Mixed conductive stretchable enzyme membrane and preparation method thereof

Abstract

The invention provides stretchable conductive hydrogel with oxidation-reduction activity. The stretchable conductive hydrogel has an interpenetrating double-network structure formed by interpenetrating brittle pure gel conductive hydrogel and stretchable hydrogel. Furthermore, a ferrocene derivative is fixed on a chain of the stretchable hydrogel through a covalent bond, and the glucose oxidase and the stretchable hydrogel are cross-linked by a normal-temperature cross-linking agent.

Description

Related Applications Cross-Referenced

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 612,381, filed on December 20, 2023, the entire content of which is incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medical devices. More specifically, the present invention relates to a stretchable conductive hydrogel with redox activity suitable for glucose monitoring. Background Art

[0003] Since the first glucose biosensor was invented by Leland Clark in 1962, biosensors have made breakthrough developments. A biosensor is a basic analytical tool that converts a biological reaction into a quantifiable signal, and generally mainly includes three core components: a biorecognition component, a detector or sensor unit, and a signal processing system. In a glucose biosensor, the recognition component used is an enzyme membrane.

[0004] Biosensors have great promise in the medical field because they play a key role in aspects such as diagnosing, monitoring, and treating health conditions. Among them, wearable biosensors can also achieve continuous health monitoring, providing an alternative to traditional inpatient and continuous patient monitoring. For example, continuous glucose monitoring systems provide mobility and continuous diagnostic data, greatly improving the quality of life of diabetic patients. However, existing continuous glucose monitoring systems must use needles, which can easily cause discomfort to patients and lead to bleeding problems.

[0005] To solve this problem, many studies have turned to developing non-invasive continuous glucose monitoring systems, such as using stretchable medical tapes or bandages that adhere to the skin to develop stretchable glucose sensors. However, the enzyme membranes responsible for catalyzing glucose into a detectable current in these sensors are mainly composed of rigid and brittle polymers. Despite the high importance of these enzyme membranes, stretchable enzyme membranes are currently lacking.

[0006] In recent years, progress in stretchable and multifunctional hydrogels has provided a potential solution for developing stretchable enzyme membranes. These hydrogels are unique materials that can combine their inherent properties with mutually exclusive properties, such as including electrical, mechanical, redox, and diffusion properties, which are very important for realizing the functionality of enzymes.

[0007] Therefore, in view of the vulnerability problem of existing enzyme membranes, the present invention provides a soft skin-friendly and stretchable glucose sensor that can be integrated into commercially available stretchable sweat patches or wound-healing bandages. Summary of the Invention

[0008] The object of the present invention is to provide a device, material or method to solve the above technical problems.

[0009] According to a first aspect of the present invention, there is provided a stretchable conductive hydrogel with redox activity. More particularly, the hydrogel comprises: an interpenetrating double network structure, which comprises: a brittle pure gel conductive hydrogel; and a stretchable hydrogel, wherein the stretchable hydrogel penetrates into the brittle pure gel conductive hydrogel to form the interpenetrating double network structure; wherein, a ferrocene derivative is fixed on the chains of the stretchable hydrogel by covalent bonds, and glucose oxidase is crosslinked with the stretchable hydrogel by a room temperature crosslinking agent.

[0010] According to an embodiment of the present invention, the hydrogel still maintains conductivity and redox properties after being stretched to 200% of its initial length.

[0011] According to an embodiment of the present invention, the brittle pure gel conductive hydrogel is poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS).

[0012] According to an embodiment of the present invention, the stretchable hydrogel is selected from polyacrylamide (PAAm), polyacrylic acid (PAAc) or gelatin methacrylate (GelMA).

[0013] According to an embodiment of the present invention, the room temperature crosslinking agent is polyethylene glycol diglycidyl ether (PEGDE).

[0014] According to an embodiment of the present invention, the ferrocene derivative comprises ferrocenium ion, ferrocene carboxylic acid, ferrocene methanol, ferrocene methyl trimethylamine, ferrocene boronic acid and ferrocene dimethylamine.

[0015] According to an embodiment of the present invention, the porosity of the brittle pure gel conductive hydrogel is 20% to 90%.

[0016] According to a second aspect of the present invention, there is provided a method for preparing a stretchable conductive hydrogel with redox activity. More specifically, the method comprises the following steps: forming a brittle pure gel conductive hydrogel with a porosity of 20% to 90%; penetrating the pure gel conductive hydrogel with a second stretchable hydrogel to form an interpenetrating double network hydrogel; fixing a ferrocene derivative on the chains of the second stretchable hydrogel in the interpenetrating double network hydrogel by covalent bonds; and crosslinking glucose oxidase with the second stretchable hydrogel using a room temperature crosslinking agent to obtain a stretchable conductive hydrogel with redox activity.

[0017] According to an embodiment of the present invention, the brittle pure gel conductive hydrogel is poly(3,4-ethylenedioxythiophene) polystyrene sulfonate.

[0018] According to an embodiment of the present invention, the second stretchable hydrogel is selected from polyacrylamide, polyacrylic acid, or methacryloyl gelatin.

[0019] According to an embodiment of the present invention, the room temperature crosslinking agent is polyethylene glycol diglycidyl ether

[0020] According to an embodiment of the present invention, the ferrocene derivatives include ferrocenium cation, ferrocene carboxylic acid, ferrocene methanol, ferrocene methyl trimethylamine, ferrocene boronic acid, and ferrocene dimethylamine.

[0021] According to a third aspect of the present invention, a non-invasive continuous blood glucose monitoring device is provided for continuously measuring the glucose concentration in an analyte and outputting a data stream related to the glucose concentration. Wherein, the continuous blood glucose monitoring device includes: A stretchable conductive film with redox activity, the film includes: An interpenetrating double network structure, which includes: A brittle pure gel conductive hydrogel; and A stretchable hydrogel, wherein the stretchable hydrogel penetrates into the brittle pure gel conductive hydrogel to form the interpenetrating double network structure; wherein, the ferrocene derivative is fixed on the chain of the stretchable hydrogel by a covalent bond, and glucose oxidase is crosslinked with the stretchable hydrogel by a room temperature crosslinking agent; and A current sensor to detect the current generated on the film due to the electrochemical oxidation reaction of hydrogen peroxide (H2O2).

[0022] According to an embodiment of the present invention, the device further includes at least one processor to process the data stream from the non-invasive continuous blood glucose monitoring device.

[0023] According to an embodiment of the present invention, it further includes a user interface to display the measured glucose concentration value.

[0024] According to an embodiment of the present invention, the user interface can be integrated into an application program of a smart phone.

[0025] According to an embodiment of the present invention, the device further includes an alarm device to remind the user when a hyperglycemic event or a hypoglycemic event is about to occur.

[0026] According to an embodiment of the present invention, the device further includes a cloud system to save the data stream and user preference settings.

[0027] According to an embodiment of the present invention, the device further includes a wireless communication module to transmit glucose concentration data to an external device. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Embodiments of the present invention will be described in more detail below with reference to the accompanying drawings, in which:

[0029] Figure 1 Schematic diagram showing a stretchable conductive hydrogel with redox activity according to an embodiment of the present invention;

[0030] Figure 2 Steps for preparing a stretchable conductive hydrogel with redox activity according to an embodiment of the present invention;

[0031] Figures 3A - 3C Properties of a stretchable conductive hydrogel with redox activity according to an embodiment of the present invention, where Figure 3A Redox properties of the hydrogel are shown, Figure 3B showing its conductivity change under 0% to 200% cyclic strain, Figure 3C showing the glucose sensitivity of the hydrogel, and Figure 3D showing the durability of the hydrogel; and

[0032] Figures 4A - 4C Related applications of a stretchable conductive hydrogel with redox activity according to an embodiment of the present invention, where Figure 4A is a schematic diagram of assembling an electrode and the device, Figure 4B and Figure 4C showing the application of the hydrogel in a skin-adhering soft glucose biosensor. DETAILED DESCRIPTION

[0033] In the following description, devices, materials, and / or preparation methods are listed as preferred embodiments. It will be apparent to those skilled in the art that modifications, including additions and / or substitutions, can be made without departing from the scope and spirit of the present invention. In the following text, specific details may be omitted to avoid obscuring the present invention; however, this document is written to enable those skilled in the art to practice the technical content disclosed herein without undue experimentation.

[0034] As used herein, the term "continuous", in the technical field of analyte detection, is a broad term that includes, but is not limited to, continuous, ongoing, or intermittent (e.g., periodic) monitoring of analyte concentration, such as measurements taken every 1 to 10 minutes.

[0035] As used herein, the term "electroactive surface" is a broad term that includes, but is not limited to, an electrode surface on which an electrochemical reaction occurs. For example, in a working electrode, the analyte being detected undergoes an enzyme-catalyzed reaction to produce hydrogen peroxide, which in turn generates a measurable current; in glucose detection, glucose oxidase produces hydrogen peroxide as a byproduct, and the hydrogen peroxide reacts with the surface of the working electrode to generate two protons (2H + ), two electrons (2e - ), and an oxygen molecule (O2), thereby generating the detected current. At the counter electrode, reducible substances such as oxygen are reduced on the electrode surface to balance the current generated by the working electrode.

[0036] As used herein, the term "analyte" is a broad term that includes, but is not limited to, substances or chemical components in biological fluids (e.g., blood, interstitial fluid, cerebrospinal fluid, lymph, urine, sweat, saliva, etc.). Analytes can include naturally occurring substances, synthetic substances, metabolites, or reaction products. In certain embodiments, the analyte measured in the sensing region, device, and method is glucose.

[0037] As used herein, the term "pure gel" refers to a hydrogel composed of a single continuous gel phase, characterized by a uniform and stable network structure. Compared with an unstable biphasic hydrogel system, the pure gel maintains consistent uniformity within and does not separate into distinct aqueous and gel phases, thus ensuring the stability of its mechanical and physical properties, making the pure gel particularly suitable for related applications that require reliability and predictable performance, such as biomedical devices, tissue engineering, and drug delivery systems.

[0038] According to a first aspect of the present invention, there is provided a stretchable conductive hydrogel having redox activity. The hydrogel is characterized in that it has a special interpenetrating double network structure, which is obtained by combining a brittle pure gel conductive hydrogel with a stretchable hydrogel. The stretchable hydrogel penetrates into the brittle pure gel conductive hydrogel to form a uniform interpenetrating double network, and simultaneously combines and retains the advantageous properties of both components. The construction of this interpenetrating three-dimensional microstructure is important for achieving efficient electron transfer between enzyme sites and conductive polymers (either directly or through a redox mediator).

[0039] In this hydrogel, a ferrocene derivative is immobilized on the chains of the stretchable hydrogel by covalent bonds, and glucose oxidase is incorporated into the hydrogel matrix by a room-temperature crosslinking agent. The crosslinking of glucose oxidase ensures the functionality of the hydrogel in redox reactions for applications such as glucose monitoring.

[0040] The brittle pure gel conductive hydrogel network is a key component in the interpenetrating structure that provides the necessary conductivity while maintaining network integrity, and can be selected from materials such as poly(3,4-ethylenedioxythiophene) polystyrene sulfonate. Further, the network is penetrated with a stretchable hydrogel, which can be selected from materials such as polyacrylamide, polyacrylic acid, or methacrylated gelatin, and these materials have excellent stretchability and mechanical properties, enabling the hydrogel to withstand significant deformation without losing its function.

[0041] The room-temperature crosslinking agent used in crosslinking includes polyethylene glycol diglycidyl ether, which can ensure crosslinking under mild conditions to maintain the activity of the enzyme and the structural integrity of the hydrogel.

[0042] The ferrocene derivatives incorporated into the hydrogel include ferrocenium ion, ferrocene carboxylic acid, ferrocene methanol, trimethylammonium ferrocenylmethyl, ferrocene boronic acid, and ferrocene dimethylamine. These derivatives have redox activity and compatibility with the hydrogel matrix, which can enhance the overall performance of the hydrogel in electrochemical applications.

[0043] In addition, the brittle pure gel conductive hydrogel network has a porosity of about 20 - 90% to optimize the permeability of the stretchable hydrogel and the overall performance of the composite material. During the hydrogel synthesis process, the porosity is precisely controlled to ensure the desired mechanical and electrical properties.

[0044] The composition and its components of the redox-active stretchable conductive hydrogel are outlined above. By integrating ferrocene derivatives and glucose oxidase in this hydrogel matrix, a multifunctional material is formed, which has considerable application potential in biosensing and wearable medical devices.

[0045] According to the second aspect of the present invention, a method for preparing a redox-active stretchable conductive hydrogel is introduced. Such hydrogels are particularly advantageous in applications that require flexibility, conductivity, and redox activity, such as in biosensors and wearable medical devices.

[0046] The preparation process starts with forming a pure gel conductive hydrogel. The porosity of this hydrogel is between 20% and 90% to optimize its performance and facilitate the subsequent penetration of the second hydrogel. The regulation of the porosity of the pure gel conductive hydrogel is quite important for forming a stable interpenetrating double-network structure, as it affects the penetration degree of the second stretchable hydrogel and the ease of binding to the conductive hydrogel.

[0047] After forming the pure gel conductive hydrogel, the penetration of the second stretchable hydrogel can then be carried out. The stretchable hydrogel will penetrate into the conductive hydrogel network to form an interpenetrating double network hydrogel, thereby combining the characteristics of the two hydrogels, namely, the conductivity of the brittle pure gel conductive hydrogel and the mechanical flexibility of the stretchable hydrogel.

[0048] Subsequently, ferrocene derivatives are immobilized on the second stretchable hydrogel chains within the interpenetrating double network structure through covalent bonds, which can ensure that the ferrocene derivatives are firmly attached to the hydrogel matrix. The ferrocene derivatives include compounds such as ferrocenium ions, ferrocene carboxylic acids, ferrocene methanol, trimethylammonium ferrocene methyl, ferrocene boronic acid, and ferrocene dimethylamine, etc., to provide redox activity.

[0049] The last step of the preparation method is to crosslink glucose oxidase with the stretchable hydrogel. This crosslinking process is carried out through a room temperature crosslinking agent (such as polyethylene glycol diglycidyl ether) to maintain the functional integrity of glucose oxidase and the structural stability of the hydrogel.

[0050] The pure gel brittle conductive hydrogel network used in this method can be selected from materials such as poly(3,4-ethylenedioxythiophene) polystyrene sulfonate, etc., which has excellent conductivity and structural rigidity. The second stretchable hydrogel can be selected from materials such as polyacrylamide, polyacrylic acid, or methacrylated gelatin, etc., which has excellent stretchability and is compatible with the conductive hydrogel.

[0051] Through the above method, a stretchable conductive hydrogel with redox activity can be prepared. This hydrogel combines the unique characteristics of its components to form a flexible conductive material and has redox activity that is quite important in a variety of applications. The hydrogel prepared by this method can still have stability, durability, and function retention under mechanical stress, so it is quite suitable for the next generation of biosensing technologies and other medical devices.

[0052] Accordingly, according to the third aspect of the present invention, a non-invasive continuous blood glucose monitoring device is provided to continuously measure the glucose concentration in the analyte and output a data stream related to the glucose concentration. This device has characteristics such as non-invasiveness, reliability, and comfort, and is particularly suitable for users (such as diabetic patients) who need to regularly monitor their blood glucose levels, and can be used as an alternative to traditional blood glucose monitoring methods.

[0053] A key feature of the device is that it includes a stretchable conductive film with redox activity, which can improve the functionality and user comfort of the overall device. The film contains an interpenetrating double-network structure, which includes a brittle pure-gel conductive hydrogel and a stretchable hydrogel. The brittle pure-gel conductive hydrogel network can be selected from poly(3,4-ethylenedioxythiophene) polystyrene sulfonate to provide the necessary conductivity, and the stretchable hydrogel is selected from materials such as polyacrylamide, polyacrylic acid, or methacrylated gelatin, which can penetrate into the brittle pure-gel conductive hydrogel to form a tight interpenetrating double-network structure. This double-network structure enables the film to remain flexible and durable under mechanical stress, maintaining its integrity and functionality.

[0054] In addition, ferrocene derivatives are covalently fixed to the chains of the stretchable hydrogel in the film, providing the redox activity required for electrochemical detection of glucose. The ferrocene derivatives include compounds such as ferrocenium ion, ferrocene carboxylic acid, ferrocene methanol, trimethylammonium ferrocenylmethyl, ferrocene boronic acid, and ferrocene dimethylamine. And a room-temperature crosslinking agent (such as polyethylene glycol diglycidyl ether) is used to crosslink glucose oxidase with the stretchable hydrogel to ensure that glucose oxidase remains functional and is firmly fixed to the film.

[0055] The device also includes a current sensor to detect the current generated on the film due to the electrochemical oxidation of hydrogen peroxide. Notably, the film can be used independently as a working electrode without an additional electrode because of its inherent electronic conductivity. The detected current intensity is related to the glucose concentration in the body, so it can provide continuous blood glucose level measurement.

[0056] The device also includes a processor to process the data stream generated from the blood glucose concentration measurement. The processed data can be displayed through a user interface, which can be integrated into a smartphone application to provide more convenient blood glucose level monitoring for users. The device also includes an alarm device to alert the user of impending hyperglycemic or hypoglycemic events to ensure timely intervention.

[0057] In addition, the device can be further equipped with a cloud system to store the data stream and user preference settings, provide backup and facilitate long-term monitoring and analysis. The device also includes a wireless communication module to transmit the blood glucose concentration data to external devices, such as smartphones or the systems of healthcare providers, which enhances the connectivity and usability of the device.

[0058] This non-invasive continuous blood glucose monitoring device represents an important breakthrough in the field of blood glucose monitoring, combining flexibility, durability, and advanced connectivity features to provide a more comprehensive solution for continuous blood glucose measurement.

[0059] Examples

[0060] Example 1: Preparation of a Stretchable Conductive Hydrogel with Redox Activity

[0061] A stretchable film is prepared by combining a conductive polymer poly(3,4-ethylenedioxythiophene) polystyrene sulfonate hydrogel with a stretchable redox hydrogel, and a redox enzyme is introduced by covalent bonding. Finally, a stretchable conductive hydrogel with redox reactivity can be obtained. As Figure 1 shown, the brittle pure gel conductive hydrogel 101 and the stretchable hydrogel 102 are infiltrated and combined to obtain a hydrogel 10 with a unique interpenetrating double network structure; in the hydrogel 10, a ferrocene derivative 103 is fixed on the chain of the stretchable hydrogel 102 by covalent bonding, and glucose oxidase 104 and the hydrogel 10 are crosslinked with a room temperature crosslinking agent to enhance the functionality of the hydrogel in the redox reaction.

[0062] This three-dimensional interpenetrating structure can minimize the distance between the enzyme active site (i.e., flavin adenine dinucleotide (FAD)) and the conductive polymer (i.e., the electrode) through the conductive network of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate, while enhancing direct electron transfer and mediated electron transfer.

[0063] The steps for preparing the above-mentioned stretchable conductive hydrogel with redox activity are as Figure 2 shown, including steps 201-204.

[0064] As shown in step 201, the first step in the preparation of the hydrogel is the synthesis of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate hydrogel. Briefly, the aqueous dispersion of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PH 1000, about 1.1 wt% by weight) is freeze-dried and redispersed, and other additives are added to increase the ionic strength of the solution to form a high-concentration (>3 wt%) suspension. It should be noted that when small molecules such as dodecylbenzenesulfonic acid (DBSA) are used to increase the ionic strength of the solution, gel formation will be induced. Increasing the solid concentration from 1.1 wt% by weight to 3 wt% by weight helps the formation of pure gel to avoid the appearance of an unstable two-phase hydrogel system. The freeze-drying process can significantly increase the porosity of the conductive network, which is beneficial to the subsequent interpenetration and infiltration of the second stretchable hydrogel network. When the storage modulus (G’) of the mixture exceeds the loss modulus (G”), it represents the completion of the preparation of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate hydrogel.

[0065] In step 202, to achieve mechanical stretchability, a brittle pure gel conductive hydrogel is infiltrated and combined with a second stretchable hydrogel network (such as polyacrylamide, polyacrylic acid, or methacrylated gelatin) to construct a double-network structure. Through infiltration and stirring, the second hydrogel network forms an interpenetrating secondary network structure with the poly(3,4-ethylenedioxythiophene) polystyrene sulfonate hydrogel, strengthening the overall mechanical properties.

[0066] In step 203, ferrocene derivatives are immobilized on the chains of the stretchable hydrogel network, thereby introducing redox functionality into the hydrogel. For example, in a polyacrylamide hydrogel, ferrocene derivatives with vinyl (C=C) groups can form covalent bonds with acrylamide monomers during the polymerization process.

[0067] In the subsequent step 204, glucose oxidase is covalently bonded to the chains of the stretchable hydrogel network through a room-temperature crosslinking agent (such as polyethylene glycol diglycidyl ether), where the use of the room-temperature crosslinking agent is to maintain the activity of the enzyme. Finally, the synthesized stretchable enzyme film is washed in a large amount of distilled water for at least 3 days for purification until the sample is balanced.

[0068] It should be noted that a dense hydrogel network can promote electron transfer between mediators, enzymes, and conductive polymer chains. For example, interpenetrating with polyacrylic acid or calcium alginate hydrogels can further enhance the performance of the poly(3,4-ethylenedioxythiophene) polystyrene sulfonate hydrogel. Among them, polyacrylic acid contains carboxyl groups (COOH), which can be connected to the amino group (NH2) of the enzyme through COOH-NH2 bonds.

[0069] In addition, stretchable hydrogels with enzymatic activity can be prepared in different orders. For example, a stretchable hydrogel with an enzyme is used as the first network, and then 3,4-ethylenedioxythiophene (EDOT) monomers are further polymerized on it. This method can provide better mechanical stretchability while maintaining the function of the enzyme.

[0070] Example 2. Properties of the stretchable conductive hydrogel with redox activity

[0071] The stretchable hydrogel has conductivity, ionic conductivity, high porosity, redox characteristics, and the ability to sense glucose. Even when stretched to 200% of its initial length, the hydrogel can still maintain its conductivity and redox characteristics, and after covalent bonding with glucose oxidase, the catalytic activity of the hydrogel is also enhanced. Due to its inherent electronic conductivity, the hydrogel enzyme film can independently serve as a working electrode in an electrochemical system without the need for an additional electrode.

[0072] As Figure 3AAs shown, after fixing the ferrocene derivative on the hydrogel, the hydrogel acquires redox properties and strain resistance. Further, the change in its conductivity was observed under cyclic strain between 0% and 200% to detect the electromechanical properties of the hydrogel. The results are as Figure 3B shown, indicating that even after severe stretching, the hydrogel still has high durability.

[0073] And as Figure 3C shown, the hydrogel has a glucose-sensitive effect after crosslinking with glucose oxidase. See Figure 3D , due to the covalent bond between the enzyme and the hydrogel, even after the hydrogel enzyme membrane is rinsed with water for one week, it still has a linear sensitivity to glucose concentrations from 10 -6 M to 10 -2 M.

[0074] Example 3. Related Applications of Stretchable Conductive Hydrogels with Redox Activity

[0075] The hydrogel prepared by the present invention can be used to prepare related devices by a simple "cut-and-paste" patterning method, which is easier to operate than traditional solution-based patterning techniques and is more suitable for large-scale production. Figure 4A shows a schematic diagram of tape-like "cut-and-paste" patterning. First, a self-supporting hydrogel film is prepared. Then, the hydrogel film is delaminated and processed into a tape-like shape. Subsequently, it can be cut into any shape using a razor, scissors, or puncher and attached to a substrate of any shape (such as a flat or curved surface). Due to its mechanical stretchability and stability, the hydrogel film tape will not crack during the above cutting and transfer processes.

[0076] In addition, through a large number of dynamic bonds in the hydrogel composite itself or by introducing additional dynamic bonds, the hydrogel film has adhesiveness. For example, during the polymerization of the second network, the main chain can be modified by introducing N-hydroxysuccinimide (NHS). NHS can react with the main amino group (-NH2) of the hydrogel through the NHS-NH2 bond, thereby increasing the high adhesiveness between the hydrogel and human skin and enhancing its sensing ability on the skin. At the same time, the stretchable hydrogel enzyme membrane can be laminated on a glass or plastic substrate to assemble a new type of touch glucose sensor. Compared with the current enzyme membrane preparation methods, the cut-and-paste method proposed by the present invention can significantly simplify the preparation process, improve the commercial potential of large-scale production, and reduce the differences between devices.

[0077] In addition, the hydrogel of the present invention is quite suitable for wearable biosensing device applications. In recent years, stretchable and elastic in-vivo integrated biosensors have received much attention in non-invasive continuous glucose monitoring, and the hydrogel enzyme film provided by the present invention has stretchability and simplicity of patterning, which is very suitable for the development of emerging stretchable and tissue-adaptive medical wearable devices. Related examples such as Figure 4B and Figure 4C shown can be applied to touch-based glucose sensors, sweat sensing patches, and wound monitoring bandages.

[0078] The foregoing description is provided to illustrate and describe the present invention and is not intended to be exhaustive or to limit the present invention to the precise form disclosed. Many modifications and variations will be obvious to those skilled in the art.

[0079] The above embodiments are selected and described to best explain the principles of the present invention and its practical applications, so that other technicians in the art can understand the various embodiments of the present invention and the various modifications suitable for the intended specific purposes.

Claims

1. A redox-active stretchable conductive hydrogel, characterized in that: include: An interpenetrating double network structure comprising: brittle pure gel conductive hydrogels; and A stretchable hydrogel, wherein the stretchable hydrogel penetrates into the brittle pure gel conductive hydrogel to form the interpenetrating double network structure; The ferrocene derivative is fixed on the chain of the stretchable hydrogel through a covalent bond, and the glucose oxidase and the stretchable hydrogel are cross-linked with a room temperature cross-linking agent.

2. The hydrogel of claim 1, wherein the hydrogel retains electrical conductivity and redox properties after being stretched to 200% of its original length.

3. The hydrogel of claim 1, wherein the brittle pure gel conductive hydrogel is poly(3,4-ethylenedioxythiophene) polystyrene sulfonate.

4. The hydrogel of claim 1, wherein the stretchable hydrogel is selected from polyacrylamide, polyacrylic acid or methacryloyl gelatin.

5. The hydrogel of claim 1, wherein the room temperature cross-linking agent is polyethylene glycol diglycidyl ether.

6. The hydrogel of claim 1, wherein the ferrocene derivative comprises ferrocenium cation, ferrocenyl carboxylic acid, ferrocenyl methanol, ferrocenyl methyl trimethyl amino, ferrocenyl boric acid and ferrocenyl dimethyl amine.

7. The hydrogel of claim 1, wherein the brittle pure gel conductive hydrogel has a porosity of 20% to 90%.

8. A method for preparing a redox-active stretchable conductive hydrogel, characterized in that: include: Formation of brittle pure gel conductive hydrogels with porosity ranging from 20% to 90%; Infiltrating the pure gel conductive hydrogel with a second stretchable hydrogel to form an interpenetrating double network hydrogel; Fixing a ferrocene derivative on the second stretchable hydrogel chain in the interpenetrating double network hydrogel via a covalent bond; and Glucose oxidase and the second stretchable hydrogel are cross-linked using a room temperature cross-linking agent to obtain a stretchable conductive hydrogel with redox activity.

9. The method of claim 8, wherein the brittle pure gel conductive hydrogel is poly(3,4-ethylenedioxythiophene) polystyrene sulfonate.

10. The method of claim 8, wherein the stretchable hydrogel is selected from polyacrylamide, polyacrylic acid or methacryloyl gelatin.

11. The method of claim 8, wherein the room temperature cross-linking agent is polyethylene glycol diglycidyl ether.

12. The method of claim 8, wherein the ferrocene derivative comprises ferrocenium cation, ferrocenyl carboxylic acid, ferrocenyl methanol, ferrocenyl methyl trimethyl amino, ferrocenyl boric acid and ferrocenyl dimethyl amine.

13. A non-invasive continuous blood glucose monitoring device for continuously measuring the glucose concentration in an analyte and outputting a data stream related to the glucose concentration, characterized in that: include: A redox-active stretchable conductive film comprising: Interpenetrating double network structure, including: brittle pure gel conductive hydrogels; and A stretchable hydrogel, wherein the stretchable hydrogel penetrates into the brittle pure gel conductive hydrogel to form the interpenetrating double network structure; wherein the ferrocene derivative is fixed to the chain of the stretchable hydrogel by covalent bonds, and the glucose oxidase is cross-linked to the stretchable hydrogel by a room temperature cross-linking agent; and A current sensor is used to detect the current generated by the electrochemical oxidation reaction of hydrogen peroxide on the membrane.

14. The device of claim 13, wherein the device further comprises at least one processor to process the data stream from the non-invasive continuous glucose monitoring device.

15. The device of claim 13, wherein the device further comprises a user interface to display the measured glucose concentration value.

16. The apparatus of claim 15, wherein the user interface is integratable into an application program of a smartphone.

17. The device of claim 13, wherein the device further comprises an alarm device to alert a user when a hyperglycemic event or a hypoglycemic event is about to occur.

18. The apparatus of claim 13, wherein the apparatus further comprises a cloud system to save data streams and user preference settings.

19. The apparatus of claim 13, wherein the apparatus further comprises a wireless communication module to transmit the glucose concentration data to an external device.

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