JPH0651060B2 - Filter material for selective removal of leukocytes - Google Patents

Description

[Detailed Description of the Invention] TECHNICAL FIELD The present invention relates to a filter material for selectively removing leukocytes, made of fibers. More specifically, the present invention relates to a filter material for selectively removing leukocytes, which efficiently removes leukocytes with minimal platelet loss from a cell suspension, such as blood, containing both platelets and leukocytes ... are mixed in during the preparation of blood for transfusion in platelet transfusion, while minimizing platelet loss, and to a filter material for selectively removing leukocytes in extracorporeal blood circulation leukocyte removal therapy for autoimmune diseases and leukemia.
The present invention relates to a filter material used in a selective leukocyte removal filter for removing leukocytes while minimizing platelet loss.

Background Art In the field of blood transfusion, platelet transfusions, which aim to improve a patient's tendency to bleed, occupy an important position. Platelet transfusions include fresh whole blood, fresh packed red blood cells, platelet-rich plasma, and platelet concentrate, but all platelet transfusions usually contain a considerable amount of white blood cells. Repeated transfusions of blood contaminated with white blood cells cause anti-white blood cell antibodies to be produced in the patient's body. In such patients, an antigen-antibody reaction occurs between the transfused white blood cells and the anti-white blood cell antibodies in the patient's body during transfusion, which can cause chills, fever, headache,
Side effects such as nausea are observed. It is also known that when a large amount of fresh lymphocytes is transfused or when the patient's immune system is weakened for some reason, the GVH reaction, in which the donor's lymphocytes attack the recipient's tissues, is likely to occur. It has also been recently discovered that the fewer contaminating white blood cells there are in platelet transfusions, the better the survival of the transfused platelets in the patient's body. For these reasons, it is desirable to remove as many contaminating white blood cells, including lymphocytes, as possible in platelet transfusions and minimize platelet loss.

Leukocyte apheresis using extracorporeal blood circulation has recently attracted attention as a new treatment method for autoimmune diseases and leukemia that does not have the side effects seen in drug therapy. In this case, too, it is naturally desirable to efficiently remove leukocytes, including lymphocytes, while minimizing the loss of platelets.

Conventionally, such leukocyte removal has been performed using a centrifugal separator such as a continuous centrifuge, but this method has the drawbacks of not being very efficient at removing leukocytes, resulting in a significant loss of other useful blood components, including platelets, and being complicated to operate, and the equipment is generally expensive.

As a means of removing leukocytes, the filter method, in which leukocytes are removed by adhering them to fibers, is characterized by high leukocyte removal efficiency, minimal loss of red blood cells and plasma components, simple operation, and generally low cost.

Takenaka et al. have disclosed that a filter made of fibers with an average diameter of 3 to 10 μm can efficiently capture leukocytes (U.S. Pat. No. 4,330,410, British Pat. No. 2002/002299).
18151B, French Patent No. 7905629, and West German Patent No. 2908722). Watanabe et al.
It has been disclosed that nonwoven fabric filters made of fibers of less than 1000 microns have a high leukocyte removal efficiency and can also increase the blood processing speed (Japanese Patent Laid-Open Publication No. 60-193468 and European Patent Application Publication No. 0155003). However, these known techniques barely mention the behavior of platelets, and in fact, when blood was passed through these known filters, a considerable amount of platelets were removed along with leukocytes.

Kuroda et al. have disclosed a method for collecting leukocytes and lymphocytes with minimal contamination by erythrocytes and platelets, using a filter whose fiber surface is coated with an antithrombogenic material (Japanese Patent Laid-Open Publication No. 55-129755). However, although there was little loss of platelets when blood was passed through this filter, the filter's ability to capture leukocytes was also small, and it was not possible to selectively remove leukocytes.

Tsuruta et al. have developed a compound with a basic nitrogen-containing functional group and a nitrogen content of 0.05
It has been disclosed that a polymer having a concentration of about 3.5% by weight makes platelets very resistant to adhesion (Japanese Patent Laid-Open Publication No. 60-119955-1
However, this prior art does not disclose anything about the behavior of leukocytes toward the polymer.

As described above, up to now, there is no known means for efficiently removing leukocytes from a cell suspension containing both platelets and leukocytes with minimal loss of platelets.

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a filter material for a selective leukocyte removal filter that can be effectively used in platelet transfusion and extracorporeal blood circulation leukocyte removal therapy, which reduces platelet loss and efficiently removes leukocytes.

The adhesion of cells to materials in general, not just fibers, is
Depends on the surface properties of the material.

To inhibit platelet adhesion, graft polymerization of hydrophilic monomers onto the surface of a material or coating the surface of a material with a hydrophilic polymer are commonly known techniques. However, the material surfaces obtained in this manner are not only less susceptible to platelet adhesion, but also generally less susceptible to leukocyte adhesion, and therefore cannot be used as a means for selectively removing leukocytes, which is the objective of the present invention, by minimizing platelet loss due to adhesion and efficiently adhering and removing leukocytes.

On the other hand, materials with basic nitrogen-containing functional groups generally have a positively charged surface in physiological fluids that suspend cells, and this allows both negatively charged platelets and white blood cells to adhere well.

The present inventors have conducted extensive research into the development of a leukocyte-selective adhesive material that will not adhere to platelets but will adhere to leukocytes. Surprisingly, they have discovered that fibers having nonionic hydrophilic groups and basic nitrogen-containing functional groups on their peripheral surface, with a basic nitrogen atom content of 0.2 to 4.0% by weight, exhibit a characteristic not found in previous fibers: they are less likely to adhere to platelets but more likely to adhere to leukocytes. Furthermore, the use of these fibers in filter materials allows for efficient removal of leukocytes while minimizing platelet loss. Based on these novel findings, the present inventors have completed the present invention. Specifically, the present invention provides a filter material for selective leukocyte removal comprising fibers, each of which comprises a body portion and a peripheral surface portion, and at least the peripheral surface portion of the fiber contains nonionic hydrophilic groups and basic nitrogen-containing functional groups, and the basic nitrogen atom content in the peripheral surface portion is 0.
2 to 4.0 wt. % of the filter material.

The reason why fibers are used in the filter material of the present invention is that they have a large surface area per weight, which allows for efficient removal of leukocytes,
Moreover, it is easy to form it into a filter shape.

The filter material of the present invention is one in which at least the peripheral surface portion of each fiber, out of the body portion and peripheral surface portion (hereinafter often simply referred to as the "surface portion"), is made of a material containing nonionic hydrophilic groups and basic nitrogen-containing functional groups. In other words, the body portion and peripheral surface portion of the fibers used in the filter material of the present invention may be formed separately, with only the peripheral surface portion being made of the material, or the body portion and peripheral surface portion may be formed integrally, or both the body portion and peripheral surface portion, i.e., the entire fiber, may be made of the material. Furthermore, the body portion includes both end surface portions of the fiber, and these both end surface portions may or may not also be made of the material.

In the present invention, examples of nonionic hydrophilic groups include hydroxyl groups and amide groups, etc. Examples of basic nitrogen-containing functional groups include primary amino groups, secondary amino groups, tertiary amino groups, quaternary ammonium groups, and nitrogen-containing aromatic ring groups such as pyridyl groups and imidazolyl groups.

In the present invention, the basic nitrogen atom refers to the nitrogen atom in the basic nitrogen-containing functional group, and in the filter material of the present invention, the content of basic nitrogen atoms in the portion containing the nonionic hydrophilic group and the basic nitrogen-containing functional group must be 0.2 to 4.0% by weight.
If the concentration is less than 0.2% by weight, the leukocytes as well as the platelets will not adhere well, and the selective removal of leukocytes will not be possible.
If the basic nitrogen atom content exceeds 4.0% by weight, both platelets and leukocytes tend to adhere, and selective leukocyte removal is also not possible. A more preferred range of basic nitrogen atom content is 0.3-1.5% by weight. The optimal basic nitrogen atom content for the various materials used in the filter material of the present invention, described below, can be selected appropriately depending on the type of functional group constituting the material and the intended conditions of use (for example, the type of anticoagulant added to the blood has a significant effect). Various anticoagulants can be used, but citric acid-based anticoagulants [ACD(a)] are particularly suitable.
cid-citrate-dextrose), CPD(citrate-phosphate-de
Heparin is preferably used because it stabilizes platelets and makes them pass through the filter more easily. When heparin is used, this is not a problem when a small amount of blood is processed in a short time using a small filter, but when the amount of blood processed increases and a larger filter is used, the platelets tend to become activated and pass through more slowly.

In the present invention, the amount of nonionic hydrophilic groups, as hydroxyl groups, amide groups or ethylene oxide units in the polyethylene oxide chain, is preferably at least equimolar to the amount of basic nitrogen atoms, more preferably at least 3 times the molar amount.

The amounts of basic nitrogen-containing functional groups and nonionic hydrophilic groups, and the content of basic nitrogen atoms can be measured by conventional known methods such as infrared absorptiometry using a multiple total reflection infrared spectrometer or elemental analysis.

The fibers of the filter material of the present invention preferably have an average diameter of 10 μm or less, more preferably less than 3 μm, because the leukocyte removal performance per unit weight of the fiber filter increases as the average diameter of the fibers decreases.
If the diameter is less than 1 μm, the filter will be easily clogged and the membranes of red blood cells will be easily damaged, causing hemolysis. Therefore, the average diameter of the fibers is preferably 0.3 μm or more. From the viewpoint of leukocyte removal performance, fibers with an average diameter of 0.5 to 2.0 μm are most preferably used.

The fiber diameter (fiber diameter) referred to in the present invention is defined by the following formula:

where χ is the fiber diameter in μm and W is
is the weight of the fiber in g, ρ is the density of the fiber in g/ ^cm³ , and l is the length of the fiber in cm. The mean diameter of the fiber is the average diameter of each fiber.

When used as a leukocyte removal filter, the filter material of the present invention can be used in the form of a simple fiber mass, or in the form of a woven or nonwoven fabric. However, woven and nonwoven fabrics are preferred because they generally have higher leukocyte removal performance per unit weight and allow the fiber filter to be thinner in the direction of blood flow, thereby reducing pressure loss and achieving a high blood treatment rate. From the standpoint of ease of manufacture (especially when the fiber diameter is small), the nonwoven fabric form is most preferred.

As mentioned above, each fiber of the filter material of the present invention may have a surface portion made of a material containing nonionic hydrophilic groups and basic nitrogen-containing functional groups, as described above, and a body portion made of a material with a different chemical composition from the surface portion. Alternatively, the entire fiber may be made of a material containing nonionic hydrophilic groups and basic nitrogen-containing functional groups, as described above. However, the former is preferred from the viewpoints of ease of manufacturing and manufacturing cost. Figure 1 shows a schematic cross-sectional view of a fiber in the former case. Surface portion 1 and body portion 2 have different chemical compositions, and the thickness of 1 is actually very thin, almost negligible compared to the diameter of the fiber. Surface portion 1 must contain nonionic hydrophilic groups and basic nitrogen-containing functional groups and have a special chemical composition with a basic nitrogen atom content of 0.2 to 4.0 wt. %, as described above. Body portion 2 may be made of a general-purpose polymer material, as described below, used for general fibers.
and then forming the surface portion 1 having the special chemical composition is technically easier and the overall cost is lower than manufacturing the entire fiber having a uniform structure from a material having this special chemical composition.

More specifically, when the body and peripheral surface portions of the fiber are integrally formed and contain nonionic hydrophilic groups and basic nitrogen-containing functional groups throughout, with the basic nitrogen atom content being 0.2-4.0% by weight, the fiber can be obtained by spinning a polymer obtained by polymerizing the monomers described below. Also, the fiber is obtained by forming a surface portion 1 having the above-mentioned special chemical composition on the peripheral surface of the body portion 2 as shown in Figure 1.
Methods for obtaining fibers in which the body portion and the surrounding surface portion are integrally formed include modifying the surface of the body portion 2 by chemical treatment, ultraviolet irradiation, low-temperature plasma treatment, etc. to form a material with the above-mentioned special chemical composition, and forming a graft polymer layer with the above-mentioned special chemical composition on the surface of the body portion 2 by surface graft polymerization.

On the other hand, when the body portion and the surrounding surface portion of the fiber are formed separately, a method can be used in which the fiber that will become the body portion is coated with a polymer material having nonionic hydrophilic groups and basic nitrogen-containing functional groups and a basic nitrogen atom content of 0.2 to 4.0 wt. %. This coating method is generally applicable regardless of the material of the body portion 2, and is preferable because it can stably form the surface portion 1 having the above-mentioned special chemical composition even if the surface of the body portion 2 is physically or chemically heterogeneous. The cross-sectional structure of the resulting fiber is also shown schematically in Figure 1.

Any conventionally known fiber can be used as the material for the body portion. Examples of such fibers include synthetic fibers such as polyester, polyamide, polyacrylonitrile, polymethyl methacrylate, polyethylene, and polypropylene; semi-synthetic fibers such as cellulose acetate; regenerated fibers such as cuprammonium rayon, viscose rayon, and viscose staple fiber; natural fibers such as cotton, silk, and wool; and inorganic fibers such as glass fiber and carbon fiber. Among these, synthetic fibers are preferred. When using fibers produced by spinning, it is natural that fibers that are easy to spin are preferred in terms of ease of production.

The average thickness of the surface portion containing nonionic hydrophilic groups and basic nitrogen-containing functional groups from the surface of the fiber is preferably about 10 Å or more. If the average thickness is less than 10 Å, it becomes difficult to completely cover the peripheral surface of the fiber with a substance containing nonionic hydrophilic groups and basic nitrogen-containing functional groups, making it difficult to selectively remove leukocytes while suppressing platelet loss. There is no particular upper limit to the average thickness. However, when a polymer containing nonionic hydrophilic groups and basic nitrogen-containing functional groups is coated on the surface of the body portion or when the peripheral surface portion is formed by graft polymerization, the upper limit of the average thickness of the peripheral surface portion obtained by coating or graft polymerization with the polymer is about 1 μm.
It is preferable that the average thickness is less than 1 μm. If the average thickness is more than 1 μm, the cost of forming the peripheral surface portion of the polymer becomes high, and if the mechanical strength of the peripheral surface portion is low, the peripheral surface portion may peel off and become mixed into the blood being filtered, which is undesirable. A more preferable range of the average thickness of the peripheral surface portion is 40 Å.
or more and 400 Å or less.

The surface of the body part 2 contains nonionic hydrophilic groups and basic nitrogen-containing functional groups by surface graft polymerization or polymer coating, and the number of basic nitrogen atoms is 0.2 to 1.
To form the 4.0 wt. % peripheral surface portion 1, a typical method is to use a polymer obtained by conventional surface graft polymerization of one or more monomers having nonionic hydrophilic groups with one or more monomers having basic nitrogen-containing functional groups, or by conventional copolymerization of these monomers. The coating material can also be synthesized by graft or block copolymerization of different monomers. When this method is applied to the fibers used in the body portion, a microphase-separated structure can be formed in the layer of the peripheral surface portion that is formed. Alternatively, the polymer having nonionic hydrophilic groups and the polymer having basic nitrogen-containing functional groups can be synthesized separately in advance, and then these polymers can be blended and used for the coating.

Monomers containing a nonionic hydrophilic group that can be used in the above graft polymerization and synthesis of the polymeric coating material include the above-mentioned monomers containing a hydroxyl group and an amide group, such as 2-hydroxyethyl (meth)acrylate.
acrylate, 2-hydroxypropyl (meth)acrylate, vinyl alcohol (polymerized as vinyl acetate,
Examples of the nonionic hydrophilic group include hydroxyl groups and amide groups, as well as polyethylene oxide chains. Among the above-mentioned monomers, 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate are preferred because of their availability, ease of handling during polymerization, and performance when blood is passed through them.

Examples of monomers containing a basic nitrogen-containing functional group include allylamine; (meth)acrylic acid derivatives such as dimethylaminoethyl (meth)acrylate, diethylaminoethyl (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 converted into quaternary ammonium salts with alkyl halides or the like.
Dimethylaminoethyl (meth)acrylate and diethylaminoethyl (meth)acrylate are preferably used because of their availability, ease of handling during polymerization, and performance when blood is passed through them.

In the production of the filter material of the present invention, the coating polymer material is coated on the fibers that will become the body portion by immersing the fibers in a solution in which the polymer material is dissolved in a suitable solvent, and then applying mechanical compression, gravity,
The excess solution can be removed from the fibers by centrifugation or the like, and the fibers can be dried in a dry gas or in a vacuum at room temperature or with heating.

Before coating, the surface of the fiber can be treated with an appropriate chemical to improve the adhesion between the polymer material and the fiber. Furthermore, by applying a heat treatment after coating, the adhesion between the fiber and the material can be strengthened, or a crosslinking reaction can be initiated within the polymer material to stabilize the fiber surface layer. Coating can be carried out simultaneously with or after spinning the fiber. When the filter material of the present invention is used as a leukocyte removal filter in the form of a woven or nonwoven fabric, coating with the polymer material can be carried out before the fiber is shaped into a woven or nonwoven fabric, or
This may be done after the material is formed into a woven or nonwoven fabric.

To use the filter material of the present invention as a leukocyte removal filter, the filter material of the present invention is packed into a suitable blood filtering vessel having a conventional blood inlet and outlet. The bulk density of the filter material when packed varies depending on the average diameter of the fibers, but is generally in the range of 0.02 to 0.
The bulk density is preferably 7 g/ ^cm3 . The bulk density here is the weight of the filter material of the present invention that effectively functions for blood treatment in a container divided by the volume of the space it occupies. When the filter material of the present invention is a woven or nonwoven fabric, it may be used as a single sheet, depending on its thickness.
The number of sheets to be stacked varies depending on the blood filtering conditions and is not critical, but usually several to several tens of sheets are used.

BEST MODE FOR CARRYING OUT THE INVENTION In order to describe the present invention in more detail, examples will be given below, but the scope of the present invention is not limited to these examples.

Examples 1 to 3 and Comparative Examples 1 to 4 2-hydroxyethyl methacrylate (hereinafter referred to as HEM
A copolymer of diethylaminoethyl methacrylate (hereinafter abbreviated as DEAMA) and diethylaminoethyl methacrylate (hereinafter abbreviated as DEAMA) was synthesized by conventional solution radical polymerization. The polymerization conditions were a monomer concentration of 1 mol/L in ethanol and azoisobutyronitrile (AIBN) 1/200 mol/L as an initiator.
The polymerization reaction was carried out at 60°C for 8 hours in the presence of HCl. The content of basic nitrogen atoms in the resulting polymer was determined by elemental analysis. A nonwoven fabric (60 g/ ^m² basis weight) made of polyethylene terephthalate fibers with an average diameter of 1.8 µm was cut into 25 mm diameter circles and immersed in a 0.1% ethanol solution of the copolymer. The excess polymer solution absorbed by the nonwoven fabric was removed by squeezing, and two pieces were placed in a filter holder and dried while blowing dry air into them.

Two pieces of the coated nonwoven fabric were placed in a filter holder (Shibata Scientific Instruments Factory Co., Ltd.).
(Thickness 1.0mm), and then ACD (acid citrate) was added as an anticoagulant.
Five ml of fresh bovine blood containing 1% tetra-dextrose was pumped at a constant flow rate of 2 ml/min at room temperature using a syringe pump. A fixed amount of blood was collected before and after passing through the nonwoven fabric, diluted with Turk's solution, and the white blood cell concentration was measured using a hemocytometer. The collected blood was also diluted 100-fold with 1% ammonium oxalate solution, and the platelet concentration in the blood was measured using a hemocytometer (Brecker-Cronkhite (B
The leukocyte removal rate and platelet passage rate were calculated using the following formula:

Table 1 shows the relationship between the content (mol %) of DEAMA units and the content (wt %) of basic nitrogen atoms in the coated copolymer of HEMA and DEAMA and the leukocyte removal rate and platelet passage rate.

The uncoated filter material (Comparative Example 4) corresponds to the filter disclosed by Watanabe et al. and has a DEAMA content of 0.
% polymer (i.e., homopolymer of HEMA) coated filter material (Comparative Example 1) corresponds to the filter disclosed by Kuroda et al.

As a selective leukocyte removal filter that efficiently removes leukocytes with little loss of platelets, the platelet passage rate is
In practice, it is necessary for the leukocyte removal rate to be 75% or more and for the leukocyte removal rate to be 85% or more.

As can be seen from Table 1, the leukocyte removal rate of the uncoated filter (Watanabe et al. filter) (Comparative Example 4) was sufficiently high at 88.8%, but the platelet passage rate was only 1.
It is low at 2.9%, and selective removal of white blood cells is not possible.
On the other hand, the filter coated with a homopolymer of HEMA (filter by Kuroda et al.) (Comparative Example 1) had a high platelet passage rate of 77.0%, but a low leukocyte removal rate of 68.3%, and this filter also did not selectively remove leukocytes.

Even when coated with a material having both nonionic hydrophilic groups and basic nitrogen-containing functional groups, as shown in Table 1, if the basic nitrogen atom content was as low as 0.11% (Comparative Example 2), the platelet passage rate was high at 91.6%, but the leukocyte removal rate was low at 66.3%, failing to achieve selective leukocyte removal. Conversely, if the basic nitrogen atom content was as high as 7.56% and there was no nonionic hydrophilic group (Comparative Example 3), the leukocyte removal rate was high at 98.1%, but the platelet passage rate was low at 3.2%, failing to achieve selective leukocyte removal. Materials with basic nitrogen atom contents of 0.53%, 1.03%, and 1.98% all simultaneously achieved leukocyte removal rates of 85% or more and platelet passage rates of 75% or more, thereby achieving selective leukocyte removal.

Examples 4 to 6: Copolymer of HEMA and trimethyl ethyl methacrylate ammonium chloride, with the content of the latter monomer unit being 5 mol% (basic nitrogen atom content being 0.52 wt%, hereinafter abbreviated as HT); copolymer of HEMA, N-vinylpyrrolidone and dimethylaminoethyl methacrylate, with each monomer unit content being 60 mol%;
30 mol%, 10 mol% (basic nitrogen atom content 1.10 wt%, hereinafter abbreviated as HVM), HEMA and monomethoxypolyethylene glycol methacrylate (23 repeating ethylene oxide units) and DEAM
A copolymer with A, the content of each monomer unit is 80
%, 5 mol %, and 15 mol % (basic nitrogen atom content: 1.12 wt %, hereinafter abbreviated as HME) were synthesized by solution polymerization in the same manner as in Example 1.
Each of these polymers was coated onto a nonwoven fabric in the same manner as in Example 1 to prepare a filter material, which was then filled into the container described in Example 1 and bovine blood was passed through to examine the permeability of blood cells.

The results are shown in Table 2. All of the filter materials coated with HT, HVM, and HME were selective leukocyte removal filter materials that were able to remove 85% or more of leukocytes and allow 75% or more of platelets to pass through.

Example 7 The same nonwoven fabric as used in Example 1 was immersed in a 1:1 mixture of N,N-diethylethylenediamine and methanol to introduce amide groups as nonionic hydrophilic groups and hydroxyl groups derived from the ester groups of the polyethylene terephthalate of the nonwoven fabric, as well as diethylamino groups as basic nitrogen-containing functional groups, onto the surface of the nonwoven fabric by an ester-amide exchange reaction. The reaction formula is shown below.

Analysis of the fiber surface using a multiple total reflection infrared spectrophotometer revealed that the ratio of ester bonds to amide bonds was approximately 9:1.
The content of basic nitrogen atoms was about 1.3% by weight.

This surface-chemically treated nonwoven fabric was cut into a circle with a diameter of 25 mm, and used as a filter in the same manner as in Example 1, and blood was passed through it (the leukocyte concentration before passing through the filter was 5740 cells/μm).
, platelet concentration 258,000 cells/μ).

The results showed a leukocyte removal rate of 86.5% and a platelet passage rate of 81.0%.
and selectively removed leukocytes.

Example 8 and Comparative Example 5 The same nonwoven fabric as used in Example 1 was cut into 67 mm x 67 mm squares, and 20 sheets were stacked and set in a column as shown in Figure 2. The nonwoven fabric filter layer 6 was set in the column body 3, which was made by combining two square frames 4, 4', and its periphery was pressed together. 5, 5' are protrusions provided on the inside of the column, which partially support the center of the nonwoven fabric filter. The effective cross-sectional area of the nonwoven fabric filter was 60 mm x 60 mm = 3600
The polymer is a copolymer of ^HEMA and DEAMA with a content of DEAMA units of 5 mol % (the content of basic nitrogen atoms is 0.53 wt %, hereinafter referred to as H
E-5) was made into a 0.1% ethanol solution, which was passed through a column containing the nonwoven fabric, and then dried by blowing dry air through it, and then thoroughly dried by vacuuming.

Fresh bovine blood 2 containing the anticoagulant ACD was passed through the column thus prepared at 37°C at a flow rate of 30 ml/min to examine the leukocyte removal rate and platelet passage rate of the filter (the leukocyte and platelet concentrations before passing through the filter were 5,800/μm and 315,000/μm, respectively) (Example 8). For comparison, a filter material not coated with HE-5 was also tested under the same conditions (Comparative Example 5).

The results showed that the uncoated filter (Watanabe et al.'s filter) had a leukocyte removal rate of 78.6% and a platelet passage rate of 78.2%, while the HE-5 coated filter (filter of the present invention) (Example 8) had a leukocyte removal rate of 89.3% and a platelet passage rate of 91.4%. When a large amount of blood (2) was passed through a filter made of uncoated filter material, platelets were able to pass through relatively easily, but at the same time the leukocyte removal rate decreased, and selective removal of leukocytes was not sufficient. In contrast, HE-
The filter of the filter material coated with 5 is
Even when a large amount of blood is passed through, the filter material of the present invention can be sufficiently selectively removed, demonstrating that the filter material of the present invention can be applied to leukocyte removal therapy using extracorporeal blood circulation.

Example 9: Fourteen sheets of a nonwoven fabric (88 g/ ^m² basis weight) made of polyethylene terephthalate fibers with an average diameter of 4.7 µm were cut into 67 mm x 67 mm squares and stacked together, packed into a column in the same manner as in Example 8, and coated with HE-5 polymer.
In the same manner, 400 ml of fresh bovine blood (white blood cell concentration 4830 cells/μ
When blood containing 284,000 platelets/μm was passed through the filter, the leukocyte removal rate was 86.1% and the platelet passage rate was 92.3%, demonstrating selective removal of leukocytes.

Example 10 and Comparative Example 6 The same nonwoven fabric as used in Example 1 was cut into 67 mm x 67 mm squares, and 12 sheets were stacked and packed into a column in the same manner as in Example 8, and coated with HE-5 polymer. 500 ml of platelet-rich plasma (white blood cell concentration: 413/μm, platelet concentration: 299,000/μm) prepared by centrifugation from fresh bovine blood containing ACD was added, and the column was charged with 500 ml of platelet-rich plasma at room temperature.
The water was allowed to fall by gravity from a height of 80 cm (Example 10).
For comparison, an uncoated filter material was also tested under similar conditions (Comparative Example 6).

The results showed that the uncoated filter material had a 100% leukocyte removal rate but a 69% platelet penetration rate.
In contrast to the low leukocyte removal rate of 7%, the filter made of HE-5 coated filter material had a leukocyte removal rate of 100% but a platelet passage rate of 93.8%, resulting in less platelet loss and selective removal of leukocytes.

Example 11 and Comparative Example 7 Eight pieces of the same nonwoven fabric as used in Example 1 were cut into circles with a diameter of 70 mm and stacked together. These were packed in a column in the same manner as in Example 8, and the effective cross-sectional area of the filter was 28.3 cm ³ and the thickness was 4 mm.
The resulting product was coated with HE-5 polymer.
300 ml of platelet concentrate (white blood cell concentration: 4675/μm, platelet concentration: 550,000/μm) prepared by centrifugation from fresh bovine blood containing ACD was allowed to fall naturally through the above column with a drop of 80 cm (Example 11). For comparison, a similar experiment was also carried out using an uncoated filter material (Comparative Example 7).

The results showed that without coating, the leukocyte removal rate was high at 93.1%, but the platelet passage rate was low at 60.5%, while the filter made of HE-5 coated filter material had a leukocyte removal rate of 92.0% and a platelet passage rate of 88.1%.
This resulted in selective removal of leukocytes with minimal platelet loss.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a schematic cross-sectional view of a fiber of the filter material of the present invention having a structure in which the peripheral surface portion and the body portion have different chemical compositions.

1: peripheral surface portion of fiber 2: body portion of fiber FIG. 2 is a cross-sectional side view of one embodiment of a filter (column) packed with the filter material of the present invention.

3: Column body 4, 4': Rectangular frame 5, 5': Protrusions 6: Nonwoven fabric filter layer 7: Blood inlet 8: Blood outlet Industrial Applicability The filter material of the present invention is highly effective as a selective leukocyte removal filter that efficiently removes leukocytes with minimal platelet loss. Using the filter material of the present invention to remove leukocytes contaminating platelet transfusions is expected to reduce transfusion side effects and extend the lifespan of transfused platelets in the patient's body. Leukocyte removal therapy using extracorporeal blood circulation for patients with autoimmune diseases or leukemia using the filter material of the present invention can efficiently remove leukocytes in a short time while minimizing the loss of other valuable blood components, thereby minimizing the burden on the patient and achieving favorable therapeutic effects.

Claims (9)

[Claims] [Claim 1] A filter material for selectively removing leukocytes, comprising fibers, each fiber consisting of a body portion and a peripheral surface portion, at least the peripheral surface portion of the fiber containing nonionic hydrophilic groups and basic nitrogen-containing functional groups, and the content of basic nitrogen atoms in the peripheral surface portion being 0.2 to 4.0% by weight. 2. The filter material of claim 1, wherein the average diameter of the fibers is 10 μm or less. 3. The filter material of claim 1, wherein the average diameter of the fibers is greater than or equal to 0.3 μm and less than 3.0 μm. 4. A filter material according to any one of claims 1 to 3 in the form of a nonwoven fabric. 5. A filter material according to any one of claims 1 to 4, wherein the peripheral surface portion and the body portion are formed separately or integrally, and the body portion is made of a material having a different chemical composition from that of the peripheral surface portion. [Claim 6] A filter material according to claim 5, wherein the peripheral surface portion is made of a polymer having a nonionic hydrophilic group and a basic nitrogen-containing functional group, the content of basic nitrogen atoms in the peripheral surface portion being 0.2 to 4.0% by weight, and the coating formed on the peripheral surface of the body portion has a chemical composition different from that of the polymer. 7. The filter material of claim 5, wherein said body portion and said peripheral surface portion are integrally formed. 8. The method of claim 7, wherein the content of basic nitrogen atoms in the peripheral surface portion containing nonionic hydrophilic groups and basic nitrogen-containing functional groups is 0.
7. The filter material of any of claims 1 to 6, wherein the content of the soluble solids in the filter material is 3 to 1.5 wt.%. 9. The method of claim 8, wherein the body portion and the peripheral surface portion are integrally formed, each of the body portion and the peripheral surface portion contains a nonionic hydrophilic group and a basic nitrogen-containing functional group, and the content of basic nitrogen atoms in each portion is 0.2 to 4.0.
10. The filter material of claim 1, wherein the weight percent is 100 wt.