Metal organic framework composite adsorbent, preparation method thereof and blood perfusion device

Abstract

The application provides a metal organic framework composite adsorbent, a preparation method thereof and a blood perfusion device, and belongs to the technical field of blood purification adsorption materials. The metal organic framework composite adsorbent provided by the application is a metal organic framework material-polysulfone material composite ball. The metal organic framework material has excellent adsorption for various toxins, the polysulfone material has good biocompatibility, mechanical strength, processing adaptability and sterilization capacity, so that the metal organic framework composite adsorbent has good blood compatibility and adsorption for toxins, and the adsorbent has less particle shedding, and is suitable for the field of whole blood perfusion. The results of examples show that the metal organic framework composite adsorbent provided by the application has excellent adsorption performance for p-cresol sulfate, indole acetic acid, bilirubin, bile acid and endotoxin, and shows excellent blood compatibility.

Description

Technical Field

[0001] This invention relates to the field of blood purification adsorption materials technology, and in particular to a metal-organic framework composite adsorbent, its preparation method, and a blood perfusion device. Background Technology

[0002] Blood perfusion adsorbents can remove contaminants such as toxins, drugs, and metabolites by non-specific or specific adsorption, thereby purifying the blood. Currently, common adsorbent materials used in blood perfusion adsorbents include activated carbon and resins. These materials can effectively adsorb and remove harmful substances such as toxins, metabolites, and immune complexes from the blood, and have wide applications in areas such as kidney disease, liver disease, immune disorders, drug overdose, and critical care.

[0003] However, clinical treatment and scientific research experiments have revealed that the aforementioned adsorbent materials generally suffer from problems such as insufficient adsorption capacity for target toxins and inadequate blood compatibility. Taking adsorbent materials for uremic hemoperfusion as an example, existing commercially available perfusion devices primarily use cross-linked polystyrene macroporous adsorbent resin, which has limited effectiveness in adsorbing and clearing uremic protein-bound toxoids. Furthermore, due to its brittle cross-linking properties, cross-linked polystyrene macroporous adsorbent resin is prone to particle shedding, affecting its blood safety. Similarly, for plasma bilirubin adsorbents used in hyperbilirubinemia and hyperbile acidemia caused by various diseases, existing commercially available products mainly use ion exchange resins with positively charged quaternary ammonium salt groups, but their blood compatibility is poor, making them unsuitable for whole blood perfusion. Therefore, effectively improving the blood compatibility of adsorbent materials and enhancing their adsorption performance for uremic protein-bound toxoids, bilirubin, and bile acids is a crucial research direction in the field of hemoperfusion adsorbent materials.

[0004] Metal-organic frameworks (MOFs) are a class of porous materials formed by the self-assembly of organic ligands and metal centers. MOF materials, with their regular porous structure and tunable chemical properties, possess excellent adsorption performance and hold significant potential value in the field of hemoperfusion. However, MOF materials often exist in the form of nano- or micron-sized powder particles, limiting their application in hemoperfusion; furthermore, the clustering effect of tiny MOF particles reduces the material's adsorption performance for target substances. Therefore, MOF materials and related products for hemoperfusion are currently rare. Summary of the Invention

[0005] The purpose of this invention is to provide a metal-organic framework composite adsorbent, its preparation method, and a blood perfusion device. The metal-organic framework composite adsorbent provided by this invention has good blood compatibility and excellent adsorption performance for different toxins.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a metal-organic framework composite adsorbent, wherein the metal-organic framework composite adsorbent is a metal-organic framework material-polysulfone material composite sphere, and the mass ratio of metal-organic framework material to polysulfone material in the metal-organic framework material-polysulfone material composite sphere is (1-10):(10-22).

[0008] Preferably, the metal-organic framework-polysulfone composite spheres are spherical or near-spherical particles, and the particle size of the metal-organic framework-polysulfone composite spheres is 0.1 to 2.5 mm.

[0009] Preferably, the metal-organic framework material includes one or more of calcium-based metal-organic frameworks, modified calcium-based metal-organic framework derivatives, zirconium-based metal-organic frameworks, and modified zirconium-based metal-organic framework derivatives.

[0010] Preferably, the modifiers of the calcium-based metal-organic framework modified derivatives and the zirconium-based metal-organic framework modified derivatives independently include one or more of polyethyleneimine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, 1,3-propanediamine, ethylenediamine, 3-dimethylaminopropylamine, tris(2-aminoethyl)amine, N,N'-di-n-propylethylenediamine, N,N-diethylethylenediamine, N,N-dibutylethylenediamine, N,N-dimethylethylenediamine, tris(3-aminopropyl)amine, 2,2'-diamino-N-methyldiethylamine, 3-diethylaminopropylamine, N'N-bis(3-aminopropyl)methylamine, 1,5-diaminopentane, N,N-diethyldivinyltriamine, 1,6-hexanediamine, and polyethylenepolyamine.

[0011] Preferably, the polysulfone material includes one or more of polysulfone, polyethersulfone, sulfonated polyethersulfone, and polyarylsulfone.

[0012] This invention also provides a method for preparing the metal-organic framework composite adsorbent described in the above technical solution, comprising the following steps:

[0013] (1) A good solvent, polysulfone material, additives and metal-organic framework material are mixed to obtain a blended modified solution;

[0014] (2) The blended modified solution obtained in step (1) is dropped into a non-good solvent of polysulfone material to perform phase separation and obtain a metal-organic framework composite adsorbent.

[0015] Preferably, the good solvent in step (1) includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

[0016] Preferably, the additives in step (1) include one or more of polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, water, ethylene glycol, n-propanol, isopropanol, glycerin, ethylene glycol methyl ether, and lithium chloride.

[0017] Preferably, the non-good solvent for the polysulfone material in step (2) includes a mixed solution of water and an organic solvent or water, wherein the organic solvent includes one or more of dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide and N-methyl-2-pyrrolidone.

[0018] The present invention also provides a blood perfusion device, wherein the adsorbent of the blood perfusion device is the metal-organic framework composite adsorbent described in the above technical solution or the metal-organic framework composite adsorbent prepared by the preparation method described in the above technical solution.

[0019] This invention provides a metal-organic framework (MOF) composite adsorbent, which is a composite sphere of MOF material and polysulfone material, wherein the mass ratio of MOF material to polysulfone material in the MOF-polysulfone composite sphere is (1-10):(10-22). The MOF-polysulfone composite adsorbent provided by this invention has excellent adsorption properties for various toxins, while the polysulfone material has good biocompatibility, mechanical strength, processing adaptability, and sterilization ability. This results in the MOF-polysulfone composite sphere exhibiting good blood compatibility and toxin adsorption, with minimal adsorbent particle shedding, making it suitable for whole blood perfusion. Example results show that the MOF-polysulfone composite adsorbent provided by this invention has excellent adsorption performance for p-cresol sulfate, indoleacetic acid, bilirubin, bile acids, and endotoxins, and exhibits excellent blood compatibility. Attached Figure Description

[0020] Figure 1 The infrared spectrum of the calcium-based metal-organic framework prepared in Example 1 of this invention;

[0021] Figure 2 The N2 adsorption-desorption isotherm of the calcium-based metal-organic framework prepared in Example 1 of this invention;

[0022] Figure 3 The pore size distribution curve of the calcium-based metal-organic framework prepared in Example 1 of this invention;

[0023] Figure 4 The infrared spectrum of the zirconium-based metal-organic framework prepared in Example 2 of this invention;

[0024] Figure 5 The N2 adsorption-desorption isotherm of the zirconium-based metal-organic framework prepared in Example 2 of this invention;

[0025] Figure 6 The pore size distribution curve of the zirconium-based metal-organic framework prepared in Example 2 of this invention;

[0026] Figure 7 The infrared spectrum of the zirconium-based metal-organic framework prepared in Example 3 of this invention;

[0027] Figure 8 The N2 adsorption-desorption isotherm of the zirconium-based metal-organic framework powder prepared in Example 3 of this invention;

[0028] Figure 9 The pore size distribution curve of the zirconium-based metal-organic framework powder prepared in Example 3 of this invention;

[0029] Figure 10 A photograph of the metal-organic framework composite adsorbent prepared in Example 11 of this invention;

[0030] Figure 11 A photograph of the metal-organic framework composite adsorbent prepared in Example 12 of this invention;

[0031] Figure 12 A photograph of the metal-organic framework composite adsorbent prepared in Example 13 of this invention. Detailed Implementation

[0032] This invention provides a metal-organic framework composite adsorbent, wherein the metal-organic framework composite adsorbent is a composite sphere of metal-organic framework material and polysulfone material.

[0033] In this invention, the mass ratio of metal-organic framework material to polysulfone material in the metal-organic framework-polysulfone composite sphere is (1-10):(10-22). In embodiments of this invention, the mass ratio of metal-organic framework material to polysulfone material can specifically be: 2:21, 1.5:20, 3:20, 1:20, 8:15, 2:22, 10:10, or 3:21. The metal-organic framework composite adsorbent provided by this invention uses polysulfone material as a carrier, dispersing the metal-organic framework material therein. This solves the problem of decreased adsorption performance caused by metal-organic framework material powder agglomeration, and also solves the problem of poor blood compatibility of metal-organic framework material powder. Simultaneously, it also solves the problem of poor toxin adsorption performance of polysulfone material, thereby enabling the metal-organic framework composite adsorbent to have good adsorption performance and blood compatibility for toxins. By controlling the mass ratio of metal-organic framework material to polysulfone material within the above range, this invention enables the adsorbent to maintain good adsorption, blood compatibility, and mechanical properties.

[0034] In this invention, the metal-organic framework-polysulfone composite spheres are preferably spherical or near-spherical particles, and the particle size of the metal-organic framework-polysulfone composite spheres is preferably 0.1–2.5 mm, more preferably 0.8–1.4 mm. In embodiments of this invention, the particle size of the metal-organic framework-polysulfone composite spheres can specifically be 0.9 mm, 1.0 mm, 1.2 mm, or 1.4 mm. This invention controls the particle size of the metal-organic framework-polysulfone composite spheres within the above-mentioned range, which is more advantageous for use as an adsorbent in hemoperfusion devices.

[0035] In this invention, the polysulfone material preferably includes one or more of polysulfone, polyethersulfone, sulfonated polyethersulfone, and polyarylsulfone, more preferably polysulfone, polyethersulfone, or sulfonated polyethersulfone. The polysulfone material used in this invention exhibits good blood compatibility.

[0036] In this invention, the metal-organic framework material preferably includes one or more of calcium-based metal-organic frameworks, modified calcium-based metal-organic framework derivatives, zirconium-based metal-organic frameworks, and modified zirconium-based metal-organic framework derivatives, and more preferably calcium-based metal-organic frameworks or modified calcium-based metal-organic framework derivatives.

[0037] In this invention, the preferred method for preparing the calcium-based metal-organic framework includes: mixing an organic ligand, a calcium source, solvent A, and a regulator to obtain a precursor solution; and subjecting the precursor solution to a coordination reaction to obtain calcium-based metal-organic framework powder.

[0038] The present invention preferably involves mixing an organic ligand, a calcium source, solvent A, and a regulator to obtain a precursor solution.

[0039] In this invention, the organic ligand preferably includes one or more of terephthalic acid, 2-aminoterephthalic acid, isophthalic acid, 2-hydroxyterephthalic acid, 4-hydroxyisophthalic acid, 2,5-dihydroxyterephthalic acid, and 2,5-diaminoterephthalic acid, more preferably terephthalic acid, 2-aminoterephthalic acid, or isophthalic acid. This invention utilizes the above-mentioned organic ligands to construct metal-organic framework powders with excellent adsorption properties.

[0040] In this invention, the calcium source preferably includes one or more of calcium chloride, calcium nitrate, and calcium carbonate, and more preferably calcium chloride. This invention uses the above-mentioned calcium source to provide calcium ions, so that the prepared metal-organic framework is a calcium-based metal-organic framework material.

[0041] In this invention, solvent A preferably includes one or more of water, ethanol, methanol, isopropanol, and butanol. In embodiments of this invention, when solvent A is a mixture of multiple solvents, solvent A can specifically be a mixed solvent composed of ethanol and water, wherein the mass ratio of ethanol to water can be 30:20 or 20:40. This invention uses the above-mentioned solvent to provide a suitable reaction environment for the coordination reaction.

[0042] In this invention, the regulator preferably includes one or more of sodium hydroxide, potassium hydroxide, acetylacetone, formic acid, acetic acid, and hydrochloric acid, more preferably sodium hydroxide, potassium hydroxide, or hydrochloric acid. By employing the above-mentioned regulator, this invention can adjust the crystal structure, pore size, and surface chemical properties of metal-organic framework materials, thereby improving the quality of these materials.

[0043] In this invention, the molar ratio of the calcium source, organic ligand, and regulator is preferably 1:(0.2-3):(0.01-50), more preferably 1:1:(1-5). By controlling the molar ratio of the calcium source, organic ligand, and regulator within the above range, this invention can adjust the crystallinity, molecular orientation, and structural morphology of the metal-organic framework material, thereby improving its adsorption performance.

[0044] In this invention, the mass ratio of the organic ligand to solvent A is preferably 1:(1-100), more preferably 1:(20-80). By controlling the mass ratio of the organic ligand to solvent A within the above range, this invention can promote the full progress of the coordination reaction.

[0045] The present invention does not have any particular limitation on the method of mixing the organic ligand, calcium source, solvent A and regulator, as long as each component can be completely dissolved in the solvent.

[0046] After obtaining the precursor solution, the present invention preferably performs a coordination reaction on the precursor solution to obtain metal-organic framework powder.

[0047] In this invention, the temperature of the coordination reaction can be 40–105°C or 80–95°C; in embodiments of this invention, the temperature of the coordination reaction can specifically be 80°C, 90°C, or 95°C. In this invention, the time of the coordination reaction can be 3–48 hours or 12–24 hours. In this invention, the coordination reaction is preferably carried out under normal pressure. This invention controls the temperature and time of the coordination reaction within the above-mentioned ranges, which is more conducive to the complete progress of the coordination reaction.

[0048] The present invention preferably involves washing and drying the solid product obtained from the coordination reaction to obtain calcium-based metal-organic framework powder. The present invention does not specify any particular method for washing and drying; conventional washing and drying methods that can adequately remove impurities and moisture from the solid product are acceptable.

[0049] In this invention, the preferred method for preparing the zirconium-based metal-organic framework includes: mixing an organic ligand, a zirconium source, solvent A, and a regulator to obtain a precursor solution; and subjecting the precursor solution to a coordination reaction to obtain zirconium-based metal-organic framework powder.

[0050] In this invention, the zirconium source preferably includes one or more of zirconium oxychloride octahydrate, zirconium chloride, zirconium nitrate, zirconium sulfate, zirconium acetylacetonate, and zirconium n-propoxide, more preferably zirconium oxychloride octahydrate, zirconium chloride, or zirconium nitrate. This invention uses the above-mentioned zirconium source to provide zirconium ions for metal-organic framework materials.

[0051] In this invention, the method for preparing zirconium-based metal-organic frameworks differs from the method for preparing calcium-based metal-organic frameworks described above in that a zirconium source is used instead of a calcium source. The remaining operations and parameters are the same as those for preparing calcium-based metal-organic frameworks, and will not be repeated here.

[0052] In this invention, the preferred method for preparing the calcium-based metal-organic framework modified derivative includes:

[0053] Calcium-based metal-organic framework powder, solvent B and graft anchoring agent are mixed and subjected to a first stirring reaction to obtain a metal-organic framework material containing graft anchoring agent.

[0054] The metal-organic framework material containing the grafted anchoring agent, the modifier, and solvent C are mixed and subjected to a second stirring reaction to obtain a calcium-based metal-organic framework modified derivative.

[0055] The present invention preferably involves mixing calcium-based metal-organic framework powder, solvent B, and graft anchoring agent, and carrying out a first stirring reaction to obtain a metal-organic framework material containing graft anchoring agent.

[0056] In this invention, solvent B preferably comprises one or more of water, ethanol, and methanol. This invention utilizes solvent B to provide a suitable reaction environment for the reaction.

[0057] In this invention, the grafting anchoring agent preferably includes one or more of tannic acid, dopamine, 3-bromopropionic acid, 3-chloropropionic acid, and 2-chloropropionic acid, more preferably tannic acid, dopamine, or 3-bromopropionic acid. By adding a grafting anchoring agent, this invention facilitates the grafting of modifiers onto metal-organic framework materials.

[0058] The present invention does not have any particular limitation on the method of mixing the calcium-based metal-organic framework powder, solvent B and graft anchoring agent, as long as the above components are fully dispersed in solvent B.

[0059] In this invention, the pH value of the system obtained by mixing the calcium-based metal-organic framework powder, solvent B, and graft anchoring agent is preferably 5-10, more preferably 6.5-8. This invention does not specifically limit the reagent used to adjust the pH value; any conventional adjusting reagent that can bring the pH value of the system to the above range is acceptable. Controlling the pH value of the system within the above range in this invention is more conducive to promoting the full reaction between the metal-organic framework powder and the graft anchoring agent.

[0060] In this invention, the temperature of the first stirring reaction can be 50–90°C or 50–80°C; in embodiments of this invention, the temperature of the first stirring reaction can specifically be 50°C, 60°C, 75°C, or 80°C. In this invention, the time of the first stirring reaction can be 6–48 hours; in embodiments of this invention, the time of the first stirring reaction can specifically be 6 hours, 12 hours, 24 hours, 32 hours, or 48 hours. Under the above conditions, the stirring in this invention enables the metal-organic framework powder and the grafted anchoring agent to react fully.

[0061] The present invention preferably involves washing the solid obtained after the first stirring reaction to obtain a metal-organic framework material containing a grafted anchoring agent. The washing method is not particularly limited in the present invention, as long as it can remove impurities from the reaction-obtained solid.

[0062] After obtaining the metal-organic framework material containing the grafted anchoring agent, the present invention preferably mixes the metal-organic framework material containing the grafted anchoring agent, the modifier and solvent C, and carries out a second stirring reaction to obtain a calcium-based metal-organic framework modified derivative.

[0063] In this invention, the modifier preferably includes one or more of polyethyleneimine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, 1,3-propanediamine, ethylenediamine, 3-dimethylaminopropylamine, tris(2-aminoethyl)amine, N,N'-di-n-propylethylenediamine, N,N-diethylethylenediamine, N,N-dibutylethylenediamine, N,N-dimethylethylenediamine, tris(3-aminopropyl)amine, 2,2'-diamino-N-methyldiethylamine, 3-diethylaminopropylamine, N'N-bis(3-aminopropyl)methylamine, 1,5-diaminopentane, N,N-diethyldiethylenetriamine, 1,6-hexanediamine, and polyethylenepolyamine, more preferably polyethyleneimine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, 1,3-propanediamine, ethylenediamine, or 3-dimethylaminopropylamine. The present invention uses the above-mentioned modifier, which can introduce amine groups into the metal-organic framework, which is more conducive to improving the adsorption performance of the adsorbent.

[0064] In this invention, solvent C preferably includes one or more of water, ethanol, and methanol. This invention uses solvent C to provide a suitable reaction environment for the reaction.

[0065] In this invention, the preferred mass ratio of the metal-organic framework powder, solvent B, graft anchoring agent, modifier, and solvent C is 1:(3-100):(0.1-3):(0.1-5):(5-100), more preferably 1:(5-80):(1-3):(1-5):(10-500). By limiting the amount of each component within the above range, this invention enables the modifier to be fully grafted onto the metal-organic framework material.

[0066] The present invention does not have any particular limitation on the method of mixing the metal-organic framework material containing the grafted anchoring agent, the modifier and the solvent C, as long as the components are mixed evenly.

[0067] In this invention, the temperature of the second stirring reaction can be 40–90°C or 40–80°C; in embodiments of this invention, the temperature of the second stirring reaction can specifically be 40°C, 50°C, 60°C, 70°C, or 80°C. In this invention, the time of the second stirring reaction can be 6–48 hours; in embodiments of this invention, the time of the second stirring reaction can specifically be 6 hours, 12 hours, 24 hours, or 48 hours. Under the above conditions, the stirring of this invention enables the metal-organic framework powder containing the grafted anchoring agent and the modifier to react fully.

[0068] Preferably, the product obtained from the second stirring reaction is washed and dried sequentially to obtain the calcium-based metal-organic framework modified derivative. The washing and drying methods are not particularly limited; conventional washing and drying methods are sufficient to remove impurities and moisture from the calcium-based metal-organic framework modified derivative.

[0069] In this invention, the preferred method for preparing the zirconium-based metal-organic framework modified derivative includes:

[0070] Zirconium-based metal-organic framework powder, solvent B and graft anchoring agent are mixed and subjected to a first stirring reaction to obtain a metal-organic framework material containing graft anchoring agent.

[0071] The metal-organic framework material containing the grafted anchoring agent, the modifier, and solvent C are mixed and subjected to a second stirring reaction to obtain a zirconium-based metal-organic framework modified derivative.

[0072] In this invention, the preparation method of the zirconium-based metal-organic framework modified derivative differs from the preparation method of the calcium-based metal-organic framework modified derivative described in the above technical solution in that zirconium-based metal-organic framework powder is used instead of calcium-based metal-organic framework powder. The remaining steps are the same as the preparation method of the calcium-based metal-organic framework modified derivative described in the above technical solution, and will not be repeated here.

[0073] The metal-organic framework composite adsorbent provided by this invention is a composite sphere of metal-organic framework material and polysulfone material. The metal-organic framework material has excellent adsorption properties for various toxins, and the polysulfone material has good biocompatibility, mechanical strength, processing adaptability and sterilization ability. This makes the metal-organic framework composite adsorbent have good blood compatibility and adsorption properties for toxins, and the adsorbent particles detach less.

[0074] This invention also provides a method for preparing the metal-organic framework composite adsorbent described in the above technical solution, comprising the following steps:

[0075] (1) A good solvent, polysulfone material, additives and metal-organic framework material are mixed to obtain a blended modified solution;

[0076] (2) The blended modified solution obtained in step (1) is dropped into a non-good solvent of polysulfone material to perform phase separation and obtain a metal-organic framework composite adsorbent.

[0077] This invention involves mixing a good solvent, polysulfone material, additives, and metal-organic framework material to obtain a blended modified solution.

[0078] In this invention, the preferred solvent comprises one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. The above-mentioned solvents exhibit good solubility for polysulfone materials.

[0079] In this invention, the additive preferably includes one or more of polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, water, ethylene glycol, n-propanol, isopropanol, glycerin, ethylene glycol methyl ether, and lithium chloride, and more preferably includes polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, water, or ethylene glycol. This invention stabilizes the mixture through the additive.

[0080] In this invention, the metal-organic framework material preferably includes one or more of calcium-based metal-organic frameworks, modified calcium-based metal-organic frameworks, zirconium-based metal-organic frameworks, and modified zirconium-based metal-organic frameworks.

[0081] In this invention, the preferred mass ratio of the good solvent, polysulfone material, additive, and metal-organic framework material is 100:(10-35):(0-5):(0.01-10), more preferably 100:(15-30):(1-4):(1-8). By controlling the amount of each component within the above range, this invention can control the exchange rate between the solvent and the unsuitable solvent, thereby affecting the structure and properties of the porous membrane of the metal-organic framework composite adsorbent, and giving the metal-organic framework composite adsorbent good adsorption properties.

[0082] In this invention, the preferred method for mixing the good solvent, polysulfone material, additives and metal-organic framework material is as follows: dissolve the polysulfone material and additives in the good solvent, add the metal-organic framework material to the obtained solution, stir and mix evenly, and then let it stand to remove bubbles to obtain a blended modified solution.

[0083] After obtaining the blended modified solution, the present invention adds the blended modified solution dropwise into a non-good solvent of polysulfone material to perform phase separation, thereby obtaining a metal-organic framework composite adsorbent.

[0084] In this invention, the non-good solvent preferably comprises a mixed solution of water and an organic solvent or water, wherein the organic solvent preferably comprises one or more of dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, and N-methyl-2-pyrrolidone. In this invention, when the non-good solvent is a mixed solution of water and an organic solvent, the volume ratio of water to organic solvent is preferably 1:(0-1), more preferably 1:(0.05-0.2).

[0085] When the above-mentioned solvent is used in this invention, it is a poor solution for polysulfone material, which can cause non-solvent-induced phase separation when mixed with the blending modification liquid to form metal-organic framework material-polysulfone material composite spheres.

[0086] In this invention, the method of dripping the blended modified solution into a non-good solvent of the polysulfone material is preferably microfluidic injection. This invention enables the blended modified solution to form droplets in air via microfluidic injection, which then drip into a non-good solvent to undergo phase inversion, forming microspheres of uniform size. This invention does not impose any particular limitation on the microfluidic injection device; a conventional microfluidic injector is sufficient. In embodiments of this invention, the microfluidic injector enables the metal-organic framework-polysulfone composite spheres to achieve a particle size of 0.1–2.5 mm.

[0087] The preparation method provided by this invention is simple and easy to operate, and can obtain metal-organic framework-polysulfone composite spheres with uniform particle size distribution, which are metal-organic framework composite adsorbents.

[0088] The present invention also provides a blood perfusion device, wherein the adsorbent of the blood perfusion device is the metal-organic framework composite adsorbent described in the above technical solution or the metal-organic framework composite adsorbent prepared by the preparation method described in the above technical solution.

[0089] This invention does not specify a particular model of hemoperfusion device; any conventional hemoperfusion device can be used. The metal-organic framework composite adsorbent provided by this invention possesses excellent mechanical stability, blood compatibility, and good adsorption capacity for toxins. Therefore, it can be used to replace the adsorbent in conventional hemoperfusion devices, exhibiting excellent adsorption performance for bilirubin, bile acids, and endotoxins, and demonstrating excellent blood compatibility, making it suitable for whole blood perfusion.

[0090] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0091] Example 1

[0092] A method for preparing a calcium-based metal-organic framework is as follows: terephthalic acid is dissolved in water, and sodium hydroxide and calcium nitrate are added sequentially and mixed evenly to obtain a precursor solution; under normal pressure, the precursor solution is heated and stirred at 95°C for 12 hours to carry out a coordination reaction; the solid obtained from the reaction is washed and dried to obtain calcium-based metal-organic framework powder; wherein the molar ratio of calcium nitrate, terephthalic acid, and sodium hydroxide is 1:1:2.2; and the mass ratio of terephthalic acid to water is 1:15.

[0093] The calcium-based metal-organic framework powder prepared in this embodiment is a white powder, and its infrared spectrum is shown below. Figure 1 As shown, from Figure 1 As can be seen, at 624cm -1 Characteristic peaks of Ca-O bonds appear at 1500–1700 cm⁻¹; -1 Characteristic peaks of carbonyl groups appear within the range of 1500–1300 cm⁻¹. -1 Characteristic peaks of carboxyl groups appear within the range.

[0094] The N2 adsorption-desorption isotherm of the calcium-based metal-organic framework powder prepared in this embodiment is as follows: Figure 2 As shown, the pore size distribution curve is as follows: Figure 3 As shown. The specific surface area of ​​the zirconium-based metal-organic framework powder prepared in this embodiment is 25.9 m². 2 / g, total pore volume is 0.08cm³ 3 / g, with an average pore size of 12.06nm.

[0095] Example 2

[0096] A method for preparing a zirconium-based metal-organic framework is as follows:

[0097] Terephthalic acid was dissolved in ethanol, and then water, acetic acid, and zirconium chloride were added and mixed evenly to obtain a precursor solution. Under normal pressure, the precursor solution was heated and stirred at 80°C for 12 hours to carry out a coordination reaction. The solid obtained from the reaction was washed, purified, and dried to obtain zirconium-based metal-organic framework powder.

[0098] The molar ratio of zirconium chloride, terephthalic acid, and acetic acid is 1:1:1; the mass ratio of terephthalic acid, ethanol, and water is 1:30:20.

[0099] The zirconium-based metal-organic framework powder prepared in this embodiment is a white powder, and its infrared spectrum is as follows: Figure 4 As shown, from Figure 4 As can be seen, at 1509 and 1573cm -1 1680cm -1 Characteristic peaks attributable to the C=C bond vibration of the benzene ring in terephthalic acid and the characteristic peak of the carbonyl group are observed. Additionally, at 565 cm⁻¹... -1 The presence of characteristic peaks belonging to Zr-O at this location confirms the successful preparation of zirconium-based metal-organic framework powder in this embodiment.

[0100] The N2 adsorption-desorption isotherm of the zirconium-based metal-organic framework powder prepared in this embodiment is as follows: Figure 5 As shown, the pore size distribution curve is as follows: Figure 6 As shown. The specific surface area of ​​the zirconium-based metal-organic framework powder prepared in this embodiment is 1176 m². 2 / g, total pore volume is 0.49cm³ 3 / g, with an average pore size of 1.69nm.

[0101] Example 3

[0102] A method for preparing a zirconium-based metal-organic framework is as follows: 2-aminoterephthalic acid is dissolved in ethanol, and then water, acetic acid, and zirconium oxychloride octahydrate are added and mixed evenly to obtain a precursor solution; under normal pressure, the precursor solution is heated and stirred at 90°C for 24 hours; after the reaction is completed, the obtained solid is washed and dried to obtain zirconium-based metal-organic framework powder.

[0103] The molar ratio of zirconium oxychloride octahydrate, 2-aminoterephthalic acid and acetic acid is 1:1:2; the mass ratio of 2-aminoterephthalic acid, ethanol and water is 1:20:40.

[0104] The zirconium-based metal-organic framework powder prepared in this embodiment is a light brown powder, and its infrared spectrum is as follows. Figure 7 As shown, from Figure 7 It can be seen that 3419cm -1 The broad peak at 1257 cm⁻¹ is due to the overlap of characteristic peaks of NH and OH. -1 The characteristic peak is attributed to CN; at 1568 cm⁻¹ -1 1427cm -1 and 1387cm -1 Asymmetric and symmetric vibration peaks belonging to the carboxylate anion appear respectively.

[0105] The N2 adsorption-desorption isotherm of the zirconium-based metal-organic framework powder prepared in this embodiment is as follows: Figure 8 As shown, the pore size distribution curve is as follows: Figure 9 As shown. The specific surface area of ​​the zirconium-based metal-organic framework powder prepared in this embodiment is 1293 m². 2 / g, total pore volume is 0.60cm³ 3 / g, with an average pore size of 1.85nm.

[0106] Example 4

[0107] A method for preparing a calcium-based metal-organic framework modified derivative: 10g of the calcium-based metal-organic framework powder prepared in Example 1 is dispersed in 500g of water, 5g of tannic acid is added, the pH is adjusted to 6.5, and the mixture is stirred and reacted at 50℃ for 24h. After washing and purification, a calcium-based metal-organic framework material containing a grafted anchoring agent is obtained. 20g of polyethyleneimine (average molecular weight 300) is dissolved in 500g of water, and the calcium-based metal-organic framework material containing the grafted anchoring agent is added. The mixture is stirred and dispersed evenly, and stirred and reacted at 60℃ for 24h. After washing and drying, a calcium-based metal-organic framework modified derivative powder is obtained. The mass ratio of the metal-organic framework powder, solvent B, grafted anchoring agent, modifier, and solvent C is 1:50:0.5:2:50.

[0108] Example 5

[0109] A method for preparing a calcium-based metal-organic framework modified derivative is as follows: 10g of the calcium-based metal-organic framework powder prepared in Example 1 is dispersed in 400g of water, 1g of dopamine is added, the pH is adjusted to 8.0, and the mixture is stirred and reacted at 45℃ for 12h. After washing and purification, a calcium-based metal-organic framework material containing a grafted anchoring agent is obtained and set aside for use. 10g of triethylenetetramine is dissolved in 200g of water, and the calcium-based metal-organic framework material containing the grafted anchoring agent is added. The mixture is stirred and dispersed evenly, and stirred and reacted at 80℃ for 24h. After washing, purification, and drying, a calcium-based metal-organic framework modified derivative powder is obtained. The mass ratio of the metal-organic framework powder, solvent B, grafted anchoring agent, modifier, and solvent C is 1:40:0.1:0.1:20.

[0110] Example 6

[0111] A method for preparing a calcium-based metal-organic framework modified derivative: 10g of the calcium-based metal-organic framework powder prepared in Example 1 is dispersed in 50g of water, and 20g of 3-chloropropionic acid is added. The pH is not adjusted, and the mixture is stirred and reacted at 80℃ for 6h. After washing and purification, a calcium-based metal-organic framework material containing a grafted anchoring agent is obtained and set aside for later use. 25g of tris(2-aminoethyl)amine is dissolved in 300g of ethanol, and the calcium-based metal-organic framework material containing the grafted anchoring agent is added. The mixture is stirred and dispersed evenly, and stirred and reacted at 70℃ for 12h. After washing, purification, and drying, a calcium-based metal-organic framework modified derivative powder is obtained. The mass ratio of the metal-organic framework powder, solvent B, grafted anchoring agent, modifier, and solvent C is 1:5:2:2.5:30.

[0112] Example 7

[0113] A method for preparing a zirconium-based metal-organic framework modified derivative: 10g of the zirconium-based metal-organic framework powder prepared in Example 2 is dispersed in 100g of water, 5g of dopamine is added, the pH is adjusted to 8.0, and the mixture is stirred and reacted at 60℃ for 48h. After washing and purification, a zirconium-based metal-organic framework material containing a grafted anchoring agent is obtained and set aside for use. 10g of 3-dimethylaminopropylamine is dissolved in 200g of water, and the zirconium-based metal-organic framework material containing the grafted anchoring agent is added. The mixture is stirred and dispersed evenly, and stirred and reacted at 70℃ for 48h. After washing, purification, and drying, a zirconium-based metal-organic framework modified derivative powder is obtained. The mass ratio of the metal-organic framework powder, solvent B, grafted anchoring agent, modifier, and solvent C is 1:10:0.5:1:20.

[0114] Example 8

[0115] A method for preparing a zirconium-based metal-organic framework modified derivative is as follows: 10g of the zirconium-based metal-organic framework powder prepared in Example 2 is dispersed in 1000g of water, 30g of 3-bromopropionic acid is added, pH adjustment is not required, and the mixture is stirred and reacted at 50°C for 32h. After washing and purification, a zirconium-based metal-organic framework material containing a grafted anchoring agent is obtained and set aside for use. 30g of polyethyleneimine (average molecular weight 300) is dissolved in 600g of water, and the zirconium-based metal-organic framework material containing the grafted anchoring agent is added. The mixture is stirred and dispersed evenly, and stirred and reacted at 50°C for 6h. After washing, purification, and drying, a zirconium-based metal-organic framework modified derivative powder is obtained. The mass ratio of the metal-organic framework powder, solvent B, grafted anchoring agent, modifier, and solvent C is 1:100:3:3:60.

[0116] Example 9

[0117] A method for preparing a calcium-based metal-organic framework modified derivative: 10g of the calcium-based metal-organic framework powder prepared in Example 1 is dispersed in 100g of water, and 20g of 3-chloropropionic acid is added. The pH is not adjusted, and the mixture is stirred and reacted at 75°C for 24h. After washing and purification, a calcium-based metal-organic framework material containing a grafted anchoring agent is obtained and set aside for later use. 10g of 1,6-hexanediamine is dissolved in 300g of ethanol, and the calcium-based metal-organic framework material containing the grafted anchoring agent is added. The mixture is stirred and dispersed evenly, and stirred and reacted at 60°C for 48h. After washing, purification, and drying, a calcium-based metal-organic framework modified derivative powder is obtained. The mass ratio of the metal-organic framework powder, solvent B, grafted anchoring agent, modifier, and solvent C is 1:10:2:1:30.

[0118] Example 10

[0119] A method for preparing a zirconium-based metal-organic framework modified derivative: 10g of the zirconium-based metal-organic framework powder prepared in Example 3 is dispersed in 500g of water, 3g of tannic acid is added, the pH is adjusted to 6.5, and the mixture is stirred and reacted at 60℃ for 24h. After washing and purification, a zirconium-based metal-organic framework material containing a grafted anchoring agent is obtained and set aside for use. 15g of polyethyleneimine (average molecular weight 600) is dissolved in 500g of water, and the zirconium-based metal-organic framework material containing the grafted anchoring agent is added. The mixture is stirred and dispersed evenly, and stirred and reacted at 70℃ for 24h. After washing, purification, and drying, a zirconium-based metal-organic framework modified derivative powder is obtained. The mass ratio of the metal-organic framework powder, solvent B, grafted anchoring agent, modifier, and solvent C is 1:50:0.3:1.5:50.

[0120] Example 11

[0121] A metal-organic framework composite adsorbent, wherein the metal-organic framework composite adsorbent is a metal-organic framework material-polysulfone material composite sphere, wherein the metal-organic framework material in the metal-organic framework material-polysulfone material composite sphere is a calcium-based metal-organic framework modified derivative, and the polysulfone material is polyethersulfone, and the mass ratio of the metal-organic framework material to the polysulfone material is 2:21.

[0122] The preparation method of the above-mentioned metal-organic framework composite adsorbent is as follows:

[0123] (1) Mix 21g of polyethersulfone, 1.2g of polyvinylpyrrolidone, and 100g of N,N-dimethylacetamide. After stirring and dissolving completely, add 2g of the calcium-based metal-organic framework modified derivative powder prepared in Example 4. Stir and disperse evenly at 40°C, and allow to stand or degas under vacuum to obtain a blended modified solution. The mass ratio of good solvent, polysulfone material, additive and metal-organic framework material is 100:21:1.2:2.

[0124] (2) The blended modified solution obtained in step (1) is subjected to a non-solvent-induced phase separation method, that is, the blended modified solution is squeezed out through the inner hole of the needle by a metering pump, forming droplets in the air and dripping into water for phase conversion, forming microspheres of uniform size. After washing and drying, a metal-organic framework composite adsorbent is obtained.

[0125] A photograph of the metal-organic framework composite adsorbent prepared in this embodiment is shown below. Figure 10 As shown. Testing revealed that the particle size of the metal-organic framework composite adsorbent prepared in this embodiment is approximately 1.2 mm.

[0126] Example 12

[0127] A metal-organic framework composite adsorbent, wherein the metal-organic framework composite adsorbent is a metal-organic framework material-polysulfone material composite sphere, wherein the metal-organic framework material in the metal-organic framework material-polysulfone material composite sphere is a calcium-based metal-organic framework modified derivative, and the polysulfone material is polyethersulfone, and the mass ratio of the metal-organic framework material to the polysulfone material is 1.5:20.

[0128] The preparation method of the above-mentioned metal-organic framework composite adsorbent is as follows:

[0129] (1) Mix 20g of polyethersulfone with 90g of N,N-dimethylacetamide, 1.5g of polyvinylpyrrolidone and 10g of N,N-dimethylformamide. After stirring and dissolving completely, add 1.5g of the calcium-based metal-organic framework modified derivative powder prepared in Example 5. Stir and disperse evenly at 30°C, and allow to stand or degas under vacuum to obtain a blended modified solution. The mass ratio of good solvent, polysulfone material, additive and metal-organic framework material is 100:20:1.5:1.5.

[0130] (2) The blended modified solution obtained in step (1) is subjected to a non-solvent-induced phase separation method, that is, the blended modified solution is squeezed out through the inner hole of the needle by a metering pump, forming droplets in the air and dripping into water for phase conversion, forming microspheres of uniform size. After washing and drying, a metal-organic framework composite adsorbent is obtained.

[0131] A photograph of the metal-organic framework composite adsorbent prepared in this embodiment is shown below. Figure 11 As shown. Testing revealed that the particle size of the metal-organic framework composite adsorbent prepared in this embodiment is approximately 1.0 mm.

[0132] Example 13

[0133] A metal-organic framework composite adsorbent, wherein the metal-organic framework material-polysulfone material composite sphere is a calcium-based metal-organic framework modified derivative, and the polysulfone material is polysulfone, with a mass ratio of metal-organic framework material to polysulfone material of 3:20.

[0134] The preparation method of the above-mentioned metal-organic framework composite adsorbent is as follows:

[0135] (1) Mix 20g of polysulfone with 100g of N,N-dimethylacetamide and 1.2g of polyvinylpyrrolidone. After stirring and dissolving completely, add 3g of the calcium-based metal-organic framework modified derivative powder prepared in Example 6. Stir and disperse evenly at 20°C, and allow to stand or degas under vacuum to obtain a blended modified solution. The mass ratio of good solvent, polysulfone material, additive and metal-organic framework material is 100:20:1.2:3.

[0136] (2) The blended modified solution obtained in step (1) is subjected to a non-solvent-induced phase separation method, that is, the blended modified solution is squeezed out through the inner hole of the needle by a metering pump, forming droplets in the air and dripping into water for phase conversion, forming microspheres of uniform size, which are then washed and dried to obtain a metal-organic framework composite adsorbent.

[0137] A photograph of the metal-organic framework composite adsorbent prepared in this embodiment is shown below. Figure 12 As shown. Testing revealed that the particle size of the metal-organic framework composite adsorbent prepared in this embodiment is approximately 1.4 mm.

[0138] Example 14

[0139] A metal-organic framework composite adsorbent, wherein the metal-organic framework material-polysulfone material composite sphere is a metal-organic framework material-polysulfone material composite sphere, wherein the metal-organic framework material in the metal-organic framework material-polysulfone material composite sphere is a zirconium-based metal-organic framework modified derivative, and the polysulfone material is polyethersulfone, and the mass ratio of the metal-organic framework material to the polysulfone material is 1:20.

[0140] The preparation method of the above-mentioned metal-organic framework composite adsorbent is as follows:

[0141] (1) Mix 20g of polyethersulfone, 1.5g of polyvinylpyrrolidone, and 100g of N,N-dimethylacetamide. After stirring and dissolving completely, add 1g of the zirconium-based metal-organic framework modified derivative powder prepared in Example 7. Stir and disperse evenly at 50°C, and allow to stand or degas under vacuum to obtain a blended modified solution. The mass ratio of good solvent, polysulfone material, additive and metal-organic framework material is 100:20:1.5:1.

[0142] (2) The blended modified solution obtained in step (1) is subjected to a non-solvent-induced phase separation method, that is, the blended modified solution is squeezed out through the inner hole of the needle by a metering pump, forming droplets in the air and dripping into the water for phase conversion, forming microspheres of uniform size, and then purified to obtain a metal-organic framework composite adsorbent.

[0143] The particle size of the metal-organic framework composite adsorbent prepared in this embodiment is approximately 1.2 mm.

[0144] Example 15

[0145] A metal-organic framework composite adsorbent, wherein the metal-organic framework material-polysulfone material composite sphere is a metal-organic framework material-polysulfone material composite sphere, wherein the metal-organic framework material in the metal-organic framework material-polysulfone material composite sphere is a zirconium-based metal-organic framework modified derivative, and the polysulfone material is polyethersulfone, and the mass ratio of the metal-organic framework material to the polysulfone material is 8:15.

[0146] The preparation method of the above-mentioned metal-organic framework composite adsorbent is as follows:

[0147] (1) Mix 15g of polyethersulfone with 100g of N,N-dimethylacetamide, stir until completely dissolved, add 8g of zirconium-based metal-organic framework modified derivative powder prepared in Example 8, stir and disperse evenly at 30°C, and let stand or degas under vacuum to obtain a blended modified solution; wherein, the mass ratio of good solvent, polysulfone material and metal-organic framework material is 100:15:1.5;

[0148] (2) The blended modified solution obtained in step (1) is subjected to a non-solvent-induced phase separation method, that is, the blended modified solution is squeezed out through the inner hole of the needle by a metering pump, forming droplets in the air and dripping into water for phase conversion, forming microspheres of uniform size. After washing and drying, a metal-organic framework composite adsorbent is obtained.

[0149] The particle size of the metal-organic framework composite adsorbent prepared in this embodiment is approximately 0.9 mm.

[0150] Example 16

[0151] A metal-organic framework composite adsorbent, wherein the metal-organic framework composite adsorbent is a metal-organic framework material-polysulfone material composite sphere, wherein the metal-organic framework material in the metal-organic framework material-polysulfone material composite sphere is a calcium-based metal-organic framework modified derivative, and the polysulfone material is polyethersulfone, and the mass ratio of the metal-organic framework material to the polysulfone material is 2:22.

[0152] The preparation method of the above-mentioned metal-organic framework composite adsorbent is as follows:

[0153] (1) Mix 22g of polyethersulfone, 1g of polyvinylpyrrolidone, and 100g of N,N-dimethylacetamide. After stirring and dissolving completely, add 2g of the calcium-based metal-organic framework modified derivative powder prepared in Example 9. Stir and disperse evenly at 50°C, and allow to stand or degas under vacuum to obtain a blended modified solution. The mass ratio of good solvent, polysulfone material, additive and metal-organic framework material is 100:22:1:2.

[0154] (2) The blended modified solution obtained in step (1) is subjected to a non-solvent-induced phase separation method, that is, the blended modified solution is squeezed out through the inner hole of the needle by a metering pump, forming droplets in the air, and dripping into a mixed solution of water and N-methyl-2-pyrrolidone (water ratio of 90wt%) for phase inversion, forming microspheres of uniform size. After washing and drying, a metal-organic framework composite adsorbent is obtained.

[0155] The particle size of the metal-organic framework composite adsorbent prepared in this embodiment is approximately 1.2 mm.

[0156] Example 17

[0157] A metal-organic framework composite adsorbent, wherein the metal-organic framework material-polysulfone material composite sphere is a metal-organic framework material-polysulfone material composite sphere, wherein the metal-organic framework material in the metal-organic framework material-polysulfone material composite sphere is a zirconium-based metal-organic framework modified derivative, and the polysulfone material is polyethersulfone, and the mass ratio of the metal-organic framework material to the polysulfone material is 10:10.

[0158] The preparation method of the above-mentioned metal-organic framework composite adsorbent is as follows:

[0159] (1) Mix 10g polysulfone, 2g sulfonated polyethersulfone, 90g N,N-dimethylacetamide, 10g N-methylpyrrolidone, and 3g polyethylene glycol. After stirring and dissolving completely, add 10g of the zirconium-based metal-organic framework modified derivative powder prepared in Example 10. Stir and disperse evenly at 45°C, and allow to stand or degas under vacuum to obtain a blended modified solution. The mass ratio of good solvent, polysulfone material, additive and metal-organic framework material is 100:10:2:10.

[0160] (2) The blended modified solution obtained in step (1) is subjected to a non-solvent-induced phase separation method, that is, the blended modified solution is squeezed out through the inner hole of the needle by a metering pump, forming droplets in the air and dripping into water for phase conversion, forming microspheres of uniform size, which are then washed and dried to obtain a metal-organic framework composite adsorbent.

[0161] The particle size of the metal-organic framework composite adsorbent prepared in this embodiment is approximately 0.6 mm.

[0162] Example 18

[0163] A metal-organic framework composite adsorbent, wherein the metal-organic framework composite adsorbent is a metal-organic framework material-polysulfone material composite sphere, wherein the metal-organic framework material in the metal-organic framework material-polysulfone material composite sphere is a zirconium-based metal-organic framework, the polysulfone material is polyethersulfone, and the mass ratio of the metal-organic framework material to the polysulfone material is 3:21;

[0164] The preparation method of the above-mentioned metal-organic framework composite adsorbent is as follows:

[0165] (1) Mix 21g of polyethersulfone, 1.2g of polyvinylpyrrolidone, and 100g of N,N-dimethylacetamide. After stirring and dissolving completely, add 3g of zirconium-based metal-organic framework powder prepared in Example 3. Stir and disperse evenly at 30°C, and allow to stand or degas under vacuum to obtain a blended modified solution. The mass ratio of good solvent, polysulfone material, additive and metal-organic framework material is 100:21:1.2:3.

[0166] (2) The blended modified solution obtained in step (1) is subjected to a non-solvent-induced phase separation method, that is, the blended modified solution is squeezed out through the inner hole of the needle by a metering pump, forming droplets in the air and dripping into water for phase conversion, forming microspheres of uniform size. After washing and drying, a metal-organic framework composite adsorbent is obtained.

[0167] The particle size of the metal-organic framework composite adsorbent prepared in this embodiment is approximately 1.1 mm.

[0168] Comparative Example 1

[0169] Following the method of Example 11, without adding metal-organic framework materials, polyethersulfone microspheres were obtained.

[0170] The polyethersulfone microspheres prepared in this comparative example have a particle size of approximately 1.1 mm.

[0171] Comparative Example 2

[0172] Following the method of Example 13, polysulfone microspheres were obtained without adding metal-organic framework materials.

[0173] The polysulfone microspheres prepared in this comparative example have a particle size of approximately 1.0 mm.

[0174] Test case

[0175] For the material samples obtained in Examples 11-18 and Comparative Examples 1-2 above, the relevant adsorption performance and safety were evaluated using commercially available perfusion resins HA130, BS330, and Cytosorb adsorbent from the United States as reference samples.

[0176] (1) Particulate release detection

[0177] The microsphere materials and reference samples prepared in Examples 11-18 and Comparative Examples 1-2 of this invention were subjected to acid washing, alkali washing, and alcohol rinsing. Then, 100 mL of each sample was placed in a plastic container with a filter screen and rinsed with water for injection until the particle detection value met the requirements of ≤200 particles / 100 mL for particles of 15 μm-25 μm and ≤100 particles / 100 mL for particles larger than 25 μm. The plastic containers containing the samples were then sealed and placed on a simulated vehicle transport platform and vibrated for 12 hours. Furthermore, the liquid in the plastic containers was compared and calculated with the blank control sample. The results are shown in Table 1 below.

[0178] Table 1. Particulate release test results of different samples

[0179]

[0180] The results show that the particle increment values ​​of samples from Examples 11-18 and Comparative Examples 1-2 are significantly lower than those of the reference sample. This indicates that the metal-organic framework composite adsorbent prepared by the method of this invention has the characteristic of low particle shedding.

[0181] (2) Adsorption performance evaluation

[0182] This invention evaluates the adsorption and removal performance of metal-organic framework materials and metal-organic framework composite adsorbents on target toxins in hemoperfusion, such as uremic protein-bound toxoids, bilirubin, bile acids, and endotoxins.

[0183] To test the adsorption performance of the metal-organic framework (MOF) powders prepared in Examples 1-10, this invention utilizes PBS buffer solution to evaluate the adsorption performance of MOFs for uremic protein-bound toxoids (p-cresol sulfate PCS and indoleacetic acid IAA) and bilirubin. Specifically: First, 250 mg of MOF powder was dissolved in PBS buffer solution, centrifuged and washed several times, and drained. Then, 10 mL of bovine serum albumin-PBS solution containing p-cresol sulfate PCS (25 mg / L), indoleacetic acid IS (25 mg / L), and bilirubin (300 μmol / L) was added. After shaking at 37°C for 2 hours, the concentration changes of the adsorbed substances were measured. The adsorption results are shown in Table 2 below.

[0184] Table 2. Toxin adsorption performance of different metal-organic framework materials

[0185]

[0186] As can be seen from Table 2, all metal-organic framework material samples from Examples 1 to 10 of the present invention exhibit excellent adsorption performance for uremic protein-bound toxoids (p-cresol sulfate PCS and indoleacetic acid IAA) and bilirubin.

[0187] Regarding the adsorption performance tests of the metal-organic framework composite adsorbents prepared in Examples 11-18 of this invention, the microspheres prepared in Comparative Examples 1-2, and the reference sample, this invention uses plasma solution to evaluate the adsorption performance of the metal-organic framework composite adsorbents and the adsorbents prepared in the comparative examples for uremic protein-bound toxoids (p-cresol sulfate PCS, indophenol sulfate IS, and indoleacetic acid IAA), bilirubin, and bile acids. Specifically: First, the metal-organic framework composite adsorbent, the adsorbent prepared in the comparative example, and the reference sample to be tested were dissolved in PBS buffer solution, centrifuged and washed several times, and drained. Then, 10 mL of plasma solution containing p-cresol sulfate (PCS) (25 mg / L), indophenol sulfate (IS) (25 mg / L), indoleacetic acid (IAA) (10 mg / L), bilirubin (300 μmol / L), bile acids (150 μmol / L), and endotoxin (2 EU / mL) were added to 1 mL of the test material obtained in the above examples and comparative examples. After shaking at 37°C for 2 hours, the concentration changes of the adsorbed substances before and after were measured. The results are shown in Table 3 below.

[0188] Table 3. Toxin adsorption performance of different adsorbents

[0189]

[0190]

[0191] As shown in Table 3, for uremic protein-bound toxoids (p-cresol sulfate PCS, indophenol sulfate IS, indoleacetic acid IAA, etc.), the metal-organic framework composite adsorbents prepared in Examples 11-18 of this invention exhibit better adsorption performance compared to HA130 hemoperfusion resin and control samples. Regarding the adsorption of bilirubin, bile acids, and endotoxins, the adsorption performance of the samples in the examples of this invention is significantly better than that of the adsorbents prepared in Comparative Examples 1-2, and is essentially close to, or even better than, that of BS330.

[0192] (3) Blood compatibility evaluation

[0193] This invention uses the hemolysis rate as a performance index to evaluate the blood compatibility of the microspheres prepared in comparative examples 11-18, the adsorbents prepared in comparative examples 1-2, and the reference sample. The magnitude of the hemolysis rate directly reflects the blood compatibility of the material; a lower value indicates better blood compatibility.

[0194] Hemolysis rate test: The test sample was washed 5 times with physiological saline, and the washed sample was tested at a bath ratio of 5g / 10mL. The sample was incubated with diluted rabbit blood at 37℃, and the absorbance of hemoglobin released from ruptured red blood cells was measured to calculate the hemolysis rate. The evaluation results of the hemolysis rate index of different materials are shown in Table 4 below:

[0195] Table 4 Evaluation results of hemolysis rate index for different adsorbents

[0196] Hemolysis rate (%) Example 11 0.3 Example 12 0.5 Example 13 0.3 Example 14 0.1 Example 15 0.3 Example 16 0.4 Example 17 0.2 Example 18 0.4 Comparative Example 1 0.3 Comparative Example 2 0.5 HA130 resin 3.9 BS resin 8.6

[0197] As shown in Table 4, the hemolysis rates of the metal-organic framework composite adsorbents obtained in Examples 11-18 of this invention are all less than 1%. These rates are similar to those of the adsorbents in Comparative Examples 1-2, which do not contain metal-organic framework materials, and are significantly lower than those of HA130 and BS330 resins. This demonstrates that the metal-organic framework composite adsorbents of this invention exhibit good blood compatibility. Furthermore, biocompatibility tests on the metal-organic framework composite adsorbents prepared in Examples 11-18 of this invention, including tests for cytotoxicity, thrombosis, coagulation, complement activation, and immunogenicity, all showed good blood compatibility.

[0198] The above results demonstrate that the metal-organic framework composite adsorbent provided by this invention exhibits excellent stability, blood compatibility, and superior adsorption capacity for toxins. Therefore, the metal-organic framework composite adsorbent prepared by this invention can be further developed into a hemoperfusion device. This hemoperfusion device can be used clinically to treat diseases and conditions such as renal failure, liver failure, acute poisoning, sepsis and septicemia, autoimmune diseases, inflammatory diseases, and hyperlipidemia.

[0199] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A metal organic framework composite adsorbent, the metal organic framework composite adsorbent is a metal organic framework material-poly sulfone material composite ball, the mass ratio of the metal organic framework material and the poly sulfone material in the metal organic framework material-poly sulfone material composite ball is (1-10) : (10-22). The metal organic framework material comprises one or more of a calcium metal organic framework modified derivative and a zirconium metal organic framework modified derivative. The modifier of the calcium metal organic framework modified derivative and the zirconium metal organic framework modified derivative independently comprises one or more of polyethyleneimine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, 1, 3-propanediamine, ethylenediamine, 3-dimethylaminopropylamine, tris (2-aminoethyl) amine, N, N'-di-n-propylethylenediamine, N, N-diethylethylenediamine, N, N-dibutylethylenediamine, N, N-dimethylethylenediamine, tris (3-aminopropyl) amine, 2, 2'-diamino-N-methyldiethylamine, 3-diethylaminopropylamine, N'N-bis (3-aminopropyl) methylamine, 1, 5-diaminopentane, N, N-diethyldivinyltriamine, 1, 6-hexanediamine.

2. The MOF composite adsorbent of claim 1, wherein, The metal organic framework material-poly sulfone material composite ball is a spherical or spherical-like particle, and the particle size of the metal organic framework material-poly sulfone material composite ball is 0.1-2.5 mm.

3. The MOF composite adsorbent of claim 1, wherein, The poly sulfone material comprises one or more of poly sulfone, poly ether sulfone, sulfonated poly ether sulfone and poly aryl sulfone. 4.A method for preparing the metal organic framework composite adsorbent according to any one of claims 1-3, comprising the following steps: (1) mixing a good solvent, a poly sulfone material, an additive and a metal organic framework material to obtain a blending modification solution; (2) dropping the blending modification solution obtained in step (1) into a non-good solvent of the poly sulfone material to perform phase separation, thereby obtaining the metal organic framework composite adsorbent.

5. The preparation method according to claim 4, characterized in that, The metal organic framework material in step (1) comprises one or more of a calcium metal organic framework modified derivative and a zirconium metal organic framework modified derivative. The method for preparing the calcium metal organic framework modified derivative comprises: mixing a calcium metal organic framework powder, a solvent B and a grafting anchor agent to perform a first stirring reaction, thereby obtaining a metal organic framework material containing the grafting anchor agent; mixing the metal organic framework material containing the grafting anchor agent, a modifier and a solvent C to perform a second stirring reaction, thereby obtaining the calcium metal organic framework modified derivative.

6. The preparation method according to claim 5, characterized in that, The method for preparing the zirconium metal organic framework modified derivative comprises: mixing a zirconium metal organic framework powder, a solvent B and a grafting anchor agent to perform a first stirring reaction, thereby obtaining a metal organic framework material containing the grafting anchor agent; mixing the metal organic framework material containing the grafting anchor agent, a modifier and a solvent C to perform a second stirring reaction, thereby obtaining the zirconium metal organic framework modified derivative.

7. The preparation method according to claim 4, characterized in that, The good solvent in step (1) comprises one or more of N, N dimethylformamide, N, N dimethylacetamide and N-methylpyrrolidone.

8. The preparation method according to claim 4, characterized in that, The additive in the step (1) includes one or more of polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, water, ethylene glycol, n-propanol, isopropanol, glycerol, ethylene glycol methyl ether and lithium chloride.

9. The preparation method according to claim 4, characterized in that, The non-good solvent of the polysulfone material in the step (2) includes a mixed solution of water and an organic solvent or water, the organic solvent including one or more of dimethyl sulfoxide, N,N dimethylacetamide, N,N dimethylformamide and N-methyl-2-pyrrolidone. 10.A blood perfusion device, wherein the adsorbent is the metal organic framework composite adsorbent according to any one of claims 1 to 3 or prepared by the method according to any one of claims 4 to 9.

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