CN111351812A - Pseudomonas aeruginosa detection method based on low-field nuclear magnetic resonance imaging - Google Patents
Pseudomonas aeruginosa detection method based on low-field nuclear magnetic resonance imaging Download PDFInfo
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- CN111351812A CN111351812A CN201811561822.1A CN201811561822A CN111351812A CN 111351812 A CN111351812 A CN 111351812A CN 201811561822 A CN201811561822 A CN 201811561822A CN 111351812 A CN111351812 A CN 111351812A
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Abstract
The invention discloses a pseudomonas aeruginosa detection method based on low-field nuclear magnetic resonance imaging, which introduces two magnetic nano-beads with different particle sizes, forms a sandwich structure after being combined with target bacteria and is separated and precipitated by a magnetic separator, and the remained solution of the small-particle-size magnetic beads can be detected in a low-field nuclear magnetic resonance instrument, and the signal intensity of an imaging image of the pseudomonas aeruginosa changes along with the change of concentration. The low-field nuclear magnetic resonance imaging method used by the invention utilizes the high efficiency of the magnetic separation technology and the magnetic signal amplification system, and can greatly improve the detection sensitivity. Meanwhile, the detection result can be displayed in an image form, and the method is more visual and convenient. Compared with the traditional low-field nuclear magnetic resonance detection method, the phenomenon that the magnetic beads are not gathered at the target can occur, the method eliminates false negative caused by the phenomenon, and the reliability of the method is improved.
Description
Technical Field
The invention belongs to the technical field of bacteria detection, and particularly relates to a pseudomonas aeruginosa detection method based on low-field nuclear magnetic resonance imaging.
Background
The low-field nuclear magnetic resonance imaging refers to nuclear magnetic resonance with the magnetic field intensity below 0.5T, and the hydrogen protons are most widely applied in the LF-MRI technology, mainly because the hydrogen protons have extremely high abundance in the nature, can generate very strong nuclear magnetic resonance signals, and have the characteristics of easy detection, convenient observation and stable existence. The main measurement indicator for low field magnetic resonance imaging is the relaxation time. LF-MRI reflects the kinetic properties of hydrogen protons primarily through measurements of the longitudinal relaxation time T1 (spin-lattice), the transverse relaxation time T2 (spin-spin) and the self diffusion coefficient. T1 and T2 measure the interaction between spin and ambient and spin, respectively. With the development of low-field nuclear magnetic resonance technology and nanotechnology, the bio-functionalized superparamagnetic nanoparticles (connected with different biomolecules such as nucleic acid, small molecules, polypeptide and antibody) are widely developed in the aspects of biological enrichment, identification and the like. The biological functionalized magnetic beads are enriched on biological macromolecules, and transverse relaxation time (T2) in the system is changed. This change can be sensitively detected using low field nuclear magnetic resonance (LF-NMR) methods. The two are combined to construct a novel biomolecule recognition method with the characteristics of extremely low detection limit, strong specificity, rapidness and the like.
Magnetic nanoparticles possess several advantages that make them well suited for use in the detection of microorganisms: (1) small particle size, difficult sedimentation, good suspension stability and high efficiency of coupling with a target product. (2) Large specific surface area and large adsorption capacity. (3) Has abundant surface active groups, and can be specifically combined with various substances with biological activity, such as biological enzyme, protein, etc. Can also be combined with specific targeting molecules on the surface, such as specific antibodies, aptamers and the like, and further applied to the separation of microorganisms. (4) The magnetic particles have certain mechanical strength and chemical stability, and can resist degradation of acid-base solutions with certain concentration and microorganisms. There is no particular requirement for the sample in the detection of microorganisms, and there is no need to adjust the pH of the sample solution. (5) Has superparamagnetism: under the existence of an external magnetic field, the magnetic particles have better responsiveness and can be rapidly aggregated, and when the external magnetic field is removed, the magnetic particles have no magnetic memory and can be uniformly dispersed without aggregation. (6) The method is simple and convenient to operate, can repeatedly separate magnetic particles under the action of an external magnetic field, has a very simple separation process, can save complex operations such as centrifugation and filtration, and saves time.
Disclosure of Invention
The invention aims to overcome the problems in the prior art, and provides a pseudomonas aeruginosa detection method based on low-field nuclear magnetic resonance imaging.
As shown in FIG. 1, the method of the present invention introduces two kinds of magnetic nanobeads with different particle sizes, forms a sandwich structure after combining with target bacteria and is separated and precipitated by a magnetic separator, and the solution of the small particle size magnetic beads can be detected in a low-field nuclear magnetic resonance instrument, and the imaging image signal intensity changes with the change of concentration.
Because large-particle-size magnetic beads are easy to aggregate and precipitate in a magnetic field, and small-particle-size magnetic beads show strong stability, pseudomonas aeruginosa aptamers are combined on the surfaces of the two magnetic beads through amido bonds, pseudomonas aeruginosa can be captured specifically, a sandwich structure of large magnetic beads, bacteria and small magnetic beads is formed, the sandwich structure can be separated and precipitated by a magnetic separator, and the small-particle-size magnetic beads which are not combined are left in a solution and are used as a detected signal substance. The higher the concentration of the pseudomonas aeruginosa is, the more small-particle-size magnetic beads can be separated along with a sandwich structure, the lower the solubility of the small-particle-size magnetic beads in the solution is, so that the relaxation time detected in a low-field nuclear magnetic resonance imager can be increased, and the quantitative detection of the pseudomonas aeruginosa can be completed through the change of the relaxation time after the pseudomonas aeruginosa is captured and the change of the color of the image.
Specifically, the technical scheme of the invention is as follows:
a pseudomonas aeruginosa detection method based on low-field nuclear magnetic resonance imaging comprises the following steps:
(1) preparing a standard curve of the dependence of the relaxation time on the concentration of pseudomonas aeruginosa:
respectively dispersing magnetic beads with two particle sizes in a solution; respectively combining the pseudomonas aeruginosa capture aptamer with the large and small magnetic beads to prepare an aptamer magnetic bead sensor containing the large and small magnetic beads, then mixing and incubating the two ligand magnetic bead sensors with pseudomonas aeruginosa solutions respectively containing different concentrations to obtain a mixed solution of the large and small magnetic beads and the pseudomonas aeruginosa, then carrying out low-field nuclear magnetic resonance imaging detection, and establishing a standard curve of the correlation between the relaxation time and the concentration of the pseudomonas aeruginosa;
(2) and (3) preparing a mixed solution containing the large and small magnetic beads of the pseudomonas aeruginosa sample and the pseudomonas aeruginosa sample according to the method, carrying out low-field nuclear magnetic resonance imaging detection, and calculating the concentration of the pseudomonas aeruginosa according to a standard curve.
In the method, the magnetic beads with the two sizes are nano magnetic beads, the diameter of the magnetic bead with the large size is 400-500nm, and 400nm, 420nm, 450nm, 470nm and 500nm can be selected; the diameter of the small-particle-size magnetic bead is 7-10nm, and can be selected from 7nm, 8nm, 9nm and 10 nm.
In the above method, the magnetic beads are iron oxide, cobalt oxide, or nickel metal oxide magnetic beads.
In the method, the surface of the magnetic bead is modified with carboxyl groups.
In the above method, the preparation method of the aptamer magnetic bead sensor comprises the following steps:
(1) dispersing the two magnetic beads in the solution respectively, adding MES buffer solution, and performing carboxyl activation to obtain two magnetic bead solutions;
(2) and respectively adding the pseudomonas aeruginosa aptamer into the two magnetic bead solutions, and incubating to obtain two aptamer magnetic bead sensors with different particle sizes.
In the method, the concentration of the magnetic beads dispersed in the solution is 0.05-0.5 mg/mL.
In the above method, the carboxyl group is activated by adding EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) and NHS (N-hydroxysuccinimide).
In the above method, the incubation method is carried out in a shaker at 30-40 ℃ for 25-35 minutes.
In the above method, before the low-field mri detection, the method further includes: and after incubation, carrying out magnetic separation on the mixed solution of the large and small magnetic beads and the pseudomonas aeruginosa, taking out the precipitate, removing the supernatant, and then placing the precipitate in low-field nuclear magnetic resonance imaging for detection.
In the above method, the method for detecting low-field magnetic resonance imaging includes: the relaxation time measurement is carried out by using a CPMG sequence, and the working conditions are as follows: after automatic shimming, a detection mode SE sequence is selected, parameters are TR:2000ms and TE:50ms, and the thickness of each layer is 2 mm.
In the above method, the pseudomonas aeruginosa capture aptamer is an aminated aptamer, and the sequence thereof is: 5' -NH2-CCCCCGTTGCTTTCGCTTTTCCTTTCGCTTTTGTTCGTTTCGTCCCTGCTTCCTTTCTTG-3'。
The invention has the advantages that:
the low-field nuclear magnetic resonance imaging method used by the invention utilizes the high efficiency of the magnetic separation technology and the magnetic signal amplification system, and can greatly improve the detection sensitivity. Meanwhile, the detection result can be displayed in an image form, and the method is more visual and convenient. Compared with the traditional low-field nuclear magnetic resonance detection method, the phenomenon that the magnetic beads are not gathered at the target can occur, the method eliminates false negative caused by the phenomenon, and the reliability of the method is improved.
The pseudomonas aeruginosa aptamer sensor based on low-field nuclear magnetic resonance imaging in the method can realize rapid and sensitive imaging detection of pseudomonas aeruginosa, and has the advantages of short detection time, more visual result and high detection effect.
Drawings
FIG. 1 is a schematic diagram of a Pseudomonas aeruginosa aptamer sensor based on low-field magnetic resonance imaging.
FIG. 2 is a transmission electron micrograph of a magnetic bead; a is a transmission electron microscope picture of surface carboxylated magnetic beads with the grain diameter of 400 nanometers; b is a transmission electron microscope image of the surface carboxylated magnetic bead with the grain diameter of 10 nanometers.
FIG. 3 shows the effect of magnetic separation of magnetic beads; a is the magnetic separation time of magnetic beads with the particle size of 10 nanometers, and b is the magnetic separation time of magnetic beads with the particle size of 400 nanometers.
FIG. 4 is a standard curve for Pseudomonas aeruginosa detection.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to specific embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention. The materials and devices used in the present invention are commercially available unless otherwise specified.
The invention is further described below with reference to the drawings and examples of the specification, but the invention is not limited thereto.
Embodiment 1 Pseudomonas aeruginosa detection method based on low-field nuclear magnetic resonance imaging
The invention utilizes the different magnetic properties of two magnetic beads with different particle sizes in a magnetic field to construct a rapid and sensitive imaging detection method, and the basic process is shown in figure 1.
1. Preparation of standard curve for correlation of relaxation time and pseudomonas aeruginosa concentration
Preparing a magnetic bead solution: ultrasonically dispersing iron oxide magnetic beads with two particle sizes and modified carboxyl groups on the surfaces in a solution for 30 minutes to prepare a magnetic bead solution, wherein the particle sizes of the two magnetic beads are respectively 10nm and 400nm, and the concentrations of the two magnetic bead solutions are respectively 0.1 mg/mL. FIG. 2 is a transmission electron micrograph of magnetic beads, and FIG. 3 shows the effect of magnetic separation of magnetic beads.
Preparation of magnetic bead-aptamer solution: firstly, two magnetic bead solutions with different particle sizes are respectively ultrasonically dispersed for 30 minutes to ensure the uniformity and stability of the magnetic bead solutions. Then, 300. mu.L of MES buffer (concentration 0.01M, pH 0.52) was added to 2mL of the magnetic bead solution. Then, 100. mu.L of EDC solution (20 mg/mL) was added and incubated at room temperature for 15 minutes, followed by 100. mu.L of NHS solution (10 mg/mL) and incubated for 30 minutes to ensure complete reaction.
(2) The aminated pseudomonas aeruginosa aptamer can be selected from: the sequence is as follows: 5'-NH2-CCC CCG TTG CTT TCGCTT TTC CTT TCG CTT TTG TTC GTT TCG TCC CTG CTT CCT TTC TTG-3' (produced by Shanghai Bioengineering Co., Ltd.).
200 mu L of aminated pseudomonas aeruginosa aptamer with the concentration of 20 mu M is respectively added into the two magnetic bead solutions, and the solution is placed in a shaking table at 37 ℃ to be shaken for 30 minutes, so that the aptamer and the magnetic beads are fully combined.
The solution was placed in a magnetic separator, unbound aptamers were separated from the solution by the magnetic separator for 5 minutes, and the precipitate was redissolved in 4.5mL of PBS buffer (0.01M, pH 7.4 containing 1% BSA) to give large and small particle size magnetic bead-aptamer solutions, respectively.
The pseudomonas aeruginosa liquid is sequentially diluted into 8 concentration gradients by physiological saline, and the concentrations are respectively as follows: 10-1、10-2、10-3、10-4、10-5、10-6、10-7、10-8. At a constant temperature of 37 ℃, 50 microliters of bacterial liquid is respectively taken, 225 microliters of prepared large-particle-size magnetic bead-aptamer solution and 225 microliters of small-particle-size magnetic bead-aptamer solution are sequentially added, and incubation is carried out for 90 minutes at 37 ℃. After 5 minutes of separation in a magnetic separator, 300. mu.l of the supernatant was taken and placed in a low-field NMR imager for relaxation time measurement.
Low-field nuclear magnetic resonance measurement: the relaxation time measurements were performed with a CPMG sequence. The working conditions were as follows: after automatic shimming, a detection mode SE sequence is selected, parameters are TR:2000ms and TE:50ms, and the thickness of each layer is 2 mm.
According to the formula Δ T ═ Tn-T0(TnRelaxation time, T, measured after the nth P.aeruginosa acquisition0Relaxation times measured after no capture of pseudomonas aeruginosa) and establishing a standard curve based thereon with the corresponding pseudomonas aeruginosa standard concentrations: 7.902X +97.56, R20.9865, linear range 3.1 × 102cfu/mL to 3.1 × 107cfu/mL, the limit of detection is 100cfu/mL, as shown in FIG. 4, 8 points were taken in the experiment, but only 6 points were linear, so that 6 points were shown.
2. Assay for Pseudomonas aeruginosa samples
Taking 50 microliters of a pseudomonas aeruginosa sample, sequentially adding 225 microliters of the prepared large-particle-size magnetic bead-aptamer solution and 225 microliters of small-particle-size magnetic bead-aptamer solution, and incubating for 90 minutes at 37 ℃. And then separating in a magnetic separator for 5 minutes, taking 300 microliters of supernatant to place in a low-field nuclear magnetic resonance imager for measuring relaxation time, then bringing the measured relaxation time into the standard curve to obtain the concentration of 635cfu/mL, and simultaneously carrying out a culture technology on the pseudomonas aeruginosa sample by using a plate counting method to obtain the concentration of 619cfu/mL of bacterial liquid. The constructed detection method is proved to have the recovery rate of 97.5 percent and good recovery rate in the actual sample detection.
Claims (10)
1. A pseudomonas aeruginosa detection method based on low-field nuclear magnetic resonance imaging is characterized by comprising the following steps:
(1) preparing a standard curve of the dependence of the relaxation time on the concentration of pseudomonas aeruginosa:
respectively dispersing magnetic beads with two particle sizes in a solution; respectively combining the pseudomonas aeruginosa capture aptamer with the large and small magnetic beads to prepare an aptamer magnetic bead sensor containing the large and small magnetic beads, then mixing and incubating the two ligand magnetic bead sensors with pseudomonas aeruginosa solutions respectively containing different concentrations to obtain a mixed solution of the large and small magnetic beads and the pseudomonas aeruginosa, then carrying out low-field nuclear magnetic resonance imaging detection, and establishing a standard curve of the correlation between the relaxation time and the concentration of the pseudomonas aeruginosa;
(2) and (3) preparing a mixed solution containing the large and small magnetic beads of the pseudomonas aeruginosa sample and the pseudomonas aeruginosa sample according to the method, carrying out low-field nuclear magnetic resonance imaging detection, and calculating the concentration of the pseudomonas aeruginosa according to a standard curve.
2. The method as claimed in claim 1, wherein the magnetic beads with two sizes are nano magnetic beads, the diameter of the magnetic bead with large size is 400-500nm, and the diameter of the magnetic bead with small size is 7-10 nm.
3. The method of claim 1 or 2, wherein the surface of the magnetic beads is modified with carboxyl groups.
4. The method of claim 3, wherein the method for preparing the aptamer magnetic bead sensor comprises the following steps:
(1) dispersing the two magnetic beads in the solution respectively, adding MES buffer solution, and performing carboxyl activation to obtain two magnetic bead solutions;
(2) and respectively adding the pseudomonas aeruginosa aptamer into the two magnetic bead solutions, and incubating to obtain two aptamer magnetic bead sensors with different particle sizes.
5. The method of claim 4, wherein the magnetic beads are dispersed in the solution at a concentration of 0.05 to 0.5 mg/mL.
6. The method of claim 4, wherein the carboxyl group is activated by adding EDC and NHS.
7. The method of claim 4, wherein the incubation is carried out in a shaker at 30-40 ℃ for 25-35 minutes.
8. The method of claim 1, further comprising, prior to performing the low-field magnetic resonance imaging examination: and after incubation, carrying out magnetic separation on the mixed solution of the large and small magnetic beads and the pseudomonas aeruginosa, taking out the precipitate, removing the supernatant, and then placing the precipitate in low-field nuclear magnetic resonance imaging for detection.
9. The method of claim 1, wherein the method of low-field magnetic resonance imaging detection comprises: the relaxation time measurement is carried out by using a CPMG sequence, and the working conditions are as follows: after automatic shimming, a detection mode SE sequence is selected, parameters are TR:2000ms and TE:50ms, and the thickness of each layer is 2 mm.
10. The method according to claim 1, wherein the pseudomonas aeruginosa capture aptamer is an aminated aptamer having the sequence:
5'-NH2-CCCCCGTTGCTTTCGCTTTTCCTTTCGCTTTTGTTCGTTTCGTCCCTGCTTCCTTTCTTG-3'。
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