Patch-type wearable metabolite detection device

Abstract

The present invention discloses a patch-type wearable metabolite detection device, including a sampling module and a detection module, the sampling module includes an overlapping biological interface layer and a sample collection layer, the biological interface layer is provided with a capillary drainage area, a sample detection area and an outlet area, the sample collection layer is provided with a sample storage area, the capillary drainage area is communicated with the sample storage area, the capillary drainage area also extends to the sample detection area, the capillary drainage area is used to quickly drain the sample to be tested collected in the sample storage area into the sample detection area, the sample detection area is used for the sample to be tested to undergo an oxidation-reduction reaction under the action of an electrode to detect biological molecules in the sample to be tested, and the outlet area is connected to the sample detection area; the detection module includes a conductive substrate and an electrode interface layer, the conductive substrate is connected in the sample detection area, and the electrode interface layer is connected to the conductive substrate. The present invention can stably, sensitively, quickly, and long-term dynamically detect and integrate multiple biological molecules.

Description

Technical Field

[0001] The present application relates to the field of detection and medical device technology, and in particular to a patch-type wearable metabolite detection device. Background Art

[0002] Metabolic diseases, as chronic diseases, have a great impact on residents' health and quality of life, and have also caused a huge medical burden on residents. Dynamic monitoring of metabolites with the help of wearable sensors can not only provide patients with more comprehensive and real-time health information, but also help to timely regulate and manage metabolite levels. It also provides convenience for patients to self-examine at home and shares the demand for medical services.

[0003] With the continuous advancement of biosensing technology and flexible electronic technology, research on wearable sensors has flourished, showing great advantages in the dynamic monitoring of human health parameters. At present, wearable sensors are attached to the wearer's skin, eye surface, oral mucosa and other epidermal tissues to achieve direct contact and sensitive detection of biological fluids such as sweat, tears, and saliva, perfectly integrating signal monitoring with the wearer's daily life, continuously and in real time reflecting the wearer's physiological indicators, and expanding the application of wearable sensors from heart rate and blood pressure monitoring, exercise steps, and calorie consumption recording to the field of medical care. However, although this type of wearable sensor is easy to wear, portable and smart, because the sensor electrode is in direct contact with the epidermis and lacks a packaging protective layer, it is easily affected by environmental factors, resulting in low stability of the sensor electrode, short working life, and difficulty in meeting the needs of accurate daily detection.

[0004] To solve the above problems, wearable sensor devices equipped with microfluidic sample collection modules are gradually being developed. After the wearable biosensor is matched with a sampling module containing a liquid storage chamber, it can protect the sensing electrode from damage by external stimuli while ensuring the continuous input of the sample to be tested; in addition, the wearable biosensor matched with a packaging module for direct sampling and detection can minimize the lag between the actual sample and the test sample, and complete the collection and replacement of the sample to be tested in a very short time. However, the above types of wearable sensor devices are difficult to balance sampling efficiency, sample replacement time, detection sensitivity and detection cost, and it is difficult to avoid the mixing and cross-contamination of the continuously secreted samples to be tested during the collection process. There are still certain technical barriers to building a sensitive, stable, small, and continuously monitored in vivo real-time detection and analysis system. Summary of the invention

[0005] Based on this, it is necessary to provide a patch-type wearable metabolite detection device to address the problems of poor stability, short working life, low efficiency of sample collection and replacement, and strong lag in dynamic monitoring of wearable sensor devices and wearable detection devices in traditional technologies. The patch-type wearable metabolite detection device of the present invention can realize stable, sensitive, rapid, and specific long-term dynamic detection of a variety of substances; the patch-type wearable metabolite detection device of the present invention can be flexibly integrated with specific sensing electrodes, miniaturized signal acquisition devices, wireless signal interaction systems and other equipment, and is widely used in real-time dynamic detection of a variety of metabolites in body fluids such as saliva, sweat, and tears. While realizing disease pre-diagnosis, it assists in building a medical big data platform and continuously advances toward the goal of "telemedicine and smart medicine".

[0006] An embodiment of the present application provides a patch-type wearable metabolite detection device.

[0007] A patch-type wearable metabolite detection device, comprising:

[0008] A sampling module, the sampling module comprising a biological interface layer for directly attaching to the epidermis and a sample collection layer for contacting a liquid environment, the biological interface layer being overlapped and connected to the sample collection layer, the biological interface layer being provided with a capillary drainage area, a sample detection area and an outlet area, the sample collection layer being provided with a sample storage area, the capillary drainage area being communicated with the sample storage area, the capillary drainage area also extending to the sample detection area, the capillary drainage area being used for quickly draining a sample to be tested collected in the sample storage area into the sample detection area, the sample detection area being used for the sample to be tested to undergo an oxidation-reduction reaction under the action of electrodes to detect biological molecules in the sample to be tested, and the outlet area being communicated with the sample detection area; and

[0009] The detection module comprises a conductive substrate and an electrode interface layer, wherein the conductive substrate is connected within the sample detection area, the electrode interface layer is connected to the conductive substrate, and the electrode interface layer is used to specifically identify and capture biological molecules in the sample to be detected.

[0010] In some embodiments, the number of the sample storage areas is multiple;

[0011] And / or, the sample storage area is curved to have an arc-shaped structure;

[0012] And / or, the outer arc edge of the sample storage area is composed of a 20°-45° arc segment with a diameter of 8.4-42 mm, the inner arc edge of the sample storage area is composed of a 20°-45° arc segment with a diameter of 7.2-36 mm, and the distance between the outer arc edge and the inner arc edge of the sample storage area is 1.2-6.4 mm;

[0013] And / or, the sample storage area has a depth of 0.2-10 mm.

[0014] In some embodiments, there are multiple capillary drainage areas, and the multiple capillary drainage areas are distributed outside the sample detection area.

[0015] In some embodiments, the capillary drainage area includes a drainage inlet and a drainage channel, the drainage inlet is connected to the sample storage area, one end of the drainage channel is connected to the drainage inlet and the other end extends to the sample detection area.

[0016] In some embodiments, the drainage inlet is a cylindrical groove, the radial cross-sectional diameter of the drainage inlet is 0.8-4 mm, and the height of the drainage inlet is 0.05-0.5 mm;

[0017] And / or, the drainage channel is a long strip-shaped groove, the width of the drainage channel is 0.2-1 mm, and the length of the drainage channel is 5-20 mm.

[0018] In some embodiments, the sample detection zone is a cylindrical groove, the inner diameter of the sample detection zone is 4.8-24 mm, and the height of the sample detection zone is 0.05-0.5 mm.

[0019] In some embodiments, the flow channel length of the outlet zone is 1.6-8 mm, the flow channel width of the outlet zone is 0.4-2 mm, and the outlet zone extends from the sample detection zone to the edge of the biological interface layer.

[0020] In some embodiments, the biological interface layer and / or the sample collection layer are made of flexible materials through a molding process, and the material of the biological interface layer and / or the sample collection layer is selected from one or more of polydimethylsiloxane (PDMS), polyethylene terephthalate (PET), polyurethane (TPU), polyimide (PI), cross-linked dextran, silica gel and agarose gel.

[0021] In some of the embodiments, the mold used in the preparation of the biological interface layer and / or the sample collection layer is made by machining, 3D printing, photolithography or laser engraving, and the mold material is selected from one or more of polystyrene (PS), cellulose, polyacrylamide (PAM), polyethylene (PE), polypropylene (PP), glass, and silicon wafer.

[0022] In some of the embodiments, the surface of the biological interface layer and / or the sample collection layer is subjected to surface modification treatment, and the surface modification treatment method includes one or more of oxygen plasma cleaning, ultraviolet light grafting and block polymer modification.

[0023] In some of the embodiments, the conductive substrate is made of conductive materials, and the conductive materials include one or more of metal materials, conductive non-metallic materials and two-dimensional conductive nanomaterials.

[0024] In some embodiments, the conductive material includes one or more of gold, silver, platinum, nickel and titanium;

[0025] And / or, the conductive non-metallic material includes one or more of carbon paste, carbon fiber and polyethylene dioxythiophene;

[0026] And / or, the two-dimensional conductive nanomaterial includes one or more of graphene, carbon nanotubes and metal nanoparticles.

[0027] In some embodiments, the conductive substrate is fixed in the sample detection area by one or more of screen printing, sputtering, transfer printing, and physical deposition;

[0028] In some embodiments, the conductive substrate is fixed to the surface of a flexible material and attached to the sample detection area, and the flexible material includes one or more of polyethylene terephthalate (PET), polyurethane (TPU) and polyimide (PI).

[0029] In some of the embodiments, the electrode interface layer is modified with biological enzyme molecules and / or inorganic bionic enzyme materials, the biological enzyme molecules include one or more of glucose oxidase, lactate oxidase and uricase, and the inorganic bionic enzyme materials include one or more of copper, cobalt metal organic framework materials (MOF), Fe3O4, and cyanocobalamin.

[0030] In some embodiments, the electrode interface layer is a three-dimensional porous structure, a planar mesh structure or a three-dimensional skeleton structure, wherein the three-dimensional porous structure includes one or more of foam carbon, foam gold, foam nickel, and foam nickel, the planar mesh structure includes one or more of carbon fiber cloth, carbon fiber paper, and carbon fiber yarn, and the three-dimensional skeleton structure includes a non-conductive protein skeleton, polymer skeleton or porous ceramic modified by two-dimensional conductive nanomaterials.

[0031] In some of the embodiments, when the electrode interface layer is used to specifically identify and capture biological molecules in the sample to be tested, an electrochemical detection method is used to collect electron transfer signals during the oxidation-reduction process of the biological molecules, wherein the electrochemical detection method includes one or more of steady-state current method (it), differential pulse voltammetry (DPV), square wave voltammetry (SWV), cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), linear sweep voltammetry (LSV), alternating current voltammetry (ACV) and anodic stripping voltammetry (ASV).

[0032] The patch-type wearable metabolite detection device of the present invention has high integration, high sensitivity, small size, and continuous detection, and can detect and analyze the dynamic change trend of metabolite levels, which is of great significance for assisting the diagnosis, treatment and prognosis of diseases. Compared with existing detection devices, the patch-type wearable metabolite detection device of the present invention has higher stability, longer working life, shorter detection time, and smaller detection lag, which meets the integration requirements of wearable detection devices; at the same time, the patch-type wearable metabolite detection device of the present invention is flexible, lightweight, and comfortable to wear. The base material can be selected from biocompatible flexible materials, which greatly reduces the foreign body sensation and allergy risk when the user wears it, laying a foundation for the user's long-term wearing and use.

[0033] The patch-type wearable metabolite detection device of the present invention realizes the organic unity of flexible electronic technology, microfluidic technology, and electrochemical sensing technology; wherein, the acquisition module is based on the capillary principle, and realizes the active drainage of the sample to be tested from the storage chamber to the detection chamber by means of the surface tension of the liquid and the force balance between the phase interfaces, thereby ensuring the rapid sampling and real-time replacement of the sample to be tested, and providing a guarantee for the long-term dynamic monitoring of the sample; the acquisition module is based on the electrochemical three-electrode system, and captures a variety of biological molecules in the sample to be tested by means of a specially modified sensing interface, and triggers the redox reaction of the biological molecules in the sample to be tested by means of a specially designed sensing electrode, and collects the steady-state signal of the redox electron transfer through the small signal acquisition device of the detection module, so as to realize the long-term dynamic detection of a variety of metabolites quickly, sensitively, and accurately, thereby constructing an easy-to-integrate and widely used patch-type wearable detection device. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present application, and those skilled in the art can obtain other drawings based on these drawings without creative work.

[0035] In order to more completely understand the present application and its beneficial effects, the following description will be given in conjunction with the accompanying drawings. In the following description, the same reference numerals represent the same parts.

[0036] Figure 1 This is a schematic diagram of the structure of a collection module of a patch-type wearable metabolite detection device according to an embodiment of the present invention;

[0037] Figure 2 This is a schematic diagram of a sample collection layer of a collection module of a patch-type wearable metabolite detection device according to an embodiment of the present invention;

[0038] Figure 3 A schematic diagram of a biological interface layer of a collection module of a patch-type wearable metabolite detection device according to an embodiment of the present invention;

[0039] Figure 4 This is a physical picture of the acquisition module of the patch-type wearable metabolite detection device according to one embodiment of the present invention;

[0040] Figure 5 This is a diagram for verifying the drainage and replacement functions of the collection module of the patch-type wearable metabolite detection device according to one embodiment of the present invention;

[0041] Figure 6 This is a physical picture of the patch-type wearable metabolite detection device before and after integration according to an embodiment of the present invention;

[0042] Figure 7 The patch-type wearable metabolite detection device according to one embodiment of the present invention is used for glucose concentration detection results, Figure 7 In the figure, the horizontal axis is time and the vertical axis is the steady-state current value.

[0043] Description of Reference Numerals

[0044] 1. Sample collection layer; 11. Sample storage area; 2. Biological interface layer; 21. Capillary drainage area; 211. Drainage inlet area; 212. Drainage channel; 22. Sample detection area; 23. Exit area. DETAILED DESCRIPTION

[0045] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below in conjunction with the accompanying drawings. In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed below.

[0046] In the description of the present invention, it should be understood that the terms "center", "longitudinal", "lateral", "length", "width", "thickness", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside", "clockwise", "counterclockwise", "axial", "radial", "circumferential" and the like indicate orientations or positional relationships based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the referred device or element must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be understood as limiting the present invention.

[0047] In the present invention, unless otherwise clearly specified and limited, the terms "installed", "connected", "connected", "fixed" and the like should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium, it can be the internal connection of two elements or the interaction relationship between two elements, unless otherwise clearly defined. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0048] In the present invention, unless otherwise clearly specified and limited, a first feature being "above" or "below" a second feature may mean that the first and second features are in direct contact, or the first and second features are in indirect contact through an intermediate medium. Moreover, a first feature being "above", "above" or "above" a second feature may mean that the first feature is directly above or obliquely above the second feature, or simply means that the first feature is higher in level than the second feature. A first feature being "below", "below" or "below" a second feature may mean that the first feature is directly below or obliquely below the second feature, or simply means that the first feature is lower in level than the second feature.

[0049] In the description of the present invention, "several" means more than one, "many" means more than two, "greater than", "less than", "exceed", etc. are understood to exclude the number itself, and "above", "below", "within", etc. are understood to include the number itself. If there is a description of "first" or "second", it is only used for the purpose of distinguishing the technical features, and cannot be understood as indicating or implying the relative importance or implicitly indicating the number of the indicated technical features or implicitly indicating the order of the indicated technical features.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0051] The present application provides a patch-type wearable metabolite detection device to solve the problem that wearable sensor devices in traditional technologies are difficult to balance sampling efficiency, sample replacement time, detection sensitivity and detection cost, and it is difficult to avoid mixing and cross-contamination of continuously secreted samples during the collection process. There are still certain technical barriers to building a sensitive, stable, small, and continuous monitoring in vivo real-time detection and analysis system. The following will be combined with the accompanying drawings to illustrate the patch-type wearable metabolite detection device.

[0052] The patch-type wearable metabolite detection device provided in the embodiments of the present application is exemplary, please refer to Figure 1As shown, Figure 1 A schematic diagram of the structure of a patch-type wearable metabolite detection device provided in an embodiment of the present application. The patch-type wearable metabolite detection device of the present application can be used for heart rate, blood pressure monitoring, exercise steps, calorie consumption recording and other purposes. The patch-type wearable metabolite detection device of the present invention can be flexibly integrated with specific sensing electrodes, miniaturized signal acquisition devices, wireless signal interaction systems and other equipment, and is widely used in real-time dynamic detection of multiple metabolites in body fluids such as saliva, sweat, and tears, and has broad prospects for the construction of medical devices for disease prediagnosis and health monitoring.

[0053] In order to more clearly illustrate the structure of the patch-type wearable metabolite detection device, the patch-type wearable metabolite detection device will be introduced below in conjunction with the accompanying drawings.

[0054] For example, see Figure 1 As shown, Figure 1 A schematic diagram of the structure of a patch-type wearable metabolite detection device provided in an embodiment of the present application. A patch-type wearable metabolite detection device includes a sampling module and a detection module.

[0055] The sampling module includes a biological interface layer 2 for directly attaching to the epidermis and a sample collection layer 1 for contacting the liquid environment. The biological interface layer 2 overlaps and is connected to the sample collection layer 1. The biological interface layer 2 is provided with a capillary drainage area 21, a sample detection area 22 and an outlet area 23. The sample collection layer 1 is provided with a sample storage area 11. The capillary drainage area 21 is connected to the sample storage area 11, and the capillary drainage area 21 also extends to the sample detection area 22. The capillary drainage area 21 is used to quickly drain the sample to be tested collected in the sample storage area 11 into the sample detection area 22. The sample detection area 22 is used for the sample to be tested to undergo an oxidation-reduction reaction under the action of the electrode to detect the biological molecules in the sample to be tested. The outlet area 23 is connected to the sample detection area 22, and the outlet area 23 is used to discharge the sample that has completed the detection in the sample detection area 22, so as to realize the replacement of the sample to be tested in the sample detection area 22. The outlet area 23 can be composed of one or more inclined direct current channels.

[0056] The detection module includes a conductive substrate and an electrode interface layer. The conductive substrate is connected to the sample detection area 22, and the electrode interface layer is connected to the conductive substrate. The electrode interface layer is used to specifically identify and capture biological molecules in the sample to be detected.

[0057] The patch-type wearable metabolite detection device of the present invention has high integration, high sensitivity, small size, and continuous detection, and can detect and analyze the dynamic change trend of metabolite levels, which is of great significance for assisting the diagnosis, treatment and prognosis of diseases. Compared with existing detection devices, the patch-type wearable metabolite detection device of the present invention has higher stability, longer working life, shorter detection time, and smaller detection lag, which meets the integration requirements of wearable detection devices; at the same time, the patch-type wearable metabolite detection device of the present invention is flexible, lightweight, and comfortable to wear. The base material can be selected from biocompatible flexible materials, which greatly reduces the foreign body sensation and allergy risk when the user wears it, laying a foundation for the user's long-term wearing and use.

[0058] In some embodiments, there are multiple sample storage areas 11.

[0059] In some embodiments, the sample storage area 11 is curved to have an arc-shaped structure.

[0060] In some of the embodiments, the outer arc edge of the sample storage area 11 is composed of a 20°-45° arc segment with a diameter of 8.4-42 mm, the inner arc edge of the sample storage area 11 is composed of a 20°-45° arc segment with a diameter of 7.2-36 mm, and the distance between the outer arc edge and the inner arc edge of the sample storage area 11 is 1.2-6.4 mm.

[0061] In some embodiments, the depth of the sample storage area 11 is 0.2-10 mm.

[0062] In some embodiments, there are multiple capillary drainage regions 21 , and the multiple capillary drainage regions 21 are distributed outside the sample detection region 22 .

[0063] In some embodiments, the capillary drainage area 21 includes a drainage inlet and a drainage channel 212 . The drainage inlet communicates with the sample storage area 11 . One end of the drainage channel 212 communicates with the drainage inlet and the other end extends to the sample detection area 22 .

[0064] In some embodiments, the drainage inlet is a cylindrical groove, the radial cross-sectional diameter of the drainage inlet is 0.8-4 mm, and the height of the drainage inlet is 0.05-0.5 mm.

[0065] In some embodiments, the drainage channel 212 is a long strip-shaped groove, the width of the drainage channel 212 is 0.2-1 mm, and the length of the drainage channel 212 is 5-20 mm.

[0066] In some embodiments, the sample detection zone 22 is a cylindrical groove, the inner diameter of the sample detection zone 22 is 4.8-24 mm, and the height of the sample detection zone 22 is 0.05-0.5 mm.

[0067] In some embodiments, the length of the flow channel of the outlet region 23 is 1.6-8 mm, the width of the flow channel of the outlet region 23 is 0.4-2 mm, and the outlet region 23 extends from the sample detection region 22 to the edge of the biological interface layer 2 .

[0068] In some of the embodiments, the biological interface layer 2 and / or the sample collection layer 1 are made of flexible materials through a molding process, and the material of the biological interface layer 2 and / or the sample collection layer 1 is selected from one or more of polydimethylsiloxane (PDMS), polyethylene terephthalate (PET), polyurethane (TPU), polyimide (PI), cross-linked dextran, silica gel and agarose gel.

[0069] In some of the embodiments, the mold used in the preparation of the biological interface layer and / or the sample collection layer is made by machining, 3D printing, photolithography or laser engraving, and the mold material is selected from one or more of polystyrene (PS), cellulose, polyacrylamide (PAM), polyethylene (PE), polypropylene (PP), glass, and silicon wafer.

[0070] In some of the embodiments, the surface of the biological interface layer 2 and / or the sample collection layer 1 is subjected to surface modification treatment, and the surface modification treatment method includes one or more of oxygen plasma cleaning, ultraviolet light grafting and block polymer modification.

[0071] In some of the embodiments, the conductive substrate is made of conductive materials, and the conductive materials include one or more of metal materials, conductive non-metallic materials and two-dimensional conductive nanomaterials.

[0072] In some embodiments, the conductive material includes one or more of gold, silver, platinum, nickel and titanium.

[0073] In some embodiments, the conductive non-metallic material includes one or more of carbon paste, carbon fiber and polyethylene dioxythiophene.

[0074] In some embodiments, the two-dimensional conductive nanomaterial includes one or more of graphene, carbon nanotubes and metal nanoparticles.

[0075] In some of the embodiments, the conductive substrate is fixed in the sample detection area 22 by one or more of screen printing, sputtering, transfer printing, and physical deposition;

[0076] In some embodiments, the conductive substrate is fixed on the surface of a flexible material and attached to the sample detection area 22 . The flexible material includes one or more of polyethylene terephthalate (PET), polyurethane (TPU) and polyimide (PI).

[0077] In some of the embodiments, the electrode interface layer is modified with biological enzyme molecules and / or inorganic bionic enzyme materials, the biological enzyme molecules include one or more of glucose oxidase, lactate oxidase and uricase, and the inorganic bionic enzyme materials include one or more of copper, cobalt metal organic framework materials (MOF), Fe3O4, and cyanocobalamin.

[0078] In some of the embodiments, the electrode interface layer is a three-dimensional porous structure, a planar mesh structure or a three-dimensional skeleton structure, wherein the three-dimensional porous structure includes one or more of foam carbon, foam gold, foam nickel, and foam nickel, the planar mesh structure includes one or more of carbon fiber cloth, carbon fiber paper, and carbon fiber yarn, and the three-dimensional skeleton structure includes a non-conductive protein skeleton, polymer skeleton or porous ceramic modified by two-dimensional conductive nanomaterials.

[0079] In some of the embodiments, when the electrode interface layer is used to specifically identify and capture biological molecules in the sample to be tested, an electrochemical detection method is used to collect electron transfer signals during the oxidation-reduction process of the biological molecules, wherein the electrochemical detection method includes one or more of steady-state current method (it), differential pulse voltammetry (DPV), square wave voltammetry (SWV), cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), linear sweep voltammetry (LSV), alternating current voltammetry (ACV) and anodic stripping voltammetry (ASV).

[0080] The patch-type wearable metabolite detection device of the present invention realizes the organic unity of flexible electronic technology, microfluidic technology, and electrochemical sensing technology; wherein, the acquisition module is based on the capillary principle, and realizes the active drainage of the sample to be tested from the storage chamber to the detection chamber by means of the surface tension of the liquid and the force balance between the phase interfaces, thereby ensuring the rapid sampling and real-time replacement of the sample to be tested, and providing a guarantee for the long-term dynamic monitoring of the sample; the acquisition module is based on the electrochemical three-electrode system, and captures a variety of biological molecules in the sample to be tested by means of a specially modified sensing interface, and triggers the redox reaction of the biological molecules in the sample to be tested by means of a specially designed sensing electrode, and collects the steady-state signal of the redox electron transfer through the small signal acquisition device of the detection module, so as to realize the long-term dynamic detection of a variety of metabolites quickly, sensitively, and accurately, thereby constructing an easy-to-integrate and widely used patch-type wearable detection device.

[0081] Example 1

[0082] This embodiment provides a patch-type wearable metabolite detection device.

[0083] A patch-type wearable metabolite detection device comprises a sampling module and a detection module.

[0084] The sampling module includes a biological interface layer 2 for directly attaching to the epidermis and a sample collection layer 1 for contacting the liquid environment. The biological interface layer 2 is overlapped and connected to the sample collection layer 1. The biological interface layer 2 is provided with a capillary drainage area 21, a sample detection area 22 and an outlet area 23.

[0085] The sample collection layer 1 is provided with a sample storage area 11. There are two sample storage areas 11, which are relatively arranged at two sides of the sample collection layer 1 and are in a symmetrical state. The sample storage area 11 is curved to form an arc-shaped structure. Figure 2 As shown, the inner arc edges of the two sample storage areas 11 face inward. The outer arc edge of the sample storage area 11 is composed of a 38° arc segment with a diameter of 21 mm, and the inner arc edge of the sample storage area 11 is composed of a 38° arc segment with a diameter of 18 mm. The distance between the outer arc edge and the inner arc edge of the sample storage area 11 is 3 mm. The two ends of the inner arc edge and the outer arc edge are respectively connected and closed by an inclined line segment with a length of 3.2 mm. The depth of the sample storage area 11 is consistent with the thickness of the sample collection layer 1, and the depth of the sample storage area 11 is 2 mm.

[0086] The capillary drainage area 21 is connected to the sample storage area 11 and extends to the sample detection area 22. The capillary drainage area 21 is used to quickly drain the sample to be tested collected in the sample storage area 11 into the sample detection area 22. There are eight capillary drainage areas 21, see Figure 3 As shown, eight capillary drainage areas 21 are distributed outside the sample detection area 22. The capillary drainage area 21 includes a drainage inlet and a drainage channel 212. The drainage inlet is connected to the sample storage area 11. One end of the drainage channel 212 is connected to the drainage inlet and the other end extends to the sample detection area 22. The drainage inlet is a cylindrical groove, the radial cross-sectional diameter of the drainage inlet is 2mm, and the height of the drainage inlet is 0.2mm. The drainage channel 212 is a long strip groove, the width of the drainage channel 212 is 0.5mm, and the length of the drainage channel 212 is 10mm. The height of the drainage channel 212 is consistent with the height of the drainage inlet, which is 0.2mm in this embodiment.

[0087] The sample detection area 22 is used for the sample to be tested to undergo an oxidation-reduction reaction under the action of the electrode to detect the biomolecules in the sample to be tested, wherein the sample to be tested includes but is not limited to directly secreted sweat, saliva, tears and other body fluids. The sample detection area 22 is a cylindrical groove, the inner diameter of the sample detection area 22 is 12mm, and the height of the sample detection area 22 is consistent with the height of the drainage inlet, which is 0.2mm in this embodiment.

[0088] The outlet area 23 is connected to the sample detection area 22. The outlet area 23 is used to discharge the sample that has been tested in the sample detection area 22, so as to realize the replacement of the sample to be tested in the sample detection area 22. The outlet area 23 can be composed of one or more inclined straight flow channels. The flow channel length of the outlet area 23 is 4 mm, and the flow channel width of the outlet area 23 is 1 mm. The height of the outlet area 23 is consistent with the height of the drainage inlet, which is 0.2 mm in this embodiment. The outlet area 23 extends from the sample detection area 22 to the edge of the biological interface layer 2.

[0089] The detection module includes a conductive substrate and an electrode interface layer. The conductive substrate is connected to the sample detection area 22, and the electrode interface layer is connected to the conductive substrate. The electrode interface layer is used to specifically identify and capture biological molecules in the sample to be detected.

[0090] In summary, in the patch-type wearable metabolite detection device of this embodiment, the total size of the acquisition module is 3 cm in length, 1.5 cm in width, and 2.5 mm in height.

[0091] Example 2

[0092] This embodiment provides a method for preparing a patch-type wearable metabolite detection device.

[0093] A method for preparing a patch-type wearable metabolite detection device comprises the following steps:

[0094] First, the mold of the acquisition module is prepared by machining or 3D printing. After the mold is prepared, isopropyl alcohol, ultrapure water and surfactant are used to clean the mold surface respectively to remove organic oil stains and surface impurities on the mold surface to ensure that the mold surface is clean and smooth.

[0095] PDMS and curing agent were mixed in a mass ratio of 10:1, and 100 μL of saturated ethanol solution containing F108 surfactant was added to every 10 g of PDMS material. After rapid stirring, vacuum was drawn to remove bubbles. Subsequently, the above PDMS mixture was evenly poured on the surface of the mold, and vacuum was drawn again to remove bubbles. Subsequently, the mold of the collection module covered with the PDMS mixture was placed in an 80°C oven for curing for 40 minutes, cooled at room temperature after curing, and then the PDMS microfluidic structure was peeled off with tweezers. At this time, the PDMS microfluidic structure was a double-layer structure.

[0096] The peeled PDMS microfluidic structure was cleaned with isopropanol and ultrapure water to remove impurities on the PDMS surface. Nitrogen was used to blow dry the water stains on the PDMS microfluidic structure, and then dust and impurities adsorbed by the PDMS material were removed with dust removal tape for later use.

[0097] The front side of the PDMS double-layer structure was cleaned with oxygen plasma, and the upper and lower structures were quickly bonded after activation for 45 seconds. The bubbles generated during the bonding process were removed with tweezers, and then fixed in a 37°C oven for 1 hour to obtain the acquisition module of the detection device. The actual picture of the acquisition module of the detection device is shown in Figure 4 shown.

[0098] The application example of the acquisition module of the above-mentioned patch-type wearable metabolite detection device is as follows:

[0099] The dye or sample to be tested is dripped into the sample storage area 11 of the collection module, so that the fluid enters the sample detection area 22 through the capillary drainage area 21 and is discharged from the outlet area 23 .

[0100] Different concentrations of brilliant blue dye were used to verify the drainage and replacement efficiency of the collection module. First, the sample storage areas 11 at both ends of the collection module were filled with 50% brilliant blue dye solution, such as Figure 5 As shown, 50% Brilliant Blue dye solution flows along the capillary drainage area 21 into the sample detection area 22, and then is discharged from the outlet area 23. During the entire drainage process, the liquid level in the sample storage area 11 gradually decreases, and the sample detection area 22 is gradually filled with dark blue dye. The entire process is an active drainage process, and no external action is required.

[0101] Then, the sample storage areas 11 at both ends of the collection module are filled with 1% brilliant blue dye solution, such as Figure 5 As shown, the 1% brilliant blue dye solution flows along the capillary drainage area 21 into the sample detection area 22, pushing the original 50% brilliant blue dye in the sample detection area 22 to flow out, and then the 1% brilliant blue dye solution is discharged from the outlet area 23. During the entire sample replacement process, the liquid level in the sample storage area 11 gradually decreases, and the 1% brilliant blue dye and the 50% brilliant blue dye in the sample detection area 22 are not obviously mixed. The light blue dye is quickly discharged from the outlet area 23 under the push of the dark blue dye, and then the entire sample detection area 22 is completely filled with the dark blue dye, indicating that the sample replacement is completed.

[0102] Figure 5 is a physical picture of the detection module of the patch-type wearable detection device of this embodiment, such as Figure 5 As shown, the detection module is integrated into the biological interface layer 2 of the sampling module, and the sensing electrode is completely located in the sample detection area 22.

[0103] The conductive substrate of the detection module is made of conductive material, which can be directly fixed in the sample detection area 22 of the sampling module, or fixed on the surface of a flexible material and then attached to the sample detection area 22 of the sampling module. The detection module is fixed on the surface of a polyurethane (TPU) flexible material by a screen printing process using conductive carbon paste and conductive silver paste. Subsequently, the integration of the biological interface layer 2 in the sampling module and the detection module is completed by a plasma cleaning step. The integrated physical diagram of the patch-type wearable metabolite detection device is shown in Figure 6 shown.

[0104] The electrode interface of the detection module is used to specifically identify and capture the biological molecules to be tested in the sample to be tested. The electrode interface can add a three-dimensional conductive structure with a large specific surface area to support organic enzyme molecules, inorganic biomimetic enzyme materials and ion-selective films, etc., to improve the detection sensitivity of the detection module. Specifically, during the preparation, a metal organic framework material is first used to integrate two-dimensional conductive nanomaterials and glucose oxidase to prepare a composite material (CNT / GOx@ZIF-8) for glucose recognition and interfacial electron transfer. It is then mixed with a film-forming agent to construct an electrode sensing interface. The metal organic framework structure is used to improve the stability of the biological enzyme, and the two-dimensional conductive material is used to improve the transfer efficiency of electrons, thereby significantly improving the detection stability and sensitivity of the detection device to glucose molecules.

[0105] The CNT / GOx@ZIF-8 composite interface material was mixed with 5% Nafion solution at a ratio of 10:1, and the electrode modification solution obtained by the mixture was dropped on the surface of the three-electrode working electrode of the detection module. After being placed at 4°C for 18 hours, a detection module for glucose sensing was obtained.

[0106] The biological interface layer 2 with electrode preparation and detection module integration is bonded to the sample collection layer 1. The bonding process includes: the front side of the double-layer structure of the collection module is cleaned with oxygen plasma, the upper and lower structures are quickly bonded after activation for 45 seconds, and the bubbles generated during the bonding process are removed by tweezers, and then fixed in a 37°C oven for 1 hour to obtain a patch-type wearable detection module.

[0107] Phosphate buffered saline (PBS) is dripped into the sample storage area 11 of the acquisition module. The phosphate buffered saline flows along the capillary drainage area 21 into the sample detection area 22 and is then discharged from the outlet area 23. During the entire drainage process, the PBS liquid level in the sample storage area 11 gradually decreases, and the sample detection area 22 is gradually filled with colorless phosphate buffer solution. A steady-state voltage is applied to the detection module, and the current change curve is collected. Subsequently, ultrapure water is dripped into the sample storage area 11, and the sample is repeatedly washed three times. Subsequently, 0 μM, 100 μM, 200 μM, 300 μM, and 400 μM glucose solutions are dripped into the sample storage area 11 of the acquisition module in sequence. Each time, a steady-state voltage is applied to the detection module after the liquid in the sample detection area 22 is stable, and then the current change curve is collected. The steady-state current curve corresponding to the solution is shown in FIG. Figure 7 As shown, the collected steady-state current value can be compared with the concentration of glucose solution. Figure 7 In the figure, the horizontal axis is time and the vertical axis is the steady-state current value.

[0108] In summary, the present invention proposes a patch-type wearable sensor that can stably, sensitively, quickly, and long-term dynamically detect and integrate multiple biological molecules. Compared with existing detection equipment, the patch-type wearable detection device has higher stability, longer working life, shorter detection time, and smaller dynamic monitoring hysteresis, which solves the problems of short working life, low efficiency of sample collection and replacement, and serious dynamic monitoring crosstalk of existing wearable detection devices. In addition, the patch-type wearable detection device proposed in the present invention is flexible, lightweight, and comfortable to wear. The base material can be made of biocompatible flexible materials, which greatly reduces the foreign body sensation and allergy risk when the user wears it, laying the foundation for the user's long-term wearing and use. At the same time, the patch-type sensor proposed in the present invention can be flexibly integrated with specific sensing electrodes, miniaturized signal acquisition devices, wireless signal interaction systems and other equipment, and is widely used in real-time dynamic detection of multiple metabolites in body fluids such as saliva, sweat, and tears. It has good versatility for constructing medical devices for disease prediagnosis and health monitoring.

[0109] In the above embodiments, the description of each embodiment has its own emphasis. For parts that are not described in detail in a certain embodiment, reference can be made to the relevant descriptions of other embodiments.

[0110] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0111] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A patch-type wearable metabolite detection device, characterized in that: include: A sampling module, the sampling module comprising a biological interface layer for directly attaching to the epidermis and a sample collection layer for contacting with a liquid environment, the biological interface layer being overlapped and connected to the sample collection layer, the biological interface layer being provided with a capillary drainage area, a sample detection area and an outlet area, the sample collection layer being provided with a sample storage area, the number of the sample storage areas being multiple, the sample storage areas being bent in an arc-shaped structure, the number of the capillary drainage areas being multiple, the multiple capillary drainage areas being distributed on the outside of the sample detection area, the capillary drainage area being communicated with the sample storage area, the capillary drainage area also extending to the sample detection area, the capillary drainage area being used to quickly drain the sample to be tested collected in the sample storage area into the sample detection area, the sample detection area being used for the sample to be tested to undergo an oxidation-reduction reaction under the action of an electrode to detect biological molecules in the sample to be tested, and the outlet area being communicated with the sample detection area; as well as The detection module comprises a conductive substrate and an electrode interface layer, wherein the conductive substrate is connected within the sample detection area, the electrode interface layer is connected to the conductive substrate, and the electrode interface layer is used to specifically identify and capture biological molecules in the sample to be detected.

2. The patch-type wearable metabolite detection device according to claim 1, characterized in that: The outer arc edge of the sample storage area is composed of a 20°-45° arc segment with a diameter of 8.4-42mm, the inner arc edge of the sample storage area is composed of a 20°-45° arc segment with a diameter of 7.2-36mm, and the distance between the outer arc edge and the inner arc edge of the sample storage area is 1.2-6.4mm.

3. The patch-type wearable metabolite detection device according to claim 1, characterized in that: The depth of the sample storage area is 0.2-10 mm.

4. The patch-type wearable metabolite detection device according to claim 1, characterized in that: The capillary drainage area includes a drainage inlet and a drainage channel, the drainage inlet is communicated with the sample storage area, one end of the drainage channel is connected to the drainage inlet and the other end extends to the sample detection area.

5. The patch-type wearable metabolite detection device according to claim 4, characterized in that: The drainage inlet is a cylindrical groove, the radial cross-sectional diameter of the drainage inlet is 0.8-4 mm, and the height of the drainage inlet is 0.05-0.5 mm; And / or, the drainage channel is a long strip-shaped groove, the width of the drainage channel is 0.2-1 mm, and the length of the drainage channel is 5-20 mm.

6. The patch-type wearable metabolite detection device according to any one of claims 1 to 5, characterized in that: The sample detection area is a cylindrical groove, the inner diameter of the sample detection area is 4.8-24 mm, and the height of the sample detection area is 0.05-0.5 mm.

7. The patch-type wearable metabolite detection device according to any one of claims 1 to 5, characterized in that: The length of the flow channel in the outlet zone is 1.6-8 mm, the width of the flow channel in the outlet zone is 0.4-2 mm, and the outlet zone extends from the sample detection zone to the edge of the biological interface layer.

8. The patch-type wearable metabolite detection device according to any one of claims 1 to 5, characterized in that: The biological interface layer and / or the sample collection layer are made of flexible materials through a molding process, and the material of the biological interface layer and / or the sample collection layer is selected from one or more of polydimethylsiloxane, polyethylene terephthalate, polyurethane, polyimide, cross-linked dextran, silica gel and agarose gel.

9. According to the patch-type wearable metabolite detection device of claim 8, the mold used in the preparation process of the biological interface layer and / or the sample collection layer is processed by mechanical processing, 3D printing, photolithography or laser engraving, and the mold material is selected from one or more of polystyrene, cellulose, polyacrylamide, polyethylene, polypropylene, glass, and silicon wafer.

10. The patch-type wearable metabolite detection device according to any one of claims 1 to 5 and 9, characterized in that: The surface of the biological interface layer and / or the sample collection layer is subjected to surface modification treatment, and the surface modification treatment method includes one or more of oxygen plasma cleaning, ultraviolet light grafting and block polymer modification.

11. The patch-type wearable metabolite detection device according to any one of claims 1 to 5 and 9, characterized in that: The conductive substrate is made of conductive materials, and the conductive materials include one or more of metal materials, conductive non-metal materials and two-dimensional conductive nanomaterials.

12. The patch-type wearable metabolite detection device according to claim 11, characterized in that: The conductive material includes one or more of gold, silver, platinum, nickel and titanium; And / or, the conductive non-metallic material includes one or more of carbon paste, carbon fiber and polyethylene dioxythiophene; And / or, the two-dimensional conductive nanomaterial includes one or more of graphene, carbon nanotubes and metal nanoparticles.

13. The patch-type wearable metabolite detection device according to any one of claims 1-5, 9, and 12, characterized in that: The conductive substrate is fixed in the sample detection area by one or more of screen printing, sputtering, transfer printing, and physical precipitation; 14. The patch-type wearable metabolite detection device according to any one of claims 1-5, 9, and 12, characterized in that: The conductive substrate is fixed on the surface of the flexible material and attached to the sample detection area. The flexible material includes one or more of polyethylene terephthalate, polyurethane and polyimide.

15. The patch-type wearable metabolite detection device according to any one of claims 1-5, 9, and 12, characterized in that: The electrode interface layer is modified with biological enzyme molecules and / or inorganic bionic enzyme materials, wherein the biological enzyme molecules include one or more of glucose oxidase, lactate oxidase and uricase, and the inorganic bionic enzyme materials include one or more of copper, cobalt metal organic framework materials, Fe3O4, and cyanocobalamin.

16. The patch-type wearable metabolite detection device according to any one of claims 1-5, 9, and 12, characterized in that: The electrode interface layer is a three-dimensional porous structure, a planar mesh structure or a three-dimensional skeleton structure, wherein the three-dimensional porous structure includes one or more of foamed carbon, foamed gold, foamed nickel, and foamed nickel; the planar mesh structure includes one or more of carbon fiber cloth, carbon fiber paper, and carbon fiber yarn; and the three-dimensional skeleton structure includes a non-conductive protein skeleton, polymer skeleton or porous ceramic modified by two-dimensional conductive nanomaterials.

17. The patch-type wearable metabolite detection device according to any one of claims 1-5, 9, and 12, characterized in that: When the electrode interface layer is used to specifically identify and capture biological molecules in the sample to be tested, an electrochemical detection method is used to collect electron transfer signals during the oxidation-reduction process of the biological molecules, wherein the electrochemical detection method includes one or more of steady-state current method, differential pulse voltammetry, square wave voltammetry, cyclic voltammetry, electrochemical impedance spectroscopy, linear sweep voltammetry, alternating current voltammetry and anodic stripping voltammetry.

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