Method for controlling adhesion of physical vapor deposited metal films to substrates and surfaces

Abstract

A method of depositing a film on a substrate with controlled adhesion. The method includes depositing the film comprising a metal, wherein the metal is deposited on the substrate using physical vapor deposition at a pressure at which a predetermined adhesion of the film to the substrate is achieved. The predetermined adhesion allows the film to be processed into a device while adhered to the substrate, but also allows the device to be removed from the substrate.

Description

[0001] This application is a divisional application of the invention patent application with application number 201980011190.8, application date February 6, 2019, entitled "Method for controlling the adhesion of physical vapor deposition metal film to substrate and surface".

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Patent Application Serial No. 15 / 892,172, filed February 8, 2018, pursuant to Section 120, the contents of which are incorporated herein by reference. Technical Field

[0004] The present invention relates to a method for controlling the adhesion force of a film deposited on a substrate, and an apparatus manufactured using the method. Background Technology

[0005] Electrochemical sensors are commonly used to detect or measure the concentration of analytes in vivo, such as glucose. Typically, in such analyte sensing systems, the analyte (or a substance derived from it) is electroactive and generates a detectable signal at an electrode in the sensor. This signal is then correlated with the presence or concentration of the analyte within the biological sample. In some conventional sensors, an enzyme that reacts with the analyte is provided, and the byproducts of this reaction are qualitatively or quantitatively determined at the electrode. In a conventional glucose sensor, an immobilized glucose oxidase catalyzes the oxidation of glucose to form hydrogen peroxide, which is then quantified by amperometric measurement (e.g., current change) through one or more electrodes.

[0006] Various electrochemical glucose sensors are multilayered, comprising electrodes situated on and / or covered by layers of various materials. Multilayer sensors possess many desirable characteristics, including the fact that the functional characteristics of such sensors can be customized by changing certain design parameters (e.g., the number of internal layers, layer thickness, electrode area, and architecture). However, the inventors of this invention have discovered that undesirable interactions between the anode and cathode 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. This disclosure addresses this need. Summary of the Invention

[0007] This disclosure reports the development of a technique for controlling the adhesion of metal films via a physical vapor deposition (PVD) process. Various PVD parameters were evaluated using multiple designs of experiments (DOE). Unexpectedly and surprisingly, it was found that pressure has the largest and most significant effect on adhesion, and that the process achieved different levels of adhesion by controlling and varying the pressure during PVD.

[0008] In one illustrative embodiment, a method of depositing a film on a substrate includes: placing the substrate in a PVD chamber; setting a gas pressure in the chamber; depositing a metal on the substrate using PVD at the pressure; and depositing a film on the metal. The pressure is associated with a predetermined adhesion force of the film to the substrate, which allows the film to be processed (e.g., cut) into one or more devices as the film adheres to and is removed from the substrate. In one or more examples, the pressure is in the range of 2-250 millitors (mTorr), the PVD power is in the range of 10 W kW to 100 kW, and the metal comprises a layer with a thickness of at least 100 Å (e.g., in the range of 600-1500 Å). In one or more embodiments, the metal comprises a plurality of layers, each deposited at a different pressure (e.g., a first layer deposited on the substrate at a pressure ranging from 50-250 mTorr, and a second layer deposited on the first layer at a pressure ranging from 2-50 mTorr).

[0009] This disclosure further reports how the deposition of rough or columnar structures in a metal film can reduce surface area contact with the substrate / surface in a highly controllable manner, and how it helps control adhesion forces when the deposition pressure is modulated. Thus, in one or more instances, the metal is at least one structured layer selected from: patterned layers, roughened layers, non-uniform layers, void-containing layers, and pillar-containing layers.

[0010] In one instance, pressure-modulated PVD deposition was used to fabricate a back-side counter electrode (BCE) for a glucose sensor, where the metal adhered to the glass substrate strongly enough to survive processing and laser cutting, but weak enough to allow for easy physical removal from the glass substrate for assembly processes.

[0011] This document also illustrates a PVD process for manufacturing electrodes and placing said electrodes on the top and back sides of a sensor flexibility. Conventional methods place electrodes only on the top side of the sensor flexibility. Therefore, embodiments of the present invention eliminate the need for multiple sensor flexibilityes in a single device. In one example, the counter electrode is placed on the back side of the flexibility, while the working electrode remains on the top side of the sensor flexibility. Example electrode surface metals of 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.

[0012] More typically, the applications of the adhesion control methods described herein include device manufacturing, where adhesion is a key factor in specific processes such as the fabrication or processing of flexible circuit arrays, microelectromechanical (MEMS) devices, semiconductor devices, and biomedical electrodes (nerve, cardiac, glucose, and lactate electrodes, etc.).

[0013] Other objects, features, and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. However, it should be understood that while some embodiments of the invention are indicated, the detailed description and specific examples are given by way of illustration rather than limitation. Many changes and modifications can be made within the scope of the invention without departing from its spirit, and the invention encompasses all such modifications. Attached Figure Description

[0014] Figure 1A-1D An ampere-type sensor having WE and CE on opposite sides is shown according to one or more embodiments.

[0015] Figure 1E An ampere-type sensor is shown that has WE and CE on the same side of the device, but spaced at least 1 micrometer-inch apart, according to one or more embodiments of the invention.

[0016] Figure 1F and Figure 1G A control sensor having an interdigitated working electrode and a counter electrode, and a reference electrode, according to one or more embodiments of the present invention, was compared. Figure 1F The structure includes a working electrode, a counter electrode, and a reference electrode located only on one side and close enough to exhibit undesirable electrode properties, wherein the sensor includes electrodes on opposite sides. Figure 1G ).

[0017] Figure 1H Several planar layered elements used in ampere-type sensors are shown.

[0018] Figure 2 A perspective view is provided illustrating a type of hypodermal sensor insertion kit, telemetry characteristic monitor transmitter device, and data receiving device and components that can be used with embodiments of the present invention.

[0019] Figure 3 A schematic diagram of a voltage regulator that can be used for measuring current in embodiments of the present invention is shown. Figure 3As shown, the regulator 300 may include an operational amplifier 310 connected in the circuit to have two inputs: Vset and Vmeasured. As shown, Vmeasured is a 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 producing a current measurement result (isig) from the regulator output.

[0020] Figure 4 An apparatus for depositing materials using sputtering, according to one or more embodiments of the present invention, is shown.

[0021] Figure 5 Test samples comprising layer stacks on a glass substrate are shown according to one or more embodiments of the present invention.

[0022] Figure 6A The illustration shows different patterns of marking and cutting types, such as knife scratches or laser cutting marks, applied to a layer stack on a glass substrate according to one or more embodiments of the present invention, which can be applied during electrode fabrication in a glucose sensor.

[0023] Figure 6B Patterns of silver layers applied to glass substrates are shown, illustrating that the adhesion of silver to glass is too weak to allow the markings on the silver layer to be replicated.

[0024] Figures 7A-7D Different adhesion scores are shown for samples manufactured under different sputtering conditions according to one or more embodiments of the present invention.

[0025] Figure 8A The test sample without gold pillars was shown, and Figure 8B Test samples with gold pillars according to one or more embodiments of the present invention are shown.

[0026] Figure 9 This is a scanning electron microscope (SEM) image of the columnar interface between a glass substrate and a gold layer according to one or more embodiments of the present invention.

[0027] Figure 10A-10D Films are shown on test samples manufactured using various sputtering conditions and after laser cutting with example electrode patterns, according to one or more embodiments of the present invention.

[0028] Figure 11 Pareto plots illustrating the normalized effects of varying pressure, power, and gold thickness on the adhesion of samples manufactured using gold pillars located at the interface between the gold layer and the glass substrate, according to one or more embodiments of the present invention.

[0029] Figure 12 This is a graph showing how the average rate varies with pressure, power, and gold thickness according to one or more embodiments of the present invention.

[0030] Figure 13 It is a contour plot of rate versus gold layer thickness and pressure according to one or more embodiments of the present invention.

[0031] Figure 14 Another test sample comprising a layer stack on a glass substrate according to one or more embodiments of the present invention is shown.

[0032] Figure 15A This invention demonstrates gold layers deposited under sputtering conditions of 100 mTorr pressure, 1.5 kW power, and 5 minutes duration, according to one or more embodiments of the invention. Figure 6A The membrane on the test sample.

[0033] Figure 15B The illustration shows a first gold layer deposited using sputtering conditions of 100 mTorr pressure, 1.5 kW power, and 5 minutes duration, and a second gold layer deposited using sputtering conditions of 4 mTorr pressure, 0.2 kW power, and 10 minutes duration, according to one or more embodiments of the present invention. Figure 14 The membrane on the test sample.

[0034] Figure 15C , 15D And 15E demonstrates having two gold layers and using Figure 15B Deposition under certain conditions Figure 14 The adhesion of the film on the test sample varies depending on the location on the surface area.

[0035] Figure 16 Pareto plots are shown illustrating the normalized effects of varying pressure, power, and gold thickness on sputtering rate according to one or more embodiments of the present invention.

[0036] Figure 17 This is a graph showing how the average sputtering rate varies with pressure, power, and gold thickness according to one or more embodiments of the present invention.

[0037] Figure 18 This is a contour plot of sputtering rate versus sputtering power (kW) and pressure (mTorr) according to one or more embodiments of the present invention.

[0038] Figure 19 This is a flowchart illustrating a method for manufacturing a sensor or sensor flexible element according to one or more embodiments of the present invention.

[0039] Figure 20An example of a back-side counter electrode sensor fabricated using the PVD method described herein is demonstrated.

[0040] Figures 21A-21C Demonstrates control sensor ( Figure 1F The SITS results of sensor 130 shown in the figure are as follows: Figure 21A and 21B The change in current (ISIG) over time (dates in May) was plotted, and Figure 21C The Vcounter was plotted as a function of time (dates in May), and... Figures 21A-21C The different traces in the diagram represent the results from different sensors.

[0041] Figure 21D-21F One or more embodiments of the present invention are shown. Figure 1G SITS results of the sensor (representing Figure 1D (The performance of the sensor), where Figure Figure 21D and 21E The plot shows how ISIG changes over time (dates in May), and Figure 21F The change of Vcounter (voltage on the counter electrode) over time (dates in May) was plotted. Figure 21D-21F The different traces in the diagram represent results from different sensors, and it shows that the smooth backside CE design is capable of supporting sensor functionality, and importantly, with... Figure 1F Compared to sensors, for Figure 1D The sensor reduces sensor-to-sensor performance variability and improves performance stability over the lifetime of the test.

[0042] Figure 22 This is a flowchart illustrating a method for manufacturing a sensor or sensor flexible element according to one or more embodiments of the present invention.

[0043] Figure 23 This demonstrates the use of one or more embodiments of the present invention. Figure 22 The flowchart is a schematic diagram of a method for manufacturing a sensor or a sensor flexible component.

[0044] Figure 24 This is a flowchart illustrating a method for depositing a film on a substrate according to one or more embodiments of the present invention.

[0045] Figure 25 This is a flowchart illustrating a method for fabricating an apparatus on a substrate according to one or more embodiments of the present invention. Detailed Implementation

[0046] Unless otherwise defined, all technical terms, symbols, and other scientific terms or proprietary terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains. In some instances, for clarity and / or ease of reference, terms may be defined herein in the sense of their commonly understood meaning, and the inclusion of such definitions herein should not necessarily be construed as indicating a material difference from their commonly understood meaning 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.

[0047] All numbers listed in the specification and related claims that refer to values ​​that can be numerically characterized by values ​​other than integers (e.g., thickness) should be understood to be modified by the term "about". Where a range of values ​​is provided, it should be understood that every intermediate value between the upper and lower limits of the range (unless the context explicitly states otherwise, one-tenth of the unit to the lower limit) and any other stated values ​​or intermediate values ​​within the range are covered within the invention. The upper and lower limits of these smaller ranges may be independently included in smaller ranges and also covered within the invention, subject to any explicitly excluded limits within the stated ranges. Where a stated range includes one or both limits, the range excluding any one or both of those included limits is also included within the invention. Furthermore, all publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials used in conjunction with the cited publications. The publications cited herein are referenced for their disclosure prior to the filing date of this application. Nothing herein shall be construed as an admission that the inventor has no right to advance the publication date by virtue of an earlier priority date or priority invention date. Furthermore, the actual publication date may differ from the date shown and requires independent verification.

[0048] As discussed in detail below, embodiments of the present invention relate to the use of electrochemical sensors for measuring the concentration of an analyte of interest or indicating the concentration of an analyte in a fluid or the concentration of a substance present. In some embodiments, the sensor is a continuous device, such as a subcutaneous, percutaneous, 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 indicating the concentration of an analyte of interest. Typically, sensors are of the type that sense the product or reactant of an enzymatic reaction between an analyte and an enzyme in the presence of oxygen to serve as a measure of the analyte in vivo or in vitro. Such sensors typically include a membrane surrounding the enzyme through which the analyte migrates. The product is then measured using an electrochemical method, and thus the output of the electrode system serves as a measure of the analyte.

[0049] The embodiments of the invention disclosed herein provide, for example, sensor types 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 utilize some form of immobilized enzyme to achieve their biological specificity. The embodiments of the present invention described herein can be adapted and implemented using a variety of known electrochemical sensor elements, including, for example, those disclosed in the following documents: U.S. Patent Applications Nos. 20050115832, 20050008671, 20070227907, 20400025238, 20110319734, 20110152654 and 13 / 707,400, filed December 6, 2012; U.S. Patents Nos. 6,001,067, 6,702,857, 6,212,416, 6,119,028, and 6,400. Nos. 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 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.

[0050] A. Illustrative embodiments and related features of the present invention

[0051] Controllable adhesion of physical vapor deposition (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 typically need to maintain very specific levels of adhesion to the surface / substrate to which they are deposited. In some cases, strong adhesion is required, while in others, weak adhesion is necessary. In the most challenging cases, a hybrid of weak and strong adhesion is required, where the adhesion is strong enough to overcome specific aspects of the application, but weak enough to allow other aspects of the application to function properly.

[0052] As shown herein, this disclosure describes an efficient method for adjusting and controlling the adhesion of PVD films deposited on surfaces / substrates. A comprehensive series of studies evaluating PVD deposition factors and their effects on adhesion properties were performed, and it was found that pressure is a key significant factor in adjusting adhesion. This single factor is a critical 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 used for depositing thin or thick films.

[0053] From a device perspective, it is of particular interest to use pressure modulation to control adhesion forces, which enables the fabrication and production of devices in which PVD layers are deposited in direct contact with a carrier substrate and can be released based on the adhesion force. Figure 1A Examples of devices for diabetes applications are shown, such as, but not limited to, continuous glucose monitoring (CGM) sensors in which electrodes are located on both sides (top and back sides) of a single sensor flexibility. As demonstrated herein, pressure modulation provides an efficient method to adjust the adhesion of the back-side electrode to the carrier substrate, enabling release at specific points throughout the downstream manufacturing process. Placing the contact pads of each electrode on either side of the sensor flexibility allows for a wider range of interconnection array schemes to the transmitter. Moreover, adjusting the adhesion can be used to minimize additional processing steps for the back-side electrode. Overall, the adhesion control demonstrated herein can be used to significantly reduce manufacturing complexity compared to conventional sensors.

[0054] Importantly, the novel methods for controlling adhesion described herein can be implemented using standard materials, equipment, and facilities associated with PVD.

[0055] Methods for forming an analyte sensor including electrodes disclosed herein may comprise multiple steps. For example, such methods may include forming a working electrode, a counter electrode, and a reference electrode on a substrate and / or forming a plurality of contact pads and / or a plurality of electrical conduits on the substrate. In some embodiments of the invention, the method includes forming a plurality of working electrodes, counter electrodes, and reference electrodes clustered together in units consisting substantially of one working electrode, one counter electrode, and one reference electrode. The electrodes are formed on the substrate, and these clustered units are longitudinally distributed in a repeating pattern on at least one longitudinal arm of the substrate. Optionally, in such methods, the working electrode is formed as an array of conductive members disposed on the 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 alters the current on the working electrode. Typically, these methods also include forming an analyte modulation layer on the analyte sensing layer, wherein the analyte modulation layer modulates the diffusion of the analyte through it.

[0056] Another embodiment of the invention is an analyte sensor device comprising a substrate including a trap housing a metal electrode composition formed using the sputtering process disclosed herein. In such embodiments, the platinum composition is structured 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 less than the average thickness of the metal composition in the central planar region by 2X. In some embodiments of the invention, the trap includes a lip surrounding the trap; and the edge region of the metal composition is located below the lip of the trap. Typically, in these embodiments, both central planar regions form the electroactive surface of the working electrode in the sensor. Sensor embodiments of the invention typically include an additional layer of material coated on the working electrode, such as an analyte sensing layer disposed on the working electrode that detectably alters the current at the working electrode in the presence of an analyte; and an analyte modulation layer disposed above the analyte sensing layer that modulates the diffusion of the analyte through it.

[0057] In a typical embodiment of the invention, electrodes are formed in wells within a substrate comprising a dielectric material (e.g., polyimide). Typically, the well contains a conductive material (e.g., Au) disposed at the bottom of the well. Optionally, the wells in the substrate are rectangular or circular. In some embodiments of the invention, the substrate comprises at least 10, 20, or 30 wells formed as a microarray. In a typical sensor embodiment, the substrate is formed such that it contains wells, the wells including a lip surrounding the well. In some methods disclosed herein, a metal composition is sputtered such that the metal composition is positioned below the lip of the well. Additionally, various different conductive elements can be disposed on the substrate. In some embodiments of the invention, the substrate comprises a plurality of reference electrodes, a plurality of working electrodes, and a plurality of counter electrodes clustered together in units consisting substantially of a working electrode, a counter electrode, and a reference electrode, and the clustered units are longitudinally distributed on the substrate in a repeating unit pattern.

[0058] 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 sputtering electrodes disposed on a substrate. In some embodiments of the invention, the analyte sensor device includes a processor and 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 some embodiments of the 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.

[0059] In some embodiments of the invention, the substrate structure comprises a flexible yet rigid and flat structure suitable for use in photolithography and etching processes. In this regard, the substrate structure typically includes at least one surface with a highly uniform flatness. The substrate structure material can comprise, for example, metals such as stainless steel, aluminum, and nickel-titanium shape memory alloys (e.g., NITINOL), as well as polymer / plastic materials such as deltamethrin. The substrate structure material can be made of or coated with a dielectric material. In some embodiments, the substrate structure is non-rigid and can be a film or insulating layer used as a substrate for patterning electrical components (e.g., electrodes, traces, etc.), such as plastics like polyimide. The initial steps in the method of the invention typically involve the formation of a substrate for the sensor. Optionally, during sensor production, a planar material sheet is formed and / or disposed on a support such as a glass or ceramic plate. The substrate structure can then be disposed on the support (e.g., a glass plate) via PVD. A series of photolithography and / or chemical masking and etching steps can then be performed to form conductive components. In illustrative form, the substrate includes a thin film of insulating material, such as a polyimide substrate used for patterning electrical components. The substrate structure may include one or more elements selected from 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.

[0060] The method of the present invention comprises forming a conductive layer on a substrate that serves as one or more sensing elements. Typically, these sensing elements include electrodes, electrical conduits (e.g., traces), contact pads, etc., formed by one of various methods known in the art for defining the geometry of active electrodes, such as photolithography, etching, and rinsing. Electrodes can then be fabricated from electrochemically active materials having a defined structure, for example, by using sputtered Pt black as the working electrode. A sensor layer (e.g., an analyte sensing enzyme layer) can then be disposed on the sensing layer by electrochemical deposition or other methods (e.g., spin coating), followed by vapor crosslinking, for example, with dialdehyde (glutaraldehyde) or carbodiimide.

[0061] In exemplary embodiments of the invention, a thin-film conductive layer is first coated onto a substrate by electrode deposition, surface sputtering, or other suitable patterning or other process steps. In one embodiment, this conductive layer may be configured as multiple thin-film conductive layers, such as an initial chromium-based layer suitable for chemical adhesion to a polyimide substrate, followed by a gold-based thin-film layer and a chromium-based thin-film layer formed sequentially. In alternative embodiments, other electrode layer configurations or materials may be used. The conductive layer is then covered with a selected photoresist coating according to conventional photolithography techniques, and a contact mask may be applied over the photoresist coating for suitable optical imaging. The contact mask typically contains one or more conductor trace patterns for appropriate exposure of the photoresist coating, followed by an etching step to retain multiple conductive sensor traces on the substrate. In an exemplary sensor configuration designed for use as a subcutaneous glucose sensor, each sensor trace may 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.

[0062] Embodiments of the present invention include a method of adding a variety of materials to one or more surfaces of one or more sputtered electrodes. One such embodiment of the invention is a method of manufacturing a sensor device (e.g., a glucose sensor) for implantation in a mammal, the method comprising the steps of: providing a substrate; forming a conductive layer on the substrate, wherein the conductive layer comprises electrodes formed by a sputtering process that produces metal pillars of a certain architecture, thereby forming an analyte sensing layer on the conductive layer, wherein the analyte sensing layer comprises a composition capable of altering 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 on 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 the diffusion of the analyte through it; and forming a capping layer disposed on at least a portion of the analyte modulation layer, wherein the capping layer further comprises pores over at least a portion of the analyte modulation layer.

[0063] In feasible embodiments of the invention disclosed herein, the analyte sensing layer includes glucose oxidase. Optionally, the device includes 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 includes 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 includes a silicone portion. Typically, the device includes a biocompatible material on its outer surface suitable for contacting biological tissue or fluids during implantation in vivo. In feasible embodiments of the invention disclosed herein, the analyte sensor device is an amperometric glucose sensor exhibiting a highly desirable oxygen response profile. In such embodiments, the amperometric glucose sensor generates a first signal in a solution comprising 100 mg / dL glucose and 5% oxygen and 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 oxygen %), and the difference between the first and second signals is less than 10%.

[0064] Additional functional coatings or capping layers can then be applied to the electrodes or other sensor elements using any of the various methods known in the art, such as spraying, dip coating, etc. Some embodiments of the invention involve depositing an analyte modulation layer over an enzyme-containing layer disposed above the working electrode. In addition to modulating the amount of one or more analytes in contact with the active sensor surface, the use of an analyte-confining membrane layer also avoids the problem of foreign material contamination of the sensor. As is known in the art, the thickness of the analyte modulation membrane layer can affect the amount of analyte reaching the active enzyme. Therefore, its application is typically performed under defined processing conditions, and its dimensional thickness is tightly controlled. The microfabrication of the underlying layer can be a factor influencing the dimensional control of the analyte modulation membrane layer and the exact composition of the analyte-confining membrane layer material itself. In this regard, several types of copolymers, such as copolymers of siloxane and non-siloxane components, have been found to be particularly useful. These materials can be microdispersed or spin-coated to controlled thicknesses. Their final architecture can also be designed using patterning and photolithography techniques consistent with other discrete structures described herein.

[0065] In some embodiments of the invention, the sensor is manufactured by applying an analyte modulation layer comprising a hydrophilic membrane coating that modulates the amount of analyte that can contact an enzyme in the sensor layer. For example, a cover layer added to the glucose sensing element of the invention may comprise a glucose restriction membrane that modulates the amount of glucose in contact with a glucose oxidase layer on the electrode. Such glucose restriction membranes can be made of a variety of materials known to be suitable for such purposes, such as silicones like polydimethylsiloxane, polyurethanes, cellulose acetate, perfluorosulfonic acids, polyester sulfonic acids (e.g., Kodak AQ), hydrogels, or any other membranes known to those skilled in the art suitable for such purposes. In some embodiments of the invention, the analyte modulation layer comprises a hydrophilic polymer. In some embodiments of the invention, the analyte modulation layer comprises a linear polyurethane / polyurea polymer and / or a branched acrylate polymer; and / or a mixture of such polymers.

[0066] In some embodiments of the method of the present invention, an adhesion promoter layer is disposed between a capping layer (e.g., an analyte modulation film layer) and an analyte sensing layer to promote their 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 properties in addition to the ability to provide sensor stability. For example, some compositions used in the adhesion promoter layer are selected to function in interference suppression and to control the mass transfer of the desired analyte. The adhesion promoter layer can be made of any of a variety of materials known in the art for promoting adhesion between such layers and can be applied by any of a variety of methods known in the art.

[0067] Finished sensors produced using such methods are typically removed quickly and easily from a support structure (if one is used), for example, by cutting along a line around each sensor on the support structure and then peeling it off. The cutting step can be performed using methods commonly used in the art, such as those incorporating a UV laser cutting apparatus for cutting the substrate layer, capping layer, and functional coating along a line surrounding or wrapping around each sensor (typically with at least a slight outward spacing from the conductive element), such that sufficient interconnect substrate and capping layer material is retained to seal the side edges of the finished sensor. As demonstrated herein, the sensor can be quickly and easily lifted from the support structure without significant further processing steps or potential damage due to stress from excessive forces applied to peel the attached sensor from the support structure, because the substrate is sufficiently weakly adhered directly to the underlying support. The support structure can then be cleaned and reused or otherwise discarded. One or more functional coatings can be applied before or after removing other sensor components from the support structure (e.g., by cutting).

[0068] Embodiments of the present invention also include a method for 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 an in vivo environment, and then sensing one or more electrical fluctuations (e.g., changes in current at a working electrode) and correlating the current change with the presence of the analyte, thereby sensing the analyte. Typically, this method includes: implanting a glucose sensor disclosed herein into the interstitial space of a diabetic individual, sensing changes in current at a working electrode in the presence of glucose; and then correlating the current change with the presence of glucose, thereby sensing glucose. Although typical embodiments of the present invention relate to a glucose sensor, the sputtering sensor electrode disclosed herein is adaptable for use with a variety of devices known in the art.

[0069] 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 some embodiments of the invention, a substrate material including sensor electrodes is disposed within a housing (e.g., the 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 and second longitudinal members 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 computer-readable program code having instructions that, when executed, cause the processor to evaluate electrochemical signal data obtained from the electrodes; and calculate the presence or concentration of the analyte based on the electrochemical signal data obtained from the electrodes. The embodiments of the invention described herein can also be adapted and implemented using, for example, ampere-type sensor structures disclosed in the following documents: U.S. Patent Application Publications Nos. 20070227907, 20400025238, 20110319734, and 20110152654, the contents of each of which are incorporated herein by reference.

[0070] B. Illustrative analyte sensor components and sensor stacking used in embodiments of the invention.

[0071] The following disclosure provides examples of typical elements / components used in sensor embodiments of the present invention. Although these elements may be described as discrete units (e.g., layers), those skilled in the art will understand that sensors can be designed to include some or all of the material properties and / or functions of the elements / components discussed below (e.g., elements acting as supporting substrate components and / or conductive components and / or matrices for sensing analytes and further serving as electrodes in the sensor). Those skilled in the art will understand that these thin-film analyte sensors are applicable to many sensor systems, such as those described below.

[0072] Figure 1A-1D Embodiments of analyte sensor devices 100a-100d are shown, the analyte sensor devices including a working electrode (WE) on a first side 102a of insulating layers 104a, 104b and a counter electrode (CE or BCE) on a second side 102b of insulating layers 104a, 104b, such that insulating layers 104a, 104b are located between CE / BCE and WE. Figure 1A-1D A reference electrode (RE) on a first side 102a of insulating layers 104a and 104b, and an insulator 106 located between RE and WE, are further shown. Metal 108 deposited on insulating layers 104a and 104b electrically contacts WE and includes a contact pad 110 for contacting WE. Metal 112 or CE on insulating layer 104a includes CE and a contact pad 114 for contacting CE. Figure 1A-1C The diagram also shows a substrate 116 on the CE and a second insulating layer 118 on the first insulating layers 104a, 104b and the metal 108.

[0073] WE comprises a metal composition 120 having an electroactive surface 122. In Figure 1A-1D In the example shown, WE includes a column 124 containing a metallic component 120 and having an electroactive surface 122.

[0074] Figure 1D An embodiment of sensor 100d is shown, wherein the back side CE is / includes a layer capable of controlling the adhesion force to the substrate and the electrodes in sensor device 100d.

[0075] Figure 1EAn analyte sensor device 100e is shown, comprising working electrodes WE and CE on a first side (same side) 126 of a substrate 128, wherein WE and CE are spatially separated by a distance D of at least 1 micrometer-inch, for example, in the range of 1 micrometer–20 micrometers. WE and CE are non-interdigitated. The distance D is large enough to reduce undesirable interactions between WE and CE (i.e., reduce the effect of oxidation at one electrode on reduction at the other electrode and vice versa).

[0076] In one or more embodiments, Figure 1A-1E The device can be manufactured using PVD and / or electroplating.

[0077] Figure 1F and 1G The structure of the control sensor 130 having an interdigitated working electrode 132, a counter electrode 134, and a reference electrode 136 on one side 126 of the device 130 is similar to embodiments 100a-100d which include electrode WE on the first side 102a and electrode CE on the second side 102b. Figure 1G The sensors are compared. The working electrode 132 and the control electrode 134 in the control device 130 also have a small gap, which causes an undesirable interaction between the electrodes 132 and 134.

[0078] In one or more embodiments, sensor 100a-e includes additional layers / coatings / components (e.g., on a WE) to enable its use as a glucose sensor (e.g., for diabetes applications), such as Figure 1H As shown in the image. Other ingredients include the following.

[0079] Base components

[0080] The sensors of this invention typically contain a substrate component (see, for example...) Figure 1D Component 104b in Figure 1H Component 402 in Figure 1E Component 128 or Figure 1A-1D (Component 116 in the document). The term "substrate composition" is used herein according to the technical terms recognized in the art and refers to a component in a device that typically provides a support matrix for multiple components stacked on top of each other and including functional sensors. In one form, the substrate composition comprises a thin film of insulating (e.g., electrically insulating and / or waterproof) material. This substrate composition can be made of a variety of materials having desired qualities such as dielectric properties, waterproofness, and hermeticity. Some materials include metal and / or ceramic and / or polymer substrates, etc.

[0081] Conductive components

[0082] The electrochemical sensor of the present invention typically comprises a conductive component disposed on a substrate component, including at least one electrode, said at least one electrode comprising a metal (see, for example, for contacting the analyte to be measured or its byproducts (e.g., oxygen and / or hydrogen peroxide)) for contacting the analyte or its byproducts (e.g., oxygen and / or hydrogen peroxide). Figure 1B-1F (WE in the text). The term "conductive component" is used herein according to recognized technical terms in the art and refers to conductive sensor elements such as electrodes, contact pads, traces, etc. An illustrative example of a conductive component is a conductive component forming a working electrode that, compared to a reference electrode, does not experience changes in the concentration of an analyte (e.g., oxygen, a co-reactant used when the analyte interacts with a composition present in analyte sensing component 410 (e.g., the enzyme glucose oxidase)) or a reaction product of such interaction (e.g., hydrogen peroxide)). This working electrode can measure an increase or decrease in current in response to exposure to a stimulus (such as a change in the concentration of the analyte or its byproducts). Illustrative examples of such elements include electrodes capable of generating a variable detectable signal in the presence of molecules (such as hydrogen peroxide or oxygen) at variable concentrations.

[0083] In addition to the working electrode, the analyte sensor of the present invention typically includes a reference electrode (RE) or a combination of a reference electrode and a counter electrode (also referred to as a quasi-reference electrode or 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 electrode / reference electrodes. One embodiment of the sensor of the present invention has two, three, four, or more working electrodes. These working electrodes in the sensor may be integrally connected or may remain separate. Optionally, the electrodes may be disposed on a single surface or side of the sensor structure. Alternatively, the electrodes may be disposed on multiple surfaces or sides of the sensor structure. In some embodiments of the present invention, the reactive surfaces of the electrodes have different relative areas / sizes, for example, 1X reference electrode, 3.2X working electrode, and 6.3X counter electrode.

[0084] Interference inhibition components

[0085] The electrochemical sensor of the present invention optionally includes an interference-suppressing component disposed between the electrode surface and the environment to be measured. Specifically, some 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 the direct oxidation of hydrogen peroxide requires a relatively high oxidation potential, sensors employing 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-suppressing component" is used herein according to recognized technical terms in the art and refers to a coating or film in the sensor that serves to suppress stray signals generated by such oxidizable species that interfere with the detection of signals generated by the analyte to be sensed. Some interference-suppressing components function through size exclusion (e.g., by excluding interfering species of a specific size). Examples of interference-inhibiting components include one or more compound layers or coatings, such as hydrophilic polyurethane, cellulose acetate (including cellulose acetate incorporating reagents such as polyethylene glycol, polyethersulfone, polytetrafluoroethylene, perfluorinated ionomer Nafion™, polyphenylene diamine, epoxy resin, etc.).

[0086] Analyte Sensing Components

[0087] The electrochemical sensor of the present invention comprises an analyte sensing component disposed on an electrode of the sensor (see, for example...). Figure 1H (Element 410 in the text). The term "analyte sensing component" is used herein according to recognized technical terms in the art and refers to a component comprising a material capable of recognizing or reacting with an analyte to be detected by an analyte sensor device. Typically, this material in the analyte sensing component typically generates a detectable signal via an electrode of the conductive component upon interaction with the analyte to be sensed. In this respect, the electrodes of the analyte sensing component and the conductive component operate in combination to generate an electrical signal that can be read by a device associated with the analyte sensor. Typically, the analyte sensing component includes an oxidoreductase (e.g., glucose oxidase) capable of reacting with molecules and / or causing a concentration change of said molecules, the concentration change of said molecules can be measured by measuring a change in current at an electrode of the conductive component (e.g., oxygen and / or hydrogen peroxide). Enzymes capable of generating molecules (e.g., hydrogen peroxide) can be disposed on electrodes according to many methods known in the art. The analyte sensing component can coat all or part of the respective electrodes of the sensor. In this context, the analyte sensing component can coat the electrodes to an equivalent extent. Alternatively, the analyte sensing component can be coated to varying degrees on different electrodes, wherein, for example, the coated surface of the working electrode is larger than the coated surface of the counter electrode and / or reference electrode.

[0088] A typical sensor embodiment of this element of the present invention utilizes an enzyme (e.g., glucose oxidase) that has been combined in a fixed proportion with a second protein (e.g., albumin) and then applied to the surface of an electrode to form a thin enzymatic component (e.g., an enzyme typically optimized for the stability properties of glucose oxidase). In a typical embodiment, the analyte sensing component comprises a mixture of GOx and HSA. In a typical embodiment of the analyte sensing component containing GOx, the GOx reacts with glucose present in the sensing environment (e.g., a mammalian body) and produces hydrogen peroxide.

[0089] As described above, enzymes and second proteins (e.g., albumin) are typically treated to form a cross-linked matrix, for example, by adding a cross-linking agent to a protein mixture. As is known in the art, cross-linking conditions can be manipulated to modulate factors such as the retention of the enzyme's biological activity, 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 a protein mixture produces 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 be used or used in place of glutaraldehyde. Other suitable cross-linking agents may also be used, as will be apparent to those skilled in the art.

[0090] As described above, in some embodiments of the 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 sensing a change in oxygen and / or hydrogen peroxide concentration). However, other useful analyte sensing components can be formed from any composition capable of generating a detectable signal that can be sensed by a conductive element upon interaction with a target analyte to detect its presence. In some embodiments, the composition comprises an enzyme that modulates the hydrogen peroxide concentration upon reaction with the analyte to be sensed. Alternatively, the composition comprises an enzyme that modulates the oxygen concentration upon reaction 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 readily incorporated into analyte sensing component compositions. Various other enzymes known in the art can generate and / or utilize compounds whose modulation can be detected by electrodes of conductive elements (such as those incorporated into the sensor designs described herein). Such enzymes include, for example, those described in Table 1, pp. 15–29 and / or Table 18, pp. 111–112, of Richard F. Taylor (ed.), Marcel Dekker; (January 7, 1991), in *Protein Immobilization: Fundamentals and Applications (Bioprocess Technology, Vol. 14)*, the entire contents of which are incorporated herein by reference.

[0091] protein components

[0092] The electrochemical sensor of the present invention optionally includes a protein component disposed between the analyte sensing component and the analyte modulation component (see, for example...). Figure 1H (Element 416 in the text). The term "protein component" is used herein according to recognized technical terms in the art and refers to a component containing carrier proteins, etc., selected to be compatible with the analyte sensing component and / or 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% and 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 invention, collagen or BSA or other structural proteins used in these contexts may be used in place of or to supplement the HSA. According to recognized practices in the art, this component is typically cross-linked onto the analyte sensing component.

[0093] Adhesion promoting ingredients

[0094] The electrochemical sensor of the present invention may contain one or more adhesion-promoting (AP) components (see, for example) Figure 1H (Element 414 in the text). The term "adhesion-promoting component" is used herein according to recognized technical terms in the art and refers to a component comprising a material selected to promote adhesion between adjacent components in a sensor. Typically, the adhesion-promoting component is disposed between an analyte-sensing component and an analyte-modifying component. Typically, the adhesion-promoting component is disposed between an optional protein component and an analyte-modifying component. The adhesion-promoting 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-promoting component includes silane compounds, such as 3-aminopropyltrimethoxysilane.

[0095] Analyte modulation components

[0096] The electrochemical sensor of the present invention includes an analyte modulation component disposed on the sensor (see, for example...). Figure 1H (Element 412 in the text). The term "analyte modulation component" is used herein according to the technically accepted terminology in the art and refers to a component that typically forms a membrane on a sensor, the function of which is to modulate the diffusion of one or more analytes (such as glucose) through the component. In some embodiments of the invention, the analyte modulation component is an analyte-restricting membrane, the function of which is to prevent or restrict the diffusion of one or more analytes (such as glucose) through the component. In other embodiments of the invention, the analyte modulation component functions to facilitate the diffusion of one or more analytes through the component. Optionally, such analyte modulation components may be formed to prevent or restrict the diffusion of one type of molecule (e.g., glucose) through the component, while simultaneously allowing or even facilitating the diffusion of other types of molecules (e.g., O2) through the component.

[0097] Regarding glucose sensors, in known enzyme electrodes, glucose and oxygen from the blood, along with some interfering substances (such as ascorbic acid and uric acid), diffuse through the primary membrane of the sensor. When glucose, oxygen, and interfering substances reach the analyte detection component, an enzyme (such as glucose oxidase) catalyzes the conversion of glucose into hydrogen peroxide and gluconolactone. The hydrogen peroxide can diffuse back through the analyte modulation component, or it can diffuse to the electrode, where it can react to form oxygen and protons to generate a current proportional to the glucose concentration. Analyte modulation sensor membrane assemblies serve several functions, including selectively allowing the glucose pathway to pass through (see, for example, U.S. Patent Application No. 2011-0152654).

[0098] Covering ingredients

[0099] The electrochemical sensor of the present invention comprises one or more covering components, typically electrically insulating and protective components (see, for example...). Figure 1H (element 406 in the text). Typically, such covering components may 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 may comprise, but are not limited to, non-toxic, biocompatible polymers such as silicone compounds, polyimides, biocompatible welding masks, epoxy acrylate copolymers, etc. Furthermore, these coatings may be photoimageable to facilitate photolithographic formation of apertures through the conductive component. Typical covering components include spinning on silicone. As is known in the art, this component may be a commercially available RTV (room temperature vulcanizing) silicone composition. In this context, a typical chemical is polydimethylsiloxane (acetoxy-based).

[0100] Figure 1H A cross-section of a typical sensor embodiment 400 of the present invention, incorporating the components discussed above, is shown. This sensor embodiment is formed of multiple components, which are typically in the form of layers of various conductive and non-conductive components disposed on each other according to methods recognized in the art and / or specific methods of the present invention disclosed herein. The components of the sensor are generally characterized herein as layers because, for example, they allow for easy characterization. Figure 1H The sensor structure shown is illustrated. However, those skilled in the art will understand that in some embodiments of the invention, the sensor components are combined such that multiple components form one or more heterogeneous layers. In this context, those skilled in the art will understand that the order of the layered components can be varied in various embodiments of the invention.

[0101] Figure 1H The illustrated embodiment includes a substrate layer 402 for supporting the sensor 400. The substrate layer 402 may be made of a material such as a metal and / or ceramic and / or polymer substrate, and may be self-supporting or further supported by another material known in the art. Embodiments of the invention include a conductive layer 404 disposed on and / or combined with the substrate layer 402. Typically, the conductive layer 404 includes one or more conductive elements that act as electrodes. The operating sensor 400 typically includes multiple electrodes, such as a working electrode, a counter electrode, and a reference electrode. Other embodiments may also include multiple working electrodes and / or counter electrodes and / or reference electrodes and / or one or more electrodes performing multiple functions, such as an electrode that acts as both a reference electrode and a counter electrode.

[0102] As discussed in detail below, many known techniques and materials can be used to produce the substrate 402 and / or conductive layer 404. In some embodiments of the invention, the circuitry of the sensor is defined by etching the disposed conductive layer 404 into a desired conductive path pattern. A typical circuitry 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 used as insulating protective cover layer 406 may comprise, but are not limited to, non-toxic biocompatible polymers such as silicone compounds, polyimides, biocompatible welding masks, epoxy acrylate copolymers, etc. 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 analytes (such as glucose) to permeate the sensor layer and be sensed by the sensing element. Holes 408 can be formed using various techniques, including laser ablation, tape masking, chemical polishing or etching, or photolithography. In some embodiments of the invention, a second photoresist may be applied to the protective layer 406 during manufacturing to define areas to be removed from the protective layer, thus forming one or more holes 408. Exposed electrodes and / or contact pads may also undergo secondary processing (e.g., through holes 408) such as additional electroplating to prepare surfaces and / or reinforce conductive areas.

[0103] exist Figure 1HIn the illustrated sensor configuration, the analyte sensing layer 410 is disposed on one or more 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 generating 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 generate a compound—hydrogen peroxide—that modulates the current at the electrode. Since this modulation of the current depends on the hydrogen peroxide concentration, and the hydrogen peroxide concentration is related to the glucose concentration, the glucose concentration can be determined by monitoring this modulation of the current. In a specific embodiment of the invention, hydrogen peroxide is oxidized at a working electrode serving as the anode (also referred to herein as the anodic working electrode), wherein the current generated is proportional to the hydrogen peroxide concentration. This modulation of the current caused by the change in hydrogen peroxide concentration can be monitored by any of a variety of sensor detector devices, such as general-purpose sensor ampere-type biosensor detectors or one of the various similar devices known in the art, such as the glucose monitoring device manufactured by Medtronic Diabetes.

[0104] In embodiments of the invention, the analyte sensing layer 410 may be applied over a portion of or over the entire area of ​​the conductive layer. Typically, the analyte sensing layer 410 is disposed on a working electrode, which may be an anode or a cathode. Optionally, the analyte sensing layer 410 may also be disposed on a counter electrode and / or a reference electrode. Methods for producing the thin analyte sensing layer 410 include: brushing the layer onto a substrate (e.g., the reactive surface of a platinum black electrode), and spin coating, dip coating and drying processes, low-shear spraying, inkjet printing, screen printing, etc. In some embodiments of the invention, brushing is used to: (1) allow for precise positioning of the layer; and (2) push the layer depth into the architecture of the reactive surface of the electrode (e.g., platinum black produced by a sputtering process).

[0105] 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 comprise a protein layer 416 disposed on the analyte sensing layer 410. Typically, the protein layer 416 comprises proteins such as human serum albumin, bovine serum albumin, etc. In some embodiments of the invention, the additional layer comprises an analyte modulation layer 412 disposed above the analyte sensing layer 410 to modulate the contact between the analyte and the analyte sensing layer 410. For example, the analyte modulation layer 412 may comprise a glucose restriction membrane that modulates the amount of glucose in contact with an enzyme (such as glucose oxidase) present in the analyte sensing layer. Such glucose restriction membranes can be made of a variety of materials known to be suitable for this purpose, such as silicone compounds like polydimethylsiloxane, polyurethane, polyurea cellulose acetate, perfluorosulfonic acid, polyester sulfonic acid (e.g., Kodak AQ), hydrogels, or any other suitable hydrophilic membrane known to those skilled in the art.

[0106] In some embodiments of the present invention, such as Figure 1H As shown, the adhesion promoter layer 414 is disposed between the analyte modulation layer 412 and the analyte sensing layer 410 to promote their contact and / or adhesion. In a specific embodiment of the invention, such as Figure 3 As shown, an adhesion promoter layer 414 is disposed between the analyte modulation layer 412 and the protein layer 416 to promote their contact and / or adhesion. 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 comprises a silane compound. In alternative embodiments, the proteins or similar molecules in the analyte sensing layer 410 can be sufficiently cross-linked or otherwise prepared to allow the analyte modulation layer 412 to be disposed in direct contact with the analyte sensing layer 410 in the absence of the adhesion promoter layer 414.

[0107] C. Typical System Embodiments of the Invention

[0108] A specific illustrative system embodiment comprises a glucose sensor, transmitter, and receiver including a sputtered / PVD electrode composition as disclosed herein, and a blood glucose meter. In this system, radio signals from the transmitter can be sent to the pump receiver at fixed time intervals (e.g., every 5 minutes) to provide real-time sensor glucose (SG) values. Values / graphs can be displayed on a monitor of the pump receiver, allowing a user to self-monitor blood glucose and deliver insulin using their own insulin pump. Typically, the sensor system disclosed herein can communicate with other medical devices / systems via wired or wireless connections. Wireless communication can include the reception of emitted radiation signals, such as those transmitted via RF telemetry, infrared transmission, optical transmission, acoustic waves, and ultrasonic waves. Optionally, the device is an integrated part of a drug infusion pump (e.g., an insulin pump). Typically, in such devices, physiological characteristic values ​​include multiple measurements of blood glucose.

[0109] Figure 2 A perspective view of a general embodiment of a subcutaneous sensor insertion system applicable to use with the sensor electrodes disclosed herein is provided, along with a block diagram of a sensor electronics device according to an illustrative embodiment of the invention. Additional elements commonly used with such sensor system embodiments are disclosed, for example, in U.S. Patent Application No. 20070163894, the contents of which are incorporated herein by reference. Figure 2 A perspective view is provided of a telemetry monitoring system 1 comprising a subcutaneous sensor kit 10, which is provided for subcutaneously placing the active portion of a flexible sensor 12, etc., at a selected site within a user's body. The subcutaneous or transdermal portion of the sensor kit 10 includes a hollow slotted insertion needle 14 with 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. A base is designed such that the sensing portion 18 engages with a connection portion 24 terminating in conductive contact pads, etc., which are also exposed through one of the insulating layers. The connection portion 24 and the contact pads are generally suitable for direct wired electrical connection to a suitable monitor 200 coupled to a display 224 to monitor the user's condition in response to signals originating from the sensor electrodes 20. As shown and described in U.S. Patent No. 5,482,473 entitled "Flexible Circuit Connector", connection portion 24 can be conveniently electrically connected to monitor 200 or characteristic monitor transmitter 200 via connector block 28 (or the like), which is incorporated herein by reference.

[0110] like Figure 2As shown, according to an embodiment of the invention, the subcutaneous sensor kit 10 can be configured or formed to work with a wired or wireless characteristic monitoring system. The proximal portion of the sensor 12 is mounted in a mounting base 30 suitable for placement on a user's skin. The mounting base 30 may be a pad having a lower surface coated with a suitable pressure-sensitive adhesive layer 32, wherein a release liner 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 comprises an upper layer 36 and a lower layer 38, wherein a connection portion 24 of the flexible sensor 12 is sandwiched between layers 36 and 38. The connection portion 24 has a front portion that engages with an active sensing portion 18 of the sensor 12, the front portion being folded at an angle to extend downward through a bore 40 formed in the lower base layer 38. Optionally, the adhesive layer 32 (or another portion of the device in contact with in vivo tissue) contains an anti-inflammatory agent for reducing inflammatory responses and / or an antibacterial agent for reducing the chance of infection. The insertion pin 14 is adapted to slide through a needle port 42 formed in the upper substrate layer 36 and through a lower bore 40 in the lower substrate layer 38 for reception. After insertion, the insertion pin 14 is withdrawn to leave the sleeve 16, which has 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 connector and cable 402, the connector being electrically coupled to the connector block 28 of the connector portion of the sensor kit 10.

[0111] exist Figure 2 In the illustrated embodiment, 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 with a connector 204. In some embodiments, the housing 206 is formed of an upper housing 214 and a lower housing 216, which are ultrasonically welded to form a waterproof (or corrosion-resistant) seal to allow cleaning by immersion (or wiping) with water, detergents, 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 may be joined together and bonded together by other methods such as snap-fit, sealing rings, RTV (silicone sealant), etc., or formed of other materials such as metal, composite materials, ceramics, etc. In other embodiments, separate housings may be eliminated, and the assembly may be simply encapsulated in epoxy resin or other moldable materials that are compatible with electronics and have considerable moisture resistance. As shown, the lower housing 216 may have a lower surface coated with a suitable pressure-sensitive adhesive layer 218, wherein a peel strip 220 is typically provided to cover and protect the adhesive layer 118 until the sensor kit telemetry characteristics monitor transmitter 200 is ready for use.

[0112] exist Figure 2 In the illustrative embodiment shown, the subcutaneous sensor kit 10 facilitates the precise placement of a flexible thin-film electrochemical sensor 12 for monitoring specific blood parameters indicative of a user's condition. The sensor 12 monitors glucose levels in the body and can be used in conjunction with external or implantable automated or semi-automated drug infusion pumps as described in U.S. Patent Nos. 4,562,751, 4,678,408, 4,685,903, or 4,573,994 to control insulin delivery in diabetic patients.

[0113] exist Figure 2 In the illustrative embodiments shown, the sensor electrode 20 can be used in various sensing applications and can be configured in various locations on a substrate structure, and further formed to include materials that allow for multiple functions. For example, the sensor electrode 20 can be used in physiological parameter sensing applications where a certain type of biomolecule acts as a catalyst. For example, the sensor electrode 20 can be used in glucose and oxygen sensors having a glucose oxidase that catalyzes the reaction with the sensor electrode 20. The sensor electrode 20, together with the biomolecule or some other catalyst, can be placed in the human body in vascular or non-vascular environments. For example, the sensor electrode 20 and the biomolecule can be placed in a vein and subjected to blood flow, or can be placed subcutaneously or in the peritoneal region of the human body.

[0114] exist Figure 2 In the illustrated embodiment of the invention, the sensor signal monitor 200 may also be referred to as sensor electronics device 200. Monitor 200 may include a power supply, a sensor interface, processing electronics (i.e., a processor), and data formatting electronics. Monitor 200 can be coupled to sensor kit 10 via a connector and cable 402, said connector being electrically coupled to connector block 28 of connection portion 24. In alternative embodiments, the cable may be omitted. In this embodiment of the invention, monitor 200 may include a suitable connector for direct connection to connection portion 24 of sensor kit 10. Sensor kit 10 may be modified to position the connector portion in different locations, for example, on top of the sensor kit to facilitate placement of monitor 200 on the sensor kit.

[0115] As described above, sensor elements and sensor embodiments can be operatively coupled to a variety of other system elements (e.g., structural elements such as puncture devices, insertion kits, etc., and electronic components such as processors, monitors, drug infusion pumps, etc.) typically used with analyte sensors, for example, to adapt them to various contexts (e.g., implantation in mammals). One embodiment of the invention includes a method for monitoring a user's physiological characteristics using embodiments of the invention comprising: an input element capable of receiving signals from a sensor based on sensed physiological characteristic values ​​of the user; and a processor for analyzing the received signals. In a typical embodiment of the invention, the processor determines the dynamic behavior of the physiological characteristic values ​​and provides observable indicators based on the determined dynamic behavior of the physiological characteristic values. 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 signals and determining the dynamic behavior includes repeatedly measuring the physiological characteristic value to obtain a series of physiological characteristic values, incorporating comparative redundancy into the sensor device, for example, in a manner designed to provide confirmatory information about sensor functionality, analyte concentration measurements, the presence of interference, etc.

[0116] Figure 3 A schematic diagram of a voltage regulator that can be used for measuring current in embodiments of the present invention is shown. Figure 3 As shown, the regulator 300 may include an operational amplifier 310 connected in the circuit to have two inputs: Vset and Vmeasured. As shown, Vmeasured is a 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 producing a current measurement result (Isig) from the regulator output.

[0117] Embodiments of the present invention include means for processing display data of measurements of a sensed physiological characteristic (e.g., blood glucose concentration) in a manner and format tailored to allow a user of the device to easily monitor and (if necessary) modulate the physiological state of the characteristic (e.g., modulating blood glucose concentration via insulin administration). An illustrative embodiment of the invention includes a device comprising: a sensor input capable of receiving signals from a sensor based on a user-sensed physiological characteristic value; a memory for storing multiple measurements of the user-sensed physiological characteristic value from the received signals from the sensor; and a display for presenting textual and / or graphical representations (e.g., text, line graphs, bar graphs, grid patterns, or combinations thereof) of the multiple 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 invention, the device is used in combination with at least one other medical device (e.g., a glucose sensor).

[0118] The illustrative system embodiment comprises 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, allowing the user to self-monitor blood glucose and deliver insulin using their own insulin pump. Typically, embodiments of the device disclosed herein communicate with a second medical device via a wired or wireless connection. Wireless communication may include the reception of emitted radiation signals that occur during signal transmission, such as via RF telemetry, infrared transmission, optical transmission, sound waves, and ultrasound transmission. Optionally, the device is an integrated part of a drug infusion pump (e.g., an insulin pump). Typically, in such devices, physiological characteristic values ​​include multiple measurements of blood glucose.

[0119] Although the analyte sensors and sensor systems disclosed herein are generally designed for implantation in mammals, the inventions disclosed herein are 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 fluid samples, including 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, synovial fluid, gastric juice, etc. Additionally, solid or dry samples can be dissolved in a suitable solvent to provide a liquid mixture suitable for analysis.

[0120] Example

[0121] Common abbreviations used in the examples include: WE working electrode; GOx glucose oxidase; HSA human serum albumin; SITS sensor in vitro testing system; GLM glucose restriction membrane (an embodiment of the analyte modulation layer); OQ operational validation; SAR surface area ratio; BTS bicarbonate testing system; and EIS electrochemical impedance spectroscopy. The BTS and SITS tests discussed in the examples are tests used to evaluate sensor performance. SITS measures the sensor signal in glucose solution over 5–7 days, along with the sensor's oxygen response, temperature response, background current, linearity, stability, acetaminophen interference, and response time. Dog tests were used to evaluate the in vivo glucose sensor performance (Isig and calculated blood glucose levels) in diabetic and non-diabetic dogs for up to 3 days, comparing glucose levels measured by the continuous glucose sensor with those measured by a blood glucose meter.

[0122] It should be understood that the present invention is not limited to the specific embodiments described, as these embodiments can, of course, vary. It should also be understood that the specialized terminology used herein is for the purpose of describing specific embodiments only and is not intended to be restrictive, as the scope of the invention is limited only by the appended claims. In the description of preferred embodiments, reference is made to the accompanying drawings, which form a part of the description, and in which specific embodiments in which the invention can be practiced are illustrated 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 invention.

[0123] However, although some embodiments of the invention are indicated, the description and specific examples are given by way of illustration rather than limitation. Many changes and modifications can be made within the scope of the invention without departing from its spirit, and the invention encompasses all such modifications.

[0124] Example 1: Sputtering equipment

[0125] Figure 4 An apparatus including a chamber 400 for depositing a material (e.g., thin film 402) using sputtering is demonstrated. Sputtering gas 404 in the chamber 400 is ionized to form ionized gas particles 406 (e.g., Ar). + The plasma is ionized. Ionized particles 406 bombard a sputtering target 408 comprising a metal composition. The collision of ionized particles 406 with the sputtering target 408 knocks off material 410 comprising the metal composition (e.g., sputtered target atoms) and accelerates material 410 412 onto the target surface on a substrate 414, thereby forming a film 402 on the substrate 414. Ionized gas particles 406 are used by a voltage U -The electric and / or magnetic fields applied by the bias electrodes accelerate the target. Particle collisions are controlled by the processing power (i.e., the power of the electric and / or magnetic fields of the sputtering gas until the ionized gas particles reach the sputtering gas) and the pressure and composition of the sputtering gas (or the composition and pressure of the ionized gas particles).

[0126] Example 2: Sputtering conditions for controlling adhesion

[0127] The following deposition conditions may affect adhesion.

[0128] ● High-pressure deposition conditions may cause the deposited film to form under stress, resulting in poor adhesion.

[0129] ●Deposition power may affect adhesion, as higher deposition rates may cause air pockets, resulting in poorer adhesion.

[0130] ● The high temperature used during deposition may evaporate all adsorbed water remaining on the surface, thereby increasing adhesion.

[0131] ● Thicker films can generate stress and result in poorer adhesion.

[0132] ● Geometric area can also affect adhesion and can be controlled by forming pillars at the interface between the film and the substrate.

[0133] In the experiments described herein, sputtering parameters, including pressure, power, temperature, and thickness, as well as combinations of these parameters, were adjusted to determine their effect on adhesion and to determine the parameters / parameter values ​​that achieve optimal adhesion for electrode processing. In one or more embodiments, the target used for adhesion (or optimal adhesion) is strong enough to maintain the adhesion of the substrate polyimide to the substrate during laser cutting, but weak enough to allow the substrate polyimide to be removed from the substrate used for sensor assemblies.

[0134] Figure 5 A test sample comprising a layer stack 500 on a glass substrate 502 is shown. The layer stack comprises a gold (Au) layer 504 on the glass substrate, a chromium (Cr) layer 506 on the Au layer 504, and a substrate polyimide layer 508 on the Cr layer 506.

[0135] Figure 6A The simulation demonstrates different patterns AE of marking and cutting types such as knife scratches or laser cutting marks that can be applied during electrode fabrication in glucose sensors or other devices, applied to a layer stack 500 on a glass substrate 502.

[0136] Figure 6B Pattern 600 of a silver layer applied to a glass substrate is shown, illustrating that the adhesion of silver to the glass is too weak to allow the reproduction of markings on the silver layer.

[0137] use Figure 6A The marked patterns shown in the figure were used to perform a feasibility-efficiency-compatibility study to discover the effects of metal (e.g., gold) sputtering conditions on Figure 5 The effect of metal / glass (e.g., metal / glass) adhesion in layered structures.

[0138] Figures 7A-7D It demonstrates how to assign adhesion scores. Figure 7A Showing when Figure 6A A score of 0 is assigned when the pattern can be accurately applied to a layer stack with the highest quality and reproduction resolution (representing the strongest adhesion of the layer stack to the glass substrate). As the score increases, the adhesion decreases, and the marked pattern cannot be reproduced well in the layer stack. Figure 7B and 7C ). Figure 7D Showing when Figure 6A The pattern could not be accurately applied to the layer stack 500 and was assigned a score of 10 when it was replicated in the layer stack (representing 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.

[0139] a. Experiment 1

[0140] Manufacturing using the sputtering conditions in Table 1 Figure 6A The test samples are shown in Table 1. Subsequently, Figure 6B The marking pattern is scratched / laser-cut into each membrane on the test sample and an adhesion score is assigned to each replica.

[0141] Table 1

[0142]

[0143] Figures 7A-7D The test results are shown. The gold layer was fabricated using sputtering conditions including 100 mT pressure, 1.6 kW power, 897 angstroms gold layer thickness, and no heating required. Figure 7D The sputtering structure in the middle.

[0144] The results showed that samples 1-6 (highlighted in Table 1) exhibited the strongest adhesion under sputtering conditions (adhesion score of 0), thus allowing for accurate reproduction. Figure 6B The mark. Figures 7A-7D Table 1 shows surprising and unexpected results: low pressure achieved extremely high adhesion, while high pressure achieved low adhesion.

[0145] b. Experiment 2

[0146] Figure 8BTest sample 1000 is shown, comprising an Au layer 1002 and pillars 1004 at the interface between the Au layer 1002 and the 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). Figure 9 This is a scanning electron microscope image of the columnar interface located between the glass substrate 1006 and the gold layer 1002.

[0147] As shown in Table 2, then use a knife to cut Figure 6B The marking pattern is scratched / laser-cut into each of the Au films 1002 in the test sample 1000 and an adhesion score is assigned to each replica.

[0148] Table 2

[0149]

[0150] Figure 5 The fabrication of a back-side counter electrode is demonstrated, which includes: 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 stack of Cr / Au layers inside the opening, and peeling the base polyimide, the Au layer, and the Cr layer together from the glass substrate.

[0151] It should be understood that the present invention is not limited to the specific embodiments described, as the embodiments can, of course, vary. It should also be understood that the terminology used...

[0152] The samples highlighted in Table 2 (samples 1-5 and 10) show that low-pressure sputtering achieved 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) achieved weak adhesion. This is hypothesized that the gold pillar reduces the gold / glass contact area and increases the effect of pressure on adhesion. The results also show that thicker films exhibit weaker adhesion to the glass substrate.

[0153] Figure 10A-10D This demonstrates gold pillar 1004 manufactured using various sputtering conditions after laser cutting with example electrode patterns. Figure 6A membrane. Figure 10A and 10B The film fabricated using a 100 mTorr pressure, 0.4 W power, and a 952 Å thick gold layer is shown. Figure 10A ) and in films fabricated using a gold layer with a pressure of 100 mTorr, a power of 1.6 W, and a thickness of 897 Å ( Figure 10B The pattern was reproduced very well. Figure 10C and 10D The film fabricated using a gold layer with a thickness of 8922 Å and a pressure of 100 mTorr, a power of 0.4 W, was demonstrated. Figure 10C ) and in films fabricated using a gold layer with a pressure of 100 mTorr, a power of 1.6 W, and a thickness of 10806 Å ( Figure 10B The pattern could not be reproduced well. These results show that when using high pressure, a relatively thin gold layer can be used to increase adhesion (adhesion decreases as the gold layer thickness increases).

[0154] Figure 11 Pareto plots are shown illustrating the normalized effects of varying factors (pressure, power, and gold thickness) on the adhesion of a sample 500 fabricated using a gold pillar 1004 located at the interface between the gold layer 504 and the glass substrate 502. In the Pareto plots, the response is the rate of change of pressure, sputtering power, and gold layer thickness, and α = 0.05 is a parameter used to determine the statistically significant factors controlling adhesion (in one or more instances, factors with a normalized effect on adhesion greater than α - 0.05 are considered statistically significant factors controlling adhesion).

[0155] Figure 12 It is a graph showing how the average rate varies with pressure, power, and gold thickness.

[0156] Figure 13 It is a contour plot of the rate versus the gold layer thickness and sputtering pressure.

[0157] DOE analysis ( Figure 11 , Figure 12 and Figure 13 The results show that pressure is the primary factor controlling adhesion when pillars 1004 are formed at the interface. Specifically, analysis shows that higher pressure and a thicker (e.g., gold) layer in the film result in weaker adhesion, while sputtering power has little effect on adhesion. Lower temperatures were found to provide weaker adhesion.

[0158] c. The effect of two gold layers on adhesion

[0159] Figure 14 Another test sample including a layer stack 1400 on a glass substrate 1402 is shown. 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 substrate polyimide layer 1410 deposited on the Cr layer 1408.

[0160] Follow the previously discussed procedure, then use a knife or laser cutter to... Figure 6BThe marking pattern was scribed into each membrane in the test samples. Table 2 compares the adhesion scores of the sample with double gold layers 1406 and 1404 (sample 11) with the adhesion scores of the sample 500 (samples 1-10) with a single gold layer 504 deposited under low or high pressure.

[0161] Figure 15A The study demonstrates gold layers 504 deposited under sputtering conditions including 100 mTorr pressure, 1.5 kW power, and 5 minutes duration. Figure 6A The test sample membrane 500. Figure 15B The study demonstrates a first gold layer 1404 deposited under sputtering conditions of 100 mTorr pressure, 1.5 kW power, and 5 minutes, and a second gold layer 1406 deposited under sputtering conditions of 4 mTorr pressure, 0.2 kW power, and 10 minutes. Figure 14 The test sample film. The results show that the test sample with a double gold layer ( Figure 14 ) compared to a sample with a gold layer 500 ( Figure 6A It has better adhesion. Therefore, the results unexpectedly and surprisingly show that the combination of high / low pressure gold layers 1404 and 1406 can significantly affect the adhesion.

[0162] Figure 15C , 15D And 15E demonstrates the use of Figure 15B The adhesion of two gold layers, 1404 and 1406, deposited under specific conditions varies depending on their position 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 apparatus.

[0163] Example 3: Controlling the sputtering rate

[0164] Perform DOE analysis to determine the process parameters that affect the sputtering rate of gold on the glass substrate without applying heat. Figure 16 Pareto plots are shown to illustrate the normalized effects of varying pressure, power, and gold thickness on sputtering rate without the application of heat. In the Pareto plots, the response is the sputtering rate in angstroms per second, and α = 0.05.

[0165] Figure 17 This is a graph showing how the average sputtering rate varies with pressure, power, and gold thickness.

[0166] Figure 18 It is a contour plot of sputtering rate versus sputtering power (kW) and pressure (mTorr).

[0167] DOE analysis ( Figure 16 , Figure 17 and Figure 18 The results show that there is an optimal pressure for the maximum sputtering rate, and the sputtering rate increases linearly with sputtering power. Therefore, as demonstrated herein, PVD conditions can be carefully selected to increase the sputtering rate and control adhesion. In one or more embodiments, DOE analysis is used to determine the sputtering parameters that achieve the fastest deposition rate and desired adhesion. Power and pressure can be used to control the sputtering rate and adhesion.

[0168] Although Examples 2-4 involve sputtering, the same results and findings (including controlling adhesion by appropriately selecting pressure) are generally applicable to depositions using PVD (e.g., including, but not limited to, electron beam deposition).

[0169] Example 4: Manufacturing of Analyte Sensor Equipment

[0170] Figure 19 , Figure 20 and Figure 1D A method for manufacturing an analytical analyte sensor device 100d is demonstrated.

[0171] Box 1900 indicates that a substrate (e.g., rigid) 2000 (e.g., glass substrate) is provided.

[0172] Box 1902 indicates, for example, the deposition of metals 2002a and 2002b on a substrate using PVD (physical vapor deposition). In one or more embodiments, the metal includes a first layer 2002a (e.g., an Au layer) on the substrate 2000 and a second layer 2002b (e.g., a Cr or Ti layer) on the first Au layer 2002a. In one or more instances, the metals 2002a and 2002b extend laterally to form contact pads 110 and 114.

[0173] 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 thicknesses of each metal layer in the range of at least 100 angstroms (e.g., 1000–9000 Å). PVD steps may include the pressure control steps described herein, e.g., Example 8. Figure 25 Steps in boxes 2500-2504. Example PVD processes include, but are not limited to, sputtering and electron beam deposition.

[0174] Box 1904 indicates the deposition of a first insulating layer 2004 on metals 2002a and 2002b. Example insulating layers include, but are not limited to, polymer layers (such as, but not limited to, polyimide).

[0175] Box 1906 indicates that a second metal 2006a, 2006b is deposited on the first insulating layers 2004, 104b and the second metal is patterned. In one or more instances, the second metal comprises two layers—a second layer 2006b comprising Au on top of a first layer 2006b comprising Cr (or Ti) and extending laterally to form contact pads 110, 114.

[0176] Box 1908 indicates the deposition of second insulating layers 2008, 118 onto first insulating layer 2004 and the deposition of second metals 2006a, 2006b onto first insulating layer 2004. Example insulating layers include, but are not limited to, polymer layers (such as, but not limited to, polyimide).

[0177] Box 1910 indicates that a first opening 2010a and a second opening 2010b are formed in the second insulating layer 2004 to expose the second metal 2006b.

[0178] Box 1912 indicates that a third metal is deposited into the first opening 2010a and onto the second metal 2006b to form the working electrode WE (see [reference]). Figure 1D ).

[0179] Box 1914 indicates that a fourth metal is deposited into the second opening 2010b and onto the second metal 2006b to form a reference electrode (RE) (see [link]). Figure 1D ).

[0180] Box 1916 indicates an additional step, comprising forming an opening in the second insulating layer 118 to expose metal contact pads 110, 114b including second metals 2006a, 2006b (see reference). Figure 1D And cure if necessary.

[0181] Box 1918 indicates that an analyte sensor is defined in 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.

[0182] Box 1920 indicates the removal (e.g., stripping) of analyte sensor 100d from substrate 2000. In one or more embodiments, the step includes removing (e.g., stripping) physical vapor deposition metals 2002a, 2002b from substrate 2000.

[0183] Box 1922 represents the final result, for example, as shown below. Figure 1DThe sensor device is shown in the figure. Metal layers 2002a, 2002b, and CE serve as the back-side counter electrode BCE and layers for controlling the adhesion force to the substrate 2000 using the pressure control methods described herein (see, for example, Examples 2-3). The substrate polyimide layers 2004 and 104b do not require patterning or etching to contact the BCE. In one or more examples, the method of Example 4 enables the fabrication of a device including a flexible element with electrodes on both sides (as shown in the figure). Figure 1F Compared to the control device shown with interdigitated electrodes on one side). As demonstrated herein, multiple (e.g., at least 36) sensors 100d removed from the substrate can all exhibit ISIG within 15% (see, for example, Figure 21D ).

[0184] Example 5: SITS results of the combined sensor in Example 4

[0185] Figures 21A-21C Demonstrated as Figure 1F The SITS results of the control sensors shown in the figure, and Figure 21D-21F Showing Figure 1G SITS results of the sensor (simulated / represented using the BCE manufactured in Example 4) Figure 1D (The performance of the device).

[0186] Figure 1G The sensor has two flexible elements:

[0187] ●Flexible component 1: The nominal electrode E3 has tape above the CE contact pad at the transmitter connection. The tape does not contact the body.

[0188] ● Flexible Component 2: The nominal E3 layer comprises a base polyimide and the nominal E3 electrode comprises Cr / Au and an adhesive tape above the WE and RE contact pad areas at the emitter connection. This flexible component is a nominal E3 flexible component manufactured solely by a metal sputtering process, and the adhesive tape does not contact the substrate.

[0189] although Figure 1D The sensor has a single flexible element containing CE, WE, and RE, but it is expected that... Figure 1D The performance of the device is similar to that of a device with two flexible elements. Figure 1G The devices have similar performance because Figure 1D Device and Figure 1G Both devices have CE electrodes on the back side opposite to the WE side.

[0190] Table 3: Used for testing Figure 1D The SITS summary for the device across 3 SITS runs. * Indicates statistically significant differences. For Figure 1DThe BCE device was tested with n = 36 devices, and for the control device, n = 36.

[0191]

[0192] for Figure 21A and 21B The data in the control sensor 130 includes Pt for the working electrode 132 and the counter electrode 134, and the reference electrode in the control sensor 130 includes Ag / AgCl. Figure 1G The WE in the sensor includes Pt, Figure 1G The CE in the sensor includes Au, and Figure 1D The REs in the sensor include Ag / AgCl.

[0193] Figure 21D-21F And the data from the sensors used for in vivo testing in pigs shown in Table 3, with Figure 1F Compared to control sensors, Figure 1G BCE device (representing Figure 1D The device improved long-term stability throughout testing, eliminated overnight Isig drift, and significantly (and surprisingly) reduced sensor variability (especially under low O2 concentration-pressure conditions). Additionally, Figure 1G The BCE did not show major differences in temperature and AC response, and no negative observations were found from visual inspection.

[0194] Figure 21C and 21F It also shows that in response to using Figure 1G The device's glucose sensing Vcounter (Vcntr) activity / motor activity compared to Figure 1F The control sensors also surprisingly decreased. Furthermore, data shows that... Figure 1G The sensor's Vcounter appears to be more stable at lower steady-state voltages.

[0195] Example 6: Manufacturing of Analyte Sensor Equipment

[0196] Figure 22 This is a flowchart illustrating a method for manufacturing a glucose sensor or a sensor flexible component (see also...). Figure 1A-1D and Figure 23 The method includes the following steps.

[0197] Box 2200 indicates the deposition of 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 comprise one or more gold layers deposited on the glass substrate 2302, followed by Cr deposited on the one or more gold layers.

[0198] 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 at least 100 angstroms (e.g., 1000–9000 Å) for each of the metal layers 2300a and 2300b. PVD steps may include the pressure control steps described herein, e.g., Example 8. Figure 25 The steps in boxes 2500-2504.

[0199] Box 2202 indicates the deposition of a first or substrate layer 116 on one or more sputtered metal layers 2300a, 2300b formed in box 2200. Example substrate layers include, but are not limited to, polymer layers (such as, but not limited to, polyimides forming the first or substrate polyimide layer). In one or more embodiments, the step includes spin-casting a polymer (e.g., polyimide) onto one or more metal layers 2300a, 2300b, and then pre-curing the polymer (e.g., polyimide).

[0200] Box 2204 indicates that the substrate 116 may be optionally patterned and / or etched to deposit one or more electrodes (e.g., WE and RE) and / or one or more contact pads 114. In one or more instances, patterning includes: depositing a dry etch mask (e.g., a photoresist dry etch mask) on the substrate 116; dry etching the substrate 116 through an opening in the dry etch mask; and stripping the dry etch mask from the substrate 116, thereby forming an etch pattern (including the first opening) in the substrate 116.

[0201] Box 2206 indicates that a metal 112 (second metal) containing CE is deposited onto an 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 instances, the steps include: sputtering or electron beam depositing the metal 112 onto a substrate 116 containing the etched pattern; depositing a mask (e.g., a photoresist wet etch mask) on the metal 112 deposited on the substrate 116; etching (e.g., wet etching) the metal through openings in the mask; and stripping the mask from the metal 112.

[0202] Box 2208 indicates the deposition of an insulating layer 104a (first insulating layer) on a substrate 116 and the deposition of metal 112 on the substrate 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 instances, the insulating layer 104a is blanket-deposited on the metal 112. In one or more further instances, the deposition includes: spin-casting the insulating layer 104a to cover the substrate 116 and the metal 112; and pre-curing the insulating layer 104a.

[0203] Box 2210 indicates the deposition and patterning of 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 instances, the steps include: sputtering / electron beam depositing a film (e.g., thin film) of metal 108 onto the first insulating layer 104a in a blanket manner; depositing a mask (e.g., a photoresist wet etching mask) on the metal sputtered onto the first insulating layer 104a; etching (e.g., wet etching) the metal through openings in the mask; and stripping the mask from the metal 108.

[0204] Box 2212 indicates the deposition of a second insulating layer 118 on the first insulating layer 104a and the deposition of metal 108 on the first insulating layer 104a. Examples of the second insulating layer include, but are not limited to, polymer layers (such as, but not limited to, polyimide forming the second insulating polyimide layer). In one or more instances, 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.

[0205] Box 2214 indicates, for example, using photolithography to pattern the second insulating layer 118 and to form an etched pattern in the second insulating layer 118, which includes a second well or second opening 2304 and a third well or third opening 2306.

[0206] Box 2216 indicates that the final curing of the structure formed in boxes 2200-2214 may be performed optionally.

[0207] Box 2218 indicates that residues may be optionally removed from the second insulating layer 118, for example, using O2.

[0208] Box 2220 represents the metal (fourth metal) and other layers required to deposit the WE. In one or more embodiments, the step includes: 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 step includes: depositing a photoresist stripping mask in the first well 2304; performing cleaning of the photoresist stripping mask (e.g., O2 plasma descaling); sputtering metal into the opening of the mask to form a metal pillar 124 extending through the opening from the exposed surface of the metal 108 in the first well 2304; and stripping / removing the mask, thereby leaving the pillar 124 on the metal 108.

[0209] Box 2222 indicates that a metal (the fifth metal) is deposited 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, using electroplating or screen printing to deposit the metal. Examples of metals used for the RE include, but are not limited to, Pt, gold, and Cr.

[0210] Box 2224 indicates the performance of a chemical step in which an additional chemically active layer / component is deposited on the WE (e.g., deposited onto a column) to enable the WE to function appropriately in a glucose sensor. Example components include, but are not limited to, one or more of the following: interference-inhibiting components as described herein, analyte-sensing component 410, protein component 416, adhesion-promoting layer 414, and analyte modulation layer 412 and / or capping layer.

[0211] Box 2226 indicates that the structure is fabricated into a separate sensor 100, for example, by cutting or laser patterning.

[0212] Box 2228 indicates the separation or removal (e.g., peeling) of individual analyte sensors 100a-d from substrate 2302. In one or more embodiments, the PVD method described herein involves adhesive force control that enables the separation of flexible elements or sensors 100a-d from substrate 2302 (e.g., glass) without damaging the CE and contact pads 110, 114. In one or more embodiments, the step includes removing (e.g., peeling) physical vapor-deposited metals 2300a, 2300b from (e.g., rigid) substrate 2002.

[0213] Box 2230 represents the final result, such as Figure 1A-1D The analyte sensor devices 100a-d, such as the glucose sensor, are shown in the figure. Figure 1A-1DExamples of bilateral single flexible sensors accommodating multiple electrodes and including electrodes on both sides of sensor flexibility 100a-d are shown, wherein the components of sensor 100a-d are flexible to form a flexible sensor (sensor flexibility). The flexibility or sensor 100a-100d includes WE and RE on the top side of the flexibility or sensor and CE on the back side of the flexibility 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 WE. However, in one or more instances, a chemical reaction is not required on the back side 102b of the flexibility or sensor 100a-d. Additional electrodes (not shown) for background sensors or differential sensors, etc., may also be included, and said electrodes may be connected to a transmitter connection scheme. Device 100a-d can be used for... Figure 3 In the voltage regulator circuit.

[0214] In one or more instances, the manufacturing method described herein can increase the working electrode area, prevent the "drift" effect, and / or simplify the manufacturing process.

[0215] Studies of the process parameters have revealed excellent process control, design control, and repeatability. The process is a high-throughput process and can be easily transferred between boards and 8'' wafers.

[0216] Example 7: Deposition of films and methods for controlling adhesion

[0217] Figure 24 This is a flowchart illustrating a method for depositing a film on a substrate. The method includes the following steps.

[0218] Box 2400 represents controlling the gas pressure in the chamber used for depositing metal using physical vapor deposition (PVD). In one or more instances, the step further includes controlling at least one additional PVD parameter selected from: the thickness of the metal, the number of metal layers, and the power used during physical vapor deposition.

[0219] Box 2402 indicates the deposition of metal on a substrate using physical vapor deposition (PVD).

[0220] Box 2404 indicates the deposition of a film on a metal.

[0221] Box 2406 indicates that the degree of adhesion of the film to the substrate is measured as a function of at least one PVD parameter (including pressure). In one or more embodiments, the measurement includes assigning an adhesion force score.

[0222] 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 thicknesses of each metal layer in the range of at least 100 angstroms (e.g., 1000-9000 Å).

[0223] Box 2408 represents the optional determination of the pressure or other PVD parameters required to achieve the desired adhesion force of the film to the substrate. In one or more instances, the step includes 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 on a Pareto chart. The adhesion scoring and determination / analysis steps of box 2408 can be executed in a processor or computer using computer-readable program code with 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 required to achieve the desired adhesion force.

[0224] Example 8: Method for manufacturing an apparatus

[0225] Figure 25 This is a flowchart illustrating a method for depositing a film or fabricating an apparatus on a substrate. The method includes the following steps.

[0226] Box 2500 indicates that a substrate (e.g., a rigid substrate) is placed in a physical vapor deposition (PVD) (e.g., sputtering) chamber.

[0227] Box 2502 indicates setting PVD conditions, which include the gas pressure in the chamber for depositing the PVD material. In one or more instances, the pressure is determined using the method described in Example 7.

[0228] Box 2504 indicates the deposition of PVD metal on a substrate using physical vapor deposition under pressure.

[0229] In one or more embodiments, the metal comprises multiple layers, each of which is deposited under different pressures.

[0230] In one or more embodiments, the PVD includes 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 which is 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 has a thickness of at least 100 angstroms (e.g., 1000-9000 Å). 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).

[0231] In one or more embodiments, the PVD-deposited metal comprises at least one structured layer selected from the following: patterned layer, roughened layer, non-uniform layer, layer containing voids, and layer including pillars.

[0232] Box 2506 represents, for example, the deposition of a film or device structure on a metal as described in Examples 4 and 6. The pressure selected in box 2602 may be associated with a predetermined adhesion force of the film to the substrate, which allows: (1) the film to be processed into a device while it is adhered to the substrate; and (2) the device to be removed (e.g., peeled off) from the substrate.

[0233] Box 2508 indicates that the membrane may optionally be processed into one or more devices. In one or more instances, the processing includes patterning or cutting the membrane.

[0234] Box 2510 indicates an optional stripping or removal device from the substrate.

[0235] Box 2512 represents the final result, for example, as shown below. Figure 1A-1D The device is shown in the illustration. In one or more embodiments, the device includes exposed surfaces S of PVD metals 2302a, 2302b, 2002a, 2002b stripped / removed from rigid substrates 2000, 2302. Example devices include, but are not limited to, devices comprising: microelectromechanical systems (MEMS) device structures, optoelectronic device structures, circuits, battery electrodes, fuel cell electrodes, or electrodes CE having electrochemically active surfaces 122. Microarrays and multi-electrode arrays can be fabricated.

[0236] As shown in this paper, studies of the process parameters have revealed excellent process control, design control, and repeatability. The process is a high-throughput process and can be easily transferred between boards and 8'' wafers.

[0237] In one or more instances, the spacing, 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 31-day period and / or the chemical products generated by the reactions of the working electrode and the counter electrode do not interfere with the performance of the electrode or the counter electrode (WE, CE) and produce harmful interactions (see [reference]). Figure 21D-21F ).

[0238] In one or more instances, in a group of at least 36 sensors 100a-100e manufactured using the methods described herein, the spacing D, arrangement, construction, and electroactivity of the working electrode WE and counter electrode CE in each sensor 100a-100e are such that the current (ISIG) output by each sensor in response to the same analyte concentration is within 15% (see [link to documentation]). Figure 21D-21F ).

[0239] In one or more embodiments, a PVD device is coupled to a processor or computer using computer-readable program code with instructions that, when executed, cause the processor or computer to control PVD deposition parameters in the PVD device to achieve a desired adhesion of the film to the substrate.

[0240] It should be understood that the present invention is not limited to the specific embodiments described, as these embodiments can, of course, vary. It should also be understood that the specialized terminology used herein is for the purpose of describing specific embodiments only and is not intended to be restrictive, as the scope of the invention is limited only by the appended claims. In the description of preferred embodiments, reference is made to the accompanying drawings, which form a part of the description, and in which specific embodiments in which the invention can be practiced are illustrated 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 invention.

[0241] However, although some embodiments of the invention are indicated, the description and specific examples are given by way of illustration rather than limitation. Many changes and modifications can be made within the scope of the invention without departing from its spirit, and the invention encompasses all such modifications.

Claims

1. A method for depositing a film on a substrate, the method comprising: Control the gas pressure in the chamber used for metal deposition using physical vapor deposition (PVD); The metal is deposited on the substrate using the PVD method; Depositing a film on the metal; as well as The degree of adhesion of the film to the substrate is measured as a function of the pressure. The metal comprises a first layer and a second layer, wherein the first layer is deposited on the substrate under a pressure ranging from 50 to 250 mTorr, and the second layer is deposited on the first layer under a pressure ranging from 2 to 50 mTorr.

2. The method of claim 1, further comprising determining the pressure required to achieve the desired adhesion force of the film to the substrate.

3. The method of claim 1, further comprising: The control is selected from at least one of the following physical vapor deposition parameters: the thickness of the metal, the number of layers of the metal, and the power used during the PVD; as well as The degree of adhesion of the film to the substrate is measured as a function of at least one PVD parameter.

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