CN114452952B - Ultrahigh crosslinked adsorption resin with bimodal pore structure, and preparation method and application thereof - Google Patents
Ultrahigh crosslinked adsorption resin with bimodal pore structure, and preparation method and application thereof Download PDFInfo
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- CN114452952B CN114452952B CN202111546715.3A CN202111546715A CN114452952B CN 114452952 B CN114452952 B CN 114452952B CN 202111546715 A CN202111546715 A CN 202111546715A CN 114452952 B CN114452952 B CN 114452952B
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- bimodal pore
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- adsorption resin
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Classifications
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
- B01J20/261—Synthetic macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
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- A—HUMAN NECESSITIES
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2207/00—Methods of manufacture, assembly or production
Abstract
The invention relates to an ultrahigh crosslinked adsorption resin with a bimodal pore structure, and a preparation method and application thereof. The ultra-high crosslinking adsorption resin with the bimodal pore structure is mainly prepared by further crosslinking a polystyrene resin matrix with the bimodal pore structure, and contains abundant micropores and mesopores. The ultra-high crosslinking adsorption resin with the bimodal pore structure can simultaneously remove the middle molecular toxin and the protein-bound uremic toxins, and especially improves the adsorption rate of the protein-bound uremic toxins.
Description
Technical Field
The invention relates to the field of blood purification, in particular to an ultrahigh crosslinked adsorption resin with a bimodal pore structure, a preparation method and application thereof, wherein the ultrahigh crosslinked adsorption resin can simultaneously adsorb and remove protein-bound toxins and medium-large molecular toxins.
Background
Uremic toxins refer to substances that are retained in the circulation and/or tissue of uremic patients and have toxic effects (resulting in pathophysiological changes). The European uremic toxin working group (EUTox) classifies uremic toxins into three major classes based on their biochemical properties: 1. water-soluble, small molecule substances that do not bind to proteins, typically having a molecular mass of less than 500, such as urea, creatinine, uric acid, and the like; 2. medium and large molecular substances, the molecular mass of which is usually more than 500, such as parathyroid hormone, beta 2-microglobulin, leptin and the like; 3. protein-binding toxoids, such as Indoxyl Sulfate (IS), indole-3-acetic acid (IAA), p-cresol sulfate (PCS), 3-carboxy-4-methyl-5-propyl-2-furanopropionic acid (CMPF), hippuric Acid (HA), and the like.
The dialysis technology can be well cleared at present aiming at small molecular substances which are water-soluble and do not combine with protein; aiming at the middle macromolecular substances, the blood filtration and the high-flux dialysis have certain clearing effects, and in addition, the blood perfusion adsorption has good adsorption effect on the middle macromolecular toxins and is widely applied clinically; however, there IS no better method for eliminating protein-bound toxins clinically, and it IS reported that the clearance rate of high-flux hemodialysis LFHD to IS and PCS IS about 30%, and the clearance rate of low-flux hemodialysis HFHD IS not more than 35%, and the clearance rate per week IS less than 1/10 of that of kidney, which causes accumulation of these substances in the body, causes related complications, affects the treatment effect of hemodialysis, and further affects the life quality of MHD patients.
The existing blood perfusion material mainly comprises active carbon and macroporous adsorption resin, and related commercial products mainly comprise an adsorba blood perfusion device of Jinbao, an HA series perfusion device of Zhuhai Jian Sail, an MG series perfusion device of Buddha Boxin and the like. Whether activated carbon or existing macroporous adsorbent resin related products are clinically used to attempt to remove protein-bound toxins, for example, HA130 hemodialyzer combined Hemodialysis (HD) HAs an overall clearance of about 45% for IS and PCS, which, although superior to HD alone, IS still not as clinically acceptable.
Therefore, there is a need for developing a novel adsorbent that has better adsorption properties for protein-bound toxins, while maintaining the adsorption properties for middle-macromolecular toxins without degradation.
Disclosure of Invention
In view of the shortcomings of the prior art, a first object of the present invention is to provide an ultra-high crosslinked adsorption resin with a bimodal pore structure, which can remove both middle molecular toxins and protein-bound uremic toxins, and in particular, improve the adsorption rate of protein-bound uremic toxins. The second object of the invention is to provide a preparation method of the ultra-high crosslinking adsorption resin with a bimodal pore structure. The third object of the invention is to provide the application of the ultra-high crosslinked adsorption resin with a bimodal pore structure in blood perfusion.
In order to achieve the first object of the present invention, an ultra-high crosslinked absorbent resin having a bimodal cell structure is mainly prepared by further crosslinking a polystyrene-based resin matrix having a bimodal cell structure, the ultra-high crosslinked absorbent resin having a bimodal cell structure containing micropores and macropores; ultra-high crosslinked adsorption resin with bimodal pore structureHas a specific surface area ranging from 600m 2 /g～1500m 2 /g; the specific surface area of the micropores is 300m 2 /g～800m 2 Per gram, the specific surface area of the macropores is 200m 2 /g～500m 2 /g; the pore volume range of the ultra-high crosslinked adsorption resin with the bimodal pore structure is 1.2cm 3 /g～2.0cm 3 /g; the micropore volume is 0.3cm 3 /g～0.6cm 3 Per g, the macropores occupy a pore volume of 0.8cm 3 /g～1.5cm 3 /g。
From the above, the ultra-high crosslinked adsorption resin with the bimodal pore structure has rich mesoporous and microporous pore structures, wherein the mesoporous comprises mesopores with the pore diameter of 2-50 nm and macropores with the pore diameter of more than 50nm, and the mesopores can adsorb medium and large molecular substances in uremic toxins; the pore diameter of the micropore is below 2nm, and the micropore can adsorb small molecule protein binding toxoid. The invention mainly improves the micropore proportion by crosslinking on the polystyrene resin matrix with a mesoporous and microporous pore channel structure, thereby improving the adsorption rate of the adsorption resin material on protein-bound uremic toxin, and not affecting the adsorption of macromolecular substances in the macroporous and macroporous pores during blood perfusion. The ultra-high crosslinking adsorption resin with the bimodal pore structure has remarkable removal effect on protein-binding toxoids such as indoxyl sulfate, paracresol sulfate and the like, and macromolecular substances such as beta 2 microglobulin, parathyroid hormone and the like.
The further technical proposal is that the ultra-high crosslinking adsorption resin with a bimodal pore canal structure is covalently connected with a grafting chain containing an alkaline group.
From the above, the invention further introduces a graft chain containing an alkaline group on the ultra-high crosslinking adsorption resin with a bimodal pore structure, and utilizes the electrostatic interaction of the alkaline group on the acidic group contained in the protein binding toxin to realize the competitive adsorption of the adsorption resin on the small molecular protein binding toxoid from albumin, thereby further improving the adsorption of the adsorption resin on the small molecular protein binding toxoid such as Indoxyl Sulfate (IS), indole-3-acetic acid (IAA), p-cresol sulfate (PCS), 3-carboxyl-4-methyl-5-propyl-2-furoic acid (CMPF), hippuric Acid (HA) and the like.
The further technical proposal is that the specific surface area of the ultra-high crosslinking adsorption resin with a bimodal pore canal structure is 700m 2 /g～1200m 2 The pore volume range of the ultra-high crosslinked adsorption resin with the bimodal pore structure is 1.4cm 3 /g～1.9cm 3 /g。
From the above, the ultra-high crosslinked adsorption resin with a bimodal pore structure preferably has the specific surface area and pore volume range in the above range, and can ensure that enough micropores and mesopores can be provided to meet the whole blood perfusion requirement.
The further technical proposal is that the average pore diameter of the ultra-high crosslinking adsorption resin with a bimodal pore canal structure is 2 nm-15 nm, preferably 4 nm-10 nm.
From the above, the average pore diameter of the ultra-high crosslinked adsorption resin with the bimodal pore structure is preferably in the above range, and the number of micropores and mesopores is proper, so that the middle macromolecular toxins and the micromolecular protein binding toxoids in the blood of uremic patients are effectively removed.
The further technical proposal is that the particle size range of the ultra-high crosslinked adsorption resin with a bimodal pore canal structure is 0.4 mm-2 mm, preferably 0.6 mm-1.2 mm.
From the above, the particle size of the ultra-high crosslinked adsorption resin with the bimodal pore structure is preferably in the above range, so that the adsorption resin has a larger specific surface area, and is convenient for purification and separation of the adsorption resin in the preparation or use process. The polystyrene-based resin matrix with the particle size and the bimodal pore structure can be obtained by controlling the polymerization reaction condition or sieving step and the like, and the particle size change after the crosslinking reaction is small.
In order to achieve the second object of the present invention, the present invention provides a method for preparing an ultra-high crosslinked adsorbent resin having a bimodal cell structure according to any one of the above-mentioned aspects, comprising the steps of:
step 1: polymerizing a styrene monomer, a polyvinyl cross-linking agent, a pore-forming agent and an initiator in a dispersion medium, such as suspension polymerization, to obtain a polystyrene resin matrix with a bimodal pore structure; the pore-forming agent comprises a good solvent and a poor solvent;
step 2: chloromethylating the polystyrene resin matrix with the bimodal pore structure, and then carrying out a crosslinking reaction to obtain the ultra-high crosslinking adsorption resin with the bimodal pore structure.
From the above, the invention adopts the cross-linking process after polymerization of the mixed pore-forming agent, firstly adopts the mixture of good solvent and poor solvent to form pores to prepare the polystyrene resin matrix with macropores and micropores, and further obtains the structure with better adsorption performance on micromolecular protein combined toxoid.
The further technical scheme is that the method further comprises the following step 3: and (3) carrying out epoxidation modification on chloromethyl remained in the ultra-high crosslinking adsorption resin with a bimodal pore structure, and then utilizing epoxy groups to graft a grafting chain containing alkaline groups.
From the above, the invention further utilizes chloromethyl remained by the post-crosslinking reaction of the resin microsphere to carry out epoxidation modification, and then utilizes the activity of the epoxy group to graft the long-chain alkaline group compound on the ultra-high crosslinking adsorption resin with a bimodal pore canal, so that the adsorption resin is provided with the alkaline group, the competitive adsorption of the adsorption resin on the micromolecule protein binding toxoid from albumin is improved, and the adsorption performance of the adsorption resin on the micromolecule protein binding toxoid is further improved.
The further technical scheme is that the epoxidation modification comprises: reacting 1-hydroxy-1, 3-epoxypropane with residual chloromethyl under alkaline conditions; the dosage of the 1-hydroxy-1, 3 epoxypropane is 2-4 times of the mass of the ultra-high crosslinking adsorption resin with a bimodal pore canal structure, the reaction temperature is 40-60 ℃, and the reaction time is 4-12 h; the epoxy group content of the epoxy modified ultrahigh crosslinked adsorption resin with the bimodal pore structure ranges from 0.1mmol/g to 0.5mmol/g.
From the above, the invention innovatively adopts the residual chloromethyl reaction after the crosslinking reaction of the 1-hydroxy-1, 3 epoxypropane and the microsphere to successfully introduce the active epoxy group onto the adsorption resin without additionally introducing other grafting connection points, thereby simplifying the preparation steps. Wherein the alkaline condition can be provided by an aqueous sodium hydroxide solution, for example, after 1-hydroxy-1, 3-epoxypropane is mixed with the ultra-high crosslinked adsorption resin having a bimodal pore structure, 2.5M to 5M aqueous sodium hydroxide solution is added at 40 ℃ to 60 ℃, thereby providing the alkaline condition. The reaction may be carried out with stirring.
The further technical scheme is that the grafting reaction comprises: reacting a polyamine compound with an epoxy group; the polyamine compound is at least one selected from polyamine and polyamine polymer, the polyamine is at least one selected from ethylenediamine, propylenediamine, butylenediamine, hexylenediamine, heptylenediamine, octylenediamine, nonylenediamine, decylenediamine, 1, 11-undecylenediamine and 1, 12-dodecyldiamine, the polyamine polymer is at least one selected from polylysine and polyethyleneimine, the molecular weight of polylysine is preferably 3600-4500, and the molecular weight of polyethyleneimine is preferably 275-25000; the polyamine compound is used in a solution mode, the mass fraction of the polyamine compound in the solution is 1% -5%, and the mass of the solution is 4-6 times of the mass of the epoxy modified ultrahigh crosslinked adsorption resin with a bimodal pore structure; the reaction temperature is 60-80 ℃ and the reaction time is 4-8 h.
From the above, the basic group-containing compound grafted on the adsorption resin can be polyamine or polyamine polymer, wherein one amino group in the molecule of the basic group-containing compound can react with epoxy group to realize grafting, and the other amino groups are used as basic groups for adsorbing small molecule protein binding toxoids. The resulting ultra-high crosslinked adsorption resin containing bimodal pore structures grafted with long chain basic groups is preferably also purified after the grafting reaction, and may be washed with pure water, for example.
The further technical scheme is that in step 1: the styrene monomer is at least one selected from styrene, methyl styrene and ethyl styrene, preferably styrene; the polyvinyl cross-linking agent is at least one selected from divinylbenzene, divinyltoluene, divinylxylene and divinylethylbenzene, preferably divinylbenzene; the styrene monomer accounts for 20-92% of the total mass of the styrene monomer and the polyvinyl cross-linking agent.
From the above, the reaction monomer used for preparing the polystyrene resin matrix with the bimodal pore structure comprises the styrene monomer of monovinyl and the crosslinking agent of polyvinyl, so that the polystyrene resin matrix is partially crosslinked, and the mechanical strength of the microsphere and the structural stability in an organic solvent are improved.
The further technical scheme is that in step 1: the pore-forming agent is a mixture of at least two substances selected from aromatic hydrocarbon, alkane, higher alcohols, higher ketones and esters; the aromatic hydrocarbon is selected from toluene and xylene; the alkane is selected from n-heptane, 200# gasoline and solid paraffin; the higher alcohols are selected from butanol, hexanol, cyclohexanol, isooctanol, n-octanol, methyl isobutyl carbinol; the higher ketone is selected from methyl isobutyl ketone, 2-hexanone, diisobutyl ketone and methyl tert-butyl ketone; the esters are selected from butyl acetate, ethyl acetate and butyl butyrate; the mass of the pore-forming agent is 70-230% of the total mass of the styrene monomer and the polyvinyl cross-linking agent.
From the above, the pore-forming agent used for preparing the polystyrene resin matrix with the bimodal pore-channel structure can be selected from the solvents, and the good solvent and the poor solvent exist in the pore-forming agent to be combined to be used as the mixed pore-forming agent.
The further technical scheme is that in step 1: the initiator is at least one selected from benzoyl peroxide, tert-butyl peroxy-2-ethylhexanoate and tert-amyl peroxy-2-ethylhexanoate, preferably benzoyl peroxide; the mass of the initiator is 0.5 to 1.5 percent of the total mass of the styrene monomer and the polyvinyl cross-linking agent.
From the above, the initiator used for preparing the polystyrene resin matrix with the bimodal pore structure is preferably an organic peroxide initiator, can effectively initiate polymerization, and has easily obtained raw materials.
The further technical scheme is that in step 1: the dispersion medium is water, and the volume ratio of the dispersion medium to the oil phase is (1-3) to 1; a dispersing agent is present in the dispersing medium, and the dispersing agent is at least one selected from gelatin, polyvinyl alcohol and carboxymethyl cellulose, preferably gelatin; the mass of the dispersing agent is 0.5-2% of the mass of the dispersing medium.
From the above, the dispersion medium used for preparing the polystyrene resin matrix with the bimodal pore structure is safe and environment-friendly, and suspension polymerization of the polystyrene resin matrix is realized through the dispersing agent. Wherein the oil phase is an oil phase formed by mixing a styrene monomer, a polyvinyl cross-linking agent, a pore-forming agent, an initiator and the like.
The further technical scheme is that in step 1: the reaction temperature of the polymerization is 50-100 ℃, preferably 70-95 ℃ and the reaction time is 12-20 h, preferably 14-18 h.
From the above, the polystyrene resin matrix with the bimodal pore structure is prepared by the method, the reaction conditions are preferable, and the polystyrene resin matrix can be gradually heated to react in stages during specific operation, for example, after an oil phase mixture forms uniform liquid drops with a certain size in a dispersion medium solution, the temperature is raised to 75 ℃, the polymerization is carried out for 3 hours, the temperature is raised to 80 ℃ for curing for 7 hours, the temperature is raised to 85 ℃, and the reaction is stopped after the curing is continued for 6 hours; or heating to 75 ℃ for polymerization for 5 hours, and heating to 80 ℃ for curing reaction overnight.
In a further technical scheme, in the step 2, chloromethylation reaction comprises: reacting chloromethyl ether with polystyrene resin matrix with bimodal pore canal structure under the action of anhydrous zinc chloride; the mass of chloromethyl ether is 4-6 times of the mass of the polystyrene-based resin matrix with a bimodal pore structure, and the mass of anhydrous zinc chloride is 0.5-1.5 times of the mass of the polystyrene-based resin matrix with a bimodal pore structure; mixing chloromethyl ether with polystyrene resin matrix with a bimodal pore structure, standing for 4-5 h at room temperature, adding anhydrous zinc chloride under stirring, and reacting at 50-52 ℃ for 8-24 h; the chlorine content of the obtained chloromethylated polystyrene-based resin matrix with the bimodal pore structure ranges from 5% to 25%.
As can be seen from the above, the chloromethylation reaction of the polystyrene resin matrix with the bimodal pore structure in the invention preferably adopts the reaction conditions, and a sufficient amount of chloromethyl is introduced, so that the subsequent crosslinking reaction and epoxidation modification are facilitated.
In a further technical scheme, in the step 2, the crosslinking reaction comprises: chloromethylated polystyrene resin matrix with a bimodal pore structure is crosslinked under the action of zinc chloride; the solvent is nitrobenzene, and the mass of the nitrobenzene is 5-7 times of that of the chloromethylated polystyrene resin matrix with a bimodal pore structure; the mass of the zinc chloride is 0.1 to 0.5 times of that of the chloromethylated polystyrene resin matrix with a bimodal pore structure; mixing nitrobenzene and chloromethylated polystyrene resin matrix with a bimodal pore structure, standing for 4-5 h at 35-45 ℃, and adding zinc chloride under stirring; the reaction temperature is 110-130 ℃, and the reaction time is 8-16 h.
From the above, the chloromethylation microsphere crosslinking reaction in the invention preferably adopts the reaction conditions, so that the post crosslinking reaction of the polystyrene resin matrix is promoted to be sufficient, more micropore pore structures are formed, and the adsorption of the micromolecular protein combined toxoid is facilitated.
In order to achieve the third object of the present invention, the present invention provides a hemoperfusion apparatus comprising the ultra-high crosslinked resin having a bimodal pore structure according to any one of the above-mentioned aspects, or the ultra-high crosslinked resin having a bimodal pore structure produced by the production method according to any one of the above-mentioned aspects.
From the above, the invention provides the application of the ultra-high crosslinked adsorption resin with the bimodal pore structure in blood perfusion, the ultra-high crosslinked adsorption resin with the bimodal pore structure can be loaded in a blood perfusion device, and the ultra-high crosslinked adsorption resin can effectively remove the medium molecular toxins and protein-bound uremic toxins in the blood of uremic patients simultaneously during blood perfusion.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1
The adsorbent of this example was prepared by the following steps:
(1) Synthesis of macroporous polystyrene resin with a bimodal pore structure:
600mL of a gelatin aqueous solution containing 1.5wt% is added into a 1000mL three-necked flask, 42g of styrene, 8g of Divinylbenzene (DVB) with the purity of 63wt%, which contains 37wt% of styrene monomers, 25g of toluene, 20g of 200# gasoline, 20g of solid paraffin and 0.5g of benzoyl peroxide are added into the three-necked flask, the mixture is heated to 75 ℃ to react for 5h under mechanical stirring, the temperature is heated to 80 ℃ to react overnight, after the reaction is finished, the mixture is cooled, acetone is extracted for 12h, water is washed until no acetone smell exists, and the mixture is filtered, dried and screened to select resin with the particle size of 0.6-1.2 mm.
(2) Chloromethylation modification of macroporous polystyrene resin with bimodal cell structure:
adding 20g of macroporous polystyrene adsorption resin into a 500mL three-necked flask, adding 100g of chloromethyl ether, and standing for 4 hours at room temperature; starting a stirrer, adding 20g of anhydrous zinc chloride, heating to 50 ℃ and reacting for 24 hours; cooling to room temperature after the reaction is finished, filtering out mother liquor, extracting with methanol for 12 hours, washing with water until no methanol smell exists, and carrying out suction filtration to obtain the dry light yellow chloromethylation modified macroporous adsorption, wherein the chlorine content is 18.1% through the test of the Buddha method.
(3) Friedel-crafts post-crosslinking reaction of macroporous polystyrene resin with a bimodal pore structure:
taking 20g of the chlorine ball obtained in the step (2), adding 140g of nitrobenzene, standing and swelling for 4h at 40 ℃, adding 10g of zinc chloride under mechanical stirring, heating and reacting for 10h at 125 ℃, and carrying out Friedel-crafts alkylation reaction on chloromethyl to form an ultrahigh crosslinked network, so that the micropore quantity is greatly enriched, and the ultrahigh crosslinked macroporous adsorption resin is obtained. The specific surface area of the obtained ultra-high crosslinked adsorption resin with the bimodal pore structure ranges from 1180m 2 /g, wherein the micropores occupy a specific surface area of 750m 2 Per g, the specific surface area of the macropores is 430m 2 /g; pore volume of 1.85cm 3 /g, wherein the micropores occupy a pore volume of 0.58cm 3 Per gram, the macropores occupy a pore volume of 1.27cm 3 And/g, average pore diameter of 6.3nm. The residual chlorine content was 3.5% by the Buddha test.
(4) Epoxidation modification of ultra-high crosslinked adsorption resin with bimodal pore structure:
50mL of macroporous resin obtained in the step (3) is taken, 150mL of 1-hydroxy-1, 3 propylene oxide is added, 100mL of 2.5M sodium hydroxide aqueous solution is dripped at 45 ℃ and stirred for reaction for 4h, the macroporous resin after epoxidation modification is obtained, after the reaction is finished, mother liquor is filtered out, 1-hydroxy-1, 3 propylene oxide is washed by methanol, and then water is washed until no methanol smell exists, thus obtaining the macroporous resin after epoxidation modification, and the epoxy group content is measured to be 0.31mmol/g.
(5) Immobilization of 1, 12-dodecanediamine:
adding 50mL of the epoxy modified ultrahigh crosslinked adsorption resin with the bimodal pore structure in a wet state into a 500mL three-necked flask, adding 200mL of absolute ethyl alcohol, adding 1, 12-dodecanediamine, stirring and dissolving, heating to 80 ℃ under mechanical stirring, keeping the temperature for reaction for 8 hours, washing with alcohol, and washing with water to obtain the ultrahigh crosslinked adsorption resin grafted with dodecylamine and with the bimodal pore structure.
Example 2
The adsorbent of this example was prepared by the following steps:
(1) Synthesis of macroporous polystyrene resin with a bimodal pore structure:
600mL of a gelatin aqueous solution containing 1.5wt% is added into a 1000mL three-necked flask, 34g of styrene, 16g of Divinylbenzene (DVB) with the purity of 63wt%, which contains 37wt% of styrene monomer, 20g of toluene, 20g of isooctanol, 40g of methyl isobutyl ketone and 0.5g of tert-butyl peroxy-2-ethylhexanoate are added into the three-necked flask, the mixture is heated to 75 ℃ under mechanical stirring to react for 5h, then the temperature is raised to 80 ℃ for overnight reaction, after the reaction is finished, the mixture is cooled, acetone is extracted for 12h, water is washed until no acetone taste exists, and the mixture is filtered, dried and screened, and resin with the particle size of 0.6-1.2 mm is selected.
(2) Chloromethylation modification of macroporous polystyrene resin with bimodal cell structure:
adding 20g of macroporous polystyrene adsorption resin into a 500mL three-necked flask, adding 100g of chloromethyl ether, and standing for 4 hours at room temperature; starting a stirrer, adding 20g of anhydrous zinc chloride, heating to 50 ℃ and reacting for 24 hours; cooling to room temperature after the reaction is finished, filtering out mother liquor, extracting with methanol for 12 hours, washing with water until no methanol smell exists, and carrying out suction filtration to obtain the dry light yellow chloromethylation modified macroporous adsorption, wherein the chlorine content tested by the Buddha method is 14.3%.
(3) Friedel-crafts post-crosslinking reaction of macroporous polystyrene resin with a bimodal pore structure:
taking 20g of the chlorine ball obtained in the step (2), adding 140g of nitrobenzene, standing and swelling for 4h at 40 ℃, adding 8g of zinc chloride under mechanical stirring, heating and reacting for 8h at 120 ℃, and carrying out Friedel-crafts alkylation reaction on chloromethyl to form an ultrahigh crosslinked network, so that the micropore quantity is greatly enriched, and the ultrahigh crosslinked macroporous adsorption resin is obtained. The specific surface area range of the obtained ultra-high crosslinked adsorption resin with the bimodal pore structure is 1090m 2 /g, wherein the micropores occupy a specific surface area of 630m 2 Per g, the specific surface area of the macropores is 460m 2 /g; pore volume of 1.97cm 3 /g, wherein the micropores occupy 0.48cm of pore volume 3 Per gram, the macropores occupy a pore volume of 1.49cm 3 And/g, average pore diameter of 7.2nm. The residual chlorine content was 4.1% by the Buddha test.
(4) Epoxidation modification of ultra-high crosslinked adsorption resin with bimodal pore structure:
50mL of macroporous resin obtained in the step (3) is taken, 150mL of 1-hydroxy-1, 3 propylene oxide is added, 100mL of 2.5M sodium hydroxide aqueous solution is dripped at 45 ℃ and stirred for reaction for 4h, the macroporous resin after epoxidation modification is obtained, after the reaction is finished, mother liquor is filtered out, 1-hydroxy-1, 3 propylene oxide is washed by methanol, and then water is washed until no methanol smell exists, thus obtaining the macroporous resin after epoxidation modification, and the epoxy group content is measured to be 0.33mmol/g.
(5) Immobilization of hexamethylenediamine:
adding 50mL of the epoxy modified ultrahigh crosslinked adsorption resin with the bimodal pore structure in a wet state into a 500mL three-necked flask, adding 200mL of absolute ethyl alcohol, adding hexamethylenediamine, stirring and dissolving, heating to 80 ℃ under mechanical stirring, keeping the temperature for reaction for 8 hours, washing with alcohol, and washing with water to obtain the ultrahigh crosslinked adsorption resin grafted with hexamethylenediamine and containing the bimodal pore structure.
Example 3
The adsorbent of this example was prepared by the following steps:
(1) Synthesis of macroporous polystyrene resin with a bimodal pore structure:
600mL of a water solution containing 1.5wt% of gelatin is added into a 1000mL three-necked flask, 50g of Divinylbenzene (DVB) with the purity of 63wt%, 50g of toluene, 20g of solid paraffin, 35g of butyl butyrate and 0.5g of tert-butyl peroxy-2-ethylhexanoate are added into the three-necked flask, the mixed organic phase is mechanically stirred, the temperature is increased to 75 ℃ for reaction for 5h, the reaction is further increased to 80 ℃ for overnight, after the reaction is finished, cooling and acetone extraction are carried out for 12h, water washing is carried out until no acetone smell exists, and the resin with the particle size of 0.6-1.2 mm is selected through suction filtration, drying and screening.
(2) Chloromethylation modification of macroporous polystyrene resin with bimodal cell structure:
adding 20g of macroporous polystyrene adsorption resin into a 500mL three-necked flask, adding 100g of chloromethyl ether, and standing for 4 hours at room temperature; starting a stirrer, adding 20g of anhydrous zinc chloride, heating to 50 ℃ and reacting for 24 hours; cooling to room temperature after the reaction is finished, filtering out mother liquor, extracting with methanol for 12 hours, washing with water until no methanol smell exists, and carrying out suction filtration to obtain the dry light yellow chloromethylation modified macroporous adsorption, wherein the chlorine content is 12.1% through the test of the Buddha method.
(3) Friedel-crafts post-crosslinking reaction of macroporous polystyrene resin with a bimodal pore structure:
taking 20g of the chlorine ball obtained in the step (2), adding 140g of nitrobenzene, standing and swelling for 4h at 40 ℃, adding 8g of zinc chloride under mechanical stirring, heating and reacting for 8h at 120 ℃, and carrying out Friedel-crafts alkylation reaction on chloromethyl to form an ultrahigh crosslinked network, so that the micropore quantity is greatly enriched, and the ultrahigh crosslinked macroporous adsorption resin is obtained. The specific surface area range of the obtained ultra-high crosslinked adsorption resin with the bimodal pore structure is 1110m 2 /g, wherein the micropores occupy a specific surface area of 610m 2 Per gram, the specific surface area of the macropores is 500m 2 /g; pore volume of 2.08cm 3 /g, wherein the micropores occupy 0.47cm of pore volume 3 /g, macroporesThe pore volume is 1.61cm 3 And/g, average pore diameter of 7.5nm. The residual chlorine content was 2.5% by the Buddha test.
(4) Epoxidation modification of ultra-high crosslinked adsorption resin with bimodal pore structure:
50mL of macroporous resin obtained in the step (3) is taken, 150mL of 1-hydroxy-1, 3 propylene oxide is added, 100mL of 2.5M sodium hydroxide aqueous solution is dripped at 45 ℃ and stirred for reaction for 4h, the macroporous resin after epoxidation modification is obtained, after the reaction is finished, mother liquor is filtered out, 1-hydroxy-1, 3 propylene oxide is washed by methanol, and then water is washed until no methanol smell exists, thus obtaining the macroporous resin after epoxidation modification, and the epoxy group content is measured to be 0.21mmol/g.
(5) Immobilization of polylysine:
adding 50mL of the epoxidized modified ultrahigh crosslinked adsorption resin with the bimodal pore structure in a wet state into a 500mL three-necked flask, adding 200mL of aqueous solution, adding polylysine with the number average molecular weight of 3600-4500, stirring for dissolution, heating to 60 ℃ under mechanical stirring, maintaining the temperature for reaction for 12h, and washing with water to obtain the ultrahigh crosslinked adsorption resin grafted with polylysine and containing the bimodal pore structure.
Example 4
The adsorbent of this example was prepared by the following steps:
(1) Synthesis of macroporous polystyrene resin with a bimodal pore structure:
600mL of a water solution containing 1.5wt% of gelatin is added into a 1000mL three-necked flask, 50g of Divinylbenzene (DVB) with the purity of 80wt% (containing 20wt% of styrene monomer), 60g of toluene, 20g of solid paraffin, 20g of methyl isobutyl carbinol and 0.5g of tert-butyl peroxy-2-ethylhexanoate are added into the three-necked flask, the temperature is increased to 75 ℃ under mechanical stirring to react for 5h, the reaction is further increased to 80 ℃ overnight, after the reaction is finished, the three-necked flask is cooled, acetone is extracted for 12h, water is washed until no acetone smell exists, and the three-necked flask is subjected to suction filtration, drying and screening, and resin with the particle size of 0.6-1.2 mm is selected.
(2) Chloromethylation modification of macroporous polystyrene resin with bimodal cell structure:
adding 20g of macroporous polystyrene adsorption resin into a 500mL three-necked flask, adding 100g of chloromethyl ether, and standing for 4 hours at room temperature; starting a stirrer, adding 20g of anhydrous zinc chloride, heating to 50 ℃ and reacting for 24 hours; cooling to room temperature after the reaction is finished, filtering out mother liquor, extracting with methanol for 12 hours, washing with water until no methanol smell exists, and carrying out suction filtration to obtain the dry light yellow chloromethylation modified macroporous adsorption, wherein the chlorine content tested by the Buddha method is 10.3%.
(3) Friedel-crafts post-crosslinking reaction of macroporous polystyrene resin with a bimodal pore structure:
and (2) adding 20g of the chlorine balls obtained in the step (2) into nitrobenzene which is 140g of resin, standing and swelling for 4h at 40 ℃, adding zinc chloride which is 10g of resin mass under mechanical stirring, heating and reacting for 12h at 120 ℃, and carrying out Friedel-crafts alkylation reaction on chloromethyl to form an ultrahigh crosslinked network, so that the micropore quantity is greatly enriched, and the ultrahigh crosslinked macroporous adsorption resin is obtained. The specific surface area of the obtained ultra-high crosslinked adsorption resin with the bimodal pore structure is 990m 2 Per g, wherein the micropores occupy a specific surface area of 582m 2 Per g, the specific surface area of the macropores is 408m 2 /g; pore volume of 1.79cm 3 /g, wherein the micropores occupy 0.42cm of pore volume 3 Per gram, the macropores occupy a pore volume of 1.37cm 3 And/g, average pore diameter of 8.1nm. The residual chlorine content was 2.8% by the Buddha test.
(4) Epoxidation modification of ultra-high crosslinked adsorption resin with bimodal pore structure:
50mL of macroporous resin obtained in the step (3) is taken, 150mL of 1-hydroxy-1, 3 propylene oxide is added, 100mL of 2.5M sodium hydroxide aqueous solution is dripped at 45 ℃ and stirred for reaction for 4h, the macroporous resin after epoxidation modification is obtained, after the reaction is finished, mother liquor is filtered out, 1-hydroxy-1, 3 propylene oxide is washed by methanol, and then water is washed until no methanol smell exists, thus obtaining the macroporous resin after epoxidation modification, and the epoxy group content is measured to be 0.21mmol/g.
(5) Immobilization of polyethyleneimine:
adding 50mL of the epoxy modified ultrahigh crosslinked adsorption resin with the bimodal pore structure in a wet state into a 500mL three-necked flask, adding 200mL of aqueous solution, adding polyethyleneimine with the number average molecular weight of 275-25000, stirring and dissolving, heating to 60 ℃ under mechanical stirring, keeping the temperature for reaction for 12 hours, and washing with water to obtain the ultrahigh crosslinked adsorption resin grafted with polyethyleneimine and containing the bimodal pore structure.
Adsorption performance test: the resins obtained in each example were used as blood perfusion adsorbents and compared with the adsorbents in commercially available HA series of zhuhai jianfan and MG series of bergamot. The plasma of uremic patients obtained clinically is adopted to adsorb according to a bath ratio of 1:10, and protein binding micromolecular toxins such as indoxyl sulfate, indole-3-acetic acid, p-cresol sulfate, hippuric acid and the like are tested, and the removal effect (adsorption rate) of macromolecular toxins in beta 2-microglobulin, parathyroid hormone and the like is tested. The results are shown in table 1 below.
Table 1 Effect of adsorbents on the clearance of protein-bound class of small and middle-large molecular toxins
Compared with the existing blood perfusion adsorbents of the healthy sail HA130 and the Boxin MG150, the ultrahigh crosslinked adsorption resin with the grafted long-chain alkaline groups and the bimodal pore structure prepared in the embodiments 1 to 4 of the invention HAs more excellent cleaning effect of small molecular protein combined toxoid and medium and large molecular toxin. The ultra-high crosslinking adsorption resin with a bimodal pore structure is designed, so that the removal effect of the ultra-high crosslinking adsorption resin on the macromolecular toxin is ensured; the residual chloromethyl in the post-crosslinking process is innovatively utilized to perform epoxy functionalization, so that active groups are provided for subsequent grafting of long-chain amino substances; the better adsorption capacity of the protein-binding micromolecular toxin is obtained by grafting long-chain alkaline groups. In addition, the ultra-high crosslinking adsorption resin with the bimodal pore structure also has good safety performance and excellent mechanical strength, and can meet the whole blood perfusion requirement.
Finally, it should be emphasized that the above description is merely of a preferred embodiment of the invention, and is not intended to limit the invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (11)
1. The ultra-high crosslinking adsorption resin with a bimodal pore structure for adsorbing and removing protein-bound toxins and macromolecular toxins by blood perfusion is characterized by being prepared by further crosslinking a polystyrene resin matrix with a bimodal pore structure, wherein the ultra-high crosslinking adsorption resin with the bimodal pore structure contains micropores and mesopores;
the specific surface area of the ultra-high crosslinked adsorption resin with the bimodal pore structure is 600m 2 /g～1200m 2 /g; the specific surface area of the micropores is 300m 2 /g～800m 2 Per gram, the specific surface area of the macropores is 200m 2 /g～500m 2 /g；
The pore volume range of the ultra-high crosslinked adsorption resin with the bimodal pore channel structure is 1.2cm 3 /g～2.0cm 3 /g; the micropore volume of the micropore is 0.3cm 3 /g～0.6cm 3 Per g, the macropores occupy a pore volume of 0.8cm 3 /g～1.5cm 3 /g；
The ultrahigh crosslinked adsorption resin with the bimodal pore structure is covalently connected with a grafting chain containing an alkaline group, the grafting chain containing the alkaline group is prepared by carrying out epoxidation modification on chloromethyl remained in the ultrahigh crosslinked adsorption resin with the bimodal pore structure, and then utilizing the grafting chain containing the alkaline group grafted by the epoxy group;
the average pore diameter of the ultra-high crosslinked adsorption resin with the bimodal pore channel structure ranges from 2nm to 15nm.
2. The ultra-high crosslinking adsorption resin with a bimodal pore structure for hemoperfusion adsorption and removal of protein bound toxins and middle and large molecular toxins according to claim 1, wherein:
the specific surface area of the ultra-high crosslinked adsorption resin with the bimodal pore structure is in the range of 700m 2 /g～1200m 2 /g；
The pore volume range of the ultra-high crosslinked adsorption resin with the bimodal pore channel structure is 1.4cm 3 /g～1.9cm 3 /g；
The particle size range of the ultra-high crosslinked adsorption resin with the bimodal pore canal structure is 0.4 mm-2 mm.
3. The ultra-high crosslinking adsorption resin with a bimodal pore structure for hemoperfusion adsorption and removal of protein bound toxins and middle and large molecular toxins according to claim 2, wherein:
the average pore diameter range of the ultra-high crosslinked adsorption resin with the bimodal pore channel structure is 4 nm-10 nm;
the particle size range of the ultra-high crosslinked adsorption resin with the bimodal pore canal structure is 0.6 mm-1.2 mm.
4. A method for preparing an ultra-high crosslinked adsorption resin with a bimodal pore structure for hemoperfusion adsorption and removal of protein bound toxins and middle and large molecular toxins according to any one of claims 1 to 3, characterized by comprising the steps of:
step 1: polymerizing a styrene monomer, a polyvinyl cross-linking agent, a pore-forming agent and an initiator in a dispersion medium to obtain a polystyrene resin matrix with a bimodal pore structure; the pore-forming agent comprises a good solvent and a poor solvent;
step 2: carrying out chloromethylation reaction on the polystyrene resin matrix with the bimodal pore structure, and then carrying out crosslinking reaction to obtain the ultrahigh crosslinked adsorption resin with the bimodal pore structure;
step 3: and (3) carrying out epoxidation modification on the chloromethyl residue of the ultrahigh crosslinked adsorption resin with the bimodal pore structure, and then utilizing epoxy groups to graft a grafting chain containing alkaline groups.
5. The method according to claim 4, wherein in the step 3:
the epoxidation modification comprises: reacting 1-hydroxy-1, 3-epoxypropane with residual chloromethyl under alkaline conditions; the dosage of the 1-hydroxy-1, 3 epoxypropane is 2-4 times of the mass of the ultra-high crosslinking adsorption resin with the bimodal pore canal structure, the reaction temperature is 40-60 ℃, and the reaction time is 4-12 h; the epoxy group content range of the ultra-high crosslinking adsorption resin with the bimodal pore canal structure after epoxidation modification is 0.1 mmol/g-0.5 mmol/g;
the grafting comprises: reacting a polyamine compound with an epoxy group; the polyamine compound is at least one selected from polyamine and polyamine polymer, the polyamine is at least one selected from ethylenediamine, propylenediamine, butylenediamine, hexamethylenediamine, heptylenediamine, octylenediamine, nonylenediamine, decylenediamine, 1, 11-undecylenediamine and 1, 12-dodecyldiamine, the polyamine polymer is at least one selected from polylysine and polyethyleneimine, the molecular weight of the polylysine is 3600-4500, and the molecular weight of the polyethyleneimine is 275-25000; the polyamine compound is used in a solution mode, the mass fraction of the polyamine compound in the solution is 1% -5%, and the mass of the solution is 4-6 times of the mass of the epoxy modified ultrahigh crosslinked adsorption resin with the bimodal pore structure; the reaction temperature is 60-80 ℃ and the reaction time is 4-8 h.
6. The method according to claim 4 or 5, characterized in that in said step 1:
the styrene monomer is at least one selected from styrene, methyl styrene and ethyl styrene; the polyvinyl cross-linking agent is at least one selected from divinylbenzene, divinyltoluene, divinylxylene and divinylethylbenzene; the styrene monomer accounts for 20% -92% of the total mass of the styrene monomer and the polyvinyl cross-linking agent;
the pore-forming agent is a mixture of at least two substances selected from aromatic hydrocarbons, alkanes, higher alcohols, higher ketones and esters; the aromatic hydrocarbon is selected from toluene and xylene; the alkane is selected from n-heptane, 200# gasoline and solid paraffin; the higher alcohols are selected from butanol, hexanol, cyclohexanol, isooctanol, n-octanol, methyl isobutyl carbinol; the higher ketone is selected from methyl isobutyl ketone, 2-hexanone, diisobutyl ketone and methyl tert-butyl ketone; the esters are selected from butyl acetate, ethyl acetate and butyl butyrate; the mass of the pore-forming agent is 70% -230% of the total mass of the styrene monomer and the polyvinyl cross-linking agent;
the initiator is at least one selected from benzoyl peroxide, tert-butyl peroxy-2-ethylhexanoate and tert-amyl peroxy-2-ethylhexanoate; the mass of the initiator is 0.5-1.5% of the total mass of the styrene monomer and the polyvinyl cross-linking agent.
7. The method of manufacturing according to claim 6, wherein:
the styrene monomer is styrene, and the polyvinyl cross-linking agent is divinylbenzene;
the initiator is benzoyl peroxide.
8. The method according to claim 4 or 5, characterized in that in said step 1:
the dispersion medium is water, and the volume ratio of the dispersion medium to the oil phase is (1-3) to 1; the dispersing medium is provided with a dispersing agent, and the dispersing agent is at least one selected from gelatin, polyvinyl alcohol and carboxymethyl cellulose; the mass of the dispersing agent is 0.5% -2% of the mass of the dispersing medium;
the reaction temperature of the polymerization is 50-100 ℃ and the reaction time is 12-20 h.
9. The method according to claim 8, wherein in the step 1:
the dispersing agent is gelatin;
the reaction temperature of the polymerization is 70-95 ℃ and the reaction time is 14-18 h.
10. The method according to claim 4 or 5, characterized in that in said step 2:
the chloromethylation reaction includes: reacting chloromethyl ether with the polystyrene resin matrix with the bimodal pore structure under the action of anhydrous zinc chloride; the mass of the chloromethyl ether is 4-6 times of the mass of the polystyrene-based resin matrix with the bimodal pore structure, and the mass of the anhydrous zinc chloride is 0.5-1.5 times of the mass of the polystyrene-based resin matrix with the bimodal pore structure; mixing chloromethyl ether with the polystyrene resin matrix with the bimodal pore structure, standing for 4-5 hours at room temperature, adding anhydrous zinc chloride under stirring, and reacting at 50-52 ℃ for 8-24 hours; the chlorine content range of the obtained chloromethylated polystyrene base resin with the bimodal pore canal structure is 5-25%;
the crosslinking reaction includes: chloromethylated polystyrene resin matrix with a bimodal pore structure is crosslinked under the action of zinc chloride; the solvent is nitrobenzene, and the mass of the nitrobenzene is 5-7 times of that of the chloromethylated polystyrene resin matrix with the bimodal pore canal structure; the mass of the zinc chloride is 0.1 to 0.5 times of the mass of the chloromethylated polystyrene resin matrix with the bimodal pore canal structure; mixing nitrobenzene and chloromethylated polystyrene resin matrix with a bimodal pore structure, standing for 4-5 h at 35-45 ℃, and adding zinc chloride under stirring; the reaction temperature is 110-130 ℃, and the reaction time is 8-16 h.
11. A blood perfusion apparatus characterized by comprising the ultra-high crosslinked adsorption resin with a bimodal pore structure for adsorbing and removing protein-bound toxins and middle-macromolecular toxins for blood perfusion according to any one of claims 1 to 3, or the ultra-high crosslinked adsorption resin with a bimodal pore structure for adsorbing and removing protein-bound toxins and middle-macromolecular toxins for blood perfusion prepared by the preparation method according to any one of claims 4 to 10.
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| CN102391407A (en) * | 2011-09-26 | 2012-03-28 | 南京大学 | Ultrahigh crosslinked resin for separating and recovering medium and high concentration volatile organic compounds (VOCs), and preparation method and application of resin |
| CN104492402A (en) * | 2014-12-31 | 2015-04-08 | 珠海健帆生物科技股份有限公司 | Preparation method of adsorbent for adsorbing low-density lipoprotein (LDL) for whole blood perfusion |
| CN109337004A (en) * | 2018-09-28 | 2019-02-15 | 健帆生物科技集团股份有限公司 | Difunctionalization multistage macroporous adsorbent resin and preparation method thereof |
| CN112791712A (en) * | 2021-01-05 | 2021-05-14 | 南开大学 | Adsorbent for removing protein-bound uremic toxin through blood perfusion and preparation method thereof |
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| CN102391407A (en) * | 2011-09-26 | 2012-03-28 | 南京大学 | Ultrahigh crosslinked resin for separating and recovering medium and high concentration volatile organic compounds (VOCs), and preparation method and application of resin |
| CN104492402A (en) * | 2014-12-31 | 2015-04-08 | 珠海健帆生物科技股份有限公司 | Preparation method of adsorbent for adsorbing low-density lipoprotein (LDL) for whole blood perfusion |
| CN109337004A (en) * | 2018-09-28 | 2019-02-15 | 健帆生物科技集团股份有限公司 | Difunctionalization multistage macroporous adsorbent resin and preparation method thereof |
| CN112791712A (en) * | 2021-01-05 | 2021-05-14 | 南开大学 | Adsorbent for removing protein-bound uremic toxin through blood perfusion and preparation method thereof |
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