CN1714292A - Plasma or serum separation membrane and filter including plasma or serum separation membrane - Google Patents
Plasma or serum separation membrane and filter including plasma or serum separation membrane Download PDFInfo
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- CN1714292A CN1714292A CN 200380103660 CN200380103660A CN1714292A CN 1714292 A CN1714292 A CN 1714292A CN 200380103660 CN200380103660 CN 200380103660 CN 200380103660 A CN200380103660 A CN 200380103660A CN 1714292 A CN1714292 A CN 1714292A
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Abstract
一种血浆或血清分离膜，其能够省略离心分离，不存在因血红细胞破坏引起的溶血，能够实现从血液中方便快速地分离血浆或血清；和一种包括血浆或血清分离膜的过滤仪。特别是，血浆或血清分离膜是一种从血液中分离血浆或血清的膜，其空隙比为30％或以下；和一种过滤仪，其包括能够实现使血浆运动速度比血细胞快的过滤件以及和过滤件的后侧顺序连接的血浆或血清分离膜。
A plasma or serum separation membrane capable of omitting centrifugation, without hemolysis caused by red blood cell destruction, capable of conveniently and quickly separating plasma or serum from blood; and a filter comprising a plasma or serum separation membrane. In particular, a plasma or serum separation membrane is a membrane that separates plasma or serum from blood and has a void ratio of 30% or less; and a filter that includes a filter element capable of moving plasma faster than blood cells And the plasma or serum separation membrane sequentially connected with the rear side of the filter element.
Description
Technical field
The present invention relates to be used for blood plasma or serum separation membrane at blood separated plasma that contains blood cell or serum composition, more particularly, relating to can be at the blood plasma or serum separation membrane and the filtrator that do not damage successful separated plasma under the erythrocytic situation or serum composition.
Background technology
Usually, in order to remove blood cell to obtain testing required blood plasma or serum from blood, people have proposed multiple diffusion barrier.
For example, Japan unexamined patent publication No.2-23831 (1990) discloses that a kind of to utilize the diameter that has of hollow be the fiber of the micropore of 0.05 to 1 μ m gathers blood plasma from blood method, the porosity of its outside surface is no more than 40%, and the porosity of inside surface is no less than 60%.
It is that 0.2 to 5.0 μ m, density are 0.1 to 0.5g/cm by mean diameter that Japan unexamined patent publication No.6-64054 (1994) has proposed a kind of
3The fibrage method of coming separated plasma or serum.
On the other hand, Japanese unexamined patent publication No.11-285607 (1999) discloses a kind of by polymeric microfibers bundle or porous polymer and the method for utilizing blood cell to separate with the difference of the movement velocity of blood plasma or serum composition.In this method, a kind of hydrophilic polymer is fixed on the surface of fiber, expands at blood plasma or the separated back of serum hydrophilic fibre, and filtrator gets clogged, and has so just stoped filtration automatically.
Yet the disclosed method of Japanese unexamined patent publication No.2-23831 (1990) has the problem of economic aspect, because use the fiber of hollow to need the expensive disposable product of producing.
Japan's unexamined patent publication No.6-64054 disclosed method can separated plasma or serum, but filter velocity is still very dissatisfied.Exert pressure and to cause sometimes that blood cell breaks, hemocytolysis (haemolysis) for improving filter velocity, and the red blood cell of seepage is to the pollution of separated blood plasma or serum.In addition, in the blood of fibrin or analog precipitation, hemocytolysis is easier to take place, and this is because the possibility that obstruction takes place in detachment process is bigger.
In the disclosed method of Japanese unexamined patent publication No.JP-A11-285607 (1999), because filter velocity changes, can not stop infiltration reliably at the time point that blood plasma or serum filtered are finished between the blood with different hematocrits and viscosity.
Summary of the invention
Consider the above-mentioned situation of these conventional arts, a target of the present invention provides a kind of blood plasma or serum separation membrane, it can be isolated blood plasma or serum composition safe and reliable and apace and don't cause erythrocytic breaking from blood, and a kind of filtrator that uses this blood plasma or serum separation membrane is provided.
For the serum in the separating blood or blood plasma components and blood cell, the inventor of present patent application discovers by insistent, hemocytolysis be separated and don't be caused to the diffusion barrier that has the micropore of specific formation by use can to blood plasma and serum composition from blood cell, and finished the present invention.
Blood plasma of the present invention or serum separation membrane are intended to isolate blood plasma or serum from blood, and it is characterized in that having and be no more than 30% porosity.
The special aspect of the another one of blood plasma of the present invention or serum separation membrane is, a plurality of through holes are provided, and is penetrated into an other side with the side from film.
The special aspect of another one of the present invention is that the diameter of through hole is in the scope of 0.05-2.0 μ m.
The another one special feature of blood plasma of the present invention or serum separation membrane is that the average surface roughness of film is no more than 100nm.
Blood plasma of the present invention or serum separation membrane also have a special aspect, and promptly blood plasma or serum separation membrane are used as the blood cell barrier film, in case the pollution that the hemostasis ball causes.
Filtrator of the present invention comprises: first filtration members, and blood plasma is faster than blood cell by its movement velocity; And according to blood plasma of the present invention or serum separation membrane, described blood plasma or serum separation membrane are linked in sequence in follow-up phase first filtration members that neutralizes.
In this description, the directly continuous situation of object of being not only that " being linked in sequence " refers to also refers to the situation between other parts insertion object.
A special aspect of filtrator of the present invention is, described filtration members is as first filtration members, blood plasma or serum separation membrane are as second filtration members, the 3rd filtration members of being made by fiber was provided in the previous stage of first filtration members, the fiber diameter of described fiber is no less than 3.0 μ m, and volume density is not more than 0.3g/cm
3
The special aspect of the another one of filtrator of the present invention is, first filtration members is made by fiber, and fiber diameter is 0.2 to 3.0 μ m, and packed density (filled density) is 0.1 to 0.5g/cm
3
Filtrator according to more broad scope of the present invention comprises: an end has the container body of opening; Be connected to the cylindrical member of container body opening in the liquid sealing mode; Be placed on first filtration members in the cylindrical member, blood plasma is faster than blood cell by its translational speed; And second filtration members, it comprises according to of the present invention and being used for from the film of blood separated plasma or serum, and in cylindrical member, be linked in sequence in follow-up phase first filtration members that neutralizes, first and second filtration members are placed in the filtrator holding portion, in the previous stage of filtrator holding portion, form the blood holding portion, and, form blood plasma or serum storage area in the downstream of filtrator holding portion.
The special aspect of another one of the present invention is, filtrator also is included in the 3rd filtration members that is provided with in the previous stage of first filtration members, and it is made by fiber, and fiber diameter is not less than 3.0 μ m, and volume density is not more than 0.3g/cm
3
The special aspect of the another one of filtrator of the present invention is, can make blood plasma have fibrinogenic characteristic in absorbing blood, blood plasma or the fibrinogen solution by its movement velocity first filtration members faster than blood cell.
The special aspect of the another one of filtrator of the present invention is, deposits the anti-coagulants composition at least one part of the inner space of filtrator.
The special aspect of the another one of filtrator of the present invention is to deposit the accelerator that quickens blood clotting at least one part of described inner space.
The special aspect of the another one of filtrator of the present invention is, it is 200 to 300mOsm/kg aqueous solution that at least one part the part from the blood holding portion to first and second filtration members has added seepage pressure.Preferable case is that aqueous solution comprises the internal standard material.
The special aspect of the another one of filtrator of the present invention is, the V/V of blood holding portion, filtrator holding portion and blood plasma or serum storage area is at 0.5-2: 1: in the scope of 1-10.
Comprise that a special aspect according to the blood testing container of filtrator of the present invention is, will be added into separated blood plasma or the strip in serum immunity blood layer analysis (immunochromatographical) diagnosticum and be stored in the blood testing container.
Description of drawings
Fig. 1 is a longitudinal sectional view, and the example of structure of filtrator of the present invention is shown;
Fig. 2 is a longitudinal sectional view, and the another one example of structure of filtrator of the present invention is shown;
Fig. 3 is a longitudinal sectional view, and the another one example of structure of filtrator of the present invention is shown;
Fig. 4 can hold the anterior schematic sectional view of the filtrator of blood separation filter according to another embodiment of the present invention;
Fig. 5 is anterior schematic sectional view, is used for explaining the process of separated plasma or serum shown in Figure 4;
Fig. 6 is anterior schematic sectional view, expression be according to another preferred embodiment filtrator;
Fig. 7 is the anterior schematic sectional view of the blood testing system of use filtrator according to a different embodiment;
Fig. 8 is anterior schematic sectional view, is used for explaining the method that adopts blood testing system separated plasma shown in Figure 7;
Fig. 9 is the anterior schematic sectional view according to blood testing container of the present invention;
Figure 10 is a longitudinal sectional view, expression be according to another embodiment of the invention blood testing container; With
Figure 11 is a longitudinal sectional view, expression be according to another embodiment of the invention blood testing container.
Embodiment
To describe the present invention in detail below.
Porosity according to blood plasma of the present invention or serum separation membrane is no more than 30%, preferably is no more than 25%.If porosity surpasses 30%, the load that red blood cell carried will become greatly so, and the possibility that hemocytolysis takes place is just bigger.
The characteristics of employed blood plasma or serum separation membrane are to have a plurality of through holes that can be penetrated into an other side from a side of film among the present invention.Although the not special restriction of the flat shape of the shape of cross section of through hole and opening had better not be used the shape that has acute angle.Therefore, preferable case is that the flat shape of opening and the shape of cross section of through hole are curve shapes, and be for example circular or oval.
Equally, also have no particular limits along the longitudinal profile shape of through hole bearing of trend, inwall can be straight line or curve on longitudinal profile.And the direction that through hole extends can be vertical mutually with the surface of film, also can form certain inclination angle with vertical direction.The longitudinal profile of through hole can be the truncated cone shape that is cut.
A kind of method as forming above-mentioned through hole typically has: the energy-ray irradiation, and for example ion irradiation irradiation, perhaps chemical treatment, the alkaline etching method after film forms for example, but be not limited thereto.In other words, in blood plasma according to the present invention or serum separation membrane, the through hole that is penetrated into opposite side from a side is to form by above-mentioned proper method after the formation of film.
The preferred diameter of through hole in the scope of 0.05-2.0 μ m, if diameter less than 0.05 μ m, the protein in the blood, lipoid and similar substance might stop up, and if diameter greater than 2.0 μ m, red blood cell since its deformation behavior can pass through film.More preferably, diameter is in the scope of 0.1 to 1.5 μ m.
Preferably, in above-mentioned blood plasma or serum separation membrane, the average surface roughness of film is no more than 100nm.If average surface roughness has surpassed 100nm, the load that red blood cell carried will become greatly so, and hemocytolysis just more likely takes place.
The constituent material of above-mentioned blood plasma or serum separation membrane includes but not limited to synthetic polymer or natural polymer.Such material for example has cellulose mixed esters, polyvinylidene fluoride, teflon, polycarbonate, polypropylene, polyester, nylon, glass and aluminium.
The blood that carries out lock out operation among the present invention can be whole blood or dilution blood sample.It also can be animal blood that blood is not limited only to human blood.Equally, blood also can be new blood or be added with for example blood of heparin, edetate or citric acid of anti-coagulants.
From the blood cell separating process of blood, blood is supplied to a side of film, and is accomplished by filtration separation blood plasma and serum for blood plasma of stating in the use or serum separation membrane.In this filter process, the direction of blood flow and the direction of filtration can be selected arbitrarily.Under the situation that blood plasma or serum are separated from the blood cell of whole blood, preferred blood flow direction and filtering direction are different, and more preferably this both direction is vertical mutually.By using different directions, just might improve separation efficiency.
Under the blood flow direction situation identical, will from through hole, block sometimes with filtering direction.Yet, separating under the situation of blood cell from dilute blood, be not easy to take place owing to block, can be selected as guaranteeing reliable separation in identical and do not cause any obstruction at blood flow direction and filtering direction.That is to say, also can be used as the blood cell barrier film according to blood plasma of the present invention or serum separation membrane.
In above-mentioned lock out operation, when red blood cell causes obstruction, filter and finish.In this case, just might take place if apply excessive pressure hemocytolysis.In having the diffusion barrier of traditional micropore, apply less pressure hemocytolysis will take place; And under situation about using according to blood plasma of the present invention or serum separation membrane, also can not take place even apply big pressure hemocytolysis.That is to say, even in filter process, apply 60kPa or littler pressure hemocytolysis also can not take place.This is because because the shape of blood plasma or serum separation membrane is a through hole, and porosity is no more than 30% and the smooth surface of film under the preferable case, therefore the damage that red blood cell causes is reduced.
If apply the pressure greater than 60kPa, red blood cell just might break gradually.Therefore, preferred applied pressure is no more than 60kPa.Blood plasma of Huo Deing or serum just can be used to obtain test value more accurately in this way.
In filtrator according to the present invention, to move than blood cell faster speed, connect by first filtration members and above-mentioned blood plasma or serum separation membrane by first filtration members for blood cell, and first filtration members was positioned on the previous stage of diffusion barrier.When the blood that does not condense was provided, blood was at first by first filtration members.At this moment, blood plasma promptly moves to blood plasma or serum separation membrane, and passes through according to blood plasma of the present invention or serum separation membrane.In this manner, just might from blood cell, separate blood plasma effectively.In this filtrator, when red blood cell blocked the through hole of blood plasma or serum separation membrane after plasmapheresis is finished, filtration was finished.
Blood plasma is faster than blood cell by the speed of first filtration members motion.For first filtration members, for example can use synthetic polymer, by the fiber that glass or porous polymer are made with very thin fibre diameter, have no particular limits.When first filtration members make the composition that material needs in can absorbing blood to measure the time, preferably this material is carried out surface treatment.As carrying out the surface-treated mediator, can use polyether-based or silicone base lubricant, hydrophilic polymer, for example polyvinyl alcohol (PVA), polyvinylpyrrolidone or natural hydrophilic polymkeric substance, perhaps polymerism surfactant, and be not specifically limited.
Under the situation that first filtration members is made by synthetic polymer or glass fibre, preferred fiber diameter is in the scope of 0.2 to 3.0 μ m.If fiber diameter is less than 0.2 μ m, hemocytolysis just might take place.On the other hand, if fiber diameter greater than 3.0 μ m, fiber just should be with High Density Packaging, so that blood plasma or serum are separated from blood cell.Like this, the quantity of filtration members increases, and cost also increases.More preferably, fibre diameter is in the scope of 0.5 to 2.5 μ m.
Satisfying fibre diameter is that 0.2 to 3.0 μ m and packing density are 0.1 to 0.5g/cm
3Condition the time, first filtration members can be made up of two or more stages.In this case, preferably, the packing density of downstream stages is higher than the packing density of upstream phase, and perhaps the packing density of downstream stages is than the height of upstream phase.Like this, just might further improve the separation efficiency of blood plasma or serum.
In the present invention, preferably, to move than blood cell faster speed, first filtration members has the fibrinogenic ability of absorption to blood plasma by foregoing first filtration members.Can absorb fibrinogenic filtrator can but not merely make by following material.Polyester-based resin, for example polyethyleneterephthalate and polybutyleneterephthalate; Nylon resin; Urethane resin; Polystyrene-based resin; By the homopolymer of poly-(methacrylic acid) ester or the resin of multipolymer formation, for example polymethyl methacrylate; And the resin that constitutes by the multipolymer or the methacrylate of polystyrene and vinyl acetate.These resins can multiplely be used in combination.In addition, preferably use polyester-based resin, this is because they have higher fibrinogen receptivity and to the balance influence of test value.
Because the sample that obtains after removing fibrinogen by absorption can so just can improve the dirigibility for various clinical trials according to the same mode of serum is handled.In addition, even, just can have no anxiously it to be used for automatic analyzer because such sample can not condense after placing a period of time yet.For example, filtrator of the present invention can be configured in the heparin tube, and in this case, the blood of being gathered just can directly separate by being reduced pressure in the inner space of heparin tube so that obtain to measure required blood plasma or serum.
A special aspect according to filtrator of the present invention is, filtrator is set, and it comprises: an end has the container body of opening; The cylindrical member that links to each other in the liquid sealing mode with the container body openend; Be placed on first filtration members in the cylindrical member, blood plasma is faster than haemocyte by its translational speed; With second filtration members, it comprises according to the present invention and being used for from the film of blood separated plasma or serum, and is linked in sequence and is placed in the cylindrical member in follow-up phase first filtration members that neutralizes.Fig. 1 has represented the example of a such filtrator to Fig. 3.
Filtrator 1 as shown in Figure 1 has container body 2, and its upper end has opening 2a, and cylindrical member 3 is inserted among the opening 2a of container body 2 hermetically.Container body 2 may be implemented as heparin tube, test tube or analog.Material as forming container body 2 can suitably use synthetic resin, glass or other materials.Cylindrical member 3 can be by forming as suitable materials such as synthetic resin and plastics.Periphery in cylindrical member 3 bottoms forms external screw, and near the interior week formation nut container body 2 openings.Cylindrical member 3 is pushed into and is fixed on the container body 2 by these external screws and nut.By the spiral part between external screw and the nut is designed to sealing state, the periphery of cylindrical member 3 just was sealingly secured on the interior week of container body 2.
In cylindrical member 3, filtration members 4 is accommodated in the top, blood plasma or serum separation membrane 5 be placed on filtration members 4 below, just be arranged on filtration members 4 back continuously.The neighboring of blood plasma or serum separation membrane 5 closely contacts with the inner periphery of cylindrical member 3.Above filtration members 4, plug 6 is connected to the opening of cylindrical member 3 upper ends.This just makes the upper end open of cylindrical member 3 be tightly connected.
By being reduced pressure in the inner space of container body 2, the blood that is captured in the cylindrical member 3 is filtered, and like this, just can separate blood plasma or serum from blood cell according to the present invention.
In filtrator shown in Figure 27, cylindrical member 9 is fixed on the container body 2 hermetically by the lip ring 8 with caoutchouc elasticity.In cylindrical member 9, the less part 9b of diameter is connected by the step 9a that is positioned at the position lower than the insertion filtration members 4 and the part of blood plasma or serum separation membrane 5.The upper end 2b of step 9a and container body 2 is relative, and lip ring 8 realizes that by O shape ring for example it is placed between step 9a and the upper end 2b.The diameter of the part 9b that the diameter of cylindrical member 9 is less is set among the opening 2a that can be pressed into container body 2.Therefore, just might be sealingly secured to the periphery of cylindrical member 9 on the interior week of container body 2 by cylindrical member 9 being pressed into container body 2 and lip ring 8 being pressed between the upper end 2b of step 9a and container body 2.9c is bigger than the diameter of the smaller-diameter portion 9b of cylindrical member 9 than the major diameter part, places filtration members 4 and blood plasma or serum separation membrane 5 at this in than major diameter part 9c.The upper end of cylindrical member 9 closely clogs with plug 6.
In filtrator shown in Figure 3 10, cylindrical member 3 is inserted in the container body 2, and is sealingly secured on the container body 2 by plug 11.Specifically, plug 11 has grip portions 11a and the center section 11b littler than grip portions 11a diameter, and the part 11c that has been reduced of diameter, and its diameter is less than center section 11b.Plug 11 is made by the material with caoutchouc elasticity, such as synthetic rubber or natural rubber.The diameter of the part 11c that diameter reduces can be set in the upper end open that can be pressed into cylindrical member 3 and go.The size of center section 11b can be pressed in the container body 2 and go.The diameter of grip portions 11a is designed to the outer dia greater than container body 2.
Therefore, as shown in Figure 3, be pressed in the cylindrical member 3 by a less part 11c of diameter that is reduced, and center section 11b is pressed in the container body 2 by the opening 2a of container body 2, cylindrical member 3 just is placed in the container body 2 regularly.
Can obviously find out that filtrator according to the present invention can be designed as multi-form structure from Fig. 1 to filtrator shown in Figure 31,7 and 10.It should be noted that the shape of container body, cylindrical member etc. is not limited only to these situations shown in the accompanying drawing.
In filtrator according to the present invention, preferably, blood plasma or serum can be by the first above-mentioned filtration members to move than blood cell faster speed, this first filtration members and be linked in sequence by second filtration members that blood plasma or serum separation membrane are formed, upstream side in first filtration members provides the 3rd filtration members, its fiber diameter is not less than 3.0 μ m, the no more than 0.3g/cm of volume density
3
This filtration members is not limited in fiber diameter and is not less than 3.0 μ m, the no more than 0.3g/cm of volume density
3Scope.As requested, fiber diameter is not less than 3.0 μ m, the no more than 0.3g/cm of volume density
3Yet,, fiber diameter had better not surpass 20 μ m.If fiber diameter has surpassed 20 μ m, just can not capture small amount of fibers albumen or the similar substance that is deposited in the blood again.If hemocytolysis less than 3.0 μ m, just more likely takes place in fiber diameter.If volume density has surpassed 0.3g/cm
3, just more may stop up.
Under the above-mentioned situation that first to the 3rd filtration members is provided, first filtration members and second filtration members are linked in sequence, and such second filtration members just is in the downstream, and the 3rd filtration members just is in the upstream side of first filtration members.
Therefore, in blood blood plasma or serum when blood cell is separated, blood is fed on the 3rd filtration members.The blood of supplying with on the 3rd filtration members is in proper order by the 3rd filtration members and first filtration members.In this case, even haemoconcentration height of supplying with or fibrin are easier to precipitation, fibrin etc. can be caught by the 3rd filtration members, thereby reduce the probability that generation is stopped up in first filtration members.Therefore, in first filtration members, red blood cell can not receive too much pressure, and cythemolytic like this incidence just can be reduced.In first filtration members, the movement velocity of blood plasma or serum is faster than blood cell.Correspondingly, blood plasma or serum pass through second filtration members, and separate from blood.Caught by second filtration members, can not leak into the downstream of second filtration members by the blood cell of first filtration members.
As previously mentioned, in the structure that first filtration members and second filtration members are linked in sequence, because the 3rd filtration members is placed on the upstream side of first filtration members, just might from blood, separate blood plasma or serum safely, and prevent that red blood cell from breaking in blood separation filter according to the present invention.
Characteristics according to filtrator of the present invention are that it holds foregoing blood separation filter of the present invention.The concrete structure of containment blood separator-filter is not particularly limited.
Fig. 4 is the anterior schematic sectional view of filtrator according to another preferred embodiment.Filtrator 21 forms by the syringe 22 that use is used to inject.In syringe 22, first filtration members 23 and second filtration members 24 are placed as and make second filtration members 24 be positioned at the downstream.On first filtration members 23, place the 3rd filtration members 25.
As shown in Figure 5, in the process of using filtrator 21, blood is supplied with from syringe 22 tops, and the piston 26 of syringe is pushed into.So just blood is exerted pressure the side that separated blood plasma or serum just can collected syringe tip 22a.
Except the method for using piston 26, another selection is, thereby from side suction separated plasma or the serum of the most advanced and sophisticated 22a of syringe 22.For example, by entry needle being installed to the most advanced and sophisticated of syringe 22 and utilizing entry needle to pierce through the plug of vacuum blood collection tube (not having expression among the figure), blood plasma or serum just can be by from the tip one side suctions and collected vacuum blood collection tube of syringe.
What Fig. 6 represented is the front cross-sectional view of filtrator according to another preferred embodiment.Filtrator 31 has the tube of being made up of housing 32 and housing 33.Housing 32 and 33 removably fixing in the liquid sealing mode by screw or similarity piece.In filtrator 31, first filtration members 23, second filtration members 24 and the 3rd filtration members 25 are installed in a similar fashion according to embodiment shown in Figure 4.Filtrator 31 has inflow entrance 32a, and blood is supplied to by it, also has flow export 33a, and blood plasma or serum are discharged by it.
In using the process of this filtrator, inflow entrance 32a is connected with syringe, and the blood that syringe is gathered pushes by piston, and blood plasma or serum just can separate from blood to 25 by first to the 3rd filtration members 23 like this, and pass through flow export 32a collection.Equally, in filtrator 31, blood plasma or serum can be separated by aspirating from the side of flow export 33a.
The housing 32 and 33 that constitutes foregoing filtrator 31 can be realized by the commercial filters filter cylinder.
In first and second embodiment, first and second filtration members are linked in sequence, and the directly contact mutually of first and second filtration members.Yet first filtration members and second filtration members not necessarily will directly connect as long as be linked in sequence from the upstream side to the downstream.Fig. 7 is equipped with the anterior schematic sectional view of the blood testing system of filtrator according to another embodiment of the present invention, and wherein first and second filtration members are separated a segment distance.
In blood testing system 41, filtrator 44 is made up of syringe 42 and filter retainer 43.In syringe 42, the mode of holding of first filtration members 23 and the 3rd filtration members 25 is that the 3rd filtration members 25 is in upstream side.The inflow entrance 43a of filter retainer 43 links to each other according to the most advanced and sophisticated 42a of liquid sealing mode and syringe 42.Second filtration members 24 is provided in filter retainer 43.The blood cell that has flow in the blood in the filter retainer 43 is caught by second filtration members 24.Like this, separated blood plasma or serum are collected by the flow export 43b of filter retainer 43.
In blood testing system 41, entry needle 45 is installed on the flow export 43b of filter retainer 43.The pin end of entry needle 45 pierces through the plug 47 that links to each other with blood plasma or serum storage container 46.Plug 47 is made by resilient material, the upper end open that its connected mode can sealed storage container 46.
On the other hand, the flow channel 49 that assembling links to each other with constant voltage suction pump 48 in the plug 47.As shown in Figure 8, after blood flow A was fed in the syringe 42, by driving constant voltage suction pump 48, the pressure of the inner space of storage container 46 was lowered, and causes blood to be sucked.The blood order that is inhaled into is through the 3rd filtration members 25, first filtration members 23 and second filtration members 24, and like this, separated blood plasma or serum are finally with regard in the collected storage container 46.
Corresponding therewith, by removing entry needle 45 and flow channel 49, just can in storage container 46, obtain separated blood plasma or serum from storage container 46.
Fig. 9 is the anterior schematic sectional view according to an embodiment of blood testing container of the present invention.Blood testing container 51 has exterior tube 52 and the cylindrical member 53 that is inserted in the exterior tube 52.Exterior tube 52 is made of the column shape container with bottom and upper end open 52a.In cylindrical member 53 is cylindrical, and its upper end has opening 53a.Downward outstanding 53b is set in the lower end of cylindrical member 53, and it is fixed with cylindrical member 53 and can separate.In cylindrical member 53, the 3rd filtration members 25, first filtration members 23 and second filtration members 24 that constitute blood separation filter of the present invention sequentially are provided with from the top down.Blood separation filter according to the present invention according to this configuration is accommodated in the cylindrical member 53.Outside, below second filtration members 24, form blood plasma or serum reserve part 53c, be used to keep the blood plasma or the serum that are filtered.The inner space of blood testing container 51 is depressurized, and the opening 52a of exterior tube 52 and the opening 53a of cylindrical member 53 are by plug 54 sealings.
Therefore, in blood testing container 51, by piercing through plug 54 with vacuum blood collection needle or analog, blood is imported in the blood holding portion 56, blood holding portion 56 extends above blood separation filter.Then, by blood collection needle being inserted into plug 54, perhaps remove to form after the vacuum blood collection needle and pass the through hole of plug 54, continued by the filtration of blood separation filter to the blood gathered for the mutual circulation of the inner space that allows cylindrical member 53 and air.Then, flow down to blood plasma or serum storage area 57 by filtering resulting blood plasma or serum, blood plasma or serum storage area 57 are set at the below via blood plasma or serum reserve part 53c.
For the concrete structure of the blood testing container that has above-mentioned blood separation filter, blood testing container according to the present invention is not limited in structure as shown in Figure 9.Also can adopt other different structures.For example, first to the 3rd filtration members 23 to 25 can be placed in the storage container of depositing separated blood plasma or serum, the container that perhaps holds first to the 3rd filtration members can be inserted in the container of depositing separated blood plasma or serum, thereby forms the blood testing container with double structure.
Figure 10 is the longitudinal sectional drawing of blood testing container according to an embodiment of the invention.Blood testing container 61 is configured by the blood collection container that use has container body 62 and cylindrical member 63.Container body 62 is made of the tubular container with bottom and upper end open 62a.
On near the interior week the upper end open 62a of container body 62, nut 62b is set.
The upper end of cylindrical member 63 has opening 63b.Outstanding downwards blood plasma or the serum water clock part 63c of formation below cylindrical member 63.Blood plasma or serum water clock part 63c are bent, so that its tip is towards the inwall of container body 62.Blood plasma or serum water clock part 63c be positioned at blood testing agent bar 64 sample-feed part 64a near, blood testing agent bar is positioned at the inside of container body 62.
In order to seal the opening 63b of cylindrical member 63, plug 65 links to each other with opening 63b.
For example rubber or synthetic rubber form plug 65 by resilient material.As resilient material, any resilient material can use, if it can sealed open 63b and the blood collection container that can keep forming by container body 62 and cylindrical member 63 in the pressure that reduces.
In cylindrical member 63, place filtrator 66.Filtrator 66 has the structure that first filtration members 23 and second filtration members 24 are linked in sequence.
In the present embodiment, blood collection container is made up of top container body 62 and cylindrical member 63.Reduce pressure in inner space to blood collection container.The decompression degree can make plug 65 by vacuum blood collection needle-penetration, and blood is gathered by inside and outside pressure differential.Specifically, the degree of decompression is approximately 1 to 90kPa.
In the present embodiment, blood collection container is made up of container body 62 and cylindrical member 63, has the first inner space A and the second inner space B in container.Specifically, filtrator 66 is made up of first filtration members 23 and second filtration members 24, is placed on the boundary between the first inner space A and the second inner space B.In the second inner space B, place blood testing agent bar.In the present invention, the modes of emplacement of blood testing agent bar 64 is for vertically extending, and sample-feed part 64a is positioned at upper end side in container body 62.
As foregoing blood testing agent bar 64, can suitably use be used for detecting the composition of blood plasma or serum be included in blood plasma or serum in the blood testing agent bar of material.
In the present embodiment, immune blood layer analysis diagnosticum bar is used as top blood testing agent bar use.Therefore, the specific composition in blood plasma or the serum just can use blood testing agent bar to detect by immune blood layer analysis (immunochromatography).
In the present embodiment, blood testing agent bar 64 is used, yet the blood testing agent bar of another embodiment can replace blood testing agent bar 64 and be placed in second space B.
To explain the blood testing method that adopts according to the blood testing container 61 of present embodiment below.
When carrying out blood testing, plug 65 is by vacuum blood collection needle-penetration.At this moment, because the inner space of blood testing container 61 is depressurized, blood just is injected among the first space A of blood collection container 61 by the vacuum blood collection needle.After blood was gathered, blood was fed into first filtration members 23, and blood plasma or serum are faster than blood cell by the movement velocity of first filtration members 23, and blood plasma or serum are directed to second filtration members 24 very soon.In second filtration members 24, blood plasma or serum pass through above-mentioned through hole, and are fed into the sample-feed part 64a of blood testing agent bar 64 by blood plasma or serum water clock part 63c.The filtration of blood can be carried out rapidly by the pressure differential of the first inner space A and the second inner space B.
In other words, after collecting blood by the vacuum blood collection needle, plug pierces through to allow the connection of outside and inner space A with blood collection needle or analog.This has just reduced the degree of pressure drop, produces pressure differential between the first inner space A and the second inner space B.Because this pressure differential, the surplus pressure in second inner space just, filtration can be carried out very soon.Then, when the through hole of second filtration members 24 is blocked by red blood cell, filter and finish.
As mentioned above, in the blood testing method of present embodiment, when using vacuum blood collection needle or analog after blood collection is in the inner space A of blood testing container 61, blood plasma or serum just can not needed the troublesome operation as centrifuging so soon from filtering out the blood, blood plasma or serum are fed into the blood testing agent bar 64 that is placed among the second inner space B.Correspondingly, finishing this process from the blood testing of taking a blood sample just can be automatically, carry out safely and can not cause possibility of infection.
Figure 11 is the longitudinal sectional view of blood testing container according to a different embodiment.In blood testing container 61 as shown in figure 10, cylindrical member 63 is connected with the top of container body 62, and still, in the blood testing container 80 of present embodiment, cylindrical member 83 is inserted in the container body 82.The plug 81 of closing cylindrical member 83 openings is not only closed the opening 83b of cylindrical member 83, and the opening 82a of closing containers main body 82.
Equally, in second blood testing container 80, owing to reduced pressure in advance in the inner space, using vacuum blood collection needle-penetration connector body, and behind the situation collection blood according to blood testing container 61, when with transporting folder (conducting jig) when piercing through plug, the filtration of blood is just carried out automatically, is supplied to blood testing agent bar 64 as the blood plasma or the serum of sample.Correspondingly, just might finish whole operations from the blood collection to the blood testing safely, and not need centrifugal separator or centrifugally operated according to the situation of blood testing container 61.
As top description, can be according to blood testing container of the present invention with multiple multi-form enforcement.Have the opening that is used for the blood testing container when the blood testing container comprises, and can hold the blood holding portion of being gathered blood, can hold the filtrator holding portion of above-mentioned first and second filtration members or first to the 3rd filtration members and be positioned at the filtrator holding portion after and when storing the blood plasma of blood plasma or serum or serum storage area, the volumetric ratio of blood holding portion, filtrator holding portion and blood plasma or serum storage area is preferably in 0.5-2: 1: in the scope of 1-10.The reasons are as follows: if the ratio of blood holding portion less than 0.5, blood volume is just inadequate with respect to the amount of filtrator, like this, just can not get after separation or can only obtain very a spot of sample.On the other hand, be supplied to if the volume of blood holding portion, surpasses the blood of the blood separation ability of filtrator greater than 2.0 in the above-mentioned ratio, like this, experimenter's burden will increase.
In blood testing container according to the present invention, as mentioned above, might utilize pressure differential to come separating blood.In this case, blood is driven by the pressure differential between blood holding portion and blood plasma or the serum storage area, realizes in the filtrator separating thereby flow into.When blood separation was carried out, the internal pressure of blood plasma or serum storage area increased, and like this, the driving force of filtration just reduces.Above-described pressure differential depends on the volume of blood plasma or serum storage area.If the volume of blood plasma or serum storage area is less than 1 in the above-mentioned ratio, driving force just is not enough to carry out blood separation, and this just causes can not obtaining or can only obtaining the problem of very a spot of sample after separation.On the contrary, if the volume ratio of blood plasma or serum storage area greater than 10, driving force is enough to carry out blood separation, yet, so a kind of configuration and inadvisable because size can increase with there is no need, cost will improve, the rejection number after the use also can increase.
In blood testing container according to the present invention, to be 200 to 350mOsm/kg aqueous solution be added into from blood holding portion (quilt gathered blood supply with herein) at least one point to the route of filtrator holding portion preferred seepage pressure.In this case, the blood of being gathered in the process before blood separation finishes just is in the same place with aqueous solution, and the concentration of blood cell will reduce in the blood like this.That is to say that the value of hematocrit will reduce.When filtrator was used for separating blood, the more little separation efficiency of the value of hematocrit was just high more, and the amount of the sample that is obtained after separating will significantly increase.Yet in clinical testing, test value is always along with dilution rate changes when blood plasma or serum are diluted.Therefore, just must dilute carefully.
In the present invention, the blood flow volume that collects is appointed as 1, the amount of the above-mentioned aqueous solution that is added is preferably in 0.2 to 5 scope.If the ratio of the aqueous solution that is added is less than 0.2, the sample size that is obtained just can increase hardly, and if the ratio of the aqueous solution that is added greater than 5, blood is just by excess dilution, abnormality will take place in the clinical trial value like this.More preferably, when the collection blood flow volume was designated as 1, the addition of above-mentioned aqueous solution was between 0.5 to 3.
The seepage pressure of the aqueous solution that is added preferably equals the seepage pressure of blood, and like this, blood cell especially red blood cell just can not break in aqueous solution and blood mixing.Therefore, the preferred seepage pressure of above-mentioned aqueous solution is between 200 to 350mOsm/kg.If less than 200mOsm/kg, red blood cell will swollenly rise and break, and when greater than 350mOsm/kg the time, erythrocytic content will dissolve and cause the abnormality of clinical trial value.More preferably, the seepage pressure of above-mentioned aqueous solution is between 250 to 300mOsm/kg.
Solute in the above-mentioned aqueous solution is not particularly limited, yet, its aqueous solution be highly acid or alkalescence or and the solute that reacts of blood component be worthless.In order to stablize the pH value, can preferably use the combination of inorganics with cushioning effect.The example of this combination includes but are not limited to citric acid and sodium hydrogen phosphate, imidazoles and hydrochloric acid, trimethylpyridine and hydrochloric acid, triethanolamine and hydrochloric acid, three (methylol) aminomethane and hydrochloric acid, or the like.Yet such combination has no particular limits, as long as cushioning effect is between pH value 6 to 8.Equally, also can preferably be used such as the salt such as sodium chloride that do not have influence on the pH value.
Equally, the internal standard material also can be added in the aqueous solution, so that the volumetric ratio of blood of being gathered and aqueous solution is more clear after they mix.Such internal standard material is very useful by the dilution rate of blood plasma that separating blood obtained or serum for accurate calculating.Use this internal standard material, the clinical trial value will be calculated exactly.The not special restriction of internal standard material, yet, it should be a kind of composition that is not present in the blood, it must be dissolved in water, it must have specific characteristics, for example can absorb ultraviolet ray, absorb infrared ray, absorption near infrared ray, have wavelength of fluorescence, its concentration in blood plasma or serum can be measured by the common survey method.This internal standard examples of substances comprises the benzotriazole based compound, the benzoxy compound, for example methyl to mesitylenic acid and octyl group to the dimethylamino ethyl benzoate, have the material of the visual absorption of this outside line, for example oxo benzene, benzoic acid and salicylic acid and metal composite that can be water-soluble, for example [Co (H
2O) 6]
2+, [Co (NH
3)
5]
2+[Fe (η-C
5H
5)
2].Equally, also can use pigment, for example indigo-blue, eosin, β carotene, malachite green, methyl blue etc.The example of fluorescent material comprises erythrosine, sulfuration rhodamine, rhodamine B, pinacyanol.Can use any material, and be not limited only to these internal standard materials recited above, as long as it is not present in the live body and gets along well measured material and assorted with regard to can not causing any problem.
In filtrator according to the present invention, preferably, the anti-coagulants composition is added at least one part of filtrator.In this case, the interpolation of anti-coagulants composition is in order to stop blood clotting.The anti-coagulants composition is added to the part that filtration members is received, for example, hold first and second filtration members of foregoing filtrator or the part of first to the 3rd filtration members, perhaps add to and be positioned at the blood holding portion of upstream side that filtration members is received part.Be added at the anti-coagulants composition under the situation of blood holding portion, the anti-coagulants composition is added to filtrator or has the part of holding detected blood in the blood testing container of filtrator.Therefore, can stop detected blood to condense immediately.Even when the anti-coagulants composition was added to the filtrator holding portion that is connected with the blood holding portion, condensing of blood can be prevented in a similar manner effectively.And, when filtering immediately by filtration members, the anti-coagulants composition can be added to the filtration members holding portion than after-stage.
As long as have the ability of abundant inhibition blood clotting, any anti-coagulants composition can be used, and is not particularly limited.The example of this anti-coagulants composition comprises the heparin slaine, for example liquaemin and heparin lithium.As the anti-coagulants composition with decalcification ability, typical example has sodium citrate, ethylenediamine tetraacetic acid, oxalic acid, sodium fluoride etc.
When using the heparin slaine, be the situation of 1mL for amount of blood collected, the addition of anti-coagulants composition is preferably in the scope of 0.5 to 50 unit, although the kind according to the anti-coagulants composition of addition changes.When using sodium citrate, ethylenediamine tetraacetic acid, oxalic acid, sodium fluoride etc., be the situation of 1mL for gathering blood flow volume, preferred addition approximately is 0.5 to 20mg.
Blood testing container of the present invention or filtrator can partly add set accelerator and promote condensing with antagonism anti-coagulants composition of blood.By adding set accelerator, might make blood clotting and gather serum sample.By adding set accelerator, the fibrinogen of not removing fully from the process of blood separation serum in filtrator just is prevented from flowing to blood plasma or serum storage area downwards by filter.Therefore, can obtain to be removed fibrinogenic serum reliably, therefore, the problem that can avoid sample to condense subsequently just.
As set accelerator, have absorbefacient dead matter, the enzyme of silica, fibrin ferment and snake venom and batroxobin for example, for example papain can be as an example.
Under the situation of set accelerator that uses enzyme such as fibrin ferment, preferably, set accelerator is added to the downstream of filtrator.If set accelerator is added to the upstream side of filtrator, blood clotting will carry out rapidly, and the blood that filtrator will be condensed blocks.This just might stop the separation of blood.In contrast, in the time of near the downstream in set accelerator is added to the filtrator holding portion, have only the fibrinogen that is not filtered the device removal to be condensed, so just can in filtration members, safety remove fibrinogen by the effect of set accelerator.
Can accomplish to understand better the present invention by following explanation to object lesson of the present invention.It should be noted that the present invention is not limited to following example.
Example 1:
Preparing one is the diffusion barrier (produced by Millipore company, production number: GTTP04700, diffusion barrier have a plurality of cross sections to be circular through hole, and the size in hole is 0.2 μ m) that the polycarbonate of 10 μ m constitutes by thickness.Diffusion barrier is cut into the small pieces that diameter is 13mm, and is placed to and can (be produced trade name: Sphinex filter retainer Sx0130000) by Millipore company by buy the filter cylinder that obtains on market.
Example 2:
Except the diameter of through hole is changed into 0.6 μ m, prepare an assessment sample by method identical in the example 1.
Example 3:
Except the diameter of through hole is changed into 2.0 μ m, prepare an assessment sample by method identical in the example 1.
Example 4:
At internal diameter is that the syringe of the 10mL of 14.5mm (is produced by JMS company, make by polypropylene) in be placed in the example 1 diffusion barrier of the through hole that constitutes by polycarbonate that uses with diameter 0.2 μ m, fiber diameter is that the 1.0g dacron of 1.8 μ m is loaded on the diffusion barrier, is compressed to 4.0cm then
3Volume, so just formed filtration members.Be used as the assessment sample through the syringe of preparing like this.
Example 5:
Being changed except the diameter of through hole is the 0.8 μ m, according to obtaining the assessment sample with quadrat method in the example 4.
Comparative Examples 1:
By having many pore sizes is that to be cut into diameter be that the 13mm size (is produced by Millipore company for diffusion barrier that the polyvinylidene fluoride of the continuous air hole of 0.22 μ m is made, trade name is Durapore, thickness is 125 μ m), and according to being placed in the filter cylinder to obtain the assessment sample with example 1 identical method.
Comparative Examples 2:
Being changed except the size of micropore is the 0.65 μ m, according to obtaining the assessment sample with Comparative Examples 1 identical method.
Comparative Examples 3:
Being changed except the diameter of micropore is the 3.0 μ m, according to obtaining the assessment sample with quadrat method in the example 1.
Comparative Examples 4:
At internal diameter is that the syringe of the 10mL of 14.5mm (is produced by JMS company, make by polypropylene) in lay in the Comparative Examples 1 diffusion barrier that the aperture is the continuous air hole of 0.22 μ m that has that uses, be the dacron of 1.8 μ m and be compressed to 4.0cm by on diffusion barrier, loading the 1.0g fiber diameter
3Volume, filtration members is set on diffusion barrier, thereby obtains the assessment sample.
Comparative Examples 5:
Employed in using Comparative Examples 3 have the diffusion barrier of through hole that the aperture is 3.0 μ m, according to obtaining the assessment sample with example 4 identical methods.
Test case 1:
Example 1 each assessment sample to example 3 and Comparative Examples 1 to Comparative Examples 3 all is used.By the haemocyte capacity that uses 100 μ L is 10% dilute blood, filters by such pressurization the shown in following table 1.The state of the blood plasma that is obtained and compare to measure by the state that above-mentioned dilute blood is carried out the blood plasma that centrifuging (10 minutes, speed is 3000rpm) obtained and whether have hemocytolysis to take place.
The result is as shown in table 1 below.
| The shape in hole | The micropore size | Filter pressure | The separating plasma state | |
| Example 1 | Through hole | 0.2μm | ?60kPa | Do not observe hemocytolysis |
| Example 2 | Through hole | 0.6μm | ?60kPa | Do not observe hemocytolysis |
| Example 3 | Through hole | 2.0μm | ?20kPa | Do not observe hemocytolysis |
| Comparative Examples 1 | Continuous air hole | 0.22μm | ?60kPa | Observe hemocytolysis |
| Continuous air hole | 0.22μm | ?20kPa | Observe hemocytolysis | |
| Comparative Examples 2 | Continuous air hole | 0.65μm | ?20kPa | Observe hemocytolysis |
| Comparative Examples 3 | Through hole | 3.0μm | ?20kPa | Red blood cell oozes out |
Test case 2:
By making the assessment sample of use- case 4,5 and Comparative Examples 4,5, supply with hematocrit and be the human blood of 46.7% 4mL, filtration can be carried out under pressure as shown in table 2 below.Like this blood plasma that is obtained with compare by same blood being carried out the blood plasma that centrifuging (10 minutes, speed is 3000rpm) obtained, check whether there is hemocytolysis by naked eyes.The result is as shown in table 2 below.
| The shape in hole | The micropore size | Filter pressure | The separating plasma state | |
| Example 4 | Through hole | 0.2μm | ?60kPa | Do not observe hemocytolysis |
| Example 5 | Through hole | 0.8μm | ?60kPa | Do not observe hemocytolysis |
| Comparative Examples 4 | Continuous air hole | 0.65μm | ?20kPa | Observe hemocytolysis |
| Comparative Examples 5 | Through hole | 3.0μm | ?20kPa | Red blood cell oozes out |
Example 6:
The blood cell barrier film that preparation is made up of polycarbonate, it has the micropore size is that 0.2 μ m, porosity are 14% through hole.The blood cell barrier film can be that the commodity of IsoporeGTTP obtain from the trade name of Millipore company, and its thickness is 10 μ m.The blood cell barrier film is cut into has diameter 13mm, and be put into can be by (produced by Millipore company, trade name is the Sphinex filter retainer, effective filtration area: 0.7cm in the filter retainer that buy to obtain
2), so just obtained the sample of assessing.
Example 7:
Except micropore size and porosity are changed into respectively 0.8 μ m and 15%, by obtaining to assess sample with example 6 identical methods.The Isopore ATTP (trade name) that is produced by Millipore company is used as the blood cell barrier film.
Example 8:
Except micropore size and porosity are changed into respectively 1.2 μ m and 23%, by obtaining to assess sample with example 6 identical methods.The Isopore RTTP (trade name) that is produced by Millipore company is used as the blood cell barrier film.
Example 9:
Except micropore size and porosity are changed into respectively 2.0 μ m and 8%, by obtaining to assess sample with example 6 identical methods.The Isopore TTTP (trade name) that is produced by Millipore company is used as the blood cell barrier film.
Example 10:
Putting into the example 6 employed micropore sizes that have in internal diameter is the 10mL syringe of 14.5mm is that 0.2 μ m, porosity are 14% blood cell barrier film, this film is cut into has diameter 14.5mm, is the 1.0g dacron of 1.8 μ m and is compressed to 4.0cm by loading fiber diameter then
3Volume filtration members is set, so just obtained the assessment sample.
Example 11:
Except micropore size and porosity are changed into respectively 0.8 μ m and 16%, by obtaining to assess sample with example 10 identical methods.
Example 12:
Except micropore size and porosity are changed into respectively 2.0 μ m and 8%, by obtaining to assess sample with example 10 identical methods.
Comparative Examples 6:
Except thickness is that the polyvinylidene fluoride diffusion barrier with many holes of 125 μ m is used as the blood cell barrier film and (is produced by Millipore company, trade name is GVWP, micropore size and porosity are respectively 0.22 μ m and 70%) outside, the assessment sample obtained according to example 6 identical methods.
Comparative Examples 7:
Except thickness is that the mixed cellulose ester membrane with many holes of 150 μ m is used as the blood cell barrier film and (is produced by Millipore company, trade name is MF-Millipore DAWP, micropore size and voidage are respectively 0.65 μ m and 81%) outside, the assessment sample obtained according to example 6 identical methods.
Comparative Examples 8:
Except micropore size and porosity are changed into respectively 5.0 μ m and 70%, by obtaining to assess sample with Comparative Examples 6 identical methods.
Comparative Examples 9:
Except micropore size and porosity are changed into respectively 3.0 μ m and 14%, by obtaining to assess sample with Comparative Examples 6 identical methods.
Comparative Examples 10:
Except using by the micropore size is the blood cell barrier film that 0.22 μ m, porosity are 70%, thickness is 125 μ m polyvinylidene fluoride constitutes, just in the Comparative Examples 6 outside the employed blood cell barrier film, by obtaining the assessment sample with example 10 identical methods.
Comparative Examples 11:
Except being that the blood cell barrier film that constitutes of 0.65 μ m, porosity are 81%, thickness is 150 μ m mixed cellulose ester membrane is just employed blood cell barrier film is used in the Comparative Examples 7, by obtaining the assessment sample with example 10 identical methods by the micropore size.
Comparative Examples 12:
Except the thickness with many holes is that the polycarbonate membrane of 9 μ m is used as the blood cell barrier film and (is produced by Millipore company, trade name is Isopore TSTP, micropore size 3.0 μ m, porosity are 14%) outside, by obtaining the assessment sample with example 10 identical methods.
Test case 3:
The blood that obtains from a healthy person is separated into blood plasma and blood cell composition by centrifugal separation.Make the use-case 6 blood cell barrier film to example 9 and Comparative Examples 6 to Comparative Examples 8, the 200 μ L blood plasma components that obtain by centrifugal separation are added and filter under the listed pressure of following table 3.Before filtering end, the other 200 μ L blood that do not carry out centrifuging are added, and filtration is proceeded.After 10 minutes, the state of the blood plasma that has been filtered and compared by the blood plasma of centrifuging and to have determined whether that hemocytolysis takes place.The result is as shown in table 3.
Table 3
| The micropore size | Porosity | Filter pressure | The separating plasma state | |
| Example 6 | ?0.2μm | ?14％ | 60kPa | Do not observe hemocytolysis |
| Example 7 | ?0.8μm | ?16％ | 60kPa | Do not observe hemocytolysis |
| Example 8 | ?1.2μm | ?23％ | 60kPa | Do not observe hemocytolysis |
| Example 9 | ?2.0μm | ?8％ | 60kPa | Observe hemocytolysis in a small amount |
| 40kPa | Do not observe hemocytolysis | |||
| Comparative Examples 6 | ?0.22μm | ?70％ | 20kPa | Observe hemocytolysis |
| Comparative Examples 7 | ?0.65μm | ?81％ | 20kPa | Observe hemocytolysis |
| Comparative Examples 8 | ?5.0μm | ?70％ | 20kPa | Red blood cell oozes out |
| Comparative Examples 9 | ?3.0μm | ?14％ | 20kPa | Red blood cell oozes out |
As clearly seen from Table 3, in example 5 in example 9, even when applied pressure is 60kPa and 40kPa, also may obtain not have the blood plasma of hemocytolysis generation, and in Comparative Examples 6 in Comparative Examples 8, can observe generation in low hemocytolysis and red blood cell infiltration in the 20kPa of pressure.
Test case 4:
Use comprises according to example 10 filtrator to example 12 and Comparative Examples 10 to the blood cell barrier film of Comparative Examples 12, and to be 46.7% human blood be filtered under the listed pressure of following table 4 hematocrit of 4mL.Protecting after 10 minutes, comparing the state of the blood plasma that obtains with through the state that the blood plasma of (3000rpm * 10 minute) is handled in centrifuging has determined whether the hemocytolysis generation.
Table 4
| The micropore size | Porosity | Filter pressure | The separating plasma state | |
| Example 10 | ?0.2μm | ?14％ | 60kPa | Do not observe hemocytolysis |
| Example 11 | ?0.8μm | ?16％ | 60kPa | Do not observe hemocytolysis |
| Example 12 | ?2.0μm | ?8％ | 60kPa | Do not observe hemocytolysis |
| Comparative Examples 10 | ?0.22μm | ?70％ | 20kPa | Observe hemocytolysis |
| Comparative Examples 11 | ?0.65μm | ?81％ | 20kPa | Observe hemocytolysis |
| Comparative Examples 12 | ?3.0μm | ?14％ | 20kPa | Red blood cell oozes out |
In example 12, hemocytolysis does not take place in example 10, just filters to stop automatically after blood plasma is filtered.In contrast, in Comparative Examples 10 in Comparative Examples 12, cythemolytic blood plasma filtered gradually or red blood cell by direct filtration.Below, will explain object lesson.
According to structure blood testing shown in Figure 7 system 41.With fiber diameter is that the 1.0g polyethylene terephthalate fiber filled syringe 42 of 1.8 μ m forms first filtration members, and filling fiber diameter then is that 3.5 μ m, volume density are 0.1g/cm
3The fiber that constitutes of 0.22g polyethylene terephthalate form the 3rd filtration members.Then these fibrous material compressions being made their overall volume is 4cm
3, form first filtration members 23 and the 3rd filtration members 25 like this.
As filter retainer 43, the Sphinex filter retainer (trade name) that employing is produced by Millipore company, as second filtrator, the micropore size is that 0.4 μ m, porosity are that 13% filtrator (produced by Millipore company, trade name is HTTP) is stamped into the 13mm diameter and is mounted.Said syringe 42 links to each other with filter retainer 43 mode as shown in Figure 7, so just constitutes filtrator.
Example 14:
Except the fiber diameter of using 0.02g is that 6.0 μ m, volume density are 0.1g/cm
3Fiber as outside the material that forms the 3rd filtration members, filtrator constitutes according to the same procedure shown in the example 13.
Example 15:
Except the fiber diameter of using 0.05g is that 10.0 μ m, volume density are 0.1g/cm
3Fiber as outside the material that forms the 3rd filtration members, filtrator constitutes according to the same procedure shown in the example 13.
Comparative Examples 13:
Except not forming the 3rd filtration members, filtrator constitutes according to the same procedure shown in the example 13.
Test case 5:
Employing is according to example 13 each filtrator to example 15 and Comparative Examples 13, blood plasma or serum storage container 46 and suction pump 48 interconnect as shown in Figure 7 and Figure 8, hematocrit is approximately 40% 4mL blood and is added in the syringe 42, carries out suction filtration after this under the pressure of 50kPa.In this way the blood plasma of Huo Deing with compare by same blood being carried out the identical blood plasma that centrifuging obtains, whether observe has hemocytolysis to exist.
Test case 6:
Employing is according to example 13 each filtrator to example 15 and Comparative Examples 13, hematocrit be approximately 40% blood be injected in the glass container with and place and condensed promoting in two minutes, after this, 4mL is added in each filtrator through the short blood that coagulates, and carries out suction filtration with method identical in the example 5 under 50kPa pressure.Whether the blood plasma of Huo Deing and same blood is handled the blood plasma obtain through centrifuging compare by this method, observing has hemocytolysis to exist.
The result is as shown in table 5 below.Whether cythemolytic existence can be determined in the following manner:
There is not hemocytolysis: and compare by the blood plasma that centrifuging obtains and not observe difference.
Slight hemocytolysis: compare with the blood plasma that obtains by centrifuging, blood plasma is rubescent slightly.
Faint hemocytolysis: compare with the blood plasma that obtains by centrifuging, blood plasma obviously takes on a red color.
Table 5
| The result of | The result of | |
| Example 13 | There is not hemocytolysis | Slight hemocytolysis |
| Example 14 | There is not hemocytolysis | There is not hemocytolysis |
| Example 15 | There is not hemocytolysis | There is not hemocytolysis |
| Comparative Examples 13 | There is not hemocytolysis | Faint hemocytolysis |
Example 16 is below measured the surfaceness of blood plasma or serum separation membrane in example 21 and Comparative Examples 14 and Comparative Examples 15 in the following manner.
In particular, the average surface roughness Ra as the filter surfaces shape is measured by AFM and DFM by the probe microscope that uses scan type.Wherein average surface roughness Ra is according to the average surface roughness Ra of JIS B0601 standard along center line, extended to adapt to surface measurements three-dimensionally, therefore, just from the surperficial average absolute that departs from of reference to designated surface.The instrument that adopts is SPI3800N and the SPA400 that SII company produces.Employed probe is as follows:
Table 6
| Dark pin end diameter | Material | Jib-length | Spring constant | |
| AFM | ?10nm | Silicon nitride | 100μm | ?0.09N/m |
| DFM | ?10nm | Silicon | 100μm | ?20.0N/m |
Sweep frequency in the measurement is 1Hz, and the number that obtains data X/Y is 256/256.
Example 16:
By polycarbonate constitute have the micropore size be 0.4 μ m, porosity be 18% and average surface roughness be that the filtrator of 58.62nm is cut into and has diameter 13mm, and be placed to and obtain an assessment sample like this by on market, buying in the filter cylinder that obtains.
Example 17:
The micropore size with 0.4 μ m, the porosity that are made of polycarbonate are 15%, and average surface roughness is that the filtrator of 24.63nm is cut into and has diameter 13mm, and be placed in the filter cylinder that can obtain by purchase, obtain an assessment sample like this.
Example 18:
The micropore size that is made of polycarbonate is that 0.4 μ m, porosity are 15%, and average surface roughness is that the filtrator of 27.53nm is cut into and has diameter 13mm, and be placed in the filter cylinder that can obtain by purchase, obtain an assessment sample like this.
Example 19:
The plastic injector of the 10mL that can obtain by purchase is filled the 1.0g fibre diameter to be 1.8 μ m and to be compressed the dacron that obtains the 4mL volume, is placed to the downstream according to the filter sample of example 16, to obtain the assessment sample.
Example 20:
The plastic injector of the 10mL that can obtain by purchase is filled fibre diameter to be 1.8 μ m and to be compressed the 1.0g dacron that obtains the 4mL volume, is placed to the downstream according to the filter sample of example 17, to obtain the assessment sample.
Example 21:
The plastic injector of the 10mL that can obtain by purchase is filled fibre diameter to be 1.8 μ m and to be compressed the 1.0g dacron that obtains the 4mL volume, is placed to the downstream according to the filter sample of example 18, to obtain the assessment sample.
Comparative Examples 14:
The micropore size that constitutes by polycarbonate be 0.45 μ m, porosity be 70% and average surface roughness be that the filtrator of 147.70nm is cut into and has diameter 13mm, and be placed in the filter cylinder that can obtain by purchase, obtain an assessment sample like this.
Comparative Examples 15:
The plastic injector of the 10mL that can obtain by purchase is filled fibre diameter to be 1.8 μ m and to be compressed the 1.0g dacron that obtains the 4mL volume, is placed to the downstream according to the filter sample of Comparative Examples 14, to obtain the assessment sample.
Test case 7:
Use is according to example 16 each diffusion barrier to example 18 and Comparative Examples 14, and hematocrit is that the blood of 10% 500 μ L forms on each diffusion barrier, after this, filters under the pressure shown in table 7 and the table 8 below respectively.Blood plasma by such acquisition and same blood is carried out the blood plasma that centrifuging obtains compare is checked hemocytolysis.
Table 7
| Average surface roughness | The micropore size | Filter pressure | The separating plasma state | |
| Example 16 | ?58.62nm | ?0.4μm | ?60kPa | There is not hemocytolysis |
| Example 17 | ?24.63nm | ?0.4μm | ?60kPa | There is not hemocytolysis |
| Example 18 | ?27.53nm | ?0.4μm | ?60kPa | There is not hemocytolysis |
| Comparative Examples 14 | ?147.70nm | ?0.45μm | ?60kPa | Hemocytolysis is arranged |
Test case 8:
Use is according to example 19 each separator-filter to example 21 and Comparative Examples 15, and the 4mL blood that collects on one's body from a healthy volunteer forms at each separator-filter, after this, filters respectively under pressure as shown in table 8.Compare through the blood plasma that centrifuging obtains by the blood plasma of such acquisition with to same blood, check hemocytolysis.
Table 8
| Average surface roughness | The micropore size | Filter pressure | The blood separation state | The sample blood volume | Residual fiber albumen commercial weight * | |
| Example 19 | ?58.62nm | ?0.4μm | ?60kPa | There is not hemocytolysis | 0.52mL | Quantization limits amount or littler |
| Example 20 | ?24.63nm | ?0.4μm | ?60kPa | There is not hemocytolysis | 0.53mL | Quantization limits amount or littler |
| Example 21 | ?27.53nm | ?0.4μm | ?60kPa | There is not hemocytolysis | 0.52mL | Quantization limits amount or littler |
| Comparative Examples 15 | ?147.70nm | ?0.45μm | ?60kPa | There is not hemocytolysis | 0.52mL | Quantization limits amount or littler |
* fibrinogenic quantization limits amount: 10mg/dL
Example 22:
The filter sample of example 16 is installed to by on the plastic injector of buying available 10mL.Fibre diameter is that 1.0 μ m, porosity are that upstream side and the volume that dacron that 90.5% glass fibre and 1.0g fibre diameter are 1.8 μ m is placed on filter sample is compressed to 4mL, obtains to assess sample like this.
Example 23:
The filter sample of example 16 is installed to by on the plastic injector of buying available 10mL.Fibre diameter is that 0.6 μ m, porosity are that upstream side and the volume that dacron that 90.4% glass fibre and 1.0g fibre diameter are 1.8 μ m is placed on filter sample is compressed to 4mL, obtains to assess sample like this.
Example 24:
The filter sample of example 16 is installed to by on the plastic injector of buying available 10mL.0.2g fibre diameter is the volume that the fiber of 1.8 μ m is compressed to 0.4mL, the 1.0g fibre diameter is that upstream side and the volume that the dacron of 1.8 μ m is placed on filter sample is compressed to 4mL then, obtains to assess sample like this.
Table 9
| Average surface roughness | The micropore size | Filter pressure | The blood separation state | The sample blood volume | Residual fiber albumen commercial weight * | |
| Example 22 | ?58.62nm | ?0.4μm | ?60kPa | There is not hemocytolysis | ?0.74mL | Quantization limits amount or littler |
| Example 23 | ?58.63nm | ?0.4μm | ?60kPa | ?0.79mL | Quantization limits amount or littler | |
| Example 24 | ?58.64nm | ?0.4μm | ?60kPa | ?0.76mL | Quantization limits amount or littler |
* fibrinogenic quantization limits amount: 10mg/dL
Industrial applicibility
In blood plasma according to the present invention or serum separation membrane because the many through holes that are penetrated into opposite side from a side of film are provided, just can be smooth and safe from blood, isolate blood plasma or serum and do not cause erythrocytic hemocytolysis. Particularly, in addition when applied pressure be 60kPa or less the time, also can isolate safely blood plasma or serum and not cause erythrocytic breaking. Therefore, just can improve the efficient that blood plasma or serum separate.
Because filtrator according to the present invention has a filtration members, blood plasma is very fast by its movement velocity, this filtration members is installed in the previous stage of blood plasma or serum separation membrane constructed according to the invention, therefore, blood plasma soon preferentially from blood to blood plasma or serum separation membrane move, so further improved the efficient of separating. In addition, even work as and use when having the whole blood sample of high hematocrite value, because blood plasma moves by filtration members rapidly, so blood plasma also can be separated reliably fast.
In addition, owing to got rid of the needs of centrifugation, filtrator or blood plasma or the very fast acquisition sample of serum separation membrane that just can the application of the invention. Therefore, the present invention is in case of emergency particularly useful.
Claims (17)
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| JP335607/2002 | 2002-11-19 | ||
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| JP124335/2003 | 2003-04-28 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102803958A (en) * | 2009-06-17 | 2012-11-28 | 白血球保健股份有限公司 | Blood filter and method for filtering blood |
| CN103293049A (en) * | 2013-05-27 | 2013-09-11 | 苏州扬清芯片科技有限公司 | Serum separation method and serum separation device |
| CN104541166A (en) * | 2012-08-08 | 2015-04-22 | 皇家飞利浦有限公司 | Plasma separation using a drop of blood |
| CN104833626A (en) * | 2014-05-16 | 2015-08-12 | 麦君宇 | Method and apparatus for biomolecular analysis |
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-
2003
- 2003-11-18 CN CNB2003801036602A patent/CN100492006C/en not_active Expired - Lifetime
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