Disclosure of Invention
The embodiment of the invention provides an analyte sensor and a preparation method thereof, wherein an adjusting layer is additionally arranged at a position of each electrode structure far away from one side of a base layer and a hollow area, wherein the base layer, the insulating combination layer and the adjusting layer are all biocompatible, so that the accuracy and the service life of the sensor are improved.
In a first aspect, embodiments of the present invention provide an analyte sensor comprising a substrate layer, a conductive structure on at least one side of the substrate layer, and an insulating structure on a side of the conductive structure remote from the substrate layer;
The conductive structure comprises an electrode structure, an electrode connecting wire and a contact, wherein the electrode structure is electrically connected with the contact through the electrode connecting wire;
The insulating structure comprises an insulating layer, wherein the insulating layer comprises a plurality of hollowed-out areas and an insulating area, and the insulating area surrounds the hollowed-out areas;
The sensor comprises an implantation area, a connection area and a lead area, wherein the implantation area and the connection area are positioned at two sides of the lead area; the counter electrode is positioned in the implantation area and exposed through the counter electrode hollowed-out area, the reference electrode is positioned in the implantation area and exposed through the reference electrode hollowed-out area, and the working electrode is positioned in the implantation area and exposed through the working electrode hollowed-out area;
The sensor further comprises a detection layer and an adjustment layer, wherein the detection layer is positioned in the working electrode hollowed-out area and is positioned on one side of the working electrode away from the basal layer, the adjustment layer comprises a first adjustment layer, a second adjustment layer and a third adjustment layer, the first adjustment layer is positioned in the counter electrode hollowed-out area and is positioned on one side of the counter electrode away from the basal layer, the second adjustment layer is positioned in the second hollowed-out area and is positioned on one side of the reference electrode away from the basal layer, the third adjustment layer is positioned on one side of the detection layer away from the basal layer, the basal layer is provided with biocompatibility, the insulation structure is provided with biocompatibility, and the adjustment layer is provided with biocompatibility.
Optionally, the insulating layer includes a first insulating layer, a second insulating layer and a third insulating layer, where the first insulating layer is located on a side of the base layer, the second insulating layer is located on a side of the first insulating layer away from the base layer, and the third insulating layer is located on a side of the second insulating layer away from the first insulating layer;
And a first conductive structure setting area is arranged between the first insulating layer and the substrate layer along the thickness direction of the substrate layer, a second conductive structure setting area is arranged between the second insulating layer and the first insulating layer, and a third conductive structure setting area is arranged between the third insulating layer and the second insulating layer, wherein the conductive structures are respectively arranged in the first conductive structure setting area, the second conductive structure setting area and the third conductive structure setting area.
Optionally, the counter electrode, the reference electrode and the working electrode are all located on one side of the substrate layer, and the counter electrode, the reference electrode and the working electrode are arranged coplanar.
Optionally, the sensor further comprises an insulating adhesive;
the insulating binder is located on one side of the base layer and between the counter electrode, the reference electrode and the working electrode.
Optionally, the sensor includes a plurality of the working electrodes, the working electrodes including at least a first working electrode and the second working electrode;
The working electrode hollowed-out area at least comprises a first working electrode hollowed-out area and a second working electrode hollowed-out area, the first working electrode is exposed through the first working electrode hollowed-out area, and the second working electrode is exposed through the second working electrode hollowed-out area;
The contacts comprise working electrode contacts, and the working electrode contacts at least comprise a first working electrode contact and a second working electrode contact;
the first working electrode is electrically connected with the first working electrode contact, and the second working electrode is electrically connected with the second working electrode contact.
Optionally, the first working electrode is used for detecting a first analyte, the second working electrode is used for detecting a second analyte, the types of the first analyte and the second analyte are different, or the detection sensitivity of the first working electrode is different from the detection sensitivity of the second working electrode.
Optionally, the first working electrode is used for detecting a first analyte, the second working electrode is used for detecting a second analyte, the types of the first analyte and the second analyte are different, or the detection sensitivity of the first working electrode is different from the detection sensitivity of the second working electrode.
Optionally, the working electrode comprises an analyte reaction area, wherein the analyte reaction area is exposed through the working electrode hollowed-out area, or the working electrode comprises a plurality of analyte reaction areas, the working electrode hollowed-out area comprises a plurality of sub-hollowed-out areas and a sub-insulating area, the sub-insulating area surrounds the sub-hollowed-out areas, and the plurality of analyte reaction areas are exposed through the sub-hollowed-out areas.
Optionally, the counter electrode comprises a plurality of sub-counter electrodes, the reference electrode comprises a plurality of reference electrodes, the contact further comprises a counter electrode contact and a reference electrode contact
The plurality of sub counter electrodes are respectively and electrically connected with the plurality of counter electrode contacts, or the plurality of sub counter electrodes are respectively and electrically connected with one counter electrode contact, the plurality of sub reference electrodes are respectively and electrically connected with the plurality of reference electrode contacts, or the plurality of sub reference electrodes are respectively and electrically connected with one reference electrode contact.
In a second aspect, embodiments of the present invention provide a method for preparing a sensor of an analyte, for preparing a sensor of an analyte according to any one of the first aspects, the method comprising:
Providing a base layer;
Preparing a conductive structure on at least one side of the substrate layer, wherein the conductive structure comprises an electrode structure, an electrode connecting wire and a contact, and the electrode structure is electrically connected with the contact through the electrode connecting wire;
Preparing an insulating structure on one side of the conductive structure away from the substrate layer; the insulation structure comprises an insulation layer, wherein the insulation layer comprises a plurality of hollowed-out areas and an insulation area, and the insulation area surrounds the hollowed-out areas; the hollowed-out area comprises a counter electrode hollowed-out area, a reference electrode hollowed-out area and a working electrode hollowed-out area; the sensor comprises an implantation area, a connection area and a lead area, wherein the implantation area and the connection area are positioned at two sides of the lead area;
Preparing a detection layer on one side of the working electrode far away from the substrate layer, wherein the detection layer is positioned in the working electrode hollow area and on one side of the working electrode far away from the substrate layer;
the method comprises the steps of preparing an adjusting layer, wherein the adjusting layer comprises a first adjusting layer, a second adjusting layer and a third adjusting layer, the first adjusting layer is located in a hollowed-out area of a counter electrode and located on one side of the counter electrode away from a basal layer, the second adjusting layer is located in a hollowed-out area of the counter electrode and located on one side of the counter electrode away from the basal layer, the third adjusting layer is located on one side of a detecting layer away from the basal layer, the basal layer is biocompatible, the insulating structure is biocompatible, and the adjusting layer is biocompatible.
Optionally, preparing a detection layer on a side of the working electrode remote from the substrate layer includes:
Coating the detection layer on one side of the working electrode hollowed-out area, which is far away from the substrate layer, in a spot coating mode;
The preparation of the regulating layer comprises the following steps:
The method comprises the steps of coating the adjusting layer on one side of the conducting structure away from the substrate layer in a spot coating mode, wherein the first adjusting layer is located in the hollowed-out area of the counter electrode and located on one side of the counter electrode away from the substrate layer, the second adjusting layer is located in the hollowed-out area of the counter electrode and located on one side of the counter electrode away from the substrate layer, and the third adjusting layer is located on one side of the detecting layer away from the substrate layer.
The embodiment of the invention provides an analyte sensor, which comprises a basal layer, a conductive structure and an insulating structure, wherein the conductive structure comprises an electrode structure, an electrode connecting wire and a contact, the electrode structure is electrically connected with the contact through the electrode connecting wire, the insulating structure comprises a plurality of hollowed-out areas and an insulating layer, and the insulating layer surrounds the hollowed-out areas. Specifically, the counter electrode is located in the implantation area and exposed through the counter electrode hollowed-out area, the reference electrode is located in the implantation area and exposed through the reference electrode hollowed-out area, and the working electrode is located in the implantation area and exposed through the working electrode hollowed-out area. Further, the sensor further comprises a detection layer and an adjusting layer, wherein the detection layer is a mixture capable of carrying out catalytic reaction and is used for realizing the monitoring function of the sensor, the adjusting layer has biocompatibility, the structural basal layer and the insulating structure have biocompatibility, the sensor is guaranteed to have better biocompatibility, and the detection accuracy and the service life are improved.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be fully described below by way of specific embodiments with reference to the accompanying drawings in the examples of the present invention. It is apparent that the described embodiments are some, but not all, embodiments of the present invention, and that all other embodiments, which a person of ordinary skill in the art would obtain without making inventive efforts, are within the scope of this invention.
It should be noted that the terms "first," "second," and the like in the description and the claims of the present invention and the above figures are used for distinguishing between similar objects and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used may be interchanged where appropriate such that the embodiments of the invention described herein may be implemented in sequences other than those illustrated or otherwise described herein. Furthermore, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a system, article, or apparatus that comprises a list of elements is not necessarily limited to those steps or elements expressly listed or inherent to such article or apparatus, but may include other elements not expressly listed or inherent to such article or apparatus.
Fig. 1 is a schematic structural view of an analyte sensor according to an embodiment of the present invention, fig. 2 is a schematic structural view of an insulating structure according to an embodiment of the present invention, fig. 3 is a schematic structural view along a section line A-A ' in fig. 1, fig. 4 is a schematic structural view along a section line B-B ' in fig. 1, fig. 5 is a schematic structural view along a section line C-C ' in fig. 1, and referring to fig. 1 to 5, an analyte sensor 10 according to an embodiment of the present invention is provided, the sensor 10 including a base layer 100, a conductive structure 200, and an insulating structure 300; the conductive structure 200 is located on at least one side of the substrate layer 100, the insulating structure 300 is located on a side of the conductive structure 200 remote from the substrate layer 100, the conductive structure 200 comprises an electrode structure 210, an electrode connection line 220 and a contact 230, the electrode structure 210 is electrically connected with the contact 230 through the electrode connection line 220, the electrode structure 210 comprises a counter electrode 211, a reference electrode 212 and a working electrode 213, the insulating structure 300 comprises an insulating layer comprising a plurality of hollowed-out areas 300a and 300B, the insulating layer 300B surrounds the hollowed-out areas 300a, the hollowed-out areas 300a comprises a counter electrode hollowed-out area 300a1, a reference electrode hollowed-out area 300a2 and a working electrode hollowed-out 300a3, the sensor 10 comprises an implant area 10a, a connection area 10B and a lead area 10C, the implant area 10a and the connection area 10C are located on both sides of the lead area 10B, the counter electrode 211 is located on the implant area 10a and is exposed through the counter electrode hollowed-out area 300a1, the reference electrode 212 is located on the implant area 10a and is exposed through the reference electrode hollowed-out area 300a2, the working electrode 213 is located on the implant area 10a and is exposed through the working electrode hollowed-out area 300a3, the sensor 10 further comprises a detection layer 400 and the adjustment layer 500, the detection layer 400 is located in the working electrode hollowed-out area 300a3 and is located at one side of the working electrode 213 far away from the substrate layer 100, the adjustment layer 500 comprises a first adjustment layer 500a, a second adjustment layer 500b and a third adjustment layer 500c, the first adjustment layer 500a is located in the counter electrode hollowed-out area 300a1 and is located at one side of the counter electrode 211 far away from the substrate layer 100, the second adjustment layer 500b is located in the reference electrode hollowed-out area 300a2 and is located at one side of the reference electrode 212 far away from the substrate layer 100, the third adjustment layer 500c is located at one side of the detection layer 400 far away from the substrate layer 100, wherein the substrate layer 100 has biocompatibility, the insulation structure 200 has biocompatibility, and the adjustment layer 500 has biocompatibility.
Specifically, referring to fig. 1 and 5, the analyte sensor 10 provided in the embodiment of the present invention includes a substrate layer 100, where the substrate layer 100 may be made of a flexible material and has insulation, and the substrate layer 100 may be made of at least one of a plurality of materials such as Polyurethane (PU), polyethylene terephthalate (PET), polyimide (PI), and Polycarbonate (PC), and the material of the substrate layer 100 is not specifically limited and may be adaptively adjusted according to actual requirements.
Further, referring to fig. 1 and 5, the sensor 10 further includes a conductive structure 200, the conductive structure 200 being located on at least one side of the substrate layer 100, and fig. 5 illustrates that the conductive structures 200 are located on one side of the substrate layer 100. Specifically, the conductive structure 200 comprises an electrode structure 210, an electrode connection 220 and a contact 230, the electrode structure 210 corresponding to a sensor electrode in the sensor 10, and the analyte may generate a corresponding detected electrochemical signal at the electrode structure 210, which is transmitted to the contact 230 via the electrode connection 220. Further, the contact 230 is electrically connected to an external electronic system (not specifically shown in the figure), the contact 230 transmits the detected signal to the external electronic system, and the electronic system can analyze the concentration, the type and the like of the analyte, so as to realize the monitoring function of the sensor 10.
Further, referring to fig. 1, the sensor 10 includes an implantation region 10a, a connection region 10b and a lead region 10c, wherein the electrode structure 210 is located in the implantation region 10a, the contact 230 is located in the connection region 10b, the electrode connection line 220 is mainly located in the lead region 10c, the electrode connection line 220 is further extended to the implantation region 10a to be electrically connected with the electrode structure 210, and the electrode connection line 220 is further extended to the connection region 10b to be electrically connected with the contact 230. By way of example, the sensor 10 may be generally used in blood glucose monitoring devices and the like, i.e., the analyte may be a blood glucose assay, with the implanted region 10a being configured to be fully inserted into the subcutaneous tissue, catalyze the analyte in interstitial fluid to react and generate an electrochemical signal, i.e., detect blood glucose concentration and the like, and the interstitial fluid has a close correlation with the glucose concentration and changes in blood, such that the sensor 10 may obtain a change in the glucose concentration in blood by monitoring the glucose concentration in interstitial fluid. The sensor 10 may also be used to monitor other substances, as embodiments of the invention are not specifically limited in this regard.
Further, the conductive structure 210 includes a counter electrode 211, a reference electrode 212, and a working electrode 213, and different electrode structures 210 are electrically connected to different contacts 230 through different electrode connection lines 220. The working electrode 213 may be made of gold, platinum, carbon, graphite, palladium, titanium, or other materials with excellent conductivity, the reference electrode 212 may be made of silver/silver chloride (Ag/AgCl), and the counter electrode 211 needs to form a potential difference with the working electrode 213, so that the electrode potential applied by the working electrode 213 can be accurately grasped, so that the counter electrode 211 may be made of multiple materials such as platinum, carbon, or other materials, and form a loop with the working electrode 213, so that the current on the working electrode 213 is smooth, and the reaction on the working electrode 213 is ensured. It should be noted that, when preparing the reference electrode 212, a silver paste is further coated on the basis of preparing the reference electrode conductive layer to prepare the substructure 212a of the reference electrode, thereby realizing the preparation of the reference electrode 212.
Specifically, referring to fig. 1, fig. 2, and fig. 5, the insulating structure 300 includes an insulating layer, the insulating layer includes a plurality of hollow areas 300a and an insulating area 300b, and the insulating area 300b surrounds the hollow areas 300a, which can be understood that the insulating structure 300 includes a plurality of hollow areas, the hollow areas are used for exposing a portion of the conductive structure 200, and the insulating area 300b included in the insulating structure 300 is a portion of the insulating structure 300 where no hollow area is provided. Further, the hollowed-out area 300a includes a counter electrode hollowed-out area 300a1, a reference electrode hollowed-out area 300a2 and a working electrode hollowed-out area 300a3, and there may be some hollowed-out areas for exposing the contact 230. Specifically, the counter electrode 211 is located in the implantation area 10a and is exposed through the counter electrode hollowed-out area 300a1, the reference electrode 212 is located in the implantation area 10a and is exposed through the reference electrode hollowed-out area 300a2, the working electrode 213 is located in the implantation area 10a and is exposed through the working electrode hollowed-out area 300a3, it can also be understood that the insulating structure 300 provides a plurality of hollowed-out areas to expose the electrode structure 210 and the contact 230, which need to be exposed by the conductive structure 200, and the rest is to ensure the stability of the electrical signal, and perform insulating coating on the sensor 10 through the insulating area 300 b. Alternatively, the insulating structure 300 may be an insulating cover plate or a printed insulating layer.
Further, referring to fig. 1, 2, and 5, the sensor 10 further includes a detection layer 400, and the detection layer 400 may be a mixture having a substrate reaction catalyzing property, and may include components such as a catalytic enzyme, a redox mediator, an enzyme activity protecting agent, and a crosslinking agent. In addition, a nanomaterial having electron transport property may be contained. The detection layer 400 may be a plurality of layers of sequentially laminated nanoparticle layers, analyte enzyme catalytic layers, and the like, wherein the nanoparticle layers are positioned between the analyte enzyme catalytic layers and the conductive layers of the working electrode 213, the strong conductivity of the nanoparticle layers can improve the transmission effect of the electric signals, and the high specific surface area of the nanoparticle layers can enhance the adhesion of enzymes on the electrode surface.
Illustratively, if the detection layer 400 includes a catalytic enzyme, the catalytic enzyme may include at least one of a variety of analyte catalytic enzymes such as glucose oxidase, glucose dehydrogenase, cellobiose dehydrogenase, lactate dehydrogenase, 3-beta-hydroxybutyrate dehydrogenase, alcohol dehydrogenase, and the like. Suitable detection substrates may be one of glucose, acetic acid, lactic acid, blood ketone, etc., or a plurality of substances therein, such as glucose and blood ketone, glucose and lactic acid, etc., may be detected simultaneously on the multifunctional sensor 10 having the plurality of working electrodes 213. If the detection layer 400 includes a redox mediator, the redox mediator may be at least one of ferrocene derivatives, ruthenium complexes, osmium ligands, cobalt phthalocyanine, copper phthalocyanine, iron phthalocyanine, and thionine. Further, the detection layer 400 may be a nano material having a catalytic substrate reaction property, which is not bioactive, for example, a noble metal nano material such as platinum and gold, a transition metal nano material such as nickel and copper, an oxide thereof, a bimetal nano material such as an alloy, and a carbon nano material such as a carbon nano tube and graphene.
Further, referring to fig. 1,2, 4 and 5, the sensor 10 further includes a regulating layer 500, where the regulating layer 500 includes a biocompatible regulating layer, i.e., the regulating layer 500 has a good biocompatibility, and the regulating layer 500 is located on a side of the electrode structure 210 away from the substrate layer 100, i.e., the regulating layer 500 is located outside, so that by providing the regulating layer 500 with a good biocompatibility in the implantation area 10a, it is ensured that the sensor 10 will not generate serious allergic reaction when implanted into subcutaneous tissue, and thus some biochemical substances generated by the allergic reaction will not accumulate at the electrode structure 200 and corrode the electrode structure 200, i.e., while ensuring that the implanted user will not generate adverse reaction, and also ensuring the service life of the sensor 10. Specifically, the adjusting layer 500 includes a first adjusting layer 500a, a second adjusting layer 500b and a third adjusting layer 500c, where the first adjusting layer 500a is located in the hollowed-out region 300a1 of the counter electrode and is located at a side of the counter electrode 211 away from the substrate layer 100, the second adjusting layer 500b is located in the hollowed-out region 300a2 of the counter electrode and is located at a side of the counter electrode 212 away from the substrate layer 100, and the third adjusting layer 500c is located at a side of the detecting layer 400 away from the substrate layer 100. The third regulation layer 500c correspondingly disposed at the working electrode 213 is a restriction outer membrane and a biocompatible outer membrane controlling the reaction rate of the catalytic substrate, and the second regulation layer 500a and the second regulation layer 500b correspondingly disposed at the counter electrode 211 and the reference electrode 212 are mixed substances of the restriction outer membrane and the biocompatible outer membrane. Since the reference electrode 212 and the counter electrode 211 are located at the implantation area 10b, and the adjusting layer 500 is additionally arranged on the two electrodes, the implanted user can be further ensured not to generate adverse reaction, and the service life of the sensor 10 is also ensured. Illustratively, to ensure that the adjustment layer 500 can be accurately fabricated on the surface of each electrode structure 300, the adjustment layer 500 can be precisely fabricated using a spot-coating process.
Further, the substrate layer 100 comprises a biocompatible substrate layer, and the insulating region 300b comprises a biocompatible insulating layer, which can be understood that the substrate layer 100, the insulating structure 300 and the adjustment layer 500 in the sensor 10 have better biocompatibility. The implanted user is ensured not to generate adverse reaction, the probability of generating adverse reaction to the user by the sensor 10 is further weakened, and the service life of the sensor 10 is also ensured.
Illustratively, the substrate layer 100 and the insulating region 300b in the sensor 10 are also biocompatible materials, and further, after the substrate layer 100, the conductive structure 200 and the insulating structure 300 are prepared, the whole substrate layer is not required to be dip-coated with a biocompatible outer film, and only the electrode structure 210 is required to be spot-coated with the adjusting layer 500, so that the whole biocompatibility is ensured, the dosage of the membrane solution is reduced, and the cost is reduced.
In summary, the sensor provided by the embodiment of the invention further comprises a detection layer and an adjustment layer, wherein the detection layer is a mixture capable of carrying out catalytic reaction and is used for realizing the monitoring function of the sensor, the adjustment layer comprises a biocompatible adjustment layer, and the first adjustment layer, the second adjustment layer and the third adjustment layer are accurately arranged at different electrode structures in a spot coating manner, so that the sensor is guaranteed to have better biocompatibility, and the monitoring accuracy and the service life are improved.
With continued reference to fig. 1 to 5, the insulating layer 300 includes a first insulating layer 310, a second insulating layer 320, and a third insulating layer 330, the first insulating layer 310 is located at one side of the base layer 100, the second insulating layer 320 is located at one side of the first insulating layer 310 away from the base layer 100, the third insulating layer 330 is located at one side of the second insulating layer 320 away from the first insulating layer, a first conductive structure arrangement region is located between the first insulating layer 310 and the base layer 100 in a thickness direction of the base layer 100, a second conductive structure arrangement region is located between the second insulating layer 320 and the first insulating layer 310, and a third conductive structure arrangement region is located between the third insulating layer 330 and the second insulating layer 320, and the conductive structures 200 are respectively arranged at the first conductive structure arrangement region, the second conductive structure arrangement region, and the third conductive structure arrangement region.
Specifically, referring to fig. 1 and 5, the insulation structure 300 includes a plurality of insulation layers including a first insulation layer 310, a second insulation layer 320, and a third insulation layer 330, and the first insulation layer 310 is located at one side of the base layer 100, the second insulation layer 320 is located at one side of the first insulation layer 310 away from the base layer 100, i.e., the first insulation layer 310, the second insulation layer 320, and the third insulation layer 330 are located at the same side of the base layer 100, and are stacked.
Further, referring to fig. 5, there is a first conductive structure arrangement region between the first insulating layer 310 and the base layer 100, a second conductive structure arrangement region between the second insulating layer 320 and the first insulating layer 310, and a third conductive structure arrangement region between the third insulating layer 330 and the second insulating layer 320, wherein the first conductive structure arrangement region, the second conductive structure arrangement region and the third conductive structure arrangement region are spaces between the insulating layers or between the insulating layers and the base layer 100 for placing the conductive structure 200, the first conductive structure arrangement region, the second conductive structure arrangement region and the third conductive structure are not specifically shown in fig. 5, and the arrangement positions of the electrode structure 210 and the electrode connection line 220 may be referred to in fig. 5 based on the first conductive structure arrangement region, the second conductive structure arrangement region and the third conductive structure.
Further, the electrode connection line 220 includes a counter electrode connection line 221 connected to the counter electrode 211, a reference electrode connection line 222 connected to the reference electrode 212, and a working electrode connection line 223 connected to the working electrode 213, as shown in fig. 5, in which the working electrode 213 is disposed between the first insulating layer 310 and the base layer 100, i.e., the working electrode 213 and the third electrode connection line 223 are disposed at the third conductive structure, the reference electrode 212 is disposed between the second insulating layer 320 and the first insulating layer 310, i.e., the reference electrode 212 and the second electrode connection line 222 are disposed at the second conductive structure, and the counter electrode 211 is disposed between the second insulating layer 320 and the third insulating layer 330, i.e., the counter electrode 211 and the first electrode connection line 221 are disposed at the first conductive structure. In fig. 5, the working electrode 213, the reference electrode 212 and the counter electrode 211 are disposed in various ways, and the arrangement order of the working electrode 213, the reference electrode 212 and the counter electrode 211 is not limited to the position of one electrode structure 210 provided in fig. 5, in other embodiments, with the side of the working electrode 213 closest to the substrate layer 100, the side of the reference electrode 213 away from the substrate layer 100, and the counter electrode 211 on the side of the reference electrode 212 away from the working electrode 213.
Further, the different insulating layers may include different hollowed-out regions 300a, the insulating layer exposing the working electrode 213 may include a working electrode hollowed-out region 300a3, the insulating layer exposing the reference electrode 212 may include a reference electrode hollowed-out region 300a2, and the insulating layer exposing the counter electrode 211 may include a counter electrode hollowed-out region 300a1. For example, if the positions of the counter electrode 211, the reference electrode 212 and the working electrode 213 are as shown in fig. 5, the counter electrode hollowed-out area 300a1 is located on the third insulating layer 330, the reference electrode hollowed-out area 300a2 is located on the second insulating layer 320, and the working electrode hollowed-out area 300a3 is located on the first insulating layer 310. The conductive structure 200 of the sensor 10 is flexibly arranged, and further, the insulating structure 300 can comprise a plurality of insulating layers, and the arrangement of the insulating layers can be adaptively adjusted according to the adjustment of the conductive structure 200, so that the structural stability and the service life of the sensor 10 are ensured.
Fig. 6 is a schematic structural view of another analyte sensor according to an embodiment of the present invention, fig. 7 is a schematic structural view of fig. 6 along a section line D-D', referring to fig. 6 and 7, the insulating layers include a fourth insulating layer 340, a fifth insulating layer 350 and a sixth insulating layer 360, the fourth insulating layer 340 and the fifth insulating layer 350 are located at both sides of the base layer 100, the sixth insulating layer 360 is located at a side of the fifth insulating layer 350 away from the base layer, a fourth conductive structure arrangement region is located between the fourth insulating layer 340 and the base layer 100 in a thickness direction of the base layer 100, a fifth conductive structure arrangement region is located between the fifth insulating layer 350 and the base layer 100, and a sixth conductive structure arrangement region is located between the sixth insulating layer 360 and the fifth insulating layer 350, and the conductive structures 200 are respectively disposed at the fourth conductive structure arrangement region, the fifth conductive structure arrangement region and the sixth conductive structure arrangement region.
Specifically, referring to fig. 6 and 7, the insulation structure 300 includes a plurality of insulation layers including a fourth insulation layer 340, a fifth insulation layer 350, and a sixth insulation layer 360, and the fourth insulation layer 340 and the fifth insulation layer 350 are located at both sides of the base layer 100, and the sixth insulation layer 360 and the fifth insulation layer 350 are located at the same layer as the base layer of the base layer 100 and are stacked.
Further, referring to fig. 7, there is a fourth conductive structure setting region between the fourth insulating layer 340 and the base layer 100, there is a fifth conductive structure setting region between the fifth insulating layer 350 and the base layer 100, and there is a sixth conductive structure setting region between the sixth insulating layer 360 and the fifth insulating layer 350, wherein the fourth conductive structure setting region, the fifth conductive structure setting region and the sixth conductive structure setting region are spaces between the insulating layers or between the insulating layers and the base layer 100 for placing the conductive structure 200, and the fourth conductive structure setting region, the fifth conductive structure setting region and the sixth conductive structure setting region are not specifically shown in fig. 7, and the arrangement positions of the electrode structure 210 and the electrode connection line 220 in fig. 7 may be referred to based on the fourth conductive structure setting region, the fifth conductive structure setting region and the sixth conductive structure setting region.
Further, referring to fig. 7, the working electrode 213 is disposed between the fifth insulating layer 350 and the base layer 100, that is, the working electrode 213 and the third electrode connecting line 223 are disposed at the fifth conductive structure, the reference electrode 212 is disposed between the sixth insulating layer 360 and the fifth insulating layer 350, that is, the reference electrode 212 and the second electrode connecting line 222 are disposed at the sixth conductive structure, and the counter electrode 211 is disposed between the fourth insulating layer 340 and the base layer 100, that is, the counter electrode 211 and the first electrode connecting line 221 are disposed at the fourth conductive structure. In fig. 7, the working electrode 213 and the counter electrode 211 are disposed on both sides of the substrate layer 100, and the reference electrode 212 is disposed on the side of the counter electrode 211 away from the substrate layer 100, and in other embodiments, the order of disposing the working electrode 213, the reference electrode 212, and the counter electrode 211 is not limited to the position of one of the electrode structures 210 provided in fig. 7.
Further, the different insulating layers may include different hollowed-out regions 300a, the insulating layer exposing the working electrode 213 may include a working electrode hollowed-out region 300a3, the insulating layer exposing the reference electrode 212 may include a reference electrode hollowed-out region 300a2, and the insulating layer exposing the counter electrode 211 may include a counter electrode hollowed-out region 300a1. For example, referring to fig. 7, if the counter electrode 211, the reference electrode 212 and the working electrode 213 are disposed at the positions shown in fig. 7, the counter electrode engraved region 300a1 is located at the fourth insulating layer 340, the reference electrode engraved region 300a2 is located at the fifth insulating layer 350, and the working electrode engraved region 300a3 is located at the sixth insulating layer 360. The conductive structure 200 of the sensor 10 is flexibly arranged, and further, the insulating structure 300 can comprise a plurality of insulating layers, and the arrangement of the insulating layers can be adaptively adjusted according to the adjustment of the conductive structure 200, so that the structural stability and the service life of the sensor 10 are ensured.
Fig. 8 is another structural schematic view along a section line C-C' in fig. 1, and referring to fig. 1 and 5, the counter electrode 211, the reference electrode 212 and the working electrode 213 are all located at one side of the base layer 100, and the counter electrode 211, the reference electrode 212 and the working electrode 213 are arranged coplanar.
Specifically, referring to fig. 8, the counter electrode 211, the reference electrode 212, and the working electrode 213 are all disposed on one side of the substrate layer 100 in a laminated manner, and are disposed in a coplanar manner (which may be understood as a co-layer arrangement). Based on the similar process of preparing the electrode structure 200, the thicknesses of the prepared counter electrode 211, reference electrode 212, and working electrode 213 are similar. Compared with the mode of laminating the counter electrode 211, the reference electrode 213 and the working electrode 213, the overall thickness of the sensor 10 can be effectively reduced, and the insulation structure between the electrode structures 210 in the lamination mode, namely the thickness of the sensor 10 can be reduced, and meanwhile, the process preparation cost of the sensor 10 can be reduced. Further, when the sensor 10 is used to implant a human body to detect blood glucose, acetic acid or ethanol, the degree of stinging perceived by the human body is reduced.
With continued reference to fig. 1 and 8, the sensor 10 further includes an insulating adhesive 311, the insulating adhesive 311 being located on one side of the substrate layer 100 and between the counter electrode 211, the reference electrode 212 and the working electrode 213.
Further, the sensor 10 may further include an insulating adhesive 311, and the insulating adhesive 311 is used to fill the gaps between the counter electrode 211, the reference electrode 212, and the working electrode 213, and then the insulating structure 300 is prepared thereon. Illustratively, after the substrate layer 100 has been prepared for the electrode structure 200, the remaining voids are filled with insulating adhesive 311, and this corresponds to planarizing the overall structure, facilitating the preparation of the insulating structure 300 thereon. The hollow region 300a is then prepared by patterning and etching the insulating structure 300. The insulating adhesive 311 may be at least one of a plurality of adhesives excellent in insulating properties such as a polyurethane adhesive, a polyimide adhesive, an epoxy adhesive, and the like.
It should be noted that, the insulating adhesive 311 may be disposed between different electrode structures 210, and may also be disposed on the outer side of the electrode structure 210, so as to ensure the adhesion effect with the substrate layer 100, and ensure the structural stability of the sensor 10.
Fig. 9 is a schematic structural diagram of another analyte sensor according to an embodiment of the present invention, referring to fig. 9, the sensor 10 includes a plurality of working electrodes 213, the working electrodes 213 include at least a first working electrode 213a and a second working electrode 213b, the working electrode hollowed-out area 300a3 includes at least a first working electrode hollowed-out area 300c1 and a second working electrode hollowed-out area 300c2, the first working electrode 213a is exposed through the first working electrode hollowed-out area 300c1, the second working electrode 213b is exposed through the second working electrode hollowed-out area 300c2, the contact 230 includes a working electrode contact 233, the working electrode contact 233 includes at least a first working electrode contact 233a and a second working electrode contact 233b, the first working electrode 213a is electrically connected to the first working electrode contact 233a, and the second working electrode 213b is electrically connected to the second working electrode contact 233 b.
The sensor 10 may include a plurality of working electrodes 213, and different working electrodes 213 may have different detection functions, for example, different working electrodes 213 may detect blood glucose, acetic acid, ethanol, and the like, respectively, or different working electrodes 213 may have different detection sensitivities, so as to obtain more accurate detection results.
Specifically, referring to fig. 9, the first working electrode 213a and the second working electrode 213b are exemplified. The working electrode hollow area 300c includes a first working electrode hollow area 300c1 and a second working electrode hollow area 300c2, and different working hollow areas 300c are disposed at different positions for exposing different working electrodes 213. Since the detection functions of the first working electrode 213a and the second working electrode 213 are different, the correspondingly connected contacts 230 are also different, thereby ensuring the progress of the detection operation. That is, the first working electrode 213a is electrically connected to the first working electrode contact 233a, and the second working electrode 213b is electrically connected to the second working electrode contact 233 b.
Specifically, as shown in FIG. 9, the first working electrode 213a is used for detecting a first analyte, the second working electrode 213b is used for detecting a second analyte, the types of the first analyte 213a and the second analyte 213b are different, or the detection sensitivity of the first working electrode 213a is different from the detection sensitivity of the second working electrode 213 b.
The sensor 10 includes a plurality of different working electrodes, and a first working electrode 213a and a second working electrode 213b are illustrated in fig. 7 and 8. The difference between the first working electrode 213a and the second working electrode 213b may be represented by the difference between the detection analytes, for example, one of glucose, β -hydroxybutyrate, uric acid, ketone, creatinine, ethanol, and lactic acid, and the embodiment of the present invention is not limited to a specific type. The difference between the first working electrode 213a and the second working electrode 213b may also be represented by a difference in detection sensitivity to the same substance.
Fig. 10 is a schematic structural view of another analyte sensor according to an embodiment of the present invention, fig. 11 is a schematic structural view of fig. 10 along a section line E-E', fig. 12 is a schematic structural view of another analyte sensor according to an embodiment of the present invention, and referring to fig. 10 to 12, the working electrode 210 includes an analyte reaction region 210c, the analyte reaction region 210c is exposed through the working electrode hollowed-out region 300a3, or the working electrode 210 includes a plurality of analyte reaction regions 210c, the working electrode hollowed-out region 300a3 includes a plurality of sub-hollowed-out regions 311a and sub-insulating regions 311b, the sub-insulating regions 311b surround the sub-hollowed-out regions 311a, and the plurality of analyte reaction regions 210c are exposed through the sub-hollowed-out regions 311 a.
Specifically, as shown in fig. 9, the working electrode 210 may include an analyte reaction area 210c, where the analyte reaction area 210c is exposed through the hollow area 300a3 of the working electrode, that is, each analyte reaction area 210c represents a test function area of the working electrode 210, and fig. 1, 6 to 9 only show that different analyte reaction areas 210c may have different shapes or arrangements. Referring to fig. 11, the working electrode 210 includes a plurality of analyte reaction regions 210c, the working electrode hollow region 300a3 includes a plurality of sub-hollow regions 311a and sub-insulating regions 311b, the sub-insulating regions 311b surround the sub-hollow regions 311a, and the plurality of analyte reaction regions 210c are exposed through the sub-hollow regions 311a, which means that in this case, the plurality of analyte reaction regions 210c correspond to different test sites of the same working electrode 210, i.e., the detection functions of the analyte reaction regions 210c are the same, and it can be understood that all are used for testing the same medium, such as blood glucose. By setting a plurality of different test potentials, the test area of the sensor 10 can be ensured to be larger, and the accuracy of detection can be improved.
Alternatively, in fig. 10 and fig. 12, only the working electrode hollow area 300a3 is used to perform a finer hollow-out division, and a plurality of sub-hollow areas may be also used to divide the electrode hollow area 300a1 and the reference hollow area 300a2, which is not particularly limited in the embodiment of the present invention.
Optionally, the counter electrode comprises a plurality of sub-counter electrodes, the reference electrode comprises a plurality of reference electrodes, the contact also comprises a counter electrode contact and a reference electrode contact, the plurality of sub-counter electrodes are respectively and electrically connected with the plurality of counter electrode contacts, or the plurality of sub-counter electrodes are respectively and electrically connected with one counter electrode contact, or the plurality of sub-reference electrodes are respectively and electrically connected with the plurality of reference electrode contacts, or the plurality of sub-reference electrodes are respectively and electrically connected with one reference electrode contact.
Further, instead of the working electrode being divided more finely, i.e. a plurality of sub-working electrodes being provided, the counter electrode may be provided as a plurality of sub-counter electrodes and the reference electrode as a plurality of sub-reference electrodes. The plurality of sub-counter electrodes are electrically connected with the plurality of counter electrode contacts, or the plurality of sub-counter electrodes are electrically connected with one counter electrode contact, which can be understood that the electrical connection relationship between the sub-counter electrodes and the counter electrode contacts can be 'many-to-many', or 'one-to-one'. Similarly, the plurality of sub-reference electrodes are electrically connected with the plurality of reference electrode contacts respectively, or the plurality of sub-reference electrodes are electrically connected with one reference electrode contact, which can be understood that the electrical connection relationship between the sub-reference electrodes and the reference electrode contacts can be 'many-to-many', or 'one-to-one'. For the schematic illustration of the electrical connection, reference can be made to the manner in which the plurality of sub-working electrodes are connected to the working electrode contacts. In summary, the electrode structure is variously arranged.
Alternatively, the sensor 10 comprises a linear sensor or a bending sensor.
The sensor 10 may have various shapes, and referring to fig. 1, the sensor 10 may include a bending sensor, which corresponds to an "L" type sensor. Further, the sensor 10 may also include other shaped structures, such as a linear sensor. For the adjustment of the shape of the sensor 10, the corresponding insulating structure 300 and conductive structure 200 need to be adaptively adjusted according to the shape of the sensor 10.
Based on the same inventive concept, the embodiment of the present invention further provides a method for preparing an analyte sensor, and fig. 13 is a schematic flow chart of a method for preparing an analyte sensor according to the embodiment of the present invention, and referring to fig. 13, the preparing method includes:
s110, providing a basal layer.
The material of the base layer may be mainly flexible and has insulation, and the base layer may be at least one of Polyurethane (PU), polyethylene terephthalate (PET), polyimide (PI), polycarbonate (PC), and the like. Furthermore, the basal layer can be selected to have certain biocompatibility, so that the probability that the prepared sensor can not produce adverse reaction to a user can be ensured, and the service life of the sensor is also ensured.
S120, preparing a conductive structure on at least one side of the substrate layer, wherein the conductive structure comprises an electrode structure, an electrode connecting wire and a contact.
Specifically, the conductive structure is located on at least one side of the substrate layer, i.e. the conductive structure comprises a plurality of electrode structures, i.e. the plurality of electrode structures may be located on the same side of the substrate layer or may be located on different sides of the substrate layer. Specifically, the conductive structure comprises an electrode structure, an electrode connecting wire and a contact, wherein the electrode structure corresponds to a sensor electrode in the sensor, and the analyte can generate a corresponding detected electrochemical signal at the electrode structure, and the signal is transmitted to the contact through the electrode connecting wire. Further, the contact is electrically connected with an external electronic system, the contact transmits detected signals to the external electronic system, and the electronic system can analyze the concentration, the type and the like of the analyte to be detected, so that the monitoring function of the sensor is realized.
Further, the sensor generally includes an implantation region, a connection region, and a lead region, wherein the electrode structure is located in the implantation region, the contact is located in the connection region, the electrode connection line is mainly located in the lead region, and the electrode connection line is further extended into the implantation region to be electrically connected with the electrode structure, and the electrode connection line is further extended into the connection region to be electrically connected with the contact. By way of example, the sensor may be generally used in blood glucose monitoring devices and the like, i.e. the analyte may be a blood glucose assay, the implanted region of which is intended to be inserted completely into the subcutaneous tissue, catalysing the analyte in the interstitial fluid to react and produce an electrochemical signal, i.e. detect blood glucose concentration and the like, the interstitial fluid having a close correlation with the glucose concentration and changes in blood, so that the sensor may obtain a change in glucose concentration in blood by monitoring the glucose concentration in the interstitial fluid. The sensor may also be used to monitor other substances, as embodiments of the invention are not particularly limited.
Further, the conductive structure comprises a counter electrode, a reference electrode and a working electrode, and different electrode structures are electrically connected with different contacts through different electrode connecting wires. The working electrode can be made of gold, platinum, carbon, graphite, palladium, titanium and other materials with excellent conductivity, the reference electrode can be made of silver/silver chloride (Ag/AgCl) materials, and the counter electrode needs to form a potential difference with the working electrode so as to accurately grasp the electrode potential applied by the working electrode, so that the counter electrode can be made of various materials such as platinum, carbon and the like, and form a loop with the working electrode, so that the current on the working electrode is smooth, and the reaction on the working electrode is ensured.
And S130, preparing an insulating structure on one side of the conductive structure far away from the basal layer, wherein the insulating structure comprises an insulating layer, the insulating layer comprises a plurality of hollow areas and insulating areas, and the insulating areas surround the hollow areas.
Specifically, the insulation structure of preparation includes the insulating layer, and the insulating layer includes a plurality of fretwork areas and insulating region to the insulating region is around the fretwork area, can understand as insulation structure includes the region of a plurality of fretwork, and the region of fretwork is used for exposing partial conductive structure, and the insulating region that insulation structure includes is the part that does not set up fretwork region in the insulation structure promptly. Further, the hollowed-out areas include a counter electrode hollowed-out area, a reference electrode hollowed-out area and a working electrode hollowed-out area, and some hollowed-out areas can be used for exposing the contacts. Specifically, the counter electrode is located in the implantation area and is exposed through the counter electrode hollow area, the reference electrode is located in the implantation area and is exposed through the reference electrode hollow area, the working electrode is located in the implantation area and is exposed through the working electrode hollow area, and the insulating structure can also be understood that the insulating structure provides a plurality of hollow areas to expose the electrode structure and the contact of the conductive structure, which need to be exposed, and the rest of the insulating structure is used for ensuring the stability of the electric signal and is used for insulating and coating the sensor through the insulating area.
Optionally, preparing the insulating structure on a side of the conductive structure away from the base layer further includes cutting the insulating structure with laser cutting, mechanical cutting, or plasma cutting to prepare the hollowed-out region and the insulating region.
Specifically, the hollow area in the insulating layer can be cut by laser cutting, mechanical cutting or plasma cutting, and the cut part is used as the hollow area for exposing part of the conductive structure, and the part which is not cut and removed is still the insulating layer and further used as the insulating area. The sensor structure may be cut before the preparation of the sensor structure is completed, or may be cut after the bonding, which is not particularly limited in the embodiment of the present invention.
And S140, preparing a detection layer on one side of the working electrode far away from the substrate layer.
Specifically, the detection layer may be a mixture having a substrate reaction catalyzing property, and may contain components such as a catalytic enzyme, a redox mediator, an enzyme activity protecting agent, and a crosslinking agent. In addition, a nanomaterial having electron transport property may be contained. The detection layer can be a plurality of layers of sequentially laminated nanoparticle layers, analyte enzyme catalysis layers and the like, wherein the nanoparticle layers are positioned between the analyte enzyme catalysis layers and the working electrode conductive layers, the strong conductivity of the nanoparticle layers can improve the transmission effect of electric signals, and the high specific surface area of the nanoparticle layers can enhance the adhesive force of enzymes on the electrode surface.
S150, preparing a regulating layer.
The sensor further comprises a regulating layer, the regulating layer comprises a biocompatible regulating layer, namely the regulating layer has good biocompatibility, the regulating layer is arranged on one side, far away from the basal layer, of the electrode structure, namely the regulating layer is arranged outside, and the regulating layer with good biocompatibility is arranged in the implantation area, so that the sensor can not generate serious anaphylactic reaction when being implanted into subcutaneous tissue, and therefore, some biochemical substances generated by the anaphylactic reaction can not be accumulated at the electrode structure to corrode the electrode structure, namely the service life of the sensor is ensured while the implanted user can not generate adverse reaction. Specifically, the regulation layer includes first regulation layer, second regulation layer and third regulation layer, and first regulation layer is located the electrode fretwork area and is located the one side of keeping away from the stratum basale to the electrode, and the second regulation layer is located the reference electrode fretwork area and is located the reference electrode and keep away from the one side of stratum basale, and the third regulation layer is located the one side of detecting the layer and keeping away from the stratum basale. The third regulating layer corresponding to the working electrode is a limiting outer membrane and a biocompatible outer membrane for controlling the reaction rate of the catalytic substrate, and the second regulating layer corresponding to the counter electrode and the reference electrode is a mixed substance of the limiting outer membrane and the biocompatible outer membrane. Because the reference electrode and the counter electrode are arranged at the implantation area, and the adjusting layer is additionally arranged on the two electrodes, the implanted user can be further ensured not to generate adverse reaction, and the service life of the sensor is also ensured.
Further, the substrate layer comprises a biocompatible substrate layer, and the insulating region comprises a biocompatible insulating layer, which can be understood as that the substrate layer, the insulating structure and the regulating layer in the sensor have better biocompatibility. Further, in the implantation area, it is ensured that the implanted user will not generate adverse reaction, the probability of adverse reaction of the sensor to the user is further weakened, and the service life of the sensor 10 is also ensured.
The substrate layer and the insulating region in the sensor are also made of biocompatible materials, and further, after the substrate layer, the conductive structure and the insulating structure are prepared, the whole substrate layer, the conductive structure and the insulating structure do not need to be dip-coated with a biocompatible outer film, and only the electrode structure is required to be coated with an adjusting layer, so that the whole biocompatibility is ensured, the dosage of film liquid is reduced, and the cost is reduced.
In summary, the sensor prepared by the method further comprises a detection layer and an adjustment layer, wherein the detection layer is a mixture capable of carrying out catalytic reaction and is used for realizing the monitoring function of the sensor, the adjustment layer comprises a biocompatible adjustment layer, and the first adjustment layer, the second adjustment layer and the third adjustment layer are arranged at different electrode structures, so that the sensor is guaranteed to have better biocompatibility, and the monitoring accuracy and the service life are improved.
Note that the above is only a preferred embodiment of the present invention and the technical principle applied. It will be understood by those skilled in the art that the present invention is not limited to the particular embodiments described herein, but is capable of various obvious changes, rearrangements and substitutions as will now become apparent to those skilled in the art without departing from the scope of the invention. Therefore, while the invention has been described in connection with the above embodiments, the invention is not limited to the embodiments, but may be embodied in many other equivalent forms without departing from the spirit or scope of the invention, which is set forth in the following claims.