High-stability renewable hemoperfusion adsorption material and preparation method thereof

Abstract

The application relates to the technical field of blood perfusion materials, in particular to a high-stability renewable blood perfusion adsorption material and a preparation method thereof. The blood perfusion material comprises a base core and nanoparticles loaded on the surface and pore wall of the base core. The nanoparticles are amino-functionalized metal organic framework materials, the base core is a macroporous crosslinked polymer resin, and the surface and pore wall of the base core contain reaction functional groups capable of reacting with amino groups. The surface of the nanoparticles contains amino groups and unsaturated metal coordination nodes. The nanoparticles are embedded into the base core at the side in contact with the base core, and the amino groups on the nanoparticles react with the reaction functional groups to form covalent bonds. The nanoparticles are also grafted with aromatic boronic acid ligands to form a functional layer. The unsaturated metal coordination nodes on the side of the nanoparticles away from the base core are grafted with zwitterionic polymer brushes to form an anti-pollution brush layer. The application can solve the technical problems of poor anti-pollution and washing resistance and short cycle life of the blood perfusion material in the prior art.

Description

Technical Field

[0001] This invention relates to the field of blood perfusion materials technology, and in particular to a highly stable renewable blood perfusion adsorbent material and its preparation method. Background Technology

[0002] Hemoperfusion is an important clinical treatment for removing endogenous or exogenous toxic substances from the blood, and it is widely used in the treatment of diseases such as uremia, liver failure, sepsis, and drug poisoning. The core of hemoperfusion lies in the adsorbent material, the performance of which directly determines the toxin removal efficiency and clinical treatment effect.

[0003] Currently, the main adsorbent materials used in clinical hemoperfusion include activated carbon and cross-linked polystyrene macroporous adsorption resins. While activated carbon exhibits broad-spectrum adsorption capacity for various toxins, its adsorption mechanism is primarily physical adsorption, resulting in poor selectivity and a risk of particulate shedding. Cross-linked polystyrene macroporous adsorption resins possess good mechanical strength and controllable pore structure, making them the most widely used in hemoperfusion; however, their specific adsorption capacity for protein-bound toxins or other toxins requiring removal is typically limited. Therefore, to improve the clearance efficiency of specific toxins, researchers often graft functional ligands onto the resin carrier, enabling the adsorbent material to recognize specific targets.

[0004] However, existing functionalized adsorbent materials face the following problems in practical applications. First, the connection stability between functional ligands and the carrier is insufficient. In existing technologies, functional ligands are usually loaded onto the carrier surface through physical adsorption or weak chemical bonding. Due to the continuous fluid shear forces and complex protein competitive adsorption in the plasma environment, functional ligands are easily detached during multiple perfusion cycles, leading to a continuous decline in adsorption capacity. Second, proteins, lipids, and other components in the blood undergo non-specific deposition on the adsorbent surface, forming a contaminant layer that covers functional sites and blocks mass transfer channels, causing a significant decrease in adsorption performance during a single perfusion cycle. Third, existing regenerable blood perfusion materials often use alkaline regeneration to restore adsorption capacity, but alkaline conditions exacerbate the detachment of functional ligands, leading to a significant decrease in adsorption capacity. On the other hand, reducing the regeneration intensity to protect the ligands makes it difficult to effectively restore adsorption capacity and may also pose certain safety risks, making it difficult to balance the safety, efficiency, and ligand stability of regeneration.

[0005] Therefore, there is an urgent need in this field for a blood perfusion adsorbent material that has a stable connection between the functional ligand and the carrier, is resistant to contamination, and can be regenerated and recycled. Summary of the Invention

[0006] (a) Technical problems to be solved In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a highly stable renewable blood perfusion adsorbent material and its preparation method, which solves the technical problems of poor anti-pollution and cleaning resistance and short cycle life of blood perfusion materials in the prior art.

[0007] (II) Technical Solution To achieve the above objectives, the main technical solutions adopted by the present invention include: In a first aspect, the present invention provides a highly stable regenerative blood perfusion adsorbent material, comprising a core and nanoparticles loaded on the surface and pore walls of the core; the nanoparticles are amino-functionalized metal-organic framework materials. The core is a macroporous cross-linked polymer resin, and its surface and pore walls contain reactive functional groups that can react with amino groups; the surface of the nanoparticles contains amino groups and unsaturated metal coordination nodes; the side of the nanoparticles in contact with the core is embedded in the core, and the amino groups on it react with the reactive functional groups to form covalent bonds; aromatic boric acid ligands are also grafted onto the nanoparticles to form a functional layer; zwitterionic polymer brushes are grafted onto the unsaturated metal coordination nodes on the side of the nanoparticles facing away from the core to form an antifouling brush layer.

[0008] Optionally, the core is obtained by copolymerization of styrene-based matrix monomers and reactive monomers containing reactive functional groups, wherein the reactive functional groups are at least one of halomethyl and epoxy groups; Unsaturated metal coordination nodes are metal nodes in metal-organic frameworks that are not coordinated to be unsaturated; nanoparticles are amino-functionalized zirconium-based metal-organic framework materials. The aromatic boric acid ligand contains a reactive group, which reacts with the amino group of the nanoparticle to form a covalent bond; the reactive group is at least one of an aldehyde group and a carboxyl group.

[0009] Optionally, the adsorbent material has a particle size of 0.5-1.5 mm; the macropores in the core have a pore size of 200-300 nm; the nanoparticles have a particle size of 20-60 nm; and among the metal nodes on the surface of the nanoparticles, unsaturated metal coordination nodes account for 10% to 50% of the total number of metal nodes. The core is a copolymer of polystyrene, divinylbenzene and chloromethylstyrene, wherein the copolymerization ratio of chloromethylstyrene is 3% to 8%; the zirconium-based metal-organic framework material is at least one of the UiO-66 series and the UiO-67 series.

[0010] Optionally, the aromatic boric acid ligand is at least one of 4-formylphenylboronic acid, 3-formylphenylboronic acid and 4-carboxyphenylboronic acid, which is covalently grafted onto the amino group on the side of the nanoparticle facing away from the core by Schiff base reduction or amide condensation, and is used to recognize glycoprotein toxins containing cis-diol in the blood. The zwitterionic polymer is at least one of polymethyl methacrylate sulfobetaine, polymethyl methacrylate carboxybetaine, and poly-2-methacryloyloxyethyl phosphocholine, which is connected to the unsaturated metal coordination nodes of the nanoparticles through Zr-OP coordination bonds.

[0011] In a second aspect, the present invention also provides a method for preparing the highly stable regenerative blood perfusion adsorbent material as described in any one of the first aspects, comprising the following steps: S1: The core is placed in an organic solvent for swelling to swell; then the nanoparticles are brought into contact with the swollen core, and then heated to allow the amino groups on the nanoparticles to react with the reactive functional groups in the core to form covalent bonds, thus obtaining the core of the anchored nanoparticles. S2: The core of the anchored nanoparticles is placed in a shrinkage solvent to shrink the core, so that the nanoparticles are embedded in the surface and pore walls of the core, thus obtaining the core of the dual-anchored nanoparticles. S3: Mix the core of the dual-anchored nanoparticles with an aromatic boric acid ligand containing reactive groups, so that the reactive groups react with the amino groups on the nanoparticles, and graft the aromatic boric acid ligands onto the nanoparticles to obtain a functionalized core. S4: The functionalized core, the organic solvent for coordination, and the atom transfer radical polymerization initiator containing phosphorus groups are mixed to allow the phosphorus groups to undergo a coordination reaction with the unsaturated metal coordination nodes on the surface of the nanoparticles, thereby obtaining the initiator-supported core. S5: The initiator-supported core is mixed with zwitterionic monomers, and the zwitterionic monomers are polymerized into zwitterionic polymer brushes using the initiator to form an anti-fouling brush layer, thus obtaining a renewable blood perfusion adsorption material.

[0012] Optionally, in step S1, the core is dispersed in a swelling organic solvent and swollen for 2-4 hours, then nanoparticles and a first acid-binding agent are added, and the reaction is carried out under heating conditions for 12-24 hours. After washing to remove the unfixed nanoparticles, the core anchored to the nanoparticles is obtained. The swelling organic solvent is a polar aprotic solvent, including at least one of dimethyl sulfoxide and N-methylpyrrolidone. The first acid-binding agent is at least one of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, and sodium carbonate.

[0013] Optionally, in step S2, the core of the anchored nanoparticles is placed sequentially in a solution with progressively increasing concentration of the shrinkage solvent, causing the core to shrink to embed and fix the nanoparticles, thereby obtaining the core of the dual-anchored nanoparticles; the shrinkage solvent is a poor solvent for the resin of the core, including at least one of methanol, ethanol and water.

[0014] Optionally, in step S3, the core of the dual-anchored nanoparticles is dispersed in a reaction solvent, aromatic boric acid ligand is added, and the mixture is heated under reflux for 6-24 hours to form a Schiff base. Then, a reducing agent is added to carry out a reduction reaction to convert the imine into a carbon-nitrogen covalent bond. After washing, the functionalized core is obtained. The reaction solvent is an alcohol solvent, including at least one of ethanol and isopropanol; the reducing agent is at least one of sodium borohydride and sodium cyanoborohydride.

[0015] Optionally, in step S4, the functionalized core is dispersed in a coordination organic solvent, an initiator containing a phosphate group and a second binding acid agent are added, and the reaction is carried out at room temperature. After the reaction is completed, the core is washed to obtain the initiator-supported core. The coordination organic solvent is selected from at least one of anhydrous ethanol and dimethyl sulfoxide; the phosphorus-containing initiator is an atom transfer radical polymerization initiator containing a phosphate group or a phosphonic acid group, including at least one of 2-bromoisobutyryloxyethyl phosphate, 2-bromoisobutyryloxyethyl phosphonic acid and 2-bromoisobutyryloxypropylphosphonic acid; the second acid-binding agent is selected from at least one of triethylamine, N,N-diisopropylethylamine and pyridine.

[0016] Optionally, in step S5, the initiator-supported core, zwitterionic monomer, and atom transfer radical polymerization catalytic system are mixed in a polar solvent and reacted at 25-40°C for 2-8 hours to obtain a zwitterionic polymer brush layer; after the reaction, the brush is washed to remove harmful residues and obtain a renewable blood perfusion adsorbent material. The polar solvent is at least one of methanol, ethanol, isopropanol and water; the atom transfer radical polymerization catalytic system is a catalytic system including copper bromide, nitrogen-containing ligands and reducing agents, including a catalytic system of cuprous bromide and nitrogen-containing ligands, a zero-valent copper catalytic system, or an organic photocatalytic system. The nitrogen-containing ligand is N,N,N',N'',N''-pentamethyldiethylenetriamine or tris(2-pyridylmethyl)amine; the reducing agent is at least one of ascorbic acid or sodium gluconate; the zwitterionic monomer is at least one of methacrylic acid sulfobetaine, methacrylic acid carboxybetaine or 2-methacryloyloxyethylphosphocholine.

[0017] (III) Beneficial Effects The beneficial effects of this invention are as follows: The highly stable regenerative blood perfusion adsorbent material and its preparation method of this invention utilize nanoparticles composed of amino-functionalized metal-organic frameworks. The organic ligand amino sites and unsaturated metal coordination nodes on these nanoparticles respectively undertake the functions of anchoring and functionalization, while simultaneously carrying functional ligands and anti-fouling brush layers. Compared with the prior art, this invention enables the functional components to be precisely positioned and firmly fixed on the surface of the adsorbent material. This allows the adsorbent material to simultaneously possess relatively stable toxin adsorption capacity and anti-protein contamination capacity under blood perfusion conditions, and also has better regenerative and recyclable capabilities.

[0018] Firstly, because this invention employs a method of introducing nanoparticles after swelling the core layer and then covalently bonding them with the reactive functional groups of the core layer via amino groups, followed by mechanical embedding of the nanoparticles by shrinking the core layer, a dual anchoring structure of covalent anchoring and shrinkage embedding is formed. Compared with the prior art, this enables the nanoparticles of this invention to obtain a fixation strength far exceeding that of a single covalent bond or a single physical embedding. Even under the continuous fluid shear force of blood perfusion and the chemical impact of regeneration and cleaning, the nanoparticles are not easily detached and can stably exist on the core.

[0019] Based on the stable existence of nanoparticles, this invention further employs a method in which the functional component (aromatic boric acid ligand) is linked to the amino groups on the nanoparticle backbone via reduced carbon-nitrogen covalent bonds, and the antifouling polymer grows outward from unsaturated defect sites on the backbone. This connects the functional component and the antifouling brush layer (composed of numerous polymer brushes) to the rigid crystalline backbone of the nanoparticles. Compared to the prior art method of directly connecting active components and other substances to the flexible segments of resin, the nanoparticles are composed of a metal-organic framework, which has a more rigid backbone structure. The anchor points on the rigid backbone will not swing arbitrarily, and the chemical bonds near the anchor points are not easily loosened by repeated pulling. In addition, the active component and the antifouling polymer of this invention have relatively high connection strength with the nanoparticles. The combination of these two factors can effectively improve the structural stability and strength of the connection between the functional component and the antifouling brush layer of this invention, making it less likely to detach during blood perfusion.

[0020] More importantly, the nanoparticles used in this invention serve as a metal-organic framework. The amino and unsaturated metal coordination nodes on the crystal skeleton are regularly arranged on the particle surface. Aromatic boric acid ligands and polymer brushes are ordered to connect / grow from these regularly arranged sites, forming an orderly alternating distribution pattern on the particle surface. The small molecular weight of the aromatic boric acid ligands adheres tightly to the particle surface, while the polymer brushes extend outward to form an outer barrier. The functional components are all located within the shielding range of the brush layer, and each aromatic boric acid ligand site is surrounded by adjacent brush chains for protection. At the same time, the polymer brushes grown therefrom are densely arranged at regular intervals, covering uniformly without exposed gaps. Adjacent brush chains support each other and work together to resist fluid shear. The dense brush layer constitutes a size exclusion barrier, allowing small molecule toxins to pass through and be adsorbed, while large molecule proteins and cells are physically blocked. If they cannot specifically recognize and bind to the aromatic boric acid ligands (phenylboronic acid ligands) of this invention, they are difficult to remain stably on the functional layer and will be carried away by the bloodstream. This achieves the unity of selective adsorption and anti-pollution protection of the functional layer.

[0021] The aforementioned robust connection structure and orderly arrangement significantly enhance the overall stability of the adsorbent material of this invention. During regeneration and cleaning, the functional layer and brush layer are less prone to detachment or damage, allowing the cleaning solution to more fully contact and elute bound toxins, resulting in a higher regeneration recovery rate and more regeneration cycles. Simultaneously, the uniform distribution of the functional components and brush layer on the particle surface ensures that the cleaning solution can evenly contact all binding sites during regeneration and cleaning, preventing problems such as cleaning dead zones caused by excessive local coverage, thus contributing to a higher regeneration recovery rate.

[0022] Furthermore, this invention utilizes nanoparticles containing both organic ligand amino sites and unsaturated metal coordination nodes. These two chemically distinct sites can independently perform different functions, avoiding problems such as insufficient grafting density or functional interference caused by competition between functional ligands and the antifouling brush layer for the same type of reaction sites. The aromatic boric acid ligand can specifically recognize blood toxins containing cis-diols and form reversible bindings, enabling dissociation and regeneration under mild alkaline conditions. The antifouling brush layer prevents non-specific protein deposition, avoiding the obscuring of the aromatic boric acid ligand binding sites. The synergy of these two components ensures that the functional layer of the adsorbent material remains fully exposed after each regeneration, continuing to perform its toxin recognition and adsorption functions. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the structural relationship between the nanoparticles and the core of the renewable blood perfusion adsorption material obtained in Example 1 of the present invention; Figure 2 This is a schematic diagram of the microstructure of the renewable blood perfusion adsorption material obtained in Example 1 of the present invention.

[0024] Figure label: 1: Core; 2: Nanoparticles; 3: Aromatic boric acid ligand; 4: Zwitterionic polymer brush. Detailed Implementation

[0025] To better explain and facilitate understanding of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0026] This invention provides a highly stable renewable blood perfusion adsorbent material and its preparation method, the preparation method comprising the following steps: S1: The core 1 is placed in a swelling organic solvent to swell it. Then, the nanoparticles 2 are brought into contact with the swollen core 1 and heated to allow the amino groups on the nanoparticles 2 to react with the reactive functional groups in the core 1 to form covalent bonds, thus obtaining a chemically anchored core 1 for the nanoparticles 2. The nanoparticles 2 are amino-functionalized metal-organic frameworks with a large number of amino groups on their surface. The core 1 is a macroporous cross-linked polymer resin containing reactive functional groups. The swelling organic solvent increases the intersegmental spacing of the resin's polymer chains, relaxes the surface, expands the surface area and pores without damaging its chain structure (at least within the reaction time of this invention). This swelling allows the nanoparticles 2 to fully contact the outer surface and inner walls of the core 1, and the amino groups on their surface form covalent bonds with a large number of reactive functional groups, stably anchoring the nanoparticles 2 to the surface and pore walls of the core 1. Because the resin chain segments are relaxed at this time, the side of the nanoparticle 2 that is in contact with the core 1 may even be able to penetrate deep into the intersegmental space, creating more favorable spatial conditions for the entry and dispersion of the nanoparticle 2.

[0027] S2: The core 1 of the chemically anchored nanoparticle 2 is placed in a shrinkage solvent, causing the core 1 to shrink. This embeds the nanoparticle 2 into the surface and pore walls of the core 1, or traps it within the pores, resulting in a core 1 of the dual-anchored nanoparticle 2. The shrinkage solvent is a poor solvent for the core 1. In this solvent, the polymer chain segments of the core 1 shrink, reducing its surface area and narrowing its pores. Since the volume of the covalently bonded nanoparticle 2 remains unchanged, the shrinking surface of the core 1 clamps the side of the nanoparticle 2 in contact with the core 1, or it is mechanically held in place by the shrinkage, forming a dual-anchoring structure of covalent anchoring and shrinkage embedding. The side facing away from the core 1 remains exposed for subsequent functionalization reactions. Thus, the fixation of the nanoparticle 2 on the core 1 is a dual anchoring structure formed by the covalent anchoring of S1 and the shrinkage embedding of S2. The covalent bonds provide chemical bonding force, and the shrinkage embedding provides mechanical holding force, making the nanoparticle 2 less prone to detachment under subsequent fluid shearing and chemical impact.

[0028] S3: The core 1 of the dual-anchored nanoparticle 2 is mixed with an aromatic boric acid compound containing reactive groups. The reactive groups react with the amino groups on the nanoparticle 2, and aromatic boric acid ligand 3 is grafted onto the nanoparticle 2 to obtain a functionalized core 1. The amino groups on the side of the nanoparticle 2 facing away from the core 1 do not participate in the covalent anchoring reaction of S1 and retain their reactivity. The reactive groups on the aromatic boric acid compound react with these amino groups to form covalent bonds, and aromatic boric acid ligand 3 is grafted onto the side of the nanoparticle 2 facing away from the core 1. Aromatic boric acid ligand 3 can specifically adsorb blood toxins containing cis-diols, and this adsorption binding is reversibly dissociated under mild alkaline conditions, providing a basis for the regeneration and recycling of the adsorbent material.

[0029] S4: The functionalized core 1 is contacted with a phosphorus-containing atom transfer radical polymerization initiator in a coordination organic solvent, allowing the initiator to coordinate with the defect sites on the metal nodes of nanoparticle 2, resulting in an initiator-supported core 1. The defect sites on the metal nodes of nanoparticle 2 are coordination active, and the phosphorus-containing initiator is anchored to these defect sites through the coordination of phosphorus with the metal. Since S3 has essentially consumed all accessible amino groups on nanoparticle 2, the phosphorus-containing initiator can only selectively coordinate with the defect sites. After anchoring through coordination bonds, the initiator can provide initiation sites for subsequent polymerization reactions.

[0030] S5: The initiator-supported core 1 is mixed with zwitterionic monomers, and the zwitterionic monomers are polymerized using the initiator to form zwitterionic polymer brush 4, which in turn forms an antifouling brush layer, resulting in a renewable blood perfusion adsorption material. The initiator, originating from regularly arranged sites on the unsaturated metal coordination nodes of nanoparticles 2, enables the grown polymer brushes to be densely and orderly arranged with regular spacing, further enhancing their interception and antifouling effects.

[0031] The highly stable, regenerative blood perfusion adsorbent material prepared by the above method includes a core 1 and several nanoparticles 2 dispersed and loaded on the surface and pore walls of the core 1. The nanoparticles 2 are made of an amino-functionalized metal-organic framework. The core 1 is a macroporous cross-linked polymer resin, and its surface and pore walls contain reactive functional groups that can react with amino groups. The nanoparticles 2 simultaneously contain amino groups and unsaturated metal coordination nodes. The side of the nanoparticles 2 in contact with the core 1 is embedded in the core 1 and is fixedly connected to the core 1 through covalent bonds formed by the reaction of the amino groups and reactive functional groups on that side. Several aromatic boric acid ligands 3 (formed after the reaction of aromatic boric acid compounds) are grafted onto the amino groups on the side of the nanoparticles 2 facing away from the core 1, forming a functional layer. Several zwitterionic polymers are grafted onto the unsaturated metal coordination nodes on the side of the nanoparticles 2 facing away from the core 1, forming an antifouling brush layer.

[0032] In this invention, a dual anchoring structure of covalent anchoring and shrinkage embedding is employed, enabling nanoparticles 2 to achieve a fixation strength far exceeding that of a single covalent bond or a single physical embedding. This ensures that the nanoparticles 2 do not detach under the continuous fluid shear force of blood perfusion and the chemical impact of regeneration and cleaning. Furthermore, the functional components and polymers selected in this invention exhibit high connection strength after being linked to the nanoparticles 2. Combined with the rigid framework anchoring points, which are less prone to wobbling, this results in high connection stability and strength between the functional components and the brush layer. Simultaneously, the regular arrangement of the metal-organic framework's crystal skeleton allows for an orderly alternating distribution of the functional components and the brush layer. This ensures that the aromatic boric acid ligands 3 adhere tightly to the particle surface, protected by the brush layer, while the densely arranged polymer brushes synergistically resist fluid shear and form a size barrier. The combination of these two factors significantly enhances the overall stability of the adsorbent material of this invention. During regeneration and cleaning, the functional layer and brush layer are less likely to detach or be damaged, and the cleaning solution can fully contact and wash away bound toxins, resulting in a higher regeneration recovery rate and more regeneration cycles.

[0033] It should be noted that in this invention, the core 1 is a macroporous cross-linked polymer resin. This resin itself has a certain non-specific adsorption capacity. Its polymer skeleton, through hydrophobic interactions and van der Waals forces, exhibits broad-spectrum adsorption of some toxins and metabolic wastes in the blood, playing a role in comprehensive clearance. Aromatic boric acid ligand 3 specifically adsorbs toxins containing cis-diol through the reversible binding of boric acid and cis-diol, playing a role in targeted clearance. The porous structure of nanoparticles 2 also assists in the adsorption of small molecule toxins. The three adsorption mechanisms are different, and their adsorption targets are different, forming a synergistic adsorption pattern in the material that complements broad-spectrum comprehensive clearance and targeted adsorption. This allows the material to have both sufficient adsorption capacity and high selective clearance efficiency for specific types of toxins. At the same time, it should be understood that the naming of the structure formed by aromatic boric acid ligand 3 and zwitterionic polymer as a functional layer and an anti-fouling brush layer in this invention does not mean that they are two separate hierarchical structures. In this application, these two structures partially overlap in spatial scale, and the use of two separate names is only for ease of understanding.

[0034] Furthermore, it should be noted that in this invention, unsaturated metal coordination nodes can also be called metal node defect sites, specifically referring to the active sites on the metal nodes where organic ligands are unsaturated in coordination. These sites are not undesirable defects in the material preparation process, but rather controllable structural features actively introduced through methods such as solvothermal methods assisted by regulators. Their existence enables zirconium nodes to have open coordination sites that can be used to coordinate with phosphorus-containing initiators.

[0035] Optionally, in S1, the core 1 is obtained by copolymerization of a styrene-based matrix monomer and a reactive monomer containing reactive functional groups, wherein the reactive functional group is at least one of halomethyl and epoxy groups. Both halomethyl and epoxy groups are highly reactive electrophilic groups that can undergo nucleophilic substitution or ring-opening reactions with the amino groups on nanoparticles 2 under heating conditions to form covalent bonds. The reaction conditions are mild and there are few side reactions.

[0036] Furthermore, in S1, the core 1 is copolymerized from polystyrene, divinylbenzene, and chloromethylstyrene. Preferably, the copolymerization ratio (molar ratio) of styrene is 82-91%, the copolymerization ratio of divinylbenzene is 6-10%, and the copolymerization ratio of chloromethylstyrene is 3-8%. The proportion of chloromethylstyrene needs to be controlled within the range of 3-8%. If the proportion is too low, the density of chloromethyl sites on the surface and pore walls of the core 1 will be insufficient, resulting in fewer covalent bonds formed between the nanoparticles 2 and the core 1, and weak chemical anchoring. If the proportion is too high, there will be more residual chloromethyl groups, and excessive chloromethylstyrene participation in copolymerization will also affect the crosslinking network structure and mechanical strength of the core 1. Divinylbenzene provides the crosslinking framework, and its proportion affects the rigidity and swelling properties of the core 1. If the proportion is too low, the degree of crosslinking of the core 1 will be insufficient, making it difficult to recover after excessive expansion in the swelling solvent, resulting in poor shrinkage embedding effect. If the proportion is too high, the core 1 will be too rigid, the swelling range will be insufficient, and the nanoparticles 2 will not be able to fully enter the intersegmental spaces.

[0037] Optionally, in S1, the macropore size of the core 1 is 200-300 nm. By controlling the pore size of the core 1, the anchoring effect of the nanoparticles 2 is ensured while avoiding problems such as excessively low specific surface area and insufficient number of effectively embedded nanoparticles 2. If the pore size is too small, the nanoparticles 2 may have difficulty entering the pores in the swollen state, failing to contact and react with the chloromethyl sites on the pore walls. This results in the nanoparticles 2 only adhering to the outer surface of the core 1 and not dispersing on the pore walls, significantly reducing the effective anchoring area. If the pore size is too large, the lower specific surface area will also lead to a smaller effective anchoring area.

[0038] Optionally, in S1, nanoparticle 2 is an amino-functionalized zirconium-based metal-organic framework. Specifically, the amino-functionalized zirconium-based metal-organic framework uses zirconium as the metal node. The amino groups in the framework provide reaction sites for covalent bonding with the chloromethyl core 1 and subsequent grafting of aromatic boric acid ligand 3. Zirconium and phosphorus-containing groups have high affinity, and the defect sites on the zirconium nodes can efficiently bind with phosphorus-containing initiators to form stable coordination anchoring sites. The two types of sites are chemically different and their functions do not interfere with each other. Further, the zirconium-based metal-organic framework is at least one of the amino-functionalized UiO-66 series and UiO-67 series metal-organic frameworks, more preferably UiO-66-NH2. The UiO-66 series, such as UiO-66-NH2, has good chemical stability and biocompatibility. The amount of zirconium ions dissolved under physiological conditions is extremely low, making it essentially harmless to the human body and more suitable for blood contact scenarios. The UiO-67 series has larger pore windows, suitable for scenarios requiring the containment of larger volume functional components.

[0039] Optionally, in S1, the particle size of nanoparticle 2 is 20-60 nm. The particle size of nanoparticle 2 needs to match the pore size of the core 1: if the particle size is too large, it cannot enter the channels of the swollen core 1 or adheres to the sides of the channels, causing pore closure; it can only anchor on the outer surface of the core 1, resulting in uneven distribution of nanoparticle 2 and low effective loading. If the particle size is too small, nanoparticle 2 may detach from the retracted channels or be completely encapsulated during the contraction in S2, and the number of amino and defect sites on individual nanoparticle 2 is small, resulting in insufficient capacity to carry functional components. The particle size range of 20-60 nm allows nanoparticle 2 to enter the 200-300 nm channels after swelling and fully contact and react with the chloromethyl sites on the pore walls, while preventing it from detaching from or being encapsulated after contraction.

[0040] Optionally, in step S1, the core 1 is dispersed in a swelling organic solvent and swelled for 2-4 hours, allowing it to fully expand from a dry state to a swelling equilibrium state, fully opening the pores so that the nanoparticles 2 can contact the chloromethyl sites on the surface of the core 1 and in its swollen or accessible chain segments. Then, nanoparticles 2 and a first acid-binding agent are added, and the reaction is carried out under heating conditions for 12-24 hours, allowing the amino groups on the nanoparticles 2 to fully react with the chloromethyl sites on the core 1, forming a sufficient number of covalent bonds to ensure the strength of the chemical anchoring. Then, the unfixed, free nanoparticles 2 are washed away, ensuring that only the anchored nanoparticles 2 participate in the functionalization reaction in subsequent steps, resulting in a chemically anchored core 1 containing nanoparticles 2. The first acid-binding agent is used to neutralize acidic byproducts (such as hydrochloric acid) generated during the reaction of amino and chloromethyl groups, preventing the accumulation of acidic byproducts from adversely affecting the metal-organic framework structure of the nanoparticles 2, and simultaneously promoting the reaction towards covalent bond formation.

[0041] Optionally, in S1, the organic solvent used for swelling is a polar aprotic solvent. Polar aprotic solvents have excellent swelling effects on polystyrene-divinylbenzene resin and do not undergo side reactions with the amino groups on nanoparticles 2 or the chloromethyl groups on the core 1. The solvent can be selected according to the actual situation. In this invention, the organic solvent used for swelling preferably includes at least one of dimethyl sulfoxide and N-methylpyrrolidone.

[0042] Optionally, in S1, the first acid-binding agent should be able to ensure a stable reaction environment and prevent side reactions. In this invention, the first acid-binding agent preferably includes at least one of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, and sodium carbonate, and can be selected as appropriate.

[0043] Optionally, prior to S1, nanoparticles 2 are prepared via the following steps: Zirconium salt, an amino-containing organic ligand, and a modifier were mixed in a solvent and reacted under heating conditions to obtain amino-functionalized metal-organic framework nanoparticles 2.

[0044] In this process, zirconium salts provide zirconium nodes, organic ligands containing amino groups (such as 2-aminoterephthalic acid) provide organic ligands and introduce amino groups, and the modifier is a monodentate carboxylic acid (monodentate carboxylic acid ligand) that can coordinate with zirconium ions. During the reaction, it competes with the organic ligands containing amino groups for coordination sites of zirconium nodes. After occupying some coordination sites, it is removed in the subsequent washing process, leaving uncoordinated and saturated zirconium nodes, i.e. defect sites.

[0045] Optionally, the type of amino-containing organic ligand is determined according to the type of the target metal-organic framework. The regulator is at least one of acetic acid and formic acid. Both acetic acid and formic acid are monodentate carboxylic acids, and their coordination ability with zirconium ions is weaker than that of bidentate carboxyl-type organic ligands such as 2-aminoterephthalic acid. They reversibly occupy coordination sites during the reaction and are easily removed after washing. By adjusting the molar ratio of the regulator to the amino-containing organic ligand, the proportion of defect sites can be further controlled. A higher regulator ratio results in more intense competition for coordination and a larger proportion of defect sites in the product. In this invention, optionally, in S1, 10% to 50% of the surface metal clusters in nanoparticle 2 are unsaturated defect sites. If the regulator ratio is too low, the proportion of defect sites is less than 10%, resulting in fewer sites available for subsequent initiator coordination, insufficient brush layer grafting density, and poor anti-fouling effect. If the proportion of regulator is too high, the defect site ratio will exceed 50%, which may damage the crystal structure integrity of the metal-organic framework, significantly reduce the chemical stability and mechanical strength of the particles, and may also degrade the framework itself under perfusion and regeneration conditions, thus failing to provide a stable binding basis.

[0046] Optionally, in S1, when washing nanoparticles 2, conventional organic solvents (such as methanol) can be used to wash them multiple times to remove unreacted raw materials and free regulators.

[0047] Optionally, in S2, nanoparticles 2 require activation before use: nanoparticles 2 are dispersed in conventional organic solvents such as methanol or ethanol at 60-70℃ and activated under vacuum for 4-12 hours. Then, they are washed again with conventional organic solvents such as methanol or ethanol to remove the coordinated acetic acid terminals, thereby activating the unsaturated metal coordination nodes. It should be noted that since nanoparticles 2 are usually prepared in advance, if they are not used directly after preparation, activation is not required; activation can be performed before actual use.

[0048] Optionally, in S2, the swelling organic solvent mixed with the core 1 of the chemically anchored nanoparticles 2 is gradually replaced with a shrinking solvent, causing the core 1 to shrink and embed the nanoparticles 2, thus obtaining the core 1 of the dual-anchored nanoparticles 2. It is necessary to gradually replace the solvent rather than directly transferring the core 1 to the shrinking solvent. This method ensures a smooth shrinkage process for the core 1, with the surface of the core 1 shrinking uniformly, uniformly binding the contact sides of the nanoparticles 2. Both covalent bonds and embedding forces are well maintained, preventing rapid shrinkage of the core 1 surface due to sudden solvent changes, which could generate internal stress, damage the formed covalent bonds, or cause microcracks in the core 1.

[0049] Optionally, in S2, the shrinkage solvent is a poor solvent for the resin of core 1, which can cause the swollen resin to shrink and retract without breaking the formed covalent bonds. Optionally, the shrinkage solvent includes at least one of methanol, ethanol, and water, as long as the shrinkage effect is ensured.

[0050] Optionally, in S2, specifically, the stepwise replacement involves sequentially transferring the core 1 of the chemically anchored nanoparticles 2 to mixed solutions of different grades of swelling organic solvents and shrinkage solvents. The volume fraction of the swelling organic solvent in each grade of the mixed solution decreases progressively. The core 1 is held in each solution for 1-2 hours to allow it to gradually shrink. Finally, it is transferred to a pure shrinkage solvent, where the core 1 shrinks gently, embedding and fixing the nanoparticles 2, thus obtaining the core 1 of the dual-anchored nanoparticles 2. Further, the volume fraction gradient of the swelling organic solvent in each grade of the mixed solution is 75%, 50%, and 25%. The core is held in each solution for 1-2 hours before finally being transferred to a pure shrinkage solvent.

[0051] Optionally, after S2 and before grafting the aromatic boric acid ligand 3 in S3, a passivation treatment is required: the core 1 of the dual-anchored nanoparticle 2 is mixed with a conversion reagent and reacted at room temperature for 1-2 hours to convert the remaining reactive functional groups on the core 1 into inert groups before proceeding with the subsequent S3 treatment. If the residual chloromethyl group is not removed, the aromatic boric acid compound may react directly with the chloromethyl group on the surface of the core 1 in S3, causing the aromatic boric acid ligand 3 to bypass the nanoparticle 2 and graft onto the surface of the core 1, failing to obtain the stable connection base provided by the rigid framework of the nanoparticle 2. Similarly, in S4 and S5, the initiator and brush layer may also be mistakenly attached to the surface of the core 1 instead of the nanoparticle 2. The passivation step hydrolyzes the residual chloromethyl group into hydroxymethyl group, rendering it electrophilic and ensuring that the functional components and brush layer in subsequent steps are only attached to the nanoparticle 2.

[0052] Optionally, the conversion reagent in the passivation step is an alkaline alcoholic solution, including at least one of sodium hydroxide methanol solution, sodium hydroxide ethanol solution, and potassium hydroxide ethanol solution. The alkaline concentration in the conversion reagent is from 0.005 to 0.05 M. The alkaline concentration needs to be controlled within an appropriate range: if the concentration is too low, the chloromethyl group will not hydrolyze completely, and residual reactive sites will not be completely eliminated. If the concentration is too high, the strongly alkaline environment may cause the zirconium-oxygen coordination bonds of nanoparticle 2 to be eroded, destroying the framework structure of the metal-organic framework.

[0053] Optionally, in step S3, the passivated dual-anchored nanoparticle 2 core 1 is dispersed in a reaction solvent, an aldehyde-containing aromatic boric acid compound is added, and the mixture is heated under reflux for 6-24 hours to form a Schiff base. A reducing agent is then added to reduce the imine to a carbon-nitrogen covalent bond, and the mixture is washed to obtain the functionalized core 1. Under reflux conditions, the aldehyde group of the aromatic boric acid compound undergoes a condensation reaction with the amino group retained on the side of the nanoparticle 2 opposite to the core 1, forming an imine bond, i.e., a Schiff base. A reducing agent is then added to reduce the imine bond to a secondary amine bond. Unreduced Schiff bases may undergo hydrolytic breakage under the weakly acidic or neutral environment of blood perfusion, leading to the detachment of the aromatic boric acid ligand 3. The reduced secondary amine bond in this application is chemically stable under these conditions, ensuring the long-term reliability of the connection between the functional layer and the nanoparticle 2. The 6-24 hour reaction time allows for sufficient condensation of the amino and aldehyde groups, ensuring a sufficiently complete grafting density of the aromatic boric acid ligand 3.

[0054] Optionally, in S3, the reaction solvent is an alcohol solvent, including at least one of ethanol and isopropanol. Alcohol solvents do not damage the structure of nanoparticle 2 or the anchored covalent bonds, and can dissolve aromatic boric acid compounds to ensure sufficient contact between them and the amino groups on nanoparticle 2, thus ensuring the grafting effect.

[0055] Optionally, in S3, the aromatic boric acid compound containing the reactive group is at least one of phenylboronic acid containing an aldehyde group and phenylboronic acid containing a carboxyl group. Further, the aromatic boric acid ligand 3 is at least one of 4-formylphenylboronic acid, 3-formylphenylboronic acid, and 4-carboxyphenylboronic acid. The aldehyde groups of 4-formylphenylboronic acid and 3-formylphenylboronic acid condense with the amino group on nanoparticle 2 to form a Schiff base, exhibiting high reactivity and mild reaction conditions. In contrast, the carboxyl group of 4-carboxyphenylboronic acid requires a condensing agent (such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and possibly an activator such as N-hydroxysuccinimide to accelerate the reaction; these auxiliary substances can be determined by those skilled in the art as needed) to form an amide bond. The reaction conditions are slightly more demanding, but the resulting amide bond exhibits superior chemical stability and is less prone to hydrolysis under physiological conditions. The appropriate ligand can be selected based on the specific circumstances. Optionally, the reducing agent in S3 can be at least one of sodium borohydride and sodium cyanoborohydride, as long as it can carry out effective reduction.

[0056] Optionally, in step S4, the functionalized core 1 is dispersed in a coordination organic solvent, and a phosphorus-containing initiator and a second acid-binding agent are added. The reaction is carried out at room temperature, and the mixture is washed to obtain the initiator-loaded core 1. The zirconium node defect sites of the nanoparticles 2 on the functionalized core 1 coordinate with the phosphorus groups of the phosphorus-containing initiator to form Zr-OP coordination bonds, anchoring the initiator to the surface of the nanoparticles 2. Zirconium has a high coordination affinity for phosphorus-containing groups, and the Zr-OP coordination bonds formed are stable and not easily broken under physiological conditions, providing stable initiation sites for the subsequent growth of the brush layer. Furthermore, the above reaction can achieve coordination bonding at room temperature without heating, avoiding the adverse effects of high temperatures on the grafted aromatic boric acid ligand 3 and the structure of the nanoparticles 2. The second acid-binding agent is also used to neutralize any acidic byproducts that may be generated during the coordination reaction, protecting the metal-organic framework structure of the nanoparticles 2 from corrosion. Finally, uncoordinated free initiator is removed by washing to ensure that the polymerization reaction in step S5 is initiated only from the anchored initiation sites.

[0057] Optionally, in S4, the organic solvent for coordination is selected from anhydrous ethanol, dimethyl sulfoxide, or mixtures thereof. Anhydrous ethanol is a mild solvent that can achieve coordination between the initiator and the defect sites without damaging the structure of nanoparticle 2 and the grafted aromatic boric acid ligand 3, and the anhydrous condition avoids competition between water and phosphorus groups for zirconium node coordination sites; dimethyl sulfoxide is suitable for initiators with low solubility, and its swelling effect on nanoparticle 2 is beneficial for the initiator to enter the pores and contact the internal defect sites.

[0058] Optionally, in S4, the phosphorus-containing initiator is an atom transfer radical polymerization initiator containing a phosphate group or a phosphonate group. In this invention, the phosphorus-containing initiator is preferably at least one of 2-bromoisobutyryloxyethyl phosphate, 2-bromoisobutyryloxyethyl phosphonic acid, and 2-bromoisobutyryloxypropylphosphonic acid. These initiators simultaneously contain a phosphate group or a phosphonate group and an α-bromoisobutyrate group. The phosphate group or phosphonate group is responsible for coordinating and anchoring with the zirconium node defect site, while the α-bromoisobutyrate group can serve as an initiation site for atom transfer radical polymerization, initiating zwitterionic monomer polymerization under the action of the catalytic system in subsequent S5, ensuring the stability of the anchoring.

[0059] Optionally, in S4, the second acid-binding agent is selected from at least one of triethylamine, N,N-diisopropylethylamine and pyridine, which can effectively inhibit the acidic environment.

[0060] Optionally, in S5, the initiator-supported core 1, zwitterionic monomers, and atom transfer radical polymerization catalytic system are mixed in a polar solvent and reacted at 25-40°C for 2-8 hours to obtain a zwitterionic polymer brush layer 4 based on the initiator. After the reaction, the residue of the atom transfer radical polymerization catalytic system is washed away. The catalytic system activates the α-bromoisobutyrate groups on the initiator to generate active free radicals, which initiate the zwitterionic monomers to grow directionally from the initiation site outwards, forming a zwitterionic polymer brush layer 4 with the rigid framework of nanoparticles 2 as hard anchoring points. The mild temperature condition of 25-40°C ensures that the catalytic system has sufficient catalytic activity to allow the polymerization reaction to proceed at a controllable rate, while avoiding problems such as uncontrolled free radical concentration, excessively wide polymer molecular weight distribution, or damage to the structure of nanoparticles 2 due to excessively high temperatures. The reaction time of 2-8 hours is also sufficient for the brush layer to grow to a sufficient length to form a dense hydration barrier, while avoiding excessively dense brush layers that would hinder the passage of small molecule toxins due to excessively long reaction times.

[0061] Optionally, in S5, the polar solvent is at least one of methanol, ethanol, isopropanol, and water. The polar solvent can dissolve the zwitterionic monomer and the components of the catalytic system, ensuring dispersibility and stability.

[0062] Optionally, in S5, the atom transfer radical polymerization catalytic system can be a catalytic system including copper bromide, a nitrogen-containing ligand, and a reducing agent; or a catalytic system including cuprous bromide and a nitrogen-containing ligand; or a zero-valent copper catalytic system; or an organic photocatalytic system. It should be noted that the above-mentioned catalytic systems are all commonly used in the field, and this invention does not impose strict requirements on the catalyst system, as long as it can effectively catalyze and ensure that the residues of related substances meet the standards or are absent. In the above systems, in the combination of copper bromide, nitrogen-containing ligand, and reducing agent (i.e., the commonly used ARGET-ATRP catalytic system), copper bromide is continuously regenerated into a catalytically active species under the action of the reducing agent, resulting in low copper usage and low residue levels. The combination of cuprous bromide and nitrogen-containing ligand is a conventional ATRP catalytic system with mature technology and good controllability. In the zero-valent copper catalytic system, zero-valent copper slowly releases cuprous ions during the reaction, resulting in even lower copper residue levels. The organic photocatalytic system does not require metal participation, fundamentally avoiding metal residue problems and is suitable for applications with strict limitations on metal residue. Those skilled in the art can choose and implement the appropriate catalytic method.

[0063] Optionally, when using a catalytic system containing copper ions, the nitrogen-containing ligand is N,N,N',N'',N''-pentamethyldiethylenetriamine or tris(2-pyridylmethyl)amine, as long as it can effectively catalyze the reaction. The reducing agent is at least one of ascorbic acid or sodium gluconate, as long as the reduction efficiency is ensured. The zwitterionic monomer is at least one of methacrylic acid sulfobetaine, methacrylic acid carboxybetaine, or 2-methacryloyloxyethylphosphocholine. The polymer brushes formed after polymerization of the above monomers all have strong hydration capabilities and can form a dense hydration layer on the brush surface, effectively blocking the non-specific adsorption of substances such as proteins and platelets.

[0064] Optionally, in S5, when the catalytic system contains copper ions, the resulting adsorbent material is washed with a chelating agent after the polymerization reaction. The chelating agent is disodium ethylenediaminetetraacetate (EDTA). Disodium EDTA has a strong complexing ability for copper ions, which can wash away residual copper ions from the material surface and pores, further reducing the metal residue in the material and ensuring the safety of the material when used in blood contact.

[0065] Optionally, the particle size of the regenerative blood perfusion adsorbent material prepared by this invention is 0.5-1.5 mm. If the particle size of the regenerative blood perfusion adsorbent material is too small, the resistance of blood flowing through the adsorption column during perfusion increases, which may lead to a decrease in perfusion efficiency and a risk of hemolysis. If the particle size is too large, the specific surface area of ​​the core 1 per unit volume decreases, resulting in insufficient total area for anchoring nanoparticles 2, which may affect the adsorption capacity.

[0066] To better understand the above technical solutions, exemplary embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although exemplary embodiments of the present invention are shown in the drawings, it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that the present invention can be understood more clearly and thoroughly, and that the scope of the present invention can be fully conveyed to those skilled in the art.

[0067] Example 1: This embodiment provides a highly stable renewable blood perfusion adsorbent material and its preparation method, including the following steps: Raw material preparation: Zirconium chloride and 2-aminoterephthalic acid were dissolved in dimethyl sulfoxide at a molar ratio of 1:1. Acetic acid was added as a regulator, and the molar ratio of acetic acid to 2-aminoterephthalic acid was 30:1. The reaction was carried out at 120℃ for 24 hours. The solid was collected by centrifugation and washed three times with methanol to obtain UiO-66-NH2 nanoparticles 2 with a particle size of approximately 30-50 nm. The number of defect sites after activation was approximately 30%.

[0068] S1: Commercially available polystyrene-divinylbenzene-chloromethylstyrene copolymer resin (styrene:divinylbenzene:chloromethylstyrene copolymer ratio of 87:7:6, pore size 250nm, particle size 0.8mm) was dispersed in dimethyl sulfoxide and swollen for 3 hours; pre-prepared UiO-66-NH2 nanoparticles 2 and triethylamine were added, with a molar ratio of triethylamine to chloromethyl groups on the resin of 2:1, and the reaction was carried out at 80℃ for 18 hours. The unfixed nanoparticles 2 were removed by washing with dimethyl sulfoxide to obtain the core 1 of chemically anchored nanoparticles 2.

[0069] S2: The core 1 of the chemically anchored nanoparticle 2 is sequentially transferred to a dimethyl sulfoxide-methanol mixture with a volume fraction of 75%, 50%, and 25% dimethyl sulfoxide. Each stage is held for 1.5 hours to allow the core 1 to gradually shrink. Finally, it is transferred to pure methanol to allow the core 1 to shrink gently and embed and fix the nanoparticle 2, thus obtaining the core 1 of the dual-anchored nanoparticle 2.

[0070] S3: First, passivation is performed: the core 1 of the dual-anchored intrinsic nanoparticle 2 is mixed with a 0.02M sodium hydroxide methanol solution, reacted at room temperature for 1.5 hours, and then washed with methanol.

[0071] The passivated core 1 was then dispersed in ethanol, and 4-formylphenylboronic acid was added. The molar ratio of 4-formylphenylboronic acid to the residual amino group on nanoparticle 2 was 3:1. The mixture was heated under reflux for 12 hours to form a Schiff base. After cooling, sodium borohydride was added. The molar ratio of sodium borohydride to 4-formylphenylboronic acid was 2:1. The Schiff base was reduced by stirring at room temperature for 4 hours. The mixture was then washed with ethanol to obtain the functionalized core 1.

[0072] S4: Functionalized core 1 was dispersed in anhydrous ethanol, and 2-(α-bromoisobutyryloxy)ethylphosphonic acid and triethylamine were added. The molar ratio of triethylamine to initiator was 2:1. The reaction was carried out at room temperature for 12 hours, and the mixture was washed with ethanol to obtain initiator-supported core 1.

[0073] S5: The initiator-supported core 1, methyl methacrylate sulfobetaine ester monomer, copper bromide, N,N,N',N'',N''-pentamethyldiethylenetriamine, and ascorbic acid were mixed in a methanol / water mixture with a volume ratio of 3:1. The molar ratio of copper bromide to monomer was 0.02:1, the molar ratio of nitrogen-containing ligand to copper bromide was 1:1, and the molar ratio of ascorbic acid to copper bromide was 2:1. The mixture was reacted at 30°C for 6 hours. After the reaction, the copper residue was removed by washing with EDTA disodium aqueous solution, followed by washing with deionized water to obtain the regenerative blood perfusion adsorbent material of this embodiment. The structural relationship between the core and nanoparticles is as follows: Figure 1 As shown, the microstructure is as follows Figure 2 As shown.

[0074] Example 2: This embodiment provides a highly stable regenerative blood perfusion adsorbent material and its preparation method. The only difference from Example 1 is that the aromatic boric acid compound in S3 is replaced by 4-carboxyphenylboronic acid instead of 4-formylphenylboronic acid, and the reaction conditions are changed from Schiff base reduction to amide condensation: the passivated core 1 is dispersed in ethanol, and 4-carboxyphenylboronic acid, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and N-hydroxysuccinimide are added. The molar ratio of 4-carboxyphenylboronic acid to the residual amino group on nanoparticle 2 is 3:1; the molar ratio of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide to 4-carboxyphenylboronic acid is 1.5:1; and the molar ratio of N-hydroxysuccinimide to 4-carboxyphenylboronic acid is 1.5:1. The reaction is carried out at room temperature for 24 hours to form amide bonds. The mixture is then washed with ethanol to obtain the functionalized core 1. The remaining steps are the same as in Example 1.

[0075] Example 3: This embodiment provides a highly stable regenerative blood perfusion adsorbent material and its preparation method. The only difference between this embodiment and Example 1 is that nanoparticles 2 are replaced with UiO-66-NH2 instead of UiO-67-NH2: Zirconium chloride and 2-amino-4,4'-biphenyldicarboxylic acid are dissolved in dimethyl sulfoxide at a molar ratio of 1:1. Acetic acid is added as a modifier, and the molar ratio of acetic acid to 2-amino-4,4'-biphenyldicarboxylic acid is 30:1. The reaction is carried out at 120°C for 24 hours. The solid is collected by centrifugation and washed three times with methanol to obtain UiO-67-NH2 nanoparticles 2. The remaining steps are the same as in Example 1.

[0076] Example 4: This embodiment provides a highly stable renewable blood perfusion adsorbent material and its preparation method. The only difference between this embodiment and Example 1 is that when preparing nanoparticles 2, the molar ratio of acetic acid to 2-aminoterephthalic acid is 50:1, and the defect site ratio of the obtained nanoparticles 2 is about 45%. The remaining steps are the same as in Example 1.

[0077] Example 5: This embodiment provides a highly stable regenerative blood perfusion adsorbent material and its preparation method. The only difference between this embodiment and Example 1 is that the passivation step is omitted: after S2 contraction, S3 is performed directly without treatment with an alkaline alcohol solution. The remaining steps are the same as in Example 1.

[0078] Comparative Example 1: This comparative example provides a blood perfusion adsorbent material and its preparation method. The only difference between this example and Example 1 is that S2 is omitted. That is, after covalent anchoring in S1, the core 1 is directly washed with methanol without the step of gradually replacing the solvent to shrink, followed by passivation and subsequent steps. The remaining steps are the same as in Example 1.

[0079] Comparative Example 2: This comparative example provides a blood perfusion adsorption material and its preparation method. The difference from Example 1 is that the introduction of nanoparticles 2 is different: UiO-66-NH2 nanoparticles 2 are directly mixed into the copolymerization reaction system of the core 1. During the preparation of the core 1, the nanoparticles 2 are dispersed in the monomer solution and polymerized together, so that the nanoparticles 2 are wrapped inside the resin matrix as part of the resin, and the core 1 coated with nanoparticles 2 is obtained. Then, based on this, S3 and subsequent steps are carried out. The material ratio and reaction conditions of each step are the same as those in Example 1.

[0080] Comparative Example 3: This comparative example provides a blood perfusion adsorption material and its preparation method. The only difference between this material and Example 1 is that the macropore size of the core 1 is 150 nm and the particle size of the nanoparticles 2 is 80-100 nm. The remaining steps are the same as in Example 1.

[0081] Comparative Example 4: This comparative example provides a blood perfusion adsorbent material and its preparation method. The only difference between this material and Example 1 is that the core 1 is not pre-swollen in S1: the dry core 1, nanoparticles 2, and acid-binding agent are directly added to dimethyl sulfoxide and reacted at 80°C for 18 hours. The remaining steps are the same as in Example 1.

[0082] The performance of the renewable blood perfusion adsorbent materials obtained in the above embodiments and comparative examples was tested according to the following methods: 1. Toxin Adsorption Performance and Anti-Protein Contamination Performance: The adsorbent material was packed into a glass perfusion column with an inner diameter of 15 mm. Phosphate buffer containing glycated albumin (500 mg / L) and bovine serum albumin (BSA, 40 g / L) was used as simulated serum. The perfusion was carried out at 37 °C at a flow rate of 1 column bed volume per minute for 2 hours. The concentrations of glycated albumin and BSA were measured before and after perfusion. The adsorption capacity of glycated albumin (mg / g) and the adsorption amount of BSA (mg / g) were calculated respectively. The results are shown in Table 1.

[0083] 2. Anchoring stability of nanoparticles: The adsorbent material was packed into a glass perfusion column with an inner diameter of 15 mm. Physiological saline was circulated through the perfusion column at a flow rate of 50 times the column bed volume for 4 hours. The flow rate was 1 times the column bed volume per minute. The zirconium ion concentration of the circulating liquid was measured, and the Zr shedding rate (%) was calculated. The results are shown in Table 1.

[0084] 3. Regeneration cycle performance: After adsorption is completed according to step 1, the adsorption is eluted with 0.1M sodium bicarbonate solution (pH 8.5) at room temperature with a solid-liquid ratio of 1:20 for 60 minutes. After washing with deionized water, the adsorption experiment is repeated according to step 1. This cycle is repeated 10 times. The regeneration recovery rate after 10 cycles is calculated as (10th adsorption capacity / first adsorption capacity × 100%). The results are shown in Table 1.

[0085] Table 1: Statistical Table of Performance Test Results of Renewable Blood Perfusion Adsorbent Materials

[0086] As can be seen from the above, Example 1 employs the dual anchoring strategy of swelling-covalent anchoring-shrinkage embedding of the present invention. By having the amino groups and defect sites on the nanoparticles 2 respectively undertake the grafting functions of the functional layer and the brush layer, the nanoparticles 2 are firmly fixed on the surface of the core 1 and the pore walls, and the functional components and the brush layer are firmly connected to the rigid skeleton and arranged in an orderly manner. As a result, the material has a high adsorption capacity for glycated albumin and strong resistance to protein contamination. The shedding rate of the nanoparticles 2 is also extremely low. After 10 cycles of 60 min each, the material as a whole still maintains a high recovery rate. This indicates that the material of Example 1 has good regeneration and recycling performance and can achieve a relatively long service life while ensuring the cleaning effect.

[0087] Example 2 uses 4-carboxyphenylboronic acid to graft the functional layer via amide condensation. The amide bond has excellent chemical stability, but the grafting density at room temperature is lower than that of the Schiff base reduction method. Therefore, the adsorption capacity of glycated albumin is slightly reduced, but the cycle recovery rate remains at a high level, indicating that the amide bond can also ensure the stable connection of the functional layer under regeneration conditions.

[0088] In Example 3, UiO-67-NH2 was used instead of UiO-66-NH2. UiO-67 has a larger pore window and a higher specific surface area, making it easier for functional components to reach the internal sites of nanoparticle 2. The accessibility of amino and defect sites is better, and its adsorption capacity of glycated albumin is improved, while the adsorption capacity of BSA is slightly reduced. However, the biphenyl ligand is longer than that of terephthalic acid, and the rigidity of the skeleton is slightly reduced. The Zr shedding rate is slightly increased, and the cycle recovery rate is slightly reduced, but it still remains at a good level.

[0089] Example 4 increased the proportion of defect sites to about 45%, increased the grafting density of the brush layer, improved the anti-protein contamination effect, and further reduced the BSA adsorption capacity; however, too many defect sites led to a decrease in the rigidity of the metal-organic framework, a slight increase in the Zr shedding rate, and a certain decrease in the stability of aromatic boric acid ligand 3. In addition, the excessively dense brush layer may also have a certain steric hindrance effect on the diffusion of toxin molecules to the aromatic boric acid ligand 3 site, resulting in a slight decrease in the adsorption capacity of glycated albumin and a slight decrease in the cycle recovery rate. However, the overall performance remained at a good level.

[0090] Example 5 omitted the passivation step, and the residual chloromethyl group on the core 1 was not eliminated. This may cause the aromatic boric acid ligand 3 and the brush layer to be mistakenly attached to the surface of the core 1 instead of the rigid framework of the nanoparticle 2. The anchoring points of the functional components on the flexible chain segments will swing, and the chemical bonds will loosen and fall off under repeated pulling, resulting in a significant reduction in the cycle recovery rate. The brush layer mistakenly attached to the surface of the core 1 is arranged in a disordered manner, and the anti-protein contamination effect is greatly reduced. The mistaken attachment of some aromatic boric acid ligand 3 to the surface of the core 1 also leads to insufficient grafting density of the functional layer on the nanoparticle 2, and a reduction in the adsorption capacity of glycated albumin.

[0091] Comparative Example 1 omitted the gradual shrinkage process, and after covalent anchoring in S1, the core 1 was directly placed in methanol for one-step shrinkage. Sudden shrinkage may cause the core 1 chain segments to tighten instantaneously, and some nanoparticles 2 to be squeezed out by the sudden shrinkage force, resulting in uneven and insufficient embedding. Although nanoparticles 2 are still covalently anchored to the core 1, the mechanical holding force is insufficient, and they are still easy to gradually loosen and fall off under the perfusion shear force. The Zr detachment rate is higher than that of Example 1. With the increase of the number of cycles, the accumulation of detachment leads to the gradual loss of the functional layer and brush layer, resulting in a lower glycated albumin adsorption capacity and cycle recovery rate than that of Example 1.

[0092] In Comparative Example 2, nanoparticles 2 were directly mixed into the resin matrix during the copolymerization stage. Most of the nanoparticles 2 were encapsulated inside the matrix and could not effectively contact the blood. The total amount of usable stable functional layers and brush layers was extremely low. The functional layers and brush layers mainly relied on their connection with the core 1 itself and were easy to detach. The small number of nanoparticles 2 exposed on the surface were only physically encapsulated and fixed without covalent bond anchoring, and may easily detach. Moreover, the high temperature and free radical environment during the copolymerization process also destroyed the skeleton structure of some nanoparticles 2, resulting in a comprehensive and significant deterioration of various properties.

[0093] In Comparative Example 3, the pore size of the core 1 was reduced to 150 nm and the particle size of the nanoparticles 2 was increased to 80-100 nm. After swelling, the nanoparticles 2 could only barely enter some of the pores and may cause blockage. Most of them remained on the outer surface of the core 1, and the contact area with the pore wall was greatly reduced. The number of covalent bond anchoring points was insufficient, the embedding was not firm, the shedding rate of nanoparticles 2 was significantly increased, the total amount of functional layer and brush layer was insufficient and unevenly distributed, the adsorption capacity of glycated albumin was greatly reduced, and the anti-protein contamination effect and cycle recovery rate were also significantly reduced.

[0094] In Comparative Example 4, the core 1 was not pre-swollen in S1. After the dry core 1 was directly added to the solvent, the chain segments failed to fully relax and expand in a short time. The nanoparticles 2 could not enter the pores of the core 1 and contact the reactive functional group sites on the pore walls. During shrinkage, the embedding force was weak due to insufficient penetration. A large number of nanoparticles 2 fell off, and the functional layer and brush layer were lost. All properties decreased significantly.

[0095] In summary, the present invention can effectively solve the technical problems of poor anti-pollution and anti-washing ability and short cycle life of blood perfusion materials in the prior art.

[0096] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A highly stable, renewable blood perfusion adsorbent material, characterized in that, It includes a base core (1) and nanoparticles (2) loaded on the surface and pore walls of the base core (1); the nanoparticles (2) are amino-functionalized metal-organic framework materials; The core (1) is a macroporous cross-linked polymer resin, and its surface and pore walls contain reactive functional groups that can react with amino groups; the surface of the nanoparticle (2) contains amino groups and unsaturated metal coordination nodes; the side of the nanoparticle (2) that is in contact with the core (1) is embedded in the core (1), and the amino groups on it react with the reactive functional groups to form covalent bonds; the nanoparticle (2) is also grafted with aromatic boric acid ligands (3) to form a functional layer; zwitterionic polymer brushes (4) are grafted onto the unsaturated metal coordination nodes on the side of the nanoparticle (2) facing away from the core (1) to form an antifouling brush layer.

2. The highly stable renewable blood perfusion adsorbent material according to claim 1, characterized in that, The core (1) is obtained by copolymerization of styrene matrix monomers and reactive monomers containing reactive functional groups, wherein the reactive functional groups are at least one of halomethyl and epoxy groups; The unsaturated metal coordination nodes are metal nodes in a metal-organic framework that are unsaturated in coordination; the nanoparticles (2) are amino-functionalized zirconium-based metal-organic framework materials. The aromatic boric acid ligand (3) contains a reactive group, which is used to react with the amino group of the nanoparticle (2) to form a covalent bond; the reactive group is at least one of aldehyde and carboxyl groups.

3. The highly stable renewable blood perfusion adsorbent material according to claim 2, characterized in that, The adsorbent material has a particle size of 0.5-1.5 mm; the macropores in the core (1) have a pore size of 200-300 nm; the nanoparticles (2) have a particle size of 20-60 nm; and among the metal nodes on the surface of the nanoparticles (2), unsaturated metal coordination nodes account for 10% to 50% of the total number of metal nodes. The core (1) is a copolymer of polystyrene, divinylbenzene and chloromethylstyrene, wherein the copolymerization ratio of chloromethylstyrene is 3% to 8%; the zirconium-based metal-organic framework material is at least one of the UiO-66 series and the UiO-67 series.

4. The highly stable renewable blood perfusion adsorbent material according to claim 2, characterized in that, The aromatic boric acid ligand (3) is at least one of 4-formylphenylboronic acid, 3-formylphenylboronic acid and 4-carboxyphenylboronic acid, which is covalently grafted onto the amino group on the side of the nanoparticle (2) facing away from the core (1) by Schiff base reduction or amide condensation, and is used to identify glycoprotein toxins containing cis-diol in the blood. The zwitterionic polymer is at least one of polymethyl methacrylate sulfobetaine, polymethyl methacrylate carboxybetaine and poly-2-methacryloyloxyethyl phosphocholine, which is connected to the unsaturated metal coordination nodes of the nanoparticles (2) through Zr-OP coordination bonds.

5. A method for preparing a highly stable regenerative blood perfusion adsorbent material according to any one of claims 1 to 4, characterized in that, Includes the following steps: S1: The core (1) is placed in an organic solvent for swelling to swell the core (1); then the nanoparticles (2) are brought into contact with the swollen core (1), and then heated to allow the amino groups on the nanoparticles (2) to react with the reactive functional groups in the core (1) to form covalent bonds, thus obtaining the core (1) of the anchored nanoparticles (2). S2: Place the core (1) of the anchored nanoparticle (2) in a shrinkage solvent to shrink the core (1) and embed the nanoparticle (2) into the surface and pore walls of the core (1) to obtain the core (1) of the double anchored nanoparticle (2). S3: Mix the core (1) of the dual-anchored nanoparticle (2) with an aromatic boric acid ligand (3) containing reactive groups, so that the reactive groups react with the amino groups on the nanoparticle (2), and graft the aromatic boric acid ligand (3) onto the nanoparticle (2) to obtain the functionalized core (1). S4: The functionalized core (1), the organic solvent for coordination, and the atom transfer radical polymerization initiator containing phosphorus groups are mixed to allow the phosphorus groups to undergo a coordination reaction with the unsaturated metal coordination nodes on the surface of the nanoparticles (2) to obtain the initiator-supported core (1). S5: The initiator-supported core (1) is mixed with zwitterionic monomers, and the zwitterionic monomers are polymerized into zwitterionic polymer brushes (4) by initiating the initiator to form an anti-fouling brush layer, thereby obtaining a renewable blood perfusion adsorption material.

6. The method for preparing the highly stable renewable blood perfusion adsorbent material according to claim 5, characterized in that, In step S1, the core (1) is dispersed in an organic solvent for swelling and swelled for 2-4 hours. Then, nanoparticles (2) and a first acid-binding agent are added, and the mixture is reacted under heating conditions for 12-24 hours. After washing to remove the unfixed nanoparticles (2), the core (1) anchored to the nanoparticles (2) is obtained. The organic solvent for swelling is a polar aprotic solvent, including at least one of dimethyl sulfoxide and N-methylpyrrolidone. The first acid-binding agent is at least one of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, and sodium carbonate.

7. The method for preparing the highly stable renewable blood perfusion adsorbent material according to claim 5, characterized in that, In step S2, the core (1) of the anchored nanoparticle (2) is placed in a solution with progressively increasing concentration of shrinkage solvent to shrink the core (1) and embed the nanoparticle (2) to obtain the core (1) of the double anchored nanoparticle (2); the shrinkage solvent is a poor solvent for the resin of the core (1), including at least one of methanol, ethanol and water.

8. The method for preparing the highly stable renewable blood perfusion adsorbent material according to claim 5, characterized in that, In step S3, the core (1) of the dual-anchored nanoparticles (2) is dispersed in the reaction solvent, aromatic boric acid ligand (3) is added, and the mixture is heated under reflux for 6-24 hours to form a Schiff base. Then, a reducing agent is added to carry out a reduction reaction to convert the imine into a carbon-nitrogen covalent bond. After washing, the functionalized core (1) is obtained. The reaction solvent is an alcohol solvent, including at least one of ethanol and isopropanol; the reducing agent is at least one of sodium borohydride and sodium cyanoborohydride.

9. The method for preparing the highly stable renewable blood perfusion adsorbent material according to claim 5, characterized in that, In step S4, the functionalized core (1) is dispersed in a coordination organic solvent, an initiator containing a phosphate group and a second acid-binding agent are added, and the reaction is carried out at room temperature. After the reaction is completed, the core (1) is washed to obtain the initiator-supported core (1). The coordination organic solvent is selected from at least one of anhydrous ethanol and dimethyl sulfoxide; the phosphorus-containing initiator is an atom transfer radical polymerization initiator containing a phosphate group or a phosphonic acid group, including at least one of 2-bromoisobutyryloxyethyl phosphate, 2-bromoisobutyryloxyethyl phosphonic acid and 2-bromoisobutyryloxypropylphosphonic acid; the second acid-binding agent is selected from at least one of triethylamine, N,N-diisopropylethylamine and pyridine.

10. The method for preparing the highly stable renewable blood perfusion adsorbent material according to claim 5, characterized in that, In step S5, the initiator-supported core (1), zwitterionic monomer and atom transfer radical polymerization catalysis system are mixed in a polar solvent and reacted at 25-40℃ for 2-8 hours to obtain a zwitterionic polymer brush (4) layer; after the reaction is completed, the material is washed to remove harmful residues and obtain a regenerable blood perfusion adsorption material. The polar solvent is at least one of methanol, ethanol, isopropanol, and water; the atom transfer radical polymerization catalytic system is a catalytic system including copper bromide, nitrogen-containing ligands, and reducing agents, including a catalytic system of cuprous bromide and nitrogen-containing ligands, a zero-valent copper catalytic system, or an organic photocatalytic system. The nitrogen-containing ligand is N,N,N',N'',N''-pentamethyldiethylenetriamine or tris(2-pyridylmethyl)amine; the reducing agent is at least one of ascorbic acid or sodium gluconate; the zwitterionic monomer is at least one of methacrylic acid sulfobetaine, methacrylic acid carboxybetaine or 2-methacryloyloxyethylphosphocholine.

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