Synthesis and functional modification of large diameter core-shell magnetic polymer microspheres

Abstract

The application relates to the technical field of biotechnology, and discloses a synthesis and functional modification technology of large-diameter core-shell type magnetic polymer microspheres, which comprises the following steps: S1, preparation and modification of polymer microspheres; S2, adsorption of magnetic fluid on the surface of the polymer microspheres; S3, surface cross-linking and functionalization of the magnetic microspheres; S4, multilayer adsorption of the magnetic fluid on the surface of the polymer microspheres; and S5, functionalization and application. The synthesis and functional modification technology of the large-diameter core-shell type magnetic polymer microspheres fills the short board of the prior art, and can amplify the preparation process of the uniform and large-diameter magnetic polymer microspheres for large-scale production. The particle size and uniformity of the core-shell type magnetic polymer microspheres depend on the size and uniformity of the polymer microsphere core, and the polymer microsphere core can have a relatively wide particle size range, and polymer microspheres with a particle size of several hundred nanometers to millimeters can be implemented through the technical scheme.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biotechnology, in particular to the synthesis and functional modification technology of large particle size core-shell magnetic polymer microspheres. BACKGROUND

[0002] The current literature and prior art technical solutions have not been able to realize the large-scale synthesis of large particle size (10-100 μm) magnetic polymer microspheres with uniform size, especially core-shell magnetic polymer microspheres.

[0003] The prior art has relatively high requirements for raw materials, and the process is very unstable, the coating amount of magnetic substances cannot be accurately controlled, and the repeatability between batches is poor. Moreover, some reagents with environmental pollution and safety hazards, such as sulfonating reagents such as sulfuric acid, are often used in the prior art process. The high requirements for raw materials, a large number of regulated reagents, and batch instability limit the production scale of the prior art, and therefore the present application provides a synthesis and functional modification technology of large particle size core-shell magnetic polymer microspheres. SUMMARY

[0004] (I) Technical problems to be solved

[0005] In view of the deficiencies of the prior art, the present application provides a synthesis and functional modification technology of large particle size core-shell magnetic polymer microspheres, which solves the problems raised in the background art.

[0006] (II) Technical solutions

[0007] In order to achieve the above purpose, the present application provides the following technical solutions: a synthesis and functional modification technology of large particle size core-shell magnetic polymer microspheres, comprising the following steps: S1, preparation and modification of polymer microspheres; S2, adsorption of magnetic fluid on the surface of the polymer microspheres; S3, surface cross-linking and functionalization of the magnetic microspheres; S4, multilayer adsorption of magnetic fluid on the surface of the polymer microspheres; and S5, functionalization and application.

[0008] Preferably, the polymer microspheres used can be polystyrene microspheres, cross-linked polystyrene microspheres, polymethyl methacrylate microspheres, etc. The particle size can be from a few hundred nanometers to a few microns. Since the shell layer of the magnetic substance is relatively thin, the particle size and uniformity of the final magnetic microspheres depend on the particle size and uniformity of the polymer microspheres. It is worth noting that the particle size range of the polymer microspheres suitable for the present application is very wide, and can be suitable for nanoscale diagnostic microspheres, sub-micron / micron scale chemiluminescent microspheres, and larger range, tens of microns to a few millimeters of large particle size microspheres. The microspheres can be commercialized high uniformity microspheres, or high uniformity microspheres can be synthesized by polymerization reaction.

[0009] Preferably, the microspheres are modified by electrostatic adsorption and hydrophobic interaction, and a layer of electronegative amphiphilic molecules, such as alkyl benzene sulfonate, alpha-olefin sulfonate, alkyl sulfonate, and other surfactants, is coated on the surface of the polymer microspheres by electrostatic adsorption and hydrophobic interaction. Preferably, sodium dodecyl benzene sulfonate or sodium dodecyl sulfate can be used. The hydrophobic end is adsorbed to the hydrophobic layer on the surface of the polymer, and the negatively charged ions are exposed to the outer hydrophilic layer.

[0010] After modifying the negative layer, the surface of the microspheres is converted into a positively charged functional group using positively charged polymer molecules, such as amino polymers such as polyacrylamide and polyethyleneimine. Preferably, polyethyleneimine is used. The positively charged amino polymers are adsorbed on the surface of the polymer microspheres by electrostatic adsorption, forming a positively charged amino functional outer layer. Specific embodiments:

[0011] Take 200g of PS-DVB microspheres and disperse them in 5000mL of water. Add 50g of sodium dodecyl sulfate while stirring. After stirring at room temperature for 2h, wash the microspheres with pure water to remove unadsorbed sodium dodecyl sulfate. After washing, disperse the microspheres in 5000mL of water, add 50g of polyethyleneimine solution, and stir at room temperature for 2h. Then wash the microspheres with pure water to remove unadsorbed polyethyleneimine.

[0012] Preferably, the magnetic fluid used is Fe3O4 magnetic nanoparticles with a size of 10-500nm, and the optimal size is 10-200nm. Fe3O4 nanoparticles are agglomerated to form magnetic fluid (usually 10-15nm Fe3O4 nanoparticles are agglomerated to form 50-200nm magnetic fluid). Commercially available oleic acid modified magnetic fluid nanoparticles can be used, or oleic acid modified magnetic fluid nanoparticles can be synthesized in one pot. Specific embodiments:

[0013] Dissolve 129.2g of ferric chloride and 87.4g of ferrous chloride in 1000mL of pure water, set the oil bath temperature to 80℃ and stir for 15min. Dissolve 100g of sodium oleate in a mixture of 200mL of water and 200mL of ethanol, and then add it to the Fe salt solution after complete dissolution by ultrasonic stirring. Continue stirring for 15min, then directly pour into 500mL of ammonia water for reaction. After 15min, set the oil bath temperature to 100℃ and age for 1.5h. After the reaction is complete, pour the reaction liquid into a fume hood and let it settle overnight. Collect the supernatant for use.

[0014] Preferably, the adsorption of the magnetic fluid on the surface of the polymer microspheres is achieved by electrostatic adsorption. The surface of the polyethyleneimine-modified polymer microspheres is positively charged, and the surface of the oleic acid-modified Fe3O4 nanoparticles is negatively charged. The magnetic substance shell is formed by the electrostatic adsorption of the magnetic substance on the surface of the polymer microspheres, and the content of the magnetic substance is 5%-15%. The content of the magnetic component can be controlled by the content of the magnetic fluid. The content of the magnetic fluid is adjusted according to the specific surface area of the microspheres. Specific embodiments:

[0015] The 200 g of polyethyleneimine-modified polymer microspheres are dispersed in 2000 mL of pure water, and 2000 mL of the magnetic fluid solution is added. After stirring at room temperature for 2 h, the unabsorbed and weakly absorbed magnetic fluid nanoparticles are removed by washing with ethanol and pure water. The single-layer-adsorbed magnetic polymer microspheres are obtained.

[0016] Preferably, in order to stabilize the magnetic shell on the surface of the microspheres, the polymer microspheres are cross-linked with a functional hydrophilic polymer. On the one hand, the cross-linking of the magnetic nanoparticles on the surface of the microspheres is strengthened. On the other hand, the functional hydrophilic polymer also provides functional groups to facilitate subsequent process steps. In addition, the modification of the hydrophilic polymer greatly reduces the non-specific adsorption of the microspheres. The functional hydrophilic polymer used in the present application is a hydrophilic polymer with amino groups, such as polyacrylamide or polyethyleneimine solution. Preferably, polyethyleneimine solution is used. Specific embodiments:

[0017] The 50 g of polyethyleneimine solution is diluted and dispersed in 5000 mL of pure water, and is mixed with 200 g of single-layer-adsorbed magnetic polymer microspheres. After uniformly adding 50 g of 1-ethyl-3-(3-dimethylaminopropyl) carbonyldiimidazole hydrochloride (EDC), the mixture is continuously stirred at room temperature for 2 h. After the reaction is completed, the unreacted impurities are removed by washing with pure water, and the amino-hydrophilic-polymer-cross-linked magnetic polymer microspheres are obtained.

[0018] Preferably, the content of the magnetic substance in the magnetic polymer microspheres can be increased by multi-layer adsorption of the magnetic fluid, thereby increasing the paramagnetism of the magnetic polymer microspheres. The content of the magnetic substance in the double-layer-adsorbed microspheres can be adjusted to 10%-20%. Furthermore, the content of the magnetic substance in the magnetic microspheres can be adjusted to 20%-50% by repeating the step. Specific embodiments:

[0019] 200g amino hydrophilic polymer cross-linked magnetic polymer microspheres are re-dispersed in 2000mL pure water, 2000mL magnetic fluid solution is added, after stirring at room temperature for 2h, the un-adsorbed and weakly adsorbed magnetic fluid nanoparticles are removed by washing with ethanol and pure water, and double-layer adsorbed magnetic polymer microspheres are obtained. After the double-layer adsorbed magnetic polymer microspheres are mixed and dispersed with a polyethyleneimine solution, EDC is added for cross-linking for 2h, and amino hydrophilic polymer modified magnetic polymer microspheres are obtained, with a surface -NH2 ligand content of 2000-3000nmol / mg.

[0020] (III) Beneficial effects

[0021] Compared with the prior art, the present application provides a synthesis and functional modification technology of large particle size core-shell magnetic polymer microspheres, which has the following beneficial effects:

[0022] The synthesis and functional modification technology of the large particle size core-shell magnetic polymer microspheres fills the short board of the prior art, and can scale up the preparation process of uniform and large particle size magnetic polymer microspheres. The particle size and uniformity of the core-shell magnetic polymer microspheres depend on the size and uniformity of the polymer microsphere core, and the polymer microsphere core can have a relatively wide range of particle sizes, from several hundred nanometers to millimeter-level polymer microspheres. The functional modification of the microsphere surface is applied by combining hydrophobic and hydrophilic interactions and charge interactions. This process is universal and can be applied to surface modification in multiple scenarios, especially the surface treatment of micro-nano materials and polymer microspheres. By creating a scheme for forming a magnetic material shell through multi-layer adsorption of magnetic nanoparticles, the content of the magnetic material shell can be controlled, the paramagnetism of the polymer microspheres can be enhanced through multi-layer adsorption, and the stability of the magnetic nanoparticles on the microsphere surface can be improved through functional hydrophilic polymer cross-linking. At the same time, the functional hydrophilic polymer molecules also introduce a large number of functional groups and reduce the non-specific adsorption of the microspheres. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0024] The present application provides a technical solution: the steps include: S1, preparation and modification of polymer microspheres; S2, adsorption of magnetic fluid on the surface of polymer microspheres; S3, cross-linking and functionalization of the surface of magnetic microspheres; S4, multi-layer adsorption of magnetic fluid on the surface of polymer microspheres; S5, functionalization and application

[0025] The used polymer microspheres can be polystyrene microspheres, cross-linked polystyrene microspheres, polymethyl methacrylate microspheres and the like polymer microspheres, and the particle size can be from several hundred nanometers to several microns. Since the shell layer of the magnetic material is thin, the particle size and uniformity of the final magnetic microspheres depend on the particle size and uniformity of the polymer microspheres. It is worth noting that the particle size range of the polymer microspheres suitable for the present application is very wide, and can be suitable for nanoscale diagnostic microspheres, and can also be suitable for sub-micron / micron scale chemiluminescent microspheres, and more widely, for microspheres with a particle size of tens of microns to several millimeters. The microspheres can be commercialized high-uniformity microspheres, or high-uniformity microspheres synthesized by polymerization reaction

[0026] The used microsphere modification is realized by electrostatic interaction and hydrophobic interaction. A layer of electronegative amphiphilic molecules such as alkyl benzene sulfonate, α-olefin sulfonate, alkyl sulfonate and the like surfactants is coated on the surface of the polymer microspheres by electrostatic adsorption and hydrophobic interaction. Preferably, sodium dodecyl benzene sulfonate or sodium dodecyl sulfate can be used. The hydrophobic end is adsorbed to the hydrophobic layer of the polymer surface, and the outer layer of the exposed hydrophilic negative ion layer.

[0027] After modifying the negative layer, the surface of the microspheres is converted into a positive functional group by using a positively charged polymer molecule, such as polyacrylamide, polyethyleneimine and the like amino polymer macromolecule, and preferably polyethyleneimine is selected. By electrostatic adsorption, the positively charged amino polymer is adsorbed on the surface of the polymer microspheres to form a positively charged amino functional outer layer. Specific embodiments:

[0028] Take 200g of PS-DVB microspheres and disperse them in 5000mL of water, add 50g of sodium dodecyl sulfate while stirring, stir at room temperature for 2h, and then wash the microspheres with pure water to remove the unabsorbed sodium dodecyl sulfate. After washing, the microspheres are re-dispersed in 5000mL of water, 50g of polyethyleneimine solution is added, stirred at room temperature for 2h, and then the microspheres are washed with pure water to remove the unabsorbed polyethyleneimine

[0029] The used magnetic fluid is Fe3O4 magnetic nanoparticles with a size of 10-500nm, and the optimal size is 10-200nm, which is formed by agglomeration of Fe3O4 nanoparticles (generally 10-15nm Fe3O4 nanoparticles are agglomerated into 50-200nm magnetic fluid). Commercialized oleic acid modified magnetic fluid nanoparticles can be selected, or oleic acid modified nanomagnetic fluid can be synthesized by one-pot method. Specific embodiments:

[0030] Take 129.2g of iron chloride and 87.4g of ferrous chloride dissolved in 1000mL of pure water, set the oil bath temperature to 80℃ stirring for 15min. 100g of sodium oleate is dissolved in a mixture of 200mL water and 200mL ethanol, after ultrasonic stirring to completely dissolve, add to the Fe salt solution, continue to stir for 15min, then pour into 500mL of ammonia water for reaction, after 15min, set the oil bath temperature to 100℃ aging for 1.5h. After the reaction is completed, pour the reaction solution into a fume hood and settle overnight, collect the supernatant for use

[0031] The adsorption of the magnetic fluid on the surface of the polymer microspheres is achieved through charge interaction. The surface of the polyethyleneimine-modified polymer microspheres is positively charged, and the oleic acid-modified Fe3O4 nanoparticles with surface electronegativity are combined on the surface of the polymer microspheres through charge interaction, forming a magnetic material shell with a content of 5%-15%. The content of the magnetic component can be controlled by the content of the magnetic fluid added, and the addition amount of the magnetic fluid is adjusted according to the specific surface area of the microspheres. Specific embodiments:

[0032] The 200g of polyethyleneimine-modified polymer microspheres are re-dispersed in 2000mL of pure water, and 2000mL of magnetic fluid solution is added. After stirring at room temperature for 2h, the un-adsorbed and weakly adsorbed magnetic fluid nanoparticles are removed by washing with ethanol and pure water. Single-layer adsorbed magnetic polymer microspheres are obtained

[0033] In order to stabilize the stability of the magnetic shell on the surface of the microspheres, the polymer microspheres are cross-linked with functional hydrophilic polymers. On the one hand, the magnetic nanoparticles are reinforced on the surface of the microspheres through cross-linking, and on the other hand, the functional hydrophilic polymer also provides functional groups to facilitate subsequent process steps. At the same time, the modification of the hydrophilic polymer also greatly reduces the non-specific adsorption of the microspheres. The functional hydrophilic polymer used in the present application is a hydrophilic polymer with amino groups, such as polyacrylamide or polyethyleneimine solution, and polyethyleneimine solution is preferably used. Specific embodiments:

[0034] The 50g of polyethyleneimine solution is diluted and dispersed with 5000mL of pure water, mixed with 200g of single-layer adsorbed magnetic polymer microspheres, and stirred uniformly. After adding 50g of 1-ethyl-3-(3-dimethylaminopropyl) carbonyl diimide hydrochloride (EDC) and stirring uniformly for 2h at room temperature, the unreacted impurities are removed by washing with pure water to obtain amino hydrophilic polymer cross-linked magnetic polymer microspheres

[0035] The content of the magnetic material in the magnetic polymer microspheres can be increased by multi-layer adsorption of the magnetic fluid, thereby increasing the paramagnetism of the magnetic polymer microspheres. The content of the magnetic material in the double-layer adsorbed microspheres can be adjusted to 10%-20%. Furthermore, by repeating this step, the content of the magnetic material in the magnetic microspheres can be adjusted to 20%-50%. Specific embodiments:

[0036] Take 200 g of amino hydrophilic polymer cross-linked magnetic polymer microspheres and disperse them in 2000 mL of pure water, add 2000 mL of magnetic fluid solution, stir at room temperature for 2 h, then wash with ethanol and pure water respectively to remove unabsorbed and weakly absorbed magnetic fluid nanoparticles, and obtain double-layer adsorbed magnetic polymer microspheres. Mix and disperse the double-layer adsorbed magnetic polymer microspheres with the polyethyleneimine solution, add EDC for cross-linking for 2 h, and obtain amino hydrophilic polymer modified magnetic polymer microspheres with a surface -NH2 ligand content of 2000-3000 nmol / mg.

[0037] Specific implementation case 13 μm single-layer adsorbed magnetic fluid magnetic polymer microsphere preparation

[0038] Preparation of magnetic fluid: dissolve 129.2 g of ferric chloride and 87.4 g of ferrous chloride in 1000 mL of pure water, set the oil bath temperature to 80°C and stir for 15 min. Dissolve 100 g of sodium oleate in a mixture of 200 mL of water and 200 mL of ethanol, completely dissolve under ultrasonic stirring, then add to the Fe salt solution, continue to stir for 15 min, then directly pour into 500 mL of ammonia water for reaction, set the oil bath temperature to 100°C after 15 min and age for 1.5 h. After the reaction is completed, pour the reaction solution into a fume hood and let it settle overnight, then collect the supernatant for use.

[0039] Single-layer adsorbed magnetic polymer microsphere preparation: take 200 g of 3 μm polystyrene microspheres and disperse them in 5000 mL of water, add 50 g of sodium dodecyl sulfate while stirring, stir at room temperature for 2 h, then wash the microspheres with pure water to remove unabsorbed sodium dodecyl sulfate. After washing, disperse the microspheres in 5000 mL of water, add 50 g of polyethyleneimine solution, stir at room temperature for 2 h, then wash the microspheres with pure water to remove unabsorbed polyethyleneimine. Disperse the polyethyleneimine modified polymer microspheres in 2000 mL of pure water, add 2000 mL of magnetic fluid solution, stir at room temperature for 2 h, then wash with ethanol and pure water respectively to remove unabsorbed and weakly adsorbed magnetic fluid nanoparticles. Obtain single-layer adsorbed magnetic polymer microspheres. Mix and disperse the single-layer adsorbed magnetic polymer microspheres with the polyethyleneimine solution (50 g of polyethyleneimine solution diluted and dispersed in 5000 mL of pure water), add 10 g of EDC for cross-linking for 2 h, then wash with pure water to remove unreacted impurities, and obtain amino hydrophilic polymer cross-linked magnetic polymer microspheres. The size of the single-layer adsorbed magnetic polymer microspheres is about 3.1 μm, the magnetic content is 9.2%, and the surface amino ligand density is 3199.7 nmol / mg.

[0040] Specific implementation case 210 micron double-layer adsorbed magnetic fluid magnetic polymer microsphere preparation

[0041] Preparation of magnetic fluid: 129.2 g of iron chloride and 87.4 g of ferrous chloride were dissolved in 1000 mL of pure water, and an oil bath was set to 80°C for stirring for 15 min. 100 g of sodium oleate was dissolved in a mixture of 200 mL of water and 200 mL of ethanol, and after complete dissolution by ultrasonic stirring, it was added to the Fe salt solution, and stirring was continued for 15 min before being directly poured into 500 mL of ammonia water for reaction. After 15 min, the oil bath temperature was set to 100°C for aging for 1.5 h. After the reaction was completed, the reaction solution was poured out and settled in a fume hood overnight, and the supernatant was collected for use.

[0042] Preparation of double-layer adsorbed magnetic polymer microspheres: 200 g of 10 μm commercial cross-linked polystyrene microspheres were dispersed in 5000 mL of water, and 50 g of sodium dodecyl sulfate was added while stirring, and after stirring at room temperature for 2 h, the microspheres were washed with pure water to remove unadsorbed sodium dodecyl sulfate. After washing, the microspheres were redispersed in 5000 mL of water, and 50 g of polyethyleneimine solution was added, and after stirring at room temperature for 2 h, the microspheres were washed with pure water to remove unadsorbed polyethyleneimine. The polyethyleneimine-modified polymer microspheres were redispersed in 2000 mL of pure water, and 2000 mL of magnetic fluid solution was added, and after stirring at room temperature for 2 h, unadsorbed and weakly adsorbed magnetic fluid nanoparticles were removed by washing with ethanol and pure water, respectively. Single-layer adsorbed magnetic polymer microspheres were obtained. The single-layer adsorbed magnetic polymer microspheres were mixed and dispersed with a polyethyleneimine solution (50 g of polyethyleneimine solution was diluted and dispersed with 5000 mL of pure water), and 10 g of EDC was added for cross-linking for 2 h, and then unreacted impurities were removed by washing with pure water, to obtain amino-hydrophilic polymer cross-linked magnetic polymer microspheres. The amino-hydrophilic polymer cross-linked magnetic polymer microspheres were redispersed in 2000 mL of pure water, and 1500 mL of magnetic fluid solution was added, and after stirring at room temperature for 2 h, unadsorbed and weakly adsorbed magnetic fluid nanoparticles were removed by washing with ethanol and pure water, respectively, to obtain double-layer adsorbed magnetic polymer microspheres. The double-layer adsorbed magnetic polymer microspheres were mixed and dispersed with a polyethyleneimine solution (50 g of polyethyleneimine solution was diluted and dispersed with 5000 mL of pure water), and 50 g of EDC was added for cross-linking for 2 h, to obtain amino-hydrophilic polymer-modified magnetic polymer microspheres. The prepared double-layer adsorbed microspheres had a particle size of about 10.3 μm, a magnetic content of 19.7%, and a surface -NH2 ligand content of 2890.3 nmol / mg.

[0043] Preparation of 350 μm multi-layer adsorbed magnetic fluid magnetic polymer microspheres

[0044] Preparation of magnetic fluid: 129.2 g of ferric chloride and 87.4 g of ferrous chloride were dissolved in 1000 mL of pure water, and an oil bath was set to 80°C for stirring for 15 min. 100 g of sodium oleate was dissolved in a mixture of 200 mL of water and 200 mL of ethanol, and after complete dissolution by ultrasonic stirring, it was added to the Fe salt solution, and stirring was continued for 15 min before being directly poured into 500 mL of ammonia water for reaction. After 15 min, the oil bath temperature was set to 100°C for aging for 1.5 h. After the reaction was completed, the reaction solution was poured out and settled in a fume hood overnight, and the supernatant was collected for use.

[0045] Preparation of multi-layer adsorbed magnetic polymer microspheres: 200 g of 50 μm commercial cross-linked polystyrene microspheres were dispersed in 5000 mL of water, and 50 g of sodium dodecyl sulfate was added while stirring. After stirring at room temperature for 2 h, the microspheres were washed with pure water to remove unadsorbed sodium dodecyl sulfate. After washing, the microspheres were redispersed in 5000 mL of water, and 50 g of polyethyleneimine solution was added. After stirring at room temperature for 2 h, the microspheres were washed with pure water to remove unadsorbed polyethyleneimine. The polyethyleneimine-modified polymer microspheres were redispersed in 2000 mL of pure water, and 1500 mL of magnetic fluid solution was added. After stirring at room temperature for 2 h, the microspheres were washed with ethanol and pure water to remove unadsorbed and weakly adsorbed magnetic fluid nanoparticles. Single-layer adsorbed magnetic polymer microspheres were obtained. The single-layer adsorbed magnetic polymer microspheres were mixed and dispersed with a polyethyleneimine solution (50 g of polyethyleneimine solution was diluted and dispersed in 5000 mL of pure water), and 10 g of EDC was added for cross-linking for 2 h. The unreacted impurities were removed by washing with pure water to obtain amino-hydrophilic polymer cross-linked magnetic polymer microspheres. The amino-hydrophilic polymer cross-linked magnetic polymer microspheres were redispersed in 2000 mL of pure water, and 1000 mL of magnetic fluid solution was added. After stirring at room temperature for 2 h, the microspheres were washed with ethanol and pure water to remove unadsorbed and weakly adsorbed magnetic fluid nanoparticles, and double-layer adsorbed magnetic polymer microspheres were obtained. The double-layer adsorbed magnetic polymer microspheres were mixed and dispersed with a polyethyleneimine solution (50 g of polyethyleneimine solution was diluted and dispersed in 5000 mL of pure water), and 50 g of EDC was added for cross-linking for 2 h to obtain amino-hydrophilic polymer-modified magnetic polymer microspheres. The double-layer adsorbed magnetic polymer microspheres were again coated according to the method of the second layer coating and surface polyethyleneimine polymer molecule cross-linking to obtain multi-layer coated magnetic polymer microspheres. The particle size of the three-layer coated magnetic polymer microspheres was 50.5 μm, the magnetic content was 27.8%, and the surface -NH2 ligand content was 2249.6 nmol / mg.

[0046] Specific implementation case 4 surface functionalization modification of magnetic polymer microspheres

[0047] Carboxylation of amino-modified magnetic microspheres: 200 g of 30 μm double-layer adsorbed magnetic polymer microspheres (magnetic content of microspheres 20.4%, -NH2 ligand content on the surface of microspheres 2513.5 nmol / mg) were dispersed in 2000 mL of pure water, 50 g of polyacrylic acid solution was added, and the microspheres were stirred for 30 min to allow the cross-linked polyethyleneimine and polyacrylic acid molecules on the surface of the microspheres to form adsorption, and then 10 g of EDC was added for cross-linking to close the amino group and introduce carboxyl functional groups. After the reaction was completed, the unreacted and weakly adsorbed impurities were washed away with pure water to obtain carboxyl-functionalized magnetic polymer microspheres, and the -COOH ligand content on the surface of the microspheres was 656.5 nmol / mg.

[0048] Blocking of unreacted groups on the microspheres: The carboxyl-functionalized magnetic polymer microspheres were dispersed in 2000 mL of pure water, 30 g of sodium ethylenediaminetetraacetate was added for dissolution and dispersion, and after stirring for 30 min, 10 g of EDC was added for cross-linking to block the residual amino groups. After blocking, the -COOH ligand content on the surface of the carboxyl-functionalized magnetic polymer microspheres was 697.3 nmol / mg.

[0049] In summary, the synthesis and functional modification technology of the large-particle-size core-shell magnetic polymer microspheres fills the short board of the prior art and can scale up the preparation process of uniform and large-particle-size magnetic polymer microspheres. The particle size and uniformity of the core-shell magnetic polymer microspheres depend on the size and uniformity of the polymer microsphere core, and the polymer microsphere core can have a relatively wide range of particle sizes, from several hundred nanometers to millimeter-level polymer microspheres, which can be implemented by the technical solution of the present application. The functional modification on the surface of the microspheres is achieved by combining hydrophilic and hydrophobic interactions and charge interactions. This process is universal and can be applied to surface modification in multiple scenarios, especially for the surface treatment of micro-nano materials and polymer microspheres. By creating a scheme for forming a magnetic material shell through multi-layer adsorption of magnetic nanoparticles, the content of the magnetic material shell can be controlled, and the paramagnetism of the polymer microspheres can be enhanced through multi-layer adsorption. The stability of the magnetic nanoparticles on the surface of the microspheres is strengthened through functional hydrophilic polymer cross-linking, which protects the magnetic components while introducing a large number of functional groups and reducing non-specific adsorption of the microspheres.

[0050] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting; it is not intended to exclude myriad other embodiments of the present application that other inventors can develop based on the same general inventive concepts embodied by the described embodiments. That is, although the present application is described in terms of particular embodiments and implementations, it is to be understood that the terminology used is for the purpose of descriptive clarity and that it should be taken in a descriptive sense and not a limiting sense.

[0051] While the embodiments of the application have been shown and described herein, it is to be understood that the application is not limited to these embodiments. Rather, it is to be understood that various modifications, changes, substitutions and alterations can be made to the embodiments of the application without departing from the spirit and scope of the application as defined by the appended claims and their equivalents.

Claims

1. A method for synthesis and functional modification of large diameter core-shell magnetic polymer microspheres, characterized in that: The steps include: S1, preparation and modification of polymer microspheres: The preparation and modification of the polymer microspheres are achieved by electrostatic interaction and hydrophilic-hydrophobic interaction. A layer of electronegative amphiphilic molecules, which are one of alkyl benzene sulfonate, alpha-olefin sulfonate, and alkyl sulfonate surfactants, is coated on the surface of the polymer microspheres by electrostatic adsorption and hydrophilic-hydrophobic interaction. The hydrophobic end is adsorbed to the hydrophobic layer on the surface of the polymer, and the negatively charged ions are exposed to the outer hydrophilic layer. After modifying the negative layer, the surface of the microspheres is converted into a positively charged functional group by using positively charged polymer molecules, which are one of polyacrylamide and polyethyleneimine amino polymers. The positively charged amino polymers are adsorbed on the surface of the polymer microspheres by electrostatic adsorption, forming a positively charged amino functionalized outer layer. S2, adsorption of magnetic fluid on the surface of polymer microspheres: The magnetic fluid is Fe3O4 magnetic nanoparticles with a size of 10-500 nm, which are agglomerated to form Fe3O4 nanoparticles. The adsorption of the magnetic fluid on the surface of the polymer microspheres is achieved by charge interaction. The surface of the polymer microspheres modified by polyethyleneimine is positively charged, and the Fe3O4 nanoparticles modified by oleic acid are negatively charged. The Fe3O4 nanoparticles are combined on the surface of the polymer microspheres by charge interaction, forming a magnetic material shell. The content of the magnetic material is 5%-15%, and the content of the magnetic component is controlled by the content of the magnetic fluid. The addition amount of the magnetic fluid is adjusted according to the specific surface area of the microspheres. S3, surface cross-linking and functionalization of magnetic microspheres: To stabilize the magnetic shell on the surface of the microspheres, functional hydrophilic polymers are used for cross-linking of the polymer microspheres. On the one hand, the magnetic nanoparticles are reinforced on the surface of the microspheres by cross-linking, and on the other hand, the functional hydrophilic polymers also provide functional groups to facilitate subsequent process steps. At the same time, the modification of the hydrophilic polymer also greatly reduces the non-specific adsorption of the microspheres. The functional hydrophilic polymer used is a hydrophilic polymer with amino groups, which is one of polyacrylamide or polyethyleneimine solution. S4, multi-layer adsorption of magnetic fluid on the surface of polymer microspheres: By multi-layer adsorption of the magnetic fluid, the content of the magnetic material in the magnetic polymer microspheres is increased, thereby increasing the paramagnetism of the magnetic polymer microspheres. The content of the magnetic material in the double-layer adsorbed microspheres is controlled to 10%-20%. S5, functionalization and application.

2. The method for synthesis and functional modification of large diameter core-shell magnetic polymer microspheres according to claim 1, characterized in that: The polymer microspheres need to be high-uniformity microspheres synthesized by commercialization or polymerization reaction.

3. The synthesis and functional modification method of large particle size core-shell type magnetic polymer microspheres according to claim 1, characterized in that: Take 200g of PS-DVB microspheres and disperse them in 5000mL of water. While stirring, add 50g of sodium dodecyl sulfate. After stirring at room temperature for 2h, wash the microspheres with pure water to remove the unadsorbed sodium dodecyl sulfate. After washing, disperse the microspheres in 5000mL of water and add 50g of polyethyleneimine solution. Stir at room temperature for 2h and then wash the microspheres with pure water to remove the unadsorbed polyethyleneimine.

4. The synthesis and functional modification method of large particle size core-shell type magnetic polymer microspheres according to claim 1, characterized in that: Take 129.2g iron chloride and 87.4g ferrous chloride dissolved in 1000mL pure water, set the oil bath temperature to 80℃ stirring for 15min, 100g sodium oleate is dissolved in 200mL water and 200mL ethanol mixture, after ultrasonic stirring completely dissolved into the Fe salt solution, continue to stir for 15min, then pour into 500mL ammonia water for reaction, 15min after setting the oil bath temperature to 100℃ aging 1.5h, after the reaction, the reaction liquid is poured out in the fume hood and settled overnight, the supernatant is collected for use.

5. The synthesis and functional modification method of large particle size core-shell magnetic polymer microspheres according to claim 1, characterized in that: 200g of polyethyleneimine modified polymer microspheres are redispersed in 2000mL of pure water, 2000mL of magnetic fluid solution is added, and stirred at room temperature for 2h, then washed with ethanol and pure water to remove unabsorbed and weakly absorbed magnetic fluid nanoparticles, and single-layer absorbed magnetic polymer microspheres are obtained.

6. The synthesis and functional modification method of large particle size core-shell magnetic polymer microspheres according to claim 1, characterized in that: 50g of polyethyleneimine solution is diluted and dispersed with 5000mL of pure water, mixed with 200g of single-layer absorbed magnetic polymer microspheres and stirred uniformly, 50g of 1-ethyl-3-(3-dimethylaminopropyl) carbonyldiimidazole hydrochloride is added and dispersed uniformly, then continue to stir at room temperature for 2h, after the reaction, the unreacted impurities are removed by washing with pure water, and amino hydrophilic polymer crosslinked magnetic polymer microspheres are obtained.

7. The synthesis and functional modification method of large particle size core-shell magnetic polymer microspheres according to claim 1, characterized in that: 200g of amino hydrophilic polymer crosslinked magnetic polymer microspheres are redispersed in 2000mL of pure water, 2000mL of magnetic fluid solution is added, and stirred at room temperature for 2h, then washed with ethanol and pure water to remove unabsorbed and weakly absorbed magnetic fluid nanoparticles, and double-layer absorbed magnetic polymer microspheres are obtained, the double-layer absorbed magnetic polymer microspheres are mixed and dispersed with polyethyleneimine solution, then 1-ethyl-3-(3-dimethylaminopropyl) carbonyldiimidazole hydrochloride is added for crosslinking for 2h, and amino hydrophilic polymer modified magnetic polymer microspheres are obtained, with a surface -NH2 ligand content of 2000-3000nmol / mg.