Electrochemical sensing electrodes and biosensors and their manufacturing methods

Abstract

A method for producing a sensing electrode is disclosed, wherein an electrode material region is applied to a substrate, a sensing chemical material is applied to cover the electrode material, and a laser is used to form laser cuts in the sensing chemical material and the electrode material according to a pattern defining at least a portion of the perimeter of the sensing electrode. The laser cuts form gaps that physically and electrically separate the sensing chemical material and electrode material inside the laser cuts from the external sensing chemical material and electrode material outside the laser cuts. The method is further capable of producing multiple sensing electrodes separated from a continuous substrate. The sensing electrodes produced by such a method are further disclosed.

Description

Technical Field

[0001] This invention relates to the field of biosensors for the electrochemical determination of analytes in fluids. Background Technology

[0002] In vivo and in vitro biosensors are commonly used to detect analytes in fluids. Electrochemical biosensors typically comprise at least one pair of electrodes supported by a substrate. An analyte-specific sensing chemical is applied over one or both electrodes, particularly the "working" electrode. In addition to the sensing chemical, a diffusion-limiting membrane is applied on top for diffusion-controlled operating modes. For these biosensors to be useful, they must be homogeneous to operate based on associated calibration. One prerequisite for factory calibration of analyte biosensors is that the sensing electrodes have a well-defined active region with a uniform coating of the sensing chemical. Furthermore, a uniform layer of the diffusion-limiting membrane is crucial.

[0003] Lasers are known to be used to define the area of ​​an electrode, thereby limiting the presence of some inactive regions. However, a persistent problem in the art is that the inhomogeneity of the sensing chemical substance and the deformation of the overlying diffusion-limiting film have become sources of inaccuracy when using sensing electrodes.

[0004] Non-homogeneous chemical substances One source of sensitivity discreteness from sensor to sensor and sensitivity drift in individual sensors is the physical inhomogeneity of the functional layers (sensing chemicals, diffusion-limiting films). Sensing chemicals are typically applied to the substrate as wet reagents (i.e., solutions). Therefore, the outer edges of the reagent may be non-uniform. In particular, the "edge effect" can deform the shape of the sensing chemical layer as it dries / cures. The outer edges of the sensing chemical can be deformed, and sensing chemical coatings in the prior art often exhibit significant thickness inhomogeneities.

[0005] Referring to Figure 1, a cross-section of a prior art sensing electrode is shown, illustrating the deformation of a sensing chemical substance on a substrate. The sensing chemical substance 10 covers a conductive electrode material 11 located on a substrate 12. The sensing chemical substance has a relatively flat inner portion 14. However, due to a drying effect, the sensing chemical substance 10 has irregular surface profiles at its outer edge portions 16 and 18. These uneven edge regions of the sensing chemical substance 10 can distort analyte measurements.

[0006] In existing technologies, the solution typically involves removing large areas of sensing chemicals through surface laser ablation. However, if any residual active chemicals remain in the ablated area, they will continue to react with the analyte. This external sensing chemical's conversion of the analyte can potentially generate an electric current during testing. Therefore, in the past, the use of surface ablation required very intense lasers to achieve complete removal of the sensing chemicals from these areas, which should not be reactive with the analyte. This increased costs and slowed down the manufacturing process of the sensing electrodes.

[0007] Non-uniform diffusion confinement membrane Another source of inhomogeneity in existing sensors involves diffusion-limiting membranes. Electrochemical biosensors, especially in vivo biosensors, are often coated with diffusion-limiting membranes to control the relative diffusion of the target analyte compared to other reactants. If the active region of the sensing electrode is non-uniformly coated with a diffusion-limiting membrane, it can lead to a reduction in the performance of the resulting sensing electrode.

[0008] Figure 2 illustrates a prior art sensing electrode 20 having a substrate 22 carrying a carbon undercoat (electrode) 24 and an overlying sensing chemical substance 26, which together extend completely to the edge 28 of the electrode 20. A diffusion-limiting film 30 is typically applied by dip coating and thus surrounds the entire sensor. Therefore, it is also located directly above the sensing chemical substance 26. At the edge 28 of the sensing electrode, the redistribution of the diffusion-limiting film due to surface tension is shown. In this configuration, the diffusion-limiting film 30 is shown to be relatively thin at the edge 28 of the sensing electrode. Arrow 32 schematically depicts the diffusion of the analyte, with the intensity of the analyte represented by the thickness of the arrow. The enhanced diffusion of the analyte at the edge puts stress on the sensing chemical substance 26 there, leading to its accelerated degradation. Therefore, sensitivity drift occurs over time.

[0009] One approach to addressing the problem of diffusion-limited film thinning in the prior art is to use wide-field laser ablation of the sensing chemical substance. Figure 3 shows a sensing electrode 20 with an outer portion 34, where the sensing chemical substance layer 26 has been removed by wide-field laser ablation. Since there is no sensing chemical substance at the edge of the biosensor, diffusion at the edge is reduced due to its relative distance from the sensing chemical substance.

[0010] However, due to the increased laser power used to ablate a large amount of the sensing chemical 26, the carbon undercoat 24 was also partially ablated. The ablation of the outer portion 34 of the sensing chemical 26 resulted in the ablation of a portion of the underlying carbon 24. Figure 3 provides a schematic diagram of the resulting step profile 36 and the non-uniform layer thickness of the diffusion-limiting film. The thickness of the removed carbon coating can reach 10 µm or more. The thinning of the film at the step allows for disproportionately large diffusion, as indicated by arrow 38 at the sensor edge. Summary of the Invention

[0011] This paper discloses methods for producing sensing electrodes and biosensors for electrochemical analytes. Novel sensing electrodes and biosensors using these sensing electrodes are also disclosed. The sensing electrodes and biosensors address problems of existing biosensors caused by inhomogeneities in the electrodes, sensing chemicals, and diffusion-limiting membranes. Compared to existing technologies, the disclosed sensing electrodes exhibit enhanced uniformity and homogeneity. Furthermore, the reduction in inactive surface area significantly improves the sensor's immunity to interfering substances.

[0012] In one aspect, a method for producing a sensing electrode comprising a substrate supporting an electrode material layer covered with a sensing chemical substance material is disclosed. The method includes applying the electrode material layer onto the substrate and applying the sensing chemical substance material onto the electrode material. After applying the sensing chemical substance, laser cutting is performed to at least partially define a configuration of the sensing electrode inside the laser cut that completely cuts through both the electrode material and the sensing chemical substance material. The laser cut creates a gap between both the electrode material and the sensing chemical substance material, physically and electrically separating the sensing electrode inside the gap from the electrode material and sensing chemical substance material outside the gap. The gap formed by the laser thereby defines a uniform, active surface area for the sensing electrode. The formed sensing electrode is isolated from the electrode material and sensing chemical substance material on the substrate but outside the generated perimeter.

[0013] On the other hand, sensing electrodes and biosensors, such as those produced by the disclosed methods, are disclosed. In one aspect, the present invention provides an electrochemical analyte sensing electrode comprising a substrate having a first surface. An electrode material region is located on the first surface, and the electrode material region is covered by a sensing chemical substance material. The electrode material and the sensing chemical substance material include a gap extending into and through the electrode material and the sensing chemical substance material to the substrate. Thus, the gap physically and electrically separates the electrode material and sensing chemical substance material inside the gap from the electrode material and sensing chemical substance material outside the gap. The electrode material and sensing chemical substance material inside the gap includes a sensing electrode isolated from the electrode material and sensing chemical substance material on the substrate outside the gap.

[0014] The object of this invention is to provide sensing electrodes and biosensors that benefit from improved sensing electrode components. The sensing electrodes have electrode components with finer edges, resulting in more precise and uniform edges compared to existing technologies. Sensing chemicals and diffusion-limiting membranes are also more uniform and homogeneous. The latter achieves uniformity by filling gaps during membrane application, thus preventing the formation of thinning regions.

[0015] In a first embodiment, a method for producing a sensing electrode is disclosed, the method comprising: applying an electrode material region to a first surface of a substrate; applying a sensing chemical material covering the electrode material region; and, after applying the sensing chemical material, guiding a laser beam to the substrate to form a laser cut in a pattern configured to define at least a portion of the perimeter of a sensing electrode, the laser cut extending through and removing any electrode material and any sensing chemical material from the pattern, and the laser cut forming a gap that physically and electrically separates the electrode material and sensing chemical material inside the laser cut from the electrode material and sensing chemical material outside the laser cut.

[0016] The second embodiment includes the method of the first embodiment, wherein the substrate has a second surface opposite to the first surface, and the method further includes applying a counter electrode and / or a reference electrode to the second surface. Alternatively, the second side may not be used as a counter electrode or a reference electrode, but rather as a second detection electrode, for example, for another analyte, or may not be used at all.

[0017] The third embodiment includes the first embodiment, wherein the counter electrode and / or reference electrode are applied to the first surface.

[0018] The fourth embodiment includes the first embodiment, further comprising applying a diffusion-limiting membrane to fill the gap after the gap is formed.

[0019] In the fifth embodiment, the method includes the first embodiment, wherein applying the sensing chemical material includes applying a wet sensing chemical material and then drying / curing it, the dried / cured sensing chemical material having portions generated by edge effects, and laser cutting is configured to physically and electrically separate the edge effect material from the sensing electrodes.

[0020] The sixth embodiment includes the method of the first embodiment, wherein the electrode material extends from the proximal electrode edge to the distal electrode edge, and a U-shaped gap is formed by laser cutting. This U-shaped gap includes a first gap portion extending longitudinally from the edge of the sensing electrode, a second gap portion extending laterally from the sensing electrode, and a third gap portion extending longitudinally. Alternatively, the laser cutting can have many different shapes to accommodate various sensing electrode configurations. The seventh embodiment includes the sixth embodiment, wherein the first gap portion, the second gap portion, and the third gap portion form a continuous gap.

[0021] The eighth embodiment is a method for producing an electrochemical analyte sensing electrode, the electrochemical analyte sensing electrode including a substrate having a first surface, the first surface including a sensing chemical substance on the electrode, the method comprising: applying an electrode material region to the first surface of the substrate; applying a sensing chemical substance covering the electrode material region; and after applying the sensing chemical substance, performing a laser cut that extends completely through the electrode material and the sensing chemical substance but not through the substrate, the laser cut being configured to define a sensing electrode inside the laser cut, the laser cut forming a gap that physically and electrically separates the electrode material and sensing chemical substance material inside the laser cut from the electrode material and sensing chemical substance material outside the laser cut, the laser cut thereby defining an active perimeter of the sensing electrode, the sensing electrode being isolated from the electrode material and sensing chemical substance outside the active perimeter.

[0022] The ninth embodiment includes the eighth embodiment, wherein the substrate has a second surface opposite to the first surface, and the method further includes applying a counter electrode and / or a reference electrode to the second surface.

[0023] In the tenth embodiment, the method includes the eighth embodiment and further includes applying a diffusion-limiting film to the sensing chemical material and filling the gaps. The eleventh embodiment includes the eighth embodiment, wherein applying the sensing chemical material includes applying a wet sensing chemical material and then drying / curing it, the dried / cured sensing chemical material having portions generated by edge effects, and laser cutting is configured to physically and electrically separate the edge effect material from the sensing electrodes.

[0024] The twelfth embodiment includes the eighth embodiment, wherein a U-shaped gap is formed by laser cutting, the U-shaped gap including a first gap portion extending longitudinally from the sensing electrode, a second gap portion extending laterally from the substrate, and a third gap portion extending longitudinally from the sensing electrode. The thirteenth embodiment includes the twelfth embodiment, wherein the first gap portion, the second gap portion, and the third gap portion form a continuous gap.

[0025] The fourteenth embodiment includes a method for producing a plurality of electrochemical analyte sensing electrodes by separating sensing electrodes from a continuous substrate. The method includes applying a plurality of electrode systems to the substrate, each electrode system including an electrode material region on the substrate and a sensing chemical substance material region covering the electrode material region; for each electrode system, performing a laser cut that extends completely through the electrode material and sensing chemical substance material but not through the substrate, each laser cut being configured to define a sensing electrode inside the laser cut, each laser cut forming a gap that physically and electrically separates the electrode material and sensing chemical substance material inside the laser cut from the electrode material and sensing chemical substance material outside the laser cut, each sensing electrode being isolated from the electrode material and sensing chemical substance material outside the gap; and separating the sensing electrodes from the substrate after performing the laser cut.

[0026] In the fifteenth embodiment, the fourteenth embodiment further includes performing laser cutting by moving the substrate relative to the laser beam and continuously guiding the laser beam over each electrode system in a plurality of electrode systems. The sixteenth embodiment includes the fourteenth embodiment, wherein each electrode system includes a proximal electrode edge and a distal electrode edge, and each laser cut forms a U-shaped gap including a first portion of a longitudinally extending sensing electrode, a second portion of a laterally extending sensing electrode, and a third portion of a longitudinally extending sensing electrode. In the seventeenth embodiment, the fourteenth embodiment further includes applying a plurality of electrode systems, including applying a sensing chemical material as a continuous strip of sensing chemical material onto the plurality of electrode systems. The eighteenth embodiment includes the seventeenth embodiment, wherein applying the plurality of electrode systems includes applying an electrode material region as a continuous strip of electrode material onto the plurality of electrode systems.

[0027] The nineteenth embodiment includes the eighteenth embodiment, wherein applying the multiple electrode systems includes applying a region of sensing chemical substance material as a continuous strip of sensing chemical substance material onto the multiple electrode systems. In the twentieth embodiment, the fourteenth embodiment further includes applying a second electrode material region, including a counter electrode and / or a reference electrode, to a substrate for each electrode system before separating the sensing electrodes.

[0028] In the twenty-first embodiment, the fourteenth embodiment further includes, for each electrode system, performing a laser cut, the laser cut comprising guiding a laser beam to a substrate to define a laser cut according to a pattern configured to define at least a portion of the perimeter of a sensing electrode, the laser cut extending through and removing any electrode material and any sensing chemical material from the pattern. The twenty-second embodiment includes the twenty-first embodiment, wherein performing each laser cut comprises moving the substrate relative to the laser beam using a roll-to-roll process.

[0029] The twenty-third embodiment includes the fourteenth embodiment and further includes filling the gap after laser cutting and before separating the sensing electrodes. In the twenty-fourth embodiment, the twenty-third embodiment further includes filling the gap by applying a diffusion-limiting film to the substrate to cover the sensing chemical substance and fill the gap.

[0030] The twenty-fifth embodiment includes an electrochemical analyte sensing electrode comprising: a substrate having a first surface; an electrode material region on the first surface; and a sensing chemical material covering the electrode material region, the electrode material and the sensing chemical material including a gap that physically and electrically separates the electrode material and sensing chemical material inside the gap from the electrode material and sensing chemical material outside the gap, the electrode material and sensing chemical material inside the gap including a sensing electrode isolated from the electrode material and sensing chemical material outside the gap.

[0031] In the twenty-sixth embodiment, the twenty-fifth embodiment further includes a sensing chemical material covering the electrode material region, the sensing chemical material forming a layered region comprising both the electrode material and the overlying sensing chemical material, the gap extending fully within the layered region. The twenty-seventh embodiment includes the twenty-sixth embodiment, wherein the gap has a width of 1 µm to 50 µm. In the twenty-eighth embodiment, the twenty-fifth embodiment includes electrode material extending distally from the proximal electrode edge, laser-cut to form a U-shaped gap, the U-shaped gap including: a first gap portion extending longitudinally from the sensing electrode; a second gap portion extending laterally from the sensing electrode; and a third gap portion extending longitudinally from the sensing electrode.

[0032] The twenty-ninth embodiment includes the twenty-eighth embodiment, wherein the first gap portion, the second gap portion, and the third gap portion form a continuous gap. In the thirtieth embodiment, the twenty-fifth embodiment includes a substrate having a second surface opposite to the first surface, and the sensing electrode further includes a counter electrode and / or a reference electrode on the second surface.

[0033] In the thirty-first embodiment, the twenty-fifth embodiment further includes a diffusion-limiting membrane that covers the sensing chemical material and fills the gaps.

[0034] The purpose of this invention is to reduce or eliminate edge effect areas that may have irregularities in shape and thickness.

[0035] Another object of the present invention is to reduce the inactive surface area by reducing the electrochemical surface area to improve the interference immunity of the sensor, wherein the interference may be non-specifically oxidized.

[0036] Another object of the present invention is to provide a sensing electrode having a well-defined active region.

[0037] Another objective is to provide a method for producing electrochemical biosensors that is applicable to roll-to-roll processes and other continuous processes.

[0038] An additional objective is to avoid using surface ablation, which was previously used to remove most of the sensing chemicals. This provides a technological advantage in terms of speed compared to using surface ablation, as it eliminates the need to scan large areas. Attached Figure Description

[0039] Figure 1 is a prior art schematic diagram illustrating edge effects, such as those occurring on drying or curing solutions, which can deform the contours of sensing chemicals.

[0040] Figure 2 is a prior art schematic diagram showing a reduced thickness of a diffusion-limiting film, wherein the electrode material and the sensing chemical material extend to the edge of the substrate below the sensing electrode.

[0041] Figure 3 is a schematic diagram of the prior art, showing the step profile of the electrode material after ablation in the region of the sensing chemical substance of the sensing electrode, and the thinning of the diffusion-limiting film obtained at the inner edge of the step.

[0042] Figure 4 is a partial schematic cross-sectional view of the substrate, electrode material, and sensing chemical material of the sensing electrode in the embodiment. In particular, Figure 4 shows the outline extending through the gap between the electrode material and the sensing chemical material, thereby separating the “active” and “inactive” electrode material and the sensing chemical material.

[0043] Figure 5 is a partial schematic cross-sectional view depicting the application of a diffusion-limiting membrane over the sensing chemistry of the sensing electrode and showing the filling of gaps to further isolate the active material from the inactive material.

[0044] Figure 6 is a schematic diagram illustrating the sensing electrodes and biosensors disclosed in a continuous (e.g., roll-to-roll) process embodiment.

[0045] illustrate The methods described herein can be used to produce various electrochemical analyte sensing electrodes and biosensors. The sensing electrodes and biosensors of this invention can be used for a wide variety of analytes that can be detected by electrochemical systems. In a particular aspect, the method provides a biosensor suitable for detecting analytes in body tissues or fluids. As an example, but not as a limitation, the sensing electrode has a specific application for detecting glucose levels in body fluids.

[0046] In a conventional manner, the disclosed biosensor is configured to have one end that is received by an instrument or similar monitoring device. The other end of the biosensor is configured to dispense a fluid sample. The biosensor includes a sensing electrode operable to electrochemically detect an analyte. The sensing electrode is electrically connected to the instrument, and the measured property is used for the determination of the analyte.

[0047] Any region of a sensing electrode electrically connected to a monitoring device may contribute to electrochemical measurements. However, this may involve regions that, as previously described, could adversely distort analyte measurements. Therefore, this disclosure provides a sensing electrode that substantially limits or excludes the involvement of external components in electrochemical measurements. This involvement is eliminated by physically and electrically isolating the sensing electrode from external materials on a substrate. These materials may remain on the substrate, but the disconnection of the sensing electrode renders the materials inactive for electrochemical measurements.

[0048] In a broader sense, the method of the present invention includes applying a region of sensing chemical substance covering an area of ​​electrode material. Laser cutting is performed, cutting through both the electrode material and the sensing chemical substance material to define the perimeter of the active region of the sensing electrode. The separated regions including the sensing chemical substance remain chemically active; for example, enzymes are still converting glucose. However, the laser gap separates these regions of the sensing chemical substance from the sensing electrode.

[0049] Therefore, this method provides a gap that physically and electrically separates active and inactive electrode materials from sensing chemical materials. Any electrode material and / or sensing chemical material on the substrate outside the gap is disconnected from the sensing electrode. The terms "external" and / or "inactive" are used to refer to materials present on the substrate but not forming part of the sensing electrode. Due to the physical disconnect between the active and inactive regions of the sensing electrode, there is no or substantially no physical or electrical connection between these regions. That is, the external material is isolated from the active sensing electrode through the gap.

[0050] It is desirable to ensure that these external materials do not contribute to electrochemical measurements, as this would distort analyte determination. Because the sensing electrode is isolated from the inactive region, it operates without being unduly affected by external materials. Without physical and / or electrical connections across the gap, external materials cannot participate in electrochemical determination.

[0051] Laser cutting The laser cut is configured to extend completely through the encountered sensing chemical material and electrode material, all the way to the substrate. Therefore, there is no physical or electrical connection between the materials on opposite sides of the gap. This cut creates a gap sufficient to isolate the sensing electrode from the outer portions of the electrode material and the sensing chemical material.

[0052] The present invention is characterized in that the sensing electrode is defined by a narrow gap extending through the electrode material and through the sensing chemical material. This gap differs from prior art methods, in which surface ablation is performed on critical areas of the sensing chemical to completely remove external sensing chemical material. In contrast, the present invention physically and electrically isolates the sensing electrode from external materials on the substrate, and eliminates the need to remove additional electrode or sensing chemical material.

[0053] In a preferred embodiment, laser cutting is performed using a narrow laser beam, forming a narrow gap. It should be understood that laser cutting only needs to create a gap wide enough to ensure that the active and inactive materials remain physically and electrically disconnected. As used herein, the term "narrow" refers to a gap with only a width sufficient to provide such a disconnect at its lower limit. A significant advantage of using the smallest possible gap is that it can be easily formed while minimizing the time and cost associated with manufacturing wider gaps. Determining an acceptable gap for a given electrode system, comprising electrode material covered by a sensing chemical substance, is within the scope of the technical capabilities in the art.

[0054] Preferably, the gap has a width that facilitates its formation, while being wide enough to ensure that the active area of ​​the sensing electrode is isolated from the external electrode material and sensing chemical material on the outside of the gap, i.e., ensuring physical and electrical separation. In embodiments, the gap may have a width between 1 µm and 50 µm, and more preferably a smaller width between 5 µm and 10 µm.

[0055] In embodiments, laser cutting includes linear laser cutting that forms a linear gap. The term "linear" refers to a laser cut or gap whose length is substantially greater than its width. On one hand, linear laser cutting is a cut in which a laser beam makes a continuous cut of a single width across the material. Therefore, linear laser cutting includes cuts formed by the laser beam scribing across a surface, thereby creating a gap with a width corresponding to the width of the laser beam. This helps to increase the production speed of laser cutting, and thus increases the production speed of biosensors. The term "linear" is not used to imply or require any particular shape of the cut; for example, it does not have to be a straight line. The shape of the laser cut will depend on the shape of the electrode.

[0056] Laser cutting can be performed in various ways. For example, various types of lasers can be used for cutting. The gap can be formed by a single or multiple scans of the laser, including using multiple lasers to make increasingly deeper cuts in sensing chemicals and electrode materials. Furthermore, the laser can operate in stop-and-go modes, where the substrate moves and stops during laser treatment of the exposure area. The laser is then moved while the substrate is stationary. Thus, the laser can be stationary while the material moves, and conversely, the material can be stationary while the laser is moving.

[0057] Linear gaps are also narrow gaps that maintain approximately the same width over their entire length. In particular, laser cutting should be distinguished from wide-field or surface laser ablation, which is used in the prior art to ablate relatively large areas of sensing chemicals, aiming to eliminate the influence of external electrode materials and sensing chemical materials on the electrodes.

[0058] There are no restrictions on the nature of the laser used, provided that it performs the laser cutting function disclosed herein. The laser and its operating parameters are selected to completely cut through the sensing chemical material and the electrode material. Preferably, the laser does not cut into the substrate, although this is not required. For example, it may be desirable to make a slight cut into the substrate to further ensure physical and electrical disconnection of the material on opposite sides of the gap. The type of laser and the selection of its operating parameters to accomplish the laser cutting are entirely within the scope of expertise in the art.

[0059] Filling gaps The separation of the active material of the sensing electrode from the inactive material on the substrate is enhanced by filling the gaps with a suitable material. Gap filling occurs after laser cutting and before the sensing electrodes are separated. A wide range of materials are available for gap filling, and the selection of the filling material is within the capabilities of those skilled in the art.

[0060] On one hand, diffusion-limiting membranes are used to fill gaps. Diffusion-limiting membranes are frequently used with electrochemical biosensors, particularly with biosensors used in vivo. Diffusion-limiting membranes regulate the absolute and relative diffusion of analytes and other substances into the sensing chemical. They are especially useful in areas where uncontrolled diffusion into the sensing chemical may occur.

[0061] The diffusion-limiting membrane, relative to the gap-filling membrane, can be applied to the sensing electrode in any manner suitable for filling the gap.

[0062] Production methods On one hand, the present invention provides a method for producing a sensing electrode. The method includes applying an electrode material region onto a substrate. Then, a sensing chemical substance material is applied to cover the electrode material region, thereby forming a "layered region" comprising the electrode material and the sensing chemical substance material. The layered region of electrode material and sensing chemical substance material is preferably used to form the sensing electrode.

[0063] After the sensing chemical substance is applied, a laser beam is directed to a layered region to form laser cuts in the electrode and sensing chemical substance materials according to a pattern configured to define at least a portion of the perimeter of the sensing electrode. The laser is operated to cut through any electrode material and any sensing chemical substance material to which it is directed. The laser cut extends through the material to the substrate, but preferably does not extend into the substrate.

[0064] Referring to Figure 4, in this embodiment, the sensing electrode 40 includes a substrate 42 covered with electrode material 44. A sensing chemical material 46 is applied over the electrode material 44, for example as a material line configured to extend from one side to the other across the sensing electrode. The sensing electrode 40 is fabricated by first applying the electrode material 44 to the substrate 42 and then covering the electrode material 44 with the sensing chemical material 46. After the sensing chemical material 46 is applied, a laser cut 48 is performed that extends through both the sensing chemical material 46 and the electrode material 44, but does not significantly penetrate into the substrate 42.

[0065] The result of the laser cutting described above is gap 50. The function of gap 50 is to physically and electrically isolate the inactive electrode material and inactive sensing chemical material located outside gap 50 from the active electrode material and active sensing chemical material located inside gap 50. Therefore, electrode 52 (see Figure 5) is defined by the laser-cut gap 50, and the periphery of electrode 52 is provided with a precisely positioned and finely laser-cut edge.

[0066] The result of the laser cutting is shown in the outline in Figure 4. The substrate 42 is coated with electrode material 44. Sensing chemical material 46 is coated on top of the electrode material 44. The laser cut 48 is positioned to cut through the sensing chemical material and electrode material up to the substrate 42, but preferably not significantly into the substrate. As shown, the laser cut separates the material on the inner side of the cut from the material on the outer side. The inner electrode material 54 constitutes the active portion of the electrode 52, and the inner sensing chemical material 56 constitutes the active sensing chemical associated with the electrode 52. These materials are isolated from the outer electrode material 58 and the outer sensing chemical 60.

[0067] Referring to Figure 5, a diffusion-limiting membrane 62 is shown applied over the sensing electrode 40. In an embodiment, the diffusion-limiting membrane is applied by dip coating and, for biocompatibility, covers the entire portion of the sensor inserted into the human body. The diffusion-limiting membrane 62 typically covers any or all portions of the sensing electrode, particularly the active sensing chemical material 56. In an embodiment, a laser cut is formed prior to the addition of the diffusion-limiting membrane or other such layers.

[0068] In one embodiment, a diffusion-limiting membrane is applied, for example, by slit-die coating on the sensor before separation. The sensor can then be separated by laser, and the separated sensor can then preferably be dip-coated with another diffusion-limiting layer and / or one or more biocompatible polymer layers. In this embodiment, the diffusion-limiting membrane is also a biocompatible membrane. If the membrane is applied only after sensor separation, gap formation and sensor separation can be completed in a single manufacturing step, as both steps can be performed using a laser.

[0069] When in use, a diffusion-limiting membrane 62 is applied such that it covers and fills the gap 50. In a typical embodiment, the gap is narrow enough that it is completely filled by the diffusion-limiting membrane during membrane coating, resulting in a very uniform morphology of the resulting membrane coating, which again has a positive impact on sensor performance.

[0070] Continuous web production This invention also provides a rapid method for producing multiple electrochemical analyte sensing electrodes and biosensors by separating them from a continuous substrate. A key feature of this invention is its significant simplification and acceleration of the commercial production of biosensors.

[0071] Referring to Figure 6, a schematic diagram of the production of a biosensor from a continuous substrate 70 is shown. Substrate 70 is used to produce the biosensor, indicated by dashed line 72. Once separated, the biosensor extends from a mechanical end 74 to a biological end 76. The method involves applying multiple electrode systems to substrate 70. Each electrode system includes an electrode material region 78 located on the substrate and a sensing chemical material region 80 covering the electrode material region. A laser beam is directed to substrate 70 along line 82. Laser cutting is shown as passing through appropriate regions of the sensing chemical material 80 and electrode material 78 in the manner previously described.

[0072] As shown, the electrode material 78 and the sensing chemical material 80 of the electrode system are both continuous strips of material. However, one or both can be applied as discrete material regions corresponding to the electrode system. These materials are applied in any suitable manner. In an embodiment, the sensing chemical material is applied, for example, by slit die coating. Both the electrode material and the sensing chemical material are applied on a surface area at least slightly larger than the final active area of ​​the sensing electrode. The outer portions are then isolated from the sensing electrode by laser cutting. Regions containing inhomogeneities or non-uniformities are then isolated.

[0073] For each electrode system, a laser cut is performed as described above, extending completely through the electrode material 78 and the sensing chemical material 80, but not significantly penetrating into the substrate 70. Each laser cut is configured to define a sensing electrode on the inner side of the laser cut, as each laser cut forms a gap that physically and electrically separates the electrode material and sensing chemical material on the inner side of the laser cut from the electrode material and sensing chemical material on the outer side of the laser cut. Each laser cut defines the active perimeter of the sensing electrode. The sensing electrode is thus isolated from the electrode material and sensing chemical material on the outer side of the active perimeter.

[0074] Laser cutting can be performed by moving the substrate and the laser beam relative to each other. Preferably, the laser beam continuously strikes an electrode system on a continuous web. After laser cutting, the sensing electrodes are separated from the substrate.

[0075] In an embodiment, each electrode system includes electrode material 78 defining a mechatronic electrode 74 and a bioelectric electrode 76. In another embodiment, a laser cut forms a U-shaped gap including a first gap portion 84 extending longitudinally from the sensing electrode, configured to be close to one side of the separated sensing electrode, as shown by a first dashed line 86. The cut then includes a second gap portion 88 extending laterally from the sensing electrode. A third gap portion 90 extending longitudinally from the sensing electrode is formed, configured to be located on the opposite side of the separated sensing electrodes, as shown by a third dashed line 92. Thus, the gap is shown as a continuous gap extending into and outside the sensing chemical material. The resulting U-shaped gap includes the majority of the electrode material covered by the sensing chemical material.

[0076] In one aspect, prior to separating the electrode systems, a second electrode material region, including a counter electrode and / or a reference electrode, can be applied to the substrate. In an embodiment, the counter electrode and / or reference electrode are applied to the side of the substrate opposite the sensing electrode. This facilitates subsequent laser cutting into the region of electrode material and sensing chemical material. In an alternative embodiment, the counter electrode and / or reference electrode can be positioned on the same side of the substrate as the working electrode. Additionally, in an embodiment, multiple working electrode systems can be placed on one or both sides of the substrate, and linear laser ablation can be used with some or all of them.

[0077] It should be further understood that the sequence of steps in the process can be changed. For example, the application of the working electrode material can occur before or after the formation of any counter electrode and / or reference electrode. The separation time of a single test strip can occur before or after the application of material (such as a diffusion-limiting membrane).

[0078] The sensing chemical is axially isolated from the conductive substrate. In this way, the upper edge 94 of the sensing chemical material 80 is well defined and unaffected by edge effects. The edge 94 of the electrode material is gap-fitted to complete the active perimeter of the sensing electrode and isolate the sensing electrode. The remaining three edges are then defined by linear ablation. A significant advantage here is the substantial reduction in the conductive surface area unmodified by the sensing chemical, thereby improving the sensor's immunity to interferences, as the lower surface area where interferences could be nonspecifically oxidized is a given.

[0079] Therefore, Figure 6 depicts laser cutting within a continuous web carrying a series of electrode systems. In this embodiment, the laser is preferably operated to move continuously relative to the web, thereby using the laser beam to cut 82 into the electrode material and the sensing chemical material. Since the laser is configured not to cut into the substrate in which there is no electrode material or sensing chemical material, no gap is created. Thus, Figure 6 shows an embodiment where the laser beam operates continuously and the gap extends between the endpoints along the edge of the sensing chemical material.

[0080] The embodiment in Figure 6 illustrates the use of this method in the formation of most of the sensing electrode perimeter. It should be understood that the concept of laser cutting through both the electrode material and the sensing chemical material can be used to define as much of the sensing electrode perimeter as possible. In extreme cases, laser cutting can scribe lines that completely surround the sensing electrode. Alternatively, this concept can be used to isolate only selected portions of the sensing electrode perimeter.

[0081] Laser cutting does not need to be continuous; this depends on the material along the cutting line. For example, if the laser is cutting along a line without sensing chemical material and electrode material, then the laser will have nothing to cut. In this respect, the laser can be programmed to dynamically adjust its power during its movement, so that if it moves over areas that should not be cut or ablated in any way, it will reduce its power or shut off the beam entirely.

[0082] Furthermore, the laser can cut along a line containing only electrode material or only sensing chemical material. In either case, the laser creates a gap in the existing material. In the case of only electrode material, the isolation of the outer electrode material outside the cut line prevents errors introduced based on interferences that could contribute to the measurement signal. In the case of only sensing chemical material, the isolation of the outer sensing chemical material outside the cut line prevents analytes and other materials from diffusing into the sensing electrode.

[0083] This gap provides a configuration to prevent the active material from connecting to the inactive material. To this end, the gap extends between the points, eliminating the possibility of achieving a physical or electrical connection by "bypassing" the gap. To achieve this, the gap extends between the endpoints, isolating the external material from the sensing electrode. This can be achieved, for example, by placing the endpoints at the side edges of the substrate or at the edges of the electrode material.

[0084] In this embodiment, the gap extends from one endpoint on one side of the substrate to an endpoint on a second side of the substrate. The endpoints may also both be located near the proximal edge of the electrode material, or one endpoint may be on one side of the substrate while the other endpoint may be at the electrode edge. As previously described, the edge of the electrode material itself serves as part of the active perimeter of the sensing electrode.

[0085] It should be further understood that the advantages of the present invention can be at least partially realized without completely isolating the sensing electrodes. For example, the gap can be configured to isolate less than all external material. In some electrode configurations, a small portion of the applied electrode material and / or sensing chemical material may be difficult to readily include within the area defined by the gap.

[0086] For example, insulating material only along the sides of the electrodes may suffice, which would significantly reduce measurement distortion that would otherwise occur. This could be achieved, for instance, by simply forming a gap extending from the proximal electrode edge to the distal electrode edge along both side edges of the substrate. The influence of external materials on the operation of the sensing electrodes would still be greatly reduced.

[0087] Sensing electrode components base This invention has broad applications in the production of sensing electrodes and biosensors. The concept is particularly applicable to the manner in which the active region of a sensing electrode is formed. Various substrates are well known in the art and are suitable for the production and use of biosensors, including, for example, in vivo biosensors. The selection of substrates for the disclosed biosensors and methods is entirely within the capabilities of those skilled in the art, and the invention is not limited to any particular substrate.

[0088] In a preferred embodiment, the substrate is a continuous material, and multiple biosensors are obtained by separating the biosensors from the continuous substrate. The term "separation" is known in the art to refer to a process in which a single biosensor is derived from a continuous web of substrate material. Various methods for separating biosensors are known in the art, and this disclosure is not limited to separation methods.

[0089] Sensing chemical substances The sensing chemical substance can be any chemical substance suitable for the electrochemical determination of the analyte. This invention is independent of the selection of the sensing chemical substance material and the manner in which it is applied to the sensing electrode.

[0090] electrode This disclosure relates to a sensing electrode for detecting an analyte by measuring the properties of the electrochemical reactions involving the analyte. As used herein, the term "electrode" refers to a conductive component configured for the electrochemical detection of an analyte.

[0091] This invention is applicable to a variety of electrode configurations. For convenience, a common electrode design is shown, in which the sensing electrode is a biosensor comprising a rectangular shape. However, the disclosed methods are advantageously applicable to any of the various electrode configurations known in the art. The electrode material can consist of any material suitable for use as an electrode in an electrochemical system. For example, but not limiting the invention, an electrode material is exemplified as a conductive carbon material. The electrode material can be applied to the substrate in any manner operable to provide an electrode. The selection of electrode materials and configurations for the disclosed methods is entirely within the capabilities of those skilled in the art, and therefore the invention is not limited to any particular electrode system.

[0092] Sensing electrodes The term "sensing electrode" refers to an electrode having a capping layer that senses a chemical substance, such that the combination of the sensing chemical substance and the electrode is configured to perform electrochemical testing of an analyte. In a particular embodiment, the sensing electrode is configured to detect an analyte in body tissue or fluid.

[0093] The sensing electrode can be combined with a counter electrode and / or a reference electrode disposed on the same substrate. In one embodiment, the counter electrode and / or the reference electrode are disposed on one side of the same substrate as the sensing electrode. However, the counter electrode and / or the reference electrode can alternatively be located on opposite sides of the substrate. Positioning the counter electrode and / or the reference electrode on opposite sides may be advantageous because it facilitates the use of a laser to cut the side with the sensing electrode.

[0094] in conclusion Existing techniques address the inhomogeneities of electrodes, sensing chemicals, and diffusion-limiting films by ablating the total area of ​​the sensing chemicals. This method, however, instead creates a narrow gap that eliminates the problem of inhomogeneities in the sensing chemicals outside the sensing electrode, effectively disconnecting them from electrochemical measurements. Analytes and potential interfering substances cannot cross this gap. This is further ensured by filling the gap, such as with portions of the diffusion-limiting film or other subsequently applied materials. Furthermore, sensing chemicals affected by edge effects are separated, thereby enhancing sensor performance. Additionally, a significant portion of the electrode material is also separated, which improves the active / inactive area ratio.

[0095] Claims terminology 10 Sensing Chemical Substances 11 Electrode Materials 12 base 14 Internal Parts 16 Sensing Chemical Substances 18 Sensing Chemical Substances 20 sensing electrodes 22 base 24 carbon base coating 26 Sensing Chemical Substances 28 edge 30 Diffusion confinement membrane 32 arrows The external part of 3426 36-step outline 38 arrows 40 sensing electrodes 42 base 44 Electrode Material 46 Sensing Chemical Substances 48 laser cutting 50mm gap (formed by laser cutting) 52 electrodes 54 Inner Electrode Material 56 inner side Sensing chemical materials 58 External Electrode Material 60 External Sensing Chemical Material 62 Diffusion confinement membrane 70 continuous substrate 72 dashed lines 74 Mechanical Biosensor End 76 Biosensor Terminal 78 Electrode Material 80 Sensing Chemical Materials 82 laser cutting 84 First gap section 86 First dashed line 88 Second gap section 90 Third gap section 92 dashed lines 94 edge.

Claims

1. A method for producing a sensing electrode, the method comprising: Apply the electrode material region to the first surface of the substrate; Apply a sensing chemical substance covering the region of the electrode material; as well as After the sensing chemical material is applied, a laser beam is directed to the substrate to form a laser cut according to a pattern configured to define at least a portion of the perimeter of the sensing electrode. The laser cutting extends through and removes any electrode material and any sensing chemical material from the pattern, and The laser cutting creates a gap that physically and electrically separates the electrode material and the sensing chemical material on the inner side of the laser cutting from the electrode material and the sensing chemical material on the outer side of the laser cutting.

2. The method of claim 1, wherein the substrate has a second surface opposite to the first surface, the method further comprising applying a counter electrode and / or a reference electrode to the second surface.

3. The method of claim 1, further comprising applying a diffusion-limiting membrane to fill the gap after forming the gap.

4. The method of claim 1, wherein applying the sensing chemical material comprises applying a wet sensing chemical material and then drying / curing it, the dried / cured sensing chemical material having portions generated by edge effects, and the laser cutting is configured to physically and electrically separate the edge effect material from the sensing electrode.

5. The method of claim 1, wherein the electrode material extends from the proximal electrode edge to the distal electrode edge, and the laser cutting forms a U-shaped gap, the U-shaped gap comprising: The first gap portion extending longitudinally along the edge of the sensing electrode, The second gap portion extending laterally along the sensing electrode, and The third gap section extending longitudinally.

6. The method of claim 5, wherein the first gap portion, the second gap portion, and the third gap portion form a continuous gap.

7. A method for producing an electrochemical analyte sensing electrode, the electrochemical analyte sensing electrode comprising a substrate having a first surface, the first surface comprising a sensing chemical substance on the electrode, the method comprising: Apply the electrode material region to the first surface of the substrate; Apply a sensing chemical substance covering the region of the electrode material; as well as After the sensing chemical substance is applied, laser cutting is performed, the laser cut extending completely through the electrode material and the sensing chemical substance material but not through the substrate. The laser cut is configured to define the sensing electrode inside the laser cut. The laser cutting creates a gap that physically and electrically separates the electrode material and the sensing chemical material on the inner side of the laser cutting from the electrode material and the sensing chemical material on the outer side of the laser cutting. The laser cutting defines the active perimeter of the sensing electrode, which is isolated from the electrode material and sensing chemical material outside the active perimeter.

8. The method of claim 7, wherein the substrate has a second surface opposite to the first surface, the method further comprising applying a counter electrode and / or a reference electrode to the second surface.

9. The method of claim 7, further comprising applying a diffusion-limiting membrane to the sensing chemical material and filling the gap.

10. The method of claim 7, wherein applying the sensing chemical material comprises applying a wet sensing chemical material and then drying / curing it, the dried / cured sensing chemical material having portions generated by edge effects, and the laser cutting is configured to physically and electrically separate the edge effect material from the sensing electrode.

11. The method of claim 7, wherein the laser cutting forms a U-shaped gap, the U-shaped gap comprising: The first gap portion extending longitudinally along the sensing electrode, The second gap portion extending laterally along the substrate, and The third gap portion extending longitudinally along the sensing electrode.

12. The method of claim 11, wherein the first gap portion, the second gap portion, and the third gap portion form a continuous gap.

13. A method for producing a plurality of electrochemical analyte sensing electrodes by separating sensing electrodes from a continuous substrate, the method comprising: Multiple electrode systems are applied to a substrate, each electrode system including an electrode material region on the substrate and a sensing chemical substance material region covering the electrode material region; For each electrode system, a laser cut is performed, the laser cut extending completely through the electrode material and the sensing chemical material but not through the substrate. Each laser cut is configured to define a sensing electrode on the inner side of the laser cut. Each laser cut creates a gap that physically and electrically separates the electrode material and the sensing chemical material on the inner side of the laser cut from the electrode material and the sensing chemical material on the outer side of the laser cut. Each sensing electrode is isolated from the electrode material and sensing chemical material outside the gap; as well as After the laser cutting is performed, the sensing electrode is separated from the substrate.

14. The method of claim 13, wherein performing the laser cutting comprises moving the substrate relative to the laser beam and continuously guiding the laser beam over each of the plurality of electrode systems.

15. The method of claim 13, wherein each electrode system includes a proximal electrode edge and a distal electrode edge, and each laser cut forms a U-shaped gap, the U-shaped gap comprising: The first portion extending longitudinally along the sensing electrode, The second portion extending laterally along the sensing electrode, and The third part extending longitudinally along the sensing electrode.

16. The method of claim 13, wherein applying the plurality of electrode systems comprises applying the sensing chemical material as a continuous strip of sensing chemical material onto the plurality of electrode systems.

17. The method of claim 13, wherein applying the plurality of electrode systems comprises applying the electrode material region as a continuous strip of electrode material over the plurality of electrode systems.

18. The method of claim 17, wherein applying the plurality of electrode systems comprises applying the sensing chemical material region as a continuous strip of sensing chemical material over the plurality of electrode systems.

19. The method of claim 13, further comprising, prior to separating the electrode systems, applying a second electrode material region comprising a counter electrode and / or a reference electrode to the substrate for each electrode system.

20. The method of claim 13, wherein, For each electrode system, laser cutting includes: A laser beam is directed to the substrate to define the laser cut according to a pattern configured to define at least a portion of the perimeter of the sensing electrode. The laser cutting extends through and removes any electrode material and any sensing chemical material from the pattern.

21. The method of claim 20, wherein performing each laser cut includes moving the substrate relative to the laser beam using a roll-to-roll process.

22. The method of claim 13, further comprising filling the gap after the laser cutting is performed and before the electrode system is separated.

23. The method of claim 22, wherein filling the gap comprises applying a diffusion-limiting membrane to the substrate to cover the sensing chemical substance and fill the gap.

24. An electrochemical analyte sensing electrode, comprising: A substrate having a first surface; An electrode material region, wherein the electrode material region is on the first surface; as well as A sensing chemical substance material, wherein the sensing chemical substance material covers the electrode material region. The electrode material and the sensing chemical material include a gap that physically and electrically separates the electrode material and sensing chemical material inside the gap from the electrode material and sensing chemical material outside the gap. The electrode material and the sensing chemical material inside the gap include the sensing electrode which is isolated from the electrode material and the sensing chemical material outside the gap.

25. The sensing electrode of claim 24, wherein the sensing chemical material covering the electrode material region forms a layered region comprising both the electrode material and the overlying sensing chemical material, the gap extending completely within the layered region.

26. The sensing electrode of claim 25, wherein the gap has a width of 1 µm to 50 µm.

27. The sensing electrode of claim 24, wherein the electrode material spans from the proximal electrode edge to the distal edge, and the laser cutting forms a U-shaped gap, the U-shaped gap comprising: The first gap portion extending longitudinally along the sensing electrode, The second gap portion extending laterally along the sensing electrode, and The third gap portion extending longitudinally along the sensing electrode.

28. The sensing electrode of claim 27, wherein the first gap portion, the second gap portion, and the third gap portion form a continuous gap.

29. The sensing electrode of claim 24, wherein the substrate has a second surface opposite to the first surface, and the sensing electrode further includes a counter electrode and / or a reference electrode on the second surface.

30. The sensing electrode of claim 24, further comprising a diffusion-limiting film covering the sensing chemical material and filling the gap.

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