Glucose sensor electrode design

Abstract

A single flexure double-sided electrode can be used for a continuous glucose monitoring sensor. In one example, a counter electrode is placed on the back side of the flexure, and a working electrode is placed on the top side of the sensor flexure. The electrode is fabricated on a physical vapor deposited metal deposited on a base substrate. The adhesion of the electrode to the base substrate is carefully controlled so that the electrode can be processed on the substrate and then removed from the substrate after processing.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under Section 120 to U.S. patent application serial number 15 / 892,162, filed on February 8, 2018, the contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to an electrode for a glucose sensor and a method for manufacturing the same. Background Art

[0004] Electrochemical sensors are commonly used to detect or measure glucose, etc. in vivo Concentration of analyte. Typically, in such analyte sensing systems, the analyte (or a substance derived therefrom) is electroactive and produces a detectable signal at an electrode in the sensor. This signal is then related to the presence or concentration of the analyte within the biological sample. In some conventional sensors, an enzyme is provided that reacts with the analyte to be measured, and the byproducts of the reaction are qualitatively or quantitatively determined at the electrodes. In one conventional glucose sensor, an immobilized glucose oxidase catalyzes the oxidation of glucose to form hydrogen peroxide, which is then quantified by amperometry (e.g., current change) through one or more electrodes.

[0005] Various electrochemical glucose sensors are multilayered, including electrodes on and / or covered by layers of various materials. Multilayer sensors have many desirable properties, including the fact that the functional properties of such sensors can be customized by changing certain design parameters (e.g., number of internal layers, layer thickness, electrode area, and architecture, etc.). However, the inventors of the present invention have found that undesirable interactions between anodes and cathodes in conventional sensors degrade sensor performance. Therefore, there is a need for sensor manufacturing methods and electrode structures that reduce or prevent undesirable cathode-anode interactions, thereby improving sensor performance. The present disclosure meets this need. Summary of the invention

[0006] The present disclosure describes an analyte sensor device (e.g., a glucose sensor) comprising: a working electrode; a counter electrode; an insulating layer, the insulating layer being located between the working electrode and the counter electrode, wherein the working electrode and the counter electrode are spatially separated by a distance of at least 1 micron, the working electrode comprising a metal composition having an electroactive surface, and the working electrode and the counter electrode are non-interdigitated. An analyte sensing layer located on the working electrode detectably changes a current at the working electrode in the presence of an analyte.

[0007] In one or more embodiments, the working electrode and the counter electrode are located on the same side of the analyte sensor device.

[0008] In other embodiments, the working electrode is located on a first side or top side of the insulating layer, and the counter electrode is located on a second side or back side of the insulating layer opposite the first side, for example, thereby placing electrodes on both the top side and the back side of the sensor flexure. Conventional approaches place electrodes only on the top side of the sensor flexure. Thus, embodiments of the present invention eliminate the need to have multiple sensor flexures in one device.

[0009] Illustrative embodiments further include: a reference electrode located on the first side of the insulating layer; an insulation located between the reference electrode and the working electrode; a first metal electrically contacting the working electrode, the first metal comprising a first contact pad; a second metal electrically contacting the counter electrode, the second metal comprising a second contact pad. Example materials for the insulating layer and the insulation include, but are not limited to, polyimide, and the working electrode, the counter electrode, the insulating layer, the insulation, and the analyte sensing layer may be flexible.

[0010] Example electrode surface metals for the counter electrode include, but are not limited to, gold, platinum, silver, etc. In one or more embodiments, the conventional electroplated platinum layer in the working electrode is replaced by a layer comprising platinum pillars, and the conventional electroplated reference electrode is replaced by a reference electrode comprising screen printed or dispensed silver-silver chloride, etc.

[0011] In yet further embodiments, the counter electrode comprises a physical vapor deposited (PVD) metal removed from a rigid substrate, or the apparatus further comprises a base layer attached to the counter electrode and a PVD metal on the base layer, and the PVD metal is removed from the rigid substrate.

[0012] As demonstrated herein, embodiments of the sensors disclosed herein exhibit surprising and unexpected performance improvements over conventional sensors. In one or more instances, the spacing, configuration, and arrangement of the working electrode and the counter electrode are such that, in response to a constant analyte concentration, (1) the current varies by less than 15% over a period of 31 days, and / or (2) chemical products produced by the reaction at each of the working electrode and the counter electrode do not interfere with or deleteriously interact with the performance of the working electrode or the counter electrode.

[0013] The present disclosure further reports the development of techniques for controlling the adhesion of PVD metal films by a PVD process. Various PVD parameters were evaluated by multiple experimental designs (DOEs). It was unexpectedly and surprisingly found that pressure had the greatest and most significant effect on adhesion, and when the pressure was controlled and varied during PVD, the process achieved different levels of adhesion.

[0014] The present disclosure further reports how deposition of rough or columnar structures in metal films can reduce the surface area contact with the substrate / surface in a highly controllable manner, which can help control adhesion when the deposition pressure is modulated.

[0015] In one or more examples, the PVD process parameters include a pressure in a range of 2-250 mTorr, a PVD power in a range of 10 Watts to 100 Kilowatts, and a metal deposited to a thickness of at least 100 Angstroms.

[0016] In one example, PVD deposition with pressure modulation is used to fabricate a backside counter electrode (BCE) for a glucose sensor, where the metal adhesion to the glass substrate is strong enough to survive machining and laser cutting, but weak enough to allow easy physical removal from the glass substrate for assembly processing.

[0017] An illustrative method of manufacturing an analyte sensor device includes providing a base substrate; depositing a metal on the base substrate using PVD; depositing a film on the metal, the film including the insulating layer, the working electrode, and the counter electrode; defining the analyte sensor in the film; and removing the analyte sensor from the base substrate. In one or more examples, the metal includes a second layer located on a first layer, the first layer being located between the second layer and the insulating layer; the first layer is deposited at the pressure including a first pressure, and the second layer is deposited at the pressure including a second pressure lower than the first pressure.

[0018] Another illustrative manufacturing method for an analyte sensor device includes: depositing the insulating layer including a first polyimide insulating layer on the metal; depositing a second metal on the first polyimide insulating layer and patterning the second metal; depositing a second insulating polyimide layer on the first insulating polyimide layer, and depositing the second metal on the first insulating polyimide insulating layer; forming a first opening and a second opening in the second insulating polyimide layer; depositing a third metal into the first opening to form a working electrode; depositing a fourth metal into the second opening to form a reference electrode (RE); defining the analyte sensor in the membrane, the membrane including: the metal, the second metal, the third metal, the fourth metal, the first insulating polyimide layer, the second insulating polyimide layer, the working electrode and the reference electrode; and removing the analyte sensor from the base substrate, wherein the metal is the counter electrode.

[0019] Yet another illustrative method of making an analyte sensor device includes:

[0020] Depositing a base layer including polyimide on the metal located on the base substrate; patterning a first opening in the base layer; depositing a second metal in the first opening to form a counter electrode; depositing the insulating layer including a first polyimide insulating layer on the base layer and the counter electrode; depositing a third metal on the first polyimide insulating layer and patterning the third metal; depositing a second insulating polyimide layer on the first insulating polyimide layer, and depositing the third metal on the first insulating polyimide insulating layer; forming a second opening and a third opening in the second insulating polyimide layer; curing the base layer, the first insulating polyimide layer, and the second insulating polyimide layer; depositing a fourth metal into the second opening to form a working electrode; depositing a fifth metal into the third opening to form a reference electrode (RE); defining the analyte sensor in the membrane, the membrane including: the base polyimide layer, the first insulating polyimide layer, the second insulating polyimide layer, and the electrode; and removing the analyte sensor from the base substrate.

[0021] In one or more embodiments, a set of at least 36 sensors manufactured using the methods presented herein each have a working electrode spaced apart from the counter electrode such that the current output by each of the sensors in response to the same analyte concentration is within 15%.

[0022] For those skilled in the art, other objects, features and advantages of the present invention will become apparent from the following detailed description. However, it is to be understood that although some embodiments of the present invention are indicated, the detailed description and specific examples are provided by way of illustration and not limitation. Many changes and modifications may be made within the scope of the present invention without departing from its spirit, and the present invention includes all such modifications. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figures 1A-1D An amperometric sensor having WE and CE on opposite sides is shown according to one or more embodiments.

[0024] Figure 1E Amperometric sensors having WE and CE on the same side of the device but separated by a distance D of at least 1 micro-inch are shown in accordance with one or more embodiments of the present invention.

[0025] Figures 1F and 1G compare the structure of a control sensor (Figure 1F) having interdigitated working electrodes, counter electrodes, and reference electrodes according to one or more embodiments of the present invention, and wherein the working electrode, counter electrode, and reference electrode are located on only one side and are close enough to exhibit undesirable electrodes, wherein the sensor includes electrodes on the opposite side (Figure 1G).

[0026] Figure 1H Multiple planar layered components used in amperometric sensors are demonstrated.

[0027] Figure 2 A perspective view is provided illustrating one type of subcutaneous sensor insertion kit, telemetric characteristic monitor transmitter device, and data receiving device, components that may be suitable for use with embodiments of the present invention.

[0028] Figure 3 FIG. 2 shows a schematic diagram of a voltage regulator that can be used to measure current in an embodiment of the present invention. Figure 3 As shown in , the potentiostat 300 can include an operational amplifier 310 connected in a circuit to have two inputs: Vset and Vmeasured. As shown, Vmeasured is the measured value of the voltage between the reference electrode and the working electrode. On the other hand, Vset is the optimal desired voltage across the working electrode and the reference electrode. The current between the counter electrode and the reference electrode is measured, thereby generating a current measurement result (isig) output from the potentiostat.

[0029] Figure 4 An apparatus for depositing material using sputtering according to one or more embodiments of the present invention is presented.

[0030] Figure 5Test samples including a layer stack on a glass substrate according to one or more embodiments of the present invention are presented.

[0031] Fig. 6A Different patterns AE of knife scratches or laser cut marks simulating marking and cutting types that may be applied during electrode processing in a glucose sensor are shown for a layer stack applied to a glass substrate according to one or more embodiments of the present invention.

[0032] Figure 6B The pattern of a silver layer applied to a glass substrate is shown, illustrating that the adhesion of the silver to the glass is too weak to allow replication of the markings on the silver layer.

[0033] Figures 7A-7D Different adhesion scores assigned to samples fabricated under different sputtering conditions in accordance with one or more embodiments of the present invention are shown.

[0034] FIG. 8A shows a test sample without gold pillars, and FIG. 8B shows a test sample with gold pillars according to one or more embodiments of the present invention.

[0035] Fig. 9 is a scanning electron microscope (SEM) image of a columnar interface between a glass substrate and a gold layer according to one or more embodiments of the present invention.

[0036] Figures 10A-10D Films on test samples fabricated using various sputtering conditions and after laser cutting with example electrode patterns are shown in accordance with one or more embodiments of the present invention.

[0037] Fig.11 A Pareto chart showing the normalized effects of varying pressure, power, and gold thickness on adhesion for samples fabricated using gold posts at the interface between a gold layer and a glass substrate in accordance with one or more embodiments of the present invention.

[0038] Fig.12 is a graph of average rate as a function of pressure, power, and gold thickness in accordance with one or more embodiments of the present invention.

[0039] Fig.13 is a contour plot of rate versus gold layer thickness and pressure according to one or more embodiments of the present invention.

[0040] Fig.14 Another test sample including a layer stack on a glass substrate according to one or more embodiments of the present invention is presented.

[0041] FIG. 15A shows a gold layer deposited using sputtering conditions of 100 mTorr pressure, 1.5 kW power, and 5 minute duration according to one or more embodiments of the present invention. Fig. 6A of the test sample.

[0042] FIG. 15B shows a first gold layer deposited using sputtering conditions of 100 mTorr pressure, 1.5 kW power, 5 minutes duration, and a second gold layer deposited using sputtering conditions of 4 mTorr pressure, 0.2 kW power, 10 minutes duration, according to one or more embodiments of the present invention. Fig.14 of the test sample.

[0043] Fig. 15C , 15D 15E shows a 3D-printed sheet having two gold layers and deposited using the conditions of FIG. 15B. Fig.14 The adhesion of the film on the test sample varies depending on the location on the surface area.

[0044] Fig.16 A Pareto chart showing the normalized effects of varying pressure, power, and gold thickness on sputtering rate in accordance with one or more embodiments of the present invention.

[0045] Fig.17 is a graph of average sputtering rate as a function of pressure, power, and gold thickness in accordance with one or more embodiments of the present invention.

[0046] Fig.18 is a contour plot of sputtering rate versus sputtering power (kW) and pressure (mTorr) according to one or more embodiments of the present invention.

[0047] Fig.19 is a flow chart illustrating a method of manufacturing a sensor or a sensor flexure according to one or more embodiments of the present invention.

[0048] Fig. 20 An embodiment of a backside counter electrode sensor fabricated using the PVD method described herein is demonstrated.

[0049] Figures 21A-21C The SITS results for the control sensor (sensor 130 shown in FIG. 1F ) are shown, where Fig.21A and 21B The current (ISIG) is plotted against time (dates in May), and Fig. 21C plotted the change of Vcounter over time (dates in May), and Figures 21A-21C The different traces in represent the results of different sensors.

[0050] Figures 21D-21FThe SITS results of the sensor of FIG. 1G according to one or more embodiments of the present invention are shown (representing Figure 1D The performance of the sensor), where Fig.21D and 21E The ISIG is plotted over time (dates in May), and Fig.21F Vcounter (voltage on the counter electrode) is plotted versus time (dates in May). Figures 21D-21F The different traces in 1 represent the results for different sensors and show that the smooth dorsal CE design is capable of supporting sensor functionality and, importantly, is superior to the sensor of FIG1F . Figure 1D The sensor reduces sensor-to-sensor performance variability and improves performance stability over the life of the test.

[0051] Fig. 22 is a flow chart illustrating a method of manufacturing a sensor or a sensor flexure according to one or more embodiments of the present invention.

[0052] Fig.23 is a demonstration of the use of one or more embodiments according to the present invention Fig. 22 Flowchart of a schematic diagram of a method of manufacturing a sensor or a sensor flexure.

[0053] Fig.24 is a flow chart illustrating a method of depositing a film on a substrate according to one or more embodiments of the present invention.

[0054] Fig.25 is a flow chart illustrating a method of fabricating a device on a substrate according to one or more embodiments of the present invention. DETAILED DESCRIPTION

[0055] Unless otherwise defined, all technical terms, symbols and other scientific terms or special words used herein are intended to have the meanings commonly understood by those skilled in the art to which the present invention belongs. In some cases, for the sake of clarity and / or ease of reference, terms with commonly understood meanings may be defined herein, and the inclusion of these definitions herein should not necessarily be interpreted as representing a substantial difference from the meanings commonly understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed by those skilled in the art using conventional methods.

[0056] All numbers listed in the specification and related claims that refer to values ​​(such as thickness) that can be numerically characterized by values ​​other than integers should be understood to be modified by the term "about". In the case of providing a range of values, it should be understood that each intermediate value between the upper and lower limits of the range (unless the context clearly stipulates otherwise, to one tenth of the unit of the lower limit) and any other stated values ​​or intermediate values ​​in the range are included in the present invention. The upper and lower limits of these smaller ranges can be independently included in smaller ranges and are also included in the present invention, subject to any explicitly excluded limits in the stated range. In the case where the stated range includes one or two limits in the limits, the range excluding any one or two limits in the limits included is also included in the present invention. In addition, all publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials combined when citing the publications. The publications cited herein are cited for their disclosures before the filing date of this application. Nothing herein shall be interpreted as admitting that the inventor has no right to advance the publication date by virtue of an earlier priority date or a priority invention date. Further, actual publication dates may vary from those shown and need to be independently verified.

[0057] As discussed in detail below, embodiments of the present invention relate to the use of electrochemical sensors to measure the concentration of an analyte of interest or a substance indicating the presence of an analyte in a fluid. In some embodiments, the sensor is a continuous device, such as a subcutaneous, transcutaneous, or intravascular device. In some embodiments, the device can analyze multiple intermittent blood samples. The sensor embodiments disclosed herein can use any known method (including invasive, minimally invasive, and non-invasive sensing techniques) to provide an output signal indicative of the concentration of the analyte of interest. Typically, the sensor senses a product or reactant of an enzymatic reaction between an analyte and an enzyme in the presence of oxygen as a in vivo or in vitro Type of measurement of the analyte. Such sensors typically include a membrane surrounding an enzyme, through which the analyte migrates. The product is then measured using electrochemical methods, and thus the output of the electrode system serves as a measure of the analyte.

[0058] Embodiments of the invention disclosed herein provide sensors of the type used, for example, for subcutaneous or transcutaneous monitoring of blood glucose levels in diabetic patients. Various implantable electrochemical biosensors have been developed to treat diabetes and other life-threatening diseases. Many existing sensor designs use some form of immobilized enzyme to achieve their biospecificity. The embodiments of the present invention described herein can be adapted and implemented using a variety of known electrochemical sensor elements, including, for example, the electrochemical sensor elements disclosed in U.S. Patent Application Nos. 20050115832, 20050008671, 20070227907, 20400025238, 20110319734, 20110152654, and 13 / 707,400 filed on December 6, 2012; U.S. Patent Nos. 6,001,067, 6,702,857, 6,212,416, 6,119,028, 6,400, 974, 6,595,919, 6,141,573, 6,122,536, 6,512,939, 5,605,152, 4,431,004, 4,703,756, 6,514,718, 5,985,129, 5,390,691, 5,391,250, 5,482,473, 5,299,571, 5,568,806, 5,494,562, 6,120,676, 6,542,765, 7,033,336, and PCT International Publication No. WO 01 / 58348, WO 04 / 021877, WO 03 / 034902, WO 03 / 035117, WO 03 / 035891, WO 03 / 023388, WO 03 / 022128, WO 03 / 022352, WO 03 / 023708, WO 03 / 036255, WO 03 / 036310, WO 08 / 042,625 and WO 03 / 074107; and European patent application EP1153571, the contents of each of which are incorporated herein by reference.

[0059] A. Illustrative Embodiments of the Invention and Related Features

[0060] Controlled adhesion of physical vapor deposited (PVD) metal films is a widespread challenge and problem throughout the MEMS and semiconductor industries, as well as in flexible circuit applications. For various applications, metal films often need to maintain very specific levels of adhesion to the surface / substrate on which they are deposited. In some cases, strong adhesion is required, while in other applications, weak adhesion is required. In the most challenging cases, a mix of weak and positive adhesion is required, where the adhesion is strong enough to withstand specific aspects of the application, but weak enough to allow other aspects of the application to function properly.

[0061] As shown herein, the present disclosure describes an effective method for adjusting and controlling the adhesion of PVD films deposited on surfaces / substrates. A series of comprehensive studies evaluating PVD deposition factors and their effects on adhesion properties were performed, and it was found that pressure was a key significant factor in adjusting adhesion. This single factor is a key component of PVD deposition and is controllable in the PVD process; therefore, pressure is an ideal factor for controlling film adhesion. The illustrative method described herein is applicable to all PVD systems for depositing thin or thick films.

[0062] Of particular interest from a device perspective is that using pressure modulation to control adhesion enables the fabrication and production of devices in which PVD layers are deposited in direct contact with a carrier substrate and simultaneously releasable based on adhesion measurements. Figure 1A Examples of devices that can be used for diabetes applications are presented, such as, but not limited to, continuous glucose monitoring (CGM) sensors where electrodes are on both sides (top and back) of a single sensor flexure. As demonstrated herein, pressure modulation provides an efficient method to adjust the adhesion of the backside electrode to the carrier substrate, thereby enabling release at specific points throughout the downstream manufacturing process. Placing the contact pads for each of the electrodes on either side of the sensor flexure enables a wider array of connection schemes to the transmitter. Moreover, adjusting the adhesion can be used to minimize the newly added processing steps for the backside electrode. Overall, the adhesion control demonstrated herein can be used to reduce manufacturing complexity by a significant margin compared to conventional sensors.

[0063] Importantly, the novel methods of controlling adhesion described herein can be accomplished using standard materials, equipment, and facilities associated with PVD.

[0064] Methods for forming an analyte sensor comprising an electrode disclosed herein may include multiple steps. For example, such methods may include forming a working electrode, a counter electrode, and a reference electrode on a base substrate and / or forming a plurality of contact pads on the base substrate and / or forming a plurality of electrical conduits on the base substrate. In certain embodiments of the present invention, the method includes forming a plurality of working electrodes, a counter electrode, and a reference electrode, the electrodes being clustered together in units consisting essentially of a working electrode, a counter electrode, and a reference electrode. The electrodes are formed on a base substrate, and the clustering units are longitudinally distributed on at least one longitudinal arm of the base substrate in a unit repeating pattern. Optionally, in such methods, the working electrode is formed as an array of conductive members disposed on a base substrate, the conductive members being circular and having a diameter between 10 μm and 400 μm, and the array comprising at least 10 conductive members. The method may further include forming an analyte sensing layer on the working electrode, wherein in the presence of an analyte, the analyte sensing layer detectably changes the current on the working electrode. Typically, these methods further comprise forming an analyte modulation layer on the analyte sensing layer, wherein the analyte modulation layer modulates diffusion of the analyte therethrough.

[0065] Yet another embodiment of the present invention is an analyte sensor device comprising a base substrate including a well, the well containing a metal electrode composition formed using the sputtering process disclosed herein. In such embodiments, the structure of the platinum composition is formed to include a central planar region and an edge or ridge region surrounding the central planar region. In such embodiments, the thickness or height of the metal composition at the edge is 2X less than the average thickness of the metal composition in the central planar region. In certain embodiments of the present invention, the well includes a lip surrounding the well; and the edge region of the metal composition is located below the lip of the well. Typically, in these embodiments, both central planar regions form the electroactive surface of the working electrode in the sensor. Sensor embodiments of the present invention typically include additional material layers coated on the working electrode, such as an analyte sensing layer disposed on the working electrode, the analyte sensing layer detectably changing the current at the working electrode in the presence of an analyte; and an analyte modulation layer disposed above the analyte sensing layer, the analyte modulation layer modulating the diffusion of the analyte through it.

[0066] In a typical embodiment of the present invention, the electrode is formed in a well of a base substrate comprising a dielectric material (e.g., polyimide). Typically, the well comprises a conductive material (e.g., Au) disposed at the bottom of the well. Optionally, the well in the base substrate is rectangular or circular. In certain embodiments of the present invention, the base substrate comprises at least 10, 20, or 30 wells formed as a microarray. In a typical sensor embodiment, the base substrate is formed so that the base substrate comprises a well, and the well comprises a lip surrounding the well. In certain methods disclosed herein, the metal composition is sputtered so that the metal composition is located below the lip of the well. In addition, various different conductive elements can be disposed on the base substrate. In some embodiments of the present invention, the base substrate comprises a plurality of reference electrodes, a plurality of working electrodes, and a plurality of counter electrodes clustered together in a unit consisting essentially of a working electrode, a counter electrode, and a reference electrode, and the clustered units are longitudinally distributed on the substrate in a unit repeating pattern.

[0067] Embodiments of the present invention include additional elements designed for use with the sensor devices disclosed herein, such as elements designed to analyze electrical signal data obtained from a sputtered electrode disposed on a base substrate. In some embodiments of the present invention, the analyte sensor device includes a processor and a computer-readable program code having instructions that, when executed, cause the processor to evaluate electrochemical signal data obtained from at least one working electrode, and then calculate the analyte concentration based on the electrochemical signal data obtained from the working electrode. In certain embodiments of the present invention, the processor compares electrochemical signal data obtained from multiple working electrodes to, for example, adapt different electrodes to sense different analytes and / or focus on different concentration ranges of a single analyte; and / or identify or characterize stray sensor signals (e.g., sensor noise, signals caused by interfering compounds, etc.) to improve the accuracy of sensor readings.

[0068] In some embodiments of the present invention, the substrate structure includes a flexible but rigid and flat structure suitable for use in photolithography mask and etching processes. In this regard, the substrate structure generally includes at least one surface with a high degree of uniform flatness. The substrate structure material may include, for example, metals such as stainless steel, aluminum and nickel-titanium memory alloys (e.g., NITINOL) and polymer / plastic materials such as Delrin. The substrate structure material may be made of or coated with a dielectric material. In some embodiments, the substrate structure is non-rigid and may be a film layer or insulating layer, which is used as a substrate for patterning electrical elements (e.g., electrodes, traces, etc.), such as plastics such as polyimide. The initial step in the method of the present invention generally includes the formation of the base substrate of the sensor. Optionally, during the production of the sensor, a planar material sheet is formed and / or placed on a support such as a glass or ceramic plate. The substrate structure may be placed on a support (e.g., a glass plate) by PVD. Then a series of photolithography and / or chemical mask and etching steps may be performed thereafter to form a conductive component. In an illustrative form, the base substrate comprises a thin film sheet of insulating material, such as a polyimide substrate for patterning electrical components. The base substrate structure may include one or more of a variety of elements including, but not limited to, carbon, nitrogen, oxygen, silicon, sapphire, diamond, aluminum, copper, gallium, arsenic, lanthanum, neodymium, strontium, titanium, yttrium, or combinations thereof.

[0069] The method of the present invention includes forming a conductive layer acting as one or more sensing elements on a base substrate. Typically, these sensing elements include electrodes, electrical conduits (e.g., traces, etc.), contact pads, etc., and the sensing elements are formed by one of the various methods known in the art for defining the geometry of active electrodes, such as photolithography, etching, and rinsing. Electrodes can then be made of electrochemically active materials with a defined architecture, for example, by using sputtered Pt black as a working electrode. Then, a sensor layer (e.g., an analyte sensing enzyme layer) can be placed on the sensing layer by electrochemical deposition or other methods (e.g., spin coating) in addition to electrochemical deposition, and then, for example, vapor crosslinking with dialdehyde (glutaraldehyde) or carbodiimide.

[0070] In an exemplary embodiment of the present invention, a base substrate is first coated with a thin film conductive layer by electrode deposition, surface sputtering or other suitable patterning or other process steps. In one embodiment, this conductive layer can be arranged as a plurality of thin film conductive layers, such as an initial chromium-based layer suitable for chemical adhesion to a polyimide base substrate, a gold-based thin film layer and a chromium-based thin film layer formed in sequence. In alternative embodiments, other electrode layer structures or materials can be used. The conductive layer is then covered with a selected photoresist coating according to conventional photolithography techniques, and a contact mask can be applied over the photoresist coating for suitable photoimaging. The contact mask typically contains one or more conductor trace patterns for properly exposing the photoresist coating, followed by an etching step to retain a plurality of conductive sensor traces on the base substrate. In an exemplary sensor configuration designed for use as a subcutaneous glucose sensor, each sensor trace can contain two or three parallel sensor elements corresponding to two or three separate electrodes (such as a working electrode, a counter electrode, and a reference electrode).

[0071] Embodiments of the invention include methods of adding multiple materials to one or more surfaces of one or more sputtered electrodes. One such embodiment of the invention is a method of making a sensor device (e.g., a glucose sensor) for implantation in a mammal, the method comprising the steps of providing a base substrate; forming a conductive layer on the base substrate, wherein the conductive layer comprises electrodes formed by a sputtering process that produces a certain structure of metal pillars, thereby forming an analyte sensing layer on the conductive layer, wherein the analyte sensing layer comprises a composition that can change the current at the electrodes in the conductive layer in the presence of an analyte (e.g., glucose oxidase); optionally forming a protein layer over the analyte sensing layer; forming an adhesion promoting layer over the analyte sensing layer or the optional protein layer; forming an analyte modulation layer disposed on the adhesion promoting layer, wherein the analyte modulation layer comprises a composition that modulates diffusion of an analyte therethrough; and forming a covering layer disposed over at least a portion of the analyte modulation layer, wherein the covering layer further comprises holes over at least a portion of the analyte modulation layer.

[0072] In a possible embodiment of the invention disclosed herein, the analyte sensing layer comprises glucose oxidase. Optionally, the device comprises an adhesion promoting layer disposed between the analyte sensing layer and the analyte modulation layer. In some embodiments of the invention, the analyte modulation layer comprises a hydrophilic comb copolymer having a central chain and a plurality of side chains coupled to the central chain, wherein at least one side chain comprises a silicone moiety. Typically, the device comprises a biocompatible material on an outer surface, the biocompatible material being suitable for being applied to the in vivoWhen implanted, the analyte sensor device contacts biological tissue or fluid. In a possible embodiment of the invention disclosed herein, the analyte sensor device is an amperometric glucose sensor that exhibits a highly desirable oxygen response curve. In such embodiments, the amperometric glucose sensor generates a first signal in a solution comprising 100 mg / dL glucose and 5% oxygen and generates a second signal in a solution comprising 100 mg / dL glucose and 0.1% oxygen (i.e., under test conditions where the only difference is the oxygen %), and the difference between the first signal and the second signal is less than 10%.

[0073] Additional functional coatings or coverings can then be applied to the electrodes or other sensor elements by any of a variety of methods known in the art (such as spraying, dipping, etc.). Some embodiments of the present invention include an analyte modulation layer deposited on top of an enzyme-containing layer disposed above a working electrode. In addition to being used to modulate the amount of one or more analytes in contact with the active sensor surface, the problem of foreign material contaminating the sensor is also avoided by utilizing an analyte limiting membrane layer. As is known in the art, the thickness of the analyte modulation membrane layer may affect the amount of analyte reaching the active enzyme. Therefore, its application is usually carried out under defined processing conditions, and its dimensional thickness is closely controlled. The microfabrication of the bottom layer may be a factor that affects the dimensional control of the analyte modulation membrane layer and the exact composition of the analyte limiting membrane layer material itself. In this regard, several types of copolymers, such as copolymers of siloxane and non-siloxane portions, have been found to be particularly useful. These materials can be microdispersed or spin-coated to a controlled thickness. Its final architecture can also be designed by patterning and photolithography techniques consistent with other discrete structures described herein.

[0074] In some embodiments of the present invention, the sensor is manufactured by applying an analyte modulation layer comprising a hydrophilic membrane coating, which can modulate the amount of analyte that can contact the enzyme of the sensor layer. For example, a covering layer added to the glucose sensing element of the present invention can include a glucose limiting membrane that modulates the amount of glucose that contacts the glucose oxidase layer on the electrode. Such glucose limiting membranes can be made of a variety of materials known to be suitable for such purposes, for example, silicones such as polydimethylsiloxane, polyurethanes, cellulose acetate, perfluorosulfonic acid, polyester sulfonic acid (e.g., Kodak AQ), hydrogels, or any other membranes known to those skilled in the art suitable for such purposes. In certain embodiments of the present invention, the analyte modulation layer comprises a hydrophilic polymer. In some embodiments of the present invention, the analyte modulation layer comprises a linear polyurethane / polyurea polymer and / or a branched acrylate polymer; and / or a mixture of such polymers.

[0075] In some embodiments of the method of the present invention, the adhesion promoter layer is arranged between the cover layer (such as analyte modulation membrane layer) and the analyte sensing layer to promote its contact and is selected to increase the stability of the sensor device. As described herein, the adhesion promoter layer is selected to provide many desired characteristics in addition to the ability to provide sensor stability. For example, some compositions used in the adhesion promoter layer are selected to work in interference suppression and control the mass transfer of the desired analyte. The adhesion promoter layer can be made of any of the various materials known in the art for promoting the bonding between such layers, and can be applied by any of the various methods known in the art.

[0076] The finished sensor produced by such a method is usually quickly and easily removed from the support structure (if a support structure is used), for example, by cutting along the line around each sensor on the support structure, and then peeling off from the support structure. The cutting step can use methods commonly used in the art such as methods including a UV laser cutting device, which is used to cut the base layer and the cover layer and the functional coating along the line around or around each sensor (usually with at least a slight outward spacing relationship between the conductive element), so that enough interconnected base layer and cover layer materials are retained to seal the side edges of the finished sensor. As shown in this article, since the base substrate is directly adhered to the support below sufficiently weakly, the sensor can be quickly and easily lifted from the support structure without significant further processing steps or potential damage caused by stress due to excessive force applied to peel the attached sensor from the support structure. The support structure can then be cleaned and reused, or otherwise discarded. One or more functional coatings can be applied before or after removing (for example, by cutting) other sensor components from the support structure.

[0077] Embodiments of the present invention also include a method of sensing an analyte (e.g., glucose) in a mammal (e.g., a diabetic patient), the method comprising: implanting an analyte sensor embodiment disclosed herein into a in vivo environment, and then sensing one or more electrical fluctuations (such as a change in current at a working electrode) and correlating the change in current with the presence of an analyte, such that the analyte is sensed. Generally, this method includes: implanting a glucose sensor disclosed herein into a tissue space of a diabetic individual, sensing a change in current at a working electrode in the presence of glucose; and then correlating the change in current with the presence of glucose, such that glucose is sensed. Although typical embodiments of the present invention relate to glucose sensors, the sputtered sensor electrodes disclosed herein may be adapted for use with a variety of devices known in the art.

[0078] As discussed in detail below, embodiments of the present invention include sensor systems that include additional elements designed to facilitate analyte sensing. For example, in certain embodiments of the present invention, a substrate material including sensor electrodes is disposed within a housing (e.g., a lumen of a catheter) and / or associated with other components that facilitate analyte (e.g., glucose) sensing. An exemplary sensor system includes a processor; a substrate including a first longitudinal member and a second longitudinal member, each of the first longitudinal member and the second longitudinal member including at least one electrode having an electrochemically reactive surface, wherein the electrochemically reactive surface generates an electrochemical signal that is evaluated by the processor in the presence of an analyte; and a computer-readable program code having instructions that, when executed, cause the processor to evaluate electrochemical signal data obtained from the electrodes; and calculate analyte presence or concentration based on the electrochemical signal data obtained from the electrodes. The embodiments of the invention described herein may also be adapted and implemented using, for example, the amperometric sensor structures disclosed in U.S. Patent Application Publication Nos. 20070227907, 20400025238, 20110319734, and 20110152654, the contents of each of which are incorporated herein by reference.

[0079] B. Illustrative Analyte Sensor Components and Sensor Stacks Used in Embodiments of the Invention

[0080] The following disclosure provides examples of typical elements / ingredients used in sensor embodiments of the present invention. Although these elements may be described as discrete units (e.g., layers), it will be appreciated by those skilled in the art that sensors may be designed to include some or all combinations of material properties and / or functions of the elements / ingredients discussed below (e.g., elements acting as supporting substrate components and / or conductive components and / or matrices for analyte sensing components and further used as electrodes in the sensor). It will be appreciated by those skilled in the art that these thin film analyte sensors may be suitable for use in many sensor systems, such as the sensor systems described below.

[0081] Figures 1A-1D Embodiments of analyte sensor devices 100a-100d are shown, which include a working electrode (WE) on a first side 102a of an insulating layer 104a, 104b and a counter electrode (CE or BCE) on a second side 102b of the insulating layer 104a, 104b, such that the insulating layer 104a, 104b is located between the CE / BCE and the WE. Figures 1A-1DFurther shown is a reference electrode (RE) on the first side 102a of the insulating layers 104a, 104b and an insulator 106 between the RE and the WE. Metal 108 deposited on the insulating layers 104a, 104b electrically contacts the WE and includes a contact pad 110 for contacting the WE. Metal 112 or CE on the insulating layer 104a includes a CE and a contact pad 114 for contacting the CE. Figures 1A-1C Also shown in FIG. 1 are a base layer 116 on the CE and a second insulating layer 118 on the first insulating layers 104 a , 104 b and the metal 108 .

[0082] The WE includes a metal composition 120 having an electroactive surface 122. Figures 1A-1D In the example shown in , the WE includes a pillar 124 comprising a metal composition 120 and having an electroactive surface 122 .

[0083] Figure 1D An embodiment of a sensor 100d is shown, wherein the backside CE is / comprises a layer capable of controlling adhesion to the substrate as well as electrodes in the sensor device 100d.

[0084] Figure 1E An analyte sensor device 100e is shown, comprising working electrodes WE and CE on a first side (same side) 126 of a substrate 128, and wherein the WE and CE are spatially separated by a distance D of at least 1 micron inch, for example, in the range of 1 micron-20 microns. The WE and CE are non-interdigitated. The distance D is large enough to reduce undesirable interactions between the WE and CE (i.e., reduce the effect of an oxidation reaction at one electrode on a reduction reaction at the other electrode and vice versa).

[0085] In one or more embodiments, Figures 1A-1E The device can be fabricated using PVD and / or electroplating.

[0086] 1F and 1G compare the structure of the control sensor 130 having an interdigitated working electrode 132 and a counter electrode 134 and a reference electrode 136 on one side 126 of the device 130 with the sensor of FIG. 1G showing embodiments 100a-100d including electrodes WE on a first side 102a and electrodes CE on a second side 102b. The working electrode 132 and the control electrode 134 in the control device 130 also have a smaller spacing, which causes undesirable interactions between the electrodes 132 and 134.

[0087] In one or more embodiments, the sensors 100a-e include additional layers / coatings / components (eg, on WE) to enable use as glucose sensors (eg, for diabetic applications), such as Figure 1HThe following are the additional ingredients.

[0088] Base ingredients

[0089] The sensors of the present invention generally comprise a substrate component (see, e.g. Figure 1D Element 104b in, Figure 1H Element 402 in, Figure 1E Element 128 or Figures 1A-1D 116 in the device). The term "base component" is used herein according to a term recognized in the art and refers to a component in the device that generally provides a supporting matrix for multiple components stacked on top of each other and including a functional sensor. In one form, the base component includes a thin film sheet of insulating (e.g., electrically insulating and / or impermeable) material. This base component can be made of a variety of materials with desired qualities (such as dielectric properties, impermeability, and airtightness). Some materials include metals and / or ceramics and / or polymer substrates, etc.

[0090] Conductive components

[0091] The electrochemical sensors of the present invention generally comprise a conductive component comprising at least one electrode disposed on a substrate component, the at least one electrode comprising a metal for contacting an analyte to be determined or its byproducts (e.g., oxygen and / or hydrogen peroxide) (see, e.g., Figure 1B -1F in WE). The term "conductive component" is used herein according to art-recognized terminology and refers to a conductive sensor element, such as an electrode, contact pad, trace, etc. An illustrative example of the conductive component is a conductive component that forms a working electrode, which can measure an increase or decrease in current in response to exposure to a stimulus (such as a change in the concentration of an analyte or its byproducts) compared to a reference electrode that does not experience a change in the concentration of an analyte (a co-reactant (such as oxygen) used when the analyte interacts with a composition present in the analyte sensing component 410 (such as the enzyme glucose oxidase) or a reaction product of this interaction (such as hydrogen peroxide). Illustrative examples of such elements include electrodes that are capable of producing a variable detectable signal in the presence of a variable concentration of a molecule (such as hydrogen peroxide or oxygen).

[0092] In addition to the working electrode, the analyte sensor of the present invention generally also includes a reference electrode (RE) or a combined reference electrode and a counter electrode (also referred to as a quasi-reference electrode or a counter electrode / reference electrode). If the sensor does not have a counter electrode / reference electrode, it may include a separate counter electrode (CE), which may be made of the same or different material as the working electrode. A typical sensor of the present invention has one or more working electrodes and one or more counter electrodes, reference electrodes and / or counter electrodes / reference electrodes. One embodiment of the sensor of the present invention has two, three or four or more working electrodes. These working electrodes in the sensor may be integrally connected or they may also remain separate. Optionally, the electrode may be placed on a single surface or side of the sensor structure. Alternatively, the electrode may be placed on multiple surfaces or sides of the sensor structure. In certain embodiments of the present invention, the reactive surfaces of the electrodes have different relative areas / sizes, such as a 1X reference electrode, a 3.2X working electrode, and a 6.3X counter electrode.

[0093] Interference suppression components

[0094] The electrochemical sensor of the present invention optionally comprises an interference suppression component disposed between the electrode surface and the environment to be determined. Specifically, certain sensor embodiments rely on the oxidation and / or reduction of hydrogen peroxide produced by an enzymatic reaction on the surface of the working electrode under a constant applied potential. Because amperometric detection based on direct oxidation of hydrogen peroxide requires a relatively high oxidation potential, sensors using this detection scheme may experience interference from oxidizable species (such as ascorbic acid, uric acid, and acetaminophen) present in biological fluids. In this context, the term "interference suppression component" is used herein according to a specialized term recognized in the art, and refers to a coating or film in the sensor that acts to suppress stray signals generated by such oxidizable species, which interfere with the detection of signals generated by the analyte to be sensed. Certain interference suppression components act by size exclusion (e.g., by excluding interfering species of a specific size). Examples of interference suppression components include one or more layers or coatings of compounds such as hydrophilic polyurethane, cellulose acetate (including cellulose acetate incorporated with agents such as poly(ethylene glycol), polyethersulfone, polytetrafluoroethylene, perfluoroionomer Nafion™, polyphenylene diamine, epoxy resins, and the like).

[0095] Analyte sensing components

[0096] The electrochemical sensors of the present invention comprise analyte sensing components disposed on electrodes of the sensor (see, e.g. Figure 1H410 in the element). The term "analyte sensing component" is used herein according to the specialized words recognized in the art, and refers to a component that includes a material capable of identifying or reacting with an analyte to be detected by the analyte sensor device. Typically, this material in the analyte sensing component generates a detectable signal via an electrode of a conductive component after interacting with the analyte to be sensed. In this regard, the analyte sensing component and the electrode of the conductive component work in a combined manner to generate an electrical signal read by a device associated with the analyte sensor. Typically, the analyte sensing component includes an oxidoreductase (e.g., glucose oxidase) that can react with a molecule and / or cause a concentration change in the molecule, and the concentration change of the molecule can be measured by measuring the current change at the electrode of the conductive component (e.g., oxygen and / or hydrogen peroxide). The enzyme capable of producing a molecule (such as hydrogen peroxide) can be placed on the electrode according to many methods known in the art. The analyte sensing component can coat all or part of each electrode of the sensor. In this context, the analyte sensing component can coat the electrode to an equivalent degree. Alternatively, the analyte sensing component may coat different electrodes to varying degrees, wherein, for example, the coated surface of the working electrode is greater than the coated surface of the counter and / or reference electrodes.

[0097] Typical sensor embodiments of this element of the invention utilize an enzyme (e.g., glucose oxidase) that has been combined with a second protein (e.g., albumin) in a fixed ratio and then applied to the surface of an electrode to form a thin enzyme component (e.g., an enzyme typically optimized for glucose oxidase stability properties). In typical embodiments, the analyte sensing component includes a GOx and HSA mixture. In typical embodiments of the analyte sensing component with GOx, GOx reacts with glucose present in the sensing environment (e.g., the body of a mammal) and produces hydrogen peroxide.

[0098] As mentioned above, the enzyme and the second protein (e.g., albumin) are typically treated to form a cross-linked matrix (e.g., by adding a cross-linking agent to the protein mixture). As known in the art, cross-linking conditions can be manipulated to modulate factors such as the retention of biological activity of the enzyme, its mechanical and / or operational stability. Illustrative cross-linking procedures are described in U.S. Patent Application Serial No. 10 / 335,506 and PCT Publication WO 03 / 035891, which are incorporated herein by reference. For example, an amine cross-linking agent (such as, but not limited to, glutaraldehyde) can be added to the protein mixture. Adding a cross-linking agent to the protein mixture will produce a protein paste. The concentration of the cross-linking agent to be added can vary depending on the concentration of the protein mixture. Although glutaraldehyde is an exemplary cross-linking agent, other cross-linking agents may also be used or used in place of glutaraldehyde. As will be apparent to those skilled in the art, other suitable cross-linking agents may also be used.

[0099] As described above, in some embodiments of the present invention, the analyte sensing component comprises a reagent (e.g., glucose oxidase) capable of generating a signal (e.g., a change in oxygen and / or hydrogen peroxide concentration) that can be sensed by a conductive element (e.g., an electrode that senses a change in oxygen and / or hydrogen peroxide concentration). However, other useful analyte sensing components can be formed by any composition capable of generating a detectable signal that can be sensed by a conductive element after interacting with a target analyte whose presence is to be detected. In some embodiments, the composition includes an enzyme that modulates the concentration of hydrogen peroxide when reacting with the analyte to be sensed. Alternatively, the composition includes an enzyme that modulates the concentration of oxygen when reacting with the analyte to be sensed. In this context, a variety of enzymes that use or generate hydrogen peroxide and / or oxygen in reactions with physiological analytes are known in the art, and these enzymes can be easily incorporated into the analyte sensing component composition. Various other enzymes known in the art can generate and / or utilize compounds, the modulation of which can be detected by electrodes of a conductive element (such as incorporated into the sensor design described herein). Such enzymes include, for example, those specifically described in Table 1, pages 15-29 and / or Table 18, pages 111-112 of Protein Immobilization: Fundamentals and Applications (Bioprocess Technology, Vol 14), Richard F. Taylor (ed.), Publisher: Marcel Dekker; (January 7, 1991), the entire contents of which are incorporated herein by reference.

[0100] Protein composition

[0101] The electrochemical sensors of the present invention optionally include a protein component disposed between the analyte sensing component and the analyte modulating component (see, e.g. Figure 1H 416 in). The term "protein component" is used herein in accordance with art-recognized terminology and refers to a component containing a carrier protein, etc., which is selected to be compatible with the analyte sensing component and / or the analyte modulation component. In a typical embodiment, the protein component includes albumin, such as human serum albumin. The HSA concentration can vary between about 0.5%-30% (w / v). Typically, the HSA concentration is about 1-10% w / v, and most typically about 5% w / v. In alternative embodiments of the present invention, collagen or BSA or other structural proteins used in these contexts can be used to replace or supplement HSA. This component is typically cross-linked on the analyte sensing component according to art-recognized protocols.

[0102] Adhesion promoting ingredients

[0103] The electrochemical sensor of the present invention may comprise one or more adhesion promoting (AP) components (see, e.g. Figure 1H 414 in the sensor). The term "adhesion promoting component" is used herein according to a term recognized in the art, and refers to a component comprising a material selected to promote adhesion between adjacent components in the sensor. Typically, the adhesion promoting component is disposed between the analyte sensing component and the analyte modulating component. Typically, the adhesion promoting component is disposed between the optional protein component and the analyte modulating component. The adhesion promoter component can be made of any of a variety of materials known in the art for promoting adhesion between such components, and can be applied by any of a variety of methods known in the art. Typically, the adhesion promoter component includes a silane compound, such as 3-aminopropyltrimethoxysilane.

[0104] Analyte Modulation Components

[0105] The electrochemical sensor of the present invention comprises an analyte modulating component disposed on the sensor (see, e.g. Figure 1H 412 in the sensor). The term "analyte modulating component" is used herein in accordance with art-recognized terminology and refers to a component that typically forms a membrane on the sensor, the function of which is to modulate the diffusion of one or more analytes (such as glucose) through the component. In certain embodiments of the present invention, the analyte modulating component is an analyte limiting membrane, the function of which is to prevent or limit the diffusion of one or more analytes (such as glucose) through the component. In other embodiments of the present invention, the function of the analyte modulating component is to promote the diffusion of one or more analytes through the component. Optionally, such analyte modulating components can be formed to prevent or limit the diffusion of one type of molecule (such as glucose) through the component, while allowing or even promoting the diffusion of other types of molecules (such as O2) through the component.

[0106] Regarding glucose sensors, in known enzyme electrodes, glucose and oxygen from blood and some interferents (such as ascorbic acid and uric acid) diffuse through the primary membrane of the sensor. When glucose, oxygen and interferents reach the analyte detection component, enzymes (such as glucose oxidase) catalyze the conversion of glucose into hydrogen peroxide and gluconolactone. Hydrogen peroxide can diffuse back through the analyte modulation component, or it can diffuse to the electrode, where hydrogen peroxide can react to form oxygen and protons to produce an electric current proportional to the glucose concentration. The analyte modulation sensor membrane assembly is used for several functions, including selectively allowing glucose access to pass therethrough (see, for example, U.S. Patent Application No. 2011-0152654).

[0107] Covering ingredients

[0108] The electrochemical sensors of the present invention comprise one or more covering components, which are typically electrically insulating protective components (see, e.g. Figure 1H Element 406 in). Typically, such covering components can be in the form of a coating, sheath or tube and are disposed on at least a portion of the analyte modulation component. Acceptable polymer coatings used as insulating protective covering components can include but are not limited to non-toxic biocompatible polymers, such as silicone compounds, polyimides, biocompatible solder masks, epoxy acrylate copolymers, etc. In addition, these coatings can be photoimageable to facilitate photolithographic formation of holes through the conductive component. Typical covering components include spinning on silicone. As known in the art, this component can be a commercially available RTV (room temperature vulcanization) silicone composition. In this context, a typical chemical is polydimethylsiloxane (based on acetoxy).

[0109] Figure 1H A cross-section of a typical sensor embodiment 400 of the present invention is shown, which includes the components discussed above. This sensor embodiment is formed of multiple components, which are generally in the form of layers of various conductive and non-conductive components disposed on each other according to art-recognized methods disclosed herein and / or specific methods of the present invention. The components of the sensor are generally characterized herein as layers because, for example, it allows for easy characterization of Figure 1H However, the skilled person will appreciate that in certain embodiments of the present invention, the sensor components are combined such that multiple components form one or more heterogeneous layers. In this context, the skilled person will appreciate that in various embodiments of the present invention, the order of layered components may be changed.

[0110] Figure 1H The embodiment shown in includes a base substrate layer 402 for supporting the sensor 400. The base substrate layer 402 can be made of materials such as metal and / or ceramic and / or polymer substrates, and the base substrate layer can be self-supporting or can be further supported by another material known in the art. An embodiment of the present invention includes a conductive layer 404 disposed on the base substrate layer 402 and / or combined with the base substrate layer. Typically, the conductive layer 404 includes one or more conductive elements that act as electrodes. The operating sensor 400 typically includes a plurality of electrodes, such as a working electrode, a counter electrode, and a reference electrode. Other embodiments may also include a plurality of working electrodes and / or counter electrodes and / or reference electrodes and / or one or more electrodes that perform multiple functions, such as an electrode that acts as both a reference electrode and a counter electrode.

[0111] As discussed in detail below, many known techniques and materials may be used to produce the substrate 402 and / or the conductive layer 404. In certain embodiments of the present invention, the circuit of the sensor is defined by etching the disposed conductive layer 404 into a desired conductive path pattern. A typical circuit for the sensor 400 includes two or more adjacent conductive paths having a region at a proximal end to form a contact pad and a region at a distal end to form a sensor electrode. An electrically insulating cover layer 406 (such as a polymer coating) may be disposed on a portion of the sensor 400. Acceptable polymer coatings for use as an insulating protective cover layer 406 may include, but are not limited to, non-toxic biocompatible polymers such as silicone compounds, polyimides, biocompatible solder masks, epoxy acrylate copolymers, and the like. In the sensor of the present invention, one or more exposed areas or holes 408 may be formed through the cover layer 406 to open the conductive layer 404 to the external environment and, for example, allow an analyte (such as glucose) to penetrate the layer of the sensor and be sensed by the sensing element. Holes 408 may be formed by a variety of techniques, including laser ablation, tape masking, chemical grinding or etching, or photolithographic development, etc. In certain embodiments of the present invention, during manufacturing, a second photoresist may also be applied to the protective layer 406 to define areas where the protective layer is to be removed to form one or more holes 408. The exposed electrodes and / or contact pads may also be subjected to secondary processing such as additional electroplating processes (e.g., through the holes 408) to prepare the surface and / or enhance the conductive area.

[0112] exist Figure 1HIn the illustrated sensor configuration, the analyte sensing layer 410 is disposed on one or more exposed electrodes of the exposed electrodes of the conductive layer 404. Typically, the analyte sensing layer 410 is an enzyme layer. Most typically, the analyte sensing layer 410 includes an enzyme capable of producing and / or utilizing oxygen and / or hydrogen peroxide, such as the enzyme glucose oxidase. Optionally, the enzyme in the analyte sensing layer is combined with a second carrier protein (such as human serum albumin, bovine serum albumin, etc.). In an illustrative embodiment, the oxidoreductase (such as glucose oxidase) in the analyte sensing layer 410 reacts with glucose to produce a compound, hydrogen peroxide, which then modulates the current at the electrode. Since this modulation of the current depends on the concentration of hydrogen peroxide, which is related to the concentration of glucose, the glucose concentration can be determined by monitoring this modulation of the current. In a specific embodiment of the present invention, hydrogen peroxide is oxidized at a working electrode (also referred to herein as an anode working electrode) as an anode, wherein the current generated is proportional to the concentration of hydrogen peroxide. This modulation of the current caused by changes in hydrogen peroxide concentration can be monitored by any of a variety of sensor detector devices, such as a Universal Sensor amperometric biosensor detector or one of various similar devices known in the art, such as the glucose monitoring device produced by Medtronic Diabetes.

[0113] In embodiments of the present invention, the analyte sensing layer 410 can be applied over a portion of the conductive layer or over the entire area of ​​the conductive layer. Typically, the analyte sensing layer 410 is disposed on a working electrode, which can be an anode or a cathode. Optionally, the analyte sensing layer 410 is also disposed on a counter electrode and / or a reference electrode. Methods for producing a thin analyte sensing layer 410 include: brushing the layer onto a substrate (e.g., a reactive surface of a platinum black electrode), as well as spin coating processes, dip coating and drying processes, low shear spraying processes, inkjet printing processes, screen printing processes, etc. In certain embodiments of the present invention, brushing is used to: (1) allow precise positioning of the layer; (2) push the layer deep into the architecture of the reactive surface of the electrode (e.g., platinum black produced by a sputtering process).

[0114] Typically, the analyte sensing layer 410 is coated and / or disposed in close proximity to one or more additional layers. Optionally, one or more additional layers include a protein layer 416 disposed on the analyte sensing layer 410. Typically, the protein layer 416 includes proteins such as human serum albumin, bovine serum albumin, etc. Typically, the protein layer 416 includes human serum albumin. In some embodiments of the present invention, the additional layer includes an analyte modulation layer 412, which is disposed above the analyte sensing layer 410 to regulate the contact of the analyte with the analyte sensing layer 410. For example, the analyte modulation membrane layer 412 may include a glucose limiting membrane that regulates the amount of glucose that contacts the enzyme (such as glucose oxidase) present in the analyte sensing layer. Such glucose limiting membranes can be made of a variety of materials known to be suitable for such purposes, for example, silicone compounds such as polydimethylsiloxane, polyurethanes, polyurea acetate cellulose, perfluorosulfonic acid, polyester sulfonic acid (such as Kodak AQ), hydrogels, or any other suitable hydrophilic membranes known to those skilled in the art.

[0115] In certain embodiments of the present invention, Figure 1H As shown in , the adhesion promoter layer 414 is disposed between the analyte modulation layer 412 and the analyte sensing layer 410 to promote contact and / or adhesion thereof. Figure 3 As shown in , the adhesion promoter layer 414 is disposed between the analyte modulation layer 412 and the protein layer 416 to promote contact and / or adhesion thereof. The adhesion promoter layer 414 can be made of any of a variety of materials known in the art to promote adhesion between such layers. Typically, the adhesion promoter layer 414 includes a silane compound. In alternative embodiments, the protein or similar molecules in the analyte sensing layer 410 can be sufficiently cross-linked or otherwise prepared to allow the analyte modulation membrane layer 412 to be placed in direct contact with the analyte sensing layer 410 in the absence of the adhesion promoter layer 414.

[0116] C. Typical System Embodiments of the Invention

[0117] A specific illustrative system embodiment consists of a glucose sensor, a transmitter and a receiver, and a blood glucose meter including a sputtering / PVD electrode composition as disclosed herein. In this system, a radio signal from a transmitter can be sent to a pump receiver at a fixed time period (e.g., every 5 minutes) to provide a real-time sensor glucose (SG) value. The value / graph can be displayed on the monitor of the pump receiver so that the user can self-monitor blood glucose and deliver insulin using his own insulin pump. Generally, the sensor system disclosed herein can communicate with other medical devices / systems via a wired or wireless connection. Wireless communication can include, for example, the reception of an emitted radiation signal that occurs when a signal is transmitted by RF telemetry, infrared transmission, optical transmission, sound waves, and ultrasonic transmission. Optionally, the device is an integrated part of a drug infusion pump (e.g., an insulin pump). Generally, in such devices, the physiological characteristic value includes multiple measurements of blood glucose.

[0118] Figure 2 A perspective view of a general embodiment of a subcutaneous sensor insertion system that may be suitable for use with the sensor electrodes disclosed herein and a block diagram of a sensor electronics device according to an illustrative embodiment of the present invention are provided. Additional elements that are commonly used with such sensor system embodiments are disclosed, for example, in U.S. Patent Application No. 20070163894, the contents of which are incorporated by reference. Figure 2 A perspective view of a telemetric property monitoring system 1 including a subcutaneous sensor kit 10 is provided, which is provided for subcutaneously placing an active portion of a flexible sensor 12, etc., at a selected location within a user's body. The subcutaneous or percutaneous portion of the sensor kit 10 includes a hollow slotted insertion needle 14 having a sharp tip 44 and a cannula 16. A sensing portion 18 of the sensor 12 is located inside the cannula 16 to expose one or more sensor electrodes 20 to the user's bodily fluids through a window 22 formed in the cannula 16. The base is designed so that the sensing portion 18 is joined to a connecting portion 24 that terminates in a conductive contact pad or the like, which is also exposed through one of the insulating layers. The connecting portion 24 and the contact pads are typically adapted for direct wired electrical connection to a suitable monitor 200 coupled to a display 214 to monitor the user's condition in response to signals originating from the sensor electrodes 20. The connecting portion 24 may be conveniently electrically connected to the monitor 200 or characteristic monitor transmitter 200 via a connector block 28 (or the like) as shown and described in US Pat. No. 5,482,473, entitled FLEX CIRCUIT CONNECTOR, which is incorporated by reference.

[0119] like Figure 2As shown in , according to an embodiment of the present invention, the subcutaneous sensor kit 10 can be configured or formed to work with a wired or wireless property monitoring system. The proximal portion of the sensor 12 is mounted in a mounting base 30 suitable for placement on the skin of a user. The mounting base 30 can be a pad having an underside surface that is coated with a suitable pressure-sensitive adhesive layer 32, wherein a release paper tape 34 is typically provided to cover and protect the adhesive layer 32 until the sensor kit 10 is ready for use. The mounting base 30 includes an upper layer 36 and a lower layer 38, wherein the connecting portion 24 of the flexible sensor 12 is sandwiched between the layers 36 and 38. The connecting portion 24 has a front portion that is joined to the active sensing portion 18 of the sensor 12, and the front portion is folded at an angle to extend downward through a bore 40 formed in the lower base layer 38. Optionally, the adhesive layer 32 (or in vivo The insertion needle 14 is adapted to be received in a sliding fit through a needle port 42 formed in the upper substrate layer 36 and through a lower bore 40 in the lower substrate layer 38. After insertion, the insertion needle 14 is withdrawn to leave the cannula 16 with the sensing portion 18 and the sensor electrode 20 in place at the selected insertion site. In this embodiment, the telemetry characteristic monitor transmitter 200 is coupled to the sensor kit 10 via a cable 402 through a connector 24, which is electrically coupled to the connector block 28 of the connector portion 24 of the sensor kit 10.

[0120] exist Figure 2 In the embodiment shown in , the telemetry characteristic monitor 400 includes a housing 206 that supports a printed circuit board 208, a battery 210, an antenna 212, and a cable 202 having a connector 204. In some embodiments, the housing 206 is formed by an upper housing 214 and a lower housing 216 that are sealed with ultrasonic welding to form a waterproof (or corrosion-resistant) seal to allow cleaning by immersion (or wiping) with water, detergent, alcohol, etc. In some embodiments, the upper housing 214 and the lower housing 216 are formed of medical grade plastic. However, in alternative embodiments, the upper housing 214 and the lower housing 216 can be connected and bonded together by other methods (such as snap fit, sealing ring, RTV (silicone sealant)) or formed by other materials such as metal, composite materials, ceramics, etc. In other embodiments, a separate housing can be eliminated and the assembly is simply potted in epoxy or other moldable materials that are compatible with electronic devices and have considerable moisture resistance. As shown, the lower housing 216 may have an underside surface coated with a suitable pressure sensitive adhesive layer 218, with a release paper tape 220 typically provided to cover and protect the adhesive layer 118 until the sensor suite telemetry characteristic monitor transmitter 200 is ready for use.

[0121] exist Figure 2 In the illustrative embodiment shown in FIG. 1 , a subcutaneous sensor kit 10 facilitates precise placement of a flexible thin film electrochemical sensor 12 for monitoring a specific type of blood parameter representative of a user's condition. The sensor 12 monitors glucose levels in the body and can be used in conjunction with an external or implantable automatic or semi-automatic drug infusion pump as described in U.S. Pat. Nos. 4,562,751; 4,678,408; 4,685,903 or 4,573,994 to control insulin delivery to a diabetic patient.

[0122] exist Figure 2 In the illustrative embodiment shown in , the sensor electrode 10 can be used in various sensing applications, and can be configured to be located in various positions on the substrate structure, and further formed to include materials that allow multiple functions. For example, the sensor electrode 10 can be used in physiological parameter sensing applications where a certain type of biomolecule is used as a catalyst. For example, the sensor electrode 10 can be used in a glucose and oxygen sensor having a glucose oxidase that catalyzes a reaction with the sensor electrode 20. The sensor electrode 10, together with the biomolecule or some other catalyst, can be placed in the human body in a vascular or non-vascular environment. For example, the sensor electrode 20 and the biomolecule can be placed in a vein and subjected to blood flow, or can be placed in the subcutaneous or peritoneal area of ​​the human body.

[0123] exist Figure 2 In the embodiment of the present invention shown in , the monitor 200 of the sensor signal may also be referred to as the sensor electronics device 200. The monitor 200 may include a power supply, a sensor interface, processing electronics (i.e., a processor), and data formatting electronics. The monitor 200 may be coupled to the sensor kit 10 via a connector via a cable 402, and the connector is electrically coupled to the connector block 28 of the connecting portion 24. In an alternative embodiment, the cable may be omitted. In this embodiment of the present invention, the monitor 200 may include an appropriate connector for connecting directly to the connecting portion 24 of the sensor kit 10. The sensor kit 10 may be modified to position the connector portion 24 in a different position, for example, at the top of the sensor kit to facilitate placement of the monitor 200 on the sensor kit.

[0124] As described above, embodiments of sensor elements and sensors can be operably coupled to various other system elements (e.g., structural elements such as piercing members, insertion kits, and electronic components such as processors, monitors, and drug infusion pumps) that are commonly used with analyte sensors, for example, to make them suitable for use in various contexts (e.g., implanted in mammals). One embodiment of the present invention includes a method for monitoring a user's physiological characteristics using an embodiment of the present invention that includes: an input element that can receive a signal based on a sensed physiological characteristic value of the user from a sensor); and a processor that is used to analyze the received signal. In a typical embodiment of the present invention, the processor determines the dynamic behavior of the physiological characteristic value and provides an observable indicator based on the dynamic behavior of the physiological characteristic value so determined. In some embodiments, the physiological characteristic value is a measure of the user's blood glucose concentration. In other embodiments, the method of analyzing the received signal and determining the dynamic behavior includes repeatedly measuring the physiological characteristic value to obtain a series of physiological characteristic values ​​to, for example, incorporate comparative redundancy into the sensor device in a manner designed to provide confirmation information about sensor function, analyte concentration measurement results, the presence of interference, etc.

[0125] Figure 3 FIG. 2 shows a schematic diagram of a voltage regulator that can be used to measure current in an embodiment of the present invention. Figure 3 As shown in , the potentiostat 300 can include an operational amplifier 310 connected in a circuit to have two inputs: Vset and Vmeasured. As shown, Vmeasured is the measured value of the voltage between the reference electrode and the working electrode. On the other hand, Vset is the optimal desired voltage across the working electrode and the reference electrode. The current between the counter electrode and the reference electrode is measured, thereby generating a current measurement result (Isig) output from the potentiostat.

[0126] Embodiments of the present invention include a device for processing display data from measurements of sensed physiological characteristics (e.g., blood glucose concentration) in a manner and format that is customized to allow a user of the device to easily monitor and (when necessary) modulate the physiological state of the characteristic (e.g., modulate blood glucose concentration by insulin administration). An illustrative embodiment of the present invention is a device comprising: a sensor input capable of receiving a signal from a sensor based on a sensed physiological characteristic value of a user; a memory for storing a plurality of measurements of the sensed physiological characteristic value of the user of the received signal from the sensor; and a display for presenting a text and / or graphical representation (e.g., text, line graph, etc., bar graph, etc., grid pattern, etc., or a combination thereof) of a plurality of measurements of the sensed physiological characteristic value. Typically, the graphical representation displays real-time measurements of the sensed physiological characteristic value. Such devices can be used in various situations, such as in combination with other medical devices. In some embodiments of the present invention, the device is used in combination with at least one other medical device (e.g., a glucose sensor).

[0127] The illustrative system embodiment consists of a glucose sensor, a transmitter and a pump receiver and a blood glucose meter. In this system, a radio signal from the transmitter can be sent to the pump receiver every 5 minutes to provide a real-time sensor glucose (SG) value. The value / graph is displayed on the monitor of the pump receiver so that the user can self-monitor blood glucose and deliver insulin using his own insulin pump. Typically, the embodiments of the device disclosed herein communicate with a second medical device via a wired or wireless connection. Wireless communication may include, for example, the reception of an emitted radiation signal that occurs when a signal is transmitted by RF telemetry, infrared transmission, optical transmission, sound waves, and ultrasonic transmission. Optionally, the device is an integrated part of a drug infusion pump (e.g., an insulin pump). Typically, in such devices, the physiological characteristic value includes multiple measurements of blood glucose.

[0128] Although the analyte sensors and sensor systems disclosed herein are generally designed to be implanted in a mammal, the invention disclosed herein is not limited to any particular environment, but can be used in a variety of contexts, such as for analyzing most in vivo and in vitro Liquid samples include biological fluids such as tissue fluid, whole blood, lymph, plasma, serum, saliva, urine, feces, sweat, mucus, tears, cerebrospinal fluid, nasal secretions, cervical or vaginal secretions, semen, pleural fluid, amniotic fluid, peritoneal fluid, middle ear effusion, joint fluid, gastric juice, etc. In addition, solid or dry samples can be dissolved in a suitable solvent to provide a liquid mixture suitable for analysis.

[0129] Examples

[0130] Common abbreviations used in the examples include: WE working electrode; GOx glucose oxidase; HSA human serum albumin; SITS sensor in vitro test system; GLM glucose limiting membrane (an embodiment of an analyte modulation layer); OQ operational qualification; SAR surface area ratio; BTS bicarbonate test system; and EIS electrochemical impedance spectroscopy. The BTS and SITS tests discussed in the examples are tests used to evaluate aspects of sensor performance. SITS measures the sensor signal in glucose solution as well as the sensor oxygen response, temperature response, background current, linearity, stability, acetaminophen interference, and response time over a 5-7 day period. The dog test is used to evaluate diabetic and non-diabetic dogs. in vivo Glucose sensor performance (Isig and calculated blood glucose levels) for up to 3 days and glucose levels measured by the continuous glucose sensor were compared to glucose levels measured by a blood glucose meter.

[0131] It should be understood that the present invention is not limited to the specific embodiments described, because the embodiments can certainly vary. It should also be understood that the special words used herein are only for the purpose of describing specific embodiments, and are not intended to be restrictive, because the scope of the present invention is limited only by the appended claims. In the description of the preferred embodiments, reference is made to the accompanying drawings that form a part of the description, and in the accompanying drawings, specific embodiments that can practice the present invention are shown by way of illustration. It should be understood that other embodiments can be utilized and structural changes can be made without departing from the scope of the present invention.

[0132] However, although indicating some embodiments of the present invention, the description and specific examples are given by way of illustration and not limitation.Many changes and modifications may be made within the scope of the present invention without departing from its spirit, and the present invention includes all such modifications.

[0133] Example 1: Sputtering equipment

[0134] Figure 4 An apparatus is shown including a chamber 400 for depositing a material (eg, a thin film 402) using sputtering. A sputtering gas 404 in the chamber 400 is ionized to form a film including ionized gas particles 406 (eg, Ar + ) plasma. Ionized particles 406 bombard sputtering target 408 including a metal composition. The collision of ionized particles 406 with sputtering target 408 knocks off material 410 including a metal composition (e.g., sputtered target atoms) and accelerates material 410 onto a target surface on a substrate 414, thereby forming film 402 on substrate 414. Ionized gas particles 406 are generated by applying a voltage U -The electric and / or magnetic fields applied by the bias electrodes accelerate the particles toward the target. Particle collisions are controlled by the process power (i.e., the power of the electric and / or magnetic fields until the ionized gas particles reach the sputtering gas) and the pressure and composition of the sputtering gas (or the ionized gas particle composition and pressure).

[0135] Example 2: Sputtering conditions for controlling adhesion

[0136] The following deposition conditions may affect adhesion.

[0137] •High pressure deposition conditions may cause the deposited film to form under stress, resulting in poor adhesion.

[0138] •Deposition power may affect adhesion because higher deposition rates may cause air pockets, resulting in poor adhesion.

[0139] •The high temperatures used during deposition may evaporate any adsorbed water remaining on the surface, thereby improving adhesion.

[0140] •Thicker films create stress and make adhesion worse.

[0141] •Geometric area may also affect adhesion and can be controlled by forming pillars at the interface between the film and substrate.

[0142] In the experiments described herein, sputtering parameters including pressure, power, temperature, and thickness, and combinations of these parameters, were adjusted to determine their effects on adhesion and to determine the parameters / parameter values ​​that achieve optimal adhesion for electrode processing. In one or more embodiments, the target for adhesion (or optimal adhesion) is strong enough to maintain adhesion of the base polyimide to the substrate during laser cutting, but weak enough to allow the base polyimide to be removed from the substrate for the sensor assembly.

[0143] Figure 5 A test sample is shown comprising a layer stack 500 on a glass substrate 502. The layer stack includes a gold (Au) layer 504 on the glass substrate, a chromium (Cr) layer 506 on the Au layer 504, and a base polyimide layer 508 on the Cr layer 506.

[0144] Fig. 6A Different patterns AE of knife scratches or laser cut marks that simulate marking and cutting types that may be applied during electrode processing in a glucose sensor or other device are shown applied to the layer stack 500 on a glass substrate 502 .

[0145] Figure 6B A pattern 600 of a silver layer applied to a glass substrate is shown, illustrating that the adhesion of the silver to the glass is too weak to allow replication of the markings on the silver layer.

[0146] use Fig. 6A Based on the marking pattern shown in Figure 1, a feasibility-efficiency-compatibility study was performed to find out whether the metal (e.g., gold) sputtering conditions have any effect on the Figure 5 The influence of metal / glass (e.g., metal / glass) adhesion on the layer structure.

[0147] Figures 7A-7D Shows how to assign adhesion scores. Fig. 7A Shown when Fig. 6A The score assigned when the pattern can be accurately applied to the layer stack with the highest quality and replica resolution (indicating the strongest adhesion of the layer stack to the glass substrate) is 0. As the score increases, the adhesion decreases and the marking pattern is not well replicated in the layer stack ( Figure 7B and 7C ). Fig.7D Shown when Fig. 6A A score of 10 is assigned when the pattern cannot be accurately applied to the layer stack 500 and is replicated in the layer stack (indicating the weakest adhesion of the layer stack to the glass substrate). This adhesion scoring method is significantly less time consuming than performing a more quantitative analysis.

[0148] a. Experiment 1

[0149] The sputtering conditions in Table 1 were used to produce Fig. 6A As shown in Table 1, the Figure 6B A marking pattern of was scribed / laser cut into each of the films on the test samples and an adhesion score was assigned to each replica.

[0150] Table 1

[0151]

[0152] Figures 7A-7D The test results are shown. The sputtering conditions included 100 mT pressure, 1.6 kW power, 897 angstroms gold layer thickness, and no heating. Fig.7D The sputtering structure in .

[0153] The results showed that the sputtering conditions for samples 1-6 (highlighted in Table 1) had the strongest adhesion (adhesion score of 0), allowing accurate replication of Figure 6B Mark. Figures 7A-7D and Table 1 show surprising and unexpected results: low pressure achieves very high adhesion, while high pressure achieves low adhesion.

[0154] b. Experiment 2

[0155] 8B shows a test sample 1000 including an Au layer 1002, which contains pillars 1004 at the interface between the Au layer 1002 and a glass substrate 1006. Different test samples 1000 were fabricated, in which the Au layer 1002 was deposited under different sputtering conditions (as shown in Table 2). Fig. 9 is a scanning electron microscope image of the columnar interface between the glass substrate 1006 and the gold layer 1002 .

[0156] As shown in Table 2, a knife was then used to Figure 6B A marking pattern of is scribed / laser cut into each of the Au films 1002 in the test sample 1000 and an adhesion score is assigned to each replica.

[0157] Table 2

[0158]

[0159] Figure 5 The fabrication of a backside counter electrode is demonstrated, comprising depositing a gold (Au) layer on a glass substrate, depositing a chromium (Cr) layer on the gold layer, depositing a polyimide containing a base polyimide on the Cr layer, forming an opening in the polyimide, depositing a Cr / Au layer stack inside the opening, and peeling the base polyimide and the Au layer together with the Cr layer from the glass substrate.

[0160] It is to be understood that this invention is not limited to particular embodiments described, as such embodiments may, of course, vary.

[0161] The samples highlighted in Table 2 (Samples 1-5 and 10) show that low pressure sputtering achieves strong adhesion (low adhesion score). On the other hand, the results for Samples 6-9 show that sputtering at high pressure (above 55 mTorr, e.g., 100 mTorr) achieves weak adhesion. It is assumed that the gold pillars reduce the gold / glass contact area and increase the effect of pressure on adhesion. The results also show that thicker films have weaker adhesion to the glass substrate.

[0162] Figures 10A-10D A gold post 1004 fabricated using various sputtering conditions after laser cutting with an example electrode pattern is shown. Fig. 6A membrane. Fig.12 A and 12B show the results of the membrane fabricated using 100 mTorr pressure, 0.4 W power, and a 952 Å thick gold layer ( Fig. 10A ) and in membranes fabricated using 100 mTorr pressure, 1.6 W power, and an 897 Å thick gold layer ( Fig. 10B ) reproduces the pattern very well. Fig. 10Cand 10D demonstrated in a membrane fabricated using 100 mTorr pressure, 0.4 W power, and a 8922 Å thick gold layer ( Fig. 10C ) and in membranes fabricated using 100 mTorr pressure, 1.6 W power, and a 10806 Å thick gold layer ( Fig. 10B ) cannot replicate the pattern well. These results show that when high pressure is used, relatively thin gold layers can be used to increase adhesion (adhesion decreases with increasing gold layer thickness).

[0163] Fig.11 A Pareto plot showing the normalized effects of varying various factors (pressure, power, and gold thickness) on adhesion of a sample 500 fabricated using gold posts 1004 located at the interface between the gold layer 504 and the glass substrate 502. In the Pareto plot, the responses are the rates obtained by varying the pressure, sputtering power, and gold layer thickness, and α = 0.05 is a parameter used to determine statistically significant factors controlling adhesion (in one or more instances, factors having a normalized effect on adhesion greater than α-0.05 are considered statistically significant factors controlling adhesion).

[0164] Fig.12 is a graph of the average rate as a function of pressure, power, and gold thickness.

[0165] Fig.13 is a contour plot of rate versus gold layer thickness and sputtering pressure.

[0166] DOE analysis ( Fig.11 , Fig.12 and Fig.13 ) showed that pressure was the primary factor controlling adhesion when forming pillars 1004 at the interface. Specifically, the analysis showed that higher pressures and thicker (e.g., gold) layers in the film achieved weaker adhesion, while sputtering power had little effect on adhesion. Lower temperatures were found to provide weaker adhesion.

[0167] c. Effect of two gold layers on adhesion

[0168] Fig.14 Another test sample is shown including a layer stack 1400 on a glass substrate 1402. The layer stack 1400 includes a first gold layer 1404 deposited on the glass substrate 1402 using high pressure sputtering conditions, a second gold layer 1406 deposited on the first gold layer 1404 using low pressure sputtering conditions, a chromium layer 1408 sputtered on the second Au layer 1406, and a base polyimide layer 1410 deposited on the Cr layer 1408.

[0169] Follow the procedure discussed previously and then use a knife or laser to cut the Figure 6BA marking pattern of was scratched into each of the films 1400 in the test samples. Table 2 compares the adhesion scores of the sample 1400 having dual gold layers 1406, 1404 (Sample 11) with the adhesion scores of the samples 500 having a single gold layer 504 deposited at low or high pressure (Samples 1-10).

[0170] FIG. 15A shows a gold layer 504 deposited using sputtering conditions of 100 mTorr pressure, 1.5 kW power, and 5 minutes duration. Fig. 6A FIG. 15B shows a film 500 of a test sample including a first gold layer 1404 deposited using a sputtering condition of 100 mTorr pressure, 1.5 kW power, and 5 minutes duration, and a second gold layer 1406 deposited using a sputtering condition of 4 mTorr pressure, 0.2 kW power, and 10 minutes duration. Fig.14 The results show that the test sample 1400 with a double gold layer ( Fig.14 ) than the sample with one gold layer 500 ( Fig. 6A ) has better adhesion. Thus, the results unexpectedly and surprisingly show that the combination of high / low pressure gold layers 1404, 1406 can significantly affect adhesion.

[0171] Fig. 15C , 15D 15E show that the adhesion of a film 1400 having two gold layers 1404, 1406 deposited using the conditions of FIG 15B varies depending on the location on the surface area. Adhesion uniformity can be increased by reducing defects and dust on the glass substrate and improving deposition uniformity in the sputtering equipment.

[0172] Example 3: Controlling the Sputtering Rate

[0173] A DOE analysis was performed to determine the process parameters that affect the sputtering rate of gold on a glass substrate when no heat is applied. Fig.16 A Pareto plot showing the normalized effect of varying pressure, power, and gold thickness on the sputtering rate when no heat is applied. In the Pareto plot, the response is the sputtering rate in angstroms per second, and α = 0.05.

[0174] Fig.17 is a graph of the average sputtering rate as a function of pressure, power, and gold thickness.

[0175] Fig.18 is a contour plot of sputtering rate versus sputtering power (kW) and pressure (mTorr).

[0176] DOE analysis ( Fig.16 , Fig.17 and Fig.18) shows that there is an optimal pressure for maximum sputtering rate, and the sputtering rate increases linearly with the sputtering power. Therefore, as shown herein, the PVD conditions can be carefully selected to increase the sputtering rate and control the adhesion. In one or more embodiments, DOE analysis is used to determine the sputtering parameters that achieve the fastest deposition rate and the desired adhesion. Power and pressure can be used to control the sputtering rate and adhesion.

[0177] Although Examples 2-4 involve sputtering, the same results and findings (including control of adhesion through proper selection of pressure) apply generally to deposition using PVD (eg, including but not limited to electron beam deposition).

[0178] Example 4: Analyte Sensor Device Fabrication

[0179] Fig.19 , Fig. 20 and Figure 1D A method of making an analyte sensor device 100d is presented.

[0180] Block 1900 represents providing a base (eg, rigid) substrate 2000 (eg, a glass substrate).

[0181] Block 1902 represents depositing metal 2002a, 2002b on a base substrate, for example using PVD (physical vapor deposition metal). In one or more embodiments, the metal includes a first layer 2002a (e.g., an Au layer) on the base substrate 2000 and a second layer (e.g., a Cr or Ti layer) 2002b on the first Au layer 2002a. In one or more examples, the metal 2002a, 2002b extends laterally to form contact pads 110, 114.

[0182] Example PVD conditions include pressures in the range of 2-250 mTorr, 70-100 mTorr, or 50-125 mTorr, power in the range of 10 W-100 kW (e.g., 0.5 kW-2 kW, e.g., 0.8 kW), and a thickness of each of the metal layers in the range of at least 100 angstroms (e.g., 1000-9000 Å). The PVD step may include the pressure control steps described herein. Example PVD processes include, but are not limited to, sputtering and electron beam deposition.

[0183] Block 1904 represents depositing a first insulating layer 2004 on the metal 2002a, 2002b. Example insulating layers include, but are not limited to, polymer layers such as, but not limited to, polyimide.

[0184] Block 1906 represents depositing a second metal 2006a, 2006b on the first insulating layer 2004, 104b and patterning the second metal. In one or more examples, the second metal includes two layers - a second layer 2006b including Au on a first layer 2006b including Cr (or Ti) and extending laterally to form contact pads 110, 114.

[0185] Block 1908 represents depositing a second insulating layer 2008, 118 onto the first insulating layer 2004 and depositing a second metal 2006a, 2006b onto the first insulating layer 2004. Example insulating layers include, but are not limited to, polymer layers such as, but not limited to, polyimide.

[0186] Block 1910 represents forming a first opening 2010 a and a second opening 2010 b in the second insulating layer 2004 to expose the second metal 2006 b .

[0187] Block 1912 represents depositing a third metal into the first opening 2010a and onto the second metal 2010b to form a working electrode WE (see Figure 1D ).

[0188] Block 1914 represents depositing a fourth metal into the second opening 2010b and onto the second metal 2006b to form a reference electrode (RE) (see Figure 1D ).

[0189] Box 1916 represents an additional step including forming an opening in the second insulating layer 118 to expose the metal contact pads 110, 114b including the second metal 2006a, 2006b (refer to Figure 1D ) and cure if necessary.

[0190] Box 1918 represents defining an analyte sensor in a membrane 2012, which includes metals 2002a, 2002b; second metals 2006a, 2006b; first insulating layers 2004, 104b; second insulating layers 2008, 118; and electrodes WE, RE.

[0191] Block 1920 represents removing 2014 (eg, stripping) the analyte sensor 100d from the base substrate 2000. In one or more embodiments, the steps include removing (eg, stripping) the physical vapor deposited metals 2002a, 2002b from the substrate 2000.

[0192] Box 1922 represents the final result, for example, Figure 1DThe sensor device shown in . The metal layers 2002a, 2002b, CE act as backside counter electrodes BCE and a layer for controlling adhesion to the base substrate 2000 using the pressure control methods described herein (see, e.g., Examples 2-3). The base polyimide layers 2004, 104b do not require patterning or etching to contact the BCE. In one or more examples, the method of Example 4 enables the manufacture of a device including one flexible member with electrodes on both sides (compared to a control device with interdigitated electrodes on one side as shown in FIG. 1F). As shown herein, multiple (e.g., at least 36) sensors 100d removed from the base substrate can all exhibit ISIG within 15% (see, e.g., Fig.21D ).

[0193] Example 5: SITS results of the combined sensor of Example 4

[0194] Figures 21A-21C The SITS results of the control sensor as shown in FIG1F are shown, and Figures 21D-21F The SITS results of the sensor of FIG1G are shown (simulation / representation of a BCE fabricated using Method Example 4). Figure 1D performance of the device).

[0195] The sensor of Figure 1G has two flexures:

[0196] • Flexure 1: Nominal electrode E3 has tape over CE contact pad at emitter connection. Tape does not touch body.

[0197] • Flexure 2: The nominal E3 layer includes base polyimide and the nominal E3 electrode includes Cr / Au and tape over the WE and RE contact pad areas at the emitter connection. This flexure is a nominal E3 flexure fabricated by a metal sputtering process only and the tape does not contact the body.

[0198] although Figure 1D The sensor has a single flexure containing CE, WE and RE, but it is expected that Figure 1D The performance of the device is similar to that of the device of FIG. 1G with two flexures because Figure 1D Both the device and the device of FIG. 1G have a CE electrode on the back side opposite to the WE.

[0199] Table 3: For testing Figure 1D SITS summary for 3 SITS runs of the device. *Indicates statistically significant differences. Figure 1D For the BCE devices, the number of devices tested was n = 36, and for the control devices, n = 36).

[0200]

[0201] for Figures 21A-21C According to the data in , the working electrode 132 and the counter electrode 134 in the control sensor 130 include Pt, and the reference electrode in the control sensor 130 includes Ag / AgCl. Figures 21D-21F 1G , the WE in the sensor of FIG. 1G includes Pt, the CE in the sensor of FIG. 1G includes Au, and the RE in the sensor of FIG. 1G includes Ag / AgCl.

[0202] Figures 21D-21F The data of the sensors used in the pig in vivo tests in Table 3 show that the BCE device of Figure 1G (denoted Figure 1D The BCE of FIG1G showed no major differences in temperature and AC response, and no negative observations were found from visual inspection.

[0203] Fig. 21C and 21F It also appears that the Vcounter (Vcntr) activity / motion in response to glucose sensing using the device of Figure 1G is surprisingly lower than the control sensor of Figure 1 F. In addition, the data shows that the Vcounter of the sensor of Figure 1G appears to be more stable at a lower steady-state voltage.

[0204] Example 6: Analyte Sensor Device Fabrication

[0205] Fig. 22 is a flow chart showing a method of making a glucose sensor or sensor flexure (see also Figures 1A-1D and Fig.23 ). The method comprises the following steps.

[0206] Block 2200 represents depositing one or more metal layers on a (e.g., rigid) substrate 2302 (e.g., glass) using physical vapor deposition (e.g., sputtering or electron beam deposition). Example metal layers 2300a, 2300b include, but are not limited to, Au, Cr, Ti, and combinations thereof. In one or more embodiments, layers 2300a, 2300b include one or more gold layers deposited on a glass substrate 2302, followed by Cr deposited on the one or more gold layers.

[0207] Example PVD conditions include a pressure in the range of 2-250 mTorr, 70-100 mTorr, or 50-125 mTorr, a power in the range of 10 W-100 kW (e.g., 0.5 kW-2 kW, e.g., 0.8 kW), and a thickness of each of the metal layers 2300a, 2300b of at least 100 angstroms (e.g., 1000-9000 Å). The PVD step may include the pressure control steps described herein.

[0208] Block 2202 represents depositing a first or base layer 116 on the one or more sputtered metal layers 2300a, 2300b formed in block 2200. Example base layers include, but are not limited to, polymer layers (such as, but not limited to, polyimide forming a first or base polyimide layer). In one or more embodiments, the step includes spin casting a polymer (e.g., polyimide) onto the one or more metal layers 2300a, 2300b, and then pre-curing the polymer (e.g., polyimide).

[0209] Block 2204 represents optionally patterning and / or etching the base layer 116 to deposit one or more electrodes (e.g., WE and RE) and / or one or more contact pads 114. In one or more examples, patterning includes: depositing a dry etch mask (e.g., a photoresist dry etch mask) on the base layer 116; dry etching the base layer 116 through the openings in the dry etch mask and stripping the dry etch mask from the base layer 116 to form an etch pattern (including the first opening) in the base layer 116.

[0210] Box 2206 represents depositing a metal 112 (second metal) containing CE onto the etched pattern. Examples of metal 112 include, but are not limited to, Au, Ti, and Cr, and combinations thereof (e.g., Au and Ti and / or Cr). In one or more examples, the steps include: sputtering or electron beam depositing the metal 112 onto the base layer 116 containing the etched pattern; depositing a mask (e.g., a photoresist wet etching mask) on the metal 112 deposited onto the base layer 116; etching (e.g., wet etching) the metal through the openings in the mask; and stripping the mask from the metal 112.

[0211] Block 2208 represents depositing an insulating layer 104a (first insulating layer) on the base layer 116 and depositing metal 112 on the base layer 116. Example insulating layers include, but are not limited to, polymer layers (such as, but not limited to, polyimide forming the first insulating polyimide layer). In one or more examples, the insulating layer 104a is blanket deposited on the metal 112. In one or more additional examples, the depositing includes: spin casting the insulating layer 104a to cover the base layer 116 and the metal 112; and pre-curing the insulating layer 104a.

[0212] Box 2210 represents depositing and patterning metal 108 (third metal) on the first insulating layer 104a. Examples of metals include Au, Ti, and Cr, and combinations thereof (e.g., Au and Ti and / or Cr). In one or more examples, the steps include: sputtering / electron beam depositing a film (e.g., thin film) of metal 108 onto the first insulating layer 104a to blanket cover the first insulating layer 104a; depositing a mask (e.g., a photoresist wet etch mask) on the metal sputtered onto the first insulating layer 104a; etching (e.g., wet etching) the metal through the openings in the mask; and stripping the mask from the metal 108.

[0213] Block 2212 represents depositing a second insulating layer 118 on the first insulating layer 104a and depositing a metal 108 on the first insulating layer 104a. Example second insulating layers include, but are not limited to, polymer layers (such as, but not limited to, polyimide forming a second insulating polyimide layer). In one or more examples, the steps include: spin casting the second insulating layer 118 onto the first insulating layer 104a and spin casting the metal 108 onto the first insulating layer 104a; and pre-curing the second insulating layer 118.

[0214] Block 2214 represents patterning the second insulating layer 118 , for example using photolithography, and forming an etch pattern in the second insulating layer 118 including a second well or second opening 2304 and a third well or third opening 2306 .

[0215] Block 2216 represents optionally performing a final cure of the structure formed in blocks 2200 - 2214 .

[0216] Block 2218 represents optionally removing residue from the second insulating layer 118, for example using O2.

[0217] Box 2220 represents the deposition of the metal (fourth metal) and other layers required to form the WE. In one or more embodiments, the steps include: depositing a metal pillar 124 into a second well / opening 2304 formed in the second insulating layer 118. Examples of metal pillars include, but are not limited to, platinum or gold pillars. In one or more embodiments, the steps include: depositing a photoresist stripping mask in the first well 2304; performing a clean (e.g., O2 plasma descumming) of the photoresist stripping mask; sputtering metal into the opening of the mask to form a metal pillar 124 extending from the exposed surface of the metal 108 in the first well 2304 through the opening; and stripping / removing the mask so that the pillar 124 remains on the metal 108.

[0218] Block 2222 represents depositing a metal (fifth metal) into the third well / opening 2306 to form a reference electrode (RE) in the third well or third opening 2306. Examples of deposition methods include, but are not limited to, depositing the metal using electroplating or screen printing. Example metals for RE include, but are not limited to, Pt, gold, and Cr.

[0219] Block 2224 represents performing a chemical step in which additional chemically active layers / components are deposited on the WE (e.g., onto a post) such that the WE has proper functionality in a glucose sensor. Example components include, but are not limited to, one or more of an interference suppression component, an analyte sensing component 410, a protein component 416, an adhesion promoting layer 414, and an analyte modulating layer 412 and / or a cover layer as described herein.

[0220] Block 2226 represents processing the structure into individual sensors 100, such as by cutting or laser patterning.

[0221] Block 2228 represents separating or removing (e.g., peeling) the individual analyte sensors 100a-d from the substrate 2302. In one or more embodiments, the PVD methods described herein involve adhesion control that enables separation of the flexure or sensor 100a-d from the substrate 2302 (e.g., glass) without damaging the CE and contact pads 110, 114. In one or more embodiments, the steps include removing (e.g., peeling) the physical vapor deposited metal 2300a, 2300b from the (e.g., rigid) substrate 2002.

[0222] Box 2230 represents the final result, such as Figures 1A-1D Analyte sensor devices 100a-d, such as glucose sensors, are shown in FIG. Figures 1A-1D Various double-sided single flexible sensor embodiments are shown that accommodate multiple electrodes and include electrodes on both sides of a sensor flexure 100a-d, and wherein the components of the sensors 100a-d are flexible to form a flexible sensor (sensor flexure). The flexure or sensor 100a-100d includes a WE and RE on the top side of the flexure or sensor and a CE on the back side of the flexure or sensor. In one or more embodiments, a smooth CE is formed on the back side 102b and has sufficient surface area to balance the electrochemical reaction occurring at the WE. However, in one or more instances, a chemical reaction is not required to occur on the back side 102b of the flexure or sensor 100a-d. Additional electrodes (not shown) for background sensors or differential sensors, etc. may also be included and may be connected to the transmitter connection scheme. The devices 100a-d may be used Figure 3 in the voltage regulator circuit.

[0223] In one or more examples, the fabrication methods described herein can increase the working electrode area, prevent "drift" effects, and / or simplify the fabrication process.

[0224] Study of the process parameters has revealed excellent process control, design control and repeatability. The process is a high throughput process and is easily transferable between plates and 8" wafers.

[0225] Example 7: Methods of depositing films and controlling adhesion

[0226] Fig.24 The invention is a flow chart showing a method for depositing a film on a substrate. The method comprises the following steps.

[0227] Block 2400 represents controlling gas pressure in a chamber for depositing metal using physical vapor deposition (PVD). In one or more examples, the steps further include controlling at least one additional PVD parameter selected from the group consisting of: thickness of metal, number of layers of metal, and power used during physical vapor deposition.

[0228] Block 2402 represents depositing a metal on a substrate using physical vapor deposition (PVD).

[0229] Block 2404 represents depositing a film on the metal.

[0230] Block 2406 represents measuring the degree of adhesion of the film to the substrate as a function of at least one PVD parameter, including pressure. In one or more embodiments, measuring includes assigning an adhesion score.

[0231] Example PVD conditions include a pressure in the range of 2-250 mTorr, 70-100 mTorr, or 50-125 mTorr, a power in the range of 10 W-100 kW (e.g., 0.5 kW-2 kW, e.g., 0.8 kW), and a thickness of each of the metal layers in the range of at least 100 Angstroms (e.g., 1000-9000 Å).

[0232] Box 2408 represents optionally determining the pressure or other PVD parameters that achieve the desired adhesion of the film to the substrate. In one or more instances, the steps include: analyzing the degree of adhesion as a function of at least one physical vapor deposition parameter to determine the relative effect of at least one physical vapor deposition parameter on the degree of adhesion. In one or more instances, the analysis includes performing a design of experiments (DOE) analysis; and plotting the degree of adhesion as a response in a Pareto chart. The adhesion score and determination / analysis steps of box 2408 can be performed in a processor or computer using a computer readable program code having instructions that, when executed, cause the processor or computer to perform a statistical analysis on the measurements obtained in box 2406 to determine the PVD parameters that achieve the desired adhesion.

[0233] Example 8: Method of manufacturing a device

[0234] Fig.25 The invention is a flow chart showing a method of depositing a film or manufacturing a device on a substrate. The method comprises the following steps.

[0235] Block 2500 represents placing a substrate (eg, a rigid substrate) into a physical vapor deposition (PVD) (eg, sputtering) chamber.

[0236] Block 2502 represents setting PVD conditions, including gas pressure in a chamber for depositing a material using PVD. In one or more examples, the pressure is determined using the method described in Example 7.

[0237] Block 2504 represents depositing a PVD metal on the substrate using physical vapor deposition under pressure.

[0238] In one or more embodiments, the metal comprises a plurality of layers, each of the plurality of layers being deposited at a different pressure.

[0239] In one or more embodiments, the PVD comprises sputtering or electron beam deposition, comprising ionizing the gas to form ionized gas particles; and accelerating the ionized gas particles onto a target comprising the metal using an electric field and / or a magnetic field, the power of the electric field and / or the magnetic field being in the range of, for example, 10 watts to 100 kW (e.g., 0.5 kilowatts to 2 kilowatts). In one or more instances, the gas pressure is in the range of 2-250 mTorr, 70-100 mTorr, or 50-125 mTorr. In one or more embodiments, the PVD metal comprises one or more layers, each of which is in the range of at least 100 angstroms (e.g., 1000-9000 Å) in thickness. In one or more instances, the PVD metal comprises a first layer and a second layer, the first layer being deposited on the substrate at a pressure in the range of 50-250 mTorr (or 5-150 mTorr), and the second layer being deposited on the first layer at a pressure in the range of 2-50 mTorr or 2-30 mTorr).

[0240] In one or more embodiments, the PVD deposited metal comprises at least one structured layer selected from the group consisting of: a patterned layer, a roughened layer, a non-uniform layer, a layer comprising voids, and a layer comprising pillars.

[0241] Block 2506 represents depositing a film or device structure on the metal, such as described in Examples 4 and 6. The pressure selected in block 2602 can be associated with a predetermined adhesion of the film to the substrate that allows: (1) processing the film into a device when the film is adhered to the substrate; and (2) removing (e.g., peeling) the device from the substrate.

[0242] Block 2508 represents optionally processing the film into one or more devices. In one or more examples, the processing includes patterning the film or cutting the film.

[0243] Block 2510 represents optionally peeling or removing the device from the substrate.

[0244] Box 2512 represents the final result, for example, Figures 1A-1D In one or more embodiments, the device includes an exposed surface S of a PVD metal 2302a, 2302b, 2002a, 2002b peeled / removed from a rigid substrate 2000, 2302. Example devices include, but are not limited to, devices including: a micro-electromechanical (MEMS) device structure, an optoelectronic device structure, a circuit, a battery electrode, a fuel cell electrode, or an electrode CE having an electrochemically active surface 122. Microarrays and multi-electrode arrays can be manufactured.

[0245] As shown herein, investigation of the process parameters has revealed excellent process control, design control and repeatability. The process is a high throughput process and is easily transferable between plate and 8" wafer.

[0246] In one or more examples, the spacing D, arrangement or configuration of the working electrode WE and the counter electrode CE in the analyte sensor devices 100a-100e is such that in response to a constant analyte concentration, the current (ISIG) varies by less than 15% over a period of 31 days and / or the chemical products generated by the reaction of the working electrode and the counter electrode do not interfere with the performance of the electrodes or the counter electrode (WE, CE) to produce deleterious interactions (see Figures 21D-21F ).

[0247] In one or more examples, in a set of at least 36 sensors 100a-100e manufactured using the methods described herein, the spacing D, arrangement, configuration, and electrical activity of the working electrode WE and the counter electrode CE in each of the sensors 100a-100e are such that the current (ISIG) output by each of the sensors in response to the same analyte concentration is within 15% (see Figures 21D-21F ).

[0248] In one or more embodiments, the PVD apparatus is coupled to a processor or computer using a computer readable program code having instructions that, when executed, cause the processor or computer to control PVD deposition parameters in the PVD apparatus to achieve desired adhesion of the film to the substrate.

[0249] It should be understood that the present invention is not limited to the specific embodiments described, because the embodiments can certainly vary. It should also be understood that the special words used herein are only for the purpose of describing specific embodiments, and are not intended to be restrictive, because the scope of the present invention is limited only by the appended claims. In the description of the preferred embodiments, reference is made to the accompanying drawings that form a part of the description, and in the accompanying drawings, specific embodiments that can practice the present invention are shown by way of illustration. It should be understood that other embodiments can be utilized and structural changes can be made without departing from the scope of the present invention.

[0250] However, although indicating some embodiments of the present invention, the description and specific examples are given by way of illustration and not limitation.Many changes and modifications may be made within the scope of the present invention without departing from its spirit, and the present invention includes all such modifications.

Claims

1. An analyte sensor device comprising: one or more sensors, each sensor comprising a sensing portion and a connecting portion, the connecting portion comprising at least one of a first contact pad or a second contact pad on the insulating layer; The sensing part comprises: a working electrode disposed on the first side of the insulating layer and electrically connected to the first contact pad, the working electrode comprising a metal composition having an electroactive surface; a counter electrode located on a second side of the insulating layer opposite the first side and electrically connected to the second contact pad, wherein the insulating layer is located between the counter electrode and the working electrode; an analyte sensing layer disposed on the working electrode, wherein the analyte sensing layer detectably changes a current at the working electrode in the presence of an analyte; and wherein: The sensing portion has a thickness that can be inserted into the sleeve, and the sensor is flexible so as to allow a fold to be formed between the sensing portion and the connecting portion; The counter electrode includes a second metal composition having adhesion that enables the second metal composition to be released from direct contact with the substrate to remove the one or more sensors from the substrate on which the one or more sensors are fabricated.

2. The apparatus according to claim 1, further comprising: The second metal composition includes a surface exposed after stripping from the substrate; a sensing portion in the casing; The connecting part is mounted on the bottom plate; said folding; a reference electrode located on the first side of the insulating layer; Insulation, the insulation being located between the reference electrode and the working electrode; a first contact metal, the first contact metal electrically contacting the working electrode, the first contact metal comprising the first contact pad; a second contact metal, the second contact metal electrically contacting the counter electrode, the second contact metal comprising the second contact pad; and wherein: The insulating layer and the insulation include polyimide, and The working electrode, the counter electrode, the insulating layer, the insulation, and the analyte sensing layer are flexible.

3. The device of claim 1, wherein the one or more sensors each comprise a glucose sensor, and the second metal composition comprises at least one structured layer selected from the group consisting of a patterned layer, a roughened layer, a non-uniform layer, a layer comprising voids, and a layer comprising pillars, the at least one structured layer controlling adhesion to the substrate.

4. The apparatus of claim 1 , wherein the working electrode and the counter electrode are spaced such that in response to a constant concentration of the analyte: The current varies by less than 15% over a 31 day period, and / or The chemical products produced by the reaction at each of the working electrode and the counter electrode do not interfere with or deleteriously interact with the performance of the working electrode or the counter electrode.

5. According to the device according to claim 1, at least 36 sensors form a group, wherein the spacing and electrical activity of the working electrode and the counter electrode of each sensor in the sensors are such that in response to the same concentration of the analyte, the current output by each sensor in the sensors is within 15%.

6. The device according to claim 1, wherein: The first contact pad and the second contact pad are located on the same side of the one or more sensors so as to face the same direction to be electrically connected to a monitor, the substrate comprises glass, and the metal composition is peeled off from the glass.

7. The device of claim 1, the device being located on the substrate, the device further comprising a base layer attached to the counter electrode and a physical vapor deposition metal layer formed in direct contact between the counter electrode and the substrate.

8. The apparatus of claim 1, wherein the adhesion force is determined by adjusting a pressure at which the second metal composition is deposited on a substrate.

9. An analyte sensor device comprising: A sensor cut from a film on a rigid substrate, the sensor comprising: a working electrode disposed on the first side of the insulating layer, the working electrode comprising a metal composition having an electroactive surface; a counter electrode located on a second side of the insulating layer opposite the first side, wherein the insulating layer is located between the counter electrode and a working electrode; and an analyte sensing layer, the analyte sensing layer being located on the working electrode, wherein: The analyte sensing layer detectably changes the current at the working electrode in the presence of an analyte; The counter electrode comprises a first physical vapor deposited metal having an exposed surface removed from direct contact with the rigid substrate, or The sensor further includes a base layer attached to the counter electrode, the base layer and the counter electrode having exposed surfaces formed by peeling the base layer and the counter electrode from the second physical vapor deposited metal on the rigid substrate.

10. The apparatus of claim 9, wherein the PVD metal comprises at least one structured layer selected from the group consisting of a patterned layer, a roughened layer, a non-uniform layer, and a layer containing voids, and wherein the at least one structured layer facilitates removal of the PVD metal from a rigid substrate or facilitates peeling of the PVD metal from the rigid substrate.

11. The apparatus of claim 9, wherein the PVD metal comprises pillars, the rigid substrate comprises glass, and the PVD metal is removed from the glass.

12. The device of claim 9, wherein the sensor comprises a sensing portion comprising the working electrode, the counter electrode, and the analyte sensing layer, wherein: After removal from the rigid substrate, the counter electrode comprising a physical vapor deposited metal is exposed over the entire back side of the sensing portion, or The back side consists essentially of the exposed surface of the counter electrode.

13. The apparatus according to claim 9, further comprising: Physical vapor deposition of metals; The insulating layer comprises a first polyimide insulating layer; a second metal disposed on the first polyimide insulating layer; a second insulating polyimide layer located on the first polyimide insulating layer and the second metal; a first opening and a second opening in the second insulating polyimide layer; a third metal located in the first opening and comprising the working electrode; and A fourth metal is located in the second opening and includes a reference electrode (RE).

14. A method of manufacturing an analyte sensor, the method comprising: A film comprising an analyte sensor is deposited on a rigid substrate, the analyte sensor comprising: a working electrode disposed on the first side of the insulating layer, the working electrode comprising a metal composition having an electroactive surface; an analyte sensing layer on the working electrode, wherein the analyte sensing layer detectably changes the current at the working electrode in the presence of an analyte; and a counter electrode located on a second side of the insulating layer opposite the first side, wherein the insulating layer is located between the counter electrode and a working electrode; and After cutting the sensor from the film, removing the sensor from the rigid substrate, wherein: The counter electrode comprises a first physical vapor deposited metal having an exposed surface removed from direct contact with the rigid substrate, or The analyte sensor also includes a base layer attached to the counter electrode, the base layer and the counter electrode having exposed surfaces formed by peeling the base layer and the counter electrode from a second physical vapor deposited metal on the rigid substrate.

15. The method according to claim 14, further comprising: placing the rigid substrate in a physical vapor deposition (PVD) chamber; setting the gas pressure in the chamber; depositing the first physical vapor deposition metal or the second physical vapor deposition metal on the rigid substrate using physical vapor deposition under the pressure; depositing an analyte sensor comprising a first physical vapor deposited metal, or depositing the analyte sensor on the second physical vapor deposited metal, wherein the pressure is associated with a predetermined adhesion of the analyte sensor to the rigid substrate, the predetermined adhesion allowing: defining the analyte sensor when the analyte sensor is adhered to the rigid substrate; and The analyte sensor is removed from the rigid substrate.

16. The method of claim 14, wherein the first physical vapor deposited metal or the second physical vapor deposited metal comprises at least one structured layer selected from the group consisting of a patterned layer, a roughened layer, a non-uniform layer, and a layer containing voids.

17. The method of claim 14, wherein the first PVD metal or the second PVD metal comprises a pillar.

18. The method of claim 15, wherein: The first physical vapor deposition metal includes a second layer located on the first layer, the first layer being located between the second layer and the insulating layer; The first layer is deposited at the pressure comprising a first pressure, and The second layer is deposited at the pressure comprising a second pressure lower than the first pressure.

19. The method of claim 14, wherein the physical vapor deposition is at a pressure in the range of 2-250 mTorr.

20. The method of claim 19, wherein the first PVD metal or the second PVD metal has a thickness of at least 100 angstroms.

21. The method of claim 20, wherein the physical vapor deposition comprises: ionizing the gas to form ionized gas particles; as well as The ionized gas particles are accelerated onto a target comprising the physical vapor deposition metal using an electric field and / or a magnetic field having a power in the range of 10 watts to 100 kilowatts.

22. The method of claim 14, wherein forming the analyte sensor further comprises: depositing the insulating layer including a first polyimide insulating layer on the physical vapor deposited metal; depositing a second metal on the first polyimide insulating layer and patterning the second metal; depositing a second insulating polyimide layer on the first polyimide insulating layer, and depositing the second metal on the first polyimide insulating layer; forming a first opening and a second opening in the second insulating polyimide layer; depositing a third metal into the first opening to form a working electrode; depositing a fourth metal into the second opening to form a reference electrode (RE); The analyte sensor is defined to include: the first physical vapor deposited metal, the first polyimide insulating layer, the second insulating polyimide layer, the working electrode and the reference electrode; as well as The analyte sensor is removed from the rigid substrate, wherein the counter electrode comprises the first physical vapor deposited metal.

23. The method of claim 14, wherein the depositing further comprises: depositing a base layer comprising polyimide on the second physical vapor deposition metal on the rigid substrate; patterning a first opening in the base layer; depositing a second metal in the first opening to form the counter electrode; depositing the insulating layer including a first polyimide insulating layer on the base layer and the counter electrode; depositing a third metal on the first polyimide insulating layer and patterning the third metal; depositing a second insulating polyimide layer on the first polyimide insulating layer, and depositing the third metal on the first polyimide insulating layer; forming a second opening and a third opening in the second insulating polyimide layer; curing the base layer, the first polyimide insulating layer and the second insulating polyimide layer; depositing a fourth metal into the second opening to form a working electrode; depositing a fifth metal into the third opening to form a reference electrode (RE); defining the analyte sensor in the membrane, the membrane comprising: the substrate layer, the first insulating polyimide layer, the second insulating polyimide layer, and the working electrode, the counter electrode, and the reference electrode; as well as The analyte sensor is removed from the rigid substrate.

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