CN112635143A - Micron-sized uniform-particle biomagnetic microspheres and preparation method thereof - Google Patents
Micron-sized uniform-particle biomagnetic microspheres and preparation method thereof Download PDFInfo
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-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
- H01F1/0018—Diamagnetic or paramagnetic materials, i.e. materials with low susceptibility and no hysteresis
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F41/00—Apparatus or processes specially adapted for manufacturing or assembling magnets, inductances or transformers; Apparatus or processes specially adapted for manufacturing materials characterised by their magnetic properties
- H01F41/02—Apparatus or processes specially adapted for manufacturing or assembling magnets, inductances or transformers; Apparatus or processes specially adapted for manufacturing materials characterised by their magnetic properties for manufacturing cores, coils, or magnets
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- Engineering & Computer Science (AREA)
- Power Engineering (AREA)
- Manufacturing & Machinery (AREA)
- Soft Magnetic Materials (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention discloses a preparation method of micron-sized uniform-particle magnetic microspheres, which comprises the steps of uniformly mixing uniform-particle ion exchange resin microspheres with ferric salt, organic alkali, polyhydric alcohol and a surfactant, enabling the surfaces of the ion exchange resin microspheres to fully adsorb the substances, transferring the ion exchange resin microspheres into a high-pressure reaction kettle, and reacting for a period of time at 170-220 ℃ to obtain the uniform-particle magnetic microspheres. In the invention, the high saturation magnetization Fe is assembled by adopting the homogeneous particle polymer core3O4The nanoclusters are highly controllable in process, uniform in particle size, fast in magnetic response and free of remanence. The magnetic microspheres prepared by the method can be used in the biomedical engineering fields of cell sorting, single cell sequencing and the like after further surface chemical modification.
Description
Technical Field
The invention relates to the field of combination of nano materials and biotechnology engineering, in particular to a preparation method of micron-sized uniform-particle magnetic microspheres for scenes such as cell sorting, single cell sequencing and the like.
Background
Magnetic microspheres, also known as magnetic beads, refer to submicron or micron-sized microspheres that have a magnetic field responsive behavior. At present, the magnetic microspheres are mainly formed by compounding superparamagnetic inorganic nanoparticles and nonmagnetic materials, wherein the superparamagnetic nanoparticles refer to ferrite type nanocrystals in a general sense, the nonmagnetic materials refer to high molecular polymers or silane in a general sense, and the complex magnetic microspheres can be formed by gradually assembling a plurality of interlayers. The magnetic microsphere can be widely applied to various fields of biomedical engineering, such as nucleic acid extraction, protein purification, immunoassay, cell sorting, specific mRNA separation and the like.
At present, various methods for preparing magnetic microspheres exist, and the magnetic microspheres can be classified into dispersion type, core-shell type, hollow type and multi-sandwich type magnetic microspheres from the structure of the magnetic microspheres. The methods all involve the compounding of a non-magnetic material with superparamagnetic nanoparticles, followed by protection and functionalization of the composite structure. The core-shell type magnetic microsphere is usually prepared by coating a layer of uniform magnetic material on a macromolecule magnetic core, and the process has the characteristics of simple preparation and short time consumption, and most of the mainstream magnetic microsphere composite magnetic nanocrystals are prepared by an in-situ coprecipitation growth method at present. The composite magnetic microsphere prepared by the in-situ coprecipitation growth method has low magnetization intensity and is difficult to control and stabilize industrially.
In the existing preparation method of the magnetic microspheres with large particle sizes, the particle size control is uniform and complex, the time consumption of the preparation process is long, the environmental pollution is large, and the process control difficulty is high. Therefore, a preparation process of large-particle-size micron-size uniform-particle magnetic microspheres which are green, environment-friendly, simple in process and good in magnetic response performance is urgently needed.
Disclosure of Invention
The invention aims to provide a preparation method of a uniform-particle micron-sized magnetic microsphere, when the micron-sized uniform-particle ion exchange resin microsphere is fully adsorbed and balanced with ferric salt, polyhydric alcohol, organic base and a surfactant, the temperature is increased to 170-220 ℃, the reaction lasts for a certain time, superparamagnetic nanoclusters are gradually generated, the magnetic nanoclusters are gradually assembled on the surface of the microsphere along with the reaction, and the obtained magnetic microsphere has the advantages of fast magnetic response, good stability and highly controllable process.
In order to achieve the purpose, the technical route disclosed by the invention comprises the following specific steps:
s1, mixing the uniform ion exchange resin microspheres, ferric salt, organic base, polyol and surfactant uniformly to absorb fully;
and S2, transferring the reaction solution to a high-pressure reaction kettle, heating for reaction for a period of time to obtain assembled magnetic microspheres, cleaning the obtained crude product, and removing the magnetic nanocluster particles with weak binding force to obtain the uniform-particle micron magnetic microspheres.
As a specific description of the embodiment of the present invention, in step S1, the assembly of the precursor is performed by using a physical adsorption method, and the steps are as follows:
mixing the uniform particle ion exchange resin microspheres with ferric salt, polyhydric alcohol, organic base and surfactant according to a certain proportion, and absorbing for a period of time under the specified concentration.
Specifically, in step S1, the uniform particle ion exchange resin microspheres are mixed with ferric salt, polyol, organic base and surfactant according to the ratio of 1g: 5-20 mmol: 50-200 g: 10-200 mmol: 0-5 g.
As a further improvement of the embodiment of the invention, in step S1, the homogeneous ion exchange resin microspheres may be cation exchange resin microspheres or anion exchange resin microspheres, and may be, for example, homogeneous ion exchange resin microspheres with strong charge characteristic groups such as sulfonic acid groups, carboxyl groups, amino groups, etc. on the surface, and the degree of crosslinking of the selected homogeneous ion exchange resin microspheres is higher than 5%. The absorption temperature of the uniform particle ion exchange resin microspheres, ferric trichloride hexahydrate, polyol, organic base and a surfactant can be selected from 0-80 ℃, and the absorption time can be selected from 0.5-48 h. The ferric salt can be one or more of ferric chloride hexahydrate, ferrous chloride tetrahydrate, ferric chloride and ferrous sulfate heptahydrate; the polyalcohol can be one or more of ethylene glycol, triethylene glycol and tetraethylene glycol; the organic base is selected from one or two of sodium citrate, sodium acetate and triethylamine, and the surfactant is selected from one of polyacrylic acid, sodium polyacrylate, polyethylene glycol, polymaleate and polyacrylamide.
In the step S2, a solvothermal method is adopted to carry out in-situ nucleation to grow the magnetic nanoclusters, the reaction liquid is transferred into a high-pressure reaction kettle, the temperature selectable range is 170-220 ℃, the temperature rise rate selectable range is 50-200 ℃/h, and the heating time is 6-72 h.
And (3) after the reaction kettle is cooled to room temperature, taking out the magnetic microsphere product, carrying out magnetic attraction separation, washing with pure water for a plurality of times, dispersing the final product in the pure water, measuring the solid content of the product, and sealing and storing at 4 ℃.
On the other hand, the invention discloses the micron-sized uniform-particle biomagnetic microspheres prepared by the preparation method of the micron-sized uniform-particle biomagnetic microspheres.
The invention has the following beneficial effects:
the reagents required by the synthesis are safe and easy to obtain, the reaction conditions are highly controllable, and the industrial implementation is easy. If ferric chloride hexahydrate is used as ferric salt, sodium acetate is used as organic base, ethylene glycol is used as polyalcohol and polyethylene glycol is used as surfactant, the reagent is relatively safe, can be stored at room temperature and is low in cost. The reaction does not involve the complex steps of low temperature, vacuum, nitrogen gas, oxygen removal and the like required by a coprecipitation method, the reaction is carried out under the conditions of room temperature and atmospheric pressure, and the industrial reproducibility is good.
The magnetic core grows on the surface of the uniform particle ion exchange resin microsphere in situ by a solvothermal method, and the magnetic core prepared by the method has high saturation magnetization, stable assembly and higher separation efficiency when being used as a magnetic carrier. The magnetic hysteresis loop of the product magnetic microsphere is measured, so that the coercive force and remanence are zero, and the saturation magnetization and the content of iron element are both higher than those of the magnetic microsphere with 4.5 mu m of certain international brand.
The magnetic microsphere prepared by the method is prone to large-size magnetic beads (5-50 mu m), and the further modification of the functional groups on the surface of the magnetic microsphere can be applied to biomedical analysis application scenes such as cell sorting or single cell sequencing.
Drawings
FIG. 1 is a schematic diagram of a preparation route of magnetic microspheres according to an embodiment of the present invention;
FIG. 2 is a representation of a scanning electron microscope of 5 μm magnetic microspheres according to an embodiment of the present invention;
FIG. 3 is a graph of the thermogravimetric profile of the main product provided by the example of the present invention;
FIG. 4 is a magnetic hysteresis loop diagram of a 5 μm magnetic microsphere provided in an embodiment of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all 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.
Unless otherwise specified, the reagents used in the following examples are commercially available from normal sources.
Preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.
Example 1
5g of styrene, 0.28g of azodiisobutyronitrile, K-300.84 g of polyvinylpyrrolidone and 100g of ethanol are added into a 250mL three-necked flask, three ports are respectively connected with a nitrogen inflow pipe, a polytetrafluoroethylene stirring paddle and a spherical condenser device, and nitrogen is introduced into the device at the stirring speed of 300rpm to protect and stir for 30 min. Then, the temperature is raised to 75 ℃ under the protection of nitrogen to initiate polymerization, 5g of styrene and 0.5g of divinylbenzene are slowly introduced every 2 hours after the polymerization is carried out for 1 hour, and the steps are repeated for 4 times in total to ensure that the total amount of the styrene in the reaction liquid reaches 25g and the total amount of the divinylbenzene reaches 2 g. The reaction is continued after the monomer is introduced until the whole polymerization process reaches 24h, and the polymerization is always protected by nitrogen. And cooling the reaction solution to room temperature, taking out the reaction solution for 1000rcf 5min, performing centrifugal separation, washing the reaction solution for 3 times by using anhydrous methanol, and performing vacuum drying on the final product at 40 ℃ for 24h to obtain the dried 5-micron-sized polystyrene microspheres.
1g of 5-micron uniform-particle polystyrene microspheres are taken, 2.5mL of glacial acetic acid is added, the materials are uniformly mixed and then are slowly stirred in a 250mL glass reactor, and the periphery of the glass reactor is cooled by an ice-water bath. 25mL of concentrated sulfuric acid is taken and gradually introduced into the polystyrene microsphere glacial acetic acid dispersion liquid protected by the ice water bath in a dropwise manner, the reaction liquid becomes dark red rapidly after dropwise addition, and the addition of the concentrated sulfuric acid is completed within half an hour. And then heating the glass reactor to 80 ℃ in a water bath for reaction for 6h, pouring the glass reactor into 1kg of snowflake crushed ice for quenching reaction at one time after the reaction is cooled, centrifugally separating the reaction solution at 1000rcf 5min, washing the reaction solution with water until the pH of the supernatant is neutral, and drying the final product at 80 ℃ in vacuum for 12h to obtain the dried 5-micron uniform-particle surface sulfonated ion exchange resin microspheres.
1g of 5-micron uniform particle surface sulfonated ion exchange resin microspheres are taken and dispersed in 150mL of ethylene glycol, 5g of ferric trichloride hexahydrate, 29.4g of sodium citrate and 3.5g of polyethylene glycol (molecular weight is 8000) are added, and then the mixture is stirred vigorously at 60 ℃ for 24 hours. The reaction suspension was transferred to a 200mL autoclave and the temperature was raised to 200 ℃ for 8 hours. And cooling the product, performing magnetic attraction separation, and washing with pure water for several times to obtain the magnetic microspheres with the total amount of 0.7 g.
Example 2
Taking 1g of 5-micron uniform-particle surface sulfonated ion exchange resin microspheres in the specific example 1, dispersing the microspheres in 150mL of ethylene glycol, adding 5g of ferric trichloride hexahydrate, 13g of anhydrous sodium acetate and 5g of polyacrylic acid (molecular weight is 20000), and then violently stirring at 60 ℃ for 24 hours. The reaction suspension is transferred into a 200mL high-pressure reaction kettle, and the temperature is increased to 200 ℃ for reaction for 12 hours. And cooling the product, performing magnetic attraction separation, and washing with pure water for several times to obtain the magnetic microspheres with the total amount of 0.8 g.
Example 3
Taking 1g of 5-micron-sized surface-carboxylated ion exchange resin microspheres from example 1, dispersing the microspheres in 120mL of triethylene glycol, adding 4.5g of ferric chloride, 21g of sodium citrate and 5g of sodium polyacrylate (molecular weight: 200000), and then vigorously stirring at 60 ℃ for 24 hours. The reaction suspension is transferred into a 200mL high-pressure reaction kettle, and the temperature is raised to 190 ℃ for reaction for 24 hours. And cooling the product, performing magnetic attraction separation, and washing with pure water for several times to obtain the magnetic microspheres with the total amount of 0.8 g.
Example 4
Taking 1g of 5 μm uniform particle surface aminated ion exchange resin microspheres in example 1, dispersing in 150mL of triethylene glycol, adding 5g of ferric trichloride hexahydrate, 7.9g of ammonium bicarbonate and 3.5g of polyacrylamide (molecular weight-3000000), and then vigorously stirring at 60 ℃ for 24 h. The reaction suspension was transferred to a 200mL autoclave and the temperature was raised to 180 ℃ for 72 hours. And cooling the product, performing magnetic attraction separation, and washing with pure water for several times to obtain the magnetic microspheres with the total amount of 0.8 g.
The solvent thermal reduction method adopted in the invention grows the superparamagnetic nanocrystal cluster, and the principle is shown in figure 1. The assembled magnetic microspheres have good superparamagnetic property and good actual use effect, meet the requirement of the magnetic microspheres on the magnetic response speed of automated sample treatment in modern biological analysis, and ensure that the scattered magnetic microspheres cannot be agglomerated again.
The magnetic microspheres of the invention can provide equivalent functionality because of ensuring that each uniform particle magnetic microsphere has equal surface area, and can have highly controllable characteristics in the fields of ultra-sensitive analysis and special scientific research, as shown in figure 2, because the adopted core ion exchange resin is a microsphere with high uniform particle size, the particle size difference coefficient CV value of the magnetic microspheres of the invention is less than 3%, and the particle size uniformity is good.
Compared with the magnetic microspheres with the diameter of M4.5 mu M and the brand similar to that of the magnetic microspheres D in the international mainstream, the magnetic microsphere D has the iron element content of about 22 percent and the saturation magnetization of about 18 emu/g; the invention can reach the content of the iron element of the magnetic bead of 31 percent and the saturation magnetization of 21emu/g, is superior to the competitive product in the aspect of superparamagnetism, and has the specific effects shown in figures 3 and 4. The dotted line in FIG. 3 is the thermogravimetric curve of the ion exchange resin microsphere, the weight loss at 700 ℃ reaches 73%, and the weight loss is mainly contributed by the thermal decomposition of the polymer microsphere body at about 480 ℃. The solid line is the thermal weight loss curve of the magnetic microsphere, the weight loss reaches 42% at 700 ℃, and the thermal decomposition of the polymer microsphere body at the temperature of 480 ℃ mainly contributes, so that the content of the iron element in the magnetic microsphere can be calculated to reach 31%.
The above is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, many variations and modifications can be made without departing from the inventive concept of the present invention, which falls into the protection scope of the present invention.
Claims (8)
1. A preparation method of micron-sized uniform-particle magnetic microspheres is characterized by comprising the following steps of:
s1, mixing the uniform ion exchange resin microspheres, ferric salt, organic base, polyol and surfactant uniformly to absorb fully;
and S2, transferring the reaction solution to a high-pressure reaction kettle, heating for reaction for a period of time to obtain assembled magnetic microspheres, cleaning the obtained crude product, and removing the magnetic nanocluster particles with weak binding force to obtain the uniform-particle micron magnetic microspheres.
2. The method for preparing micron-sized homogeneous biomagnetic microspheres according to claim 1, wherein in the step S1, the homogeneous ion exchange resin microspheres are mixed with ferric salt, polyhydric alcohol, organic base and surfactant according to a ratio of 1g: 5-20 mmol: 50-200 g: 10-200 mmol: 0-5 g.
3. The method for preparing micron-sized, uniform-particle biomagnetic microspheres according to claim 1, wherein the uniform-particle ion exchange resin microspheres in step S1 can be cation exchange resin microspheres or anion exchange resin microspheres, such as uniform-particle resin microspheres with strong charged groups, such as sulfonic groups, carboxyl groups, amino groups, etc., on the surface, and the degree of crosslinking of the uniform-particle resin microspheres is higher than 5%.
4. The method for preparing micron-sized homogeneous biomagnetic microspheres according to claim 1, wherein in the step S1, the adsorption temperature of the homogeneous ion exchange resin microspheres, ferric trichloride hexahydrate, polyol, organic base and surfactant is selected from a range of 0-80 ℃, and the adsorption time is selected from a range of 0.5-48 h.
5. The method for preparing micron-sized, uniform-particle biomagnetic microspheres according to claim 1, wherein the ferric salt in step S1 can be one or more selected from ferric chloride hexahydrate, ferrous chloride tetrahydrate, ferric chloride and ferrous sulfate heptahydrate; the polyalcohol can be one or more of ethylene glycol, triethylene glycol and tetraethylene glycol; the organic base is selected from one or more of sodium acetate, sodium citrate, ammonium acetate and triethylamine, and the surfactant can be selected from one of polyacrylic acid, sodium polyacrylate, polyethylene glycol, polymaleate and polyacrylamide.
6. The method for preparing micron-sized homogeneous particle biomagnetic microspheres according to claim 1, wherein in the step S2, the reaction temperature ranges from 170 ℃ to 220 ℃, and the temperature rise rate can be selected from 50 ℃/h to 200 ℃/h, and the reaction time ranges from 6h to 72 h.
7. A micron-sized homogeneous biomagnetic microsphere prepared according to the preparation method of the micron-sized homogeneous biomagnetic microsphere of any one of claims 1 to 6.
8. The micron-sized homogeneous particle biomagnetic microspheres according to claim 7, which can be used in the fields of chemiluminescence immunoassay, nucleic acid/protein separation and purification, cell sorting and single cell sequencing biomedical engineering after further surface modification.
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| CN114634220A (en) * | 2022-01-18 | 2022-06-17 | 华东理工大学 | Method for photodegrading organic arsenide |
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