Plasma adsorber for double adsorption of bilirubin and cytokines and use thereof

Abstract

The application provides a plasma adsorber for double adsorption of bilirubin and cytokines and an application thereof. The plasma adsorber comprises a column body and a double-function adsorbent. The column body is provided with an interface for connecting an extracorporeal circulation pipeline at each end. The double-function adsorbent is filled in the column body. A filter screen is arranged at the opening of each end of the column body. The volume of the double-function adsorbent in the column body accounts for 60% to 90% of the volume of the column body. The double-function adsorbent is polystyrene-divinylbenzene macroporous resin with a chlorine content less than 1.5% and capable of adsorbing bilirubin and cytokines simultaneously. The pH value of the double-function adsorbent in an initial state is 5.0 to 6.0. After aging, the pH value of the double-function adsorbent is 4.5 to 6.0. The plasma adsorber provided by the application adopts one adsorption column, can adsorb bilirubin and cytokines simultaneously, reduces the difficulty of medical operation, can reduce the probability of sensitization, 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 plasma adsorber that dually adsorbs bilirubin and cytokines and its application. Background Technology

[0002] Liver failure is a clinical syndrome characterized by severe impairment or decompensation of the liver's functions in synthesis, detoxification, excretion, and biotransformation, caused by multiple factors. It is characterized by symptoms such as impaired coagulation function, jaundice, and hepatic encephalopathy, and has an extremely high mortality rate. Massive hepatocyte death, exceeding the liver's regenerative capacity, is considered the core event in the development of liver failure. Direct injury and immune-mediated inflammatory damage are two major factors in this process. In recent years, an increasing number of scholars favor the "second-strike theory" centered on immune-inflammatory damage. This theory posits that after direct damage to hepatocytes by viruses, pathogens, and toxic factors, an excessive and persistent immune-inflammatory response, mediated by enterotoxins ("endotoxin → immune mechanism → cytokine storm"), causes a "second-strike" on the liver, ultimately leading to liver failure.

[0003] In related technologies, a common treatment for liver failure is the double plasmamolecules adsorption system (DPMAS). DPMAS adds an adsorbent capable of adsorbing medium to large molecular weight toxins to the existing bilirubin adsorption therapy. DPMAS can not only adsorb bilirubin but also remove inflammatory mediators without consuming plasma. However, because DPMAS uses two adsorption columns simultaneously, it suffers from operational complexity and the drawback of the bilirubin adsorption column being an anion exchange resin, which increases the probability of sensitization. Summary of the Invention

[0004] The present invention aims to provide a plasma adsorber that can dually adsorb bilirubin and cytokines and its application. The plasma adsorber that dually adsorbs bilirubin and cytokines uses an adsorption column, which can not only adsorb bilirubin and cytokines at the same time, reducing the difficulty of medical and nursing operations, but also reduce the probability of sensitization, which is beneficial to improving the safety of blood purification.

[0005] To address the aforementioned problems, a first aspect of the present invention provides a plasma adsorbent for the dual adsorption of bilirubin and cytokines, comprising: a column and a bifunctional adsorbent, wherein the two ends of the column are respectively provided with interfaces for connecting to an extracorporeal circulation pipeline, the bifunctional adsorbent is filled in the column, and filter screens are provided at the openings at both ends of the column, wherein the volume of the bifunctional adsorbent in the column occupies 60% to 90% of the volume of the column;

[0006] The bifunctional adsorbent is prepared by multi-stage washing of polystyrene-divinylbenzene macroporous resin, which can simultaneously adsorb bilirubin and cytokines, so that the pH value of the bifunctional adsorbent in the initial state is 5.0 to 6.0, and the pH value of the bifunctional adsorbent after aging is 4.5 to 6.0.

[0007] The polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines is formed by modifying polystyrene-divinylbenzene macroporous resin through chloromethylation and post-crosslinking reaction, and the chlorine content of the polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines is less than 1.5%.

[0008] Furthermore, the bifunctional adsorbent in the plasma adsorbent has an adsorption capacity of not less than 0.8 μmol / mL resin for bilirubin in the initial state, and the bifunctional adsorbent has an adsorption capacity of not less than 1000 pg / mL for IL-6 in the initial state.

[0009] Furthermore, the bifunctional adsorbent has a particle size of 250 μm to 500 μm, an average pore size of 2 nm to 20 nm, and a specific surface area of ​​300 m². 2 / g to 1200m 2 / g, pore volume range is 0.8cm³ 3 / g to 2.0cm 3 / g.

[0010] Furthermore, the bifunctional adsorbent is prepared using the following method:

[0011] A polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines was prepared, wherein the polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines was formed by modifying polystyrene-divinylbenzene macroporous resin through chloromethylation and post-crosslinking reaction.

[0012] The polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines was sequentially washed with acid, alkali, water, and alcohol to adjust the pH value of the polystyrene-divinylbenzene macroporous resin to 5.0 to 6.0, thereby obtaining the bifunctional adsorbent.

[0013] Furthermore, the polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines is prepared by the following method:

[0014] Polystyrene-divinylbenzene macroporous resin is prepared by suspension polymerization of styrene monomers and crosslinking agent divinylbenzene in a dispersion medium under the action of porogen and initiator.

[0015] Halogenated hydrocarbons were added to the polystyrene-divinylbenzene macroporous resin to swell for 2 to 4 hours, and then isooctanol was added to continue swelling for 1 to 2 hours to obtain the swollen polystyrene-divinylbenzene macroporous resin.

[0016] The swollen polystyrene-divinylbenzene macroporous resin was subjected to a chloromethylation reaction to obtain a chloromethylated intermediate resin.

[0017] The chloromethylated intermediate resin was subjected to a post-crosslinking reaction to obtain a polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines.

[0018] Furthermore, the amount of isooctanol used is 10% to 30% of the mass of the polystyrene-divinylbenzene macroporous resin.

[0019] Furthermore, the interfaces at both ends of the column are a blood inlet interface and a bleeding interface, respectively. The blood inlet interface and the bleeding interface are respectively connected to the extracorporeal circulation pipeline. The column includes a mesh frame, and the mesh frame near the bleeding interface is covered with non-woven fabric with a pore size of 200 mesh.

[0020] Furthermore, the column includes a cylindrical body, the diameter of which is smaller than ...

[0021] Furthermore, the ratio of the axial length of the column to its maximum diameter is 2.5 to 4.0.

[0022] A second aspect of the invention provides an application of a plasma adsorber that dually adsorbs bilirubin and cytokines for extracorporeal blood purification in patients with liver failure.

[0023] The plasma adsorbent for dual adsorption of bilirubin and cytokines described in this invention and its application utilize a bifunctional adsorbent packed within a column. This adsorbent can simultaneously adsorb bilirubin and cytokines, allowing the plasma adsorbent to achieve dual adsorption of bilirubin and cytokines with only one adsorption column. This simplifies and expedites the pre-filling and tubing connection processes before use, reducing the operational difficulty for medical personnel. Furthermore, the bifunctional adsorbent is a neutral resin, which can adsorb bilirubin without relying on strongly basic ion exchange groups, resulting in a low risk of irritation and allergic reactions to blood cells and fewer side effects, thus improving the safety of blood purification. In addition, the chlorine content of the bifunctional adsorbent is less than 1.5%, which enhances the safety of the plasma adsorbent and allows it to maintain a stable pH value over a longer storage period, contributing to the stability of its adsorption performance. The initial pH value of this bifunctional adsorbent is set to 5.0 to 6.0 to simulate the physiological environment of the human body. Under these conditions, the bifunctional adsorbent can achieve efficient adsorption of weakly polar bilirubin, bile acids, and strongly polar cytokines through hydrophobic interactions, π-π stacking interactions, molecular sieving, and weak electrostatic synergistic effects, thereby enhancing its adsorption capacity for bilirubin and cytokines. Even after aging, the pH value of the bifunctional adsorbent remains at 4.5 to 6.0, which allows the plasma adsorber to maintain a good adsorption rate for bilirubin and cytokines, thus further maintaining the stability of its adsorption performance. Attached Figure Description

[0024] Figure 1 This is a schematic diagram of the pore size distribution of the bifunctional adsorbent provided in the embodiments of the present invention;

[0025] Figure 2 This is a schematic diagram of the water contact angle test of the bifunctional adsorbent provided in the embodiments of the present invention;

[0026] Figure 3 This is a process flow diagram for preparing bifunctional adsorbents provided in an embodiment of the present invention;

[0027] Figure 4 This is a schematic diagram of the structure of a plasma adsorber that dually adsorbs bilirubin and cytokines, as provided in an embodiment of the present invention. Detailed Implementation

[0028] 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.

[0029] It should be noted that, unless otherwise specified, the embodiments and features described in the present invention can be combined with each other.

[0030] 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.

[0031] Furthermore, although the present invention describes each step in the preparation process in the form of S210 and S220, this description is only for ease of understanding, and the form of S210 and S220 does not indicate a limitation on the order of the steps.

[0032] The first aspect of this application provides a plasma adsorbent for dual adsorption of bilirubin and cytokines, comprising: a column and a bifunctional adsorbent (i.e., an adsorbent with dual adsorption functions of bilirubin and cytokines), the two ends of the column are respectively provided with interfaces for connecting to extracorporeal circulation pipelines, the bifunctional adsorbent is filled in the column, and filters are provided at the openings at both ends of the column.

[0033] The bifunctional adsorbent is a polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines. The chlorine content of the bifunctional adsorbent is less than 1.5%. The pH value of the bifunctional adsorbent in its initial state is 5.0 to 6.0, and the pH value of the bifunctional adsorbent after aging is 4.5 to 6.0.

[0034] The plasma adsorbent provided in this embodiment, which dually adsorbs bilirubin and cytokines, utilizes a bifunctional adsorbent packed within the column. This adsorbent can simultaneously adsorb bilirubin and cytokines, achieving dual adsorption of both through a single adsorption column. This simplifies and expedites pre-filling and tubing connection procedures, reducing the operational complexity for medical personnel. Furthermore, the bifunctional adsorbent is a neutral resin, independent of strongly alkaline ion exchange groups, minimizing the risk of irritation and allergic reactions to blood cells and reducing side effects, thus enhancing the safety of blood purification. Additionally, the chlorine content of the bifunctional adsorbent is less than 1.5%, which not only improves the safety of the plasma adsorbent but also ensures a stable pH value over a longer storage period, contributing to the stability of the adsorption performance. The initial pH value of this bifunctional adsorbent is set to 5.0 to 6.0 to simulate the physiological environment of the human body. Under these conditions, the bifunctional adsorbent can achieve efficient adsorption of weakly polar bilirubin, bile acids, and strongly polar cytokines through hydrophobic interactions, π-π stacking interactions, molecular sieving, and weak electrostatic synergistic effects, thereby enhancing its adsorption capacity for bilirubin and cytokines. Even after aging, the pH value of the bifunctional adsorbent remains at 4.5 to 6.0, which allows the plasma adsorber to maintain a good adsorption rate for bilirubin and cytokines, thus further maintaining the stability of its adsorption performance.

[0035] Based on the above embodiments, as an optional implementation, the bifunctional adsorbent in the plasma adsorbent initially adsorbs bilirubin at a rate of not less than 0.8 μmol / mL resin, and initially adsorbs IL-6 at a rate of not less than 1000 pg / mL resin. That is, each mL of bifunctional adsorbent initially adsorbs not less than 0.8 μmol of bilirubin and not less than 1000 pg of IL-6. Therefore, the bifunctional adsorbent in the plasma adsorbent exhibits good adsorption capacity for both bilirubin and IL-6.

[0036] Based on the above embodiments, as an optional implementation, after aging for 2 years, the bifunctional adsorbent in the plasma adsorber exhibits a decrease rate of 'a' for bilirubin and a decrease rate of 'b' for IL-6, where 'a' ≤ 6% and 'b' ≤ 10%. Therefore, after 2 years of aging, the bifunctional adsorbent in the plasma adsorber still maintains a high adsorption rate for bilirubin and IL-6, and the bifunctional adsorbent provided in this embodiment has good adsorption stability.

[0037] It is understood that the initial state in this embodiment refers to the original state of the bifunctional adsorbent within 2 months after its preparation, before it has been used or subjected to environmental effects. In the initial state, the storage conditions of the bifunctional adsorbent are 1~40℃ and below 80% relative humidity, and it does not need to be stored away from light. Aging, on the other hand, is the state of the bifunctional adsorbent after it has been stored for 2 years without being used under the storage conditions specified by the product, and it is affected by time or environmental factors. In the aging state, the storage conditions of the bifunctional adsorbent are 1~40℃ and below 80% relative humidity, and it does not need to be stored away from light.

[0038] Based on the above embodiments, as an optional implementation, the bifunctional adsorbent in the plasma adsorbent has a particle size of 250 μm to 500 μm, an average pore size range of 2 nm to 20 nm, and a specific surface area range of 300 m². 2 / g to 1200m 2 / g, pore volume range is 0.8cm³ 3 / g to 2.0cm 3 / g. This ensures that the plasma adsorber has good adsorption performance for bilirubin and cytokines.

[0039] Based on the above embodiments, as an optional implementation, the bifunctional adsorbent has pores of different sizes. The bifunctional adsorbent has the highest proportion of pores with a size range of 2nm to 10nm, and the lowest proportion of pores with a size greater than 100nm. According to the different pore sizes, the bifunctional adsorbent has pores smaller than 2nm (micropores), which can adsorb small molecules; pores with a size range of 2nm to 50nm (mesopores), which can adsorb proteins, toxins, and drugs; and pores with a size range greater than 50nm (macropores), which can adsorb macromolecules and biomolecules, etc. Figure 1 As shown, Figure 1 The circular lines represent the differential pore volume distribution, indicating the volume increase per unit change in pore diameter. The peaks in the circular lines indicate which pore diameter is most abundant. The triangular lines represent the cumulative pore volume distribution, indicating the total pore volume of pores less than or equal to a certain diameter. The triangular lines indicate the total volume of pores smaller than a certain diameter. Combined with... Figure 1 It can be seen that the pore size of the bifunctional adsorbent in the plasma adsorber is mainly distributed between 2nm and 50nm. Among them, a significant peak appears in the 2nm to 10nm range, indicating that the pores with a pore size range of 2nm to 10nm account for the highest proportion of the bifunctional adsorbent. The slope of the integral curve for the pores with a pore size range of 50nm to 100nm slows down but still shows an upward trend. This indicates that the bifunctional adsorbent is mainly composed of small and medium pores, but there is still a certain proportion of large pores. However, the proportion of large pores is lower than that of pores with a pore size range of 2nm to 50nm, and the number of pores with a pore size greater than 100nm is relatively small. Therefore, in this embodiment, the pores with a pore size range of 2nm to 10nm account for the highest proportion, which can improve the specific surface area and adsorption capacity of the bifunctional adsorbent. Meanwhile, the macropores with a pore size range of 50nm to 100nm and above 100nm can provide sufficient reaction sites for the chloromethylation of intermediate resin and the formation of new cross-linking channels without clogging the channels. They also provide sufficient binding sites for the final resin, avoiding competitive binding of bilirubin, bile acids and cytokines. The combination of pores with different sizes is beneficial to further improve the adsorption efficiency of the plasma adsorbent for target substances of different sizes.

[0040] Based on the above embodiments, as an optional implementation method, combined with Figure 3 As shown, this bifunctional adsorbent was prepared using the following method:

[0041] Step S210: Prepare a polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines.

[0042] In this embodiment, a polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines is prepared, comprising:

[0043] Step S211: Styrene monomers and crosslinking agent divinylbenzene are subjected to suspension polymerization in a dispersant under the action of a porogen and an initiator to obtain polystyrene-divinylbenzene macroporous resin.

[0044] Specifically, a styrene monomer, a crosslinking agent (divinylbenzene), a porogen, and an initiator are mixed to form an oil phase. A dispersant is dispersed in water to form an aqueous phase. The oil phase is added to the aqueous phase and stirred. After the oil phase forms uniform droplets of a certain size in the aqueous phase, the temperature is raised to 50℃~100℃ for suspension polymerization. After reacting for 12h~20h, the suspension polymerization product is cleaned, dried, and polystyrene-divinylbenzene macroporous resin is obtained. As an optional embodiment, the suspension polymerization reaction can be carried out by gradually increasing the temperature in stages. For example, after the oil phase forms uniform droplets of a certain size in the aqueous phase, the temperature can be raised to 75℃ for polymerization and setting for 3h, then raised to 80℃ for curing for 7h, and then raised to 85℃ for further curing for 6h before stopping the reaction.

[0045] 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 mass fraction of the styrene monomer in the monomer mixture is 55% to 92%. The mass fraction of the crosslinking agent divinylbenzene in the monomer mixture is 8% to 45%. The monomer mixture consists of the styrene monomer and the crosslinking agent divinylbenzene. Therefore, using the styrene monomer and the crosslinking agent divinylbenzene as the reactive monomers is beneficial for improving the mechanical strength and structural stability of the polystyrene-divinylbenzene macroporous resin.

[0046] Based on the above embodiments, as an optional implementation, the porogen is a mixture of two or more aromatic hydrocarbons, alkanes, higher alcohols, and higher ketones. Aromatic hydrocarbons and alkanes are good solvents; aromatic hydrocarbons include at least one selected from toluene, ethylbenzene, xylene, and n-propylbenzene; alkanes include at least one selected from n-heptane, solid paraffin, and gasoline. Higher alcohols and higher ketones are poor solvents; higher alcohols include at least one selected from butanol, isooctyl alcohol, and methyl isobutyl methanol; higher ketones include at least one selected from methyl isobutyl ketone and 2-hexanone. The mass of the porogen accounts for 70% to 230% of the total mass of the monomer mixture.

[0047] Based on the above embodiments, as an optional implementation, the initiator is selected from one or a combination of several of benzoyl peroxide, tert-butyl peroxide-2-ethylhexanoate, and tert-amyl peroxide-2-ethylhexanoate, and the mass of the initiator accounts for 0.5% to 1.5% of the total mass of the monomer mixture. Therefore, the above initiator can effectively initiate the suspension polymerization reaction of styrene monomers and the crosslinking agent divinylbenzene, and the initiator is relatively inexpensive.

[0048] Based on the above embodiments, as an optional implementation, the dispersant is selected from one or a combination of gelatin, polyvinyl alcohol, and methylcellulose; preferably, the dispersant is gelatin. The concentration of the dispersant in the aqueous phase is 0.1 wt% to 1 wt%, and the volume ratio of the aqueous phase to the oil phase is (1-3):1. This stabilizes the dispersion of droplets, prevents aggregation or coalescence, ensures uniform and controllable polymerization, and the dispersant is safer and more environmentally friendly.

[0049] Step S212: Add halogenated hydrocarbons to polystyrene-divinylbenzene macroporous resin to swell for 2 to 4 hours, then add isooctanol to continue swelling for 1 to 2 hours to obtain swollen polystyrene-divinylbenzene macroporous resin.

[0050] Specifically, a halogenated hydrocarbon is added to a polystyrene-divinylbenzene macroporous resin, and the mixture is stirred and swollen at 25°C to 35°C for 2 to 4 hours. Then, isooctanol is added and the swelling continues for another 1 to 2 hours, allowing the isooctanol to fully penetrate the pores of the polystyrene-divinylbenzene macroporous resin, thus obtaining the swollen polystyrene-divinylbenzene macroporous resin. Therefore, adding the halogenated hydrocarbon first during the swelling process allows the pores of the polystyrene-divinylbenzene macroporous resin to be fully opened. Adding isooctanol as a co-solvent / phase transfer aid further improves the wettability of the pores, ensuring the uniformity of the subsequent chloromethylation reaction. This compensates for the uneven wettability of the polystyrene-divinylbenzene macroporous resin caused by the halogenated hydrocarbon, which could lead to localized over-reaction or incomplete reaction in the subsequent chloromethylation reaction.

[0051] Based on the above embodiments, as an optional implementation, the amount of isooctanol used is 10% to 30% of the mass of the polystyrene-divinylbenzene macroporous resin. Therefore, the amount of isooctanol used within the above range is beneficial for further ensuring the wettability of the pores of the polystyrene-divinylbenzene macroporous resin.

[0052] Based on the above embodiments, as an optional implementation, the halogenated hydrocarbon is at least one of dichloroethane and dichloromethane. The amount of halogenated hydrocarbon used is 150% to 200% of the mass of the polystyrene-divinylbenzene macroporous resin.

[0053] Step S213: The swollen polystyrene-divinylbenzene macroporous resin is subjected to a chloromethylation reaction to obtain a chloromethylated intermediate resin.

[0054] Specifically, chloromethyl ether is added dropwise to the swollen polystyrene-divinylbenzene macroporous resin at 0–20°C. After the addition is complete, the temperature is raised to 30°C to 50°C, and a chloromethylation reaction is carried out for 4–8 hours under the catalysis of anhydrous zinc chloride to obtain a chloromethylated intermediate resin.

[0055] Based on the above embodiments, as an optional implementation method, the amount of chloromethyl ether is 1 to 2 times the mass of polystyrene-divinylbenzene macroporous resin, and the amount of anhydrous zinc chloride is 0.5 to 1.5 times the mass of polystyrene-divinylbenzene macroporous resin.

[0056] Step S214: The chloromethylated intermediate resin is subjected to a post-crosslinking reaction to obtain a polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines.

[0057] Specifically, after filtering the chloromethylated intermediate resin, anhydrous zinc chloride is added to the chloromethylated intermediate resin, and a post-crosslinking reaction is carried out under the catalysis of anhydrous zinc chloride. The temperature of the post-crosslinking reaction is 40℃ to 110℃, and the reaction time is 6h to 12h, so that the chlorine content of the post-crosslinking product is less than 1.5%, thus obtaining a polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines. As an optional embodiment, the post-crosslinking reaction is carried out by gradient heating. After adding anhydrous zinc chloride to the chloromethylated intermediate resin, the temperature is first raised to 40℃ and stirred for 30min to ensure sufficient contact between the anhydrous zinc chloride and the chloromethyl sites. Then, the temperature is slowly raised to 80℃ and the reaction is held at a constant temperature for 12h. After the crosslinking reaction is completed, the mixture is cooled to room temperature and filtered to obtain a polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines.

[0058] Based on the above embodiments, as an optional implementation method, the amount of anhydrous zinc chloride used is 0.1 to 0.5 times the mass of the chloromethylated intermediate resin.

[0059] Step S220: The polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines is sequentially washed with acid, alkali, water and alcohol to make the pH value of the polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines 5.0 to 6.0, thus obtaining a bifunctional adsorbent.

[0060] Specifically, 2% hydrochloric acid was added to a polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines, immersing the resin in the hydrochloric acid. After stirring at room temperature for 4 hours, the hydrochloric acid was drained. Then, purified water was added to the resin, immersing it in the purified water. After stirring at room temperature for 1 hour, the purified water was drained. Finally, a 2% sodium hydroxide solution was added to the resin. Polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines was immersed in sodium hydroxide solution and stirred at room temperature for 4 hours. The sodium hydroxide solution was then drained. Purified water was then added to the resin, immersing it completely in the purified water. The mixture was stirred at room temperature for 1 hour, after which the purified water was drained. The pH of the washed resin was measured, and the number of washes was controlled to maintain a pH between 5.0 and 6.0. The resin was then rinsed with alcohol at least four times, for 3 hours each time, to remove organic matter. Subsequently, polystyrene-divinylbenzene macroporous resin, which can simultaneously adsorb bilirubin and cytokines, is assembled into a column to obtain a plasma adsorber that dually adsorbs bilirubin and cytokines.

[0061] Based on the above embodiments, as a preferred embodiment, acid neutralization is further included between alkaline washing and water washing. Specifically, after alkaline washing, the polystyrene-divinylbenzene macroporous resin, which can simultaneously adsorb bilirubin and cytokines, is acid-washed using a low-concentration acid, such as hydrochloric acid with a mass concentration of 0.75%. Therefore, using a low-concentration acid wash after alkaline washing avoids the residue of alkaline substances after alkaline washing, preventing saponification reactions during resin storage due to residual alkaline substances, which could damage the resin skeleton structure and lead to problems such as chain breakage and hydrolysis. Simultaneously, water washing after the low-concentration acid wash prevents the pH value of the polystyrene-divinylbenzene macroporous resin, which can simultaneously adsorb bilirubin and cytokines, from becoming too low.

[0062] The method for preparing the bifunctional adsorbent provided in this embodiment involves, after obtaining the polystyrene-divinylbenzene macroporous resin and before chloromethylation, stepwise swelling of the polystyrene-divinylbenzene macroporous resin with halogenated hydrocarbons and isooctanol. This fully expands the pores of the polystyrene-divinylbenzene macroporous resin, improves the wettability of the pores, ensures the uniformity of the subsequent chloromethylation reaction, and ensures that the chloromethyl groups are uniformly distributed within the pores of the polystyrene-divinylbenzene macroporous resin, thereby improving the uniformity of adsorption sites. After chloromethylation, a post-crosslinking reaction can improve the structural strength of the polystyrene-divinylbenzene macroporous resin, effectively controlling the ability of polystyrene-divinylbenzene to simultaneously adsorb bilirubin and cytokines. The generation of microparticles in macroporous resins is beneficial to improving the safety of polystyrene-divinylbenzene macroporous resins that can simultaneously adsorb bilirubin and cytokines. After preparing polystyrene-divinylbenzene macroporous resins that can simultaneously adsorb bilirubin and cytokines, the pH of the bifunctional adsorbent can be adjusted by sequentially washing it with acid, alkali, acid neutralization, water, and alcohol to maintain it within a suitable range. This not only improves the adsorption capacity of the bifunctional adsorbent but also enhances its stability, ensuring good adsorption stability even after aging. Furthermore, multiple washing processes can reduce the residual organic matter within the bifunctional adsorbent, further controlling the generation of microparticles.

[0063] Based on the above embodiments, as an optional implementation, the volume of the bifunctional adsorbent in the column occupies 60% to 90% of the column volume. Therefore, by controlling the volume of the bifunctional adsorbent in the column within this range, the blood chamber volume of the plasma adsorber can be maintained at a lower level, reducing the risk of hypotension. If the volume of the bifunctional adsorbent in the column is less than 60%, the blood chamber volume of the plasma adsorber will increase, increasing the probability of hypotension in patients. If the volume of the bifunctional adsorbent in the column exceeds 90%, the bifunctional adsorbent cannot be fully agitated during pre-filling of the plasma adsorber, which is not conducive to the discharge of air bubbles within the plasma adsorber, increasing the pre-filling and degassing time during use and affecting the efficiency of blood purification.

[0064] Based on the above embodiments, as an optional implementation method, combined with Figure 4As shown, the column of the plasma adsorbent includes a cap 4, a sealing plug 5, an end cap 3, a cylinder 1, and a mesh frame 2. The cylinder 1 has openings at both ends along the axial direction. The cylinder 1 is hollow, and the bifunctional adsorbent is filled inside. The end cap 3 seals the openings of the cylinder 1 and is connected to the cylinder 1 by a locking nut. The sealing plug 5 provides a seal during storage and transportation of the plasma adsorbent and is removed before use. The end cap 3 has a blood nozzle and a cover body protruding axially from the cylinder 1. The cover body surrounds the blood nozzle, and the cover body and blood nozzle are integrally formed. The blood nozzle and the inner space of the cover body are connected. The cover body extends into the inner cavity of the cylinder 1, and part of the outer peripheral wall of the cover body contacts part of the inner wall of the cylinder 1. The mesh frame 2 is located between the end of the cover body and the cylinder 1. A nylon filter screen is installed on the mesh frame 2, covering the end opening of the cylinder 1. The cap 4 is used to close the blood nozzle to achieve a seal. One end cap 3 has a plasma inlet port, and the other end cap 3 has a plasma outlet port. Both ports are connected to the extracorporeal circulation tubing. The mesh frame 2 near the plasma outlet port is covered with non-woven fabric with a pore size of 200 mesh. Therefore, by adding non-woven fabric with a pore size of 200 mesh to the plasma outlet port, the number of particles flushed out of the plasma adsorber can be effectively reduced, ensuring that the plasma adsorber has a filtration rate of no less than 90% for particles larger than 30 μm. Simultaneously, it effectively reduces blood flow resistance, keeping blood flow fluctuations below 5 ml / min.

[0065] Based on the above embodiments, as an optional implementation, the ratio of the axial length of the cylinder 1 to its maximum diameter is 2.5 to 4.0. Therefore, by setting the length-to-diameter ratio of the cylinder 1 within the above range, dead zones and eddies can be prevented, effectively reducing the blood flow pressure within the plasma adsorber during blood purification, minimizing the impact on blood cells, and improving the safety of the plasma adsorber.

[0066] Based on the above embodiments, as an optional implementation, the end of the cylinder 1 with the plasma inlet is defined as the first end, and the end of the cylinder 1 with the plasma outlet is defined as the second end, with the diameter of the first end being smaller than the diameter of the second end. Therefore, by setting the diameter of the first end to be smaller than the second end, it facilitates the removal of air bubbles during pre-priming of the plasma absorber, making operation more convenient. It also reduces the pressure at the plasma bleeding end, and allows blood to pass through the plasma absorber in a shorter time, reducing the risk of coagulation. As a preferred embodiment, the ratio of the diameter of the first end to the diameter of the second end is 0.95:1 to 0.99:1.

[0067] The second aspect of this application provides an application of a plasma adsorber that dually adsorbs bilirubin and cytokines. As described in the first aspect, the plasma adsorber that dually adsorbs bilirubin and cytokines can simultaneously adsorb bilirubin and cytokines and can be used for extracorporeal blood purification in liver failure, thereby delaying the progression of liver failure.

[0068] The plasma adsorber with dual adsorption of bilirubin and cytokines provided in this embodiment is used for extracorporeal blood purification in liver failure. It can slow down the progression of liver failure, and has a low risk of allergic reactions to blood cells and few side effects, which helps to improve the safety of blood purification.

[0069] 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.

[0070] Example 1

[0071] This embodiment provides a method for preparing a bifunctional adsorbent, including the following steps:

[0072] (1) Add 600 mL of gelatin aqueous solution to a 1000 mL three-necked flask as the aqueous phase, and then add 43.6 g of styrene, 6.4 g of divinylbenzene (DVB), 30 g of toluene, 36 g of solid paraffin and 0.5 g of benzoyl peroxide to form an oil phase. Under mechanical stirring, stir to form uniform droplets, then heat to 75 °C for suspension polymerization reaction for 3 h, then heat to 80 °C for curing for 7 h, then heat to 85 °C for curing for another 6 h and then stop the reaction. The reaction products are washed with hot water, rinsed with acetone and dried, and then sieved to select polystyrene-divinylbenzene macroporous resin with a particle size of 0.3 mm to 1.0 mm.

[0073] (2) Take 500g of polystyrene-divinylbenzene macroporous resin and add 1000mL of dichloromethane. Stir and swell at 30℃ for 3h. Then add 100g of isooctanol and continue to swell for 1.5h to allow isooctanol to fully penetrate into the resin pores and obtain the swollen polystyrene-divinylbenzene macroporous resin.

[0074] (3) Slowly add 50g of anhydrous zinc chloride (Lewis acid catalyst) to the swollen polystyrene-divinylbenzene macroporous resin. At 10°C, slowly add 500g of chloromethyl ether to the swollen polystyrene-divinylbenzene macroporous resin at a rate of 8mL / min. After the addition is complete, raise the temperature to 40°C and react at a constant temperature for 6h. The tail gas is absorbed by 10% sodium hydroxide aqueous solution and then discharged. After the reaction is completed, cool the reaction product to room temperature and filter to obtain chloromethylated intermediate resin.

[0075] (4) Slowly add 50g of anhydrous zinc chloride (Lewis acid catalyst) to the chloromethylated intermediate resin and carry out the post-crosslinking reaction by gradient heating. That is, first heat to 40℃ and stir and disperse for 30min to make the catalyst fully contact the chloromethyl sites, then slowly heat to 80℃ and keep the temperature constant for 12h. After the crosslinking reaction is completed, cool to room temperature after the reaction is completed, and filter to obtain polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines.

[0076] (5) Add 2% hydrochloric acid to the polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines, so that the polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines is immersed in hydrochloric acid. After stirring at room temperature for 4 hours, drain the hydrochloric acid. Then add purified water to the polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines, so that the polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines is immersed in purified water. After stirring at room temperature for 1 hour, drain the purified water. Water; then add a 2% sodium hydroxide solution to the polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines, so that the polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines is immersed in the sodium hydroxide solution. After stirring at room temperature for 4 hours, drain the sodium hydroxide solution. Then add 0.75% hydrochloric acid to the polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines to neutralize the excess alkali. After stirring at room temperature for 30 minutes, drain the solution. Repeat twice. Purified water was added to the polystyrene-divinylbenzene macroporous resin, which can simultaneously adsorb bilirubin and cytokines, to immerse the resin in the purified water. After stirring at room temperature for 1 hour, the purified water was drained. The pH of the washed polystyrene-divinylbenzene macroporous resin was measured, and the pH was maintained between 5.0 and 6.0 by controlling the number of washes. The resin was then rinsed with alcohol at least four times, for 3 hours each time, to remove organic matter. Finally, the polystyrene-divinylbenzene macroporous resin was assembled into a column to obtain a plasma adsorbent that dually adsorbs bilirubin and cytokines.

[0077] The bifunctional adsorbent prepared above was filled into a column with 100-mesh filters at both ends and assembled into a plasma adsorbent that adsorbs both bilirubin and cytokines. The volume of the column is 400 mL, the amount of bifunctional adsorbent is 330 mL, the length-to-diameter ratio of the column is 2.8, and a non-woven fabric with a pore size of 200 mesh is covered on the mesh frame near the bleeding end interface of the column. Both the blood inlet interface and the bleeding end interface at both ends of the column are Luer connectors.

[0078] Comparative Example 1

[0079] This comparative example provides a method for preparing a bifunctional adsorbent, which is basically the same as the preparation method in Example 1, except that the amount of chloromethyl ether added in step (3) is different. The amount of chloromethyl ether added in this comparative example is 2000g.

[0080] Comparative Example 2

[0081] This comparative example provides a method for preparing a bifunctional adsorbent, which is basically the same as the preparation method in Example 1. The only difference is that the polystyrene-divinylbenzene macroporous resin in this comparative example was not swollen in dichloromethane and isooctyl alcohol before chloromethylation, i.e. step (2) is missing. After obtaining the polystyrene-divinylbenzene macroporous resin, the chloromethylation step (3) and subsequent processing steps are directly carried out.

[0082] Comparative Example 3

[0083] This comparative example provides a method for preparing a bifunctional adsorbent, which is basically the same as the preparation method in Example 1. The only difference is that in step (5), the pH value of the final bifunctional adsorbent is controlled between 3.0 and 4.0 by reducing the number of water washings.

[0084] Experimental Example 1:

[0085] The chlorine content of the bifunctional adsorbents in Example 1 and Comparative Examples 1 to 3 was detected by means of manual titration or automatic potentiometric titration. The specific calculation formulas for these two methods are as follows:

[0086] Formula for calculation by artificial titration:

[0087] C1%=(C1V1-C2V2)×0.03545 / m×100%

[0088] Where: C 1： The actual molar concentration of AgNO3 standard solution (mol / L);

[0089] C 2： The actual molar concentration of the KSCN standard solution (mol / L);

[0090] m is the actual mass (g) of the resin.

[0091] Automatic potentiometric titrator calculation formula:

[0092] C1% = C1V1 × 0.03545 / m × 100%

[0093] Where: C 1： The actual molar concentration of AgNO3 standard solution (mol / L);

[0094] m is the actual mass (g) of the resin.

[0095] The results obtained after calculation are shown in Table 1.

[0096] Table 1

[0097]

[0098] As shown in Table 1, the bifunctional adsorbent in Example 1 has a lower chlorine content compared to Comparative Example 1. This indicates that increasing the amount of chloromethyl ether increases the chlorine content of the bifunctional adsorbent, but this reduces its safety. In Comparative Example 2, swelling was not performed before chloromethylation, resulting in incomplete chloromethylation and therefore a lower chlorine content. In Example 1, by controlling the amount of chloromethyl ether, the chlorine content of the bifunctional adsorbent can be kept within a low range, which is beneficial to improving the safety of the bifunctional adsorbent.

[0099] Experimental Example 2:

[0100] The adsorption rates of cytokines such as bilirubin, bile acids, and IL-6 of the bifunctional adsorbents in Example 1 and Comparative Examples 1 to 3 were detected using the following specific test methods:

[0101] The bifunctional adsorbents prepared in Example 1 and Comparative Examples 1 to 3 were used to simulate the plasma of patients with clinical liver failure by adding bilirubin, bile acids, and IL-6 to the plasma of healthy individuals. Adsorption was carried out at a bath ratio of 1:10 between the bifunctional adsorbent and the plasma. The adsorption rates of the bifunctional adsorbents in Example 1 and Comparative Examples 1 to 3 for bilirubin, bile acids, and IL-6 were tested, and the results are shown in Table 2.

[0102] Table 2

[0103]

[0104] As shown in Table 2, the bifunctional adsorbent in Example 1 exhibits significantly higher adsorption rates for bilirubin, bile acids, and cytokines such as IL-6 compared to the bifunctional adsorbents in Comparative Examples 1 and 2. This is because the bifunctional adsorbent in Example 1 is weakly polar (with a contact angle of 91.61° with water), while the bilirubin molecule contains multiple hydroxyl and amino groups, readily forming multiple hydrogen bonds with the functional groups on the weakly polar bifunctional adsorbent. Bile acids are weakly polar, containing single polar groups of carboxyl and hydroxyl groups, which bind to the weakly polar bifunctional adsorbent through single hydrogen bonds and dipole interactions. Cytokines such as IL-6 are strongly bipolar molecules, and are synergistically adsorbed through the mild electrostatic attraction and hydrogen bonds of the weakly polar bifunctional adsorbent. In Comparative Example 1, the increased chlorine content enhances the polarity of the bifunctional adsorbent, leading to a weakened hydrophobic interaction with bilirubin, bile acids, and cytokines, resulting in a lower adsorption rate. The bifunctional adsorbent in Comparative Example 2 was not swollen with dichloromethane and isooctyl alcohol, resulting in insufficient chloromethylation sites and thus fewer binding sites for the target substances, leading to lower adsorption rates for bilirubin, bile acids, and cytokines.

[0105] Experimental Example 3:

[0106] Using the assembly method in Example 1, the bifunctional adsorbents in Example 1 and Comparative Examples 1 to 3 were respectively assembled into plasma adsorbents that adsorb both bilirubin and cytokines. Apart from the difference in the bifunctional adsorbent, the other assembly materials of each plasma adsorbent that adsorbs both bilirubin and cytokines were the same.

[0107] The circulating fluid particles of the plasma adsorbers that dually adsorb bilirubin and cytokines in Example 1 and Comparative Examples 3 were detected respectively using the following methods:

[0108] After pre-rinsing each plasma adsorber with 1500 mL of physiological saline, each plasma adsorber was connected to 500 mL of physiological saline via tubing to form a closed circulation system. After circulation for 2 hours, the circulating solution was obtained. The number of particles in each circulating solution was measured, and the results are shown in Table 3.

[0109] Table 3

[0110]

[0111] As can be seen from Table 3, compared with Comparative Example 2, the plasma adsorbent for dual adsorption of bilirubin and cytokines in Example 1 has a significantly smaller number of particles. This is because the bifunctional adsorbent in Comparative Example 2 was not subjected to swelling treatment with dichloromethane and isooctyl alcohol, resulting in insufficient chloromethylation reaction, which is not conducive to secondary cross-linking. This leads to lower mechanical strength of the bifunctional adsorbent, resulting in a larger number of particles. Therefore, the plasma adsorbent for dual adsorption of bilirubin and cytokines in Comparative Example 2 may indicate a relatively higher risk of sensitization.

[0112] Experimental Example 4:

[0113] An aging test was conducted on the plasma adsorbents for dual adsorption of bilirubin and cytokines in Example 1 and the plasma adsorbents for dual adsorption of bilirubin and cytokines in Comparative Examples 1 to 3. The pH of the storage solution and the adsorption performance of each plasma adsorbent were measured. The specific test methods are as follows:

[0114] According to YY / T 0681.1-2018 "Test Methods for Sterile Medical Device Packaging: Part 1 Guidelines for Accelerated Aging Tests", the aging formula is: AAT=RT. Y / AAF, AAF=Q 10 [(TAA-TRA) / 10] Among them, AAT: accelerates aging time; RT Y : Expected aging time; AAF: Accelerating aging factor; T AA Accelerated aging temperature; T RA Ambient temperature.

[0115] According to the guide, take Q. 10 =2.0, T AA =60℃; The plasma adsorber with dual adsorption function should be stored in a dry, well-ventilated, and clean environment at 1~60℃. The most stringent condition, 60℃, is selected as the aging reference temperature, therefore T RA =60℃; Expected aging time RTY = 2 years 1 month = 761 days. Therefore, the accelerated aging factor AAF = 2.0. (60-30) / 10 =8; Accelerated aging time: AAT = 761 days / 8 = 95.1 days, calculated as 96 days. Therefore, each plasma adsorbent was aged at 60℃ for 96 days, and the pH value and adsorption performance of the preservation solution of each plasma adsorbent were tested. The results are shown in Table 4.

[0116] Table 4

[0117]

[0118] As shown in Table 4, the initial pH value and the pH value after aging of the plasma adsorber for dual adsorption of bilirubin and cytokines in Example 1 are not significantly different, with a pH decrease rate of only 6.05%. Furthermore, after aging, the adsorption rates of bilirubin and IL-6 by the plasma adsorber for dual adsorption of bilirubin and cytokines are also not significantly different, with the adsorption rate of bilirubin decreasing by only 0.76% and the adsorption rate of IL-6 decreasing by only 5.3%. This indicates that the plasma adsorber for dual adsorption of bilirubin and cytokines in Example 1 has good pH stability and adsorption stability. In Comparative Example 3, the plasma adsorbent that dually adsorbs bilirubin and cytokines showed a decrease in pH and adsorption rate of bilirubin exceeding 10% after aging, and a decrease in adsorption rate of IL-6 approaching 10%. This indicates that the adsorption stability of the plasma adsorbent in Comparative Example 3 also decreased after aging. This is because the introduction of chlorine into the styrene resin results in a large number of C-Cl bonds on the molecular chain, which have low bond energy and poor stability, making them prone to homolytic cracking after aging. The released chlorine free radicals react with hydrogen ions in the water, causing significant pH changes in the product. The lower pH weakens the interaction between the resin and bilirubin and IL-6, thus reducing the adsorption capacity of the plasma adsorbent. This demonstrates that controlling the pH of the bifunctional adsorbent between 5.0 and 6.0 in this embodiment is beneficial for improving the adsorption stability of the plasma adsorbent.

[0119] As can be seen from Experimental Examples 1 to 4, compared with Comparative Examples 1 and 3, the plasma adsorber for dual adsorption of bilirubin and cytokines in Example 1 has better safety and effectiveness, and can maintain a stable pH value and adsorption performance stability over a long storage period.

Claims

1. A plasma adsorbent that dually adsorbs bilirubin and cytokines, characterized in that, The product includes: a column and a bifunctional adsorbent. The column has interfaces at both ends for connecting to an extracorporeal circulation pipeline. The bifunctional adsorbent is filled in the column. Filter screens are provided at the openings at both ends of the column. The volume of the bifunctional adsorbent in the column accounts for 60% to 90% of the volume of the column. The bifunctional adsorbent is prepared by multi-stage washing of polystyrene-divinylbenzene macroporous resin, which can simultaneously adsorb bilirubin and cytokines, so that the pH value of the bifunctional adsorbent in the initial state is 5.0 to 6.0, and the pH value of the bifunctional adsorbent after aging is 4.5 to 6.

0. The polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines is formed by modifying polystyrene-divinylbenzene macroporous resin through chloromethylation and post-crosslinking reaction, and the chlorine content of the polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines is less than 1.5%.

2. The plasma adsorbent for dual adsorption of bilirubin and cytokines according to claim 1, characterized in that, The bifunctional adsorbent in the plasma adsorbent has an adsorption capacity of not less than 0.8 μmol / mL of bilirubin in the initial state, and the bifunctional adsorbent has an adsorption capacity of not less than 1000 pg / mL of IL-6 in the initial state.

3. The plasma adsorbent for dual adsorption of bilirubin and cytokines according to claim 1, characterized in that, The bifunctional adsorbent has a particle size of 250 μm to 500 μm, an average pore size of 2 nm to 20 nm, and a specific surface area of ​​300 m². 2 / g to 1200m 2 / g, pore volume range is 0.8cm³ 3 / g to 2.0cm 3 / g.

4. The plasma adsorbent for dual adsorption of bilirubin and cytokines according to claim 1, characterized in that, The bifunctional adsorbent was prepared by the following method: A polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines was prepared, wherein the polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines was formed by modifying polystyrene-divinylbenzene macroporous resin through chloromethylation and post-crosslinking reaction. The polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines was sequentially washed with acid, alkali, water, and alcohol to adjust the pH value of the polystyrene-divinylbenzene macroporous resin to 5.0 to 6.0, thereby obtaining the bifunctional adsorbent.

5. The plasma adsorbent for dual adsorption of bilirubin and cytokines according to claim 4, characterized in that, The polystyrene-divinylbenzene macroporous resin capable of simultaneously adsorbing bilirubin and cytokines was prepared by the following method: Polystyrene-divinylbenzene macroporous resin is prepared by suspension polymerization of styrene monomers and crosslinking agent divinylbenzene in a dispersion medium under the action of porogen and initiator. Halogenated hydrocarbons were added to the polystyrene-divinylbenzene macroporous resin to swell for 2 to 4 hours, and then isooctanol was added to continue swelling for 1 to 2 hours to obtain the swollen polystyrene-divinylbenzene macroporous resin. The swollen polystyrene-divinylbenzene macroporous resin was subjected to a chloromethylation reaction to obtain a chloromethylated intermediate resin. The chloromethylated intermediate resin was subjected to a post-crosslinking reaction to obtain a polystyrene-divinylbenzene macroporous resin that can simultaneously adsorb bilirubin and cytokines.

6. The plasma adsorbent for dual adsorption of bilirubin and cytokines according to claim 5, characterized in that, The amount of isooctanol used is 10% to 30% of the mass of the polystyrene-divinylbenzene macroporous resin.

7. The plasma adsorbent for dual adsorption of bilirubin and cytokines according to claim 1, characterized in that, The two ends of the column have an inlet port and a outlet port, respectively. The inlet port and the outlet port are connected to the extracorporeal circulation tubing. The column includes a mesh frame, and the mesh frame near the outlet port is covered with non-woven fabric with a pore size of 200 mesh.

8. The plasma adsorbent for dual adsorption of bilirubin and cytokines according to claim 7, characterized in that, The column includes a cylindrical body, the diameter of which is smaller than ...

9. The plasma adsorbent for dual adsorption of bilirubin and cytokines according to claim 1, characterized in that, The ratio of the axial length of the column to its maximum diameter is 2.5 to 4.

0.

10. An application of a plasma adsorber that dually adsorbs bilirubin and cytokines, characterized in that, The plasma adsorber that dually adsorbs bilirubin and cytokines is used for extracorporeal blood purification in liver failure.

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