METHOD FOR MANUFACTURING AT LEAST ONE ELECTRODE OF AN ANALYTE SENSOR
20230273143 · 2023-08-31
Assignee
Inventors
Cpc classification
A61B5/1486
HUMAN NECESSITIES
A61B5/14865
HUMAN NECESSITIES
A61B5/14532
HUMAN NECESSITIES
A61B5/14503
HUMAN NECESSITIES
G01N27/327
PHYSICS
International classification
G01N27/327
PHYSICS
C12Q1/00
CHEMISTRY; METALLURGY
Abstract
A method for manufacturing at least one electrode (110) of an analyte sensor (112) is disclosed. The method comprises the following steps: a) providing (116) a stencil (118), wherein the stencil (118) comprises a first stencil side (120), a second stencil side (122) and at least one through hole (124) reaching from the first stencil side (120) to the second stencil side (122), wherein at least one of the first stencil side (120) and the second stencil side (122) has first wettability properties; b) providing (126) a substrate (128), wherein the substrate (128) comprises a first side (130) and a second side (134); c) applying (136) the stencil (118) to the first side (130) of the substrate (128); d) applying (138) a low viscosity composition (140) into the through hole (124) of the stencil (118), wherein the low viscosity composition (140) has second wettability properties opposing to the first wettability properties of the at least one of the first stencil side (120) and the second stencil side (122); e) drying (141) the low viscosity composition (140); f) obtaining (142) the at least one electrode (110).
Claims
1. A method for manufacturing at least one electrode of an analyte sensor, the method comprising the following steps: a) Providing a stencil, wherein the stencil comprises a first stencil side, a second stencil side and at least one through hole reaching from the first stencil side to the second stencil side, wherein at least one of the first stencil side and the second stencil side has first wettability properties; b) providing a substrate, wherein the substrate comprises a first side and a second side; c) applying the stencil to the first side of the substrate; d) applying a low viscosity composition into the through hole-(424) of the stencil, wherein the low viscosity composition has second wettability properties opposing to the first wettability properties of the at least one of the first stencil side and the second stencil side; e) drying the low viscosity composition; f) obtaining the at least one electrode.
2. The method according to claim 1, wherein the first wettability properties are hydrophobic or hydrophilic, wherein the second wettability properties are hydrophobic or hydrophilic.
3. The method according to claim 1, wherein the second wettability properties are hydrophilic, wherein both stencil sides have the same first wettability properties, wherein the first wettability properties are hydrophobic.
4. The method according to claim 1, wherein a whole surface of the stencil has first wettability properties, wherein the first wettability properties are hydrophobic.
5. The method according to claim 3, wherein the stencil is hydrophobized with silicon.
6. The method according to claim 1, wherein the low viscosity composition comprises water and/or an osmium based polymer.
7. The method according to claim 1, wherein the viscosity of the low viscosity composition is ≤ 200 mPas, preferably ≤ 100 mPas, more preferably ≤ 50 mPas.
8. The method according to claim 1, wherein the first side of the substrate has third wettability properties opposing to the first wettability properties, wherein the third wettability properties are hydrophilic or hydrophobic.
9. The method according to claim 1, wherein the stencil has a thickness of ≥ 50 .Math.m, preferably of ≥ 100 .Math.m, more preferably ≥ 500 .Math.m.
10. The method according to claim 1, wherein the stencil comprises a plurality of through holes, wherein the through holes have diameters of ≤ 4 mm, preferably ≤ 1 mm, more preferably ≤ 0.5 mm.
11. The method according to claim 1, wherein first side of the substrate comprises at least one conductive material.
12. The method according to claim 1, wherein the obtaining of the electrode comprises removing the stencil from the substrate.
13. A method for manufacturing at least one analyte sensor, the method comprising manufacturing at least one electrode according to the method of claim 1, wherein the method further comprises obtaining the analyte sensor by cutting the substrate.
14. Analyte sensor for determining at least one analyte in a sample of bodily fluid, wherein the analyte sensor comprises at least one electrode manufactured by using a method according to claim 1.
15. Use of the analyte sensor according to claim 14 for detecting at least one analyte in a sample.
Description
SHORT DESCRIPTION OF THE FIGURES
[0128] Further optional features and embodiments will be disclosed in more detail in the subsequent description of embodiments, preferably in conjunction with the dependent claims. Therein, the respective optional features may be realized in an isolated fashion as well as in any arbitrary feasible combination, as the skilled person will realize. The scope of the invention is not restricted by the preferred embodiments. The embodiments are schematically depicted in the Figures. Therein, identical reference numbers in these Figures refer to identical or functionally comparable elements.
[0129] In the Figures:
[0130]
[0131]
[0132]
[0133]
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0134]
[0135] The analyte sensor 112 may be configured to perform a detection of an analyte by acquiring at least one measurement signal for conducting at least one medical analysis. In particular, the analyte sensor 112 may be an electrochemical sensor. Specifically, the electrochemical sensor may be adapted to generate the at least one measurement signal which may, directly or indirectly, indicate a presence and/or an extent of the electrochemical detection reaction, such as at least one current signal and/or at least one voltage signal. The measurement may be a qualitative and/or a quantitative measurement. Still, other embodiments are feasible.
[0136] The analyte sensor 112 may be, in particular, an in vivo sensor. As particularly preferred, the analyte sensor 112 may be a fully or partially implantable analyte sensor 112 which may, particularly, be adapted for performing the detection of the analyte in a bodily fluid of a user in a subcutaneous tissue, particularly in an interstitial fluid. The analyte sensor 112 may be adapted to be fully or at least partly arranged within the body tissue of a patient or a user. For this purpose, the analyte sensor 112 may comprise an insertable portion. Other parts or components of the analyte sensor 112 may remain outside of the body tissue, e.g. counter electrode and/or reference electrode or combined counter/reference electrode may remain outside of the body tissue. Preferably, all electrodes of the implantable analyte sensor may be arranged at the end of a body of the analyte sensor. Preferably, the insertable portion may fully or partially comprise a biocompatible surface, which may have as little detrimental effects on the user or the body tissue as possible, at least during typical durations of use. For this purpose, the insertable portion may be fully or partially covered with at least one biocompatibility membrane layer, such as at least one polymer membrane, for example a gel membrane.
[0137] Alternatively, the analyte sensor 112 may be an ex vivo or in-vitro sensor. The analyte sensor 112 may comprise at least one test element such as at least one electrochemical test element configured for detecting the analyte by using at least one electrochemical measurement, such as the measurement of at least one voltage and/or at least one current. Additionally or alternatively, other types of test elements may be used. The test element preferably is a test strip, i.e. a strip-shaped test element, such as a test element having a strip length of 5 mm to 100 mm, preferably 10 mm to 50 mm, and a strip width of preferably 1 mm to 30 mm, preferably 3 mm to 10 mm. The thickness of the test strips preferably is below 2 mm, preferably below 500 .Math.m. The test strip preferably may be flexible such as deformable by hand. The test element may comprise one or more chemical reagents, also denoted test chemicals, which, in presence of the analyte to be detected, are capable of performing one or more detectable detection reactions. With regard to the chemical reagents comprised in the test elements, reference may be made e.g. to J. Hoenes et al.: The Technology Behind Glucose Meters: Test Strips, Diabetes Technology & Therapeutics, Volume 10, Supplement 1, 2008, S-10 to S-26. Other types of chemical reagents are possible and may be used for performing the present invention.
[0138] The bodily fluid may be a fluid, in particular a liquid, which is typically present in a body or a body tissue of the user or the patient and/or may be produced by the body of the user or the patient. Preferably, the bodily fluid may be selected from the group consisting of blood and interstitial fluid. However, additionally or alternatively, one or more other types of bodily fluids may be used, such as saliva, tear fluid, urine or other body fluids. In case of an in vivo sensor, during the detection of the at least one analyte, the bodily fluid may be present within the body or body tissue. Thus, the analyte sensor 112 may, specifically, be configured for detecting the at least one analyte within the body tissue.
[0139] The analyte may be an element, component, or compound being present in the body fluid, wherein the presence and/or the concentration of the analyte may be of interest to the user, the patient, to medical staff, such as a medical doctor. In particular, the analyte may be or may comprise at least one arbitrary chemical substance or chemical compound which may participate in the metabolism of the user or the patient, such as at least one metabolite. As an example, the at least one analyte may be selected from the group consisting of glucose, cholesterol, triglycerides, lactate, in particular glucose. Additionally or alternatively, however, other types of analytes may be used and/or any combination of analytes may be determined. The determining of the at least one analyte specifically may, in particular, be an analyte-specific detection. Without restricting further possible applications, the present invention is described herein with particular reference to detecting and/or monitoring of glucose, in particular in an interstitial fluid.
[0140] The analyte sensor 112 may comprise at least one electrochemical cell comprising at least one pair of electrodes. Specifically, the analyte sensor 112 may comprise at least one working electrode 114, shown e.g. in
[0141] The electrode 110 may be an entity of the analyte sensor configured for contacting the bodily fluid, either directly or via at least one semi-permeable membrane or layer. The electrode 110 may be embodied in a fashion that an electrochemical reaction may occur at at least one surface of the electrode 110. In particular, the electrode 110 may be embodied in a manner that oxidative processes and/or reductive processes may take place at selected surfaces of the electrodes.
[0142] The electrode 110 may comprise an electrically conductive material. The electrically conductive material may be or may comprise a substance which is designed for conducting an electrical current through the substance. For this purpose, a highly conductive material having a low electrical resistance is preferred, in particular to avoid a dissipation of electrical energy carried by the electrical current within the substance. Preferably, the electrically conductive material may be selected from a noble metal, especially gold; or from an electrically conductive carbon material; however, further kinds of conductive materials may also be feasible.
[0143] The electrode 110, in particular the working electrode 114, further may comprise the at least one chemical reagent disposed on the electrically conductive material. The chemical reagent may be or may comprise at least a polymeric material, specifically at least a polymeric material and at least a metal containing complex. The metal containing complex may be selected from the group of transition metal element complexes, specifically the metal containing complex may be selected from osmium-complexes, ruthenium-complexes, vanadium-complexes, cobalt-complexes, and iron-complexes, such as ferrocenes, such as 2-aminoethylferrocene. Even more specifically, the chemical reagent may be a polymeric transition metal complex as described for example in WO 01/36660 A2, the content of which is included by reference. In particular, the chemical reagent may comprise a modified poly (vinylpyridine) backbone loaded with poly(bi-imidizyl) Os complexes covalently coupled through a bidentate linkage. The chemical reagent may further be described in Feldmann et al, Diabetes Technology & Therapeutics, 5 (5), 2003, 769-779, the content of which is included by reference.
[0144] The method for manufacturing the at least one electrode 110 of the analyte sensor 112 comprises the following steps: [0145] a) (denoted with reference number 116) providing a stencil 118, shown e.g. in
[0151] Specifically, the present invention proposes a method for manufacturing the at least one electrode 110, in particular the working electrode 114, by stencil printing of working electrode fields. The method is in particular applicable for mass production of analyte sensors 112. Use of stencil printing may allow manufacturing sharp edges and sharp 90° corners within small areas of about <= 3 mm which is not possible with other mass production coating methods.
[0152] The stencil, such as shown in
[0153] The stencil 118 may comprise at least one foil 144 having the at least one through hole 124. For example, the foil may be a metal foil or a plastic foil. Generally, arbitrary flexible foils can be used as stencil which are hydrophobic on both sides. In particular, foils having low surface energy, specifically, a low polar fraction of surface energy, may be used. For example, the polar fraction of the surface energy may be < 10 mN/m, preferably < 5 mN/m, wherein the polar fraction of the surface energy may be measurable by the Owens, Wendt, Rabel and Kaelble (OWKR)-method. Additional siliconization may be advantageous. In particular, if the material of the stencil may be magnetic, this may allow improved fixing of the stencil on the substrate. For example, the stencil may comprise at least one siliconized liner. Other kinds of foils may also be feasible. The providing of the stencil 118 may comprise manufacturing the stencil 118 and/or selecting a prefabricated stencil 118. As outlined above, the stencil 118 comprises the at least one through hole 124. The providing of the stencil 118 may comprise cutting and/or punching the through hole into the foil 144. The through hole 124 may be cut into the foil 144 by laser cutting and/or punching. The through hole 124 may have the geometry and/or shape of the electrode to be manufactured. The stencil 118 may comprise a plurality of through holes 124. The through holes 124 may have diameters of ≤ 4 mm, preferably ≤ 1 mm, more preferably ≤ 0.5 mm. The stencil 118 may have a pre-defined or selected thickness. The thickness of the stencil 118 may define a wet film thickness later on during printing. For example, the stencil 118 may have a thickness of ≥ 50 .Math.m, preferably of ≥ 100 .Math.m, more preferably ≥ 500 .Math.m. The stencil 118 may be provided, in particular manufactured, using a sheet-process and/or at least one roll-to-roll-process.
[0154] The stencil 118 may have a planar shape. The stencil 118 may, specifically, have an elongated shape, such as a sheet or strip shape or a bar shape; however, other kinds of shapes may also be feasible.
[0155] The stencil sides 120, 122 may be opposing, planar sides of the stencil 118. The first stencil side 120 may be the side of the stencil 118 facing away from the substrate 128 when the stencil 118 is applied onto the substrate 128. The second stencil side 122 may be the side of the stencil 118 in contact with the substrate 128 when the stencil 118 is applied onto the substrate 128. The orientation of the stencil 118 may be pre-defined with respect to the substrate 128. However, embodiments may be possible wherein the first stencil side 120 and the second stencil side 122 are interchangeable, such that the stencil 118 can be used in both orientations.
[0156] The wettability property may be surface wettability which relates, in particular, to surface free energy and geometric structures. The wettability property may be one or more of hydrophobic, hydrophilic, polar, or non-polar. At least one of the first stencil side 120 and the second stencil side 122 may have opposing wettability properties than the low viscosity composition 140, in particular opposed polarities. At least one of the first stencil side 120 and the second stencil side 122 may be hydrophobic and the low viscosity composition 140 may be hydrophilic. Preferably both stencil sides 120, 122 may be hydrophobic. In particular, a whole or overall surface of the stencil 118 may be hydrophobic. For example, the stencil 118 may be hydrophobized with silicon. Alternatively, at least one of the first stencil side 120 and the second stencil side 122 may be hydrophilic and the low viscosity composition 140 may be hydrophobic. Repulsive forces between the at least one stencil side 120, 122 and of the low viscosity composition 140 have the effect that the low viscosity composition 140 is fixed within the stencil 118, in particular the through hole 124, such that the substrate 128 is not wetted over an area defined by the through hole 124. Reduced shearing of the low viscosity composition 140 compared to dispensing cannulas with small diameters can be achieved.
[0157] A surface of the substrate 128, in particular the surface of the first side 130 facing the stencil 118, may have third wettability properties opposing to the first wettability properties. Specifically, said surface of the substrate 128 may be hydrophilic or hydrophobic.
[0158] The substrate 128 may be an arbitrary element designed to carry one or more other elements disposed thereon or therein. Particularly preferred, the substrate 128 may be a planar substrate. The substrate 128 may, specifically, have an elongated shape, such as a strip shape or a bar shape; however, other kinds of shapes may also be feasible. Specifically, the substrate 128 may be a sheet. For example, the substrate 128 may be provided as rolled-up sheet or tape. The substrate 128 may be printed with the low viscosity composition and may be cut subsequently into the individual analyte sensors.
[0159] The substrate 128 may comprise at least partially, preferably completely, at least one electrically insulating material, especially in order to avoid unwanted currents between electrically conducting elements as carried by the substrate. By way of example, the electrically insulating material may be selected from polyethylene terephthalate (PET) or polycarbonate (PC); however, other kinds of electrically insulating materials may also be feasible.
[0160] The first side of the substrate 128 may comprise at least one conductive material 132. The providing of the substrate 128 in step b) may comprise applying a layer of conductive material 132 onto a side, in particular a first side of the electrically insulating material. The layer may, specifically, have an elongated shape, such as a strip shape or a bar shape; however, other kinds of shapes may also be feasible. In general, the layer may, partially or completely, cover a respective side of substrate 128. In a preferred embodiment, in which the layer may only partially cover a portion of the respective side of the substrate 128, an insulating layer may, partially or completely, cover remaining portions of substrate 128. The applying of the layer of the conductive material 132 may comprise at least one process of depositing the conductive material 132 on the substrate 128. In particular, the process may be selected from at least one of squeegee coating, chemical bath deposition, vacuum evaporation, sputtering, atomic layer deposition, chemical vapor deposition, spray pyrolysis, electrodeposition, anodization, electro-conversion, electro-less dip growth, successive ionic adsorption and reaction, molecular beam epitaxy, molecular vapor phase epitaxy, liquid phase epitaxy, inkjet printing, gravure printing, flexo printing, screen printing, stencil printing, slot die coating, doctor blading, and solution-gas interface techniques. For example, the substrate may be a carbon-coated substrate. The carbon-coated substrate may be manufactured using squeegee coating with purchased carbon pastes. For example, the substrate may be a gold-coated substrate. The substrate may be conductive on both sides. The second side 134 of the substrate 128 may, preferably, be blank, or may, as an alternative, comprise the at least one electrically insulating material.
[0161] The applying of the stencil 118 on the substrate 128 in step c) may comprise depositing the stencil 118 on the first side 130 of the substrate 128. The stencil 118 may be applied to the substrate 128 without using additional adhesive on its second stencil side 122. For example, the own weight of the stencil 118 may be sufficient. Additionally or alternatively, the stencil 118 may be fixed and/or weighed down on its outer edges. Additionally or alternatively, in case of a roll to roll process the stencil 118 may be spanned over the substrate 128. The low viscosity composition may be prevented to flow under the stencil 118 because of the hydrophobic and/or hydrophilic-interaction.
[0162] The low viscosity composition 140 may be an arbitrary substance which comprises at least two different components, i.e. at least one first component and at least one second component. The low viscosity composition 140 may comprise and/or may build and/or may form the chemical reagent of the electrode. Specifically, the low viscosity composition 140 may comprise water and/or an osmium based polymer. The low viscosity composition 140 may comprise reactive components for forming the chemical reagent. Other additives such as thickeners and/or surfactants may be omitted. Thus, in an embodiment, the low viscosity composition does not comprise a thickener and/or a surfactant.
[0163] Specifically, the low viscosity composition 140 may be a fluid and/or a paste. The viscosity of the low viscosity composition may be ≤ 200 mPas, preferably ≤ 100 mPas, more preferably ≤ 50 mPas. For example, the viscosity of the low viscosity composition may be about 50 mPas. For example, the viscosity of the low viscosity composition may be < 100 mPas at 20° C. with a shear rate of 10 s.sup.-1. The viscosity may be determined using a cone-plate viscometer. Such techniques are generally known to the skilled person.
[0164] An embodiment of step d) of the method is shown in
[0165] An application quantity per area of the low viscosity composition 140 may be variable. The application quantity may be defined by the thickness of the stencil 118.
[0166] In step e), the method comprises at least one drying step in which the low viscosity composition 140 is fully or partially dried. Thus, the low viscosity composition 140 may be fixed during drying, in particular such that essentially no bleeding occurs. The drying in step e) may comprise fully or partially removing one or more solvents from the low viscosity composition 140 and/or by initiating one or more chemical reactions within the low viscosity composition 140, such as cross-linking reactions. In the latter case, the at least one chemical reaction may be initiated by internal factors, such as one or more initiators contained within the low viscosity composition 140, and/or may be initiated by one or more external influences, such as heat and/or electromagnetic radiation. The drying may be performed at room temperature or higher temperatures. For example, the drying may be performed at temperatures of ≤ 50° C. The drying may comprise one or more of: a heating; an exposure to hot gas, such as hot air; an exposure to electromagnetic radiation, preferably electromagnetic radiation in the ultraviolet spectral range. The drying may be performed, in particular, before removing the stencil 118 from the substrate 128. However, embodiments in which the low viscosity composition 140 is only partially dried, i.e. not fully cured or dried, before removing the stencil 118 are feasible. In this case, an additional drying may be performed after removing the stencil 118.
[0167] Specifically, the low viscosity composition is only partially dried in the drying step. For example, in a batch process the stencil 118 may be used several times or in a roll-to-toll process the stencil 118 may be removed from the substrate 128 as soon as possible. In these cases, the stencil 118 may be removed from the substrate after reaching form stability in the drying step.
[0168] The method may comprise repeating step d), in particular for applying subsequently more than one layer of the low viscosity composition 140 onto the substrate 128.
[0169] After the fully or partially drying of the low viscosity composition 140 the stencil 118 may be removed from the substrate 128. The obtaining the electrode 110 in step f) may comprise a process of completing the manufacturing of the electrode 110. The obtaining may comprise final manufacturing steps. As outlined above, the obtaining of the electrode 110 may comprise removing the stencil 118 from the substrate 128. The obtaining may comprise further steps such as cleaning the substrate 128. In case, in step e), the low viscosity composition was only partially dried, step f) may comprise additional drying to finish the drying. The stencil may be removed during drying.
[0170]
[0171]
[0172]
TABLE-US-00001 List of reference numbers 110 electrode 112 analyte sensor 114 working electrode 116 providing a stencil 118 stencil 120 first stencil side 122 second stencil side 124 through hole 126 providing a substrate 128 substrate 130 first side 132 conductive material 134 second side 136 applying the stencil 138 applying a low viscosity composition 140 low viscosity composition 141 drying 142 obtaining the electrode 144 foil 146 squeegee or wiper 148 arrow 150 test field 152 first liner roll 154 second liner roll 156 first substrate roll 158 second substrate roll 160 fixing frame 162 Pressure table