JP2007259995A - Plasma sampling kit, extracorporeal circulation circuit equipped with plasma sampling kit, and method for separating plasma component from blood - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a plasma sampling kit which separates plasma easily even with a plasma separating membrane having a small membrane area, improves plasma separation efficiency significantly compared to a conventional blood sampling method, and allows to start blood examination immediately. <P>SOLUTION: The plasma sampling kit (1) comprises a housing (2), a plasma separating membrane (3) arranged in almost middle or bottom of the housing, and a blood inlet port (4) and a blood outlet port (5) located below the plasma separating membrane (3). The inflow angle (θ) of the blood from the blood inlet port (4) to the housing (2) is set between about 0° and 90°. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention provides a plasma collection kit capable of reliably separating plasma components from blood even with a small membrane area,
The present invention relates to an extracorporeal circuit with a plasma collection kit and a method for separating plasma components from blood.

During hemodialysis, blood (whole blood) is collected from the extracorporeal circuit in order to confirm the status of hemodialysis (for example, whether harmful components in the target blood are steadily removed) A blood test is performed by separating plasma components from blood (whole blood).
As a means of blood collection, a syringe is connected to the blood collection port of the extracorporeal circuit to collect blood. However, in these blood collection means, blood is collected and then centrifuged to obtain plasma. Since blood and blood cell components must be separated, it takes time before blood tests.
Further, as in Patent Documents 1 to 3, a plasma separation membrane is disposed in the middle or lower part of an elongated cylindrical housing, and blood is allowed to pass from upstream to downstream of the plasma separation membrane to collect plasma components at the bottom of the housing. The invention to be described is described.
However, the invention of Patent Document 1 takes time to separate because blood is allowed to flow naturally from the upstream of the plasma separation membrane.
Further, the inventions of Patent Documents 2 and 3 are vacuum blood collection tubes, and the blood must be introduced into the vacuum blood collection tube by inserting a syringe from which blood is collected in advance or a needle (of a blood collection device) punctured into the patient into the lid. I must.

Japanese Patent Laid-Open No. 11-194126 JP 2001-321366 A JP 2001-321366 A

  The problem to be solved by the present invention is that the means for collecting blood by connecting a syringe to the blood collection port of the extracorporeal circuit must collect the blood and then separate the plasma components after collecting the blood. Since it does not become necessary, it takes time and time to blood test. The invention of Patent Document 1 takes time to separate blood, and the inventions of Patent Documents 2 and 3 use a syringe that collects blood in advance or a needle that punctures a patient (of a blood collection device). Therefore, it must be introduced into the vacuum blood collection tube.

Therefore, as a result of intensive studies to solve the above problems, the present inventors have reached the following invention.
[1] In the present invention, a plasma separation membrane (3, 13) is disposed in a substantially middle or substantially lower part of the housing (2, 12), and a blood inlet (<13>) is provided below the plasma separation membrane (3, 13). 4, 14) and a plasma collection kit (1, 11) provided with blood outlets (5, 15).
[2] The plasma according to [1], wherein the angle (θ) at which blood flows from the blood inlet (4, 14) into the housing (2, 12) is formed from approximately 0 ° to approximately 90 °. A collection kit (1, 11) is provided.
[3] The present invention provides the plasma collection kit (1, 11) according to [1] or [2], wherein a hydrophobic gas-permeable membrane (7, 17) is attached to the housing (2, 12).
[4] The present invention provides the plasma collection kit (1, 11) according to any one of [1] to [3], wherein the plasma collection port (8, 18) is attached to the housing (2, 12). To do.
[5] In the present invention, any one of [1] to [4], in which connectors (62, 62) are attached to the blood inlet 4 and blood outlet 5 via connecting tubes (61, 61), respectively. A plasma collection kit (1) is provided.
[6] In the present invention, a tubular member (12B) is attached to the lower portion of the housing (12), a partition wall (12C) is disposed inside the tubular member (12B), and blood is applied to the tubular member (12B). There is provided a plasma collection kit (11) according to any one of [1] to [4], wherein an inlet (14) and a blood outlet (15) are formed.
[7] The present invention provides an extracorporeal circuit (60, 80) equipped with the plasma collection kit (1, 11) according to any one of [1] to [6].
[8] In the present invention, blood circulating in the extracorporeal circuit (60, 80) is passed through the hydrophobic air-permeable membrane (7, 17) to the housing (2, 12) in an open state to the blood flow. Plasma components are collected in the plasma collection space (6, 16) of the main body (2, 12) while being introduced from the inlet (4, 14) and brought into contact with the surface of the plasma separation membrane (3, 13) [1]. To [6], the method for separating plasma components from blood using the plasma collection kit (1, 11) according to any one of the above.

In the present invention, (1) the plasma separation membranes 3 and 13 are disposed below the housings 2 and 12, and the blood inlets 4 and 14 and the blood outlets 5 and 15 are disposed below the plasma separation membranes 3 and 13. Using the blood plasma collection kits 1 and 11, blood circulating in the extracorporeal circulation circuits 60 and 80 is introduced into the housings 2 and 12 in an open state from the blood inlets 4 and 14, and the plasma separation membranes 3 and 13 are introduced. Since the surface of the plasma separation membranes 3 and 13 always flows and the resistance of the membrane is small, plasma separation is easy even with the plasma separation membranes 3 and 13 having a small membrane area.
(2) Since the plasma component can be separated in a short time while circulating blood extracorporeally and the amount required for blood test can be collected, the separation efficiency of plasma is much better than conventional blood sampling means, and blood test can be performed immediately You can start.
(3) A tubular member 12B having a blood inlet 14 and a blood outlet 15 formed therein is provided at the lower part of the housing 12 with a partition wall 12C disposed therein. Body).

1, 2 and 3 are schematic views of the plasma collection kit of the present invention, and FIG. 4 is a schematic view of an extracorporeal circuit 80 incorporating the plasma collection kit 1 of the present invention.
[Plasma collection kits 1 and 11]
As illustrated in FIGS. 1 and 2, the plasma collection kits 1 and 11 of the present invention have plasma separation membranes 3 and 13 disposed substantially in the middle or lower part of the cylindrical housings 2 and 12, respectively. Below the membranes 3 and 13, blood inlets 4 and 14 and blood outlets 5 and 15 are arranged.
[Plasma separation membranes 3, 13]
The plasma separation membranes 3 and 13 may be any known membrane (flat membrane) that can separate plasma.
The plasma separation membrane 3 is attached to the housings 2 and 12 by a known means.
For example, the apparatus (fixed) may be directly attached to the inner wall surfaces of the housings 2 and 12 by thermal welding or the like, or as shown in FIG. The fixed frame 2A may be mounted on the lower portion of the housing 2.

[Blood inlets 4, 14 and blood outlets 5, 15]
The angle θ of the blood inlets 4 and 14 (the angle θ at which blood flows from the blood inlets 4 and 14 to the housings 2 and 12) is substantially 0 ° in the illustration of FIG. Also, as illustrated in FIG.
“An angle θ of the blood inlets 4 and 14” means an angle at which the horizontal line L of the plasma separation membrane 3 and an extension line of the center line C of the blood inlet 4 intersect as illustrated in FIG.
In the illustration of FIG. 1, since the center line C of the horizontal line L is substantially parallel, the angle θ is approximately 0 °, but when the blood inlet 4 is arranged so that the center line C is inclined to the upper left, An extension line of the horizontal line L and the center line C intersects, and the angle θ approaches approximately 90 ° as the intersection angle increases. In addition, since it exceeds about 90 degrees and less than 180 degrees is symmetrical with about 90 degrees to about 0 degrees, it is interpreted as being included in about 0 degrees to about 90 degrees.
When the angle θ is close to approximately 0 ° as illustrated in FIG. 1, the area where the blood contacts the surface of the plasma separation membrane 3 is increased, and the membrane resistance is small, so that the separation efficiency is improved.
In the present invention, it may be in the range of approximately 0 ° to approximately 90 °.
The arrangement of the blood outlets 5 and 15 may be parallel to the length direction of the housing 2 as illustrated in FIG. 1, or the length of the housings 2 and 12 as illustrated in FIGS. You may arrange | position so that it may become substantially 90 degrees with a horizontal direction.
The blood inlets 4 and 14 and the blood outlets 5 and 15 are attached to the housings 2 and 12 by known means.
For example, as illustrated in FIG. 1, the blood inlet 4 and the blood outlet 5 are formed in a lid portion 2B formed as a separate part from the housing 2, and the lid portion 2B is formed on the lower portion of the housing 2 or the fixed frame 2A. It may be attached to the lower part.
Further, as illustrated in FIG. 2, a tubular member 12B is attached to the lower portion of the housing 12 by separate parts or integral molding, and a partition wall 12C is disposed inside the tubular member 12B, so that a blood inlet is provided in the tubular member 12B. 14 and blood outlet 15 may be formed.
The plasma collection kit 11 illustrated in FIG. 2 can attach the tubular member 12B to the port (slit plug) of the extracorporeal circuit with one touch.

[Hydrophobic ventilation membranes 7, 17]
As illustrated in FIGS. 1 and 2, hydrophobic gas permeable membranes 7 and 17 are attached to the housings 2 and 12. Thereby, the plasma collected in the housings 2 and 12 at the time of blood collection (at the time of plasma collection) can be prevented from directly touching the outside air.
The hydrophobic gas permeable membranes 7 and 17 can be anything as long as the plasma collection spaces 6 and 16 of the housings 2 and 12 can be vented to the outside and do not permeate external germs or the like or are formed of a sterilizing material. good.
As shown in FIGS. 1 and 2, the top surfaces of the housings 2 and 12 are preferable as the attachment positions of the hydrophobic gas permeable membranes 7 and 17 to the housings 2 and 12, but may be the side portions of the housings 2 and 12.
It is preferable that the hydrophobic gas permeable membranes 7 and 17 can be sealed (sealed) to the housings 2 and 12 when a necessary amount of plasma is secured in the housings 2 and 12. For example, as in the case of the plasma separation membrane 3, it may be mounted (fixed) on a lid formed as a separate part from the housing 2, and the lid may be mounted on the top of the housing 2. The lid and the upper part of the housing 2 may be structured to be screwed together so that they can be loosened (when collecting plasma) or sealed (sealed) (when collecting plasma).
[Collection port 8, 18]
As illustrated in FIGS. 1 and 2, the collection ports 8 and 18 may be attached so that the plasma collected in the housings 2 and 12 can be collected with a syringe or the like. The collection ports 8 and 18 may be either female connectors or male connectors, for example. As illustrated in FIGS. 1 and 2, the positions of the collection ports 8 and 18 to be attached to the housings 2 and 12 are preferably the side portions of the housings 2 and 12. As long as it is a side portion, it may be anywhere between substantially upper and lower portions of the housings 2 and 12.

As illustrated in FIG. 3, the plasma collection kit 1 of FIG. 1 is connected to the blood inlet 4 and the blood outlet 5 so that they can be attached to a port 15 disposed in the middle of the extracorporeal circuit 60. Connectors (also called adapters) 62 and 162 can be attached via 61 and 61.
As shown in FIG. 3, the connector (also referred to as an adapter) 62 may have any shape and structure as long as it has at least the inlet 63 and the engaging portion 64 of the port 65.
The port 65 may have any shape and structure as long as it has at least a plug having a slit into which the inlet 63 can be inserted and a portion (cap 66 or the like) that can engage the connector 62.
In the extracorporeal circuit 60 to which the plasma collection kit 1 of FIG. 1 is attached, at least two ports 65 may be arranged in the middle of the venous circuit or the arterial circuit. More preferably, a clamp 67 capable of blocking and opening the blood flow path may be disposed between the two ports 65 and 65 as necessary.
The plasma collection kit 11 illustrated in FIG. 2 can attach the tubular member 12B to the port (plug with slit) of the extracorporeal circulation circuit with one touch, so that the extracorporeal circulation circuit 60 to which this is attached has at least one port 65 disposed therein. It only has to be done.
[Method for separating plasma components from blood]
The plasma collection kits 1 and 11 of the present invention can separate plasma components from blood as follows. The blood circulating in the extracorporeal circuit 61 is introduced into the housings 2 and 12 in an open state from the blood inlets 4 and 14 and brought into contact with the surfaces of the plasma separation membranes 3 and 13 while the plasma components are accommodated in the housing. Two or twelve plasma collection spaces 6 and 16 can be collected.
That is, the plasma collection kit 1 introduces blood circulating in the extracorporeal circulation circuit at an angle of approximately 0 ° from the blood inlet 4 on the lower side of the housing 2 in the open state. Since blood always contacts the surface of the plasma separation membrane 3 in a fluidized state due to its fluid pressure, the internal pressure of the extracorporeal circuit, etc., plasma components can be collected in the plasma collection space 6 of the housing 2.
The blood plasma collection kit 11 introduces blood circulating in the extracorporeal circulation circuit into the housing 12 in an open air state at an angle of approximately 0 ° from the blood inlet 14 on the lower side. Since blood always contacts the surface of the plasma separation membrane 13 in a fluidized state due to its fluid pressure, the internal pressure of the extracorporeal circuit, etc., plasma components can be collected in the plasma collection space 16 of the housing 12.

Examples and comparative examples in which plasma is collected using an extracorporeal circuit 80 incorporating the plasma collection kit 1 of the present invention using bovine blood will be described.
[Plasma collection kit 1]
The cylindrical housing 2 was made with a commercially available disposable syringe. The lid 2B with the blood inlet 4 and the blood outlet 5 used components of a blood circuit manufactured by Kawasumi Chemical. The plasma separation membrane 3 used was fixed to the fixed frame 2A.
A plasma collecting kit 1 shown in FIG. 1 was prepared by attaching the fixed frame 2A to the lower part of the housing 2 and attaching the lid 2B to the lower part of the fixed frame 2A.
The plasma separation membrane 3 is a polysulfone membrane (BTS-SP300) manufactured by Nippon Pole Co., Ltd. (hydrophilic treatment).
GF; pore size 2.2 μm, film thickness 330 μm, membrane area approximately 6 cm ² ) was used.
[External circulation circuit]
As shown in FIG. 4, the extracorporeal circuit 80 connects the arterial circuit 82 and the venous circuit 83 of the blood circuit “Kami Line” manufactured by Kawasumi Chemical Co., and the plasma collection kit 1 of FIG. I made it.
The extracorporeal circuit 80 is arranged from the upstream side to the downstream side with a pump tube 86 (attached to the blood pump 87), a plasma collection kit 1, a venous chamber 84 (connected to the manometer 85), a pinch cock 90, and an arterial circuit 82. And the downstream side of the venous circuit 83 were connected to a container 38 containing bovine blood (immersed in a thermostatic chamber 89).
[Method of preparing bovine blood]
As an anticoagulant for collecting bovine blood, 150 mL of ACD-A solution was added per liter of bovine blood. The hematocrit value of bovine blood was measured, and physiological saline was added to adjust the hematocrit value to 30%.
[Bovine blood circulation test]
(Example: Plasma collection in an open atmosphere)
In the extracorporeal circuit 80 of FIG. 4, 1 L of bovine blood was circulated at a flow rate of 200 mL / min. The downstream side of the venous chamber 84 was squeezed with a pinch cock 90 to adjust the pressure to about 50 mmHg. The housing 2 was opened to the atmosphere, and the appearance of plasma exuding through the plasma separation membrane 3 was observed.
(Comparative Example 1: Plasma collection by syringe operation)
With the pusher (not shown) (used for the syringe) attached to the housing 2 of the extracorporeal circuit 80 in FIG. 4, blood is circulated in the same manner as in the embodiment, and the pusher is pulled, thereby separating plasma. I checked if it was possible.
(Comparative Example 2: Plasma collection by pressure only; no blood circulation)
The upstream side of the housing 2 and the downstream side of the venous chamber 84 of the extracorporeal circuit 80 in FIG. 4 are clamped with metal forceps (not shown), and air is introduced into the venous chamber 84 with a syringe (not shown). Then, it was confirmed whether plasma could be separated by applying pressure and leaving it as it was.

（比較例１：シリンジ操作による血漿採取）
シリンジの押し子を引っ張っても、血漿は分離できず、最終的には血漿分離膜３が破れてしまった。
（比較例２：圧力のみによる血漿採取；血液循環なし）
約50mmHgの圧力をかけて30分間放置したが、血漿分離膜３が若干濡れた程度の血漿しか得られなかった。70mmHg、100mmHgと圧力を高くしていったが、充分な血漿は得られず、100mmHg付近で試験部品の血漿分離膜の接合部からリークしてしまった。
［考察］
（実施例：大気開放状態での血漿採取）は、10分間で約3mLの血漿が得られ、循環を継続しても血漿分離膜の目詰まりは特に観察されなかった。
（比較例１：シリンジ操作による血漿採取）や（比較例２：圧力のみによる血漿採取；血液循環なし）では、得られた血漿量は1mL未満であった。本実施例、比較例１、２に使用した血漿分離膜３は膜面積が約6cm²と小さいので、充分量の血漿が分離できなかったと考えられる。（実施例：大気開放状態での血漿採取）は、血液ポンプ１６の拍動による影響や、血漿分離膜３の表面が常に流動しており境膜抵抗が小さいため、膜面積が約6cm²の血漿分離膜３でも血漿分離が可能になったと考えられる。 [Test results]
(Example: Plasma collection in an open atmosphere)
From the start of circulation, it was observed that plasma gradually began to flow through the plasma separation membrane 3. The separated plasma volume is shown in Table 1 below, and about 3 mL of plasma was separated in 10 minutes.

(Comparative Example 1: Plasma collection by syringe operation)
Even when the pusher of the syringe was pulled, the plasma could not be separated, and eventually the plasma separation membrane 3 was broken.
(Comparative Example 2: Plasma collection by pressure only; no blood circulation)
Although it was allowed to stand for 30 minutes under a pressure of about 50 mmHg, only plasma with a degree of wetness of the plasma separation membrane 3 was obtained. Although the pressure was increased to 70 mmHg and 100 mmHg, sufficient plasma was not obtained, and leaked from the junction of the plasma separation membrane of the test part around 100 mmHg.
[Discussion]
(Example: Plasma collection in an open atmosphere), about 3 mL of plasma was obtained in 10 minutes, and clogging of the plasma separation membrane was not particularly observed even when circulation was continued.
In (Comparative Example 1: Plasma collection by syringe operation) and (Comparative Example 2: Plasma collection by pressure only; no blood circulation), the amount of plasma obtained was less than 1 mL. Since the plasma separation membrane 3 used in this Example and Comparative Examples 1 and 2 has a membrane area as small as about 6 cm ² , it is considered that a sufficient amount of plasma could not be separated. (Example: Plasma collection in the open air state) is the effect of the pulsation of the blood pump 16 and the surface of the plasma separation membrane 3 is always flowing and the membrane resistance is small, so the membrane area is about 6 cm ² It is considered that the plasma separation membrane 3 also enabled plasma separation.

Schematic of the plasma collection kit of the present invention Schematic of the plasma collection kit of the present invention Schematic of the plasma collection kit of the present invention Schematic of extracorporeal circuit with plasma collection kit

Explanation of symbols

DESCRIPTION OF SYMBOLS 1,11 Plasma collection kit 2,12 Housing 2A Fixed frame 2B Cover part 3,13 Plasma separation membrane 4,14 Blood inlet 5,15 Blood outlet 6,16 Plasma collection space 7,17 Hydrophobic ventilation membrane 12B Tubular member 12C 8, 18 Collection port 60, 80 Extracorporeal circuit 61 Connection tube 62 Connector 63 Inlet 64 Engagement part 65 Port 66 Cap 67 Clamp 82 Arterial circuit 83 Venous circuit 84 Venous chamber 85 Manometer 86 Pump tube 87 Blood pump 88 Cattle blood container 89 thermostatic chamber 90 pinch cock

Claims (8)

  A plasma separation membrane (3, 13) is disposed substantially at the middle or lower part of the housing (2, 12), and a blood inlet (4, 14) and a blood flow are disposed below the plasma separation membrane (3, 13). Plasma collection kit (1, 11), characterized in that outlets (5, 15) are arranged.   The plasma collection kit according to claim 1, wherein an angle (θ) at which blood flows from the blood inlet (4, 14) into the housing (2, 12) is formed from approximately 0 ° to approximately 90 °. (1, 11).   The plasma collection kit (1, 11) according to claim 1 or 2, wherein a hydrophobic gas-permeable membrane (7, 17) is attached to the housing (2, 12).   The plasma collection kit (1, 11) according to any one of claims 1 to 3, wherein a plasma collection port (8, 18) is mounted on the housing (2, 12). .   The connector (62, 62) is attached to the blood inlet 4 and the blood outlet 5 via connection tubes (61, 61), respectively. Plasma collection kit (1) according to claim.   A tubular member (12B) is attached to the lower part of the housing (12), a partition wall (12C) is disposed inside the tubular member (12B), and a blood inlet (14) and blood are placed in the tubular member (12B). The plasma collection kit (11) according to any one of claims 1 to 4, wherein an outflow port (15) is formed.   An extracorporeal circuit (60, 80) equipped with the plasma collection kit (1, 11) according to any one of claims 1 to 6.   The blood circulating in the extracorporeal circuit (60, 80) is passed through the hydrophobic air-permeable membrane (7, 17) to the housing (2, 12) opened to the atmosphere from the blood inlet (4, 14). The plasma component is collected in the plasma collection space (6, 16) of the main body (2, 12) while being introduced and brought into contact with the surface of the plasma separation membrane (3, 13). A method for separating plasma components from blood using the plasma collection kit (1, 11) according to any one of claims 6.

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