Abstract
An analyte sensor for determining at least one analyte and a method for producing an analyte sensor are disclosed. The analyte sensor has a substrate. A working electrode and a conductive layer are located on different sites on the substrate. A layer having silver and/or a silver compound partially covers the conductive layer. A protective layer covers (i) the layer having silver, and also covers (ii) a portion of the conductive layer. The disclosed analyte sensor significantly reduces noise during measurements. The method can be performed in an easier manner compared to producing prior art analyte sensors and allows considerably higher tolerances during production.
Claims
1. An analyte sensor for determining an analyte, comprising: a substrate; a working electrode and a conductive layer located on different sites on the substrate; a silver comprising layer partially covering the conductive layer; and a protective layer covering (i) the silver comprising layer fully apart from at least one area accessible to a body fluid having the analyte, and (ii) a portion of the conductive layer.
2. The analyte sensor according to claim 1, wherein the conductive layer, the silver comprising layer and the protective layer form at least one further electrode selected from the group consisting of a counter electrode, a reference electrode and a combined counter/reference electrode.
3. The analyte sensor according to claim 2, wherein the at least one further electrode is or comprises a single combined counter/reference electrode.
4. The analyte sensor according to claim 2, wherein the working electrode is located on a first side of the substrate and wherein the at least one further electrode is located on a second side of the substrate, wherein the first side and the second side of the substrate are positioned opposite each other.
5. The analyte sensor according to claim 4, wherein the working electrode and the at least one further electrode are located on the substrate in a manner that a geometrical projection of a site of the working electrode onto the second side of the substrate on which the at least one further electrode is located does not result in overlap between the geometrical projection of the site of the working electrode and the site of the at least one further electrode.
6. The analyte sensor according to claim 1, wherein the conductive layer comprises an electrically conductive carbon material.
7. The analyte sensor according to claim 1, wherein the silver comprising layer comprises Ag/AgCl.
8. The analyte sensor according to claim 1, wherein the portion of the conductive layer covered by the protective layer is of 20% to 80%.
9. The analyte sensor according to claim 1, wherein the protective layer is a hydrophobic layer.
10. The analyte sensor according to claim 1, wherein the protective layer is a membrane comprising a plurality of holes configured to provide access to the layer comprising silver for the body fluid having the analyte.
11. The analyte sensor according to claim 1, wherein the layer comprising silver comprises an exposed cutting edge which provides access to the layer comprising silver for the body fluid comprising the analyte.
12. The analyte sensor according to claim 1, wherein the analyte sensor is a flat sensor.
13. The analyte sensor according to claim 1, wherein the analyte sensor is partially implantable.
14. A method for producing an analyte sensor according to claim 1, the method comprising: a) providing a raw substrate; b) applying a conductive layer on the raw substrate; c) applying a silver comprising layer in a manner that it partially covers the conductive layer; d) applying a protective layer in a manner that it covers the silver comprising layer and a portion of the conductive layer; e) preparing a working electrode; and f) cutting the raw substrate to obtain the analyte sensor.
15. The method according to claim 14, wherein: the protective layer is applied to fully cover the silver comprising layer; the protective layer comprises a plurality of holes configured to provide access to the layer comprising silver for a body fluid having the analyte; and/or after cutting the raw substrate, the silver comprising layer has an exposed cutting edge which provides access to the layer comprising silver for a body fluid having the analyte.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0140] The above-mentioned aspects of exemplary embodiments will become more apparent and will be better understood by reference to the following description of the embodiments taken in conjunction with the accompanying drawings, wherein:
[0141] FIG. 1 schematically illustrates an aerial view of an analyte sensor according to this disclosure;
[0142] FIGS. 2A and 2B schematically illustrate a method for producing an analyte sensor according to this disclosure;
[0143] FIGS. 3A-3E schematically illustrate selected steps for producing an exemplary embodiment of the analyte sensor according to this disclosure;
[0144] FIG. 4 schematically illustrates recorded values for a temporal development of an equivalent series resistance (ESR) of the analyte sensor according to this disclosure compared to a prior art analyte sensor; and
[0145] FIG. 5 schematically illustrates an equivalent circuit diagram of the analyte sensor according to this disclosure.
DESCRIPTION
[0146] The embodiments described below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may appreciate and understand the principles and practices of this disclosure.
[0147] FIG. 1 schematically illustrates an aerial view of the analyte sensor 110 according to this disclosure. It is particularly emphasized here that the dimensions as used in FIG. 1 are not to scale. The analyte sensor 110 may, as depicted there, be a flat sensor that can be partially implantable for continuously monitoring an analyte, in particular by performing a continuous measurement of one or more analytes in a subcutaneous tissue, preferably in a body fluid, especially in an interstitial fluid or in blood. For this purpose, the analyte sensor 110 may be configured to convert the one or more analytes into an electrically charged entity by using an enzyme. Specifically, the one or more analytes may comprise glucose, which may be converted into an electrically charged entity by using at least one of glucose oxidase (GOD) or glucose dehydrogenase (GHD) as the enzyme. However, the analyte sensor 110 may also be applicable to other analytes and/or to other processes for monitoring an analyte.
[0148] As illustrated in FIG. 1, the analyte sensor 110 comprises an electrically insulating substrate 112. As described above in more detail, the substrate 112 may, in particular, be an elongated planar substrate 112, specifically having a strip shape or a bar shape, which may, preferably, be flexible and/or deformable and/or bendable, and is designated for carrying the further layers as described below. Using the planar substrate 112 may, in particular, facilitate providing the flat sensor. The substrate 112 may comprise at least one electrically insulating material, preferably selected from the group as indicated above, especially in order to avoid unwanted currents between electrically conducting elements carried by the substrate 112.
[0149] As further depicted in FIG. 1, the planar substrate 112 has a first side 114 and a second side 116, wherein the first side 114 and the second side 116 are positioned in an opposite fashion with respect to each other. In the exemplary embodiment of the analyte sensor 110 as shown in FIG. 1, a working electrode 118 is located on the first side 114 of the planar substrate 112 while a further electrode 120 is located on the second side 116 of the planar substrate 112. As further illustrated there, the working electrode 118 and the further electrode 120 are located on the substrate 112 in a manner that a geometrical projection of the site of the working electrode 118 onto the second side 116 of the substrate 112 on which the further electrode 120 is located does not result in overlap between the geometrical projection of the site of the working electrode 118 and the site of the further electrode 120. As an alternative, placing both the working electrode 118 and the further electrode 120 on different sites on the same side of the substrate 112 may also be feasible.
[0150] The further electrode 120 may, preferably, be a counter electrode, a reference electrode and/or a combined counter/reference electrode. As particularly preferred, the further electrode may be or comprise a single combined counter/reference electrode, such that the analyte sensor 110 could be considerably small to be used as implantable sensor.
[0151] As further depicted in FIG. 1, the further electrode 120 comprises a conductive layer 122, 124 which directly covers, preferably fully, both the first side 114 and the second side 116 of the substrate 114. Preferably, the conductive layer 122, 124 may comprise an electrically conductive material, specifically selected from a noble metal, especially gold; or, as particularly preferred, from an electrically conductive carbon material; however, further kinds of conductive materials may also be feasible. As an alternative, the conductive layer 122, 124 may comprise a layered structure, such as described above in more detail.
[0152] As further illustrated in FIG. 1, a silver comprising layer 126 partially covers the conductive layer 124 on the second side 116 of the substrate 114. As already indicated above, the silver comprising layer 126 may, preferably, comprise Ag/AgCl, which can, in particular, be generated from an original AgCl layer during use of the analyte sensor 110, wherein elemental Ag may be formed from the AgCl over the use of the analyte sensor 110. As further already indicated above, the portion of the conductive layer 124 which may be covered by the silver comprising layer 124 can, preferably, be of 5% to 30%, more preferred of 10% to 25%, in particular of 15% to 20%, of the surface of the conductive layer 124 on the second side 116 of the substrate 114 that is located in an opposite fashion with respect to the second side 116 of the substrate to which the conductive layer 124 is applied to.
[0153] As further depicted in FIG. 1, a protective layer 128 covers the silver comprising layer 126 and a portion of the conductive layer 124 on the second side 116 of the substrate 114. As further already indicated above, the portion of the conductive layer 124 on the second side 116 of the substrate 114 which is covered by the protective layer 128 may, preferably, be of 20% to 80%, more preferred of 25% to 75%, specifically of 30% to 70%, in particular of 40% to 60%. As illustrated in FIG. 4, it could be experimentally demonstrated that leaving the remaining section of the accessible surface of the conductive layer 124 on the second side 116 of the substrate 114 uncovered by the protective layer 128 can, in a surprising manner, drastically reduce the measured equivalent series resistance (ESR) of the analyte sensor 110.
[0154] As further illustrated in FIG. 1, the silver comprising layer 126 is fully covered by the protective layer 128 apart from an accessible area 130 which provides access to the silver comprising layer 126 for the body fluid that comprises the one or more analytes. As schematically depicted here, the silver comprising layer 126 may comprise an exposed cutting edge 132 which provides the desired access to the silver comprising layer 126 for the body fluid comprising the one or more analytes. Herein, the cutting edge 132 may be a surface on the silver comprising layer 126 generated by removing a portion of the protective layer 128 from the surface of the silver comprising layer 126 when performing a cutting process during which a raw substrate is cut into appropriate pieces configured to form the individual analyte sensors 110. As further schematically depicted here, the protective layer 128 may, alternatively or in addition, be a membrane 134 which comprises a plurality of holes 136, wherein the holes 136 are designed to provide access to the silver comprising layer 126 for the body fluid comprising the one or more analytes. Independently from the selected arrangement, the desired selective access to the silver comprising layer 126 for the body fluid comprising the one or more analytes allows determining the one or more analytes from an interaction of the body fluid with the silver comprising layer 126.
[0155] In a further embodiment (not depicted here), an electrically insulating layer may cover a further portion of the conductive layer 124, specifically a portion of the conductive layer 124 which is not covered by the silver comprising layer 126 and/or the protective layer 128 and which is not part of the accessible surface 130 to the conductive layer 124 that is left free from the protective layer 128. Herein, the electrically insulating layer may be or comprise an electrically insulating varnish; however, other electrically insulating materials may also be feasible.
[0156] FIG. 2 schematically illustrates a method 140 for producing the analyte sensor 110 according to this disclosure.
[0157] A raw substrate 142 is provided in a providing step 144 according to step a). As already indicated above, the raw substrate 142 has the same insulating material and the same thickness as the substrate 112 but differs from the substrate 112 by a length and a width. The individual analyte sensors 110 each comprising the substrate 112 may be isolated from the raw substrate 142 by using a cutting process as described above in more detail. For ease of processing, the raw substrate 142 may, preferably, be designated for being used in a roll-to-roll process and may, in particular, be provided as a roll.
[0158] The conductive layer 122, 124 is applied in a first applying step 146 according to step b) to the raw substrate 142, preferably, in a fashion that it may directly cover, preferably fully, both the first side 114 and the second side 116 of the substrate 114.
[0159] The silver comprising layer 126 is applied in a second applying step 148 according to step c) in a manner that it partially covers the conductive layer 124 as applied to the second side 116 of the substrate 114 in a fashion as described above in more detail.
[0160] The protective layer 128 is applied in a third applying step 150 according to step d) in a manner that it covers a portion of the conductive layer 124 and the silver comprising layer 126 fully apart from the accessible area 130 which provides access to the silver comprising layer 126 for the body fluid that comprises the one or more analytes as further described above in more detail.
[0161] The working electrode 118 is prepared in a preparing step 152 according to step e), preferably on an opposite side of the raw substrate 142.
[0162] The raw substrate 142 is cut in a cutting step 154 according to step f) into appropriate pieces, specifically by using a laser cutting process, in order to obtain the desired analyte sensor 110.
[0163] As schematically illustrated in FIG. 2A, the working electrode 118 may be prepared in the preparing step 152 prior to the cutting of the raw substrate 142 in the cutting step 154. However, in an alternative embodiment as depicted in FIG. 2B, the working electrode 118 may be prepared in the preparing step 152 after the cutting of the raw substrate 142 in the cutting step 154. For respective procedures and involved advantages of the corresponding arrangements of the preparing step 152 and the cutting step 154, reference may be made to the corresponding description above.
[0164] FIG. 3 schematically illustrates selected method steps for producing an exemplary embodiment of the method 140 for producing the analyte sensor 110. In a top view, the selected method steps are shown for a single analyte sensor; however, in practice the method may, typically, comprise producing a plurality of analyte sensors 110 in a simultaneous fashion on the single raw substrate 142.
[0165] As depicted in FIG. 3A, the raw substrate 142, which comprises a body of polyethylene terephthalate (PET) that may, preferably, be plain or, as an alternative (not depicted here), coated with an Au layer, in particular having a thickness of 50 nm to 200 nm, specifically of 100 nm, is provided according to the providing step 144. In particular, the raw substrate 142 as illustrated here is identical with the substrate 112 of the analyte sensor 110 since, as indicated above, only a single analyte sensor 110 is produced in this exemplary embodiment.
[0166] As depicted in FIG. 3B, the raw substrate 142 as provided according to the providing step 144 is covered, preferably fully, with carbon paste which may form the conductive layer 124 according to the first applying step 146.
[0167] As depicted in FIG. 3C, a portion of the conductive layer 124 as provided during the first applying step 146 is covered with an Ag/AgCl paste in order to form the silver comprising layer 126 according to the second applying step 148.
[0168] FIG. 3D depicts a process step as known from prior art in which a thermoplastic polyurethane (TPU) is applied as the protective layer 128 in a manner that it fully covers both the conductive layer 124 and the silver comprising layer 126 fully apart from the accessible area 130 which provides access to the silver comprising layer 126 for the body fluid that comprises the one or more analytes. Remaining sections on the same side of the raw substrate 142 are coated with an insulating layer 158. As a result, a prior art analyte sensor 160 is obtained, in which the accessible area 130 amounted to about 0.025 mm.sup.2.
[0169] In contrast hereto, FIG. 3E depicts the third applying step 150 in which the thermoplastic polyurethane (TPU) is applied as the protective layer 128 in a manner that it covers the silver comprising layer 126 fully apart from the accessible area 130 which provides access to the silver comprising layer 126 for the body fluid that comprises the one or more analytes but leaves an accessible surface 156 to the conductive layer 124 which is maintained free from the protective layer 128. As a result, the exemplary analyte sensor 110 according to this disclosure is obtained, in which the accessible area 130, again, amounted to about 0.025 mm.sup.2. However, the accessible surface 156 to the conductive layer 124 which was left free from the protective layer 128 amounted to about 1.4 mm.sup.2. Consequently, a size of the accessible surface 156 to the conductive layer 124 clearly exceeds the size of the accessible area 130 to the silver comprising layer 126, in particular by a factor of at least 10, preferably of at least 25, more preferred of at least 50.
[0170] FIG. 4 illustrates measured values of an equivalent series resistance (ESR) in Ohms over a period of time covering 2.25 days of [0171] three individual exemplary analyte sensors 110 according to this disclosure having a setup as schematically depicted in FIG. 3E; and [0172] three individual exemplary prior art analyte sensors 160 having a setup as schematically depicted in FIG. 3D.
[0173] As demonstrated in FIG. 4, compared to the three exemplary prior art analyte sensors 160 the three exemplary analyte sensors 110 according to this disclosure exhibit after a running-in period 162 during a measuring period 164 [0174] a considerably decreased value for the ESR; [0175] a considerably reduced variation of the ESR over the corresponding exemplary analyte sensors 110; and [0176] a considerably diminished duration of the running-in period 162.
[0177] These advantageous observations can, in particular, be explained by a reduced impact of the exposed cutting edges 132, which vary from one analyte sensor 110 to another analyte sensor 110, mainly due to process tolerances, as well as of the holes 136 comprised by the membrane 134 covering the silver comprising layer 126 on the value of the ESR. In a similar fashion, the impact of the initial water uptake which induces the generally observed increase of the values of the ESR during the running-in period 162 is reduced by the predominant contribution of the accessible surface 156 to the ESR.
[0178] These effects are summarized in a model as schematically illustrated in FIG. 5 which comprises an equivalent circuit diagram 170 that represents the analyte sensor 110 according to this disclosure. During a fast-transient measurement of the analyte sensor 110, a capacity of a double layer Cal acts as a shunt capacitor in both the working electrode 118 and the further electrode 120 and can, thus, be disregarded when measuring the equivalent series resistance (ESR) of the analyte sensor 110. As a result, the ESR of the analyte sensor 110 in this model may only depend on a sum of [0179] a membrane resistance R.sub.mem in the working electrode 118; [0180] a solution resistance R.sub.sol; and [0181] a parallel resistance in the further electrode 120 as generated by a membrane resistance R.sub.mem and an additional resistance R.sub.ace which can be attributed to the accessible surface 156 to the conductive layer 124 as illustrated in FIGS. 1 and 3F.
[0182] Owing to the well-known relationship that a value for a total resistor of a plurality of parallel resistors is always lower than the value of each of the resistors, the total ESR, consequently, exhibits a lower value in the analyte sensor 110 according to this disclosure as represented by the equivalent circuit diagram 170 of FIG. 5. As a result, the model can at least explain the considerably decreased value for the ESR observed in the measurements as illustrated in FIG. 4.
[0183] While exemplary embodiments have been disclosed hereinabove, the present invention is not limited to the disclosed embodiments. Instead, this application is intended to cover any variations, uses, or adaptations of this disclosure using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.
LIST OF REFERENCE NUMBERS
[0184] 110 analyte sensor [0185] 112 substrate [0186] 114 first side [0187] 116 second side [0188] 118 working electrode [0189] 120 further electrode [0190] 122 conductive layer [0191] 124 conductive layer [0192] 126 silver comprising layer [0193] 128 protective layer [0194] 130 accessible area [0195] 132 cutting edge [0196] 134 membrane [0197] 136 holes [0198] 140 method for producing an analyte sensor [0199] 142 raw substrate [0200] 144 providing step [0201] 146 first applying step [0202] 148 second applying step [0203] 150 third applying step [0204] 152 preparing step [0205] 154 cutting step [0206] 156 accessible surface [0207] 158 insulating layer [0208] 160 prior art analyte sensor [0209] 162 running-in period [0210] 164 measuring period [0211] 170 equivalent circuit diagram
