Blood filter cartridge

The blood filter cartridge can filter almost total volume of drawn blood efficiently which comprises a blood filtering material and a holder containing the blood filtering material, wherein the holder is provided with a blood reservoir which connects with an inflow side of the blood filtering material and a filtrate receiver which connects with an outflow side of the blood filtering material.

BACKGROUND OF THE INVENTION
 This invention relates to a blood filter cartridge for the preparation of a
 plasma or serum sample from whole blood.
 The type or concentration of blood components, such as metabolites,
 proteins, lipids, electrolytes, enzymes, antigens, and antibodies, is
 measured, in general, using a plasma or serum sample obtained by
 centrifuging whole blood. However, centrifuging takes labor and time.
 Particularly, centrifuging is unsuitable for an urgent case of measuring a
 small number of samples promptly and in site inspection, because of
 requiring a centrifuge and electricity. Thereupon, it has been
 investigated to separate serum from whole blood by filtration.
 Several filtration methods using glass fiber filter have been developed
 wherein whole blood is charged into the glass fiber put in a column from
 one side of the column, and pressurized or evacuated to obtain plasma or
 serum from the other side (Japanese Patent KOKOKU Nos. 44-14673, 5-52463,
 Japanese Patent KOKAI Nos. 2-208565, 4-208856).
 However, practical filtration methods capable of obtaining an amount of
 plasma or serum from whole blood necessary for measuring by an automatic
 analyzer have not been developed except a part of items, such as blood
 sugar.
 On the other hand, the inventors developed a blood filter cartridge
 composed of a filter holder and a syringe. The filter holder is composed
 of a holder body which contains filter material and a cap which is screwed
 on the holder body. The filter material consists of, e.g. two sheets of
 glass fiber filter, one sheet of cellulose filter and one sheet of
 polysulfone microporous membrane (FIG. 1 of EP 785430 A1)
 Another blood filter cartridge composed of a holder body and a cap was also
 developed. The holder body consists of a plasma receiver located on the
 upper side and a filter chamber located on the underside. The filter
 material put in the filter chamber is composed of six sheets of glass
 fiber filter and one sheet of polysulfone microporous membrane (Example 1
 of EP 785012A1).
 The inventors further developed various blood filter cartridges, and their
 patent applications were made (Japanese Patent KOKAI 10-227788, 10-185909,
 10-185780, etc.)
 However, since the above blood filter cartridges are of a type of attaching
 a suction nozzle to the blood inlet and sucking blood from a blood
 collecting tube, a part of blood essentially remains in the blood
 collecting tube and the suction nozzle without filtered. As a result, the
 volume of drawn blood increases to add a burden to a person who takes a
 medical inspection. Particularly, in the case of clinical assay using a
 dry analytical element, although analysis of plural items can be achieved
 by using about 100 to 500 .mu.l plasma, the volume of drawn blood, in
 general, exceeds 10 ml.
 SUMMARY OF THE INVENTION
 An object of the invention is to provide a blood filter cartridge which can
 prepare a plasma or serum sample from a mall volume of blood efficiently.
 The inventors investigated eagerly in order to solve the above problems,
 and found that, by the conventional system, blood inevitably remains in
 the blood collecting tube due to sucking blood from the tube, and
 moreover, remains in the suction nozzle due to the slender shape of the
 blood collecting tube which increases the lift from the blood level in the
 tube to the blood filter cartridge.
 Thereupon, they devised to add a blood reservoir to the blood filter
 cartridge, and succeeded in filtering almost the total volume of drawn
 blood by pouring the blood drawn by a blood drawing syringe, and thereby
 decreasing the volume of drawn blood sharply.
 Thus, the present invention provides a blood filter cartridge which
 comprises a blood filtering material and a holder containing the blood
 filtering material, wherein the holder is provided with a blood reservoir
 which connects with an inflow side of the blood filtering material and a
 filtrate receiver which connects with an outflow side of the blood
 filtering material.

1 . . . Blood Filter Cartridge
 10, 60 . . . Holder body
 11, 63 . . . Glass fiber filter chamber (blood filter chamber)
 12, 64 . . . Microporous membrane chamber (blood filter chamber)
 13 . . . Inclined portion
 14 . . . Flange
 15 . . . Glass fiber filter-placing portion
 16 . . . Funnel-shaped disc portion
 17 . . . Blood inlet
 18 . . . Space
 19 . . . Step portion
 20, 67 . . . Cap
 21 . . . Outer wall
 22 . . . Inner wall
 24 . . . Flange
 25 . . . Rib
 26 . . . Projection
 27 . . . Filtrate passage
 28 . . . Pent roof
 29 . . . Filtrate outlet
 30 . . . Blood filtering material
 31 . . . Glass fiber filter
 32 . . . Polysulfone microporous membrane
 40, 61 . . . Blood reservoir
 41 . . . Passage
 42 . . . Leg
 50, 70 . . . Filtrate receiver
 65, 66 . . . Perforated plate
 DETAILED DESCRIPTION OF THE INVENTION
 Although the type of the blood filtering material is not limited, in the
 filtering material of the invention, it is thought that the filter
 material to be used does not trap blood cells only by the surface, but
 catches to remove blood cells gradually by entangling at first large blood
 cell components and then smaller blood cell components in the space
 structure with permeating in the thickness direction in total of the
 filtering material, called the volumetric filtration or depth filtration.
 Preferable blood filtering material are glass fiber filter, aggregate of
 extra fine fibers, three dimensional porous body, and the like, and a
 combination of glass fiber filter or aggregate of extra fine fibers and
 microporous membrane is particularly preferred.
 Preferable glass fiber filter has a density of about 0.02 to 0.5
 g/cm.sup.3, preferably about 0.03 to 0.2 g/cm.sup.3, more preferably about
 0.05 to 0.13 g/cm.sup.3, a retainable particle size of about 0.6 to 9
 .mu.m preferably 1 to 5 .mu.m. By treating the surface of glass fiber with
 hydrophilic polymer as disclosed in Japanese Patent KOKAI Nos. 2-208676,
 4-208856, filtration proceeds more fast and smoothly. Lectin or other
 reactive reagent or modifier may be incorporated into glass fiber, or
 glass fiber may be treated therewith. Two or more glass fiber filters may
 be superimposed.
 As the extra fine fibers forming the aggregate of extra fine fibers, there
 are organic extra fine fibers and metal fibers. Preferable organic extra
 fine fibers are made of polyester, polypropylene, polyamide, polyethylene,
 cellulose or the like, and also include carbon fibers. Metal fibers are
 made of aluminum, copper, gold or the like. A suitable size (diameter) of
 the fiber is 0.2 to 2.5 .mu.m, preferably 0.3 to 2.3 .mu.m, more
 preferably 0.4 to 2.2 .mu.m, on average.
 The aggregate of extra fine fibers is produced by spinning polyester,
 polypropylene, polyamide, polyethylene or the like by an ordinary spinning
 method, such as melt blow (Japanese Patent KOKAI 9-143081, 10-211277,
 etc.). It is possible to obtain plasma or serum containing blood cells in
 only a small amount without hemolysis and being suitable for clinical
 assay by the above blood filtering material.
 Optionally, the surface of the fibers can be modified, e.g. by the
 deposition of platinum or carbon or coating with a hydrophilic polymer
 membrane, such as gelatin or polyvinyl pyrrolidone.
 The form of the aggregate of extra fine fibers is woven fabric, knitted
 fabric, nonwoven fabric, floe in irregular form, bundle of parallel
 fibers, or the like. A suitable bulk density is about 0.05 to 0.6
 g/cm.sup.3, preferably about 0.08 to 0.5 g/cm.sup.3.
 Since blood cell components are trapped mainly by the entangled portions of
 the extra fine fibers, a preferable void volume is great in order that
 filtration proceeds efficiently. As an indicator corresponding to void
 volume or filtrate volume of plasma, the water permeation speed mentioned
 previously is suitable. The aggregates of extra fine fibers particularly
 suitable for plasma separation are having a water permeation speed of
 about 1.0 to 1.3 ml/sec.
 The size of the aggregate of extra fine fibers can be set according to the
 volume of blood sample to be supplied or the volume of blood plasma
 necessary for assays. For example, discs of the aggregate of extra fine
 fibers about 20 mm in diameter are stacked in a thickness of about 2 to 10
 mm.
 The three dimensional porous bodies suitable for the blood filter cartridge
 are disclosed in Japanese Patent KOKAI 10-185910, and has a mean poro size
 of 5 to 50 .mu.m.
 Microporous membranes having blood cell-separating ability of which the
 surface has been made hydrophilic separate whole blood into blood cells
 and plasma specifically without hemolysis to the degree of substantially
 influencing analytical values. A suitable pore size of the microporous
 membrane is smaller than the retaining particle size of glass fiber
 filter, the aggregate of extra fine fibers or the three dimensional porous
 body, and is 0.2 .mu.m or more, preferably about 0.3 to 5 .mu.m, more
 preferably about 0.5 to 4.5 .mu.m, particularly preferably about 1 to 3
 .mu.m. The void content of the microporous membrane is preferably higher,
 and a suitable void content is about 40 to 95%, preferably about 50 to
 95%, more preferably about 70 to 95%. Illustrative of the microporous
 membranes are polysulfone membrane, fluorine-containing polymer membrane,
 etc. The surface of the membrane may be hydrolyzed or may be rendered
 hydrophilic by a hydrophilic polymer or an activating agent.
 Preferable microporous membranes are polysultone membrane, cellulose
 acetate membrane, cellulose nitrate membrane, hydrophilic polytetrafluoro
 ethylene membrane, polyamide membrane and the like, and particularly
 preferred one is polysulfone membrane. In the blood filtering material of
 the invention, the glass fiber filter, the aggregate of extra fine fibers
 and the three dimensional porous body are located on the blood inlet side
 and the microporous membrane is located on the filtrate outlet side. The
 most preferable blood filtering material is a combination of the glass
 fiber filter or the aggregate of extra fine fibers and polysulfone
 membrane laminated in this order from the blood inlet side.
 Respective layers may be integrated by joining each other using partially
 disposed (e.g. spots) adhesive, according to disclosures in Japanese
 Patent KOKAI Nos. 62-138756-8, 2-105043, 3-16651, etc.
 A suitable thickness of the glass fiber filter varies according to the
 plasma volume to be recovered and density (void content) and area of the
 glass fiber filter. A necessary amount of plasma for analyzing plural
 items using dry analytical elements is 100 to 500 .mu.l. In practical
 viewpoint, a glass fiber filter having a density of about 0.02 to 0.2
 g/cm.sup.3 and an area of 1 to 5 cm.sup.2 is suitable. In this case, a
 suitable thickness of the glass fiber filter is about 1 to 10 mm,
 preferably about 2 to 8 mm, more preferably about 4 to 6 mm. The above
 thickness can be made by superposing 2 to 10 sheets, preferably 3 to 8
 sheets of glass fiber filter.
 A suitable thickness of the microporous membrane is about 0.05 to 0.5 mm,
 preferably about 0.1 to 0.3 mm, and the number of the microporous membrane
 is usually one. However, two or more sheets of microporous membrane may be
 used, if necessary.
 The blood filtering material is placed in a holder having a blood inlet and
 a plasma outlet. The holder is, in general, formed of a body containing
 the blood filtering material and a cap, and each of them is provided with
 at least one aperture. One is used as the blood inlet, and the other is
 used as the filtrate outlet, optionally further as a suction port. A
 suction port may be provided separately. In the case that the holder is
 rectangular and is provided with the cap on a side of the holder, both of
 the blood inlet and the plasma outlet may be provided on the holder body.
 The volume of the filter chamber which contains the blood filtering
 material is necessary to be greater than the total volume of the blood
 filtering material both in a dry state and in a swelled state upon
 absorbing a sample (whole blood). When the volume of the filter chamber is
 smaller than the total volume of the blood filtering material, filtration
 does not proceed efficiently and hemolysis occurs. A suitable ratio of the
 volume of the filter chamber to the total volume of the blood filtering
 material in a dry state is, in general, 101 to 200%, preferably 110 to
 150%, more preferably 120 to 140%, although the ratio varies according to
 the swelling degree of the filtering material. An actual volume is set
 depending on the necessary amount of plasma or serum, and is about 0.5 to
 2.5 ml, usually about 0.6 to 2.2 ml.
 Besides, it is preferable that the periphery of the blood filtering
 material is closely fitted to the wall of the filter chamber so as not to
 form a bypass of whole blood without passing the filtering material.
 The blood filter cartridge is made into a closed structure except the blood
 inlet and the plasma outlet by attaching a cap to the holder body.
 As the material of the holder, thermoplastic or thermosetting plastics are
 preferable. Illustrative of the plastics are general-purpose plystyrene,
 high impact polystyrene, methacrylate resin, polyethylene, polypropylene,
 polyester, nylon, polycarbonate, etc. The material may be transparent or
 opaque.
 Fitting of the cap to the holder body may be any means, such as adhesion
 using adhesive or fusion welding. On that occasion, either periphery of
 the holder body or of the cap is located on the inside, or both
 peripheries are butted. The fitting may be in a state of detachable
 utilizing screws or the like.
 The shape of the blood filtering material is not restricted, but disc and
 polygon is preferable in view of production. By rendering the size of the
 blood filtering material slightly greater than the inside section of the
 holder body (i.e. filter chamber), breakthrough of blood at the periphery
 of the filtering material can be prevented. To render the shape square is
 preferable because of no generation of cutting loss. Moreover, cut pieces
 of glass fiber filter can also be served.
 To the holder, the blood reservoir and the filtrate receiver are provided.
 The blood reservoir stores blood being fed to the blood filtering material,
 and is connected to a blood inlet directly or through a passage. The
 attaching position of the blood reservoir is any position of the side
 wall, the top or the bottom of the holder. However, even when the blood
 reservoir is attached to the bottom, it is preferable to arrange the
 position and the capacity capable of being impregnated into a part of the
 blood filtering material by self weight of the blood poured into the blood
 reservoir. Therefore, the level of a prescribed volume of blood poured in
 the reservoir is made upper than the underside of the blood filtering
 material presumed without permeating blood into the blood filtering
 material. The shape of the blood reservoir is not restricted. A suitable
 capacity of the blood reservoir is, in the case of the preparation of a
 sample for dry analysis, about 0.2 to 5 ml, usually about 0.5 to 2 ml.
 When the blood reservoir is connected to the blood inlet through a
 passage, the volume of the passage is incorporated into the capacity. When
 there is a space on the inlet side of the blood filtering material, the
 space is also incorporated into the capacity. In the case that there is a
 space under the blood filtering material where the blood inlet is provided
 at the periphery, it is preferable to provide a partition plate having a
 hole at the center or small holes over the whole area so that bubbles upon
 the finish of blood filtration pass the hole or small holes to be spread
 over the whole body of the blood filtering material.
 The filtrate receiver receives plasma or serum which is the filtrate
 discharge from the filtrate outlet, and the filtrate outlet is located
 above the liquid level of the filtrate receiver. The filtrate outlet may
 be provided on the upper part of the side wall of the filtrate receiver or
 a pipe standing on the inside of the filtrate receiver. The filtrate
 receiver is made into various shapes in connection with various factors,
 such as the relation to the position of sucking analytical sample, the
 relation to the blood filtering chamber, the relation to optional other
 parts, and the like, and, in general, cylindrical or square. The bottom of
 the filtrate receiver is flat, funnel-shaped, round or the like. The
 volume of the filtrate receiver is, in the case of preparation of
 analytical sample for dry analysis, about 100 to 900 .mu.l, usually about
 200 to 600 .mu.l, and has a depth of about 3 to 12 mm and a width
 (diameter a side length) of about 5 to 11 mm. As to the position of the
 position of the filtrate outlet, the underside of the filtrate outlet is
 located higher than the designed liquid level of the filtrate receiver by
 about 0.5 to 5 mm, usually about 1 to 2 mm. Although the volume of
 filtrate varies according to the hematocrit value of blood, the designed
 liquid level is of filtering blood having a hematocrit value of 20 to 60%.
 The filtrate receiver may be integrated with or separated from the holder.
 Heretofore, the blood filter cartridge is explained about the type of
 introducing blood from the underside of the blood filtering material and
 discharging the filtrate from the upside. However, the blood filter
 cartridge of the invention may be an opposite type, i.e. feeding blood
 from the upside of the blood filtering material and discharging the
 filtrate from the underside.
 EXAMPLES
 Example 1
 A blood filter cartridge of the inventors is illustrated in FIGS. 1-3. FIG.
 1 is a longitudinal section of the blood filter cartridge in the assembled
 state, FIG. 2 is a plan view thereof, and FIG. 3 is a bottom view of the
 cap which constitutes the blood filter cartridge.
 The blood filter cartridge is, as shown in FIG. 1, composed of a holder 1
 consisting of a holder body 10 and a cap 20 and blood filtering material
 30 consisting of a glass fiber filter 31 and a microporous membrane 32.
 The holder body 10 is made of high-impact polystyrene resin, and has a
 glass fiber filter chamber 11 for containing the glass fiber filter 31 and
 a microporous membrane chamber 12 for containing a polysulfone microporous
 membrane as the microporous membrane 32 above the glass fiber filter
 chamber 11. The microporous membrane chamber 12 has a diameter greater
 than the glass fiber filter chamber, and the periphery of the microporous
 membrane 32 is nipped by the step portion 19 formed on the boundary
 between the glass fiber filter chamber 11 and the microporous membrane
 chamber 12 and the bottom of the cap 20 so as not to form a leakage
 without passing the blood filtering material. An inclined portion 13 which
 stands upward slightly obliquely is formed at the outer periphery of the
 step portion 19, and a flange 14 is formed outward at the upper end of the
 inclined portion 13.
 On the other hand, the bottom of the holder body 10 is in the form of a
 shallow funnel, and a step portion is formed as a glass fiber
 filter-placing portion 15 at the periphery of the funnel-shaped disc
 portion 16. A circle hole is provided as the blood inlet 17 at the center
 of the funnel-shaped portion 16. The glass fiber filter-placing portion 15
 also functions as a spacer which separates the glass fiber filter 31 from
 the bottom and forms a space 18 for spreading the liquid to be filtered
 over the whole surface of the glass fiber filter 31.
 The holder body 10 is provided with a messtin-shaped blood reservoir 40 on
 the left side in FIG. 1, and a passage 41 connecting the blood reservoir
 40 to the blood inlet 17 gradually descends from the center of the bottom
 of the reservoir 40 toward the blood inlet 17. Three legs 42 are formed on
 the bottom of the holder body 10 radially at regular intervals.
 The cap 20 has an outer wall 21 and an inner wall 22 formed concentrically
 and a filtrate receiver 50 for storing the filtrate. The outer wall 21 is
 in the form of a taper having the same inclination angle as the inclined
 portion 13, and the outside diameter of the outer wall 21 is the same as
 the inside diameter of the inclined portion 13. That is, the outer wall 21
 is fitable to the inclined 13 in a sealed state. A flange 24 is formed
 outward at the periphery of the outer wall 21, and the flange 24 is bonded
 to the flange 14 of the holder body 10 by ultrasonic welding. As shown in
 FIG. 3, a rib 25 is formed on the underside of the flange 24 so as to
 concentrate the ultrasonic energy there to be bonded to each other to
 ensure sealing. The rib 25 disappears after bonding.
 As shown in FIG. 3, twelve projections 26 are formed at the bottom of the
 cap 20 at almost regular intervals. The projection 26 prevent the
 polysulfone microporous membrane 32 from adhering to the bottom.
 A chimney-shaped filtrate passage 27 is formed upward penetrating the
 bottom of the cap 20, and a pent roof 28 is formed horizontally at the
 upper end of the filtrate passage 27 so as to prevent spouting of the
 filtrate. The pent roof 28 has the form of a combination of two half
 circles, and the periphery of the large half circle conforms to the
 periphery of the filtrate passage 27. The discharge port 29 of the
 filtrate is provide obliquely at the upper end of the filtrate passage 27,
 and has the form of a lower half ellipse. Screens (opposite faces) 23 are
 formed on both sides from the filtrate outlet 29 to the upper edge of the
 filtrate receiver 50 in order to prevent scattering of filtrate.
 The above blood filter cartridge has a diameter of the glass fiber filter
 chamber 11 of 20. 1 mm and a depth thereof of 5.9 mm, a diameter of the
 microporous membrane chamber 12 of 21.0 mm, a diameter of the upper end of
 the inclined portion of 22.5 mm and a depth thereof of 2.10 mm, a diameter
 at the lower end of the outer periphery of the outer wall 21 of 20.98 mm
 and a height between the underside thereof and the flange 24 of 2.0 mm, an
 inside diameter of the inner wall 22 of 15.0 mm, and an inside diameter of
 the filtrate receiver 50 of 7.5 mm. The glass fiber filter 31 consists of
 six lass fiber filter sheets each having a diameter of 20.0 mm and a
 thickness of 0.91 mm, and the microporous membrane consists of one
 polysulfone microporous membrane having a diameter of 20.9 mm and a
 thickness of 150 .mu.m. The filtrate outlet 29 has a longitudinal diameter
 of 1.3 mm and a lateral diameter of 1.2 mm. The thickness of the pent roof
 28 is 1 mm, and the distance between both screens (the distance of the
 opposite faces 23) is 2 mm.
 Example 2
 Another blood filter cartridge of th e invention is illustrated in FIG. 4.
 The blood filter cartridge is in pressurizing type, composed of a
 cylindrical holder body 60 and a filtrate receiver 70 provided on the left
 side of the holder body 60 in FIG. 4.
 The upper part of the holder body 60 is a blood reservoir 61, and the lower
 part is a blood filter chamber. The main part of the blood filter chamber
 is a glass fiber filter chamber 63, and the underside therefrom is
 slightly enlarged to form a polystyrene membrane chamber 64. These blood
 filtering materials are held by perforate d plates 65, 66 so as not to
 escape therefrom.
 A pressure cap 67 is mounted to the upper opening, and the inside of the
 holder body 60 can be pressurized by pumping air.
 The bottom of the holder body 60 is a slope so that the filtrate is
 streamed into the filtrate receiver 70.