CN113125384A - Probe, circulating tumor cell detection equipment and preparation method - Google Patents
Probe, circulating tumor cell detection equipment and preparation method Download PDFInfo
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- CN113125384A CN113125384A CN202110233566.9A CN202110233566A CN113125384A CN 113125384 A CN113125384 A CN 113125384A CN 202110233566 A CN202110233566 A CN 202110233566A CN 113125384 A CN113125384 A CN 113125384A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/55—Specular reflectivity
- G01N21/552—Attenuated total reflection
- G01N21/553—Attenuated total reflection and using surface plasmons
- G01N21/554—Attenuated total reflection and using surface plasmons detecting the surface plasmon resonance of nanostructured metals, e.g. localised surface plasmon resonance
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/59—Transmissivity
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/59—Transmissivity
- G01N2021/5903—Transmissivity using surface plasmon resonance [SPR], e.g. extraordinary optical transmission [EOT]
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses a probe, a method for preparing the probe and circulating tumor cell detection equipment using the probe. The probe comprises a light fiber core, a fiber cladding, a nano gold film and a reflector, wherein the fiber cladding wraps the peripheral wall of the light fiber core, the nano gold film wraps the peripheral wall of the fiber cladding, the reflector seals one end of the light fiber core, the reflecting surface of the reflector faces the light fiber core, a grating is arranged on the peripheral wall of the light fiber core, and the outer side surface of the nano gold film is modified with plasmodium protein VAR2 CSA. When the guided mode of the fiber core transmitted in the fiber core passes through the grating, the cladding mode can be excited due to the phase matching condition. When capturing CTC, the plasmodium protein VAR2CSA influences a cladding mode, so that the energy of a fiber core guided mode is changed, and whether the CTC is contained in a sample to be detected or not can be read from an output spectrum.
Description
Technical Field
The invention relates to the technical field of detection equipment, in particular to a probe capable of identifying circulating tumor cells, a method for preparing the probe and circulating tumor cell detection equipment using the probe.
Background
Swelling of circulationTumor Cells (CTC). The earliest approved CTC clinical testing device by the Food and Drug Administration (FDA) was the CellSearch of the Strong Diagnostics, Inc. (Janssen Diagnostics)TMThe first generation of CTC detection technology, belonging to the flow forward enrichment fluorescence labeling technology, is characterized or limited by being capable of detecting only CTCs of epithelial origin, and its markers are EpCAM, DAPI, cytokeratin and CD 45. CellSearch is therefore approved only for metastatic breast, colorectal and prostate cancer. An additional disadvantage is that the specificity is not sufficient, since inflammation may also cause epithelial cells to enter the blood.
The second generation of CTC detection technology is an immunomagnetic bead negative enrichment technology, and is used together with a PCR or FISH technology, and besides the limitation of the first generation technology, the reliability of the result is more difficult to judge due to an additional detection means.
Even the most recent detection means for CTCs in China has its own limitations. The metabolism of tumor cells is dependent or addictive, partly on glycolysis and partly on glutamine metabolism. CTCell significance of positron emission tomography-X-ray computer tomography (PET-CT) detection technology principle based on glycolysis metabolism characteristicsTMOnly tumors that depend on glycolysis.
Disclosure of Invention
The present invention is directed to a probe, a method of manufacturing the probe, and a device for detecting circulating tumor cells using the probe, which solve one or more of the problems of the prior art and provide at least one of the advantages.
In order to solve the technical problems, the technical scheme includes that the probe comprises a light fiber core, an optical fiber cladding, a nanogold film and a reflector, the optical fiber cladding wraps the peripheral wall of the light fiber core, the nanogold film wraps the peripheral wall of the optical fiber cladding, the reflector seals one end of the light fiber core, the reflecting surface of the reflector faces the light fiber core, a grating is arranged on the peripheral wall of the light fiber core, and the outer side surface of the nanogold film is modified with plasmodium protein VAR2 CSA.
When the fiber core guided mode transmitted in the fiber core passes through the grating, part of energy in the fiber core guided mode is coupled to the fiber cladding to excite the cladding mode due to the phase matching condition. And the excited cladding mode couples partial energy to the nano-gold film to excite the surface plasma wave. And the surface plasma wave is extremely sensitive to the change near the surface of the nano gold film due to energy concentration. When the plasmodium protein VAR2CSA modified on the surface of the nano gold film captures CTC, the vicinity of the surface of the nano gold film is changed, surface plasma waves are influenced, and further the coupling efficiency of a fiber core guided mode and a cladding mode can be influenced, so that the detection function is realized.
In some embodiments of the invention, the direction of extension of the grating is at an angle θ, 15 ° ≦ θ ≦ 25 °, to the axis of the optical fiber core. The included angle range can be adapted to the measurement parameters of the biological sample in the aqueous solution, and the detection precision can be obviously reduced if the included angle range exceeds the measurement parameters.
In some embodiments of the present invention, the grating has a length of 1-2 cm. Too short grating length will result in insufficient spectral depth, and too long grating length will affect experimental operation and increase operation difficulty.
In some embodiments of the present invention, the thickness of the nano gold thin film is 45 to 55 nm. An excessively thick gold thin film may reduce the excitation success rate of surface plasmon resonance thereof.
In some embodiments of the present invention, the mirror is plated with a gold film of 200-250 nm. The reflectivity is reduced by an excessively thin gold film of the reflector, which causes energy loss and reduces the performance of the probe.
In another aspect, the present invention provides a method for preparing the probe, which includes the step of modifying the plasmodium protein VAR2CSA on the outer surface of the nanogold thin film:
1) cleaning the nano gold film;
2) soaking the nano gold film in 11-mercaptoundecanoic acid solution to form a self-assembled monolayer of mercapto compound on the surface of the nano gold film, and washing to remove the excessive 11-mercaptoundecanoic acid solution;
3) soaking the nano-gold film in a mixed solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), activating carboxyl on the self-assembled monolayer film, and then washing to remove the redundant mixed solution;
4) and (3) soaking the nano gold film in a plasmodium protein VAR2CSA solution for 1-4 h to obtain the nano gold film.
In some embodiments of the present invention, the concentration of the 11-mercaptoundecanoic acid solution in step 2 is 4 to 6mmol/L, and the solvent used is absolute ethanol. The method comprises the steps of firstly washing for 5-15 min by using absolute ethyl alcohol and then washing by using deionized water to remove the unreacted 11-mercaptoundecanoic acid solution.
In some embodiments of the present invention, the mixed solution in step 3 is prepared by mixing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride solution with a concentration of about 50mmmol/L and N-hydroxysuccinimide solution with a concentration of about 50mmmol/L in a volume ratio of (1-3): 1. The unreacted mixed solution was removed by flushing with a buffer solution. The buffer solution can be Phosphate Buffered Saline (PBS).
In some embodiments of the invention, the plasmodium protein VAR2CSA solution of step 4 is at a concentration of 1 μmol/L.
The invention also provides circulating tumor cell detection equipment which is provided with the probe. The probe plasmodium protein VAR2CSA can affect the coupling efficiency of a fiber core guided mode and a cladding mode when capturing CTC, so that the energy change of the fiber core guided mode can be realized, and whether the CTC is contained in a sample to be detected or not can be read from an output spectrum.
Compared with the prior art, the invention has the beneficial effects that:
a biological probe using the plasmodium protein VAR2CSA is provided, which can directly capture CTC by a method of specific binding with CTC polysaccharide, does not need to be identified by markers such as EpCAM, DAPI, cytokeratin, CD45 and the like as in the prior art, can detect different types of CTC, and improves the detection accuracy. The probe is based on fiber bragg grating surface plasma resonance, and the circulating tumor cell detection method using plasmodium protein VAR2CSA as a biological probe has the advantages of rapid detection and in-situ detection. After the circulating tumor cell detection equipment completes detection, CTC can be stripped from the probe in a biomolecule competition mode without damaging the probe, so that the probe can be reused.
Drawings
FIG. 1 is a schematic view of the structure of a probe according to example 1;
FIG. 2 is a spectrum of a test sample of example 2;
the reference numbers are respectively: 1. the optical fiber comprises an optical fiber cladding, 2 optical fiber cores, 3 gratings, 4 nano gold films, 5 reflectors, 6 optical fiber core guided modes, 7 cladding modes, 8 plasmodium proteins VAR2CSA, 9 circulating tumor cells CTC and 10 surface ion waves.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to specific embodiments, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1 preparation of Probe
Selecting germanium-doped optical fiber capable of improving photosensitivity as an optical fiber core 2, and preparing a grating 3 on the optical fiber core 2 by a phase mask method. Ultraviolet laser emitted by the excimer laser irradiates the phase mask plate after passing through the reflector 5 and the cylindrical mirror, and the inclination angle of the phase mask plate is adjusted, so that the inclined grating 3 can be written into the optical fiber core 2.
The surface of the optical fiber cladding 1 is plated with a nano gold film 4 by a magnetron sputtering method. Firstly, a vacuum pump is utilized to vacuumize a coating cavity to enable the vacuum degree to reach 10-3Pa; secondly, filling argon into the coating cavity, controlling the vacuum degree to be about 5Pa, adding an electric field of 0.8kV at two ends of the two electrodes to ionize the argon, bombarding the metal target by ionized particles,the atoms are adsorbed on the surface of the optical fiber cladding 1 after being off-target. In order to ensure that the film plated on the surface of the optical fiber cladding 1 is more uniform, the optical fiber is rotated around the optical axis of the optical fiber at a constant speed while the film is plated, so that the uniform attachment of gold atoms is ensured. The coating process is generally 40-50 seconds.
The reflector 5 can be prepared by adopting the same coating method of coating the nano gold film 4, the coating time is properly prolonged to about 10 minutes, and the reflector 5 is ensured to have enough thickness.
And performing plasmodium protein VAR2CSA 8 modification on the coated optical fiber. 1) And (3) cleaning the probe plated with the gold nano-film by using absolute ethyl alcohol to remove pollutants such as dust on the surface of the probe. 2) Preparing 11-undecament acid solution with concentration of 5mmol/L by absolute ethyl alcohol, soaking the probe in the solution for 12h to form a layer of self-assembled monolayer (SAM) of sulfhydryl compound on the surface of the gold film, washing the probe with absolute ethyl alcohol for 10min to remove 11-undecament acid molecules on the surface of the gold film without forming the self-assembled monolayer, and cleaning the probe with deionized water for 20min to remove residual ethyl alcohol and 11-undecament acid molecules. 3) Preparing solution of EDC and NHS with concentration of 50mmol/L by deionized water, mixing EDC and NHS according to proportion of EDC: NHS: 3:1, soaking the probe in the mixed solution for 1h, activating carboxyl on the sulfhydryl compound self-assembled membrane, washing the probe for 10min by using buffer solution, and washing the residual EDC and NHS clean. 4) Soaking the probe in a prepared plasmodium protein VAR2CSA solution with the concentration of 1 mu mol/L for 2h, wherein carboxyl on the surface self-assembly membrane SAM of the gold membrane is combined with free amino on the plasmodium protein VAR2CSA, and the plasmodium protein is fixed on the surface of the gold membrane to form the biological probe. The biotype probe with the plasmodium protein VAR2CSA 8 can directly capture CTC by utilizing the specific binding method of the biotype probe and circulating tumor cell CTC 9 polysaccharide. When the fiber core guided mode 6 transmitted in the fiber core 2 passes through the grating 3, part of the energy in the fiber core guided mode 6 is coupled to the fiber cladding 1 to excite the cladding mode 7 because the phase matching condition is satisfied. And the excited cladding mode 7 couples part of energy to the nano-gold thin film 4 to excite the surface plasmon wave 10. And the plasmodium protein VAR2CSA 8 combined with the circulating tumor cell CTC 9 influences the coupling efficiency of the optical fiber core guided mode 6 and the cladding mode 7, thereby realizing the detection function.
Example 2 verification of CTC detection device
To verify the feasibility of the probe for CTC detection, negative samples (sample solutions of only normal cells) and positive samples (sample solutions with CTC concentration of 1/10 mL) were tested separately. The probe prepared in example 1 was inserted into the negative sample and the positive sample, respectively, and a spectrum was recorded every 30 seconds for half an hour, and the experimental results are shown in fig. 2. The experimental result shows that when only normal cells exist in the sample solution, the output spectrum of the probe is basically unchanged; when the sample solution contains a small amount of CTC, the spectrum of the spectrogram in the surface plasmon wave absorption region is obviously changed (see the wave trough in the spectrogram of FIG. 2). The experimental results prove that the probe can detect the CTC concentration of 1/10 mL of sample solution, and the intensity variation value of the calibration mode (as shown by an arrow in figure 2) is more than 0.2dB (which is far more than the measurement error of the probe per se, namely 0.02 dB). The blood of healthy people does not contain CTC, and the content of CTC in 10ml of blood of a common patient is only 1-10, so the accuracy of the probe can meet the actual measurement requirement.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (10)
1. The probe is characterized by comprising a light fiber core, a light fiber cladding, a nanogold film and a reflector, wherein the light fiber cladding wraps the peripheral wall of the light fiber core, the nanogold film wraps the peripheral wall of the light fiber cladding, the reflector seals one end of the light fiber core, the reflecting surface of the reflector faces the light fiber core, a grating is arranged on the peripheral wall of the light fiber core, and the outer side surface of the nanogold film is modified with plasmodium protein VAR2 CSA.
2. The probe of claim 1, wherein: the extending direction of the grating and the axis of the light fiber core form an included angle theta which is more than or equal to 15 degrees and less than or equal to 25 degrees.
3. The probe of claim 1, wherein: the length of the grating is 1-2 cm.
4. The probe of claim 1, wherein: the thickness of the nano gold film is 45-55 nm.
5. The probe of claim 1, wherein: the reflector is formed by plating a 200-250 nm gold film.
6. The method for preparing the probe of claim 1, comprising the step of modifying the outer surface of the nanogold thin film with the plasmodium protein VAR2 CSA:
1) cleaning the nano gold film;
2) soaking the nano gold film in 11-mercaptoundecanoic acid solution to form a self-assembled monolayer of mercapto compound on the surface of the nano gold film, and washing to remove the excessive 11-mercaptoundecanoic acid solution;
3) soaking the nano gold film in a mixed solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, activating carboxyl on the self-assembled monolayer, and then washing to remove the redundant mixed solution;
4) and (3) soaking the nano gold film in a plasmodium protein VAR2CSA solution for 1-4 h to obtain the nano gold film.
7. The method according to claim 6, wherein the concentration of the 11-mercaptoundecanoic acid solution in step 2 is 4 to 6mmol/L, and the solvent used is absolute ethanol.
8. The method according to claim 6, wherein the mixed solution in the step 3 is prepared by mixing a 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride solution having a concentration of about 50m mmol/L and an N-hydroxysuccinimide solution having a concentration of about 50m mmol/L in a volume ratio of (1-3): 1.
9. The method according to claim 6, wherein the concentration of the plasmodium protein VAR2CSA solution in step 4 is 1 μmol/L.
10. A circulating tumor cell detection apparatus comprising the probe of any one of claims 1 to 5.
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