CN114288997A - Adsorption resin with self-anticoagulation property and preparation method and application thereof - Google Patents
Adsorption resin with self-anticoagulation property and preparation method and application thereof Download PDFInfo
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- CN114288997A CN114288997A CN202111545342.8A CN202111545342A CN114288997A CN 114288997 A CN114288997 A CN 114288997A CN 202111545342 A CN202111545342 A CN 202111545342A CN 114288997 A CN114288997 A CN 114288997A
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- anticoagulation
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- 239000011347 resin Substances 0.000 title claims abstract description 239
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 105
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- 238000000034 method Methods 0.000 claims description 45
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Images
Abstract
The invention provides an adsorption resin with self-anticoagulation, a preparation method and an application thereof, wherein the adsorption resin with self-anticoagulation is obtained by taking ultrahigh cross-linked macroporous adsorption resin as a carrier to immobilize heparin, reacting the heparin with an epoxy group to immobilize the heparin on the carrier, carrying out epoxy modification on the epoxy group by residual chloromethyl on the ultrahigh cross-linked macroporous adsorption resin, and carrying out chloromethylation reaction and secondary cross-linking reaction on the ultrahigh cross-linked macroporous adsorption resin by taking primarily cross-linked polystyrene-based macroporous resin as a matrix. The adsorption resin with self-anticoagulation is grafted with heparin substances on the macroporous adsorption resin subjected to secondary crosslinking, so that the ultrahigh crosslinked macroporous adsorption resin has self-anticoagulation effect while maintaining the adsorption performance.
Description
Technical Field
The invention relates to the technical field of blood purification, in particular to an adsorption resin with self-anticoagulation and a preparation method and application thereof.
Background
The blood perfusion technique is widely used for the treatment of uremia, acute poisoning, nephropathy, liver disease, critical illness and some immune diseases, and occupies an increasingly important position in the field of blood purification. The principle of the blood perfusion technology is that the blood of a patient is led to the outside of the body by means of power and is contacted with an adsorbent with a special adsorption function in a blood perfusion device to remove endogenous or exogenous toxicants or pathogenic substances in the blood of the patient, so that the aim of blood purification is fulfilled.
The blood perfusion technique is the same as other blood purification techniques, and after human blood is taken out of the body, in order to avoid treatment interruption caused by blood coagulation, heparin needs to be injected into a patient for the first time before treatment, and heparin needs to be dynamically added according to the blood coagulation state of the patient in the treatment process. Because the blood perfuses to adsorb and remove endogenous and exogenous toxin substances in the blood through the adsorbent, compared with products such as a dialyzer, a plasma separator and the like, the contact area between the adsorbent and the blood in the blood perfusor is larger, the human coagulation system is easier to activate to cause coagulation, and therefore, heparin with larger dosage is often needed to be used. If the dosage of heparin is too large, serious adverse events such as bleeding and even death can be caused.
In view of this, research and development of a blood perfusion device or an adsorbent with a self-anticoagulation function have important significance for reducing the dosage of heparin and improving the treatment safety in the blood perfusion treatment process.
Disclosure of Invention
The invention aims to solve the defects in the prior art, provides the adsorbent with the self-anticoagulation effect, does not need to additionally increase an anticoagulant in the blood perfusion process, and can even reduce the dosage of the first dose of heparin, thereby effectively improving the safety of treatment.
In order to solve the above problems, a first aspect of the present invention provides an adsorption resin with self-anticoagulation, wherein the adsorption resin uses a super-crosslinked macroporous adsorption resin as a carrier, heparin is immobilized, the heparin reacts with an epoxy group to be immobilized on the carrier, the epoxy group is obtained by performing epoxy modification on residual chloromethyl on the super-crosslinked macroporous adsorption resin, and the super-crosslinked macroporous adsorption resin is obtained by using a once-crosslinked polystyrene-based macroporous resin as a matrix and performing chloromethylation reaction and a secondary crosslinking reaction.
Further, the specific surface area range of the ultrahigh crosslinked macroporous adsorption resin is 600m2G to 1500m2In the pore volume range of 1.2cm3G to 2.1cm3(ii)/g, average pore size ranging from 2nm to 15nm, particle size ranging from 0.4mm to 2 mm; the immobilization amount of the heparin ranges from 0.05mg/mL to 0.5 mg/mL.
The second aspect of the present invention provides a method for preparing an adsorption resin having self-anticoagulation, comprising:
carrying out suspension polymerization on a styrene monomer and a polyvinyl crosslinking agent to prepare polystyrene-based macroporous resin;
performing chloromethylation reaction on the polystyrene-based macroporous resin to prepare a chlorine ball;
carrying out post-crosslinking reaction on the chlorine spheres to prepare the ultrahigh crosslinked macroporous adsorption resin;
carrying out epoxy modification on the ultrahigh cross-linked macroporous adsorption resin to prepare epoxy modified macroporous adsorption resin, wherein the epoxy modified macroporous adsorption resin contains epoxy groups;
and (3) carrying out grafting reaction on the epoxy modified macroporous adsorption resin, and grafting heparin on the epoxy group to obtain the adsorption resin with self-anticoagulation.
Further, the post-crosslinking reaction of the chlorine ball comprises the following steps:
and swelling the chlorine balls in a swelling agent, and carrying out post-crosslinking reaction under the action of a catalyst, wherein the reaction temperature of the post-crosslinking reaction is 110-130 ℃, and the reaction time is 8-16 h.
Further, the epoxy modification of the ultrahigh cross-linked macroporous adsorption resin comprises the following steps:
reacting the ultrahigh crosslinked macroporous adsorption resin with 1-hydroxy-1, 3-epoxypropane for 4 to 12 hours at 40 to 60 ℃ in an alkaline environment to obtain epoxy modified macroporous adsorption resin containing epoxy groups, wherein the content of the epoxy groups is 0.1 to 0.5mmol/g, and the volume ratio of the ultrahigh crosslinked macroporous adsorption resin to the 1-hydroxy-1, 3-epoxypropane is 1: 2 to 1: 4.
further, the epoxy modified macroporous adsorption resin is subjected to a grafting reaction, and heparin is grafted on the epoxy group, and the method comprises the following steps:
reacting the epoxy modified macroporous adsorption resin and heparin salt solution for 8 to 24 hours in an acid environment at 60 to 80 ℃, wherein the volume ratio of the epoxy modified macroporous adsorption resin to the heparin salt solution is 1: 4 to 1: 6, the mass fraction of the heparin salt solution is 1-5%.
Further, the acidic environment is a reaction environment with a pH value between 3 and 5.
Further, the styrene monomer and the polyvinyl crosslinking agent are polymerized by suspension, and the method comprises the following steps:
under the action of a pore-forming agent and an initiator, carrying out suspension polymerization on a styrene monomer and a polyvinyl crosslinking agent in a dispersion medium, wherein the reaction temperature of the suspension polymerization is 50-100 ℃, the reaction time is 12-20 h, the styrene monomer accounts for 20-92% of the total mass of the styrene monomer and the polyvinyl crosslinking agent, and the polyvinyl crosslinking agent accounts for 8-80% of the total mass of the styrene monomer and the polyvinyl crosslinking agent.
Further, the chloromethylation reaction of the polystyrene-based macroporous resin comprises the following steps:
carrying out chloromethylation reaction on the polystyrene-based macroporous resin and chloromethyl ether under the action of a catalyst, wherein the reaction temperature of the chloromethylation reaction is 50-52 ℃, the reaction time is 8-24 h, and the mass ratio of the polystyrene-based macroporous resin to the chloromethyl ether is 1: 4 to 1: 6.
the third aspect of the present invention provides a use of an adsorption resin with auto-anticoagulation property, wherein the adsorption resin with auto-anticoagulation property according to any one of the first aspect or the adsorption resin with auto-anticoagulation property prepared by the preparation method according to any one of the second aspect is used as an adsorbent in blood perfusion.
The preparation method of the adsorption resin with the self-anticoagulation property comprises the steps of preparing polystyrene-based macroporous resin by adopting a suspension polymerization reaction, taking the first crosslinked resin polystyrene-based macroporous resin as a carrier, introducing a large amount of chloromethyl on the first crosslinked resin carrier by virtue of a chloromethylation reaction, carrying out secondary crosslinking process treatment by virtue of a Friedel-crafts alkylation reaction, converting the chloromethyl into a super-high crosslinked structure, forming a super-high crosslinked network structure, greatly enriching the number of micropores, wherein the super-high crosslinked macroporous adsorption resin takes hydrophobic polystyrene as a framework, has better stability, large crosslinking density and high strength, has rich pore channel structures and huge specific surface area, and is beneficial to improving the adsorption capacity of the super-high crosslinked macroporous adsorption resin; then, carrying out epoxy modification reaction on the residual chloromethyl and 1-hydroxy-1, 3 epoxypropane after the post-crosslinking reaction, successfully introducing an active epoxy group onto the ultrahigh crosslinked macroporous adsorption resin prepared by the post-crosslinking reaction, and grafting heparin molecules onto the ultrahigh crosslinked macroporous adsorption resin by using the activity of the epoxy group, thereby grafting heparin substances onto the secondarily crosslinked macroporous adsorption resin, so that the ultrahigh crosslinked macroporous adsorption resin has self-anticoagulation effect while keeping the adsorption performance; the preparation method provided by the invention has the advantages of simple process flow, mild reaction conditions and higher safety in the reaction process, and is suitable for industrial production, the adsorption resin with self-anticoagulation prepared by the method does not need to additionally increase the anticoagulant in the blood perfusion process, even the dosage of the heparin first agent can be reduced, the adverse events of blood coagulation or bleeding caused by the anticoagulation of heparin can be greatly reduced, and the safety of blood perfusion treatment is improved.
Drawings
Fig. 1 is a process flow chart for preparing an adsorption resin with auto-anticoagulation property provided by the embodiment of the invention.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below.
It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
In addition, the terms "comprising," "including," "containing," and "having" are intended to be non-limiting, i.e., that other steps and other ingredients can be added that do not affect the results. Materials, equipment and reagents are commercially available unless otherwise specified.
In addition, although the invention has described the forms of S1, S2, S3 and the like for each step in the preparation, the description is only for the convenience of understanding, and the forms of S1, S2, S3 and the like do not represent the limitation of the sequence of each step.
The embodiment of this application provides in a first aspect an adsorption resin with from anticoagulation, this adsorption resin uses super high cross-linking macroporous adsorption resin as the carrier, the immobilized heparin, heparin reacts with the epoxy group and immobilized on the carrier, the epoxy group is carried out epoxy modification by the remaining chloromethyl on super high cross-linking macroporous adsorption resin and is obtained.
Specifically, the ultrahigh cross-linked macroporous adsorption resin is obtained by taking primary cross-linked polystyrene-based macroporous resin as a matrix through a chloromethylation reaction and a secondary cross-linking reaction, the ultrahigh cross-linked macroporous adsorption resin contains residual chloromethyl, and the specific surface area range of the ultrahigh cross-linked macroporous adsorption resin is 600m2G to 1500m2In the pore volume range of 1.2cm3G to 2.1cm3(ii)/g, average pore size ranging from 2nm to 15nm, particle size ranging from 0.4mm to 2 mm; in some preferred embodiments, the ultra-high cross-linked macroporous adsorbent resin has a specific surface area in the range of 700m2G to 1200m2In the pore volume range of 1.4 cm/g3G to 2.0cm3(ii) a mean pore diameter in the range of 4nm to 10nm and a particle size in the range of 0.6mm to 1.2 mm.
The residual quantity of chloromethyl in the ultra-high cross-linked macroporous absorbent resin is between 1 percent and 7 percent, after the epoxy modification is carried out on the residual chloromethyl on the ultra-high cross-linked macroporous absorbent resin, the content of epoxy group is between 0.1mmol/g and 0.5mmol/g, and the immobilization quantity range of heparin on the absorbent resin with self-anticoagulation is between 0.05mg/mL and 0.5 mg/mL; in some preferred embodiments, the residual amount of chloromethyl group in the ultra-high cross-linked macroporous adsorbent resin is between 2% and 5%, and the immobilized amount of heparin on the adsorbent resin with self-anticoagulation is between 0.1mg/mL and 0.4 mg/mL.
Fig. 1 is a process flow diagram for preparing an adsorbent resin with auto-anticoagulation properties provided in the examples of the present application. Referring to fig. 1, a second aspect of the embodiments of the present application provides a method for preparing an adsorption resin having auto-anticoagulation property, including:
and step S1, carrying out suspension polymerization on the styrene monomer and the polyvinyl crosslinking agent to obtain the polystyrene-based macroporous resin.
Specifically, a styrene monomer and a polyvinyl crosslinking agent are subjected to suspension polymerization in a dispersion medium under the action of a pore-forming agent and an initiator to prepare the polystyrene macroporous resin, wherein the reaction temperature of the suspension polymerization is 50-100 ℃, the reaction time is 12-20 h, the styrene monomer accounts for 20-92% of the total mass of the monomer, the polyvinyl crosslinking agent accounts for 8-80% of the total mass of the monomer, and the monomer consists of the styrene monomer and the polyvinyl crosslinking agent.
The prepared polystyrene-based macroporous resin has a particle size ranging from 0.4mm to 2mm, and in some preferred embodiments, the polystyrene-based macroporous resin has a particle size ranging from 0.6mm to 1.2 mm.
In order to further increase the reactivity of the suspension polymerization, the temperature of the suspension polymerization is 75 ℃ to 98 ℃ and the reaction time is 14h to 18 h. In order to ensure that the styrene monomer and the polyvinyl crosslinking agent are subjected to full crosslinking reaction, simultaneously the pore-forming agent is evaporated out, and the purity of the polystyrene macroporous resin is improved, on the basis of the above embodiment, the suspension polymerization reaction is non-isothermal reaction, and the temperature of the suspension polymerization reaction is gradually increased, specifically, after the styrene monomer, the polyvinyl crosslinking agent, the pore-forming agent and the initiator form droplets with uniform size in a dispersion medium, a mixed solution is obtained, the temperature of the mixed solution is increased to 75 ℃, the temperature of the mixed solution is kept for reaction for 3 hours to 8 hours, the temperature of the mixed solution is increased to 80 ℃, the temperature of the mixed solution is kept for reaction for 5 hours to 8 hours, the reaction temperature of the mixed solution is increased to 95 ℃ to 98 ℃, and the reaction is stopped after the temperature of the mixed solution is kept for reaction for 6 hours to 12 hours.
Wherein, the styrene monomer is one or the combination of two of styrene, methyl styrene and ethyl styrene, and when the styrene monomer is the mixture of the two, the styrene monomer and the ethyl styrene monomer are mixed in any proportion; in some preferred embodiments, the styrenic monomer is styrene.
The polyvinyl crosslinking agent is one or a combination of several of divinylbenzene (DVB for short), divinyltoluene, divinylxylene and divinylethylbenzene, and when the polyvinyl crosslinking agent is a mixture of several, the polyvinyl crosslinking agent and the divinyl toluene are mixed in any proportion; in some preferred embodiments, the polyvinyl-based crosslinker is divinylbenzene.
The pore-foaming agent is one or a combination of a plurality of aromatic hydrocarbon, alkane, higher alcohol, higher ketone and ester, wherein the aromatic hydrocarbon is toluene and/or xylene; the alkane is one or a combination of more of n-heptane, 200# gasoline and solid paraffin; the higher alcohol is one or more of butanol, hexanol, cyclohexanol, isooctanol, n-octanol and methyl isobutyl carbinol, and the higher ketone is one or more of methyl isobutyl ketone, 2-hexanone, diisobutyl ketone and methyl tert-butyl ketone; the esters are one or a combination of butyl acetate, ethyl acetate and butyl butyrate; when the porogen is a mixture of several kinds, it is mixed with each other in an arbitrary ratio. The ratio of the total mass of the pore-foaming agent and the monomer is 70-230%, wherein the monomer consists of a styrene monomer and a polyvinyl crosslinking agent.
The initiator is organic peroxide, optionally, the organic peroxide is one or a combination of several of benzoyl peroxide, tert-butyl peroxy-2-ethylhexanoate and tert-amyl peroxy-2-ethylhexanoate, and when the initiator is a mixture of several, the initiators are mixed with each other in any proportion; in some preferred embodiments, the initiator is benzoyl peroxide. The ratio of the total mass of the initiator to the total mass of the monomers is 0.5% to 1.5%, wherein the monomers consist of styrene monomers and polyvinyl crosslinking agents.
The volume ratio of the dispersion medium to the mixed organic phase is 1: 1 to 3: 1, wherein the mixed organic phase is a mixture consisting of a styrene monomer, a polyvinyl cross-linking agent, a pore-forming agent and an initiator.
The dispersing medium comprises a dispersing agent and water, wherein the dispersing agent is dissolved in the water to form the dispersing medium, the dispersing agent comprises any one of gelatin, polyvinyl alcohol or carboxymethyl cellulose, and in some preferred embodiments, the dispersing agent is gelatin. The dosage of the dispersant is 0.5 to 2 percent of the mass of the dispersion medium
And step S2, performing chloromethylation reaction on the polystyrene-based macroporous resin to obtain the chlorine ball.
Specifically, carrying out chloromethylation reaction on polystyrene-based macroporous resin and chloromethyl ether under the action of a catalyst, wherein the reaction temperature of the chloromethylation reaction is 50-52 ℃, the reaction time is 8-24 h, and the mass ratio of the polystyrene-based macroporous resin to the chloromethyl ether is 1: 4 to 1: 6, wherein the catalyst is at least one of zinc chloride, ferric chloride and aluminum chloride, and the dosage of the catalyst is 0.5 to 1.5 times of the mass of the polystyrene-based macroporous resin.
More specifically, soaking polystyrene-based macroporous resin in chloromethyl ether, standing for 4-5 h at normal temperature, adding a catalyst, and carrying out chloromethylation reaction at the reaction temperature of 50-52 ℃ until the reaction is finished. Therefore, the activity of the chloromethylation reaction can be improved, and more chloromethyl groups can be introduced to the polystyrene macroporous resin.
After the chloromethylation reaction is finished, cooling to normal temperature, filtering out mother liquor, extracting with methanol, then washing with water until no methanol smell exists, carrying out suction filtration, and drying to obtain light yellow chlorine spheres, wherein the chlorine content range in the chlorine spheres tested by the Flohard method is 5-25%.
And step S3, carrying out post-crosslinking reaction on the chlorine spheres to obtain the ultrahigh crosslinked macroporous adsorption resin.
Specifically, the chlorine spheres are swelled in a swelling agent, and subjected to post-crosslinking reaction under the action of a catalyst, wherein the reaction temperature of the post-crosslinking reaction is 110 ℃ to 130 ℃, and the reaction time is 8h to 16h, wherein the catalyst is at least one of zinc chloride, ferric chloride and aluminum chloride, and the dosage of the catalyst is 0.1 time to 0.5 time of the mass of the polystyrene-based macroporous resin.
More specifically, the chlorine spheres are swelled in a swelling agent, left to stand at 35 ℃ to 45 ℃ for 4h to 5h, then added with a catalyst, and subjected to post-crosslinking reaction at a reaction temperature of 110 ℃ to 130 ℃ until the reaction is completed.
The embodiment of this application carries out the chloromethylation reaction through adding excessive chloromethyl ether in the embodiment, thereby introduce a large amount of chloromethyl on once cross-linking resin carrier (i.e. polystyrene base macroporous resin), it carries out the processing of secondary crosslinking process to recycle the Friedel-crafts alkylation reaction, convert the chloromethyl into super high cross-linking structure, form super high cross-linking network structure, the micropore quantity has greatly been richened, this super high cross-linking macroporous absorbent resin uses the polystyrene of hydrophobicity as the skeleton, stability is better, and cross-linking density is big, high strength, have abundant pore structure, huge specific surface area, be favorable to improving this super high cross-linking macroporous absorbent resin's adsorption capacity.
The swelling agent is at least one of nitrobenzene, substituted nitrobenzene, dichloroethane, and o-dichlorobenzene, and in some preferred embodiments, the swelling agent is nitrobenzene. The amount of the swelling agent is 5 to 7 times of the mass of the polystyrene-based macroporous resin.
After the post-crosslinking reaction is finished, cooling to normal temperature, filtering out mother liquor, washing with water, extracting with acetone, then washing with water until no acetone smell exists, carrying out suction filtration, and drying to obtain the ultrahigh crosslinking macroporous adsorption resin. The specific surface area range of the ultrahigh cross-linked macroporous adsorption resin prepared by post cross-linking reaction is 600m2G to 1500m2Per g, preferably 700m2G to 1200m2(ii)/g; pore volume in the range of 1.2cm3G to 2.1cm3Per g, preferably 1.4cm3G to 2.0cm3(ii)/g; an average pore diameter in the range of 2nm to 15nm, preferably 4nm to 10 nm; the resin particle size ranges from 0.4mm to 2mm, preferably from 0.6mm to 1.2 mm; the residual quantity of chloromethyl in the ultra-high cross-linked macroporous absorbent resin is between 1% and 7%, preferably between 2% and 5%.
And step S4, carrying out epoxy modification on the ultrahigh cross-linked macroporous adsorption resin to obtain the epoxy modified macroporous adsorption resin, wherein the epoxy modified macroporous adsorption resin contains epoxy groups.
Specifically, reacting the ultrahigh cross-linked macroporous adsorption resin with 1-hydroxy-1, 3-epoxypropane for 4 to 12 hours at 40 to 60 ℃ in an alkaline environment to obtain epoxy modified macroporous adsorption resin containing an epoxy group, wherein the epoxy group content is 0.1 to 0.5mmol/g, and the volume ratio of the ultrahigh cross-linked macroporous adsorption resin to the 1-hydroxy-1, 3-epoxypropane is 1: 2 to 1: 4.
more specifically, the ultrahigh cross-linked macroporous adsorption resin and 1-hydroxy-1, 3-epoxypropane are uniformly mixed, an alkaline aqueous solution is dripped at the temperature of 40-60 ℃, and the mixture reacts for 4-12 hours to prepare the epoxy modified macroporous adsorption resin containing the epoxy group, wherein the molar concentration of the alkaline aqueous solution is 2.5-5 mol/L, the strong base can be sodium hydroxide or potassium hydroxide, and the strong base can also be a mixture of sodium hydroxide and potassium hydroxide.
In the embodiment of the application, the chloromethyl on the ultrahigh cross-linked macroporous adsorption resin and the 1-hydroxy-1, 3 epoxypropane are subjected to an epoxy modification reaction, so that an active epoxy group is successfully introduced into the ultrahigh cross-linked macroporous adsorption resin, and more active epoxy groups can be introduced into the excessive 1-hydroxy-1, 3 epoxypropane on the ultrahigh cross-linked macroporous adsorption resin.
And after the epoxy modification reaction is finished, filtering out the mother liquor, washing with methanol, washing with water until no methanol smell exists, carrying out suction filtration and drying to obtain the epoxy modified macroporous adsorption resin, wherein the content of the epoxy group in the epoxy modified macroporous adsorption resin is measured to be 0.1mmol/g to 0.5 mmol/g.
And step S5, carrying out grafting reaction on the epoxy modified macroporous adsorption resin, and grafting heparin on the epoxy group to obtain the macroporous adsorption resin with self-anticoagulation.
Specifically, the epoxy modified macroporous adsorption resin and heparin salt solution react for 8 to 24 hours in an acid environment at 60 to 80 ℃, wherein the volume ratio of the epoxy modified macroporous adsorption resin to the heparin salt solution is 1: 4 to 1: 6, the mass fraction of the heparin salt solution is 1 to 5 percent.
More specifically, the epoxy modified macroporous adsorption resin and the heparin salt solution are uniformly mixed, an acid solution is added, the reaction environment is adjusted to be acidic, the temperature of the mixed solution is raised to 60-80 ℃, the heat preservation reaction is carried out for 8-24 h until the reaction is finished, and the mixed solution is washed by water to obtain the heparin grafted ultrahigh cross-linked macroporous adsorption resin, namely the macroporous adsorption resin with self-anticoagulation, wherein the grafting amount of heparin on the macroporous adsorption resin with self-anticoagulation is determined to be 0.05-0.5 mg/mL, and the preferred grafting amount of heparin is 0.1-0.4 mg/mL.
In the embodiment of the application, the activity of an epoxy group is utilized to graft heparin molecules onto the ultrahigh cross-linked macroporous adsorption resin, so that the heparin substances are grafted onto the macroporous adsorption resin subjected to secondary cross-linking, and the ultrahigh cross-linked macroporous adsorption resin has a self-anticoagulation effect while the adsorption performance of the ultrahigh cross-linked macroporous adsorption resin is maintained; in addition, the excessive heparin salt solution can introduce more heparin substances on the ultrahigh cross-linked macroporous adsorption resin.
Wherein the heparin salt solution is aqueous solution of heparin salt, and the heparin salt is one or combination of more of heparin sodium, heparin calcium, heparin potassium and heparin lithium; in some preferred embodiments, the heparin salt is heparin sodium, which may be commercially available pharmaceutical grade low molecular weight heparin sodium or commercially available pharmaceutical grade sodium heparin.
In order to ensure that the grafting reaction has high reactivity and avoid destroying the activity of heparin, on the basis of the above examples, the acidic environment is a reaction environment with a pH value between 3 and 5. The kind of the acidic solution for adjusting the pH value is not further limited in the examples of the present application, and optionally, the pH value of the reaction environment is adjusted to between 3 and 5 by adding a hydrochloric acid solution.
According to the preparation method of the adsorption resin with the self-anticoagulation, firstly, the polystyrene-based macroporous resin is prepared through suspension polymerization, the polystyrene-based macroporous resin of the primary crosslinking resin is used as a carrier, a large amount of chloromethyl is introduced to the carrier of the primary crosslinking resin through chloromethylation, and then the secondary crosslinking process is carried out through Friedel-crafts alkylation reaction, the chloromethyl is converted into an ultrahigh crosslinking structure, so that an ultrahigh crosslinking network structure is formed, the number of micropores is greatly enriched, the ultrahigh crosslinking macroporous adsorption resin takes hydrophobic polystyrene as a framework, the stability is better, the crosslinking density is high, the strength is high, the porous structure is rich, the specific surface area is large, and the adsorption capacity of the ultrahigh crosslinking macroporous adsorption resin is favorably improved; then, carrying out epoxy modification reaction on the residual chloromethyl and 1-hydroxy-1, 3 epoxypropane after the post-crosslinking reaction, successfully introducing an active epoxy group onto the ultrahigh crosslinked macroporous adsorption resin prepared by the post-crosslinking reaction, and grafting heparin molecules onto the ultrahigh crosslinked macroporous adsorption resin by using the activity of the epoxy group, thereby grafting heparin substances onto the secondarily crosslinked macroporous adsorption resin, so that the ultrahigh crosslinked macroporous adsorption resin has self-anticoagulation effect while keeping the adsorption performance; the preparation method provided by the embodiment of the application has the advantages of simple process flow, mild reaction conditions, higher safety in the reaction process and suitability for industrial production, the adsorption resin with self-anticoagulation prepared by the method does not need to be additionally added with anticoagulant in the blood perfusion process, the dosage of a heparin first agent can be reduced, the dosage of the heparin first agent can be reduced, adverse events of blood coagulation or bleeding caused by the anticoagulation of heparin can be greatly reduced, and the safety of blood perfusion treatment is improved.
A third aspect of the embodiments of the present application provides a use of an adsorption resin having auto-anticoagulation property for an adsorbent in blood perfusion.
In the embodiment of this application will have from the adsorption resin of anticoagulation and be applied to blood perfusion, need not additionally to increase the anticoagulant at the blood perfusion in-process, can also reduce the quantity of the first agent of heparin even, can reduce coagulation or bleeding adverse events because of using the anticoagulation of heparin to appear by a wide margin, improved the security of blood perfusion treatment.
In order to further illustrate the present invention, the following examples are given to further illustrate the present invention. The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified; materials, reagents and the like used in examples of the present invention are commercially available unless otherwise specified.
Example 1
This example provides a method for preparing an adsorption resin with auto-anticoagulation, which comprises the following steps:
(1) suspension polymerization:
adding 600mL of aqueous solution containing 1.5 wt% of gelatin into a 1000mL three-neck flask, adding a mixed organic phase consisting of 42g of styrene, 8g of divinylbenzene (DVB for short) with the purity of 63 wt%, 50g of toluene, 30g of 200# gasoline and 0.5g of benzoyl peroxide, heating to 75 ℃ under mechanical stirring for reaction for 5h, heating to 80 ℃ for reaction for 5h, heating to 95-98 ℃ for heat preservation for 6 h-8 h, fully crosslinking and curing, evaporating a toluene pore-forming agent, cooling after the reaction is finished, extracting with acetone for 12h, washing with water until no acetone smell exists, carrying out suction filtration, drying, screening, and selecting resin with the particle size of 0.6-1.2 mm to obtain the polystyrene-based resin.
(2) Chloromethylation reaction:
adding 20g of polystyrene macroporous resin into a 500mL three-necked flask, adding 100g of chloromethyl ether, standing for 4h at normal temperature, starting a stirrer, adding 20g of zinc chloride, heating to 50 ℃ and reacting for 24 h; after the reaction is finished, cooling to normal temperature, filtering out mother liquor, extracting with methanol for 12h, washing with water until no methanol smell exists, carrying out suction filtration, and drying to obtain light yellow chlorine spheres, wherein the chlorine content in the chlorine spheres is 18.5% as tested by a Flohard method.
(3) Post-crosslinking reaction:
taking 20g of the chlorine ball prepared 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 ℃, carrying out Friedel-crafts alkylation reaction on chloromethyl to form a super-high crosslinked network, greatly enriching the number of micropores, cooling to normal temperature after the reaction is finished, filtering out mother liquor, washing, extracting with acetone, then washing with water until acetone smell does not exist, carrying out suction filtration, drying to obtain super-high crosslinked macroporous adsorption resin, and determining that the specific surface area of the super-high crosslinked macroporous adsorption resin obtained by a secondary crosslinking process is 1069m2Per g, pore volume 1.51cm3The content of residual chlorine in the ultrahigh cross-linked macroporous adsorbent resin is 3.8 percent by Flohard method test.
(4) Epoxy modification of the ultrahigh cross-linked macroporous adsorption resin:
and (3) taking 50mL of the ultrahigh cross-linked macroporous adsorption resin obtained in the step (3), adding 150mL of 1-hydroxy-1, 3-epoxypropane, dropwise adding 100mL of 2.5mol/L sodium hydroxide aqueous solution at 45 ℃, stirring and reacting for 4h to obtain epoxy modified macroporous adsorption resin containing an epoxy group, filtering out a mother solution after the reaction is finished, washing 1-hydroxy-1, 3-epoxypropane with methanol, and then washing with water until no methanol smell exists to obtain epoxy modified macroporous adsorption resin containing the epoxy group, wherein the content of the epoxy group is determined to be 0.29 mmol/g.
(5) Grafting reaction:
adding 50mL of epoxy modified macroporous adsorption resin containing an epoxy group in a water-wet state into a 500mL three-neck flask, adding 200mL of aqueous solution, adding 10g of medicinal-grade common heparin sodium powder, stirring and dissolving, then dropwise adding hydrochloric acid solution to adjust the pH value of the mixed solution to be between 3 and 4, starting mechanical stirring, heating the mixed solution to 80 ℃, carrying out heat preservation reaction for 12 hours at 80 ℃, after the reaction is finished, using purified water to carry out grafting reaction on the epoxy modified macroporous adsorption resin which does not participate in the grafting reaction to obtain heparin grafted ultrahigh cross-linked macroporous adsorption resin, namely macroporous adsorption resin with auto-anticoagulation, wherein the grafting amount of heparin on the macroporous adsorption resin with auto-anticoagulation is determined to be 0.33 mg/mL.
Example 2
This example provides a method for preparing an adsorption resin with auto-anticoagulation, which comprises the following steps:
(1) suspension polymerization:
adding 600mL of aqueous solution containing 1.5 wt% of gelatin into a 1000mL three-neck flask, adding a mixed organic phase consisting of 38g of styrene, 12g of divinylbenzene (DVB for short) with the purity of 63 wt%, 60g of toluene, 40g of methyl isobutyl carbinol and 0.5g of tert-butyl peroxy-2-ethylhexanoate, heating to 75 ℃ under mechanical stirring for reaction for 5h, heating to 80 ℃ for reaction for 5h, heating to 95-98 ℃ for heat preservation for 12h, fully crosslinking and solidifying, evaporating toluene and methyl isobutyl carbinol pore-forming agents, cooling after the reaction is finished, extracting with acetone for 12h, washing with water until no acetone smell exists, carrying out suction filtration, drying, screening, and selecting resin with the particle size of 0.6-1.2 mm to obtain the polystyrene-based macroporous resin.
(2) Chloromethylation reaction:
adding 20g of polystyrene macroporous resin into a 500mL three-necked flask, adding 100g of chloromethyl ether, standing for 4h at normal temperature, starting a stirrer, adding 20g of zinc chloride, heating to 50 ℃ and reacting for 24 h; after the reaction is finished, cooling to normal temperature, filtering out mother liquor, extracting with methanol for 12h, washing with water until no methanol smell exists, carrying out suction filtration, and drying to obtain light yellow chlorine spheres, wherein the chlorine content in the chlorine spheres is 16.5% as tested by a Flohard method.
(3) Post-crosslinking reaction:
taking 20g of the chlorine ball prepared 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 ℃, carrying out Friedel-crafts alkylation reaction on chloromethyl to form a super-high cross-linked network, greatly enriching the number of micropores, cooling to normal temperature after the reaction is finished, filtering out mother liquor, washing, extracting with acetone, then washing with water until acetone smell does not exist, carrying out suction filtration, drying to obtain super-high cross-linked macroporous adsorption resin, and determining that the specific surface area range of the super-high cross-linked macroporous adsorption resin obtained by a secondary cross-linking process is 1169m2Per g, pore volume 1.91cm3The content of residual chlorine in the ultrahigh cross-linked macroporous adsorbent resin is 3.2 percent by Flohard method test.
(4) Epoxy modification of the ultrahigh cross-linked macroporous adsorption resin:
and (3) taking 50mL of the ultrahigh cross-linked macroporous adsorption resin obtained in the step (3), adding 150mL of 1-hydroxy-1, 3-epoxypropane, dropwise adding 100mL of 2.5mol/L sodium hydroxide aqueous solution at 45 ℃, stirring and reacting for 4h to obtain epoxy modified macroporous adsorption resin containing an epoxy group, filtering out a mother solution after the reaction is finished, washing 1-hydroxy-1, 3-epoxypropane with methanol, and then washing with water until no methanol smell exists to obtain epoxy modified macroporous adsorption resin containing the epoxy group, wherein the content of the epoxy group is determined to be 0.22 mmol/g.
(5) Grafting reaction:
adding 50mL of epoxy modified macroporous adsorption resin containing an epoxy group in a water-wet state into a 500mL three-neck flask, adding 200mL of aqueous solution, adding 10g of medicinal low-molecular-weight heparin sodium powder, stirring for dissolving, dropwise adding hydrochloric acid solution to adjust the pH value of the mixed solution to be between 3 and 4, starting mechanical stirring, heating to 80 ℃, keeping the temperature at 80 ℃ for reaction for 12 hours, after the reaction is finished, using purified water to carry out grafting reaction on the epoxy modified macroporous adsorption resin which does not participate in the grafting reaction to obtain heparin grafted ultrahigh cross-linked macroporous adsorption resin, namely macroporous adsorption resin with auto-anticoagulation, wherein the grafting amount of heparin on the macroporous adsorption resin with auto-anticoagulation is determined to be 0.19 mg/mL.
Example 3
This example provides a method for preparing an adsorption resin with auto-anticoagulation, which comprises the following steps:
(1) suspension polymerization:
adding 600mL of aqueous solution containing 1.5 wt% of gelatin into a 1000mL three-neck flask, adding a mixed organic phase consisting of 31.5g of divinylbenzene, 18.5g of ethylstyrene, 50g of toluene, 50g of methyl isobutyl ketone and 0.5g of tert-butyl peroxy-2-ethylhexanoate, heating to 75 ℃ under mechanical stirring, reacting for 5h, heating to 80 ℃ for reacting for 5h, heating to 95-98 ℃ for preserving the temperature for 12h, fully crosslinking and curing, evaporating a toluene and methyl isobutyl ketone pore-forming agent, cooling after the reaction is finished, extracting for 12h by acetone, washing by water until no acetone smell exists, carrying out suction filtration, drying, screening, and selecting resin with the particle size of 0.6-1.2 mm to obtain the polystyrene-based macroporous resin.
(2) Chloromethylation reaction:
adding 20g of polystyrene macroporous resin into a 500mL three-necked flask, adding 100g of chloromethyl ether, standing for 4h at normal temperature, starting a stirrer, adding 20g of zinc chloride, heating to 50 ℃ and reacting for 24 h; after the reaction is finished, cooling to normal temperature, filtering out mother liquor, extracting with methanol for 12h, washing with water until no methanol smell exists, carrying out suction filtration, and drying to obtain light yellow chlorine spheres, wherein the chlorine content in the chlorine spheres is 12.5% as tested by a Flohard method.
(3) Post-crosslinking reaction:
taking 20g of the chlorine ball prepared 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 a superhigh crosslinked networkComplexing, greatly enriching the number of micropores, cooling to normal temperature after the reaction is finished, filtering out mother liquor, washing, extracting with acetone, washing with water until no acetone smell exists, suction filtering, drying to obtain the ultrahigh cross-linked macroporous adsorption resin, and determining that the specific surface area range of the ultrahigh cross-linked macroporous adsorption resin obtained by the secondary cross-linking process is 909m2Per g, pore volume 1.81cm3The content of residual chlorine in the ultrahigh cross-linked macroporous adsorbent resin is 2.8 percent by Flohard method test.
(4) Epoxy modification of the ultrahigh cross-linked macroporous adsorption resin:
and (3) taking 50mL of the ultrahigh cross-linked macroporous adsorption resin obtained in the step (3), adding 150mL of 1-hydroxy-1, 3-epoxypropane, dropwise adding 100mL of 2.5mol/L sodium hydroxide aqueous solution at 45 ℃, stirring and reacting for 4h to obtain epoxy modified macroporous adsorption resin containing an epoxy group, filtering out a mother solution after the reaction is finished, washing 1-hydroxy-1, 3-epoxypropane with methanol, and then washing with water until no methanol smell exists to obtain epoxy modified macroporous adsorption resin containing the epoxy group, wherein the content of the epoxy group is determined to be 0.19 mmol/g.
(5) Grafting reaction:
adding 50mL of epoxy modified macroporous adsorption resin containing an epoxy group in a water-wet state into a 500mL three-neck flask, adding 200mL of aqueous solution, adding 10g of medicinal-grade common heparin sodium powder, stirring and dissolving, then dropwise adding hydrochloric acid solution to adjust the pH value of the mixed solution to be between 3 and 4, starting mechanical stirring, heating to 80 ℃, carrying out heat preservation reaction for 12 hours at 80 ℃, after the reaction is finished, using purified water to carry out grafting reaction on the epoxy modified macroporous adsorption resin which does not participate in the grafting reaction to obtain heparin grafted ultrahigh cross-linked macroporous adsorption resin, namely macroporous adsorption resin with self-anticoagulation, wherein the grafting amount of heparin on the macroporous adsorption resin with self-anticoagulation is determined to be 0.26 mg/mL.
Example 4:
this example provides a method for preparing an adsorption resin with auto-anticoagulation, which comprises the following steps:
(1) suspension polymerization:
adding 600mL of aqueous solution containing 1.5 wt% of gelatin into a 1000mL three-neck flask, adding a mixed organic phase consisting of 40g of divinylbenzene, 10g of ethylstyrene, 60g of toluene, 50g of ethyl acetate and 0.5g of tert-butyl peroxy-2-ethylhexanoate, heating to 75 ℃ under mechanical stirring for 5 hours of reaction, heating to 80 ℃ for 5 hours of reaction, heating to 95-98 ℃ for heat preservation for 12 hours, fully crosslinking and curing, evaporating toluene and ethyl acetate pore-forming agent, cooling after the reaction is finished, extracting with acetone for 12 hours, washing with water until no acetone smell exists, carrying out suction filtration, drying, screening, and selecting resin with the particle size of 0.6-1.2 mm to obtain the polystyrene macroporous resin.
(2) Chloromethylation reaction:
adding 20g of polystyrene macroporous resin into a 500mL three-necked flask, adding 100g of chloromethyl ether, standing for 4h at normal temperature, starting a stirrer, adding 20g of zinc chloride, heating to 50 ℃ and reacting for 24 h; after the reaction is finished, cooling to normal temperature, filtering out mother liquor, extracting with methanol for 12h, washing with water until no methanol smell exists, carrying out suction filtration, and drying to obtain light yellow chlorine spheres, wherein the chlorine content in the chlorine spheres is 11.7% as tested by a Flohard method.
(3) Post-crosslinking reaction:
taking 20g of the chlorine ball prepared 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 12h at 120 ℃, carrying out Friedel-crafts alkylation reaction on chloromethyl to form a super-high cross-linked network, greatly enriching the number of micropores, cooling to normal temperature after the reaction is finished, filtering out mother liquor, washing, extracting with acetone, then washing with water until acetone smell does not exist, carrying out suction filtration, drying to obtain super-high cross-linked macroporous adsorption resin, and determining that the specific surface area range of the super-high cross-linked macroporous adsorption resin obtained by a secondary cross-linking process is 890m2Per g, pore volume 1.71cm3The content of residual chlorine in the ultrahigh cross-linked macroporous adsorbent resin is 2.5 percent by Flohard method test.
(4) Epoxy modification of the ultrahigh cross-linked macroporous adsorption resin:
and (3) taking 50mL of the macroporous resin obtained in the step (3), adding 150mL of 1-hydroxy-1, 3-epoxypropane, dropwise adding 100mL of 2.5mol/L sodium hydroxide aqueous solution at 45 ℃, stirring and reacting for 4h to obtain the epoxy modified macroporous adsorption resin containing the epoxy group, filtering out a mother solution after the reaction is finished, washing the 1-hydroxy-1, 3-epoxypropane with methanol, and then washing with water until no methanol smell exists, namely the epoxy modified macroporous adsorption resin containing the epoxy group has the epoxy group content of 0.17mmol/g through determination.
(5) Grafting reaction:
adding 50mL of epoxy modified macroporous adsorption resin containing an epoxy group in a water-wet state into a 500mL three-neck flask, adding 200mL of aqueous solution, adding 10g of medicinal low-molecular-weight heparin sodium powder, stirring for dissolving, dropwise adding hydrochloric acid solution to adjust the pH value of the mixed solution to be between 3 and 4, starting mechanical stirring, heating to 80 ℃, keeping the temperature at 80 ℃ for reaction for 12 hours, after the reaction is finished, using purified water to carry out grafting reaction on the epoxy modified macroporous adsorption resin which does not participate in the grafting reaction to obtain heparin grafted ultrahigh cross-linked macroporous adsorption resin, namely macroporous adsorption resin with auto-anticoagulation, wherein the grafting amount of heparin on the macroporous adsorption resin with auto-anticoagulation is determined to be 0.15 mg/mL.
The effect of the macroporous adsorbent resin with auto-anticoagulation property according to the present invention will be described below with reference to specific tests and test effects.
The macroporous adsorbent resin with self-anticoagulation property prepared in examples 1 to 4 was used as a blood perfusion adsorbent, and a commercially available adsorbent (a commercially available zhahijian sail HA130 adsorbent) was used as a control group, and the adsorbents of each group were added to plasma of uremia patients obtained clinically, and the ratio of the adsorbent: plasma 1: adsorbing the plasma at a ratio of 10(V/V, namely volume ratio), after shaking for 2 hours at 37 ℃, finishing adsorption, and taking the plasma for detection to obtain the removal effect on large molecular toxins such as beta 2-microglobulin and parathyroid hormone shown in table 1; in addition, to compare the self-anticoagulation effect, fresh rabbit blood was collected, each adsorbent was incubated with the freshly collected rabbit blood at 37 ℃ respectively, and the blood coagulation time was observed and recorded, and the specific results of the adsorption performance and the self-anticoagulation effect of the adsorbents in each example and the adsorbent in the control group are shown in table 1.
TABLE 1
As can be seen from table 1, the macroporous adsorbent resin with auto-anticoagulation property in examples 1 to 4 improves the blood compatibility of the secondary cross-linked adsorbent resin by grafting heparin, and does not need collodion coating, thereby avoiding the loss of adsorption property due to pore blocking of the coating, and the macroporous adsorbent resin with auto-anticoagulation property in examples 1 to 4 HAs better adsorption property compared with the HA130 adsorbent (i.e. control group) coated with collodion. In addition, the macroporous adsorption resin with self-anticoagulation in the embodiments 1 to 4 of the invention HAs excellent anticoagulation performance after heparin grafting, the whole blood coagulation time of the macroporous adsorption resin is free from any coagulation phenomenon within 120min, and the conventional HA130 adsorbent is coagulated within 48min without adding heparin anticoagulation, so that the macroporous adsorption resin with self-anticoagulation remarkably improves the anticoagulation effect, and can meet the requirement of realizing the self-anticoagulation function in blood perfusion with a blood perfusion time of more than 2 h.
Although the present disclosure has been described above, the scope of the present disclosure is not limited thereto. Various changes and modifications may be effected therein by one of ordinary skill in the pertinent art without departing from the spirit and scope of the present disclosure, and these changes and modifications are intended to be within the scope of the present disclosure.
Claims (10)
1. The adsorption resin with the self-anticoagulation property is characterized in that the adsorption resin takes ultrahigh cross-linked macroporous adsorption resin as a carrier to immobilize heparin, the heparin reacts with an epoxy group to be immobilized on the carrier, the epoxy group is obtained by carrying out epoxy modification on residual chloromethyl on the ultrahigh cross-linked macroporous adsorption resin, and the ultrahigh cross-linked macroporous adsorption resin is obtained by taking once cross-linked polystyrene-based macroporous resin as a matrix through a chloromethylation reaction and a secondary cross-linking reaction.
2. The adsorption resin with self-anticoagulation property according to claim 1, wherein the ultrahigh cross-linked macroporous adsorption resin has a specific surface area in the range of 600m2G to 1500m2In the pore volume range of 1.2cm3G to 2.1cm3(ii)/g, average pore size ranging from 2nm to 15nm, particle size ranging from 0.4mm to 2 mm; the immobilization amount of the heparin ranges from 0.05mg/mL to 0.5 mg/mL.
3. A method for preparing an adsorption resin having self-anticoagulation, comprising:
carrying out suspension polymerization on a styrene monomer and a polyvinyl crosslinking agent to prepare polystyrene-based macroporous resin;
performing chloromethylation reaction on the polystyrene-based macroporous resin to prepare a chlorine ball;
carrying out post-crosslinking reaction on the chlorine spheres to prepare the ultrahigh crosslinked macroporous adsorption resin;
carrying out epoxy modification on the ultrahigh cross-linked macroporous adsorption resin to prepare epoxy modified macroporous adsorption resin, wherein the epoxy modified macroporous adsorption resin contains epoxy groups;
and (3) carrying out grafting reaction on the epoxy modified macroporous adsorption resin, and grafting heparin on the epoxy group to obtain the adsorption resin with self-anticoagulation.
4. The method for preparing the adsorption resin with self-anticoagulation property according to claim 3, wherein the step of subjecting the chlorine spheres to post-crosslinking reaction comprises:
and swelling the chlorine balls in a swelling agent, and carrying out post-crosslinking reaction under the action of a catalyst, wherein the reaction temperature of the post-crosslinking reaction is 110-130 ℃, and the reaction time is 8-16 h.
5. The method for preparing the adsorption resin with the self-anticoagulation property according to claim 3, wherein the epoxy modification of the ultrahigh crosslinked macroporous adsorption resin comprises the following steps:
reacting the ultrahigh crosslinked macroporous adsorption resin with 1-hydroxy-1, 3-epoxypropane for 4 to 12 hours at 40 to 60 ℃ in an alkaline environment to obtain epoxy modified macroporous adsorption resin containing epoxy groups, wherein the content of the epoxy groups is 0.1 to 0.5mmol/g, and the volume ratio of the ultrahigh crosslinked macroporous adsorption resin to the 1-hydroxy-1, 3-epoxypropane is 1: 2 to 1: 4.
6. the method for preparing the adsorption resin with self-anticoagulation according to claim 3, wherein the epoxy modified macroporous adsorption resin is subjected to a grafting reaction to graft heparin onto the epoxy group, comprising:
reacting the epoxy modified macroporous adsorption resin and heparin salt solution for 8 to 24 hours in an acid environment at 60 to 80 ℃, wherein the volume ratio of the epoxy modified macroporous adsorption resin to the heparin salt solution is 1: 4 to 1: 6, the mass fraction of the heparin salt solution is 1-5%.
7. The method for preparing an adsorption resin having self-anticoagulation property according to claim 6, wherein the acidic environment is a reaction environment having a pH value of 3 to 5.
8. The method for preparing an adsorption resin with self-anticoagulation property according to claim 3, wherein the step of polymerizing the styrene-based monomer and the polyvinyl-based crosslinking agent by suspension comprises:
under the action of a pore-forming agent and an initiator, carrying out suspension polymerization on a styrene monomer and a polyvinyl crosslinking agent in a dispersion medium, wherein the reaction temperature of the suspension polymerization is 50-100 ℃, the reaction time is 12-20 h, the styrene monomer accounts for 20-92% of the total mass of the styrene monomer and the polyvinyl crosslinking agent, and the polyvinyl crosslinking agent accounts for 8-80% of the total mass of the styrene monomer and the polyvinyl crosslinking agent.
9. The method for preparing an adsorption resin with self-anticoagulation according to claim 3, wherein the chloromethylation reaction of the polystyrene-based macroporous resin comprises:
carrying out chloromethylation reaction on the polystyrene-based macroporous resin and chloromethyl ether under the action of a catalyst, wherein the reaction temperature of the chloromethylation reaction is 50-52 ℃, the reaction time is 8-24 h, and the mass ratio of the polystyrene-based macroporous resin to the chloromethyl ether is 1: 4 to 1: 6.
10. use of the adsorption resin having self-anticoagulation property according to claim 1 or 2 or the adsorption resin having self-anticoagulation property prepared by the preparation method according to any one of claims 3 to 9 as an adsorbent for hemoperfusion.
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