CN114778643A - Wearable micro-needle sensor for tissue fluid detection and preparation method thereof - Google Patents
Wearable micro-needle sensor for tissue fluid detection and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a wearable micro-needle sensor for detecting interstitial fluid and a preparation method thereof, and relates to the field of wearable equipment. The wearable sensor includes: the micro-needle substrate and formed in at least one working electrode and reference electrode on the substrate, the working electrode includes from supreme electrically conductive metal layer and the transmission layer that sets gradually down, the reference electrode includes from supreme electrically conductive metal layer and the Ag AgCl layer that sets gradually down, electrically conductive metal layer all includes electrode zone and wire, the transmission layer covers the top at the electrode zone, the transmission layer adopts graphite alkene combined material. The wearable sensor has the advantages of high sensitivity, wide measurement range and simple manufacture, and can be attached to the surface of skin to realize the real-time rapid detection of tissue fluid.
Description
Technical Field
The invention belongs to the technical field of wearable detection equipment, and particularly relates to a wearable micro-needle sensor for detecting tissue fluid and a preparation method thereof.
Background
At present, the biochemical indexes of human bodies are mostly detected by detecting the contents of blood sugar, lactic acid, sodium ions, potassium ions, pH and the like in blood and physiological electric signals. However, blood sample collection is mostly invasive, and can only complete the detection of blood content at a certain time, and cannot be monitored in real time, and real-time data collection cannot be provided for monitoring human health. At present, the collection of physiological electric signals is mostly pasted on the surface of skin, conductive paste is needed, and the quality of the obtained physiological signals is low. Therefore, how to rapidly, rapidly and non-invasively detect blood components and physiological electrical signals is a major research focus.
Interstitial fluid (interstitial fluid) is fluid that exists between cells, is produced by the filtration of plasma through the walls of the capillary artery at the end of the capillary, and has substantially the same composition as plasma. Therefore, the real-time continuous detection of the tissue fluid can replace the monitoring of blood to a certain extent, can reflect the change of blood component content, and provides data support for the real-time monitoring of human health. The contents of metabolites such as glucose, lactic acid, sodium ions, potassium ions, pH and the like contained in the interstitial fluid and reflecting the health condition of a human body can replace blood components to reflect the physiological condition of the human body to a certain extent, so that the accurate monitoring of the contents of the components of the interstitial fluid is particularly important.
Disclosure of Invention
The invention aims to provide a wearable micro-needle sensor for detecting tissue fluid, which has high detection precision and wide detection range.
The invention also aims to provide a preparation method of the wearable micro-needle sensor for detecting the interstitial fluid, which has the advantages of simple process, easy control of various parameters and strong repeatability.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a preparation method of a wearable microneedle sensor for detecting interstitial fluid comprises the following steps:
s1) forming conductive metal layers of a working electrode and a reference electrode on the microneedle substrate by a magnetron sputtering method;
s2) electrochemically reducing the graphene composite material on the conductive metal layer of the working electrode in different voltage ranges according to requirements to form a transmission layer, and then dropwise adding a glucose oxidase layer on the corresponding transmission layer to obtain a glucose sensor, or dropwise adding a sodium ion sensitive layer on the corresponding transmission layer to obtain a sodium ion sensor; or the transmission layer formed under a special voltage directly acts as a sensor;
s3) forming a silver nanolayer on the conductive metal layer of the reference electrode and chlorinating the silver nanolayer to obtain an Ag/AgCl layer.
In step S2), the step of electrochemically reducing the graphene composite material includes: the graphene oxide, the aniline monomer and the metal salt are mixed according to a certain proportion to form electroplating mother liquor, and the electroplating mother liquor is subjected to electrochemical reduction under a certain voltage.
Further, the aniline monomer and the metal salt are mixed at a ratio of 1:0.010, or 1:0.015, or 1:0.02, as required.
Further, the metal salt contains Cu2+、Ca2+、Fe3+、Ni2+、Co2+、PtCl6 2-、Zn2+、AuCl4 -、PdCl4 2-、Mn2+A metal salt.
Further, in the step S2), (1) the graphene composite material forms a transmission layer under the voltage of 0.4V to-1.4V, and then respectively dripping 20-30 mu L of glucose oxidase solution and airing to form a glucose oxidase layer as a glucose sensor;
(2) forming a transmission layer on the graphene composite material under the voltage of 0.4V to-1.4V, and then respectively dropwise adding sodium ion sensitive layers to serve as sodium ion sensitive sensors;
(3) the graphene composite material forms a transmission layer under the voltage of 0.4V to-1.4V, and is directly used as an electric signal sensor for detecting physiological electric signals;
(4) the graphene composite material forms a transmission layer under the voltage of 0.9V to-1.4V, and the transmission layer is directly used as a pH sensitive layer and used as a pH sensor; the sensor can directly detect pH value because the reduced voltage is from 0.9V to-1.4V and the reduced polyaniline is different. And the measurement mode is different from the measurement of other sensors, and the measurement modes cannot interfere with each other.
And S2), after a glucose oxidase layer is formed, coating silk fibroin solution on the glucose oxidase layer, drying, and coating glutaraldehyde on the surface of the silk fibroin layer to form a protein cross-linked layer.
In step S3), after the Ag/AgCl layer is formed, the method further includes: and coating agar containing saturated potassium chloride and a polyvinyl butyral solution on the surface of the Ag/AgCl layer, and then drying.
The preparation method is in step S3), the electric signals collected by all the sensors are transmitted to the external display device through the external circuit wireless bluetooth.
The invention also provides a wearable micro-needle sensor for detecting the tissue fluid, which comprises: the micro-needle substrate and be formed in at least one working electrode and reference electrode on the substrate, the working electrode includes from supreme conductive metal layer and the transmission layer that sets gradually down, the reference electrode includes from supreme conductive metal layer and the Ag AgCl layer that sets gradually down, conductive metal layer all includes electrode zone and wire, the transmission layer covers the top at the electrode zone, the transmission layer adopts graphite alkene combined material.
Further, the microneedle substrate comprises protein microneedles and a composite film; the protein micro-needle is used as an electrode, and the composite film is used as a conducting circuit.
Further, silk fibroin or wool keratin, or a complex of protein and polymer is adopted as the protein microneedle. Specifically, the protein microneedle adopting the compound of the protein and the polymer is a microneedle obtained by mixing and pouring silk fibroin solution and polyurethane solution.
The conductive metal layer is one or more of platinum, palladium, silver and gold. Preferably, the conductive metal layer is Au.
The graphene composite material comprises a graphene sheet layer and metal nanoparticles doped in the graphene sheet layer, wherein the doping amount of the metal nanoparticles is controllable according to needs. Preferably, the graphene composite material comprises graphene and palladium nanoparticles uniformly dispersed on the surface of the graphene.
The transmission layer can be prepared by reducing the graphene oxide composite material under different reduction voltages according to requirements; the four working electrodes are divided into the following types according to the reduction voltage range of the transmission layer and the difference of whether the detection layer is additionally arranged or not and the type of the detection layer:
the transmission layer of the working electrode is formed under the voltage of 0.4V to-1.4V and is provided with a glucose oxidase layer, and the glucose oxidase layer is also covered with a protein crosslinking layer to form a glucose sensor;
the transmission layer of the working electrode is formed under the voltage of 0.4V to-1.4V and is provided with a sodium ion sensitive layer to form a sodium ion sensor;
the transmission layer of the working electrode forms an electrode which can be directly used as a physiological electric signal detection electrode under the voltage of 0.4V to-1.4V to form an electric signal sensor;
the transmission layer of the working electrode is formed under the voltage of 0.9V to-1.4V to directly form a pH sensor; thereby being capable of detecting glucose, sodium ions, physiological electrical signals and pH in real time.
Furthermore, the glucose oxidase layer is also covered with a protein crosslinking layer, so that oxidase can be effectively fixed through the protein crosslinking layer, and the oxidase activity can be stored for a long time, so that the sensor has a long service life and high sensitivity.
Furthermore, an agar protective layer and a high polymer material protective layer are sequentially arranged on the Ag/AgCl layer of the reference electrode. Preferably, the agar protective layer adopts agar containing saturated potassium chloride, and the high polymer material protective layer adopts a polyvinyl butyral film, so that the service life of the product is further prolonged.
Further, the electrode also comprises a counter electrode, wherein the counter electrode comprises a conductive metal layer, and the conductive metal layer comprises an electrode area and a lead; and the glucose sensor is matched with the glucose sensor to measure the current.
The beneficial effects are that: the protein micro-needle is used as a substrate, and a plurality of sensors are integrated for simultaneous monitoring. The graphene composite material is used as the transmission layer, and metal nano in the transmission layer is uniformly distributed on the surfaces of polyaniline and graphene, so that the sensitivity of the sensor can be improved. The protein micro-needle can be reduced in usage, and can be decomposed by human body after being broken, so that the protein micro-needle can not remain on body surface. The wearable sensor has the advantages of high sensitivity, wide measurement range and simple manufacture, and can be attached to the surface of skin to realize the real-time rapid detection of tissue fluid.
Drawings
Fig. 1 is a schematic structural diagram of a wearable sensor for interstitial fluid detection according to embodiment 1 of the present invention;
FIG. 2 is a schematic structural diagram of a working electrode A according to the present invention;
FIG. 3 is a schematic view of the working electrode B according to the present invention;
FIG. 4 is a schematic structural diagram of a working electrode C according to the present invention;
FIG. 5 is a schematic structural diagram of a working electrode D according to the present invention;
FIG. 6 is a schematic diagram of a reference electrode according to the present invention.
The reference numerals are summarized as follows: 1-a micro-needle substrate, wherein,
2-conductive metal layer, 21-conducting wire, 22-electrode area;
3-a transport layer;
4 a-glucose oxidase layer, 4 c-sodium ion sensitive layer;
5-a protein cross-linked layer;
6-Ag/AgCl layer;
7-agar protective layer;
8-a polymer material protective layer;
A. b, C, D-working electrode; e-a counter electrode; f-reference electrode.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are not indicated by manufacturers and are commercially available.
The wearable micro-needle sensor for detecting interstitial fluid and the preparation method thereof according to the embodiment of the invention are specifically described below.
Example 1
The embodiment provides a preparation method of a wearable microneedle sensor for detecting interstitial fluid, which comprises the following steps:
(1) the method comprises the following steps of (1) sputtering gold on a microneedle substrate by taking natural silk fibroin as the microneedle substrate to obtain six metal regions which are respectively used as conductive metal layers of six electrodes, wherein each conductive metal layer comprises a lead and an electrode region, and the line width of the lead is 1 mm; wherein E serves as a counter electrode, F serves as a reference electrode, and the remaining four serve as working electrodes A, B, C, D;
(2) adding aniline and palladium chloride into 0.5 mg/mL graphite oxide solution, wherein the aniline is 0.5 mol/L and the palladium chloride is 0.5 mmol/L, and uniformly stirring; the working electrodes A, C and D respectively obtain the transmission layers of the glucose sensor, the sodium ion sensor and the electric signal sensor under the pressure of 0.4V to-1.4V; electroplating the working electrode B at 0.9V to-1.4V to directly obtain a transmission layer of the pH sensor;
(3) dripping 20 mul of oxidase solution on a transmission layer of a working electrode A to form a glucose oxidase layer, dripping 10 mul of 1wt% silk fibroin solution after air drying, then air drying again, dripping 10 mul of 1wt% glutaraldehyde to form a protein crosslinking layer, and obtaining an enzyme sensor; a pH sensor is directly prepared on a transmission layer of the working electrode B; dropwise adding a sodium ion sensitive layer on the transmission layer of the working electrode C to obtain a sodium ion sensor; the transmission layer of the working electrode D is directly used as an electric signal sensor of physiological electric signals;
(4) dripping 10 mu L of silver nano layer on the electrode area of the reference electrode, after drying, dripping 10 mu L of 0.05 mol/L ferric chloride on the surface of the reference electrode for 5 s, washing with water, drying in the air, dripping 10 mu L of polyvinyl butyral solution containing 79.1 mg on the surface of the reference electrode, and drying in the air to obtain a polymer composite material protective layer;
(5) all sensors transmit collected electric signals to devices such as mobile phones through external circuits through Bluetooth.
Example 3
The embodiment provides a preparation method of a wearable sensor for detecting interstitial fluid, which comprises the following steps: it differs from example 2 in that: in the step (2), the concentration of palladium chloride is 1 mmol/L.
Example 3
A wearable microneedle sensor for detecting interstitial fluid, as shown in fig. 1 to 6, comprises a microneedle substrate 1, six electrodes, namely four working electrodes A, B, C, D, a counter electrode E and a reference electrode F, are arranged on the microneedle substrate 1;
the bottom layers of the four working electrodes A, B, C, D, the counter electrode E and the reference electrode F are all conductive metal layers 2, and the conductive metal layers 2 comprise lead wires 21 and electrode regions 22; the four working electrodes A, B, C, D are provided with a transmission layer 3 on the electrode regions 22 of the conductive metal layer 2,
a glucose oxidase layer 4a is arranged on the transmission layer 3 of the working electrode A to form an enzyme sensor; the transmission layer 3 of the working electrode B is directly used as an electrode of the pH sensor to form the pH sensor; a sodium ion sensitive layer 4C is arranged on the transmission layer 3 of the working electrode C to form a sodium ion sensor; the transmission layer 3 of the working electrode D can be directly used as an electrode for detecting physiological electric signals to form an electric signal sensor, so that the four working electrodes A, B, C, D can simultaneously realize real-time detection of glucose, sodium ions, pH and physiological electric signals; all the sensors transmit the collected electric signals to equipment such as a mobile phone and the like through an external circuit through Bluetooth;
an Ag/AgCl layer 6 is arranged on the conductive metal layer of the reference electrode F, and an agar protective layer 7 and a high polymer material protective layer 8 are sequentially arranged on the Ag/AgCl layer of the reference electrode F.
The microneedle substrate 1 is a protein microneedle, and the protein microneedle adopts silk fibroin or wool keratin. In this embodiment, the microneedle substrate 1 is made of a natural silk fibroin material. In other embodiments, the protein microneedles may also be made of a composite of protein and polymer, such as microneedles formed by casting a mixture of silk fibroin solution and polyurethane solution.
The conductive metal layer 2 is one or more of platinum, palladium, silver and gold. In this embodiment, the conductive metal layer 2 is Au.
In this embodiment, the line width of the conductive line 21 is 1 mm.
The transmission layer 3 is made of graphene composite material. In this example, the graphene composite material contains platinum nanoparticles dispersed uniformly.
In this embodiment, the glucose oxidase layer 4a of the working electrode a is further covered with a protein cross-linked layer 5, and the oxidase can be effectively immobilized through the protein cross-linked layer 5, and the oxidase activity can be stored for a long time, so that the sensor has a long service life and high sensitivity.
In the embodiment, the agar protective layer adopts agar containing saturated potassium chloride, and the high polymer material protective layer adopts a polyvinyl butyral film, so that the service life of the product is further prolonged.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
Claims (8)
1. A preparation method of a wearable microneedle sensor for detecting interstitial fluid is characterized by comprising the following steps:
s1) forming conductive metal layers of a working electrode and a reference electrode on the microneedle substrate by a magnetron sputtering method;
s2) electrochemically reducing the graphene composite material on the conductive metal layer of the working electrode under different conditions to form a transmission layer, and dripping a glucose oxidase layer on the corresponding transmission layer to obtain a glucose sensor, or dripping a sodium ion sensitive layer on the corresponding transmission layer to obtain a sodium ion sensor; or the transmission layer formed under a special voltage directly acts as a sensor;
s3) forming a silver nanolayer on the conductive metal layer of the reference electrode and chlorinating the silver nanolayer to obtain an Ag/AgCl layer.
2. The method for preparing a wearable microneedle sensor for detecting interstitial fluid according to claim 1, wherein in step S2), the step of electrochemically reducing graphene composite material under different conditions comprises: mixing graphene oxide, aniline monomer and metal salt according to a certain proportion to form electroplating mother liquor, and carrying out electrochemical reduction under a certain voltage; the aniline monomer and the metal salt are mixed according to the mixing ratio of 1:0.010, or 1:0.015, or 1:0.02 as required; the metal salt contains Cu2+、Ca2+、Fe3+、Ni2+、Co2+、PtCl6 2-、Zn2+、AuCl4 -、PdCl4 2-、Mn2+A metal salt; the voltage is between 0.4V and-1.4V or between 0.9V and-1.4V.
3. The preparation method of the wearable microneedle sensor for interstitial fluid detection according to claim 1, wherein in step S2), (1) the graphene composite forms a transmission layer under a voltage of 0.4V to-1.4V, and then 20 to 30 μ L of glucose oxidase solution is respectively added dropwise and dried to form a glucose oxidase layer as a glucose sensor;
(2) the graphene composite material forms a transmission layer under the voltage of 0.4V to-1.4V, and sodium ion sensitive layers are respectively dripped to be used as sodium ion sensitive sensors;
(3) the graphene composite material forms a transmission layer under the voltage of 0.4V to-1.4V, and is directly used as an electric signal sensor for detecting physiological electric signals;
(4) the graphene composite material forms a transmission layer under the voltage of 0.9V to-1.4V, and the transmission layer is directly used as a pH sensitive layer and used as a pH sensor.
4. The method for preparing a wearable microneedle sensor for interstitial fluid detection according to claim 1 or 3, wherein a glucose oxidase layer is formed, a silk fibroin solution is coated on the glucose oxidase layer, and after drying, glutaraldehyde is coated on the surface of the silk fibroin layer to form a protein cross-linked layer.
5. The method for preparing a wearable microneedle sensor for interstitial fluid detection according to claim 1, wherein in step S3), after the Ag/AgCl layer is formed, the method further comprises the following steps: and coating agar containing saturated potassium chloride and a polyvinyl butyral solution on the surface of the Ag/AgCl layer, and then drying.
6. The method for preparing a wearable microneedle sensor for interstitial fluid detection according to claim 1, wherein after step S3), the electrical signals collected by all sensors are transmitted to an external display device through external circuit wireless bluetooth.
7. A wearable microneedle sensor for interstitial fluid detection, prepared according to the method of any one of claims 1 to 6, comprising: the micro-needle electrode comprises a micro-needle substrate, four working electrodes and four reference electrodes, wherein the four working electrodes and the four reference electrodes are formed on the substrate, the working electrodes comprise conductive metal layers and transmission layers which are sequentially arranged from bottom to top, the reference electrodes comprise conductive metal layers and Ag/AgCl layers which are sequentially arranged from bottom to top, the conductive metal layers comprise electrode areas and conducting wires, and the transmission layers cover the electrode areas;
the preparation of the transmission layer can be obtained by reducing the graphene oxide composite material under different reduction voltages according to requirements; the four working electrodes are divided into the following types according to the reduction voltage range of the transmission layer and the difference of whether the detection layer is additionally arranged or not and the type of the detection layer:
a transmission layer of the working electrode is formed under the voltage of 0.4V to-1.4V and is provided with a glucose oxidase layer, and the glucose oxidase layer is also covered with a protein crosslinking layer to form a glucose sensor;
the transmission layer of the working electrode is formed under the voltage of 0.4V to-1.4V and is provided with a sodium ion sensitive layer to form a sodium ion sensor;
the transmission layer of the working electrode forms an electrode which can be directly used as a physiological electric signal detection electrode under the voltage of 0.4V to-1.4V to form an electric signal sensor;
the transmission layer of the working electrode forms a pH sensor directly under the voltage of 0.9V to-1.4V; thereby being capable of detecting glucose, sodium ions, physiological electric signals and pH in real time;
and an agar protective layer and a high polymer material protective layer are sequentially arranged on the Ag/AgCl layer of the reference electrode.
8. The wearable microneedle sensor for detecting the interstitial fluid according to claim 7, wherein the graphene composite material comprises graphene sheet layers and metal nanoparticles doped in the graphene sheet layers, wherein the doping amount of the metal nanoparticles is controllable as required.
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| CN117783248A (en) * | 2023-12-28 | 2024-03-29 | 北京大学 | Flexible wearable potassium ion detection sensor and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117783248A (en) * | 2023-12-28 | 2024-03-29 | 北京大学 | Flexible wearable potassium ion detection sensor and preparation method thereof |
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