Self-anticoagulation blood fat adsorbent as well as preparation method and application thereof

Abstract

The invention provides a self-anticoagulation blood fat adsorbent as well as a preparation method and application thereof, and the preparation method of the self-anticoagulation blood fat adsorbent comprises the following steps: preparing macroporous resin with suspension double bonds on the surface; the preparation method comprises the following steps: under the action of a first initiator, carrying out grafting reaction on macroporous resin with a carboxyl-containing monomer, a sulfonic acid group-containing monomer and a hydroxyl-containing monomer at the same time to prepare the self-anticoagulation blood fat adsorbent, wherein the carboxyl group-containing monomer, the sulfonic group-containing monomer and the hydroxyl group-containing monomer all contain unsaturated double bonds. The self-anticoagulation blood fat adsorbent provided by the invention has good strength, not only has good adsorption performance on low-density lipoprotein, but also has a self-anticoagulation effect, can be directly used for whole blood perfusion, and is beneficial to improving the safety of blood purification.

Description

Technical Field

[0001] This invention relates to the field of blood purification technology, and more specifically, to a self-anticoagulating lipid adsorbent, its preparation method, and its application. Background Technology

[0002] Hemoperfusion refers to the process of introducing blood into a perfusion device containing a fixed adsorbent, where harmful substances in the blood are adsorbed through physical or chemical adsorption, thus achieving blood purification. Lipid adsorption, during hemoperfusion, utilizes the specific adsorption of low-density lipoprotein (LDL) by the adsorbent to reduce the LDL content in the blood, thereby preventing cardiovascular diseases caused by atherosclerosis.

[0003] The lipid adsorption columns used in related technologies are mainly the Liposober series adsorption columns from Japan. These columns consist of cellulose gels immobilized with dextran sulfate. After plasma separation, they utilize electrostatic interactions to adsorb low-density lipoproteins from the plasma, thereby lowering blood lipids. However, cellulose gels suffer from low strength. During blood adsorption, the cellulose gel is subjected to the impact force of the plasma, potentially leading to gel breakage. This not only affects its adsorption performance but also increases the safety risks during blood purification. Summary of the Invention

[0004] The present invention aims to provide a self-anticoagulating lipid adsorbent, its preparation method and application. The self-anticoagulating lipid adsorbent has good strength, not only has good adsorption performance for low-density lipoprotein, but also has self-anticoagulation effect, and can be directly used for whole blood perfusion, which is beneficial to improving the safety of blood purification.

[0005] To address the above problems, a first aspect of the present invention provides a method for preparing a self-anticoagulating lipid adsorbent, comprising the following steps:

[0006] Preparation of macroporous resins with dangling double bonds on the surface;

[0007] Under the action of a first initiator, the macroporous resin is simultaneously grafted with a monomer containing a carboxyl group, a monomer containing a sulfonic acid group, and a monomer containing a hydroxyl group to obtain the self-anticoagulant lipid adsorbent.

[0008] The monomers containing carboxyl groups, sulfonic acid groups, and hydroxyl groups all contain unsaturated double bonds.

[0009] Furthermore, the carboxyl-containing monomer is acrylic acid and / or methacrylic acid;

[0010] The monomer containing sulfonic acid groups is 2-acrylamido-2-methylpropanesulfonic acid;

[0011] The hydroxyl-containing monomer is hydroxyethyl methacrylate and / or hydroxyethyl acrylate.

[0012] Furthermore, the molar ratio between the carboxyl-containing monomer, the sulfonic acid-containing monomer, and the hydroxyl-containing monomer is 1:(1-3):(2-4).

[0013] Furthermore, the total mass of the carboxyl-containing monomer, the sulfonic acid-containing monomer, and the hydroxyl-containing monomer is 5% to 20% of the mass of the macroporous resin.

[0014] Furthermore, the first initiator is a water-soluble thermal initiator, which is ammonium persulfate and / or potassium persulfate, and the mass of the first initiator is 1% to 10% of the mass of the macroporous resin.

[0015] Furthermore, the grafting reaction is carried out at a temperature of 40°C to 80°C for a time of 6 hours to 24 hours.

[0016] Furthermore, before the macroporous resin undergoes the grafting reaction, it further includes:

[0017] The macroporous resin is placed in purified water for swelling, wherein the mass of the purified water is 1.2 to 3.6 times the mass of the macroporous resin.

[0018] Furthermore, the preparation of the macroporous resin with dangling double bonds on its surface includes:

[0019] Styrene monomers and divinylbenzene are subjected to suspension polymerization in a dispersion medium under the action of a porogen and a second initiator to obtain a primary crosslinked macroporous resin, wherein the surface of the primary crosslinked macroporous resin contains dangling double bonds.

[0020] A second aspect of the present invention provides a self-anticoagulant lipid adsorbent, which is prepared by the preparation method described in the first aspect, wherein the self-anticoagulant lipid adsorbent uses a macroporous resin as a carrier, and the carrier is immobilized with carboxyl groups, sulfonic acid groups and hydroxyl groups.

[0021] A third aspect of the present invention provides a self-anticoagulant lipid adsorbent prepared by the preparation method described in the first aspect, or the application of the self-anticoagulant lipid adsorbent described in the second aspect in whole blood perfusion.

[0022] The self-anticoagulating lipid adsorbent, its preparation method, and its application described in this invention utilize a macroporous resin with dangling double bonds on its surface as a matrix. Macroporous resins have high strength and a low risk of breakage due to plasma impact, thus improving the safety of the self-anticoagulating lipid adsorbent during use. The dangling double bonds on the surface of the macroporous resin can undergo grafting reactions with monomers containing carboxyl groups, sulfonic acid groups, and hydroxyl groups, immobilizing these groups on the macroporous resin. This results in a large number of negative charges on the surface of the self-anticoagulating lipid adsorbent, enabling the adsorption of low-density lipoproteins through electrostatic interactions. Simultaneously, the combined action of the carboxyl, sulfonic acid, and hydroxyl groups provides a heparin-like effect, giving the self-anticoagulating lipid adsorbent physiological properties similar to heparin. Therefore, during whole blood perfusion, it can adsorb coagulation factor IV (calcium ions) in the blood, achieving a self-anticoagulating effect. Furthermore, by directly grafting carboxyl-containing monomers, sulfonic acid-containing monomers, and hydroxyl-containing monomers onto macroporous resins, the preparation process can be simplified, the preparation efficiency improved, and the ratio of carboxyl, sulfonic acid, and hydroxyl groups on the anticoagulant lipid adsorbent can be more easily controlled. Moreover, the steric hindrance effect can be reduced, the activity of carboxyl, sulfonic acid, and hydroxyl groups can be better utilized, and the adsorption of low-density lipoprotein and coagulation factor IV can be improved. Attached Figure Description

[0023] Figure 1 This is a process flow diagram for preparing a self-anticoagulant lipid adsorbent provided in an embodiment of the present invention. Detailed Implementation

[0024] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0025] It should be noted that, unless otherwise specified, the embodiments and features described in the present invention can be combined with each other.

[0026] Furthermore, the terms "comprising," "including," "containing," and "having" are non-restrictive and can refer to the addition of other steps and components that do not affect the results. Unless otherwise specified, all materials, equipment, and reagents are commercially available.

[0027] Furthermore, although the present invention describes each step in the preparation process in the form of S110, S120, S130 and S140, this description is only for ease of understanding. The forms such as S110, S120, S130 and S140 do not indicate a limitation on the order of the steps.

[0028] Combination Figure 1 As shown, the first aspect of this application provides a method for preparing a self-anticoagulating lipid adsorbent, comprising the following steps:

[0029] Step S110: Prepare a macroporous resin with dangling double bonds on its surface.

[0030] Specifically, styrene monomers and divinylbenzene are subjected to suspension polymerization in a dispersion medium under the action of a porogen and a second initiator to obtain a primary cross-linked macroporous resin. The surface of the primary cross-linked macroporous resin contains dangling double bonds.

[0031] More specifically, a styrene monomer, divinylbenzene, a porogen, and a second initiator are mixed to form an oil phase, and a dispersant is dispersed in water to form an aqueous phase. The oil phase is then added to the aqueous phase, and the stirring speed is adjusted. After the oil phase forms uniform droplets of a certain size in the aqueous phase, the temperature is raised to 60℃~90℃ for suspension polymerization. After reacting for 6h~18h, the suspension polymerization product is cleaned and dried to obtain a one-time cross-linked macroporous resin. The surface of this one-time cross-linked macroporous resin retains dangling double bonds. The stirring speed is 80rpm~180rpm. Therefore, the macroporous resin prepared by this method not only has dangling double bonds but also a rich pore structure, giving it an extremely high specific surface area, which is beneficial for improving the adsorption capacity of macroporous adsorption resins. Furthermore, the process for preparing the one-time cross-linked macroporous resin is simpler and less time-consuming, thus improving the preparation efficiency.

[0032] Based on the above embodiments, as an optional implementation, the styrene monomer is selected from at least one of styrene, methylstyrene, and ethylstyrene; preferably, the styrene monomer is styrene; the divinylbenzene is selected from at least one of o-divinylbenzene, m-divinylbenzene, and p-divinylbenzene. The styrene monomer accounts for 10% to 50% of the total mass of the styrene monomer and divinylbenzene, and the divinylbenzene accounts for 20% to 80% of the total mass of the styrene monomer and divinylbenzene. Therefore, using monovinyl styrene monomers and divinylbenzene as reactive monomers allows the macroporous resin to undergo one-time crosslinking, which is beneficial for improving the mechanical strength and structural stability of the macroporous resin in organic solvents.

[0033] The porogen is one or a combination of several selected from oil-soluble polymers, higher aliphatic hydrocarbons, aromatic hydrocarbons, and higher fatty alcohols. Specifically, the oil-soluble polymer is one or a combination of several selected from polystyrene with a molecular weight of 2000–50000, polymethyl methacrylate with a molecular weight of 1000–20000, and polyethylene with a molecular weight of 5000–30000, accounting for 0–20% of the total mass of the porogen; the higher aliphatic hydrocarbon is one or a combination of several selected from n-heptane, 92-octane gasoline, and liquid paraffin, accounting for 0–60% of the total mass of the porogen; the aromatic hydrocarbon is one or a combination of several selected from toluene, xylene, and biphenyl, accounting for 0–50% of the total mass of the porogen; and the higher fatty alcohol is one or a combination of several selected from n-dodecyl alcohol, n-tetradecyl alcohol, cyclohexanol, and methyl isobutyl methanol, accounting for 0–30% of the total mass of the porogen. The mass of the porogen accounts for 80% to 200% of the total mass of the styrene monomers and divinylbenzene. Therefore, using oil-soluble polymers as porogens can enable macroporous resins to have ultra-large pores that adsorb low-density lipoprotein (LDL). Using higher aliphatic hydrocarbons, aromatic hydrocarbons, and higher aliphatic alcohols as porogens can help adjust the pore structure of macroporous resins, thereby adjusting the pore volume and pore size of macroporous resins.

[0034] The second initiator is an oil-soluble thermal initiator, which is one or a combination of several of benzoyl peroxide, tert-butyl peroxide-2-ethylhexanoate, azobisisobutyronitrile, and azobisisoheptanenitrile. The mass of the second initiator accounts for 0.5% to 5% of the total mass of styrene monomers and divinylbenzene. Therefore, the above-mentioned initiator can effectively initiate the suspension polymerization reaction of styrene monomers and divinylbenzene, and the price of the initiator is relatively low.

[0035] The dispersant is composed of organic polymers or inorganic powders. The organic polymers are one or a combination of several of hydroxymethyl cellulose, gelatin, polyvinyl alcohol, and sodium alginate. The inorganic powders are one or a combination of several of magnesium carbonate, calcium carbonate, and talc. The concentration of the dispersant in the aqueous phase is 0.1 wt% to 1 wt%, and the mass of the oil phase is 30% to 80% of the mass of the aqueous phase. This stabilizes the dispersion of droplets, prevents aggregation or coalescence, ensures uniform and controllable polymerization, and makes the dispersant safer and more environmentally friendly.

[0036] Step S120: Under the action of the first initiator, the macroporous resin is simultaneously grafted with a carboxyl-containing monomer, a sulfonic acid-containing monomer, and a hydroxyl-containing monomer to prepare an anticoagulant lipid adsorbent; wherein the carboxyl-containing monomer, the sulfonic acid-containing monomer, and the hydroxyl-containing monomer all contain unsaturated double bonds.

[0037] Specifically, the macroporous resin is placed in purified water for swelling. After swelling, a monomer containing a carboxyl group, a monomer containing a sulfonic acid group, a monomer containing a hydroxyl group, and a first initiator are added to the swollen macroporous resin. The temperature is raised to 40°C to 80°C for grafting reaction. After 6 to 24 hours of reaction, the grafting reaction product is cleaned, dried, and the self-anticoagulant lipid adsorbent is obtained. Therefore, by simultaneously grafting macroporous resin with monomers containing carboxyl groups, sulfonic acid groups, and hydroxyl groups, the macroporous resin can simultaneously contain carboxyl, sulfonic acid, and hydroxyl groups. After the carboxyl and sulfonic acid groups dissociate, they carry a negative charge, giving the surface of the self-anticoagulant lipid adsorbent a large number of negative charges. This allows it to adsorb low-density lipoprotein through electrostatic interactions. At the same time, the combined action of the carboxyl, sulfonic acid, and hydroxyl groups can act like heparin, giving the self-anticoagulant lipid adsorbent physiological properties similar to heparin. Thus, during whole blood perfusion, it can adsorb coagulation factor IV (calcium ions) in the blood, achieving a self-anticoagulant effect. Furthermore, by directly grafting carboxyl-containing monomers, sulfonic acid-containing monomers, and hydroxyl-containing monomers onto macroporous resins, compared to grafting compounds containing all three groups, several advantages are achieved. First, it eliminates the need to synthesize compounds simultaneously containing all three groups, simplifying the preparation process, improving efficiency, and making it easier to control the ratio of carboxyl, sulfonic acid, and hydroxyl groups on the self-anticoagulant lipid adsorbent. This increases the similarity between the self-anticoagulant lipid adsorbent and heparin, further enhancing its self-anticoagulant properties. Second, the molecular chains of these three monomers are shorter than those of compounds containing all three groups, reducing steric hindrance and allowing for better utilization of the activity of the carboxyl, sulfonic acid, and hydroxyl groups. This enhances the adsorption of low-density lipoprotein and coagulation factor IV.

[0038] Based on the above embodiments, as an optional implementation, the monomer containing a carboxyl group is acrylic acid and / or methacrylic acid; the monomer containing a sulfonic acid group is 2-acrylamido-2-methylpropanesulfonic acid; and the monomer containing a hydroxyl group is hydroxyethyl methacrylate and / or hydroxyethyl acrylate. Thus, the monomer containing a carboxyl group has an unsaturated double bond and a carboxyl group, which can react with the double bonds on the macroporous resin through the unsaturated double bond to immobilize the carboxyl group on the macroporous resin; the monomer containing a sulfonic acid group has an unsaturated double bond and a sulfonic acid group, which can react with the double bonds on the macroporous resin through the unsaturated double bond to immobilize the sulfonic acid group on the macroporous resin; and the monomer containing a hydroxyl group has an unsaturated double bond and a hydroxyl group, which can react with the double bonds on the macroporous resin through the unsaturated double bond to immobilize the hydroxyl group on the macroporous resin. Furthermore, the competition rates of these substances among the carboxyl-containing monomers, sulfonic acid-containing monomers, and hydroxyl-containing monomers are relatively close, resulting in similar reaction efficiencies. When reacting with macroporous adsorption resins, it is easier to control the grafting amounts of carboxyl, sulfonic acid, and hydroxyl groups onto the anticoagulant adsorbent, thereby making it easier to control the ratio among these three groups.

[0039] Based on the above embodiments, as an optional implementation, the molar ratio between the carboxyl-containing monomer, the sulfonic acid-containing monomer, and the hydroxyl-containing monomer is 1:(1-3):(2-4). Therefore, the ratio of the carboxyl-containing monomer, the sulfonic acid-containing monomer, and the hydroxyl-containing monomer within the above range is beneficial for further improving the anticoagulant effect of the self-anticoagulant lipid adsorbent.

[0040] Based on the above embodiments, as an optional implementation, the total mass of the carboxyl-containing monomer, the sulfonic acid-containing monomer, and the hydroxyl-containing monomer is 5% to 20% of the mass of the macroporous resin. This improves the grafting efficiency of the carboxyl-containing monomer, the sulfonic acid-containing monomer, and the hydroxyl-containing monomer on the macroporous resin, which is beneficial for further enhancing the adsorption of low-density lipoprotein and coagulation factor IV.

[0041] Based on the above embodiments, as an optional implementation, the first initiator is a water-soluble thermal initiator, specifically ammonium persulfate and / or potassium persulfate, and the mass of the first initiator is 1% to 10% of the mass of the macroporous resin. Therefore, by selecting the above-mentioned substances as initiators, it is possible to promote the interconnection of unsaturated double bonds of carboxyl-containing monomers, sulfonic acid-containing monomers, and hydroxyl-containing monomers with double bonds on the macroporous resin, thereby grafting carboxyl groups, sulfonic acid groups, and hydroxyl groups onto the macroporous resin.

[0042] Based on the above embodiments, as an optional implementation, the macroporous resin is swollen in purified water, with the mass of the purified water being 1.2 to 3.6 times the mass of the macroporous resin. Thus, by swelling the macroporous resin in excess purified water, the pore structure of the macroporous resin can be expanded, providing smoother diffusion channels for carboxyl-containing monomers, sulfonic acid-containing monomers, and hydroxyl-containing monomers, allowing them to react fully with the macroporous resin.

[0043] The preparation method of the self-anticoagulating lipid adsorbent provided in this embodiment uses a macroporous resin with dangling double bonds on its surface as a matrix. Macroporous resin has high strength and a low risk of breakage due to plasma impact, thus improving the safety of the self-anticoagulating lipid adsorbent during use. The dangling double bonds on the surface of the macroporous resin can undergo grafting reactions with monomers containing carboxyl groups, sulfonic acid groups, and hydroxyl groups, immobilizing these groups on the macroporous resin. This results in a large number of negative charges on the surface of the self-anticoagulating lipid adsorbent, enabling adsorption of low-density lipoproteins through electrostatic interactions. Simultaneously, the combined action of the carboxyl, sulfonic acid, and hydroxyl groups provides a heparin-like effect, giving the self-anticoagulating lipid adsorbent physiological properties similar to heparin. Therefore, during whole blood perfusion, it can adsorb coagulation factor IV (calcium ions) in the blood, achieving a self-anticoagulating effect. Furthermore, by directly grafting carboxyl-containing monomers, sulfonic acid-containing monomers, and hydroxyl-containing monomers onto macroporous resins, the preparation process can be simplified, the preparation efficiency improved, and the ratio of carboxyl, sulfonic acid, and hydroxyl groups on the anticoagulant lipid adsorbent can be more easily controlled. Moreover, the steric hindrance effect can be reduced, the activity of carboxyl, sulfonic acid, and hydroxyl groups can be better utilized, and the adsorption of low-density lipoprotein and coagulation factor IV can be improved.

[0044] A second aspect of this application provides a self-anticoagulating lipid adsorbent, which is prepared using the preparation method described in the first aspect. This self-anticoagulating lipid adsorbent uses a macroporous resin as a carrier, on which carboxyl groups, sulfonic acid groups, and hydroxyl groups are immobilized.

[0045] The self-anticoagulating lipid adsorbent provided in this embodiment contains carboxyl, sulfonic acid, and hydroxyl groups, giving it a large number of negative charges on its surface. This allows it to adsorb low-density lipoproteins through electrostatic interactions. Furthermore, the combined action of these three groups (carboxyl, sulfonic acid, and hydroxyl groups) enables it to function like heparin, giving it physiological properties similar to heparin. Therefore, during whole blood perfusion, it can adsorb coagulation factor IV (calcium ions) in the blood, achieving a self-anticoagulating effect.

[0046] The third aspect of this application provides an application of a self-anticoagulating lipid adsorbent in whole blood perfusion. The self-anticoagulating lipid adsorbent provided in this embodiment can adsorb coagulation factor IV (calcium ions) in the blood to achieve a self-anticoagulating effect. It can be directly used in whole blood perfusion. During whole blood perfusion, the use of anticoagulants can be reduced or avoided, which is beneficial to reducing the risk of bleeding and improving the safety of whole blood perfusion.

[0047] To provide a more detailed description of the present invention, specific embodiments will be used to further illustrate the invention. Unless otherwise specified, the experimental methods used in the embodiments of the present invention are conventional methods; unless otherwise specified, the materials and reagents used in the embodiments of the present invention are commercially available.

[0048] Example 1

[0049] This embodiment provides a method for preparing a self-anticoagulating lipid adsorbent, comprising the following steps:

[0050] (1) Preparation of macroporous resin with dangling double bonds on the surface: 400 mL of an aqueous solution containing 0.2% hydroxymethyl cellulose was added to a 1000 mL three-necked flask and stirred until the hydroxymethyl cellulose was completely dissolved to obtain an aqueous phase. Subsequently, 15 g of styrene, 45 g of divinylbenzene, 5 g of polystyrene with a molecular weight of 50,000, 50 g of toluene, 35 g of methyl isobutyl methanol, and 0.6 g of benzoyl peroxide were added to a beaker and stirred until homogeneous to obtain an oil phase. After the oil phase was evenly dispersed, it was added to the aqueous phase, the rotation speed was adjusted to 160 rpm, and the reaction temperature was adjusted to 80 °C for 10 hours. After the reaction was completed, the resin was washed three times with water to remove excess dispersant. Then, the resin was extracted multiple times with alcohol using a Soxhlet extractor to remove residual porogen. After drying and sieving, macroporous resin with a particle size between 0.3 and 0.6 mm was selected to obtain a one-crosslinked macroporous resin.

[0051] (2) Preparation of self-anticoagulant lipid adsorbent: Take 20g of the macroporous resin that is cross-linked once in step (1), add 50g of purified water to fully swell, then add 0.4g of 2-acrylamido-2-methylpropanesulfonic acid, 1.2g of methacrylic acid, 0.4g of hydroxyethyl methacrylate and 0.05g of ammonium persulfate, stir evenly, heat to 75℃ and react for 24 hours. After the reaction is completed, wash away the residual monomer and initiator with a large amount of purified water, and dry to obtain self-anticoagulant lipid adsorbent.

[0052] Example 2

[0053] This embodiment provides a method for preparing a self-anticoagulating lipid adsorbent, comprising the following steps:

[0054] (1) Preparation of macroporous resin with dangling double bonds on the surface: 360 mL of a 0.5% polyvinyl alcohol aqueous solution was added to a 1000 mL three-necked flask and stirred until the polyvinyl alcohol was completely dissolved to obtain an aqueous phase. Subsequently, 18 g of methylstyrene, 40 g of m-divinylbenzene, 5 g of polymethyl methacrylate with a molecular weight of 10000, 40 g of liquid paraffin, 32 g of cyclohexanol, 18 g of xylene, and 0.8 g of tert-butyl peroxide-2-ethylhexanoate were added to a beaker and stirred until homogeneous to obtain an oil phase. After the oil phase was evenly dispersed, it was added to the aqueous phase, the rotation speed was adjusted to 120 rpm, and the reaction temperature was adjusted to 70 °C for 8 hours. After the reaction was completed, the resin was washed three times with water to remove excess dispersant. Then, the resin was extracted multiple times with alcohol using a Soxhlet extractor to remove residual pore-forming agent. After drying and sieving, macroporous resin with a particle size between 0.3 and 0.6 mm was selected to obtain a one-crosslinked macroporous resin.

[0055] (2) Preparation of self-anticoagulant lipid adsorbent: Take 30g of the macroporous resin that is cross-linked once in step (1), add 72g of purified water to fully swell, then add 1.2g of 2-acrylamido-2-methylpropanesulfonic acid, 3g of methacrylic acid, 0.8g of hydroxyethyl methacrylate and 0.2g of potassium persulfate, stir evenly, heat to 70℃ and react for 18 hours. After the reaction is completed, wash away the residual monomer and initiator with a large amount of purified water, and dry to obtain self-anticoagulant lipid adsorbent.

[0056] Example 3

[0057] This embodiment provides a method for preparing a self-anticoagulating lipid adsorbent, comprising the following steps:

[0058] (1) Preparation of macroporous resin with dangling double bonds on the surface: 420 mL of an aqueous solution containing 1% talc was added to a 1000 mL three-necked flask and stirred until the talc was completely dispersed to obtain an aqueous phase. Subsequently, 24 g of ethylstyrene, 48 g of o-divinylbenzene, 10 g of polyethylene with a molecular weight of 30000, 40 g of n-heptane, 30 g of n-dodecanol, 10 g of biphenyl, and 1.2 g of azobisisobutyronitrile were added to a beaker and stirred until homogeneous to obtain an oil phase. After the oil phase was evenly dispersed, it was added to the aqueous phase, the rotation speed was adjusted to 100 rpm, and the reaction temperature was adjusted to 75 °C for 12 hours. After the reaction, the resin was washed three times with water to remove excess dispersant. Then, the resin was extracted multiple times with alcohol using a Soxhlet extractor to remove residual pore-forming agent. After drying and sieving, macroporous resin with a particle size between 0.3 and 0.6 mm was selected to obtain a one-crosslinked macroporous resin.

[0059] (2) Preparation of self-anticoagulant lipid adsorbent: Take 25g of the macroporous resin that is cross-linked once in step (1), add 60g of purified water to fully swell, then add 0.5g of 2-acrylamido-2-methylpropanesulfonic acid, 2g of acrylic acid, 0.6g of hydroxyethyl acrylate and 0.3g of potassium persulfate, stir evenly, heat to 60℃ and react for 24 hours. After the reaction is completed, wash away the residual monomer and initiator with a large amount of purified water, and dry to obtain self-anticoagulant lipid adsorbent.

[0060] Comparative Example 1

[0061] This comparative example provides an adsorbent, which is a single-crosslinked macroporous resin, prepared by the method in step (1) of Example 1.

[0062] Comparative Example 2

[0063] This comparative example provides an adsorbent, which is a single-crosslinked macroporous resin, prepared by the method in step (1) of Example 2.

[0064] Comparative Example 3

[0065] This comparative example provides an adsorbent, which is a single-crosslinked macroporous resin, prepared by the method in step (1) of Example 3.

[0066] Experimental Example 1

[0067] The adsorption performance of the adsorbents for low-density lipoprotein in each embodiment and comparative example was tested. The specific test methods are as follows:

[0068] The self-anticoagulant lipid adsorbents prepared in Examples 1 to 3 were used as the experimental group, and the single-crosslinked macroporous resins prepared in Comparative Examples 1 to 3 were used as the control group. 1 mL of each adsorbent group and commercially available liposober adsorbent were accurately measured and added to 10 mL of high-lipid plasma with a concentration of 10 mmol / mL. The adsorption was carried out at 37°C and 140 rpm for 2 hours with shaking. The plasma before and after adsorption was collected to detect the levels of low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), and the adsorption rates of LDL, TC, and TG were calculated. The concentrations of LDL, TC, and TG in the plasma before adsorption were 9.8 mmol / L, 7.6 mmol / L, and 3.8 mmol / L, respectively. The results are shown in Table 1.

[0069]

[0070] As shown in Table 1, compared with Comparative Examples 1 to 3, the self-anticoagulant lipid adsorbents in Examples 1 to 3 exhibit significantly better adsorption performance for low-density lipoprotein, total cholesterol, and triglycerides in plasma than the single-crosslinked macroporous resins in Comparative Examples 1 to 3. This indicates that by simultaneously grafting carboxyl-containing monomers, sulfonic acid-containing monomers, and hydroxyl-containing monomers onto the single-crosslinked macroporous resin, the adsorption capacity for low-density lipoprotein, total cholesterol, and triglycerides in plasma can be significantly improved. Furthermore, the self-anticoagulant lipid adsorbent provided in this application has the same adsorption capacity for low-density lipoprotein, total cholesterol, and triglycerides as commercially available liposober, but its strength is significantly higher than that of commercially available liposober.

[0071] Experimental Example 2

[0072] The whole blood clotting time of the adsorbent in each embodiment and each comparative example was tested, and the specific test methods are as follows:

[0073] The self-anticoagulant lipid adsorbents prepared in Examples 1 to 3 were used as experimental groups, the single-crosslinked macroporous resins prepared in Comparative Examples 1 to 3 were used as control groups, glass beads were used as positive controls to promote coagulation, and no resin or coagulation-promoting substance was added as a negative control. 1 mL of each adsorbent group, positive control, and commercially available liposober adsorbent were accurately measured into plastic test tubes, and 2 mL of freshly collected rabbit blood was added. The tubes were incubated at 37°C, and the coagulation time of the rabbit blood was observed and recorded. The coagulation time results for each example, comparative example, and liposober are shown in Table 2.

[0074] Table 2

[0075]

[0076] As shown in Table 2, compared to Comparative Examples 1 to 3, the whole blood coagulation time of the self-anticoagulant lipid adsorbents in Examples 1 to 3 all exceeded 2 hours. This indicates that the self-anticoagulant properties of the self-anticoagulant lipid adsorbents in Examples 1 to 3 are significantly better than those of the single-crosslinked macroporous resins in Comparative Examples 1 to 3. Therefore, this application, by simultaneously grafting carboxyl-containing monomers, sulfonic acid-containing monomers, and hydroxyl-containing monomers onto a single-crosslinked macroporous resin, exhibits good adsorption of coagulation factors, meeting the 2-hour self-anticoagulant performance requirement for whole blood perfusion. Furthermore, the whole blood coagulation time of the self-anticoagulant lipid adsorbent provided in this application is also significantly better than that of commercially available liposober. In addition, the coagulation times of the positive control group (with 1 mL of procoagulant glass beads added) and the negative control group (blank group) are also within a reasonable range, demonstrating the rationality and reliability of the test results in Table 2.

[0077] Therefore, by simultaneously grafting carboxyl-containing monomers, sulfonic acid-containing monomers, and hydroxyl-containing monomers onto a single-crosslinked macroporous resin, the adsorption capacity for low-density lipoprotein, total cholesterol, and triglycerides can be significantly improved. Furthermore, the self-anticoagulant lipid adsorbent in this application also has excellent anticoagulant effects and can be used for lipid adsorption in whole blood perfusion, thereby improving the safety of whole blood perfusion.

[0078] While the disclosure is as stated above, its scope of protection is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of this disclosure, and all such changes and modifications will fall within the protection scope of this invention.

Claims

1. A method for the preparation of a self-anticoagulant liposorbent, characterized in that, The method comprises the following steps: Preparation of macroporous resin containing suspended double bonds on the surface; Under the action of a first initiator, the macroporous resin is simultaneously grafted with a carboxyl-containing monomer, a sulfonic acid group-containing monomer, and a hydroxyl-containing monomer to obtain the self-anticoagulation lipid adsorbent; The carboxyl-containing monomer, the sulfonic acid group-containing monomer, and the hydroxyl-containing monomer all contain unsaturated double bonds.

2. The method for preparing the self-anticoagulation lipid adsorbent according to claim 1, wherein the carboxyl-containing monomer is acrylic acid and / or methacrylic acid; the sulfonic acid group-containing monomer is 2-acrylamido-2-methylpropanesulfonic acid; and the hydroxyl-containing monomer is hydroxyethyl methacrylate and / or hydroxyethyl acrylate. The molar ratio of the carboxyl-containing monomer, the sulfonic acid group-containing monomer, and the hydroxyl-containing monomer is 1:(1-3):(2-4). The total mass of the carboxyl-containing monomer, the sulfonic acid group-containing monomer, and the hydroxyl-containing monomer is 5% to 20% of the mass of the macroporous resin. The first initiator is a water-soluble thermal initiator, and the water-soluble thermal initiator is ammonium persulfate and / or potassium persulfate. The mass of the first initiator is 1% to 10% of the mass of the macroporous resin.

3. The method of claim 1, wherein the anticoagulant liposorb is prepared by the steps of: The reaction temperature of the grafting reaction is 40°C to 80°C, and the reaction time is 6h to 24h.

4. The method of claim 1, wherein the anticoagulant liposorb is prepared by the steps of: Before the macroporous resin is subjected to the grafting reaction, the method further comprises:

5. The method of claim 1, wherein the anticoagulant liposorb is prepared by the steps of: The macroporous resin is placed in purified water for swelling, and the mass of the purified water is 1.2 times to 3.6 times of the mass of the macroporous resin.

6. The method of claim 1, wherein the anticoagulated lipidsorbent is prepared by the steps of: The preparation of the macroporous resin containing suspended double bonds on the surface comprises:

7. The method of claim 1, wherein the anticoagulant liposorb is prepared by the steps of: Styrene monomers and divinylbenzene are subjected to suspension polymerization in a dispersion medium under the action of a porogen and a second initiator to obtain a primary crosslinked macroporous resin containing suspended double bonds on the surface. The self-anticoagulation lipid adsorbent is prepared by the method according to any one of claims 1 to 8, and the macroporous resin is used as a carrier, and the carrier is loaded with carboxyl groups, sulfonic acid groups, and hydroxyl groups.

8. The method of claim 1, wherein the anticoagulated lipidsorbent is prepared by the steps of:

10. The self-anticoagulation lipid adsorbent prepared by the method according to any one of claims 1 to 8, or the use of the self-anticoagulation lipid adsorbent according to claim 9 in whole blood perfusion. ​ 9. A self-anticoagulating liposorber, characterized by ​ ​

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