Blood treatment material

Abstract

[Problem] To provide a blood treatment material achieving both water permeability enabling removal of water in blood, and highly efficient adsorption performance for eliminating inflammatory cells, inflammatory cytokines, etc. [Solution] The present invention provides a blood treatment material comprising a hollow-fiber membrane with the surface thereof modified by a ligand including an amino group, wherein the arithmetic average roughness (RaA) in the radial direction of the surface of the hollow-fiber membrane to be brought into contact with blood is 0.10-0.80 μm as calculated using a laser microscope.

Description

Blood Processing Materials

[0001] The present invention relates to blood treatment materials.

[0002] A hollow fiber membrane is a cylindrical semipermeable membrane, and is generally known to have the function of selectively allowing substances to permeate through minute pores present on its surface.

[0003] For this reason, hollow fiber membranes are used in various applications in liquid separation processes, for example, medical applications such as hemodialysis and hemofiltration. A known hemodialysis method involves passing blood through a hollow fiber membrane, allowing water and low-molecular-weight substances in the blood, such as uremic toxins, to permeate the membrane and then diffuse and be removed from the membrane.

[0004] For example, Patent Document 1 discloses that proteins such as IL-6 can be adsorbed and removed by using a hollow fiber membrane made of a copolymer of acrylonitrile and sodium methallylsulfonate, to which a ligand such as an IgG antibody is immobilized.

[0005] Patent Document 2 discloses that by introducing polyethyleneimine onto the surface of a hollow fiber membrane made of a copolymer of acrylonitrile and sodium methallylsulfonate and making the membrane surface positively charged, contact phase activation can be inhibited during ex vivo treatment of blood, etc., and the production of kallikrein in the blood can be suppressed, thereby suppressing anaphylactoid reactions.

[0006] Patent Document 3 discloses that DNA can be adsorbed and removed by using a hollow fiber membrane made of polyethersulfone containing ion exchange particles inside the membrane.

[0007] In recent years, it has become clear that in blood purification therapy for patients with acute renal failure complicated by septic shock or chronic renal failure whose hemodynamics has become unstable, it is not enough to simply remove small molecules and proteins from the blood; it is also desirable to remove inflammatory cells such as activated leukocytes from the blood.

[0008] Known examples of materials that can remove inflammatory cells such as activated leukocytes include a material in which a ligand having an amino group is attached to the surface of a sea-island composite fiber (Patent Document 4).

[0009] Patent No. 4224621 Patent No. 4579916 Patent No. 6378090 Patent No. 5298719

[0010] However, although Patent Document 1 discloses that IL-6 can be adsorbed by a hollow fiber membrane having an IgG antibody immobilized on the surface, it does not disclose the adsorption performance of activated leukocytes.

[0011] Patent Document 2 aims to delay contact phase activation while inhibiting endotoxin removed from blood during extracorporeal circulation from returning to the blood by backfiltration, but does not describe adsorption and removal of inflammatory cells such as activated leukocytes.

[0012] Since hydrophilic particles are physically mixed into the hollow fiber membrane described in Patent Document 3, there is a concern that the hydrophilic particles may be eluted into the blood when used for extracorporeal circulation.

[0013] As mentioned above, blood treatment materials using hollow fiber membranes have been developed for the diffusion and removal of water and proteins such as inflammatory cytokines from blood, but none have been developed for the adsorption of inflammatory cells such as activated leukocytes. Therefore, there is a need for the development of hollow fiber membranes that can not only remove water and other substances from blood but also adsorb and remove pathogenic substances such as inflammatory cells and inflammatory cytokines.

[0014] Therefore, an object of the present invention is to provide a blood treatment material that combines water permeability for removing water from blood with highly efficient adsorption and removal performance for inflammatory cells, inflammatory cytokines, and the like.

[0015] As a result of intensive research conducted by the inventors to solve the above-mentioned problems, they discovered that by roughening the membrane surface that comes into contact with blood in a hollow fiber membrane, it is possible to achieve both water permeability and highly efficient adsorption and removal performance of inflammatory cells, inflammatory cytokines, and the like.

[0016] That is, the present invention includes the following (1) to (7). (1) A blood treatment material comprising a hollow fiber membrane whose surface is modified with a ligand containing an amino group, wherein the arithmetic mean roughness (RaA) in the radial direction of the surface of the hollow fiber membrane that comes into contact with blood, calculated using a laser microscope, is 0.10 to 0.80 μm. (2) The blood treatment material according to (1), wherein the arithmetic mean roughness (RaA) is 0.30 to 0.60 μm. (3) The blood treatment material according to (1) or (2), wherein the surface that comes into contact with blood is the inner surface of the hollow fiber membrane. (4) The blood treatment material according to any of (1) to (3), wherein the inner diameter of the hollow fiber membrane is 150 to 400 μm. (5) The blood treatment material according to any one of (1) to (4), wherein the material of the hollow fiber membrane is a copolymer of a hydrophobic polymer selected from the group consisting of polyacrylonitrile, polymethyl methacrylate, polystyrene, polysulfone, polyethersulfone, polyester, copolymers thereof, and mixtures thereof, and a hydrophilic polymer selected from the group consisting of polymethallylsulfonic acid, polymethallylsulfonate salts, polystyrenesulfonic acid, polystyrenesulfonate salts, sulfonated polysulfone, sulfonated polyethersulfone, copolymers thereof, and mixtures thereof, and cellulose acetate. (6) The blood treatment material according to any one of (1) to (5), wherein the blood treatment material is used for adsorption and removal of activated leukocytes and inflammatory cytokines. (7) A blood purification column comprising the blood treatment material according to any one of (1) to (6).

[0017] The blood treatment material of the present invention can adsorb and remove inflammatory cells, inflammatory cytokines, etc. with high efficiency while maintaining water permeability.

[0018] FIG. 10 is a diagram illustrating how to determine the arithmetic mean roughness.

[0019] The present invention will be described in detail below.

[0020] The blood treatment material of the present invention comprises a hollow fiber membrane whose surface is modified with a ligand containing an amino group, and is characterized in that the arithmetic mean roughness (RaA) in the radial direction of the surface of the hollow fiber membrane that comes into contact with blood, as calculated using a laser microscope, is 0.10 to 0.80 μm.

[0021] "Blood treatment" means the adsorption and removal of blood components using an appropriate material.

[0022] "Blood components" refers to components that make up blood, including, for example, cells in blood and humoral factors in blood.

[0023] "Cells in blood" refers to cells contained in blood, including, for example, white blood cell components such as granulocytes, monocytes, neutrophils, and eosinophils, as well as red blood cells and platelets.

[0024] "Inflammatory cells" refer to cells in the blood that have been activated by proteins such as inflammatory cytokines. Specific examples include activated leukocytes, activated platelets, and activated leukocyte-activated platelet complexes. When the blood treatment material according to this embodiment is used for the purpose of treating patients with inflammatory diseases or patients with renal diseases complicated by inflammatory diseases, activated leukocytes are preferred as the substance to be removed.

[0025] "Humoral factors in blood" refers to organic substances dissolved in blood. Specific examples include urea, β2-microglobulin, cytokines, proteins such as IgE and IgG, and polysaccharides such as lipopolysaccharide (LPS). Among these, proteins such as cytokines and polysaccharides such as LPS are preferred as substances to be adsorbed and removed when treating patients with inflammatory diseases, and urea and β2-microglobulin are preferred as substances to be adsorbed and removed when treating patients with renal diseases. Furthermore, when the purpose of use is to treat patients with inflammatory diseases or patients with renal diseases complicated with inflammatory diseases, inflammatory cytokines are more preferred as substances to be adsorbed and removed.

[0026] The term "inflammatory cytokine" refers to a group of proteins that are produced by various cells, including immunocompetent cells, in response to stimuli such as infection or trauma, and are released extracellularly to act. Examples of such cytokines include interferon α, interferon β, interferon γ, interleukin 1 to interleukin 15, tumor necrosis factor α, tumor necrosis factor β, high mobility group box-1, erythropoietin, and monocyte chemotactic factor.

[0027] "Adsorption" refers to a state in which a substance adheres to a material and does not easily detach, or a state of adsorption equilibrium. There are no particular limitations on the principle of adsorption, but it refers to a state in which a substance adheres to a material due to intermolecular forces such as electrostatic interactions, hydrophobic interactions, hydrogen bonds, and van der Waals forces, or a state in which a substance adheres physically, such as through cell adhesion or phagocytosis by leukocytes.

[0028] The term "blood treatment material" refers to a material containing a hollow fiber membrane as at least a part of the material, and includes hollow fiber membranes alone and hollow fiber membranes immobilized or mixed with an appropriate reinforcing material. The immobilization or mixing operation may be performed before or after processing into the hollow fiber membrane shape.

[0029] The hollow fiber membrane can be made of any known material used in blood treatment. Considering the possibility that water-soluble components alone may cause the hollow fiber membrane to swell due to the moisture in the blood, resulting in blockage of the micropores, and the ease of introducing ligands, a copolymer of a hydrophobic polymer and a hydrophilic polymer is preferred as the material for the hollow fiber membrane. In this specification, "hydrophobic polymer" refers to a polymer that is insoluble in water. "Water-insoluble" means that the dry weight of the polymer before and after immersion in water is 1% or less. This dry weight change is the ratio of the dry weight of the solids remaining after immersing the polymer in 37°C water in an amount 9 times its dry weight for 1 hour, removing it with tweezers, etc., and vacuum-drying the remaining water at 50°C or below to the dry weight of the material before immersion. In this specification, "hydrophilic polymer" refers to a polymer that is soluble in water. "Water-soluble" means that the polymer is immersed in water at 37°C in an amount 9 times the dry weight of the polymer for 1 hour, then removed with tweezers or the like, and the remaining water is vacuum-dried at 50°C or less, after which the change in dry weight of the remaining solid content is 50% or more.

[0030] Among the materials for the hollow fiber membrane, examples of hydrophobic polymers include polymers selected from the group consisting of polyolefins such as polyethylene and polypropylene, polyacrylonitrile, polyacrylates such as polymethyl acrylate and polyethyl acrylate, polymethacrylates such as polymethyl methacrylate and polyethyl methacrylate, polystyrene, aromatic polyethersulfones such as polysulfone and polyethersulfone, aromatic polyetherketones such as polyetherketone and polyetheretherketone, polyamideimide, polyamide 6 and nylon 6,6, polyurethane, polyester, copolymers thereof, and mixtures thereof. In view of copolymerizability with hydrophilic polymers and ease of immobilizing amino group-containing ligands, the hydrophobic polymer is preferably a polymer selected from the group consisting of polyacrylonitrile, polymethyl methacrylate, polystyrene, polysulfone, polyethersulfone, polyester, copolymers thereof, and mixtures thereof, with polyacrylonitrile being more preferred.

[0031] Among the materials for the hollow fiber membrane, examples of hydrophilic polymers include polymethallyl sulfonic acid, polymethallyl sulfonates (e.g., sodium salts, potassium salts, ammonium salts), polystyrene sulfonic acid, polystyrene sulfonates (e.g., sodium salts, potassium salts, ammonium salts), sulfonated aromatic polyethersulfones such as sulfonated polysulfones and sulfonated polyethersulfones, polyvinylpyrrolidone, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, copolymers thereof, and mixtures thereof, as well as cellulose, cellulose acetate, carboxymethylcellulose, and mixtures thereof. From the viewpoint of copolymerizability and compatibility with the hydrophobic polymer, the hydrophilic polymer is preferably a polymer selected from the group consisting of polymethallyl sulfonic acid, polymethallyl sulfonates, polystyrene sulfonic acid, polystyrene sulfonates, sulfonated polysulfones, sulfonated polyethersulfones, copolymers thereof, and mixtures thereof, as well as cellulose acetate, and more preferably polymethallyl sulfonic acid or polymethallyl sulfonates.

[0032] When the material of the hollow fiber membrane is a copolymer of the above-mentioned hydrophobic polymer and the above-mentioned hydrophilic polymer, the hydrophobic polymer and the hydrophilic polymer may be combined in any manner. Considering the polymerizability of the monomer and the ease of ligand introduction, for example, a copolymer of a hydrophobic polymer selected from the group consisting of polyacrylonitrile, polymethyl methacrylate, polystyrene, polysulfone, polyethersulfone, polyester, copolymers thereof, and mixtures thereof, and a hydrophilic polymer selected from the group consisting of polymethallyl sulfonic acid, polymethallyl sulfonate, polystyrene sulfonic acid, polystyrene sulfonate, sulfonated polysulfone, sulfonated polyethersulfone, copolymers thereof, and mixtures thereof, and cellulose acetate is preferred. More specifically, a copolymer consisting of a combination of polyacrylonitrile and polymethallylsulfonic acid or a salt thereof, a combination of polystyrene and polystyrenesulfonic acid or a salt thereof, a combination of polysulfone and sulfonated polysulfone, or a combination of polyethersulfone and sulfonated polyethersulfone is preferred, and a copolymer consisting of a combination of polyacrylonitrile and polymethallylsulfonic acid or a salt thereof is more preferred.

[0033] The membrane thickness of the hollow fiber membrane may be appropriately determined depending on the intended use. For example, when used for extracorporeal circulation, the membrane thickness of the hollow fiber membrane is preferably 20 to 80 μm, more preferably 30 to 70 μm, and most preferably 40 to 60 μm.

[0034] The inner diameter of the hollow fiber membrane may be appropriately determined according to the membrane thickness and outer diameter of the hollow fiber membrane. For example, when used for extracorporeal circulation, the inner diameter of the hollow fiber membrane is preferably 150 to 400 μm, more preferably 200 to 300 μm.

[0035] The inner diameter of the hollow fiber membrane can be calculated using the following formula 1. Here, the membrane thickness refers to the average value of the membrane thicknesses of 16 randomly selected hollow fiber membranes measured with a 1000x magnification lens of a microwatcher (e.g., VH-Z100, manufactured by Keyence Corporation). The outer diameter of the hollow fiber membrane refers to the average value of the outer diameters of 16 randomly selected hollow fiber membranes measured with a laser displacement meter (e.g., LS5040T, manufactured by Keyence Corporation).

[0036] Inner diameter of hollow fiber membrane (μm) = outer diameter of hollow fiber membrane - 2 × membrane thickness ... Equation 1

[0037] When blood is treated with a hollow fiber membrane, the substances to be removed appear larger than their actual size due to the effects of Brownian motion, etc., and therefore, in order for the pores to adsorb the substances to be removed, the pore size on the surface must be larger than the size of the substances to be removed. Therefore, although it depends on the size of the substances to be removed, the pore size on the surface of the hollow fiber membrane is generally preferably 0.1 to 50 nm, and more preferably 1 to 30 nm.

[0038] "Water permeability" refers to the amount of water passing through the through-holes present in the hollow fiber membrane. The larger the pore diameter or the greater the number of pores, the greater the number of water flow paths, and therefore the higher the water permeability of the hollow fiber membrane. The water permeability of a hollow fiber membrane is preferably 1.5 to 5.0 L / h / mmHg, more preferably 1.5 to 3.0 L / h / mmHg, even more preferably 1.7 to 3.0 L / h / mmHg, and even more preferably 1.7 to 2.5 L / h / mmHg. Water permeability can be calculated using the following formula 2.

[0039] Water permeability (L / h / mmHg) = Filtration volume (L) / Time (h) / Water pressure (mmHg) ... Equation 2

[0040] The surface of the hollow fiber membrane that comes into contact with blood may be either the inner surface or the outer surface of the hollow fiber membrane, but the inner surface of the hollow fiber membrane is preferred as the surface that comes into contact with blood, as this provides a more uniform blood flow path and less dead space.

[0041] "Arithmetic mean roughness (Ra)" is an index that quantifies surface smoothness as specified in JIS B 0601:2001. In this specification, it refers to the radial irregularities on the surface of a hollow fiber membrane that comes into contact with blood. Specifically, a laser microscope (e.g., an ultra-deep 3D shape measuring microscope VK-9710, manufactured by Keyence Corporation) equipped with a laser confocal optical system, two-dimensional scanning capability, and line roughness analysis functionality (e.g., shape analysis application VK-H1A1 / VK-H2A1, manufactured by Keyence Corporation) is used to capture images of the surface at a 50x objective lens magnification. When measuring the outer surface of a hollow fiber membrane, a pre-dried hollow fiber membrane is placed directly on the sample stage and images are captured. When measuring the inner surface, a pre-dried hollow fiber membrane is cut into a semi-cylindrical shape to expose the inner surface, and images are captured. Ten different positions are selected from the obtained image in random directions and locations, and line segments are extracted in the radial direction of the hollow fiber membrane. The arithmetic mean roughness can be calculated from the extracted reference length l (here, the term "line segment" is synonymous with the reference length l; when the length of the extracted line segment is 20 μm, the reference length l is 20 μm). This operation is performed on images from three different fields of view, and the average value is taken as the arithmetic mean roughness (Ra) of the hollow fiber membrane. Figure 1 shows the extracted reference length l (μm), the profile curve, and the average line. The arithmetic mean roughness is calculated by averaging the absolute values ​​(μm) of the deviations (μm) from the average line of this extracted portion to the profile curve, and is calculated using the following formula 3. Here, Ra refers to the arithmetic mean roughness, and f(x) is a function representing the surface irregularity shape at an arbitrary position x in the laser microscope image. In this specification, the arithmetic mean roughness (Ra) is calculated using a reference length l of 20 μm.

[0042]

[0043] When measuring the arithmetic mean roughness (Ra), it is necessary to dry the hollow fiber membrane beforehand, taking into consideration changes in shape due to hydration of the surface and changes in the wet state due to evaporation of water.

[0044] The "mean line" refers to a line obtained by replacing a profile curve with a straight line using the least squares method, as specified in JIS B 0601:2001.

[0045] The "contour curve" is the curve that traces the contour of the material surface when an image of the material surface to be measured is captured using a laser microscope, as shown in Figure 1, and is also called the measurement cross-sectional curve.

[0046] The arithmetic mean roughness (Ra) of the surface of the hollow fiber membrane that comes into contact with blood must be 0.10 to 0.80 μm, preferably 0.20 to 0.70 μm, and more preferably 0.30 to 0.60 μm, because forming sufficient unevenness on the surface makes it easier for cells in the blood to recognize the material and because the membrane has a sufficient specific surface area allows for highly efficient adsorption and removal of humoral factors in the blood. Any of the preferred lower limits can be combined with any of the preferred upper limits.

[0047] The "diametric direction of the hollow fiber membrane" means a direction perpendicular to the longitudinal direction of the hollow fiber membrane when the direction of travel (extrusion method) when the hollow fiber membrane is extruded by spinning is defined as the longitudinal direction of the hollow fiber membrane, and can also be referred to as the circumferential direction.

[0048] The term "ligand" refers to a compound that modifies at least the surface of the hollow fiber membrane that comes into contact with blood. If the surface that comes into contact with blood is the inner surface of the hollow fiber membrane, the inner surface is modified with a ligand. If the surface that comes into contact with blood is the outer surface of the hollow fiber membrane, the outer surface is modified with a ligand. For surfaces that do not come into contact with blood, modification with a ligand is not important. It is preferable that the ligand is distributed over the entire surface to be modified. There are no particular restrictions on the chemical structure of the ligand, as long as it contains an amino group.

[0049] Examples of the "amino group" include amino groups derived from primary amines such as methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, and dodecylamine; amino groups derived from secondary amines such as methylhexylamine, diphenylmethylamine, and dimethylamine; amino groups derived from amines having an unsaturated alkyl chain such as allylamine; amino groups derived from tertiary amines such as trimethylamine, triethylamine, dimethylethylamine, phenyldimethylamine, and dimethylhexylamine; amino groups derived from amines having an aromatic ring such as 1-(3-aminopropyl)imidazole, pyridin-2-amine, and 3-sulfoaniline; and amino groups derived from amines having an aromatic ring such as tris(2-aminoethyl)amine, ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, pentaethylenehexamine, hexaethyleneheptamine, heptaethyleneoctamine, octaethylenenonamine, and dipropylene glycol. Examples of the amino group include an amino group derived from a compound (hereinafter referred to as "polyamine") in which two or more amino groups are bonded via an alkyl chain, an aromatic compound, a heterocyclic compound, a carbocyclic compound, or the like, such as triamine, polyethyleneimine, N-methyl-2,2'-diaminodiethylamine, N-acetylethylenediamine, or 1,2-bis(2-aminoethoxyethane). Of these, an amino group derived from ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, pentaethylenehexamine, hexaethyleneheptamine, heptaethyleneoctamine, octaethylenenonamine, dipropylenetriamine, polyethyleneimine, N-methyl-2,2'-diaminodiethylamine, N-acetylethylenediamine, or 1,2-bis(2-aminoethoxyethane) is more preferred, and an amino group derived from ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, polyethyleneimine, or polyethyleneimine is even more preferred. The polyamine may be linear, branched, or cyclic.Furthermore, the hydrogen atoms bonded to the basic nitrogen atoms contained in the polyamine may be substituted with a substituent such as an alkyl group having 1 to 10 carbon atoms, an unsaturated alkyl group such as a vinyl group or an allyl group, an aryl group such as a phenyl group, a naphthyl group or an anthracyl group, or a heteroaryl group such as an imidazolyl group, a pyridyl group or a piperidyl group. There are no particular limitations on the number or substitution positions of the substituents.

[0050] The surface of the hollow fiber membrane must be modified with a ligand containing an amino group (e.g., an amino group derived from a polyamine). The surface modification can be achieved, for example, by electrostatic interaction between the hollow fiber membrane surface and the ligand (e.g., electrostatic interaction between an anionic functional group such as a sulfonic acid group and a cationic functional group such as a polyamine). Alternatively, a specific functional group present on the surface of the hollow fiber membrane can be directly bonded (covalently bonded, hydrogen bonded, etc.) to the ligand. Alternatively, a specific functional group present on the surface of the hollow fiber membrane can be bonded to the ligand via a spacer derived from a reactive functional group. Examples of such spacers include sulfonic acid groups, amide groups, carboxyl groups, sulfonamide groups, ureido groups, and ether groups. When anionic functional groups (e.g., sulfonic acid groups) are included as components constituting the hollow fiber membrane, surface modification by electrostatic interaction is preferred due to the ease of surface modification.

[0051] There are no particular restrictions on the amino group content, but in order to exhibit sufficient adsorption performance for charged organic substances such as blood components, it is preferably 0.05 mmol or more per 1 g of dry weight of the hollow fiber membrane, and in consideration of the effect on the pH of blood, it is preferably 1.00 mmol or less per 1 g of dry weight of the hollow fiber membrane. In other words, the amino group content is preferably 0.05 to 1.00 mmol, more preferably 0.10 to 0.50 mmol, and even more preferably 0.10 to 0.30 mmol per 1 g of dry weight of the hollow fiber membrane. Any preferred lower limit can be combined with any preferred upper limit.

[0052] The amino group content can be measured by acid-base titration using hydrochloric acid or an aqueous solution of sodium hydroxide.

[0053] When the component constituting the hollow fiber membrane is an acrylonitrile / sodium methallylsulfonate copolymer, the hollow fiber membrane can be produced, for example, by the following method, but is not limited to this method.

[0054] Acrylonitrile and sodium methallylsulfonate were added, and the resulting polymer with [η] = 3.2 was polymerized in DMSO, and further diluted to obtain a spinning solution with a total concentration of 13.0 wt%. Next, using a core-sheath hollow fiber membrane spinneret with an inner diameter of 0.25 mm and a slit width of 0.1 mm, this spinning solution was discharged from the sheath at a rate of 1.4 ml / min, and an 80 wt% aqueous DMSO solution was injected from the core as a coagulation liquid. The spinneret temperature was 50°C, and the discharged filament was passed through 80 mm in air (room temperature), then introduced into a coagulation bath of water at 30°C to coagulate, washed in water at 35°C, and wound up to obtain a hollow fiber membrane.

[0055] Regarding the ratio of acrylonitrile to sodium methallylsulfonate added when preparing the spinning dope, the amount of acrylonitrile added is preferably 60 to 95 mol % from the viewpoint of spinnability and yarn strength, and the amount of sodium methallylsulfonate added is preferably 5 to 40 mol % from the viewpoint of modifying the surface with a ligand for sufficiently adsorbing and removing the target substance to be removed.

[0056] Examples of methods for modifying the surface of the hollow fiber membrane prepared by the above method with a ligand include, for example, when the ligand is a polyamine, a method of impregnating the hollow fiber membrane with a polyamine solution or a method of passing a polyamine solution through the inside of the hollow fiber membrane, but the method is not limited to these methods.

[0057] Examples of solvents for dissolving polyamines include water, aqueous solutions containing salts (e.g., phosphate buffer, borate buffer, ammonium chloride buffer, aqueous sodium hydroxide solution, saline, aqueous sodium carbonate solution, and aqueous sodium hydrogen carbonate solution), and mixed solvents thereof, with water being preferred.

[0058] The pH of the solution in which the polyamine is dissolved is preferably 7 to 12.

[0059] The polyamine concentration in the solution in which the polyamine is dissolved is preferably 0.04 to 20 g / L.

[0060] The impregnation temperature when the hollow fiber membrane is impregnated is preferably 10 to 80°C, more preferably 20 to 60°C.

[0061] When the hollow fiber membrane is impregnated, the impregnation time is preferably 30 minutes to 24 hours, more preferably 1 hour to 8 hours.

[0062] To maintain the water permeability, which is one of the characteristics of hollow fiber membranes, the hollow fiber membranes are typically packed into a column after spinning. When surface treatment is performed, the hollow fiber membranes are packed into the column, and then a surface treatment solution prepared with water is passed through the hollow fiber membrane to modify the membrane surface. Therefore, the hollow fiber membranes produced by the above method have relatively smooth surfaces with no roughness, regardless of whether they are surface-modified with a ligand. It has been confirmed in the comparative examples described below that the hollow fiber membranes produced by the above method have almost no roughness on the surface that comes into contact with blood.

[0063] The present inventors have discovered that by modifying the surface of a hollow fiber membrane with an organic solvent, it is possible to impart roughness to the surface of the hollow fiber membrane while maintaining the water permeability of the hollow fiber membrane. Methods for imparting roughness to the surface of the hollow fiber membrane that comes into contact with blood include, but are not limited to, impregnating the hollow fiber membrane with the solvent shown below or passing the solvent shown below through the inside of the hollow fiber membrane.

[0064] Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, acetone, dimethyl sulfoxide, or a mixed solvent of these with water, toluene, xylene, nitrobenzene, chloroform, dichloromethane, carbon tetrachloride, hexane, and heptane, of which N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, tetrahydrofuran, acetonitrile, acetone, dimethyl sulfoxide, or a mixed solvent of these with water is preferred, dimethyl sulfoxide or a mixed solvent of dimethyl sulfoxide and water is more preferred, and a mixed solvent of dimethyl sulfoxide and water is even more preferred. Any of the solvents may be used alone, or two or more may be combined to form a mixed solvent.

[0065] When a mixed solvent of dimethyl sulfoxide and water is used as the mixed solvent, the concentration of dimethyl sulfoxide is preferably 10 to 50% by weight. The same applies to mixed solvents of other solvents and water.

[0066] The impregnation temperature when the hollow fiber membrane is impregnated is preferably 10 to 80°C, more preferably 20 to 60°C.

[0067] When impregnating a hollow fiber membrane, if the impregnation time is too long, there is a concern that the hollow fiber membrane may be excessively dissolved depending on the material of the hollow fiber membrane, whereas if the impregnation time is too short, there is a concern that sufficient roughness may not be imparted to the membrane surface. Therefore, the impregnation time is usually preferably 30 minutes to 5 hours, more preferably 1 to 4 hours, and even more preferably 1 to 3 hours.

[0068] When a solvent is passed through the inside of the hollow fiber membrane, if the flow rate is too high, the hollow fiber membrane may be excessively dissolved depending on the material of the hollow fiber membrane, so the flow rate is preferably 0.1 to 2.0 mL / min, and more preferably 0.3 to 1.5 mL / min. The same applies when passing the solvent through the outside of the hollow fiber membrane.

[0069] When a solvent is passed through the inside of the hollow fiber membrane, if the passage time is too long, there is a concern that the hollow fiber membrane may be excessively dissolved depending on the material of the hollow fiber membrane, and therefore the passage time is usually preferably 30 minutes to 5 hours, more preferably 1 to 4 hours, and even more preferably 1 to 3 hours. The same applies when the solvent is passed through the outside of the hollow fiber membrane.

[0070] When a solvent is passed through the inside of the hollow fiber membrane, the temperature of the solvent is preferably 10 to 80° C., more preferably 20 to 60° C. The same applies when the solvent is passed through the outside of the hollow fiber membrane.

[0071] The blood treatment material according to this embodiment can be used as a carrier to be packed in a blood purification column. When the blood treatment material is packed in a blood purification column, the blood treatment material may be a hollow fiber membrane bundle composed of a plurality of hollow fiber membranes. In particular, when extracorporeal circulation is performed for the purpose of treating patients with inflammatory diseases, the blood treatment material is suitably used as a carrier for adsorbing and removing activated leukocytes and / or inflammatory cytokines. When a blood purification column equipped with the blood treatment material is used as an extracorporeal circulation column for blood purification therapy, blood drawn outside the body may be passed directly through the column, or may be used in combination with a plasma separation membrane or the like.

[0072] The term "inflammatory disease" refers to all diseases that induce an inflammatory response in the body, and includes, for example, systemic lupus erythematosus, malignant rheumatoid arthritis, multiple sclerosis, ulcerative colitis, Crohn's disease, drug-induced hepatitis, alcoholic hepatitis, hepatitis A, hepatitis B, hepatitis C, hepatitis D, or hepatitis E, sepsis (e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, fungal sepsis), influenza, acute respiratory distress syndrome (ARDS, also referred to as acute respiratory distress syndrome or acute respiratory distress syndrome), acute lung injury (ALI), pancreatitis, idiopathic interstitial pneumonia (IDP), and the like. fibrosis (IPF), inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), transfusion of blood products, organ transplantation, reperfusion injury after organ transplantation, cholecystitis, cholangitis, neonatal blood type incompatibility, etc. Among inflammatory diseases, examples include drug-induced hepatitis, alcoholic hepatitis, hepatitis A, hepatitis B, hepatitis C, hepatitis D, or hepatitis E, sepsis (e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, fungal sepsis), influenza, acute respiratory distress syndrome, acute lung injury, pancreatitis, and idiopathic interstitial pneumonia, for which causative substances are released into the blood and for which blood purification is particularly expected to be therapeutically effective.

[0073] The blood purification performance of a blood treatment material can be evaluated, for example, by evaluating the removal rate of activated leukocytes. The removal rate of activated leukocytes can be calculated, for example, by filling a container having an inlet and an outlet with the blood treatment material, passing a liquid containing activated leukocytes through the container, and calculating the removal rate from the change in the concentration of activated leukocytes at the inlet and outlet.

[0074] Since activated leukocytes are cells and the degree of leukocyte activation varies among individuals, a removal rate of 6% or more of activated leukocytes can be determined to be significant. On the other hand, when blood is passed through the inside of a hollow fiber membrane, excessive adsorption of activated leukocytes to the hollow fiber membrane can cause clogging and raise concerns about an increase in circulation pressure. Therefore, a removal rate of activated leukocytes of 80% or less is preferred.

[0075] Another method for evaluating the blood purification performance of a blood treatment material is to measure the interleukin-8 (hereinafter referred to as IL-8) adsorption rate. IL-8 is a type of inflammatory cytokine contained in blood components, and is known to be present in significantly elevated levels in blood components of patients with inflammatory diseases, particularly those with diseases caused by bronchiolitis or viral infections. Therefore, IL-8 is a suitable blood component for evaluating blood purification performance. The higher the IL-8 adsorption rate, the higher the blood purification performance of the blood treatment material can be determined to be.

[0076] The blood purification column of the present invention is characterized by comprising the above-mentioned blood treatment material.

[0077] The blood purification column according to this embodiment can be used to purify or remove a target blood component from a liquid containing blood components, etc., and can be used, for example, to separate a specific blood component. Among blood components, the column is preferably used to adsorb and remove cells in blood and humoral factors in blood, and is particularly preferably used as a blood purification column for adsorbing and removing activated leukocytes and / or inflammatory cytokines.

[0078] The shape of the container for the blood purification column may be any shape, as long as it has inlet and outlet ports for a liquid containing blood components, inlet and outlet ports for a dialysate solution, and a case that allows the blood treatment material to be filled into the case. In one embodiment, hollow fiber membranes are cut to the required length, bundled together in the required number, and placed in a cylindrical case. Then, temporary caps are attached to both ends, and a potting agent is placed on both ends of the hollow fiber membranes. After the potting agent has solidified, both ends of the hollow fiber membranes are cut so that both ends are open. Headers are attached to both ends of the case, and the nozzles of the headers and case are plugged to obtain a hollow fiber membrane-packed column. From the viewpoint of ensuring a sufficient amount of dialysate flows uniformly, the filling rate of the hollow fiber membranes (the volume of the hollow fiber membranes relative to the volume of the case) is preferably 80% or less, and more preferably 70% or less. Furthermore, in order to maintain the adsorption and removal performance of activated leukocytes and / or inflammatory cytokines per column, the filling rate of the hollow fiber membrane (the volume of the hollow fiber membrane relative to the volume of the case) is preferably 20% or more, and more preferably 30% or more.

[0079] The blood purification column may be filled with the blood treatment material alone, or in combination with other hollow fiber membranes and various packing materials. Examples of packing materials include sheet-shaped fibers such as knitted fabrics, woven fabrics, and nonwoven fabrics, as well as membranes, particles, and hydrogels. The blood treatment material packed in the column is preferably a hollow fiber membrane bundle composed of multiple hollow fiber membranes.

[0080] The blood purification column may be used, for example, to treat patients with the above-mentioned inflammatory diseases or renal diseases, or to treat patients with renal diseases complicated with inflammatory diseases. Renal diseases include chronic renal failure and acute renal failure.

[0081] In the treatment of patients with renal failure, blood purification therapy using blood purification columns that use dialysis membranes or ultrafiltration membranes made from natural materials such as cellulose or synthetic polymers such as polysulfone, polymethyl methacrylate, and polyacrylonitrile as separation materials is widely used to remove uremic toxins and waste products from the blood. In particular, blood purification columns that use hollow fiber membranes as separation materials are highly important in the field of dialyzers because of their advantages, such as reduced extracorporeal blood circulation volume and high efficiency in removing substances from blood.

[0082] By using the blood purification column of this embodiment in the treatment of patients with inflammatory diseases such as acute lung injury and kidney diseases such as acute renal failure, it is expected that the unstable blood circulation dynamics of the patients will improve. Specifically, in the case of inflammatory diseases, it is expected that the column will be able to adsorb and remove excessively produced inflammatory cytokines and inflammatory cells in the blood, and in the case of kidney diseases, it is expected that the column will be able to remove water from the blood of patients with excess water due to renal failure or the like.

[0083] The blood treatment material of the present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples.

[0084] (Preparation of Blood Treatment Material 1) "SepXiris" (registered trademark: Baxter Corporation, medical device approval number: 22500BZX00401000), a hollow fiber membrane composed of an acrylonitrile / sodium methallylsulfonate copolymer and having polyethyleneimine on its surface, was disassembled with a pipe cutter, and the removed hollow fiber membrane (inner diameter: 240 μm, membrane thickness: 50 μm) was used as Blood Treatment Material 1. The amino group content per 1 g of dry weight of Blood Treatment Material 1 and the arithmetic mean roughness (Ra) of the surface of Blood Treatment Material 1 were calculated by analyzing Blood Treatment Material 1.

[0085] Measurement of the amino group content contained in blood treatment material 1: The amino group content contained in blood treatment material 1 was determined by subjecting the blood treatment material 1 to acid-base back titration. ３ 1.5 g of blood treatment material 1 was added to a recovery flask, and the flask was left to stand in a dryer at normal pressure and 80°C for 48 hours to obtain a dried blood treatment material 1. Next, 1.0 g of the blood treatment material 1 and 50 cm of 6M aqueous sodium hydroxide solution were placed in a polypropylene container. ３ The mixture was stirred for 30 minutes, and the blood treatment material 1 was filtered off using filter paper. ３ The blood treatment material 1 was added to the mixture and stirred for 30 minutes, and the blood treatment material 1 was filtered using filter paper. The blood treatment material 1 was added to ion-exchanged water, and washing and filtration procedures were repeated until the pH of the filtrate after filtration of the added ion-exchanged water reached 7, thereby obtaining a desalted blood treatment material 1. The desalted blood treatment material 1 was left to stand for 8 hours under vacuum conditions in a vacuum dryer set at 30°C. Next, 1.0 g of the blood treatment material 1 and 30 cm of 0.1 M hydrochloric acid were placed in a polypropylene container. ３ After stirring, 5 cm of the solution alone was added. ３ The solution was extracted and transferred to a polypropylene container. Next, 0.1 M aqueous sodium hydroxide solution was added to the extracted solution in an amount of 0.1 cm. ３The solution was then stirred for 10 minutes after the addition, and the pH of the solution was measured. The procedure of stirring for 10 minutes after the addition of the 0.1 M aqueous sodium hydroxide solution and measuring the pH was repeated 100 times in the same manner. The amount of 0.1 M aqueous sodium hydroxide solution added when the pH of the solution exceeded 8.5 was taken as the titer per gram of blood treatment material 1. The amino group content per gram of blood treatment material 1 was calculated using the titer per gram and the following equation 4. The results are shown in Table 1.

[0086] Amino group content (mmol / g) per 1 g of dry weight of blood treatment material 1 = (amount of 0.1 M hydrochloric acid added (30 cm ３ ) / Amount of hydrochloric acid extracted (5 cm ３ )} × titer per 1 g of blood treatment material 1 (cm ３ / g) × concentration of aqueous sodium hydroxide solution (0.1 mol / L) Equation 4

[0087] Measurement of the arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood treatment material 1: Blood treatment material 1 was cut into a length of 5 cm, and then further cut into a semi-cylindrical shape to expose the inner surface, which was then vacuum dried for 16 hours at 25° C. The inner surface of the dried blood treatment material 1 was imaged using a laser microscope (Keyence Corporation; Ultra-Deep 3D Shape Measuring Microscope VK-9710) with an objective lens at a magnification of 50x. Ten different positions were selected in random directions and locations from the profile curve of one hollow fiber membrane in the obtained image, with a reference length 1 of 20 μm. These line segments were extracted in the radial direction of the hollow fiber membrane, and the line segments were analyzed in a line roughness mode using the analysis software installed on the VK-9710 to measure the arithmetic mean roughness (Ra) in the radial direction of the inner surface (in accordance with JIS B 0601:2001). The above procedure was carried out for each of the three fields of view, and the average value of the values ​​obtained was used to obtain the arithmetic mean roughness (Ra) in the radial direction of the inner surface of the blood treatment material 1. The results are shown in Table 1.

[0088] Measurement of water permeability of blood treatment material 1: A hollow fiber membrane module was prepared by bundling 124 pieces of blood treatment material 1, filling them into a housing approximately 5 mm in diameter and 10 cm in length, and potting both ends with an epoxy resin-based chemical reaction adhesive "Quick Mender" (registered trademark) manufactured by Konishi Co., Ltd., and cutting to create an opening. Next, the inside of the hollow fiber membrane of the module was filled with water, and a water pressure of 100 mmHg was applied to the inside of the hollow fiber membrane for 15 minutes, and the filtration amount per unit time flowing out to the outside of the hollow fiber membrane was measured. The water permeability was calculated using the following equation 2.

[0089] Water permeability (L / h / mmHg) = Filtration volume (L) / Time (h) / Water pressure (mmHg) ... Equation 2

[0090] (Preparation of Blood Treatment Material 2) A hollow fiber membrane module was prepared by bundling 124 pieces of the above-mentioned blood treatment material 1, filling them into a housing with a diameter of approximately 5 mm and a length of 10 cm, and potting both ends with an epoxy resin-based chemical reaction adhesive "Quick Mender" (registered trademark) manufactured by Konishi Co., Ltd., and cutting and opening the housing. Next, a 50 wt % DMSO aqueous solution at 30°C was passed through the inside of the hollow fiber membrane of the module at a flow rate of 0.63 mL / min for 1 hour, and water at a flow rate of 0.63 mL / min for 1 hour, to obtain Blood Treatment Material 2.

[0091] Measurement of Amino Group Content in Blood Treatment Material 2: The amino group content in blood treatment material 2 was measured by the same procedure as in blood treatment material 1. The results are shown in Table 1.

[0092] Measurement of the arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood processing material 2: The arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood processing material 2 was measured by performing the same procedure as for blood processing material 1. The results are shown in Table 1.

[0093] Measurement of water permeability of blood treatment material 2: The water permeability of blood treatment material 2 was measured by the same procedure as for blood treatment material 1. The results are shown in Table 1.

[0094] (Preparation of Blood Treatment Material 3) Blood treatment material 3 was obtained by the same procedure as in the preparation method of blood treatment material 2, except that the time for passing the 50 wt % DMSO aqueous solution was changed to 2 hours.

[0095] Measurement of Amino Group Content in Blood Treatment Material 3: The amino group content in Blood Treatment Material 3 was measured by the same procedure as in Blood Treatment Material 1. The results are shown in Table 1.

[0096] Measurement of the arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood processing material 3: The arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood processing material 3 was measured by performing the same procedure as for blood processing material 1. The results are shown in Table 1.

[0097] Measurement of water permeability of blood treatment material 3: The water permeability of blood treatment material 3 was measured by the same procedure as for blood treatment material 1. The results are shown in Table 1.

[0098] (Preparation of Blood Treatment Material 4) Blood treatment material 4 was obtained by the same procedure as in the preparation method of blood treatment material 2, except that the time for passing the 50% by weight aqueous DMSO solution was changed to 3 hours.

[0099] Measurement of Amino Group Content in Blood Treatment Material 4: The amino group content in Blood Treatment Material 4 was measured by the same procedure as in Blood Treatment Material 1. The results are shown in Table 1.

[0100] Measurement of the arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood treatment material 4: The arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood treatment material 4 was measured by performing the same procedure as for blood treatment material 1. The results are shown in Table 1.

[0101] Measurement of water permeability of blood treatment material 4: The water permeability of blood treatment material 4 was measured by the same procedure as for blood treatment material 1. The results are shown in Table 1.

[0102] (Preparation of Blood Treatment Material 5) Blood treatment material 5 was obtained by carrying out the same operations as in the preparation method of blood treatment material 2, except that the DMSO concentration of the DMSO aqueous solution was changed to 10 wt %.

[0103] Measurement of Amino Group Content in Blood Treatment Material 5: The amino group content in Blood Treatment Material 5 was measured by the same procedure as in Blood Treatment Material 1. The results are shown in Table 1.

[0104] Measurement of the arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood processing material 5: The arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood processing material 5 was measured by performing the same procedure as for blood processing material 1. The results are shown in Table 1.

[0105] Measurement of water permeability of blood treatment material 5: The water permeability of blood treatment material 5 was measured by the same procedure as for blood treatment material 1. The results are shown in Table 1.

[0106] (Preparation of Blood Treatment Material 6) Blood treatment material 6 was obtained by the same procedure as in the preparation method of blood treatment material 2, except that the time for passing the 50 wt % DMSO aqueous solution was changed to 6 hours.

[0107] Measurement of Amino Group Content in Blood Treatment Material 6: The amino group content in blood treatment material 6 was measured by the same procedure as in blood treatment material 1. The results are shown in Table 1.

[0108] Measurement of the arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood processing material 6: The arithmetic mean roughness (Ra) in the radial direction of the inner surface of blood processing material 6 was measured by performing the same procedure as for blood processing material 1. The results are shown in Table 1.

[0109] Measurement of water permeability of blood treatment material 6: The water permeability of blood treatment material 6 was measured by the same procedure as for blood treatment material 1. The results are shown in Table 1.

[0110] Example 1

[0111] Measurement of activated leukocyte removal rate of blood treatment material 2: A hollow fiber membrane module was prepared by bundling 124 strands of blood treatment material 2 and filling a housing approximately 5 mm in diameter and 10 cm in length. Both ends were potted with Konishi Co., Ltd.'s epoxy resin-based chemical reaction adhesive "QuickMender" (registered trademark), and then cutting and opening the housing. Next, healthy human volunteer blood, to which LPS had been added at 70 EU / mL, was activated by shaking at 65 rpm at 37°C for 30 minutes. The blood was then passed through the hollow fiber membrane of the module at a flow rate of 0.63 mL / min, and blood samples were collected at the module inlet and outlet. The module outlet sample was collected after 6.5 minutes of blood flow, with the time when blood entered the module being designated as 0 minutes. The collected samples were analyzed using a multi-parameter automated hematology analyzer, and the activated leukocyte removal rate of blood treatment material 2 was determined using the following equation 5. The results are shown in Table 2.

[0112] Activated leukocyte removal rate (%) = (concentration of activated leukocytes in blood after blood flow test (10 ２ cells / μL) / (Activated leukocyte concentration in blood before blood flow test (10 ２ cells / μL))...Formula 5

[0113] Measurement of IL-8 adsorption rate of blood treatment material 2: To confirm the IL-8 adsorption performance of blood treatment material 2, blood treatment material 2 was immersed in a liquid containing IL-8 for a predetermined time, then removed, and the IL-8 adsorption rate was measured from the difference in the amount of IL-8 in the liquid before and after immersion. The measurement method is shown below.

[0114] A 50 cm portion of the blood treatment material 2 was removed and placed in a polypropylene container. 1 cm of fetal bovine serum (hereinafter referred to as FBS) prepared to have an IL-8 concentration of 2000 pg / mL was added to the container. ３ The blood was mixed by inversion for 1 hour in an incubator at 37°C, and the IL-8 concentration in the FBS was measured by enzyme-linked immunosorbent assay (ELISA). The IL-8 adsorption rate was calculated from the IL-8 concentrations before and after inversion mixing using the following formula 6. The results are shown in Table 2.

[0115] IL-8 adsorption rate (%) = {IL-8 concentration (pg / mL) before mixing by inversion - IL-8 concentration (pg / mL) after mixing by inversion} / IL-8 concentration (pg / mL) before mixing by inversion × 100 (Equation 6)

[0116] Example 2 Using blood treatment material 3, the activated leukocyte removal rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 2.

[0117] Example 3 Using blood treatment material 4, the activated leukocyte removal rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 2.

[0118] Example 4 Using blood treatment material 5, the activated leukocyte removal rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 2.

[0119] Comparative Example 1 Using blood treatment material 1, the activated leukocyte removal rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 2.

[0120] Comparative Example 2 Using blood treatment material 6, the activated leukocyte removal rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 2.

[0121]

[0122] In Table 1, the amino group content indicates the content of amino groups present on the surface of the hollow fiber membrane, and the arithmetic mean roughness (Ra) indicates the arithmetic mean roughness (Ra) in the radial direction of the inner surface of the hollow fiber membrane.

[0123]

[0124] In Table 2, the IL-8 adsorption rate indicates the rate of IL-8 adsorption and removal by the blood treatment material, and the activated leukocyte removal rate indicates the rate of activated leukocyte removal and removal by the blood treatment material.

[0125] The above results demonstrate that the blood treatment material of the present invention can adsorb and remove activated leukocytes and IL-8 more efficiently than blood treatment materials having an arithmetic mean roughness (Ra) in the radial direction of the inner surface of the hollow fiber membrane, which is the surface that comes into contact with blood, of less than 0.10 μm or more than 0.80 μm.

[0126] The blood treatment material of the present invention is water permeable and can adsorb and remove activated leukocytes, inflammatory cytokines, etc. with high efficiency, and therefore can be used as an adsorption carrier for extracorporeal circulation.

Claims

1. The hollow fiber membrane has a surface modified with a ligand containing an amino group, The blood treatment material has an arithmetic mean roughness (RaA) in the radial direction of the surface of the hollow fiber membrane that comes into contact with blood, the RaA being calculated using a laser microscope and being 0.10 to 0.80 μm.

2. 2. The blood treatment material according to claim 1, wherein the arithmetic mean roughness (RaA) is 0.30 to 0.60 μm.

3. 3. The blood treating material according to claim 1, wherein the surface in contact with blood is an inner surface of the hollow fiber membrane.

4. 3. The blood treatment material according to claim 1, wherein the hollow fiber membrane has an inner diameter of 150 to 400 μm.

5. The material of the hollow fiber membrane is a hydrophobic polymer selected from the group consisting of polyacrylonitrile, polymethyl methacrylate, polystyrene, polysulfone, polyethersulfone, polyester, copolymers thereof, and mixtures thereof; a hydrophilic polymer selected from the group consisting of polymethallyl sulfonic acid, polymethallyl sulfonate, polystyrene sulfonic acid, polystyrene sulfonate, sulfonated polysulfone, sulfonated polyethersulfone, and copolymers thereof, as well as mixtures thereof, and cellulose acetate; 3. The blood treatment material according to claim 1, which is a copolymer of the above formula (1) and (2).

6. 3. The blood treatment material according to claim 1, which is used for adsorbing and removing activated leukocytes and inflammatory cytokines.

7. A blood purification column comprising the blood treatment material according to claim 1 or 2.