Hollow fiber membrane, method for manufacturing a hollow fiber membrane, and hollow fiber membrane module

Abstract

To provide a technique that allows a gas separation hollow fiber membrane, normally used in an oxygenator, to have long-term stable biocompatibility, by a simple and easy method, and also keeps the film hydrophobic.SOLUTION: A hollow fiber membrane contains polyolefin, and hydrophilic polymer. Nitrogen atoms derived from the hydrophilic polymer excluding the portions of secondary amide bonds are contained by 0.0030 mass% or more and 0.8750 mass% or less. The nitrogen gas permeability is 5 mL / [min cm2 bar] or more.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to hollow fiber membranes and hollow fiber membrane modules, and is suitably used in applications that suppress the deterioration of membrane separation performance due to the adhesion of blood components, proteins, and organic matter. In particular, the present invention relates to a hollow fiber membrane type artificial lung for removing carbon dioxide and other carbon dioxide gases from the blood and adding oxygen to the blood in extracorporeal blood circulation. [Background technology]

[0002] Membrane oxygenators, which use porous membranes, are widely used as extracorporeal circulation devices and circulatory support cardiopulmonary bypass devices during open-heart surgery for cardiac diseases. Membrane oxygenators mainly use hollow fiber membranes, and gas exchange in the blood is performed through these membranes. There are two methods of blood perfusion to the oxygenator: the internal perfusion method, in which blood flows inside the hollow fiber membrane and gas flows outside the membrane, and the external perfusion method, in which blood flows outside the hollow fiber membrane and gas flows inside the membrane.

[0003] In hollow fiber membrane oxygenators, the inner or outer surface of the hollow fiber membrane comes into contact with the blood, and this contact affects platelet adhesion and activation. In particular, in external perfusion oxygenators, where the outer surface of the hollow fiber membrane comes into contact with the blood, the turbulent blood flow is likely to affect platelet adhesion and activation.

[0004] Medical separation membranes that come into contact with bodily fluids and blood face serious problems when proteins and platelets adhere to them, leading to decreased membrane performance and triggering biological reactions. In particular, in artificial lungs, (1) platelet adhesion to the hollow fiber membrane surface and (2) leakage of plasma components due to protein adhesion to the hollow fiber membrane surface and internal pores (plasma leak) can occur, reducing the usable membrane surface area for gas exchange and decreasing gas exchange capacity. Therefore, there is a need to impart biocompatibility to separation membranes, and various studies are being conducted to address this.

[0005] For example, a coating method wherein the surface has a polymer containing alkoxyalkyl (meth)acrylamide as a main constituent (Patent Document 1) has been disclosed. Furthermore, a method of coating polymethoxyethyl acrylate (PMEA) (Patent Document 2) has been disclosed. In addition, a method using heparin as a coating method for improving antithrombogenicity of artificial lungs has also been disclosed (Patent Document 3).

[0006] In addition, the technique of safely and easily suppressing adhesion of platelets and proteins by imparting a biocompatible hydrophilic polymer such as vinylpyrrolidone is used not only for hollow fiber membranes for artificial lungs. A method for forming a membrane by dissolving a copolymer of vinylpyrrolidone and vinyl acetate in a membrane-forming stock solution made of polysulfone (Patent Document 4) has been disclosed.

[0007] Furthermore, methods for imparting polyvinylpyrrolidone (Patent Document 5) or a copolymer of polyvinylpyrrolidone and vinyl acetate (Patent Document 6) to a membrane have been disclosed, and these hollow fiber membranes have improved protein adhesion compared to membranes before modification. [Prior Art Literature] [Patent Documents]

[0008] [Patent Document 1] Japanese Unexamined Patent Publication No. 2004-357826 [Patent Document 2] Japanese Patent No. 3908839 [Patent Document 3] Japanese Unexamined Patent Publication No. 2020-127705 [Patent Document 4] WO2013 / 012024 [Patent Document 5] Japanese Unexamined Patent Publication No. Hei 3-16626 [Patent Document 6] Japanese Unexamined Patent Publication No. 2011-78974 [Summary of Invention] [Problem to be Solved by Invention]

[0009] The method described in Patent Document 1 is unsuitable for use as a material that will come into contact with blood for extended periods because acrylamide exhibits genotoxicity. Furthermore, while PMEA exhibits excellent biocompatibility in the method described in Patent Document 2, the low solubility of the coating agent in solvents necessitates the use of methanol, a highly toxic substance, as a solvent during coating. This raises concerns that the organic solvent during coating may deform the fine membrane structure. Therefore, structural control may be required to maintain membrane performance each time coating conditions change. Additionally, there are limitations on the optimal film thickness, and when coating separation membranes, the coating may alter the membrane's separation performance, making application to gas exchange membranes and separation membranes such as artificial lungs difficult. The method described in Patent Document 3, which uses heparin, has the problem of causing allergies because heparin is a biologically derived material. Furthermore, since heparin itself is consumed as blood coagulation is inhibited, maintaining the blood coagulation inhibitory effect during prolonged use is difficult.

[0010] The method described in Patent Document 4 has the disadvantage that, because hydrophilic units are present throughout the entire membrane and the hollow fiber membrane is uniformly hydrophilized in the cross-sectional direction, hydrophobicity cannot be maintained in artificial lungs used for gas exchange, making plasma leakage more likely. In addition, in the methods described in Patent Documents 5 and 6, since hydrophilic polymers are present throughout the entire membrane, when a hollow fiber membrane is used as a gas exchange membrane, the hydrophilic polymers contribute to the seepage of plasma components into the pores inside the membrane, which can accelerate the occurrence of plasma leakage.

[0011] These effects have only been observed in protein permeable membranes where hydrophilic polymers are present throughout the membrane, and have not been observed in hollow fiber membranes for artificial lungs where hydrophobicity of the membrane must be maintained for gas exchange purposes.

[0012] While the currently widely used method of applying biocompatible hydrophilic polymers, including vinylpyrrolidone, is simple and highly effective, depending on the amount and method of application, it can hydrophilize the membrane even in the cross-sectional direction. Therefore, its application to artificial lung hollow fiber membranes has not been achieved.

[0013] In other words, the present invention has been made in view of the above circumstances, and aims to provide a technology that, by a simple method, imparts stable biocompatibility over a long period of time to hollow fiber membranes used for gas exchange in artificial lungs, while maintaining the hydrophobicity of the membrane.

[0014] The object of the present invention is to provide a high-performance hollow fiber membrane and hollow fiber membrane module that exhibits minimal platelet and protein adhesion. In other words, the objective is to provide a hollow fiber membrane and hollow fiber membrane module that can maintain biocompatibility for a longer period of time and exhibit stable and excellent gas permeability performance. [Means for solving the problem]

[0015] The inventors conducted diligent research to solve the above problems. As a result, they found that hollow fiber membranes and hollow fiber separation membrane modules with reduced platelet and protein adhesion can be achieved by the following configuration. That is, the invention is as follows. (1) comprising polyolefin and hydrophilic polymer, The above hydrophilic polymer contains 0.0030% by mass or more and 0.8750% by mass or less nitrogen atoms derived from parts other than the secondary amide bond, Nitrogen gas permeability of 5 mL / [min·cm] 2 A hollow fiber membrane that is [bar] or larger. (2) The hollow fiber membrane according to (1) above, wherein the nitrogen atom is a nitrogen atom derived from a primary amide bond and / or a nitrogen atom derived from a tertiary amide bond. (3) The hydration energy density of the hydrophilic polymer calculated based on the following formula (1) is 167 to 213 kJ·mol -1 ·nm -3 The hollow fiber membrane described in (1) or (2) above.

[0016]

number

[0017] [In equation (1), the hydration energy of monomer unit i is the absolute value of the difference between the energy of monomer unit i in water and the energy of monomer unit i in vacuum, N represents the total number of monomer species constituting the copolymer, and i represents an integer between 1 and N.] Hydration energy density of monomer unit i (kJ·mol) -1 ·nm -3 )= (Hydration energy of monomer unit i) / (Volume of monomer unit i) ... (Equation 2) (4) The hydrophilic polymer has vinylpyrrolidone units, A hollow fiber membrane according to (1) or (2) above, comprising 0.026% by mass or more and 7.000% by mass or less of the vinylpyrrolidone unit. (5) The hollow fiber membrane according to (1) or (2) above, wherein the content of the hydrophilic polymer on one surface of the hollow fiber membrane is greater than the content of the hydrophilic polymer on the other surface. (6) The hollow fiber membrane according to (1) or (2) above, wherein the hydrophilic polymer further comprises vinyl carboxylate units. (7) The hollow fiber membrane according to (6) above, wherein the number of carbon atoms at the side chain ends of the vinyl carboxylate unit is 1 to 9. (8) A hollow fiber membrane according to either (1) or (2) above, which is a uniform membrane. (9) The hollow fiber membrane according to (1) or (2) above, wherein the polyolefin is polypropylene. (10) A method for producing a hollow fiber membrane according to (1) or (2) above, comprising the following step 1.

[0018] Step 1: A step in which a hydrophilic solution is brought into contact with a hollow fiber membrane and then irradiated with radiation. (11) The method for producing a hollow fiber membrane according to (10), wherein in step 1 above, the hydrophilic solution is brought into contact with only one surface of the hollow fiber membrane. (12) A hollow fiber membrane module comprising the hollow fiber membrane described in (1) or (2) above. [Effects of the Invention]

[0019] According to the present invention, it is possible to provide a hollow fiber membrane and a hollow fiber membrane module that imparts biocompatibility to a hydrophobic hollow fiber membrane commonly used in artificial lungs, as well as a method for manufacturing a hollow fiber membrane that imparts biocompatibility. [Brief explanation of the drawing]

[0020] [Figure 1] Photographs showing the platelet adhesion state in Examples 1-16. [Figure 2] Photographs showing the platelet adhesion state in Comparative Examples 1 and 2. [Modes for carrying out the invention]

[0021] The hollow fiber membrane of the present invention comprises a polyolefin and a hydrophilic polymer, and contains 0.0030% to 0.8750% by mass of nitrogen atoms derived from the portion of the hydrophilic polymer other than the secondary amide bond, with a nitrogen gas permeability of 5 mL / [min·cm]. 2 The present invention is a hollow fiber membrane with a thickness of [bar] or more. The present invention will be described below.

[0022] The hollow fiber membrane of the present invention contains a polyolefin. The inclusion of a polyolefin in the hollow fiber membrane allows for both hydrophobicity and gas permeability. While the polyolefin is not particularly limited, polypropylene is preferred from the viewpoint of gas permeability and other factors.

[0023] The hollow fiber membrane of the present invention contains 0.0030% by mass or more and 0.8750% by mass or less nitrogen atoms derived from the portion of the hydrophilic polymer other than the secondary amide bond, per 100% by mass of the hollow fiber membrane. When the content of nitrogen atoms derived from the portion of the hydrophilic polymer other than the secondary amide bond, per 100% by mass of the hollow fiber membrane, is 0.0030% by mass or more, a sufficient effect of imparting biocompatibility is obtained. On the other hand, when it is 0.8750% by mass or less, the hydrophobicity of the hollow fiber membrane is maintained, and since no gel is formed due to crosslinking of the hydrophilic polymer itself, a decrease in the gas permeability of the hollow fiber membrane can be suppressed. Therefore, the hollow fiber membrane of the present invention contains 0.0030% by mass or more and 0.8750% by mass or less nitrogen atoms derived from the portion of the hydrophilic polymer other than the secondary amide bond, per 100% by mass of the hollow fiber membrane. Furthermore, the amount of nitrogen atoms derived from the portion of the hydrophilic polymer other than the secondary amide bond in 100% by mass of the hollow fiber membrane is more preferably 0.0033% by mass or more and 0.1250% by mass or less, and even more preferably 0.0050% by mass or more and 0.01250% by mass or less.

[0024] Furthermore, as long as the nitrogen atoms originating from parts of the hydrophilic polymer other than the secondary amide bonds are 0.0030% by mass or more and 0.875% by mass or less, there are no particular limitations on which part the nitrogen atoms originate from, but it is preferable that the nitrogen atoms originate from primary amide bonds and / or tertiary amide bonds. In other words, in the present invention, it is preferable that the nitrogen atoms originating from primary amide bonds and / or tertiary amide bonds of the hydrophilic polymer are 0.0030% by mass or more and 0.8750% by mass or less.

[0025] The nitrogen atom content derived from hydrophilic polymers in 100% by mass of hollow fiber membrane can be determined by measuring using a trace nitrogen analyzer (ND-100 model, Mitsubishi Chemical Corporation) via oxidative decomposition-chemiluminescence. Furthermore, the origin of nitrogen atoms from specific functional groups can be identified by TOF-SIMS measurement to determine the type of secondary ion containing nitrogen atoms, or by extracting the hydrophilic polymer with organic solvents such as ethanol, butanol, or hexane. 1This can be confirmed by measuring H-NMR. Furthermore, when the hydrophilic polymer contains an amide group, 1 By H-NMR measurement, the ratio of each amide bond can be calculated from the ratio of peak areas derived from primary amide bonds, secondary amide bonds, and tertiary amide bonds.

[0026] The hollow fiber membrane of the present invention has a nitrogen gas permeability of 5 mL / [min·cm 2 ·bar] or more. The nitrogen gas permeability of the hollow fiber membrane of the present invention is 5 mL / [min·cm 2 ·bar] or more, whereby sufficient gas permeation performance as an artificial lung is satisfied. The nitrogen gas permeability of the hollow fiber membrane is more preferably 10 mL / [min·cm 2 ·bar] or more, still more preferably 50 mL / [min·cm 2 ·bar] or more. Although no particular upper limit is set for the nitrogen gas permeability of the hollow fiber membrane, a hollow fiber membrane with high gas permeability is prone to causing plasma leakage, so 120 mL / [min·cm 2 ·bar] or less is preferable.

[0027] The hydrophilic polymer in the present invention means a polymer having a hydrophilic unit. In order to improve biocompatibility, the hollow fiber membrane of the present invention comprises a polyolefin and a hydrophilic polymer. Here, the hydrophilic unit means a unit such that a polymer consisting only of hydrophilic units has high water solubility, and the solubility of the polymer consisting only of hydrophilic units in water at room temperature (20°C) is 1% or more by mass.

[0028] As a result of diligent research, it has become clear that in order to achieve optimal hydrophilicity in the hollow fiber membrane of the present invention, which is necessary to balance biocompatibility and gas permeability, it is important to control the hydrophilicity of the functional group containing a nitrogen atom within the hydrophilic unit. It has been found that polymers having amide bonds other than secondary amide bonds are preferred as hydrophilic units, and polymers having amines, primary or tertiary amide bonds, or heterocyclic compounds containing a nitrogen atom are more preferred. Here, suitable examples of hydrophilic units include amines such as vinylamine, allylamine, lysine, and diallylmethylammonium chloride, primary or tertiary amide bonds such as methacrylamide, ethyl carbamate, N,N-dimethylmethacrylamide, and vinylpyrrolidone, or units having heterocyclic compounds containing a nitrogen atom such as 2-vinylpyridine. Since polymers having such hydrophilic units can improve biocompatibility, the hollow fiber membrane of the present invention has a hydrophilic polymer.

[0029] Furthermore, when the functional group containing nitrogen atoms within the hydrophilic unit is a side chain, the smaller the molecular weight of the side chain, the thinner the layer containing the hydrophilic polymer, as this allows for better biocompatibility and easier maintenance of gas permeability. Therefore, it is preferable that the molecular weight of the nitrogen atom-containing side chain of the hydrophilic polymer of the present invention is small.

[0030] The hollow fiber membrane of the present invention preferably has a layer containing a hydrophilic polymer, the thickness of which is 99.0 nm or less. The hydrophilic polymer is preferably localized on the surface of the hollow fiber membrane on the side that comes into contact with biological components. If the hydrophilic polymer is present inside the hollow fiber membrane, biological components will seep into the membrane, increasing the amount of protein adhering to the inside of the membrane, thus reducing plasma leak resistance. Furthermore, from the viewpoint of suppressing a decrease in the gas permeability of the hollow fiber membrane, the thickness of the layer containing the hydrophilic polymer is preferably 75.0 nm or less, more preferably 30 nm or less, and even more preferably 5.0 nm or less. In addition, from the viewpoint of better exhibiting the antithrombotic properties of the hydrophilic polymer, the thickness of the layer containing the hydrophilic polymer is preferably 0.1 nm or more, more preferably 0.2 nm or more.

[0031] The thickness of the layer containing the hydrophilic polymer is determined by etching the film from the surface in the film thickness direction using GCIB-TOF-SIMS (Gas Cluster Ion Gun-Mounted Time-of-Flight Secondary Ion Mass Spectrometry), and measuring the peak intensity of secondary ions originating from the hydrophilic polymer at the etching depth. If the ratio of the peak intensity of secondary ions originating from the hydrophilic polymer to the peak intensity of secondary ions originating from the hollow fiber film material is above a certain level, that depth is considered to be the layer containing the hydrophilic polymer. By determining the depth from the surface to the layer containing the hydrophilic polymer, the thickness of the layer containing the hydrophilic polymer can be determined.

[0032] The hydrophilic polymer in this invention has a hydration energy density of 167 to 213 kJ·mol, calculated based on formula (1). -1 ·nm -3 In this case, the effect of imparting biocompatibility is sufficiently obtained, the hydrophobicity of the hollow fiber membrane is maintained, and plasma leakage is less likely to occur, which is preferable. When the hydrophilicity is appropriately adjusted, the hydration energy density is 175-190 kJ·mol. -1 ·nm -3 This is preferable.

[0033] Hydration energy refers to the energy change a system gains when a solute is placed in an aqueous solution. The unit of hydration energy is, for example, J·mol. -1 These are some examples of what is used.

[0034] The hydration energy of a monomer unit is the absolute value obtained by subtracting the energy of that monomer unit in a vacuum from its energy in water.

[0035] Hydration energy density refers to the hydration energy per unit volume. The unit of hydration energy density is kJ·mol, depending on the unit of hydration energy. -1 ·nm -3 This is used.

[0036] The energy of monomer units in a vacuum and in water can be calculated using the following method.

[0037] First, we will optimize the molecular model of the monomer units described above. Density functional theory will be used for structural optimization. The functional used will be B3LYP, and the basis set will be 6-31G(d,p). Furthermore, the word "opt" will be set as the word to be included in the input file.

[0038] Next, the energy in a vacuum and the energy in water are calculated for the structure optimized as described above.

[0039] The energy in a vacuum is calculated using density functional theory. The functional used is B3LYP, and the basis set is 6-31G(d,p).

[0040] The energy in water is calculated using a density functional. The functional used is B3LYP, and the basis set is 6-31G(d,p). Furthermore, to calculate the energy in water, a continuous dielectric model is used, with the following keywords: SCRF=(PCM, G03Gefaults, Read, Solvent=Water) Radii=UAHF Alpha = 1.20 The hydration energy of the above monomer units can be determined by calculating the SCF energy in a vacuum and in water. Here, the SCF energy is the value of E written in the row labeled "SCF Done:".

[0041] The above energy calculations were performed using Gaussian09, Revision D.01 (registered trademark), quantum chemistry calculation software from Gaussian.

[0042] The hydration energy density of the above hydrophilic polymer is defined based on the following equation (1).

[0043]

number

[0044] [In equation (1) above, the hydration energy of monomer unit i is the absolute value obtained by subtracting the energy of monomer unit i in vacuum from the energy of monomer unit i in water, N represents the total number of monomer species constituting the copolymer, and i represents an integer between 1 and N.] The volume of the above monomer units can be calculated, for example, using the Connollysurface method in MaterialsStudio® from BIOVIA. The parameters used in this calculation are as follows: GridResolution=Coarse Glidinterval=0.075nm vdWfactor=1.0 Connollyradius = 0.1nm The monomer unit volume in formula (1) above shall be the structure optimized as described above.

[0045] There is no particular upper limit to the total number N of monomer species constituting the hydrophilic polymer described above, but 2 is most preferred.

[0046] In this invention, the mole fraction of formula (1) is calculated from the peak area measured using a nuclear magnetic resonance (NMR) spectrometer, as described later. If the mole fraction cannot be calculated by NMR measurement due to reasons such as overlapping peaks, the mole fraction may be calculated by elemental analysis.

[0047] Among these, vinylpyrrolidone units are preferred as hydrophilic units because they are highly versatile and are also used as stabilizers for medical tablets; in other words, polymers containing vinylpyrrolidone units are more preferred as hydrophilic polymers.

[0048] The hollow fiber membrane of the present invention preferably contains a hydrophilic polymer that includes vinylpyrrolidone units, with the vinylpyrrolidone units present in an amount of 0.026% by mass or more and 7.000% by mass or less per 100% by mass of the hollow fiber membrane. By setting the vinylpyrrolidone unit content to 0.026% by mass or more per 100% by mass of the hollow fiber membrane, the effect of imparting biocompatibility can be sufficiently enhanced. On the other hand, when the vinylpyrrolidone unit content per 100% by mass of the hollow fiber membrane is 7.000% by mass or less, the hydrophobicity of the hollow fiber membrane is maintained, making plasma leakage less likely, and furthermore, the crosslinking of the hydrophilic polymer itself does not cause a decrease in the gas permeability of the hollow fiber membrane; therefore, a vinylpyrrolidone unit content of 7.000% by mass or less is preferred. The vinylpyrrolidone unit content per 100% by mass of the hollow fiber membrane is more preferably 0.030% by mass or more and 0.993% by mass or less, and even more preferably 0.046% by mass or more and 0.099% by mass or less.

[0049] In the present invention, the content of vinylpyrrolidone units in 100% by mass of the hollow fiber membrane can be determined by converting the nitrogen atom content to the vinylpyrrolidone unit content using the following formula, since each vinylpyrrolidone unit (molecular weight: 111) contains 1 nitrogen atom (atomic weight 14) relative to the nitrogen atom content determined by trace nitrogen analysis.

[0050] Vinylpyrrolidone unit content = Nitrogen content [mass%] × (molecular weight of vinylpyrrolidone unit / atomic weight of nitrogen) Generally, the adhesion of platelets and proteins to a surface is thought to occur when the higher-order structure of the protein changes, exposing hydrophobic regions within it, and then adhering due to hydrophobic interactions with the material surface. On the other hand, bound water, whose mobility is restricted by hydrogen bonds, exists around cells such as platelets and proteins, as well as on the material surface. Therefore, it is said that if the hydrophilicity of the material surface is too strong, the bound water around the proteins will also be trapped, making it difficult to sufficiently suppress protein adhesion. In other words, it can be inferred that setting an appropriate balance between the hydrophobicity and hydrophilicity of the material surface is important for suppressing the adhesion of cells such as platelets and proteins.

[0051] Based on the above, it is important that a certain amount of hydrophilic polymer is present on the outer surface of the hollow fiber membrane that comes into contact with biological components such as blood, thereby conferring biocompatibility, in order to maintain gas permeability.

[0052] In this invention, biocompatibility means that thrombus formation on the surface of the hollow fiber membrane is suppressed due to anti-platelet adhesion and anti-protein adhesion properties. Since the reduction in the membrane area used for gas exchange in the hollow fiber membrane does not occur due to thrombus formation on the hollow fiber membrane, it is possible to maintain gas permeability performance.

[0053] Antiplatelet adhesion can be evaluated by measuring the number of platelets attached to the hollow fiber membrane, as described later.

[0054] Furthermore, since plasma leakage occurs when proteins adhere to the pores of the hollow fiber membrane, causing the membrane to become hydrophilic, having anti-protein adhesion properties makes it possible to prevent plasma leakage.

[0055] In the present invention, it is preferable that the hydrophilic polymer content on one surface of the hollow fiber membrane (based on the normalized value of secondary ion peak intensity) is greater than the hydrophilic polymer content on the other surface (based on the normalized value of secondary ion peak intensity). More preferably, it is preferable that the hydrophilic polymer content on the outer surface of the hollow fiber membrane is greater than the hydrophilic polymer content on the inner surface. This imparts biocompatibility by the hydrophilic polymer only to the surface that comes into contact with biological components. However, if the hydrophilic polymer is also present on the other surface and inside the cross-section of the hollow fiber membrane, which is the non-blood-contact portion, when blood flows, plasma may seep into the hydrophilized hollow fiber interior due to the hydrophilic polymer, potentially causing plasma leakage. Therefore, it is preferable that the hydrophilic polymer is only present on the blood-contact portion of the hollow fiber membrane. For these reasons, in the present invention, it is preferable that the hydrophilic polymer is substantially absent in the non-blood-contact portion, and the hydrophilic polymer does not weaken the hydrophobicity of the hollow fiber membrane itself, thereby preventing plasma leakage in the cross-sectional direction of the hollow fiber membrane. Therefore, it is preferable that the hydrophilic polymer is localized on one surface of the hollow fiber membrane.

[0056] The hydrophilic polymer content on one surface is preferably 80% or less, more preferably 40% or less of the hydrophilic polymer content on the other surface, and even more preferably 10% or less of the hydrophilic polymer content on the other surface, based on the normalized value of the secondary ion peak intensity, with the hydrophilic polymer content on the other surface set to 100%.

[0057] Methods for increasing the hydrophilic polymer content on one surface of a hollow fiber membrane compared to the other surface, and for ensuring the hydrophilic polymer is present on only one surface, include methods such as immobilizing the hydrophilic polymer on a hydrophobic hollow fiber membrane or mixing the hydrophilic polymer into the membrane stock solution during the manufacturing of the hollow fiber membrane and then forming the film. However, to efficiently localize the hydrophilic polymer only on the surface that comes into contact with blood, the method of immobilizing the hydrophilic polymer on a hydrophobic hollow fiber membrane is more preferable.

[0058] In this invention, the hydrophilic polymer content on each surface of the hollow fiber membrane can be determined by measuring the amount of secondary ions derived from the hydrophilic polymer on each of the inner and outer surfaces using TOF-SMS. - , and C4HNO - The sum of the peak intensities of the secondary ions (C2H) derived from the polyolefin hollow fiber membrane is used. - The normalized value of the secondary ion peak intensity, obtained by dividing by the peak intensity of the ion peak, is used as a reference for comparison. If the hydrophilic polymer content (based on the normalized value of the secondary ion peak intensity) is higher on one surface than on the other surface, it is considered that there is a large amount of hydrophilic polymer on one surface, meaning that the hydrophilic polymer content (based on the normalized value of the secondary ion peak intensity) on one surface of the hollow fiber membrane is greater than the hydrophilic polymer content (based on the normalized value of the secondary ion peak intensity) on the other surface.

[0059] The hydrophilic polymer in the hollow fiber membrane of the present invention preferably has vinyl carboxylate units. Vinyl carboxylate units are hydrophobic, and when vinyl carboxylate units are present in the hydrophilic polymer, it is possible to optimize the effect of the hydrophilic polymer on imparting biocompatibility to the substrate. A vinyl carboxylate unit refers to a repeating unit represented as "-CH(OCO-R)-CH2-" (where R is a hydrocarbon group). Generally, the more carbon atoms there are at the end R of the side chain of the vinyl carboxylate unit, the higher the hydrophobicity. Therefore, in order to maintain the hydrophobicity of the hollow fiber membrane after the application of the hydrophilic polymer, it is preferable to use a vinyl carboxylate unit with 1 or more carbon atoms at the end R of the side chain. On the other hand, if the hydrophilic polymer itself is highly hydrophobic, the water solubility of the hydrophilic polymer decreases. Therefore, it is preferable to have fewer carbon atoms at the end R of the side chain of the vinyl carboxylate unit in the hydrophilic polymer, and more preferably 9 or less. Examples of vinyl carboxylate units with 1 to 9 carbon atoms at the R terminal of the side chain include vinyl acetate (1 carbon atom), vinyl propionate (2 carbon atoms), vinyl butanoate (3 carbon atoms), vinyl pentanoate (4 carbon atoms), vinyl hexanoate (5 carbon atoms), vinyl heptanoate (6 carbon atoms), vinyl nonanoate (8 carbon atoms), and vinyl decanoate (9 carbon atoms). The R terminal of the side chain of the vinyl carboxylate unit may also contain a branched structure such as an isopropyl group or a tert-butyl group. Examples include vinyl pivalate (4 carbon atoms) and vinyl 2-ethylhexanoate (7 carbon atoms). Furthermore, the smaller the molecular weight of the vinyl carboxylate, which is the side chain of the hydrophilic polymer, the thinner the layer containing the hydrophilic polymer, as this allows for better biocompatibility and easier maintenance of gas permeability. Therefore, a smaller number of carbon atoms at the end of the vinyl carboxylate side chain is preferable. The vinyl carboxylate units in the hydrophilic polymer in the hollow fiber membrane of the present invention are particularly preferably vinyl acetate units with one carbon atom in the side chain and vinyl propionate units with two carbon atoms.

[0060] The hydrophilic polymer in this invention preferably has vinylpyrrolidone units and vinyl carboxylate units. The mole fraction of each unit in the copolymer of vinylpyrrolidone units and vinyl carboxylate units varies depending on the structure of the vinyl carboxylate unit, but is generally preferably 0.1 to 0.8, and the hydration energy density calculated based on formula (1) is 167 to 213 kJ·mol. -1 ·nm -3 It is preferable that the following conditions be met.

[0061] As the number of carbon atoms in the vinyl carboxylate unit increases, the hydrophobicity increases. Therefore, when the vinyl carboxylate has a large number of carbon atoms, it is preferable to have a low mole fraction of the vinyl carboxylate unit in the hydrophilic polymer. In particular, when the vinyl carboxylate unit is a vinyl acetate unit, a mole fraction of 0.2 to 0.8 is preferably used in the hydrophilic polymer, and more preferably 0.35 to 0.65. However, from the viewpoint of water solubility, a mole fraction of 0.60 or less for the vinyl acetate unit is preferable, and considering ease of handling, 0.35 to 0.50 is even more preferable. When a copolymer having vinylpyrrolidone units and vinyl carboxylate units is used as the hydrophilic polymer, both alternating copolymers and random copolymers can be used. In these cases, the vinylpyrrolidone units and vinyl acetate units are adjacent to each other, resulting in a high inhibitory effect on protein adhesion, and these copolymers are preferably used.

[0062] In the present invention, the hollow fiber membrane is preferably a uniform membrane. Uniform membranes generally have higher gas permeability compared to heterogeneous or asymmetric membranes, and are therefore suitable for gas exchange applications. In the present invention, a uniform membrane refers to a membrane in which the pore distribution within the hollow fiber membrane is uniformly distributed in the cross-sectional direction of the membrane, and the structure of the inner and outer surfaces of the hollow fiber membrane is identical, resulting in a symmetrical structure.

[0063] The hollow fiber membrane in this invention is preferably composed of a polyolefin. While the details of the hollow fiber membrane are not particularly limited as long as it is composed of a polyolefin, it is more preferably made of polypropylene, which can be industrially produced as a uniform membrane.

[0064] Since the hollow fiber membrane of the present invention is made of hydrophobic polyolefin, the inner and outer surfaces of the hollow fiber membrane are hydrophobic. Even when a hydrophilic polymer is applied to the hollow fiber membrane, if the amount is appropriate, the hydrophobicity of the entire membrane is maintained, so that it does not allow liquid to permeate and maintains plasma leak resistance.

[0065] One method for immobilizing a hydrophilic polymer on a hollow fiber membrane is to apply a hydrophilic solution to the surface of the hollow fiber membrane, and then crosslink the hollow fiber membrane and the hydrophilic polymer by radiation irradiation, heat treatment, or a crosslinking agent to immobilize them. Alternatively, the crosslinking reaction may be carried out by radiation irradiation or heat treatment while the hollow fiber membrane is in contact with the hydrophilic solution. The method for manufacturing the hollow fiber membrane in the present invention is not particularly limited, but it is preferable that the manufacturing method includes a step (referred to as step 1) of irradiating the hollow fiber membrane with radiation while the hydrophilic solution is in contact with it. Here, a hydrophilic solution refers to a polymer having hydrophilic units, that is, a solution containing a hydrophilic polymer.

[0066] Generally, a radiation dose of 5 to 50 kGy is preferred for step 1.

[0067] Alternatively, a crosslinking reaction may be carried out by heat treatment instead of step 1, in which case a heating temperature of 120 to 300°C is preferred.

[0068] The step of immobilizing the hydrophilic polymer onto the hollow fiber membrane may be performed before the hollow fiber membrane is assembled into the module case, after the hollow fiber membrane is assembled into the module case, or after the hollow fiber membrane is immobilized onto the module case. In particular, a manufacturing method including step 1, in which the hydrophilic solution is brought into contact with the hollow fiber membrane and then crosslinked and immobilized by radiation before the hollow fiber membrane is assembled into the module case, is preferred because it is less likely to cause deformation of the module materials other than the hydrophilic solution and the hollow fiber membrane due to heat or crosslinking agents.

[0069] In this invention, the radiation used in step 1 includes alpha rays, beta rays, gamma rays, X-rays, ultraviolet rays, and electron beams. Furthermore, blood-contact materials need to be sterilized, and radiation sterilization methods using gamma rays or electron beams are widely used. In other words, crosslinking using radiation irradiation allows for simultaneous immobilization of the hollow fiber membrane and hydrophilic polymer, as well as sterilization. When sterilization and crosslinking are performed simultaneously, an irradiation dose of 15 kGy or more is preferable. However, if the irradiation dose is 50 kGy or more, crosslinking and decomposition within the hydrophilic polymer, as well as deterioration of the hollow fiber membrane and module materials other than the hollow fiber membrane, occur, so a dose of 15 kGy or more and 50 kGy or less is preferable.

[0070] Furthermore, by using antioxidants during radiation irradiation, it is possible to control crosslinking reactions within hydrophilic polymers and prevent the modification of polyolefins, which are the materials for hollow fiber membranes. Antioxidants, as used here, are molecules that readily donate electrons to other molecules. Examples include, but are not limited to, water-soluble vitamins such as vitamin C, polyphenols, alcohols such as methanol, ethanol, propanol, ethylene glycol, propylene glycol, and glycerin, sugars such as glucose, galactose, mannose, and trehalose, inorganic salts such as sodium hydrosulfite, sodium pyrosulfite, and sodium dithionate, uric acid, cysteine, and glutathione. These antioxidants may be used individually or in mixtures of two or more. When used in blood contact materials for medical applications according to the present invention, antioxidants with low biotoxicity are preferably used, and ethanol, n-propanol, 2-propanol, ethylene glycol, propylene glycol, and glycerin are selected. If the amount of antioxidant is too high, it will suppress the crosslinking between the hollow fiber membrane and the hydrophilic polymer, and if it is too low, it will not adequately prevent the deterioration of materials. The amount of antioxidant added to the hydrophilic solution varies depending on the type of antioxidant, but in the case of ethanol, n-propanol, and 2-propanol in particular, an amount of 0.01% by mass or more and 10.0% by mass or less is preferably used, and more preferably 0.05% by mass or more and 1.0% by mass or less.

[0071] When the adsorption equilibrium constant of hydrophilic polymers to hollow fiber membranes is high, the amount of adsorption to the hollow fiber membrane is large, leading to increased hydrophilicity of the hollow fiber membrane and often a decrease in plasma leak resistance. In this case, the amount of hydrophilic polymer immobilized on the hollow fiber membrane surface can be adjusted by lowering the concentration of the hydrophilic polymer in the hydrophilic solution or by reducing the amount of hydrophilic solution used for the hollow fiber membrane.

[0072] When the hollow fiber membrane is polypropylene and the hydrophilic polymer is a copolymer of vinylpyrrolidone and vinyl acetate, the hydrophilic polymer concentration in the hydrophilic solution is preferably 20 ppm or more and 70,000 ppm or less, and more preferably 200 ppm or more and 1,000 ppm or less. The ethanol concentration is preferably 0.01% by mass or more and 10.0% by mass or less, and more preferably 0.1% by mass or more and 1.0% by mass or less. When the hollow fiber membrane is polypropylene and the hydrophilic polymer is a copolymer of vinylpyrrolidone and vinyl propionate, the hydrophilic polymer concentration in the hydrophilic solution is preferably 20 ppm or more and 70,000 ppm or less, and more preferably 200 ppm or more and 500 ppm or less. The ethanol concentration is preferably 0.01% by mass or more and 10.0% by mass or less, and more preferably 0.1% by mass or more and 1.0% by mass or less.

[0073] In the method for manufacturing a hollow fiber membrane of the present invention, a preferred method is to contact only one surface of the hollow fiber membrane with a hydrophilic solution in step 1. That is, in a manufacturing method in which a hydrophilic solution is contacted only on either the inner or outer surface of the hollow fiber membrane, radiation is irradiated while the hydrophilic solution is in contact with only one surface of the hollow fiber membrane. When the hydrophilic solution is contacted on the outer surface of the hollow fiber membrane, the ends of the hollow fiber membrane are embedded in a resin or the like to prevent the hydrophilic solution from seeping into the hollow fiber, and then radiation is irradiated to crosslink and fix the membrane. After that, the portion of the hollow fiber embedded in the resin is cut to obtain a hollow fiber membrane in which the hydrophilic polymer has been crosslinked and fixed to the outer surface. Furthermore, when the hollow fiber membrane is crosslinked and fixed while incorporated into a module case, the ends of the hollow fiber membrane can be separated from the outer and inner surfaces by a retaining plate or retaining resin of the module case. This allows the hydrophilic solution to remain only in the space in contact with the outer surface of the hollow fiber, and by irradiating it with radiation in this state, a hollow fiber membrane module can be obtained that incorporates a hollow fiber membrane in which the hydrophilic polymer has been crosslinked and fixed to the outer surface.

[0074] On the other hand, when the hydrophilic solution is brought into contact only with the inner surface, the hydrophilic solution is injected into the hollow fiber membrane, sealed, and then irradiated with radiation to crosslink the hydrophilic polymer. When injecting the hydrophilic solution into the interior, pressurized injection is preferable, and therefore, it is preferable for the crosslinking to occur when the hollow fiber membrane is inserted into and held in a module case. As the sealing material for the ends of the hollow fiber membrane, urethane resin, epoxy resin, or acrylic resin are preferred. From the viewpoint of resistance to radiation irradiation and biocompatibility, urethane resin is more preferred. Furthermore, as the module case into which the hollow fiber membrane is inserted, polypropylene, polystyrene, or polycarbonate are preferably used from the viewpoint of radiation resistance.

[0075] The hollow fiber membrane module of the present invention includes the hollow fiber membrane of the present invention. The way in which the hollow fiber membrane is incorporated into the hollow fiber membrane module of the present invention is not particularly limited, and the hollow fiber membrane can be used in bundles, layers, or coils, and its shape is not particularly limited.

[0076] The hollow fiber membrane module of the present invention is particularly suitable for use in hollow fiber membrane type artificial lungs for removing carbon dioxide and other carbon dioxide gases from the blood and adding oxygen to the blood in extracorporeal blood circulation. When used as a hollow fiber membrane type artificial lung, it is used in combination with circuits / catheters for withdrawing and returning blood to the outside of the body, pumps, blood reservoirs or warming devices, gas lines or gas cylinders, gas regulators, vital signs monitors, and device monitors. [Examples]

[0077] The present invention will be described below with reference to examples and comparative examples, but the present invention is not limited to these examples.

[0078] <Polypropylene hollow fiber membrane> The hollow fiber membranes used were made of polypropylene, with an outer diameter of 380 μm, an inner diameter of 280 μm, and a film thickness of 50 μm. The pore size measured by the bubble point method was 0.2 μm or less.

[0079] <Evaluation Method> (Nitrogen atom content in hollow fiber membrane) The nitrogen atom content in 100% by mass of hollow fiber membrane was determined by drying a hollow fiber membrane immobilized with a nitrogen-containing hydrophilic polymer, cutting it to a constant mass, and measuring the amount of nitrogen atoms contained within using a trace nitrogen analyzer (ND-100 model, Mitsubishi Chemical Corporation) by oxidative decomposition-reduced-vacuum chemiluminescence method. More specifically, 15 cm of hollow fiber membrane was thermally decomposed and oxidized, and the resulting nitric oxide was measured by chemiluminescence. Quantitative determination was calculated from a calibration curve prepared with pyridine standard solution. The measurement settings were as follows.

[0080] Electric furnace temperature: Pyrolysis section: 800℃, Catalyst section: 900℃, Main O2 flow rate: 300mL / min, Sub O2 flow rate: 300mL / min, Ar flow rate: 400mL / min, Sensing mode: High The average of three measurements was used as the measured value, and the value was rounded to the fifth decimal place.

[0081] (Nitrogen gas permeability of hollow fiber membranes) The gas permeability of the hollow fiber membrane was determined by measuring the pressure change on the permeation side per unit time using an external pressure method at a measurement temperature of 37°C, in accordance with the pressure sensor method of JIS K7126-1 (2006), and calculating the volume of the permeated gas. The supply pressure of nitrogen gas was 0.04 MPa (gauge pressure), and the volume on the permeation side was 475.9 cm³. 3 The measurement time was set to 4 minutes. The hollow fiber membrane was in a module shape with a length of 7 cm and sealed with epoxy resin, and the gas permeability was determined using the following formula. The average value of the results of three measurements was used as the measured value, and the value was rounded to the first decimal place.

[0082] Nitrogen gas permeability = Permeation gas volume [mL] / [Time [min] × Hollow fiber membrane outer surface [cm²] 2 ] × pressure difference [bar] (Hydration energy density of hydrophilic polymers) The hydration energy of a monomer unit is defined by the molecular model of the monomer unit.

[0083] The monomer-based molecular model was calculated using a structure in which the terminal ends of the repeating units were straight-chain alkanes.

[0084] For quantum chemical calculations, we used Gaussian09, Revision D.01 (registered trademark) from Gaussian, Inc., and for Connollysurface, we used MaterialsStudio (registered trademark) from BIOVIA.

[0085] The hydration energy of the above monomer units was calculated using the following method.

[0086] First, the monomer units in a vacuum were structurally optimized, and then the energy in a vacuum and in water was calculated for the optimized structure.

[0087] In the structural optimization process, density functional theory was used. The functional used was B3LYP, and the basis set was 6-31G(d,p). Furthermore, the keyword "opt" was set as the keyword to be included in the input file.

[0088] The energy in water was calculated using a density functional. The functional used was B3LYP, and the basis set was 6-31G(d,p).

[0089] The energy in water was calculated using density functional theory. The functional used was B3LYP, and the basis set was 6-31G(d,p). Furthermore, to calculate the energy in water, a continuous dielectric model was used, with the following keywords:

[0090] SCRF=(PCM, G03Gefaults, Read, Solvent=Water) Radii=UAHF Alpha = 1.20 Furthermore, the volume per monomer unit was calculated using the Connollysurface method.

[0091] The parameters used were as follows:

[0092] GridResolution=Coarse Gridinterval=0.075nm vdWfactor=1.0 Connollyradius = 0.1nm The hydration energy density of the hydrophilic polymer described above is defined by equation (1) above, based on the hydration energy and the volume calculated using the Connollysurface method. The volume of the monomer unit in equation (1) above is that of the structure optimized above. The hydration energy density was rounded to the first decimal place.

[0093] (Mole fraction of monomer units) 2 mg of hydrophilic polymer was dissolved in 2 mL of 99.7% chloroform-D (Wako Pure Chemical Industries, Ltd., 0.05 V / V% with TMS), placed in an NMR sample tube, and measured using NMR (JEOL; Superconducting FTNMREX-270). The temperature was kept at room temperature, and 32 NMR cycles were performed. From the measurement results, a region area of ​​3A was observed, enclosed by the baseline and the peak originating from a proton (3H) bonded to a carbon atom adjacent to the nitrogen atom of vinylpyrrolidone, which was present at concentrations of 2.7 to 4.3 ppm. PVP The area A is the region enclosed by the peak and baseline, which originates from the proton (1H) bonded to the α-carbon of vinyl carboxylate, observed at 4.3-5.2 ppm. VC From, A PVP / ( A PVP +A VC The value of ) was calculated and used as the mole fraction of vinylpyrrolidone units. The mole fraction was calculated by rounding to two decimal places.

[0094] (Content of vinylpyrrolidone units in hollow fiber membranes) The content of vinylpyrrolidone units in 100% by mass of the hollow fiber membrane was calculated by converting the nitrogen atom content to vinylpyrrolidone unit content using the following formula, considering that each vinylpyrrolidone unit (molecular weight: 111) contains 1 nitrogen atom (atomic weight: 14). The value was rounded to the fourth decimal place.

[0095] Vinylpyrrolidone unit content = Nitrogen content [mass%] × (molecular weight of vinylpyrrolidone unit / atomic weight of nitrogen) (Content of hydrophilic polymers on the inner and outer surfaces of the hollow fiber membrane) The hydrophilic polymer content on the inner and outer surfaces of the hollow fiber membrane was determined by measuring the signal intensity of nitrogen atom ions derived from the hydrophilic polymer using TOF-SIMS. More specifically, using TOF-SIMS5 (ION-TOF), secondary ions derived from the hydrophilic polymer, i.e., CNO3, were measured. - (m / z=42.00.) and C4HNO -The sum of the peak intensities of the negative secondary ions detected at (m / z=84.04) is used to determine the chain hydrocarbon C2H of the polyolefin substrate. - The hydrophilic polymer content (based on the normalized value of the secondary ion peak intensity) was determined by dividing the value by the peak intensity of the negative secondary ion (m / z=25.01).

[0096] Content of hydrophilic polymers on the surface (based on the normalized value of secondary ion peak intensity) ={(CNO - Secondary ion peak intensity [Counts] + (C4HNO - (Secondary ion peak intensity [Counts]) / C2H - Ion peak intensity [Counts] In the measurement, the primary ion Bi3 ++ Secondary ion polarity: negative ions only, primary ion acceleration voltage: 30kV, pulse width: 12.5ns, bunching present, detection mass range (m / z): 0-1500, raster size: 200μm, number of scans: 16, number of pixels: 256, measurement vacuum (before sample introduction): 4×10 -7 The test voltage was set to Pa or less, with charge fusion enabled, and the subsequent acceleration was 9.5 kV. For the hollow fiber membrane surface to be measured, the outer surface was measured in the hollow fiber state, and for the inner surface, the fiber was cut along its longitudinal direction to expose the inner surface. Ionic intensity was measured by taking 16 measurements of the average ionic intensity in a 200 μm square area of ​​the surface at a depth of 1-3 nm from the surface, calculating the average, and rounding to the fifth decimal place.

[0097] (Thickness of the layer containing hydrophilic polymer in the hollow fiber membrane) A hollow fiber membrane with a hydrophilic polymer containing nitrogen atoms immobilized on it was dried, and the peak intensity of secondary ions originating from the hydrophilic polymer and the secondary ions originating from the hollow fiber membrane material were measured while etching the surface with the immobilized hydrophilic polymer in the depth direction using GCIB-TOF-SIMS. The thickness of the hydrophilic polymer layer was determined by the amount of secondary ions originating from the hydrophilic polymer, CNO3. - and C4HNO -The sum of the peak intensities is used for C2H, the material of the hollow fiber membrane. - The etching distance in the depth direction where the value obtained by dividing the ion peak intensity by the etching distance is 0.5 or greater was defined as the layer containing the hydrophilic polymer.

[0098] More specifically, using TOF-SIMS5 (manufactured by ION-TOF), we can identify CNO, a negative secondary ion derived from a hydrophilic polymer. - (m / z=42.00.) and C4HNO - The sum of the peak intensities of the negative secondary ions detected at (m / z=84.04) is used to determine the chain hydrocarbon C2H of the polyolefin in the hollow fiber membrane substrate. - If the value obtained by dividing the negative secondary ion peak intensity (m / z=25.01) by the depth was 0.5 or greater, that depth was considered to be a layer containing a hydrophilic polymer.

[0099] Criteria for determining layers containing hydrophilic polymers: {(CNO - Secondary ion peak intensity [Counts] + (C4HNO - (Secondary ion peak intensity [Counts]) / C2H - Ion peak intensity [Counts] ≥ 0.5 The maximum depth to which a layer containing a hydrophilic polymer was detected from the surface, i.e., the maximum etching distance, was defined as the thickness of the layer containing the hydrophilic polymer.

[0100] In the measurement, the primary ion Bi3 ++ Secondary ion polarity: negative ions only, primary ion acceleration voltage: 30kV, pulse width: 12.5ns, bunching present, detection mass range (m / z): 0-1500, raster size: 200μm, scan rate: 1 scan / cycle, number of pixels: 128 pixels, measurement vacuum level (before sample introduction): 4×10 -7 The parameters were set to be below Pa, with charge merging, and the subsequent acceleration voltage was 9.5kV.

[0101] The etching ion was Ar-GCIB, the etching ion acceleration voltage was set to 0.25kV, and the Ar cluster size was set to 1600 (median).

[0102] The etching depth was determined by measuring the etching depth of the measurement area after measurement using a stylus-type surface roughness meter, and dividing the result by the total number of etching cycles to determine the etching depth per cycle. The secondary ion peak intensity from the outermost surface up to 8 μm was measured, and {(CNO - Secondary ion peak intensity [Counts] + (C4HNO - (Secondary ion peak intensity [Counts]) / C2H - The maximum etching depth at which the ion peak intensity [Counts] ≥ 0.5 was calculated as the thickness of the layer containing the hydrophilic polymer. The lower limit of the hydrophilic polymer layer thickness determined by this measurement was 5.0 nm.

[0103] For the hollow fiber membranes to be measured, the outer surface was measured in its hollow fiber form, while for the inner surface, the fibers were cut along their longitudinal direction to expose the inner surface. The intensity of the secondary ion peaks was determined by measuring the average intensity of the secondary ion peaks over a 200 μm square area.

[0104] (Amount of protein attachment) Hollow fiber membranes, 1.5 m long and sealed at both ends with epoxy resin, were either immobilized with a hydrophilic polymer or left untreated, and washed with PBS (Phosphate Buffered Saline). Next, the hollow fiber membranes were immersed in 10 mL of 80 g / L albumin / PBS solution and incubated at 37°C for 72 hours. After washing the hollow fiber membranes with PBS, they were immobilized with 2.5% glutaraldehyde / physiological saline solution and dried. Next, the hollow fiber membranes were immersed in 1.8 mL of working reagent from a BCA assay kit ("THERMO Scientific"®, product number: 23235, "MicroBCA"® Protein Assay Kit), incubated at 60°C for 60 minutes, and the absorbance of the working reagent at 562 nm after the reaction was measured to determine the amount of protein remaining on the fibers. The measured values ​​were rounded to two decimal places.

[0105] (Number of platelet attachments) For the platelet adhesion test, hollow fiber membranes with their outer surfaces exposed were attached to the bottom of a sample cup and arranged in a row. After contact with fresh human blood, the washed and fixed hollow fiber membranes were observed using a Scanning Electron Microscope (SEM). More specifically, as shown below, 10% ACD-A blood collection was performed to obtain platelet-rich PRP by centrifuging at 160G for 25 minutes. The hollow fiber membranes fixed to the bottom of the sample cup were pre-washed with PBS. After dispensing 1 mL of PRP into the sample cup, 100 μM of ADP (Adenosine diphosphate) was added as a platelet activation stimulant, and the sample was shaken for 15 minutes. After 15 minutes, the PRP in the sample cup was discarded, 1 mL of physiological saline was added, and the shaking and discarding process was repeated about 10 times to remove the platelets from the sample cup by washing. Next, a 2.5% glutaraldehyde / saline solution was added to the sample cup and allowed to stand for at least one hour to immobilize the platelets attached to the hollow fiber membrane. After immobilization, the immobilization solution was discarded, the sample was washed with sterile water for injection, and dried in a vacuum dryer (Tokyo Rika Kikai, FD-1) for at least one hour. For SEM observation, Pt sputtering (Hitachi High-Tech Fielding, E-1045) was performed with a discharge current of 15 mA and a time of 40 seconds, and platelets attached to the outer surface of the hollow fiber membrane were observed using an SEM (Hitachi High-Tech Fielding, SEMEDX Type-HS-3000). Observation was performed at a magnification of 1500x and a field of view of 4.35 × 10⁻⁶. 4 μm 2 The average value of 20 fields of view was used as the platelet attachment count. The number of platelets counted per field of view was limited to 50. If the count exceeded 50, it was treated as 50, and the average value was calculated, rounded to the first decimal place, to determine the platelet attachment count. Furthermore, if multiple platelets were stretched or deformed, making individual counting impossible, and platelet attachment was observed across the majority, thrombus formation was considered present.

[0106] (Example 1) The ends of a polypropylene hollow fiber membrane were sealed so that only the outer surface was in contact with the liquid. This hollow fiber membrane was immersed in a hydrophilic solution and irradiated with 25 kGy of gamma rays. The hydrophilic solution was a random copolymer of vinylpyrrolidone units and vinyl acetate units (BASF's "KOLLIDON" (registered trademark) VA64, with a mole fraction of vinylpyrrolidone units of 0.6) and contained 0.1% by mass of ethanol. After gamma ray irradiation, the hollow fiber membrane was washed with PBS, and the nitrogen content, protein adhesion, platelet adhesion count, and nitrogen gas permeability of the hollow fiber membrane were measured.

[0107] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high nitrogen gas permeability.

[0108] (Example 2) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 200 ppm of a random copolymer of vinylpyrrolidone units and vinyl acetate units (BASF's "KOLLIDON" (registered trademark) VA64, with a mole fraction of vinylpyrrolidone units of 0.6) and 0.1% by mass of ethanol.

[0109] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high nitrogen gas permeability.

[0110] (Example 3) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 1000 ppm of a random copolymer of vinylpyrrolidone units and vinyl acetate units (BASF's "KOLLIDON" (registered trademark) VA64, with a mole fraction of vinylpyrrolidone units of 0.6) and 0.1% by mass of ethanol.

[0111] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high nitrogen gas permeability.

[0112] (Example 4) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 10,000 ppm of a random copolymer of vinylpyrrolidone units and vinyl acetate units (BASF's "KOLLIDON" (registered trademark) VA64, with a mole fraction of vinylpyrrolidone units of 0.6) and 0.1% by mass of ethanol.

[0113] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high nitrogen gas permeability.

[0114] (Example 5) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 70,000 ppm of a random copolymer of vinylpyrrolidone units and vinyl acetate units (BASF's "KOLLIDON" (registered trademark) VA64, with a mole fraction of vinylpyrrolidone units of 0.6) and 0.1% by mass of ethanol.

[0115] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high nitrogen gas permeability.

[0116] (Example 6) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 20 ppm of a random copolymer of vinylpyrrolidone units and vinyl propionate units (weight-average molecular weight 55,000, mole fraction of vinylpyrrolidone units 0.6) and 0.1% by mass of ethanol.

[0117] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high nitrogen gas permeability.

[0118] (Example 7) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 200 ppm of a random copolymer of vinylpyrrolidone units and vinyl propionate units (weight-average molecular weight 55,000, mole fraction of vinylpyrrolidone units 0.6) and 0.1% by mass of ethanol.

[0119] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high nitrogen gas permeability.

[0120] (Example 8) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 1000 ppm of a random copolymer of vinylpyrrolidone units and vinyl propionate units (weight-average molecular weight 55,000, mole fraction of vinylpyrrolidone units 0.6) and 0.1% by mass of ethanol.

[0121] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, demonstrating high biocompatibility and high nitrogen gas permeability.

[0122] (Example 9) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 1000 ppm of a random copolymer of vinylpyrrolidone units and vinyl propionate units (weight-average molecular weight 55,000, mole fraction of vinylpyrrolidone units 0.6) and 10.0% by mass of ethanol.

[0123] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high nitrogen gas permeability.

[0124] (Example 10) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 5000 ppm of a random copolymer of vinylpyrrolidone units and vinyl propionate units (weight-average molecular weight 55,000 (weight-average molecular weight 55,000, mole fraction of vinylpyrrolidone units 0.6)) and 10.0% by mass of ethanol.

[0125] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high nitrogen gas permeability.

[0126] (Example 11) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 300 ppm of a random copolymer of vinylpyrrolidone units and vinyl butanoate units (weight-average molecular weight 42,000, mole fraction of vinylpyrrolidone units 0.6) and 0.5% by mass of ethanol.

[0127] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high gas permeability.

[0128] (Example 12) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 300 ppm of a random copolymer of vinylpyrrolidone units and vinyl nonanoate units (weight-average molecular weight 4,400, mole fraction of vinylpyrrolidone units 0.8) and 10.0% by mass of ethanol.

[0129] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high gas permeability.

[0130] (Example 13) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 300 ppm of a random copolymer of vinylpyrrolidone units and vinyl decanoate units (weight-average molecular weight 19,000, mole fraction of vinylpyrrolidone units 0.8) and 10.0% by mass of ethanol.

[0131] The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high gas permeability.

[0132] (Example 14) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 300 ppm of a random copolymer of vinylpyrrolidone units and vinyl pivalate units (weight-average molecular weight 3,900, mole fraction of vinylpyrrolidone units 0.7) and 1.0% by mass of ethanol. The results are shown in Table 1. The hollow fiber membrane exhibited low levels of protein adhesion and platelet adhesion, resulting in high biocompatibility and high gas permeability. (Example 15) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 5000 ppm of a random copolymer of vinylpyrrolidone units and vinyl propionate units (weight-average molecular weight 55,000, mole fraction of vinylpyrrolidone units 0.6) and 20.0% by mass of ethanol.

[0133] The results are shown in Table 1. The hollow fiber membrane had a slightly higher amount of protein attachment but a lower number of platelet attachments, indicating high biocompatibility. (Example 16) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 7500 ppm of a random copolymer of vinylpyrrolidone units and vinyl propionate units (weight-average molecular weight 55,000, mole fraction of vinylpyrrolidone units 0.6) and 30.0% by mass of ethanol.

[0134] The results are shown in Table 1. The hollow fiber membrane had a high amount of protein attachment and a low number of platelet attachments, but was highly biocompatible.

[0135] (Comparative Example 1) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution that did not contain a random copolymer of vinylpyrrolidone units and vinyl carboxylate units, and contained 0.1% by mass of ethanol.

[0136] The results are shown in Table 1. The hollow fiber membranes had high levels of protein adhesion and platelet attachment, indicating low biocompatibility.

[0137] (Comparative Example 2) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the hydrophilic solution was different. The hydrophilic solution was a solution containing 20 ppm of a random copolymer of vinylpyrrolidone units and vinyl acetate units (BASF's "KOLLIDON" (registered trademark) VA64, with a mole fraction of vinylpyrrolidone units of 0.6) and 0.1% by mass of ethanol.

[0138] The results are shown in Table 1. The hollow fiber membrane had a low amount of protein attachment but a high number of platelet attachments, indicating poor biocompatibility.

[0139] (Comparative Example 3) The treatment and evaluation were carried out in the same manner as in Example 1, except that the composition of the nitrogen solution was different. The nitrogen solution was a solution containing 700,000 ppm of a random copolymer of vinylpyrrolidone units and vinyl acetate units (BASF's "KOLLIDON" (registered trademark) VA64, with a mole fraction of vinylpyrrolidone units of 0.6) and 0.1% by mass of ethanol.

[0140] The results showed a high concentration of hydrophilic polymers, leading to the formation of a hydrophilic polymer gel, making it unsuitable for use as a hollow fiber membrane.

[0141] Table 2 shows the hydrophilic polymer used in each example and comparative example, the number of carbon atoms at the end of the side chain of the vinyl carboxylate unit of the hydrophilic polymer, the mole fraction of the vinylpyrrolidone unit, and the hydration energy density of the hydrophilic polymer.

[0142] [Table 1]

[0143] In the table, "Hollow Fiber Membrane Nitrogen Content (mass%)" refers to the content (mass%) of nitrogen atoms originating from parts of the hydrophilic polymer other than the secondary amide bonds in 100% by mass of the hollow fiber membrane.

[0144] In the table, "Vinylpyrrolidone content in hollow fiber membrane (mass%)" refers to the content (mass%) of vinylpyrrolidone units in 100% by mass of the hollow fiber membrane.

[0145] [Table 2] [Industrial applicability]

[0146] While blood components are used as an example of the contact liquid in this invention, it is not limited to blood components. For example, cell suspensions consisting of somatic cells or germ cells, somatic stem cells, induced pluripotent stem cells, or embryonic hepatocytes processed from cells, microorganisms, plant culture cells, or biological tissues; blood products such as platelet preparations or red blood cell preparations; or dispersions of synthetic microparticles, inorganic microparticles, vesicles, etc. Furthermore, these contact liquids are not limited to those mentioned above, and applications to rainwater, seawater, soil liquid, or synthetic polymer solutions in the environment are also included. These solutions can also be used as oxygenation membranes or degassing membranes.

Claims

1. It comprises polyolefin and hydrophilic polymer, The hydrophilic polymer contains 0.0030% by mass or more and 0.8750% by mass or less nitrogen atoms derived from the portion other than the secondary amide bond, Nitrogen gas permeability is 5 mL / min·cm ２ • bar] or higher, A hollow fiber membrane in which the content of the hydrophilic polymer on one surface of the hollow fiber membrane is greater than the content of the hydrophilic polymer on the other surface.

2. The hollow fiber membrane according to claim 1, wherein the nitrogen atom is a nitrogen atom derived from a primary amide bond and / or a nitrogen atom derived from a tertiary amide bond.

3. The hydration energy density of the hydrophilic polymer calculated based on the following formula (1) is 167 to 213 kJ / mol －１ nm －３ The hollow fiber membrane according to claim 1 or 2. [Math 1] [In equation (1), the hydration energy of monomer unit i is the absolute value obtained by subtracting the energy of monomer unit i in vacuum from the energy of monomer unit i in water, N represents the total number of monomer species constituting the copolymer, and i represents an integer between 1 and N.] Hydration energy density of monomer unit i (kJ·mol) －１ nm －３ ) = (Hydration energy of monomer unit i) / (Volume of monomer unit i) ... Equation (2)

4. The hydrophilic polymer has vinylpyrrolidone units, The hollow fiber membrane according to claim 1 or 2, comprising 0.026% by mass or more and 7.000% by mass or less of the vinylpyrrolidone unit.

5. The hollow fiber membrane according to claim 1 or 2, wherein the hydrophilic polymer has vinyl carboxylate units.

6. The hollow fiber membrane according to claim 5, wherein the number of carbon atoms at the side chain ends of the vinyl carboxylate unit is 1 to 9.

7. The hollow fiber membrane according to claim 1 or 2, which is a uniform membrane.

8. The hollow fiber membrane according to claim 1 or 2, wherein the polyolefin is polypropylene.

9. A method for producing a hollow fiber membrane according to claim 1 or 2, comprising the following step 1. Step 1: A step in which a hydrophilic solution is brought into contact with only one surface of the hollow fiber membrane, and then radiation is applied.

10. A hollow fiber membrane module comprising the hollow fiber membrane described in claim 1 or 2.

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