Biosensor and analyte monitoring apparatus

Abstract

Provided in the present disclosure are a biosensor and an analyte monitoring apparatus. The biosensor comprises a first electrode provided with a sensing layer, and a polymer film, wherein the polymer film at least covers the sensing layer and the first electrode. The polymer film comprises a first film layer and a second film layer, wherein the first film layer comprises a substance which may damage the sensing layer and / or the first electrode in the case of direct contact, and compared with the first film layer, the second film layer is closer to the first electrode, so as to separate the first film layer from the sensing layer and the first electrode. By means of the present disclosure, a biosensor and an analyte monitoring apparatus with a wider material selection range can be provided, and thus can meet the requirements of more application scenarios.

Description

Biosensors and analyte monitoring devices Technical Field

[0001] The present disclosure relates to the field of new chemical materials, and in particular to a biosensor and an analyte monitoring device. Background Art

[0002] Biosensors are analytical devices that tightly combine biological materials, bio-derived materials, or biomimetic materials with optical, electrochemical, temperature, piezoelectric, magnetic, or micromechanical physical and chemical sensors or sensing microsystems. They can usually be used to quickly detect certain specific chemicals in the human body, such as glucose, ketone bodies, and uric acid.

[0003] Biosensors generally employ a sensing layer on a working electrode. This layer contains substances specific to the analyte, such as enzymes, antibodies, and ligands. During monitoring, the analyte reacts with the sensing layer, generating a signal. Analysis of this signal provides information on the analyte's level. In biosensors, the working electrode and sensing layer are often covered with polymer films with various functionalities, such as diffusion-limiting membranes, anti-interference membranes, and temperature compensation membranes.

[0004] However, in existing biosensors, in order to avoid damaging internal structures such as electrodes and sensing layers, the materials used for polymer membranes are usually selected to be harmless or have low impact on electrodes and enzymes, which limits the material selection and performance optimization of the functional layer. Summary of the Invention

[0005] The present disclosure is made in view of the above-mentioned state of the prior art, and its purpose is to provide a biosensor and analyte monitoring device with a wider range of material selections, which can be applicable to the needs of more application scenarios.

[0006] To this end, the first aspect of the present disclosure provides a biosensor, which includes a first electrode provided with a sensing layer, and a polymer film, wherein the polymer film covers at least the sensing layer and the first electrode, and the polymer film includes a first film layer and a second film layer, wherein the first film layer includes a substance that will cause damage to the sensing layer and / or the first electrode when in direct contact, and the second film layer is closer to the first electrode than the first film layer to separate the first film layer from the sensing layer and the first electrode.

[0007] In the first aspect of the present disclosure, the polymer film of the biosensor includes a second film layer and a first film layer, the first film layer includes a substance that is harmful to the sensing layer and / or the first electrode, and the second film layer is provided to separate the first film layer from the internal structure (sensing layer and first electrode), thereby reducing the adverse effects of the harmful substances in the first film layer on the sensing layer and the first electrode (for example, corrosion leading to damage to the integrity of the internal structure and loss of functionality). That is, in the present disclosure, a breakthrough is made in selecting a first film layer that includes a substance that has a negative impact on the electrode structure, and the design of the second film layer is used to solve the performance bottleneck problem caused by limited material selection in traditional designs, which can expand the selection range of functional film layer (first film layer) materials, improve the performance and versatility of the biosensor, and also help improve the stability and reliability of the sensor, providing new ideas and possibilities for the innovation and application expansion of biosensor technology. As a result, a biosensor with a wider range of material selection can be provided, which can be applicable to the needs of more application scenarios.

[0008] In the biosensor according to the first aspect of the present disclosure, the first film layer can optionally be configured to reduce the effects of sterilizing gas on the sensing layer during gas sterilization of the biosensor. In this case, the biosensor can be sterilized using gas sterilization. Compared to biosensors without the first film layer, the biosensor of the present disclosure experiences a significantly reduced decrease in sensitivity before and after sterilization, maintaining a high sensitivity after sterilization. This provides a biosensor that is resistant to sterilizing gas.

[0009] In the biosensor involved in the first aspect of the present disclosure, optionally, the first membrane layer is made of a first solution, and the first solution includes a first type of polymer and a solvent.

[0010] In the biosensor of the first aspect of the present disclosure, the first polymer may optionally be polyurethane. In this case, providing a first film layer comprising polyurethane can help limit the permeation of sterilization gas during gas sterilization of the biosensor, forming an isolation barrier to reduce the effects of the sterilization gas on the sensing layer, particularly the effects of gaseous ethylene oxide on the active substances in the sensing layer, thereby enabling the biosensor to be sterilized using gas sterilization.

[0011] In the biosensor according to the first aspect of the present disclosure, optionally, in the first solution, the mass fraction of the first type of polymer is 0.1% to 15%, thereby helping the first membrane layer to limit the permeation of sterilization gas during gas sterilization.

[0012] In the biosensor according to the first aspect of the present disclosure, the solvent of the first solution may optionally damage the sensing layer and / or the first electrode upon direct contact. In this case, selecting a solvent with stronger solubility for certain specific polymers (for example, certain non-polar or highly polar solvents can dissolve a wider range of polymers, including those difficult to process with traditional solvents) can help expand the range of polymer materials available for the first film layer.

[0013] In the biosensor according to the first aspect of the present disclosure, the solvent of the first solution is optionally an organic solvent, wherein the organic solvent is a mixed solvent of any one or more of tetrahydrofuran, dichloromethane, and N,N-dimethylacetamide. This facilitates dissolution of the first type of polymer using the organic solvent.

[0014] In the biosensor involved in the first aspect of the present disclosure, optionally, the first membrane layer has a diffusion-limiting effect on an analyte sensed by the biosensor.

[0015] In the biosensor involved in the first aspect of the present disclosure, optionally, the first film layer has biocompatibility.

[0016] In the biosensor according to the first aspect of the present disclosure, optionally, the first solution includes a first type of polymer, the first type of polymer being a polyurethane, the first type of polymer having a soft segment, and the soft segment accounting for 5% to 50% of the first type of polymer. Because the proportion of the soft segment affects the performance of the polyurethane material, in this case, selecting an appropriate soft segment proportion can enable the polyurethane material to have good mechanical properties and biocompatibility.

[0017] In the biosensor according to the first aspect of the present disclosure, the first solution optionally includes a first polymer, the first polymer being a polyurethane, the first polymer having hydrophilic groups, and the proportion of the hydrophilic groups in the first polymer being 1% to 30%. The proportion of the hydrophilic groups in the polyurethane affects the properties of the polyurethane material. In this case, selecting an appropriate proportion of the hydrophilic groups can impart good hydrophilicity and biocompatibility to the polyurethane material.

[0018] In the biosensor according to the first aspect of the present disclosure, optionally, the thickness of the first film layer is 1 μm to 100 μm. In this case, selecting a first film layer with a suitable thickness can effectively achieve the intended effect.

[0019] In the biosensor according to the first aspect of the present disclosure, optionally, the substance in the second film layer does not react with the substance in the first film layer, thereby facilitating the formation of the second film layer that can separate the first film layer from the internal structure (sensing layer and first electrode).

[0020] In the biosensor according to the first aspect of the present disclosure, the second membrane layer optionally includes a second polymer, which is a cationic or anionic polymer or a copolymer formed from a neutral monomer. In this case, the second membrane layer does not react with the two polymers in the first membrane layer, facilitating the formation of a second membrane layer that separates the first membrane layer from the internal structure (sensing layer and first electrode). Furthermore, the second polymer can be dissolved in a low-corrosive or non-corrosive solvent, allowing the formed second membrane layer to directly contact the internal structure without damaging the internal structure. Furthermore, the second membrane layer has minimal permeability restriction on analytes, facilitating the passage of analytes through the second membrane layer and contact with the sensing layer.

[0021] In the biosensor according to the first aspect of the present disclosure, optionally, the second film layer has a thickness of 1 μm to 30 μm, thereby effectively separating the first film layer from the internal structure through the second film layer.

[0022] In the biosensor according to the first aspect of the present disclosure, the polymer film may optionally further include other functional film layers, wherein the other functional film layers are selected from any one or more of an anti-interference layer, a biocompatible layer, an antibacterial layer, a temperature compensation layer, and a signal enhancement layer. Thus, an appropriate functional film layer can be selected as needed.

[0023] In the biosensor according to the first aspect of the present disclosure, the polymer film optionally further includes a third film layer, the third film layer being a biocompatible layer, and the first film layer being located between the second film layer and the third film layer. This can help further improve the biocompatibility of the biosensor.

[0024] In the biosensor according to the first aspect of the present disclosure, the biocompatible layer optionally includes a third polymer, which is a polyurethane containing hydrophilic groups or a cross-linked water-soluble polyurethane. In this case, the third polymer is also a polyurethane, which can further improve the biocompatibility of the biosensor and partially block the entry of sterilization gases during the sterilization process, further enhancing the protective effect of the polymer film on the biosensor.

[0025] In the biosensor according to the first aspect of the present disclosure, optionally, when the third polymer is the polyurethane containing hydrophilic groups, the hydrophilic groups in the third polymer account for 20% to 50%. This enables the biocompatible layer containing the third polymer to have good biocompatibility, thereby further improving the biocompatibility of the biosensor.

[0026] In the biosensor according to the first aspect of the present disclosure, optionally, the biocompatible layer has a thickness of 1 μm to 30 μm, thereby helping to improve the biocompatibility of the biosensor.

[0027] In the biosensor involved in the first aspect of the present disclosure, optionally, the analyte sensed by the biosensor is one or more.

[0028] In the biosensor according to the first aspect of the present disclosure, optionally, the sensing layer comprises one or more of glucase, lactase, and hydroxybutyrate dehydrogenase, thereby enabling selection of a suitable sensitive substance according to the type of analyte.

[0029] In the biosensor according to the first aspect of the present disclosure, optionally, the biosensor further includes a second electrode different from the first electrode, and the polymer film also covers the second electrode, thereby enabling the second electrode to be protected by the polymer film.

[0030] A second aspect of the present disclosure provides an analyte monitoring device, comprising an electronic component and the biosensor according to the first aspect of the present disclosure, wherein the electronic component is electrically connected to the biosensor.

[0031] According to the present disclosure, a biosensor and an analyte monitoring device with a wider range of material selection can be provided, which can be applicable to the needs of more application scenarios. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG1 is a diagram showing an application scenario of a biosensor involved in an example of the present disclosure.

[0033] FIG. 2 is a schematic diagram illustrating a biosensor according to an example of the present disclosure.

[0034] FIG. 3 is a schematic diagram illustrating a polymer film according to an example of the present disclosure.

[0035] FIG. 4 is a schematic diagram showing a polymer film covering an implant portion according to an example of the present disclosure.

[0036] FIG5 is a diagram showing the appearance of the biosensor according to Example 1 of the present disclosure after sterilization.

[0037] FIG6 is a diagram showing the appearance of the biosensor of Comparative Example 1 of the present disclosure after sterilization.

[0038] Explanation of reference numerals: 100 ...analyte monitoring device, 1 ...sensor, 11 ...implantation portion, 12 ...connection portion, 13 ...first electrode, 14 ...sensing layer, 2 ...electronic component, 3 ...polymer membrane, 31 ...first membrane layer, 32 ...second membrane layer, 33 ...third membrane layer. DETAILED DESCRIPTION

[0039] The preferred embodiments of the present disclosure are described in detail below with reference to the accompanying drawings. In the following description, identical components are assigned identical reference numerals, and duplicate descriptions are omitted. In addition, the accompanying drawings are merely schematic, and the proportions of the dimensions of the components and the shapes of the components may differ from the actual ones.

[0040] It should be noted that the terms "including" and "having" and any variations thereof in this disclosure, such as a process, method, system, product or device that includes or has a series of steps or units, are not necessarily limited to those steps or units clearly listed, but may include or have other steps or units that are not clearly listed or are inherent to these processes, methods, products or devices.

[0041] A first aspect of the present disclosure relates to a biosensor for monitoring an analyte. The biosensor disclosed herein may be referred to simply as a sensor, or as a monitoring probe, a sensing probe, or an electrode probe. In some examples, the biosensor disclosed herein is resistant to sterilizing gases and can be sterilized using gas sterilization.

[0042] In the present disclosure, the analyte may be one or more of glucose, acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase, creatine, creatinine, DNA, fructosamine, glutamine, hormones, ketone bodies, lactic acid, lactate, oxygen, peroxide, prostate-specific antigen, prothrombin, RNA, thyroid-stimulating hormone, and troponin. This is merely an example, and the analyte may also be other substances not shown.

[0043] In the present disclosure, biosensors may be named using the "target analyte + sensor" format. For example, when the target analyte is glucose, the biosensor may be referred to as a glucose sensor. For another example, when there are multiple target analytes, the biosensor may be referred to as a multi-analyte sensor. For example, when there are two target analytes, the biosensor may be referred to as a dual-analyte sensor.

[0044] A second aspect of the present disclosure relates to a first film layer of a biosensor. The first film layer may be an isolation layer. The first film layer can limit the permeation of sterilization gas during gas sterilization of the biosensor, forming an isolation barrier to reduce the impact of the sterilization gas on the biosensor's sensing layer (described later). In the example of the present disclosure where the first film layer is an isolation layer, the first film layer of the biosensor of the present disclosure may also be referred to as an isolation film, a spacer layer, a sterilization layer, etc.

[0045] The third aspect of the present disclosure relates to an analyte monitoring device, which may include electronic components and biosensors. The analyte monitoring device of the present disclosure may also be referred to as a continuous monitoring device or a monitoring system, etc. In the present disclosure, the analyte monitoring device may use the naming method of "target analyte + monitoring device". For example, when the target analyte is glucose, the analyte monitoring device may also be referred to as a glucose monitoring device. For another example, when there are multiple target analytes, the analyte monitoring device may also be referred to as a multi-analyte monitoring device. For example, when there are two target analytes, the analyte monitoring device may also be referred to as a dual-analyte monitoring device.

[0046] Hereinafter, the biosensor (hereinafter referred to as the sensor) involved in the present disclosure will be described by taking glucose as an example with reference to the accompanying drawings.

[0047] Figure 1 is a diagram showing an application scenario of a sensor 1 according to an example of the present disclosure. Figure 2 is a schematic diagram showing a sensor 1 according to an example of the present disclosure.

[0048] In some examples, the sensor 1 can be used to monitor the analyte. In some examples, the sensor 1 can be used in conjunction with the electronic component 2. Specifically, referring to Figure 1, the sensor 1 can be combined with the electronic component 2 to form an analyte monitoring device 100, so that the analyte monitoring device 100 is located on the host's body surface, and the sensor 1 is partially located under the host's skin, so that the analyte can be monitored by the sensor 1. It should be noted that although the application scenario of the sensor 1 is exemplarily described here as cooperating with the electronic component 2 to monitor the analyte in the host's body, the sensor 1 can also be placed in other different test environments to detect the analyte. For example, the sensor 1 can be placed in an in vitro test solution to detect the analyte; at the same time, it is not necessary to be combined with the electronic component 2 to form the analyte monitoring device 100 to be used. For example, the sensor 1 can also be electrically connected to an external test circuit for monitoring.

[0049] In some examples, the sensor 1 may include an implant portion 11 (see FIG2 ). The implant portion 11 may be implanted subcutaneously in the host, and when in use, the implant portion 11 may be located subcutaneously in the host and in contact with the analyte. Thus, the analyte in the host body can be monitored by the sensor 1. In some examples, the sensor 1 may include a connection portion 12 (see FIG2 ). The implant portion 11 may be electrically connected to the electronic component 2 via the connection portion 12. When in use, the implant portion 11 may be located subcutaneously, and the connection portion 12 may be located outside the body, and therefore, the connection portion 12 may also be referred to as an in vitro portion.

[0050] In some examples, sensor 1 may include a first electrode 13 (see FIG2 ). A sensing layer 14 may be disposed on first electrode 13. Analytes may react with sensing layer 14 on first electrode 13, generating an electrical signal. This current signal may be analyzed and processed to obtain information about the analyte level. In other words, first electrode 13 may also be referred to as a working electrode.

[0051] In some examples, the sensor 1 may include a second electrode. The second electrode may be the same as or different from the first electrode 13. For example, the second electrode may be a reference electrode or a counter electrode. For another example, the second electrode may be a second working electrode, and the analyte sensed by the second working electrode may be the same as or different from the first electrode 13. In some examples, the sensor 1 may include a third electrode. The third electrode may be a reference electrode or a counter electrode and different from the second electrode. In some examples, the sensor 1 may include a working electrode, a reference electrode, and a counter electrode. Thus, a sensor 1 with a three-electrode system can be formed to monitor the analyte. In some examples, the sensor 1 may include a fourth electrode. The fourth electrode may be a second working electrode, a reference electrode, a counter electrode, or a blank electrode for improving the measurement accuracy of the sensor 1. In some examples, the fourth electrode may be different from the first electrode, the second electrode, and the third electrode.

[0052] In some examples, the analyte sensed by sensor 1 may be one or more analytes. In some examples, the analyte may be selected from any one or more of glucose, lactate, and ketone bodies. When the analyte is a ketone body, the ketone body level can be reflected by monitoring the level of β-hydroxybutyrate.

[0053] In some examples, the sensing layer 14 may include a sensitive substance that can promote the reaction of the analyte. The sensing substance can be selected according to the object to be detected. For example, when the analyte is glucose, the sensing layer 14 may include glucase. In some examples, the sensing layer 14 may include one or more of glucase, lactase, and hydroxybutyrate dehydrogenase. Thus, a suitable sensitive substance can be selected according to the type of analyte. In some examples, the glucase may be glucose oxidase or glucose dehydrogenase. In some examples, the sensing layer 14 can be formed by applying an enzyme solution containing the sensing substance to the working electrode. In some examples, the sensing layer 14 can be formed by spin coating, dip pulling, drop coating, spraying, printing, etc.

[0054] In some examples, when there are multiple analytes, a sensing layer corresponding to each analyte can be provided on the first electrode, or multiple working electrodes can be provided, with a sensing layer corresponding to each analyte provided on each working electrode. For example, in some examples, the sensor 1 can be a dual-analyte sensor capable of simultaneously monitoring glucose and ketones. Two working electrodes can be provided, with a glucose sensing layer comprising glucase and a ketone sensing layer comprising hydroxybutyrate dehydrogenase provided on each working electrode, respectively.

[0055] In some examples, the sensor 1 may include a polymer membrane 3 (shown later).

[0056] In some examples, the polymer membrane 3 can control the diffusion of the analyte. That is, the polymer membrane 3 can have a selective permeability / diffusion-restricting effect on the analyte. In some examples, the polymer membrane 3 can cover at least the sensing layer 14. Thus, the polymer membrane 3 can control the amount of analyte permeation—that is, the amount of analyte entering the sensing layer 14—and thereby help ensure that the magnitude of the electrical signal generated by the analyte contacting the sensing layer 14 falls within the linear response range of the sensor 1.

[0057] In some examples, the polymer film 3 can be biocompatible. In some examples, the polymer film 3 can cover the implantable portion 11 of the sensor 1 (shown later). This can make the sensor 1 biocompatible. In this disclosure, "biocompatible" means that the relative cell survival rate in the cytotoxicity test results is above 90%, indicating good biocompatibility.

[0058] In some examples, the polymer film 3 may include a functional film layer. The functional film layer can be configured based on application needs. For example, the functional film layer can be selected from any one or more of a sterilization layer, an anti-interference layer, a biocompatible layer, an antibacterial layer, a temperature compensation layer, and a signal enhancement layer. Thus, the appropriate functional film layer can be selected as needed, making the sensor 1 suitable for a wider range of application scenarios. In some examples, the functional film layer can also be other known functional film layers, not limited to those described in this disclosure.

[0059] In some examples, the polymer membrane 3 can limit the permeation of sterilization gas when the sensor 1 is gas sterilized. For example, the polymer membrane 3 can limit the permeation of ethylene oxide (hereinafter referred to as EO). Thus, a sensor 1 resistant to sterilization gas can be provided. That is to say, the sensor 1 of the present disclosure can be sterilized by gas sterilization, and compared with the sensor 1 without the polymer membrane 3, the sensor 1 of the present disclosure has a greatly reduced sensitivity decrease before and after sterilization, and can still maintain a high sensitivity after sterilization. In some examples, the polymer membrane 3 can cover at least the sensing layer 14 and the first electrode 13. Thus, the erosion of the internal structure (sensing layer 14 and the first electrode 13) by the sterilization gas during sterilization can be reduced, and the internal structure can be protected.

[0060] FIG. 3 is a schematic diagram showing a polymer film 3 according to an example of the present disclosure.

[0061] In some examples, the polymer film 3 may include a first film layer 31 (see FIG3 ). In some examples, the polymer film 3 may include a second film layer 32 (see FIG3 ). In some examples, the second film layer 32 may be closer to the first electrode 13 than the first film layer 31 .

[0062] In some examples, the first film layer 31 may include a substance that, upon direct contact, may damage the sensing layer 14 and / or the first electrode 13. In some examples, the second film layer 32 may separate the first film layer 31 from the sensing layer 14 and the first electrode 13. In this case, if the first film layer 31 includes a substance that is harmful to the sensing layer 14 and / or the first electrode 13, the second film layer 32 may be provided to separate the first film layer 31 from the internal structure (sensing layer 14 and first electrode 13), thereby mitigating the adverse effects of the harmful substance in the first film layer 31 on the sensing layer 14 and the first electrode 13 (e.g., corrosion leading to damage to the integrity of the internal structure and loss of functionality).

[0063] That is, in the present disclosure, a breakthrough is made by selecting a first film layer 31 that includes a substance that has a negative impact on the electrode structure, and utilizing the design of a second film layer 32 to resolve the performance bottleneck problem caused by limited material selection in traditional designs. This can expand the range of material options for the functional film layer (first film layer 31), improve the performance and versatility of the sensor 1, and also help improve the stability and reliability of the sensor 1, providing new ideas and possibilities for the innovation and application expansion of biosensor technology. As a result, a sensor 1 with a wider range of material options can be provided, which can be applied to the needs of more application scenarios.

[0064] In the present disclosure, the second film layer 32 separating the first film layer 31 from the internal structure may also be referred to as a protective layer.

[0065] In some examples, the substance in the second film layer 32 may not react with the substance in the first film layer 31. This facilitates the formation of the second film layer 32 that can separate the first film layer 31 from the internal structure (sensing layer 14 and first electrode 13).

[0066] In some examples, the first film layer 31 can be made of a first solution. The first solution can be applied to a target location to form the first film layer 31. The target location refers to the location where the first film layer 31 is desired to be formed. For example, the first solution can be applied to the implant portion 11 to form the first film layer 31. In some examples, the first solution can be applied to the target location to form the first film layer 31 by spin coating, dip coating, drop coating, spray coating, or the like.

[0067] In some examples, the first solution may include a first type of polymer and a solvent. The type of the first polymer may be selected based on desired functionality. For example, in an example where the first film layer 31 is biocompatible, the first polymer may be a biocompatible material. For another example, when the first film layer 31 is an anti-interference layer, the first polymer may be a material that has anti-interference properties against the target interferent.

[0068] In some examples, the solvent of the first solution can be selected to dissolve the first polymer. In some examples, the solvent of the first solution may damage the sensing layer 14 and / or the first electrode 13 upon direct contact. In such cases, selecting a solvent with stronger solubility that can dissolve certain specific polymers (for example, certain non-polar or highly polar solvents can dissolve a wider range of polymers, including those that are difficult to process with traditional solvents) can help expand the range of polymer materials available for the first film layer 31.

[0069] In some examples, the first film layer 31 can be configured to reduce the effects of sterilizing gas on the sensing layer 14 during gas sterilization of the sensor 1. In this case, the sensor 1 can be sterilized using gas sterilization. Compared to biosensors without the first film layer 31, the sensor 1 of the present disclosure experiences a significantly reduced decrease in sensitivity before and after sterilization, maintaining a high sensitivity even after sterilization. This provides a sensor 1 that is resistant to sterilizing gas. In the present disclosure, the first film layer 31 configured to reduce the effects of sterilizing gas on the sensing layer 14 during gas sterilization of the sensor 1 can also be referred to as an isolation layer or sterilization layer. In some examples, the sensor 1 of the present disclosure can be sterilized using ethylene oxide.

[0070] The polymer membrane 3 of the present disclosure is described below by taking the sterilization gas as ethylene oxide and the first membrane layer 31 configured to reduce the effect of the sterilization gas on the sensing layer 14 when the sensor 1 is subjected to gas sterilization as an example.

[0071] In some examples, the first film layer 31 may include a first type of polymer. In other words, in some examples, the first solution may include a first type of polymer. In some examples, the first type of polymer may restrict the permeation of a sterilizing gas (e.g., ethylene oxide). Thus, the first film layer 31 formed by the first solution including the first type of polymer may restrict the permeation of the sterilizing gas.

[0072] In some examples, the first membrane layer has a diffusion-limiting effect on the analyte sensed by the sensor 1. In some examples, the first membrane layer is biocompatible.

[0073] In some examples, the first type of polymer can be polyurethane. Polyurethane is a material with good physical and mechanical properties, blood compatibility and biocompatibility, and ethylene oxide generally does not cause structural changes or denaturation of polyurethane when it comes into contact with polyurethane at room temperature and pressure. In this case, by providing a first film layer 31 comprising polyurethane, the penetration of sterilizing gas can be limited when the sensor 1 is gas sterilized, forming an isolation barrier to reduce the impact of the sterilizing gas on the sensing layer 14, especially the impact of gaseous ethylene oxide on the active substances (such as sensitive substances) in the sensing layer 14; and the first film layer 31 comprising polyurethane has good biocompatibility, which can improve the safety of the sensor 1 when implanted subcutaneously in the host; in addition, the first film layer 31 also has a permeation-restricting effect on specific analytes (such as glucose), which can enable the polymer membrane 3 to act as a semipermeable membrane. In some examples, the first type of polymer can have a carbamate group.

[0074] In some examples, the first type of polymer may have a soft segment, and in the first type of polymer, the proportion of the soft segment may be 5% to 50%. In this case, the properties of the first type of polymer can be adjusted by adjusting the proportion of the soft segment. In some examples, preferably, the proportion of the soft segment is 10% to 25%. In some examples, when the first type of polymer is polyurethane, the polyurethane may have a soft segment. Since the proportion of the soft segment will affect the performance of the polyurethane material, in this case, by selecting an appropriate proportion of the soft segment, the polyurethane material can have good mechanical properties and biocompatibility. In some examples, the elasticity, modulus, softness and water absorption of the polyurethane can be adjusted by adjusting the proportion of the soft segment in the polyurethane, thereby adjusting the permeability of the first film layer 31 to the analyte and the biocompatibility of the first film layer 31 itself. In some examples, the soft segment may include a component containing an epoxy functional group. For example, the soft segment may include polyethylene oxide (PEO).

[0075] In some examples, the polyurethane can be a block copolymer consisting of a soft segment and a hard segment. In some examples, in the polyurethane, the soft segment can be composed of hydroxyl-containing molecules such as polyester polyols, polyether alcohols, polycaprolactones, and polylactic acid-glycolic acid copolymers of varying molecular weights. In some examples, in the polyurethane, the hard segment can be composed of compounds such as diisocyanates and low molecular weight short chain extenders. In some examples, the diisocyanate can be an aliphatic isocyanate. For example, the diisocyanate can be 1,6-hexamethylene diisocyanate (HDI), 4,4'-dicyclohexylmethane diisocyanate (HMDI), or isophorone diisocyanate (IPDI). In some examples, the short chain extender can be 1,4-butanediol.

[0076] In some examples, the polyurethane may be a polycarbonate polyurethane, a polyether polyurethane, and / or a polyester polyurethane. In some examples, the polyurethane may include one or more of aliphatic polyether polyurethane, aliphatic polyether polyurethane urea, cycloaliphatic polyether polyurethane, cycloaliphatic polyether polyurethane urea, aromatic polyether polyurethane, aromatic polyether polyurethane urea, aliphatic polyester polyurethane, aliphatic polyester polyurethane urea, cycloaliphatic polyester polyurethane, cycloaliphatic polyester polyurethane urea, aromatic polyester polyurethane, and aromatic polyester polyurethane urea.

[0077] In some examples, the first type of polymer may be a zwitterionic polyurethane. In this case, this type of polyurethane has the flexibility and scalability of a polyether chain, while also possessing the properties of zwitterionic groups. Zwitterionic groups with different properties can be introduced as needed to adjust the properties of the first film layer 31. In some examples, the zwitterionic groups in the zwitterionic polyurethane may include amine groups, carboxyl groups, and / or sulfonic acid groups. In this case, the introduction of specific zwitterionic groups can improve the hydrophilicity and biocompatibility of the first film layer 31.

[0078] In some examples, the first polymer may have a hydrophilic group. This allows the first polymer to have a certain degree of hydrophilicity, thereby improving the biocompatibility of the first film layer 31. Furthermore, ethylene oxide can react with some types of hydrophilic groups. That is, the first polymer containing hydrophilic groups that react with ethylene oxide can adsorb ethylene oxide to a certain extent, thereby further improving the isolation effect of the first film layer 31 against ethylene oxide. In some examples, the hydrophilic groups may include hydroxyl groups, carboxyl groups, and / or ether groups.

[0079] In some examples, the hydrophilic groups may account for 1% to 30% of the first polymer. For example, the hydrophilic groups may account for 1%, 2%, 5%, 6%, 8%, 10%, 12%, 13%, 15%, 16%, 17%, 18%, 20%, 22%, 25%, 26%, 27%, 28%, 29%, or 30% of the first polymer. The proportion of the hydrophilic groups in the first polymer may affect the performance of the first polymer. In this case, by adjusting the proportion of the hydrophilic groups, the relevant properties of the first polymer can be adjusted, thereby adjusting the performance of the first film layer 31.

[0080] In some examples, when the first polymer is polyurethane, the hydrophilic group content can range from 1% to 30%. In this case, selecting an appropriate hydrophilic group content can ensure that the polyurethane material exhibits excellent hydrophilicity and biocompatibility. Furthermore, polyurethane containing hydrophilic groups reactive with ethylene oxide can absorb some of the ethylene oxide during sterilization, introducing epoxy groups, further enhancing the sterilization gas barrier properties of the first membrane layer 31. In some examples, the hydrophilic group content of the first polymer can preferably range from 10% to 25%. In some examples, the permeability coefficient of the first membrane layer 31 to the analyte can be adjusted by adjusting the hydrophilic groups in the polyurethane. For example, increasing the proportion of hydrophilic groups in the polyurethane can increase its dispersibility in the liquid phase, thereby improving the permeability of the first membrane layer 31 to the analyte. Conversely, decreasing the proportion of hydrophilic groups in the polyurethane can reduce the permeability of the first membrane layer 31 to the analyte. In some examples, the hydrophilicity of the polyurethane can be increased by introducing a block containing hydrophilic groups.

[0081] In some examples, the first solution may include an organic solvent. The first type of polymer may be soluble in the organic solvent. This facilitates the formation of the first solution and, in turn, the formation of the first film layer 31. In some examples, the organic solvent may be a mixed solvent of one or more of tetrahydrofuran, dichloromethane, and N,N-dimethylacetamide. This allows the first type of polymer to be dissolved in the organic solvent.

[0082] In some examples, the mass fraction of the first type of polymer in the first solution can be 0.1% to 15%. For example, the mass fraction of the first type of polymer in the first solution can be 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%. This can help the first membrane layer 31 limit the permeation of the sterilizing gas during gas sterilization. In some examples, preferably, the mass fraction of the first type of polymer in the first solution can be 0.1% to 5%. In this case, the first membrane layer 31 can have a suitable analyte permeability coefficient while limiting the permeation of the sterilizing gas.

[0083] In some examples, the thickness of the first membrane layer 31 can be 1 μm to 100 μm. In this case, selecting a first membrane layer 31 of an appropriate thickness can effectively achieve the intended function. It should be noted that different functional layers can have different thicknesses depending on actual needs. For example, in some examples where the first membrane layer 31 serves as an isolation layer, the thickness of the first membrane layer 31 can preferably be 1 μm to 40 μm. For example, the thickness of the first membrane layer 31 can be 1 μm, 5 μm, 8 μm, 10 μm, 12 μm, 15 μm, 18 μm, 20 μm, 22 μm, 25 μm, 28 μm, 30 μm, 32 μm, 35 μm, 38 μm, or 40 μm. In this case, selecting a first membrane layer 31 of an appropriate thickness can effectively serve as an isolation barrier, thereby improving the resistance of the sensor 1 to sterilization gas. Furthermore, it can also ensure that the first membrane layer 31 has an appropriate analyte permeability coefficient. In some examples, the thickness of the first membrane layer 31 can preferably be 10 μm to 30 μm. In this case, it is possible to balance the isolation effect of the first membrane layer 31 on the sterilization gas and the analyte permeation coefficient.

[0084] In some examples, as described above, the polymer film 3 may include a second film layer 32. In some examples, the second film layer 32 may be used to separate the sensing layer 14 from the first film layer 31. That is, the second film layer 32 may be closer to the first electrode 13 than the first film layer 31. This can mitigate the adverse effects of the organic solvent in the first film layer 31 on the sensing layer 14 and the first electrode 13 (e.g., corrosion leading to damage to the internal structural integrity and loss of functionality).

[0085] In some examples, the second film layer 32 can be made of a second solution. In some examples, the second solution can be applied to the implant portion 11 to form the second film layer 32. In some examples, the second solution can be applied to the target location by spraying, spin coating, or dip coating to form the second film layer 32.

[0086] In some examples, the second solution may include a second type of polymer. In other words, the second film layer 32 may include the second type of polymer. The second type of polymer may not react with the first type of polymer. This facilitates the formation of the second film layer 32 that can separate the first film layer 31 from the internal structure (sensing layer 14 and first electrode 13).

[0087] In some examples, the second type of polymer can be a copolymer formed by anionic and cationic polymers or neutral monomers. In this case, the second film layer 32 does not react with the two polymers in the first film layer 31; a low-corrosive or non-corrosive solvent can be used to dissolve the second type of polymer, so that the formed second film layer 32 directly contacts the internal structure (sensing layer 14 and first electrode 13) without damaging the internal structure; the formed second film layer 32 also has minimal permeability restrictions on the analyte, allowing the analyte to pass through the second film layer 32 and contact the sensing layer 14. In addition, the second type of polymer is insoluble in the organic solvent in the first solvent, which can reduce the possibility of the formed film layer falling off and inhibit the interaction between the two film layers, thereby improving the overall stability of the polymer film 3.

[0088] In some examples, the second polymer may be chitosan or carboxymethyl acrylate. In some examples, the second polymer may be selected from one or more of polyethylene glycol-block-polystyrene, polyacrylic acid-block-polystyrene, polyacrylic acid-co-polystyrene, polyacrylamide-block-polystyrene, polyacrylamide-co-polystyrene, poly-2-vinylpyridine-block-polystyrene, poly-4-vinylpyridine-co-polystyrene, poly-4-vinylpyridine-co-polyvinyl pyrrolidone, poly-2-vinylpyridine-co-polystyrene, poly-4-vinylpyridine-block-polystyrene, poly-4-vinylpyridine-co-polyacrylamide, polyethoxyethyl acrylate-co-polyhydroxyethyl acrylate, and polyethoxypropyl acrylate-co-polyvinyl alcohol.

[0089] In some examples, the solvent of the second solution can be a lower alcohol solution, an inorganic salt buffer solution, or a mixed solution of a lower alcohol and an inorganic salt buffer solution. This can dissolve the second polymer, facilitating subsequent coating of the second solution. In some examples, the solvent of the second solution can be methanol, ethanol, or a mixed solution of ethanol and phosphate buffer solution.

[0090] In some examples, the thickness of the second film layer 32 may be 1 μm to 30 μm. For example, the thickness of the second film layer 32 may be 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 22 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, or 30 μm. Thus, the second film layer 32 can effectively separate the first film layer 31 from the internal structure. In some examples, preferably, the thickness of the second film layer 32 may be 1 μm to 20 μm. In some examples, preferably, the thickness of the second film layer 32 may be 8 μm to 15 μm. In some examples, preferably, the thickness of the second film layer 32 may be no less than 10 μm.

[0091] In some examples, the thickness ratio of the second film layer 32 to the first film layer 31 can be 1:1 to 1:10. For example, the thickness ratio of the second film layer 32 to the first film layer 31 can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, or 1:10. This facilitates separating the first film layer 31 from the internal structure (sensing layer 14 and first electrode 13) by the second film layer 32. In some examples, preferably, the thickness ratio of the second film layer 32 to the first film layer 31 can be 1:1 to 1:5.

[0092] In some examples, the polymer film 3 may further include other functional film layers. Here, "other functional film layers" refer to other film layers other than the first film layer 31 and the second film layer 32. By providing other functional film layers, the polymer film 3 can have other desired functionalities. For example, in some examples, the other functional film layers can be selected from any one or more of an anti-interference layer, a biocompatible layer, an antibacterial layer, a temperature compensation layer, and a signal enhancement layer. Thus, a suitable functional film layer can be selected as needed. In some examples, the other functional film layers can also be other known functional film layers, not limited to those described in this disclosure.

[0093] For example, in some examples, the polymer film 3 may include a third film layer 33 (see FIG3 ). The third film layer 33 may be biocompatible and serve as the outermost layer of the polymer film 3 (i.e., the film layer furthest from the first electrode 13 ). In this case, the biocompatibility of the sensor 1 may be improved. That is, in some examples, the third film layer 33 may be a biocompatible layer.

[0094] In some examples, the first film layer 31 may be located between the third film layer 33 and the second film layer 32. It should be noted that, in the present disclosure, the first film layer 31 has been adjusted to have good biocompatibility, and the third film layer 33 is added to further improve the biocompatibility and reliability of the sensor 1. The third film layer 33 is not necessarily required.

[0095] In some examples, the third film layer 33 can be made of a third solution. In some examples, the third solution can be applied to the implant portion 11 to form the third film layer 33. In some examples, the third solution can be applied to the target location by spraying, spin coating, or dip coating to form the third film layer 33. In some examples, the third solution can include a third type of polymer. In other words, the third film layer 33 can include a third type of polymer. The third type of polymer can be a biocompatible polymer. This allows the formation of a biocompatible third film layer 33, thereby helping to improve the biocompatibility of the sensor 1.

[0096] In some examples, the third polymer may be polyurethane. In this case, the third polymer is also polyurethane, which can further improve the biocompatibility of the sensor 1 and partially block the entry of sterilization gas during the sterilization process of the sensor 1, further improving the protective effect of the polymer film 3 on the sensor 1.

[0097] In some examples, the third polymer can be a polyurethane containing hydrophilic groups. In this case, the third film layer 33 containing the third polymer can have good biocompatibility. In addition, the polyurethane containing hydrophilic groups that react with ethylene oxide can react with ethylene oxide during sterilization, absorbing some of the ethylene oxide and introducing epoxy groups, further increasing the hydrophilicity of the third film layer 33 and, in turn, improving the biocompatibility of the polymer film 3.

[0098] In some examples, the proportion of hydrophilic groups in the third type of polymer can be 20% to 50%. For example, the proportion of hydrophilic groups in the third type of polymer can be 20%, 22%, 25%, 28%, 30%, 32%, 35%, 37%, 40%, 42%, 45%, 48%, or 50%. As a result, the third film layer 33 comprising the third type of polymer can have good biocompatibility, thereby further improving the biocompatibility of the sensor 1. In some examples, preferably, the proportion of hydrophilic groups in the third type of polymer can be 30% to 50%. In some examples, preferably, the proportion of hydrophilic groups in the third type of polymer can be no less than 30%.

[0099] In some examples, the third type of polymer can be a cross-linked water-soluble polyurethane. In this case, the water-soluble polyurethane has good biocompatibility, thereby enabling the formed third film layer 33 to have good biocompatibility. In some examples, the third type of polymer can be polyethylene glycol block polyurethane, polymethacrylate block polyurethane, polyvinyl alcohol block polyurethane, or polypropylene alcohol block polyurethane.

[0100] In some examples, the solvent of the third solution can be an organic solvent or other mixed solvent. The third type of polymer can be dissolved in the organic solvent. This facilitates the formation of the third solution and, in turn, the formation of the third film layer 33. In some examples, the organic solvent can be a mixed solvent of any one or more of tetrahydrofuran, dichloromethane, and N,N-dimethylacetamide. This allows the third type of polymer to be dissolved in an organic solvent. In some examples, the solvent of the third solution can include water. This facilitates the dissolution of the third type of polymer.

[0101] In some examples, the mass fraction of the third type of polymer in the third solution can be 0.1% to 15%. For example, the mass fraction of the third type of polymer in the third solution can be 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%. This allows for the formation of a third film layer 33 having good biocompatibility. In some examples, preferably, the mass fraction of the first type of polymer in the first solution can be 0.1% to 5%.

[0102] In some examples, the thickness of the third film layer 33 may be 1 μm to 30 μm. For example, the thickness of the third film layer 33 may be 1 μm, 3 μm, 5 μm, 6 μm, 8 μm, 10 μm, 12 μm, 14 μm, 15 μm, 16 μm, 18 μm, 20 μm, 22 μm, 25 μm, 26 μm, 28 μm, or 30 μm. This can help improve the biocompatibility of the sensor 1. In some examples, preferably, the thickness of the third film layer 33 may be 10 μm to 20 μm.

[0103] Figure 4 is a schematic diagram showing a polymer film 3 covering an implant 11 according to an example of the present disclosure. In Figure 4 , the polymer film 3 is magnified and the structure of the implant 11 is simplified for a clearer illustration, but this should not be construed as limiting the present disclosure.

[0104] In some examples, the polymer film 3 can cover the implant portion 11 (see FIG4 ). In some examples, the polymer film 3 can cover each electrode on the implant portion 11. For example, the polymer film 3 can cover the first electrode 13 and the second electrode. Thus, the first electrode 13 and the second electrode can be protected by the polymer film 3. For another example, the polymer film 3 can cover the first electrode 13, the second electrode, and the third electrode on the implant portion 11. Thus, each electrode can be protected by the polymer film 3. In some examples, the polymer film 3 can completely cover the implant portion 11. Thus, the safety of the sensor 1 when implanted subcutaneously in the host can be improved.

[0105] In some examples, the thickness of the polymer film 3 may be no greater than 100 μm. In this case, the polymer film 3 can be stably adhered to the implant portion 11, and the implant portion 11 occupies less space overall, which can reduce discomfort after implantation under the host's skin, thereby improving wearing comfort.

[0106] In some examples, the thickness of the polymer film 3 may be 15 μm to 200 μm. In some examples, the thickness of the polymer film 3 may be 15 μm to 100 μm. For example, the thickness of the polymer film 3 may be 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm, or 100 μm. In some examples, preferably, the thickness of the polymer film 3 may be 30 μm to 60 μm.

[0107] In some examples, the sensor 1 may include a substrate. In some examples, the various electrodes of the sensor 1 may be disposed on a substrate. For example, the first electrode, the second electrode, the third electrode, and / or the fourth electrode may be disposed on a substrate. In some examples, the substrate may be a flexible substrate. The flexible substrate may be generally made of at least one of polyethylene (PE), polypropylene (PP), polyimide (PI), polystyrene (PS), polyethylene terephthalate (PET), and polyethylene naphthalate (PEN). In addition, in other examples, the flexible substrate may also be generally made of metal foil, ultra-thin glass, a single-layer inorganic film, a multi-layer organic film, or a multi-layer inorganic film. In some examples, the substrate may also be a non-flexible substrate. The non-flexible substrate may generally include ceramics, aluminum oxide, or silicon dioxide with weaker conductivity. As a result, it can be implanted into the body surface (e.g., the superficial layer of the skin, etc.) without the need for an auxiliary implantation device (e.g., a puncture needle).

[0108] In some examples, each electrode of the sensor 1 can be independently made of at least one of gold, glassy carbon, graphite, platinum, silver, silver chloride, palladium, titanium, or iridium, thereby ensuring good electrical conductivity without affecting the electrochemical reaction of each electrode.

[0109] In some examples, preferably, the sensor 1 may include a first electrode 13 provided with a sensing layer 14, and a polymer film 3, the polymer film 3 may cover at least the sensing layer 14 and the first electrode 13, the polymer film may include a first film layer 31 and a second film layer 32, the second film layer 32 may be closer to the first electrode 13 than the first film layer 31, the first film layer 31 may be configured to reduce the impact of the sterilization gas on the sensing layer 14 when the sensor 1 is gas sterilized, the first film layer 31 may be made of a first solution, the first solution may include a first type of polymer and an organic solvent, and the first type of polymer may be polyurethane. In this case, the polymer membrane 3 of the sensor 1 includes a second membrane layer 32 and a first membrane layer 31. By providing the first membrane layer 31 comprising polyurethane, the penetration of the sterilization gas can be restricted during gas sterilization of the sensor 1, forming an isolation barrier to reduce the effect of the sterilization gas on the sensing layer 14, particularly the effect of gaseous ethylene oxide on the active substances in the sensing layer 14. This allows the sensor 1 to be sterilized using gas sterilization. Compared to biosensors without the first membrane layer 31, the biosensor disclosed herein significantly reduces the decrease in sensitivity before and after sterilization. The sensor 1 can maintain high sensitivity even after sterilization. Furthermore, the polyurethane first film layer 31 has good biocompatibility, enhancing the safety of the sensor 1 when placed subcutaneously. Furthermore, the first film layer 31 restricts the permeation of analytes, acting as a semipermeable membrane. Furthermore, the second film layer 32 separates the first film layer 31 from the internal structure (sensing layer 14 and first electrode 13), mitigating adverse effects of organic solvents in the first film layer 31 on the sensing layer 14 and first electrode 13 (e.g., corrosion leading to loss of internal structural integrity and functionality). This provides a sensor 1 that is resistant to sterilizing gases.

[0110] In some examples, preferably, the sensor 1 includes a first electrode 13 provided with a sensing layer 14, and a polymer film 3, the polymer film 3 covers at least the sensing layer 14 and the first electrode 13, the polymer film includes a first film layer 31 and a second film layer 32, the first film layer 31 includes a substance that will cause damage to the sensing layer 14 and the first electrode 13 when in direct contact, and the second film layer 32 is closer to the first electrode 13 than the first film layer 31 to separate the first film layer 31 from the sensing layer 14 and the first electrode 13.

[0111] Embodiments of the present disclosure may include:

[0112] A. A biosensor comprising a first electrode provided with a sensing layer, and a polymer film, the polymer film covering at least the sensing layer and the first electrode, the polymer film comprising a first film layer and a second film layer, the first film layer comprising a substance that would damage the sensing layer and / or the first electrode upon direct contact, the second film layer being closer to the first electrode than the first film layer to separate the first film layer from the sensing layer and the first electrode.

[0113] B. A biosensor, which may include a first electrode provided with a sensing layer, and a polymer film, wherein the polymer film may cover at least the sensing layer and the first electrode, and the polymer film may include a first film layer and a second film layer, wherein the second film layer may be closer to the first electrode than the first film layer, and the first film layer may be configured to reduce the effect of the sterilization gas on the sensing layer when the sensor is subjected to gas sterilization.

[0114] In some examples, Embodiment A and Embodiment B can each independently be combined with any one or more of the following additional elements: Element 1: The first film layer includes a substance that can damage the sensing layer and / or the first electrode upon direct contact. Element 2: The first film layer can be configured to reduce the effects of sterilization gas on the sensing layer during gas sterilization of the sensor.

[0115] Element 3: The first membrane layer is made from a first solution comprising a first polymer and a solvent. Element 4: The first polymer is polyurethane. Element 5: The polyurethane can be polycarbonate polyurethane, polyether polyurethane, and / or polyester polyurethane. Element 6: The mass fraction of the first polymer is 0.1% to 15%. Element 7: The solvent in the first solution can damage the sensing layer and / or the first electrode upon direct contact. Element 8: The solvent in the first solution is an organic solvent. Element 9: The first polymer can be a zwitterionic polyurethane. Element 10: The first polymer has a soft segment. Element 11: The soft segment accounts for 5% to 50% of the first polymer. Element 12: The first polymer has a hydrophilic group. Element 13: The hydrophilic group accounts for 1% to 30% of the first polymer. Element 14: The thickness of the first membrane layer is 1 μm to 100 μm.

[0116] Element 15: The second film layer may include a second type of polymer. Element 16: The substance in the second film layer may be non-reactive with the substance in the first film layer. Element 17: The second type of polymer may be non-reactive with the first type of polymer. Element 18: The second type of polymer may be an anionic or cationic polymer or a copolymer formed from a neutral monomer. Element 19: The thickness of the second film layer may be 1 μm to 30 μm. Element 20: The thickness ratio of the second film layer to the first film layer may be 1:1 to 1:10.

[0117] Element 21: The polymer membrane also includes other functional membrane layers, selected from any one or more of an anti-interference layer, a biocompatible layer, an antibacterial layer, a temperature compensation layer, and a signal enhancement layer. Element 22: The polymer membrane also includes a third membrane layer, which is a biocompatible layer. The first membrane layer is located between the second and third membrane layers. Element 23: The biocompatible layer includes a third polymer, which is a polyurethane containing hydrophilic groups or a cross-linked water-soluble polyurethane.

[0118] Element 24: The biosensor senses one or more analytes. Element 25: The sensing layer includes one or more of glucase, lactase, and hydroxybutyrate dehydrogenase. Element 26: When there are multiple analytes, a sensing layer corresponding to each analyte can be provided on the first electrode, or multiple working electrodes can be provided with a sensing layer corresponding to each analyte on each working electrode. Element 27: The sensor can be a dual-analyte sensor capable of simultaneously monitoring glucose and ketones. Element 28: The first membrane layer can have a selective permeability / diffusion restriction effect on the analyte. Element 29: The first membrane layer can be biocompatible.

[0119] In summary, in the first aspect of the present disclosure, a sensor 1 having a wider range of material choices can be provided. In particular, a sensor 1 having resistance to sterilization gas can also be provided.

[0120] As previously described, the second aspect of the present disclosure provides a first membrane layer 31 of a sensor 1. This first membrane layer 31 can limit the permeation of sterilizing gas during gas sterilization of the sensor 1, forming an isolation barrier to reduce the impact of the sterilizing gas on the sensing layer 14 of the sensor 1. In other words, the second aspect of the present disclosure provides an isolation layer for the sensor 1.

[0121] The first film layer 31 involved in the second aspect of the present disclosure is consistent with the first film layer 31 in the sensor 1 described in the first aspect of the present disclosure. The specific components and proportions can be found in the description of the first aspect and will not be repeated here.

[0122] In some examples, the first film layer 31 can be configured to reduce the impact of the sterilization gas on the sensing layer 14 when the sensor 1 is sterilized with gas. In some examples, the first film layer 31 can cover the first electrode 13 and the sensing layer 14 of the sensor 1. This can protect the first electrode 13 and the sensing layer 14.

[0123] In some examples, the first film layer 31 can be made of a first solution, which can include a first type of polymer and an organic solvent. The first type of polymer can be polyurethane. In this case, the first film layer 31 including polyurethane can limit the permeation of the sterilization gas during gas sterilization of the sensor 1, forming an isolation barrier to reduce the impact of the sterilization gas on the sensing layer 14, especially the impact of gaseous ethylene oxide on the active substances in the sensing layer 14, so that the sensor 1 can be sterilized using gas sterilization. Compared with the sensor 1 without the first film layer 31, the sensor 1 provided with the first film layer 31 has a significantly reduced decrease in sensitivity before and after sterilization, and can still maintain a high sensitivity after sterilization. In addition, the first film layer 31 including polyurethane has good biocompatibility, which can improve the safety of the sensor 1 when implanted subcutaneously in the host. In addition, the first film layer 31 also has a permeation-restricting effect on specific analytes (such as glucose), which can act as a semipermeable membrane.

[0124] In some examples, the first film layer 31 can also be used in other scenarios where it is necessary to limit the permeation of ethylene oxide, and the first film layer 31 can be set on the predetermined target. In other words, the second aspect of the present disclosure can provide a first film layer 31 that can limit the permeation of sterilization gas.

[0125] In some examples, the preparation method of the first film layer 31 may include: preparing a first solution; coating the first solution on a predetermined position; and drying to form the first film layer 31 .

[0126] As previously mentioned, the third aspect of the present disclosure relates to an analyte monitoring device 100 .

[0127] In some examples, the analyte monitoring device 100 may include an electronic component 2 and a sensor 1 electrically connected to the electronic component 2 (see Figure 1). Thus, the analyte can be monitored by the sensor 1. The sensor 1 described in the third aspect of the present disclosure is consistent with the sensor 1 in the first aspect of the present disclosure. The specific structure and details can be found in the description of the first aspect of the present disclosure, which will not be repeated here. That is to say, in some examples, the analyte monitoring device 100 may include an electronic component 2 and the sensor 1 described in the first aspect of the present disclosure. Thus, a sensor 1 with a wider range of material selection and a wider functionality can be provided, and the analyte monitoring device 100 including the sensor 1 can be suitable for the needs of more application scenarios.

[0128] In particular, in some examples, analyte monitoring device 100 may include a sensor 1 that is resistant to sterilization gas. That is, in some examples, analyte monitoring device 100 may include a sensor 1 with an isolation layer. In this case, sensor 1 is resistant to sterilization gas, and sensor 1 can be assembled with electronic assembly 2 and sterilized by gas, without having to sterilize sensor 1 separately by radiation.

[0129] In some examples, the analyte monitoring device 100 can be assembled as one piece at the factory, and the user does not need to perform additional operations to assemble the electronic component 2 and the sensor 1 when using it. This can facilitate user use. It should be noted that although the sensor 1 provided in the present disclosure can be designed as an integral part with the electronic component 2, if necessary, the two can also be configured to be separable and matched. "Integrated design" should not be understood as a limitation on the sensor 1 of the present disclosure.

[0130] In summary, according to the present disclosure, a sensor 1 and an analyte monitoring device 100 having a wider range of material selections can be provided. In particular, a sensor 1 and an analyte monitoring device 100 having resistance to sterilization gas can be provided.

[0131] To further illustrate the present disclosure, the sensor 1 and the first film layer 31 provided by the present disclosure are described in detail below with reference to the embodiments, taking the first film layer 31 as an isolation layer as an example, and the beneficial effects achieved by the present disclosure are fully illustrated with reference to comparative examples.

[0132] It should be noted that, in the examples and comparative examples of the present disclosure, unless otherwise specified, the reagents and instruments used are all commercially available products.

[0133] First, a plurality of sensors including a first electrode provided with a sensing layer of glucose enzyme are prepared.

[0134] [Example]

[0135] According to Tables 1-1 and 1-2, a first solution, a second solution, and a third solution were prepared (some examples did not have a third solution). The prepared sensors were sequentially coated with the second solution to form a second film layer, the first solution to form a first film layer, and the third solution to form a third film layer, to produce sensors having polymer membranes according to Examples 1 to 11. PEO in Tables 1-1 and 1-2 refers to a hydrophilic group and soft segment, and PEGDGE refers to polyethylene glycol diglycidyl ether. Experiments were conducted using polyurethanes containing PEO as an example.

[0136] Table 1-1

[0137] Table 1-2

[0138] [Comparative Example 1]

[0139] A commercially available continuous glucose monitoring system (Shenzhen Silicon-Based Sensing Technology Co., Ltd., model: GS1) was selected as comparative example 1.

[0140] [Comparative Example 2]

[0141] The sensor of Comparative Example 2 was prepared according to the same steps as Example 1, except that the second film layer (protective layer) was not provided.

[0142] [Comparative Example 3]

[0143] The sensor of Comparative Example 3 was prepared according to the same steps as Example 4. The difference from Example 4 was that the thickness of the first film layer (isolation layer) was 50 μm.

[0144] [Comparative Example 4]

[0145] The sensor of Comparative Example 4 was prepared according to the same steps as Example 1, with the difference from Example 1 being that the polyether polyurethane in the first solution contained 50% PEO.

[0146] Test the performance of the sensor:

[0147] (1) Cytotoxicity test (biocompatibility test)

[0148] Taking the sensors of Example 1 and Example 9 as an example, a cytotoxicity test was performed, specifically: a control group and an experimental group were designed, the control group included a blank group (blank control cell culture fluid was added), a negative control group (high-density polyethylene extract (non-toxic substance) was added), and a positive control group (latex glove extract (toxic substance) was added). The experimental group included the first solution of Example 1 and the third solution of Example 9 at different concentrations. For details, see Table 2. Cells were inoculated in the experimental group and the control group, and the cell survival rate was measured after incubation. The cytotoxicity test results are shown in Table 2.

[0149] Table 2

[0150] (2) Sensitivity test

[0151] The sensors of each Example and each Comparative Example were sterilized using ethylene oxide under the following sterilization conditions: temperature: 52±3°C, humidity: 30-85%, exposure time: 360 minutes, concentration: 600±40 mg / L. Figure 5 shows the appearance of the sensor of Example 1 after sterilization, and Figure 6 shows the appearance of the sensor of Comparative Example 1 after sterilization.

[0152] The sensitivity of each sensor was tested before and after sterilization. Specifically, the sensor was exposed to standard phosphate buffered saline (PBS) buffer with varying glucose concentrations at 37°C ± 1°C. The response current at each glucose concentration was measured and fitted to a standard curve. The sensitivity of each sensor was then calculated based on the fitted standard curve. The glucose concentrations were as follows: 2.2 mM (millimoles per liter), 5 mM, 10 mM, 15 mM, 20 mM, and 25 mM. The measured sensitivities are shown in Table 3. In Table 3, the decrease in sensitivity = (sensitivity before sterilization - sensitivity after sterilization) / sensitivity before sterilization * 100%. A greater decrease in sensitivity (also called attenuation) indicates a greater impact of ethylene oxide and a weaker sensor resistance to ethylene oxide. Conversely, a smaller decrease in sensitivity indicates a stronger sensor resistance to ethylene oxide.

[0153] Table 3

[0154] Result Analysis

[0155] As can be seen from Figures 5 and 6, the appearance of the sensor of Example 1 did not change significantly after sterilization, while the sensor of Comparative Example 1 changed and turned significantly green (it should be noted that in order to comply with the provisions of the Patent Examination Guidelines, the drawings were changed to black and white in this disclosure), indicating that the sensor of Comparative Example 1 without the first film layer was corroded after sterilization.

[0156] As can be seen from Table 3, the sensitivity of the sensors in each Example decreased very little before and after sterilization, indicating that the sensors in each Example were resistant to ethylene oxide. In contrast, the sensitivity of the sensors in each Comparative Example decreased significantly after sterilization, with some experiencing undetectable sensitivity. The following is a detailed analysis:

[0157] In Comparative Example 1, because the commercially available product does not have a first film layer like the present invention, the sensitivity of the sensor drops significantly after sterilization, and therefore the sensor of Comparative Example 1 cannot be gas sterilized using ethylene oxide. In Comparative Example 2, because the second film layer is not provided, the electrode is corroded after coating the first solution containing an organic solvent, resulting in no sensitivity being detected. This indicates that the second film layer of the present invention can effectively protect the electrode. In Comparative Example 3, because the thickness of the first film layer is 50 μm, the excessive increase in film thickness causes the first film layer to have too large a diffusion resistance to glucose, and effective sensitivity cannot be detected. In Comparative Example 4, the PEO content in the first film layer is 50%, that is, the content of soft segments and hydrophilic groups is 50%. The overall hydrophilicity of the first film layer is high, and the diffusion resistance to glucose is small, which makes the sensor have a higher sensitivity before sterilization, but also causes the first film layer to have a poor isolation effect on ethylene oxide, and the sensitivity of the sensor drops significantly after sterilization.

[0158] By comparing Example 1 and Examples 2-3, it can be found that increasing the film thickness leads to a decrease in sensitivity, but the degree of sensitivity attenuation after sterilization is also reduced, indicating that increasing the thickness of the first film layer can reduce the damage to the electrode caused by ethylene oxide sterilization.

[0159] By comparing Example 1 and Example 4, it can be found that because the concentration and thickness of the polyether polyurethane in Example 4 are greater than those in Example 1, the degree of sensitivity attenuation after sterilization is reduced, but the overall sensitivity of Example 4 is lower than that of Example 1.

[0160] By comparing Example 1 and Examples 5-6, it can be found that Examples 5-6 respectively use different concentrations of polyether polyurethane to prepare the first film layer. Due to the different solution concentrations, there is a slight difference in the sensitivity before sterilization and the sensitivity attenuation after sterilization, but there is no significant difference.

[0161] By comparing Example 1 and Examples 7-8, it can be found that Examples 7-8 use different types of polyurethanes, respectively. Since these two types of polyurethanes are more hydrophobic than polyether polyurethanes, the first membrane layer has a greater diffusion resistance to glucose and a lower sensitivity. However, the sensitivity attenuation amplitude after sterilization is also reduced accordingly, indicating that different types of polyurethanes can have an isolation effect.

[0162] By comparing Example 1 and Examples 9-11, it can be found that Examples 9-11 are sensors that add a third film layer of different components. Due to the increase in the overall film thickness of the polymer film, the sensitivity of the sensors of Examples 9-11 is reduced compared to Example 1, but the sensitivity attenuation after sterilization is also reduced accordingly, which has a stronger protective effect; and the third solution of Example 9 shows stronger biocompatibility than the first solution of Example 1 in the cytotoxicity test, indicating that adding a third film layer helps to improve the biocompatibility of the sensor.

[0163] In summary, the sensors in each embodiment exhibit strong resistance to ethylene oxide (i.e., sterilizing gas). In comparison, the sensors obtained in the comparative examples cannot achieve the performance and effects of the sensors obtained in the aforementioned embodiments. The protective film (second film layer) disclosed herein can mitigate the adverse effects of harmful substances in the first film layer on the internal structure.

[0164] According to the present disclosure, a biosensor with a wider range of material options can be provided, which can be applicable to the needs of more application scenarios.

[0165] Although the present disclosure has been described in detail above with reference to the accompanying drawings and examples, it will be understood that the above description does not limit the present disclosure in any form. Those skilled in the art may modify and change the present disclosure as needed without departing from the spirit and scope of the present disclosure, and such modifications and variations all fall within the scope of the present disclosure.

Claims

1. A biosensor, characterized in that: The biosensor comprises a first electrode provided with a sensing layer, and a polymer film, The polymer film at least covers the sensing layer and the first electrode, and the polymer film includes a first film layer and a second film layer. The first film layer includes a substance that will damage the sensing layer and / or the first electrode when in direct contact. The second film layer is closer to the first electrode than the first film layer to separate the first film layer from the sensing layer and the first electrode.

2. The biosensor according to claim 1, wherein The first film layer is configured to reduce the influence of sterilization gas on the sensing layer when the biosensor is subjected to gas sterilization.

3. The biosensor according to claim 1 or 2, characterized in that The first film layer is made of a first solution, which includes a first type of polymer and a solvent.

4. The biosensor according to claim 3, wherein The first type of polymer is polyurethane.

5. The biosensor according to claim 4, wherein In the first solution, the mass fraction of the first type of polymer is 0.1% to 15%.

6. The biosensor according to claim 3, wherein The solvent of the first solution may damage the sensing layer and / or the first electrode when in direct contact.

7. The biosensor according to claim 6, wherein The solvent of the first solution is an organic solvent, and the organic solvent is a mixed solvent of any one or more of tetrahydrofuran, dichloromethane and N,N-dimethylacetamide.

8. The biosensor according to claim 1, wherein The first membrane layer has a diffusion-limiting effect on the analyte sensed by the biosensor.

9. The biosensor according to claim 1, wherein The first film layer is biocompatible.

10. The biosensor according to claim 8 or 9, characterized in that The first solution includes a first type of polymer, the first type of polymer is polyurethane, the first type of polymer has a soft segment, and in the first type of polymer, the soft segment accounts for 5% to 50%.

11. The biosensor according to claim 8 or 9, characterized in that The first solution includes a first type of polymer, the first type of polymer is polyurethane, the first type of polymer has a hydrophilic group, and in the first type of polymer, the hydrophilic group accounts for 1% to 30%.

12. The biosensor according to claim 1, wherein The thickness of the first film layer is 1 μm to 100 μm.

13. The biosensor according to claim 1, wherein The substance in the second film layer does not react with the substance in the first film layer.

14. The biosensor according to claim 1 or 13, characterized in that The second film layer includes a second type of polymer, which is an anionic or cationic polymer or a copolymer formed by a neutral monomer.

15. The biosensor according to claim 1 or 13, characterized in that The thickness of the second film layer is 1 μm to 30 μm.

16. The biosensor according to claim 1, wherein The polymer film further comprises other functional film layers, and the other functional film layers are selected from any one or more of an anti-interference layer, a biocompatible layer, an antibacterial layer, a temperature compensation layer, and a signal enhancement layer.

17. The biosensor according to claim 1 or 2, characterized in that The polymer film further includes a third film layer, which is a biocompatible layer. The first film layer is located between the second film layer and the third film layer.

18. The biosensor according to claim 17, wherein The biocompatible layer includes a third type of polymer, which is a polyurethane containing a hydrophilic group or a cross-linked water-soluble polyurethane.

19. The biosensor according to claim 18, wherein When the third type of polymer is the polyurethane containing hydrophilic groups, the hydrophilic groups account for 20% to 50% of the third type of polymer.

20. The biosensor according to claim 17, wherein The biocompatible layer has a thickness of 1 μm to 30 μm.

21. The biosensor according to claim 1, wherein The analyte sensed by the biosensor is one or more analytes.

22. The biosensor according to claim 1 or 21, characterized in that The sensing layer includes one or more of glucase, lactase and hydroxybutyrate dehydrogenase.

23. The biosensor according to claim 1, wherein The biosensor further includes a second electrode different from the first electrode, and the polymer film also covers the second electrode.

24. An analyte monitoring device, characterized in that The biosensor comprises an electronic component and the biosensor according to any one of claims 1 to 23, wherein the electronic component is electrically connected to the biosensor.

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