Glucose sensor electrode design
阅读说明：本技术 葡萄糖传感器电极设计 (Glucose sensor electrode design ) 是由 阿克希尔·斯里尼瓦桑 巴里·P·彭 罗伯特·C·穆契奇 泰勒·R·黄 于 2019-02-06 设计创作，主要内容包括：一种单个挠性件双侧电极可用于连续葡萄糖监测传感器。在一个实例中,对电极置于挠性件的背侧,而工作电极置于传感器挠性件的顶侧。所述电极在沉积于基底衬底上的物理气相沉积金属上制造。仔细地控制所述电极对所述基底衬底的粘附力,使得所述电极可以在所述基底上加工并且随后在加工后从所述基底上移除。(A single flexure double-sided electrode may be used in a continuous glucose monitoring sensor. In one example, the counter electrode is placed on the backside of the flexure and the working electrode is placed on the topside of the sensor flexure. The electrodes are fabricated on physical vapor deposition metal deposited on a base substrate. The adhesion of the electrode to the base substrate is carefully controlled so that the electrode can be processed on the base and subsequently removed from the base after processing.)
1. An analyte sensor apparatus, comprising:
a working electrode;
a counter electrode;
an insulating layer located between the working electrode and the counter electrode, wherein:
the working electrode is spatially separated from the counter electrode by a distance of at least 1 micrometer,
the working electrode comprises a metal composition having an electroactive surface, and
the working electrode and the counter electrode are non-interdigitated; and
an analyte sensing layer on the working electrode, wherein the analyte sensing layer detectably changes the current at the working electrode in the presence of an analyte.
2. The device of claim 1, wherein the working electrode and the counter electrode are located on the same side of the analyte sensor device that includes a glucose sensor.
3. The apparatus of claim 1, wherein:
the working electrode is located on a first side of the insulating layer; and is
The counter electrode is on a second side of the insulating layer opposite the first side.
4. An analyte sensor apparatus, comprising:
a working electrode on a first side of the insulating layer, the working electrode comprising a metal composition having an electroactive surface;
a counter electrode on a second side of the insulating layer opposite the first side, wherein the insulating layer is between the counter electrode and the working electrode; and
an analyte sensing layer on the working electrode, wherein the analyte sensing layer detectably changes the current at the working electrode in the presence of an analyte.
5. The apparatus of claim 4, further comprising:
a reference electrode on the first side of the insulating layer;
an insulation between the reference electrode and the working electrode;
a first metal in electrical contact with the working electrode, the first metal comprising a first contact pad;
a second metal in electrical contact with the counter electrode, the second metal comprising a second contact pad; and wherein:
the insulating layer and the insulation comprise polyimide, and
the working electrode, the counter electrode, the insulating layer, the insulation, and the analyte sensing layer are flexible.
6. The device of claim 4, wherein the device is a glucose sensor.
7. The apparatus of claim 4, wherein:
the counter electrode comprises a physical vapor deposition metal removed from a rigid substrate, or
The apparatus further includes a base layer attached to the counter electrode and a physical vapor deposition metal on the base layer, the physical vapor deposition metal being removed from the rigid substrate.
8. The apparatus of claim 7, wherein the physical vapor deposition metal comprises at least one structured layer selected from the group consisting of: a patterned layer, a roughened layer, a non-uniform layer, and a layer comprising voids.
9. The apparatus of claim 7, wherein the physical vapor deposition metal comprises pillars.
10. The apparatus of claim 4, wherein the working electrode and the counter electrode are spaced such that, in response to a constant concentration of the analyte:
the current changes by less than 15% over a period of 31 days, and/or
Chemical products produced by the reaction at each of the working electrode and the counter electrode do not interfere with or deleteriously interact with the performance of the working electrode or the counter electrode.
11. A set of at least 36 sensors according to claim 4, wherein the spacing and electrical activity of the working and counter electrodes of each of the sensors is such that the current output by each of the sensors is within 15% in response to the same concentration of the analyte.
12. A method of manufacturing an analyte sensor apparatus, the method comprising:
depositing a working electrode on the first side of the insulating layer, the working electrode comprising a metallic composition having an electroactive surface;
depositing a counter electrode on a second side of the insulating layer, wherein the insulating layer is located between the counter electrode and the working electrode; and
depositing an analyte sensing layer on the working electrode, wherein the analyte sensing layer detectably changes the current at the working electrode in the presence of an analyte.
13. The method of claim 12, further comprising:
providing a base substrate;
depositing a metal on the base substrate using Physical Vapor Deposition (PVD);
depositing a film on the metal, the film comprising the insulating layer, the working electrode, and the counter electrode;
defining the analyte sensor in the membrane; and
removing the analyte sensor from the base substrate.
14. The method of claim 13, further comprising:
placing the base substrate in a Physical Vapor Deposition (PVD) chamber;
setting a gas pressure in the chamber;
depositing the metal on the base substrate using physical vapor deposition at the pressure;
depositing the film on the metal, wherein the pressure is associated with a predetermined adhesion of the film to the substrate that allows:
defining the analyte sensor when the membrane is adhered to the base substrate; and
removing the analyte sensor from the base substrate.
15. The method of claim 13, wherein the metal comprises at least one structured layer selected from the group consisting of: a patterned layer, a roughened layer, a non-uniform layer, and a layer comprising voids.
16. The method of claim 13, wherein the metal comprises a post.
17. The method of claim 13, wherein:
the metal comprises a second layer on a first layer, the first layer being between the second layer and the insulating layer;
the first layer is deposited under the pressure comprising a first pressure, and
the second layer is deposited at the pressure comprising a second pressure lower than the first pressure.
18. The method of claim 13, wherein the physical vapor deposition is at a pressure in a range of 2-250 mtorr.
19. The method of claim 18, wherein the metal is at least 100 angstroms thick.
20. The method of claim 19, wherein the physical vapor deposition comprises:
ionizing the gas to form ionized gas particles; and
accelerating the ionized gas particles onto a target comprising the metal using an electric and/or magnetic field having a power in a range of 10 watts to 100 kilowatts.
21. The method of claim 13, wherein depositing the film further comprises:
depositing the insulating layer comprising a first polyimide insulating layer on the metal;
depositing a second metal on the first polyimide insulating layer and patterning the second metal;
depositing a second insulating polyimide layer on the first insulating polyimide layer and depositing the second metal on the first insulating polyimide insulating layer;
forming a first opening and a second opening in the second insulating polyimide layer;
depositing a third metal into the first opening to form a working electrode;
depositing a fourth metal into the second opening to form a Reference Electrode (RE);
defining the analyte sensor in the membrane, the membrane comprising: the metal, the second metal, the third metal, the fourth metal, the first insulating polyimide layer, the second insulating polyimide layer, the working electrode, and the reference electrode; and
removing the analyte sensor from the base substrate, wherein the metal is the counter electrode.
22. The method of claim 12, wherein the depositing further comprises:
depositing a base layer comprising polyimide on the metal on the base substrate;
patterning a first opening in the base layer;
depositing a second metal in the first opening, thereby forming a counter electrode;
depositing the insulating layer comprising a first polyimide insulating layer on the base layer and the counter electrode;
depositing a third metal on the first polyimide insulating layer and patterning the third metal;
depositing a second insulating polyimide layer on the first insulating polyimide layer and depositing the third metal on the first insulating polyimide insulating layer;
forming a second opening and a third opening in the second insulating polyimide layer;
curing the base layer, the first insulating polyimide layer and the second insulating polyimide layer;
depositing a fourth metal into the second opening to form a working electrode;
depositing a fifth metal into the third opening to form a Reference Electrode (RE);
defining the analyte sensor in the membrane, the membrane comprising: the base polyimide layer, the first insulating polyimide layer, the second insulating polyimide layer, and the electrode; and
removing the analyte sensor from the base substrate.
Technical Field
The present invention relates to an electrode for a glucose sensor and a method for manufacturing the same.
Background
Electrochemical sensors are commonly used to detect or measure the concentration of an analyte in vivo, such as glucose. Typically, in such analyte sensing systems, the analyte (or a substance derived therefrom) is electroactive and produces a detectable signal at an electrode in the sensor. This signal is then correlated with the presence or concentration of the analyte within the biological sample. In some conventional sensors, an enzyme is provided that reacts with the analyte to be measured, with the by-products of the reaction being either qualitative or quantitative at the electrodes. In one conventional glucose sensor, 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.
Various electrochemical glucose sensors are multi-layered, including electrodes on and/or covered by layers of various materials. Multilayer sensors have many desirable characteristics, including the fact that: the functional characteristics of such sensors can be tailored by varying certain design parameters (e.g., number of internal layers, layer thicknesses, electrode area and architecture, etc.). However, the inventors of the present invention have found that undesirable interactions between the anode and cathode in conventional sensors degrade sensor performance. Accordingly, there is a need for sensor fabrication methods and electrode structures that reduce or prevent undesirable cathode-anode interactions, thereby improving sensor performance. The present disclosure satisfies this need.
Disclosure of Invention
The present disclosure describes an analyte sensor apparatus (e.g., a glucose sensor) comprising: a working electrode; a counter electrode; an insulating layer positioned between the working electrode and the counter electrode, wherein the working electrode is spatially separated from the counter electrode by a distance of at least 1 micron, the working electrode comprises a metallic composition having an electroactive surface, and the working electrode and the counter electrode are non-interdigitated. An analyte sensing layer on the working electrode detectably changes the current at the working electrode in the presence of an analyte.
In one or more embodiments, the working electrode and the counter electrode are located on the same side of the analyte sensor apparatus.
In other embodiments, the working electrode is located on a first or top side of an insulating layer and the counter electrode is located on a second or back side of the insulating layer opposite the first side, e.g., so that the electrodes are located on both the top and back sides of the sensor flexure. Conventional approaches place the electrodes only on the top side of the sensor flexure. Thus, embodiments of the present invention eliminate the need to have multiple sensor flexures in one device.
The illustrative embodiment further comprises: a reference electrode on the first side of the insulating layer; an insulation between the reference electrode and the working electrode; a first metal in electrical contact with the working electrode, the first metal comprising a first contact pad; a second metal in electrical contact with the counter electrode, the second metal comprising a second contact pad. Example materials for the insulating layer and the insulation include, but are not limited to, polyimide, and the working electrode, the counter electrode, the insulating layer, the insulation, and the analyte sensing layer may be flexible.
Exemplary electrode surface metals for the counter electrode include, but are not limited to, gold, platinum, silver, and the like. In one or more embodiments, the conventional electroplated platinum layer in the working electrode is replaced with a layer comprising platinum posts, and the conventional electroplated reference electrode is replaced with a reference electrode comprising screen printed or dispensed silver-silver chloride or the like.
In yet further embodiments, the counter electrode comprises a Physical Vapor Deposition (PVD) metal removed from a rigid substrate, or the apparatus further comprises a base layer attached to the counter electrode and a PVD metal located on the base layer, and the PVD metal is removed from the rigid substrate.
As shown herein, embodiments of the sensors disclosed herein exhibit surprising and unexpected performance improvements over conventional sensors. In one or more instances, the working electrode and the counter electrode are spaced, configured, and arranged such that, in response to a constant analyte concentration, (1) the current varies by less than 15% over a 31 day period, and/or (2) chemical products produced by reactions at each of the working electrode and the counter electrode do not interfere with or deleteriously interact with the performance of the working electrode or the counter electrode.
The present disclosure further reports developing techniques for controlling the adhesion of PVD metal films by PVD processes. Various PVD parameters were evaluated by multiple design of experiments (DOE). It was unexpectedly and surprisingly found that pressure had the greatest and most significant effect on adhesion, and that the process achieved different levels of adhesion when the pressure was controlled and varied during PVD.
The present disclosure further reports how deposition of rough or columnar structures in a metal film reduces surface area contact with the substrate/surface in a highly controlled manner, helping to control adhesion when modulating deposition pressure.
In one or more examples, the PVD process parameters include a pressure in a range of 2-250mTorr, a PVD power in a range of 10 watts to 100 kilowatts, and depositing a metal to a thickness of at least 100 angstroms.
In one example, PVD deposition with pressure modulation is used to fabricate a Backside Counter Electrode (BCE) for glucose sensors, where the adhesion of metal to the glass substrate is strong enough to survive machining and laser cutting, but weak enough to allow easy physical removal from the glass substrate used for the assembly process.
One illustrative method of manufacture for an analyte sensor apparatus includes: providing a base substrate; depositing a metal on the base substrate using PVD; depositing a film on the metal, the film comprising the insulating layer, the working electrode, and the counter electrode; defining the analyte sensor in the membrane; and removing the analyte sensor from the base substrate. In one or more examples, the metal includes a second layer on a first layer, the first layer being between the second layer and the insulating layer; the first layer is deposited at the pressure comprising a first pressure and the second layer is deposited at the pressure comprising a second pressure lower than the first pressure.
Another illustrative method of manufacture for an analyte sensor apparatus includes: depositing the insulating layer comprising a first polyimide insulating layer on the metal; depositing a second metal on the first polyimide insulating layer and patterning the second metal; depositing a second insulating polyimide layer on the first insulating polyimide layer and depositing the second metal on the first insulating polyimide insulating layer; forming a first opening and a second opening in the second insulating polyimide layer; depositing a third metal into the first opening to form a working electrode; depositing a fourth metal into the second opening to form a Reference Electrode (RE); defining the analyte sensor in the membrane, the membrane comprising: the metal, the second metal, the third metal, the fourth metal, the first insulating polyimide layer, the second insulating polyimide layer, the working electrode, and the reference electrode; and removing the analyte sensor from the base substrate, wherein the metal is the counter electrode.
Yet another illustrative method of manufacturing for an analyte sensor apparatus includes:
depositing a base layer comprising polyimide on the metal on the base substrate; patterning a first opening in the base layer; depositing a second metal in the first opening, thereby forming a counter electrode; depositing the insulating layer comprising a first polyimide insulating layer on the base layer and the counter electrode; depositing a third metal on the first polyimide insulating layer and patterning the third metal; depositing a second insulating polyimide layer on the first insulating polyimide layer and depositing the third metal on the first insulating polyimide insulating layer; forming a second opening and a third opening in the second insulating polyimide layer; curing the base layer, the first insulating polyimide layer and the second insulating polyimide layer; depositing a fourth metal into the second opening to form a working electrode; depositing a fifth metal into the third opening to form a Reference Electrode (RE); defining the analyte sensor in the membrane, the membrane comprising: the base polyimide layer, the first insulating polyimide layer, the second insulating polyimide layer, and the electrode; and removing the analyte sensor from the base substrate.
In one or more embodiments, a set of at least 36 sensors fabricated using the methods presented herein each have a working electrode spaced apart from the pair of electrodes such that the current output by each of the sensors is within 15% in response to the same analyte concentration.
Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating some embodiments of the present invention, are given by way of illustration and not limitation. Many changes and modifications may be made within the scope of the present invention without departing from the spirit thereof, and the invention includes all such modifications.
Drawings
Fig. 1A-1D illustrate an amperometric sensor having a WE and a CE on opposite sides in accordance with one or more embodiments.
Fig. 1E illustrates an amperometric sensor of WE and CE having a distance D of at least 1 micrometer inch on the same side of the device, in accordance with one or more embodiments of the present invention.
Fig. 1F and 1G compare the structure of a control sensor (fig. 1F) having interdigitated working and counter and reference electrodes in accordance with one or more embodiments of the present invention, and in which the working, counter and reference electrodes are located on only one side and are close enough to exhibit an undesirable electrode, with the sensor including an electrode on the opposite side (fig. 1G).
Fig. 1H illustrates a plurality of planar layered elements for use in an amperometric sensor.
Figure 2 provides a perspective view illustrating one type of subcutaneous sensor insertion kit, telemetry characteristic monitor transmitter device and data receiving device, components that may be suitable for use with embodiments of the present invention.
FIG. 3 shows a schematic diagram of a voltage regulator that may be used to measure current in an embodiment of the invention. As shown in fig. 3, voltage regulator 300 may include an operational amplifier 310 connected in circuit to have two inputs: vset and Vmeasured. As shown, Vmeasured is a measure of the voltage between the reference electrode and the working electrode. Vset, on the other hand, is the optimum desired voltage across the working and reference electrodes. The current between the counter electrode and the reference electrode is measured, producing a current measurement (isig) output from the potentiostat.
FIG. 4 illustrates an apparatus for depositing material using sputtering according to one or more embodiments of the invention.
Fig. 5 shows a test sample comprising a stack of layers on a glass substrate according to one or more embodiments of the invention.
Fig. 6A illustrates different patterns a-E of knife-scribed or laser-cut marks simulating the type of marks and cuts that may be applied during electrode processing in a glucose sensor, applied to a layer stack on a glass substrate, according to one or more embodiments of the invention.
Fig. 6B shows a pattern of silver layer applied on a glass substrate, showing that the adhesion of silver to glass is too weak to allow replication of the marks on the silver layer.
Fig. 7A-7D illustrate different adhesion scores assigned to samples fabricated under different sputtering conditions, in accordance with one or more embodiments of the present invention.
Fig. 8A shows a test sample without gold posts, and fig. 8B shows a test sample with gold posts according to one or more embodiments of the invention.
Fig. 9 is a Scanning Electron Microscope (SEM) image of a columnar interface between a glass substrate and a gold layer according to one or more embodiments of the invention.
10A-10D illustrate films on test samples fabricated using various sputtering conditions and after laser cutting with example electrode patterns, in accordance with one or more embodiments of the present invention.
Fig. 11 shows a pareto chart of the normalized effect of varying pressure, power, and gold thickness on adhesion of samples fabricated using gold pillars located at the interface between the gold layer and the glass substrate, according to one or more embodiments of the invention.
FIG. 12 is a graph of average rate as a function of pressure, power, and gold thickness according to one or more embodiments of the invention.
Fig. 13 is a contour plot of rate versus gold layer thickness and pressure in accordance with one or more embodiments of the invention.
Fig. 14 illustrates another test sample including a stack of layers on a glass substrate according to one or more embodiments of the invention.
Fig. 15A shows a film on the test sample of fig. 6A including a gold layer deposited using sputtering conditions of 100mTorr pressure, 1.5kW power, 5 minute duration, in accordance with one or more embodiments of the present invention.
Fig. 15B illustrates a film on the test sample of fig. 14 including a first layer of gold deposited using sputtering conditions of 100mTorr pressure, 1.5kW power, 5 minute duration and a second layer of gold deposited using sputtering conditions of 4mTorr pressure, 0.2kW power, 10 minute duration in accordance with one or more embodiments of the present invention.
Fig. 15C, 15D and 15E show that the adhesion of the film on the test sample of fig. 14 with two gold layers and deposited using the conditions of fig. 15B varies depending on the location on the surface area.
FIG. 16 illustrates a pareto chart of the normalized effect of varying pressure, power, and gold thickness on sputtering rate, according to one or more embodiments of the invention.
FIG. 17 is a graph of average sputtering rate as a function of pressure, power, and gold thickness according to one or more embodiments of the invention.
FIG. 18 is a line contour plot of sputtering rate versus sputtering power (kW) and pressure (mTorr) in accordance with one or more embodiments of the invention.
FIG. 19 is a flow chart illustrating a method of manufacturing a sensor or sensor flexure according to one or more embodiments of the present invention.
FIG. 20 illustrates fabrication of a backside counter electrode sensor embodiment using the PVD methods described herein.
FIGS. 21A-21C illustrate SITS results for a control sensor (
FIGS. 21D-21F illustrate SITS results (representing performance of the sensor of FIG. 1D) for the sensor of FIG. 1G, where FIGS. 21D and 21E plot the change in ISIG over time (day of 5 months) and FIG. 21F plots Vcounter (voltage on counter electrode) over time (day of 5 months), in accordance with one or more embodiments of the present invention. The different traces in fig. 21D-21F represent the results of different sensors and show that the smooth backside CE design has the ability to support sensor functionality and, importantly, reduce sensor-to-sensor performance variability and improve performance stability over the life of the test for the sensor of fig. 1D compared to the sensor of fig. 1F.
FIG. 22 is a flow chart illustrating a method of manufacturing a sensor or sensor flexure in accordance with one or more embodiments of the present invention.
FIG. 23 is a schematic diagram illustrating a method of manufacturing a sensor or sensor flexure using the flowchart of FIG. 22, in accordance with one or more embodiments of the invention.
FIG. 24 is a flow diagram illustrating a method of depositing a film on a substrate according to one or more embodiments of the invention.
FIG. 25 is a flow diagram illustrating a method of fabricating a device on a substrate according to one or more embodiments of the invention.
Detailed Description
Unless defined otherwise, all technical terms, symbols, and other scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In some instances, terms having commonly understood meanings may be defined herein for clarity and/or ease of reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is commonly understood in the art. Those skilled in the art will readily understand and generally employ many of the techniques and procedures described or referenced herein using routine methodology.
All numbers expressing values which can be numerically characterized with a value other than an integer (e.g., thickness) recited in the specification and the associated claims are to be understood as being modified by the term "about". Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. In addition, all publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications cited herein are incorporated by reference for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such publication by virtue of an earlier priority date or priority date of invention. Furthermore, the actual publication date may be different from that shown and require independent verification.
As discussed in detail below, embodiments of the present invention relate to the use of an electrochemical sensor to measure an analyte of interest or to indicate the concentration of an analyte or a substance present in a fluid. In some embodiments, the sensor is a continuous device, such as a subcutaneous, percutaneous, or intravascular device. In some embodiments, the device may analyze a plurality of intermittent blood samples. The sensor embodiments disclosed herein may use any known method, including invasive, minimally invasive, and non-invasive sensing techniques, to provide an output signal indicative of the concentration of the analyte of interest. Typically, the sensor is of the type that senses the product or reactant of an enzymatic reaction between an analyte and an enzyme in the presence of oxygen 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 electrochemical methods, and thus the output of the electrode system serves as a measure of the analyte.
Embodiments of the invention disclosed herein provide sensor types for subcutaneous or transcutaneous monitoring of blood glucose levels in diabetic patients, for example. Various implantable electrochemical biosensors have been developed to treat diabetes and other life-threatening diseases. Many existing sensor designs use some form of immobilized enzyme to achieve their biospecificity. The embodiments of the invention described herein may be adapted and implemented using a variety of known electrochemical sensor elements, including, for example, electrochemical sensor elements disclosed in the following documents: U.S. patent application nos. 20050115832, 20050008671, 20070227907, 20400025238, 20110319734, 20110152654 and 13/707,400 filed 12/6/2012; U.S. Pat. nos. 6,001,067, 6,702,857, 6,212,416, 6,119,028, 6,400,974, 6,595,919, 6,141,573, 6,122,536, 6,512,939, 5,605,152, 4,431,004, 4,703,756, 6,514,718, 5,985,129, 5,390,691, 5,391,250, 5,482,473, 5,299,571, 5,568,806, 5,494,562, 6,120,676, 6,542,765, 7,033,336, and PCT international publications nos. 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.
A. Illustrative embodiments and related features of the invention
The controlled adhesion of Physical Vapor Deposition (PVD) metal films is a widely presented challenge and problem throughout the MEMS and semiconductor industries as well as in flexible circuit applications. For various applications, metal films are often required to maintain very specific adhesion levels to the surface/substrate on which they are deposited. In some cases, strong adhesion is desired, while in other applications, weak adhesion is desired. In the most challenging cases, it is desirable to mix weak adhesion with and adhesion, where the adhesion is strong enough to withstand a particular aspect of an application, but weak enough for other aspects of the application to function properly.
As demonstrated herein, the present disclosure describes an effective method for adjusting and controlling the adhesion of PVD films deposited on a surface/substrate. A series of comprehensive studies were performed to evaluate PVD deposition factors and their effect on adhesion properties, and pressure was found to be a key significant factor in adjusting adhesion. This single factor is a key component of PVD deposition and is controllable in the PVD process; therefore, pressure is a desirable factor for controlling film adhesion. The illustrative methods described herein are applicable to all PVD systems for depositing thin or thick films.
From a device point of view, it is of particular interest to use pressure modulation to control adhesion so that it is possible to manufacture and produce devices in which the PVD layer is deposited in direct contact with the carrier substrate and at the same time is releasable on the basis of adhesion measurements. Fig. 1A illustrates an example of a device such as may be used for diabetes applications, such as but not limited to a Continuous Glucose Monitoring (CGM) sensor where the electrodes are on both sides (topside and backside) of a single sensor flexure. As demonstrated herein, pressure modulation provides an efficient method to adjust the adhesion of the backside electrode to the carrier substrate, enabling release at specific points throughout the downstream manufacturing process. Placing the contact pads of each of the electrodes on either side of the sensor flexure enables a wider array of connection schemes to the transmitter. Moreover, adjusting the adhesion may be used to minimize newly added processing steps for the backside electrode. In general, adhesion control as demonstrated herein can be used to reduce manufacturing complexity by significant edge compared to conventional sensors.
Importantly, the novel methods of controlling adhesion described herein can be achieved using standard materials, equipment, and facilities associated with PVD.
Methods for forming an analyte sensor including an electrode disclosed herein may include multiple steps. For example, such methods may include forming a working electrode, a counter electrode, and a reference electrode on a base substrate and/or forming a plurality of contact pads on a base substrate and/or forming a plurality of electrical conduits on a base substrate. In certain embodiments of the invention, the method comprises forming a plurality of working electrodes, counter electrodes, and reference electrodes, the electrodes being clustered together in a unit consisting essentially of one working electrode, one counter electrode, and one reference electrode. The electrodes are formed on a base substrate, and the clustering units are longitudinally distributed on at least one longitudinal arm of the base substrate in a unit repeating pattern. Optionally, in such methods, the working electrode is formed as an array of conductive members disposed on the base substrate, the conductive members being circular and between 10 μm and 400 μm in diameter, and the array comprising at least 10 conductive members. The method can further include forming an analyte sensing layer on the working electrode, wherein the analyte sensing layer detectably changes the current on the working electrode in the presence of the analyte. Typically, these methods further comprise forming an analyte modulation layer on the analyte sensing layer, wherein the analyte modulation layer modulates diffusion of the analyte therethrough.
Yet another embodiment of the present invention is an analyte sensor apparatus comprising a base substrate comprising a well containing a metal electrode composition formed using a sputtering process disclosed herein. In such embodiments, the structure of the platinum composition is formed to include a central planar region and an edge or ridge region surrounding the central planar region. In such embodiments, the thickness or height of the metal composition at the edges is 2X less than the average thickness of the metal composition in the central planar region. In some embodiments of the invention, the well comprises a lip surrounding the well; and the edge region of the metallic composition is located below the lip of the well. Typically, in these embodiments, both central planar regions form the electroactive surfaces of the working electrodes in the sensor. Sensor embodiments of the invention generally include an additional layer of material coated on the working electrode, such as an analyte sensing layer disposed on the working electrode that detectably changes the current at the working electrode in the presence of an analyte; and an analyte modulation layer disposed over the analyte sensing layer, the analyte modulation layer modulating diffusion of the analyte therethrough.
In an exemplary embodiment of the invention, the electrodes are formed in wells of a base substrate comprising a dielectric material (e.g., polyimide). Typically, the well includes a conductive material (e.g., Au) disposed at the bottom of the well. Optionally, the wells in the base substrate are rectangular or circular. In certain embodiments of the invention, the base substrate comprises at least 10, 20 or 30 wells formed as a microarray. In a typical sensor embodiment, a base substrate is formed such that the base substrate includes a well that includes a lip surrounding the well. In certain methods disclosed herein, the metal composition is sputtered such that the metal composition is located under the lip of the well. In addition, various conductive elements may be disposed on the base substrate. In some embodiments of the invention, the base substrate comprises a plurality of reference electrodes, a plurality of working electrodes, and a plurality of counter electrodes clustered together in a unit consisting essentially of one working electrode, one counter electrode, and one reference electrode, and the clustered units are distributed longitudinally on the base in a unit repeating pattern.
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 base substrate. In some embodiments of the invention, the analyte sensor apparatus comprises 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 an analyte concentration based on the electrochemical signal data obtained from the working electrode. In certain embodiments of the invention, the processor compares electrochemical signal data obtained from multiple working electrodes, for example to adapt different electrodes to sense different analytes and/or to focus on different concentration ranges of a single analyte; and/or identifying or characterizing stray sensor signals (e.g., sensor noise, signals caused by interfering compounds, etc.) to improve the accuracy of the sensor readings.
In some embodiments of the invention, the base structure comprises a flexible but rigid and flat structure suitable for use in photolithographic masking and etching processes. In this regard, the base structure typically comprises at least one surface having a highly uniform flatness. The substrate structure material may comprise, for example, metals such as stainless steel, aluminum and nickel titanium memory alloys (e.g., NITINOL), and polymer/plastic materials such as delrin, etc. The base structure material may be made of or coated with a dielectric material. In some embodiments, the base structure is non-rigid and may be a film layer or an insulating layer that serves as a substrate for patterning electrical elements (e.g., electrodes, traces, etc.), such as a plastic like polyimide. The initial step in the method of the invention generally involves the formation of the base substrate of the sensor. Optionally, during sensor production, the flat sheet of material is formed and/or mounted on a support such as a glass or ceramic plate. The base structure may be mounted on a support (e.g. a glass plate) by PVD. This may then be followed by a series of lithographic and/or chemical masking and etching steps to form the conductive components. In an illustrative form, the base substrate comprises a thin film sheet of insulating material, such as a polyimide substrate for patterning electrical components. The base substrate structure may include one or more of a variety of elements including, but not limited to, carbon, nitrogen, oxygen, silicon, sapphire, diamond, aluminum, copper, gallium, arsenic, lanthanum, neodymium, strontium, titanium, yttrium, or combinations thereof.
The method of the present invention comprises forming a conductive layer that acts as one or more sensing elements on a base substrate. Typically, these sensing elements include electrodes, electrical conduits (e.g., traces, etc.), contact pads, etc., which are formed by one of various methods known in the art for defining the geometry of the active electrodes, such as photolithography, etching, and rinsing. The electrode can then be made of an electrochemically active material with a defined architecture, for example by using sputtered Pt black as the working electrode. The sensor layer (e.g., analyte sensing enzyme layer) can then be disposed on the sensing layer by electrochemical deposition or other methods other than electrochemical deposition (e.g., spin coating), followed by vapor crosslinking with, for example, dialdehyde (glutaraldehyde) or carbodiimide.
In an exemplary embodiment of the invention, a base substrate is first coated with a thin film conductive layer by electrode deposition, surface sputtering, or other suitable patterning or other process steps. In one embodiment, this conductive layer may be provided as a plurality of thin film conductive layers, such as an initial chromium-based layer suitable for chemical adhesion to a polyimide base substrate, a gold-based thin film layer and a chromium-based thin film layer that are subsequently formed in sequence. In alternative embodiments, other electrode layer configurations or materials may be used. The conductive layer is then covered with a selected photoresist coating in accordance with conventional photolithography techniques, and a contact mask may be applied over the photoresist coating for suitable photoimaging. The contact mask typically contains one or more patterns of conductor traces for proper exposure of the photoresist coating, followed by an etching step to leave a plurality of conductive sensor traces on the base substrate. In an exemplary sensor configuration designed for use as a subcutaneous glucose sensor, each sensor trace may contain two or three parallel sensor elements corresponding to two or three separate electrodes (e.g., a working electrode, a counter electrode, and a reference electrode).
Embodiments of the invention include methods of adding a plurality of materials to one or more surfaces of one or more sputtering 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 base substrate; forming a conductive layer on a base substrate, wherein the conductive layer comprises an electrode formed by a sputtering process that produces a metal pillar of a certain architecture, thereby forming an analyte sensing layer on the conductive layer, wherein the analyte sensing layer comprises a composition that can alter the current at the electrode 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 diffusion of an analyte therethrough; and forming a cover layer disposed on at least a portion of the analyte modulating layer, wherein the cover layer further comprises an aperture over at least a portion of the analyte modulating layer.
In a possible embodiment of the invention disclosed herein, the analyte sensing layer comprises 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 modulating layer comprises a hydrophilic comb copolymer having a central chain and a plurality of side chains coupled to the central chain, wherein at least one side chain comprises a silicone moiety. Typically, the device includes a biocompatible material on the outer surface that is suitable for contacting biological tissue or fluid when implanted in vivo. In a possible embodiment of the invention disclosed herein, the analyte sensor apparatus is an amperometric glucose sensor that exhibits a highly desirable oxygen response curve. In such embodiments, the amperometric glucose sensor generates a first signal in a solution comprising 100mg/dL glucose and 5% oxygen and a second signal in a solution comprising 100mg/dL glucose and 0.1% oxygen (i.e., the only difference is in the test conditions of oxygen%), and the first signal and the second signal differ by less than 10%.
Additional functional coatings or overlays can then be applied to the electrodes or other sensor elements by any of a variety of methods known in the art (e.g., spray coating, dip coating, etc.). Some embodiments of the invention include an analyte modulation layer deposited over an enzyme-containing layer disposed over a working electrode. By utilizing the analyte limiting membrane layer in addition to modulating the amount of one or more analytes in contact with the active sensor surface, the problem of foreign materials contaminating the sensor is avoided. As is known in the art, the thickness of the analyte modulating membrane layer may affect the amount of analyte that reaches the active enzyme. Therefore, their application is usually carried out under defined processing conditions and their dimensional thickness is closely controlled. Microfabrication of the bottom layer may be a factor affecting the dimensional control of the analyte modulating membrane layer and the exact composition of the analyte limiting membrane layer material itself. In this regard, several types of copolymers, for example, copolymers of silicone and non-silicone moieties, have been found to be particularly useful. These materials can be microdispersed or spin-coated to a controlled thickness. Its final architecture may also be designed by patterning and lithography techniques consistent with the other discrete structures described herein.
In some embodiments of the invention, the sensor is made by a method of applying an analyte modulating layer comprising a hydrophilic membrane coating that can modulate the amount of analyte that can come into contact with the enzyme of the sensor layer. For example, a cover layer added to a glucose sensing element of the invention may include a glucose limiting membrane that modulates the amount of glucose that is in contact with the glucose oxidase layer on the electrodes. Such glucose limiting membranes may be made of a variety of materials known to be suitable for such purposes, for example, silicones such as polydimethylsiloxane, polyurethanes, cellulose acetate, perfluorosulfonic acid, polyestersulfonic acid (e.g., Kodak AQ), hydrogels or any other membrane known to those skilled in the art suitable for such purposes. In certain embodiments of the present invention, the analyte modulating layer comprises a hydrophilic polymer. In some embodiments of the invention, the analyte modulating layer comprises a linear polyurethane/polyurea polymer and/or a branched acrylate polymer; and/or mixtures of such polymers.
In some embodiments of the methods of the present invention, an adhesion promoter layer is disposed between the cover layer (e.g., the analyte modulating membrane layer) and the analyte sensing layer to facilitate contact thereof and is selected to increase stability of the sensor device. As described herein, the adhesion promoter layer is selected to provide a number of desirable characteristics in addition to the ability to provide sensor stability. For example, some compositions used in the adhesion promoter layer are selected to play a role in interference suppression and control mass transport of the desired analyte. The adhesion promoter layer may be made of any of a variety of materials known in the art for promoting adhesion between such layers, and may be applied by any of a variety of methods known in the art.
Finished sensors produced by such methods are typically quickly and easily removed from the support structure (if a support structure is used), for example, by cutting along a line around each sensor on the support structure, and then peeling from the support structure. The cutting step may use methods commonly used in the art, such as methods incorporating UV laser cutting devices for cutting the base and cover layers and functional coating along lines (typically in at least slightly outwardly spaced relation to the conductive elements) that surround or wrap around each sensor, such that sufficient interconnecting base and cover layer material remains to seal the side edges of the finished sensor. As demonstrated herein, because the base substrate is sufficiently weakly adhered directly to the underlying support, the sensor can be quickly and easily lifted from the support structure without significant further processing steps or potential damage due to stresses created by excessive force applied to peel the attached sensor from the support structure. The support structure may then be cleaned and reused, or otherwise discarded. One or more functional coatings may be applied before or after other sensor components are removed (e.g., by cutting) from the support structure.
Embodiments of the invention also include a method of sensing an analyte (e.g., glucose) in a mammal (e.g., a diabetic patient), the method comprising: the analyte sensor embodiments disclosed herein are implanted into an in vivo environment and then sense one or more electrical fluctuations (e.g., a change in current at the working electrode) and correlate the change in current to the presence of the analyte such that the analyte is sensed. Generally, the method comprises: implanting a glucose sensor disclosed herein within a tissue gap of a diabetic individual, sensing a change in current at a working electrode in the presence of glucose; and then correlating the change in current with the presence of glucose such that glucose is sensed. Although exemplary embodiments of the present invention relate to glucose sensors, the sputtered sensor electrodes disclosed herein may be adapted for use with a variety of devices known in the art.
As discussed in detail below, embodiments of the present invention include sensor systems that include additional elements designed to facilitate analyte sensing. For example, in certain embodiments of the present invention, a substrate material comprising sensor electrodes is disposed within a housing (e.g., a lumen of a catheter) and/or associated with other components that facilitate analyte (e.g., glucose) sensing. One exemplary sensor system includes a processor; a substrate comprising a first longitudinal member and a second longitudinal member, each of the first longitudinal member and the second longitudinal member comprising 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 electrode; and calculating analyte presence or concentration based on the electrochemical signal data obtained from the electrode. Embodiments of the invention described herein may also be adapted and implemented using amperometric sensor configurations such as those disclosed in: U.S. patent application publication nos. 20070227907, 20400025238, 20110319734, and 20110152654, the contents of each of which are incorporated herein by reference.
B. Illustrative analyte sensor compositions and sensor stacks for use in embodiments of the invention
The following disclosure provides examples of typical elements/compositions used in sensor embodiments of the present invention. Although these elements may be described as discrete units (e.g., layers), one skilled in the art will appreciate that the sensor may be designed to contain a combination of some or all of the material properties and/or functions of the elements/components discussed below (e.g., elements that act as supporting substrate components and/or conductive components and/or matrices for analyte sensing components and further serve as electrodes in the sensor). Those skilled in the art will appreciate that these thin film analyte sensors may be adapted for use in a number of sensor systems, such as those described below.
Fig. 1A-1D illustrate embodiments of
WE includes a
Fig. 1D illustrates an embodiment of the sensor 100D, wherein the backside CE is/comprises a layer capable of controlling adhesion to the substrate and to the electrodes in the sensor device 100D.
Fig. 1E illustrates an analyte sensor apparatus 100E that includes working electrodes WE and CE on a first side (the same side) 126 of a
In one or more embodiments, the devices of FIGS. 1A-1E can be fabricated using PVD and/or electroplating.
Fig. 1F and 1G compare the structure of a
In one or more embodiments, the
Base composition
The sensors of the present invention generally comprise a substrate composition (see, e.g., element 104b in FIG. 1D,
Conductive component
Electrochemical sensors of the invention generally comprise a conductive composition comprising at least one electrode comprising a metal for contacting the analyte or a byproduct thereof (e.g., oxygen and/or hydrogen peroxide) to be determined (see, e.g., WE in fig. 1B-1F) disposed on a substrate composition. The term "conductive component" is used herein according to art-recognized dedication and refers to conductive sensor elements, such as electrodes, contact pads, traces, and the like. Illustrative examples of such conductive elements are those forming a working electrode that can measure an increase or decrease in current in response to exposure to a stimulus, such as a change in the concentration of an analyte or a byproduct thereof, as compared to a reference electrode that does not undergo a change in the concentration of an analyte (a co-reactant (e.g., oxygen) used when the analyte interacts with a composition present in the
In addition to the working electrode, the analyte sensors of the present invention typically comprise a Reference Electrode (RE) or a combined reference and counter electrode (also referred to as a quasi-reference electrode or counter/reference electrode). If the sensor does not have a counter/reference electrode, it may contain a separate Counter Electrode (CE), which may be made of the same or different material as the working electrode. Typical sensors of the invention have one or more working electrodes and one or more counter, reference and/or counter/reference electrodes. One embodiment of the sensor of the present invention has two, three, or four or more working electrodes. The working electrodes in the sensor may be integrally connected or they may be kept separate. Optionally, the electrodes may be disposed on a single surface or side of the sensor structure. Alternatively, the electrodes may be arranged on multiple surfaces or sides of the sensor structure. In certain embodiments of the invention, the reactive surfaces of the electrodes have different relative areas/sizes, e.g., a 1X reference electrode, a 3.2X working electrode, and a 6.3X counter electrode.
Interference suppressing component
The electrochemical sensors of the invention optionally comprise an interference suppressing component disposed between the electrode surface and the environment to be measured. In particular, certain sensor embodiments rely on the oxidation and/or reduction of hydrogen peroxide generated by an enzymatic reaction on the surface of the working electrode at a constant applied potential. Because amperometric detection based on direct oxidation of hydrogen peroxide requires a relatively high oxidation potential, sensors employing this detection scheme may experience interference from oxidizable species present in biological fluids (such as ascorbic acid, uric acid, and acetaminophen). In this context, the term "interference suppressing component" is used herein according to art-recognized terminology and refers to a coating or film in the sensor that functions to suppress stray signals generated by such oxidizable species that interfere with detecting signals generated by the analyte to be sensed. Certain interference-inhibiting components act by size exclusion (e.g., by excluding interfering species of a particular size). Examples of interference rejection components include one or more compound layers or coatings, such as hydrophilic polyurethanes, cellulose acetates (including cellulose acetates incorporating agents such as poly (ethylene glycol), polyethersulfones, polytetrafluoroethylene, perfluoroionomers, Nafion @TMPolyphenylenediamine, epoxy resins, etc.).
Analyte sensing element
The electrochemical sensors of the present invention comprise an analyte sensing constituent disposed on an electrode of the sensor (see, e.g.,
Typical sensor embodiments of this element of the invention utilize an enzyme (e.g. glucose oxidase) that has been combined with a second protein (e.g. albumin) in a fixed ratio and then applied to the surface of an electrode to form a thin enzyme component (e.g. an enzyme that is typically optimized for glucose oxidase stability properties). In typical embodiments, the analyte sensing constituent comprises a mixture of GOx and HSA. In typical embodiments of analyte sensing compositions having GOx, the GOx reacts with glucose present in the sensing environment (e.g., the body of a mammal) and produces hydrogen peroxide.
As described above, the enzyme and the second protein (e.g., albumin) are typically treated to form a cross-linked matrix (e.g., by adding a cross-linking agent to the protein mixture). As is known in the art, the crosslinking conditions can be manipulated to modulate factors such as the retained biological activity of the enzyme, its mechanical and/or operational stability. Illustrative crosslinking 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 crosslinking agent (such as, but not limited to, glutaraldehyde) can be added to the protein mixture. The addition of a cross-linking agent to the protein mixture results in a protein paste. The concentration of the crosslinking reagent to be added may vary depending on the concentration of the protein mixture. While glutaraldehyde is an exemplary crosslinking reagent, other crosslinking reagents may also be used or substituted for glutaraldehyde. Other suitable crosslinking agents may also be used, as will be apparent to those skilled in the art.
As described above, in some embodiments of the invention, the analyte sensing component comprises a reagent (e.g., glucose oxidase) capable of producing a signal (e.g., a change in oxygen and/or hydrogen peroxide concentration) that can be sensed by a conductive element (e.g., an electrode that senses a change in oxygen and/or hydrogen peroxide concentration). However, other useful analyte sensing components can be formed from any composition that is capable of producing a detectable signal upon interaction with a target analyte whose presence is to be detected that can be sensed by the conductive element. In some embodiments, the composition includes an enzyme that modulates the hydrogen peroxide concentration upon reaction with the analyte to be sensed. Alternatively, the composition includes 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 produce and/or utilize compounds whose modulation can be detected by electrodes of a conductive element (as incorporated into the sensor designs described herein). Such enzymes include, for example, Richard f.taylor (ed.), publisher: marcel Dekker; (1991, 1, 7 days) "protein immobilization: the enzymes described in detail in tables 1, 15-29 and/or tables 18, 111-112 of the basic principles and Applications (Bioprocess Technology, Vol.14), which are incorporated herein by reference in their entirety.
Protein component
The electrochemical sensors of the invention optionally comprise a protein component disposed between the analyte sensing component and the analyte modulating component (see, e.g.,
Adhesion promoting ingredients
The electrochemical sensors of the present invention can comprise one or more adhesion-promoting (AP) components (see, e.g.,
Analyte modulating composition
The electrochemical sensors of the present invention comprise an analyte modulating constituent disposed on the sensor (see, e.g.,
With regard to glucose sensors, in known enzyme electrodes, glucose and oxygen from the blood and some interferents (such as ascorbic acid and uric acid) diffuse through the primary membrane of the sensor. When glucose, oxygen and interferents reach the analyte sensing constituent, an enzyme (e.g., glucose oxidase) catalyzes the conversion of glucose to hydrogen peroxide and gluconolactone. The hydrogen peroxide may diffuse back through the analyte modulating component, or it may diffuse to an electrode where it may react to form oxygen and protons to produce an electrical current proportional to the glucose concentration. The analyte modulating sensor membrane assembly serves several functions, including selectively allowing the passage of glucose therethrough (see, e.g., U.S. patent application 2011-.
Covering composition
The electrochemical sensors of the present invention comprise one or more covering elements (see, e.g.,
FIG. 1H illustrates a cross-section of an
The embodiment shown in FIG. 1H includes a
As discussed in detail below, the
In the sensor configuration shown in fig. 1H,
In embodiments of the present invention, the
Typically, the
In certain embodiments of the present invention, as illustrated in fig. 1H, an
C. Exemplary System embodiment of the invention
One specific illustrative system embodiment consists of a glucose sensor, transmitter and receiver, and a blood glucose meter comprising a sputter/PVD electrode composition as disclosed herein. In this system, a radio signal from the transmitter may be sent to the pump receiver for a fixed period of time (e.g., every 5 minutes) to provide a real-time Sensor Glucose (SG) value. The values/graphs may be displayed on a monitor of the pump receiver so that a user can self-monitor blood glucose and deliver insulin using his own insulin pump. Generally, the sensor systems disclosed herein may communicate with other medical devices/systems through wired or wireless connections. Wireless communication may include, for example, reception of transmitted radiation signals that occur when signals are transmitted by RF telemetry, infrared transmission, optical transmission, acoustic and ultrasonic transmission, and the like. Optionally, the device is an integral part of a drug infusion pump (e.g. an insulin pump). Typically, in such devices, the physiological property value comprises a plurality of measurements of blood glucose.
FIG. 2 provides a perspective view of one general embodiment of a subcutaneous sensor insertion system that may be suitable for use with the sensor electrodes disclosed herein, as well as a block diagram of sensor electronics in accordance with one illustrative embodiment of the present 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 by reference. Fig. 2 provides a perspective view of a telemetry characteristic monitoring system 1 including a
As shown in fig. 2, a
In the embodiment shown in fig. 2, the telemetry
In the illustrative embodiment shown in fig. 2,
In the illustrative embodiment shown in fig. 2, the
In the embodiment of the invention shown in fig. 2, the monitor 200 of the sensor signal may also be referred to as the sensor electronics 200. Monitor 200 may contain a power supply, a sensor interface, processing electronics (i.e., a processor), and data formatting electronics. The monitor 200 may be coupled to the
As described above, embodiments of sensor elements and sensors may be operably coupled to various other system elements typically used with analyte sensors (e.g., structural elements such as piercing members, insertion sets, and electronic components such as processors, monitors, drug infusion pumps, etc.), for example, to make them suitable for use in various contexts (e.g., implanted within a mammalian body). One embodiment of the invention includes a method of monitoring physiological characteristics of a user using an embodiment of the invention comprising: an input element capable of receiving a signal from a sensor based on a sensed physiological characteristic value of a user); and a processor for analyzing the received signal. In an exemplary embodiment of the invention, the processor determines a dynamic behavior of the value of the physiological property and provides an observable indicator based on the dynamic behavior of the value of the physiological property so determined. In some embodiments, the physiological property value is a measure of the blood glucose concentration of the user. In other embodiments, methods of analyzing received signals and determining dynamic behavior include repeatedly measuring physiological property values to obtain a series of physiological property values to redundantly incorporate comparisons into a sensor device, e.g., in a manner designed to provide confirmation information about sensor function, analyte concentration measurements, the presence of interference, etc.
FIG. 3 shows a schematic diagram of a voltage regulator that may be used to measure current in an embodiment of the invention. As shown in fig. 3, voltage regulator 300 may include an operational amplifier 310 connected in circuit to have two inputs: vset and Vmeasured. As shown, Vmeasured is a measure of the voltage between the reference electrode and the working electrode. Vset, on the other hand, is the optimum desired voltage across the working and reference electrodes. The current between the counter electrode and the reference electrode is measured, producing a current measurement (Isig) output from the potentiostat.
Embodiments of the invention include an apparatus that processes display data from measurements of a sensed physiological characteristic (e.g., blood glucose concentration) in the following manner and format: the manner and format is tailored to allow a user of the device to easily monitor and, if necessary, modulate the physiological state of the characteristic (e.g., modulate blood glucose concentration via insulin administration). An illustrative embodiment of the invention is an apparatus comprising: a sensor input capable of receiving a signal from a sensor, the signal based on a sensed physiological characteristic value of a user; a memory for storing a plurality of measurements of a sensed physiological characteristic value of a user of received signals from a sensor; and a display for presenting textual and/or graphical representations (e.g., text, line graphs, etc., bar graphs, etc., grid patterns, etc., or combinations thereof) of the plurality of measurements of the sensed physiological property values. Typically, the graphical representation displays real-time measurements of the sensed values of the physiological property. Such devices may be used in various situations, for example in combination with other medical equipment. In some embodiments of the invention, the device is used in combination with at least one other medical device (e.g., a glucose sensor).
An illustrative system embodiment consists of a glucose sensor, a transmitter and pump receiver, and a blood glucose meter. In this system, a radio signal from the transmitter may be sent to the pump receiver every 5 minutes to provide a real-time Sensor Glucose (SG) value. The values/graphs are displayed on the monitor of the pump receiver so that the user can self-monitor blood glucose and deliver insulin using his own insulin pump. Generally, embodiments of the devices disclosed herein communicate with a second medical device through a wired or wireless connection. Wireless communication may include, for example, reception of transmitted radiation signals that occur when signals are transmitted by RF telemetry, infrared transmission, optical transmission, acoustic and ultrasonic transmission, and the like. Optionally, the device is an integral part of a drug infusion pump (e.g. an insulin pump). Typically, in such devices, the physiological property value comprises a plurality of measurements of blood glucose.
Although the analyte sensors and sensor systems disclosed herein are generally designed to be implantable within a mammal, the invention disclosed herein is not limited to any particular environment, but may be used in a variety of contexts, for example, for analyzing most in vivo and in vitro liquid samples, including biological fluids such as interstitial fluid, whole blood, lymph fluid, plasma, serum, saliva, urine, stool, sweat, mucus, tears, cerebrospinal fluid, nasal secretions, cervical or vaginal secretions, semen, pleural fluid, amniotic fluid, peritoneal fluid, middle ear effusion, joint fluid, gastric fluid, and the like. Alternatively, a solid or dry sample may be dissolved in a suitable solvent to provide a liquid mixture suitable for analysis.
Examples of the invention
Common abbreviations used in the examples include: a WE working electrode; GOx glucose oxidase; HSA human serum albumin; an SITS sensor in-vitro test system; a GLM glucose-limiting membrane (one example of an analyte modulating layer); OQ operation confirmation; SAR surface area ratio; BTS bicarbonate test system; and EIS electrochemical impedance spectroscopy. The BTS and SITS tests discussed in the examples are tests used to assess aspects of sensor performance. SITS measures sensor signal in glucose solution and sensor oxygen response, temperature response, background current, linearity, stability, acetaminophen interference and response time within 5-7 days. The dog test is used to evaluate the in vivo glucose sensor performance (Isig and calculated blood glucose levels) of diabetic and non-diabetic dogs for up to 3 days, and to compare the glucose levels measured by a continuous glucose sensor with those measured by a glucometer.
It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. In the description of the preferred embodiments, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration specific embodiments in which the invention may be practiced. It is to be understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention.
However, while indicating some embodiments of the invention, the description and specific examples are given by way of illustration and not limitation. Many changes and modifications may be made within the scope of the present invention without departing from the spirit thereof, and the invention includes all such modifications.
Example 1: sputtering apparatus
Fig. 4 illustrates an apparatus including a
Example 2: sputtering conditions for adhesion control
The following deposition conditions may affect adhesion.
High pressure deposition conditions may cause the deposited film to form under stress, resulting in poor adhesion.
The deposition power may affect adhesion, as higher deposition rates may cause air pockets, resulting in poor adhesion.
The high temperatures used during deposition may evaporate any adsorbed water remaining on the surface, thereby improving adhesion.
Thicker films will produce stress and make adhesion worse.
The geometric area may also affect adhesion, and may be controlled by the formation of pillars at the interface between the film and the substrate.
In the experiments described herein, sputtering parameters including pressure, power, temperature and thickness, and combinations of these parameters were adjusted to determine their effect on adhesion and to determine the parameters/parameter values that achieve the best adhesion for electrode processing. In one or more embodiments, the target for adhesion (or optimal adhesion) is strong enough to maintain adhesion of the base polyimide to the substrate during laser cutting, but weak enough to allow removal of the base polyimide from the substrate for the sensor assembly.
Fig. 5 shows a test sample comprising a
Fig. 6A shows different patterns a-E of a knife scratch or laser cut mark applied to a
Fig. 6B shows a pattern 600 of a silver layer applied to a glass substrate, showing that the adhesion of silver to glass is too weak to allow replication of the indicia on the silver layer.
Using the marking pattern shown in fig. 6A, a feasibility-efficiency-compatibility study was performed to discover the effect of metal (e.g., gold) sputtering conditions on metal/glass (e.g., metal/glass) adhesion in the layer structure of fig. 5.
Figures 7A-7D illustrate how adhesion scores are assigned. Fig. 7A shows that the score assigned is 0 when the pattern of fig. 6A can be accurately applied to the layer stack with the highest mass and replica resolution (representing the strongest adhesion of the layer stack to the glass substrate). As the score increases, the adhesion decreases and the marking pattern does not replicate well in the layer stack (fig. 7B and 7C). Fig. 7D shows the score assigned as 10 when the pattern of fig. 6A cannot be accurately applied to the
a.Experiment 1
The test samples of fig. 6A were produced using the sputtering conditions of table 1. The marking pattern of fig. 6B was then scribed/laser cut into each of the films on the test sample and each replica was assigned an adhesion score as shown in table 1.
TABLE 1
Fig. 7A-7D show the test results. The sputtered structure in fig. 7D was fabricated using sputtering conditions including 100mT pressure, 1.6kW power, a gold layer thickness of 897 angstroms, and no heating required.
The results show that the sputtering conditions for samples 1-6 (highlighted in table 1) have the strongest adhesion (adhesion score of 0), allowing the mark of fig. 6B to be accurately reproduced. Figures 7A-7D and table 1 show surprising and unexpected results: low pressure achieves very high adhesion, while high pressure achieves low adhesion.
b.
Fig. 8B shows a test sample 1000 comprising an Au layer 1002, the test sample including pillars 1004 at the interface between the Au layer 1002 and the glass substrate 1006. Different test samples 1000 were fabricated in which Au layers 1002 were deposited under different sputtering conditions (as shown in table 2). Fig. 9 is a scanning electron microscope image of the columnar interface between the glass substrate 1006 and the gold layer 1002.
As shown in table 2, the marking pattern of fig. 6B was then scribed/laser cut into each of the Au films 1002 in the test sample 1000 using a knife and an adhesion score was assigned to each replicate.
TABLE 2
Fig. 5 illustrates the fabrication of a backside counter electrode, which includes: depositing a gold (Au) layer on a glass substrate, depositing a chromium (Cr) layer on the gold layer, depositing a polyimide comprising a base polyimide on the Cr layer, forming an opening in the polyimide, depositing a Cr/Au layer stack inside the opening and peeling the base polyimide and Au layers together with the Cr layer from the glass substrate.
It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used is intended to be in the nature of words of description
The samples highlighted in table 2 (samples 1-5 and 10) show that strong adhesion (low adhesion score) is achieved by low pressure sputtering. On the other hand, the results of samples 6-9 show that sputtering performed at high pressure (above 55mTorr, e.g., 100mTorr) achieves weak adhesion. The gold posts are assumed to reduce the gold/glass contact area and increase the effect of pressure on adhesion. The results also show that the thicker films have weaker adhesion to the glass substrate.
Fig. 10A-10D show the film of fig. 6A containing gold posts 1004 fabricated using various sputtering conditions after laser cutting with an example electrode pattern. FIGS. 12A and 12B illustrate the use of 100mTorr pressure, 0.4W power, andin films made with thick gold layers (FIG. 10A) and under the application of 100mTorr pressure, 1.6W power, and
Fig. 11 shows a pareto plot of the normalized effect of varying different factors (pressure, power, and gold thickness) on the adhesion of a
Fig. 12 is a graph of average rate as a function of pressure, power and gold thickness.
Fig. 13 is a contour plot of rate versus gold layer thickness and sputtering pressure.
DOE analysis (fig. 11, 12 and 13) shows that pressure is the primary factor controlling adhesion when forming the pillars 1004 at the interface. In particular, analysis shows that higher pressures and thicker (e.g., gold) layers in the film achieve weaker adhesion, while sputtering power has little effect on adhesion. Lower temperatures were found to provide weaker adhesion.
c.Influence of two gold layers on adhesion
Fig. 14 shows another test sample comprising a
The previously discussed procedure was followed, and the marking pattern of fig. 6B was then scribed into each of the
Fig. 15A shows a
Fig. 15C, 15D, and 15E show that the adhesion of the
Example 3: controlling sputtering rate
DOE analysis was performed to determine process parameters that affect the sputtering rate of gold on a glass substrate when no heat was applied. Fig. 16 shows a pareto plot of the normalized effect on sputtering rate of varying pressure, power and gold thickness in the absence of applied heat. In the pareto plot, the response is the sputtering rate in angstroms per second, and α is 0.05.
FIG. 17 is a graph of average sputtering rate as a function of pressure, power, and gold thickness.
FIG. 18 is a contour plot of sputtering rate versus sputtering power (kW) and pressure (mTorr).
DOE analysis (fig. 16, 17 and 18) shows that there is an optimum pressure for maximum sputtering rate, and that the sputtering rate increases linearly with sputtering power. Thus, 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.
Although examples 2-4 refer to sputtering, the same results and findings (including control of adhesion by appropriate selection of pressure) are generally applied to deposition using PVD (e.g., including, but not limited to, electron beam deposition).
Example 4: analyte sensor device fabrication
Fig. 19, 20, and 1D illustrate a method of manufacturing an analyte sensor apparatus 100D.
Block 1900 represents providing a base (e.g., rigid) substrate 2000 (e.g., a glass substrate).
Block 1902 represents depositing metals 2002a, 2002b (physical vapor deposition of metals) on a base substrate, for example, using PVD. In one or more embodiments, the metal includes a first layer 2002a (e.g., Au layer) on the base substrate 2000 and a second layer (e.g., Cr or Ti layer) 2002b on the first Au layer 2002 a. In one or more examples, the metals 2002a, 2002b extend laterally to form
Exemplary PVD conditions include a pressure in a range of 2-250mTorr, 70-100mTorr, or 50-125mTorr, a power in a range of 10W-100kW (e.g., 0.5kW-2kW, e.g., 0.8kW), and a pressure in a range of at least 100 angstroms (e.g.,) A thickness of each of the metal layers within the range of (a). The PVD step may include a pressure control step as described herein, for example, the step of block 2600 + 2604 in FIG. 26 of example 9. Example PVD processes include, but are not limited to, sputtering and electron beam deposition.
Block 1904 represents depositing a first insulating layer 2004 over the metals 2002a, 2002 b. Example insulating layers include, but are not limited to, polymer layers (such as, but not limited to, polyimide).
Block 1906 represents depositing and patterning a second metal 2006a, 2006b on the first insulating layer 2004, 104 b. In one or more examples, the second metal includes two layers — a second layer 2006b including Au on a first layer 2006b including Cr (or Ti) and extends laterally to form the
Block 1908 represents depositing the second insulating layers 2008, 118 onto the first insulating layer 2004 and depositing the second metals 2006a, 2006b onto the first insulating layer 2004. Example insulating layers include, but are not limited to, polymer layers (such as, but not limited to, polyimide).
Block 1910 represents forming a first opening 2010a and a second opening 2010b in the second insulating layer 2004 to expose the second metal 2006 b.
Block 1912 represents depositing a third metal into the first opening 2010a and onto the second metal 2010b to form the working electrode WE (see fig. 1D).
Block 1914 represents depositing a fourth metal into the second opening 2010b and onto the second metal 2006b to form a Reference Electrode (RE) (see fig. 1D).
Block 1916 represents additional steps including forming openings in the second insulating layer 118 to expose the
Block 1918 represents defining the analyte sensor in a film 2012 that includes metals 2002a, 2002 b; a second metal 2006a, 2006 b; first insulating layers 2004, 104 b; the second insulating layers 2008, 118; and electrodes WE, RE.
Block 1920 represents removing 2014 (e.g., peeling) the analyte sensor 100d from the base substrate 2000. In one or more embodiments, the steps include removing (e.g., stripping) the pvd metals 2002a, 2002b from the substrate 2000.
Block 1922 represents the final result, e.g., a sensor device as shown in FIG. 1D. The metal layers 2002a, 2002b, CE serve as the backside counter electrode BCE and a layer for controlling adhesion to the base substrate 2000 using the pressure control methods described herein (see, e.g., examples 2-3). The base polyimide layers 2004, 104b do not require patterning or etching to contact the BCE. In one or more examples, the method of example 4 enables the manufacture of a device comprising 1 flexure with electrodes on both sides (as compared to a control device with interdigitated electrodes on one side as shown in fig. 1F). As shown herein, a plurality (e.g., at least 36) of sensors 100D removed from the base substrate may all exhibit ISIG within 15% (see, e.g., fig. 21D).
Example 5: SITS results for the combinational sensor of example 4
Fig. 21A-21C show SITS results for the control sensor as shown in fig. 1F, and fig. 21D-21F show SITS results for the sensor of fig. 1G (simulating/representing performance of the device of fig. 1D with BCE fabricated using method example 4).
The sensor of fig. 1G has two flexures:
the flexure 1: nominal electrode E3 had adhesive tape over the CE contact pad at the emitter connection. The tape does not contact the body.
The flexure 2: the nominal E3 layer included a base polyimide and the nominal E3 electrode included Cr/Au and adhesive tape over the WE and RE contact pad areas at the emitter connections. This flexure is a nominal E3 flexure manufactured by a metal sputtering process only, and the tape does not contact the body.
Although the sensor of fig. 1D has a single flexure including CE, WE, and RE, the performance of the fig. 1D device is expected to be similar to that of the fig. 1G device with two flexures, since both the fig. 1D and 1G devices have CE electrodes on the backside of the opposite side of the WE.
Table 3: SITS summary for 3 SITS runs testing the apparatus of fig. 1D. Indicates statistically significant differences. For the BCE device of fig. 1D, the number of devices tested is n-36, and for the control device, n-36).
For the data in fig. 21A-21C, the working
Data for sensors used in vivo pig testing in fig. 21D-21F and table 3 show the BCE device of fig. 1G (representing the device of fig. 1D) compared to the control sensor of fig. 1F) Improved long term stability throughout the test, elimination of overnight Isig drift, and significant (and unexpected) reduction in sensor variability, especially at low O2Concentration-pressure conditions). In addition, the BCE of fig. 1G did not exhibit major differences in temperature and AC response, and no negative observations were found from visual inspection.
Fig. 21C and 21F also show that vcounter (vcntr) activity/motion in response to glucose sensing using the device of fig. 1G is also surprisingly reduced compared to the control sensor of fig. 1F. Furthermore, the data shows that Vcounter for the sensor of fig. 1G appears to be more stable at lower steady state voltages.
Example 6: analyte sensor device fabrication
FIG. 22 is a flow chart illustrating a method of manufacturing a glucose sensor or sensor flexure (see also FIGS. 1A-1D and 23). The method comprises the following steps.
Block 2200 represents depositing one or more metal layers on a (e.g., rigid) substrate 2302 (e.g., glass) using physical vapor deposition (e.g., sputtering or e-beam deposition).
Exemplary PVD conditions include a pressure in a range of 2-250mTorr, 70-100mTorr, or 50-125mTorr, a power in a range of 10W-100kW (e.g., 0.5kW-2kW, e.g., 0.8kW), and a power of at least 100 angstroms (e.g.,) The thickness of each of the
Block 2202 represents depositing a first or
Block 2204 represents optionally patterning and/or etching the
Block 2206 represents depositing metal 112 (second metal) containing CE onto the etched pattern. Examples of
Block 2208 represents depositing an insulating layer 104a (first insulating layer) on the
Block 2210 represents depositing and patterning a metal 108 (third metal) on the first insulating layer 104 a. 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: a film (e.g., thin film) of
Block 2212 represents depositing the second insulating layer 118 on the first insulating layer 104a and depositing the
Block 2214 represents, for example, patterning the second insulating layer 118 using photolithography and forming an etch pattern in the second insulating layer 118 including the second well or
Block 2216 represents optionally performing a final cure of the structure formed in blocks 2200-2214.
Block 2218 indicates optionally using O, for example2The residue is removed from the second insulating layer 118.
Block 2220 represents depositing the metal (fourth metal) and other layers needed to form the WE. In one or more embodiments, the steps include: metal pillar 124 is deposited into second well/
Block 2222 represents depositing a metal (fifth metal) into third well/
Block 2224 represents performing a chemical step in which an additional chemically active layer/component is deposited over the WE (e.g., onto the pillars) so that the WE has the proper function in the glucose sensor. Example components include, but are not limited to, one or more of interference suppressing components,
Block 2226 represents machining the structure into
Block 2228 represents separating or removing (e.g., peeling)
Block 2230 represents the final result, such as the
In one or more examples, the fabrication methods described herein may increase working electrode area, prevent "drift" effects, and/or simplify the fabrication process.
Studies of process parameters have found excellent process control, design control and repeatability. The process is a high throughput process and can be easily transferred between the plate and the 8 "wafer.
Example 7: method for depositing film and controlling adhesion
FIG. 24 is a flow chart illustrating a method of depositing a film on a substrate. The method comprises the following steps.
Block 2400 represents controlling a gas pressure in a chamber for depositing a metal using Physical Vapor Deposition (PVD). In one or more instances, the steps additionally include: controlling at least one further PVD parameter selected from: thickness of metal, number of layers of metal, and power used during physical vapor deposition.
Block 2402 represents depositing a metal on a substrate using Physical Vapor Deposition (PVD).
Block 2404 represents depositing a film on the metal.
Block 2406 depicts measuring a degree of adhesion of the film to the substrate as a function of at least one PVD parameter (including pressure). In one or more embodiments, measuring includes assigning an adhesion score.
Exemplary PVD conditions include a pressure in a range of 2-250mTorr, 70-100mTorr, or 50-125mTorr, a power in a range of 10W-100kW (e.g., 0.5kW-2kW, e.g., 0.8kW), and a pressure in a range of at least 100 angstroms (e.g.,
Block 2408 represents optionally determining a pressure or other PVD parameter to achieve a desired adhesion of the film to the substrate. In one or more instances, the steps include: the extent of adhesion as a function of the at least one physical vapor deposition parameter is analyzed to determine the relative effect of the at least one physical vapor deposition parameter on the extent of adhesion. In one or more instances, the analyzing includes performing a design of experiment (DOE) analysis; and the degree of adhesion is plotted in the pareto chart as a response. The adhesion scoring and determining/analyzing steps of block 2408 may be performed in a processor or computer using computer readable program code having instructions that, when executed, cause the processor or computer to perform a statistical analysis on the measurements obtained in block 2406 to determine PVD parameters to achieve a desired adhesion.
Example 8: method of manufacturing a device
FIG. 25 is a flow chart illustrating a method of depositing a film on a substrate or fabricating a device. The method comprises the following steps.
Block 2500 represents placing a substrate (e.g., a rigid substrate) in a Physical Vapor Deposition (PVD) (e.g., sputtering) chamber.
Block 2502 represents setting PVD conditions including gas pressure in a chamber for depositing material using PVD. In one or more examples, the pressure is determined using the method described in example 7.
Block 2504 represents depositing PVD metal on a substrate using physical vapor deposition under pressure.
In one or more embodiments, the metal comprises a plurality of layers, each deposited at a different pressure.
In one or more embodiments, the PVD comprises sputtering or electron beam deposition, including ionizing the gas to form ionized gas particles; and accelerating the ionized gas particles onto a target comprising the metal using an electric and/or magnetic field having a power in a range of, for example, 10 watts to 100kW (e.g., 0.5kW to 2 kW). In one or more examples, the gas pressure is in the range of 2-250mTorr, 70-100mTorr, or 50-125 mTorr. In one or more embodiments, the PVD metal includes one or more layers, each at least 100 angstroms (e.g.,) Within the range of (a). In one or more examples, the PVD metal includes a first layer deposited on the substrate at a pressure in a range of 50-250mTorr (or 5-150mTorr) and a second layer deposited on the first layer at a pressure in a range of 2-50mTorr or 2-30 mTorr).
In one or more embodiments, the PVD deposited metal comprises at least one structured layer selected from: a patterned layer, a roughened layer, a non-uniform layer, a layer containing voids, and a layer comprising pillars.
Block 2506 represents depositing a film or device structure on a metal, such as described in examples 4 and 6. The pressure selected in block 2602 may be associated with a predetermined adhesion of the film to the substrate that allows: (1) processing the film into a device while the film is adhered to the substrate; and (2) removing (e.g., peeling) the device from the substrate.
Block 2508 represents optionally processing the film into one or more devices. In one or more examples, the processing includes patterning a film or cutting the film.
Block 2510 represents optionally peeling or removing the device from the substrate.
Block 2512 represents the final result, e.g., the device as shown in FIGS. 1A-1D. In one or more embodiments, the apparatus includes exposed surfaces S of the PVD metals 2302a, 2302b, 2002a, 2002b stripped/removed from the
As shown herein, studies of process parameters have found excellent process control, design control, and repeatability. The process is a high throughput process and can be easily transferred between the plate and the 8 "wafer.
In one or more examples, the separation D, arrangement, or configuration of the working electrode WE and counter electrode CE in the
In one or more examples, in a set of at least 36
In one or more embodiments, a PVD apparatus is coupled to a processor or computer using computer readable program code having instructions that, when executed, cause the processor or computer to control PVD deposition parameters in the PVD apparatus to achieve a desired adhesion of the film to the substrate.
It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. In the description of the preferred embodiments, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration specific embodiments in which the invention may be practiced. It is to be understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention.
However, while indicating some embodiments of the invention, the description and specific examples are given by way of illustration and not limitation. Many changes and modifications may be made within the scope of the present invention without departing from the spirit thereof, and the invention includes all such modifications.