Patent Application
20120165176
1. Field of the Invention
The present invention relates to a blood processing filter for removing undesirable components such as aggregates and leukocytes from blood, to a blood circuit system that uses the blood processing filter, and to a centrifugation method that centrifuges blood that is contained in the system.
2. Related Background Art
In the field of blood transfusion, so-called “leukocyte-free blood transfusion” in which a blood preparation is transfused after removing leukocytes contained in the blood preparation is in widespread use. This is because it has been found that relatively minor side effects accompanying blood transfusion, such as headache, nausea, chill, or non hemolytic febrile transfusion reaction, or serious side effects which seriously affect the blood recipient, such as alloantigen sensitization, viral infection, or post-transfusion graft-versus-host disease (GVHD), are mainly caused by leukocytes contained in the blood preparation used for blood transfusion.
Several leukocyte removal methods are available. Of these, a filter method is currently in widespread use due to advantages such as excellent leukocyte removal capability, easy operation, and a low cost. For example, Japanese Patent Laid-Open No. 2000-342680 discloses a leukocyte removal device in which a housing that houses a filter member is composed of a flexible resin.
In this connection, in order to separate blood into a plurality of components to manufacture blood preparations, centrifugation is performed in a state in which the blood is contained in a reservoir bag. In some cases, a separation process is performed in which not only the reservoir bag, but also a blood circuit system in which a filter for filtering a specific component after centrifugation or a recovery bag for recovering a specific component is previously connected to the reservoir bag is inserted into a centrifuge cup of a centrifugal machine.
In general, many of the aforementioned centrifuge cups have a round shape such as a circular shape in a planar view or an elliptical shape in a planar view. Hence, an operation performed to store a tabular blood processing filter that is difficult to bend inside a centrifuge cup together with a recovery bag or a reservoir bag has been complicated. Further, it is also necessary for the width of the blood processing filter to be less than the width of the centrifuge cup. Hence, in order to broaden the range of adaptation of a blood processing filter with respect to small centrifuge cups, it is preferable to reduce the width of the blood processing filter. However, since it is also necessary to retain a filtration cross-sectional area that is required by a blood processing filter, there is a limit to the extent to which the width of a blood processing filter can be reduced.
An object of the present invention is to provide a blood processing filter, a blood circuit system, and a method for centrifugation that facilitate an operation to store the blood processing filter or blood circuit system in a centrifuge cup, and that easily adapt to small centrifuge cups also, while retaining the filtration cross-sectional area of the blood processing filter.
The present invention provides a blood processing filter including a flexible container having an inlet and an outlet for blood, and a sheet-like filter member arranged so as to divide inside of the flexible container into one side and another side; wherein:
an annular seal part is formed by integrally sealing a complete periphery of the filter member and the flexible container at near a very edge of the filter member; and
the blood processing filter is retained in a curved shape that curves as viewed from a predetermined one direction that is orthogonal to a thickness direction by rigidity of the seal part.
A case will now be considered in which, for example, the above described blood processing filter is used as one component of a blood circuit system. In this case, when centrifuging blood that is inside a reservoir bag of the blood circuit system, the blood processing filter is stored in the centrifuge cup together with the reservoir bag and the like. Generally, many centrifuge cups of this kind have a round shape such as a circular shape in a planar view or an elliptical shape in a planar view, and many of such centrifuge cups have a round inner surface such as a cylindrical surface or an elliptic cylindrical surface. Since the above described blood processing filter has a curved shape, the blood processing filter can be smoothly inserted into a centrifuge cup by aligning the curved shape of the blood processing filter with the curved shape of an inner wall surface of the centrifuge cup. Hence, an operation to store the blood processing filter in the centrifuge cup is performed with ease. Further, since the blood processing filter has a curved shape, the width thereof can be reduced while retaining the area of the filter surface. Hence, the above described blood processing filter is easily adaptable to small centrifuge cups also, while retaining the filtration cross-sectional area thereof.
Further, the above described blood processing filter may have an approximately rectangular shape, and may be curved so as to have one pair of sides of an identical curved shape and another pair of sides that form parallel straight lines.
The present invention further provides a blood circuit system that includes a reservoir bag that contains blood, a blood processing filter that is connected to the reservoir bag and is used for filtering a blood component obtained by centrifuging blood in the reservoir bag, and a recovery bag that is connected to the blood processing filter and is used to contain the blood component;
wherein the blood processing filter includes: a flexible container having an inlet that communicates with the reservoir bag through a tube, and an outlet that communicates with the recovery bag through a tube; and a sheet-like filter member arranged so as to divide inside of the flexible container into one side and another side; wherein an annular seal part is formed by integrally sealing a complete periphery of the filter member and the flexible container at near a very edge of the filter member, and the blood processing filter is retained in a curved shape that curves as viewed from a predetermined one direction that is orthogonal to a thickness direction by rigidity of the seal part.
According to the above described blood circuit system, the blood processing filter, the reservoir bag, and the recovery bag are stored together in a centrifuge cup when centrifuging blood that is in the reservoir bag. Generally, many centrifuge cups of this kind have a round shape such as a circular shape in a planar view or an elliptical shape in a planar view, and many of such centrifuge cups have a round inner surface such as a cylindrical surface or an elliptic cylindrical surface. Since the blood processing filter of the above described blood circuit system has a curved shape, the blood processing filter can be smoothly inserted into a centrifuge cup by aligning the curved shape of the blood processing filter with the curved shape of an inner wall surface of the centrifuge cup. Hence, an operation to store the blood processing filter in the centrifuge cup is performed with ease. Further, since the blood processing filter has a curved shape, the width thereof can be reduced while retaining the area of the filter surface. Hence, the above described blood circuit system easily adapts to a small centrifuge cup also, while retaining the filtration cross-sectional area of the blood processing filter.
The present invention also provides a method for centrifugation that includes:
a storing step of storing, in a centrifuge cup of a centrifugal machine, a blood circuit system including a reservoir bag that contains blood, a blood processing filter that is connected to the reservoir bag and that is used for filtering a blood component obtained by centrifuging blood in the reservoir bag, and a recovery bag that is connected to the blood processing filter and that is used to contain the blood component; and
a centrifugation step of centrifuging the blood in the reservoir bag by rotating the centrifuge cup in which the blood circuit system is stored using the centrifugal machine; wherein:
the blood processing filter includes: a flexible container having an inlet that communicates with the reservoir bag through a tube, and an outlet that communicates with the recovery bag through a tube; and a sheet-like filter member arranged so as to divide inside of the flexible container into one side and another side; wherein an annular seal part is formed by integrally sealing a complete periphery of the filter member and the flexible container at near a very edge of the filter member, and the blood processing filter is retained in a curved shape that curves as viewed from a predetermined one direction that is orthogonal to a thickness direction by rigidity of the seal part; and
in the storing step, the blood processing filter is arranged inside the centrifuge cup by aligning a curved face of the blood processing filter with a curved shape of an inner wall surface of the centrifuge cup.
According to the above described method for centrifugation, the blood processing filter, the reservoir bag, and the recovery bag are stored together in a centrifuge cup when centrifuging blood in the reservoir bag. Generally, many centrifuge cups of this kind have a round shape such as a circular shape in a planar view or an elliptical shape in a planar view, and many of such centrifuge cups have a round inner surface such as a cylindrical surface or an elliptic cylindrical surface. According to the above described method for centrifugation, the blood processing filter is arranged inside the centrifuge cup by aligning a curved face of the blood processing filter with the curved shape of an inner wall surface of the centrifuge cup. Hence, an operation to store the blood processing filter in the centrifuge cup is performed with ease. Further, since the blood processing filter has a curved shape, the width thereof can be reduced while retaining the area of the filter surface. Hence, the above described method for centrifugation easily adapts to a small centrifuge cup also, while retaining the filtration cross-sectional area of the blood processing filter.
According to the present invention, a blood processing filter, a blood circuit system, and a method for centrifugation can be provided that facilitate an operation to store the blood processing filter or blood circuit system in a centrifuge cup, and that easily adapt to a small centrifuge cup also, while retaining the filtration cross-sectional area.
A blood processing filter 10 of the present embodiment that is shown in
The filter 10 has a pair of long sides 10a that form parallel straight lines, and a pair of short sides 10b that curve in the same shape as each other. The dimensions of the long sides 10a and the dimensions of the short sides 10b that are measured along a curve, of the filter 10 are appropriately set in a mariner that takes into consideration a filtration cross-sectional area required for the filter 10 are the like.
As shown in the drawings, the filter 10 includes a sheet-like filter member 1, a flexible container 3 that houses the filter member 1, an inside joining portion 5 that defines a blood processing region R, and an outside joining portion 6.
The container 3 is constituted by a flexible sheet. An inlet 7 is provided on a curved face F1 side on an outer side of the container 3, and an outlet 8 is provided on a curved face F2 side on an inner side of the container 3. Ports 7a and 8a that are used for connecting to a tube are provided in the inlet 7 and the outlet 8, respectively. When causing an erythrocyte fraction to flow downward by gravitational force, the filter 10 is arranged in the vertical direction such that the inlet 7 is at an upper position and the outlet 8 is at a lower position so that blood that flows in from the inlet 7 flows vertically downward and reaches the outlet 8.
The inside joining portion 5 is formed in a belt-like, rectangular ring shape around the entire circumference that is adjacent to a peripheral portion of the filter member 1, and integrally joins the filter member 1 and the container 3. The inside joining portion 5 is a portion that is modified to have a property that does not allow blood to penetrate therethrough as a result of the filter member 1 and the container 3 being welded and hardened. Hence, blood that is introduced into the filter 10 from the inlet 7 is discharged from the outlet 8 without spreading to outside of the inside joining portion 5. More specifically, a space that is surrounded by the inside joining portion 5 is the blood processing region R for processing blood, and the inside joining portion 5 has a function that seals the blood processing region R. Furthermore, the filter member 1 divides the blood processing region R into a space on the inlet 7 side and a space on the outlet 8 side. Hence, after blood from the inlet 7 passes through the filter member 1 inside the blood processing region R, the blood is discharged from the outlet 8.
The inside joining portion 5 is hardened and has a certain level of rigidity. In contrast, the filter member 1 and the container 3 are constituted by a flexible material and are capable of deforming relatively easily. Accordingly, the overall three-dimensional shape of the filter 10 largely depends on the three-dimensional shape of the inside joining portion 5, and is retained by means of the rigidity of the inside joining portion 5.
In the filter 10, the inside joining portion 5 is formed in a curved shape. More specifically, the long sides 5a and 5a of the inside joining portion 5 that forms a rectangle in a front view form parallel straight lines. As viewed from a direction that is parallel to the long sides 5a and 5a, the short sides 5b and 5b curve in the same shape so as to form, for example, an arc. Because the inside joining portion 5 has the above described three-dimensional shape, the overall three-dimensional shape of the filter 10 is retained in the aforementioned curved shape by the rigidity of the inside joining portion 5.
The outside joining portion 6 seals the container 3 in the thickness direction of the filter 10 in order to protect the filter member 1 more reliably from the external environment. The outside joining portion 6 is provided so as to form the outer circumference of the rectangular container 3.
The filter 10 is manufactured by the following method. First, a material for a sheet-like filter member material is prepared that is capable of adsorbing aggregates or leukocytes included in blood. The aforementioned material is cut into a predetermined size to obtain the filter member 1, Cutting of the filter member material can be carried out using a knife, an ultrasonic cutter, or a laser cutter.
A flexible material is preferable as the filter member material, and examples thereof include a fiber structure such as a nonwoven fabric manufactured by a melt-blow method, a porous material (a sponge-like structure) having consecutive pores, and a porous membrane. A material composed of a fiber structure, a porous material, or a porous membrane, or a material that employs any of these materials as a base material and whose surface is chemically or physically modified may also be used as the filter member material. A single layer of a fiber structure, a porous material, or a porous membrane may be used as the filter member material, or a plurality of layers in which these materials are combined may be used as the filter member material.
Examples of the raw material of the above described fiber structure include polyester, polypropylene, polyamide, polyacrylonitrile, polytrifluoroethylene, polymethyl methacrylate, and polystyrene. When using a fiber structure as the filter member 1 or as a base material thereof, the fiber structure may be composed of fibers having an almost uniform diameter, or may be a material in which a plurality of types of fibers that differ in fiber diameter are commingled, as disclosed in International Publication No. WO 97/232266. In order to reduce the number of leukocytes in blood after filtration to 5×106/unit, the average diameter of fibers forming the filter member 1 is preferably 3.0 μm or less, and more preferably is between 0.9 and 2.5 μm.
Examples of the raw material of the aforementioned porous material or porous membrane include polyacrylonitrile, polysulfone, cellulose acetate, polyvinyl formal, polyester, polyacrylate, polymethacrylate, and polyurethane. In order to reduce the number of leukocytes in blood after filtration to 5×106/unit, the average pore diameter of the porous material or the porous membrane is preferably 2 μm or more and less than 10 μm.
Next, a resin sheet or film having flexibility for forming the container 3 is prepared. Examples of the raw material of the container 3 include: soft polyvinyl chloride; polyurethane; ethylene-vinyl acetate copolymer; polyolefin such as polyethylene and polypropylene; hydrogenated styrene-butadiene-styrene copolymer; a thermoplastic elastomer such as styrene-isoprene-styrene copolymer or the hydrogenated product thereof; and mixtures of the thermoplastic elastomer and a softening agent such as polyolefin, ethylene-ethyl acrylate, or the like. Of these, soft polyvinyl chloride, polyurethane, polyolefin, and thermoplastic elastomers containing these as a major component are particularly preferable as the raw material of the container 3, because they offer excellent permeability with respect to high-pressure steam or electron beams for sterilization, and also have toughness to withstand a load at a time of centrifugation.
By formation of the inside joining portion 5, the filter member 1 and the container 3 are integrally joined and the blood processing region R of the filter 10 is defined. The inside joining portion 5 and the outside joining portion 6 can be formed, for example, by high frequency welding.
The method of forming the inside joining portion 5 will now be described more specifically. A tabular intermediate product is prepared in which the filter member 1 is inserted between the two resin sheets forming the container 3. The resin sheets and the filter member 1 are inserted in a rectangular ring-shaped mold and subjected to high-frequency heating. At a rectangular ring-shaped heated portion that corresponds to the mold, the filter member 1 and the container 3 are integrally welded, and the hard inside joining portion 5 that has a rectangular ring shape is formed. In this process, by using a mold that has a curved shape, the inside joining portion 5 that has a curved shape corresponding to the shape of the mold can be formed while curving the aforementioned intermediate product.
The inlet port 7a and the outlet port 8a are respectively provided at predetermined positions of the container 3 by, for example, welding. It is sufficient that the inlet port 7a and the outlet port 8a allow the blood processing region R and the outside to communicate through the inlet 7 and the outlet 8. The filter 10 is manufactured by performing the above described process.
As shown in
The blood circuit system 50 further includes the aforementioned filter 10 and a bag 24 for recovering an erythrocyte fraction. The inlet 7 of the filter 10 communicates with the bag 23 through a tube T3. The outlet 8 of the filter 10 communicates with the upper side of the bag 24 through a tube T4.
Clamps C1, C2, C3 and C4 are disposed partway along the tubes T1, T2, T3 and T4, respectively. In this connection, the bag 23 is used according to necessity, and is used for temporarily accumulating an erythrocyte fraction Q (see
Note that a configuration may also be adopted in which a blood processing filter is also disposed partway along the tube T1 to enable filtration of a plasma fraction P when transferring the plasma fraction P to the bag 22 through the tube T1.
Centrifugation of the blood that has been recovered in the reservoir bag 21 is performed to separate and recover the plasma fraction P and the erythrocyte fraction Q from the blood inside the reservoir bag 21. In this case, the blood circuit system 50 is set in a bag holding portion 62 of a centrifugal machine 60 shown in
The centrifuge cup 62b has a size with a diameter of XC and a depth of YC. It is desirable that a ratio (YF/YC) between a length YF in the longitudinal direction of the filter 10 and the depth YC of the centrifuge cup 62b is between 0.5 and 1.0, and a ratio between 0.7 and 0.9 is preferable. If the ratio YF/YC is less than 0.5, in some cases the dimensions of the filter 10 may be too small. In contrast, if the ratio YF/YC exceeds 1.0, there is a possibility that a portion of the filter 10 will protrude from the centrifuge cup 62b and interfere with the centrifugal machine, which may result in damage to the filter 10.
(Storing Step): As shown in
The reservoir bag 21 is arranged on the inner curved face F2 side of the filter 10. Since the reservoir bag 21 that contains blood is roundish, it is easy to stably arrange the reservoir bag 21 along the curved face F2. Further, since the empty bags 22, 23 and 24 are relatively thin and also change shape easily, the bags 22, 23 and 24 are arbitrarily disposed in any of the remaining gaps. Next, the centrifuge cup 62b that accommodates the blood circuit system 50 in the above described manner is mounted inside the outer container 62a.
(Centrifugation Step): Subsequently, by starting the centrifugal machine 60 and rotating the centrifuge cup 62b for a predetermined time period, the blood in the reservoir bag 21 is centrifuged inside the reservoir bag 21. As a result, as shown in
(Component Recovery Step): Next, the erythrocyte fraction Q in the reservoir bag 21 is transferred to the bag 23 through the tube T2. Thereafter, the erythrocyte fraction Q in the bag 23 is transferred to the filter 10 through the tube T3, and leukocytes are removed therefrom by the filter member 1 of the filter 10. The erythrocyte fraction Q that has passed through and been filtered by the filter 10 is recovered in the recovery bag 24 through the tube T4. On the other hand, the plasma fraction P in the reservoir bag 21 is transferred to the bag 22 through the tube T1 and recovered.
Next, operational advantages of the above described filter 10, blood circuit system 50, and centrifugation method are described.
Because a blood processing filter of this kind has a hard inside joining portion, it is difficult to deform the blood processing filter when storing the blood processing filter in a centrifuge cup. Among the components constituting a blood circuit system, the blood processing filter is a relatively large component that is difficult to deform and consequently is a factor that makes the storing step complicated. However, since the filter 10 is retained in a curved shape as described above, the filter 10 can be smoothly inserted inside the centrifuge cup 62b by aligning the outer curved face F1 with the curved shape of the inner wall surface 62c of the centrifuge cup 62b. Hence, in comparison to a tabular blood processing filter that is not curved, an operation to store the filter 10 in the centrifuge cup 62b is easily carried out, and the step of storing the blood circuit system 50 in the centrifuge cup 62b is performed with ease.
Further, since the filter 10 is difficult to deform, it is necessary for the diameter of a centrifuge cup to which the blood circuit system 50 can be applied to be larger than the width of the filter 10. In this case, the term “width of the filter 10” refers to, as shown in
Since the filter 10 has a curved shape, the width thereof can be reduced while retaining the area of the filter surface. Hence, the filter 10 easily adapts to a small centrifuge cup also, while retaining the filtration cross-sectional area thereof. Because the filtration cross-sectional area of the filter 10 is retained, the time required for filtration of the erythrocyte fraction Q in the blood circuit system 50 is reduced.
Since use of the filter 10 also enables a reduction in the size of a centrifuge cup, it is possible to increase the number of centrifuge cups that are arranged in a centrifugal machine, and thus the efficiency of centrifugation work can be improved.
Further, as shown in
Note that the present invention is not limited to the above described embodiment. For example, according to the filter 10 of the embodiment, the long sides 10a form parallel straight lines and the short sides 10b are curved. However, according to the present invention a configuration may also be adopted in which the short sides of the filter form parallel straight lines and the long sides are curved. Further, although the inlet 7 is provided in the outer curved face F1 and the outlet 8 is provided in the inner curved face F2 in the filter 10, according to the present invention the outlet may be provided in the outer curved face and the inlet may be provided in the inner curved face. Furthermore, although according to the embodiment the filter 10 forms a curved shape along a cylindrical surface, according to the present invention, for example, the filter may form a curved shape along a different kind of cylindrical surface (for example, an elliptic cylindrical surface) or along a conical surface.
The present inventors prepared curved-shaped blood processing filters for test use, and prepared respective blood circuit systems 50 (
The present inventors prepared a total of four kinds of blood processing filters for test use which, as shown in Table 1, consisted of examples 1 and 2, a comparative example, and a reference example. Of these, the filters of examples 1 and 2 were curved so as to have a cylindrical surface, and as shown in
As shown in
The filter member of each filter included first to third filter elements as described below. The filter member of each filter was produced by stacking four sheets of a first filter element, one sheet of a second filter element, 32 sheets of a third filter element, one sheet of the second filter element, and four sheets of the first filter element in that order. The filter elements had the following specifications:
First filter element: fiber diameter 12 μm, mass per unit area 30 g/m, thickness 0.2 mm
Second filter element: fiber diameter 1.6 μm, mass per unit area 66 g/m, thickness 0.4 mm
Third filter element: fiber diameter 1.2 μm, mass per unit area 40 g/m, thickness 0.2 mm
In this connection, the first filter elements function as a prefilter that removes contaminants and the like, and as a post-filter that secures a space on the outlet side. The second and third filter elements function as a main filter that removes leukocytes and the like.
The samples filtered by the respective filters were erythrocyte preparations that were stored for three days at 4° C. The filtration conditions consisted of filtration at room temperature with a filtering drop of 1.2 m, and the filter outlet tube length was 60 cm. For each filter, a time from initial flow of the sample to the filter from the reservoir bag until the sample disappeared from the reservoir bag, filter inlet tube, and a filtration surface on the inlet side of the filter was measured. The measured times are shown in Table 1 as filtration times.
In this connection, the long-axis width of a centrifuge cup of the centrifuge apparatus used for the tests was 65 mm. However, since the filter of the reference example had a length A of 72 mm, it was not possible to accommodate the filter of the reference example in a centrifuge cup and therefore centrifugation of the reference example could not be performed. With respect to the filter of the reference example, a filtration time in a case where an erythrocyte preparation was filtered under similar conditions as examples 1 and 2 and the comparative example is shown in Table 1 as a reference.
Since the length A was the same for each of examples 1 and 2 and the comparative example, the respective blood processing filters thereof could be stored in centrifuge cups having the same internal diameter. In contrast, the length C differed among the examples 1 and 2 and the comparative example, being longest in example 2 (75 mm), followed by example 1 (61 mm), and the comparative example (57 mm) in length order. Hence, the sizes of the respective filtration cross-sectional areas also differed, the filtration cross-sectional area being largest in example 2 (55.5 mm2), followed by example 1 (452 mm2), and the comparative example (42.2 mm2) in size order. Due to the differences in the filtration cross-sectional areas, example 2 (151 min) had the shortest filtration time, followed by example 1 (250 min), and the comparative example (317 min). Based on the above results, it was confirmed that even when the length A is the same, in comparison to the tabular filter of the comparative example, the filtration times were shorter for the filters of examples 1 and 2 that had a curved shape. Of these, it was confirmed that example 2 that had the longest length B (largest curvature) had the shortest filtration time.
Further, comparing example 2 and the reference example, it was found that the filtration cross-sectional areas were approximately equal and that the filtration times were also approximately equal. However, because the filter of the reference example had a tabular shape, the length A thereof was large and, as described above, the reference example could not be stored in a centrifuge cup having a long-axis width of 65 mm. Hence, it was confirmed that the range of application of a curved-shaped filter with respect to small centrifuge cups is broadened in comparison to a tabular filter having the same filtration cross-sectional area and for which a filtration time is also the same.
Thus, it was confirmed that by making a blood processing filter in a curved shape, the adaptation range thereof is broadened to smaller centrifuge cups while retaining the filtration cross-sectional area and maintaining the filtration time.
Note that a filter that has a curved shape such that an angle α shown in
According to the present invention, by making a blood processing filter a curved shape, an operation to store a blood circuit system in a centrifuge cup is facilitated, and it is possible to easily adapt to small centrifuge cups also, while retaining the filtration cross-sectional area of the blood processing filter.
| Number | Date | Country | |
|---|---|---|---|
| 61427297 | Dec 2010 | US |
