CN114080246A - Blood treatment filter and method for producing blood preparation - Google Patents
Blood treatment filter and method for producing blood preparation Download PDFInfo
- Publication number
- CN114080246A CN114080246A CN202080049839.8A CN202080049839A CN114080246A CN 114080246 A CN114080246 A CN 114080246A CN 202080049839 A CN202080049839 A CN 202080049839A CN 114080246 A CN114080246 A CN 114080246A
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- blood
- filter
- nonwoven fabric
- filtration
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- A61M1/0218—Multiple bag systems for separating or storing blood components with filters
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
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- A—HUMAN NECESSITIES
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- B01D29/01—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with flat filtering elements
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01D39/14—Other self-supporting filtering material ; Other filtering material
- B01D39/16—Other self-supporting filtering material ; Other filtering material of organic material, e.g. synthetic fibres
Abstract
An object is to provide a blood processing filter having excellent leukocyte removal rate and filtration time (filtration rate). The aforementioned problems can be solved by the following blood filter. A blood processing filter, comprising: the blood filter comprises a filter layer comprising a nonwoven fabric, fibers of the nonwoven fabric having a degree of orientation X in the X-axis plane direction of the filter layer and a degree of orientation Y in the Y-axis plane direction orthogonal to the X-axis plane direction, and a maximum value of a ratio of the degree of orientation X to the degree of orientation Y (degree of orientation X/degree of orientation Y) is 1.2 or more.
Description
Technical Field
The present invention relates to a blood treatment filter and a method for producing a blood preparation.
Background
In the field of blood transfusion, in addition to so-called whole blood transfusion in which a whole blood product obtained by adding an anticoagulant to blood collected from a donor is transferred, so-called component transfusion in which a blood component required by a recipient is separated from a whole blood product and the blood component is infused is generally performed. Component transfusion includes red blood cell transfusion, platelet transfusion, plasma transfusion, and the like depending on the type of blood component required by a recipient, and blood preparations used for these transfusions include red blood cell preparations, platelet preparations, plasma preparations, and the like.
Recently, so-called leukapheresis blood transfusion, in which leukocytes contained in a blood product are removed and then the blood product is transferred, has been widely used. This is because it is known that severe side effects such as headache, nausea, chills, nonhemolytic fever, etc. accompanying blood transfusion, alloantigen sensitization which seriously affects the recipient, viral infection, and GVHD after blood transfusion are mainly caused by leukocytes mixed in blood preparations used for blood transfusion. In order to prevent slight side effects such as headache, nausea, chills, fever, etc., it is said that leukocytes in blood preparations are removed to a residual rate of 10-1～10-2The following may be used. In order to prevent alloantigen sensitization and viral infection, which are serious side effects, it is said that leukocytes need to be removed to a residual rate of 10-4～10-6The following.
In recent years, for the treatment of diseases such as rheumatism and ulcerative colitis, a clinical effect is high by performing a leukoreduction therapy using extracorporeal circulation of blood.
The current methods for removing leukocytes from blood preparations differ roughly by the following 2 methods: a centrifugal separation method in which leukocytes are separated and removed by using a centrifugal separator by utilizing a difference in specific gravity between blood components; and a filter method of removing leukocytes using a filter element including a fiber aggregate such as a nonwoven fabric or a porous structure having continuous pores. The filter method for removing leukocytes by adhesion or adsorption is currently most popular because of its advantages such as easy operation and low cost.
In recent years, in medical practice, a new demand has been made for a leukocyte removal filter. One of the requirements is to further reduce the size and weight of the filter in order to reduce the cost for disposing the filter. The reason is that the filter after filtering blood corresponds to infectious waste, and the cost of disposal is generally spent at a unit price per unit weight. By downsizing, unnecessary cost can be further suppressed for medical institutions.
In this case, the idea of efficient filter design is that it is appropriate to increase the effective utilization rate of the filter material used in the filter. By improving the effective utilization rate, even a small amount of the filter material can adsorb a sufficient amount of leukocytes in blood. As means therefor, the following methods are often used: when blood flows into the filter, the filter material is uniformly distributed in a direction in which the blood spreads perpendicularly to the blood flow (generally, in the planar direction of the filter), whereby the blood spreads uniformly into the filter, resulting in an improvement in the effective utilization rate.
As a specific example thereof, patent document 1 discloses that a nonwoven fabric, which is one type of filter material, is used to improve the uniformity in the planar direction (to make the texture good), thereby improving the leukocyte removal rate of the filter material.
Further, patent document 2 discloses the following technique: by appropriately controlling the flow rate (infiltration coefficient) of blood in the planar direction and the vertical direction of the filter, both the improvement of the leukocyte removal rate and the reduction of the filtration time can be achieved.
Documents of the prior art
Patent document
Patent document 1: international publication No. 2004/050146
Patent document 2: international publication No. 2005/120600
Disclosure of Invention
Problems to be solved by the invention
It was found that, in the case of the filter material of patent document 1 in which nonwoven fabric fibers are uniformly distributed, aggregates contained in blood are uniformly clogged on the surface of the nonwoven fabric, and the risk of blood waste due to the extension of the filtration time and the stoppage of filtration is high, and therefore, the filter material is not suitable for filtration. In addition, it was found that since blood having a low viscosity immediately passes through the filter, the retention time in the filter is too short, and the leukocyte removal rate is low. That is, there are the following problems: only certain blood with a suitable viscosity and as far as possible free of aggregates of a size inducing clogging can be filtered.
Patent document 2 does not specify anisotropy of flow in a plane, and therefore does not consider how to control the flow in a plane so as to be effectively used, and as a result, a drift occurs in the plane, and a filtering performance cannot be sufficiently exhibited. That is, because of the reason that the in-plane flow is not uniform, the low-viscosity blood passes only through a part of the filter, and the entire filter is not used, so that there is a problem that the filtration performance is insufficient, and the filter design needs to be changed depending on the properties of the blood.
The purpose of the present invention is to provide a blood treatment filter having excellent leukocyte removal rate and filtration time (filtration rate).
Means for solving the problems
As a result of intensive studies, the present inventors have found that the above-mentioned problems can be solved by adjusting the direction of fibers of a nonwoven fabric contained in a filter layer constituting a filter medium. The present inventors have also found that the above-described problems can be solved by providing a predetermined space inside a filter layer constituting a filter medium.
Namely, the present invention is as follows.
[1] A blood processing filter, comprising:
a container having an inlet portion and an outlet portion for blood, and
a filter material disposed between the inlet portion and the outlet portion in the container,
the filter material comprises a filter layer,
the filter layer comprises a non-woven fabric,
the fibers of the nonwoven fabric have a degree of orientation X in the X-axis plane direction of the filter layer and a degree of orientation Y in the Y-axis plane direction orthogonal to the X-axis plane direction,
the maximum value of the ratio of the orientation degree X to the orientation degree Y (orientation degree X/orientation degree Y) is 1.2 or more.
[2] The blood treatment filter according to [1], wherein the maximum value of the orientation degree X/the orientation degree Y is 1.4 or more.
[3] The blood treatment filter according to [1] or [2], wherein the aforementioned filter layer is configured in such a manner that: the ratio (Ac/Am) of the degree of orientation (Ac) of the fibers in the plane direction of the filter layer perpendicular to the filtration direction to the degree of orientation (Am) of the fibers in the plane direction of the filter layer parallel to the filtration direction is 1.2 or more.
[4] The blood treatment filter according to [3], wherein Ac/Am is 1.4 or more.
[5] The blood treatment filter according to [1] or [2], wherein the aforementioned filter layer is configured in such a manner that: the ratio (Am/Ac) of the degree of orientation (Am) of the fibers in the plane direction of the filter layer parallel to the filtration direction to the degree of orientation (Ac) of the fibers in the plane direction of the filter layer orthogonal to the filtration direction is 1.2 or more.
[6] The blood treatment filter according to [5], wherein Am/Ac is 1.4 or more.
[7] The blood treatment filter according to any one of [1] to [6], wherein the nonwoven fabric is a polyester nonwoven fabric.
[8] A blood processing filter, comprising:
a container having an inlet portion and an outlet portion for blood, and
a filter material disposed between the inlet portion and the outlet portion in the container,
the filter material comprises more than one filter layer,
the filter layer has a space in which the maximum length in the planar direction is 50 [ mu ] m or more and the maximum length in the thickness direction is 15 [ mu ] m or more in a cross section in the thickness direction.
[9] The blood treatment filter according to [8], wherein a filling rate of the filter layer is 0.09 to 0.26.
[10] The blood treatment filter according to [8] or [9], wherein a difference between a minimum in-plane porosity in a thickness direction and a maximum in-plane porosity in the thickness direction of the filter layer is 0.08 to 0.28.
[11] The blood treatment filter according to [10], wherein the minimum porosity in the thickness direction is 0.72 to 0.85 and the maximum porosity in the thickness direction is 0.85 to 1.00.
[12]According to [8]～[11]The blood treatment filter according to any one of the above items, wherein the filter layer has a specific surface area of 0.50 to 1.50m2/g。
[13] The blood treatment filter according to any one of [8] to [12], wherein the critical wetting surface tension of the filter layer is 70 to 100 dyn/cm.
[14] A method for producing a blood product, comprising a step of passing blood containing leukocytes through a blood treatment filter according to any one of [1] to [13 ].
ADVANTAGEOUS EFFECTS OF INVENTION
According to the present invention, a blood processing filter excellent in leukocyte removal rate and filtration time (filtration rate) can be provided.
Drawings
Fig. 1 is a schematic view of a blood treatment filter according to an embodiment of the present invention.
Fig. 2 is a cross-sectional view of the blood treatment filter of fig. 1.
Fig. 3 is a schematic view of a blood treatment filter according to an embodiment of the present invention.
Fig. 4 is a schematic view of a plane of the blood treatment filter of fig. 3 as viewed from the front.
FIG. 5 is a view showing a method of regulating Ac: Am.
FIG. 6 is a view showing a method of regulating Ac: Am.
Fig. 7 shows a method for testing leukocyte removal performance.
FIG. 8A shows a cross section in the thickness direction of the filter layer of example A1 (cut surface obtained by cutting in the thickness direction).
Fig. 8B is an enlarged view of the cross section of fig. 8A.
FIG. 9 shows the in-plane porosity in the thickness direction of the filter layer of example A1.
FIG. 10 shows the in-plane porosity in the thickness direction of the filter layer of example A12.
Fig. 11 shows the in-plane porosity in the thickness direction of the filter layer of comparative example a 1.
Fig. 12 shows the in-plane porosity in the thickness direction of the filter layer of comparative example a 2.
Fig. 13 shows an example of a method for producing a nonwoven fabric.
Detailed Description
Hereinafter, a mode for carrying out the present invention (hereinafter, referred to as the present embodiment) will be described in detail. The present invention is not limited to the following embodiments, and various modifications can be made within the scope of the present invention.
Hereinafter, unless otherwise clearly stated, the term "blood" includes blood and blood component-containing liquids. Examples of the liquid containing a blood component include blood preparations. Examples of the blood preparation include a whole blood preparation, an erythrocyte preparation, a platelet preparation, and a plasma preparation.
< 1 st blood treatment Filter >
One embodiment of the present invention relates to a blood treatment filter including:
a container having an inlet portion and an outlet portion for blood, and
a filter material disposed between the inlet portion and the outlet portion in the container,
the filter medium includes a filter layer (hereinafter also referred to as "the 1 st filter layer"),
the filter layer comprises a non-woven fabric,
the fibers of the nonwoven fabric have a degree of orientation X in the X-axis plane direction of the filter layer and a degree of orientation Y in the Y-axis plane direction orthogonal to the X-axis plane direction,
the maximum value of the ratio of the orientation degree X to the orientation degree Y (orientation degree X/orientation degree Y) is 1.2 or more.
By adjusting the direction of the fibers of the nonwoven fabric contained in the filtration layer, an excellent leukocyte removal rate and an excellent filtration time (filtration rate) can be exhibited.
Fig. 1 is a schematic view of an embodiment of a blood processing filter (leukocyte removal filter), and fig. 2 is a sectional view taken along line II-II of fig. 1.
As shown in fig. 1 and 2, the blood treatment filter 10 includes a flat container 1 and a substantially dry filter medium 5 accommodated therein. The container 1 containing the filtering material 5 comprises two elements: an inlet-side vessel having an inlet 3, and an outlet-side vessel having an outlet 4. The space in the flat container 1 is partitioned into an inlet-side space 7 and an outlet-side space 8 by the filter medium 5.
In the blood treatment filter 1, the inlet-side container and the outlet-side container are arranged so as to sandwich the filter medium 5, and both containers are configured such that the outer edge portion 9 of the filter medium 5 is sandwiched and gripped by gripping portions provided at a part of each container.
In one embodiment, the filter medium and the container may be joined by welding or the like to each other to hold the filter medium in the container.
[ Container ]
Examples of the material of the container include a hard resin and a flexible resin.
Examples of the hard resin include phenol resin, acrylic resin, epoxy resin, formaldehyde resin, urea resin, silicone resin, ABS resin, nylon, polyurethane, polycarbonate, vinyl chloride, polyethylene, polypropylene, polyester, and styrene-butadiene copolymer.
The flexible resin preferably has thermal and electrical properties similar to those of the filter layer. Examples of the flexible resin include soft polyvinyl chloride, polyurethane, ethylene-vinyl acetate copolymer, polyolefin such as polyethylene and polypropylene, hydrogenated product of styrene-butadiene-styrene copolymer, thermoplastic elastomer such as styrene-isoprene-styrene copolymer or hydrogenated product thereof, and a mixture of thermoplastic elastomer and a softening agent such as polyolefin and ethylene-ethyl acrylate. The flexible resin is preferably soft polyvinyl chloride, polyurethane, an ethylene-vinyl acetate copolymer, polyolefin, or a thermoplastic elastomer containing these as a main component, and more preferably soft polyvinyl chloride or polyolefin.
In the case where the shape of the container is, for example, a flat plate-like filter medium, a polygonal shape such as a square shape or a hexagonal shape, a flat shape such as a circular shape or an elliptical shape may be formed in accordance with the shape (for example, fig. 1 and 2). In addition, when the filter medium is cylindrical, the container is also preferably cylindrical.
[ Filter Material ]
(the 1 st Filter layer)
The filter medium comprises more than one layer of the 1 st filter layer. In the case where the filter includes a plurality of the 1 st filter layers, the plurality of the 1 st filter layers may be the same or different, respectively.
The 1 st filter layer preferably comprises a nonwoven fabric. The nonwoven fabric is preferably laminated. The material of the nonwoven fabric is not particularly limited, and examples thereof include polyester (e.g., polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)), polyamide, polyacrylonitrile, polymethyl methacrylate, polyethylene, polypropylene, and the like. By using such a material, denaturation of blood can be prevented. The material of the nonwoven fabric is preferably polyester, more preferably PET or PBT, from the viewpoint of affinity with blood preparations and wettability with blood. The nonwoven fabric may be formed of only one material, or may be formed of a plurality of materials.
The nonwoven fabric contained in the 1 st filter layer may have a coating layer on its surface. In the present specification, a nonwoven fabric having no coating layer is also referred to as a "fibrous base material". By appropriately selecting the material of the coating layer, the zeta potential of the surface can be easily set to 0mV or more.
The coating layer, for example, preferably comprises a copolymer comprising monomer units having a nonionic hydrophilic group and monomer units having a basic nitrogen-containing functional group. By using the copolymer having a basic nitrogen-containing functional group, positive charging can be imparted to the surface of the nonwoven fabric by coating treatment, and affinity with white blood cells can be improved.
Examples of the monomer unit having a nonionic hydrophilic group include monomer units derived from: 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, vinyl alcohol, (meth) acrylamide, N-vinylpyrrolidone, and the like. The monomer unit having a nonionic hydrophilic group is preferably a monomer unit derived from 2-hydroxyethyl (meth) acrylate from the viewpoints of ease of availability, ease of handling during polymerization, performance during blood circulation, and the like. The monomer units derived from vinyl alcohol are generally produced by hydrolysis after the polymerization of vinyl acetate.
Examples of the monomer unit having a basic nitrogen-containing functional group include monomer units derived from: (meth) acrylic acid derivatives such as diethylaminoethyl (meth) acrylate, dimethylaminoethyl (meth) acrylate, dimethylaminopropyl (meth) acrylate, and 3-dimethylamino-2-hydroxypropyl (meth) acrylate; styrene derivatives such as p-dimethylaminomethylstyrene and p-diethylaminoethylstyrene; vinyl derivatives of nitrogen-containing aromatic compounds such as 2-vinylpyridine, 4-vinylpyridine and 4-vinylimidazole; and derivatives of the above vinyl compounds which are quaternary ammonium salts with alkyl halides and the like. From the viewpoints of ease of obtaining, ease of handling during polymerization, performance during blood circulation, and the like, the monomer unit having a basic nitrogen-containing functional group is preferably a monomer unit derived from diethylaminoethyl (meth) acrylate and dimethylaminoethyl (meth) acrylate.
When the total mass of the fiber base material and the coating layer is 1g, the mass of the coating layer is preferably about 0.1 to 40.0 mg. By setting the coating amount in such a range, uniform coating becomes easy, and problems such as clogging of blood cells or deterioration of filtration performance due to uneven flow of blood can be avoided.
The quality of the coating layer can be calculated, for example, by the following procedure. The nonwoven fabric (fiber base material) before the coating layer was dried in a dryer set at 60 ℃ for 1 hour, and then left in the dryer for 1 hour or more, and the mass (Ag) was measured. The nonwoven fabric having the coating layer supported thereon was dried in a dryer at 60 ℃ for 1 hour in the same manner, and then allowed to stand in the dryer for 1 hour or more, and the mass (Bg) was measured. The mass of the coating layer was calculated from the following calculation formula.
The mass of the coating layer was set to (1g) (mg/g) ═ B-a) × 1000/B of the total of the nonwoven fabric (fiber base material) and the coating layer
The method for forming the coating layer on the fiber base material is not particularly limited, and examples thereof include a method in which the fiber base material is immersed in a coating solution containing a monomer and/or a polymer (copolymer) and, if necessary, a solvent, and the like, and then the coating solution is appropriately removed (immersion method); a method (transfer method) in which a roll impregnated with a coating liquid is brought into contact with a fiber base material to perform coating.
The nonwoven fabric contained in the filtration layer 1 preferably has a basic nitrogen-containing functional group in its peripheral surface portion.
The peripheral surface portion of the nonwoven fabric refers to the entire portion of the nonwoven fabric exposed to the outside. That is, when the nonwoven fabric has the coating layer, the peripheral surface portion is a surface portion of the coating layer. In the case where the nonwoven fabric has no coating layer, the peripheral surface portion refers to a surface portion of the fiber base material.
The peripheral surface portion of the nonwoven fabric may further have a nonionic hydrophilic group.
When the basic nitrogen-containing functional group is present in the peripheral surface portion of the nonwoven fabric, the affinity of the nonwoven fabric with leukocytes in blood is increased, and the leukocyte removal performance can be improved.
Further, when the nonionic hydrophilic group is present in the peripheral surface portion of the nonwoven fabric, the wettability of the nonwoven fabric surface to blood increases, the effective filtration area (actually the area used for filtration) of the nonwoven fabric improves, and as a result, both effects of reducing the filtration time and improving the removal performance of leukocytes and the like are obtained.
Examples of the method for forming a non-woven fabric having a non-ionic hydrophilic group and a basic nitrogen-containing functional group on the peripheral surface portion thereof include a method for coating a non-woven fabric with a coating material containing a monomer and/or a polymer having a non-ionic hydrophilic group and a basic nitrogen-containing functional group; in the case of a nonwoven fabric having no coating layer, a method of spinning using a fiber material containing a monomer and/or a polymer having a nonionic hydrophilic group and a basic nitrogen-containing functional group is exemplified.
The ratio of the amount of the substance of the basic nitrogen-containing functional group to the total amount of the substances of the nonionic hydrophilic group and the basic nitrogen-containing functional group in the peripheral surface portion of the nonwoven fabric is preferably 0.2 to 50.0 mol%, more preferably 0.25 to 10 mol%, further preferably 1 to 5 mol%, most preferably 2 to 4 mol%. The content of the basic nitrogen-containing functional group and the nonionic hydrophilic group can be determined by analysis by NMR, IR, TOF-SIMS, or the like. By defining the ratio of the basic nitrogen-containing functional group to the nonionic hydrophilic group in this manner, it is possible to ensure stable wettability with respect to blood, suppress unnecessary clogging due to blood components such as platelets, and effectively remove leukocytes and the like.
Examples of the nonionic hydrophilic group include an alkyl group, an alkoxy group, a carbonyl group, an aldehyde group, a phenyl group, an amide group, and a hydroxyl group.
As the basic nitrogen-containing functional group, there may be mentioned, for example, -NH2、-NHR1、-NR2R3、-N+R4R5R6(R1、R2、R3、R4、R5And R6Alkyl group having 1 to 3 carbon atoms).
(degree of orientation)
The fibers of the nonwoven fabric contained in the 1 st filter layer have a degree of orientation X in the X-axis plane direction of the 1 st filter layer and a degree of orientation Y in the Y-axis plane direction orthogonal to the X-axis plane direction, and the maximum value of the ratio of the degree of orientation X to the degree of orientation Y (degree of orientation X/degree of orientation Y) is 1.2 or more. Hereinafter, the maximum value of the orientation degree X/the orientation degree Y is also referred to as "maximum orientation degree ratio".
"degree of orientation" means the degree to which the fibers are oriented in a given direction. For example, a large degree of orientation of the fibers in the X-axis direction means that the fibers are aligned in parallel with the X-axis direction to a large extent.
"X-axis planar direction" refers to any direction in the planar direction of the 1 st filter layer.
"Y-axis plane direction" refers to a direction orthogonal to the X-axis among the plane directions of the 1 st filter layer.
"planar direction" refers to a direction orthogonal to the thickness direction of the 1 st filter layer.
"the maximum value of the degree of orientation X/the degree of orientation Y (maximum degree of orientation ratio)" means the maximum value among the respective values of the degree of orientation X/the degree of orientation Y in all the plane directions of the 1 st filter layer.
The orientation degree can be calculated from the orientation index. The orientation index means the degree of orientation of the fibers in a predetermined direction, as with the degree of orientation, but the larger the degree of orientation, the smaller the orientation index. For example, the index of orientation of the fiber in the X-axis direction is determined based on the cross-sectional area of the fiber in a plane orthogonal to the X-axis direction. When the fibers are aligned parallel to the X-axis direction, the area of the fibers on a plane orthogonal to the X-axis direction decreases. That is, the orientation index with respect to the X-axis direction decreases.
When the orientation index in the X-axis plane direction is an orientation index X and the orientation index in the Y-axis plane direction orthogonal to the X-axis plane direction is an orientation index Y, the orientation degree X/the orientation degree Y can be expressed as an orientation index Y/an orientation index X.
The orientation index X and the orientation index Y of the nonwoven fabric were obtained by X-ray CT and image analysis using the following methods. The X-ray CT apparatus and the image analysis software used are as follows.
X-ray CT apparatus: high resolution 3 DX-ray microscope nano3DX manufactured by Rigaku Corporation
Image analysis software: ImageJ
A nonwoven fabric sample for X-ray CT measurement was cut in the plane to 2.5 mm. times.2.5 mm, and the X-ray CT measurement was carried out on the total thickness without cutting in the thickness direction. The measurement conditions were as follows.
Image resolution: 0.54 μm/pix
Exposure time: 18 seconds per sheet
Projection number: 1500 pieces/180 degree
X-ray tube voltage: 40kV
X-ray tube current: 30mA
An X-ray target: cu
Measurement site: central part of section of sample end without influence on plane
The coordinate axes of the nonwoven fabric are set so that the X-axis plane direction is the X-axis, the Y-axis plane direction is the Y-axis, and the thickness direction is the Z-axis. The XY plane corresponds to the plane of the nonwoven fabric.
The X-ray CT measurement is performed on a tomographic X-ray image, and the tomographic X-ray image is a rectangular parallelepiped trimmed to have an X-axis × Y-axis × Z-axis of 500 μm × 500 μm × total thickness. This is taken as a three-dimensional image 1.
For the three-dimensional image 1, median filtering (median filter) of an image processing method is performed at a radius of 2pix, and then region segmentation is performed by applying Otsu's method of an image processing method. The luminance value of the pixel after the area division is set so that air is 0 and the fiber of the nonwoven fabric is 255. The image thus obtained is taken as a three-dimensional image 2.
Segmentation (segmentation) by an image processing method is performed on the pixels of the luminance value 255 of the three-dimensional image 2, and a fiber having the number of pixels of 10000pix or less among fibers connected to one luminance value 255 is removed as noise. The luminance value of the pixel was set so that the air was 0 and the fiber of the nonwoven fabric was 255, and the image thus obtained was defined as a three-dimensional image 3.
In the three- dimensional image 3, 1 image is scanned in one time in the Z direction perpendicular to the XY plane for all the pixels of the XY planeThe total number of points whose luminance values have changed from 0 to 255 and points whose luminance values have changed from 255 to 0 is obtained as a projection area A by image analysisXY. Similarly, the total number of scans in the X direction with respect to the YZ plane is defined as the projection area AYZThe total number of scans in the Y direction for the ZX plane is defined as the projection area AZX. From these projected areas, the orientation index X and the orientation index Y are obtained by the following equations.
Orientation index X ═ AYZ/(AXY+AYZ+AZX)
Orientation index Y ═ AZX/(AXY+AYZ+AZX)
In short, the orientation index is obtained by calculating the cross-sectional area (projected area) when the nonwoven fabric is observed in the direction and further performing proportional distribution so that the total of the projected areas in the three-dimensional directions becomes 1. That is, the orientation index in each direction is a number of 0 to 1, and the stronger the orientation in that direction, the smaller the orientation index becomes. In other words, if the nonwoven fabric is completely isotropic, the orientation index in the X, Y, Z direction is all 0.33.
The maximum value (maximum orientation ratio) of the orientation degree X/the orientation degree Y is 1.2 or more, preferably 1.3 to 2.0, and more preferably 1.4 to 1.8. When the filter medium includes a plurality of the 1 st filter layers, the maximum orientation ratio of the nonwoven fabrics contained in at least one of the 1 st filter layers may be 1.2 or more, but the maximum orientation ratio of the nonwoven fabrics contained in all of the 1 st filter layers is preferably 1.2 or more. By using at least one layer of the 1 st filter layer including a nonwoven fabric having a maximum orientation ratio of 1.2 or more, it is possible to consciously induce a blood flow path in the surface of the 1 st filter layer in any of high-viscosity blood containing aggregates, low-viscosity blood, and blood having an intermediate viscosity therebetween, depending on the properties of the blood, and to effectively utilize the 1 st filter layer and/or form an optimal flow path. This improves the fluidity of blood and the ability to remove leukocytes. When the maximum orientation ratio is 2.0 or less, the blood inducibility in the plane of the 1 st filtration layer can be suppressed from becoming too high, and thus the fluidity and the leukocyte removal performance tend to be improved.
In the blood treatment filter according to the first embodiment, the first filtration layer 1 is preferably disposed as follows: the ratio (Ac/Am) of the degree of orientation (Ac) of the fibers of the nonwoven fabric in the plane direction of the 1 st filter layer orthogonal to the filtration direction to the degree of orientation (Am) of the fibers of the nonwoven fabric in the plane direction of the 1 st filter layer parallel to the filtration direction is 1.2 or more. Ac/Am is more preferably 1.3 to 2.0, and still more preferably 1.4 to 1.8.
"filtration direction" refers to the direction of blood flow within the blood treatment filter, corresponding to the direction from the inlet portion to the outlet portion of the container.
"the planar direction of the 1 st filter layer orthogonal to the filter direction" refers to a direction 13 orthogonal to the filter direction 12 when the plane of the 1 st filter layer 11 is viewed from the front, as shown in fig. 3 and 4, for example.
"the planar direction of the 1 st filter layer parallel to the filtration direction" refers to a direction 14 parallel to the filtration direction 12 when the plane of the 1 st filter layer 11 is viewed from the front, as shown in fig. 3 and 4, for example.
In the case of treating blood which has a low viscosity, a high flow rate and is less likely to remove leukocytes, when Ac/Am is 1.2 or more, the infiltration rate of the blood into the 1 st filtration layer becomes slow, and the retention time of the blood in the 1 st filtration layer is prolonged, so that the leukocyte removal ability can be improved.
In the blood treatment filter according to the first embodiment, the first filtration layer 1 is preferably disposed as follows: the ratio (Am/Ac) of the degree of orientation (Am) of the fibers of the nonwoven fabric in the plane direction of the 1 st filter layer parallel to the filtration direction to the degree of orientation (Ac) of the fibers of the nonwoven fabric in the plane direction of the 1 st filter layer orthogonal to the filtration direction is 1.2 or more. Am/Ac is more preferably 1.3 to 2.0, still more preferably 1.4 to 1.8.
When blood having a high viscosity, a low flow rate and a long filtration time is treated, the rate of infiltration of the 1 st filtration layer with blood becomes high if Am/Ac is 1.2 or more, and the filtration time can be shortened.
Ac/Am or Am/Ac can be adjusted appropriately by changing the orientation of the 1 st filtration layer. Further, as shown in FIG. 5, for example, the nonwoven fabric having a predetermined maximum orientation ratio is cut at a predetermined rotation angle by changing the direction of the nonwoven fabric, thereby forming a1 st filtration layer having a predetermined Ac/Am or Am/Ac. As a result, it was possible to easily confirm how the ratio of Ac to Am becomes by using the line vector by arbitrarily changing the direction of the nonwoven fabric for which the maximum orientation ratio is known.
Further, as shown in FIG. 6, the Am ≈ Ac can be formed by cutting the nonwoven fabric having the maximum orientation ratio 1.2 while changing the direction thereof. In this case, at first glance, the same performance as that of a filter using a nonwoven fabric having a maximum orientation degree ratio of 1.0 is observed, but in practice, the fibers in the filter are oriented obliquely, whereby blood can be induced and a constant residence time in the filter can be ensured. This makes it possible to cope with blood having a moderate viscosity and containing a small amount of aggregates, and having a high flow and leukocyte removal ability.
Further, although the in-plane impregnation coefficient (Ky) of patent document 2 is similar to Ac or Am in the present specification, Ky is a versatile filter material characteristic derived from the fluidity of the liquid in the planar direction, and cannot be directly subdivided into values of Ac and Am.
(filling Rate)
The 1 st filter layer preferably has a filling factor of 0.04 to 0.40, more preferably 0.06 to 0.30, and further preferably 0.08 to 0.22.
When the filling rate of the filtration layer 1 is 0.40 or less, clogging of blood cells is reduced, and the processing speed tends to be improved. When the filling rate is 0.04 or more, the number of times of contact with white blood cells or the like increases, and the capture rate of white blood cells or the like tends to be improved, and the mechanical strength of the nonwoven fabric tends to be improved.
The filling ratio of the 1 st filtration layer was measured by the following method. The area, thickness, and mass of the 1 st filter layer cut to an arbitrary size in the plane direction and the specific gravity of the fibrous material of the nonwoven fabric constituting the 1 st filter layer were measured and calculated by the following formula (10).
Filling rate of [1 st filter layer ]Mass (g) ÷ { area in plane direction of the 1 st filter layer (cm)2) X thickness (cm) of the 1 st filtration layer]Specific gravity (g/cm) of the fibrous material of the nonwoven fabric constituting the 1 st filtration layer3)
(10)
(texture index)
The 1 st filtration layer preferably has a texture index of 15 or more and 70 or less corresponding to a thickness of 0.5 mm. When the texture index is 70 or less, the structure of the 1 st filtration layer in the thickness direction is uniform in the direction of the filtration surface, and blood flows uniformly through the 1 st filtration layer, and the removal ability of leukocytes and the like tends to be improved or the processing speed tends to be improved. On the contrary, if the texture index is 15 or more, clogging is less likely to occur due to a decrease in liquid flow resistance, and the processing speed is improved. The texture index is more preferably 15 or more and 65 or less, further preferably 15 or more and 60 or less, particularly preferably 15 or more and 50 or less, and most preferably 15 or more and 40 or less.
The texture index is a value obtained by irradiating light from below the nonwoven fabric and detecting the light by a charge coupled device camera (hereinafter, simply referred to as a CCD camera), and multiplying a variation coefficient (%) of absorbance of the porous body (nonwoven fabric) detected by each pixel of the CCD camera by 10 times.
The texture index can be measured, for example, by a formation tester (FMT-MIII (Nomura corporation, 2002, S/N: 130). The basic settings of the measuring instrument are not changed from the time of factory sale, and the total number of pixels of the CCD camera can be measured at about 3400, for example. Specifically, the measurement size may be set to 7cm × 3cm (1 pixel size is 0.78mm × 0.78mm) so that the total number of pixels is about 3400, but the measurement size may be changed so that the total number of pixels is equal to 3400 depending on the shape of the sample.
Since the texture index is greatly affected by the thickness of the nonwoven fabric, the texture index corresponding to a thickness of 0.5mm was calculated by the following method.
First, three nonwoven fabrics having a thickness of 0.5mm or less were prepared, and the texture index and the thickness thereof were measured. The thickness of the nonwoven fabric was measured at any 4 points using a constant pressure thickness gauge (e.g., model FFA-12, manufactured by OZAKI) at a measurement pressure of 0.4N, and the average value of the measured values was defined as the thickness of the nonwoven fabric. Next, two of the three nonwoven fabrics thus measured were superposed so as to have a thickness of 0.5mm or more, and the texture index and the thickness were measured for the two nonwoven fabrics in the superposed state. After the measurement of the texture index of all three combinations was completed, a regression line formula of the thickness and the texture index was obtained, and from this formula, the texture index corresponding to a thickness of 0.5mm was obtained.
When the thickness of the two nonwoven fabrics does not reach 0.5mm, the texture index can be measured by superposing a plurality of nonwoven fabrics so that the superposed thickness becomes 0.5mm or more, and then reducing the nonwoven fabrics so that the superposed thickness becomes 0.5mm or less. The texture index of all nonwoven fabrics having a thickness of 0.5mm or less after the overlapping is measured, and a regression line formula of the thickness and the texture index is obtained, and the texture index having a thickness of 0.5mm is obtained by interpolation from the formula.
On the other hand, when the thickness of one nonwoven fabric was more than 0.5mm, three nonwoven fabrics were prepared, and two of the three nonwoven fabrics were superposed to measure the texture index and the thickness. The texture index of the combination of all nonwoven fabrics can be measured to obtain a regression line expression of the thickness and the texture index, and the texture index with a thickness of 0.5mm can be obtained by extrapolation from the expression.
Preferably, three or more nonwoven fabrics used for measuring the texture index are cut out from the same filter layer. Generally, they are substantially homogeneous nonwoven fabrics, that is, nonwoven fabrics having the same physical properties (material, fiber diameter, bulk density, packing ratio, etc.). However, when a necessary number of substantially homogeneous nonwoven fabrics cannot be measured from the same filter layer, the measurement may be performed by combining nonwoven fabrics of the same type of filter layer.
(specific surface area)
The specific surface area of the 1 st filter layer is preferably 0.8m2A ratio of 3.2m to g2The ratio of the carbon atoms to the carbon atoms is less than g. If the specific surface area is 3.2m2When the concentration is lower than the predetermined value,/g, adsorption of useful components such as plasma proteins to the filter element in blood treatment is suppressed, and the recovery rate of the useful components tends to be improved. When the specific surface area is 0.8m2When the amount of the adsorbed leukocytes or the like is larger than or equal to g, the ability to remove leukocytes or the like tends to be improved.
The specific surface area of the 1 st filtration layer is more preferably 1.0m2A ratio of 3.2m to g2A ratio of 1.1m or less per gram22.9m or more per g2A specific ratio of 1.2m to less than g22.9m or more per g2Less than g, most preferably 1.2m22.6 m/g or more2The ratio of the carbon atoms to the carbon atoms is less than g.
The specific surface area is a surface area of the 1 st filtration layer per unit mass, and is a value measured by a BET adsorption method using krypton as an adsorption gas, and can be measured, for example, by using a Tri-Star 3000 apparatus manufactured by Micromeritics.
The larger the specific surface area of the 1 st filtration layer is, the larger the area capable of adsorbing cells, plasma proteins and the like when blood is treated with the same quality filtration layer is.
(air permeation resistance)
The air permeability resistance of the first filter layer 1 is preferably 25 pas · m/g or more and 100 pas · m/g or less, more preferably 30 pas · m/g or more and 90 pas · m/g or less, and further preferably 40 pas · m/g or more and 80 pas · m/g or less.
When the air permeation resistance is 25Pa · s · m/g or more, the number of times of contact with white blood cells or the like increases, and it tends to become easy to trap white blood cells or the like. When the air permeation resistance is 100 pas · m · g or less, clogging of blood cells is reduced, and the processing speed tends to be improved.
The air permeation resistance of the 1 st filter layer is a value measured as a differential pressure generated when the 1 st filter layer is flown with a fixed flow rate of air, and is a value as follows: a filter layer 1 was placed on the air-permeable vent of an air permeability test apparatus (for example, KES-F8-AP1, manufactured by Katotech K.K Co., Ltd.), and air was measured at 4mL/cm2The pressure loss (Pa · s/m) generated when the flow rate per second was allowed to permeate for about 10 seconds was divided by the weight per unit area (g/m) of the first filtration layer 12) And the resulting value. The cut-out portion was changed and measured 5 times, and the average value was defined as the air permeation resistance.
The high air permeability resistance of the 1 st filter layer means that air does not easily pass through, and the fibers constituting the 1 st filter layer are entangled in a compact or uniform state, indicating that the 1 st filter layer has a property that blood preparation does not easily flow. On the other hand, the low air permeability resistance of the 1 st filtration layer means that the fibers constituting the 1 st filtration layer are coarse or entangled in a nonuniform state, indicating that the 1 st filtration layer has a property of allowing the blood preparation to flow easily.
(mean flow pore size)
The mean flow pore size of the filtration layer 1 is preferably less than 8.0. mu.m. When the average flow pore size is less than 8.0. mu.m, the number of contacts with white blood cells or the like increases, and the white blood cells or the like tend to be easily captured. When the average flow pore size is 1.0 μm or more, clogging of blood cells is reduced, and the processing speed tends to increase. The average flow pore diameter is more preferably 1.5 μm or more and 7.5 μm or less, still more preferably 2.5 μm or more and 7.0 μm or less, particularly preferably 3.5 μm or more and 6.5 μm or less, and most preferably 4.5 μm or more and 6.5 μm or less.
The mean flow pore size of the filtration layer 1 can be measured by ASTM F316-86 using Perm-Porometer CFP-1200AEXS (automatic pore size distribution measuring System for porous Material), manufactured by PMI.
(critical wetting surface tension)
The Critical Wetting Surface Tension (CWST) of the 1 st filtration layer is preferably 70dyn/cm or more, more preferably 75dyn/cm or more. By ensuring stable wettability to blood in the 1 st filtration layer having such critical wetting surface tension, it is possible to efficiently remove leukocytes and the like while passing platelets in the blood preparation. The upper limit of CWST is not particularly limited, and may be, for example, 200dyn/cm, 150dyn/cm, 100dyn/cm, or the like.
CWST is a value obtained by the following method. That is, aqueous solutions of different concentrations of sodium hydroxide, calcium chloride, sodium nitrate, acetic acid or ethanol are produced so that the surface tension varies by 2 to 4 dyn/cm. For the surface tension (dyn/cm) of each aqueous solution, 94-115 parts are obtained from an aqueous sodium hydroxide solution, 90-94 parts are obtained from an aqueous calcium chloride solution, 75-87 parts are obtained from an aqueous sodium nitrate solution, 72.4 parts are obtained from pure water, 38-69 parts are obtained from an aqueous acetic acid solution, and 22-35 parts are obtained from an aqueous ethanol solution ("revision 2 edition of the basic code for chemical Explorer, edited by the society of chemistry Japan, pill good, 1975, page 164). The aqueous solutions having different surface tensions of 2 to 4dyn/cm thus obtained were placed on a nonwoven fabric in 10 drops each from an aqueous solution having a low surface tension in this order, and left for 10 minutes. After leaving for 10 minutes, the nonwoven fabric was defined as wet when 9 or more out of 10 drops were absorbed, and non-wet when less than 9 drops were absorbed out of 10 drops. When the nonwoven fabric is measured sequentially from a liquid having a small surface tension, the nonwoven fabric changes from a wet state to a non-wet state. In this case, the CWST value of the nonwoven fabric is defined as the average value of the surface tension value of the liquid in the wet state observed last and the surface tension value of the liquid in the non-wet state observed first. For example, when the nonwoven fabric is wet with a liquid having a surface tension of 64dyn/cm and non-wet with a liquid having a surface tension of 66dyn/cm, the CWST value of the nonwoven fabric is 65 dyn/cm.
(average fiber diameter)
The average fiber diameter of the nonwoven fabric contained in the filtration layer 1 is preferably 0.3 to 3.0. mu.m, more preferably 0.5 to 2.5. mu.m. By being within this range, clogging can be avoided while improving the leukocyte removal performance.
The average fiber diameter is a value obtained by the following procedure.
That is, a portion that is considered to be substantially uniform is sampled from a nonwoven fabric that actually constitutes the filter layer or one or more nonwoven fabrics that are substantially homogeneous therewith at several locations, and a photograph of fibers in the sampled nonwoven fabric is taken using a scanning electron microscope so that the diameter thereof can be expressed.
The photographs were taken continuously until a total of 100 diameters were taken. For the photograph thus obtained, the diameters of all the fibers shown were measured. Diameter here refers to the width of the fiber in a direction at right angles to the fiber axis. The average fiber diameter was determined as the value obtained by dividing the sum of the measured diameters of all the fibers by the number of fibers. However, the following data are not included: if the diameter of a plurality of fibers cannot be accurately measured due to the shadow of other fibers after the overlapping, if the plurality of fibers are fused to form thick fibers, fibers having significantly different diameters may be mixed, and the focus of the photograph may be shifted to make the boundary of the fibers unclear.
When the filter layer includes a plurality of nonwoven fabrics, the nonwoven fabrics are different in the diameter of the measured fiber, and therefore, the boundary surface between the two is found and the average fiber diameter of each is measured again. The phrase "the average fiber diameters are significantly different" as used herein means that the difference is considered to be statistically significant.
(bulk Density)
The bulk density of the No. 1 filter layer is preferably 0.05-0.50 g/cm3More preferably 0.07 to 0.40g/cm3More preferably 0.10 to 0.30g/cm3. If the bulk density of the No. 1 filter layer is 0.50g/cm3Hereinafter, the flow resistance of the 1 st filtration layer decreases, clogging of blood cells decreases, and the processing speed tends to be improved. Further, when the bulk density is 0.05g/cm3As described above, the number of times of contact with white blood cells or the like increases, and the white blood cells or the like tend to be easily captured, and there is a possibility that the mechanical strength of the 1 st filter layer increases.
The "bulk density of the 1 st filtration layer" was determined as follows: the nonwoven fabric was cut out from a portion considered to be uniform in a size of 2.5cm × 2.5cm, and the basis weight (g/m) was measured by the method described below2) And thickness (cm), obtained by dividing the weight per unit area by the thickness. The cut portions were changed and the weight per unit area and the thickness were measured 3 times, and the average value was defined as the bulk density.
The weight per unit area of the 1 st filtration layer was determined as follows: the nonwoven fabric was sampled from a portion which had a size of 2.5cm × 2.5cm and was considered to be uniform, and the weight of the nonwoven fabric sheet was measured and converted into a mass per square meter. In addition, the thickness of the 1 st filter layer was determined as follows: the nonwoven fabric was sampled from a portion considered to be uniform and having a size of 2.5cm × 2.5cm, and the thickness of the center (1 position) thereof was measured with a constant pressure thickness gauge. The load pressure of the thickness gauge was set to 0.4N, and the area of the measuring part was set to 2cm2。
(Heat of crystallization and Heat of melting of Crystal)
The blood treatment filter is generally subjected to sterilization treatment by a steam heating treatment before use. It is considered that the physical structure of the nonwoven fabric included in the filter layer is largely changed by the steam heating treatment. However, if the nonwoven fabric shrinks in the planar direction, the structure of the grip portion may become unstable in the blood processing filter having the structure shown in fig. 1 and 2, for example, and the ability to remove leukocytes and the like and the processing performance of the blood processing filter may be deteriorated.
From this viewpoint, the amount of heat of non-crystallization of the nonwoven fabric contained in the filtration layer before the steam heating treatment is preferably 5J/g or less, more preferably 3J/g or less, still more preferably 2J/g or less, and particularly preferably 1J/g or less. The "amount of uncrystallized heat" is an index indicating the crystallinity of the resin, and a smaller value means a higher crystallinity of the resin.
By using a filter layer using a nonwoven fabric satisfying the heat of non-crystallization, the filtration performance and handling property of the blood treatment filter are improved.
For example, in a blood treatment filter in which a filter medium including a filter layer is sandwiched and held between rigid containers as shown in fig. 1 and 2, the strength of repulsion of the filter medium against the holding portion of the container is increased even after the steam heating treatment, and the sandwiching between the container holding portion and the filter medium is maintained in a firm state, so that the side leakage phenomenon can be suppressed, and the ability to remove leukocytes and the like can be improved. The side leakage phenomenon refers to a phenomenon in which blood leaks between the grip portion and the filter medium without passing through the filter medium, and flows from the inlet portion space to the outlet portion space.
In addition, in the case of a blood treatment filter in which a filter medium is sandwiched between flexible containers and the filter medium are joined together by high-frequency welding, the strength of the joint between the container and the filter medium is improved and the resistance to centrifugation of the blood treatment filter (the difficulty of cracking of the joint between the container and the filter medium when the blood treatment filter is centrifuged (when centrifugal force is applied)) is improved by controlling the amount of uncrystallized heat of the nonwoven fabric to be constant or less. The reason why the strength of the high-frequency welded joint between the container and the filter medium is improved when the uncrystallized heat amount of the nonwoven fabric contained in the filter layer is controlled to be equal to or less than a fixed value is not clear, but it is considered that the higher the crystallinity, the higher the repulsive force of the nonwoven fabric at the time of high-frequency welding, the more excessive melting due to pressure bonding of the nonwoven fabric is suppressed, and the uniform (without occurrence of a trap hole or the like due to the excessive melting) joint can be formed.
Further, the value obtained by subtracting the amount of heat of non-crystallization from the amount of heat of crystal fusion before the steam heating treatment of the nonwoven fabric included in the filtration layer is preferably 50J/g or more, more preferably 55J/g or more, further preferably 60J/g or more, and particularly preferably 65J/g or more. The "value obtained by subtracting the amount of heat of crystallization from the amount of heat of fusion" is also an index indicating the degree of crystallization of the resin, and a larger value means a higher degree of crystallization of the resin. By further increasing the crystallinity, the change in physical properties (shrinkage and the like) of the filter layer before and after the steam heating treatment is further suppressed, and the removal ability of leukocytes and the like is increased as described above.
The amount of heat of crystallization and the amount of heat of fusion of the crystals are values measured by a Differential Scanning Calorimetry (DSC) method for a nonwoven fabric (fiber base material). The following describes the measurement method.
3 to 4mg of nonwoven fabric (fiber base material) was separated and mounted in an aluminum standard container, and an initial temperature rise curve (DSC curve) was measured under an atmosphere of an initial temperature of 35 ℃, a temperature rise rate of 10 ℃/min, and a nitrogen flow of 50 mL/min. An exothermic peak and a melting peak (endothermic peak) were detected from the initial temperature rise curve (DSC curve), and the amount of heat of crystallization (J/g) and the amount of heat of crystal melting (J/g) were calculated by dividing the amount of heat (J) obtained from each peak area by the mass of the nonwoven fabric.
As the measuring apparatus, for example, TA-60WS System manufactured by Shimadzu corporation can be used.
(degree of X-ray crystallinity)
In the present embodiment, the X-ray crystallinity of the nonwoven fabric included in the filter layer before the steam heating treatment is preferably 60 or more, more preferably 63 or more, and further preferably 66 or more. Further increase in crystallinity of the nonwoven fabric and change in physical properties (shrinkage and the like) of the filter layer before and after the steam heating treatment are suppressed, and the ability to remove leukocytes and the like is increased as described above.
The X-ray crystallinity was measured by X-ray diffraction method.
The measurement can be performed by the following measurement procedures 1) to 5) using an X-ray diffraction apparatus (for example, miniflexiii (Rigaku Corporation, model 2005H 301)).
1) One nonwoven fabric (fiber base material) having a size of 3cm × 3cm was mounted on the sample table.
2) The measurement was carried out under the following conditions.
Scan range: 5-50 degree
Sampling width (width of collected data): 0.02 degree
Scanning speed: 2.0 °/min
Voltage: 30kV
Current: 15mA
3) After the measurement, data in which peaks of an amorphous portion and a crystalline portion were separated were obtained.
4) From the data of 3), the amorphous peak area (Aa) and the total peak area (At) were determined. For example, the "automatic peak separation" function is performed by opening the data measured in 3) using analytical software (MDI JADE 7). As a result, the amorphous peak area (Aa) and the total peak area (At) were automatically calculated.
5) The crystallinity was calculated from the amorphous peak area (Aa) and the total peak area (At) by the following formula.
Degree of crystallinity (%) - (At-Aa)/At × 100
The nonwoven fabric having an uncrystallization heat amount of 5J/g or less, the nonwoven fabric having a value obtained by subtracting the uncrystallization heat amount from the crystal melting heat amount of 50J/g or more, and the nonwoven fabric having an X-ray crystallinity of 60 or more can be easily produced by selecting the materials and production conditions thereof, for example, as described later.
(area shrinkage ratio)
In the present embodiment, the area shrinkage of the nonwoven fabric is preferably 10% or less, more preferably 3% or less, particularly preferably 2% or less, and most preferably 1% or less. When the area shrinkage rate is 10% or less, the uniformity of the pore diameter is maintained even after the sterilization treatment, and the variation in the treatment rate can be prevented, and the stable performance balance tends to be exhibited, which is preferable.
In this regard, since polybutylene terephthalate has a higher crystallization rate and is more likely to have higher crystallinity than other polyester fibers, for example, polyethylene terephthalate fibers, even when severe steam heating treatment such as high-temperature high-pressure sterilization is performed, shrinkage in the planar direction (reduction in area shrinkage rate is more likely) is less likely to occur, and thus stable removal ability of leukocytes and the like and treatment speed can be exhibited regardless of sterilization conditions.
The area shrinkage of the nonwoven fabric is a value calculated by accurately measuring the vertical and horizontal dimensions of a nonwoven fabric (fibrous base material) cut into a square of about 20cm × 20cm, fixing the nonwoven fabric without using a needle or the like, heat-treating the nonwoven fabric at 115 ℃ for 240 minutes, and then measuring the vertical and horizontal dimensions again.
Area shrinkage (%) is (length of the nonwoven fabric before heat treatment in the longitudinal direction (cm) × length of the nonwoven fabric before heat treatment in the transverse direction (cm) × length of the nonwoven fabric after heat treatment in the longitudinal direction (cm) × length of the nonwoven fabric after heat treatment in the transverse direction (cm))/(length of the nonwoven fabric before heat treatment in the longitudinal direction (cm) × length of the nonwoven fabric before heat treatment in the transverse direction (cm)) × 100
In the case where the blood treatment filter is manufactured by sandwiching and holding the filter medium between 2 members of the container members constituting the outlet portion side and the inlet portion side of the rigid container (for example, in the case shown in fig. 1 and 2), when the filter medium includes a plurality of nonwoven fabrics, when a nonwoven fabric having high crystallinity is used as the nonwoven fabric in contact with the outlet portion side container (the nonwoven fabric disposed at the position closest to the outlet portion side container), the sandwiching of the filter medium by the grip portion of the outlet portion side container after the steam heating treatment can be made stronger, and thereby a phenomenon (side leakage phenomenon) in which blood directly flows from the inlet portion space into the outlet portion space without passing through the filter medium and leaks between the grip portion and the filter medium is suppressed, the removal capability of leukocytes and the like is improved, and the performance as the blood treatment filter can be further improved.
That is, when the blood treatment filter is manufactured by sandwiching and holding the filter medium between 2 members of the container members constituting the outlet side and the inlet side of the rigid container, the nonwoven fabric in contact with the container member on the outlet side among the nonwoven fabrics included in the filter medium is preferably provided with (1), and more preferably with (2) and/or (3) in addition to (1).
(1) The amount of heat of non-crystallization before steam heating is 5J/g or less
(2) The heat of crystallization before steam heating minus the heat of non-crystallization is 50J/g or more
(3) The X-ray crystallinity before steam heating treatment is 60 or more
In addition, when the blood treatment filter is manufactured by sandwiching and holding the filter medium between 2 members of the container members constituting the outlet side and the inlet side of the rigid container, if the crystallinity of all the nonwoven fabrics included in the filter medium is high, is excellent in the ability to remove leukocytes and the like after steam heating, but is poor in the ease of clamping, holding, or bonding the filter material with a container material because of the increased repulsive strength of the filter material, therefore, from the viewpoint of productivity at the time of manufacturing the blood treatment filter, it is preferable that the degree of crystallinity of the nonwoven fabrics other than the nonwoven fabrics in contact with the inlet-side container and the outlet-side container (or the nonwoven fabrics in contact with the inlet-side container and the outlet-side container and the nonwoven fabrics of a predetermined number of sheets (usually one to several sheets) arranged adjacent thereto) among the nonwoven fabrics included in the filter medium is not excessively high.
For example, in the case where the filter medium held by the rigid container includes a2 nd filter layer (described later) and a1 st filter layer in this order from the inlet portion side, it is preferable that, from the viewpoint of productivity at the time of manufacturing the blood treatment filter, the nonwoven fabric in contact with the outlet portion side container (and a predetermined number of nonwoven fabrics disposed adjacent thereto) among the plurality of nonwoven fabrics included in the 1 st filter layer satisfy at least the above (1), and a part or all of the nonwoven fabrics do not satisfy the above (1), or even satisfy the requirement, have a larger amount of uncrystallized heat before steam heating than the nonwoven fabric in contact with the outlet portion side container.
[2 nd Filter layer ]
The blood treatment filter may contain a further filter layer in addition to the 1 st filter layer within a range not impairing the effects of the present invention. For example, the blood treatment filter may further comprise more than one 2 nd filter layer between the inlet portion of the container and the 1 st filter layer.
The 2 nd filter layer preferably has a structure suitable for removal of micro aggregates contained in blood. The 2 nd filter layer preferably comprises a nonwoven fabric. Examples of the material of the nonwoven fabric include the same materials as those of the nonwoven fabric contained in the 1 st filter layer.
The average fiber diameter of the nonwoven fabric contained in the 2 nd filtration layer is preferably 3 to 60 μm, more preferably 4 to 40 μm, further preferably 30 to 40 μm and/or 10 to 20 μm, from the viewpoint of removing fine aggregates in blood.
In the mode in which the 2 nd filter layer is disposed upstream of the 1 st filter layer, even when aggregates are generated in blood, the aggregates are captured by the nonwoven fabric of the 2 nd filter layer on the upstream side (inlet side) where the meshes are large, and the aggregates of the nonwoven fabric of the 1 st filter layer reaching the downstream side (outlet side) where the meshes are fine are reduced. Therefore, clogging of the 1 st filter layer caused by the aggregates is suppressed.
The bulk density of the 2 nd filter layer is preferably 0.05-0.50 g/cm3More preferably 0.10 to 0.40g/cm3. If the bulk density of the 2 nd filter layer is 0.50g/cm3In the following, clogging of the nonwoven fabric due to trapping of aggregates, white blood cells, and the like is suppressed, and the filtration rate tends to be improved. Further, when the bulk density of the nonwoven fabric is 0.05g/cm3As described above, the ability to capture aggregates increases, clogging of the nonwoven fabric of the 1 st filtration layer is suppressed, the filtration rate tends to improve, and the mechanical strength of the nonwoven fabric tends to improve.
[3 rd Filter layer ]
The filter medium of the blood treatment filter may further include one or more 3 rd filter layers between the 1 st filter layer and the outlet portion of the container, as long as the effects of the present invention are not impaired.
The filter medium of the blood treatment filter may further include one or more 2 nd filter layers between the inlet portion and the 1 st filter layer of the container, and one or more 3 rd filter layers between the 1 st filter layer and the outlet portion of the container.
The structure of the 3 rd filter layer may be appropriately adjusted according to the required performance.
The 3 rd filter layer preferably includes a known filter medium such as a fibrous porous medium such as a nonwoven fabric, woven fabric, or mesh, or a porous body having three-dimensional mesh-like continuous pores. Examples of the raw material include polypropylene, polyethylene, styrene-isobutylene-styrene copolymer, polyurethane, and polyester. From the viewpoint of productivity and welding strength of the blood treatment filter, the 3 rd filter layer preferably includes a nonwoven fabric. Since the flow of blood becomes more uniform, it is particularly preferable that the 3 rd filter layer has a plurality of projections by embossing or the like.
The average fiber diameter of the nonwoven fabric contained in the filtration layer 3 is preferably 3 to 60 μm, more preferably 4 to 40 μm, further preferably 30 to 40 μm and/or 10 to 20 μm.
In the case of a blood treatment filter having a flat and flexible container, it is preferable to dispose the 3 rd filter layer because the filter layer is pressed against the outlet side container by the positive pressure on the inlet side generated during filtration and the outlet side container is prevented from adhering to the filter layer by the negative pressure on the outlet side and interfering with blood flow, and the adhesion between the flexible container and the filter layer is improved.
For the purpose of controlling the selective separation of blood cells, the hydrophilicity of the surface, and the like, the surface of each nonwoven fabric constituting the filter layer may be modified by a known technique such as coating, chemical treatment, radiation treatment, and the like.
< method for manufacturing blood treatment Filter 1 >
The method for producing the nonwoven fabric (fibrous base material) is not limited, and the nonwoven fabric can be produced by either a wet method or a dry method. The melt blowing method is particularly preferably used in order to stably obtain a nonwoven fabric having an appropriate maximum orientation ratio.
An example of the melt-blowing method will be described as a method for producing a nonwoven fabric (fibrous base material). In the melt blowing method, a molten polymer stream melted in an extruder is filtered through an appropriate filter, introduced into a molten polymer introduction portion of a melt blowing die head, and then ejected from an orifice-shaped nozzle. Simultaneously with this, the heated gas introduced into the heated air introduction section is introduced into a heated air ejection slit formed by a melt blowing die head and a die lip, and ejected therefrom, so that the ejected molten polymer is refined to form ultrafine fibers, and the formed ultrafine fibers are laminated to obtain a nonwoven fabric. Further, when the nonwoven fabric is subjected to heat treatment using a heat suction drum, a hot plate, hot water, a hot air heater, or the like, a nonwoven fabric having a desired crystallinity can be obtained.
The method for producing a nonwoven fabric having a maximum orientation ratio of 1.2 or more is not particularly limited, and examples thereof include a method in which a nonwoven fabric is spun by a melt-blowing method and the take-up speed of a collecting conveyor (or a roll) at the time of collection is increased. When the winding speed is increased, the fibers are strongly oriented in the winding direction (longitudinal direction) of the conveyor, and the difference in orientation degree between the fibers and the direction (width direction) perpendicular to the winding direction is relatively increased.
In addition, although the nonwoven fabric having a small weight per unit area (weight per unit area) and a small thickness is formed by the above method, a filter having a desired weight or thickness can be produced by increasing the number of laminated nonwoven fabrics. Alternatively, if the conveyor is designed to collect the nonwoven fabric in a circulating manner, the nonwoven fabric can be discharged onto the conveyor a plurality of times, and the nonwoven fabric having a predetermined weight per unit area can be collected. This method improves the production efficiency of the filter medium because the nonwoven fabric can be easily handled because of its high weight per unit area when assembled to the filter medium, and because it is not necessary to increase the number of laminated layers excessively.
Further, there is also a method of reducing the discharge amount of the polymer from 1 spinneret per unit time (single-hole discharge amount). When the discharge amount is reduced, the fibers constituting the nonwoven fabric become finer, and therefore the fibers are strongly oriented in the winding direction of the conveyor. However, when the average fiber diameter of the fibers changes, the leukocyte removal rate and the filtration time are affected by the change, and therefore it is preferable that the discharge amount is not largely changed.
In addition, it is also effective to use a polymer having a low intrinsic viscosity so that the resin is drawn thinner. For example, among polyesters, polybutylene terephthalate resins are generally lower in melting point and melt viscosity than polyethylene terephthalate resins, and therefore, by using polybutylene terephthalate resins, nonwoven fabrics having a high degree of orientation in the longitudinal direction during spinning can be easily produced. In addition, since the melting point of a copolymer (copolymer) or a polymer containing impurities such as additives is easily lowered as compared with a so-called homopolymer (single polymer) in selecting a resin, the melt viscosity can be optimally adjusted by appropriately selecting these resins.
More specifically, a nonwoven fabric having a maximum orientation ratio of 1.2 or more can be produced by using a PBT resin under the following conditions.
Capture conveyor speed: 4.0 to 6.0 (m/sec)
Single-hole ejection amount: 0.10 to 0.21 (g/(min. hole)))
Intrinsic Viscosity (IV): 0.63 to 0.82(dL/g)
Die temperature: 270 to 290 (DEG C)
Air pressure: 0.25 to 0.40(MPa)
In the above case, it is found that the melt viscosity (shear rate 100 (1/sec), 280 ℃ C.) is 100 to 500(Pa · s).
Among them, a means of first setting the intrinsic viscosity and the single-hole discharge amount and the die temperature and adjusting the conveyor speed while confirming the degree of orientation is effective. The reason is that, depending on the melt viscosity of the resin depending on the intrinsic viscosity and the die temperature, the die may be broken by applying a strong pressure to the die at the time of ejection, and therefore, the single-hole ejection rate has to be set low. Further, when the die temperature is set to 290 ℃ or lower, in the case of PBT, discoloration of the fiber due to decomposition of the resin can be suppressed, and therefore, it is preferable.
However, since the single-hole ejection rate is a parameter directly related to the average fiber diameter of the nonwoven fabric, when the ejection rate is changed, the pressure of the heated air must be adjusted at the same time to obtain a predetermined average fiber diameter. For example, when the ejection amount is reduced, the average fiber diameter can be maintained by reducing the pressure of the heated air. After the single-hole ejection rate is set, it is necessary to calculate and set a collection time on the conveyor in order to obtain a predetermined weight of the nonwoven fabric. That is, since the single-hole discharge amount also affects the production amount of the nonwoven fabric, it is necessary to return to the selection of the resin and the discharge amount again in consideration of the productivity and quality of the nonwoven fabric.
Finally, the distance between the nozzle and the conveyor does not significantly affect the orientation ratio of the nonwoven fabric, but is important as a means for adjusting the thickness of the nonwoven fabric. The thickness can be reduced by adjusting the distance between the nozzle and the conveyor to be 3-60 cm. Particularly, when the average fiber diameter is 1 to 3 μm, the bulk density can be easily adjusted to 0.10 to 0.30g/cm by adjusting the distance between the nozzle and the conveyor to 3 to 10cm3。
< 2 nd blood treatment Filter >
One embodiment of the present invention relates to a blood treatment filter including:
a container having an inlet portion and an outlet portion for blood, and
a filter material disposed between the inlet portion and the outlet portion in the container,
the filter medium includes one or more filter layers (hereinafter also referred to as "the 1 st filter layer"),
the filter layer has a space in which the maximum length in the planar direction is 50 [ mu ] m or more and the maximum length in the thickness direction is 15 [ mu ] m or more in a cross section in the thickness direction.
The first filtration layer 1 has a predetermined space in the inside thereof, and can exhibit an excellent leukocyte removal rate and an excellent filtration time (filtration rate).
[ Container ]
The container was as described in the item < 1 st blood treatment filter >.
[ Filter Material ]
(the 1 st Filter layer)
The filter medium comprises more than one layer of the 1 st filter layer. In the case where the filter includes a plurality of the 1 st filter layers, the plurality of the 1 st filter layers may be the same or different. The thickness of the first filtration layer 1 may be, for example, 0.1mm to 0.8mm, 0.3mm to 0.6mm, 0.4 to 0.5mm, or the like. The average thickness of the 1 st filtration layer can be measured by sampling at least 3 positions (for example, 1 position from the left end to the vicinity of the center, 1 position near the center, and 1 position from the vicinity of the center to the right end) in the spinning width direction in consideration of the variation in physical properties during spinning. The sample size was 2.5cm × 2.5cm, and the thickness was measured at the center (1 position) with a constant pressure thickness gauge. The load pressure of the thickness gauge was set to 0.4N, and the area of the measuring part was set to 2cm2. When the spinning width direction was not specified, the measurement was performed by sampling a portion used as a filter unit of the filter.
The 1 st filter layer preferably comprises a nonwoven fabric. The nonwoven fabric was as described in the item < 1 st blood treatment filter >.
The nonwoven fabric contained in the 1 st filter layer may have a coating layer on its surface. The coating layer was as described in the item < 1 st blood treatment filter >.
The nonwoven fabric contained in the filtration layer 1 preferably has a basic nitrogen-containing functional group in its peripheral surface portion. The peripheral surface portion of the nonwoven fabric may further have a nonionic hydrophilic group. For the basic nitrogen-containing functional group, and the nonionic hydrophilic group, as described in the item < 1 st blood treatment filter >.
(inner space)
The 1 st filter layer has, in a cross section in the thickness direction (a cross section cut in the thickness direction), a space in which the maximum length in the planar direction is 50 μm or more and the maximum length in the thickness direction is 15 μm or more (see, for example, fig. 8A and 8B). By having such a size of the space, clogging due to blood cells, micro aggregates, etc. contained in blood is avoided, and the effective filtration area is increased, whereby leukocyte removal performance and filtration time can be improved. When the filter medium contains a plurality of the 1 st filter layers, at least one of the 1 st filter layers may have the internal space, but preferably all of the 1 st filter layers have the internal space.
The maximum length of the space in the planar direction is preferably 50 to 2000. mu.m, more preferably 100 to 1500. mu.m, and still more preferably 200 to 1000. mu.m.
The maximum length of the space in the thickness direction is preferably 15 to 200. mu.m, more preferably 15 to 150. mu.m, and still more preferably 20 to 100. mu.m.
By setting the upper limit of the maximum length in the plane direction and the thickness direction as described above, the bias flow of blood is suppressed, and the effective filter area can be further increased. In addition, blood is prevented from remaining in the filter layer 1, and a decrease in the amount of blood collected can be avoided.
The inner space of the 1 st filter layer can be measured by the following method. The size of the internal space of the 1 st filtration layer does not substantially change between a state in which the 1 st filtration layer is housed in the blood treatment filter and a state in which the 1 st filtration layer is taken out of the blood treatment filter.
A portion having the average properties (air permeation resistance, density, etc.) of the filter layer was sampled from one 1 st filter layer. Specifically, in consideration of variation in physical properties during spinning, samples were taken at least at 3 locations in the spinning width direction (for example, 1 location from the left end to the center vicinity, 1 location near the center, and 1 location from the center vicinity to the right end), and the internal space of the cross section in the thickness direction of the sample was measured. When the spinning width direction was not specified, a sample was taken from the portion used as the filter portion of the filter.
The length of the internal space is determined by using a pore size analysis software (PHENOM POROMETRIC) of SEM (ProX) manufactured by Phenomold corporation. The void detection condition is the initial setting condition of the software described below. However, when Detection is insufficient, for example, when the holes overlap each other, the hole Detection conditions (Min Contrast, large Shared boundaries, reduction, Min Detection, etc.) may be appropriately adjusted.
The specific measurement method for the internal space is as follows.
(1) A sample of the 1 st filtration layer was taken to be about 10mm by about 3mm in size, with 10mm sides for cross-sectional observation. 3 samples of about 10mm by about 3mm size were used for the measurement.
At this time, the 1 st filtration layer was cut so that the cross section of the sample was not crushed. Since observation needs to be performed while maintaining the three-dimensional structure of the 1 st filtration layer, the 1 st filtration layer is immersed in a solution (for example, water, 20% ethanol water, or ethanol water in the case of low hydrophilicity), and then immersed in liquid nitrogen, and the 1 st filtration layer that is sufficiently frozen is broken.
In the case where the fibers are not broken (for example, in the case where the fibers are not cut and bent, or in the case where the 1 st filter layer is small enough not to be broken), a method is employed in which a fixing resin (such as an epoxy resin) different from the fibers constituting the 1 st filter layer is poured between the fibers and cured, and then the cross section is polished and observed.
(2) The shooting magnification is set to a magnification (preferably 100 times) at which the entire thickness of the 1 st filter layer can be observed. The magnification can be optimized according to the thickness of the 1 st filter layer and the size of the internal space.
(3) Sectional photographs of 3 sites were taken per sample. For the image obtained by the cross-sectional imaging, the pore size in the plane direction and the pore size in the thickness direction were obtained using pore diameter analysis software (pherom pore analysis). The average value of the maximum spatial length 9 points of each cross-sectional captured image was taken as the maximum spatial length.
The initial setting of the aperture analysis software (pherom pore) is as follows.
Min shared borders：0.3
Exclose edge particles: not select
Conductance：0.3
Min detection size：2.5
Foreground kernel size：15
Segmenter anisotropic diffuse conductance：10
Segmenter anisotropic diffuse iterations：5
Segmenter gradient function type：normal
Segmenter WS lower threshold：0.001
Merging min size ratio：2
Merging kernel size：3
(porosity)
The 1 st filter layer preferably has an in-plane porosity that varies in the thickness direction. The in-plane porosity refers to a ratio of pores existing in a plane corresponding to a prescribed position in the thickness direction. High in-plane porosity means low in-plane fiber density. Specifically, the in-plane porosity of 1 means that there is no in-plane fiber. The variation in-plane porosity means, for example, that the ratio of pores present in a plane corresponding to the 1 st position in the thickness direction is different from the ratio of pores present in a plane corresponding to the 2 nd position in the thickness direction.
For example, fig. 9 shows the in-plane porosity in the thickness direction of the nonwoven fabric of example a 1. "position" in fig. 9 indicates a prescribed position in the thickness direction (distance from the surface of the first filter layer 1), and "porosity" indicates porosity existing in a plane corresponding to the prescribed position in the thickness direction. Fig. 9 shows the in-plane porosity variation in the thickness direction. On the other hand, fig. 11 shows the in-plane porosity in the thickness direction of the nonwoven fabric of comparative example a1, and the variation in the in-plane porosity is small. By varying the in-plane porosity in the thickness direction, clogging can be avoided in the entire first filter layer 1 in addition to the internal space included in the first filter layer 1.
In the thickness direction except for the portions up to 80 μm from both ends, the smallest in-plane porosity is referred to as "the smallest in-plane porosity", and the largest in-plane porosity is referred to as "the largest in-plane porosity". The difference between the minimum in-plane porosity and the maximum in-plane porosity is preferably 0.08 to 0.28, more preferably 0.10 to 0.20. Within such a range, clogging can be avoided and excellent leukocyte removal performance can be exhibited. The reason why the portion ranging from both ends to 80 μm in the thickness direction is excluded is that the porosity cannot be measured stably because the portion is affected by fluffing of fibers in the vicinity of the surface of the 1 st filter layer.
The in-plane minimum porosity and the in-plane maximum porosity may be appropriately changed depending on the blood to be treated. For example, in the case of processing blood having a high viscosity, the porosity may be increased to avoid clogging. On the other hand, when blood having a low viscosity and a large number of leukocytes is processed, the porosity may be decreased to improve the leukocyte removal performance. Although not particularly limited, the in-plane minimum porosity is preferably 0.72 to 0.85, more preferably 0.75 to 0.83. The in-plane maximum porosity is preferably 0.85 to 1.00, more preferably 0.87 to 0.95.
The in-plane porosity of the 1 st filter layer in the thickness direction can be measured by the following method.
From one 1 st filtration layer, at least 3 portions (for example, 1 portion from the left end to the vicinity of the center, 1 portion near the center, and 1 portion from the vicinity of the center to the right end) in the spinning width direction were sampled in consideration of variation in physical properties at the time of spinning, and the porosity of the sample was calculated by X-ray CT measurement. When the spinning width direction cannot be specified, 3 points are sampled from the portion used as the filter portion of the filter. The X-ray CT apparatus and the image analysis software used are as follows.
X-ray CT apparatus: high resolution 3 DX-ray microscope nano3DX manufactured by Rigaku Corporation
Image analysis software: ImageJ
The sample for X-ray CT measurement was cut in-plane to 2.5 mm. times.2.5 mm, and the X-ray CT measurement was directly performed on the entire thickness. Wherein the measured thickness is 0.1mm or more.
The measurement conditions are as follows.
Image resolution: 0.54 μm/pix
Exposure time: 18 seconds per sheet
Projection number: 1500 pieces/180 degree
X-ray tube voltage: 40kV
X-ray tube current: 30mA
An X-ray target: cu
The thickness direction of the nonwoven fabric is defined as the Z axis, an arbitrary direction perpendicular to the Z axis is defined as the X axis, and a direction perpendicular to the X axis and the Z axis is defined as the Y axis. The XY plane corresponds to the plane of the nonwoven fabric. The X-ray measurement site in the sample is selected from the central portion in the plane having no influence on the cut surface of the sample end.
The X-ray CT measurement is performed on a tomographic X-ray image, and the tomographic X-ray image is a rectangular parallelepiped trimmed to have an X-axis × Y-axis × Z-axis of 500 μm × 500 μm × total thickness. This is taken as a three-dimensional image 1.
For the three-dimensional image 1, median filtering (median filter) of an image processing method is performed at a radius of 2pix, and then region segmentation is performed by applying Otsu's method of an image processing method. The luminance value of the pixel was set so that air was 0 and the fiber of the nonwoven fabric was 255. The image thus obtained is taken as a three-dimensional image 2.
Segmentation (segmentation) by an image processing method is performed on the pixels of the luminance value 255 of the three-dimensional image 2, and a fiber having the number of pixels of 10000pix or less among fibers connected to one luminance value 255 is removed as noise. The luminance value of the pixel was set so that the air was 0 and the fiber of the nonwoven fabric was 255, and the image thus obtained was defined as a three-dimensional image 3.
In the three-dimensional image 3, the two-dimensional porosity of each region for 1pix is obtained by the following equation on the Z-axis in the thickness direction.
Porosity is the number of pixels of air (luminance value 0) in the XY plane of thickness 1 pix/the total number of pixels of the XY plane of thickness 1pix
The porosity was obtained for all pixels in the Z-axis direction (all thickness directions).
For at least one of the 3 samples, it is preferable that the in-plane minimum porosity, the in-plane maximum porosity, and the difference thereof are contained within the above numerical range.
(filling Rate)
The 1 st filter layer preferably has a filling factor of 0.09 to 0.26, more preferably 0.12 to 0.19. When the filling rate of the filtration layer 1 is 0.26 or less, clogging of blood cells and fine aggregates is reduced, and the processing speed tends to be improved. When the filling rate of the 1 st filter layer is 0.09 or more, the number of times of contact with white blood cells or the like increases, and the capture rate of white blood cells or the like tends to improve, and the mechanical strength of the filter medium tends to improve.
The filling ratio of the 1 st filtration layer was measured by the following method. The area, thickness, and mass of the 1 st filter layer in the planar direction and the specific gravity of the fibrous material of the nonwoven fabric constituting the 1 st filter layer were measured and calculated by the following formula (10). The weight per unit area was determined as follows: the nonwoven fabric was sampled from a portion which had a size of 2.5cm × 2.5cm and was considered to be uniform, and the weight of the nonwoven fabric sheet was measured and converted into a mass per square meter. In addition, the thickness of the 1 st filter layer was determined as follows: the nonwoven fabric was sampled from a portion considered to be uniform and having a size of 2.5cm × 2.5cm, and the thickness of the center (1 position) thereof was measured with a constant pressure thickness gauge. The load pressure of the thickness gauge was set to 0.4N, and the area of the measuring part was set to 2cm2。
Filling rate [ [ mass (g) of the 1 st filter layer)/(area (cm) of the 1 st filter layer in the plane direction2) X thickness (cm) of the 1 st filtration layer]Specific gravity (g/cm) of the fibrous material of the nonwoven fabric constituting the 1 st filtration layer3)
(10)
(texture index)
For the texture index of the 1 st filtration layer, the term < 1 st blood treatment filter > is used.
(specific surface area)
The specific surface area of the No. 1 filter layer is preferably 0.50m21.50 m/g or more2The ratio of the carbon atoms to the carbon atoms is less than g. If the specific surface area is 1.50m2When the concentration is lower than the above range,/g, adsorption of useful components such as plasma proteins to the filter layer in blood treatment is suppressed, and the recovery rate of the useful components tends to be improved. When the specific surface area is 0.50m2When the amount of the adsorbed leukocytes or the like is larger than or equal to g, the ability to remove leukocytes or the like tends to be improved. The specific surface area of the No. 1 filter layer is more preferably 0.70m2More than gAnd 1.45m2A ratio of 1.10m or less per gram21.40 m/g or more2The ratio of the carbon atoms to the carbon atoms is less than g.
The specific surface area was measured as described in the item < 1 st blood treatment filter >.
(air permeation resistance)
The air permeability resistance of the 1 st filtration layer was as described in the item < 1 st blood treatment filter >.
(mean flow pore size)
The 1 st filtration layer preferably has a mean flow pore size of less than 8.0 μm. When the average flow pore size is less than 8.0. mu.m, the number of contacts with white blood cells or the like increases, and the white blood cells or the like tend to be easily captured. When the average flow pore size is 1.0 μm or more, clogging of blood cells is reduced, and the processing speed tends to increase. The average flow pore diameter is more preferably 1.5 μm or more and 7.5 μm or less, still more preferably 2.5 μm or more and 7.0 μm or less, and most preferably 3.5 μm or more and 6.0 μm or less.
The average flow pore size was measured as described in the item < 1 st blood treatment filter >.
(critical wetting surface tension)
The Critical Wetting Surface Tension (CWST) of the filtration layer 1 is preferably 70dyn/cm or more, more preferably 85dyn/cm or more, and further preferably 95dyn/cm or more. By ensuring stable wettability to blood in the 1 st filtration layer having such critical wetting surface tension, it is possible to efficiently remove leukocytes and the like while passing platelets in the blood preparation. The upper limit of CWST is not particularly limited, and may be, for example, 200dyn/cm, 150dyn/cm, 100dyn/cm, or the like.
The measurement of CWST was as described in the item < 1 st blood treatment Filter >.
(average fiber diameter)
The average fiber diameter of the nonwoven fabric contained in the 1 st filtration layer was as described in the item < 1 st blood treatment filter >.
[2 nd Filter layer ]
The filter medium of the blood treatment filter may contain a further filter layer in addition to the 1 st filter layer within a range not impairing the effects of the present invention. For example, the filter medium may further include one or more 2 nd filter layers between the inlet portion of the container and the 1 st filter layer.
The 2 nd filtration layer was as described in the item < 1 st blood treatment filter >. The filling ratio of the 2 nd filter layer is preferably 0.04 to 0.36, and more preferably 0.07 to 0.29. When the filling ratio of the 2 nd filter layer is 0.36 or less, clogging of the nonwoven fabric due to trapping of aggregates can be suppressed, and the filtration rate tends to be improved. On the other hand, when the concentration is 0.04 or more, the capturing ability of aggregates increases, clogging of the 1 st filtration layer is suppressed, and the filtration rate tends to be improved, and the mechanical strength of the nonwoven fabric tends to be improved.
[3 rd Filter layer ]
The filter medium of the blood treatment filter may further include one or more 3 rd filter layers between the 1 st filter layer and the outlet portion of the container, as long as the effects of the present invention are not impaired. The filter medium of the blood treatment filter may further include one or more 2 nd filter layers between the inlet portion and the 1 st filter layer of the container, and one or more 3 rd filter layers between the 1 st filter layer and the outlet portion of the container.
The 3 rd filtration layer was as described in the item < 1 st blood treatment filter >.
< method for manufacturing blood treatment Filter No. 2 >
The method for producing the nonwoven fabric (fibrous base material) is not limited, and the nonwoven fabric can be produced by either a wet method or a dry method. In the case where a desired space is formed inside the 1 st filter layer, the melt-blowing method is preferably employed.
An example of the melt-blowing method will be described as a method for producing a nonwoven fabric (fibrous base material). In the melt blowing method, a molten polymer stream melted in an extruder is filtered through an appropriate filter, introduced into a molten polymer introduction portion of a melt blowing die head, and then ejected from an orifice-shaped nozzle. Simultaneously with this, the heated gas introduced into the heated air introduction section is introduced into a heated gas ejection slit formed by a melt blowing die head and a die lip, and ejected therefrom, the ejected molten polymer is made fine to form ultrafine fibers, and the formed ultrafine fibers are stacked on a collecting conveyor and a collecting drum, thereby obtaining a nonwoven fabric. Further, when the nonwoven fabric is subjected to heat treatment using a heat suction drum, a hot plate, hot water, a hot air heater, high-pressure steam sterilization, or the like, a nonwoven fabric having a small shrinkage rate and a stable shape can be obtained.
When the nonwoven fabric is collected by a rotary conveyor, the fibers discharged from the rotary conveyor are stacked, whereby the stacked nonwoven fabrics can be spun. When the collection is performed by using a take-up belt conveyor, the stacked nonwoven fabrics can be spun by providing a plurality of rows of spinnerets in the longitudinal direction, even if the spinnerets are not of a rotary type. Here, by appropriately cooling the fiber discharged from the spinneret and the newly discharged fiber superposed on the fiber until they are laminated, a predetermined space can be formed inside the filter layer. Examples of the cooling method include a method of naturally cooling the fiber layer by extending the time until the fiber layer is laminated on the fiber layer. On the other hand, when the conveyor has a suction function, the fibers are stably collected and are ventilated, thereby obtaining a cooling effect. If the cooling is excessive, the fiber layer is peeled off without fusion of the fibers at all, and a single nonwoven fabric cannot be formed, so that the handling property is deteriorated or the blood recovery rate is reduced.
The rotation speed of the collecting conveyor, the length of the meltblowing die, the spinning width, the distance (DCD) between the meltblowing die and the collecting drum, and the like can be appropriately adjusted, thereby adjusting the internal space of the filter layer.
The nonwoven fabric described in the present specification may be spun under the following conditions.
Number of meltblown die spinnerets: 5 to 30(hole/cm)
Capture conveyor rotation speed: 100 to 400 (m/min)
Ejection moving speed: 0.06 to 0.10m/s
Single-hole ejection amount: 0.12 to 0.20 (g/(min. hole))
Amount of heated air: 100 to 400 (Nm)3/hr)
·DCD：50～1000(mm)
Among the conditions of particular importance are the conveyor rotation speed and the ejection movement speed.
The means for stacking the nonwoven fabrics while rotating the collecting conveyor in the longitudinal direction of the nonwoven fabrics is effective because the amount of nonwoven fabrics applied per unit time and unit area is reduced, and the internal space of the filter layer can be relatively increased. In particular, by increasing the rotation speed, the uniformity of the nonwoven fabric is improved and the internal space of the filter layer is increased.
Further, a means for ejecting the fibers by providing a time difference in the width direction, rather than ejecting the fibers simultaneously from the spinneret in the width direction, is effective because the internal space in the plane direction can be increased. In this principle, when the discharge area is reciprocated, a time interval is provided between the previous discharge and the subsequent discharge, and thereby the previous fiber layer is cooled during this time, and the fiber layer is less likely to be fused with the subsequent fiber layer, and as a result, the internal space in the planar direction can be increased. This effect is further increased if the time interval is large.
Further, since the previous fiber layer is cooled by reducing the ejection moving speed, the internal space in the planar direction can be further increased. Here, the discharge moving speed refers to a moving speed of the discharge spinneret region in the width direction per unit time calculated by the following equation.
< formula >
The ejection moving speed is the width length of the collecting conveyor (m)/(switching time(s) × the number of spinnerets in the width direction)
For example, in FIG. 13, 8 spinning nozzles each having a collecting conveyor width of 1.6m and a collecting conveyor width of 20cm were provided. In this case, when spinning is continuously performed while switching every 2.5 seconds from the spinneret 1 at the right end to the spinneret 8 at the left end in fig. 13, the discharge moving speed is 1.6/(2.5 × 8) ═ 0.08 m/s. The ejection moving speed indicates a substantial speed at which the ejection area expands in the width direction.
In the case where the same effect is to be obtained more easily than the case where the time-difference discharge is performed in the width direction, the same effect can be obtained by reciprocating the meltblowing die head itself in the width direction with respect to the conveyor or by reciprocating the conveyor in the width direction with respect to the die head instead.
The number of die orifices per unit length is an effective parameter from the viewpoint of improving the uniformity of the nonwoven fabric in the planar direction and controlling the size of the internal space within an appropriate range. The single-hole discharge amount and the DCD are effective in relatively controlling the internal space by adjusting the amount of nonwoven fabric applied per unit time and the thickness of the nonwoven fabric. In particular, if the single-hole ejection rate is reduced, cooling of the fiber layer is promoted, and the internal space can be relatively increased. However, if it is too small, the resin becomes too fine, and a phenomenon of fly (fly) occurs without being trapped by the conveyor, so that it is preferable to adjust the resin to a fixed range.
It is effective to increase the amount of heated air so that the average fiber diameter of the nonwoven fabric can be adjusted to obtain a fixed leukocyte removal ability. However, if the amount is too high, the resin becomes too fine, and a phenomenon of scattering (fly) occurs without being trapped by the conveyor, and therefore, it is preferable to adjust the amount to be equal to or less than a fixed value in accordance with the single-hole discharge amount.
< method for removing leukocytes >
The leukocyte removal method includes, for example: and a step of removing leukocytes from the leukocyte-containing liquid by passing the leukocyte-containing liquid through a blood treatment filter.
Here, the leukocyte-containing liquid is a body fluid containing leukocytes and synthetic blood, and specifically, it is whole blood, a thick red blood cell solution, a washed red blood cell suspension, a thawed red blood cell concentrate, synthetic blood, platelet-poor plasma (PPP), platelet-rich plasma (PRP), plasma, frozen plasma, a platelet concentrate, Buffer Coating (BC), or the like, a liquid composed of whole blood and a single or a plurality of blood components prepared from whole blood, a solution obtained by adding an anticoagulant, a preservative solution, or the like to these liquids, a whole blood preparation, a red blood cell preparation, a platelet preparation, a plasma preparation, or the like.
The liquid obtained by treating the liquid by the method of the present embodiment is referred to as a leukocyte-removed liquid.
Hereinafter, an embodiment of a method for preparing each blood preparation by removing leukocytes by the leukocyte removal method will be described.
(preparation of leukocyte-depleted Whole blood preparation)
A whole blood preparation prepared by adding Citrate Phosphate Dextrose (CPD), Citrate Phosphate Dextrose Adenine-1 (CPDA-1), Citrate Phosphate 2-glucose (CP2D), Acid Citrate Dextrose Formula-a (Acid Citrate Dextrose Formula-a) (ACD-a), Acid Citrate Dextrose Formula-B (Acid Citrate Dextrose Formula-B) (ACD-B), a preservative fluid such as heparin, an anticoagulant, and the like to blood collected is prepared, and then white blood is removed from the whole blood preparation by using the blood treatment filter of the present embodiment, whereby a leukocyte-removed whole blood preparation can be obtained.
In the case of leukocyte-removed whole blood preparation production, when leukocytes are removed before storage, it is preferable that leukocyte removal is performed on whole blood stored at room temperature or under refrigeration using a blood processing filter within 72 hours, more preferably within 24 hours, particularly preferably within 12 hours, and most preferably within 8 hours after blood collection, at room temperature or under refrigeration, thereby obtaining a leukocyte-removed whole blood preparation. In the case of leukocyte removal after storage, leukocyte removal can be achieved by removing leukocytes from whole blood stored at room temperature under refrigeration or freezing, preferably within 24 hours before use, using a blood treatment filter.
(preparation of leukocyte-depleted erythrocyte preparation)
The collected whole blood is added with preservation solution such as CPD, CPDA-1, CP2D, ACD-A, ACD-B, heparin and the like, and anticoagulant. The separation method of each blood component includes: a case where the whole blood is centrifuged after leukocytes are removed; and the case where red blood cells are removed after centrifugation of whole blood or white blood cells are removed from red blood cells and BC.
When the whole blood is centrifuged after the leukocytes are removed from the whole blood, the leukocyte-removed whole blood is centrifuged to obtain a leukocyte-removed red blood cell preparation.
When whole blood is centrifuged before leukocyte removal, the centrifugation conditions are: separating into erythrocyte and PRP; and strong centrifugation conditions for separation into erythrocytes, BC, PPP. A leukocyte-removed erythrocyte preparation can be obtained by adding a preservation solution such AS SAGM, AS-1, AS-3, AS-5, MAP or the like to erythrocytes separated from whole blood or erythrocytes containing BC AS necessary, and then removing leukocytes from the erythrocytes using a leukocyte removal filter.
In the preparation of a leukocyte-depleted red blood cell preparation, whole blood stored at room temperature or under refrigeration may be centrifuged preferably within 72 hours, more preferably within 48 hours, particularly preferably within 24 hours, and most preferably within 12 hours after blood collection.
In the case of leukocyte removal before preservation, it is preferable that leukocyte removal is performed by removing leukocytes using a blood treatment filter at room temperature or under refrigeration within 120 hours, more preferably within 72 hours, particularly preferably within 24 hours, and most preferably within 12 hours after blood collection from an erythrocyte preparation preserved at room temperature or under refrigeration, thereby obtaining a leukocyte-removed erythrocyte preparation. In the case of leukocyte removal after storage, it is preferable that leukocyte removal red blood cell preparations can be obtained by removing leukocytes from red blood cell preparations stored at room temperature, under refrigeration or under freezing, within 24 hours before use, by using a blood treatment filter.
(preparation of leukocyte-removed platelet preparation)
The collected whole blood is added with preservation solution such as CPD, CPDA-1, CP2D, ACD-A, ACD-B, heparin and the like, and anticoagulant.
The separation method of each blood component includes: a case where the whole blood is centrifuged after leukocytes are removed; and the case where white blood cells are removed from PRP or platelets after centrifugation of whole blood.
In the case of centrifugation after removal of leukocytes from whole blood, leukocyte-removed platelet preparations can be obtained by subjecting leukocyte-removed whole blood to centrifugation.
When whole blood is centrifuged before leukocyte removal, the centrifugation conditions include: separating into erythrocyte and PRP; and strong centrifugation conditions for separation into erythrocytes, BC, PPP. In the case of weak centrifugation conditions, leukocyte-removed platelet preparations can be obtained by centrifugation after removing leukocytes from PRP separated from whole blood by a blood treatment filter, or leukocyte-removed platelet preparations can be obtained by centrifugation of PRP to obtain platelets and PPP and then removing leukocytes by a blood treatment filter. In the case of strong centrifugation conditions, the BC separated from the whole blood is set to one unit or several to ten or more unit cells, and the resulting substance is added with a storage solution, plasma, or the like as necessary and centrifuged to obtain platelets, and the obtained platelets are subjected to a blood treatment filter to remove leukocytes, whereby a leukocyte-removed platelet preparation can be obtained.
In the preparation of a leukocyte-depleted platelet preparation, whole blood stored at room temperature is preferably centrifuged within 24 hours, more preferably within 12 hours, and particularly preferably within 8 hours after blood collection. In the case of leukocyte removal before storage, it is preferable that the leukocyte removal platelet preparation can be obtained by removing leukocytes from a platelet preparation stored at room temperature by using a blood treatment filter at room temperature within 120 hours, more preferably within 72 hours, particularly preferably within 24 hours, and most preferably within 12 hours after blood collection. In the case of leukocyte removal after storage, it is preferable that leukocyte removal platelet products can be obtained by removing leukocytes from platelet products stored at room temperature, under refrigeration or under freezing, or by using a blood treatment filter within 24 hours before use.
(preparation of leukocytopheresis plasma preparation)
The collected whole blood is added with preservation solution such as CPD, CPDA-1, CP2D, ACD-A, ACD-B, heparin and the like, and anticoagulant.
The separation method of each blood component includes: a case where the whole blood is centrifuged after leukocytes are removed; and the case where leukocytes are removed from PPP or PRP after centrifugation of whole blood.
When whole blood is subjected to leukocyte removal and then centrifugal separation, the leukocyte-removed whole blood is subjected to centrifugal separation, whereby a leukocyte-removed plasma preparation can be obtained.
When whole blood is centrifuged before leukocyte removal, the centrifugation conditions include: separating into erythrocyte and PRP; and strong centrifugation conditions for separation into erythrocytes, BC, PPP. In the case of weak centrifugation conditions, the PRP is centrifuged through a blood treatment filter to remove leukocytes, and then a leukocyte-removed plasma preparation is obtained by centrifugation, or the PRP is centrifuged to PPP and platelets, and then leukocytes are removed through a blood treatment filter, and thus a leukocyte-removed plasma preparation can be obtained. Under the condition of strong centrifugation, leukocyte removal can be performed by removing the leukocyte from the PPP by using a blood treatment filter.
In the production of a leukoreduced plasma preparation, whole blood stored at room temperature or under refrigeration may be centrifuged preferably within 72 hours, more preferably within 48 hours, particularly preferably within 24 hours, and most preferably within 12 hours after blood collection. The leukocyte-removed plasma preparation can be obtained by removing leukocytes from a plasma preparation stored at room temperature or under refrigeration, preferably within 120 hours, more preferably within 72 hours, particularly preferably within 24 hours, most preferably within 12 hours after blood collection, using a blood treatment filter at room temperature or under refrigeration. In the case of leukocyte removal after storage, it is preferable that leukocyte removal is performed from a plasma preparation stored at room temperature or under refrigeration or freezing within 24 hours before use by removing leukocytes with a blood treatment filter, thereby obtaining a leukocyte-removed plasma preparation.
The form of the blood preparation from the blood collection to the leukocyte depletion can be any of the following forms: collecting blood with a blood collection needle connected to a container for whole blood, connecting the container containing whole blood or centrifugally separated blood components to a blood treatment filter, and removing leukocytes; or, blood is collected by a circuit in which at least a blood collection needle, a blood container and a blood treatment filter are aseptically connected, and leukocyte removal is performed before or after centrifugal separation; alternatively, the container containing the blood components obtained by the automatic blood sampling device is connected to a blood processing filter or leukocyte removal is performed by a blood processing filter connected in advance, and the present embodiment is not limited to these embodiments. In addition, whole blood is centrifuged into components by an automatic component blood collection device, and after a storage solution is added as needed, any one of red blood cells, red blood cells including BC, platelets, PRP and PPP is immediately introduced into a blood processing filter to remove leukocytes, thereby obtaining a leukocyte-removed red blood cell preparation, a leukocyte-removed platelet preparation or a leukocyte-removed plasma preparation.
In the present embodiment, the leukocyte removal can be performed by flowing leukocyte-containing blood through the blood treatment filter via the tube by utilizing a drop from a container containing a leukocyte-containing liquid provided at a position higher than the blood treatment filter; alternatively, the leukocyte-containing blood may be passed through the blood treatment filter while being pressurized from the inlet side of the blood treatment filter and/or may be passed through the blood treatment filter while being depressurized from the outlet side of the blood treatment filter by using a pump or the like.
Examples
The present invention will be described below based on examples, but the present invention is not limited to these examples. The performance of the blood treatment filter was measured by the following method.
(evaluation of leukocyte removal ability-evaluation of filtration time)
As blood used for evaluation, the following whole blood was used: to 400mL of blood immediately after blood collection, 56mL of a CPD solution as an anticoagulant was added, mixed, and allowed to stand for 2 hours. Hereinafter, the blood prepared for blood evaluation is referred to as "blood before filtration".
However, in the blood transfusion market, room-temperature stored blood and refrigerated stored blood are sometimes used, and therefore, both cases are evaluated at this time.
A blood bag filled with the blood before filtration and the inlet of the blood treatment filter after steam heating treatment were connected by a vinyl chloride tube 40cm having an inner diameter of 3mm and an outer diameter of 4.2 mm. Further, the outlet port of the blood treatment filter and the blood bag for collection were connected to each other by 85cm of a vinyl chloride tube having the same inner diameter of 3mm and outer diameter of 4.2 mm. Then, the blood before filtration was allowed to flow into the blood treatment filter from the upper part of the blood bag filled with the blood before filtration at a drop height of 140cm, and the filtration time was measured until the amount of blood flowing into the blood bag for collection became 0.2 g/min.
Further, 3mL of blood (hereinafter referred to as post-filtration blood) was collected from the blood bag for collection. The leukocyte removal ability was evaluated by determining the number of remaining leukocytes. The number of leukocytes in the residual leukocytes was measured by flow cytometry (FACSCAnto, BECTON DICKINSON Co., Ltd.) and calculated as follows. The white blood cell count was measured by sampling 100. mu.L of each blood sample and using a Leucocount kit (Becton Dickinson and Company, Japan).
Residual white blood cell number log [ leukocyte concentration (per μ L) (blood after filtration) ] × blood volume (mL)
The filter shape (14 nonwoven fabrics, effective filtration area 45 cm)2) In the case of the blood preserved under the conditions (2), the number of remaining white blood cells is less than 1X 10 in the case of either the blood preserved at room temperature or the blood preserved under refrigeration6This is a practically ideal leukocyte removal filter, since the completion of filtration can be achieved within 45 minutes. Preferably within 40 minutes, more preferably within 35 minutes, and still more preferably within 30 minutes. This is because, if the filtration time is short, more blood can be filtered per unit time in a limited space in the blood center, and the work efficiency is improved. In addition, if the filtration time is long, quality defects such as hemolysis are not expected, and the preparation is discarded.
If the number of the residual white blood cells is less than 1 × 10 per bag6(less than 6Log/Bag) can prevent serious side effects. It is not necessary to satisfy all the requirements of either room-temperature stored blood or refrigerated stored blood with 1 type of filter, because there is no practical problem if an appropriate filter is provided depending on the use environment. Preferably 5.8Log/Bag or less, more preferably 5.5Log/Bag or less, and still more preferably 5.3Log or less. Since the blood varies greatly among individuals, it is known that the number (logarithm) of residual leukocytes is normally distributed even for the same filter type, and the standard deviation is approximately 0.20 Log. That is, a safer blood preparation can be prepared in consideration of a variation of 1 σ part (65%) at 5.8Log or less, a variation of 2 σ parts at 5.5Log or less, a variation of 3 σ parts at 5.3Log or less, in other words, a preparation can be prepared in consideration of a high blood-related ratio of 99.7% at 5.3Log, and the risk of blood transfusion side effects due to the number of remaining leukocytes can be dramatically suppressed.
[ example 1]
(production of Filter layer)
Polybutylene terephthalate (PBT) is spun by a melt-blowing method to form a nonwoven fabric (fiber base). Here, the PBT resin had an intrinsic viscosity of 0.82(dL/g), a single hole ejection rate of 0.21 (g/(min. hole)), a pressure of heated air at the time of ejection of 0.30(MPa), and a collecting conveyor speed of 4.1 (m/sec). The collecting conveyor was circulated for 8.0 minutes to form a nonwoven fabric on the conveyor. The die temperature during spinning was 280 ℃ and the distance between the nozzle and the collecting conveyor was 6 cm.
The obtained fiber base material was coated with a hydrophilic polymer by the following method to obtain a nonwoven fabric having a coating layer (1 st filter layer). The hydrophilic polymer used contained no carboxyl group, and the carboxyl group equivalent of the nonwoven fabric after coating was 122. mu. eq/g, as was the carboxyl group equivalent of the fiber base material.
A copolymer of 2-hydroxyethyl methacrylate (hereinafter abbreviated as HEMA) and diethylaminoethyl methacrylate (hereinafter abbreviated as DEAMA) was synthesized by a usual solution radical polymerization. The polymerization was carried out at 60 ℃ for 8 hours in the presence of 1/200 moles of Azoisobutyronitrile (AIBN) as an initiator at a monomer concentration of 1 mole/L in ethanol. The fibrous base material was immersed in the resulting ethanol solution of the hydrophilic polymer. The fiber base material taken out of the polymer solution was pressed to remove the excess polymer solution absorbed, and the polymer solution was dried while sending dry air to form a coating layer covering the surface of the fiber base material.
The ratio of the amount of substance of the basic nitrogen-containing functional group to the total of the amounts of substance of the nonionic group and the basic nitrogen-containing functional group in the peripheral surface portion (surface portion of the coating layer) of the obtained 1 st filter layer was 3.0 mol%, and the mass of the coating layer in 1g of the 1 st filter layer was 1.5mg/g (fibrous base material + coating layer).
The physical properties of the first filtration layer 1 are shown in Table 1.
(preparation of blood treatment Filter)
The 1 st filtration layer 14 was cut so that Am: Ac was 1.2:1 (the direction of high degree of orientation was coincident with Am), and the resulting sheet was packed to an effective filtration area of 45cm2The soft container (2) is ultrasonically welded to produce a blood treatment filter.
The blood treatment filter was subjected to a steam heating treatment at 115 ℃ for 59 minutes, and then vacuum-dried at 40 ℃ for 15 hours or more. The performance of the blood treatment filter is shown in table 1.
[ examples 2 to 10]
A nonwoven fabric (fiber base material) was produced in the same manner as in example 1, except that the intrinsic viscosity, the single-hole discharge amount, the collecting conveyor speed, and the cycle time of the collecting conveyor of the PBT resin were changed as shown in table 1.
Coating was carried out in the same manner as in example 1 to obtain the 1 st filtration layer. The physical properties of the first filtration layer 1 are shown in Table 1.
As shown in Table 1, a blood treatment filter was produced in the same manner as in example 1, except that the direction of high orientation was made to coincide with Am. The performance of the blood treatment filter is shown in table 1.
[ examples 11 to 20]
Examples 11 to 20 correspond to examples 1 to 10, respectively. In examples 11 to 20, blood treatment filters were produced in the same manner as in examples 1 to 10, except that the direction of the filtration layer 1 in examples 1 to 10 was changed so that the direction of high degree of orientation was made to match Ac as shown in Table 2. The performance of the blood treatment filter is shown in table 2.
[ examples 21 to 30]
Examples 21 to 30 correspond to examples 1 to 10, respectively. In examples 21 to 30, blood treatment filters were produced in the same manner as in examples 1 to 10 except that the direction of the filtration layer 1 in examples 1 to 10 was changed so that Am and Ac were 1:1. The performance of the blood treatment filter is shown in table 3. In examples 21 to 30, blood having a higher viscosity and containing relatively more aggregates than the room-temperature-preserved blood used in examples 1 to 20 was used.
Comparative example 1
A nonwoven fabric (fiber base material) was produced in the same manner as in example 1 except that the intrinsic viscosity of the PBT resin was changed to 0.85(dL/g), the single hole ejection amount was changed to 0.23 (g/(min. hole)), the pressure of the heated air at the time of ejection was changed to 0.32(MPa), the speed of the collecting conveyor was changed to 3.5 (m/sec), and the cycle time of the collecting conveyor was changed to 7.3 minutes.
The coating was carried out in the same manner as in example 1 to obtain a filter layer. The physical properties of the filter layer are shown in Table 4.
As shown in Table 4, a blood treatment filter was produced in the same manner as in example 1, except that the direction of high orientation was made to coincide with Am. The performance of the blood treatment filter is shown in table 4.
Comparative example 2
A blood treatment filter was produced in the same manner as in comparative example 1 except that the direction of the filtration layer in comparative example 1 was changed to match the direction of high degree of orientation with Ac as shown in Table 4. The performance of the blood treatment filter is shown in table 4.
Comparative example 3
A nonwoven fabric (fiber base material) was produced in the same manner as in example 1 except that the intrinsic viscosity of the PBT resin was changed to 0.88(dL/g), the single hole ejection amount was changed to 0.25 (g/(min. hole)), the pressure of the heated air at the time of ejection was changed to 0.35(MPa), the speed of the collecting conveyor was changed to 3.2 (m/sec), and the cycle time of the collecting conveyor was changed to 6.7 minutes.
The coating was carried out in the same manner as in example 1 to obtain a filter layer. The physical properties of the filter layer are shown in Table 4. The degree of orientation of the nonwoven fabric of the filter layer of comparative example 3 was completely isotropic.
A blood treatment filter was produced in the same manner as in example 1. The performance of the blood treatment filter is shown in table 4.
Comparative example 4
A blood treatment filter was produced in the same manner as in comparative example 1 except that the direction of the filtration layer in comparative example 1 was changed so that Am: Ac was 1:1. The performance of the blood treatment filter is shown in table 4. In comparative example 4, blood having a higher viscosity and containing relatively many aggregates than the room-temperature-preserved blood used in comparative example 1 was used.
Comparative example 5
The performance of the blood treatment filter of comparative example 3 was evaluated using blood having a higher viscosity and containing a relatively large amount of aggregates than the room-temperature stored blood used in comparative example 3. The results are shown in Table 4.
[ Table 1]
[ Table 2]
[ Table 3]
[ Table 4]
From the results of examples 1 to 30 and comparative examples 1 to 5, it is understood that by adjusting the ratio of Am to Ac appropriately so that the maximum orientation ratio of the nonwoven fabric is 1.2 or more and further in accordance with the properties of blood, a better filtration time or white blood cell count can be achieved than when the nonwoven fabric of comparative example having a more isotropic orientation is used.
In particular, it is understood from the results of examples 21 to 30 that the nonwoven fabric having the maximum orientation ratio of 1.2 or more can filter blood having high viscosity in a short time and can reduce the number of remaining white blood cells even when Am: Ac is 1:1. This suggests that when the orientation degree of the nonwoven fabric is high, a channel through which blood flows is formed, and that a constant flow rate is maintained without clogging even with high-viscosity blood, and as a result, the filtration time is shortened. Further, it was shown that, by preventing the flow channel from being closed, the effective utilization of the filter medium is improved, and even with respect to the number of residual white blood cells which are originally in a trade-off relationship, the effect of improvement is obtained as compared with comparative example 4 (conventional product).
Further, in examples 2 to 9, the number of remaining leukocytes in the refrigerated hemofiltration was 5.5Log or less and the filtration time was 40 minutes or less, and it was found that the preparation quality and the workability were improved by improving the leukocyte removal ability. In particular, in examples 2 to 6, the number of remaining leukocytes was 5.3Log or less, and the leukocyte removal ability was further improved.
Further, in examples 12 to 19, the number of remaining leukocytes in room temperature hemofiltration was 5.8Log or less and the filtration time was 40 minutes or less, and improvement of the preparation quality and improvement of the workability due to improvement of the leukocyte removal ability were found. In particular, in examples 12 to 16, the filtration time was 35 minutes or less, and the working effect was further improved.
Further, in examples 22 to 29, the number of remaining leukocytes was 5.5Log or less, and the filtration time was 40 minutes or less, and it was found that the preparation quality and the workability were improved by improving the leukocyte removal ability. In examples 22 to 27, the filtration time was 30 minutes or less, and the working efficiency was further improved. In particular, in examples 22 to 25, the number of remaining leukocytes was 5.3Log or less, and the leukocyte removal ability was further improved.
From the above results, it is understood that the filtration performance is further improved for the nonwoven fabric having the maximum orientation ratio of 1.28 to 2.0, and the performance is further improved for the nonwoven fabric having the maximum orientation ratio of 1.28 to 1.42.
Next, performance comparison by whole blood filtration was performed using a conventional leukocyte removal filter or a filter layer manufactured by a manufacturing method described in a known literature.
[ example 31]
(preparation of blood treatment Filter)
The 1 st filtration layer 14 used in example 1 was cut into 3cm square so that Am: Ac was 1.2:1 (the direction of high degree of orientation was coincident with Am), and the resulting sheet was packed in an effective filtration area of 9cm2The soft container (2) is ultrasonically welded to produce a blood treatment filter. This is because known filters have various sizes, and in order to perform the evaluation with the same size, only a small filter can be used for the relative evaluation.
The blood treatment filter was subjected to a steam heating treatment at 115 ℃ for 59 minutes, and then vacuum-dried at 40 ℃ for 15 hours or more. The performance of the blood treatment filter is shown in table 5.
(evaluation of leukocyte removal ability-evaluation of filtration time)
As blood used for evaluation, the following whole blood was used: to 80mL of blood immediately after blood collection, 11.2mL of CPD solution as an anticoagulant was added, mixed, and allowed to stand for 2 hours. Hereinafter, the blood prepared for blood evaluation is referred to as "blood before filtration".
However, in the blood transfusion market, room-temperature stored blood and refrigerated stored blood are sometimes used, and therefore, both cases are evaluated at this time.
A blood bag filled with the blood before filtration and the inlet of the blood treatment filter after steam heating treatment were connected by a vinyl chloride tube 40cm having an inner diameter of 3mm and an outer diameter of 4.2 mm. Further, the outlet port of the blood treatment filter and the blood bag for collection were connected to each other by 85cm of a vinyl chloride tube having the same inner diameter of 3mm and outer diameter of 4.2 mm. Then, the blood before filtration was allowed to flow into the blood treatment filter from the upper part of the blood bag filled with the blood before filtration at a drop height of 140cm, and the filtration time was measured until the amount of blood flowing into the blood bag for collection became 0.2 g/min.
Further, 3mL of blood (hereinafter referred to as post-filtration blood) was collected from the blood bag for collection. The leukocyte removal ability was evaluated by determining the number of remaining leukocytes. The method of measuring the number of remaining white blood cells is as described above.
In the above filter shape (14 sheets of nonwoven fabric, effective filtration area 9 cm)2) When the above conditions are applied, the number of remaining leukocytes in either of the room-temperature stored blood and the refrigerated stored blood is less than 5.3 Log/bagg, and filtration completion can be achieved within 45 minutes, and the filter element is therefore considered to be a practically ideal leukocyte removal filter element.
The number of remaining leukocytes is preferably 5.12Log/Bag or less, more preferably 4.95Log/Bag or less, and further preferably 4.77Log/Bag or less. The filtration time is preferably 40 minutes or less, more preferably 35 minutes or less, and further preferably 30 minutes or less.
The filtration time value was the same as in the case of the normal filter size described in examples 1 to 30. This is because the effective filtration area is 1/5 in the case of a normal filter, and since the amount of filtered blood is 1/5, the amount of blood flowing through the filter medium per unit area is the same for both. The filtering time can be specified at the same time as in the case of a normal filter.
However, the number of remaining white blood cells is less than 0.2X 10 per bag as a standard since the blood volume is 1/56(less than 5.3Log/Bag), the standard deviation is approximately about 0.18Log, so the appropriate performance value changes. The results of the performance test of the small blood treatment filter are shown in table 5.
Comparative examples 6 and 7
eWBF3J manufactured by Haemonetics Corporation was removed, and a filter layer having an average fiber diameter of 1.6 to 1.8 μm and a relatively fine mesh was collected and subjected to blood filtration through a mini-filter in the same manner as in example 31. However, the nonwoven fabric had a basis weight of 88g/m2Therefore, 15 sheets of nonwoven fabric were stacked and used to make the weight of the nonwoven fabric used for the filter uniform.
Since the maximum orientation ratio was 1.65, the films were laminated on a filter so that Am: Ac was 1.65:1 and 1:1.65, and evaluated. The test results are shown in table 5.
Comparative examples 8 and 9
RZ-2000F manufactured by Ltd, Kasei Medical co., Ltd, was removed, and a filtration layer having an average fiber diameter of 1.3 μm and fine meshes was collected, and blood filtration was performed through a small filter in the same manner as in example 31. However, the nonwoven fabric had a basis weight of 40g/m2Therefore, 32 sheets of nonwoven fabric were stacked and used.
Since the maximum orientation ratio was 1.13, the films were laminated on a filter so that Am: Ac was 1.13:1 and 1:1.13, and evaluated. The test results are shown in table 5.
[ comparative examples 10 to 13]
The leukocyte removal filter included in the Compolow system manufactured by Fresenius Kabi was removed, 2 kinds of filter layers having a small average fiber diameter and different bulk densities were collected, and blood filtration was performed by a mini-filter using each filter layer in the same manner as in example 31. However, the basis weights of the nonwoven fabrics were 55g/m, respectively2、53g/m2Therefore, 23 and 24 nonwoven fabrics were used in a stacked state. The test results are shown in table 5. Unit area weight 55g/m2The nonwoven fabrics of (4) are described in comparative examples 10 and 11, and the basis weights of the nonwoven fabrics are 53g/m2The nonwoven fabrics of (3) are described in comparative examples 12 and 13.
Comparative examples 14 and 15
Nonwoven fabrics described in example 60 of Japanese patent application laid-open No. H10-508343 were produced. However, as conditions not described in the present example of the production conditions, the resin viscosity was 0.82g/dL, the center-to-center distance of each nozzle was 0.1cm, the nozzle was configured in 1 row of 200 nozzles, and the inclination angle of the nozzle was 0 degrees. As a result, a nonwoven fabric having the physical properties described in examples was obtained, and blood filtration was performed through a mini-filter in the same manner as in example 31 of the present application. The nonwoven fabric had a basis weight of 54g/m2Therefore, 24 sheets of nonwoven fabric were stacked and used. The test results are shown in table 5.
Comparative examples 16 and 17
The PBT nonwoven fabric described in example 1 of International publication No. 2018/034213 was usedBlood filtration was performed through a mini-filter in the same manner as in example 31 of the present application. The weight per unit area of the nonwoven fabric was 22g/m2Therefore, 59 sheets of nonwoven fabric were stacked and used. The test results are shown in table 5.
[ Table 5]
Next, the effect of forming the internal space of the nonwoven fabric was confirmed by the following test using a red blood cell preparation having a higher viscosity than that of whole blood and capable of detecting the filtration time with higher accuracy.
(leukocyte removal Performance of blood treatment Filter)
300g of a red Blood cell Preparation manufactured according to European standards (the Guide to the Preparation, Use and Quality assessment of Blood Components 19 th edition (2017)) was used as a Blood Preparation, and the Blood Preparation was filtered and collected at a natural fall of 110cm by using Blood treatment filters of examples and comparative examples to obtain a filtered Blood Preparation. Here, the drop height means a distance from the lowest part of the bag before filtration to which the red blood cell preparation is added to the lowest part of the bag after filtration (top plate of the balance in the example of fig. 7) for recovering the red blood cell preparation.
Next, the number of remaining white blood cells was calculated according to the following calculation formula.
Residual white blood cell count log [ (white blood cell concentration in blood preparation after filtration) × (blood recovery amount after filtration) ]
The leukocyte concentration in the blood preparation before and after filtration was measured using a leukocyte count measuring kit "LeucoCOUNT" manufactured by Becton, Dickinson and Company (BD Co.) and a flow cytometer FACS CantoII manufactured by BD Co.
[ evaluation criteria for the number of remaining leukocytes ]
Very good: less than 5.0
Good: 5.0 or more and less than 5.5
X: 5.5 or more
Each bag if white blood cell remainsLess than 1 x 106(less than 6Log/Bag) prevents serious side effects similar to whole blood. However, it is known that the red blood cell preparation has a standard deviation of about 0.30Log in the normal distribution of the number of residual white blood cells when the same filter type is used, depending on the blood properties, due to the difference in the original whole blood and the variation in the handedness of the red blood cell preparation in production. In other words, if the amount is less than 5.0Log, a preparation can be prepared in consideration of a high blood-related ratio of 99.7% or more, and the risk of blood transfusion side effects due to the number of remaining white blood cells can be dramatically suppressed. On the other hand, if less than 5.5Log, the correlation ratio of 90% is satisfied, and therefore, the correlation ratio can be practically used.
(filtration time)
In the above "(leukocyte removal performance of blood processing filter)", the time (minutes) required for starting the flow of the erythrocyte preparation to the blood processing filter until the increase in the mass of the erythrocyte preparation collection bag after the filtration is stopped is taken as the filtration time (minutes). The stop of the increase in the mass of the recovery bag means a time when the change in the mass of the recovery bag is 0.1 g/min or less by measuring the mass of the recovery bag every 1 minute from the start of filtration. The final 1 minute at which the mass increase was stopped was determined to be included in the filtration time and calculated.
[ evaluation standards ]
Very good: less than 20 minutes
Good: 20 minutes or more and less than 26 minutes
X: over 26 minutes
The filtration time of the erythrocyte preparation is practically less than 26 minutes, based on the actual performance of the conventional leukocyte removal filter (Asahi Kasei Medical co., Ltd filter R-S11 for erythrocyte preparation). And even more preferably less than 20 minutes.
(blood loss Rate)
The collection was terminated when the change in weight of the collection bag in 1 minute was 0.1g or less, and the balance value at the termination of the collection was used as the blood collection amount. The blood loss rate is obtained by the following equation.
Blood loss ratio (%) × (blood amount before filtration (g) -blood recovery amount (g))/blood amount before filtration (g)
[ evaluation standards ]
Very good: less than 8.0 percent
Good: more than 8.0 percent and less than 9.2 percent
X: over 9.2 percent
Although the red blood cell preparation was used at this time in a combined amount of 300g, the amount of blood collected before filtration actually varies among individuals, and therefore the amount of blood collected needs to be calculated at a loss rate. Based on the actual results of the conventional leukocyte removal filter (Asahi Kasei Medical co., Ltd filter for red blood cell preparation R-S11), the blood loss rate required to be less than 9.2% in practical use. Even more preferably less than 8.0%. By doing so, the loss of useful blood can be reduced. As a result, the number of bags of preparation administered to the same patient can be reduced at the time of blood transfusion, and therefore cost reduction and work efficiency of the medical institution can be achieved.
Example A1
(production of Filter layer)
Polybutylene terephthalate (PBT) is spun by a melt-blowing method to form a nonwoven fabric (fiber base). The rotary conveyor type device was used for the trapping. As the meltblowing die, 10 stages of a meltblowing die having a spinneret number of 10hole/cm and a die length of one tenth (0.20m) relative to a collecting width (2m) of the collecting conveyor were disposed. A method of spinning from the end in the width direction with a time difference is employed. The discharge rate per hole was set to 0.17 (g/(min. hole)), the rotation speed of the collecting conveyor was set to 220 m/min, the switching time per spinneret was set to 4.1 seconds, and the discharge traveling speed was set to 0.07 m/sec. Further, the distance (DCD) between the melt blowing die and the collecting conveyor was adjusted to 50 mm. The die temperature during spinning was 280 ℃.
The obtained nonwoven fabric was coated with a hydrophilic polymer by the following method to obtain a nonwoven fabric having a coating layer (1 st filter layer). After the nonwoven fabric was immersed in an ethanol solution (concentration: 1.5g/L) of a hydrophilic polymer, the nonwoven fabric taken out of the polymer solution was pressed to remove the excess polymer solution absorbed, and the polymer solution was dried while sending dry air to form a coating layer covering the outer peripheral surface of the nonwoven fabric.
The ratio of the amount of substance of the basic nitrogen-containing functional group to the total of the amounts of substance of the nonionic group and the basic nitrogen-containing functional group in the peripheral surface portion (surface portion of the coating layer) of the obtained 1 st filter layer was 3.0 mol%, and the mass of the coating layer in 1g of the 1 st filter layer was 3mg/g (fibrous base material + coating layer).
The physical properties of the first filtration layer 1 are shown in Table 6. Further, the variation of the in-plane porosity of the 1 st filter layer in the thickness direction is as shown in FIG. 9.
(preparation of blood treatment Filter)
As the 2 nd filter layer and the 3 rd filter layer, the following were used: 30 (g/m)2) Air permeation resistance per unit area weight: 0.03(kPa · s · m/g) polyethylene terephthalate (hereinafter referred to simply as "PET") nonwoven fabric.
From the upstream to the downstream of the blood flow, 4 filter layers 2, 16 filter layers 1, and 4 filter layers 3 were laminated in this order. The laminate was sandwiched between 2 sheets of flexible vinyl chloride resin sheets having ports (ports) serving as inlet and outlet ports for blood, and the filter medium and the flexible sheet were welded and integrated at their peripheral portions by a high-frequency welding machine to produce a filter having an effective filtration area of 43cm2The blood processing filter of (1). The blood treatment filter was subjected to autoclaving at 115 ℃ for 59 minutes, and then various performances were tested. The results are shown in Table 6.
Example A2
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the spinning width was changed to 1.6m, 8 spinnerets were arranged in the width direction, and the spinneret switching time was adjusted so that the discharge moving speed was changed to 0.08 to 0.09 m/sec. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6.
Example A3
A filtration layer 1 and a blood treatment filter were prepared in the same manner as in example A1, except that the spinning width was changed to 1.8m, 9 spinnerets were arranged in the width direction, and the spinneret switching time was adjusted so that the discharge moving speed was changed to 0.07 to 0.08 m/sec. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6.
Example A4
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the spinneret switching time was adjusted so that the discharge moving speed was changed to 0.06 to 0.07 m/sec, and a retention time of 15 seconds was provided when the discharge region was repeated. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6.
Example A5
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the spinneret switching time was adjusted so that the discharge traveling speed was changed to 0.09 m/sec, the rotational speed of the collecting conveyor was changed to 225 to 230 m/min, the length of the meltblowing die was changed to 0.40m, and 5 spinnerets were arranged in the width direction. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6.
Examples A6 to A8
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the rotational speed of the collecting conveyor was changed to 223 to 228 m/min in example A6, 220 to 225 m/min in example A7, and 215 to 220 m/min in example A8. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6.
Example A9
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the spinneret switching time was adjusted so that the discharge moving speed was changed to 0.08 to 0.09 m/sec, the length of the meltblowing die was changed to 0.40m, and 5 spinnerets were arranged in the width direction. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6.
Example A10
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the spinneret switching time was adjusted so that the discharge moving speed was changed to 0.07 to 0.08 m/sec and the DCD was changed to 48 to 50 mm. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6.
Example A11
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the spinneret switching time was adjusted so that the discharge moving speed was changed to 0.06 to 0.07 m/sec and the DCD was changed to 46 to 48 mm. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6.
Example A12
A No. 1 filtration layer and a blood treatment filter were prepared in the same manner as in example A1, except that the rotational speed of the collecting conveyor was changed to 220 to 225 m/min and the DCD was changed to 58 to 60 mm. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6. Further, the variation of the in-plane porosity of the 1 st filter layer in the thickness direction is as shown in FIG. 10.
Example A13
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the spinneret switching time was adjusted so that the discharge moving speed was changed to 0.06 to 0.07 m/sec, the collecting conveyor rotating speed was changed to 220 to 225 m/min, DCD was changed to 55 to 60mm, the melt-blowing die length was changed to 0.153m, and the spinneret 13 was disposed in the width direction. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6.
Example A14
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the spinneret switching time was adjusted so that the discharge moving speed was changed to 0.06 to 0.07 m/sec, the rotational speed of the collecting conveyor was changed to 225 to 230 m/min, DCD was changed to 60 to 65mm, the length of the meltblowing die was changed to 0.153m, and the spinnerets 13 were arranged in the width direction. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 6.
Examples A15 and A16
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1 except that the spinneret switching time was adjusted so that the discharge traveling speed was changed to 0.06 to 0.07 m/sec, the rotational speed of the collecting conveyor was changed to 225 to 228 m/min in example A15, and was changed to 220 to 225 m/min in example A16. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 7.
Example A17
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the spinneret switching time was adjusted so that the discharge moving speed was changed to 0.06 to 0.07 m/sec. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 7.
Examples A18 and A19
A filtration layer 1 and a blood treatment filter were prepared in the same manner as in example A1, except that DCD was changed to 55 to 60mm in example A18, to 40 to 45mm in example A19, and that the single-hole ejection rate was changed to 0.28 g/min/hole in example A18 and to 0.18 g/min/hole in example A19. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 7.
Examples A20 to A22
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1 except that the concentration of the hydrophilic polymer solution during coating was changed to 0.3g/L in example A20, 1.0g/L in example A21, and 5.0g/L in example A22. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 7.
Examples A23 and A24
A filter layer 1 and a blood treatment filter were produced in the same manner as in example A1 except that DCD was changed to 55 to 60mm in example A23 and to 45 to 50mm in example A24. The nonwoven fabric (fibrous base material) was subjected to the pressure treatment at a weak pressure in example a23 and at a strong pressure in example a24, thereby adjusting the filling ratio. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 7.
Comparative example A1
A filtration layer 1 and a blood treatment filter were produced in the same manner as in example A1, except that the length of the melt blowing die was changed to 0.3m and the spinning width was changed to 0.3m, and that ejection was not performed with a time lag. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 7. Further, the variation of the in-plane porosity of the 1 st filter layer in the thickness direction is as shown in FIG. 11.
Comparative example A2
A filtration layer 1 and a blood treatment filter were prepared in the same manner as in comparative example A1, except that the single-hole ejection rate was changed to 0.24 g/min/hole. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 7. Further, the variation of the in-plane porosity of the 1 st filter layer in the thickness direction is as shown in FIG. 12.
Comparative example A3
A No. 1 filtration layer and a blood treatment filter were prepared in the same manner as in comparative example A1, except that the single-hole discharge amount was changed to 0.23 g/min/hole and the DCD was changed to 45 to 50 mm. The physical properties of the filtration layer 1 and the performance of the blood treatment filter are shown in Table 7.
Comparative example A4
As the collecting device, a non-rotating belt conveyor type mesh was used, and spinning was performed while sucking the fiber under the mesh. Using a PET resin, a nonwoven fabric was formed by a method in which the single-hole discharge amount was 0.08 g/min/hole, the DCD was adjusted to 50mm, the length of the meltblowing die was 0.3m, the spinning width was 0.3m, and the moving speed of the belt conveyor was 0.05 m/sec, and no discharge was performed with a time lag. The obtained nonwoven fabric was coated with a hydrophilic polymer in the same manner as in example a1 to prepare a1 st filter layer. The physical properties of the first filtration layer 1 are shown in Table 7.
Using the obtained filtration layer 1, a blood treatment filter was produced in the same manner as in example A1. Various properties of the blood treatment filter are shown in table 7.
[ Table 6]
[ Table 7]
Industrial applicability
By forming the filter using a nonwoven fabric having a maximum orientation ratio controlled to be not less than a predetermined value or by using a filter layer having a predetermined space inside, the effects of shortening the blood filtration time and reducing the number of remaining white blood cells can be obtained. This is considered to have industrial applicability because it has advantages of improving blood quality in the transfusion market, shortening the time required for preparation production in the production field, and improving productivity.
Description of the reference numerals
1 … container, 3 … inlet port, 4 … outlet port, 5 … filter medium, 7 … inlet port side space, 8 … outlet port side space, outer edge portion of 9 … filter medium, 10 … blood treatment filter, 11 … first filtration layer, 12 … filtration direction, 13 … plane direction orthogonal to filtration direction, 14 … plane direction parallel to filtration direction, 15 … blood flow (inlet port), 16 … blood flow (outlet port), maximum length in 17 … plane direction, maximum length in 18 … thickness direction
Claims (14)
1. A blood processing filter, comprising:
a container having an inlet portion and an outlet portion for blood, and
a filter material disposed between the inlet portion and the outlet portion in the container,
the filter material comprises a filter layer and a filter layer,
the filter layer comprises a non-woven fabric,
the fibers of the nonwoven fabric have a degree of orientation X in the X-axis plane direction of the filter layer and a degree of orientation Y in the Y-axis plane direction orthogonal to the X-axis plane direction,
the maximum value of the orientation degree X/the orientation degree Y, which is the ratio of the orientation degree X to the orientation degree Y, is 1.2 or more.
2. The blood treatment filter according to claim 1, wherein a maximum value of the orientation degree X/the orientation degree Y is 1.4 or more.
3. The blood treatment filter according to claim 1 or 2, wherein the filter layer is configured in such a manner that: the ratio of the degree of orientation (Ac) of the fibers in the plane direction of the filter layer perpendicular to the filtration direction to the degree of orientation (Am) of the fibers in the plane direction of the filter layer parallel to the filtration direction, i.e., Ac/Am, is 1.2 or more.
4. The blood treatment filter according to claim 3, wherein Ac/Am is 1.4 or more.
5. The blood treatment filter according to claim 1 or 2, wherein the filter layer is configured in such a manner that: the ratio of the degree of orientation (Am) of the fibers in the plane direction of the filter layer parallel to the filtration direction to the degree of orientation (Ac) of the fibers in the plane direction of the filter layer orthogonal to the filtration direction, i.e., Am/Ac, is 1.2 or more.
6. The blood treatment filter according to claim 5, wherein Am/Ac is 1.4 or more.
7. The blood treatment filter according to any one of claims 1 to 6, wherein the nonwoven fabric is a polyester nonwoven fabric.
8. A blood processing filter, comprising:
a container having an inlet portion and an outlet portion for blood, and
a filter material disposed between the inlet portion and the outlet portion in the container,
the filter material comprises more than one filter layer,
the filter layer has a space in which the maximum length in the plane direction is 50 [ mu ] m or more and the maximum length in the thickness direction is 15 [ mu ] m or more in a cross section in the thickness direction.
9. The blood treatment filter according to claim 8, wherein the filter layer has a filling factor of 0.09 to 0.26.
10. The blood treatment filter according to claim 8 or 9, wherein a difference between a minimum in-plane porosity in a thickness direction and a maximum in-plane porosity in the thickness direction of the filter layer is 0.08 to 0.28.
11. The blood treatment filter according to claim 10, wherein the minimum in-plane porosity in the thickness direction is 0.72 to 0.85, and the maximum in-plane porosity in the thickness direction is 0.85 to 1.00.
12. The blood treatment filter according to any one of claims 8 to 11, wherein the filter layer has a specific surface area of 0.50 to 1.50m2/g。
13. The blood treatment filter according to any one of claims 8 to 12, wherein the filtration layer has a critical wetting surface tension of 70 to 100 dyn/cm.
14. A method for producing a blood product, comprising a step of passing blood containing leukocytes through the blood treatment filter according to any one of claims 1 to 13.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019130515 | 2019-07-12 | ||
| JP2019-130515 | 2019-07-12 | ||
| JP2019-130505 | 2019-07-12 | ||
| JP2019130505 | 2019-07-12 | ||
| PCT/JP2020/027030 WO2021010319A1 (en) | 2019-07-12 | 2020-07-10 | Blood processing filter and method for producing blood products |
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| CN114080246A true CN114080246A (en) | 2022-02-22 |
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| CN202080049839.8A Pending CN114080246A (en) | 2019-07-12 | 2020-07-10 | Blood treatment filter and method for producing blood preparation |
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|---|---|
| JP (1) | JP7340020B2 (en) |
| CN (1) | CN114080246A (en) |
| WO (1) | WO2021010319A1 (en) |
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| JP7340020B2 (en) | 2023-09-06 |
| JPWO2021010319A1 (en) | 2021-01-21 |
| WO2021010319A1 (en) | 2021-01-21 |
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