Patent Description:
Monitoring certain body functions, more particularly monitoring one or more concentrations of certain analytes, plays an important role in the prevention and treatment of various diseases. Without restricting further possible applications, the invention is described in the following with reference to glucose monitoring in an interstitial fluid. However, the invention can also be applied to other types of analytes. Blood glucose monitoring may, specifically, be performed by using electrochemical sensors besides optical measurements. Examples of electrochemical sensors for measuring glucose, specifically in blood or other body fluids, are known from <CIT>, <CIT>, <CIT>, <CIT> or <CIT>.

In addition to "spot measurements" in which a sample of a body fluid is taken from a user, i.e. a human or an animal, in a targeted fashion and examined with respect to the analyte concentration, continuous measurements have become increasingly established. Thus, in the recent past, continuous measuring of glucose in the interstitial tissue, also referred to as "continuous glucose monitoring" or abbreviated to "CGM", has been established as another important method for managing, monitoring, and controlling a diabetes state. Herein, an active sensor region is applied directly to a measurement site which is, generally, arranged in an interstitial tissue, and may, for example, convert glucose into an amended entity by using an enzyme, in particular, glucose oxidase, generally abbreviated to "GOD". As a result, the detectable current may be related to the glucose concentration and can, thus, be used as a measurement variable. Examples of such transcutaneous measurement systems are described in <CIT> or <CIT>.

Typically, current continuous monitoring systems are transcutaneous systems or subcutaneous systems. Accordingly, the actual electrochemical sensor or at least a measuring portion thereof may be arranged under the skin of the user. However, an evaluation and control part of the system, which may also be referred to as a "patch", may, generally, be located outside of the body of a user. Herein, the electrochemical sensor may, generally, be applied by using an insertion instrument, which is, in an exemplary fashion, described in <CIT>. However, other types of insertion instruments are also known. Further, a measurement device which may also acts as a control part may, typically, be required which may be located outside the body tissue and which has to be in communication with the electrochemical sensor. Generally, communication is established by providing at least one electrical contact between the electrochemical sensor and the measurement device, wherein the contact may be a permanent electrical contact or a releasable electrical contact. Other techniques for providing electrical contacts, such as by appropriate spring contacts, are generally known and may also be applied.

In continuous glucose measuring systems, the concentration of the analyte glucose may be determined by employing an electrochemical sensor comprising an electrochemical cell having at least a working electrode and a counter electrode. Herein, the working electrode may have a reagent layer comprising an enzyme with a redox active enzyme co-factor adapted to support an oxidation of the analyte in the body fluid. Further, the working electrode, usually, has a supporting layer of copper deposited on a substrate on which gold contacts are galvanically deposited. This kind of arrangement, however, lacks mechanical flexibility since bending the electrochemical sensor may easily result in a delamination of gold and copper from the substrate. As a result, the may copper become electrochemically accessible, whereby an oxidation current may be generated as a leakage current which may capable of influencing the measurement.

<CIT> discloses an enzyme electrode comprising a carrier, an enzyme immobilized on a part of the outer surface of the carrier, a coating film consisting of a thin film permeable for a substrate for the enzyme and coating the portion where the enzyme is immobilized, and an internal electrode capable of applying voltage to the portion. A GOD electrode was prepared by using a mini-grid electrode as the internal electrode. For this purpose, a solution comprising GOD in a solvent was placed on a storage layer and the solvent was removed by evaporation. Thereafter, a gold mini-grid electrode was placed and fixed by a nylon net on the resulting storage layer. Further, GOD solution was placed on the gold mini-grid electrode through the nylon net and the solvent was made to evaporate, until, eventually, the gold mini-grid electrode was connected with a lead wire by means of a conductive bonding agent.

<CIT> discloses an electrochemical sensor that employs multiple electrode areas that are exposed for contact with a body fluid. In <FIG> there are counter electrode covers (<NUM>), working electrode covers (<NUM>) and reference electrode covers (<NUM>) shown, which are located on one side of a base substrate (<NUM>).

<CIT> discloses an electrochemical-based analytical test strip for the determination of an analyte (e.g. glucose) in a bodily fluid sample with an electrically insulating base layer and a patterned conductor layer. The pattered conductor layer includes a counter electrode and working electrode, wherein the working electrode has electrochemically inert areas, which are configured as squares, and electrochemically active areas, which are configured as lattice.

<CIT> discloses an electrode system for measuring the concentration of an analyte under in-vivo conditions, comprising a counter-electrode having an electrical conductor, a working electrode having an electrical conductor on which an enzyme layer containing immobilized enzyme molecules for catalytic conversion of the analyte is arranged, and a diffusion barrier that slows the diffusion of the analyte from body fluid surrounding the electrode system to enzyme molecules down. The system provides the enzyme layer in the form of multiple fields that are arranged on the conductor of the working electrode at a distance from each other. For this purpose, the working electrode is covered by an electrically insulating layer, wherein the multiple fields are arranged on top of openings a comprised by the electrically insulating layer.

Despite the advantages implied by the above-mentioned devices and methods known in the art, still, technical challenges remain, in particular, with regard to design and manufacturing of electrochemical sensors. Especially, the current design of the electrochemical sensors which are manufactured in accordance with the process as disclosed in <CIT> requires that an enzyme paste is deposited very accurately into openings as comprised by an electrically insulating layer in order to thoroughly cover the electrically conducting surface of the working electrode.

It is therefore an objective of the present invention to provide an electrochemical sensor for electrochemically detecting glucose in a sample of a body fluid as well as a method for manufacturing the electrochemical sensor, which at least partially avoid the short-comings of known devices and methods of this kind.

In particular, it is desirable to provide an electrochemical sensor which, on one hand, may comprise a mechanically flexible sensor design while, on the other hand, manufacturing efforts may be reduced in comparison to known manufacturing processes, specifically, with regard to an increase of the position tolerance.

This problem is solved by an electrochemical sensor for electrochemically detecting glucose in a sample of a body fluid having the features of the independent claims as well as by a method for manufacturing the electrochemical sensor. Preferred embodiments of the invention, which may be realized in an isolated way or in any arbitrary combination, are disclosed in the dependent claims.

As used herein, the term "sensor system", which may, alternatively, also be denoted by the term "sensor assembly", refers to a device which is configured for conducting at least one medical analysis. For this purpose, the sensor system may be a device configured for performing at least one diagnostic purpose and, specifically, comprising at least one analyte sensor for performing the at least one medical analysis. The sensor system may, specifically, comprise an assembly of two or more components capable of interacting with each other, such as in order to perform one or more diagnostic purposes, such as in order to perform the medical analysis. Specifically, the two or more components may be capable of performing at least one detection of the at least one analyte in the body fluid and/or in order to contribute to the at least one detection of the at least one analyte in the body fluid. As described below in more detail, the sensor system comprises an assembly having at least one first component adapted for detecting at least one analyte in a sample of a body fluid, especially, by performing at least one measurement, at least one second component configured for performing at least one measurement in interoperation with the at least first component and for determining an analyte value in the sample of the body fluid by evaluating the at least one measurement, and at least one third component configured for providing interoperation between the at least one first component and the at least one second component.

As generally used, the terms "patient" and "user" may refer to a human being or an animal, independent from whether the human being or animal, respectively, may be in a healthy condition or may suffer from one or more diseases. As an example, the patient or the user may be a human being or an animal suffering from diabetes. However, additionally or alternatively, the invention may be applicable to other types of users, patients or diseases.

As further used herein, the term "body fluid" may, generally, refer to a fluid, in particular a liquid, which may typically be present in a body or a body tissue of the user or the patient and/or which may be produced by the body of the user or the patient. Preferably, the body fluid may be selected from the group consisting of blood and interstitial fluid. However, additionally or alternatively, one or more other types of body fluids may be used, such as saliva, tear fluid, urine or other body fluids. During the detection of the at least one analyte, the body fluid may be present within the body or body tissue. Thus, the sensor may at least be configured for detecting the at least one analyte within the body tissue.

As further used herein, the term "analyte" may refer to an arbitrary 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, or to a medical staff, such as to a medical doctor. Particularly, 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. Additionally or alternatively, however, other types of analytes may be used and/or any combination of analytes may be determined. The detection 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 in the following with particular reference to a monitoring of glucose in an interstitial fluid. As generally used, at least one property of the analyte may be characterized by a "value" related to this property, such as a concentration, of the analyte. However, other kinds of properties may also be feasible, such as interfering substances or "interferents", i.e. additional redox active substances comprised by the body fluid which may be oxidized in a similar manner and may, thus, generate further electrons which may be detectable as an additional current.

The electrochemical sensor according to the present invention is for detection of glucose in a sample of a body fluid.

In a first aspect of the present invention, an electrochemical sensor for electrochemically detecting glucose in a sample of a body fluid as defined in the appended claim <NUM> is disclosed. Accordingly, the electrochemical sensor comprises a substrate having a proximal region and a distal region, wherein the proximal region comprises at least one contact element which is configured to communicate with a measurement device, wherein the electrochemical sensor comprises at least one working electrode located in the distal region located on the front side of the substrate and at least one counter electrode located on the back side of the substrate, wherein the working electrode has a plurality of enzyme fields, each enzyme field comprising at least one enzyme, the enzyme being configured for providing a reaction with the glucose, wherein the working electrode further comprises at least one conductive trace, wherein each of the enzyme fields is partially located on the conductive trace, wherein the working electrode comprises a multiplicity of conductive traces, the multiplicity of conductive traces forming a grid, wherein the electrochemical sensor further comprises at least one reference electrode, wherein the reference electrode is located in the proximal region of the substrate.

As used herein, the term "electrochemical sensor" refers to a sensor which is adapted for performing at least one electrochemical measurement, in particular a plurality or series of electrochemical measurements, in order to detect the at least one substance as comprised within the body fluid by using an amperometric method. Especially, the term "electrochemical measurement" refers to a detection of an electrochemically detectable property of the substance, such as an electrochemical detection reaction, by employing amperometric methods. Thus, for example, the electrochemical detection reaction may be detected by applying and comparing one or more electrode potentials. Specifically, the electrochemical sensor may be adapted to generate at least one electrical 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.

In a particularly preferred embodiment of the present invention, the electrochemical sensor may be fully or a partially implantable and may, thus, be adapted for performing the detection of the glucose in the body fluid in a subcutaneous tissue, in particular, in an interstitial fluid. As used herein, the terms "implantable" or "subcutaneous" refer to be fully or at least partly arranged within the body tissue of the patient or the user. For this purpose, the electrochemical sensor may comprise an insertable portion, wherein the term "insertable portion" may generally refer to a part or component of an element configured to be insertable into an arbitrary body tissue while other parts or components may remain outside of the body tissue. Preferably, the insertable portion may fully or partially comprise a biocompatible surface, i.e. a surface which may have as little detrimental effects on the user, the patient, 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 biocompatible membrane, such as at least one polymer membrane or gel membrane which, on one hand, may be permeable for the body fluid or at least for the glucose as comprised therein and which, on the other hand, may retain sensor substances, such as one or more test chemicals within the electrochemical sensor, thus preventing a migration thereof into the body tissue.

Further, the electrochemical sensor comprises a substrate having a proximal region and a distal region, wherein the proximal region of the substrate comprises at least one contact element which is configured to communicate with the measurement device. As generally used, the term "contact element" refers to a unit which is configured for communication with the measurement device and which may, thus, comprise at least one electrical contact being adapted to provide an electrical contact with a corresponding electrical contact of the measurement device. However, other kinds of communication between the electrochemical sensor the measurement device may also be conceivable, in particular by using a contact element which may be adapted for wireless communication.

As generally used, the term "substrate" refers to an arbitrarily shaped body which is configured for carrying and/or supporting elements which are located on the substrate. For this purpose, the substrate may, preferably, comprise an electrically insulating material which can provide sufficient mechanical stability for the elements located on the substrate and, in addition, electrical insulation for electrodes and corresponding lead wires. Preferably, the substrate can be a flexible substrate which may, especially, comprise a bendable, electrically insulating material which may be biocompatible. Herein, the bendable and electrically insulating material may comprise at least one of polyimide (PI), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polypropylene (PP), polyamide (PA), flexible glass, or silicon. However, other electrically insulating and biocompatible materials may also be used as the substrate.

Preferably, the substrate refers to a three-dimensional form which predominantly extends in two directions, which are usually denoted by the terms "length" and "width", respectively, while the third direction, which is usually denoted by the term "height", is less pronounced. In particular, both the length and the width of the substrate exceed the height of the substrate by a factor of at least <NUM>, preferably of at least <NUM>, more preferred of at least <NUM>. Moreover, the electrochemical sensor may be provided in form of a test element, in particular a test stripe, in which the length of the substrate may exceed the width of the substrate by a factor of at least <NUM>, preferably of at least <NUM>, more preferred of at least <NUM>. However, other extensions of the substrate may also be feasible.

Further, the terms "proximal region" and "distal region" refer to respective partitions of the substrate, which can be assigned by either term by considering whether they carry and/or support the at least one contact element configured to communicate with the measurement device or not. As a result, the partition of the substrate, which carries and/or supports the at least one contact element configured to communicate with the measurement device, is denominated as the "proximal region", whereas the partition of the substrate, which carries and/or supports the at least one working electrode as described below in more detail, is denoted as the "distal region". Therefore, it can be feasible that the proximal region and the distal region are distinct regions on the substrate which respect to each other. However, it may also be possible that an overlap may exist between the proximal region and the distal region.

According to the present invention, the electrochemical sensor is arranged in form of a multiple field sensor. As a result, the working electrode comprises a plurality of enzyme fields, such as <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or more enzyme fields. In contrast to a usual enzyme layer which is, typically, provided in a manner that it at least partially or, preferably, fully covers a surface of the working electrode which may be configured to contact the body fluid in form of a single continuous layer, the term "enzyme fields" refers to individual areas on the respective surface of the working electrode, wherein each of the individual areas which are configured to contact the body fluid comprises the enzyme but is located at a distance from each of adjacent enzyme fields. Herein, each of the enzyme fields comprises the at least one enzyme which is configured for providing a reaction with the glucose, wherein, the enzyme is provided in the same concentration for each of the enzyme fields. As a result of providing the same concentration, a more homogeneous electrical field can be generated within the working electrode.

Consequently, the enzyme fields may, preferably, be arranged side by side with respect of each other in a parallel manner on the respective surface of the working electrode, wherein adjacent enzyme fields are separated from each other by a gap which is maintained free from the enzyme. Preferably, adjacent enzyme fields may be spaced at least <NUM>, preferably at least <NUM>, distant from each other. As a result, a series of multiple individual enzyme fields of a single working electrode can be considered as a plurality of working electrodes arranged in series, thus, providing an improvement of a signal-to-noise ratio of the measurement signal.

In particular contrast to <CIT> as cited above, wherein the working electrode is covered by an electrically insulating layer, wherein the multiple fields are arranged on top of openings as comprised by the electrically insulating layer, the working electrode in accordance with the present invention further comprises at least one conductive trace, wherein each of the enzyme fields is at least partially located on the at least one conductive trace, in particular, on top of the at least one conductive trace. As used herein, the tem "at least partially" refers to an arrangement in which a particular enzyme field may only cover a partition of the conductive trace or, as an alternative, in which the particular enzyme field may cover a partition of the conductive trace but, concurrently, also a further distinct part of the substrate apart from the conductive trace. As generally used, the term "conductive trace" refers to at least one electrically conducting, preferably non-corrosive, especially biocompatible, material that is provided in form of an individual track which extends at least in the distal region of the substrate but may, preferentially, be connected to at least one lead wire or be continued as the at least one lead wire in the proximal region of the substrate, wherein the lead wire may be configured for providing electrical connection between the working electrode and the at least one contact element which is configured to communicate with the measurement device. Herein, the term "track" refers to a three-dimensional form of the trace which predominantly extends in one direction, which is usually denoted by the term "length", while the other two directions, which are usually denoted by the terms "width" and "height", respectively, are less pronounced. In particular, the length of the conductive trace may exceed both the width and the height of the conductive trace by a factor of at least <NUM>, preferably of at least <NUM>, more preferred of at least <NUM>. Herein, the height of the conductive trace may, preferably, assume a thickness of <NUM>-<NUM>. Thus, in particular contrast to <CIT> as cited above, position requirements are considerably reduced when the plurality of the enzyme fields are at least partially located on the at least one conductive trace.

In a particularly preferred embodiment, the working electrode comprises a multiplicity of conductive traces, thus, advantageously further reducing the position requirements during placement of the plurality of the enzyme fields. Herein, the multiplicity of the conductive traces may be provided in an arbitrary manner, however, providing the multiplicity of conductive traces in form of a grid may, especially, be preferred. However, other kinds of arrangements may also be feasible. As generally used, the term "grid" implies a regular arrangement in which distances between adjacent conductive traces are selected from a single value or from a small interval of deviations compared to the distance, such as less than <NUM> %, preferably less than <NUM> %, of the distance. As a further advantage, placing the multiplicity of the conductive traces in form of a grid may, further, simplify the manufacturing of the working electrode.

In a further, particularly preferred embodiment, the non-corrosive, electrically conducting material as used for the at least one conductive trace may comprise gold which is known to be easily deposited, thus, further simplifying the manufacturing of the working electrode. In order to further facilitate a deposition of the electrically conducting material, at least one non-corrosive bonding agent, may, in particular, be used in addition to the gold. Preferably, the bonding agent may be selected from at least one of titanium or palladium, both of which are known to be suited for this purpose, wherein a layer having a thickness of <NUM>-<NUM>, preferably of <NUM>-<NUM>, may, especially, be appropriate, on which the non-corrosive, electrically conducting material, in particular, the gold, may be located. Herein, the bonding agent may, especially, be used for enhancing adhesion of the electrically conducting material on the surface of the substrate. Thus, this bonding agent may also be used for the other electrodes located on the substrate. However, other kinds of non-corrosive, electrically conducting materials and/or bonding agents may also be conceived.

In a particular embodiment of the present invention, the conductive trace can comprise a first partition and a second partition, wherein the first partition may be located in the distal region while the second partition may be located in the proximal region. As indicated above, the second partition of the conductive trace located in the proximal region can, thus, be considered as being continued as the at least one lead wire of the working electrode in the proximal region of the substrate which is configured for providing electrical connection between the working electrode and the at least one contact element. This kind of arrangement may, as an alternative view, also be considered as overlap between the first partition and the second partition of the conductive trace. Since copper is known as a corrosive material upon exposure to the body fluid, causing the copper to oxidize, thus, gradually changing bright copper surfaces to tarnish, it is preferred in this particular embodiment that the at least the first partition of the conductive trace may be devoid of copper while the second partition of the conductive trace may, still, comprise copper as one of the electrically conducting material or the bonding agent for a further electrically conducting material. As a result, the at least one lead wire which may comprise copper in the proximate region may, especially, profit from an enhanced mechanical stability of copper traces compared to gold traces.

In a further embodiment of the present invention, the substrate may be partially covered by a solder resist in a manner that the solder resist at least partially covers the proximal region of the substrate. Herein, the solder resist may, preferably, partially cover the substrate in a manner that the distal region of the substrate is devoid of the solder resist. As generally used, the term "solder resist" refers to a thin lacquer-like layer of polymer usually applied to conductive traces, such as in a printed circuit board (PCB), in order to, on one hand, provide a protection against oxidation and, on the other hand, to avoid forming of solder bridges between adjacent solder pads. Since it is preferred in the particular embodiment as described above that the at least the first partition of the conductive trace which is located in the distal region of the substrate may be devoid of copper, it may, preferably, be possible to provide the electrochemical sensor without a solder resist within the distal region of the substrate, thus, allowing the sample of the body fluid to better contact the plurality of the enzyme fields, whereas the solder resist may be advantageous in an embodiment in which the second partition of the conductive trace which is located in the proximal region of the substrate may comprise copper.

In a particularly preferred embodiment, the electrochemical sensor may comprise a three-electrode arrangement as described in the following. Herein, the working electrode may have a test chemistry which comprises carbon paste having carbon particles and a polymer binder as a conductive substance, manganese dioxide (MnO<NUM>), preferably in particulate form, as a catalyst and/or a mediator, and at least one of the enzymes glucose oxidase (GOD) or glucose dehydrogenase (GDH) which may be applied to a surface of a polyimide substrate in form of a plurality of enzyme fields. Further, the working electrode, in addition, has a multiplicity of conductive traces in form of a grid, wherein the conductive traces may comprise gold, which may be located on a layer of at least one of titanium or palladium acting as non-corrosive bonding agent. For sake of increasing mechanical stability of the electrochemical sensor, the conductive traces in the proximal reason may comprise copper as electrically conducting material or bonding agent. In order to achieve protection from copper oxidation, a solder resist may cover the proximal region of the substrate. In accordance with the present invention, each of the enzyme fields is at least partially located on the multiplicity of the conductive traces, thereby, in particular, contributing to a simplified manufacturing of the electrochemical sensor. Further, the counter electrode may be or comprise a gold electrode while the reference electrode may be or comprise an Ag/AgCl electrode, wherein both electrodes are maintained free from the enzyme. The three-electrode arrangement as described herein may, thus, allow applying an electrical potential between the working electrode and the reference electrode and measuring the raw current generated hereby, preferably, between the working electrode and the counter electrode. Further, the substrate comprises a front side and a back side, wherein the working electrode and the reference electrode may be located on the front side of the substrate, while the counter electrode may be located on the back side of the substrate.

Based on the at least one measurement signal, the measurement device may generate an additional value related to the measurement signal. As generally used, a sensitivity S of the electrochemical sensor may, thus, be obtained by measuring a raw current I as the measurement signal using the electrochemical sensor, an taking into account a concentration c of the analyte, such as the glucose. In an ideal representation, the sensitivity S of the electrochemical sensor may, generally, be defined by Equation (<NUM>): <MAT> wherein the term I<NUM> refers to a possible zero current, which may originate from interferents being present in the body fluid. In case of a sensitivity drift, the raw current I may, thus, be measured and the sensitivity S may, subsequently, be corrected. In practice, Equation (<NUM>) is empirically known to hold true for a glucose concentration up to <NUM>/dl to <NUM>/dl whereas a more complex behavior appears for higher concentrations.

In a further aspect of the present invention, a method for manufacturing an electrochemical sensor, in particular an electrochemical sensor as described elsewhere in this document, is disclosed. The method is defined in the appended claim <NUM>.

Herein, the method comprises the indicated steps a) to c) which may, preferably, be performed in the given order, starting with step a). However, steps b) and c) may also be performed in a different order or at least partially concurrently. Accordingly, the method comprises the following steps:.

In a particularly preferred embodiment, placing the at least one conductive trace may comprise printing a first preparation comprising at least one non-corrosive, electrically conducting material, preferably gold, and, preferably, a volatile solvent on a position which may be intended for this purpose on the substrate. Herein, the printing may be performed in a manner that the layer of the non-corrosive, electrically conducting material may assume a thickness of <NUM>-<NUM>. Preferably, the layer of the non-corrosive, electrically conducting material may be printed on an additional layer comprising at least one non-corrosive bonding agent, especially, selected from at least one of titanium or palladium, having a thickness of <NUM>-<NUM>, preferably of <NUM>-<NUM>, in order to enhance adhesion of the layer of the non-corrosive, electrically conducting material, in particular the gold, on the substrate.

Similarly, in a further particularly preferred embodiment, placing the plurality of enzyme fields on the conductive trace may comprise printing a second preparation comprising glucose oxidase and/or glucose dehydrogenase as the enzyme, manganese dioxide as the catalyst, carbon particles, and a polymer binder, on the positions which may be intended for this purpose at least partially on the at least one conductive trace.

For further details concerning the method, reference may be made to the description of the electrochemical sensor as provided elsewhere in this document.

As used herein, the term "measurement device" refers to an arbitrary device which can be handled independently from the electrochemical sensor. The measurement device may, especially, be configured to perform the at least one amperometric measurement by using the electrodes of the electrochemical sensor, in particular, to detect at least one direct current signal and at least one current response, preferably, concurrently or subsequently. For this purpose, the measurement device may, preferably, be adapted for applying an electrical potential between the at least one working electrode and the at least one reference electrode of the electrochemical sensor and for measuring a raw current generated hereby, preferably, between the working electrode and the at least one counter electrode of the electrochemical sensor. However, other embodiments may also be feasible.

Further, the measurement device may be configured to derive at least one item of information regarding a glucose value related to the glucose in the sample of the body fluid from this detection. For this purpose, the measurement device may comprise at least one electronic evaluation device interacting with the electrochemical sensor, in particular, in order to derive the at least one glucose value from the at least one signal. Thus, the electronics unit may comprise at least one evaluation device comprising at least one data processing device, such as one or more of a microcontroller, an application-specific integrated circuit (ASIC), a Field-Programmable Gate Array (FPGA). However, other kinds of devices may also be feasible.

The electrochemical sensor as well as the method for manufacturing the electrochemical sensor according to the present invention exhibit a number of advantages with respect to known methods and devices. In contrast hereto, the present method may, on one hand, allow providing a simplified sensor design while, on the other hand, the manufacturing efforts can, significantly, be reduced in comparison to known manufacturing processes, specifically, since they allow increasing the position tolerance of the enzyme fields by placing the enzyme fields on a conductive trace or on a grid formed by a plurality of conductive traces, whereby a noticeable simplification of the manufacturing process can be achieved.

This manufacturing process is in further contrast to known electrochemical sensors that comprise an arrangement in which the working electrode has a supporting layer of copper deposited on a substrate on which gold contacts are deposited. In contrast hereto, the arrangement according to the present invention comprises mechanical flexibility since bending the electrochemical sensor may not result in a delamination of the conductive traces and the enzyme fields from the substrate, whereby leakage currents which may influence the measurement can be avoided.

Further details of the invention may be derived from the following disclosure of preferred embodiments. The features of the embodiments may be realized in an isolated way or in any combination. The invention is not restricted to the embodiments. The embodiments are schematically depicted in the figures. Identical reference numbers in the figures refer to identical elements or functionally identical elements or elements corresponding to each other with regard to their functions.

<FIG> schematically illustrates an electrochemical sensor <NUM> for electrochemically detecting at least one analyte in a sample of a body fluid not according to the present invention, wherein the electrochemical sensor <NUM> constitutes a part of a sensor system <NUM> which is configured for electrochemically detecting at least one analyte in a sample of a body fluid.

<FIG> illustrates the electrochemical sensor <NUM> and the sensor system <NUM> in a top view showing a front side <NUM> of a substrate <NUM> comprised by the electrochemical sensor <NUM>. In this particular embodiment, the substrate <NUM> is a flexible substrate, thus, comprising a biocompatible bendable, electrically insulating material, in particular, a polyimide. However, other flexible biocompatible materials may also be feasible. Herein, the substrate <NUM> has a proximal region <NUM> and a distal region <NUM>, wherein the proximal region is configured to carry and/or support contact elements <NUM> which are adapted to communicate with a measurement device, which is schematically depicted here using the reference sign <NUM>, that can be handled independently from the electrochemical sensor <NUM> and which may be configured in a manner to perform at least one amperometric measurement by using the electrochemical sensor <NUM> and to derive at least one item of information regarding an analyte value related to the analyte in the sample of the body fluid from this at least one measurement.

As schematically depicted in <FIG>, the contact elements <NUM> may be provided in form of a plurality of electrical contacts which are configured to provide electrical contact with corresponding electrical contacts of the measurement device <NUM>. However, one or more contact elements <NUM> which may be adapted for wireless communication with the measurement device <NUM> may also be feasible. Thus, while a partition of the substrate <NUM> which may be configured to carry and/or support the contact elements <NUM> is denoted as the proximal region <NUM>, a further partition of the substrate <NUM>, which may be configured to carry and/or support a working electrode <NUM> as described below in more detail is denominated as the distal region <NUM>. As schematically shown in <FIG>, the proximal region <NUM> and the distal region <NUM> may be provided as two distinct regions on the substrate <NUM>, wherein it may, however, also be possible that an overlap may exist between the proximal region <NUM> and the distal region <NUM>.

In the particular embodiment of <FIG>, the electrochemical sensor <NUM> has a three-electrode arrangement comprising the working electrode <NUM>, a counter electrode <NUM>, and a reference electrode <NUM>. Herein, the distal region <NUM> of the substrate <NUM> comprises the working electrode <NUM>, while a counter electrode <NUM> may extend over both the distal region <NUM> and the proximal region <NUM>, whereas the reference electrode <NUM> may be located in the proximal region <NUM> of the substrate <NUM>. Further, both the working electrode <NUM> and the reference electrode <NUM> may, as depicted in <FIG>, be located on the front side <NUM> of the substrate <NUM> while the counter electrode <NUM> may, as shown in <FIG>, be located on a back side <NUM> of the substrate <NUM>. Herein, each of the electrodes <NUM>, <NUM>, <NUM> are connected to the contact elements <NUM> by a lead wire <NUM> configured for providing electrical connection between the respective electrode <NUM>, <NUM>, <NUM> and the at least one corresponding contact element <NUM>.

As schematically depicted in <FIG>, the working electrode <NUM> comprises a conductive trace <NUM>, wherein, in this particular embodiment, the conductive trace <NUM> comprises gold as a non-corrosive, electrically conducting material. As can be seen in <FIG>, the conductive trace <NUM> may, additionally, comprise a thin layer <NUM> of titanium as a non-corrosive bonding agent, thus, improving adhesion between the conductive trace <NUM> and the substrate <NUM>. As an alternative, palladium may also be used as the non-corrosive bonding agent. As schematically depicted in <FIG>, the conductive trace <NUM> may, preferably, assume a three-dimensional form which predominantly extends in one direction usually denoted as length the conductive trace <NUM>, while the other two directions usually denoted as width and height of the conductive trace <NUM>, respectively, are less pronounced. In particular, the length of the conductive trace <NUM> may exceed both the width and the height of the conductive trace <NUM> by a factor of at least <NUM>, preferably of at least <NUM>, more preferred of at least <NUM>.

In particular, the conductive trace <NUM> may comprise a first partition <NUM> located in the distal region <NUM> and a second partition <NUM> located in the proximal region <NUM> of the substrate <NUM>. Herein, the second partition <NUM> of the conductive trace <NUM> which is located in the proximal region <NUM> of the substrate <NUM> can, thus, be considered as being continued as the lead wire <NUM> connecting the working electrode <NUM> with the at least one corresponding contact element <NUM>. In this particularly preferred embodiment of the electrochemical sensor <NUM>, at least the first partition <NUM> of the conductive trace <NUM> is devoid of copper whereas the second partition <NUM> of the conductive trace <NUM> may comprise copper as an electrically conducting material or as a bonding agent for a further electrically conducting material, especially, in order to provide increased mechanical stability to the lead wire <NUM>.

Further, the working electrode has a plurality of enzyme fields <NUM>, wherein each enzyme field <NUM> comprises a test chemistry having at least one enzyme, in particular, glucose oxidase (GOD) and/or glucose dehydrogenase (GDH). As a result, the enzyme is, by itself and/or in combination with other components, configured for providing a reaction with the analyte. Further, the test chemistry may comprise one or more auxiliary components, in particular, a carbon paste having carbon particles and a polymer binder as a conductive substance and manganese dioxide (MnO<NUM>), preferably in particulate form, as a catalyst and/or a mediator. Each of the enzyme fields <NUM> is located on the substrate <NUM> in a manner that it at least partially covers the conductive trace <NUM>.

As schematically depicted in <FIG>, the working electrode <NUM> comprises <NUM> enzyme fields <NUM> which are arranged side by side with respect of each other, hereby forming a series of enzyme fields <NUM>. However, other kinds of arrangements are also feasible, such as <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or more enzyme fields which may be arranged in the same or in a different manner as long as they at least partially cover the conductive trace <NUM>. As a result, adjacent enzyme fields may be separated from each other by a gap <NUM> which is maintained free from the enzyme. Preferably, the gap <NUM> between adjacent enzyme fields may assume at least <NUM>, preferably at least <NUM>. Consequently, the series of the multiple individual enzyme fields <NUM> can be considered as a plurality of working electrodes <NUM> arranged in series, thus, being capable of improving a signal-to-noise ratio of the measurement signal. Thus, in particular contrast to <CIT> as cited above, position requirements are considerably reduced when the plurality of the enzyme fields <NUM> are at least partially located on the conductive trace <NUM>.

Further, <FIG> schematically illustrate two profiles of the electrochemical sensor <NUM> which are not to scale. Herein, the side view as depicted in <FIG> shows a first profile <NUM> through the substrate <NUM> in the distal region <NUM> at a location at which the substrate <NUM> carries the conductive trace <NUM> whereas <FIG> depicts a second profile <NUM> through the substrate <NUM> in the proximal region <NUM>, again, at a location at which the substrate <NUM> carries the conductive trace <NUM>. In this exemplary embodiment, the substrate <NUM> having a thickness of <NUM> is covered on both sides by the thin layer <NUM> of titanium having a thickness of <NUM>-<NUM>, preferably of <NUM>-<NUM>, as the non-corrosive bonding agent. Further, on the back side <NUM> of the substrate <NUM> the counter electrode <NUM> is located on the titanium layer <NUM> while on the front side <NUM> of the substrate <NUM> the conductive trace <NUM> as part of the working electrode <NUM> is located on the titanium layer <NUM>. Herein, both the counter electrode <NUM> and the conductive trace <NUM> of the working electrode <NUM> may have a thickness of <NUM>-<NUM>, such as <NUM>. As already indicated above, the working electrode <NUM> further comprises the plurality of the enzyme fields <NUM> which are arranged side by side with respect of each other in a manner that they at least partially cover the conductive trace <NUM>, whereby adjacent enzyme fields <NUM> are separated from each other by the gap <NUM> which is maintained free from the enzyme.

As can be derived from the second profile <NUM> as shown in <FIG>, the substrate <NUM> is, preferably, covered by a solder resist <NUM> in the proximal region of the substrate. Herein, the solder resist <NUM> comprises a lacquer-like layer of polymer having a thickness of <NUM>-<NUM>, which is applied here, on one hand, to provide a protection against oxidation, and, on the other hand, to avoid forming of solder bridges between adjacent electrically conducting areas. In contrast hereto, the distal region <NUM> of the substrate <NUM>, preferably, remains devoid of the solder resist <NUM>. This arrangement as schematically depicted in <FIG> is possible since, as described above, the first partition <NUM> of the conductive trace <NUM> which is located in the distal region <NUM> of the substrate <NUM> in the exemplary embodiment of <FIG> comprises gold as a non-corrosive, electrically conducting material but is devoid of copper, thereby, removing a potential source of oxidation. As a result, providing the electrochemical sensor <NUM> without the solder resist <NUM> within the distal region <NUM> of the substrate <NUM>, thus, allows the sample of the body fluid to better contact the plurality of the enzyme fields <NUM>, whereas the solder resist <NUM> may be advantageous in the second partition <NUM> of the conductive trace <NUM> which is located in the proximal region <NUM> of the substrate <NUM> that may comprise copper in order to achieve an increased mechanical stability.

In a particularly preferred embodiment of the electrochemical sensor <NUM> according to the present invention as illustrated in <FIG> which presents the front side <NUM> of the substrate <NUM> of the electrochemical sensor <NUM>, the working electrode <NUM> comprises a multiplicity of conductive traces <NUM>. As a particular advantage, the position requirements during placement of the plurality of the enzyme fields <NUM> may, thus, further be reduced. The multiplicity of conductive traces <NUM> is provided in form of a grid <NUM>. As a result, a regular arrangement of the multiplicity of the conductive traces <NUM> in which the gaps <NUM> between adjacent conductive traces <NUM> may be selected from a single value or from a small interval of deviations compared to the distance, such as less than <NUM> %, preferably less than <NUM> %, of the distance. As can be seen from <FIG>, placing the multiplicity of the conductive traces <NUM> in form of the grid <NUM> can, further, simplify the manufacturing of the working electrode <NUM>.

For a presentation of the back side <NUM> and the profile <NUM>, <NUM> of the electrochemical sensor <NUM> as illustrated in <FIG>, reference may be made to <FIG>, respectively.

Further, <FIG> schematically demonstrates the advantage of the electrochemical sensor <NUM> according to the present invention with regard to facilitating the positioning of the plurality of the enzyme fields <NUM> on the substrate <NUM> compared to a prior art electrochemical sensor <NUM> as manufactured according to the state of the art.

For depositing <NUM> an enzyme paste very accurately into openings <NUM> comprised by an electrically insulating layer <NUM> in order to thoroughly cover an electrically conducting surface <NUM> of the working electrode <NUM> by screen printing, a silkscreen <NUM> is used for manufacturing the electrochemical sensor <NUM> according to the state of the art as shown in <FIG>. However, this method is applicable only as long as the electrically insulating layer <NUM> is very well positioned with respect to the electrically conducting surface <NUM> of the working electrode <NUM> and silkscreen <NUM>. As can be seen in <FIG>, a lateral shift <NUM> of the electrically insulating layer <NUM> may result in a positing which does not allow manufacturing the working electrode <NUM> as required.

Claim 1:
An electrochemical sensor (<NUM>) for electrochemically detecting glucose in a sample of a body fluid, wherein the electrochemical sensor (<NUM>) comprises a substrate (<NUM>) having a proximal region (<NUM>) and a distal region (<NUM>), wherein the proximal region (<NUM>) comprises at least one contact element (<NUM>) which is configured to communicate with a measurement device (<NUM>), wherein the electrochemical sensor comprises at least one working electrode (<NUM>) located in the distal region (<NUM>) of the substrate and at least one counter electrode (<NUM>), wherein the working electrode (<NUM>) has a plurality of enzyme fields (<NUM>), each enzyme field (<NUM>) comprising at least one enzyme, the enzyme being configured for providing a reaction with glucose, wherein the working electrode (<NUM>) further comprises at least one conductive trace (<NUM>), wherein each of the enzyme fields (<NUM>) is partially located on the conductive trace (<NUM>), wherein the enzyme fields are individual areas on the respective surface of the working electrode, wherein each of the individual areas which are configured to contact the body fluid comprises the enzyme but is located at a distance from each of adjacent enzyme fields, wherein the contact element (<NUM>) comprises at least one electrical contact being adapted to provide an electrical contact with a corresponding electrical contact of the measurement device, wherein the enzyme comprises glucose oxidase and/or glucose dehydrogenase, wherein the substrate (<NUM>) further comprises a front side (<NUM>) and a back side (<NUM>), wherein the working electrode (<NUM>) is located on the front side (<NUM>) of the substrate (<NUM>),
characterised in that
the counter electrode (<NUM>) is located on the back side (<NUM>) of the substrate (<NUM>), wherein the working electrode (<NUM>) comprises a multiplicity of conductive traces (<NUM>), the multiplicity of the conductive traces forming a grid (<NUM>), and wherein the electrochemical sensor (<NUM>) further comprises at least one reference electrode (<NUM>), wherein the reference electrode (<NUM>) is located in the proximal region (<NUM>) of the substrate (<NUM>).