CN115399756A - Multi-parameter SERS active microneedle for in-situ detection of inflammatory environment - Google Patents
Multi-parameter SERS active microneedle for in-situ detection of inflammatory environment Download PDFInfo
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- CN115399756A CN115399756A CN202211116354.3A CN202211116354A CN115399756A CN 115399756 A CN115399756 A CN 115399756A CN 202211116354 A CN202211116354 A CN 202211116354A CN 115399756 A CN115399756 A CN 115399756A
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Images
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- A—HUMAN NECESSITIES
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- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
- A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
- A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
Abstract
The invention provides a micro-needle for multi-parameter Surface Enhanced Raman Scattering (SERS) activity detection, which is used for detecting the change of various indexes in an inflammatory environment. The invention provides a preparation method of the multi-parameter SERS active microneedle, which comprises the steps of microneedle preparation, surface adhesion layer coating, metal nanoparticle modification and Raman active molecule chemical fixation. The invention also provides a method for detecting changes of each index in an inflammatory environment by using the SERS active microneedle. The invention adopts the surface enhanced Raman scattering effect of the metal nanoparticles to amplify the signal of the structural change of the active molecules at the detection part, reflects the change of various indexes in the environment to be detected and realizes the in-situ and rapid detection of the inflammation part. Meanwhile, sample pretreatment is not needed, the detection environment is not damaged, and the detection cost is greatly reduced. The invention can be used for monitoring the development process of inflammation in clinic and provides a feasible method for diagnosing and tracking inflammation-related diseases.
Description
Technical Field
The invention belongs to the technical field of biosensing, and relates to a multi-parameter SERS active microneedle and a preparation method and a use method thereof.
Background
The inflammatory environment is associated with a variety of chronic diseases, such as cancer, diabetes, obesity, or autoimmune diseases. Oxidative stress in inflammatory environments results in changes in a number of signals, such as a decrease in pH, an increase in Reactive Oxygen Species (ROS) concentration, and the like. Changes of various biomarkers can also occur in the inflammatory environment related to diseases, such as rheumatoid factors in rheumatoid arthritis patients, carcinoembryonic antigens in cancer patients, and the like. The detection of physical or biochemical indexes in the inflammatory environment is an important means for judging the occurrence and development process of diseases. Routine blood detection, computed tomography, nuclear magnetic resonance and the like are commonly used in clinic, but the methods usually have complicated steps and long time consumption, or cause radiation to patients and detection personnel; meanwhile, the conventional method lacks universality for disease screening, and can be operated only by professional personnel, so that the 'medical difficulty' delays the medical time of a patient, makes early disease discovery and tracking difficult, and easily misses the optimal intervention period.
In addition, failure during implantation surgery is also associated with inflammation. Improper implantation operation, acidic substances generated by the degradation of the implanted material, or adverse biochemical reactions between the material and autologous tissues can also cause strong inflammatory reactions in the microenvironment, and finally, the implantation fails. For postoperative tracking of a patient, imaging methods such as computed tomography and the like are often adopted to periodically evaluate postoperative healing conditions, so that the problems are also solved, and whether an implant material causes inflammatory reaction in a microenvironment of an implant part or not can not be reflected in time. Therefore, it is necessary to develop a new detection method to solve the above problems.
The Surface Enhanced Raman Scattering (SERS) has the advantages of short time, sensitive signal, nondestructive detection and the like of the traditional Raman detection, but the single SERS detection is difficult to penetrate through a biological barrier to obtain deep information. The microneedle can penetrate into the skin in a minimally invasive mode, and the needle point position can reach the dermis layer, so that the combination of the microneedle and the SERS can break through the blockage of the biological barrier to the Raman laser, and subcutaneous deep information can be obtained. The recent prior art combines SERS and micropin for detect the multiple signal in the subcutaneous microenvironment, the change of a certain index of control, but adopt the micropin to draw the interstitial fluid mostly, later need take out the micropin from the internal follow-up experiment that carries out, can't realize the in situ detection, can't avoid the influence of environmental factor to the detection material after taking out.
Therefore, the invention aims to solve the problems that the SERS active microneedle for in-situ detection of inflammatory environment is developed, the damage to a patient is reduced, the detection time is shortened, the detection steps are simplified, and the preliminary screening and tracking of diseases are easier.
Technical scheme
The invention aims to provide a multi-parameter SERS active microneedle for in-situ and rapid detection of inflammation-related indexes and a preparation and detection method thereof.
The inflammation-related index is pH, redox (redox) potential, ROS content, etc., but is not considered to be limited to the above parameters, and any index of inflammatory environment different from normal environment can be used as the inflammation-related index in the present invention.
In order to achieve the above object, according to an aspect of the present invention, a multiparameter SERS-active microneedle is provided, where the microneedle is a high light transmittance microneedle with a surface modified with a plurality of raman-active molecules, and the surface of the microneedle is coated with an adhesion layer and a noble metal nanoparticle layer with a surface enhanced raman scattering effect.
The main body of the high light transmission microneedle is made of polymer or inorganic material;
further, the polymer is one or more of polymethyl methacrylate, polycarbonate, polyvinyl chloride, polystyrene, polyethylene terephthalate, polyether sulfone and derivatives thereof, acrylonitrile-butadiene-styrene, polyvinyl fluoride, polyamide, styrene/acrylonitrile copolymer, polyhydroxyethyl methacrylate, cellulose acetate, ethylene-vinyl acetate copolymer and the like.
Further, the inorganic material is one or a combination of more of quartz glass, optical fiber, transparent ceramic and the like.
The microneedles have a shape gradually shrinking towards the ends.
Further, the shape is a combined shape of one or more of a conical shape, a polygonal pyramid shape, a cross pyramid shape, and various irregular pyramid shapes, and a combined shape of a cylindrical shape, a prismatic shape, and a conical shape.
The diameter of the bottom of the microneedle is 200-1000 microns, and the height of the microneedle is 400-1500 microns.
Further, the microneedle is a single microneedle or a microneedle array with the distance between every two microneedles being 400-2000 micrometers.
The adhesion layer is a polymer coating with phenolic hydroxyl groups.
Further, the polymer with phenolic hydroxyl is one or a combination of plant polyphenol, polydopamine, levodopa and the like.
Further, the plant polyphenol is catechol, gallic acid, procyanidin, lignan, quercetin, curcumin, resveratrol, etc.
The noble metal nano-particles are nano-particles of one or two of gold, silver and the like.
Further, the noble metal nanoparticles are preferably silver nanoparticles.
Further, the diameter of the silver nano example is preferably 20 to 125 nm.
1. The Raman active molecule is at least one of pH response molecule 4-mercaptobenzoic acid, 4-mercaptopyridine, redox response molecule anthraquinone-2-carboxylic acid and ROS response molecule p-aminophenol, but is not considered to be limited to the three, and is the Raman active molecule responding to any abnormal index in the inflammatory environment.
Further, the pH response molecule is an organic compound containing sulfydryl and conjugated pi bonds, such as 4-mercaptobenzoic acid, 4-mercaptopyridine and the like.
Further, the redox response molecule is an organic compound containing a quinone structure, such as anthraquinone-2-carboxylic acid and the like.
Further, the ROS response molecule is a conjugated organic compound containing sulfydryl and amino, such as p-aminophenol and the like.
According to another aspect of the present invention, the preparation of the multi-parameter SERS-active microneedle comprises the steps of:
(1) Obtaining polymer micro-needles by soft lithography, or obtaining inorganic micro-needles by wet etching;
(2) Coating an adhesive layer on the needle point of the microneedle;
(3) Modifying gold or silver nanoparticles on the adhesion layer;
(4) A plurality of Raman active molecules are respectively fixed on the metal nanoparticles.
In an embodiment of the present invention, the step of preparing the polymer microneedle main body includes pouring a monomer solution of a polymer into a Polydimethylsiloxane (PDMS) mold (specifically, obtaining the PDMS mold according to a preparation scheme of the mold in the patent with the application number of 202010594079.4), and performing vacuum or centrifugal de-bubbling, and then performing cross-linking and curing to obtain the polymer microneedle main body.
In another aspect of the present invention, a method for preparing the multiparameter SERS-active microneedle is provided, wherein the step of preparing the inorganic microneedle main body includes fixing a material for preparing the inorganic microneedle main body on a support, immersing a terminal of the material in a corrosive solution, and etching the terminal for a period of time to form a single microneedle or microneedle array having a tip.
In an embodiment of the present invention, the step of coating the adhesion layer includes immersing the prepared microneedle tip into a polymer solution containing phenolic hydroxyl groups, and reacting for 10 minutes to 4 hours to form the adhesion layer.
In an embodiment of the present invention, the step of modifying the silver nanoparticles includes placing the microneedle coated with the adhesion layer in a watch glass, sequentially adding 0.01 to 0.1mol/L of silver nitrate solution, 1 to 5mol/L of sodium hydroxide solution, ammonia water and 0.05 to 0.5mol/L of glucose solution, reacting for 10 to 30 minutes, and controlling the temperature to be 20 to 60 ℃.
In another embodiment of the present invention, the step of modifying the gold or silver nanoparticles includes placing the microneedle coated with the adhesion layer in a sputtering apparatus, sputtering the gold or silver nanoparticles on the surface of the microneedle tip, and adjusting parameters of the apparatus, such as sputtering time, sputtering power, and the like, to ensure that a single layer of metal nanoparticles is adsorbed on the surface of the microneedle.
In an embodiment of the present invention, the step of fixing the plurality of active raman molecules includes immersing the microneedle tip portion modified with the metal nanoparticles in a raman active molecule solution, and fixing the active molecules on the surfaces of different microneedles respectively through strong interaction between the thiol group and the metal.
The multiparameter SERS-active microneedles for in situ detection were obtained as described previously.
According to another aspect of the present invention, a method of using the above multi-parameter SERS-active microneedle is provided. The method comprises the steps of placing a detected object on a Raman detection instrument platform, inserting the multi-parameter SERS active microneedle for detecting the inflammation indexes into a detection environment, measuring the Raman spectrum corresponding to each parameter immediately after focusing, and calculating the concentration of the corresponding index according to the change of the relative intensity of the characteristic peak of the spectrum.
The detection object or the detection environment is detected liquid or living tissue.
The various indicators in the inflammatory environment are pH, redox potential and ROS concentration.
The raman laser scanning time for each pixel is 30 seconds.
The invention has the advantages that:
the invention provides a preparation method of a multi-parameter SERS active microneedle, which aims to realize in-situ detection of an inflammation environment, simplify detection steps, reduce sampling amount and shorten detection time, so that a multi-parameter SERS active microneedle for in-situ and rapid detection of the inflammation environment is obtained by modifying a noble metal particle with a surface enhanced Raman scattering effect on the surface of a microneedle coated with an adhesion layer and a method for chemically fixing a Raman active molecule. Compared with the prior art, the invention has the following characteristics and advantages: (1) Compared with metal microneedles, the high-transparency SERS active microneedles prepared by the method can realize in-situ detection, namely the microneedles are not required to be taken out during detection, so that structural changes of a detected object after the detected object is taken out due to oxidation and other reactions of the substance in the air can be avoided, and particularly for the substances which are similar to ROS and are easy to attenuate, the problems can be avoided, and in-situ and accurate detection can be realized. (2) The adhesive layer containing phenolic hydroxyl on the surface of the microneedle can ensure that the noble metal nanoparticles are firmly adsorbed on the surface of the microneedle in the puncturing process. Compared with the method that other researchers inject metal particles loaded with Raman active molecules into a detection part, the method can avoid physiological toxicity caused by the residue of metal nanoparticles in vivo and improve the safety in the detection process. (3) The particle size of the metal nanoparticles on the surface of the microneedle prepared by the method is about 100 nanometers, and compared with metal particles with other particle sizes, the metal nanoparticles have a better SERS enhancement effect, and the detection limit of the SERS microneedle is expanded. (4) According to the method, the nonuniformity of signals is avoided by introducing an internal standard peak, and the reliability of the SERS detection result is greatly improved. (5) The multi-parameter SERS active microneedle prepared by the invention can obtain multiple indexes in a detection environment, realizes high-flux detection and further improves the reliability of a detection result. (6) Compared with the common clinical disease diagnosis methods such as routine blood detection, computed tomography, nuclear magnetic resonance and the like, the multi-parameter SERS active microneedle prepared by the invention can simplify the detection steps, reduce the sampling amount, shorten the detection time, facilitate the operation of medical personnel and reduce the pain of patients. In conclusion, the multi-parameter SERS active microneedle prepared by the invention can be used for in-situ and rapid detection of relevant parameters, and obtaining accurate and high-flux detection results of inflammatory environments, and is suitable for preliminary screening of inflammation-related diseases and follow-up of disease processes in clinic.
Drawings
Fig. 1 is a flow chart of a process for preparing a multi-parameter SERS-active microneedle according to the present invention;
FIG. 2 shows SERS active microneedles prepared by the present invention and using polymethyl methacrylate as the main body material of the microneedles, and silver nanoparticles on the tips and bottom surfaces of the microneedles;
FIG. 3 is a fiber optic single microneedle prepared by wet etching in the present invention;
FIG. 4 is a Raman spectrum response diagram of the SERS active microneedle prepared by the invention to rhodamine 6G;
FIG. 5 is a SERS spectrogram and an intensity-concentration relation graph obtained when the SERS active microneedle prepared by the invention detects the concentrations of pH, redox and ROS in the gradient solution;
fig. 6 shows SERS spectra obtained by measuring pH, redox potential and ROS concentration of the SERS-active microneedle prepared according to the present invention when applied to the hind paw of acute inflammation in mice, and specific values obtained from the intensity-concentration relationship.
Detailed Description
The invention provides a preparation method of a multi-parameter SERS active microneedle for in-situ detection of inflammatory environment, and the technical scheme provided by the invention will be described in detail with reference to the accompanying drawings and specific examples, which are only used for explaining the invention, but not to be construed as limiting the invention.
Example 1
In this embodiment, a method for preparing a polymer microneedle having a raman enhancement effect is provided.
The preparation steps of the microneedle are as follows:
(1) High-transparency polymethyl methacrylate micro-needle body obtained by soft photoetching method
The monomer solution of methyl methacrylate was cast into a PDMS mold, vacuum debubbled, and crosslinked for 45 seconds under uv light. The microneedles were peeled from the mold, washed with 75% ethanol and ultrapure water, and then polymer microneedle bodies having high light transmission properties were obtained.
(2) Coating poly-dopamine adhesion layer with phenolic hydroxyl group on the needle point part of the microneedle
Dopamine powder was added to Tris-HCl buffer at pH 8.5 to prepare a 2mg/mL dopamine solution. Sticking the back of the microneedle by using a medical traceless adhesive tape, only exposing the needle point part, immersing the microneedle into the dopamine solution, and carrying out autopolymerization for 2 hours at room temperature to obtain the dopamine-coated microneedle.
(3) Modifying silver nanoparticles on the adhesion layer
0.03mol/L silver nitrate solution, 2.5mol/L sodium hydroxide solution and 0.1mol/L glucose solution are prepared. 1.5mL of silver nitrate solution, 0.75mL of sodium hydroxide solution, 0.2mL of ammonia water and 4.5mL of glucose solution were sequentially added to a petri dish containing a microneedle, and the mixture was reacted for 15 minutes. After washing with ultrapure water, the mixture was stored in a nitrogen atmosphere at 4 ℃.
The microneedle for modifying silver nanoparticles is shown in figure 2. The SERS activity of the microneedle is detected by adopting rhodamine 6G, and the spectrogram is shown in an attached figure 4.
Example 2
In this embodiment, a method for preparing an inorganic microneedle is provided, wherein the inorganic microneedle is obtained by wet etching an optical fiber. The optical fiber was cut to a length of 2 cm and the polymer protective layer of the optical fiber was stripped. Fixing a single optical fiber or an optical fiber array which is arranged regularly on a bracket, soaking the lower end of the optical fiber in 10-49% hydrofluoric acid solution, immersing the optical fiber in the hydrofluoric acid solution to a depth of 0.5-5 mm, and corroding for 10 minutes-4 hours to form a single microneedle or microneedle array with a tip. FIG. 3 shows the silicon dioxide micro-needle obtained after the fiber is corroded by hydrofluoric acid.
Example 3
In this embodiment, a method for modifying metal nanoparticles is provided, where the modification method is an ion sputtering method, and different types of metal nanoparticles can be sputtered by replacing targets made of different metal materials. Taking sputtering gold nanoparticles as an example, fixing a gold target on a cathode, fixing the point position of the microneedle facing the target, setting the sputtering time to be 30 s-30 min, vacuumizing, and sputtering the gold nanoparticles.
Example 4
In this example, a method of preparing a pH sensitive SERS-active microneedle is provided, the microneedle having the same shape parameters as in example 1.
The specific preparation steps of the pH sensitive microneedle are as follows:
the steps for modifying the microneedles are described in example 1, and are not described herein. 4-mercaptobenzoic acid was added to a mixed solvent of ethanol and water of the same volume to prepare a 1 mmol/L4-mercaptobenzoic acid solution. And (3) immersing the microneedle with the surface modified with the metal nanoparticles into the solution, shaking for 30 minutes, and cleaning with ultrapure water to obtain the pH-sensitive microneedle.
Example 5
In this example, a method of preparing a redox sensitive SERS-active microneedle having the same shape parameters as in example 1 is provided.
The preparation method of the redox sensitive microneedle comprises the following specific steps:
the steps of modifying the microneedles are described in example 1, and are not described herein. Anthraquinone-2-carboxylic acid, dicyclohexylcarbodiimide, N-hydroxysuccinimide were added to dimethyl sulfoxide at the ratio of 2mg/mL, 1.6mg/mL, 2.3mg/mL, respectively, and stirring was continued at room temperature for 3 hours. Cystamine dihydrochloride was dissolved in the above solution at a concentration of 0.45mg/mL, and after overnight storage at 4 ℃ the supernatant was collected and diluted 100-fold with ethanol. The microneedle with the surface modified with the metal nanoparticles is immersed in the solution, shaken for 30 minutes, and then kept stand for 6 hours. After being washed by ultrapure water, the microdose sensitive to redox is obtained.
Example 6
In this example, a method of making a SERS-active microneedle sensitive to ROS is provided, the microneedle having the same shape parameters as in example 1.
The specific preparation steps of the ROS sensitive microneedle are as follows:
the preparation of the metal nanoparticle modified microneedles is described in example 1 and will not be described herein. Preparing 2mmol/L p-mercaptoaniline solution with isopropanol as solvent, and ultrasonic treating to dissolve. And (3) immersing the microneedle with the surface modified with the metal nanoparticles into the solution, oscillating for 30 minutes, and cleaning to obtain the ROS sensitive microneedle.
Example 7
In this example, methods for establishing pH, redox potential, and ROS concentration and Raman peak intensity are provided.
The three SERS-active microneedles prepared in examples 4, 5, and 6 were immersed in solutions with gradient pH, redox potential, and ROS concentration, respectively. Wherein, the gradient pH values are respectively 4, 5, 6, 7 and 8, the gradient redox values are respectively 417.0, 456.1, 479.8, 511.6 and 599.8 millivolts, and the gradient ROS concentrations are respectively 30, 60, 120, 240 and 480ng/mL. Obtained by a Raman detection instrumentThe raman spectrum of the solution. Respectively corresponding the three indexes to 1143cm -1 、1606cm -1 、1143cm -1 The intensity of the characteristic peak at (A), divided by the respective internal standard peak (1183 cm, respectively) -1 、1667cm -1 、1077cm -1 ) And obtaining the peak intensity ratio of the intensity, and obtaining the intensity-concentration relation corresponding to the three indexes through calculation. Fig. 5 shows raman spectra obtained by three microneedles, and the calculated intensity-concentration relationship of the three indexes.
Example 8
Three SERS active microneedles prepared in examples 4, 5 and 6 were inserted into the hindfoot pad of an anesthetized inflammatory mouse and placed in a Raman detection platform. And the control platform focuses the laser on the detection position to obtain a corresponding in-situ SERS spectrogram, and calculates and obtains specific inflammation related parameters of the part according to the intensity-concentration relation diagram in the figure 5. The resulting SERS spectra and corresponding parameter values are shown in fig. 6.
Claims (13)
1. The multiparameter SERS active microneedle is characterized in that the microneedle has a shape gradually shrinking towards the tail end, the diameter or side length of the bottom of the microneedle is 200-1000 micrometers, and the height of each microneedle is 400-1500 micrometers.
2. The multi-parameter SERS-active microneedle according to claim 1, wherein the host material of the microneedle is a highly transparent polymer or a highly transparent inorganic material.
3. A multiparameter SERS-active microneedle according to claim 2, in which the highly transparent polymer is a copolymer of one or more of polymethylmethacrylate, polycarbonate, polyvinyl chloride, polystyrene, polyethylene terephthalate, polyethersulfone and derivatives thereof, acrylonitrile-butadiene-styrene, polyvinyl fluoride, polyamide, styrene/acrylonitrile copolymer, polyhydroxyethylmethacrylate, cellulose acetate, and ethylene-vinyl acetate copolymer.
4. The multiparameter SERS-active microneedle according to claim 2, wherein the highly transparent inorganic material is one or more of quartz glass, optical fiber, and transparent ceramic such as calcium fluoride.
5. The multi-parameter SERS-active microneedle according to claim 1, wherein an adhesive layer is coated on the surface of the microneedle.
6. The multiparameter SERS-active microneedle according to claim 5, wherein the adhesion layer is any one or more of plant polyphenol containing phenolic hydroxyl groups, polydopamine and levodopa.
7. The multi-parameter SERS active microneedle of claim 6, wherein the plant polyphenol is catechol, gallic acid, procyanidins, lignans, quercetin, curcumin, resveratrol.
8. The multiparameter SERS-active microneedle according to claim 1, wherein the surface of the microneedle is modified with noble metal nanoparticles having a particle size of 20-125 nm.
9. The multi-parameter SERS-active microneedle according to claim 1, wherein the microneedle surface has chemically immobilized thereon a plurality of raman-active molecules.
10. The multi-parameter SERS-active microneedle of claim 9, wherein the raman-active molecule is at least one of pH-responsive molecule 4-mercaptobenzoic acid, 4-mercaptopyridine, redox-responsive molecule anthraquinone-2-carboxylic acid, ROS-responsive molecule para-aminophenol.
11. A method for preparing a multiparameter SERS-active microneedle according to any one of claims 1 to 10, wherein the preparation of the microneedle comprises the following steps:
(1) Preparing a microneedle main body by soft lithography or wet etching;
(2) Coating an adhesion layer on the surface of the microneedle;
(3) Modifying noble metal nanoparticles on the adhesion layer;
(4) Raman active molecules are chemically immobilized on the noble metal nanoparticles.
12. A method of using the multi-parameter SERS-active microneedle according to any of claims 1 to 10, wherein the method of use is in situ detection.
13. The method for detecting the multiparameter SERS active microneedle according to claim 12, wherein the in-situ detection is performed by placing a detection object on a Raman detection platform, inserting the multiparameter SERS active microneedle into a detection environment, and adjusting the position of the detection platform to focus laser on the surface of the microneedle to obtain an SERS spectrum.
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