensor is configured for implantation from about 1 to 30 days). However, it is understood that the membrane system can be modified for use in other devices, for example, by including only one or more of the domains, or additional domains.

[0261] In some examples, the membrane system can include an electrode domain. The electrode domain is provided to ensure that an electrochemical reaction occurs between the electroactive surfaces of the working electrode and the reference electrode, and thus the electrode domain can be situated more proximal to the electroactive surfaces than the interference and / or enzyme domain. The electrode domain can include a coating that maintains a layer of water at the electrochemically reactive surfaces of the sensor. In other words, theAttorney Docket No. 0981-PCT01electrode domain can be present to provide an environment between the surfaces of the working electrode and the reference electrode, which facilitates an electrochemical reaction between the electrodes.

[0262] A wide variety of configurations and combinations for the various layers in the membrane system are encompassed by the examples. In various examples, any of the domains described herein can be omitted, altered, substituted for, and / or incorporated together without departing from the spirit of the preferred examples. It is to be understood that sensing membranes modified for other sensors, for example, can include fewer or additional layers. For example, in some examples, the membrane system can comprise one electrode layer, one enzyme layer, and two bioprotective layers, but in other examples, the membrane system can comprise one electrode layer, two enzyme layers, and one bioprotective layer. In some examples, the bioprotective layer can be configured to function as the diffusion resistance domain and control the flux of the analyte (e.g., fructosamine) to the underlying membrane layers.

[0263] In some examples, a sensing membrane comprising one or more domains of polymeric membranes can be formed from materials such as polytetrafluoroethylene, silicone, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyurethanes, cellulosic polymers, polyethylene oxide), polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers.

[0264] In examples, a sensing membrane is disposed over the electroactive surfaces of the continuous transcutaneous analyte sensor and includes one or more domains or layers of a membrane system. In general, the sensing membrane functions to control the flux of a biological fluid there through and / or to protect sensitive regions of the sensor from contamination by the biological fluid, for example. Some conventional electrochemical enzyme-based analyte sensors generally include a sensing membrane that controls the flux of the analyte being measured, protects the electrodes from contamination of the biological fluid, and / or provides an enzyme that catalyzes the reaction of the analyte with a co-factor, for example. See, e.g., U.S. Patent Publication No. 2005-0245799A1 and U.S. Pat. No. 7,497,827, which are incorporated herein by reference in their entirety.Attorney Docket No. 0981-PCT01

[0265] The sensing membranes of the present disclosure can include any membrane configuration suitable for use with any analyte sensor (such as described in more detail above). In general, the sensing membranes of the present disclosure include one or more domains, all or some of which can be adhered to or deposited on the analyte sensor as is appreciated by one skilled in the art. In examples, the sensing membrane generally provides one or more of the following functions: 1) protection of the exposed electrode surface from the biological environment, 2) diffusion resistance (limitation) of the analyte, 3) a catalyst for enabling an enzymatic reaction, 4) limitation or blocking of interfering species, and 5) hydrophilicity at the electrochemically reactive surfaces of the sensor interface, such as described in the abovereferenced U.S. patents and patent publications.

[0266] In some examples, one or more domains of the membranes are formed from materials such as silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyurethanes, cellulosic polymers, polyethylene oxide), polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers. U.S. Patent Publication No. 2005-0245799A1, which is incorporated herein by reference in its entirety, describes biointerface and sensing membrane configurations and materials that can be applied to the presently disclosed sensor.Electrode Domain

[0267] In some examples, the membrane system comprises an optional electrode domain. The electrode domain is provided to ensure that an electrochemical reaction occurs between the electroactive surfaces of the working electrode and the reference electrode, and thus the electrode domain is preferably situated more proximal to the electroactive surfaces than the enzyme domain. Preferably, the electrode domain includes a semipermeable coating that maintains a layer of water at the electrochemically reactive surfaces of the sensor, for example, a humectant in a binder material can be employed as an electrode domain; this allows for the full transport of ions in the aqueous environment. The electrode domain can also assist in stabilizing the operation of the sensor by overcoming electrode start-up and drifting problemsAttorney Docket No. 0981-PCT01caused by inadequate electrolyte. The material that forms the electrode domain can also protect against pH-mediated damage that can result from the formation of a large pH gradient due to the electrochemical activity of the electrodes.

[0268] In examples, the electrode domain includes a flexible, water- swellable, hydrogel film having a “dry film” thickness of from about 0.5 micron or less to about 20 microns or more, more preferably from about 0.5, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. “Dry film” thickness refers to the thickness of a cured film cast from a coating formulation by standard coating techniques.

[0269] In certain examples, the electrode domain is formed of a curable mixture of a urethane polymer and a hydrophilic polymer. Particularly preferred coatings are formed of a polyurethane polymer having carboxylate functional groups and non-ionic hydrophilic polyether segments, wherein the polyurethane polymer is crosslinked with a water soluble carbodiimide (e.g., l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC))) in the presence of polyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

[0270] Preferably, the electrode domain is deposited by spray or dip-coating the electroactive surfaces of the sensor. More preferably, the electrode domain is formed by dipcoating the electroactive surfaces in an electrode solution and curing the domain for a time of from about 15 to about 30 minutes at a temperature of from about 40 to about 55° C. (and can be accomplished under vacuum (e.g., 20 to 30 mmHg)). In examples wherein dip-coating is used to deposit the electrode domain, a preferred insertion rate of from about 1 to about 3 inches per minute, with a preferred dwell time of from about 0.5 to about 2 minutes, and a preferred withdrawal rate of from about 0.25 to about 2 inches per minute provide a functional coating. However, values outside of those set forth above can be acceptable or even desirable in certain examples, for example, dependent upon viscosity and surface tension as is appreciated by one skilled in the art. In examples, the electroactive surfaces of the electrode system are dip-coated one time (one layer) and cured at 50° C. under vacuum for 20 minutes.

[0271] Although an independent electrode domain is described herein, in some examples, sufficient hydrophilicity can be provided in the interference domain and / or enzyme domain (the domain adjacent to the electroactive surfaces) so as to provide for the full transport of ions in the aqueous environment (e.g. without a distinct electrode domain).Attorney Docket No. 0981-PCT01Interference Domain

[0272] In some examples, an optional interference domain is provided, which generally includes a polymer domain that restricts the flow of one or more interferants. In some examples, the interference domain functions as a molecular sieve that allows analytes and other substances that are to be measured by the electrodes to pass through, while preventing passage of other substances, including interferants such as ascorbate and urea (see U.S. Pat. No.6,001,67 to Shults). Some known interferants are caffeic acid, dopamine, L-tyrosine, 3-o-methyldopa, L- alpha- methyldopa, homocysteine, carbidopa, cresols (e.g., m-cresol, an insulin preservative), parabens (drug preservatives), and the like.

[0273] Several polymer types that can be utilized as a base material for the interference domain include polyurethanes, polymers having pendant ionic groups, and polymers having controlled pore size, for example. In some examples, the interference domain includes a thin, hydrophobic membrane that is non-swellable and restricts diffusion of low molecular weight species. The interference domain is permeable to relatively low molecular weight substances but restricts the passage of higher molecular weight substances. Other systems and methods for reducing or eliminating interference species that can be applied to the membrane system of the present disclosure are described in U.S. Pat. No. 7,816,004, U.S. Patent Publication No. 2005-0176136A1, U.S. Pat. No. 7,81,195, and U.S. Pat. No. 7,715,893. In some alternative examples, a distinct interference domain is not included.

[0274] In examples, the interference domain is deposited onto the electrode domain (or directly onto the electroactive surfaces when a distinct electrode domain is not included) for a domain thickness of from about 0.5 micron or less to about 20 microns or more, more preferably from about 0.5, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. Unfortunately, the thin thickness of the interference domains conventionally used can introduce variability in the membrane system processing. For example, if too much or too little interference domain is incorporated within a membrane system, the performance of the membrane can be adversely affected.Enzyme Domain

[0275] In some examples, the membrane system further includes an enzyme domain disposed more distally from the electroactive surfaces than the interference domain (orAttorney Docket No. 0981-PCT01electrode domain when a distinct interference is not included). In some examples, the enzyme domain is directly deposited onto the electroactive surfaces (when neither an electrode or interference domain is included). In other representative examples, the enzyme domain is deposited on the surface of an interference domain. In examples, the enzyme domain provides an enzyme to catalyze the reaction of the analyte and its co-reactant, as described in more detail below. Preferably, the enzyme domain includes polyphenol oxidase.

[0276] For an enzyme-based electrochemical fructosamine sensor to perform well, the sensor's response is preferably limited by neither enzyme activity nor co-reactant concentration. Because enzymes, including polyphenol oxidase, are subject to deactivation as a function of time even in ambient conditions, this behavior is compensated for in forming the enzyme domain. Preferably, the enzyme domain is constructed of aqueous dispersions of colloidal polyurethane polymers including the enzyme. However, in alternative examples the enzyme domain is constructed from materials with oxygen-enhancing performance, or high oxygen solubility, for example, silicone, or fluorocarbon, in order to provide a supply of excess oxygen during transient ischemia. Preferably, the enzyme is immobilized within the domain. See U.S. Pat. No. 7,379,765.

[0277] In examples, the enzyme domain is deposited onto the interference domain for a domain thickness of from about 0.5 micron or less to about 20 microns or more, more preferably from about 0.5, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. However, in some examples, the enzyme domain is deposited onto the electrode domain or directly onto the electroactive surfaces. Preferably, the enzyme domain is deposited by spray or dip coating. More preferably, the enzyme domain is formed by dip-coating the electrode domain into an enzyme domain solution and curing the domain for from about 15 to about 30 minutes at a temperature of from about 40 to about 55° C. (and can be accomplished under vacuum (e.g., 20 to 30 mmHg)). In examples wherein dip-coating is used to deposit the enzyme domain at room temperature, a preferred insertion rate of from about 1 inch per minute to about 3 inches per minute, with a preferred dwell time of from about 0.5 minutes to about 2 minutes, and a preferred withdrawal rate of from about 0.25 inch per minute to about 2 inches per minute provide a functional coating. However, values outside of those set forth above can be acceptable or even desirable in certain examples, for example, dependent upon viscosity and surface tension as is appreciated by one skilled in the art. In examples, the enzyme domain isAttorney Docket No. 0981-PCT01formed by dip coating two times (namely, forming two layers) in a coating solution and curing at 50° C. under vacuum for 20 minutes. However, in some examples, the enzyme domain can be formed by dip-coating and / or spray-coating one or more layers at a predetermined concentration of the coating solution, insertion rate, dwell time, withdrawal rate, and / or desired thickness.Resistance Domain

[0278] In examples, the membrane system includes a resistance domain disposed more distal from the electroactive surfaces than the enzyme domain. Although the following description is directed to a resistance domain for a fructosamine sensor, the resistance domain can be modified for other analytes and co-reactants as well.

[0279] The resistance domain includes a semi-permeable membrane that controls the flux of fructosamine to the underlying enzyme domain, preferably rendering oxygen in a non-ratelimiting excess. As a result, the upper limit of linearity of fructosamine measurement is extended to a much higher value than that which is achieved without the resistance domain. In examples, the resistance domain exhibits an oxygen to fructosamine permeability ratio such that one-dimensional reactant diffusion is adequate to provide excess oxygen at all reasonable fructosamine and oxygen concentrations found in the subcutaneous matrix.

[0280] In alternative examples, a lower ratio of oxygen-to-fructosamine can be sufficient to provide excess oxygen by using a high oxygen solubility domain (for example, a silicone or fluorocarbon-based material or domain) to enhance the supply / transport of oxygen to the enzyme domain. If more oxygen is supplied to the enzyme, then more fructosamine can also be supplied to the enzyme without creating an oxygen rate-limiting excess. In alternative examples, the resistance domain is formed from a silicone composition, such as is described in U.S. Patent Publication No. US 2005 / 0090607 filed Oct. 28, 2003 and entitled, “SILICONE COMPOSITION FOR BIOCOMPATIBLE MEMBRANE.”

[0281] In some examples, the presently disclosed continuous fructosamine monitoring (CFM) sensor includes a resistance domain to control the diffusion of fructosamine and oxygen to the CFM sensor, fabricated easily and reproducibly from commercially available materials. A suitable resistance domain component is a polyurethane or polyurethaneurea (hereinafter, collectively referred to as “PU”) which can be a thermoplastic polyurethane or polyurethaneurea or blend thereof. Polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a difunctional hydroxyl-containing material. A polyurethaneureaAttorney Docket No. 0981-PCT01is a polymer produced by the condensation reaction of a diisocyanate and a difunctional amine-containing material. Exemplary diisocyanates include aliphatic diisocyanates containing from about 4 to about 8 methylene units. Diisocyanates containing cycloaliphatic moieties can also be useful in the preparation of the polymer and copolymer components of the membranes of the present disclosure.

[0282] In some examples, a PU polymer is provided with a hard segment and a soft segment, where the soft segment comprises two or more polycarbonate segments, polydimethylsiloxane segments, and polyalkyene oxide segments. In examples, a PU polymer is provided with a hard segment of about 35-45 weight percent, and a soft segment (remainder weight percent + up to 10 weight percent chain extender), where the soft segment comprises two or more polycarbonate segments, polydimethylsiloxane segments, and polyalkyene oxide segments. In examples, the soft segment comprises 35-45 weight percent polycarbonate segments and 15-20 weight percent poly dimethylsiloxane segments, the remainder weight percent being hard segment and chain extender. In other examples, the soft segment comprises 35-45 weight percent polyakylene segments and 15-20 weight percent polydimethylsiloxane segments the remainder weight percent being hard segment and chain extender. In other examples, the soft segment comprises 35-45 weight percent total of both polyakylene segments and polycarbonate segments, and 15-20 weight percent polydimethylsiloxane segments the remainder weight percent being hard segment and chain extender. In examples, the polyalkylene segment comprises poly(tetramethylene oxide) (PTMO). In examples, PU polymer is provided with a hard segment and a soft segment, where the soft segment comprises two or more polycarbonate segments, polydimethylsiloxane segments, and polyalkyene oxide segments blended with a polyvinylpyrrolidone (PVP).

[0283] In some examples, a diffusion resistance layer (RL) of the presently disclosed CFM includes the aforementioned PU polymer and / or PU polymer-PVP blend that provides stable, predicable fructosamine and oxygen permeation and blocks at least some interfering agents. It will be appreciated that the hard / soft segment chemical composition, weight percentage of hard / soft segment, topology and block length distribution will impact the RL phase separation, hard segment / soft segment interaction, fructosamine permeability, solubility of RL formulation for coating / dispensing and drying / curing processes and thus, influence sensor performance and stability.

[0284] In other examples, materials that forms the basis of the matrix of the resistance domain can be any of those known in the art as appropriate for use as membranes in sensorAttorney Docket No. 0981-PCT01devices and as having sufficient permeability to allow relevant compounds to pass through it, for example, to allow fructosamine to pass through the membrane from the sample under examination in order to reach the active enzyme or electrochemical electrodes. Examples of materials which can be used to make non-polyurethane type membranes include vinyl polymers, poly ethers, polyesters, polyamides, inorganic polymers such as poly siloxanes and polycarbosiloxanes, natural polymers such as cellulosic and protein-based materials, poly(vinyl alcohol)-quatemized stilbazol (PVA-SbQ), and mixtures or combinations thereof.

[0285] In some examples, the resistance domain is deposited onto the enzyme domain to yield a domain thickness from about 0.5 micron or less to about 20 microns or more, more preferably from about 0.5, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. Preferably, the resistance domain is deposited onto the enzyme domain by spray coating or dip coating. In certain examples, spray coating is the preferred deposition technique. The spraying process atomizes and mists the solution, and therefore most or all of the solvent is evaporated prior to the coating material settling on the underlying domain, thereby minimizing contact of the solvent with the enzyme.

[0286] In examples, the resistance domain is deposited on the enzyme domain by spraycoating a solution of from about 1 wt. % to about 5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent. In spraying a solution of resistance domain material, including a solvent, onto the enzyme domain, it is desirable to mitigate or substantially reduce any contact with enzyme of any solvent in the spray solution that can deactivate the underlying enzyme of the enzyme domain. Tetrahydrofuran (THF) is one solvent that minimally or negligibly affects the enzyme of the enzyme domain upon spraying. Other solvents can also be suitable for use, as is appreciated by one skilled in the art.

[0287] Although a variety of spraying or deposition techniques can be used, spraying the resistance domain material and rotating the sensor at least one time by 180° can provide adequate coverage by the resistance domain. Spraying the resistance domain material and rotating the sensor at least two times by 120 degrees provides even greater coverage (one layer of 360° coverage), thereby ensuring resistivity to fructosamine, such as is described in more detail above.Attorney Docket No. 0981-PCT01

[0288] In examples, the resistance domain is spray-coated and subsequently cured for a time of from about 15 to about 90 minutes at a temperature of from about 40 to about 60° C. (and can be accomplished under vacuum (e.g., 20 to 30 mmHg)). A cure time of up to about 90 minutes or more can be advantageous to ensure complete drying of the resistance domain. While not wishing to be bound by theory, it is believed that complete drying of the resistance domain aids in stabilizing the sensitivity of the fructosamine sensor signal. It reduces drifting of the signal sensitivity over time, and complete drying is believed to stabilize performance of the fructosamine sensor signal in lower oxygen environments.

[0289] Advantageously, sensors with the membrane system described herein, including an electrode domain and / or interference domain, an enzyme domain, and a resistance domain, provide stable signal response to increasing fructosamine levels of from about 0 to about 1000 pmol, and sustained function (at least 90% signal strength) even at low oxygen levels (for example, at about 0.6 mg / L 02). While not wishing to be bound by theory, it is believed that the resistance domain provides sufficient resistivity, or the enzyme domain provides sufficient enzyme, such that oxygen limitations are seen at a much lower concentration of oxygen as compared to prior art sensors.

[0290] In examples, a sensor signal with a current in the picoampere range or less is provided, which is described in more detail elsewhere herein. However, the ability to produce a signal with a current in the picoampere range can be dependent upon a combination of factors, including the electronic circuitry design (e.g., A / D converter, bit resolution, and the like), the membrane system (e.g., permeability of the analyte through the resistance domain, enzyme concentration, and / or electrolyte availability to the electrochemical reaction at the electrodes), and the exposed surface area of the working electrode. For example, the resistance domain can be designed to be more or less restrictive to the analyte depending upon to the design of the electronic circuitry, membrane system, and / or exposed electroactive surface area of the working electrode.

[0291] Accordingly, in examples, the membrane system is designed with a sensitivity of from about 1 pA / pmol to about 100 pA / pmol, preferably from about 5 pA / pmol to 25 pA / pmol, and more preferably from about 4 to about 10 pA / pmol. While not wishing to be bound by any particular theory, it is believed that membrane systems designed with a sensitivity in the preferred ranges permit measurement of the analyte signal in low analyte and / or low oxygen situations. Namely, conventional analyte sensors have shown reduced measurement accuracy in low analyte ranges due to lower availability of the analyte to the sensor and / or have shownAttorney Docket No. 0981-PCT01increased signal noise in high analyte ranges due to insufficient oxygen necessary to react with the amount of analyte being measured. While not wishing to be bound by theory, it is believed that the membrane systems of the present disclosure, in combination with the electronic circuitry design and exposed electrochemical reactive surface area design, support measurement of the analyte in the picoampere range or less, which enables an improved level of resolution and accuracy in both low and high analyte ranges not seen in the prior art.

[0292] Because fructosamine is typically present in low concentrations (-200 -300 micromolar (pm), relative to other analytes (e.g., glucose, lactate, ketones: 1 -10 millimolar), the present device and method comprise one or more methods and / or techniques to improve signal transduction of fructosamine to a measurable current, for example, surface chemistry, amplification, and advanced electrochemistry techniques to extricate the fructosamine signal from the noise produced from the physiologic milieu. In examples, the electrode surface can be roughened by a few orders of magnitude to enhance the signal magnitude supported, given that signal should scale linearly with electrode surface area. In examples, alone or in combination with the above example, a redox mediator with high affinity to H2O2 may be employed to amplify the signal to detectable levels. In other examples, alone or in combination with the above examples, differential electrochemical waveforms, such as differential pulse voltammetry and square wave voltammetry, to enable subtraction of the background from the glycated protein signal are used. In other examples, alone or in combination with the above examples, chronocoulometry can also be performed to time-integrate an accumulated charge so as to boost the glycated protein signal. In other examples, alone or in combination with the above examples, multiple electrodes are used so as to provide a subtractable signal. In examples, at least one additional working electrode is provided comprising a membrane that is devoid of enzyme or a membrane containing a deactivated enzyme to perform differential sensing, allowing subtraction of background or common-mode noise. Examples of an additional electrodes that are blank or have deactivated enzyme are disclosed in co-assigned US-20210379370-A1.

[0293] In some examples, gated amperometric detection is used to provide greater interference tolerance and to amplify the signal produced by fructosamine detection. In some examples, an analyte sensor circuit can be recurrently turned off and turned back on. During a period in which the sensor is turned off, an analyte (e.g., fructosamine) continues to interact with a sensor enzyme, which develops a signal that can be sensed. For, when a sensor circuit is off, fructosamine continues to react with fructosamine 6-kinase enzyme to produceAttorney Docket No. 0981-PCT01fructosamine 6-phosphate, which accumulates. When the sensor circuit is turned on, the accumulated fructosamine 6-phosphate creates a much stronger signal than occurs without accumulation. Importantly, some interference materials do not exhibit such an accumulation effect, so the signal-to-noise (or background or interference) ratio is improved. Thus, while the presence of interference materials can cause an error in a fructosamine sensor estimate (because the interference material(s) impacts the raw signal observed from the sensor), the impact of interference material(s) can be reduced by gating the analyte sensor circuit to increase the signal-to-noise ratio between the fructosamine signal and the interfering material.Gated Amperometric Detection

[0294] In humans, serum levels of glycated protein (e.g. glycated albumin, glycated HbAlc, and fructosamine) are in the micromolar range (pM). Thus, monitoring of glycated albumin, glycated HbAlc, and fructosamine levels), e.g., by continuous or semi-continuous monitoring, is useful for providing health information to a user or health care provider. The concentration of glycated albumin and glycated HbAlc present about the sensing membrane is low, e.g., below 1 millimolar (mM). Thus, methods of detecting and utilizing low signals therefrom is provided in the present disclosure.

[0295] In some examples, an analyte sensor circuit may be recurrently turned off and turned back on. During a period in which the sensor is turned off, an analyte (e.g., glycated protein) continues to interact with a sensor enzyme, which develops a signal that may be sensed. For, when a sensor circuit is off, glycated protein continues to react with hydroxysteroid dehydrogenase enzyme to indirectly produce hydrogen peroxide, which accumulates. When the sensor circuit is turned on, the accumulated hydrogen peroxide creates a much stronger signal than occurs without accumulation. Importantly, some interference materials, such as uric acid and acetaminophen, do not exhibit such an accumulation effect, so the signal-to-noise (or background or interference) ratio is improved. Thus, while the presence of acetaminophen (or other interference materials) may cause an error in a glycated protein sensor estimate (because the acetaminophen impacts the raw signal observed from the sensor), the impact of acetaminophen may be reduced by gating the analyte sensor circuit to increase the signal-to-noise ratio between the glycated protein signal and the interfering material.

[0296] Gating the sensor circuit can be used alone or in combination with one or interference layers as disclosed and discussed herein. With reference to FIG. 10A, a schematic illustration of various example electronic components that may be part of a medical deviceAttorney Docket No. 0981-PCT01system 200. In an example, the system 200 may include sensor electronics 105 and a base 290. While a specific example of division of components between the base 290 and sensor electronics 105 is shown, it is understood that some examples may include additional components in the base 290 or in the sensor electronics 105, and that some of the components (e.g., a battery or supercapacitor) that are shown in the sensor electronics 105 may be alternatively or additionally (e.g., redundantly) provided in the base 290.

[0297] In examples, the base 290 may include the analyte sensor 34 and a battery 292. In some examples, the base 290 may be replaceable, and the sensor electronics 105 may include a debouncing circuit (e.g., gate with hysteresis or delay) to avoid, for example, recurrent execution of a power-up or power down process when a battery is repeatedly connected and disconnected or avoid processing of noise signal associated with removal or replacement of a battery.

[0298] The sensor electronics 105 may include electronics components that are configured to process sensor information, such as sensor data, and generate transformed sensor data and displayable sensor information. The sensor electronics 105 may, for example, include electronic circuitry associated with measuring, processing, storing, or communicating continuous analyte sensor data, including prospective algorithms associated with processing and calibration of the sensor data. The sensor electronics 105 may include hardware, firmware, and / or software that enables measurement of levels of the analyte via a glucose sensor. Electronic components may be affixed to a printed circuit board (PCB), or the like, and can take a variety of forms. For example, the electronic components may take the form of an integrated circuit (IC), such as an Application-Specific Integrated Circuit (ASIC), a microcontroller, and / or a processor.

[0299] As shown in FIG. 10A, the sensor electronics 105 may include a measurement circuit 203 (e.g., potentiostat), which may be coupled to the analyte sensor 34 and configured to recurrently obtain analyte sensor readings using the analyte sensor 34, for example by continuously or recurrently measuring a current flow indicative of analyte concentration. The sensor electronics 105 may include a gate circuit 294, which may be used to gate the connection between the measurement circuit 203 and the analyte sensor 34. In an example, the analyte sensor 34 accumulates charge over an accumulation period, and the gate circuit 294 is opened so that the measurement circuit 203 can measure the accumulated charge. Gating the analyte sensor 34 may improve the performance of the sensor system by creating a larger signal to noise or interference ratio (e.g., because charge accumulates from an analyte reaction, butAttorney Docket No. 0981-PCT01sources of interference, such as the presence of acetaminophen near a glucose sensor, do not accumulate, or accumulate less than the charge from the analyte reaction). The sensor electronics 105 may also include a processor 201, which may retrieve instructions 207 from memory 209 and execute the instructions 207 to determine control application of bias potentials to the analyte sensor 34 via the potentiostat, interpret signals from the sensor 34, or compensate for environmental factors. The processor 201 may also save information in data storage memory 209 or retrieve information from data storage memory 209. In various examples, data storage memory 209 may be integrated with memory 209, or may be a separate memory circuit, such as a non-volatile memory circuit (e.g., flash RAM). Examples of systems and methods for processing sensor analyte data are described in more detail herein and in U.S. Pat. Nos.7,310,544 and 6,931,327.

[0300] In other examples, voltammetry is used to augment the signal-to-noise characteristic of the obtained signal. In this case, a time-varying potential is applied to the sensor and the corresponding current is measured. Voltammetry may comprise linear sweep voltammetry, cyclic voltammetry, differential pulse voltammetry, and square-wave voltammetry. Examples of gated amperometry, for continuous analyte monitoring, are disclosed in co-assigned U.S. Patent No. 12029560, which is incorporated herein by reference.

[0301] FIG. 10B shows prophetic current plotted against fructosamine concentration for a continuous glycated protein sensor. Data points measured for a sensor using gated amperometry and normal (non-gated) amperometry across a range of fructosamine concentrations is approximated. The data is expected to show a larger current response (which may be detected by an analyte sensor system) for gated amperometry than for normal amperometry. The data for normal amperometry is expected to show a linear relationship between current and glycated protein concentration, indicated by line 1002. The data for gated amperometry also is expected to show a linear relationship between current and fructosamine concentration (indicated by line 1004), but the slope may be steeper, and the values higher for gated amperometry. The steeper slope may allow for more effective differentiation between fructosamine concentration levels.

[0302] A baseline analyte concentration is a concentration of analyte (fructosamine in this example) corresponding to a zero level of current at the analyte sensor. The presently disclosed methods using gated amperometry methods described herein can result in a relatively constant baseline concentration after about 0.1 hours, 0.5 hours, 1 hours, or 2 hours.Attorney Docket No. 0981-PCT01

[0303] In examples, a sensor signal has a current in the picoAmp range, which is described in more detail elsewhere herein. However, the ability to produce a signal with a current in the picoAmp range can be dependent upon a combination of factors, including the electronic circuitry design (e.g., A / D converter, bit resolution, and the like), the membrane system (e.g., permeability of the analyte through the resistance domain, enzyme concentration, and / or electrolyte availability to the electrochemical reaction at the electrodes), and the exposed surface area of the working electrode. For example, the resistance domain can be designed to be more or less restrictive to the analyte depending upon to the design of the electronic circuitry, membrane system, and / or exposed electroactive surface area of the working electrode.

[0304] Accordingly, in one example, the membrane system is designed with a sensitivity of from about 1 pA / pM to about 100 pA / pM. In other examples, the sensitivity is from about 5 pA / pM to 25 pA / pM. In further examples, the sensitivity is from about 4 to about 7 pA / pM. While not wishing to be bound by any particular theory, it is believed that membrane systems designed with a sensitivity in the above ranges permit measurement of the analyte signal in low analyte and / or low oxygen situations. Namely, conventional analyte sensors have shown reduced measurement accuracy in low analyte ranges due to lower availability of the analyte to the sensor and / or have shown increased signal noise in high analyte ranges due to insufficient oxygen necessary to react with the amount of analyte being measured. While not wishing to be bound by theory, it is believed that the membrane systems of the present disclosure, in combination with the electronic circuitry design and exposed electrochemical reactive surface area design, support measurement of the analyte in the picoAmp range, which enables an improved level of resolution and accuracy in both low and high analyte ranges not seen in the prior art.

[0305] In examples, sampling rates of glycated protein is performed by the device at constant or random intervals. In examples, sampling rates of glycated protein is performed by the device at 1 / sec, 1 / min, 1 / 5 min, or longer. In examples, averaging samples is used to derive and provide a single measure with greater confidence over a given time period. In examples, a sampling bit resolution is chosen corresponding to a maximum peak-to-peak signal at an applied voltage to provide a reliable and accurate signal. In examples, a sampling bit resolution is 12 bit, 16 bit or more.

[0306] In examples, the disclosed device is configured to measure and provide continuous estimated glycated serum protein values. In examples, the disclosed device is configured toAttorney Docket No. 0981-PCT01measure and provide “trending” data and / or present to a user rate-of-change metrics alone or in combination with measured and / estimated glycated serum protein values. In examples, the disclosed device measures two or more analytes, at least one is continuously monitored, e.g., glucose, and the device is further configured to measure and provide to a user a single glycated serum protein value over a longer time duration, e.g., each day, once per week, or once over the duration of the device’s intended use.Interference-Free Membrane Systems

[0307] In general, it is believed that appropriate solvents and / or deposition methods can be chosen for one or more of the domains of the membrane system that form one or more transitional domains such that interferants do not substantially permeate there through. Thus, sensors can be built without distinct or deposited interference domains, which are non-responsive to interferants. While not wishing to be bound by theory, it is believed that a simplified multilayer membrane system, more robust multilayer manufacturing process, and reduced variability caused by the thickness and associated oxygen and fructosamine sensitivity of the deposited micron-thin interference domain can be provided.Biointerface Membrane / Layer

[0308] In examples, the sensor includes a porous material disposed over some portion thereof, which modifies the host's tissue response to the sensor. In some examples, the porous material surrounding the sensor advantageously enhances and extends sensor performance and lifetime by slowing or reducing cellular migration to the sensor and associated degradation that would otherwise be caused by cellular invasion if the sensor were directly exposed to the in vivo environment. Alternatively, the porous material can provide stabilization of the sensor via tissue ingrowth into the porous material in the long term. Suitable porous materials include silicone, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinyl alcohol (PVA), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyamides, polyurethanes, cellulosic polymers, polyethylene oxide), polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers, as well as metals, ceramics, cellulose, hydrogel polymers, poly(2-hydroxyethyl methacrylate,Attorney Docket No. 0981-PCT01pHEMA), hydroxyethyl methacrylate, (HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC), high density polyethylene, acrylic copolymers, nylon, polyvinyl difluoride, poly anhydrides, poly(l-lysine), poly(L-lactic acid), hydroxyethylmethacrylate, hydroxyapeptite, alumina, zirconia, carbon fiber, aluminum, calcium phosphate, titanium, titanium alloy, nitinol, stainless steel, and CoCr alloy, or the like, such as are described in U.S. Pat. No. 7,875,293 and U.S. Pat. No. 7,192,450.

[0309] In some examples, the porous material surrounding the sensor provides unique advantages in vivo (e.g., one to 14 days) that can be used to enhance and extend sensor performance and lifetime. However, such materials can also provide advantages in the long term too (e.g., greater than 14 days). Particularly, the in vivo portion of the sensor (the portion of the sensor that is implanted into the host's tissue) is encased (partially or fully) in a porous material. The porous material can be wrapped around the sensor (for example, by wrapping the porous material around the sensor or by inserting the sensor into a section of porous material sized to receive the sensor). Alternately, the porous material can be deposited on the sensor (for example, by electrospinning of a polymer directly thereon). In yet other alternative examples, the sensor is inserted into a selected section of porous biomaterial. Other methods for surrounding the in vivo portion of the sensor with a porous material can also be used as is appreciated by one skilled in the art.

[0310] The porous material surrounding the sensor advantageously slows or reduces cellular migration to the sensor and associated degradation that would otherwise be caused by cellular invasion if the sensor were directly exposed to the in vivo environment. Namely, the porous material provides a barrier that makes the migration of cells towards the sensor more tortuous and therefore slower. It is believed that this reduces or slows the sensitivity loss normally observed over time.

[0311] In examples wherein the porous material is a high oxygen solubility material, such as porous silicone, the high oxygen solubility porous material surrounds some of or the entire in vivo portion of the sensor. In some examples, a lower ratio of oxygen-to -fructo s amine can be sufficient to provide excess oxygen by using a high oxygen soluble domain (for example, a silicone-or fluorocarbon-based material) to enhance the supply / transport of oxygen to the enzyme membrane and / or electroactive surfaces. It is believed that some signal noise normally seen by a conventional sensor can be attributed to an oxygen deficit. Silicone has high oxygen permeability, thus promoting oxygen transport to the enzyme layer. By enhancing the oxygen supply through the use of a silicone composition, for example, fructosamine concentration canAttorney Docket No. 0981-PCT01be less of a limiting factor. In other words, if more oxygen is supplied to the enzyme and / or electroactive surfaces, then more fructosamine can also be supplied to the enzyme without creating an oxygen rate-limiting excess. While not being bound by any particular theory, it is believed that silicone materials provide enhanced bio-stability when compared to other polymeric materials such as polyurethane.

[0312] In examples, a biointerface layer, at least partially functioning as, or in combination with, a drug releasing membrane is used. The biointerface and / or drug releasing membrane may include, for example, materials including a hard- soft segment polymer with hydrophilic and optionally hydrophobic domains, all of which are described in more detail elsewhere herein, can be employed to improve sensor function in the long term (e.g., after tissue ingrowth). In examples, the materials including a hard-soft segment polymer with hydrophilic and optionally hydrophobic domains are configured to release a combination of a derivative form of dexamethasone or dexamethasone acetate with dexamethasone such that one or more different rates of release of the anti-inflammatory is achieved and the useful life of the sensor is extended. Other suitable drug releasing membranes of the present disclosure can be selected from silicone polymers, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polyurethane urea polymers and copolymers, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinyl alcohol (PVA), poly vinyl acetate, ethylene vinyl acetate (EVA), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyamides, and blends thereof, cellulosic polymers and copolymers and blends thereof, polyethylene oxide) and copolymers and blends thereof, polypropylene oxide) and copolymers and blends thereof, polysulfones and block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers cellulose, hydrogel polymers, poly(2-hydroxyethyl methacrylate, pHEMA) and copolymers and blends thereof, hydroxyethyl methacrylate, (HEMA) and copolymers and blends thereof, polyacrylonitrile-polyvinyl chloride (PAN-PVC) and copolymers and blends thereof, acrylic copolymers and copolymers and blends thereof, nylon and copolymers and blends thereof, polyvinyl difluoride, polyanhydrides, poly(l-lysine), poly(L-lactic acid), hydroxyethylmethacrylate and copolymers and blends thereof, and hydroxyapeptite and copolymers and blends thereof.Attorney Docket No. 0981-PCT01

[0313] In examples, the porous structure provides access for fructosamine permeation while allowing drug release / elute. In examples, as the bioactive agent releases / elutes from the porous structure, fructosamine transport can increase, for example, so as to offset any attenuation of fructosamine transport from the aforementioned immune response factors.

[0314] When used herein, the terms “membrane” and “matrix” are meant to be interchangeable. In these examples, the aforementioned porous material is a biointerface membrane comprising a first domain that includes an architecture, including cavity size, configuration, and / or overall thickness, that modifies the host's tissue response, for example, by creating a fluid pocket, encouraging vascularized tissue ingrowth, disrupting downward tissue contracture, resisting fibrous tissue growth adjacent to the device, and / or discouraging barrier cell formation. The biointerface membrane in examples covers at least the sensing mechanism of the sensor and can be of any shape or size, including uniform, asymmetrically, or axi-symmetrically covering or surrounding a sensing mechanism or sensor.

[0315] A second domain of the biointerface membrane is optionally provided that is impermeable to cells and / or cell processes. A bioactive agent is optionally provided that is incorporated into the at least one of the first domain, the second domain, the sensing membrane, or other part of the implantable device, wherein the bioactive agent is configured to modify a host tissue response. In examples, the biointerface includes a bioactive agent, the bioactive agent being incorporated into at least one of the first and second domains of the biointerface membrane, or into the device and adapted to diffuse through the first and / or second domains, in order to modify the tissue response of the host to the membrane.

[0316] Due to the small dimension(s) of the sensor (sensing mechanism) of the present disclosure, some conventional methods of porous membrane formation and / or porous membrane adhesion are inappropriate for the formation of the biointerface membrane onto the sensor as described herein. Accordingly, the following examples exemplify systems and methods for forming and / or adhering a biointerface membrane onto a small structured sensor as defined herein. For example, the biointerface membrane or release membrane of the present disclosure can be formed onto the sensor using techniques such as electrospinning, molding, weaving, direct-writing, lyophilizing, wrapping, and the like.

[0317] In examples wherein the biointerface is directly-written onto the sensor, a dispenser dispenses a polymer solution using a nozzle with a valve, or the like, for example as described in U.S. Publication No. 2004 / 0253365 Al. In general, a variety of nozzles and / or dispensersAttorney Docket No. 0981-PCT01can be used to dispense a polymeric material to form the woven or non-woven fibers of the biointerface membrane.Methods for Determining Fructosamine Levels from a Continuous Fructosamine Monitor

[0318] As described herein, the continuous analyte monitoring system 104 can comprise one or more single analyte sensors, and / or a multi-analyte sensor (e.g., glucose and fructosamine) in a co-axial or co-planar configuration. In certain embodiments, continuous analyte monitoring system 104 can monitor a patient’s fructosamine levels to determine measured fructosamine values for comparison with expected fructosamine values. In some examples, the continuous analyte monitoring system 104 can be further configured to sense potassium, creatinine, and / or 1,5 AG alone or in combination with fructosamine.

[0319] Generally, measured fructosamine levels can be generated based on the electrochemical detection of hydrogen peroxide (H202) at a suitably polarized noble metal (e.g., platinum, palladium, rhodium, iridium, etc.) electrode. Alternatively, a mediated system can be used where an organic or metal-center redox mediator can be employed to reduce the overpotential required to detect a redox current.

[0320] Glycated protein, for example, fructosamine can be monitored in a single step, single-enzyme reaction, with H2O2 as the detected product. In examples, the flavin adenine dinucleotide (FAD)-dependent enzyme is a thermally stable mutant fructosyl-amino acid oxidase enzyme with an amino acid substitution at T60A, A188G, M244L, N257S, L261M and combinations thereof. In examples, the enzyme is a flavin adenine dinucleotide (FAD)-dependent enzyme. In this example, the flavin adenine dinucleotide (FAD)-dependent enzyme is fructosamine oxidase (FAOx). FAOx catalyzes the oxidation of the C-N bond between the nitrogen and the amino portion of the fructosamine and the Cl of the fructosyl moiety. The resulting Schiff base is readily hydrolyzed to glucosone and an amino acid. After the catalytic cycle, the reduced FAD is oxidized by molecular oxygen with concomitant release of H2O2, which correlates with fructosamine concentration. This single-enzyme cascade for fructosamine detection is depicted in FIG. 11 A. Here, two protons and two electrons are transferred from fructosamine to the FAOx enzyme, yielding Schiff base as product and forming reduced FAD, also called FADH2. The FADH2-co-factor is then oxidized by molecular oxygen, yielding electrochemically detectable hydrogen peroxide with the subsequent regeneration of FAD. In the case of a mediator for FAOx enzyme, as depicted in FIG. 11B, this action is based on the regeneration of FAD after the oxidation of theAttorney Docket No. 0981-PCT01fructosamine substrate, which occurs when reduced FAD reacts with molecular oxygen. In the absence of oxygen, a direct electron transfer to an electrode can be completed between an oxidized mediator and reduced FAD. In examples, fructosamine oxidase (FAOx) present in one of one or more polymer layers. In examples, fructosamine oxidase (FAOx) is arranged in a stacked polymer layer configuration. In examples, the flavin adenine dinucleotide (FAD)-dependent enzyme is a thermally stable mutant fructosyl-amino acid oxidase enzyme with an amino acid substitution at T60A, A188G, M244L, N257S, L261M and combinations thereof. In examples, fructosamine oxidase (FAOx) is arranged on a first working electrode and a spatially separated second working electrode is configured for additional analyte detection, for example, glucose, ketone, lactate, alcohol, potassium or combinations thereof. Additional second working electrode can be independently controlled relative to the first working electrode.

[0321] Exemplary membrane constructions for the single-enzyme cascade for glycated protein detection using fructosamine as an example are shown in FIGs 12A and 12B. FIG.12A depicts a membrane construction including interference layer 156 adjacent working electrode (wire or electrodes 824, 825, 924, 925 previously discussed above) having fructosamine oxidase (FAOx) enzyme in polymer layer 151. Resistance layer 151 for modulating glycated protein is shown adjacent to polymer layer 151. In examples, one or more additional layers, including but not limited to a biointerface layer and / or drug releasing layer (e.g. anti-inflammatory, vasodilator) is deposited adjacent the resistance layer 152 (not shown.)

[0322] FIG. 12B depicts a membrane construction including a mediator layer 155 adjacent working electrode (wire or electrodes 824, 825, 924, 925 previously discussed above) having fructosamine oxidase (FAOx) enzyme in polymer layer 151. In examples, fructosamine oxidase (FAOx) enzyme is immobilized in polymer layer 151. In examples, immobilized includes, without limitation, physically entrapped in the polymer layer or covalently bound to the polymer layer. In examples, an interference layer (not shown) can be used adjacent mediator layer 155. In examples, an interferent layer can be excluded. Resistance layer 152, providing for modulating glycated protein through membrane, is shown adjacent to polymer layer 151. In examples, one or more additional layers, including but not limited to a biointerface layer and / or drug releasing layer (e.g. anti-inflammatory, vasodilator) is deposited adjacent the resistance layer 152 (not shown.)

[0323] Glycated protein levels, e.g., fructosamine levels can also be detected by a multianalyte or a single analyte sensor based on a multi-step, three-enzyme reaction cascade, againAttorney Docket No. 0981-PCT01with H2O2 as the detected product, as depicted in FIG. 13. In examples, three enzymes are used in a cascade, fructosamine 6-kinase (FN6K), pyruvate kinase, and pyruvate oxidase present in the sensing portion of the device. The measurement of fructosamine is based on the monitoring of the adenosine diphosphate (ADP) generated from adenosine triphosphate (ATP) by the FN6K-catalyzed phosphorylation of a glycated protein, for example, fructosamine. The generated ADP is subsequently subjected to sequential enzymatic reactions with pyruvate kinase and pyruvate oxidase. The quantity of H2O2 produced by pyruvate oxidase correlates with fructosamine concentration if the reaction cascade is designed such that the rate-limiting reactant is the glycated protein rather than oxygen.

[0324] Exemplary membrane constructions for the three-enzyme cascade for glycated protein detection using fructosamine as an example are shown in FIGs 13A and 13B. In examples, fructosamine 6-kinase (FN6K), pyruvate kinase, and pyruvate oxidase are present in one or more polymer layers. In examples, one or more of fructosamine 6-kinase (FN6K), pyruvate kinase, and pyruvate oxidase are immobilized, independently, in one or more polymer layers. In examples, fructosamine 6-kinase (FN6K), pyruvate kinase, and pyruvate oxidase are arranged in a stacked polymer layer configuration. In examples, fructosamine 6-kinase (FN6K), pyruvate kinase, and pyruvate oxidase are arranged and / or immobilized in the same or different polymer layers. In examples, fructosamine 6-kinase (FN6K), pyruvate kinase, and pyruvate oxidase are arranged on a first working electrode in one or more polymer layers and a spatially separated second working electrode is configured for additional analyte detection, for example, glucose, ketone, lactate, alcohol, potassium or combinations thereof. Additional second working electrode can be independently controlled relative to the first working electrode.

[0325] FIG. 14A depicts a membrane construction for a three-enzyme cascade including interference layer 156 adjacent working electrode (wire or electrodes 824, 825, 924, 925 previously discussed above) having, independently, fructosamine 6-kinase (FN6K), pyruvate kinase, and pyruvate oxidase enzymes (Enzyme 1, Enzyme 2, Enzyme 3), and adenosine triphosphate (ATP), and phosphoenolpyruvate (PEP) co-factors (not shown) in one or more polymer layers 150, 151. Resistance layer 152 for modulating glycated protein (e.g., fructosamine) is shown adjacent to polymer layer 150. In examples, one or more additional layers, including but not limited to a biointerface layer and / or drug releasing layer (e.g. antiinflammatory, vasodilator) is deposited adjacent the resistance layer 151 (not shown.) In examples, one or more additional layers, including but not limited to a biointerface layer and / orAttorney Docket No. 0981-PCT01drug releasing layer (e.g. anti-inflammatory, vasodilator) is deposited adjacent the resistance layer 152 (not shown.)

[0326] In examples, some or all of adenosine triphosphate (ATP), and phosphoenolpyruvate (PEP) co-factors are immobilized within one or more polymer layers with their corresponding enzyme. In examples, co-factors ATP and PEP are physically entrapped in a polymer layer or covalently bound to their respective enzymes, or with the polymer layer. Pyruvate oxidase, by way of example, is aerobic and hence requires a steady supply of oxygen that is provided using a resistance layer 152.

[0327] FIG. 14B depicts a membrane construction for a three-enzyme cascade including mediator layer 155 adjacent working electrode (wire or electrodes 824, 825, 924, 925 previously discussed above) having, independently, fructosamine 6-kinase (FN6K), pyruvate kinase, and pyruvate oxidase enzymes (Enzyme 1, Enzyme 2, Enzyme 3), and adenosine triphosphate (ATP), and phosphoenolpyruvate (PEP) co-factors (not shown) in one or more polymer layers 150, 151. In examples, an interference layer (not shown) can be used adjacent mediator layer 155. In examples, an interference layer can be excluded. Resistance layer 152 for modulating glycated protein (e.g., fructosamine) is shown adjacent to polymer layer 150. In examples, one or more additional layers, including but not limited to a biointerface layer and / or drug releasing layer (e.g. anti-inflammatory, vasodilator) is deposited adjacent the resistance layer 152 (not shown.) In examples, one or more additional layers, including but not limited to a biointerface layer and / or drug releasing layer (e.g. anti-inflammatory, vasodilator) is deposited adjacent the resistance layer 152 (not shown.)

[0328] In the membrane constructions of FIGs. 14A and 14B, one or more additional gas-permeable CO2 ion selective electrodes (ISE), allowing diffusion of CO2, reaction with water to form carbonic acid, and dissociation to bicarbonate and hydrogen ions, so as to cause a detectable pH change, can be employed to detect and quantify the carbon dioxide (CO2) byproduct of the oxidation of pyruvate by pyruvate oxidase, which can be correlated with glycated protein detection or used to complement peroxide correlation with the glycated protein.

[0329] It should be understood that one or more of the membrane constructs of FIGs. 12A, 12B, 14A, and 14B can be used in the planar sensor assemblies 800, 900 and / or in a wire configuration, alone or in combination with other analyte sensor systems as discussed herein. In examples, the planar sensor assemblies 800, 900 and / or in a wire configuration, include the above membrane constructs on a first electrode and further include a second electrode with oneAttorney Docket No. 0981-PCT01or more polymer layers comprising NAD(P)+-dependent dehydrogenase enzyme such as glucose dehydrogenase, alcohol dehydrogenase, D-3-hydroxybutyrate dehydrogenase, or combinations thereof. In examples the second electrode can be the same or different conductive / electroactive material, receive the same or different potential and / or be independent of the first electrode. Additional electrodes can also be used. In examples, one or more of the additional electrodes can be configured for different electrochemical interrogation techniques, e.g. voltammetry, chronocolometry, etc.

[0330] Polymer layers 150, 151 in examples, of the analyte sensing portion further comprise at least one globular protein, e.g., at least one globular protein comprises albumin. In examples, polymer layers 150, 151 include an enzyme stabilizing amount of serum albumin (human or animal).

[0331] In examples, polymer layers 150, 151 comprise one or more functional polymer membranes that function as a resistance layer, a blocking layer, an electrode layer, a biointerface layer / biocompatible layer, and combinations thereof.

[0332] In examples, polymer layers 150, 151 comprise a biointerface layer comprising an anti-inflammatory agent or tissue response modifying agent. Exemplary anti-inflammatory agent, tissue response modifying agents, or vasodilators. Exemplary anti-inflammatory agent, tissue response modifying agents, or vasodilators, anti-inflammatory agent or tissue response modifying agent include pilocarpine, dexamethasone, dexamethasone acetate, or a salt thereof, a nitric oxide (NO) releasing molecule, polymer, or oligomer, phenoxybenzamine HCL, Nicardapine, Phentolamine, Nitroglycerine, Nitroprusside, Hydralazine, Diphenylhydramine, Epinephrine, Aspirin, minoxidil, Celecoxib, nifedipine, Verapamil, L-arginine HCL, Nisoldipine, Menthyl nicotinate (NICOMENTHYL® 20), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), Everolimus, MCC950, Empagliflozin, and combinations thereof.

[0333] In examples, polymer layers 150, 151 independently comprise a biointerface layer having a polymer chain having polyurethane segments and / or polyurea segments. In examples, the biointerface layer comprises a polymer chain having both hydrophilic and hydrophobic regions. In examples, the biointerface layer comprises a polymer chain having one or more zwitterionic compounds. In examples, polymer layers 150, 151 independently comprise a waterborne polyurethane polymer or copolymer.

[0334] In examples, polymer layers 150, 151 independently comprise waterborne polyurethane polymer or copolymer comprising zwitterionic functional groups. In examples,Attorney Docket No. 0981-PCT01polymer layers 150, 151 independently comprise a polymer backbone having one or more zwitterionic compounds.

[0335] In examples, polymer layers 150, 151 independently comprise a polymer chain having polyurethane segments and / or polyurea segments. In examples, polymer layers 150, 151 independently comprise a polymer chain having both hydrophilic and hydrophobic regions.

[0336] In examples, polymer layers 150, 151 independently comprise a polymer with a heterocyclic group. In examples, polymer layers 150, 151 independently comprise a polymer chain having poly(l-vinyl imidazole), poly(4-vinyl pyridine), poly(2-vinyl pyridine), acrylonitrile, acrylamide, and / or copolymers and / or quatemized forms thereof. In examples, polymer layers 150, 151 independently comprise a copolymer including styrene.

[0337] In examples mediator layer 155 comprises at least one transition metal or at least one transition metal complex. In examples mediator layer 155 comprises ruthenium, osmium, iridium, rhodium, cobalt, iron, or alloys thereof. In examples mediator layer 155 comprises a ruthenium complex, an osmium complex, an iridium complex, a rhodium complex, a cobalt complex, an iron complex, or combinations thereof. In examples, the ruthenium complex, the osmium complex, the iridium complex, the rhodium complex, the cobalt complex, or the iron complex independently comprises monodentate, bidentate, tridentate, tetradentate, or higher denticity ligands. In examples, the monodentate, bidentate, tridentate, tetradentate, or higher denticity ligands comprise one or more of bipyridine, biimidazole, phenanthroline, or pyridyl(imidazole). In examples, the mediator or the electron transfer agent is covalently coupled to a polymer. In examples, the polymer comprises poly(4-vinylpyridine), poly(2-vinylpyridine), polyvinylimidazole, or copolymer thereof.Definitions

[0338] The phrases “biointerface membrane” and “biointerface layer” as used interchangeably herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a permeable membrane (which can include multiple domains) or layer that functions as a bioprotective interface between host tissue and an implantable device. The terms “biointerface” and “bioprotective” are used interchangeably herein.Attorney Docket No. 0981-PCT01

[0339] The term “cofactor” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to one or more substances whose presence contributes to or is required for analyte-related activity of an enzyme. Analyte-related activity can include, but is not limited to, any one of or a combination of binding, electron transfer, and chemical transformation. Cofactors are inclusive of coenzymes, non-protein chemical compounds, metal ions and / or metal organic complexes. Coenzymes are inclusive of prosthetic groups and co-substrates.

[0340] The term “continuous” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an uninterrupted or unbroken portion, domain, coating, or layer.

[0341] The phrases “continuous analyte sensing” and “continuous multi-analyte sensing” as used herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the period in which monitoring of analyte concentration is continuously, continually, and / or intermittently (but regularly) performed, for example, from about every second or less to about one week or more. In further examples, monitoring of analyte concentration is performed from about every 2, 3, 5, 7,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 seconds to about every 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25, 3.50, 3.75, 4.00, 4.25, 4.50, 4.75, 5.00, 5.25, 5.50, 5.75, 6.00, 6.25, 6.50, 6.75, 7.00, 7.25, 7.50, 7.75, 8.00, 8.25, 8.50, 8.75, 9.00, 9.25, 9.50 or 9.75 minutes. In further examples, monitoring of analyte concentration is performed from about 10, 20, 30, 40 or 50 minutes to about every 1, 2, 3, 4, 5, 6, 7 or 8 hours. In further examples, monitoring of analyte concentration is performed from about every 8 hours to about every 12, 16, 20, or 24 hours. In further examples, monitoring of analyte concentration is performed from about every day to about every 1.5, 2, 3, 4, 5, 6, or 7 days. In further examples, monitoring of analyte concentration is performed from about every week to about every 1.5, 2, 3 or more weeks.

[0342] The term “coupled” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to two or more system elements or components that are configured to be at least one of electrically, mechanically, thermally, operably, chemically or otherwise attached. For example, an element is “coupled” if theAttorney Docket No. 0981-PCT01element is covalently, communicatively, electrostatically, thermally connected, mechanically connected, magnetically connected, or ionically associated with, or physically entrapped, adsorbed to or absorbed by another element. Similarly, the phrases “operably connected”, “operably linked”, and “operably coupled” as used herein may refer to one or more components linked to another component(s) in a manner that facilitates transmission of at least one signal between the components. In some examples, components are part of the same structure and / or integral with one another as in covalently, electrostatically, mechanically, thermally, magnetically, ionically associated with, or physically entrapped, or absorbed (i.e. “directly coupled” as in no intervening element(s)). In other examples, components are connected via remote means. For example, one or more electrodes can be used to detect an analyte in a sample and convert that information into a signal; the signal can then be transmitted to an electronic circuit. In this example, the electrode is “operably linked” to the electronic circuit. The phrase “removably coupled” as used herein may refer to two or more system elements or components that are configured to be or have been electrically, mechanically, thermally, operably, chemically, or otherwise attached and detached without damaging any of the coupled elements or components. The phrase “permanently coupled” as used herein may refer to two or more system elements or components that are configured to be or have been electrically, mechanically, thermally, operably, chemically, or otherwise attached but cannot be uncoupled without damaging at least one of the coupled elements or components, covalently, electrostatically, ionically associated with, or physically entrapped, or absorbed.

[0343] The term “distal” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a region spaced relatively far from a point of reference, such as an origin or a point of attachment.

[0344] The term “domain” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a region of a membrane system that can be a layer, a uniform or non-uniform gradient (for example, an anisotropic region of a membrane), or a portion of a membrane that is capable of sensing one, two, or more analytes. The domains discussed herein can be formed as a single layer, as two or more layers, as pairs of bi-layers, or as combinations thereof.

[0345] The term “drift” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a specialAttorney Docket No. 0981-PCT01or customized meaning), and refers without limitation to a progressive increase or decrease in signal over time that is unrelated to changes in host systemic analyte concentrations. While not wishing to be bound by theory, it is believed that drift may be the result of a local decrease in glycated protein transport to the sensor, for example, due to formation of a foreign body capsule (FBC), or due to an insufficient amount of interstitial fluid surrounding the sensor, which results in reduced oxygen and / or glycated protein transport to the sensor. In examples, an increase in local interstitial fluid may slow or reduce drift and thus improve sensor performance. Drift may also be the result of sensor electronics, or algorithmic models used to compensate for noise or other anomalies that can occur with electrical signals in, for example, the femtoAmp range, the picoAmp range, the nanoAmp range, the microAmp range, the milliAmp range, the Amp range, etc.

[0346] The term “electrochemically reactive surface” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the surface of an electrode where an electrochemical reaction takes place. In examples this reaction is faradaic and results in charge transfer between the surface and its environment. In examples, hydrogen peroxide produced by an enzyme-catalyzed reaction of an analyte being oxidized on the surface results in a measurable electronic current.

[0347] The term "electrolysis" as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meeting), and refers without limitation to electrooxidation or electroreduction (collectively, “redox”) of a compound, either directly or indirectly, by one or more enzymes, cofactors, or mediators.

[0348] The phrase "hard segment" as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an element of a copolymer, for example, a polyurethane, a polycarbonate polyurethane, or a polyurethane urea copolymer, which imparts resistance properties, e.g., resistance to bending or twisting. The phrase "hard segment" can be further characterized as a crystalline, semi-crystalline, or glassy material with a glass transition temperature determined by dynamic scanning calorimetry (“Tg”) typically above ambient temperature.Attorney Docket No. 0981-PCT01

[0349] The term “host” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to mammals, for example humans.

[0350] The terms “indwelling,” “in dwelling,” “implanted,” or “implantable” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to objects including sensors that are inserted, or configured to be inserted, subcutaneously (i.e. in the layer of fat between the skin and the muscle), intracutaneously (i.e. penetrating the stratum comeum and positioning within the epidermal or dermal strata of the skin), or transcutaneously (i.e. penetrating, entering, or passing through intact skin), which may result in a sensor that has an in vivo portion and an ex vivo portion. The term “indwelling” also encompasses an object which is configured to be inserted subcutaneously, intracutaneously, or transcutaneously, whether or not

[0351] The terms “interferants” and “interfering species” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to effects and / or species that interfere with the measurement of an analyte of interest in a sensor to produce a signal that does not accurately represent the analyte measurement. In examples of an electrochemical sensor, interfering species are compounds which produce a signal that is not analyte- specific due to a reaction on an electrochemically active surface and / or a compound that reduces catalytic turnover of an enzyme for an analyte or at least partially deactivates the enzyme.

[0352] The term “in vivo” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is inclusive of the portion of a device (for example, a sensor) adapted for insertion into and / or existence within a living body of a host.

[0353] The term “ex vivo” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and without limitation is inclusive of a portion of a device (for example, a sensor) adapted to remain and / or exist outside of a living body of a host.Attorney Docket No. 0981-PCT01

[0354] The term and phrase “mediator” and “redox mediator” as used herein are broad terms and phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to any chemical compound or collection of compounds capable of electron transfer, either directly, or indirectly, between an analyte, analyte precursor, analyte surrogate, analyte-reduced or analyte-oxidized enzyme, or cofactor, and an electrode surface held at a potential. In examples the mediator accepts electrons from, or transfer electrons to, one or more enzymes or cofactors, and / or exchanges electrons with the sensor system electrodes. In examples, mediators are transition-metal coordinated organic molecules which are capable of reversible oxidation and reduction reactions. In other examples, mediators may be organic molecules or metals which are capable of reversible oxidation and reduction reactions. In examples, electrochemical mediators form at least two stable redox states and can interchange between reduced and oxidized forms readily.

[0355] The term “membrane” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a structure configured to perform functions including, but not limited to, protection of the exposed electrode surface from the biological environment, diffusion resistance (limitation) of the analyte, service as a matrix for a catalyst (e.g., one or more enzymes) for enabling an enzymatic reaction, limitation or blocking of interfering species, provision of hydrophilicity at the electrochemically reactive surfaces of the sensor interface, service as an interface between host tissue and the implantable device, modulation of host tissue response via drug (or other substance) release, and combinations thereof. When used herein, the terms “membrane” and “matrix” are meant to be interchangeable.

[0356] The phrase “membrane system” as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane that can be comprised of two or more domains, layers, or layers within a domain, and is typically constructed of materials of a few microns thickness or more, which is permeable to oxygen and is optionally permeable to, e.g., glycated protein or another analyte. In examples, the membrane system comprises an enzyme, which enables an analyte reaction to occur whereby a concentration of the analyte can be measured.Attorney Docket No. 0981-PCT01

[0357] The term “noise,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, a signal detected by the sensor or sensor electronics that is unrelated to analyte concentration and can result in reduced sensor performance. One type of noise has been observed during the few hours (e.g., about 2 to about 24 hours) after sensor insertion. After the first 24 hours, the noise may disappear or diminish, but in some hosts, the noise may last for about three to four days. In some cases, noise can be reduced using predictive modeling, artificial intelligence, and / or algorithmic means. In other cases, noise can be reduced by addressing immune response factors associated with the presence of the implanted sensor, such as using a drug releasing layer with at least one bioactive agent. For example, noise of one or more exemplary biosensors as presently disclosed can be determined and then compared qualitatively or quantitatively. By way of example, by obtaining a raw signal timeseries with a fixed sampling interval (in units of pA), a smoothed version of the raw signal timeseries can be obtained, e.g., by applying a 3rd order lowpass digital Chebyshev Type II filter. Others smoothing algorithms can be used. At each sampling interval, an absolute difference, in units of pA, can be calculated to provide a smoothed timeseries. This smoothed timeseries can be converted into units of mg / dL, (the unit of “noise”), using a glycated protein sensitivity timeseries, in units of pA / pM / dL, where the glycated protein sensitivity time series is derived by using a mathematical model between the raw signal and reference glycated protein measurements (e.g., obtained from ELISA or LC-MS / MS). Optionally, the timeseries can be aggregated as desired, e.g., by hour or day. Comparison of corresponding timeseries between different exemplary biosensors with the presently disclosed drug releasing layer and one or more bioactive agents provides for qualitative or quantitative determination of improvement of noise.

[0358] The term “optional” or “optionally” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and, without limitation, means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0359] The term “planar” as used herein is to be interpreted broadly to describe sensor architecture having a substrate including at least a first surface and an opposing second surface, and for example, comprising a plurality of elements arranged on one or more surfaces or edges of the substrate. The plurality of elements can include conductive or insulating layers or elements configured to operate as a circuit. The plurality of elements may or may not beAttorney Docket No. 0981-PCT01electrically or otherwise coupled. In examples, planar includes one or more edges separating the opposed surfaces.

[0360] The term “polyampholytic polymer” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to polymers comprising both cationic and anionic groups. Such polymers can be prepared to have about equal numbers of positive and negative charges, and thus the surface of such polymers can be about net neutrally charged. Alternatively, such polymers can be prepared to have an excess of either positive or negative charges, and thus the surface of such polymers can be net positively or negatively charged, respectively.

[0361] The term “proximal” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the spatial relationship between various elements in comparison to a particular point of reference. For example, some examples of a device include a membrane system having a biointerface layer and an enzyme domain or layer. If the sensor is deemed to be the point of reference and the enzyme domain is positioned nearer to the sensor than the biointerface layer, then the enzyme domain is more proximal to the sensor than the biointerface layer.

[0362] The phrases “sensing portion,” “sensing membrane,” and / or “sensing mechanism” as used herein are broad phrases, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to the part of a biosensor and / or a sensor responsible for the detection of, or transduction of a signal associated with, a particular analyte or combination of analytes. In examples, the sensing portion, sensing membrane, and / or sensing mechanism generally comprise an electrode configured to provide signals during electrochemically reactions with one or more membranes covering electrochemically reactive surface. In examples, such sensing portions, sensing membranes, and / or sensing mechanisms are capable of providing specific quantitative, semi-quantitative, qualitative, semi qualitative analytical signals using a biological recognition element combined with a transducing and / or detecting element.

[0363] During general operation of the analyte measuring device, biosensor, sensor, sensing region, sensing portion, or sensing mechanism, a biological sample, for example, bloodAttorney Docket No. 0981-PCT01or interstitial fluid, or a component thereof contacts, either directly, or after passage through one or more membranes, an enzyme, for example, fructosyl-amino acid oxidase, DNA, RNA, or a protein or aptamer, for example, one or more periplasmic binding protein (PBP) or mutant or fusion protein thereof having one or more analyte binding regions, each region capable of specifically or reversibly binding to and / or reacting with at least one analyte. The interaction of the biological sample or component thereof with the analyte measuring device, biosensor, sensor, sensing region, sensing portion, or sensing mechanism results in transduction of a signal that permits a qualitative, semi-qualitative, quantitative, or semi-qualitative determination of the analyte level, for example, glycated protein, glucose, ketone, lactate, potassium, etc., in the biological sample.

[0364] In examples, the sensing region or sensing portion can comprise at least a portion of a conductive substrate or at least a portion of a conductive surface, for example, a wire (coaxial) or conductive trace or a substantially planar substrate including substantially planar trace(s), and a membrane. In examples, the sensing region or sensing portion can comprise a non-conductive body, a working electrode, a reference electrode, and a counter electrode (optional), forming an electrochemically reactive surface at one location on the body and an electronic connection at another location on the body, and a sensing membrane affixed to the body and covering the electrochemically reactive surface. In some examples, the sensing portion comprise a WE and RE, where a redox full-cell is formed and current is passed between the WE and RE at the prescribed bias voltage. In some examples, the sensing portion comprise a WE, RE, and CE where a half cell is established between the WE and RE to ensure the maintenance of a stable bias potential unaffected by the current flowing between WE and CE. In examples, the CE is designed to be highly polarizable (i.e. Pt). In some examples, the sensing membrane further comprises an enzyme domain, for example, an enzyme domain, and an electrolyte phase, for example, a free-flowing liquid phase comprising an electrolytecontaining fluid described further below. The terms are broad enough to include the entire device, or only the sensing portion thereof (or something in between).

[0365] In other examples, the sensing region can comprise one or more periplasmic binding protein (PBP) including mutant or fusion protein thereof, or aptamers having one or more analyte binding regions, each region capable of specifically and reversibly binding to at least one analyte. Alterations of the aptamer or mutations of the PBP can contribute to or alter one or more of the binding constants, long-term stability of the protein, including thermal stability, to bind the protein to a special encapsulation matrix, membrane or polymer, or to attach aAttorney Docket No. 0981-PCT01detectable reporter group or “label” to indicate a change in the binding region or transduce a signal corresponding to the one or more analytes present in the biological fluid. Specific examples of changes in the binding region include, but are not limited to, hydrophobic / hydrophilic environmental changes, three-dimensional conformational changes, changes in the orientation of amino / nucleic acid side chains in the binding region of proteins, and redox states of the binding region. Such changes to the binding region provide for transduction of a detectable signal corresponding to the one or more analytes present in the biological fluid.

[0366] In examples, the sensing region determines the selectivity among one or more analytes, so that only the analyte which has to be measured leads to (transduces) a detectable signal. The selection may be based on any chemical or physical recognition of the analyte by the sensing region, where the chemical composition of the analyte is unchanged, or in which the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.

[0367] The term “sensitivity” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an amount of signal (e.g., in the form of electrical current and / or voltage) produced by a predetermined amount (unit) of the measured analyte. For example, in one example, a sensor has a sensitivity (or slope) of from about 1 to about 100 picoAmps of current for every pM of analyte.

[0368] The terms “sensing membrane” and “membrane system” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refers without limitation to a permeable or semi-permeable membrane that can comprise one or more domains or layers and constructed of materials of a few pm thickness or more, which are permeable to oxygen and may or may not be permeable to an analyte of interest. In examples, the sensing membrane or membrane system can comprise an immobilized fructosyl-amino acid oxidase (FAOx), or a fructosamine 6-kinase, a pyruvate kinase, a pyruvate oxidase cascade, which allows an electrochemical reaction to occur to measure a concentration of glycated protein.

[0369] The phrase "soft segment" as used herein is a broad phrase, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to an element of a copolymer,Attorney Docket No. 0981-PCT01for example, a polyurethane, a polycarbonate-polyurethane, or a polyurethane urea copolymer, which imparts flexibility to the chain. The phrase "soft segment" can be further characterized as an amorphous material with a low Tg, e.g., a Tg not typically higher than ambient temperature or normal mammalian body temperature.

[0370] The terms “zwitterion” and “zwitterionic compound” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to compounds in which a neutral molecule of the compound has a unit positive and unit negative electrical charge at different locations within the molecule. Such compounds are a type of dipolar compounds, and are also sometimes referred to as “inner salts.”

[0371] A “zwitterion precursor” or “zwitterionic compound precursor” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to any compound that is not itself a zwitterion, but can become a zwitterion in a final or transition state through chemical reaction. In some embodiments described herein, devices comprise zwitterion precursors that can be converted to zwitterions prior to in vivo implantation of the device. Alternatively, in some embodiments described herein, devices comprise zwitterion precursors that can be converted to zwitterions by some chemical reaction that occurs after in vivo implantation of the device. Such reactions are known to the skilled in art and include ring opening reaction, addition reaction such as Michael addition. This method is especially useful when the polymerization of betaine containing monomer is difficult due to technical challenges such as solubility of betaine monomer to achieve desired physical properties such as molecular weight and mechanical strength. Post-polymerization modification or conversion of betaine precursor can be a practical way to achieve desired polymer structure and composition. Examples of such as precursors include tertiary amines, quaternary amines, pyridines, and others detailed herein.

[0372] A “zwitterion derivative” or “zwitterionic compound derivative” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to any compound that is not itself a zwitterion, but rather is the product of a chemical reaction where a zwitterion is converted to a non-zwitterion. Such reactions can be reversible, such that under certain conditions zwitterion derivatives can act as zwitterion precursors. For example, hydrolyzable betaine esters formed from zwitterionic betaines are cationic zwitterionAttorney Docket No. 0981-PCT01derivatives that under the appropriate conditions are capable of undergoing hydrolysis to revert to zwitterionic betaines.

[0373] The term “polyzwitterions” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to polymers where a repeating unit of the polymer chain is a zwitterionic moiety. Polyzwitterions are also known as polybetaines. Since polyzwitterions have both cationic and anionic groups, they are a type of polyampholytic polymer. They are unique, however, because the cationic and anionic groups are both part of the same repeating unit, which means a polyzwitterion has the same number of cationic groups and anionic groups whereas other polyampholytic polymers can have more of one ionic group than the other. Also, polyzwitterions have the cationic group and anionic group as part of a repeating unit. Polyampholytic polymers need not have cationic groups connected to anionic groups, they can be on different repeating units and thus may be distributed apart from one another at random intervals, or one ionic group may outnumber the other.

[0374] As employed herein, the following abbreviations apply: Eq and Eqs (equivalents); mEq (milliequivalents); M (molar); mM (millimolar) pM (micromolar); nM (nanomolar); pM (picomolar); fM (femtomolar); N (Normal); mol (moles); mmol (millimoles); pmol (micromoles); nmol (nanomoles); g (grams); mg (milligrams); pg (micrograms); Kg (kilograms); L (liters); mL (milliliters); dL (deciliters); pL (microliters); cm (centimeters); mm (millimeters); pm (micrometers); nm (nanometers); h and hr (hours); min (minutes); s and sec (seconds);0C. (degrees Centigrade); mV (millivolts); pV (microvolts); mA (milliamperes); pA (microamperes); pA (picoamperes); fA (femtoamperes).Additional Considerations

[0375] The methods disclosed herein comprise one or more steps or actions for achieving the methods. The method steps and / or actions may be interchanged with one another without departing from the scope of the claims. In other words, unless a specific order of steps or actions is specified, the order and / or use of specific steps and / or actions may be modified without departing from the scope of the claims.

[0376] As used herein, a phrase referring to “at least one of’ a list of items refers to any combination of those items, including single members. As an example, “at least one of: a, b, or c” is intended to cover a, b, c, a-b, a-c, b-c, and a-b-c, as well as any combination withAttorney Docket No. 0981-PCT01multiples of the same element (e.g., a-a, a-a-a, a-a-b, a-a-c, a-b-b, a-c-c, b-b, b-b-b, b-b-c, c-c, and c-c-c or any other ordering of a, b, and c).

[0377] The previous description is provided to enable any person skilled in the art to practice the various aspects described herein. Various modifications to these aspects will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other aspects. Thus, the claims are not intended to be limited to the aspects shown herein, but is to be accorded the full scope consistent with the language of the claims, wherein reference to an element in the singular is not intended to mean “one and only one” unless specifically so stated, but rather “one or more.” Unless specifically stated otherwise, the term “some” refers to one or more. All structural and functional equivalents to the elements of the various aspects described throughout this disclosure that are known or later come to be known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the claims. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims. No claim element is to be construed under the provisions of 35 U.S.C. § 112(f) unless the element is expressly recited using the phrase “means for” or, in the case of a method claim, the element is recited using the phrase “step for.”

[0378] While various examples of the invention have been described above, it should be understood that they have been presented by way of example only, and not by way of limitation. Likewise, the various diagrams may depict an example architectural or other configuration for the disclosure, which is done to aid in understanding the features and functionality that can be included in the disclosure. The disclosure is not restricted to the illustrated example architectures or configurations, but can be implemented using a variety of alternative architectures and configurations. Additionally, although the disclosure is described above in terms of various example examples and aspects, it should be understood that the various features and functionality described in one or more of the individual examples are not limited in their applicability to the particular example with which they are described. They instead can be applied, alone or in some combination, to one or more of the other examples of the disclosure, whether or not such examples are described, and whether or not such features are presented as being a part of a described example. Thus the breadth and scope of the present disclosure should not be limited by any of the above-described example examples.

[0379] All references cited herein are incorporated herein by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradictAttorney Docket No. 0981-PCT01the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.

[0380] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special or customized meaning unless expressly so defined herein.

[0381] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide example instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as ‘known’, ‘normal’, ‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular example of the invention. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and / or’ unless expressly stated otherwise. Similarly, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and / or’ unless expressly stated otherwise.

[0382] The term “comprising as used herein is synonymous with “including.” “containing,” or “characterized by” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0383] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the termAttorney Docket No. 0981-PCT01‘about.’ Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0384] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention to the specific examples and examples described herein, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.Example Embodiments

[0385] Clause 1 : A device for measurement of a concentration of glycated serum protein, the device comprising: an analyte sensing portion configured to generate a signal associated with a concentration of a glycated serum protein, the analyte sensing portion comprising a flavin adenine dinucleotide (FAD)-dependent enzyme or an adenosine triphosphate (ATP)-dependent enzyme; a working electrode (WE); and a counter electrode (CE) and / or a reference electrode (RE).

[0386] Clause 2: The device of Clause 1, wherein the device comprises a transcutaneous glycated protein sensor.

[0387] Clause 3: The device of any one of the previous Clauses, wherein the device comprises a subcutaneous glycated protein sensor.

[0388] Clause 4: The device of any one of the previous Clauses, wherein the device comprises a continuous glycated protein sensor.

[0389] Clause 5: The device of any one of the previous Clauses, wherein the glycated serum protein is glycated hemoglobin Ale.

[0390] Clause 6: The device of any one of the previous Clauses, wherein the glycated serum protein is glycated albumin.

[0391] Clause 7: The device of any one of the previous Clauses, wherein the glycated serum protein is fructosamine.Attorney Docket No. 0981-PCT01

[0392] Clause 8: The device of any one of the previous Clauses, wherein the working electrode comprises metal, metal alloy, carbon, graphite, carbon fiber, carbon nanotubes, conductive polymer, a doped conductive polymer, or combinations thereof.

[0393] Clause 9: The device of any one of the previous Clauses, wherein the working electrode is configured as a wire or present on a planar substrate.

[0394] Clause 10: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises a first working electrode and a second working electrode.

[0395] Clause 11: The device of any one of the previous Clauses, wherein the reference electrode is external from the analyte sensing portion upon implantation.

[0396] Clause 12: The device of any one of the previous Clauses, wherein the first working electrode is configured to generate a first signal associated with a first analyte.

[0397] Clause 13: The device of any one of the previous Clauses, wherein the second working electrode is configured to generate a signal associated with a second analyte, the second analyte being chemically different from the first analyte.

[0398] Clause 14: The device of any one of the previous Clauses, wherein the second working electrode is configured to operate at a potential different from the first working electrode.

[0399] Clause 15: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises a polymer layer adjacent the working electrode.

[0400] Clause 16: The device of any one of the previous Clauses, wherein the working electrode comprises fructosyl-amino acid oxidase (FAOx) adjacent thereto.

[0401] Clause 17: The device of any one of the previous Clauses, wherein the working electrode comprises a fructosamine 6-kinase, a pyruvate kinase, a pyruvate oxidase or combinations thereof adjacent the working electrode.

[0402] Clause 18: The device of any one of the previous Clauses, wherein the polymer layer comprises a first polymer layer adjacent the working electrode and a second polymer layer adjacent the first polymer layer.

[0403] Clause 19: The device of any one of the previous Clauses, wherein the working electrode comprises a first working electrode and a second working electrode, the first and the second electrodes being the same or different composition.Attorney Docket No. 0981-PCT01

[0404] Clause 20: The device of any one of the previous Clauses, wherein the polymer layer comprises a first polymer layer adjacent the first working electrode and a second polymer layer adjacent the second working electrode, the first and the second polymer layers being the same or different.

[0405] Clause 21: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises a flavin adenine dinucleotide (FAD)-dependent enzyme.

[0406] Clause 22: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises a first flavin adenine dinucleotide (FAD)-dependent enzyme and a second flavin adenine dinucleotide (FAD)-dependent enzyme, the first and the second flavin adenine dinucleotide (FAD)-dependent enzymes being different.

[0407] Clause 23: The device of any one of the previous Clauses, wherein the polymer layer comprises a single polymer layer, the first flavin adenine dinucleotide (FAD)-dependent enzyme and the second flavin adenine dinucleotide (FAD)-dependent enzyme being present in the single polymer layer.

[0408] Clause 24: The device of any one of the previous Clauses, wherein the polymer layer comprises a first polymer layer and a second polymer layer adjacent the first polymer layer, the first flavin adenine dinucleotide (FAD)-dependent enzyme is present in the first polymer layer and the second flavin adenine dinucleotide (FAD)-dependent enzyme are present in the second polymer layer, the first and the second polymer layers being the same or different.

[0409] Clause 25: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises a first working electrode and a second working electrode, a first polymer layer adjacent the first working electrode, and a second polymer layer adjacent the second working electrode, wherein the first flavin adenine dinucleotide (FAD)-dependent enzyme is present in the first polymer layer and the second flavin adenine dinucleotide (FAD)-dependent enzyme is present in the second polymer layer, the first and the second polymer layers being the same or different.

[0410] Clause 26: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises a first working electrode and a second working electrode, a first polymer layer adjacent the first working electrode, and a second polymer layer adjacent the second polymer layer, wherein the first flavin adenine dinucleotide (FAD)-dependent enzyme is present in the first polymer layer and the second flavin adenine dinucleotide (FAD)-Attorney Docket No. 0981-PCT01dependent enzyme is present in the second polymer layer, the first and the second polymer layers being the same or different.

[0411] Clause 27: The device of any one of the previous Clauses, wherein the first flavin adenine dinucleotide (FAD)-dependent enzyme is fructosyl-amino acid oxidase (FAOx) and the second flavin adenine dinucleotide (FAD)-dependent enzyme is glucose oxidase (GOx), lactate oxidase, or combinations thereof.

[0412] Clause 28: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises a flavin adenine dinucleotide (FAD)-dependent enzyme and a NAD(P)+-dependent dehydrogenase enzyme.

[0413] Clause 29: The device of any one of the previous Clauses, wherein the NAD(P)+-dependent dehydrogenase enzyme is hydroxysteroid dehydrogenase enzyme or glucose dehydrogenase.

[0414] Clause 30: The device of any one of the previous Clauses, wherein the NAD(P)+-dependent dehydrogenase enzyme is glucose dehydrogenase, alcohol dehydrogenase, D-3-hydroxybutyrate dehydrogenase, or combinations thereof.

[0415] Clause 31: The device of any one of the previous Clauses, wherein the flavin adenine dinucleotide (FAD)-dependent enzyme is fructosyl-amino acid oxidase (FAOx) and the NAD(P)+-dependent dehydrogenase enzyme is glucose dehydrogenase, alcohol dehydrogenase, D-3-hydroxybutyrate dehydrogenase, or combinations thereof.

[0416] Clause 32: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises a first working electrode and a second working electrode, a first polymer layer adjacent the first working electrode, and a second polymer layer adjacent the second electrode, wherein the first polymer layer comprises the at least one flavin adenine dinucleotide (FAD)-dependent enzyme and the second polymer layer comprises the at least one NAD(P)+-dependent dehydrogenase enzyme.

[0417] Clause 33: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises a first working electrode and a second working electrode, a first polymer layer adjacent the first working electrode, and a second polymer layer adjacent the second polymer layer, wherein the first polymer layer comprises the at least one flavin adenine dinucleotide (FAD)-dependent enzyme and the second polymer layer comprises the at least one NAD(P)+-dependent dehydrogenase enzyme.Attorney Docket No. 0981-PCT01

[0418] Clause 34: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises a flavin adenine dinucleotide (FAD)-dependent enzyme and a glucose responsive enzyme, a 1,5-anydroglucitol (1,5-AG) responsive enzyme, a potassium sensor, or combinations thereof.

[0419] Clause 35: The device of any one of the previous Clauses, wherein the flavin adenine dinucleotide (FAD)-dependent enzyme is a thermally stable mutant fructosyl-amino acid oxidase enzyme with an amino acid substitution at T60A, A188G, M244L, N257S, L261M and combinations thereof.

[0420] Clause 36: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises at least one ATP-dependent enzyme.

[0421] Clause 37: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises at least two different ATP-dependent enzymes and a flavin adenine dinucleotide (FAD)-dependent enzyme.

[0422] Clause 38: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises at least two different ATP-dependent enzymes, a flavin adenine dinucleotide (FAD)-dependent enzyme, and a glucose responsive enzyme, a 1,5-anydroglucitol (1,5-AG) responsive enzyme, a potassium sensor, or combinations thereof.

[0423] Clause 39: The device of any one of the previous Clauses, wherein the at least two different ATP-dependent enzymes comprise fructosamine 6-kinase and pyruvate kinase.

[0424] Clause 40: The device of any one of the previous Clauses, wherein the flavin adenine dinucleotide (FAD)-dependent enzyme is pyruvate oxidase.

[0425] Clause 41: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises fructosamine 6-kinase, pyruvate kinase, and pyruvate oxidase.

[0426] Clause 42: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises fructosamine 6-kinase, pyruvate kinase, pyruvate oxidase and glucose oxidase enzyme.

[0427] Clause 43: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises fructosamine 6-kinase, pyruvate kinase, pyruvate oxidase and a NAD(P)+-dependent dehydrogenase enzyme.Attorney Docket No. 0981-PCT01

[0428] Clause 44: The device of any one of the previous Clauses, wherein the NAD(P)+-dependent dehydrogenase enzyme is glucose dehydrogenase, alcohol dehydrogenase, D-3-hydroxybutyrate dehydrogenase, or combinations thereof.

[0429] Clause 45: The device of any one of the previous Clauses, wherein the analyte sensing portion comprises fructosamine 6-kinase, pyruvate kinase, pyruvate oxidase, and a glucose responsive enzyme, a 1,5-anydroglucitol (1,5-AG) responsive enzyme, a potassium sensor, or combinations thereof.

[0430] Clause 46: The device of any one of the previous Clauses, wherein the analyte sensing portion further comprises adenosine triphosphate (ATP), phosphoenolpyruvate, or combinations thereof.

[0431] Clause 47: The device of any one of the previous Clauses, wherein the adenosine triphosphate (ATP), the phosphoenolpyruvate, or combinations thereof are immobilized.

[0432] Clause 48: The device of any one of the previous Clauses, wherein the polymer layer comprises a first polymer layer and a second polymer layer adjacent the first polymer layer, the first polymer layer comprising fructosamine 6-kinase and adenosine triphosphate (ATP), the second polymer layer comprising pyruvate kinase or pyruvate oxidase and the phosphoenolpyruvate.

[0433] Clause 49: The device of any one of the previous Clauses, wherein the polymer layer comprises a first polymer layer adjacent a first electrode and a second polymer layer adjacent the first polymer layer, the first polymer layer comprising fructosamine 6-kinase and adenosine triphosphate (ATP), the second polymer layer comprising pyruvate kinase or pyruvate oxidase and the phosphoenolpyruvate and the and a third polymer layer adjacent a second working electrode, the third polymer layer comprising glucose oxidase, a NAD(P)+-dependent dehydrogenase enzyme, or combinations thereof.

[0434] Clause 50: The device of any one of the previous Clauses, wherein the NAD(P)+-dependent dehydrogenase enzyme is glucose dehydrogenase, alcohol dehydrogenase, D-3-hydroxybutyrate dehydrogenase, or combinations thereof.

[0435] Clause 51: The device of any one of the previous Clauses, wherein the polymer layer comprises a waterborne polyurethane polymer or copolymer.

[0436] Clause 52: The device of any one of the previous Clauses, wherein the polymer layer comprises a zwitterionic functional group.Attorney Docket No. 0981-PCT01

[0437] Clause 53: The device of any one of the previous Clauses, wherein the polymer layer comprises a waterborne polyurethane polymer or copolymer comprising zwitterionic functional groups.

[0438] Clause 54: The device of any one of the previous Clauses, wherein the polymer layer comprises a polymer chain having polyurethane segments and / or polyurea segments.

[0439] Clause 55: The device of any one of the previous Clauses, wherein the polymer layer comprises a polymer chain having both hydrophilic and hydrophobic regions.

[0440] Clause 56: The device of any one of the previous Clauses, wherein the polymer layer comprises a polymer backbone having one or more zwitterionic compounds.

[0441] Clause 57: The device of any one of the previous Clauses, wherein the polymer layer comprises a polymer with a heterocyclic group.

[0442] Clause 58: The device of any one of the previous Clauses, wherein the polymer layer comprises a polymer chain having poly(l-vinyl imidazole), poly(4-vinyl pyridine), poly (2- vinyl pyridine), acrylonitrile, acrylamide, and / or copolymers and / or quatemized forms thereof.

[0443] Clause 59: The device of any one of the previous Clauses, wherein the polymer layer comprises a copolymer including styrene.

[0444] Clause 60: The device of any one of the previous Clauses, wherein the analyte sensing portion further comprises a mediator or an electron transfer agent.

[0445] Clause 61: The device of any one of the previous Clauses, wherein the at least one mediator or electron transfer agent comprise at least one transition metal or at least one transition metal complex.

[0446] Clause 62: The device of any one of the previous Clauses, wherein the mediator or the electron transfer agent comprises ruthenium, osmium, iridium, rhodium, cobalt, iron, or alloys thereof.

[0447] Clause 63: The device of any one of the previous Clauses, wherein the mediator or the electron transfer agent comprises a ruthenium complex, an osmium complex, a iridium complex, a rhodium complex, a cobalt complex, an iron complex, or combinations thereof.

[0448] Clause 64: The device of any one of the previous Clauses, wherein the ruthenium complex, the osmium complex, the iridium complex, the rhodium complex, the cobalt complex,Attorney Docket No. 0981-PCT01or the iron complex independently comprises monodentate, bidentate, tridentate, tetradentate, or higher denticity ligands.

[0449] Clause 65: The device of any one of the previous Clauses, wherein the monodentate, bidentate, tridentate, tetradentate, or higher denticity ligands comprise one or more of bipyridine, biimidazole, phenanthroline, or pyridyl(imidazole).

[0450] Clause 66: The device of any one of the previous Clauses, wherein the mediator or the electron transfer agent is covalently coupled to a polymer.

[0451] Clause 67: The device of any one of the previous Clauses, wherein the polymer comprises poly(4-vinylpyridine), poly(2-vinylpyridine), polyvinylimidazoles, or copolymers thereof.

[0452] Clause 68: The device of any one of the previous Clauses, wherein the analyte sensing portion further comprising at least one globular protein.

[0453] Clause 69: The device of any one of the previous Clauses, wherein the at least one globular protein comprises albumin.

[0454] Clause 70: The device of any one of the previous Clauses, wherein the albumin is serum albumin.

[0455] Clause 71: The device of any one of the previous Clauses, wherein the analyte sensing portion further comprising one or more functional polymer membranes selected from a resistance layer, a blocking layer, an electrode layer, a biointerface layer, and combinations thereof.

[0456] Clause 72: The device of any one of the previous Clauses, wherein the biointerface layer comprises an anti-inflammatory agent or tissue response modifying agent.

[0457] Clause 73: The device of any one of the previous Clauses, wherein the biointerface layer comprises a polymer chain having polyurethane segments and / or polyurea segments.

[0458] Clause 74: The device of any one of the previous Clauses, wherein the biointerface layer comprises a polymer chain having both hydrophilic and hydrophobic reg...

Claims

Attorney Docket No. 0981-PCT01CLAIMS1. A therapy management system, comprising:one or more memories comprising executable instructions; andone or more processors in data communication with the one or more memories and configured to execute the executable instructions to:monitor at least measured fructosamine levels and glucose levels of a host during a time period to obtain measured fructosamine data and measured glucose data;determine at least a glucose metric of the host based on the measured glucose levels; determine an expected fructosamine value based on the glucose metric;compare the expected fructosamine value to a measured fructosamine value based on the measured Fructosamine data; andprovide a determination of at least one of a risk, a presence, or a progression of kidney dysfunction and personalized therapy management guidance to the host based on the comparison.

2. The therapy management system of claim 1, wherein the glucose metric comprises a mean glucose value calculated as an average of measured glucose values over the time period.

3. The therapy management system of claim 1, wherein determining the expected fructosamine value comprises applying the formula: expected fructosamine value (pmol / L) = 1.9391 x (mean glucose value (mg / dL) + 20).

4. The therapy management system of claim 1, wherein determining at least one of the risk, the presence, or the progression of kidney dysfunction comprises determining a risk score for kidney dysfunction of the host.

5. The therapy management system of claim 1, wherein:the at least one of the risk, the presence, or the progression of kidney dysfunction and the therapy management guidance are presented to the host on a display device; andthe at least one of the risk, the presence, or the progression of kidney dysfunction and the therapy management guidance comprise at least one of a visual, audible, or tactile alert.Attorney Docket No. 0981-PCT016. The therapy management system of claim 1, wherein the at least one of the risk, the presence, or the progression of kidney dysfunction and the therapy management guidance are additionally transmitted to a healthcare provider of the host.

7. The therapy management system of claim 1, wherein determining the at least one of the risk, the presence, or the progression of kidney dysfunction further comprises determining a risk, a presence, or a progression of proteinuria.

8. The therapy management system of claim 1 , wherein the host is determined to be at low risk of kidney dysfunction when the comparison indicates a difference between the expected fructosamine value and the measured fructosamine value that is less than about 10 pmol / L.

9. The therapy management system of claim 8, wherein the host is determined to be at increased risk of kidney dysfunction when the difference exceeds 10 pmol / L.

10. The therapy management system of claim 8, wherein the magnitude of the difference is correlated to a progression level of kidney dysfunction.

11. The therapy management system of claim 1, further comprising:monitoring at least one of measured 1,5-anhydroglucitol levels, measured creatinine levels, measured potassium levels, or measured lactate levels during the time period to obtain additional measured analyte data.

12. The therapy management system of claim 11, further comprising:determining a risk of proximal tubule dysfunction based on the additional measured analyte data.

13. The therapy management system of claim 11, further comprising:receiving medication data from the host; and providing the at least one of the risk, the presence, or the progression of kidney dysfunction and the therapy management guidance based on the medication data.Attorney Docket No. 0981-PCT0114. The therapy management system of claim 13, wherein the medication data includes logged use of renin-angiotensin-aldosterone system inhibitors (RAASi) or SGLT-2 inhibitors.

15. A method for generating personalized therapy management guidance for kidney disease using the device of claim 1, comprising:monitoring at least measured fructosamine levels and glucose levels of a host during a time period to obtain measured Fructosamine data and measured glucose data;determining at least a glucose metric of the host based on the measured glucose levels; determining an expected Fructosamine value based on the glucose metric; comparing the expected Fructosamine value to a measured fructosamine value based on the measured Fructosamine data; andproviding a determination of a risk, a presence, and / or a progression of kidney dysfunction and personalized therapy management guidance to the host based on the comparison.

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