CN106153599B - receptor-containing and receptor-free titanium dioxide nano metal film Raman chip and manufacturing method thereof - Google Patents
receptor-containing and receptor-free titanium dioxide nano metal film Raman chip and manufacturing method thereof Download PDFInfo
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Abstract
A titanium dioxide nanometer metal film Raman chip with or without a receptor and a manufacturing method thereof are disclosed, wherein the chip consists of a Surface Enhanced Raman Scattering (SERS) film and a carrier thereof, the carrier comprises three types of capillary type, small box type and microfluidic channel type, and the SERS-film is divided into two types of modification with or without the receptor, namely six Raman chips; the manufacturing method is characterized in that a control standard is set, and the steps of SERS-film manufacturing can be controlled: 1. the titanium dioxide film is pulled by a sol-gel method and is subjected to bulk crystallization; 2. growing a nano silver foil/silver particle two-layer SERS-film by photocatalysis; 3. according to the requirement of detecting a target object, namely a donor molecule, modifying a receptor molecule specifically coordinated and combined on a two-layer SERS-film by utilizing a hydrogen bond binding force or an immunological binding force to form a three-layer SERS-film; the Raman chip can be applied to environmental pollution control detection, drug and warfare agent detection, pesticide residue detection, food harmful additive screening, large-scale early cancer Raman screening and the like.
Description
Technical Field
the invention relates to the field of Raman analysis chips in the spectral analysis technology, in particular to a Raman chip with or without a receptor titanium dioxide nano metal film and a manufacturing method thereof.
background
A Raman sample pool which is formed by mixing and sucking nano silver particles and a liquid phase sample into a capillary tube by using a surface near field enhanced Raman scattering (SERS) effect principle is most commonly adopted, various Raman sample pool technical schemes are disclosed, for example, a TiO 2 nanotube array is firstly constructed on the inner wall of the capillary tube, a capillary sample pool CN102706857A which is formed by coupling Sn ions and modifying silver nanoparticles on the surface of the TiO 2 tube array, a multifunctional surface enhanced Raman scattering substrate preparation method, a photonic crystal with a three-dimensional porous ordered Si0 2 inverse opal structure is prepared in the capillary tube, then the capillary sample pool CN103257134A which is formed by modifying gold nanoparticles in the Si0 2 inverse opal structure by using an in-situ reduction or electrostatic adsorption method, a capillary tube-based surface enhanced Raman scattering substrate preparation method, a Raman channel Raman chip CN203929645U which is formed by mixing and injecting nano silver particles and the liquid phase sample into a nano microfluidic metal column group, a Surface Enhanced Raman Scattering (SERS) effect principle, a Surface Enhanced Raman Scattering (SERS) analysis technology which is established by using the nano silver particles and the liquid phase sample mixing and the liquid phase sample effect principle, and a.
For years, in many laboratory research works, various ordered and disordered array substrates such as 'micron-nanometer' pits, triangular cones, carbon nanotubes, cellosilk and the like are developed and applied on a flat plate, or a filter membrane and filter paper are directly used as the substrate, and then nano silver or gold sol is dripped or silver or gold nano particles are decorated to be used as an SERS substrate; the SERS substrate with the silver or gold nanoparticle film directly modified on the transparent flat plate is also available, and the ordered nano-pit and cone array SERS substrate is commercially available, so that a user needs to prepare silver nano sol for use, which not only causes inconvenience in preparing silver sol, but also causes insufficient sensitivity of the enhancement factor to analysis of a plurality of low-abundance trace samples.
Currently, there are three limitations and problems associated with using liquid phase samples in combination with silver nanoparticle blend injection into various raman sample cells: firstly, the raman enhancement activity function of silver nanoparticles is easily degraded and destroyed by the oxidation process in the air, and the storage life of the raman enhancement activity is short, about two weeks, so that no silver nanoparticle with long raman enhancement activity storage life is commercially available so far. Many silver nanoparticles used in Raman analysis laboratories are prepared by themselves, namely the silver nanoparticles can be used after being prepared, which is very inconvenient in the conventional Raman analysis service detection, and a silver nanoparticle-Raman sample cell chip which has long storage activity and is convenient to use is eagerly sold; secondly, quantitatively detecting low-abundance trace substances by SERS (surface enhanced Raman scattering) of a liquid-phase sample, wherein the sensitivity is not high enough, the uniformity, stability and repeatability of a detection result are not good enough, and quantitative analysis is a key problem which is not solved for many years; and thirdly, the gas phase sample is difficult to mix silver nanoparticles uniformly with the gas phase sample due to the large silver particles, so that the Raman sample pool chip mixed with the silver nanoparticles in the gas phase sample is not suitable for use.
The SERS Raman chips of the microfluidic channel type at home and abroad are not disclosed, one is the Raman chip which can flow when SERS metal nano particles are mixed with a liquid phase sample in the microfluidic channel, and the other is the Raman chip which can flow when the SERS metal nano particles are modified and fixed in the microfluidic channel and both the liquid phase sample and a gas phase sample can flow in the microfluidic channel; the domestic examples are CN102706857A and CN203929645U, namely one, and CN103257134A is the other Raman chip. Abroad, for example, the method of injecting a mixed solution of silver sol and two oligonucleotides into a microfluidic channel reported by Tachan Park (Tachan Park, Lab Chip,2005,5:437-442) is the former Raman Chip, and the method has the same limitations and disadvantages as the conventional Raman sample pool in which a liquid phase sample and nano silver particles are mixed and sucked into a capillary tube, and the method of Gang L Li and the like (appl. Phys. Lett.,2005,87,074101) firstly prepares hemispherical dimethyl siloxane on a substrate by using a photoetching technology, then uses electron beams to evaporate and partially deposit a silver nano film on the substrate, and assembles the latter Raman Chip of the microfluidic channel.
In the 2004 paper "the international conference paper of photoelectron and spectrum of Beijing nanostructure and material, SPIE,5635: 31-37", the inventor guides research and development, and has disclosed that the nano "silver foil/silver particle" -film found in theoretical simulation has "conventional hot spot" + "unconventional hot spot", the concentration of the hot spot of the structure design is particularly high, and the sensitivity will be increased particularly accordingly. In 2013, the study growth table paper "J.Phys.chem.C 2013,117, 6861-; however, limited to our level of understanding at that time, the two most critical control and three best control criteria parameters were not addressed: firstly, influencing links which are the most sensitive and the most critical and need to be controlled for the quality of the SERS nano silver particle film, namely requiring that the photocatalytic control growth realizes that most silver particles are close and the gap is close to 0 and less than 3nm, and simultaneously the diameter of most silver particles is just conjugated with the wavelength of an excitation laser beam, is not solved; secondly, multiple reflections caused by the thickness of the titanium dioxide film are not noticed, and the coherence quality of the light beam of the excited sample is seriously disturbed due to the participation of the back reflection of the silver foil, so that the enhancement efficiency of the SERS film is reduced, and the important problem is not noticed at that time, so that the problem of controlling the thickness of the titanium dioxide film is not researched and solved; and thirdly, the most important thing is that the optimal control standard parameters of three key processes are not discussed and proposed in the whole process of the production process of the SERS film, and the method is very important for ensuring the quality of each piece of SERS film produced, particularly the consistency and stability of products, which is a problem that the development of high-performance SERS chips at home and abroad is not solved at present, and the high-performance SERS chips cannot be developed without solving the problem.
disclosure of Invention
the invention relates to a titanium dioxide nano metal film Raman chip with or without a receptor, which consists of two parts, a carrier and a surface enhanced Raman scattering active film, namely an SERS-film; the carrier is of a capillary type, a small box type and a microfluidic channel type, and the SERS-film is divided into two types of titanium dioxide nano metal films with and without receptor modification; the SERS-film grows on the inner walls or transparent windows of the three carriers in an adherent way, and the manufacturing steps are as follows: firstly, plating a titanium dioxide nano film by adopting a sol-gel method and carrying out bulk crystallization; secondly, growing a nano metal film on the surface of the titanium dioxide film by a controllable photocatalysis method, wherein the nano metal film is a nano silver foil/silver particle film which is a high-sensitivity two-layer SERS-film; and thirdly, modifying the receptor molecules with specific coordination binding force on the surfaces of the two SERS-films by utilizing hydrogen bond binding force or immunological binding force according to the requirement of Raman analysis on the donor molecules of the target object to form a three-layer SERS-film with good specificity and ultrahigh sensitivity, wherein the number of the receptor molecules of the third layer is designed according to the requirement of Raman analysis on the number of the donor molecules of the target object to form a multi-receptor modified three-layer SERS-film, the two-layer SERS-film Raman chip is a Raman chip without receptor modification, is an intermediate product in the production process of the receptor modified three-layer SERS-film Raman chip, and is assembled into the ultrahigh-sensitivity three-layer SERS-film Raman chip by using the three-layer SERS-film.
the realization of a nano 'silver foil/silver particle' film is a difficult problem, and the basic requirements are as follows: the silver foil is thin and nano-scale, the silver particles are firmly attached to the silver foil and closely attached to the silver foil, and most of the silver particle scales are in resonance coupling with the wavelength of the excitation laser beam; the nano silver foil/silver particle two-layer SERS-film is characterized in that a titanium dioxide sol-gel film is coated on a glass substrate with good transparency in an adherent manner, the film is subjected to high-temperature baking and annealing, the dispersed dot type film is converted into an anatase type random dot matrix spot crystallization film, the thickness of the film is equal to or close to half wavelength or quarter wavelength of an excitation laser beam in the film, the nano silver foil/silver particle film is grown through ultraviolet light catalysis, the method utilizes the high photocatalysis efficiency of each spot of anatase type crystallization random lattice, and the lattice background substrate is still amorphous titanium dioxide gel film, the characteristic of extremely low photocatalytic efficiency is that a nano silver foil/silver particle film is naturally grown, the silver foil of the film is required to be very thin, most silver particles are close to each other, and the diameter of silver nano particles is equal to or close to lambda/2 or lambda/4.
best best best st st st st st st 2 545 stThe method is characterized in that when the optimal design parameters are established by a high-sensitivity SERS Raman active substrate, the optimal film thickness is established by a high-sensitivity SERS film-thin film.
In order to carry out Raman analysis on ultra-low abundance trace molecules, a receptor molecule film with a specific binding site between a third layer and a donor molecule of a detection target object is modified on the basis of a Raman chip two-layer SERS-film, and the method is characterized in that the type of the receptor molecule is determined by utilizing the existing experience of hydrogen bond chemistry or immunochemistry according to the coordination binding requirement of the donor molecule of the detection target object analyzed by the Raman chip and the selection of a hydrogen bond binding force or an immunological binding force mode, and the receptor molecule is modified on the surface of a two-layer SERS nano silver foil/silver particle film to form the three-layer SERS-film by utilizing the coordination binding force; when modifying some three-layer SERS-films, a transitional coupling molecular film needs to be modified in advance, and the affinity characteristics of the interface of some coupling molecular films and the silver interface of a nano silver foil/silver particle film are not good as those of the gold interface, a layer of gold atom film needs to be plated on the nano silver foil/silver particle film, so that the nano silver foil/silver particle gold-plated film becomes a nano metal silver foil/silver particle gold-plated film.
In order to realize the molecular Raman analysis of the ultra-low abundance trace detection target 'donor', the three-layer SERS-film Raman chip modified by a hydrogen bond bonding force and an immunological bonding force receptor can further improve the sensitivity, the signal-to-noise ratio and the specificity, and a sample concentration and enrichment system and a cleaning system are required to be configured when in use, and the device is characterized in that a controllable micro-flow driver of a gas phase or liquid phase sample is configured at a sample inlet and a sample outlet of the three-layer SERS-film Raman chip modified by the hydrogen bond bonding force and the immunological bonding force receptor to drive the controllable quantitative circulation flow of the gas phase or liquid phase sample, so that the concentration and the enrichment of the 'donor' molecule in a 'hot spot' on the surface of the three-layer SERS-film of the ultra-low abundance trace detection target 'donor' molecule are; and then, the flow of gas with very low Raman activity or purified water is utilized to complete the cleaning of background molecules of the Raman spectrum of the detection target object, and the signal-to-noise ratio and the specificity of the Raman fingerprint spectrum of the molecular characteristic of the detection target donor are improved.
The capillary type double-layer SERS-film Raman chip is an intermediate product, has high sensitivity and good repeatability and consistency, can keep Raman enhancement activity all the year round and is very convenient to use, and is characterized in that a hollow thin-wall hard neutral glass or quartz glass capillary with good transparency is adopted, the conventional tube type is round and can also be designed into non-round shapes, the inner diameter of the tube is about hundreds of microns, the tube length is generally 10-120 cm, a titanium dioxide film is manufactured by a sol-gel method and clings to the inner wall of the capillary tube, the titanium dioxide film is converted into a bulk grain crystallization film after high-temperature baking annealing, a nano silver foil/silver particle film is grown through photocatalysis, wherein most of silver particles are adjacent, and the particle size is conjugated with the wavelength of an; cleaning the capillary tube with purified water, drying with nitrogen, and sealing; the sealing of the capillary can be sealed by a tight cover, a wax seal and a tapering seal, the Raman active storage life of the chip of the tapering seal can exceed one year, two fine lines are respectively carved at two ends near the tapering seal, when in use, the capillary is broken at the lines, the sealing is opened, and a liquid phase sample is sucked or a gas phase sample is injected for Raman detection.
st st stas shown in FIG. 4, the method and apparatus for SERS-coating of capillary Raman chips is characterized in that a controllable coating lifting machine (5) and a coating liquid siphon system are utilized to construct a capillary SERS-coating apparatus, a coating solvent is sucked into/discharged from a capillary to produce an SERS-coating, the controllable coating lifting machine (5) is provided with a controllable vertical moving lifting part for lifting a moving liquid pool (6) sealed by a vacuum rubber plug, a plurality of capillaries (1) are vertically inserted into a small section in a vacuum rubber plug (10), the moving liquid pool (6) controlled by the coating lifting machine is communicated with a fixed liquid pool (7) through a vacuum rubber tube (8) to form a siphon system, after a proper amount of siphon coating liquid (9) is added, the siphon coating system is utilized to drive the capillary to suck/discharge the coating liquid in/out, the controllable coating lifting machine (5) is used for setting parameters, the coating program is automatically operated to finish coating, the optimal thickness control of the film in the capillary by adjusting the liquid level of the capillary to reduce the liquid surface of the film, the film modified by adjusting the capillary, the optimal liquid level of the capillary, the film is discharged, the optimal film is automatically baked film-coating process of titanium dioxide film-coating process is finished by a controllable coating lifting machine, the optimal baking process of a capillary film-coating lifting machine, the optimal film-coating process of a capillary film-coating machine, the optimal film-coating machine is finished by the optimal film-coating process of a random film-coating machine, the capillary film-coating machine, the film-coating machine.
st stAs shown in FIG. 5, another method and apparatus for SERS-coating of capillary Raman chips is characterized in that a plurality of capillaries (1) are vertically inserted into a vacuum rubber stopper (10) in a linear arrangement by a method for controlling the suction/discharge of capillary by using the adsorption force of the capillaries and the pressure of precisely adjusted nitrogen, the pipe of a precise pressure regulating valve (15) of a nitrogen bottle (16) is connected to another vacuum rubber stopper (10), two vacuum rubber stoppers and a glass tube with a vent valve (12) form a closed chamber (14), the other end of the capillary is immersed into a small section under the surface of titanium dioxide sol in a coating liquid tank (13) and is inclined at about 15 degrees from the surface of the coating liquid, the coating liquid is sucked into the capillary by using the surface adsorption force of the capillary, the titanium dioxide is discharged out of the capillary at the set optimal speed by adjusting the precise pressure regulating valve (15) of the nitrogen bottle, the titanium dioxide sol is finally discharged at the speed of the titanium dioxide sol, the thickness of the titanium dioxide sol-gel adhered to the inner wall of the capillary after the optimum thickness of the titanium dioxide film is completed, the process, the capillary is placed in a baking furnace at about 450 degrees, the temperature of the optimum modification by precisely adjusted, the modification by the modification of the capillary, the modification of the chip is adjusted by the modification, the chip is modified film, the chip is dried chip, the chip is dried after the chip is dried, the chip is dried, the chip is washed chip, the chip is dried, the chip is washed chip, the chip is.
The small box type multi-receptor modified Raman chip is characterized in that in the small box type Raman chip, a substrate and a cavity of an SERS-film adopt a split design, in the process of plating the titanium dioxide nano silver foil/silver particle film, a controllable film plating lifting machine (5) is adopted to manufacture two layers of SERS-films on flat glass with good transparency, a grating type multi-receptor molecular film is modified on the grating, one receptor molecular film is modified into one line in the grating, the number of the receptor molecular species can reach dozens, the modification process adopts a controllable multi-ink-jet needle head to write a plurality of receptor molecule sols into a grating multi-receptor molecule film on a small box type two-layer SERS-film, a pair of sample inlet and outlet channels is designed on the small box cavity, and the grating type multi-receptor molecule modified three-layer SERS-membrane substrate and the small box cavity are tightly packaged into a grating type modified multi-receptor small box type Raman chip.
The method is characterized in that in the microfluidic multichannel Raman chip, the multichannel structure is designed into grating arrangement, on the basis of the same two-layer SERS-film, a plurality of receptors are modified into three-layer SERS-films distributed in a matrix type grating shape, each receptor point line grating is modified with a plurality of different receptors, one receptor is modified into a point spot, the receptor types among the receptor gratings are different, and the number of the most modified receptors can be more than hundreds; the process for modifying the multi-receptor adopts a controllable multi-ink-jet needle head to write a plurality of receptor molecular sols into a multi-receptor molecular film arranged in a matrix form; the cavity of the microfluidic multichannel is also designed into grating-shaped arrangement with the same distance, the sample inlet and the sample outlet can be designed into one pair for each channel, or multiple pairs of sample inlet and sample outlet can be designed in groups, and finally the matrix-arranged multi-receptor molecular film substrate and the microfluidic multichannel cavity are tightly assembled into the matrix-modified multi-receptor microfluidic multichannel Raman chip.
The invention has the advantages that:
1. Compared with the current conventional capillary doped silver nanoparticle sample pool, the capillary type two-layer SERS nano silver foil/silver particle film Raman chip has 1-magnitude order higher sensitivity, two ends of the product are sealed, the nano silver foil/silver particle film is stored in an air-isolated mode, and the Raman activity storage period is very long; the kit is convenient to use, can be used for environmental pollution control detection, food harmful additive screening and pesticide residue detection, and is particularly suitable for application in large-scale early cancer Raman popularization screening.
2. In the future, the capillary Raman sample pool chip patent commodity can be conveniently used for the extensive early cancer Raman screening work; we have adopted capillary doped silver nanoparticle sample pool to research the screening lung cancer and early mastopathy method, and have achieved much better progress than other serum screening methods which are now widely used, the screening of early lung cancer needs to further improve the sensitivity and specificity of the system. The capillary type double-layer SERS nano silver foil/silver particle membrane Raman chip, the microfluidic channel type Raman chip and the small box type Raman chip provide important support for breakthrough of screening method research of early lung cancer and other early cancers in the future.
The key point of the research of the screening method for improving the early lung cancer and other early cancers is to improve the sensitivity and specificity of detection, the metabolic markers of lung cancer cells are not enough and incomplete only by collecting serum samples for screening, and then the markers of various Volatile Organic Compounds (VOCs) in exhaled air of a lung cancer patient and the EBC immune markers of lung tumor lesions brought out by the airflow of the exhaled air are collected for carrying out immune Raman screening, so that the combination of the exhaled air Raman screening and the serum Raman screening is very favorable for improving the sensitivity and specificity of the early cancer Raman screening.
drawings
FIG. 1 nano silver foil/silver particle two-layer SERS-film, and optimal manufacturing control method and optimal control standard parameter creation thereof
FIG. 2(A) is a relation curve of titanium dioxide film thickness to transmission peak position, which is used to detect the titanium dioxide film thickness by using the transmission peak position of the transmission spectrum, and (B) the early stage experimental result is used to demonstrate and conveniently explain the on-line establishment of the relation curve of W to d
FIG. 3(A) creating SPR peak height optimal control standard parameter H 545 and photocatalytic time optimal control standard parameter tau st of online fluorescence visible absorption spectrum, and (B) preliminary experimental results for demonstrating and conveniently explaining online creating H 545
FIG. 4 fabrication of capillary-type Raman chips using a controlled coating pulling machine and a siphoning system for the coating solution
FIG. 5 shows the fabrication of a capillary-type Raman chip by using capillary adsorption force and precise adjustment of nitrogen pressure control
FIG. 6 is a schematic diagram of a capillary-type SERS-film Raman chip
FIG. 7 is a flow chart of a process for manufacturing a small-box Raman chip
FIG. 8 is a schematic diagram of a structure of a microfluidic channel type Raman chip modified by multiple receptor molecules
FIG. 9 shows the results of preliminary experiments using (A) two-layer SERS-film capillary type chip with the same concentration of R6g10 -7 Mol/L, compared with the best results of (B) capillary doped silver nanoparticle sample cell
FIG. 10 comparison of sensitivity of a two-layer SERS-membrane preliminary developed with a capillary doped silver particle sample cell, (A) SERSp results for detection at the same concentration of R6g10 -6 Mol/L, and (B) SERSp results for detection with serum from the same healthy person
Detailed Description
1. Specific implementation method of capillary type receptor-free titanium dioxide nano metal film Raman chip
Referring to fig. 6, the structure of the capillary type raman chip is characterized in that a TiO 2 film (2) is plated in a capillary (1), a nano silver foil/silver particle film (3) grows on the TiO 2 film, an acceptor molecular film (4) is modified on the film, two ends of a sample inlet and outlet sealing section (5') of the capillary are respectively provided with a fine nick, and the nicks can be conveniently broken and opened for later use before the chip is used, wherein the specific implementation method of the capillary type raman chip comprises the following steps:
the first step is as follows: cleaning a hard neutral glass or quartz glass capillary tube, wherein the inner diameter is about 0.5mm, the outer diameter is 1.0mm, and the length is 100 mm;
Secondly, preparing TiO 2 sol, namely mixing 50mL of butyl titanate and 3mL of acetylacetone and stirring for 10min (called solution A), simultaneously mixing 110mL of absolute ethyl alcohol, 1.4mL of deionized water and 0.2mL of nitric acid and stirring for 10min (called solution B), then dropwise adding the solution B into the solution A in the stirring process of the solution A, and continuously stirring for 30min to finally form TiO 2 sol;
Thirdly, preparing a layer of titanium dioxide film with the optimum film thickness design requirement of lambda/2 n or lambda/4 n on the inner wall of the capillary tube by using a controllable coating drawing machine (50-300mm/min) and a siphon principle assembly device or a precise pressure regulating valve-nitrogen controllable blowing coating system according to the wavelength lambda of an excitation laser beam and by using a sol-gel method, establishing a control standard parameter d st of the optimum film thickness by using A circulation multiple times of pre-tests, comparing the control standard with the design index of the optimum film thickness to achieve the equality or the approach of the control standard parameter and the design index, and specifically producing the optimum titanium dioxide film by adjusting the optimum drawing speed upsilon of the controllable coating drawing machine shown in figure 4 or the pressure of the precise pressure regulating valve shown in figure 5, blowing the titanium dioxide sol out of the capillary tube at the speed upsilon, transferring the control standard of the optimum film thickness to the control standard upsilon st of the optimum control speed, and establishing a relation d-upsilon curve between the film thickness d and the separation speed;
Through A circulation multiple times of preliminary tests, the optimal control standard temperature T st and time T st parameters of anatase crystallization can be found in the range of about 400-450 ℃, the standard parameters are used for controlling the density of anatase crystallization random lattice spots of titanium dioxide film transformation, and the diameter of most of silver particles is exactly equal to or close to the half-wavelength lambda/2 or the quarter-wavelength lambda/4 of the excitation laser beam when most of silver particles are close to each other;
The fifth step, using controllable coating film pulling machine as figure 4, or using capillary force as figure 5, sucking AgNO 3 solution with concentration of 0.003M into capillary, and irradiating with UV lamp with wavelength of 254nm and power of 6W, the distance between capillary and UV lamp is about 6cm, under the irradiation of UV lamp through TiO 2 photocatalysis process, reducing silver ion of silver nitrate on the surface of TiO 2 film to generate silver nano particle film, the structure of silver nano particle film is dense single-layer silver nano particle film tightly combined on very thin silver foil, the size of nano particle is regulated by using light catalytic time, using on-line fluorescence visible absorption spectrum detection method as figure 3, detecting on-line optimum control standard SPR 545nm emission peak height H 545 with titanium dioxide 545nm as base, tau st as reference standard, making the gap of most silver nano particles close to zero, which is key to ensure high enhancement factor, injecting and blowing out AgNO 3 solution in Raman tube, replacing AgNO 3 new solution, using intelligent exchange system 3 for many times;
and a sixth step: the implementation method of the immunoreceptor-modified capillary-type titanium dioxide nano silver foil/silver particle membrane Raman chip is characterized in that on the basis of a two-layer SERS-membrane, according to the experience of immunology related to heat formation, an immunoreceptor coating solution is replaced in a coating solution pool shown in a figure 4 or a figure 5, and if necessary, the immunoreceptor-modified coating procedure can be completed by using the related coupling coating solution, so that the immunoreceptor-modified three-layer SERS-membrane capillary Raman chip is manufactured; if the Raman activity of some immune receptors is too low, Raman marker molecules with higher plating activity need to be added, and the relevant plating solution can be replaced;
The seventh step: the implementation method of the hydrogen bond receptor modified capillary type titanium dioxide nano silver foil/silver particle membrane Raman chip is characterized in that on the basis of the two-layer SERS-membrane, according to experience about heat formation of hydrogen bond combination, coating liquid about the hydrogen bond receptor is replaced in a coating liquid pool shown in a figure 4 or a figure 5, and a hydrogen bond receptor modified coating program is completed;
eighth step: the hydrogen bond receptor modified capillary type Raman chip can be designed into a gas phase or liquid phase sample Raman chip and can be repeatedly used; plating an electric heating film on the outer surface of a capillary of a reusable hydrogen bond receptor modified capillary type Raman chip, heating properly, cleaning the inner wall of the capillary chip by using cleaning solution and nitrogen, so that donor-receptor composite molecules on the surface of the SERS-film modified by the receptor are unbound, and the function of the capillary type titanium dioxide nano 'silver foil/silver particle' film Raman chip modified by the hydrogen bond receptor in the original state is recovered;
And ninth step, after the functional technological process of the TiO 2 -silver nanoparticle film on the inner wall of the capillary tube is completed, cleaning the inner wall, drying the inner wall by nitrogen, adding a sealing cover or wax sealing or flame sealing to seal two open ends of the capillary tube, and finally storing the capillary tube in a dark place, wherein the Raman active storage life of more than 1 year can be ensured.
the early research progress that we have preliminarily developed a capillary type titanium dioxide nano silver foil/silver particle film Raman chip, compared with the latter by SERSp experimental results, the sensitivity of the former is higher by one order of magnitude than that of the latter, FIG. 9A shows SERSp results of R6g10 -7 -Mol/L concentration of the titanium dioxide nano silver foil/silver particle film Raman chip, and FIG. 9(B) shows SERSp results of R6g10 -7 Mol/L concentration of the conventional silver nanoparticle-doped capillary sample pool;
2. Method for implementing small box type Raman chip
for example, the four manufacturing process steps of the small-box type raman chip are as follows:
The first step is as follows: plating a titanium dioxide nano gel film on the surface of a film base (17) with good transparency by a controllable film plating drawbench, and then putting the film at the optimal baking temperature for crystallization to complete the transformation (18) of random lattice anatase crystallization;
The second step is that: putting the titanium dioxide crystallized film in silver nitrate solution, and generating an optimal nano silver foil (19)/silver particle film (20) through photocatalytic reduction;
The third step: modifying a specific receptor molecular membrane on the surface of a nano silver foil/silver particle membrane by using a hydrogen bond bonding force or an immunological bonding force, and if the number of detected target donor molecular species is more than or equal to 3, separately modifying a plurality of receptor molecular membranes into a grating type (21) distribution; when a grating-shaped multi-receptor molecular film Raman chip is used in a Raman analysis experiment, the SERSp with the same number as the number of the gratings needs to be detected;
The fourth step: and tightly bonding and packaging the sample inlet capillary (23) and the sample outlet capillary (22) which are bonded with the Raman chip capsule cover and the transparent window glass plated with the SERS-film to assemble the capsule type Raman chip.
3. implementation method of microfluidic channel type Raman chip
The microfluidic channel type Raman chip modified by multi-receptor molecules can be designed into a single channel type and a multi-channel type:
Firstly, a microfluidic single-channel type multi-receptor molecule modified Raman chip,
The first step is as follows: plating a titanium dioxide nano silver foil/silver particle film (18-20) on the inner wall of a glass sheet of a Raman detection window (17);
The second step is that: modifying a plurality of to tens of 'receptor' molecular spot membranes (24) on the surface, and arranging the 'receptor' molecular spot membranes on a straight line, wherein the size of the spots is 0.5-1 mm; the coordination binding force of the receptor molecule and the Raman detection target donor molecule can have two modes of hydrogen bond binding force and immunological binding force;
the third step: the linear type multi-receptor molecular spot manufacturing process can be completed by adopting a controllable multi-ink-jet needle head;
The fourth step: the controllable electric heating film is plated on the outer wall of the quartz glass sheet window of the hydrogen bond binding receptor, so that the repeated use of proper heating can be provided, the used donor-receptor composite molecules are dissociated and combined, and the state of the Raman chip before use is recovered;
The fifth step: a sample inlet and outlet through hole-sample dripping vessel (26) is designed on the channel cavity (25) or connected with a sample inlet and outlet capillary tube so as to be connected with a controllable micro-flow driver of a liquid phase sample and a gas phase sample, and the shape of the sample cell cavity is generally designed into a semi-cylindrical groove shape (27);
And a sixth step: the microfluidic single-channel multi-receptor molecule modified SERS-membrane and the channel cavity (25) are assembled into a multi-receptor molecule modified microfluidic single-channel Raman chip.
Secondly, the manufacturing of the microfluidic multichannel Raman chip modified by the multi-receptor molecules can design a multichannel structure into a grating type in parallel, multiple receptors are modified into three layers of SERS-films distributed in a dotted grating shape in an array mode on the same two layers of SERS-films, multiple different types of receptors are modified on each receptor dotted grating, the receptors are arranged into three layers of SERS-films modified by multiple receptors in a dotted grating shape in a matrix mode according to one type of receptor and one point spot, the number of the types of the most modified receptors can be more than one hundred, and other implementation methods are the same as the above.
Third, the previous research progress, the "TiO 2 photocatalysis-silver foil/silver particle" membrane pre-developed in the previous stage, compared with the "capillary tube + doped optimal silver colloid" by using R6g10 -6 Mol/L to perform SERSp comparison experiment, the former sensitivity is higher by a plurality of orders than the latter, the former sensitivity is obviously higher by a plurality of orders in figure 10(A), the former sensitivity is also obviously higher by a plurality of orders than the latter by using serum of the same healthy person as a sample, the former sensitivity is higher by a plurality of orders in figure 10(B), two smaller Raman peaks of 1435 and 1635cm -1 are detected in the SERSp of R6g10 - 6 Mol/L in figure 10(A-1) due to the former sensitivity, the former sensitivity is not detected in the SERSp of R6g10 -6 Mol/L in figure 10(A-2), the same situation also occurs in the comparison detection of serum samples, the SERSp 1530 spectrum of the serum of figure 10(B-1) has two smaller Raman peaks of SERCM -1 and the serum 10 -6 in the B-6 Sp spectrum of the figure 10 (B-1).
4. Specific implementation method of three-layer SERS-membrane Raman chip modified by immune binding receptor
The first step is as follows: and (3) designing to improve the sensitivity of the Raman chip again: when the ultra-low abundance trace substance molecule Raman analysis without the receptor modification is carried out, one effective method is to utilize a three-layer SERS-film Raman chip modified by an immunological binding receptor and a controllable micro-driver configured with a gas-phase or liquid-phase sample to implement the circulating flow of a quantitative sample through the chip, so that the quantitative detection target donor molecule sample is combined with the receptor molecule on the film when continuously flowing through the surface of the three-layer SERS-film to generate a receptor-donor composite molecule, namely, a composite molecule firmly combined with an antibody-antigen, and the donor molecule combined on the three-layer SERS-film of the chip is enriched. Then the pipeline of the sample controllable micro-driver is turned to a cleaning agent purified water or nitrogen supply source to clean other non-detected background molecules in the chip, so that the interference background can be effectively reduced, and the signal-to-noise ratio of the Raman fingerprint spectrum of the receptor-donor composite molecule is improved;
Secondly, the manufacturing process of the high-efficiency silver foil/silver nanoparticle gold-coated film is basically the same as that of the silver foil/silver nanoparticle film, and the nano silver foil/silver particle gold-coated film can be finished through photocatalysis only by replacing the silver nitrate AgNO 3 coating liquid with chloroauric acid HAuCl 4 coating liquid with proper concentration in a few minutes at the final stage of the silver particle film plating;
The third step: the implementation method for manufacturing the three-layer SERS-membrane modified by the immune receptor can completely use all 'antigen-antibody' related knowledge and experience accumulated by immunology for reference, the adopted immune binding force is the antigen-antibody binding force, and the receptor molecule (antibody or antigen) corresponding to the target-donor molecule can be found according to the pyrogenic 'immunology' as long as the target-donor molecule (antigen or antibody) to be detected in a sample is determined to be the (antigen or antibody) molecule and the design of the specific binder to be modified in the Raman chip is determined;
The fourth step: only 1 or 2 immune receptors are used for modifying the three-layer SERS-membrane Raman chip, a capillary carrier design can be adopted, when the number of the immune receptors is more than or equal to 3, the Raman chip modified by the grating-shaped receptors needs to adopt two designs, namely a small box type Raman chip (shown in figure 7) and a microfluidic channel type Raman chip (shown in figure 8), and in the small box type Raman chip modified by the grating-shaped receptors, each receptor molecule is modified into a grating line in a grating; in the microfluidic channel type raman chip modified with a point-line receptor, each receptor molecule is modified into a receptor spot in a point line; the number of types of multi-receptor modification is designed according to market needs, and disease screening, diagnosis, food safety detection, pesticide residue screening and the like can adopt a Raman chip detection scheme with the number of types of multi-immune receptors more than or equal to 3, and the number of types of immune receptors can reach tens to one hundred at most.
5. Specific implementation method of three-layer SERS-film Raman chip for modifying receptor by hydrogen bond combination
The manufacturing process method of the three-layer SERS-film in the Raman chip for modifying the receptor by hydrogen bond combination is basically the same as that of the Raman chip for the immune receptor, and the main differences are as follows:
firstly, the method comprises the following steps: the preparation of the hydrogen bond combined receptor modified three-layer SERS-film can completely use all 'donor-receptor' related knowledge and experience accumulated by hydrogen bond chemistry for reference, and the method is applied to the hydrogen bond receptor modified three-layer SERS-film Raman chip; FIG. 8 is a schematic diagram showing the structure of a microfluidic channel type Raman chip modified with various receptor molecules;
Secondly, the method comprises the following steps: because the binding force of hydrogen bonds is relatively small, an electric heating film can be arranged on the outer surface of the glass sheet base of the three-layer SERS-film for heating, so that donor molecules bound with a receptor are unbound, and a controllable micro-driver drives a cleaning agent, purified water or nitrogen to clean the chip, so that the chip can be reused;
thirdly, the method comprises the following steps: when the ultra-low abundance trace substance molecule Raman analysis without the receptor modification is performed, the three-layer SERS-film Raman chip modified by the hydrogen bond-bound receptor and the enrichment of the detection target molecule thereof are the most effective method, and the chip is used for configuring a controllable micro-driver of a gas-phase or liquid-phase sample, controlling the quantitative sample to flow through the chip, so that the detection target donor molecule generates the accumulation of the hydrogen bond coordination 'receptor-donor' combination, realizing the enrichment of the detection target donor molecule at a detection point and effectively improving the sensitivity of the Raman fingerprint spectrum analysis of the ultra-low abundance trace substance molecule; and then, cleaning the background interfering molecules which cannot be combined with the receptor in the chip by using a cleaning agent, purified water or nitrogen through the chip, so that the signal-to-noise ratio of the Raman analysis of the ultra-low abundance trace substance molecules can be effectively improved.
Claims (9)
1. a Raman chip with or without a receptor titanium dioxide/nano metal composite membrane comprises a carrier and a surface enhanced Raman scattering active membrane, wherein the active membrane is referred to as SERS-membrane for short; the carrier is of a capillary type, a small box type and a microfluidic channel type; the SERS-film grows on the inner walls or transparent windows of the three carriers in an adherent way, and the manufacturing steps are as follows: firstly, plating a titanium dioxide nano film by adopting a sol-gel method and carrying out bulk crystallization; secondly, growing a nano silver foil/silver particle film on the surface of the titanium dioxide film by a controllable photocatalysis method; the Raman chip with the receptor titanium dioxide/nano metal composite membrane also comprises a third step of modifying the receptor molecules with specific coordination binding force on the surface of the two-layer SERS-membrane prepared in the second step by utilizing hydrogen bond binding force or immunological binding force according to the requirement of Raman analysis target object donor molecules; the nano silver foil/silver particle two-layer SERS-film prepared in the second step is characterized in that a titanium dioxide sol-gel film is coated on the inner wall of a transparent carrier or the wall of a transparent window in an adherent manner, the film is subjected to high-temperature baking and annealing to be converted into an anatase type random dot matrix spot crystallization film in a scattering mode, the thickness of the film is equal to or close to the half wavelength or the quarter wavelength of an excitation laser beam in the film, the nano silver foil/silver particle film is grown through ultraviolet light catalysis, the silver particles are close to each other, and the diameter of the silver particles is equal to or close to lambda/2 or lambda/4.
2. a Raman chip with and without receptor titanium dioxide/nano metal composite film as claimed in claim 1, wherein the second step is to prepare a nano "silver foil/silver particle" two-layer SERS-film, wherein three design indexes are that the thickness d best of titanium dioxide is λ/2n or λ/4n, n is the average refractive index of the film, the diameter φ best of silver particle is λ/2 or λ/4 and the gap between silver particles is close to 0nm but not more than 2nm, in the process of preparing the nano "silver foil/silver particle" two-layer SERS-film, the thickness d of titanium dioxide film is adjusted by adjusting the film-forming pulling speed of titanium dioxide sol-gel, i.e. velocity θ v that the liquid surface is separated from the substrate, the relation d- θ d curve of film thickness d to liquid surface separation velocity θ is established by on-line preliminary experiment, the relation d- θ f curve to n is established by on-line adjustment experiment, the adjustment experiment is established by multiple times of controlling the cycle of the standard parameter system A, the control standard θ v st is established by the measured fluorescence visible light spectrum, the theoretical transmittance curve is established by the method, the curve is established by adjusting the time curve of the peak emission time after the film thickness d is adjusted by baking, the curve of titanium dioxide film thickness d-g curve, the curve is established by adjusting the curve of the film thickness curve of the film-g curve of the film-.
3. The raman chip of claim 1 wherein the second SERS-membrane is modified to form a third SERS-membrane with specific binding sites to the donor molecules of the target object, wherein the second SERS-membrane is modified by modifying the second SERS-membrane to form a third SERS-membrane with specific binding sites to the donor molecules of the target object according to the coordination and binding requirements of the target donor molecules analyzed by the raman chip and the selection of the "hydrogen bonding" or "immunological bonding" methods; or before modifying the three-layer SERS-film, a transitional coupling molecular film needs to be modified in advance, and when the affinity characteristics of the interface of some coupling molecular films and the silver interface of the nano silver foil/silver particle film are not as good as those of the gold interface, a layer of gold atom film needs to be plated on the nano silver foil/silver particle film to enable the nano silver foil/silver particle film to become a nano metal silver foil/silver particle gold-plated film, and according to the coordination and combination requirements of a target donor molecule detected by Raman chip analysis and the selection of a 'binding force hydrogen bond' or 'immunological binding force' mode, a 'receptor' molecule is modified on the surface of the SERS-film prepared in the second step; or before the modification, modifying a transition coupling molecular film on the surface in advance, or modifying a gold atom film and a transition coupling molecular film at one time to form a nano metal silver foil/silver particle gold-plating film.
4. The receptor-containing and receptor-free titanium dioxide/nano metal composite membrane Raman chip as claimed in claim 1, wherein the three-layer SERS-membrane Raman chip modified by the hydrogen bonding force and the immunological bonding force and modified by the receptor is required to be provided with a sample concentration and enrichment system and a cleaning system when in use, and is characterized in that a controllable micro-flow driver of a gas phase or liquid phase sample is arranged at a sample inlet and a sample outlet of the three-layer SERS-membrane Raman chip modified by the hydrogen bonding force and the immunological bonding force and drives the controllable quantitative circulation of the gas phase or liquid phase sample to effectively realize the concentration and enrichment of 'donor' molecules in 'hot spots' on the surface of the three-layer SERS-membrane by the ultra-low-abundance trace detection target, so that the quantitative or semi-quantitative Raman analysis sensitivity is improved; and then, the flow of gas with very low Raman activity or purified water is utilized to complete the cleaning of background molecules of the Raman spectrum of the detection target object, and the signal-to-noise ratio and the specificity of the Raman fingerprint spectrum of the molecular characteristic of the detection target donor are improved.
5. The receptor-free titanium dioxide/nano metal composite film raman chip as claimed in claim 1, wherein the SERS-film raman chip prepared in the second step, in which the carrier is a capillary type, is an intermediate product, and is characterized in that a hollow thin-walled hard neutral glass or quartz glass capillary is used, the conventional tube type is circular or non-circular, the inner diameter of the tube is 500 μm, the tube length is 10 to 120 cm, a titanium dioxide film is manufactured by a sol-gel method by being closely attached to the inner wall of the capillary tube, the titanium dioxide film is converted into a shot crystallization film after high-temperature baking annealing, a nano "silver foil/silver particle" film is grown by photocatalysis, wherein silver particles are closely attached, and the particle size is conjugated with the wavelength of an excitation; cleaning the capillary tube with purified water, drying with nitrogen, and sealing; the capillary is sealed by a tight cover, a wax seal and a tapering seal, two fine lines are respectively carved at two ends near the tapering seal, when in use, the capillary is broken at the lines, the seal is opened, and a liquid phase sample is sucked or a gas phase sample is injected for Raman detection.
st st st6. the method for manufacturing Raman chips with and without receptors on titanium dioxide/nano metal composite films as claimed in claim 1, wherein the carrier is a capillary-type Raman chip SERS-film coating method, the SERS-film coating method is implemented by using a capillary coating system composed of a controllable intelligent coating and pulling machine (5) and a coating liquid siphon system, a capillary SERS-film coating device is constructed, a coating solvent is sucked into/discharged from a capillary to manufacture SERS-film, the controllable intelligent coating and pulling machine (5) is provided with a controllable vertical moving and pulling part for pulling a moving liquid pool (6) sealed by a vacuum rubber plug, a plurality of capillaries (1) are vertically inserted into a small section of a vacuum rubber plug (10), the moving liquid pool (6) controlled by the coating and pulling machine is communicated with a fixed liquid pool (7) through a vacuum rubber (8) to form a siphon system, after a proper amount of coating solution (9) is added, the coating liquid level in the coating liquid system is utilized, the suction/discharge of the coating liquid in the capillaries is driven, the suction/discharge of the capillaries, the coating liquid in-film coating liquid pool is controlled by a controllable intelligent pulling machine parameter setting, an automatic operation is automatically operated, a capillary modification process, a titanium dioxide/nano metal composite film coating process is modified by a capillary film coating process, a capillary film coating process of online modification process, a titanium dioxide/nano metal film coating process, a film coating process is controlled by a capillary film coating process, a capillary film coating process of a capillary film coating process, a capillary film coating process of a capillary film coating process.
st st7. The manufacturing method of Raman chip with and without receptor titanium dioxide/nano metal composite film as claimed in claim 1, wherein the carrier is a capillary-type Raman chip SERS-film coating method, which comprises forming a capillary coating system by using a controllable intelligent coating and pulling machine (5) and a coating liquid siphon system, controlling the suction/discharge of coating solvent into/from the capillary by using capillary adsorption force and precisely adjusted nitrogen pressure, inserting a plurality of capillaries (1) in a straight line arrangement into a small section of vacuum rubber plug (10), connecting the pipeline of a precise pressure regulating valve (15) of a nitrogen bottle (16) to another vacuum rubber plug (10), forming a sealed chamber (14) by using two vacuum rubber plugs and a glass tube with a vent valve (12), immersing the other end of the capillary into a small section under the surface of titanium dioxide sol in a coating liquid pool (13), inclining 15 degrees with the coating liquid surface, finally discharging the speed of titanium dioxide sol at one time to determine the thickness of the titanium dioxide sol-gel adhered to the inner wall of the capillary tube, after the procedure of the titanium dioxide film is finished, placing the capillary in a high temperature baking furnace, precisely adjusted to modify the modification temperature T3583 and modify the modification time, the film, after the film is finished, the procedure, the chip is dried by using a light, the capillary-film coating process, the capillary-film coating process of the capillary-film coating film, the capillary-film coating process, the capillary-film is changed into a silver film coating process, the chip is dried, the chip is dried, the chip, the.
8. The method for preparing a Raman chip with or without an acceptor titanium dioxide/nano-metal composite membrane according to claim 1, wherein when the carrier is in a small box shape, the substrate and the cavity of the SERS-film adopt a split design, in the process of plating the titanium dioxide nano silver foil/silver particle film, a controllable lifting film plating machine is adopted to manufacture two layers of SERS-films on flat glass, a grating type multi-receptor molecular film is modified on the surface of the substrate, one receptor molecular film is modified into one line in the grating, the modification process of the receptor adopts a controllable multi-ink-jet needle head, writing a plurality of receptor molecule sols into a grating-shaped multi-receptor molecule film on a small box type two-layer SERS-film, a pair of sample inlet and outlet channels is designed on the small box cavity, and the grating type multi-receptor molecule modified three-layer SERS-membrane substrate and the small box cavity are tightly packaged into a grating type modified multi-receptor small box type Raman chip.
9. the method as claimed in claim 1, wherein when the carrier is a microfluidic channel type, the raman chip modifies multiple receptor types of films into a matrix type structure, wherein in the microfluidic multi-channel raman chip, the multi-channel structure is designed into a grating arrangement, on the basis of the same two-layer SERS-film, multiple receptors are modified into three-layer SERS-films distributed in a matrix type dotted line grating shape, each receptor dotted line grating is modified with multiple different types of receptors, one receptor is modified into a spot, and the receptor types of each receptor grating are different; the process for modifying the multi-receptor adopts a controllable multi-ink-jet needle head to write a plurality of receptor molecular sols into a multi-receptor molecular film arranged in a matrix form; the cavity of the microfluidic multichannel is also designed into grating-shaped arrangement with the same distance, the sample inlet and the sample outlet can be designed into one pair for each channel, or multiple pairs of sample inlet and sample outlet can be designed in groups, and finally the matrix-arranged multi-receptor molecular film substrate and the microfluidic multichannel cavity are tightly assembled into the matrix-modified multi-receptor microfluidic multichannel Raman chip.
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