Soft sample sensor

Abstract

To provide biomechanically compatible transdermal sensors.SOLUTION: Flexible analyte sensors are provided. Flexible analyte sensors may be flexible continuous analyte sensors that facilitate continuous monitoring of an analyte such as blood glucose. The flexible analyte sensor may have a relatively flexible conductive or non-conductive core, may be formed from a plurality of substantially planar layers, or may be configured to transform from a freestanding sensor ex vivo to a non-freestanding sensor in vivo.SELECTED DRAWING: Figure 3

Description

Technical Field

[0001] Incorporation by reference of related applications All claims of priority, or corrections thereof, identified in the application data sheet are hereby incorporated by reference into this specification under 37 CFR 1.57. This application claims the benefit of U.S. Provisional Application No. 62 / 448,295, filed on January 19, 2017. The foregoing application is hereby incorporated by reference in its entirety and made an explicit part of this specification.

[0002] This disclosure generally relates to sensors, and more particularly to continuous analyte sensors.

Background Art

[0003] Diabetes is a disease in which the pancreas cannot produce sufficient insulin (type I or insulin-dependent) and / or insulin is ineffective (type 2 or non-insulin-dependent). In a diabetic state, the victim suffers from hyperglycemia, which can cause numerous physiological disorders associated with the deterioration of small blood vessels, such as kidney dysfunction, skin ulcers, or bleeding into the vitreous of the eye. Hypoglycemic reactions (hypoglycemia) can be induced by inadvertent overdosage of insulin, or after normal administration of insulin or hypoglycemic agents accompanied by abnormal exercise or insufficient food intake.

[0004] Traditionally, people with diabetes carry around a self-monitoring blood glucose (SMBG) monitor, which typically requires an uncomfortable finger-prick method. Lacking comfort and convenience, people with diabetes usually only measure their blood glucose levels two to four times a day. Unfortunately, such time intervals are quite wide, and it may be too late for people with diabetes to notice hyperglycemia or hypoglycemia, sometimes leading to dangerous side effects. Alternatively, blood glucose levels can be continuously monitored by a sensor system comprising a skin-surface sensor assembly. The sensor system may have a wireless transmitter that transmits measurement data to a receiver capable of processing and displaying information based on the measurement results.

[0005] Implantable and transdermal glucose sensors were developed to continuously measure glucose levels. However, many implantable glucose sensors have problems causing complications when implanted in the body and only provide short-term, inaccurate sensing of blood glucose.

[0006] The skin is a complex viscoelastic tissue. Its mechanical properties are dynamic, changing with age, depending on the skin area, and varying from person to person. Therefore, realizing a biomechanically compatible transcutaneous sensor can be a challenge.

[0007] This “Background Art” is provided to briefly introduce the context for the subsequent “Summary of the Invention” and “Modes for Carrying Out the Invention.” This “Background Art” is not intended to help determine the scope of the claimed subject matter, nor to be considered as limiting the claimed subject matter to implementations that solve any or all of the disadvantages or problems presented above. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] U.S. Patent No. 6,001,067 [Patent Document 2] U.S. Patent Application No. 13 / 788,375 [Patent Document 3] U.S. Patent Application Publication No. US-2006-0020187-A1 [Patent Document 4] U.S. Patent Application Publication No. US-2008-0119703-A1 [Patent Document 5] U.S. Patent Application Publication No. US-2007-0213611-A1 [Patent Document 6] U.S. Patent Application Publication No. US-2007-0027385-A1 [Patent Document 7] U.S. Patent Application Publication No. US-2005-0143635-A1 [Patent Document 8] U.S. Patent Application Publication No. US-2007-0020641-A1 [Patent Document 9] U.S. Patent Application Publication No. US-2007-002064-A11 [Patent Document 10] U.S. Patent Application Publication No. US-2005-0196820-A1 [Patent Document 11] U.S. Patent No. 5,517,313 [Patent Document 12] U.S. Patent No. 5,512,246 [Patent Document 13] U.S. Patent No. 6,400,974 [Patent Document 14] U.S. Patent No. 6,711,423 [Patent Document 15] U.S. Patent No. 7,308,292 [Patent Document 16] U.S. Patent No. 7,303,875 [Patent Document 17] U.S. Patent No. 7,289,836 [Patent Document 18] U.S. Patent No. 7,289,204 [Patent Document 19] U.S. Patent No. 5,156,972 [Patent Document 20] U.S. Patent No. 6,528,318 [Patent Document 21] U.S. Patent No. 5,738,992 [Patent Document 22] U.S. Patent No. 5,631,170 [Patent Document 23] U.S. Patent No. 5,114,859 [Patent Document 24] U.S. Patent No. 7,273,633 [Patent Document 25] U.S. Patent No. 7,247,443 [Patent Document 26] U.S. Patent No. 6,007,775 [Patent Document 27] U.S. Patent No. 7,074,610 [Patent Document 28] U.S. Patent No. 6,846,654 [Patent Document 29] U.S. Patent No. 7,288,368 [Patent Document 30] U.S. Patent No. 7,291,496 [Patent Document 31] U.S. Patent No. 5,466,348 [Patent Document 32] U.S. Patent No. 7,062,385 [Patent Document 33] U.S. Patent No. 7,244,582 [Patent Document 34] U.S. Patent No. 7,211,439 [Patent Document 35] U.S. Patent No. 7,214,190 [Patent Document 36] U.S. Patent No. 7,171,312 [Patent Document 37] U.S. Patent No. 7,135,342 [Patent Document 38] U.S. Patent No. 7,041,209 [Patent Document 39] U.S. Patent No. 7,061,593 [Patent Document 40] U.S. Patent No. 6,854,317 [Patent Document 41] U.S. Patent No. 7,315,752 [Patent Document 42] U.S. Patent No. 7,312,040 [Patent Document 43] U.S. Patent No. 5,711,861 [Patent Document 44] U.S. Patent No. 6,642,015 [Patent Document 45] U.S. Patent No. 6,654,625 [Patent Document 46] U.S. Patent No. 6,565,509 [Patent Document 47] U.S. Patent No. 6,514,718 [Patent Document 48] U.S. Patent No. 6,465,066 [Patent Document 49] U.S. Patent No. 6,214,185 [Patent Document 50] U.S. Patent No. 5,310,469 [Patent Document 51] U.S. Patent No. 5,683,562 [Patent Document 52] U.S. Patent No. 6,579,690 [Patent Document 53] U.S. Patent No. 6,484,046 [Patent Document 54] U.S. Patent No. 6,103,033 [Patent Document 55] U.S. Patent No. 6,512,939 [Patent Document 56] U.S. Patent No. 6,424,847 [Patent Document 57] U.S. Patent Application Publication No. US-2005-0245799-A1 [Patent Document 58] U.S. Patent Application Publication No. US-2006-0229512-A1 [Patent Document 59] U.S. Patent Application Publication No. US-2007-0173709-A1 [Patent Document 60] U.S. Patent Application Publication No. US-2006-0253012-A1 [Patent Document 61] U.S. Patent No. 7,074,307 [Patent Document 62] U.S. Patent Application Publication No. US-2005-0176136-A1 [Patent Document 63] U.S. Patent No. 7,081,195 [Patent Document 64] U.S. Patent Application Publication No. US-2005-0054909-A1 [Patent Document 65] U.S. Patent Application Publication No. US-2005-0090607-A1 [Patent 66] U.S. Patent No. 4,803,243 [Patent Document 67] U.S. Patent No. 4,686,044 [Patent Document 68] U.S. Patent Application Publication No. US-2007-0244379-A1 [Patent Document 69] U.S. Patent Application Publication No. US-2005-0027463-A1 [Patent Document 70] U.S. Patent No. 6,329,161 [Patent Document 71] US 4,703,756 [Patent Document 72] U.S. Patent Application Publication No. US-2007-0027370-A1 [Patent Document 73] U.S. Patent Application Publication No. US-2008-0083617-A1 [Patent Document 74] U.S. Patent Application Publication No. US-2008-0108942-A1 [Patent Document 75] U.S. Patent Application Publication No. US-2009-0018424-A1 [Patent Document 76] U.S. Patent No. 9,131,885 [Non-patent literature]

[0009] [Non-Patent Document 1] Updike et al., "Diabetes Care 5," pp. 207-21 (1982) [Non-Patent Document 2] Rhodes et al., Anal. Chem., 66: pp. 1520-1529 (1994) [Overview of the project] [Means for solving the problem]

[0010] Flexible specimen sensors, such as flexible continuous specimen sensors, are disclosed in various embodiments. A flexible specimen sensor may be provided as part of a continuous specimen sensor system having a housing that contains sensor electronics, from which the flexible specimen sensor extends. A flexible specimen sensor may be configured for in vivo implantation so that the flexible specimen sensor penetrates the patient's skin from the sensor electronics housing to perform transcutaneous or subcutaneous specimen measurement.

[0011] The flexible sample sensor may comprise a low-elasticity flexible core, such as a low-elasticity flexible metal core, according to several embodiments. In other embodiments, the flexible sample sensor may comprise a low-elasticity flexible non-metallic core, or may be formed from a plurality of substantially planar flexible layers.

[0012] Compared to conventional in vivo sensors, flexible specimen sensors can reduce or eliminate post-implantation stress and / or associated tissue reactions to the local tissue surrounding the sensor, such as micro-movements and pressure of the sensor during in vivo use, skin deformation caused by various movements that can induce interfacial stress, tissue abrasion due to displacement of the transdermal sensor relative to local tissue, local inflammation and metabolism, production of cytokines and other cellular products, microbleeding, lymph node destruction, interstitial fluid mixing, and the occurrence of foreign body reactions. By reducing tissue reactions to the sensor (e.g., inflammation of surrounding tissue and / or encapsulation of the sensor), signal quality and reliability can be further improved compared to conventional transdermal sensors. For example, the first-day effect after sensor implantation, where sensor signal quality can be impaired by inflammation resulting from sensor implantation, can be reduced or eliminated. More specifically, flexible specimen sensors can reduce frequent micro-movements that can cause repetitive tissue damage and chronic inflammation. Reducing these acute and chronic effects of inflammatory reactions can reduce the occurrence of faulty sensor data and / or negative effects on sensor accuracy. In addition, reducing the sliding motion of the sensor in the local sensing area can help reduce disturbances at the delicate tissue sensor interface and prevent the re-determination of local interstitial fluid composition and glucose concentration gradients that could cause fluctuations in the sensor signal.

[0013] Furthermore, soft specimen sensors may facilitate tissue accumulation and reduce or eliminate painful sensations induced by microscopic movements of the sensor relative to local tissue, thus improving the user experience, especially when the housing and electronic components fixed to the sensor are further miniaturized. Moreover, by reducing the movement of the sensor relative to local tissue, the force on the sensor is reduced, extending the functional life of the sensor itself, thereby reducing the patient cost and frequency of needle punctures for the insertion of new sensors.

[0014] In some embodiments, the flexible sample sensor may have a Young's modulus smaller than that of tantalum (for example, approximately 186 gigapascals (GPa)). As another example, in some embodiments, the flexible sample sensor may have a Young's modulus smaller than that of platinum (for example, approximately 147 GPa). In some embodiments, the flexible sample sensor may have a Young's modulus that is substantially the same as that of the surrounding tissue. The flexible sample sensor may have a flexural modulus of less than 150 GPa (for example, for a metal-core flexible sample sensor), or less than 5 GPa, less than 2 GPa, or less than 1 1 / 2 GPa (for example, for a polymer-core or fiber-reinforced core flexible sample sensor).

[0015] In some embodiments, a flexible specimen sensor may have a first rigidity before implantation and a second rigidity in the body. For example, the rigidity of the sensor may be reduced in response to the interaction between the sensor and the bioenvironment. In various embodiments, the sensor may deform from a substantially freestanding sensor to a substantially non-freestanding sensor in response to changes in temperature, fluid absorption, chemical reactions, or applied or removed electromagnetic fields.

[0016] In one embodiment, a continuous sample sensor configured for use in vivo is provided, comprising: an elongated core; a working electrode disposed on the elongated core; and a membrane covering at least a portion of the working electrode, the membrane comprising an enzyme layer, the portion of the continuous sample sensor extending from the sensor electronic equipment housing, and the membrane configured to have a buckling force of less than 0.25 Newtons (N).

[0017] Another embodiment provides a continuous sample sensor configured for use in vivo, the continuous sample sensor comprising: an elongated conductor having a working electrode, the elongated conductor having a plurality of substantially planar layers, a portion of the plurality of substantially planar layers configured to extend from the housing of the continuous sample sensor system having a buckling force of less than 0.25 Newtons (N) as a whole; and a membrane covering at least a portion of the working electrode, the membrane comprising an enzyme layer.

[0018] Another embodiment provides a continuous sample sensor configured for use in vivo, the continuous sample sensor comprising an elongated conductor having a working electrode, wherein the elongated conductor is configured to be both an in vitro self-supporting elongated conductor and an in vivo non-self-supporting elongated conductor, and a membrane covering at least a portion of the working electrode, the membrane comprising an enzyme layer.

[0019] Various configurations of the subject technology will be readily apparent to those skilled in the art from this disclosure, and it will be understood that these various configurations of the subject technology are illustrated and described as illustrative. As understood, the subject technology enables other and different configurations, and some of its details can be modified in various other respects, all without departing from the scope of the subject technology. Accordingly, the summary, drawings, and detailed description of the invention should be considered illustrative and not restrictive.

[0020] Therefore, embodiments of the present invention will be described in detail, with particular emphasis on highlighting their advantageous features. These embodiments illustrate novel and non-obvious sensor signal processing and calibration systems and methods shown in the accompanying drawings, which are for illustrative purposes only, not to scale, and instead are intended to illustrate the principles of the present disclosure. These drawings include the following figures, where similar numbers indicate similar parts. [Brief explanation of the drawing]

[0021] [Figure 1]This is a schematic diagram of a continuous sample sensor system mounted on a host and communicating with multiple exemplary devices. [Figure 2] This is a block diagram illustrating the electronic components associated with the sensor system shown in Figure 1. [Figure 3] This is a schematic bottom perspective view illustrating a continuous sample sensor system having a self-contained continuous sample sensor extending from the housing of the continuous sample sensor system. [Figure 4] This is a schematic bottom perspective view illustrating a continuous sample sensor system having a non-self-supporting continuous sample sensor extending from the housing of the continuous sample sensor system. [Figure 5A] This is a schematic side cross-sectional view illustrating a portion of the sample sensor. [Figure 5B] This is a schematic perspective view illustrating a part of the sample sensor. [Figure 5C] This is a schematic side cross-sectional view illustrating a portion of the sample sensor. [Figure 6A] This is a schematic end-face cross-sectional view of the sample sensor shown in Figure 5A, cut along the line 6-6. [Figure 6B] This is a schematic cross-sectional view of the membrane for the sample sensor. [Figure 7] This is a schematic perspective view illustrating a part of the sample sensor. [Figure 8] This is a schematic diagram illustrating the response of an autonomous sample sensor to an external force. [Figure 9] This is a schematic diagram illustrating the response of a non-autonomous sample sensor to an external force. [Figure 10] This is a schematic perspective view illustrating a portion of an elongated polymer core with a conductive trace for a sample sensor. [Figure 11] Figure 10 is a schematic perspective view of a co-extrusion molding manufacturing system for an elongated polymer core having a conductive trace. [Figure 12] This is a schematic perspective view illustrating a portion of another elongated polymer core having a conductive trace for a sample sensor. [Figure 13] This is a schematic perspective view illustrating a portion of an elongated polymer core for a sample sensor. [Figure 14]Figure 13 is a schematic perspective view of a squeegee manufacturing system for elongated polymer cores. [Figure 15] This is a schematic perspective view illustrating a portion of another elongated polymer core having a conductive wire trace for a sample sensor. [Figure 16] Figure 12 is a schematic perspective view of a wire trace-lamination manufacturing system for elongated polymer cores. [Figure 17] Figure 12 is a schematic perspective view of an induction heating manufacturing system for trace lamination on an elongated polymer core. [Figure 18] This is a schematic perspective view illustrating a portion of an elongated polymer core having conductive trace and deposition electrode pads for a sample sensor. [Figure 19] This is a schematic perspective view illustrating a portion of the elongated fiber-reinforced core within an elongated insulator for a sample sensor. [Figure 20] This is a schematic perspective view illustrating a portion of an elongated fiber-reinforced core within an elongated insulator having a conductive trace for a sample sensor. [Figure 21] This is a schematic perspective view illustrating an elongated insulator, conductive trace, and a portion of the elongated fiber-reinforced core within the insulated sensor for a sample sensor. [Figure 22] This is a schematic perspective view illustrating the trailing end portion of an elongated fiber-reinforced core within an elongated insulator for a sample sensor. [Figure 23] This is a schematic perspective view illustrating a portion of the elongated insulator, conductive trace, insulated sensor, and elongated fiber-reinforced core within the reference electrode for a sample sensor. [Figure 24] Figure 23 is a schematic perspective view illustrating the rear end portion of the sensor. [Figure 25A] This is a schematic perspective view illustrating a portion of an elongated metalized Kevlar core within an elongated insulator for a sample sensor. [Figure 25B] This is a schematic perspective view illustrating a portion of an elongated metallized single-fiber Kevlar core within an elongated insulator for a sample sensor. [Figure 26]Figure 25A is a schematic perspective view illustrating the rear end portion of the sensor. [Figure 27] This is a schematic perspective view illustrating a portion of another elongated polymer core for a sample sensor at various stages during stencil printing of the working electrode and the conductive trace thereon. [Figure 28] This is a schematic perspective view illustrating a portion of a sample sensor having multiple substantially planar layers. [Figure 29] Figure 28 is a schematic perspective view illustrating the rear end portion of the sensor. [Figure 30] This is a schematic perspective view illustrating a sheet having multiple planar layers. [Figure 31] This is a schematic side view illustrating a sample preparation device for generating a sample sensor reel from the sheet shown in Figure 30. [Figure 32] Figure 30 is a schematic perspective view illustrating the process for generating a sample sensor with rounded edges from a sheet. [Figure 33] This is a schematic perspective view illustrating a segmented sensor structure having counter electrodes. [Figure 34A] Figure 33 is a schematic perspective view illustrating a sample sensor having a counter electrode and rounded edges formed from the individualized sensor structure. [Figure 34B] This is a schematic perspective view illustrating another individualized sample sensor. [Figure 35] This figure shows a pair of graphs illustrating the exemplary background noise reduction characteristics of a flexible sample sensor using sputter-coated platinum as the electrode material. [Figure 36] This figure shows a graph illustrating the typical bending characteristics of a flexible sample sensor. [Figure 37] This is a schematic cross-sectional view of a portion of a sample sensor having an elongated hydrophilic structure. [Figure 38] This is a schematic cross-sectional view of a portion of a sample sensor undergoing a chemical / biological softening process. [Figure 39] This is a schematic perspective view of a sample sensor with a chemical / biological softening structure. [Figure 40]This is a schematic diagram of a sample sensor undergoing immersion coating in a self-contained configuration. [Figure 41] This is a schematic diagram of some sample sensors where the immersion coating process for a non-self-supporting configuration was unsuccessful. [Figure 42] This is a schematic side view of a portion of a sample sensor extending from a self-contained housing generated by an applied electromagnetic field. [Figure 43] This is a schematic side view of a portion of the sample sensor extending from a non-self-supporting housing. [Figure 44] This is a schematic perspective view of a magnetic field control structure for a continuous sample sensor system. [Figure 45] This is a schematic perspective view of an electromagnetic field control structure for a continuous sample sensor system. [Figure 46] This figure shows a uniformly scaled graph illustrating the typical fatigue characteristics of various soft sample sensors. [Figure 47] This figure shows a logarithmic scale graph illustrating the typical fatigue characteristics of various soft sample sensors. [Figure 48] This figure shows a graph illustrating the typical buckling force characteristics of a flexible sample sensor. [Modes for carrying out the invention]

[0022] Throughout the document, similar reference numbers refer to similar elements. Elements are not scaled to scale unless otherwise specified.

[0023] The following description and examples illustrate in detail several exemplary implementations, embodiments, and configurations of the disclosed invention. Those skilled in the art will recognize that there are numerous variations and modifications of the invention that fall within the scope of the invention. Therefore, the description of some exemplary embodiments should not be considered limiting to the scope of the invention.

[0024] definition To facilitate understanding of the various embodiments described herein, numerous terms are defined below.

[0025] As used herein, the term “specimen” is a broad term, and given its ordinary and conventional meaning to those skilled in the art (not limited to its special meaning or meaning adapted to specific conditions), it further refers, but is not limited to, substances or chemical components in biological fluids (e.g., blood, interstitial fluid, cerebrospinal fluid, lymph, or urine) that can be analyzed. A specimen may include natural substances, artificial substances, metabolites, and / or reaction products. In some embodiments, a specimen is a specimen for measurement by a sensor head, device, and method. However, without limitation, acarboxyprothrombin, acylcarnitine, adenine phosphoribosyltransferase, adenosine deaminase, albumin, alpha-fetoprotein, amino acid composition (arginine (Krebs cycle), histidine / urocanic acid, homocysteine, phenylalanine / tyrosine, tryptophan), androstenedione, antipyrine, arabinitol optical isomer, arginase, benzoylecgonine (cocaine), biotinidase, biopterin, C-reactive protein, carnitine, carnosinase, CD4, ceruloplasmin, chenodeoxycholic acid, chloroquine, cholesterol, cholinesterase, conjugated 1-β-hydroxycholic acid, cortisol, creatine kinase, creatine kinase MM isoenzyme, cyclosporine A, D-penicillamine, deethylchloroquine Dehydroepiandrosterone sulfate, DNA (acetylation polymorphism), alcohol dehydrogenase, α1-antitrypsin, cystic fibrosis, Duchenne / Becker muscular dystrophy, specimen-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, β-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber's hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, sex differentiation, 21-deoxycortisol), desbutylhalofantrin, dihydropteridine reductase, diphtheria / tetanus antitoxin, erythrocyte arginase, erythrocyte protoporphyrin, esterase D, fatty acids / acylglycine, free β-human chorionic gonadotropin, free erythrocyte porphyrin, free thyroxine (FT4),Free triiodothyronine (FT3), fumarylacetase, galactose / galactose-1-phosphate, galactose-1-phosphate uridyltransferase, gentamicin, sample-6-phosphate dehydrogenase, glutathione, glutathione peroxidase, glycocholic acid, glycosylated hemoglobin, halophanthrin, hemoglobin variant, hexosaminidase A, human erythrocyte carbonic anhydrase I, 17-α-hydroxyprogesterone, hypoxanthine phosphoribosyltransferase, immunoreactive Lipsin, lactate, lead, lipoprotein ((a), B / Al, β), lysozyme, mefloquine, netylmycin, phenobarbiton, phenytoin, phytan / pristanic acid, progesterone, prolactin, prolidase, purine nucleoside phosphorylase, quinine, inverted triiodothyronine (rT3), selenium, serum pancreatic lipase, shisomycin, somatomedin C, specific antibodies (adenovirus, antinuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's disease virus, dengue virus, guinea pig, tapeworm, dysentery Meba, Enterovirus, Giardia lamblia, Helicobacter pylori, Hepatitis B virus, Herpesvirus, HIV-1, IgE (Atopic disease), Influenza virus, Donovan's leishmania, Leptospirosis, Measles / Mumps / Rubella, Leprosy, Mycoplasma pneumoniae, Myoglobin, Irocystida, Parainfluenza virus, Plasmodium falciparum, Poliovirus, Pseudomonas aeruginosa, Respiratory syncytial virus, Rickettsia (Grassland fever), Schistosomiasis mansoni, Toxoplasma gondii, Treponema pallidum, Creutzia Other specimens are also intended, including those containing Trypanosoma sulcata / Langer's Trypanosoma, vesicular stomatitis virus, Wuchereria bancrofti, yellow fever virus), specific antigens (hepatitis B virus, HIV-1), succinylacetone, sulfadoxine, theophylline, thyroid-stimulating hormone (TSH), thyroxine (T4), thyroxine-binding globulin, trace elements, transferrin, UDP-galactose-4-epimerase, urea, uroporphyrinogen I synthase, vitamin A, leukocytes, and zinc protoporphyrin. Naturally occurring salts, sugars, proteins, fats, vitamins, and hormones in blood or interstitial fluid are also included.In some embodiments, the sample may be something that is naturally present in biological fluids, such as metabolites, hormones, antigens, antibodies, etc. Alternatively, the sample may be something that is introduced into the body, such as a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based artificial blood, or a drug or pharmaceutical composition, which are not limited to insulin, ethanol, cannabis (marijuana, tetrahydrocannabinol, hashish), inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons), cocaine (crack cocaine), stimulants (amphetamine, methamphetamine, Ritalin, Cylart, Preludin, Didrex, Prestate, Volanil, Sandrex, Pregin), This includes sedatives (tranquilizers such as barbiturates, methacarone, Valium, Librium, Miltown, Serax, Iquanil, and tranxen), hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin), narcotics (heroin, codeine, morphine, opium, meperidin, Percocet, Percodan, Tusionex, fentanyl, Darvon, Talwin, Romotil), designer drugs (fentanyl, meperidin, amphetamine, methamphetamine, and analogs of phencyclidine, e.g., ecstasy), anabolic steroids, and nicotine. Metabolites of drugs and pharmaceutical compositions are also intended as samples. For example, samples can also be analyzed of neurochemical compounds and other chemicals produced in the body, such as ascorbic acid, uric acid, dopamine, norepinephrine, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid (FHIAA).

[0026] The terms “microprocessor” and “processor” as used herein are broad terms, and are given their ordinary and conventional meanings to those skilled in the art (not limited to any special meaning or meaning adapted to any particular condition), but do not limit them to computer systems, state machines, and similar devices that respond to and perform arithmetic logic operations using logic circuits that process basic instructions.

[0027] The term “calibration” as used herein is a broad term, given its ordinary and conventional meaning to those skilled in the art (not limited to its special meaning or meaning adapted to special conditions), and further, but not limited to, the process of determining the relationship between sensor data and corresponding reference data, which may be used to convert sensor data into meaningful values ​​substantially equivalent to the reference data, either with or without real-time use of the reference data. In some embodiments, i.e., in a continuous sample sensor, calibration may be updated or recalibrated over time when changes in the relationship between sensor data and reference data occur, for example, due to changes in sensitivity, baseline, transport, metabolism, and the like (at the factory, in real time, and / or retrospectively).

[0028] The terms “calibration data” and “calibration data stream” as used herein are broad terms, and are given their ordinary and conventional meanings to those skilled in the art (not limited to special meanings or meanings tailored to specific conditions), and further, but not limited to, data transformed from a raw state to another state using a function, such as a transformation function, including by the use of sensitivity, in order to provide meaningful values ​​to the user.

[0029] As used herein, the term “algorithm” is a broad term, and given its ordinary and conventional meaning to those skilled in the art (not limited to its special meaning or meaning adapted to specific conditions), it refers to a computational process (e.g., a program) that involves transforming information from one state to another, for example, by using computer processing.

[0030] As used herein, the term “count” is a broad term, given its ordinary and conventional meaning to those skilled in the art (without being limited to any special meaning or meaning adapted to specific conditions), and further, though not limited, refers to a unit of measurement of a digital signal. In one example, a raw data stream measured in units of counts is directly related to voltage (e.g., converted by an A / D converter) and directly related to current from the working electrode.

[0031] As used herein, the term “sensor” is a broad term, given its ordinary and conventional meaning to those skilled in the art (not limited to its special meaning or meaning adapted to specific conditions), and further, without limitation, refers to a component or area of ​​a device that can quantify a sample. A “lot” of sensors generally refers to a group of sensors manufactured on the same day or around the same time, using the same process and tools / materials.

[0032] The terms “glucose sensor” and “component for determining the amount of glucose in a biological sample” as used herein are broad terms, and are given their usual and conventional meanings to those skilled in the art (not limited to special meanings or meanings adapted to special conditions), and further, but not limited to, any mechanism (e.g., enzymatic or non-enzymatic) capable of quantifying glucose. For example, in some embodiments, a membrane containing glucose oxidase that catalyzes the conversion of oxygen and glucose to hydrogen peroxide and gluconate is utilized, which Glucose + O2 → Gluconate H2O2 This is illustrated by the following chemical reaction.

[0033] Since there are proportional changes in the co-reacting compound O2 and the product H2O2 for each glucose molecule being metabolized, the glucose concentration can be determined by monitoring the current change in either the co-reacting compound or the product using electrodes.

[0034] The terms “operably connected” and “operably linked,” as used herein, are broad terms, and given their ordinary and conventional meanings to those skilled in the art (not limited to their special meanings or meanings adapted to specific conditions), they refer, but not limited to, to one or more components being linked to another component in a manner that enables the transmission of signals between those components. For example, one or more electrodes may be used to detect the amount of glucose in a sample and convert that information into a signal, such as an electrical or electromagnetic signal, which may be transmitted to an electronic circuit. In this case, the electrodes are “operably linked” to the electronic circuit. These terms are broad enough to include wireless connectivity.

[0035] The term "decide" encompasses a wide variety of actions. For example, "deciding" can include calculating, computing, processing, deriving, investigating, searching (e.g., searching within a table, database, or other data structure), confirming, and similar actions. It can also include receiving (e.g., receiving information), accessing (e.g., accessing data in memory), and similar actions. Furthermore, it can include resolving, selecting, choosing, calculating, deriving, confirming, and / or similar actions. Deciding can also include confirming that a parameter matches a given criterion, including that the threshold criterion is met, passed, or exceeded.

[0036] The term “substantially” as used herein is a broad term, given its ordinary and conventional meaning to those skilled in the art (not limited to its special meaning or meaning adapted to special conditions), and further, without limitation, refers to the majority but not necessarily the whole, of what is specified.

[0037] As used herein, the term “host” is a broad term, given its ordinary and conventional meaning to those skilled in the art (not limited to any special meaning or meaning adapted to specific conditions), and further, without limitation, refers to mammals, especially humans.

[0038] As used herein, the term “continuous sample (or glucose) sensor” is a broad term, and given its ordinary and conventional meaning to those skilled in the art (without being limited to its special meaning or meaning adapted to special conditions), it refers to a device that measures the concentration of a sample continuously or in a continuous manner, for example, at time intervals ranging from fractions of a second to a maximum of, for example, 1, 2, or 5 minutes or more. In one exemplary embodiment, the continuous sample sensor is a glucose sensor, such as that described in U.S. Patent No. 6,001,067, which is incorporated herein by reference in its entirety.

[0039] The term “continuous sample (or glucose) sensing” as used herein is a broad term, given its ordinary and conventional meaning to those skilled in the art (and not limited to its special meaning or meaning adapted to specific conditions), and further, without limitation, refers to a period during which the monitoring of a sample is performed continuously or in a continuous manner, for example, at time intervals ranging from fractions of a second to a maximum of, for example, one, two, or five minutes or more.

[0040] As used herein, the term “sensing membrane” is a broad term, given its ordinary and conventional meaning to those skilled in the art (not limited to its special meaning or meaning adapted to specific conditions), and moreover, it may consist of two or more domains, and typically refers to a permeable or semipermeable membrane made of a material several microns or more thick that is permeable to oxygen but may or may not be permeable to glucose. In one example, the sensing membrane contains an immobilized glucose oxidase enzyme, which can undergo an electrochemical reaction to measure glucose concentration.

[0041] As used herein, the term “sensor data” is a broad term, given its ordinary and conventional meaning to those skilled in the art (without being limited to its special meaning or meaning adapted to specific conditions), and further, without limitation, refers to any data associated with a sensor, such as a continuous sample sensor. Sensor data includes a raw data stream of analog or digital signals (or other signals received from another sensor) directly relating to a measured sample from a sample sensor, or simply a data stream, and even calibrated and / or filtered raw data. In one example, sensor data includes digital data in units of “counts” converted from an analog signal (e.g., voltage or current) by an A / D converter, and includes one or more data points representing glucose concentration. Thus, the terms “sensor data point” and “data point” generally refer to a digital representation of sensor data at a specific time. These terms, in a broad sense, encompass multiple data points spaced over time from a sensor, such as a substantially continuous glucose sensor, including individual measurement results obtained at time intervals ranging from fractions of a second to, for example, 1, 2, or 5 minutes or more. In another example, sensor data may include integrated digital values ​​representing one or more data points averaged over a period of time. Sensor data may also include calibrated data, smoothed data, filtered data, transformed data, and / or other data associated with the sensor.

[0042] As used herein, the term “sensor electronic equipment” is a broad term and refers to any component of a device configured to process data, including, but not limited to, its ordinary and conventional meaning to those skilled in the art (and not limited to any special or specific meaning).

[0043] The terms “sensitivity” or “sensor sensitivity” as used herein are broad terms and are given their ordinary and conventional meanings to those skilled in the art (not limited to special meanings or meanings adapted to special conditions), and further, but not limited to, the amount of signal produced by the concentration of the measured sample, or the measured chemical species (e.g., H2O2) associated with the measured sample (e.g., glucose). For example, in one embodiment, the sensor has a sensitivity of about 1 to about 300 picoamperes of current for every 1 mg / dL of glucose sample.

[0044] As used herein, the term “sample” is a broad term and refers to a sample of a host body, including, but not limited to, body fluids, such as blood, serum, plasma, interstitial fluid, cerebrospinal fluid, lymph, eye fluid, saliva, oral fluid, urine, excrement, or exudate, in its ordinary and conventional sense to those skilled in the art.

[0045] The term “calibration” as used herein is a broad term and refers to the relationship between sensor data and corresponding reference data and / or the process of determining that relationship, but is not limited to its ordinary and conventional meaning to those skilled in the art (and is not limited to any special meaning or meaning adapted to specific conditions). In some embodiments, i.e., in a continuous sample sensor, calibration may be updated or recalibrated over time if changes in the relationship between sensor data and reference data occur, for example, due to changes in sensitivity, baseline, transport, metabolism, and the like.

[0046] The terms “continuous” or “sequentially” as used herein in relation to sample sensing are broad terms and are given their usual and conventional meanings to those skilled in the art (not limited to any special meanings or meanings adapted to specific conditions), but refer to continuous, ongoing, or intermittent (e.g., periodic) monitoring of sample concentration, such as performing measurements approximately every 1 to 10 minutes. A continuous sample sensor will be understood to generally measure sample concentration continuously without requiring any initial user operation and / or interaction for each measurement, as described for a continuous glucose sensor in, for example, U.S. Patent No. 6,001,067. These terms include situations where data gaps may exist (e.g., when a continuous glucose sensor is temporarily not providing data).

[0047] As used herein, the term “count” is a broad term and refers to a unit of measurement of a digital signal, given its ordinary and conventional meaning to those skilled in the art (not limited to any special meaning or meaning adapted to specific conditions). For example, a raw data stream or raw data signal measured in units of counts may directly relate to a voltage (e.g., converted by an A / D converter) that directly relates to a current from the working electrode. In some embodiments, these terms may refer to data integrated or averaged over a certain time period (e.g., 5 minutes).

[0048] As used herein, the term “crosslinking” is a broad term, and is given its usual and conventional meaning to those skilled in the art (not limited to any special meaning or meaning adapted to specific conditions), but refers to the formation of a chemical bond (e.g., a covalent bond, an ionic bond, a hydrogen bond, etc.) that links one polymer (or oligomer) chain to another, or a process that increases the bonding strength of one polymer (or oligomer) chain to the other. Crosslinking can be formed, for example, through various reactions or processes, such as chemical processes initiated by heat, pressure, catalysts, radiation, and the like.

[0049] The term "distal to..." as used herein is a broad term, and is given its usual and conventional meaning to those skilled in the art (not limited to any special meaning or meaning adapted to specific conditions), but refers to the spatial relationship between various elements relative to a particular reference point. Generally, this term indicates that one element is located farther from the reference point than another element.

[0050] The term "proximal to..." as used herein is a broad term, and is given its usual and conventional meaning to those skilled in the art (not limited to any special meaning or meaning adapted to specific conditions), but refers to the spatial relationship between various elements relative to a particular reference point. Generally, this term indicates that one element is located closer to the reference point than another element.

[0051] The terms “electrochemical reaction surface” and “electroactive surface” as used herein are broad terms, and are given their usual and conventional meanings to those skilled in the art (not limited to special meanings or meanings adapted to special conditions), but refer to any surface on which an electrochemical reaction occurs. As a non-limiting example, in an electrochemical glucose sensor, the working electrode measures hydrogen peroxide (H2O2) on an electroactive surface. Hydrogen peroxide is produced by an enzymatic catalyzed reaction of the detected sample and reacts with the electroactive surface to generate a detectable current. For example, glucose can be detected using glucose oxidase (GOX), which produces hydrogen peroxide as a byproduct. Hydrogen peroxide reacts with the surface of the working electrode (e.g., the electroactive surface) and reacts with two protons (2H2O2). + ), 2 electrons (2e - ), and one oxygen molecule (O2) are produced, generating a detectable electric current.

[0052] The terms “electrical connection” and “electrical contact” as used herein are broad terms and refer to any connection between two conductors known to those skilled in the art, given their ordinary and conventional meanings (not limited to any special meaning or meaning adapted to a special condition). In one embodiment, electrodes are in an electrically connected state (e.g., electrically connected) to the electronic circuitry of a device. In another embodiment, however, two materials, such as two metals, may be in electrical contact with each other so that an electric current can flow from one of the two materials to the other.

[0053] As used herein, the terms “electronic equipment,” “sensor electronic equipment,” and “system electronic equipment” are broad terms and are given their ordinary and conventional meanings to those skilled in the art (not limited to any special meanings or meanings adapted to specific conditions), and refer to electronic equipment configured to be operablely coupled to a sensor and to measure, process, receive, and / or transmit data associated with the sensor, and / or electronic equipment configured to communicate with a flow control device, to control, and / or monitor fluid metering by the flow control device.

[0054] The term “elongated conductor” as used herein is a broad term and is given its ordinary and conventional meaning to those skilled in the art (not limited to its special meaning or meaning adapted to special conditions), and does not limit itself to an elongated body formed at least partially of a conductive material and including any number of coatings that may be formed thereon. For example, “elongated conductor” may mean a bare elongated conductive core (e.g., a metal wire), an elongated conductive core coated with one, two, three, four, five or more layers of material, each of which may or may not be conductive, or an elongated non-conductive core having conductive coatings, traces, and / or electrodes, each of which may or may not be conductive, and coated with one, two, three, four, five or more layers of material.

[0055] As used herein, the term “host” is a broad term, and is given its usual and conventional meaning to those skilled in the art (not limited to any special meaning or meaning adapted to specific circumstances), but does not refer to plants or animals, such as humans.

[0056] As used herein, the term “extrabiotic component” is a broad term and refers, in its ordinary and conventional sense to those skilled in the art (not limited to its special or specific meaning), to any part of a device (e.g., a sensor) adapted to remain and / or be present outside the host organism.

[0057] As used herein, the term “in vivo part” is a broad term and refers, in its ordinary and conventional sense to those skilled in the art (not limited to its special or specific meaning), to any part of a device (e.g., a sensor) that is inserted into and / or adapted to be present within the body of a host.

[0058] As used herein, the term “multiaxial bending” is a broad term, and is given its usual and conventional meaning to those skilled in the art (not limited to any special meaning or meaning adapted to specific conditions), but it refers to a preference for bending in multiple planes or around multiple axes.

[0059] The terms “operatably connected,” “operatably linked,” “operatably connected,” and “operatably linked,” as used herein, are broad terms and refer to one or more components linked to one or more other components, with their ordinary and conventional meanings to those skilled in the art (not limited to any special meaning or meaning adapted to a particular condition). These terms may refer to mechanical connections, electrical connections, or any connection that enables the transmission of signals between components. For example, one or more electrodes may be used to detect the amount of a sample in a specimen and convert that information into a signal, which can be transmitted to a circuit. In such an example, the electrodes are “operatably linked” to an electronic circuit. These terms include wired and wireless connections.

[0060] As used herein, the term “potentiostat” is a broad term and refers to an electronic device that controls the potential between a working electrode and a reference electrode in one or more preset values, given its ordinary and conventional meaning to those skilled in the art (but not limited to any special meaning or meaning adapted to specific conditions).

[0061] The term “processor module” as used herein is a broad term and is given its ordinary and conventional meaning to those skilled in the art (not limited to any special meaning or meaning adapted to any particular condition), but does not limit itself to computer systems, state machines, processors, their components, and similar devices that are designed to perform arithmetic or logical operations using logic circuits that process basic instructions and drive the computer.

[0062] The terms “raw data,” “raw data stream,” “raw data signal,” “data signal,” and “data stream,” as used herein, are broad terms and refer to analog or digital signals from a sample sensor that directly relate to the sample being measured, without being limited to their ordinary and conventional meanings to those skilled in the art (and not limited to any special meanings or meanings adapted to specific conditions). For example, a raw data stream is digital data in units of “counts” converted by an A / D converter from an analog signal (e.g., voltage or current) representing the sample concentration. These terms may broadly include multiple data points spaced over time from a substantially continuous sample sensor, each containing individual measurement results obtained at time intervals ranging from fractions of a second to, for example, 1, 2, or 5 minutes or more. In some embodiments, these terms may refer to data integrated or averaged over a certain time period (e.g., 5 minutes).

[0063] As used herein, the terms “sensor” and “sensor system” are broad terms, and refer to any device, component, or area of ​​device that can quantify a sample, in their ordinary and conventional sense to those skilled in the art (not limited to any special sense or sense adapted to specific conditions).

[0064] As used herein, the term “sensor session” is a broad term and is given its ordinary and conventional meaning to those skilled in the art (not limited to any special meaning or meaning adapted to specific conditions), but refers to a period of time during which a sensor is in use, for example, but not limited to the time the sensor is implanted (for example, by a host) and the time the sensor is removed (for example, the removal of the sensor from the host’s body and / or the system electronics (for example, disconnection from the system electronics)).

[0065] As used herein, the terms “membrane system” and “membrane” are broad terms, and are given their ordinary and conventional meanings to those skilled in the art (not limited to any special meaning or meaning adapted to specific conditions), but refer to a permeable or semipermeable membrane that may consist of one or more layers and be permeable to oxygen, but may or may not be permeable to the sample of interest. In one example, the membrane system includes an immobilized glucose oxidase enzyme, which can undergo an electrochemical reaction to measure glucose concentration.

[0066] The terms “substantial” and “substantially” as used herein are broad terms, and are given their ordinary and conventional meanings to those skilled in the art (not limited to any special meaning or meaning adapted to specific conditions), but refer to a sufficient amount to impart the desired function.

[0067] Within the following explanation, in some cases, other definitions may be presented depending on the context in which the term is used.

[0068] As used herein, the following abbreviations are used: Eq and Eqs (equivalents), mEq (milliequivalents), M (molar concentration), mM (millimolear concentration), μM (micromolar concentration), N (normality), mol (mol), mmol (millimole), μmol (micromolar), nmol (nanomole), g (gram), mg (milligram), μg (microgram), Kg (kilogram), L (liter), mL (milliliters), dL (decimeters). The following units are applicable: siliters, microliters (μL), centimeters (cm), millimeters (mm), micrometers (μm), nanometers (nm), hours (h and hr), minutes (min), seconds (s and sec), Celsius (℃), Fahrenheit (℃), Pascals (Pa), kilopascals (kPa), megapascals (MPa), gigapascals (GPa), pounds per square inch (Psi), and kilopounds per square inch (kPsi).

[0069] System Overview / General Description In vivo continuous sample sensing technology may rely on in vivo sensors having a stiffness (e.g., stiffness defined by Young's modulus, flexural modulus, and / or buckling force) determined based on minimum stiffness to ensure successful coating of the sensor within the membrane and smooth glucose concentration measurement.

[0070] Young's modulus, also known as the modulus of elasticity, is a mechanical property of linear elastic solid materials that defines the relationship between stress (force per unit area) and strain (proportional deformation) in a material. The flexural modulus is an intensile property of an object that can be calculated as the stress-to-strain ratio in bending deformation, or as the tendency of a material to bend. The flexural modulus of an object is often determined from the slope of the stress-strain curve produced by a bending test (such as the ASTM D 790 bending test) and can be expressed in units of force per unit area. For isotropic materials such as metals in some configurations, Young's modulus and flexural modulus may be the same. However, for some objects, such as elongated polymer objects, the flexural modulus may differ from Young's modulus. Buckling force can be defined as the maximum compressive load that can be applied to an object until buckling occurs.

[0071] For example, metal-clad tantalum wires are sometimes used as bare core sensing elements for continuous sample sensors. These sensing elements are coated within a membrane to form the final sensor. The overall stiffness of the sensor in these configurations can be considerably higher than that of the surrounding skin and adipose tissue. It has been found that this type of stiffness mismatch can cause a fundamental compliance mismatch that can worsen the foreign body giant cell response to the sensor in vivo. Essentially, the difference in stiffness between the sensor and the surrounding tissue can lead to increased stress at the interface between the tissue and the sensor as movement increases. Because the sensor is stiffer, this can cause additional damage to the surrounding tissue after the initial injury, thus reactivating the inflammatory cascade.

[0072] A wide range of elastic moduli have been reported for various skin layers: 5-1000 MPa for the stratum corneum with water loss, 56-260 kPa for the dermis, and 0.12-23 kPa for SubQ tissue. The Young's modulus of tantalum core sensors can be as high as 27 × 10^6 psi or 186 GPa, which is more than 6000 times the Young's modulus of living skin tissue (for example, Young's modulus in the range of 0.1-260 kPa for tissues other than the stratum corneum). This poses a significant problem for biomechanical compatibility.

[0073] This specification describes a flexible specimen sensor for continuous specimen monitoring with enhanced biocompatibility. The systems and methods described herein provide a reduced modulus mismatch sensor with a flexible tissue-compatible core to improve device-tissue interaction. The flexible specimen sensor described herein offers improved biocompatibility while maintaining mechanical properties that facilitate manufacturing operations such as coating processes for the sensor. The flexible specimen sensor described herein can reduce post-insertion injury from micromovements and minimize sensor noise caused by tissue damage.

[0074] The following description and examples illustrate embodiments of the present invention with reference to the drawings. In the drawings, elements of the embodiments of the present invention are labeled with reference numerals. These reference numerals are reproduced below in relation to the descriptions of the features of the corresponding drawings.

[0075] Sensor system Figure 1 shows an exemplary system 100 in several exemplary implementation configurations. System 100 comprises a continuous sample sensor system 101 comprising a sensor electronic device 112 and a continuous sample sensor 110. System 100 may include other devices and / or sensors, such as a drug delivery pump 102 and a glucose meter 104. The continuous sample sensor 110 may be physically connected to the sensor electronic device 112 and may be integrated with the continuous sample sensor 110 (e.g., permanently mounted) or may be detachably mounted to the continuous sample sensor 110. The sensor electronic device 112, the drug delivery pump 102, and / or the glucose meter 104 may be coupled with one or more devices, such as display devices 114, 116, 118, and / or 120.

[0076] In some exemplary implementations, System 100 may include a cloud-based sample processor 490 configured to analyze sample data (and / or other patient-related data) provided via Network 406 (e.g., via wired, wireless, or a combination thereof) from other devices associated with a host (also referred to as a patient), such as a sensor system 101 and display devices 114, 116, 118, and / or 120, and to generate a report providing high-level information, such as statistics, with respect to samples measured over a specific time frame. A detailed description of using a cloud-based sample processing system is found in U.S. Patent Application No. 13 / 788,375, “Cloud-Based Processing of Analyte Data,” filed on March 7, 2013, which is incorporated herein by reference in its entirety. In some implementations, one or more steps of a factory calibration algorithm can be performed in the cloud.

[0077] In some exemplary implementations, the sensor electronic device 112 may include electronic circuitry associated with measuring and processing data generated by the continuous sample sensor 110. This generated continuous sample sensor data may also include algorithms that can be used to process and calibrate the continuous sample sensor data, although these algorithms may be provided in other ways. The sensor electronic device 112 may include hardware, firmware, software, or a combination thereof for providing measurement of sample levels via a continuous sample sensor, such as a continuous glucose sensor. An exemplary implementation of the sensor electronic device 112 is described further below with reference to Figure 2.

[0078] In one implementation, the factory calibration algorithm described herein may be performed by sensor electronic equipment.

[0079] As noted, the sensor electronic device 112 may be coupled (for example, wirelessly and similarly) with one or more devices, such as display devices 114, 116, 118, and / or 120. The display devices 114, 116, 118, and / or 120 may be configured to present information (and / or issue alarms), such as sensor information transmitted by the sensor electronic device 112 for display on the display devices 114, 116, 118, and / or 120.

[0080] The display devices may include a relatively small key fob-like display device 114, a relatively large handheld display device 116, a mobile phone 118 (e.g., a smartphone, tablet, and similar), a computer 120, and / or other user devices configured to display at least information (e.g., drug delivery information, discrete self-monitoring glucose readings, heart rate monitors, calorie intake monitors, and similar).

[0081] In one implementation, the factory calibration algorithm described herein may be performed, at least in part, by the display device.

[0082] In some exemplary implementations, the relatively small, key fob-like display device 114 may include a wristwatch, belt, necklace, pendant, jewelry, adhesive patch, pager, key fob, plastic card (e.g., credit card), identification (ID) card, and / or similar. This small display device 114 may have a relatively small display (e.g., smaller than the large display device 116) and may be configured to display several types of displayable sensor information, such as numbers and arrows or color codes.

[0083] In some exemplary implementations, the relatively large handheld display device 116 may include a handheld receiver device, a palmtop computer, and / or similar. This large display device may have a relatively large display (for example, larger than the small display device 114) and may be configured to display information such as a graph display of continuous sensor data, including current sensor data and historical sensor data output by the sensor system 100.

[0084] In some exemplary implementations, the continuous sample sensor 110 comprises a sensor for detecting and / or measuring a sample, and the continuous sample sensor 110 may be configured to continuously detect and / or measure a sample as a non-invasive device, subcutaneous device, transcutaneous device, and / or intravascular device. In some exemplary implementations, the continuous sample sensor 110 may analyze multiple intermittent blood samples, but other samples may also be used.

[0085] In some exemplary implementations, the continuous sample sensor 110 may include a glucose sensor configured to measure glucose in blood or interstitial fluid using one or more measurement techniques such as enzymatic measurement, chemical measurement, physical measurement, electrochemical measurement, spectrophotometric measurement, polarization measurement, calorimetry, iontophoresis measurement, radiometric measurement, immunochemical measurement, and similar measurements. In implementations where the continuous sample sensor 110 includes a glucose sensor, the glucose sensor may include a device capable of measuring glucose concentration and may measure glucose using a variety of techniques, including invasive, minimally invasive, and non-invasive sensing techniques (e.g., fluorescence monitoring), and provide data such as a data stream indicating the concentration of glucose in the host body. The data stream may be sensor data (raw and / or filtered data) that can be converted into a calibrated data stream used to provide glucose values ​​to the host, such as a user, patient, or caregiver (e.g., parent, relative, guardian, teacher, doctor, nurse, or other individual interested in the host's health). Furthermore, the continuous sample sensor 110 may be implanted as at least one of the following soft sample sensors: an implantable glucose sensor, a transcutaneous glucose sensor implanted in or placed outside the host's blood vessels, a subcutaneous sensor, a refillable subcutaneous sensor, or an intravascular sensor.

[0086] While the disclosure herein refers to several implementations comprising a continuous sample sensor 110 including a glucose sensor, the continuous sample sensor 110 may also include other types of flexible sample sensors. Furthermore, while some implementations refer to the glucose sensor as an embedded glucose sensor, other types of devices capable of detecting glucose concentration and providing an output signal representing glucose concentration may also be used. In addition, while the description herein refers to glucose as a sample to be measured, processed, and similarly operated, other samples may also be used, including, for example, ketone bodies (e.g., acetone, acetoacetate, and β-hydroxybutyrate, lactate, etc.), glucagon, acetyl-CoA, triglycerides, fatty acids, intermediates in the citric acid cycle, choline, insulin, cortisol, testosterone, and similar substances.

[0087] Figure 2 shows an example of a sensor electronic device 112 in several exemplary implementation forms. The sensor electronic device 112 may include a sensor electronic device configured to process sensor information, such as sensor data, via a processor module, and to generate transformed sensor data and displayable sensor information. For example, the processor module may transform the sensor data into one or more of the following: filtered sensor data (e.g., one or more filtered sample concentration values), raw sensor data, calibrated sensor data (e.g., one or more calibrated sample concentration values), rate of change information, trend information, acceleration / deceleration rate information, sensor diagnostic information, location information, alarm / alert information, calibration information which may be determined by a factory calibration algorithm such as those disclosed herein, sensor data smoothing and / or filtering algorithms, and / or similar.

[0088] In some embodiments, the processor module 214 is configured to accomplish a substantial, but not all, portion, of the data processing, including data processing related to factory calibration. The processor module 214 may be integrated with the sensor electronics 12 and / or located remotely, such as within one or more of the devices 114, 116, 118, and / or 120 and / or the cloud 490. In some embodiments, the processor module 214 may include a plurality of smaller subcomponents or submodules. For example, the processor module 214 may include an alert module (not shown) or a predictive module (not shown), or other suitable modules that can be used to efficiently process data. When the processor module 214 consists of a plurality of submodules, the submodules may be located within the processor module 214, including within the sensor electronics 112 or other associated devices (e.g., 114, 116, 118, 120, and / or 490). For example, in some embodiments, the processor module 214 may be located at least partially within the cloud-based sample processor 490, or elsewhere within the network 406.

[0089] In some exemplary implementations, the processor module 214 may be configured to calibrate sensor data, and the data storage memory 220 may store calibrated sensor data points as converted sensor data. Furthermore, in some exemplary implementations, the processor module 214 may be configured to wirelessly receive calibration information from a display device, such as devices 114, 116, 118, and / or 120, in order to enable calibration of sensor data from the sensor 110. Furthermore, the processor module 214 may be configured to perform additional algorithmic processing on the sensor data (e.g., calibrated and / or filtered data and / or other sensor information), and the data storage memory 220 may be configured to store converted sensor data and / or sensor diagnostic information associated with the algorithm. The processor module 214 may be further configured to store and use calibration information determined from factory calibration, as described below.

[0090] In some exemplary implementations, the sensor electronics 112 may include an application-specific integrated circuit (ASIC) 205 coupled to a user interface 222. The ASIC 205 may further include a potentiostat 210, a telemetry module 232 for transmitting data from the sensor electronics 112 to one or more devices such as devices 114, 116, 118, and / or 120, and / or other components for signal processing and data storage (e.g., a processor module 214 and a data storage memory 220). Figure 2 shows the ASIC 205, but other types of circuitry may also be used, including a field-programmable gate array (FPGA), one or more microprocessors configured to provide (if not all) of the processing performed by the sensor electronics 12, analog circuits, digital circuits, or a combination thereof.

[0091] In the example shown in Figure 2, the potentiostat 210 is coupled to a continuous sample sensor 110, such as a glucose sensor, to generate sensor data from the sample via a first input port 211 for sensor data. The potentiostat 210 may also provide a voltage to the continuous sample sensor 110 via a data line 212, biasing the sensor to the measurement of a value indicating the sample concentration in the host (e.g., current and similar) (also referred to as the analog portion of the sensor). The potentiostat 210 may have one or more channels depending on the number of working electrodes of the continuous sample sensor 110.

[0092] In some exemplary implementations, the potentiostat 210 may include a resistor that converts the current value from the sensor 110 into a voltage value, while in some exemplary implementations, a current-frequency converter (not shown) may also be configured to continuously integrate the measured current value from the sensor 110, for example, using a charge counting device. In some exemplary implementations, an analog-to-digital converter (not shown) may binarize the analog signal from the sensor 110 into a so-called "count" to enable processing by the processor module 214. The resulting count may be directly related to the current measured by the potentiostat 210, which may be directly related to a sample level, such as glucose levels in the host body.

[0093] The telemetry module 232 may be operably connected to the processor module 214 and may provide hardware, firmware, and / or software that enables wireless communication between the sensor electronics 112 and one or more other devices such as a display device, processor, network access device, and the like. Various wireless technologies that may be implemented in the telemetry module 232 include Bluetooth®, Bluetooth® Low-Energy, ANT, ANT+, and ZigBee. (Registered trademark)This includes IEEE 802.11, IEEE 802.16, cellular radio access technologies, radio frequency (RF), infrared (IR), paging network communications, magnetic induction, satellite data communications, spread spectrum communications, frequency hopping communications, near-field communications, and / or similar technologies. In some exemplary implementations, the telemetry module 232 includes a Bluetooth® chip, although Bluetooth® technology may be implemented in combination with the telemetry module 232 and the processor module 214.

[0094] The processor module 214 can control the processing performed by the sensor electronics 112. For example, the processor module 214 may be configured to process data from the processor (e.g., counts), filter the data, calibrate the data, perform fail-safe checks, and / or similar operations.

[0095] In some exemplary implementations, the processor module 214 may include a digital filter, such as an infinite impulse response (IIR) or finite impulse response (FIR) filter. This digital filter can smooth the raw data stream received from the sensor 110. Generally, the digital filter is programmed to filter data sampled at predetermined time intervals (also referred to as the sample rate). In some exemplary implementations, such as when the potentiostat 210 is configured to measure a sample (e.g., glucose and / or similar) at discrete time intervals, these time intervals determine the sampling rate of the digital filter. In some exemplary implementations, the potentiostat 210 may be configured to measure a sample continuously, for example, using a current-frequency converter. In these current-frequency converter implementations, the processor module 214 may be programmed to request digital values ​​from the integrator of the current-frequency converter at predetermined time intervals (capture time). These digital values ​​obtained from the integrator by the processor module 214 can be averaged over the capture time due to the continuity of the current measurement. In that sense, the capture time can be determined by the sampling rate of the digital filter.

[0096] The processor module 214 may further comprise a data generator (not shown) configured to generate data packages to be transmitted to devices such as display devices 114, 116, 118, and / or 120. Furthermore, the processor module 214 may generate data packets to be transmitted to these external sources via the telemetry module 232. In some exemplary implementations, the data packages may be customizable to each display device, as noted, and / or may include available data such as timestamps, displayable sensor information, converted sensor data, identifier codes for the sensor and / or sensor electronics 112, raw data, filtered data, calibrated data, rate of change information, trend information, error detection or correction, and / or similar.

[0097] The processor module 214 may also include program memory 216 and other memories 218. The processor module 214 may be coupled to a communication interface such as a communication port 238 and a power source such as a battery 234. Furthermore, the battery 234 may be further coupled to a battery charger and / or regulator 236 to supply power to the sensor electronics 12 and / or charge the battery 234.

[0098] The program memory 216 may be implemented as semi-static memory for storing data such as identifiers for the coupled sensor 110 (e.g., sensor identifiers (IDs)) and code (also referred to as program code) that configures the ASIC 205 to perform one or more of the operations / functions described herein. For example, the program code may configure the processor module 214 to process and filter data streams or counts, perform calibration methods described below, perform fail-safe checks, and perform similar operations.

[0099] Memory 218 may also be used to store information. For example, a processor module 214 having memory 218 may be used as a system cache memory to provide temporary storage for recent sensor data received from the sensor. In some exemplary implementations, memory may include memory storage components such as read-only memory (ROM), random access memory (RAM), dynamic RAM, static RAM, non-static RAM, easily erasable programmable read-only memory (EEPROM), rewritable ROM, flash memory, and similar.

[0100] The data storage memory 220 is often coupled to the processor module 214 and may be configured to store various sensor information. In some exemplary implementations, the data storage memory 220 stores one or more days of continuous sample sensor data. For example, the data storage memory may store 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, and / or 30 days (or more) of continuous sample sensor data received from the sensor 110. The stored sensor information may include one or more of the following: timestamp, raw sensor data (one or more raw sample concentration values), calibrated data, filtered data, converted sensor data, and / or other displayable sensor information, calibration information (e.g., pre-calibration information from reference BG values ​​and / or factory calibration), sensor diagnostic information, and similar information.

[0101] The user interface 222 may include various interfaces such as one or more buttons 224, a liquid crystal display (LCD) 226, a vibrator 228, an acoustic transducer (e.g., a speaker) 230, a backlight (not shown), and / or similar. Components with the user interface 222 may provide controls for interacting with a user (e.g., a host). One or more buttons 224 may enable, for example, toggles, menu selections, option selections, status selections, yes / no responses to on-screen questions, a "turn off" function (e.g., for alarms), an "acknowledged" function (e.g., for alarms), a reset, and / or similar. The LCD 226 may provide the user with, for example, visual data output. The acoustic transducer 230 (e.g., a speaker) may provide an audible signal in response to triggers for several alerts, such as current and / or predicted hyperglycemia and hypoglycemia. In some exemplary implementations, the audible signal may be distinguished by timbre, volume, duty cycle, pattern, duration, and / or similar. In some exemplary implementations, an audible signal may be configured to be silenced (e.g., acknowledged or turned off) by pressing one or more buttons 224 on the sensor electronic device 112 and / or by signaling to the sensor electronic device 112 using a button or selection on a display device (e.g., a key fob, a mobile phone, and / or similar).

[0102] While sound and vibration alarms are described with respect to Figure 2, other alarm generation mechanisms may also be used. For example, in several exemplary implementations, tactile alarms are provided that include a poking mechanism configured to “poke” or physically touch the patient in response to one or more alarm conditions.

[0103] The battery 234 may be connected in an operable manner to the processor module 214 (and possibly other components of the sensor electronics 12) to supply the necessary power to the sensor electronics 112. In some exemplary implementations, the battery is a lithium manganese dioxide battery, but any battery of appropriate size and power can be used (e.g., AAA batteries, nickel-cadmium batteries, zinc-carbon batteries, alkaline batteries, lithium batteries, nickel-metal hydride batteries, lithium-ion batteries, zinc-air batteries, zinc-mercury batteries, silver-zinc batteries, or sealed batteries). In some exemplary implementations, the battery is rechargeable. In some exemplary implementations, multiple batteries may be used to power the system. In yet another implementation, the receiver may be powered transcutaneously, for example, via inductive coupling.

[0104] The battery charger and / or regulator 236 may be configured to receive energy from an internal and / or external charger. In some exemplary implementations, the battery regulator (or balancer) 236 regulates the recharging process by reducing the excess charging current so that all cells or batteries in the sensor electronic device 112 are fully charged without overcharging other cells or batteries. In some exemplary implementations, (one or more) batteries 234 are configured to be charged via an inductive and / or wireless charging pad, but other charging and / or power supply mechanisms may also be used.

[0105] One or more communication ports 238, also referred to as external connectors, may be provided to enable communication with other devices, for example, a PC communication (com) port may be provided to enable communication with a system that is separate from or integrated with the sensor electronics 112. The communication ports may include, for example, serial (e.g., Universal Serial Bus or "USB") communication ports to enable communication with another computer system (e.g., a PC, personal digital assistant or "PDA", server, or similar). In some exemplary implementations, the sensor electronics 112 may transmit historical data to a PC or other computing device (e.g., a specimen processor as disclosed herein) for retrospective analysis by patients and / or physicians. As another example of data transmission, factory information may also be transmitted from the sensor or from a cloud data source to an algorithm.

[0106] One or more communication ports 238 may further comprise a second input port 237 from which calibration data can be received, and an output port 239 that may be used to transmit calibrated data, or data to be calibrated, to a receiver or mobile device. Figure 2 schematically illustrates these embodiments. While these ports may be physically separated, it will be understood that in alternative implementations, the functions of both the second input port and the output port may be provided by a single communication port.

[0107] In some continuous sample sensor systems, the skin-contacting portion of the sensor electronics is simplified to minimize the complexity and / or size of the skin-contacting electronics, and may provide only raw, calibrated, and / or filtered data to a display device configured to perform calibration and other algorithms necessary to display the sensor data. However, the sensor electronics 112 may be implemented (for example, via the processor module 214) to run a prospective algorithm used to generate converted sensor data and / or displayable sensor information, which includes an algorithm for evaluating the clinical acceptability of reference and / or sensor data; an algorithm for evaluating calibration data to perform the best calibration based on the patient criteria of the study; an algorithm for evaluating the quality of calibration; an algorithm for comparing the time corresponding to estimated sample values ​​with the time corresponding to measured sample values; an algorithm for analyzing the variability of estimated sample values; an algorithm for evaluating the stability of the sensor and / or sensor data; an algorithm for detecting signal artifacts (noise); an algorithm for replacing signal artifacts; an algorithm for determining the rate of change and / or trend of sensor data; an algorithm for performing dynamic and intelligent sample value estimation; an algorithm for performing diagnoses on the sensor and / or sensor data; an algorithm for setting operating modes; an algorithm for evaluating data for anomalies; and / or similar algorithms.

[0108] Although separate data storage and program memory are illustrated in Figure 2, various configurations can also be used. For example, one or more memories may be used to provide a storage space that can accommodate the data processing and storage requirements of the sensor electronic device 112.

[0109] Figure 3 shows an exemplary implementation of a continuous sample sensor system 101, in which at least a portion of the continuous sample sensor 110 is mounted together with a housing 300 (for example, positioned and configured outside the housing 300, with a portion extending from there for percutaneous insertion). The housing 300 may be a sensor electronic equipment housing that forms an enclosure for the sensor electronic equipment 112.

[0110] As shown in Figure 3, at least a portion of the continuous sample sensor 110 may extend from the opening 304 in the bottom surface 302 of the housing 300. The portion of the continuous sample sensor 110 extending from the housing 300 may be the portion of the sensor 110 that extends beyond the plane defined by the bottom surface 302 in some implementations. In various implementations, the portion of the continuous sample sensor 110 extending from the housing 300 may be a part of a continuous sample sensor having additional parts disposed within the housing 300 (for example, in an implementation where the interior or proximal end of the sensor 110 is coupled to the sensor electronics 112 at a location within the housing 300), or the portion of the continuous sample sensor 110 extending from the housing 300 may be substantially the entire continuous sample sensor (for example, in an implementation where the proximal end of the continuous sample sensor 110 is coupled to the sensor circuit 112 at or near the bottom surface 302 of the housing 300). The housing 300 may form a pod that is attached to the host's skin, with its bottom surface 302 in contact with the host's skin, and the continuous sample sensor 110 penetrating into the host's skin. For example, the bottom surface 302 may be to which a biocompatible adhesive can be attached to directly attach the bottom surface 302 to the host's skin or the housing 300, and / or it may be attached to the host's skin by surrounding adhesive or other attachment mechanisms.

[0111] In the example in Figure 3, the continuous sample sensor 110 is a substantially self-supporting sensor that maintains its shape and position without any supporting force, regardless of its orientation relative to gravity. In the configuration of Figure 3, the portion of the continuous sample sensor 110 extending from the housing 300 may have a Young's modulus in the range of, for example, 500 MPa to 147 GPa, a flexural modulus greater than, for example, 2 GPa or 5 GPa, and / or a buckling force greater than, for example, 0.25 Newtons (N), greater than 0.02 N, greater than 0.01 N, greater than 0.001 N, or greater than the weight of the portion of the sensor 110 itself under gravity, so that the portion of the continuous sample sensor 110 extending from the housing 300 in various mounting configurations is soft but self-supporting.

[0112] As shown in Figures 3 and 4, the sensor 110 may be formed from an elongated body such as an elongated conductor. In some implementations, as described in more detail below, the elongated conductor comprises an elongated conductive core. In other implementations, as described in more detail below, the elongated conductor comprises an elongated non-conductive core such as a polymer core or a fiber core. In other implementations, as described in more detail below, the elongated conductor comprises a plurality of substantially planar layers.

[0113] Figure 4 shows another exemplary configuration of the continuous sample sensor system 101, in which at least a portion of the continuous sample sensor 110 is mounted with a housing 300 extending in a non-freestanding configuration. In the configuration of Figure 4, the shape and position of the portion of the continuous sample sensor 110 extending with respect to the housing 300 may be affected by the orientation of the continuous sample sensor 110 and / or the housing 300 with respect to gravity and / or other forces such as contact forces or fluid forces from an external object or gas. The configuration of the continuous sample sensor 110 shown in Figure 4 may be described as a non-freestanding or "wet noodle" configuration.

[0114] The configurations shown in Figures 3 and 4 may illustrate different implementations of the continuous sample sensor 110 (e.g., a self-supporting and a non-self-supporting configuration, respectively), or the configurations shown in Figures 3 and 4 may represent different states of the same continuous sample sensor 110. For example, the configuration in Figure 3 may be an in vitro configuration in which the continuous sample sensor 110 is not yet implanted and is a self-supporting sensor. After implantation (e.g., insertion into the skin of a host), the continuous sample sensor 110 may, in some embodiments, transform into a non-self-supporting sensor in vivo.

[0115] As described in more detail below, the continuous sample sensor 110 may comprise an elongated conductor configured to be a self-supporting elongated conductor outside the body and a non-self-supporting elongated conductor inside the body, and configured to change from a self-supporting elongated conductor to a non-self-supporting elongated conductor in response to (i) contact between at least a portion of the elongated conductor and the patient's tissue, (ii) temperature changes over a transition temperature (e.g., a transition temperature in the range of 78°F to 100°F in some implementations), (iii) absorption of fluid (e.g., water) from the patient's tissue by at least a portion of the elongated conductor, (iv) biological and / or chemical reactions between the fluid from the patient's tissue and at least a portion of the elongated conductor, and / or (v) an electromagnetic field (e.g., an electric field, a magnetic field, or a combination of electric and magnetic fields generated by, for example, a sensor electronic device for the continuous sample sensor or an external electronic device).

[0116] In the configuration of Figure 4, the non-self-supporting continuous sample sensor 110 may have a Young's modulus of less than 500 MPa, a flexural modulus of less than 2-5 GPa or less than 1.5 GPa, and / or a buckling force of less than 0.25 Newtons (N), less than 0.02 N, less than 0.01 N, less than 0.001 N, or substantially 0 or less than the weight of the extending portion of the sensor 110 itself under gravity (the gravity generated by the Earth in the range from sea level to 500 km). In one or more embodiments, in the configuration of Figure 4 (e.g., in vivo configuration), the continuous sample sensor 110 may have a Young's modulus that is substantially the same as the Young's modulus of the tissue in which the sensor is implanted (e.g., a Young's modulus between 0.1 kPa and 300 kPa in various implementation forms).

[0117] In some embodiments, the sensor is configured and positioned to monitor a single sample. However, in other embodiments, the sensor is configured and positioned to monitor multiple samples, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more different samples. In yet another embodiment, the sensor is configured to monitor at least one sample substantially continuously and at least one sample intermittently. The substantially continuously monitored sample and the intermittently monitored sample may be the same sample or different samples.

[0118] In some embodiments, the sensor is implanted in the host body and configured to generate in vivo signals associated with a sample in the host during a sensor session. In some embodiments, the duration of the sensor session ranges from less than about 10 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, or 50 minutes to about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or longer. In some embodiments, the duration of the sensor session ranges from about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours to about 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or longer. In some embodiments, the duration of a sensor session is less than about 0.25 days, 0.25 days, 0.5 days, 0.75 days, 1 to about 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days or more.

[0119] The specimen sensor may be configured for any type of implantation, such as percutaneous implantation, subcutaneous implantation, or implantation within the host's circulatory system (e.g., within a blood vessel such as a vein or artery). In addition, the sensor may be configured to be fully implantable or implantable in vitro (e.g., within an extracorporeal blood circulation device such as a cardiac bypass device or hemodialysis device). U.S. Patent Application Publication US-2006-0020187-A1, incorporated herein by reference to the extent that its disclosure does not contradict the disclosure contained herein, describes an exemplary continuous specimen sensor that may be used for percutaneous implantation by insertion into the abdominal tissue of a host. U.S. Patent Application Publication US-2008-0119703-A1, incorporated herein by reference to the extent that its disclosure does not contradict the disclosure contained herein, describes an exemplary embodiment of a continuous specimen sensor that may be used for insertion into a host's vein (e.g., via a catheter). In some embodiments, the sensor is configured and positioned for in vitro use.

[0120] As an example, though not limited to them, a wide variety of suitable detection methods include, but are not limited to, enzyme detection methods, chemical detection methods, physical detection methods, electrochemical detection methods, immunochemical detection methods, optical detection methods, radiation measurement detection methods, calorimetry detection methods, protein binding detection methods, and microscale detection methods, and other techniques may be used, although they may be employed in some embodiments. Additional descriptions of usable sample sensor configurations and detection methods can be found in U.S. Patent Application Publications US-2007-0213611-A1, US-2007-0027385-A1, US-2005-0143635-A1, US-2007-0020641-A1, US-2007-002064-A11, and US-2005-0196. U.S. Patent No. 820-A1, U.S. Patent No. 5,517,313, U.S. Patent No. 5,512,246, U.S. Patent No. 6,400,974, U.S. Patent No. 6,711,423, U.S. Patent No. 7,308,292, U.S. Patent No. 7,303,875, U.S. Patent No. 7,289,836, U.S. Patent No. 7,289,204, U.S. Patent No. 5,156,972, U.S. Patent No. 6,528,318, U.S. Patent No. 5,738,992, U.S. Patent No. 5,631 ,170, US Patent No. 5,114,859, US Patent No. 7,273,633, US Patent No. 7,247,443, US Patent No. 6,007,775, US Patent No. 7,074,610, US Patent No. 6,846,654, US Patent No. 7,288,368, US Patent No. 7,291,496, US Patent No. 5,466,348, US Patent No. 7,062,385, US Patent No. 7,244,582, US Patent No. 7,211, U.S. Patent Nos. 439, 7,214,190, 7,171,312, 7,135,342, 7,041,209, 7,061,593, 6,854,317, 7,315,752, and 7,312,040 are published, and all of these are incorporated herein by reference to the extent that their disclosures do not contradict the disclosures contained herein.

[0121] While several sensor configurations and manufacturing methods are described herein, it should be understood that any of the various known sensor configurations may be employed in conjunction with the sample sensor systems and manufacturing methods described herein, for example, Ward et al. U.S. Patent No. 5,711,861, Vachon et al. U.S. Patent No. 6,642,015, Say et al. U.S. Patent No. 6,654,625, Say et al. U.S. Patent No. 6,565,509, Heller U.S. Patent No. 6,514,718, Essenpreis et al. U.S. Patent No. 6,465,066, Offenbacher et al. U.S. These include U.S. Patent No. 6,214,185, U.S. Patent No. 5,310,469 by Cunningham et al., and U.S. Patent No. 5,683,562 by Shaffer et al., U.S. Patent No. 6,579,690 by Bonnecaze et al., U.S. Patent No. 6,484,046 by Say et al., U.S. Patent No. 6,103,033 by Say et al., U.S. Patent No. 6,512,939 by Colvin et al., U.S. Patent No. 6,424,847 by Mastrototaro et al., and others, all of which are incorporated herein by reference to the extent that their disclosures do not contradict the disclosures contained herein. The sensors described in the patent documents specified above do not encompass all applicable sample sensors. It will be understood that the disclosed embodiments are applicable to a variety of sample sensor configurations. It should be noted that many of these embodiments, for example, the membrane systems described below, can be implemented not only in in vivo sensors but also in extra vivo sensors such as blood glucose meters (SMBG).

[0122] In some embodiments, the sensor is configured and positioned to be implanted within a body structure. During use, the in vivo portion of the sensor is bent around one or more axes. This bending may occur intermittently or infrequently, depending on factors such as the nature of the implantation site (e.g., the type and thickness of the surrounding tissue), the type or amount of host activity, and / or the configuration of the sensor.

[0123] In one embodiment, the sensor is configured and positioned for percutaneous implantation. An exemplary percutaneous implantation site is the abdomen, which includes the abdominal wall with multiple layers (e.g., skin, fascia, fat, muscle) that can move laterally and / or slide relative to one another (e.g., in response to host movement). The fascia can sometimes slide, stretch, or move a short distance across the underlying fat or muscle tissue.

[0124] In some embodiments, when a sensor is implanted percutaneously, the in vivo portion passes through the skin and penetrates the underlying tissue layer. Depending on the nature of the implantation site, the sensor may pass through two or more tissue layers. As a result, voluntary or involuntary movements by the host can move through the tissue layers, which can then apply various forces to the implanted sensor. Similarly, if the sensor is implanted within the host's circulatory system, such as a vein or artery, and the host moves (e.g., moves the arm, wrist, and / or hand), forces can be applied to the implanted sensor.

[0125] When certain forces (e.g., forces that bend the sensor along an undesirable bending axis) are applied to a conventional sensor, these can cause damage to the sensor and / or the surrounding tissue. In contrast, some sensors in these embodiments are configured and positioned to bend and / or flex in response to forces applied by surrounding tissue and / or body movement (e.g., simultaneously along several bending axes in several corresponding arrangements or continuously along the length of the sensor). Flexible specimen sensors, such as those disclosed herein, can reduce the risk of host tissue damage and sensor damage while maintaining sensor accuracy.

[0126] In some embodiments, the sensor is configured and positioned to possess a unique combination of strength and flexibility, enabling it to withstand intermittent and / or repeated bending and / or flexing around multiple axes, often simultaneously in various bending configurations, for at least one, two, three, or more days while implanted, and to measure at least one specimen after implantation. In some embodiments, the sensor is configured and positioned to bend and / or flex at one, two, three, or more points along its length (e.g., along the length corresponding to the biological portion implanted in the host body) or continuously. In addition, or alternatively, the sensor may be able to bend around multiple axes (e.g., multi-axial bending) and / or in multiple planes. As described in more detail elsewhere herein, the components of the sensor may be handled, formed, and / or combined in such a manner that they result in the necessary combination of strength or flexibility, enabling some sensor embodiments to provide substantially accurate continuous specimen data while withstanding the implantation environment for at least one, two, three, or more days.

[0127] In some embodiments, the in vivo portion of the sensor may have a Young's modulus substantially the same as that of the tissue in which the sensor is implanted, so that the sensor conforms to the tissue and substantially does not create resistance to the movement of the tissue.

[0128] The Young's modulus, flexural modulus, and / or buckling force of the continuous sample sensor 110 (the portion of the continuous sample sensor 110 extending from the sensor electronic equipment housing) can, in some embodiments, be substantially determined by the Young's modulus, flexural modulus, and / or buckling force of the elongated core structure relative to the sensor (e.g., relative to that portion of the sensor). In various embodiments, the elongated core structure can be implemented as an elongated non-conductive core, such as an elongated conductive core, an elongated polymer core, or an elongated fibrous core (e.g., a core formed from one or more paraamide synthetic fibers such as Kevlar® fibers).

[0129] Figures 5A, 5B, and 5C illustrate one embodiment (e.g., an in vivo portion) of a flexible continuous sample sensor 110 in a mounting configuration including an elongated conductive core. As shown in Figure 5A, the continuous sample sensor 110 may comprise an elongated conductor 502 comprising an elongated core 510 and a first layer 512 at least partially surrounding the core 510. The first layer 512 may comprise a working electrode (e.g., located within a window 506), and a film 508 may be disposed on the working electrode. In the examples in Figures 5A to 5C, the core 510 may be mounted as a flexible conductive core configured and positioned to conform to multiaxial bending. In some embodiments, the core 510 and the first layer 512 may be formed from ordinary soft metals or metal alloys. In some embodiments, the elongated conductor 502 may be 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 nonconductive material. In some embodiments, the elongated conductor comprises multiple layers. In some embodiments, there are at least two concentric (e.g., annular) layers, such as a core 510 formed from a first material and a first layer 512 formed from a second material. However, in some embodiments, additional layers may be included. In some embodiments, the layers are coaxial.

[0130] The elongated conductor 502 may be long, thin, yet flexible and tough. For example, in some embodiments, the minimum dimensions of the elongated conductor are less than about 0.1 inches, 0.075 inches, 0.05 inches, 0.025 inches, 0.01 inches, 0.004 inches, 0.002 inches, or 12 microns. Although the elongated conductor 502 is illustrated in Figures 5A to 5C as having a circular cross-section, in other embodiments, the cross-section of the elongated conductor may be oval, elliptical, rectangular, triangular, polygonal, star-shaped, C-shaped, T-shaped, X-shaped, Y-shaped, irregular, or similar. In some embodiments, the core 510 of the elongated conductor 502 may be mounted as a wire electrode. The wire electrode core may be a cladding having one or more additional conductive layers (e.g., an insulating layer interposed for electrical insulation). The conductive layers may be made of any suitable material. In some embodiments, it may be desirable to employ a conductive layer containing conductive particles (i.e., particles of conductive material) in a polymer or other binder.

[0131] In some embodiments, the elongated core having a low flexural modulus of elasticity of the elongated conductor may be clad with a surface metal cladding. The elongated core may be formed from a low-elasticity polymer, metal, metal alloy, or a combination thereof having a Young's modulus of less than 27 × 10⁶ psi (186 GPa). The surface metal may include one or more metals such as platinum and platinum alloys. The elongated core and the surface metal may be configured to be coaxially arranged in the longitudinal direction and may have a total diameter of less than 100 microns. Preferably, the low-elasticity core polymer, metal, or alloy also has biocompatibility and provides fatigue resistance to mechanical bending and twisting.

[0132] Examples of low-elasticity metals and metallic alloys that can be used to form the low-elasticity elongated core 510 include copper, gold, magnesium, silver, tin, titanium, various titanium alloys (e.g., β-type titanium alloys, Ti-13Nb-13Zr, Ti-12Mo-6Zr-2Fe, Ti-15Mo, Ti-5Mo-5Zr-3Al, Ti-35Nb-7Zr-5Ta, Ti-9Nb-13Ta-4.6Zr), and / or zinc.

[0133] In some embodiments, the elongated core 510 (e.g., a non-conductive mounting form of the core 510) comprises a non-conductive material (e.g., a flexible polymer / polymer material including polyurethane and / or polyimide and / or a shape-memory or other state-change polymer material as described herein). In some embodiments, the elongated core 510 is formed from a softenable shape-memory thermoplastic material and may comprise a copolymer (e.g., a block or segmented copolymer) and another polymer. The other polymer may be blended with the copolymer to act as a reverse plasticizer. Suitable polymers may include polyether urethanes, polyester urethanes, polyether polyesters, polyether polyamides, polynorbornene, high molecular weight (e.g., greater than 100 kDa) poly(methyl methacrylate), poly(alkyl methacrylate) copolymers, polystyrene copolymers, filler-modified epoxy network structures, chemically crosslinked amorphous polyurethanes, poly((methyl methacrylate)-co-(N-vinyl-2-pyrrolidone))-PEG semi-IPN, HDI-HPED-TEA network structures, biodegradable copolyester-urethane network structures, and copolymers thereof.

[0134] In addition to providing structural support, resilience, and flexibility, in some embodiments the core 510 (or its components) facilitates the electrical conduction of electrical signals from the working electrode to sensor electronic equipment (not shown), as described elsewhere in this specification. Those skilled in the art will understand that additional configurations are possible.

[0135] Referring again to Figures 5A to 5C, in some embodiments, the first layer 512 is formed from a conductive material. The working electrode may be formed by the exposed portion of the surface of the first layer 512. Thus, the first layer 512 may be formed from a material configured to provide a suitable electrically active surface for the working electrode, and the material may include, but is not limited to, platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, conductive polymers, alloys, and / or similar.

[0136] As shown in Figures 5A to 5C, the second layer 504 may, in some embodiments, surround at least a portion of the first layer 512, thereby defining the boundary of the working electrode. In some embodiments, the second layer 504 functions as an insulator and is formed from an insulating material such as polyimide, polyurethane, parylene, or other known insulating materials. For example, in one embodiment, the second layer 504 is disposed on the first layer and configured so that the working electrode is exposed through a window 506. In another embodiment, an elongated conductor is provided comprising a core 510, a first layer 512, and a second layer 504, and the working electrode is exposed by removing a portion of the second layer 504, thereby forming a window 506, through which the electroactive surface of the working electrode (e.g., the exposed surface of the first layer) is exposed. In some embodiments, the working electrode is exposed by removing a portion of the second layer and (optionally) a third or other layer (e.g., thereby forming a window 506). Removing coating material from one or more layers of an elongated conductor (for example, to expose the electroactive surface of a working electrode) can be done manually, by excimer laser, chemical etching, laser cutting, grit blasting, or similar methods.

[0137] In some embodiments, the sensor further comprises a third layer 514 containing a conductive material. In further embodiments, the third layer 514 may comprise a reference electrode, which may be formed from a silver-containing material coated on a second layer (e.g., an insulator). The silver-containing material may comprise any of a variety of materials, which may take various forms, such as Ag / AgCl polymer paste, paint, polymer-based conductive mixtures, and / or commercially available inks. The third layer 514 may be processed using a paste / dip / coating process, for example, using a die-metered dip coating process. In one exemplary embodiment, an Ag / AgCl polymer paste is applied to an elongated body by dip coating the body (e.g., using meniscus coating technique), then stretching the body through a die and measuring the coating to a precise thickness. In some embodiments, multiple coating steps are used to build up the coating to a predetermined thickness. Such stretching methods may be used to form one or more electrodes within the device shown in Figure 5B.

[0138] In some embodiments, silver particles in an Ag / AgCl solution or paste may have an average particle size associated with a maximum particle size of 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. Silver chloride particles in an Ag / AgCl solution or paste may have an average particle size associated with a maximum particle size of 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. Silver particles and silver chloride particles may be incorporated in a silver chloride particle:silver particle ratio of about 0.01:1 to 2:1 by weight, or about 0.1:1 to 1:1. The silver particles and silver chloride particles are then mixed with a carrier (e.g., polyurethane) to form a solution or paste. In some embodiments, the Ag / AgCl component accounts for about 10% to about 65% by weight, or about 20% to about 50% by weight, or about 23% to about 37% by weight of the total Ag / AgCl solution or paste. In some embodiments, the Ag / AgCl solution or paste has a viscosity (under ambient conditions) of about 1 to about 500 centipoise, or about 10 to about 300 centipoise, or about 50 to about 150 centipoise.

[0139] In some embodiments, Ag / AgCl particles are mixed into a polymer such as polyurethane, polyimide, or the like to form a silver-containing material for the reference electrode. In some embodiments, the third layer 514 is cured, for example, by using a furnace or other curing process. In some embodiments, a coating of a fluid-permeable polymer with conductive particles (e.g., carbon particles) is applied to the reference electrode and / or the third layer 514. In some embodiments, a layer of insulating material may be placed on top of a portion of the silver-containing material.

[0140] In some embodiments, the elongated conductor 502 further comprises one or more intermediate layers disposed between the core and the first layer. For example, in some embodiments, the intermediate layer is an insulator, a conductor, a polymer, and / or an adhesive.

[0141] The ratio between the thickness of the Ag / AgCl layer and the thickness of the insulator (e.g., polyurethane or polyimide) layer is intended to be controlled to allow a certain tolerance (e.g., an error associated with the etching process) that does not result in the sensor failing (e.g., due to defects resulting from the etching process cutting deeper than intended, thereby unintentionally exposing an electroactive surface). This ratio may vary depending on the type of etching process used, whether it is laser cutting, grit blasting, chemical etching, or some other etching method. In one embodiment where laser cutting is performed to remove the Ag / AgCl layer and the polyurethane layer, the ratio of the thickness of the Ag / AgCl layer to the thickness of the polyurethane layer may be about 1:5 to about 1:1, or about 1:3 to about 1:2.

[0142] In some embodiments, the core of a continuous sample sensor comprises a non-conductive polymer, and the first layer comprises a conductive material. Such sensor configurations can sometimes reduce material costs, increase flexibility, and / or provide state-change properties. For example, in some embodiments, the core is formed from a non-conductive polymer such as a nylon or polyester filament, thread, or string, which may be coated and / or plated with a conductive material such as platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, conductive polymers, and alloys, or combinations thereof.

[0143] As shown in Figures 5A and 5C, the sensor 110 may also include a membrane 508 covering at least a portion of the working electrode. In some embodiments, the sensor 110 includes a membrane 508 in contact with an electroactive surface (e.g., at least the working electrode). As described elsewhere in this specification, the embedded sensor may be subjected to repeated bending and / or flexing along multiple axes. To withstand this harsh handling and provide sample data over one, two, three, or more days, the sensor membrane may be configured to withstand repeated compression, flexing, and tensile forces while substantially maintaining its membrane function (e.g., without tearing, buckling, or breaking). Thus, the sensor membrane may be strong and resilient. Shore hardness is a measure of the elasticity of a material. In some embodiments, the film 508 comprises a polymer having a Shore hardness of at least about 65A, 70A, 75A, 80A, 85A, 90A, 95A, 30D, 35D, 40D, 45D, 50D, 55D, 60D, or higher. In some embodiments, the polymer has a Shore hardness from about 70A to about 55D. Polymers having a Shore hardness in the range of about 70A to about 55D include, but are not limited to, polyurethanes, polyimides, silicones, and the like, as described elsewhere in this specification.

[0144] In some embodiments, the entire membrane is formed from one or more polymers having a Shore hardness of about 70A to about 55D. However, in other embodiments, only a portion of the membrane, such as a membrane layer or domain, is formed from one of these polymers. In one exemplary embodiment, the outer layer of the membrane is formed from a polymer having a Shore hardness of about 70A to about 55D. In some embodiments, approximately the outer 5%, 10%, 15%, 20%, 25%, 30%, 35%, 35%, 40%, 45%, or 50% of the membrane is formed from a polymer having a Shore hardness of about 70A to about 55D. In some embodiments, the resistance domain is formed from a polymer having a Shore hardness of about 70A to about 55D. Additional membrane domains are also formed from polymers having a Shore hardness within this range, in other embodiments. In one embodiment, at least a portion of the membrane is formed from a polymer having a Shore hardness of about 70A to about 55D, and the enzyme is disposed within that polymer.

[0145] As described herein, the film may be formed by any preferred method. It may be desirable to form the film on various exposed electrodes of the sensor in some embodiments by immersing the sensor for different lengths, masking, controlled UV curing, printing, and / or similar methods.

[0146] Figure 6A is a cross-sectional view of the sensor shown in Figure 5A, cut along the line 6-6. As shown in Figure 6A, the film 508 may be deposited on the electroactive surface of the sensor and may include multiple domains or layers, as described in more detail below. In some embodiments, the film comprises a single layer. In some embodiments, the single layer comprises one or more functional domains (e.g., parts or regions). In other embodiments, the film comprises two or more layers. In some embodiments, each layer performs a different function. In some embodiments, multiple layers may perform the same function. The film 508 may be deposited on an exposed electroactive surface using known thin-film techniques (e.g., spraying, electrodeposition, immersion, and similar techniques). In one exemplary embodiment, each domain is deposited by immersing the sensor in a solution and forging the sensor at a rate that yields the appropriate domain thickness. In another exemplary embodiment, each domain is deposited by spraying the solution onto the sensor over a period of time that yields the appropriate domain thickness. Generally, film systems may be arranged (deposited) on an electroactive surface using methods understood by those skilled in the art.

[0147] Generally, a membrane system may comprise multiple domains, such as an electrode domain 602, an interference domain 604, an enzyme domain 606 (e.g., including glucose oxidase), and / or a resistance domain 608, as shown in Figure 6A, and may also include a highly oxygen-soluble domain and / or a bioprotective domain (not shown), as described in more detail in U.S. Patent Application Publication US-2005-0245799-A1 and further described below. The membrane system may be deposited on an exposed electroactive surface using known thin-film techniques (e.g., vapor deposition, spraying, electrodeposition, immersion, and similar techniques). However, in alternative embodiments, other deposition processes (e.g., physical and / or chemical deposition processes), including, for example, ultrasonic deposition, electrostatic deposition, evaporation deposition, sputtering deposition, pulsed laser deposition, high-speed oxygen fuel deposition, thermal evaporator deposition, electron beam evaporator deposition, reactive sputtering molecular beam epitaxy deposition, atmospheric pressure chemical vapor deposition (CVD), atomic layer CVD, hot-wire CVD, low-pressure CVD, microwave plasma-assisted CVD, plasma-enhanced CVD, fast thermal CVD, remote plasma-enhanced CVD, and ultra-high vacuum CVD, may be useful in providing one or more insulating and / or film layers. However, the film system may be arranged (or deposited) on an electroactive surface using known methods, as will be understood by those skilled in the art. For ease of processing, for example, in the calibration of a certain dual-action electrode glucose sensor, when an enzyme is employed, each electrode may be immersed in an enzyme domain containing the enzyme. Subsequently, the enzyme on one of the working electrodes (e.g., a second working electrode) may be denatured / inactivated, for example, by exposure to UV or other irradiation, or by exposure to other agents or treatment methods known in the art for denaturing enzymes.In some embodiments, one or more domains of a membrane system are formed from materials such as silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, polyurethane homopolymers, copolymers, terpolymers, polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethyl methacrylate (PMMA), polyetheretherketone (PEEK), polyurethane, cellulose polymer, polysulfone, and block copolymers of these materials, including, for example, diblock, triblock, alternating, random, and graft copolymers. U.S. Patent Application Publication No. US-2005-0245799-A1 describes the configurations and materials of applicable biointerfaces and membrane systems.

[0148] In selected embodiments, the membrane system comprises an electrode domain 602. The electrode domain 602 is provided to ensure that an electrochemical reaction occurs between the electroactive surface of the working electrode and the reference electrode, and therefore the electrode domain may be located proximal to the electroactive surface, closer than the interference domain 604 and / or the enzyme domain 606. The electrode domain 602 may comprise a coating that maintains a layer of water on the electrochemical reaction surface of the sensor. In other words, the electrode domain may provide an environment between the surface of the working electrode and the reference electrode that facilitates the electrochemical reaction between the electrodes. For example, a humectant in the binder can be employed as an electrode domain, which enables complete ion transport in an aqueous environment. The electrode domain can also facilitate the stabilization of the sensor's operation by accelerating electrode starting and drift problems caused by inappropriate electrolytes. The material forming the electrode domain may also provide an environment that protects against pH-mediated damage that may result from the formation of a large pH gradient due to the electrochemical activity of the electrodes.

[0149] In one embodiment, the electrode domain comprises a hydrophilic polymer film (e.g., a soft water-swellable hydrogel) having a “dry film” thickness of about 0.05 microns or less to about 20 microns or more, or about 0.05, 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 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, or about 3, 2.5, 2, or 1 micron or less to about 3.5, 4, 4.5, or 5 microns or more. The “dry film” thickness refers to the thickness of the cured film cast from a coating compound using standard coating techniques.

[0150] In some embodiments, the electrode domain 602 is formed from a curable mixture of a urethane polymer and a hydrophilic polymer. In some embodiments, the coating is formed from a polyurethane polymer having carboxylate or hydroxyl functional groups and a nonionic hydrophilic polyether segment, the polyurethane polymer being crosslinked with a water-soluble carbodiimide (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence of polyvinylpyrrolidone and cured at a moderate temperature of about 50°C.

[0151] In some embodiments, the electrode domain 602 is formed from a hydrophilic polymer (e.g., polyamide, polylactone, polyimide, polylactam, functionalized polyamide, functionalized polylactone, functionalized polyimide, functionalized polylactam, or a combination thereof) that makes the electrode domain substantially more hydrophilic than the domains above it (e.g., interference domain, enzyme domain). In some embodiments, the electrode domain 602 is formed substantially as a whole and / or primarily from a hydrophilic polymer. In some embodiments, the electrode domain is formed substantially as a whole from PVP. In some embodiments, the electrode domain 602 is formed as a whole from a hydrophilic polymer. Useful hydrophilic polymers include, but are not limited to, poly-N-vinylpyrrolidone (PVP), poly-N-vinyl-2-piperidone, poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam, poly-N-vinyl-3-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-caprolactam, poly-N-vinyl-3-ethyl-2-pyrrolidone, poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole, poly-N,N-dimethylacrylamide, polyvinyl alcohol, polyacrylic acid, polyethylene oxide, poly-2-ethyl-oxazoline, copolymers thereof, and mixtures thereof. In some embodiments, a blend of two or more hydrophilic polymers may be used. In some embodiments, the hydrophilic polymers are not crosslinked. In alternative embodiments, crosslinking may be carried out by adding a crosslinking agent such as EDC, or by irradiating with a wavelength sufficient to promote crosslinking between hydrophilic polymer molecules, which is believed to form more meandering diffusion pathways through the domains.

[0152] Electrode domains formed from hydrophilic polymers (e.g., PVP) have been shown to substantially reduce the break-in time of sample sensors, such as glucose sensors utilizing cellulosic interference domains, as described in more detail elsewhere herein. In some embodiments, single-component electrode domains formed from a single hydrophilic polymer (e.g., PVP) have been shown to substantially reduce the break-in time of glucose sensors to less than about 2 hours, less than about 1 hour, less than about 20 minutes, and / or substantially immediate.

[0153] Generally, sensor break-in is the length of time (after implantation) required for the sensor signal to substantially represent the sample concentration. Sensor break-in includes both membrane break-in and electrochemical break-in, which are described in more detail elsewhere in this specification. In some embodiments, the break-in time is less than about 2 hours. In other embodiments, the break-in time is less than about 1 hour. In yet other embodiments, the break-in time is less than about 30 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, or less. In one embodiment, sensor break-in occurs substantially immediately. Advantageously, in embodiments where the break-in time is about 0 minutes (substantially immediate), the sensor can, for example, begin to provide substantially accurate sample (e.g., glucose) concentrations almost immediately after insertion, and membrane break-in does not limit the start-up time.

[0154] In some embodiments, providing a flexible sensor (for example, a sensor having a flexural modulus of less than 2-5 GPa or a Young's modulus of less than 147 GPa, or a sensor substantially matching the modulus of one or more layers of the tissue in which the sensor is implanted) can shorten the break-in time and / or prevent day-first effects that follow the break-in time, such as mismeasurements caused by tissue reactions (e.g., inflammation) to the newly implanted sensor.

[0155] Furthermore, by providing electrode domains that are substantially more hydrophilic than subsequent, more distal membrane layers or domains (e.g., layers distal to the electroactive surface, such as overlying domains, interference domains, or enzyme domains), the rate at which the membrane system is supplied with moisture by the surrounding host tissue is increased, thereby shortening the break-in time of the embedded sensor. Increasing the degree of hydrophilicity of the electrode domains with respect to the overlying layer (e.g., distal layers in contact with the electrode domains, such as interference domains or enzyme domains) increases the water absorption rate, which can consequently shorten the sensor break-in time. The hydrophilicity of the electrode domains can be substantially increased by the appropriate selection of a hydrophilic polymer, based on their hydrophilicity with respect to each other and to the overlying layer (e.g., cellulosic interference domains), some polymers being substantially more hydrophilic than the overlying layer. In an exemplary embodiment, PVP forms the electrode domain, and the interference domain is formed from a blend of cellulose derivatives, including, but not limited to, cellulose acetate-butyrate and cellulose acetate. Since PVP is substantially more hydrophilic than cellulosic interference domains, it is believed that PVP rapidly draws water into the membrane to the electrode domain, enabling the sensor to function with the desired sensitivity and accuracy, starting within a substantially shortened time period after implantation. The reduced sensor break-in time shortens the length of time the host must wait to obtain sensor readings, which is advantageous not only in ambulatory applications but especially in time-sensitive hospital settings.

[0156] When the water absorption rate of an upper domain (e.g., a domain above an electrode domain) is lower than that of the electrode domain (e.g., at membrane equilibrium), the difference in water absorption rates between the two domains can promote membrane equilibrium and therefore membrane break-in. That is, increasing the difference in hydrophilicity (e.g., between the two domains) can result in higher water absorption, and consequently, a reduction in membrane break-in time and / or sensor break-in time. As described elsewhere in this specification, the relative hydrophilicity of the electrode domain compared to the upper domain can be modulated by the selection of a more hydrophilic material for the formation of the electrode domain (and / or a more hydrophobic material for the upper domain). For example, an electrode domain containing a hydrophilic polymer that can absorb a larger amount of water may be selected instead of a second hydrophilic polymer that can absorb less water than a first hydrophilic polymer. In some embodiments, the difference in water content between the electrode domain and the upper domain (e.g., at or after membrane equilibrium) ranges from about 1% or less to about 90% or more. In other embodiments, the difference in water content between the electrode domain and the domain above it ranges from about 10% or less to about 80% or more. In yet another embodiment, the difference in water content between the electrode domain and the domain above it ranges from about 30% or less to about 60% or more. In some embodiments, the electrode domain absorbs 5 wt.% or less to 95 wt.% or more of water compared to adjacent (superior) domains (e.g., domains further away from the electrode domain, distal to the electroactive surface), or about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 wt.% to about 55, 60, 65, 70, 75, 80, 85, 90, or 95 wt.% of water.

[0157] In another example, the water absorption rate of a polymer can be influenced by other factors, such as the polymer's molecular weight, though not limited to these factors. For instance, the water absorption rate of PVP depends on its molecular weight, which is typically between approximately 40 kDa and 360 kDa, with low molecular weight PVP (e.g., 40 kDa) absorbing water faster than high molecular weight PVP. Therefore, modulofactors such as molecular weight that affect the water absorption rate of a polymer can facilitate the appropriate selection of materials for electrode domain processing. In one embodiment, a lower molecular weight PVP is selected to shorten the break-in time.

[0158] Electrode domains 602 can be deposited by known thin-film deposition techniques (e.g., spray coating or immersion coating of the electroactive surface of the sensor). In some embodiments, electrode domains are formed by immersion coating the electroactive surface in an electrode domain solution (e.g., 5, 10, 15, 20, 25, or 30% or more PVP in deionized water) and curing the domains for about 15 to 30 minutes at a temperature of about 40°C to about 55°C (this can also be performed under vacuum (e.g., 20 to 30 mmHg)). In embodiments where immersion coating is used to deposit electrode domains, an insertion rate of about 1 to about 3 inches per minute into the electrode domain solution is often used, with a residence time of about 0.5 to about 2 minutes, and a withdrawal rate of about 0.25 to about 2 inches per minute from the electrode domain solution results in a functional coating. However, values ​​deviating from those stated above may be acceptable or even desirable in some embodiments, depending on, for example, the solution viscosity and solution surface tension, as will be understood by those skilled in the art. In one embodiment, the electroactive surface of the electrode system is coated once (one layer) by immersion coating and cured at 50°C under vacuum for 20 minutes. In another embodiment, the electroactive surface of the electrode system is coated once by immersion coating and cured at 50°C under vacuum for 20 minutes, followed by a second immersion coating and cured at 50°C under vacuum for 20 minutes (two layers). In yet another embodiment, the electroactive surface may be coated three or more times (three or more layers) by immersion coating. In yet another embodiment, one, two, three or more layers of PVP are applied to the electroactive surface by spray coating or vapor deposition. In some embodiments, a crosslinking agent (e.g., EDC) is added to the electrode domain casting solution to promote crosslinking within the domains (e.g., between electrode domain polymer components, latex, etc.). However, in some alternative embodiments, no crosslinking agent is used, and the electrode domains are substantially uncrosslinked.

[0159] In some embodiments, the deposited PVP electrode domains have a “dry film” thickness of about 0.05 microns or less to about 20 microns, or about 0.05, 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 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, or about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns. Although independent electrode domains are described herein, in some embodiments, sufficient hydrophilicity can be provided within the interference domain and / or enzyme domain (domain adjacent to the electroactive surface) to allow complete ion transport in an aqueous environment (e.g., without separate electrode domains). In these embodiments, electrode domains are not required.

[0160] An elongated core (e.g., an elongated conductive core or an elongated non-conductive core) may have a Young's modulus or flexural modulus (e.g., at least an in-vivo Young's modulus or flexural modulus) large enough (e.g., greater than 500 MPa) to maintain its shape during immersion (e.g., the core is not bent by forces from the surface of the immersion fluid when the core is immersed in the fluid). In some embodiments, the Young's modulus or flexural modulus may be increased during immersion (e.g., by applying an electromagnetic field or by cooling to a threshold temperature). In other embodiments, the Young's modulus or flexural modulus may decrease in a biological environment as described in more detail thereafter (e.g., by temperature rise, wetting or hydration of one or more layers or other structures, application or removal of an electromagnetic field, or by chemical or biological reactions).

[0161] Elongated cores (for example, elongated conductive or nonconductive cores for a portion of a continuous sample sensor configured to extend from a sensor electronics housing) may have a buckling force (e.g., at least an in vitro buckling force) large enough (e.g., greater than 0.25 N, greater than 0.02 N, greater than 0.01 N, greater than 0.001 N, or greater than the weight of the core under gravity) to allow the core to maintain its shape during immersion (e.g., the core is not bent by forces from the surface of the immersion fluid when the core is immersed in the fluid). In some embodiments, the buckling force may be increased during immersion (e.g., by applying an electromagnetic field or by cooling to a threshold temperature). In other embodiments, the buckling force may be decreased in vivo as described in more detail below (e.g., by temperature rise, wetting or hydration of one or more layers or other structures, application or removal of an electromagnetic field, or by chemical or biological reactions).

[0162] Interfering substances are molecules or other chemical species that are reduced or oxidized at the electrochemically reactive surface of the sensor, either directly or via an electron transfer agent, and generate a false positive sample signal (e.g., a non-sample-related signal). This false positive signal makes the host's sample concentration (e.g., glucose concentration) appear higher than the true sample concentration. False positive signals are a clinically serious problem in some conventional sensors. For example, if a host is in a dangerously hypoglycemic state and has ingested an interfering substance (e.g., acetaminophen), a false high glucose signal may cause the host to believe they are normal (or, in some cases, hyperglycemic). As a result, the host may make inappropriate treatment decisions, such as doing nothing when the appropriate course of action is to start feeding. In another example, if a host is consuming acetaminophen while in a normal or hyperglycemic state, the false high glucose signal caused by acetaminophen may cause the host to believe their glucose concentration is significantly higher than the true concentration. Here again, as a result of a false high glucose signal, the host may make inappropriate treatment decisions, such as giving itself too much insulin, which could ultimately lead to a dangerous hypoglycemic episode.

[0163] In some embodiments, an interference domain 604 is provided that substantially restricts or blocks the flow of one or more interfering chemical species through it, thereby substantially preventing false signal amplification. As described in more detail herein, some known interfering chemical species for glucose sensors include acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylates, tetracycline, trazamide, tolbutamide, triglycerides, and uric acid. Generally, the interference domain in some embodiments has low permeability to one or more of the interfering chemical species compared to the measured chemical species, for example, products of enzymatic reactions measured on an electroactive surface, such as H2O2, but not limited to H2O2.

[0164] In one embodiment, the interference domain is formed from one or more cellulose derivatives. The cellulose derivatives may include, but are not limited to, cellulose esters and cellulose ethers. Generally, cellulose derivatives include polymers such as cellulose acetate, cellulose acetate butyrate, 2-hydroxyethylcellulose, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate trimellitate, and the like, as well as copolymers and terpolymers with other cellulose or non-cellulose monomers. Cellulose is a polysaccharide polymer of β-D-glucose. While cellulose derivatives may be used in some embodiments, other polymeric polysaccharides having properties similar to cellulose derivatives may also be employed in other embodiments. Descriptions of cellulose interference domains are found in U.S. Patent Publications US-2006-0229512-A1, US-2007-0173709-A1, US-2006-0253012-A1, and US-2007-0213611-A1, all of which are incorporated herein by reference to the extent that their disclosures do not contradict the disclosures contained herein.

[0165] In some embodiments, the equivalent glucose signal response (measured by a sensor) of the interferant is 50 mg / dL or less. In some embodiments, the interferant generates an equivalent glucose signal response of 40 mg / dL or less. In some embodiments, the interferant generates an equivalent glucose signal response of less than 30, 20, or 10 mg / dL. In one exemplary embodiment, the interferant domain is configured to substantially block acetaminophen from passing through it, and the equivalent glucose signal response of acetaminophen is less than 30 mg / dL.

[0166] In alternative embodiments, the interference domain is configured to substantially block a therapeutic dose of acetaminophen. The term “therapeutic dose,” as used herein, is a broad term and is given its usual and conventional meaning to those skilled in the art (not limited to any special meaning or meaning tailored to a particular condition), but refers to the amount of substance necessary to cause a cure for a disease, relieve pain, or correct a sign of a deficiency in a particular factor in food, such as an effective dose used with a therapeutically applied compound, such as a drug. For example, a therapeutic dose of acetaminophen may be the amount of acetaminophen needed to relieve a headache or reduce a fever. As a further example, 1,000 mg of acetaminophen taken orally, such as by swallowing two 500 mg tablets of acetaminophen, is a therapeutic dose frequently taken for a headache. In some embodiments, the interference membrane is configured to block a therapeutic dose of acetaminophen, such that the equivalent glucose signal response to acetaminophen is less than about 60 mg / dL. In one embodiment, the interference membrane is configured to block a therapeutic dose of acetaminophen, with an equivalent glucose signal response of less than approximately 40 mg / dL. In another embodiment, the interference membrane is configured to block a therapeutic dose of acetaminophen, with an equivalent glucose signal response of less than approximately 30 mg / dL.

[0167] In some alternative embodiments, additional polymers such as NAFION® may be used in combination with cellulose derivatives to provide equivalent and / or enhanced functionality of the interference domains. For example, a layer of 5 wt.% NAFION® casting solution was applied by, for example, dipping-coating at least one layer of cellulose acetate onto a previously applied (e.g., cured) layer of 8 wt.% cellulose acetate, and then dipping-coating at least one layer of NAFION® onto the needle sensor. Any number of coatings or layers formed in any order may be suitable for forming interference domains.

[0168] In some alternative embodiments, other types of polymers that may be used as the base material for the interference domain include, for example, polyurethanes, polymers having pendant ion groups, and polymers having controlled pore sizes. In one such alternative embodiment, the interference domain comprises a thin hydrophobic membrane that is non-swelling and restricts the diffusion of high molecular weight chemical species. The interference domain is permeable to relatively low molecular weight substances such as hydrogen peroxide, but restricts the passage of higher molecular weight substances, including glucose and ascorbic acid. Other systems and methods for reducing or eliminating interfering chemical species that may be applied to membrane systems are described in U.S. Patent No. 7,074,307, U.S. Patent Publication No. US-2005-0176136-A1, U.S. Patent No. 7,081,195, and U.S. Patent Publication No. US-2005-0143635-A1, all of which are incorporated herein by reference to the extent that their disclosures do not contradict the disclosures contained herein. In some alternative embodiments, a separate interference domain is not included.

[0169] In some embodiments, the interference domains are deposited directly on either the electroactive surface of the sensor or the distal surface of the electrode domains, with domain thicknesses ranging from about 0.05 microns to about 20 microns, or from about 0.05, 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 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, or from about 1, 1.5, or 2 microns to about 2.5 or 3 microns. In some embodiments, thicker films may be preferable, but thinner films may be used because they have less effect on the diffusion rate of hydrogen peroxide from the enzyme film to the electroactive surface.

[0170] Generally, the film systems of some embodiments may be formed and / or deposited on an exposed electroactive surface (e.g., one or more of the working electrode and reference electrode) using known thin-film techniques (e.g., casting, spray coating, forging, electrodeposition, dipping coating, and similar), although casting, printing, or other known applied techniques may also be utilized. The interference domains 604 may be deposited by spray or dipping coating (as an example). In an exemplary embodiment of a needle-type (transdermal) sensor as described herein, the interference domain 604 is formed by immersing the sensor in an interference domain solution using an insertion speed of about 0.5 inches / min to about 60 inches / min, or about 1 inch / min, a residence time of about 0 minutes to about 2 minutes, or about 1 minute, and a withdrawal speed of about 0.5 inches / min to about 60 inches / min, or about 1 inch / min, and curing (drying) the domain between about 1 minute to about 30 minutes, or about 3 minutes to about 15 minutes (and may be performed at room temperature or under vacuum (e.g., 20 to 30 mmHg)). In an exemplary embodiment involving a cellulose acetate butyrate interference domain, the curing (i.e., drying) time of 3 minutes is sometimes between each layer being applied. In another exemplary embodiment employing a cellulose acetate interference domain, a curing (i.e., drying) time of 15 minutes is used between each layer being applied.

[0171] In some embodiments, the immersion process can be repeated at least once and up to 10 or more times. In other embodiments, immersion is performed only once. The number of immersion process repetitions used depends on the cellulose derivative used, its concentration, the conditions during deposition (e.g., immersion), and the desired thickness (e.g., a sufficient thickness to provide functional blockage of a particular interference), as well as similar factors. In some embodiments, 1 to 3 microns may be used as the thickness of the interference domain, but values ​​deviating from these may be acceptable or even desirable in some embodiments, depending on, for example, viscosity and surface tension, as will be understood by those skilled in the art. In one exemplary embodiment, the interference domain is formed from three layers of cellulose acetate butyrate. In another exemplary embodiment, the interference domain is formed from 10 layers of cellulose acetate. In yet another embodiment, the interference domain is formed from one layer of a blend of cellulose acetate and cellulose acetate butyrate. In alternative embodiments, the interference domain may be formed using known methods and combinations of cellulose acetate and cellulose acetate butyrate, as will be understood by those skilled in the art. In some embodiments, the electroactive surface may be cleaned, smoothed, or otherwise treated in some way before the interference domain is applied. In some embodiments, the interference domains of some embodiments may be useful as bioprotective or biocompatible domains, i.e., domains that form an interface with host tissue when implanted in an animal (e.g., a human) due to their stability and biocompatibility. In yet other embodiments, other parts of the membrane system, such as enzyme domains and / or resistance domains, may be configured to block interference. In yet another embodiment, the interference domains may be located either distally or proximal to the electroactive surface, farther or closer than other membrane domains. For example, in some embodiments, the interference domains may be located distally to the electroactive surface, farther than enzyme domains or resistance domains.

[0172] In some embodiments, the membrane system further includes an enzyme domain 606 located distal to the electroactive surface, farther from the interference domain, although other configurations may be desirable. In some embodiments, the enzyme domain 606 provides an enzyme that catalyzes the reaction of a sample and its co-reaction compounds, as described in more detail below. In some embodiments of the glucose sensor, the enzyme domain 606 contains glucose oxidase (GOX), but other oxidases, such as galactose oxidase or uricase oxidase, may also be used. In some embodiments, the enzyme domain is configured and arranged to detect at least one of the following: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, CO2, chloride, creatinine, glucose, gamma glutamine transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, metabolic markers, drugs, various minerals, various metabolites, and / or the like. In a further embodiment, the sensor is configured and arranged to detect two or more of the following: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, CO2, chloride, creatinine, glucose, gamma glutamine transpeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, metabolic markers, drugs, various minerals, various metabolites, and / or the like.

[0173] For an enzyme-based electrochemical glucose sensor to function correctly, the sensor's response cannot be limited by either enzyme activity or co-reaction compound concentration. Since enzymes, including glucose oxidase, are deactivated over time even under ambient conditions, this behavior is compensated for when forming an enzyme domain. In some embodiments, the enzyme domain consists of an aqueous dispersion of a colloidal polyurethane polymer containing the enzyme. However, in alternative embodiments, the enzyme domain consists of an oxygen-enhancing material, such as silicone or carbon fluoride, which supplies excess oxygen during transient ischemia. The enzyme can be immobilized within the domain. See, for example, U.S. Patent Application Publication US-2005-0054909-A1, incorporated herein by reference to the extent that its disclosure does not contradict the disclosure contained herein. In some embodiments, the enzyme domain 606 may be deposited on the interference domain 604 with a domain thickness of about 0.05 microns to about 20 microns, or from about 0.05, 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 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, or from about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns. Meanwhile, in some embodiments, the enzyme domain 606 may be deposited directly onto the electroactive surface. The enzyme domain may be deposited by spray or immersion coating. In one embodiment of a needle-type (transdermal) sensor as described herein, the enzyme domain is formed by immersing an interference domain-coated sensor in an enzyme domain solution and curing the domain at a temperature of about 40°C to about 55°C for about 15 to about 30 minutes (which may also be carried out under vacuum (e.g., 20 mmHg to 30 mmHg)).In embodiments where immersion coating is used to deposit enzyme domains at room temperature and provide a functional coating, the insertion rate used may be about 0.25 inches per minute to about 3 inches per minute, the residence time about 0.5 minutes to about 2 minutes, and the withdrawal rate about 0.25 inches per minute to about 2 inches per minute. However, values ​​deviating from those stated above may be acceptable or even desirable in some embodiments, depending on, for example, viscosity and surface tension, as will be understood by those skilled in the art. In one embodiment, the enzyme domains are formed by immersion coating twice in an enzyme domain solution (i.e., forming two layers) and curing at a temperature of 50°C under vacuum for 20 minutes. However, in some embodiments, the enzyme domains may be formed by immersion coating and / or spray coating one or more layers at a predetermined concentration, insertion rate, residence time, withdrawal rate, and / or desired thickness of the coating solution.

[0174] Enzyme sample sensors depend on the reaction rate of the enzymes they contain. As those skilled in the art will understand, in order to calculate the concentration of one reactant / sample (for example, using a defined amount of enzyme), all other reactants / co-reactants are present in excess. However, in the body, this is often not the case, and sometimes the sample is in excess. Therefore, in some embodiments, the sensor membrane is configured and positioned to restrict the diffusion of the sample into the enzyme domain, thereby allowing for accurate measurement of the sample. In some embodiments, the membrane system includes a resistive domain 608 located distal to the electroactive surface, farther from the enzyme domain. The following description concerns the resistive domain for glucose sensors, but the resistive domain can also be modified for other samples and co-reactants.

[0175] With respect to glucose sensors, there is an excess molar concentration of glucose with respect to the amount of oxygen in the blood; that is, there are typically more than 100 glucose molecules for every free oxygen molecule in the extracellular fluid (see Updike et al., "Diabetes Care 5," pp. 207–21 (1982), incorporated herein by reference to the extent that their disclosure does not contradict the disclosure contained herein). However, immobilized enzyme-based glucose sensors that employ oxygen as a co-reactant may be supplied with a non-rate-limiting excess amount of oxygen so that the sensor responds linearly to changes in glucose concentration while it is not responding to changes in oxygen concentration. In particular, when the glucose monitoring reaction is oxygen-limited, linearity is not achieved beyond a minimum glucose concentration. Unless a semipermeable membrane is placed over the enzyme domain to control the glucose and oxygen fluxes, a linear response to glucose levels can only be obtained for glucose concentrations up to approximately 40 mg / dL. However, in clinical practice, a linear response to glucose levels is desirable up to at least approximately 400 mg / dL.

[0176] The resistance domain 608 may comprise a semipermeable membrane that controls the flux of oxygen and glucose to the underlying enzyme domain, thereby providing a non-rate-limiting excess of oxygen. As a result, the upper limit of the linearity of the glucose measurement is extended to a considerably higher value than that achieved without the resistance domain. In one embodiment, the resistance domain 608 exhibits an oxygen-to-glucose permeability ratio of about 50:1 or less to about 400:1 or more, or about 200:1. As a result, one-dimensional reactant diffusion is sufficient to provide excess oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix (see Rhodes et al., Anal. Chem., 66:1520-1529 (1994), incorporated herein by reference to the extent that the disclosure does not contradict the disclosure contained herein).

[0177] In alternative embodiments, a low oxygen-to-glucose ratio may be sufficient to provide excess oxygen by using a highly oxygen-soluble domain (e.g., 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, more glucose may also be supplied to the enzyme without causing an oxygen-limiting excess. In alternative embodiments, the resistance domain is formed from a silicone composition such as that described in U.S. Patent Application Publication US-2005-0090607-A1, which is incorporated herein by reference to the extent that its disclosure does not contradict the disclosure contained herein.

[0178] In one embodiment, the resistance domain 608 comprises a polyurethane membrane having both hydrophilic and hydrophobic regions to control the diffusion of glucose and oxygen to the sample sensor, and this membrane is readily and regeneratively fabricated from commercially available materials. Preferred hydrophobic polymer components are polyurethane or polyether urethane urea. Polyurethane is a polymer produced by the condensation reaction of a diisocyanate with a bifunctional hydroxyl-containing material. Polyurethane urea is a polymer produced by the condensation reaction of a diisocyanate with a bifunctional amine-containing material. Diisocyanates that can be used include, but are not limited to, aliphatic diisocyanates containing about 4 to about 8 methylene units. Diisocyanates containing alicyclic moieties may also be useful in the preparation of polymer and copolymer components of the membrane in some embodiments. The material forming the basis of the hydrophobic matrix of the resistive domain may be any material known in the art that is suitable for use as a membrane in a sensor device and has sufficient permeability to allow relevant compounds to pass through, for example, oxygen molecules to pass from the sample under investigation through the membrane to reach active oxygen or electrochemical electrodes. Examples of materials that can be used to form non-polyurethane membranes include inorganic polymers such as vinyl polymers, polyethers, polyesters, polyamides, polysiloxanes and polycarbosiloxanes, natural polymers such as cellulosic and protein-based materials, and mixtures or combinations thereof.

[0179] In one embodiment, the hydrophilic polymer component is polyethylene oxide. For example, one useful hydrophobic-hydrophilic copolymer component is a polyurethane polymer containing about 20% hydrophilic polyethylene oxide. The polyethylene oxide portion of the copolymer is thermodynamically driven to separate from the hydrophobic portion and hydrophobic polymer component of the copolymer. The 20% polyethylene oxide-based soft segment portion of the copolymer used to form the final blend influences the water absorption and subsequent glucose permeability of the membrane.

[0180] In some embodiments, the resistive domains are formed from a silicone polymer modified to allow sample (e.g., glucose) transport.

[0181] In some embodiments, the resistance domain is formed from a silicone polymer / hydrophobic-hydrophilic polymer blend. In one embodiment, the hydrophobic-hydrophilic polymer used in the blend may be any suitable hydrophobic-hydrophilic polymer, including, but not limited to, polyethers such as polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate, polyvinyl alcohol, polyacrylic acid, polyethylene glycol, or polypropylene oxide, and copolymers thereof, including, for example, diblock, triblock, alternating, random, comb-shaped, star-shaped, dendritic, and graft copolymers (block copolymers are described in U.S. Patents 4,803,243 and 4,686,044, both of which are incorporated herein by reference to the extent that their disclosures do not contradict the disclosures contained herein). In one embodiment, the hydrophobic-hydrophilic polymer is a copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO). Suitable polymers include, but are not limited to, PEO-PPO diblock copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblock copolymers, alternating block copolymers of PEO-PPO, random copolymers of ethylene oxide and propylene oxide, and blends thereof. In some embodiments, the copolymers are optionally substituted with hydroxy substituents. Commercially available examples of PEO and PPO copolymers include the PLURONIC® brand of polymers available from BASF®. In one embodiment, PLURONIC® F-127 is used. Other PLURONIC® polymers include PPO-PEO-PPO triblock copolymers (e.g., PLURONIC®® products). Other suitable commercially available polymers include, but are not limited to, the SYNPERONICS® products available from UNIQEMA®.U.S. Patent Application Publication US-2007-0244379-A1, which is incorporated herein by reference to the extent that such disclosure does not conflict with the disclosure contained herein, describes a system and method suitable for the resistance and / or other domains of film systems.

[0182] In some embodiments, the resistance domain 608 is deposited on the enzyme domain 606 to form a domain thickness of about 0.05 microns to about 20 microns, or from about 0.05, 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 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, or from about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns. The resistance domain can be deposited on the enzyme domain by vapor deposition, spray coating, printing, or immersion coating. In one embodiment, spray coating is a preferred deposition technique. The spraying process atomizes the solution into a mist, so that most or all of the solvent evaporates before the coating material settles on the underlying domain, thereby minimizing contact between the solvent and the enzyme.

[0183] In another embodiment, physical deposition (e.g., ultrasonic deposition) is used to coat one or more of the film domains onto an electrode, and the deposition apparatus and process include an ultrasonic nozzle that generates a mist of microdroplets in a vacuum chamber. In these embodiments, the microdroplets move turbulently in the vacuum chamber, isotropically impacting and adhering to the surface of the substrate. Advantageously, depositions as described above can be implemented to result in higher production throughput of the film deposition process (e.g., at least about 20 to about 200 or more electrodes per chamber), higher consistency of the film on each sensor, and improved uniformity of sensor performance, as described below, for example.

[0184] In some embodiments, depositing resistive domains (for example, using one of the techniques described above) involves forming a film system that substantially blocks or resists ascorbates (known electrochemical interferants in hydrogen peroxide measuring glucose sensors). In the process of depositing resistive domains, a structural form may be formed characterized in that ascorbates are substantially impermeable through it.

[0185] In one embodiment, the resistance domain 608 is deposited on the enzyme domain 606 by spray coating a solution consisting of about 1 wt.% to about 5 wt.% of a polymer and about 95 wt.% to about 99 wt.% of a solvent. When spraying the solution of the resistance domain material, including the solvent, onto the enzyme domain, it is desirable to reduce or substantially reduce contact between the solvent in the spray solution and the enzyme, which can deactivate the enzyme beneath the enzyme domain. Tetrahydrofuran (THF) is one solvent that has minimal or negligible effect on the enzyme of the enzyme domain after spraying. As will be known to those skilled in the art, the use of other solvents may also be preferable.

[0186] While various spraying or deposition techniques can be used, spraying the resistive domain material and rotating the sensor at least once by 180° typically results in adequate coating by the resistive domains. As described in more detail above, spraying the resistive domain material and rotating the sensor at least twice by 120° results in greater coating (one layer of 360° coating), thereby ensuring resistance to glucose.

[0187] In some embodiments, the resistance domains 608 are spray-coated and then cured at a temperature of about 40°C to about 60°C for a period of about 15 minutes to about 90 minutes (and this can be carried out under vacuum (e.g., 20 to 30 mmHg)). Curing times of up to about 90 minutes or more may be advantageous to ensure complete drying of the resistance domains.

[0188] In one embodiment, the resistive domain is formed by spray coating at least six layers (i.e., rotating the sensor 120° 17 times for at least six layers of 360° coating) and curing at a temperature of 50°C under vacuum for 60 minutes. However, the resistive domain can also be formed by immersion coating or spray coating of any or more layers, depending on the concentration of the solution, insertion speed, residence time, withdrawal speed, and / or the desired thickness of the resulting film. In addition, curing in a convection oven may also be employed.

[0189] In some embodiments, a variable frequency microwave oven may be used to cure film domains / layers. Generally, microwave ovens directly excite the rotational modes of the solvent. As a result, microwave ovens cure the coating from the inside out, rather than from the outside in, as in conventional convection ovens. This direct rotational mode excitation is responsible for the "fast" curing typically observed in microwave ovens. In contrast to conventional microwave ovens, which rely on fixed-frequency radiation to cause arcing of dielectric (metal) substrates when placed in a conventional microwave oven, variable frequency microwave (VFM) ovens emit thousands of frequencies within 100 milliseconds, which substantially eliminates arcing of dielectric substrates. As a result, film domains / layers can be cured even after deposition on metal electrodes, as described herein. VFM curing can increase the rate and completeness of solvent evaporation from the liquid film solution applied to the sensor compared to the rate and completeness of solvent evaporation observed for curing in conventional convection ovens. In some embodiments, VFM is used in conjunction with curing by a convection oven to further reduce curing time. In some sensor applications where a film is cured before being applied to an electrode (see, for example, U.S. Patent Application Publication US-2005-0245799-A1, which is incorporated herein by reference to the extent that such disclosure does not contradict the disclosure contained herein), a conventional microwave oven (for example, a fixed-frequency microwave oven) may be used to cure the film layer.

[0190] Various therapeutic (bioactive) drugs may be used with sample sensor systems of several embodiments. In some embodiments, the therapeutic agent is an anticoagulant. In some embodiments, the anticoagulant is provided in the sample sensor system to prevent blood clotting in or on the sensor (e.g., in or on the catheter, or in or on the sensor). In some embodiments, the therapeutic agent is an antimicrobial agent, such as an antibiotic or antifungal compound, but is not limited to these. In some embodiments, the therapeutic agent is an antiseptic and / or disinfectant. The therapeutic agent may be used alone or in combination of two or more of these. The therapeutic agent may be dispersed throughout the material of the sensor (and / or catheter). In some embodiments, the membrane system of some embodiments contains the therapeutic agent, which is incorporated into at least part of the membrane system or incorporated into the device and adapted to diffuse through the membrane. There are various systems and methods for incorporating the therapeutic agent into the membrane. In some embodiments, the therapeutic agent is incorporated during the manufacture of the membrane system. For example, the therapeutic agent may be blended before curing the membrane system or after the manufacture of the membrane system, for example, by coating, absorbing, solvent casting, or adsorption of the bioactive agent into the membrane system. While therapeutic agents may be incorporated within the membrane system, in some embodiments, the therapeutic agent may be administered simultaneously with, before, or after, the insertion of the device, for example, intravenously by oral administration, or locally by subcutaneous injection near the implantation site. Combinations of therapeutic agents incorporated within the membrane system and local and / or systemic administration of the therapeutic agent may be used in some embodiments.

[0191] As a non-limiting example, in some embodiments, the sample sensor 110 is a continuous electrochemical sample sensor configured to include at least one working electrode and at least one reference electrode, configured to measure a signal associated with the concentration of a sample in a host. The output signal is typically a raw data stream used, for example, to provide a useful value of the measured sample concentration in the host to a patient or physician. However, the sample sensor in some embodiments includes at least one additional working electrode configured to measure at least one additional signal, as described elsewhere in this specification. For example, in some embodiments, the additional signal is associated with the baseline and / or sensitivity of the sample sensor, thereby allowing monitoring of changes in the baseline and / or sensitivity that may occur over time.

[0192] Generally, electrochemical continuous sample sensors define a relationship between a sensor-generated measurement result meaningful to the user (e.g., patient or physician) (e.g., current in units of pA, nA, or digital counts after A / D conversion) and a reference measurement result (e.g., glucose concentration in mg / dL or mmol / dL). For example, in the case of an implantable diffusion-based glucose oxidase electrochemical glucose sensor, the sensing mechanism generally relies on linear phenomena with respect to glucose concentration, which include, for example, (1) the diffusion of glucose through a membrane system (e.g., biointerface membranes and membrane systems) placed between the implantation site and / or the electrode surface, (2) enzymatic reactions within the membrane system, and (3) the diffusion of H2O2 into the sensor. Because of this linearity, sensor calibration can be understood by solving the equation y = mx + b, where y represents the sensor signal (e.g., count), x represents the estimated glucose concentration (e.g., mg / dL), m represents the sensor sensitivity to glucose (e.g., count / mg / dL), and b represents the baseline signal (e.g., count). When both sensitivity m and baseline (background) b change in vivo over time, calibration can be improved by solving for m and b using at least two independent matched data pairs (x1, y1; x2, y2), thus enabling glucose estimation when only the sensor signal y is available. Matched data pairs are formed by matching reference data (e.g., one or more reference glucose data points from a blood glucose meter, or similar) with substantially time-corresponding sensor data (e.g., one or more glucose sensor data points), and may provide one or more matched data pairs as described in concurrently pending U.S. Patent Application Publication No. US-2005-0027463-A1, which is incorporated herein by reference to the extent that such disclosure does not contradict the disclosure contained herein.In some implantable glucose sensors, such as those described in more detail in U.S. Patent No. 6,329,161 by Heller et al., incorporated herein by reference to the extent that the disclosure does not contradict the disclosure contained herein, the sensing layer utilizes an immobilized medium (e.g., a redox compound) instead of a diffusion medium to electrically connect the enzyme to the working electrode. In some implantable glucose sensors, such as those described in more detail in U.S. Patent No. 4,703,756, incorporated herein by reference to the extent that the disclosure does not contradict the disclosure contained herein, the system has two oxygen sensors housed in an oxygen-permeable housing, one sensor being immutable and the other contacting glucose oxidase to enable differential measurement of oxygen content in body fluids or tissues indicating glucose levels. Various systems and methods for measuring glucose in a host are known, all of which may benefit from some of all of the embodiments and may result in sensors having a signal-to-noise ratio that is substantially unaffected by inconsistent noise.

[0193] Advantageously, continuous sample monitoring is enabled. For example, when the sample is glucose, continuous glucose monitoring allows for strict glucose control, thereby reducing morbidity and mortality rates among diabetic hosts. In some embodiments, the additional interaction requirements with patients do not place an undue burden on healthcare staff.

[0194] An advantage is that there is no net sample (e.g., blood) loss to the host, which is a crucial feature in some clinical settings. For example, in neonatal intensive care units, hosts are extremely small, and even the loss of a few milliliters of blood can be life-threatening. Furthermore, by returning the bodily fluid sample to the host instead of sending it to a waste container, the accumulation of biohazardous waste requiring specialized disposal procedures is significantly reduced. The integrated sensor system component, when used in conjunction with the sample sensor placed inside, is described in more detail below.

[0195] Various known sensor configurations and / or features can be employed in conjunction with the sensor systems described herein, for example, Ward et al. U.S. Patent No. 5,711,861, Vachon et al. U.S. Patent No. 6,642,015, Say et al. U.S. Patent No. 6,654,625, Say et al. U.S. Patent No. 6,565,509, Heller U.S. Patent No. 6,514,718, Essenpreis et al. U.S. Patent No. 6,465,066 U.S. Patent No. 6,214,185 by Offenbacher et al., U.S. Patent No. 5,310,469 by Cunningham et al., and U.S. Patent No. 5,683,562 by Shaffer et al., U.S. Patent No. 6,579,690 by Bonnecaze et al., U.S. Patent No. 6,484,046 by Say et al., U.S. Patent No. 6,512,939 by Colvin et al., U.S. Patent No. 6,424,847 by Mastrototaro et al. U.S. Patent Application No. 6,424,847, U.S. Patent Application Publication No. US-2006-0020187-A1 by Brister et al., U.S. Patent Application Publication No. US-2007-0027370-A1 by Brauker et al., U.S. Patent Application Publication No. US-2005-0143635-A1 by Kamath et al., U.S. Patent Application Publication No. US-2007-0027385-A1 by Brister et al., U.S. Patent Application Publication No. US-2007-0213611-A1 by Simpson et al., Simpson These include U.S. Patent Publication No. US-2008-0083617-A1 by Brister et al., U.S. Patent Publication No. US-2008-0119703-A1 by Brister et al., U.S. Patent Publication No. US-2008-0108942-A1 by Brister et al., and U.S. Patent Publication No. US-2009-0018424-A1 by Kamath et al., all of which (for example) are incorporated herein by reference to the extent that their disclosures do not contradict the disclosures contained herein. It should be understood that the patents and publications referenced above do not encompass all applicable sample sensors, and that, in general, the disclosed embodiments are applicable to a variety of sample sensor configurations.

[0196] Additional features and details that may be included, particularly for sensors having elongated conductive or nonconductive cores, are described in U.S. Patent No. 9,131,885, which is incorporated herein by reference in its entirety to the extent that its disclosure does not contradict the disclosure contained herein.

[0197] The embodiment of the sensor 110 described above in relation to Figures 5A, 5B, 5C, and 6A includes an elongated conductive core, but this is merely illustrative.

[0198] In other embodiments, elongated nonconductive structures, such as elongated polymer structures or elongated fibrous structures, may be used as the core. In yet another embodiment, the sensor 110 may be formed from a plurality of substantially planar layers. In embodiments including an elongated nonconductive core, the core may have conductive traces and / or other contacts and form an elongated conductor as described in more detail below in relation to various embodiments.

[0199] In various embodiments, continuous sample sensors 110 comprising a metal core, a polymer core, or a fiber core, and / or a plurality of substantially planar layers have been described. Generally, in various embodiments, the metal core, polymer core, fiber core, or planar layer sensor may have a Young's modulus less than 147 GPa, a flexural modulus less than 147 GPa (e.g., for metal core mounting configurations) or less than 2 to 5 GPa (e.g., for polymer core or fiber-reinforced core mounting configurations), and / or flexibility defined by a buckling force less than 0.25 N, less than 0.02 N, less than 0.01 N, less than 0.001 N, or in some embodiments substantially zero or less than the weight of the sensor itself. It will be understood that in isotropic materials, the Young's modulus reflects the flexural modulus and therefore may reflect the stiffness of the sensor. In various embodiments, the core material (e.g., in embodiments using an elongated conductive or non-conductive core) and / or layers of material (e.g., layers formed around the elongated core or one of a plurality of substantially planar layers) may be a phase-changing material having Young's modulus, flexural modulus, and / or buckling force that decrease from in vitro values ​​to in vivo values ​​so that the implanted sensor softens after implantation. Thus, the continuous sample sensor (or at least the supporting structure inside, such as the core or substantially planar or other layers) may be relatively rigid in vitro (e.g., self-supporting) to facilitate the manufacturing, packaging, and / or implantation processes, and relatively flexible in vivo (e.g., non-self-supporting).

[0200] In addition, fatigue life is a measure of the sensor's ability to withstand the embedded environment. In some embodiments, the fatigue life of a sensor 110 having a metal core, a polymer core, or a fiber core, or formed from multiple substantially planar layers, is at least 1,000 cycles of bending from about 28° to about 110° with a bending radius of about 0.125 inches.

[0201] In the configuration shown in Figure 6A, the film 508 is formed on a substantially circular body 502 and substantially surrounds the core in cross-section. This is merely illustrative. In other embodiments, the film 508 may include a plurality of substantially planar film layers disposed on a substantially planar working electrode, as in the example shown in Figure 6B.

[0202] As shown in Figure 6B, the electrode domain 602 may be a substantially planar layer formed on a substantially planar conductive layer 610. The conductive layer 610 may be platinum, a platinum alloy, or other conductive coating formed on a substantially planar layer 612 beneath, for example, a silver trace layer or core (e.g., a substantially cylindrical core of an elongated body). The trace layer 612 or core may be formed on one or more additional substantially planar layers, such as an insulating layer, a working electrode layer, an auxiliary electrode layer, a reference electrode layer, a counter electrode layer, and / or other conductive layers as described herein. In the example of Figure 6, the interference domain 604 is implemented as a substantially planar interference layer formed on a substantially planar electrode domain 602, the enzyme domain 606 is implemented as a substantially planar enzyme layer formed on a substantially planar interference domain, and the resistance domain 608 is implemented as a substantially planar interference layer formed on a substantially planar enzyme domain. In other embodiments, biointerfaces or bioprotective domains (not shown) may be incorporated into the membrane system to facilitate control of foreign body reactions. For example, biointerface or bioprotective domains may be used to reduce biomaterial-related inflammation or decrease the bioattachment rate of the membrane, thereby extending the lifespan of the implanted device. In various embodiments, any of the domains described above (for example, those disclosed in Figure 6A or Figure 6B) may be omitted, modified, replaced, and / or incorporated together without departing from the spirit of the preferred embodiment. For example, in some embodiments, electrode domains may be absent. In some of these embodiments, interference domains may be designed to perform the function of electrode domains.

[0203] In embodiments such as the embodiment shown in FIG. 6B where sensor 110 is formed from a plurality of substantially planar layers, membrane 508 can be formed locally on the working electrode (e.g., using printing or other patterned deposition operations) such that there is substantially no membrane material on other parts of sensor 110. In this way, the cost of the sensor can be reduced by reducing the amount of unused membrane material (e.g., membrane material formed away from the working electrode) formed on the sensor.

[0204] Membrane 508 of FIG. 6A and the variations described herein can also be implemented in various sensors having non-conductive (e.g., polymer or fiber core). For example, FIG. 7 illustrates a continuous analyte sensor having an elongated non-conductive core. In this particular embodiment, sensor 700 (e.g., one implementation of continuous analyte sensor 110) includes an elongated core 702 configured and arranged to accommodate multi-axis bending. Elongated core 702 (e.g., a non-conductive implementation of core 510) includes a non-conductive material (e.g., a soft polymer / polymer material including polyurethane and / or polyimide and / or a shape memory or other state-changing polymer material as described herein). Working electrode 704 can be disposed on elongated core 702. Reference or counter electrode 706 can also be disposed on elongated core 702. Membrane 508 can be disposed on core 702 and cover at least working electrode 704. Conductive paths 708 and 710 (e.g., conductive traces) can run along the length of elongated non-conductive core 702 and connect working electrode 704 and reference or counter electrode 706, respectively, to sensor electronics (not shown). Generally, core 702 and the conductive features formed thereon (e.g., one or more working electrodes, reference or counter electrodes, conductive traces, etc.) can form an elongated conductor for soft analyte sensor 110.

[0205] In various embodiments, the sensor of FIG. 7 can be configured and arranged such that the fatigue life of the sensor is at least 1,000 cycles of bending from about 28° to about 110° with a bending radius of about 0.125 inches. The non-conductive core 702 can have a Young's modulus, for example, less than 147 GPa, less than 1 GPa, less than 1 MPa, or between 1 kPa and 1 MPa (by way of example).

[0206] In some embodiments, the non-conductive core 702 can be formed from a material configured to respond in vivo to environmental effects from the tissue in which the sensor 110 is embedded and / or to external effects such as an electromagnetic field applied or removed from the outside, causing it to soften. For example, the non-conductive core 702 can be formed from a shape memory material having a temperature-dependent Young's modulus, bending modulus, and / or buckling force in some embodiments. For example, when the sensor 700 is embedded in a host, the temperature increase of the core 702 caused by absorbing heat from the host tissue (for example, host tissue having a temperature between 78°F and 98°F) can soften the core 702 such that the Young's modulus, bending modulus, and / or buckling force of the core 702 is reduced (for example, 5-fold, 10-fold, 100-fold, or more than 100-fold). As another example, the hydration of the core 702 caused by absorbing a fluid such as water from the host tissue can cause the softening of the core 702 such that the Young's modulus, bending modulus, and / or buckling force of the core 702 is reduced (for example, 5-fold, 10-fold, 100-fold, or more than 100-fold). In some embodiments, the Young's modulus, bending modulus, and / or buckling force can be reduced by a response on the order of one, two, three, or more than three orders of magnitude to the absorption of heat and liquid from the host tissue.

[0207] For example, the core 702 may be formed from a softenable shape-memory thermoplastic material. The softenable shape-memory thermoplastic material may include copolymers (e.g., block or segmented copolymers) and other polymers. The other polymers may be blended with the copolymer to act as reverse plasticizers. Suitable copolymers may include polyurethanes, polyester urethanes, polyether polyesters, and / or polyether polyamides. In one preferred example, the core 702 may be formed from a polyester / polyether block copolymer with high molecular weight phenoxy. Other examples of shape memory polymers that can be used to form core 702 include polynorbornene, high molecular weight (e.g., greater than 100 kDa) poly(methyl methacrylate), poly(alkyl methacrylate) copolymer, polystyrene copolymer, filler-modified epoxy network structure, chemically crosslinked amorphous polyurethane, poly((methyl methacrylate)-co-(N-vinyl-2-pyrrolidone))-PEG semi-IPN, HDI-HPED-TEA network structure, and biodegradable copolyester-urethane network structure.

[0208] For example, a softenable shape-memory thermoplastic material may be formed from a blend of polymer materials appropriately selected to set the stiffness of the core 702 in vitro (e.g., self-standing stiffness) and determine the transition temperature (e.g., between 78°F and 98°F) at which the core 702 substantially softens (e.g., becomes non-self-standing in some implementation forms). The core 702 may be hydrophilic to further lower the transition temperature by absorbing water in vivo, thereby accelerating the softening of the core 702 after implantation. As will be described in more detail below, the polymer materials may be blended and appropriately shaped using an extruder in some embodiments.

[0209] Figures 8 and 9 show examples of self-supporting and non-self-supporting sensors 110. For example, the configuration in Figure 8 may represent an in vivo configuration of sensor 110 where sensor 110 is a self-supporting sensor (e.g., a sensor with a Young's modulus and / or flexural modulus greater than 500 MPa, or a buckling force substantially greater than the weight of the sensor under gravity). For example, the configuration in Figure 9 may represent an in vivo configuration of sensor 110 where sensor 110 is a non-self-supporting sensor (e.g., a sensor with a Young's modulus and / or flexural modulus less than 500 MPa, or a buckling force less than 0.01 N, or a buckling force substantially less than the weight of the sensor under gravity). Sensors like those shown in Figure 9 may become non-self-supporting after transitioning from a self-supporting sensor like the one shown in Figure 8, or may be permanently non-self-supporting sensors in some implementations.

[0210] As shown in Figure 8, the self-supporting sensor 110 may bend or deform when a sufficient force 800 is applied to it, as indicated by arrow 802, and may return to the same shape and position as before the application of force 800 when the application of force is stopped, as indicated by arrow 804. As shown in Figure 9, the non-self-supporting sensor 110 may bend or deform in various configurations when a sufficient force (e.g., a force greater than the buckling force of sensor 110) 900 is applied to it, as indicated by arrow 902, and may remain in the bent or deformed shape when the application of force is stopped, as indicated by arrow 904. The force 900 in Figure 9 may be greater than the force 800 in Figure 8 in some scenarios. However, in some configurations, the buckling force of sensor 110 may be reduced so that the force 800 can cause the buckling shown in Figure 9 (e.g., by in vivo implantation).

[0211] In various embodiments, elongated cores such as core 510 in Figures 5A–6A and / or core 702 in Figure 7 may be formed from a nonconductive material that can be formed into a thin, elongated structure. In further embodiments, the nonconductive material is a polymer. The polymer may be a nylon or polyester filament, thread or string, etc. In some embodiments, the elongated body is non-planar and therefore has a non-rectangular cross-section, as described herein. However, in some embodiments, the elongated body is planar. In some embodiments, the minimum dimensions (e.g., diameter or width) of the elongated body are less than about 0.004 inches. However, in some embodiments, relatively large or small sensor diameters are also acceptable, as described elsewhere herein.

[0212] The sensor 700 illustrated in Figure 7 can be manufactured using various techniques as described herein. In some embodiments, the working electrode 704 is provided by depositing a conductive material (e.g., at least one of platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, conductive polymers, and alloys) onto an elongated body. In some embodiments, the conductive material is an ink, paint, or paste and is deposited using thick-film and / or thin-film deposition techniques known in the art, such as screen printing, jet printing, block printing, and / or other techniques as described herein. However, in some embodiments, the working electrode material is plated onto the elongated body using plating techniques known in the art, such as electroplating, but not limited to electroplating. The reference and / or counter electrode may be provided by depositing a silver-containing material onto an elongated body. Similar to the working electrode, the silver-containing material of the interference electrode may be deposited using thick-film and / or thin-film deposition techniques, various printing techniques known in the art, and / or plating. The film 508 can be applied to at least the working electrode using one or more processes as described herein. In particular, in some embodiments, the film is applied by applying a polymer having a Shore hardness of about 70A to about 55D. As described with reference to Figures 6A and 6B, the film may consist of multiple layers and / or domains.

[0213] Various exemplary arrangement configurations and manufacturing processes for the continuous sample sensor 110 having a non-conductive core 702 are described in relation to Figures 10 to 27. In particular, Figures 10 to 18 and 27 illustrate non-conductive polymer core mounting configurations for the sensor 110, and Figures 19 to 26 illustrate fiber core mounting configurations for the sensor 110. Next, various mounting configurations in which the sensor 110 has multiple substantially planar layers are described in relation to Figures 28 to 34. Various features and properties of the flexible sample sensor 110 relating to mounting configurations with a flexible metal core, a flexible non-conductive core, and / or multiple planar layers are described in relation to Figures 35 to 45.

[0214] In the examples in Figures 10-18 and 27, a polymer system or polymer core 702 is described, and various methods and configurations for forming a flexible specimen sensor having a working (e.g., platinum) electrode with a clearly defined surface area, a reference (e.g., silver and / or silver chloride) electrode, one or more conductive traces for interface between the electrode and the sensor electronic device 112, and suitable insulation / patterns for the sensor electronic device interface are described.

[0215] As shown in Figure 10, the polymer core 702 for the flexible sample sensor 110 may have an elliptical cross-sectional shape 1002 and may be provided with one or more conductive traces 1000 thereon. The conductive traces 1000 may be formed from, for example, carbon black, platinum, platinum-iridium, silver / silver chloride, or other suitable conductive materials. The elliptical cross-sectional shape of the core 702 may result in enhanced torsion and / or orientation control for the sensor 110, which may be beneficial during sensor manufacturing to prevent twisting in the “line” during the reel-to-reel process. For example, an elliptical cross-sectional shape (or a similar cross-sectional shape such as a rectangular cross-sectional shape with a major axis dimension greater than the orthogonal minor axis dimension) may result in a preferred bending axis parallel to the major axis. In this way, potential bending damage to structures such as electrodes and / or traces formed on the core may be reduced. In the example of Figure 10, the conductive traces 1000 are formed in grooves on the opposite side of the major axis of the core 702. By providing an elliptical cross-section to the elongated sensor body, the advantages of a large surface area without sharp edges can be obtained for the electrode configuration. Therefore, an electrode with a relatively large surface area can be formed, which may be beneficial for sensing and averaging glucose measured in interstitial fluid and minimizing the effects of local environmental fluctuations. Forming a sensor with an elliptical cross-section without sharp edges reduces local stress and tissue damage, facilitating a more desirable implantation design.

[0216] Figure 11 shows a manufacturing system for forming a core 702 and / or conductive trace 1000. As shown in Figure 11, the manufacturing system 100 may be an extrusion system comprising a filament extruder 1102 for extruding the core 702 from a blend of copolymer and other polymer materials, such as those described above. The filament extruder 1102 may be a twin-screw extruder configured to blend and extrude the core 702 (for example). In the example of Figure 11, the conductive trace 1000 is co-extruded with the core 702 using trace extruders 1104 and 1106. A coolant 1108 may then cool the output of the extrusion system to form an elongated core structure 1110, such as a core structure having the polymer core 702 and the conductive trace 1000.

[0217] However, this is merely illustrative. In other embodiments, conductive traces, such as the conductive trace 1200 in Figure 12, may be deposited in grooves, such as the groove 1300 in Figure 13, after the formation of the grooved core 702 (e.g., via extrusion). For example, trace 1200 may be deposited in the groove 1300 using a squeegee 1400 after the core 702 has been formed, as illustrated in Figure 14. In one embodiment, trace 1200 is formed by wiping into the groove 1300 by moving a squeegee 1400 along the core 702 with a liquid conductor 1402 (e.g., a conductive ink such as a polymer liquid in which carbon, platinum, silver, or other conductive particles are suspended) as indicated by arrow 1404.

[0218] In other embodiments, a conductive ribbon, such as a metal ribbon, may be laminated (e.g., thermally laminated) into one or more grooves 1300 within a non-conductive core 702. Figure 16 shows an exemplary mounting configuration in which the core 702 includes a pair of conductive ribbon traces 1600 (e.g., silver or silver chloride traces) disposed in grooves on the opposite side of the core 702.

[0219] Figure 15 shows a manufacturing system that may be used to place the trace 1600 into a groove in the core 702. As shown in Figure 15, the core 702 and the trace 1600 may be fed (for example, between a reel, spool, or other feeder equipment) through a fiber heater 1502 and a laminating die 1504, thereby heating and laminating the trace 1600 onto the core 702 to form an elongated conductive core structure 1510 for the flexible sample sensor 110. However, the system in Figure 15 is merely illustrative. Figure 16 shows another exemplary manufacturing system that may be used to laminate a conductive trace onto the core 702. In the example in Figure 16, an induction heater 1700 is used to heat the trace 1600 before it comes into contact with the core 702. As illustrated in Figure 17, after heating by an induction heater 1700, a positioning guide 1702 may be used to guide the core 702 and the heated trace 1600 between rollers 1704, generating contact pressure between the heated trace 1600 and the core 702, laminating the trace 1600 onto the core 702 to form an elongated conductive core structure 1710 for the flexible sample sensor 110. In this way, heat and pressure can be applied exclusively to the trace 1600 so as to avoid heating of the core 702 and potential related problems and / or defects (e.g., constriction and fracture under heating and tension in the reel-to-reel process).

[0220] In various practical configurations, one or more portions of trace 1600 may be used to form part of a working electrode or reference electrode for a flexible sample sensor 110, or trace 1600 may be used to conductively couple the respective electrodes to the sensor electronics, for example, at the rear end of a core 702 located proximal to or inside the sensor electronics housing, as in the mounting configurations of traces 708 and 710 in Figure 7. Figure 18 shows an exemplary elongated conductive core (for example, a mounting configuration of traces 1000, 1200, or 1600) formed from an elongated polymer core 702 together with trace 1800, and an electrode 1802 formed on trace 1800 and in conductive contact with trace 1800.

[0221] The electrode 1802 may be formed, for example, by pad printing, stencil printing, aerosol jet printing, or other suitable deposition or printing processes as will be understood by those skilled in the art. Pad printing, as an example useful for explanation, includes supplying conductive ink from a container into electrode-shaped recesses in a substrate, pressing a transfer pad onto the conductive ink in the electrode-shaped recesses to lift the conductive ink having the electrode shape onto the transfer pad, pressing the transfer pad together with the electrode-shaped conductive ink onto the core 702 and trace 1800, and depositing conductive ink having the desired shape onto the core 702 which is conductively in communication with the trace 1800. Stencil printing and aerosol jet printing will be described in more detail below, for example, in reference to Figure 27.

[0222] In various examples of Figures 7, 10, 12, 15, and 18, other layers (e.g., insulating layers, additional electrode layers, film layers, or similar) are formed on one or more portions of the core 702 and / or traces disposed thereon using one or more methods as described herein, thereby forming a finished flexible sample sensor for coupling to the sensor electronic device 112.

[0223] In some embodiments, the core 702 may include materials and / or components that are resistant to mechanical fatigue and thermal deformation. For example, in some embodiments, the non-conductive core 702 may be implemented as a fibrous core having one or more fibrous elements. The fibrous elements can prevent the sensor substrate from exhibiting thermally related expansion and contraction, which may be desirable, for example, in a reel-to-reel manufacturing process.

[0224] Figure 19 shows an exemplary implementation of a nonconductive core for a flexible sample sensor, which is implemented using a bundle of fibers 1901. The fibers 1901 may be, for example, paraamide synthetic fibers such as Kevlar® fibers, which prevent changes in core diameter caused by heating under tension during co-extrusion and provide longitudinal strength to prevent expansion and contraction. The fibers 1901 may be encapsulated within an elongated insulator 1900. The elongated insulator 1900 may be formed from a thermoplastic adhesive in several implementations. For example, forming the elongated insulator 1900 from a thermoplastic adhesive can increase the adhesion of subsequent metal ribbons for forming conductive traces. The elongated insulator 1900 and the fiber core 702 may be co-extruded to form an elongated nonconductive core structure 1902 for a flexible sample sensor 110. In addition, the fiber-reinforced nonconductive core may offer the advantage of resistance to axial deformation, which can help maintain the surface area and electrical connectivity of the electrodes to the sensor.

[0225] As shown in Figure 20, one or more conductive traces, such as conductive trace 2000, may be formed on the elongated insulator 1900. The conductive trace 2000 may be, for example, a platinum or platinum alloy trace (as an example), and may be attached to the elongated insulator 1900 by applying heat and pressure to the trace 2000 and the elongated insulator 1900 using a heater and laminating die as described above in relation to Figure 15, thereby at least partially melting the trace 2000 and / or the elongated insulator 1900 and laminating the trace 2000 onto the elongated insulator 1900. As shown in Figure 21, the patterned insulating layer 2100 may be formed on a portion of the trace 2000 such that a window 2102 in the insulating layer 2100 is formed on a portion of the trace 2000 that is to be used as an electrode (e.g., a working electrode). Although only one side of the elongated conductive core structure 2101 is shown in Figure 21, in some implementation configurations, the conductive trace 2000 (see, for example, Figure 20) and patterned insulating layer 2100 are formed on the opposite side of the core 1902, thereby forming a working electrode on the first side of the body 2101 and additional (e.g., working, reference, or opposing) electrodes on the opposing second side of the body 2101. As shown in Figure 19, the core structure 1902 may be formed by a substantially cylindrical fiber bundle 1901 encapsulated within an elongated insulator having an elliptical cross-section, which provides a measure of torsion and / or orientation control over the core structure 1902 and a large surface area for electrode configuration. Some of the embodiments described herein have two grooves, traces, and / or electrodes formed on opposite sides of the core, but alternative embodiments may have three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more grooves, traces, and / or electrodes. In some of these alternative embodiments, the grooves, traces, and / or electrodes may be substantially symmetrical along the longitudinal axis of the elongated core. For example, in one embodiment having three grooves, traces, and / or electrodes, the three grooves, traces, and / or electrodes may be substantially equal in distance from the longitudinal axis of the elongated core and aligned substantially equally with respect to a cross-sectional perspective view of the elongated body.

[0226] FIG. 22 shows an exemplary rear or proximal end 2200 of an elongated conductor formed from a non-conductive fiber reinforcement core (e.g., proximal to the sensor electronics from the distal end shown in FIG. 21), showing how a bundle of fibers 1901 encapsulated within an elongated insulator 1900 can extend to the rear end, and showing how an insulating layer 2100 can be patterned at the rear end.

[0227] Specimen sensing using a soft specimen sensor with a fiber reinforcement core can be improved in some embodiments by providing a sensing area for additional working electrodes, counter electrodes, and / or reference electrodes and providing spatial signal averaging from multiple electrodes. For example, in some embodiments, a fiber core soft specimen sensor can include mirror symmetrically oriented conductive traces 2000 (e.g., platinum or platinum-based ribbon) and a coaxial coating 2302 (e.g., an AgCl coating) for both spatial averaging of the working signal and increased reference loading as shown in FIG. 23. As shown, a coaxial insulating layer 2300 can be disposed between the coating 2302 and the trace 2000 and can serve to electrically insulate the coating 2302 from the trace 200. Windows 2303 (e.g., cutouts in the insulating layer 2300) can be provided to form working electrodes symmetrically disposed on a first side 2304 and a second side 2306 of the soft elongated conductor 2301. Since the insulating layer 2300 and the electrode layer 2302 extend around the entire circumference of the fiber reinforcement core in the example of FIG. 23, the formation and / or patterning of these layers can be faster, less complex, and / or less costly than forming a ribbon-type layer as shown, for example, in FIG. 21.

[0228] Figure 24 shows an exemplary rear or proximal end 2400 of an elongated conductor 2301 formed from a non-conductive fiber-reinforced core having a coaxial coating 2302, illustrating how a bundle of fibers 1901 encapsulated within the elongated insulator 1900 may extend to the rear end, and how the insulating layer 2300 and coating 2302 may be patterned at the rear end to form a notch 2402 into which, for example, sensor electronics 112 or electrical contacts can be coupled to the sensor. In various embodiments, various additional layers, such as one or more film layers as described herein, may be formed on at least the exposed portion of the trace 2000 within windows 2102 and 2303 to form working electrodes.

[0229] The fiber-reinforced core examples described above in relation to Figures 19-24 are merely illustrative. Figure 25A shows another implementation of a fiber-reinforced core for a flexible sample sensor. In the example in Figure 25A, the core 702 is formed from a bundle 2501 of fibers (e.g., paraamide synthetic fibers such as Kevlar® fibers), and a conductive coating 2500 (e.g., platinum or platinum-based cladding, or metallic cladding such as platinum sputtering coating) is formed on this bundle. In this way, a window 2503 in the coaxial insulating layer 2504 that substantially encapsulates the metal-clad core may allow the working electrode to be formed from a portion of the metal-clad fiber core itself. As shown in Figure 25A, a coaxial conductive layer 2502 (e.g., a silver or silver chloride electrode layer) may be arranged around at least a portion of the insulating layer 2504, thereby providing a reference electrode.

[0230] It should be noted that the example in Figure 25A, in which a bundle of metal-clad nonconductive fibers is used as an elongated conductor for a flexible sample sensor, is merely illustrative. As shown in the example in Figure 25B, a nonconductive fiber-reinforced core 702 for a flexible sample sensor may be formed from a single fiber having a conductive coating 2500 and substantially surrounded by an insulating layer 2504 (e.g., the polymer material includes polyurethane and / or polyimide) and a conductive layer 2502. In the example in Figure 25B, the working electrode formed within the window (e.g., notched region) 2503 of the insulating layer 2504 may be sufficiently flexible so that a film coating procedure other than drip coating (e.g., vapor coating) can be used to deposit a film 508 on the exposed portion of the conductive coating 2500 within the window 2503.

[0231] In any of the embodiments described herein, including the embodiment illustrated in Figure 25A or Figure 25B, the sensitivity of the working electrode can be increased by increasing its surface area. For example, in one embodiment, the surface area of ​​the working electrode is increased by using metal nanoparticles such as platinum nanoparticles, or nanoparticles formed from other conductive materials. In one embodiment, conductive nanoparticles can be mixed into a matrix that forms a conductive coating. In an alternative embodiment, conductive nanoparticles can be bonded (e.g., by covalent bonds) to the surface of a non-conductive fiber core. Since conductive nanoparticles can result in a larger surface area, a faster oxidation rate of the measured chemical species (e.g., hydrogen peroxide) can be achieved, thereby resulting in a sensor with higher sensor sensitivity.

[0232] Figure 26 shows an exemplary rear or proximal end 2610 of an elongated conductor formed from a non-conductive fiber-reinforced core having a metal coating 2500, illustrating how a bundle of fibers 1901 encapsulated within the elongated insulator 1900 may extend to the rear end, and how the insulating layer 1900 may be patterned at the rear end to form a notch 2600 into which the metallized core is exposed for coupling the working electrode to the sensor electronic device 112.

[0233] In embodiments where the core 702 is implemented as a fiber core, the core 702 may contain a number of fibers (e.g., one or more single fibers of braided or woven fibers) suitable for producing a desired core diameter, stiffness, and / or longitudinal strength. For example, a single fiber core may have a diameter of 12 microns or less in some embodiments. In some embodiments, a metal or polymer core may be formed with a relatively small diameter or major axis (e.g., a diameter or major axis between 10 and 50 microns) to reduce the stiffness, flexural modulus, and / or buckling force of the core, along with or in addition to the material selection for the core.

[0234] In some embodiments, the in vivo portion of the soft specimen sensor has a metal core, polymer core, or fiber core, thereby reducing the interface area between the sensor and the host tissue, and thus reducing the conversion of mechanical force from the tissue to the interface. For example, the length of the in vivo portion may be between 1 mm and 5 mm in some embodiments.

[0235] In various embodiments, conductive structures such as electrodes and / or conductive traces (for example, for coupling electrodes to sensor electronic equipment 112) may be formed on a non-conductive core using stencil printing or jet printing procedures. Figure 27 shows an example of a core 702 that is implemented as a polymer core, which may have a patterned mask or stencil 2702 that substantially surrounds at least a portion of the core 702 and includes openings such as openings 2704 and 2706. A conductive material such as a metallic material (e.g., platinum or a platinum alloy) may be applied to the stencil 2702 within openings 2704 and 2706 and wiped away (e.g., wiped with a squeegee) so that the conductive material is formed only within openings 2704 and 2706. Next, as indicated by arrow 2708, the stencil 2702 can be removed while leaving the conductive material deposited on the core 702 to form conductive traces 2712 corresponding to the shapes of electrodes 2710 (e.g., working or reference electrodes for a soft sample sensor) and openings 2704 and 2706. However, the process in Figure 27 is merely illustrative. In some embodiments, conductive structures such as electrodes 2710 and traces 2712 (e.g., mounting configurations of electrodes 704 and / or 706 and traces 708 and / or 710) may be printed on the core 702 (e.g., using an aerosol jet printer where a sheath gas flow is used to focus a stream of conductive ink droplets to form a high-resolution conductive structure on the core 702).

[0236] Various implementations of the flexible continuous sample sensor 110 having a wire-type (e.g., metal, polymer, conductive, non-conductive, and / or fiber) core have been described herein as examples, but these examples are for illustrative purposes only. In other embodiments, the sensor 110 may be formed from a plurality of substantially planar layers.

[0237] For example, Figure 28 is a perspective view of the in-vivo portion of a continuous sample sensor 110 implemented using a plurality of planar layers 2800. As shown in Figure 28, in some embodiments, the sensor 110 may comprise a substantially planar insulating layer 2802, a substantially planar first electrode layer 2808 disposed on a first side of the insulating layer 2802, and a substantially planar second electrode layer 2806 disposed on a second side opposite the insulating layer 2802. In various embodiments, the insulating layer 2802 may be an insulating polymer layer formed from polyethylene, polyimide, and / or a state-change material (e.g., a temperature-dependent shape memory polymer, a hydration-dependent shape memory polymer, a chemical-dependent state-change material, or a field-dependent state-change material as described herein).

[0238] The first electrode layer 2808 may be formed from a metallic material such as platinum, platinum-iridium, gold, palladium, iridium, or alloys thereof, graphite, carbon, or a conductive polymer. At least a portion of the first electrode layer 2808 may form the working electrode for the sensor 110 and may be disposed within a window 2811 in an additional insulating layer 2810 (e.g., an additional insulating polymer layer). A trace layer 2804, such as a silver or silver alloy trace layer, may be disposed on the first side of the insulating layer 2802 and may extend along the surface of the insulating layer 2802 between the insulating layer 2802 and the additional insulating layer 2810, and between the insulating layer 2802 and the first electrode layer 2808.

[0239] In this way, the trace layer 2804 can form a conductive coupling between the first electrode layer 2808 (e.g., the working electrode) and the sensor electronic device 112 (not shown in Figure 28) or an electrical contact. The second electrode layer 2806 may be formed from, for example, silver, silver chloride, or other suitable electrode material. The second electrode layer 2806 may form a reference electrode for the sensor 110. One or more film layers on the film 508 may be formed on the first electrode layer 2808 within at least the window 2811, as described above in relation to Figure 6B (for example, the conductive layer 610 in Figure 6B may be one implementation of the layer 2808 in Figures 28 and / or 32).

[0240] As shown in Figure 28, each of the layers 2800 is substantially planar (for example, including a substantially planar surface in contact with at least one other substantially planar surface of another layer), but the outer edge 2820 may be rounded so that the cross-sectional profile 2822 of the sensor 110 is substantially elliptical, as described herein.

[0241] Figure 29 shows the rear (e.g., proximal) end portion 2900 of the sensor 110 in the mounting configuration of Figure 28. As shown in Figure 29, the second electrode layer 2806 and the insulating layer 2810 may have features such as a notch 2906 and an additional window 2909 configured to couple with the sensor electronic equipment 112 (not shown). In mounting configurations in which the sensor 110 comprises a plurality of substantially planar layers 2800, the edge portions 2904 of the sensor 110 may be coated to prevent electrical crosstalk between layers, or otherwise treated in some way (e.g., by an insulating coating).

[0242] A sensor 110, which is implemented with multiple substantially planar layers 2800, can be formed, for example, by patterning all traces and electrodes in a large sheet format, and then pieceping the large sheet containing all the desired layers into individual sensors. Figure 30 shows an example of a planar sheet having multiple planar layers that can form a pieced sensor 110 in one embodiment.

[0243] As shown in Figure 30, a planar sheet of insulating material 2802' may be provided (for example, an insulating polymer sheet formed from a phase-changing material such as polyethylene, polyimide, other polymers, and / or temperature-dependent shape memory polymers, hydration-dependent shape memory polymers, chemical / biodependent phase-changing materials, or field-dependent phase-changing materials as described herein). The sheet 2802' may be provided and may be coated with a planar sheet of trace material (for example, silver) 2808' that substantially covers a first side of the sheet 2802'. The trace material 2808' may be deposited using any of a variety of metal deposition techniques, such as sputtering, screen printing, or other deposition techniques as described herein.

[0244] Sheet 2810' may be deposited in a pattern that covers adjacent layers of conductive (e.g., trace) material 2808' while leaving predefined surface areas (e.g., strips as shown in Figure 30) of the conductive material 2808' uncovered for deposition of the electrochemical film material and / or electrode material. Sheet 2810' may, for example, be deposited on a predefined area of ​​a planar sheet of electrode material with an insulating material (e.g., silicon dioxide (SiO2) or silicon nitride (SiN) x The insulating material (e.g., polyurethane dispersion in organic solvent, thermoplastic silicone polycarbonate urethane, or polydimethylsiloxane (PDMS)) may be deposited using radio frequency (RF) sputtering or screen printing onto a planar trace layer. The sheet 2810' may be deposited with gaps forming conductive strips of material as shown in Figure 30, leaving a desired portion of the trace layer 2808' uncovered. In this way, laser cutting or laser skiving of the insulating material to define windows to the electrode strips is avoided, thereby reducing the production time and cost of the flexible sample sensor. However, this is merely illustrative. In some embodiments, a completely planar sheet of insulating material may be deposited on a planar sheet of trace material and patterned using laser skiving or other preferred techniques.

[0245] Sheet 2802' may comprise a planar sheet of the reference electrode material (e.g., a planar sheet of silver or silver chloride) on the second side (e.g., the side opposite to the side on which the trace layer is formed, not shown in Figure 30) by providing a sheet of the reference electrode material on sheet 2802' or by providing sheet 2802' on a pre-formed sheet of the reference electrode material. Various additional materials, such as insulating materials, electrode materials, or film materials as described herein, may be deposited, laminated, printed, wiped, or otherwise provided to form a sheet structure 3000 on which multiple sensors can be sectionalized.

[0246] In one preferred example, sheet 3000 may be formed by preparing a sheet of silver tracing material 2808' and screen printing (or otherwise depositing) an insulating sheet 2810' to cover a portion of the silver tracing material sheet, leaving other portions uncovered. In another preferred example, sheet 3000 may be formed by preparing a sheet of silver tracing material, attaching one or more strips 2808' of platinum or platinum alloy foil to the sheet of silver tracing material while the sheet is wet, and screen printing (or otherwise depositing) an insulating sheet 2810' to cover the remaining portion of the silver tracing material sheet. In yet another preferred example, sheet 3000 may be formed by preparing a sheet of titanium or titanium alloy tracing material, sputtering strips 2808' of platinum or platinum alloy material onto the sheet of titanium or titanium alloy tracing material, and screen printing (or otherwise depositing) an insulating sheet 2810' to cover the remaining portion of the silver tracing material sheet.

[0247] A strip of film material, as described in relation to Figure 6B, can be printed along the strip 2808' or deposited in some other way such that the film material is formed only on the working electrode of each sensor, and the rest of the fragmented sensor is substantially free of film material. In this way, the cost of film material for each sensor can be substantially reduced compared to, for example, immersion coating of a wire-core sensor.

[0248] Figure 31 shows an example of a framing device that may be used to framing individual sensors 110. As shown in Figure 31, the sheet 3000 may be fed by rollers 3100 into a path of a cutting device 3102 (e.g., a block of evenly spaced blades such as metal blades, a linear array of a laser cutting machine, or a linear array of a waterjet cutting machine) which cuts the sheet 3000 into individual sensor strips 110' that form reels, each containing a plurality of non-framing sensors 110. Each sensor strip 110' may then be cut and / or further processed (e.g., rounded and / or edge-coated) to framing the reels to form individual sensors 110. Alternatively, the cutting device 3102 may be configured to slice the sheet 3000 in two orthogonal directions in order to framing individual sensors from the sheet 3000 in the cutting device 3102.

[0249] Figure 32 shows a schematic diagram of the process for forming a flexible sample sensor 110 from a sheet 3000. As indicated by arrow 3200, the sheet 3000 may be cut (e.g., using apparatus 3102) to form multiple fragmented sensor structures, such as fragmented sensor structure 110'. The fragmented sensor structure 110' may have multiple substantially planar layers 2800 having substantially rectangular cross-sectional profiles and substantially flat edges 3202. However, as indicated by arrow 3204, each fragmented sensor structure may be further processed (e.g., in an additional thermoforming process such as hot pressing) to round the edges of the round fragmented sensor structure 110', thereby forming a fragmented sensor 110 having rounded sidewalls 3206 and a substantially elliptical cross-sectional profile 3208. This hot pressing can be performed more economically before cutting the fragmented series of configured wires. However, this is merely illustrative. In some implementations, the cutting device 3102 may be configured to separate the sensor 110 into individual pieces during a common cutting operation and round the edges of the sensor 110, or a substantially rectangular sensor may be provided.

[0250] The multiple substantially planar layers 2800 shown in Figure 32 are the same as the layers described above in relation to Figure 28. However, this arrangement of layers is merely illustrative, and other arrangements of layers are also envisioned. For example, various configurations are envisioned for the sensor 110 in which the multiple planar layers are arranged to perform multiple sample sensing (e.g., using a dedicated arrangement of multiple working electrodes or membrane layers) and / or to provide a counter electrode. For example, as shown in Figure 33, a fragmented sensor structure 110' cut from a sheet of planar sensor layers may comprise a counter electrode 3305.

[0251] In the exemplary implementation shown in Figure 33, the individualized sensor structure 110' comprises a counter electrode 3305 disposed between a first substantially planar insulating layer 3302 on the first side of the counter electrode 3305 and a second substantially planar insulating layer 3303 on the second side of the counter electrode 3305. A substantially planar first electrode layer 3308 (e.g., a platinum or platinum alloy electrode layer) may be formed on the first substantially planar insulating layer 3302. A substantially planar second electrode layer 3306 (e.g., a silver or silver chloride electrode layer) may be formed on the second substantially planar insulating layer 3303. An additional insulating layer 3310 may be formed on the substantially planar first electrode layer 3308. A window 3311 may be formed within the substantially planar insulating layer 3310 to expose a portion of the electrode layer 3308 and form a working electrode for the sensor 110. The film 508 (not explicitly shown in Figure 33) may be formed on at least the exposed portion of layer 3308 within the window 3311. For example, the exposed portion of layer 3308 may be one implementation of the conductive layer 610 in Figure 6B.

[0252] They can be formed by depositing sheets of insulating material separated by a space corresponding to the width of the window 3311 on a sheet of electrode material, or by substantially covering a sheet of electrode material with a continuous sheet of insulating material, for example by removing strips of insulating material from a sheet of electrode material, such as those described above in relation to Figures 30-32, where each strip has a width corresponding to the width of the window 3311.

[0253] As shown in Figure 33, the individualized sensor structure 110' may have a plurality of substantially planar layers 2800 having substantially rectangular cross-sectional profiles. However, as shown in Figure 34A, each individualized sensor structure may be further processed (e.g., by an additional cutting and / or grinding process) to round the edges of the round individualized sensor structure 110', resulting in an individualized sensor 110 having rounded sidewalls 3400 and substantially elliptical cross-sectional profiles 3402.

[0254] As shown in Figure 34A, the electrode layer 3308 may form part of the working electrode, extending along the length of the sensor 110 and conductively coupling the working electrode to the sensor electronics 112 (not shown in Figure 34). However, this is merely illustrative. As shown in Figure 34B, the multiple planar layers 2800 of the sensor 110 may include an additional trace layer 3420 (e.g., a silver or silver alloy trace layer) disposed between the insulating layer 3302 and the electrode layer 3308. As illustrated, the trace layer 3420 may extend along the length of the sensor 110 and provide a conductive coupling between the local electrode layer 3308 within the window 3311 and the sensor electronics 112 (not shown in Figure 34B).

[0255] The multiple planar layers 2800 in various implementation configurations described in relation to Figures 28, 32, 34A, and / or 34B can generally form an elongated conductor for the soft sample sensor 110. The multiple planar layers 2800 can generally have a Young's modulus and / or flexural modulus of less than, for example, 147 GPa, less than 1.5 GPa, less than 1 GPa, less than 1 MPa, or less than 1 kPa. The multiple planar layers 2800 can generally have a buckling force (for example) of less than, for example, 0.25 N, less than 0.02 N, less than 0.01 N, less than 0.001 N, or less than or greater than the weight of the multiple planar layers 2800 under gravity. The Young's modulus, flexural modulus, and / or buckling force of multiple planar layers may remain substantially unchanged in in vitro and in vivo configurations, or one or more of the substantially planar layers 2800, such as layer 2802 (Figure 28), or 3303, 3302, and / or 3310 (Figure 34A / 34B), may be a state-change material that becomes more flexible in vivo than in vitro due to, for example, changes in temperature, changes in hydration, chemical and / or biological reactions with host tissue, or changes in the applied electric field. For example, after insertion into the patient's skin, the Young's modulus and / or flexural modulus of the aggregate of multiple substantially planar layers or the aggregate of additional layers formed on a wire-type core may decrease in various implementation forms, for example, from above 1 GPa to below 1 GPa, below 1 MPa, and below 1 kPa. After insertion into the patient's skin, the buckling force of the aggregate of multiple substantially planar layers or the aggregate of wire-type cores and additional layers formed thereon can decrease, for example, from a magnitude exceeding the weight of the multiple planar layers 2800 under gravity to a magnitude less than the weight of the multiple planar layers 2800 under gravity, or from greater than 0.01 N to less than 0.01 N. In this way, an ex vivo self-supporting sensor 110 can be provided, replacing an in vivo non-self-supporting sensor.

[0256] While the examples in Figures 28 and 34 show a single working electrode, the planar sheet embodiment facilitates the formation of multiple working electrodes in various arrangements on the sensor (for example, for spatial signal averaging and / or multiple sample sensing), enabling the fabrication of multi-sample sensors such as glucose and lactate dual-sample sensors.

[0257] Various advantages, such as background reduction and noise reduction, can be provided by flexible sample sensors as described herein, as shown in graphs 3500 and 3600 in Figure 35, respectively. For example, flexible core wires with a low modulus of elasticity, as described herein, may be more suitable for long-term transdermal use, for example, by low-level FBGC encapsulation, compared with, for example, tantalum core wires. Furthermore, the use of depositing working electrode materials such as platinum by sputter coating in a cleanroom can result in improved electrochemical performance with respect to background signal and absolute noise reduction, as shown in comparative graphs 3500 and 3600, respectively.

[0258] Figure 36 shows graphs of exemplary three-point bending loads for five exemplary sensor mounting configurations, which may provide another measure of the flexibility of soft specimen sensors. In particular, in the examples of Figure 36, the first curve 3602 corresponds to a load in units of Newtons (N) as a function of elongation in millimeters for a sensor having a tantalum core with a diameter of 4 / 1000 inch. Curve 3604 corresponds to a load in units of Newtons (N) as a function of elongation in millimeters for a sensor having a tantalum core with a diameter of 3 / 1000 inch. Curve 3606 corresponds to a load in units of Newtons (N) as a function of elongation in millimeters for a sensor having a tantalum core with a diameter of 2 / 1000 inch. Curve 3608 corresponds to a load in units of Newtons (N) as a function of elongation in millimeters for a sensor having a nylon (e.g., nylon 6) core with a diameter of 8 / 1000 inch. Curve 3610 corresponds to a load in Newtons (N) as a function of extension in millimeters for a sensor having multiple substantially planar layers (equipped with polymer substrates) with a total thickness of 3 / 1000 of an inch. Curves 3602, 3604, 3606, 3608, and 3610 may represent the results of a bending test over a 0.5-inch span at a speed of 1 inch / min.

[0259] As described herein, in some embodiments, flexible specimen sensors may be formed from materials that partially change state from substantially self-supporting to substantially non-self-supporting after implantation. Figure 37 shows an example of a sensor 110 having several substantially planar layers, such as layers 3700 and 3702 (for example, layers corresponding to one or more of the layers 2800 in Figure 28 or Figure 36). In the example of Figure 37, the sensor 110 includes a hydrophilic layer 3700 (for example, a hydrophilic polymer as described herein) configured to absorb fluids such as water (H2O), as indicated by arrow 3704. In the configuration illustrated in Figure 37, a portion 3706 of layer 3700 absorbs bodily fluids from the host tissue. A hydration interface 3710 between the wet portion 3706 and the unwet portion 3708 may penetrate into the interior of layer 3700 as layer 3700 absorbs host bodily fluids, as indicated by arrow 3712. After hydration, the Young's modulus and / or flexural modulus of layer 3700 may be reduced, for example, from greater than 1 GPa to less than 1 GPa, less than 1 MPa, or less than 1 kPa in various embodiments, and / or the buckling force of layer 3700 may be reduced, for example, from greater than 0.01 N to less than 0.01 N, or from a magnitude greater than the weight of multiple planar layers 2800 under gravity to a magnitude less than the weight of multiple planar layers 2800 under gravity. Layer 3700 may be configured to hydrate within hours, minutes, or seconds from in vivo placement (for example). The length of time for the transition from self-supporting to non-self-supporting state may be determined so that coating and / or other manufacturing operations involving fluids do not cause undesirable transitions.

[0260] Figure 38 shows an example of the transition of sensor 110 from an autonomous sensor to a non-autonomous sensor via chemical and / or bioreactions. In the example of Figure 38, a non-conductive (e.g., polymer) core 3800 (e.g., one implementation of the non-conductive core 702 and conductive traces 1000, 1600, 1800, or 2000 as described herein) containing a conductive trace 3802 may include one or more portions 3804 that undergo chemical and / or bioreactions in vivo with the host's tissues and / or bodily fluids. For example, a portion 3804 may be formed from a soluble material such as processed collagen, silk, hair, and / or other natural or synthetic materials that can be broken down in the host body. As shown in Figure 38 and indicated by arrow 3806, a portion 3804 may be dissolved in vivo such that sensor 110 loses material from the recess 3808, reducing the rigidity of the sensor.

[0261] As shown in Figure 39, portion 3804 may extend beyond the edge 3900 of the region of the sensor 110 where the film 508 is formed, so that portion 3804 can interact with and directly interface with the host tissue. Portion 3804 may also extend beneath the film 508, dissolving from beneath the film 508, thereby reducing the rigidity of the portion of the sensor 110 where the film 508 is disposed.

[0262] Figure 40 shows a partial example of a sensor 110 having field-dependent stiffness that can be made rigid by applying an electromagnetic field. As shown in Figure 40, during an immersion coating operation in which the sensor 110 is immersed in a film fluid 4000, an electric or magnetic field 4002 may be applied in the immersion direction to increase the stiffness of the sensor 110 in that direction.

[0263] As shown in Figure 41, without the application of the field 4002, the stiffness of the sensor 110 may be low enough so that the sensor 110 can be deformed by the surface tension of the fluid 4000. Therefore, in some embodiments, the sensor 110 may comprise an electrically or magnetically alignable material that stiffens in a desired direction after the application of a given field.

[0264] In the examples in Figures 40 and 41, field 4002 is an externally applied field generated, for example, by the immersion coating equipment during immersion coating. In other embodiments, the stiffness of sensor 110 may be modified and / or controlled by sensor electronics 112 when the sensor is incorporated into a sensor system such as sensor system 101 (Figure 1). For example, as shown in Figure 42, sensor electronics within housing 300 may generate a field 4200 that stiffens sensor 110 before insertion into patient skin. After removing field 4200, sensor 110 may transition from a self-supporting sensor in Figure 42 to a non-self-supporting sensor in Figure 43, or vice versa.

[0265] Figures 44 and 45 show exemplary configurations of electromagnetic field generating components that may be used, for example, to control the stiffness of the sensor 110 from within the housing 300. In some embodiments, these electromagnetic field generating components may be part of the sensor electronics 112, which may be part of a skin assembly (for example, on the sensor electronics housing) that is bonded to the patient's skin.

[0266] In the example in Figure 44, the magnetic field generating component 4400, which can be housed within the housing 300, comprises a pair of magnetic field generating components (e.g., magnets) 4404 and 4406 on a substrate 4402. As illustrated, the simultaneously aligned magnetic fields 4408 and 4410 generated by magnets 4404 and 4406, respectively, can generate an overall magnetic field that extends from the housing 300 and stiffens the sensor 110. The magnets 4404 and 4406 may be provided in an aligned configuration as shown in Figure 44 before inserting the sensor 110 into the patient's skin. As indicated by arrow 4414, for example, after rotating magnet 4406 in direction 4412 (e.g., only 180 degrees on a rotating platform 4411), the direction of the magnetic field 4410 of magnet 4406 may be reversed, forming a counter-field 4410' that cancels out the field 4408 of magnet 4404. In this way, the magnetic field applied to stiffen the sensor 110 (for example, for insertion or other pre-insertion processes) can be removed so that the sensor becomes non-self-supporting within the body. The rotation of the magnet 4406 can be performed automatically or manually by the user (for example, by activating a button that is coupled to the platform 4411 and accessible on the outer surface of the housing 300).

[0267] In the example shown in Figure 45, the electric field generating component 4500, which may be housed within the housing 300, comprises an electric field generator 4504 on a substrate 4502. As illustrated, the electric field 4506 may be generated by the field generator 4504 using power supplied by a power supply 4508 (e.g., a battery) to stiffen the sensor 110. The field generator 4504 and power supply 4508 are provided in a powered placement configuration before the sensor 110 is inserted into the patient's skin, and power is supplied to the field generator 4505 along a conductive trace 4510 on the substrate. A mechanism 4520 (e.g., an actuated circuit breaker) may be provided that can be operated to cut the trace 4510, thereby permanently cutting off the power supply to the field generator 4505. In this way, the electric field applied to stiffen the sensor 110 (e.g., for insertion or other pre-insertion processes) can be removed so that the sensor becomes non-self-supporting in the body. The mechanism 4512 can be operated automatically or manually by the user (for example, by activating a button that is coupled to the platform 4411 and accessible on the outer surface of the housing 300).

[0268] Figures 46 and 47 show graphs 4600 (uniform scale) and 4700 (logarithmic scale) of fatigue characteristics for various exemplary soft specimen sensors, respectively. In particular, fatigue characteristic curves 4602, 4604, 4606, and 4608 are shown for sensors with tantalum wire cores of diameters of 0.007", 0.004", 0.003", and 0.002", respectively. As illustrated, in the example wire cores, the 0.002" core wire has the longest fatigue life (i.e., the highest fatigue endurance limit), followed by the 0.003" core. The fatigue characteristics of the 0.004" core wire can be seen to be relatively similar to those of the 0.007" core.

[0269] Figure 48 shows a graph illustrating the buckling forces for various exemplary soft sample sensors. The buckling force values ​​in the graph in Figure 48 are reflected in the table below.

[0270] [Table 1]

[0271] In particular, for wire core sensors having a length of 0.402" (sometimes referred to as the "standard length" or "Std length" in this specification in Figure 48) (for example, metal core sensors as described herein in several embodiments), the buckling force may be 0.0110 N, 0.0481 N, or 0.136 N for core diameters (or semi-major axes) of 2 / 1000, 3, or 4 inches, respectively. For wire core sensors having a length of 0.307" (sometimes referred to as the "short length" in this specification in Figure 48), the buckling force may be 0.0222 N, 0.0791 N, or 0.241 N for core diameters (or semi-major axes) of 2 / 1000, 3, or 4 inches, respectively. The lengths in Figure 48 and the table above may correspond to a portion of the length of a continuous sample sensor extending from a sensor electronic housing in various mounting configurations. The buckling force of a polymer core sensor or a sensor formed from multiple planar layers as described herein (for example, for a portion of the sensor extending from the sensor electronic housing and / or having a length between 0.2" and 0.5") may be substantially smaller than the buckling force of a wire core sensor in Figure 48 and the table above. For example, the buckling force of a polymer core sensor or a sensor formed from multiple planar layers may be less than 0.25 N, less than 0.02 N, less than 0.01 N, or less than 0.001 N in various implementations. Furthermore, the buckling force may be reduced in vivo with respect to the in vivo buckling force as described herein in various implementations.

[0272] Various examples of state-change continuous sample sensors having elongated conductors that change from self-supporting and non-self-supporting elongated conductors in vitro depending on temperature, hydration, bio / chemical, or field conditions in the sensor environment are described herein. Temperature, hydration, bio / chemical, or field-dependent state-change sensors are sometimes described herein independently, but it will be understood that the materials and arrangement configurations of the various layers of the sensors described herein may, in a preferred combination, result in any or all combinations of the temperature, hydration, bio / chemical, and / or field-dependent state-change characteristics described herein.

[0273] In particular, it will be understood that in sensor mounting configurations consisting of multiple planar layers formed from individualized sheets, sensors having relatively low moduli in vitro and in vivo, such as permanent non-self-supporting sensors, can be formed (for example, sensors formed from multiple substantially planar layers having a Young's modulus of less than 1 GPa, less than 1 MPa, or less than 1 kPa, a flexural modulus of less than 1 GPa, less than 1 MPa, or less than 1 kPa, and / or a buckling force of less than 0.25 N, less than 0.02 N, less than 0.01 N, less than 0.001 N, or less than the weight of the sensor).

[0274] For many plastics, compressive stiffness is higher than tensile stiffness, and therefore the neutral surface (to the right of the middle of the beam) shifts upward (for example, a smaller net cross-sectional area in compression has sufficient stiffness to resist a larger cross-sectional area under tension). For many polymer materials, compressive and tensile stiffness are not the same, and therefore Young's modulus and flexural modulus are not the same either. In some scenarios (for example, for plastic parts subjected to mostly tensile loads), mechanical properties can be characterized by Young's modulus. However, for sensors that can be subjected to mostly bending loads and are exposed to a wide mixture of stress directions (for example, in the region of highest load), flexural modulus can be a more accurate indicator of their mechanical properties than Young's modulus.

[0275] In embodiments where the sensor is a non-self-supporting sensor outside of a living organism, the sensor deployment mechanism may include dedicated components for deploying the non-self-supporting sensor. For example, in the case of a self-supporting sensor, the sensor may be positioned within the lumen of an insertion needle that is inserted into the host's skin along with the sensor and withdrawn, leaving the sensor embedded in the skin. For non-self-supporting sensors, in some embodiments, a folding deployment mechanism or a coil winding / unwinding mechanism is provided within the needle to control the position of the sensor and, if desired, utilize the internal space inside the lumen of the cylindrical needle. In embodiments where the sensor is too soft for the needle / cannula to deliver, a pre-connected C-shaped needle deployment system may be used.

[0276] Exemplary sensors and sensor systems Sensor Embodiment 1: A continuous sample sensor configured for use in a living body, comprising: an elongated core; a working electrode disposed on the elongated core; and a membrane covering at least a portion of the working electrode, the membrane including an enzyme layer, the portion of which extends from the sensor electronic equipment housing, and the membrane configured to have a buckling force of less than 0.25 Newtons (N).

[0277] Sensor Embodiment 2: A continuous sample sensor of Sensor Embodiment 1, comprising an elongated conductive core having a Young's modulus of less than 147 GPa.

[0278] Sensor Embodiment 3: A continuous sample sensor of Sensor Embodiment 2, further comprising a layer of conductive material covering at least a portion of an elongated conductive core.

[0279] Sensor Embodiment 4: A continuous sample sensor of Sensor Embodiment 3, wherein the elongated conductive core comprises at least one material selected from the group consisting of copper, gold, magnesium, silver, tin, titanium, titanium alloy, and zinc.

[0280] Sensor Embodiment 5: A continuous sample sensor of Sensor Embodiment 4, wherein the conductive material includes a conductive material selected from the group consisting of platinum, platinum-iridium, gold, palladium, iridium, alloys thereof, graphite, carbon, and conductive polymers.

[0281] Sensor Embodiment 6: A continuous sample sensor of Sensor Embodiment 3, further comprising a layer of insulating material covering at least a portion of a layer of conductive material, wherein the working electrode is partially formed by a window in the insulating material layer that exposes the electrode portion of the layer of conductive material.

[0282] Sensor Embodiment 7: A continuous sample sensor of Sensor Embodiment 6, further comprising an additional conductive layer covering at least a portion of the insulating material layer, wherein the additional conductive layer includes a reference electrode.

[0283] Sensor Embodiment 8: A continuous sample sensor according to any one of Sensor Embodiments 1 to 7, wherein the elongated core includes an elongated polymer core, and the portion of the elongated core has a flexural modulus of less than 1 1 / 2 GPa.

[0284] Sensor Embodiment 9: A continuous sample sensor of Sensor Embodiment 8, further comprising at least one conductive trace extending along the length of an elongated polymer core, the portion of which of the conductive traces includes a working electrode.

[0285] Sensor Embodiment 10: A continuous sample sensor of Sensor Embodiment 8, wherein the elongated polymer core includes an elongated elliptical polymer core, and at least one conductive trace extends along the elongated elliptical polymer core.

[0286] Sensor Embodiment 11: A continuous sample sensor of Sensor Embodiment 10, wherein the working electrode includes a portion of at least one conductive trace.

[0287] Sensor Embodiment 12: A continuous sample sensor according to any one of Sensor Embodiments 1 to 11, wherein the elongated core includes an elongated fiber core.

[0288] Sensor Embodiment 13: A continuous sample sensor of Sensor Embodiment 12, wherein the elongated core further includes an elongated insulator substantially surrounding the elongated fiber core and at least one conductive trace extending along the elongated insulator.

[0289] Sensor Embodiment 14: A continuous sample sensor of Sensor Embodiment 12, wherein the elongated fiber core includes one or more Kevlar fibers.

[0290] Sensor Embodiment 15: A continuous sample sensor of Sensor Embodiment 14, wherein the elongated core further comprises a conductive coating on one or more Kevlar fibers, and a portion of the one or more Kevlar fibers having the conductive coating forms the working electrode.

[0291] Sensor System Embodiment 16: A continuous specimen sensor system comprising a continuous specimen sensor according to any one of Sensor Embodiments 1 to 15 and a sensor electronic device configured to process sensor signals from the continuous specimen sensor, wherein the sensor electronic device is disposed within a sensor electronic device housing, and the sensor electronic device housing is configured to be mounted on the outside of the patient's skin.

[0292] Sensor Embodiment 17: A continuous sample sensor according to any one of Sensor Embodiments 1 to 15, wherein the elongated core portion has a buckling force of less than 0.02 N.

[0293] Sensor Embodiment 18: A continuous sample sensor of Sensor Embodiment 17, wherein the elongated core portion has a bending modulus of elasticity between 0.1 kPa and 300 kPa.

[0294] Sensor Embodiment 19: A continuous sample sensor configured for use in a living organism, comprising: an elongated conductor having a working electrode, the elongated conductor comprising a plurality of substantially planar layers, the plurality of substantially planar layers configured to extend from the housing of the continuous sample sensor system having a buckling force of less than 0.25 Newtons (N) as a whole; and a membrane covering at least a portion of the working electrode, the membrane comprising an enzyme layer.

[0295] Sensor Embodiment 20: A continuous sample sensor of Sensor Embodiment 19, comprising a plurality of substantially planar layers, an insulating polymer layer, a first electrode layer disposed on a first side of the insulating polymer layer, and a second electrode layer disposed on a second side opposite the insulating polymer layer, wherein the working electrode includes a portion of the first electrode layer, and the second electrode layer includes a reference electrode.

[0296] Sensor Embodiment 21: A continuous sample sensor of Sensor Embodiment 20, further comprising an additional insulating polymer layer formed on a first electrode layer, the additional insulating polymer layer comprising a window defining the working electrode.

[0297] Sensor Embodiment 22: A continuous sample sensor of Sensor Embodiment 21, wherein the film is disposed on the first electrode layer within a window in an additional insulating polymer layer, and the additional insulating polymer layer is substantially free of the film outside the window.

[0298] Sensor Embodiment 23: A continuous sample sensor of Sensor Embodiment 21, wherein multiple substantially planar layers have substantially elliptical outer surfaces in cross-section.

[0299] Sensor Embodiment 24: A continuous sample sensor of Sensor Embodiment 21, wherein the insulating polymer layer comprises first and second insulating polymer layers, and a plurality of substantially planar layers further comprises a counter electrode layer disposed between the first insulating polymer layer and the second insulating polymer layer.

[0300] Sensor Embodiment 25: A continuous sample sensor of sensor embodiment 20, further comprising a plurality of substantially planar layers, the conductive trace layer disposed between the first electrode layer and the insulating polymer layer.

[0301] Sensor Embodiment 26: A continuous sample sensor of Sensor Embodiment 25, wherein the plurality of substantially planar layers further include an additional insulating polymer layer formed on a conductive trace layer, the additional insulating polymer layer comprising a window defining the working electrode.

[0302] Sensor Embodiment 27: A continuous sample sensor according to any one of Sensor Embodiments 19 to 26, wherein an additional portion of the elongated conductor is substantially free of a film.

[0303] Sensor Embodiment 28: A continuous sample sensor configured for use in a living body, comprising: an elongated conductor having a working electrode, wherein the elongated conductor is configured to be both an externally self-supporting elongated conductor and an internally non-self-supporting elongated conductor; and a membrane covering at least a portion of the working electrode, the membrane comprising an enzyme layer.

[0304] Sensor Embodiment 29: A continuous specimen sensor of Sensor Embodiment 28, wherein the elongated conductor is configured to change from a self-supporting elongated conductor to a non-self-supporting elongated conductor in response to contact between at least a portion of the elongated conductor and the patient's tissue.

[0305] Sensor Embodiment 30: A continuous sample sensor according to any one of the sensor embodiments 28 to 29, wherein the elongated conductor is configured to change from a self-supporting elongated conductor to a non-self-supporting elongated conductor at a transition temperature between 78 and 100 degrees Fahrenheit.

[0306] Sensor Embodiment 31: A continuous sample sensor according to any one of the sensor embodiments 28 to 30, wherein the elongated conductor is configured to change from an independent elongated conductor to an independent elongated conductor in response to the absorption of bodily fluids from patient tissue by at least a portion of the elongated conductor.

[0307] Sensor Embodiment 32: A continuous sample sensor according to any one of the sensor embodiments 28 to 31, wherein the elongated conductor is configured to change from an independent elongated conductor to an independent elongated conductor in response to a chemical reaction between bodily fluids from patient tissue and at least a portion of the elongated conductor.

[0308] Sensor Embodiment 33: A continuous sample sensor according to any one of the sensor embodiments 28 to 32, wherein the elongated conductor is configured to change from a self-supporting elongated conductor to a non-self-supporting elongated conductor in response to an electromagnetic field generated by a sensor electronic device for a continuous sample sensor.

[0309] Sensor Embodiment 34: A continuous sample sensor according to any one of the sensor embodiments 28 to 33, wherein the elongated conductor includes an elongated conductive core.

[0310] Sensor Embodiment 35: A continuous sample sensor according to any one of Sensor Embodiments 28 to 34, wherein the elongated conductor includes an elongated polymer core.

[0311] Sensor Embodiment 36: A continuous sample sensor according to any one of the sensor embodiments 28 to 35, wherein the elongated conductor comprises a plurality of substantially planar layers.

[0312] Sensor System Embodiment 37: A continuous specimen sensor system comprising a continuous specimen sensor according to any one of the sensor embodiments 28 to 36 and a sensor electronic device configured to process sensor signals from the continuous specimen sensor, wherein the sensor electronic device is disposed within a housing configured to be mounted on the outside of a patient's skin.

[0313] Sensor system embodiment 38: In vivo, the elongated conductor has a buckling force of less than 0.01 N, a continuous sample sensor system of sensor embodiment 37.

[0314] Sensor Embodiment 39: A continuous sample sensor according to any one of the sensor embodiments 28 to 38, wherein the non-self-supporting elongated conductor has a weight under gravity and a buckling force that is less than that weight under gravity.

[0315] Any feature of a particular sensor embodiment is generally applicable, that is, it can be combined independently with any other aspect or embodiment described herein. Furthermore, any feature of a sensor embodiment can be combined in part or in whole with any other sensor embodiment described herein, in any form, for example, one, two, three or more embodiments may be combined in whole or in part. Furthermore, any feature of a sensor embodiment can be optional with respect to other aspects or embodiments. Any aspect or embodiment of a method as described herein may be performed by a sensor, system, or device of another aspect or embodiment, and any aspect or embodiment of a sensor, system, or device may be configured to perform a method of another aspect or embodiment.

[0316] The methods disclosed herein include one or more steps or actions for achieving the described method. 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 particular order of steps or actions is specified, the order and / or use of any particular steps and / or actions may be modified without departing from the scope of the claims.

[0317] The connections between elements shown in some of the diagrams represent exemplary communication paths. Additional communication paths may be included, whether direct or via intermediate paths, to further facilitate the exchange of information between elements. These communication paths may be bidirectional, enabling elements to exchange information.

[0318] The various operations of the methods described above can be performed by any suitable means capable of performing the operations, such as various hardware and / or software components, circuits and / or modules. In general, any operation shown in the figures can be performed by the corresponding functional means capable of performing the operation.

[0319] The various exemplary logic blocks, modules, and circuits described in connection with this disclosure (such as the block in Figure 2) may be implemented or may be implemented by a digital signal processor (DSP), an application-specific integrated circuit (ASIC), a field-programmable gate array signal (FPGA) or other programmable logic device (PLD), discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. The processor may be a microprocessor, but in alternative embodiments, the processor may be any commercially available processor, controller, microcontroller, or state machine. The processor may be implemented as a combination of computing devices, for example, a combination of a DSP and a microprocessor, multiple microprocessors, one or more microprocessors working with a DSP core, or any other such configuration.

[0320] In one or more embodiments, the various functions described may be implemented in hardware, software, firmware, or a combination thereof. If implemented in software, the functions may be stored on or transmitted via computer-readable media as one or more instructions or codes. Computer-readable media include both computer storage media and communication media, including media that facilitate the transfer of computer programs from one location to another. Storage media may be any available media accessible by a computer. Examples, but not limited to, such computer-readable media may include various types of RAM, ROM, CD-ROM, or other optical disk storage devices, magnetic disk storage devices, or other magnetic storage devices, or other media accessible by a computer that can be used to carry or store desired program code in the form of instructions or data structures. Any connection may also be referred to as computer-readable media. For example, if software is transmitted from a website, server, or other remote source using coaxial cable, fiber optic cable, twisted pair, digital subscriber line (DSL), or wireless technologies such as infrared, radio, and microwave, then coaxial cable, fiber optic cable, twisted pair, DSL, or wireless technologies such as infrared, radio, WiFi, Bluetooth®, RFID, NFC, and microwave are included in the definition of medium. As used herein, disk and disc include compact disc (CD), laserdisc®, optical disc, digital versatile disc (DVD), floppy disk, and Blu-ray® disc, where disk typically reproduces data magnetically and disc optically using a laser. Thus, in some embodiments, computer-readable medium may include non-temporary computer-readable medium (e.g., tangible medium). In addition, in some embodiments, computer-readable medium may include temporary computer-readable medium (e.g., signals).The combinations mentioned above should also be included within the scope of computer-readable media.

[0321] Some embodiments may include a computer program product for performing the operations described herein. For example, such a computer program product may include a computer-readable medium on which instructions are stored (and / or encoded), and the instructions are executable by one or more processors for performing the operations described herein. In some embodiments, the computer program product may include packaging material.

[0322] Software or instructions may be transmitted over a transmission medium. For example, if software is transmitted from a website, server, or other remote source using coaxial cable, fiber optic cable, twisted pair, digital subscriber line (DSL), or wireless technologies such as infrared, radio, and microwave, then coaxial cable, fiber optic cable, twisted pair, DSL, or wireless technologies such as infrared, radio, and microwave are included in the definition of a transmission medium.

[0323] Furthermore, it will be understood that modules and / or other suitable means for performing the methods and techniques described herein may be downloaded and / or obtained by a user terminal and / or a base station, where applicable. For example, such a device may be coupled to a server to facilitate the transfer of means for performing the methods described herein. Alternatively, the various methods described herein may be provided via storage means (e.g., physical storage media such as RAM, ROM, compact disks (CDs) or floppy disks), thereby allowing the user terminal and / or base station to obtain the various methods after coupling or providing the storage means to the device. Furthermore, other suitable techniques for providing the methods and techniques described herein to a device may also be utilized.

[0324] It will be understood that the claims are not limited to the exact configurations and components illustrated above. Various modifications, changes, and variations may be made to the arrangements, configurations, and details of the methods and apparatus described above without departing from the scope of the claims.

[0325] Unless otherwise defined, all terms (including technical and scientific terms) are given their ordinary and customary meanings to those skilled in the art, and are not limited to any special or specific meanings unless expressly defined herein. It should be noted that the use of any particular term in describing certain features or aspects of the Disclosure should not be construed as implying that the term is redefined herein to be limited to specific characteristics of the features or aspects of the Disclosure to which it relates. Terms and phrases used in this application, and their variations thereof, should be construed as unrestrictive, rather than restrictive, unless expressly provided otherwise, particularly in the appended claims.As previously stated, the word “includes” should be read as “includes without limitation,” “includes without limitation,” or similar phrases; the word “equips,” as used herein, is synonymous with “includes,” “contains,” or “characterized,” and is comprehensive or unrestricted, not excluding additional uncited elements or method steps; the word “has” should be interpreted as “has at least”; the word “includes” should be interpreted as “includes without limitation”; the word “examples” is used to give examples of items in the description, not an exhaustive or limiting list; adjectives such as “known,” “usual,” “standard,” and similar words are used in the description. Items should not be interpreted as limiting items to a given time period or items currently available at a given time, but rather as encompassing known, common, or standard techniques that may be available or known at any point in the present or future; and the use of words such as “preferred,” “desired,” “desired,” and similar words should not be understood as implying that certain features are critical, essential, or even more important to the structure or function of the invention, but rather as merely intended to highlight alternative or additional features that may or may not be available in particular embodiments of the invention. Similarly, groups of items linked by the conjunction “and” should not be interpreted as requiring all of those items to be present in the group, but rather as “and / or” unless otherwise explicitly stated. Likewise, groups of items linked by the conjunction “or” should not be interpreted as requiring mutual exclusivity among the group, but rather as “and / or” unless otherwise explicitly stated.

[0326] If a range of values ​​is provided, it is understood that the upper and lower limits of the range, as well as the values ​​between the upper and lower limits, are included within the embodiment.

[0327] With regard to the substantially plural and / or singular use of words herein, those skilled in the art can appropriately change plurals to singulars and / or singulars to plurals depending on the context and / or application. Various singular / plural substitutions may be explicitly stated herein for clarity. The indefinite articles "a" or "an" in the original English text do not exclude the plural. A single processor or other unit may perform the functions of several items described in the claims. The mere fact that certain measurements are referenced in different dependent claims does not imply that combinations of these measurements cannot be used advantageously. Reference numerals in the claims should not be construed as limiting scope.

[0328] Furthermore, a person skilled in the art would understand that if a particular number of claim enumerations is intended to be introduced, such intention is explicitly stated in the claim, and if there is no such enumeration, such intention is not present. For example, to aid understanding, an appendix claim may introduce a claim enumeration by including the introductory phrases “at least one” and “one or more.” However, even if such phrases are used in the original English text, the introduction of a claim enumeration with the indefinite article “a” or “an” should not be interpreted as implying that a particular claim containing such an introduced claim enumeration is limited to embodiments containing only one such enumeration, even if the claim includes the introductory phrase “one or more” or “at least one” and an indefinite article such as “a” or “an” (for example, “a” and / or “an” should typically be interpreted as meaning “at least one” or “one or more”), and the same applies to the use of the definite article used to introduce a claim enumeration. In addition, even if a specific number of claims are explicitly listed, a person skilled in the art will recognize that such a list should typically be interpreted as meaning at least the number listed (for example, an unadorned list of "two lists" without other modifiers typically means at least two lists, or more than two lists). Furthermore, when a conventional phrase similar to "at least one of A, B, and C, etc." is used, such a construction is generally intended to be understood by a person skilled in the art as including a single member, for example, including any combination of the listed items (for example, "a system having at least one of A, B, and C" includes, but is not limited to, a system having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.).When a conventional expression similar to "at least one of A, B, or C" is used, it is generally intended that a person skilled in the art will understand this conventional expression (for example, "a system having at least one of A, B, or C" includes, but is not limited to, a system having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). Furthermore, a person skilled in the art will understand that substantially any separate word or phrase indicating two or more alternative words, whether in the description, claims, or drawings, should be understood as intending the possibility of including one of the words, any of the words, or both. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B" or "A and B".

[0329] All figures used herein to express quantities of components, reaction conditions, etc., should be understood in all cases to be modified by the word “approximately.” Therefore, unless otherwise stated, numerical parameters described herein are approximate and may vary depending on the desired properties to be obtained. At a minimum, no attempt is made to limit the application of the principle of equivalents to the claims of any application claiming priority to this application, but each numerical parameter should be interpreted in light of significant figures and conventional rounding methods.

[0330] All references cited herein are incorporated herein by reference in their entirety. In the event of any conflict between any publication or patent or patent application incorporated herein by reference and any disclosure contained herein, this specification shall supersede and / or prevail over such conflicting material.

[0331] Headings are included herein for reference and to help identify the various sections. These headings are not intended to limit the scope of the concepts described therein. Such concepts may be applicable throughout the entire specification.

[0332] Furthermore, although the foregoing has been illustrated to some extent with diagrams and examples for clarity and understanding, it will be obvious to those skilled in the art that several changes and modifications may be made. Therefore, the description and examples should not be interpreted as limiting the scope of the invention to the specific embodiments and examples described herein, but rather as encompassing all modifications and alternative forms that are associated with the true scope and spirit of the invention.

[0333] The various systems and methods described can be fully implemented and / or controlled in any number of computing devices. Typically, instructions are laid out on a generally non-temporal computer-readable medium, and these instructions are sufficient to enable a processor in a computing device to implement the methods of the present invention. The computer-readable medium may be a hard drive or solid-state storage device having instructions that, when executed, are loaded into random-access memory. For example, input to the application from multiple users or from any one user may be by any number of suitable computer input devices. For example, a user may input data related to the calculation by employing a keyboard, mouse, touchscreen, joystick, trackpad, other pointing device, or other such computer input device. Data may also be input using an inserted memory chip, hard drive, flash drive, flash memory, optical medium, magnetic medium, or other types of file storage medium. Output may be sent to the user using a video graphics card or integrated graphics chipset coupled to a display which may be viewed by the user. Alternatively, a printer may be employed to output a hard copy of the results. With this teaching given, it will be understood that any number of other tangible outputs may also be contemplated by the present invention. For example, the outputs may be stored in memory chips, hard drives, flash drives, flash memory, optical media, magnetic media, or other types of outputs. It should also be noted that the present invention may be implemented on any number of different types of computing devices, such as personal computers, laptop computers, notebook computers, netbook computers, handheld computers, personal digital assistants, mobile phones, smartphones, tablet computers, and devices specifically designed for these purposes.In one implementation, a user of a smartphone or Wi-Fi-connected device downloads a copy of the application from a server to their device using a wireless internet connection. Appropriate authentication procedures and secure transaction processes may be in place to ensure payment is made to the seller. The application may be downloaded over a mobile connection or over Wi-Fi or other wireless network connection. The application can then be executed by the user. Such a network system may provide a suitable computing environment for one implementation where multiple users make separate inputs to the system and method. In the following systems where a factory calibration scheme is intended, multiple inputs may allow multiple users to input relevant data simultaneously. [Explanation of symbols]

[0334] 12 Sensor Electronic Devices 100 Systems 101 Continuous Sample Sensor System 102 Drug delivery pump 104 Glucose Meter 110 Continuous Sample Sensors 110' Sensor strip 112 Sensor Electronic Devices 114, 116, 118, 120 Display devices 114 A relatively small display device similar to a key fob. 116. Relatively large handheld display devices 118 Mobile phone 120 Computers 205 Application-Specific Integrated Circuits (ASICs) 210 potentiostat 211 First input port 214 Processor Modules 216 Program Memory 218 memory 220 data storage memory 222 User Interface 224 buttons 226 Liquid Crystal Display (LCD) 228 Vibrator 230 Acoustic transducers (e.g., speakers) 232 Remote Measurement Module 234 Batteries 236 Regulator 237 Second input port 238 communication ports 239 output ports 300 Housing 302 Bottom 304 Opening 406 Network 490 Cloud-based sample processors 502 Slender conductor 504 Second Layer 506 windows 508 Membrane 510 Thin core 512 First layer 514 The third layer 602 Electrode Domain 604 Interference Domain 606 Enzyme Domains 608 Resistive Domain 610 A substantially planar conductive layer 612 layers 700 sensors 702 Slender core 704 Working electrode 706 Reference or Opposite Electrode 708, 710 Conductive paths 800 power 900 power 1000 conductive traces 1002 Cross-sectional shape 1102 Filament Extrusion Machine 1108 Refrigerant 1104, 1106 Trace extrusion molding machine 1110 Slender core structure 1200 Conductive Trace 1300 Groove 1400 squeegee 1402 Liquid Conductors 1502 Textile Heater 1504 Laminating Die 1510 Elongated conductive core structure 1600 Conductive Ribbon Trace 1700 induction heater 1702 Positioning Guide 1704 Roller 1710 Elongated conductive core structure 1800 traces 1802 Electrode 1900 Elongated insulator 1901 Fiber bundle 1902 Elongated non-conductive core structure 2000 Conductive Trace 2100 Pattern-forming insulating layer 2101 Elongated conductive core structure 2102 Window 2300 Insulating layer 2301 Soft elongated conductor 2302 Electrode layer 2302 Coating 2303 Window 2304 First side 2306 Second side 2400 Proximal end 2402 Notch 2500 Coating 2501 bundle 2504 Insulating layer 2503 Window 2504 Coaxial Insulation Layer 2600 notch 2702 Stencil 2704, 2706 Opening 2710 Electrode 2712 Trace 2800 layers 2802 Insulating layer 2802' Insulating material 2804 Trace Layer 2806 Second electrode layer 2808 First electrode layer 2808' Tracing material (e.g., silver) 2810 Insulating layer 2810' Seat 2811 Window 2820 Outer edge 2822 Cross-sectional profile 2900 End part 2904 Edge 2906 Notch 2909 Window 3000 seats 3100 Roller 3102 Cutting device 3202 A virtually flat edge 3206 Round side wall 3208 Substantially elliptical cross-sectional profile 3302 Insulating layer 3303 Insulating layer 3305 Counter electrode 3306 Second electrode layer 3308 layers 3310 Insulating layer 3311 Window 3400 Round side wall 3402 Substantially elliptical cross-sectional profile 3420 trace layer 3500, 3600 graph 3602 The first curve 3604 Curve 3606 Curve 3608 Curve 3610 curve 3700, 3702 layer 3700 Hydrophilic layer 3706 Partial 3706 Wet area 3708 Unwetted parts 3710 Hydration interface 3800 Non-conductive (e.g., polymer) core 3802 Conductive Trace 3804 parts 3900 yen 4000 membrane fluid 4002 Electric field or magnetic field 4200 places 4400 Magnetic Field Generating Component 4402 Base material 4404, 4406 Magnetic field generation components 4408, 4410 magnetic field 4410' Opposing magnetic field 4411 Rotating Platform 4412 direction 4500 Electric Field Generating Component 4502 Base material 4504 Electric field generator 4505 Electric field generator 4506 Electric field 4508 Power supply 4510 Conductive Trace 4520 Mechanism 4600 evenly spaced graph Fatigue characteristic curves for 4602, 4604, 4606, and 4608. 4700 logarithmic scale graph

Claims

1. A continuous sample sensor configured for use in vivo, A long, slender core, An operating electrode is disposed on the aforementioned elongated core, The system comprises a membrane system covering at least a portion of the working electrode, The continuous sample sensor is configured to be a self-supporting elongated conductor outside the body, and to be a non-self-supporting elongated conductor inside the body when exposed to a temperature change over a transition temperature range from 78°F to 100°F (26°C to 38°C). The membrane system comprises a semipermeable membrane for controlling the flux of the sample, A continuous sample sensor in which a portion of the continuous sample sensor is configured to extend from the sensor electronic equipment housing.

2. The aforementioned elongated core comprises an elongated conductive core, The continuous sample sensor according to claim 1, wherein the portion extending from the sensor electronic equipment housing has a Young's modulus of less than 500 MPa in vivo and a Young's modulus between 500 MPa and 147 GPa outside the body.

3. The continuous sample sensor according to claim 2, further comprising a layer of conductive material covering at least a portion of the elongated conductive core.

4. The continuous sample sensor according to claim 3, wherein the elongated conductive core comprises at least one material selected from the group consisting of copper, gold, magnesium, silver, tin, titanium, titanium alloy, and zinc.

5. The continuous sample sensor according to claim 4, wherein the conductive material includes a conductive material selected from the group consisting of platinum, platinum-iridium, gold, palladium, iridium, alloys thereof, graphite, carbon, and conductive polymers.

6. The continuous sample sensor according to claim 3, further comprising a layer of insulating material covering at least a portion of the layer of conductive material, wherein the working electrode is partially formed by a window in the insulating material layer that exposes the electrode portion of the layer of conductive material.

7. The continuous sample sensor according to claim 6, further comprising an additional conductive layer covering at least a portion of the insulating material layer, wherein the additional conductive layer includes a reference electrode.

8. The continuous sample sensor according to claim 1, wherein the elongated core includes an elongated polymer core, and a portion extending from the sensor electronic device housing has a flexural modulus of less than 1.5 GPa in vivo.

9. The continuous sample sensor according to claim 8, further comprising at least one conductive trace extending along the length of the elongated polymer core, wherein a portion of the conductive trace includes the working electrode.

10. The continuous sample sensor according to claim 8, wherein the elongated polymer core includes an elongated elliptical polymer core, and at least one conductive trace extends along the elongated elliptical polymer core.

11. The continuous sample sensor according to claim 10, wherein the working electrode includes a portion of the at least one conductive trace.

12. The continuous sample sensor according to claim 1, wherein the elongated core includes an elongated fiber core.

13. The aforementioned elongated core is The elongated insulator surrounding the aforementioned elongated fiber core, The continuous sample sensor according to claim 12, further comprising at least one conductive trace extending along the elongated insulator.

14. The continuous sample sensor according to claim 12, wherein the elongated fiber core comprises one or more Kevlar fibers.

15. The continuous sample sensor according to claim 14, wherein the elongated core further comprises a conductive coating on one or more Kevlar fibers, and a portion of the one or more Kevlar fibers having the conductive coating forms the working electrode.

16. A continuous specimen sensor system comprising a continuous specimen sensor according to any one of claims 1 to 15 and a sensor electronic device configured to process sensor signals from the continuous specimen sensor, wherein the sensor electronic device is disposed within the sensor electronic device housing, and the sensor electronic device housing is configured to be mounted on the outside of a patient's skin.

17. The continuous sample sensor according to any one of claims 1 to 15, wherein the portion extending from the sensor electronic equipment housing is configured to have a buckling force of less than 0.25 Newtons (N) in vivo and a buckling force greater than 0.25 Newtons (N) outside the body when pressed in a direction parallel to the longitudinal direction of the continuous sample sensor.

18. The continuous sample sensor according to claim 17, wherein the portion extending from the sensor electronic device housing has a Young's modulus between 0.1 kPa and 300 kPa in a living organism.

19. The continuous sample sensor according to claim 18, wherein the continuous sample sensor is formed from a plurality of substantially planar layers.

20. A continuous sample sensor configured for use in vivo, A continuous sample sensor comprising an elongated body equipped with an working electrode, wherein the elongated body comprises a plurality of planar layers, the continuous sample sensor is configured to be a self-supporting elongated body in vitro and a non-self-supporting elongated body in vivo when the self-supporting elongated body is exposed to temperature changes over a transition temperature range of 78°F to 100°F (26°C to 38°C), a portion of the plurality of planar layers is configured to extend from the housing of the continuous sample sensor system, and the portion extending from the housing of the continuous sample sensor system, when pressed in a direction parallel to the longitudinal direction of the continuous sample sensor, has as a whole a buckling force of less than 0.25 Newtons (N) in vivo and a buckling force greater than 0.25 Newtons (N) in vivo.

21. The aforementioned plurality of planar layers are Polymer layer and A first electrode layer disposed on the first side of the polymer layer, A second electrode layer disposed on the second side opposite the polymer layer, wherein the working electrode includes a portion of the first electrode layer, and the second electrode layer includes a reference electrode. A continuous sample sensor according to claim 20, including the following:

22. The continuous sample sensor according to claim 21, further comprising an additional polymer layer formed on the first electrode layer, the additional polymer layer comprising a window defining the working electrode.

23. A membrane covering at least a portion of the working electrode, the membrane further comprising an enzyme layer, The continuous sample sensor according to claim 22, wherein the film is disposed on the first electrode layer within the window in the additional polymer layer.

24. The continuous sample sensor according to claim 22, wherein the plurality of planar layers have an elliptical outer surface in cross-section.

25. The continuous sample sensor according to claim 22, wherein the polymer layer comprises first and second polymer layers, and the plurality of planar layers further comprises a counter electrode layer disposed between the first polymer layer and the second polymer layer.

26. The continuous sample sensor according to claim 21, wherein the plurality of planar layers further include conductive traces.

27. The continuous sample sensor according to claim 26, wherein the plurality of planar layers further include an additional polymer layer formed on the conductive trace, the additional polymer layer comprising a window defining the working electrode.

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