JPH01265971A - Blood purification device - Google Patents

Abstract

PURPOSE:To make it possible to adsorb and remove a cause substance from the blood highly efficiently by leading the blood to a mixer through a plasma separator and a plasma purifier, and mixing it with a concentrated blood. CONSTITUTION:The blood removed from a human body or from a blood container is led in to a plasma separator 4 from a blood leading-in port 1, and separated into a concentrated blood component and a plasma component. The separated plasma is led in to a plasma purifier 7 through a plasma separation circuit, and adsorbed and processed by an adsorption material stored in the purifier 7. The purified plasma processed in the plasma purifier 7 is mixed again with the concentrated blood from the plasma separator 4 in a mixer, and after that, returned to the human body or the blood container.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a blood purification device that adsorbs and separates pathogenic substances from blood with high selectivity.

[Prior Art] In recent years, plasma exchange therapy has been used as a treatment for diseases in which a specific component in a body fluid causes severe symptoms. This therapy is particularly effective in cases where dialysis of the pathogenic substance is difficult, including autoimmune diseases such as myasthenia gravis, rheumatoid arthritis, and erythema
It is indicated for immune-related diseases such as glomerulonephritis, bronchial asthma, and polyneuritis, rejection reactions associated with organ transplants, liver failure, hypertension, and cancer diseases.

However, because this plasma exchange therapy indiscriminately removes all plasma components, immunoglobulins, which are pathogenic substances,
There is a problem in that not only fibrinogen, immune complexes, etc. are removed, but also albumin and other useful components are lost. Lack of plasma and plasma preparations as replacement fluid in Kada;
Many problems have been pointed out, including serum hepatitis, AIDS, co-occurrence of allergic diseases, and side effects. For this reason, research is underway into a self-plasma purification method that selectively removes large molecular weight proteins such as immunoglobulin, fibrinogen, and immune complexes, which are pathogenic substances, and returns self-purified plasma containing albumin and other useful components to the patient. It has been implemented and is being implemented again.

Conventionally, adsorbents used in such self-plasma purification methods include porous resins (for example, Amberlite X A D, which is a styrene divinylbenzene copolymer)
-4 [Amberlite
, inorganic porous materials (for example, porous glass, ceramics, etc.), and affinity adsorbents are known. However, conventionally used porous resins and ion exchangers not only have low adsorption capacity but also have low adsorption specificity, so they adsorb albumin, etc. in body fluids, so they not only have insufficient therapeutic effects (but are also safe). In addition, although inorganic porous materials have relatively good adsorption capacity and properties, they are still insufficient for practical use.Furthermore, affinity adsorbents have excellent adsorption capacity and properties. However, biological affinity adsorbents that utilize biological interactions have been shown to be promising as adsorbents for purifying body fluids. Because the raw materials are expensive and difficult to obtain, the stability of the ligand is poor, and side effects may occur due to the inherent physiological effects of the ligand, or side effects due to antigenicity if the ligand is eluted. There was a risk of the occurrence of

In order to solve these drawbacks, the present inventors have conducted extensive research and have found that an adsorbent consisting of an insoluble carrier bound to a heterocyclic compound, a dipeptide, or a derivative thereof is filled into a container having a fluid inlet/outlet. discovered that an adsorption device consisting of No. 61-45773, Japanese Patent Application Publication No. 62-536
No. 69).

However, in order to efficiently remove pathogenic substances from blood, when blood is directly flowed into an adsorption device that is densely packed with insoluble carriers, pressure loss occurs due to adhesion of blood cell components, etc. This resulted in an increase in blood flow rate and blockage of the blood flow path, making it impossible to efficiently remove the pathogenic substance.

Therefore, the present inventors have discovered that by separating blood with a plasma separator and then purifying the separated plasma with an adsorption device, pathogenic substances can be efficiently removed without damaging blood cell components.

Conventionally, devices using centrifugation and devices using porous filtration membranes have been known as plasma separation devices that can be used for the above purpose. Devices using centrifugation have drawbacks in that they cannot completely prevent blood cell components from entering the plasma flow path, are expensive, and are complicated to connect with other devices. On the other hand, as devices using porous filtration membranes, a hollow fiber type and a Hei 11M type are known. The flat membrane type, which uses a flat plate-shaped filtration membrane, has a wider selection range of membranes than the hollow fiber type, which uses a hollow fiber filtration membrane, and has high stability in membrane performance (and the shape of the filtration module Since a wide range of plasma separation devices can be selected, it is expected that a compact and high-performance plasma separation device will be realized.

However, in the case of the flat membrane type, the thin layer flow path for blood, which is the most important part of the filtration module structure, is provided in contact with the filtration membrane in a highly uniform and stable state, while also achieving miniaturization of the device. It was considered difficult to achieve this goal. As a method to solve this problem, a blood flow path regulating plate with an uneven surface is provided on one side of the filtration membrane to form a blood flow path with an extremely precise thickness and achieve good plasma separation performance. proposals have been made. (Unexamined Japanese Patent Publication No. 5
No. 7-25857) [Problems to be Solved by the Invention] By using such a small and high-performance plasma separator, the plasma separated by the plasma separator can be purified with high efficiency by the adsorption device, Extracorporeal circulation Tiff
1 (It is expected that a blood purification device with less burden on patients will be realized, but even blood purification devices using the plasma separation device proposed above do not yet have sufficient performance. There was a desire to develop a more compact and high-performance purification device.

The present invention has been made in view of the above circumstances, and its purpose is to provide a small and high-performance blood purification device that can highly efficiently adsorb and remove pathogenic substances from blood and place less physical burden on patients. It is in.

[Means for Solving the Problems] The blood purification device of the present invention that solves the above conventional problems has the following features:
A blood purification device having a blood inlet and a blood outlet, the blood introduced from the blood inlet being purified and drawn out from the blood outlet, wherein the blood introduced from the blood inlet is converted into 1111 condensed blood. a plasma separator that separates the blood into plasma; a plasma purifier that purifies the plasma separated by the plasma separator; a mixer that mixes the concentrated blood and the plasma purified by the plasma purifier; a blood circulation circuit that leads the blood from the blood inlet through the plasma separator and the mixer to the blood outlet;

The present invention is characterized in that it includes a plasma separation circuit that causes the plasma separated in the plasma separator to flow into the mixer via the plasma purifier.

[Function] With the above configuration, in the blood purification device of the present invention, blood removed from a human body or a blood container is introduced into the device from the blood inlet, and then separated from the blood inlet of the plasma separator. The blood is introduced into the vessel and separated into concentrated blood components and plasma components. Plasma flowing out from the plasma outlet of the plasma separator is introduced into the plasma purifier through a plasma separation circuit, and is adsorbed by an adsorbent contained in the purifier. The purified plasma processed in the plasma purifier is mixed again with concentrated blood drawn out from the blood outlet of the plasma separator in the mixer, and then returned to the human body or the blood container through the blood outlet.

[Example] Hereinafter, the present invention will be described in detail with reference to the drawings.

FIG. 1 shows the overall configuration of a blood purification device according to an embodiment of the present invention. In FIG. 1, l is a blood introduction port through which blood is introduced from the human body or a blood container;
The blood introduced from the blood pump 2 and the chamber 3 are sent to the blood inlet 4a of the plasma separator 4. The concentrated blood after filtration is allowed to flow out from the blood outflow port 4b, and the separated plasma component is also allowed to flow out from the plasma outflow port 4c. Plasma components flowing out from the plasma outlet 4C are sent to a plasma purifier 7 via a plasma pump 5 and a chamber 6. This plasma purifier 7 purifies the plasma introduced from the plasma introducing lower a and causes the purified plasma to be discharged from the plasma deriving lower b. The purified plasma drawn out from the plasma outflow lower b is adapted to flow into one inlet of the mixer 8. The other inlet of this mixer 8 has a blood outlet 4b of the plasma separator 4.
Concentrated blood flowing out from the tube is allowed to flow in,
The mixer 8 mixes the inflowing concentrated blood and purified plasma components and sends the mixture to the blood outlet 10.

A constant temperature bath 9 is provided upstream of the blood outlet lO, and this constant temperature bath 9 keeps the circulating blood at a constant temperature. Note that the blood introduction port 1. A blood circulation circuit consisting of a chamber 3, a plasma separator 4, a mixer 8, a constant temperature bath 9, and a blood outlet lO is driven by a blood pump 2, and
A plasma distribution circuit including a plasma separator 4, a chamber 6, a plasma purifier 7, and a mixer 8 is driven by a plasma pump 5, respectively. In addition, plasma pump 5
If the driving force of the plasma pump 5 becomes too strong, the suction force from the plasma separator 4 to the plasma outlet 4c will become strong, which will destroy blood cells and cause hemolysis. It must be controlled so that it is smaller than the force.

In the blood purification device configured as described above, blood removed from the human body or blood container is introduced into the circuit from the blood inlet 1, passes through the blood pump 2, chamber 3, and plasma separator 4.
The blood is introduced into the blood inlet 4a and separated into concentrated blood components containing blood cells and plasma components. Plasma flowing out from the plasma outlet 4c of the plasma separator 4 passes through the plasma pump 5 and chamber 6, is introduced into the plasma purifier 7 from the plasma introduction lower a, and is adsorbed by the adsorbent in the purifier 7. After that, the plasma is discharged from the plasma outlet lower b. The purified plasma processed in the plasma purifier 7 is mixed again with the concentrated blood components flowing out from the blood outlet 4b of the plasma separator 4 in the mixer 8, and then passes through a constant temperature bath 9 and is sent through the blood outlet IO. returned to the human body or blood container.

FIG. 2 is an exploded perspective view showing the specific structure of the plasma separator 4. As shown in FIG. The plasma separator 4 is constructed by inserting a pusher 12 through an O-ring 13 into a cylindrical body 11 having a blood inlet 4a, a blood outlet 4b, and a plasma outlet 4c. A filtration membrane 17 with a shaped part, a flat flow path regulating body 20, and a plasma flow path forming body 16 for securing a flow path for plasma are housed together.

That is, a circular plasma flow channel forming body 16 made of a screen mesh or nonwoven fabric with an opening 14 in the center and plasma passage holes 15 near the periphery is sandwiched between circular filters 11117 with protrusions at the top and bottom, respectively. , sealing its periphery and the periphery of the central opening to form a membrane unit 18;
This membrane unit 18 is provided with a central opening 14 and a plasma passage hole 15 corresponding to the unit 18, and the plasma passage hole 1
Flat flow path regulators 20 with sealing material 19 pasted on the outer periphery of the membrane units 1 and 5 are alternately arranged.
8 and the flow path regulating body 20 are integrally joined. Membrane unit 18 consisting of these filtration 11117 and plasma flow path forming body 16. The plasma separator 4 is assembled by stacking a plurality of flow path regulators 20 one on top of the other. FIG. 3 is a sectional view showing the assembled state.

In the plasma separator 4, the blood flowing in from the blood inlet 4a is filtered while passing through the blood flow path formed between the filtration membrane 17 and the flow path regulator 20 shown in FIG. It is filtered by membrane 17.

Each protrusion 17a of the filtration 11117 supports the filtration membrane 17 and prevents deformation by the flow path regulating body 20 provided on the upper part thereof, and secures a blood flow path in the gap between the protrusions 17a. It is something to do.

The protrusions 17a have a height H of 20 to 200 μm, a bottom diameter R of 100 to 100 μm, an interval between the apexes of the protrusions 17a of 300 to 2000 μm, and an area occupied by the protrusions 17a relative to the entire film surface. It is preferable that the height H is 50 to 1100u, and the bottom diameter R is more preferably
is 200 to 500 μm, and the interval between the peaks of the protrusions 17a is 5
00 to 1000 μm, and the area occupied by the protrusion 17a to the entire membrane surface is preferably 5 to 15%, and the flow path regulator 20 is made of a hard material with a Brinell hardness of 10 or more, and the thickness T is 10 ~200μm further 20-50μm
The reason why it is preferable is as follows.

That is, as a result of intensive research into the structure of a new compact and high-performance flat membrane type plasma separation device, the present inventor first eliminated the conventional blood flow path regulating plate with protrusions and instead created a structure with protrusions on the surface of the filtration membrane. We have discovered that by forming shaped parts, we can achieve miniaturization of the module. Furthermore, as a result of researching the structure of a blood filtration device using this filtration membrane, we found that a hard flow path regulator was installed on the top of the filtration membrane with the protrusions, and the shape of the protrusions was set as described above. We have discovered that this enables the formation of a highly uniform and stable thin-layer blood flow path, resulting in high blood filtration performance.

The height of each protrusion 17a on the surface of the filter membrane 17a is an important factor that defines the thickness of the blood flow path. From the viewpoint of filtration engineering, if the height of the protrusion 17a is less than 20 μm,
If the blood flow channel thickness becomes too thin, high pressure loss will occur, and if it exceeds 200 μm, the shear rate cannot be increased and sufficient blood filtration cannot be obtained.

From the above, the height of the protrusion 17a is 20 to 200 um.
The height is preferably constant, but is not necessarily limited, and the height may vary stepwise along the blood flow direction.

It has also been found that the distance between the individual protrusions 17a is one of the most important factors for forming a uniform and stable blood flow path. That is, the interval between the protrusions 17a is 300 μm.
If it is less than 2,000 μm, it will cause a decrease in the effective membrane area and an excessive increase in pressure loss, while if it exceeds 2,000 μm, the membrane will become slightly distorted and sag, making it difficult to ensure a uniform and stable blood flow path. Therefore, the interval between the protrusions 17a is preferably 300 to 2000 μm, particularly preferably 500 to 1000 μm.
The distribution state of 7a is desirably uniform over the entire surface of the filtration pJJ l 7a, but is not particularly limited as long as it does not disturb uniform blood flow.

If the bottom diameter of the protrusion 17a is less than 100 μm, it is difficult to support and form a uniform blood flow path;
If the area exceeds 10, the occupied area becomes too large.
0 to 1000 μm is preferable, especially 200 to 500 μm
is preferred.

Furthermore, if the area occupied by the protrusion 17a is less than 3%, it is difficult to support and form a uniform blood flow path, and if it exceeds 20%, it is necessary to increase the size of the device in order to obtain a sufficient effective filtration area. It is preferably 3 to 20%, particularly preferably 5 to 15%.

The height H1, the bottom diameter R1, and the distance between the apexes of the protrusion 17a were determined by projecting a section of the filtration 1i17 enlarged 100 times using a projector, and the area occupied by the protrusion 17a was determined from each measured value.

As a method for manufacturing the above-mentioned filtration membrane 17, ilJ! A method in which a filtration membrane is formed on a metal roll on which a protrusion pattern is carved as an intaglio at the time of membrane formation, and protrusions made of the same material as the filtration membrane is formed on the membrane surface, and a protrusion pattern. A method of applying resin to the recesses of a metal roll carved as an intaglio plate and transferring it onto a smooth filtration membrane, or using a screen printing plate and ultraviolet or electron beam curing resin to create a smooth filtration film. Print a protrusion pattern on the membrane,
Examples include, but are not limited to, a method of curing the material by subsequently irradiating it with ultraviolet rays or electron beams.

The rffi path regulator 20 is preferably made of a hard material in order to form a highly uniform and stable thin-layer blood flow path. Materials with Brinell hardness in this range include polyethylene, polypropylene, polyester, polycarbonate, etc., and refer to materials that do not cause deformation such as dents when they come into contact, and have a Brinell hardness of 10 or more. It will be done.

Here, the Brinell hardness is determined by the following equation according to JIS Z2243.

WaπDh Hl: Brinell hardness (kg/mm2) P: Weight of steel ball <kg) D: Diameter of ball (mm) d: Diameter of depression (mm) h: Depth of depression (mm) If the thickness of the flow path regulator 20 is less than 10 μm, it will be difficult to support and form a uniform blood flow path, and if it exceeds 200 μm, the device will need to be larger.
The thickness is preferably 10 to 200 μm, particularly preferably 20 to 50 μm.

In addition, in order to form a highly uniform and stable thin-layer blood flow path in the plasma separator 4, another necessary condition is that the membrane unit is free from distortion and wrinkles and maintains sufficient flatness. It turned out that it had to be. Specifically, the material of the filtration 11117 is polyolefin, such as polypropylene or polyethylene, which has excellent compatibility with blood, and when filtration membranes made of these materials are bonded together to form a membrane unit, the heat seal method is not used. , Is the filtration membrane material resin in the seal part almost completely? 8. Due to the fusion process, the dimensions of the seal part shrink, resulting in loss of flatness of the membrane unit and insufficient filtration performance.In contrast, in the ultrasonic welding method, the contact surface between the filtration membranes is Sufficient sealing strength can be obtained by melting only the vicinity, and the flatness of the membrane unit is also sufficiently maintained, resulting in excellent filtration performance.

FIG. 5 is a sectional view showing the plasma purifier 7 in a cross-sectional view. The single plasma purifier 7 collects particles in a cylindrical container 21 comprising a plasma introduction lower a and a plasma outlet lower b. The cylindrical container 21 is filled with an adsorbent 22, which is held in the cylindrical container 21 by filters 23 and 24 provided near the plasma introduction lower a and the plasma removal lower b.

The material constituting the cylindrical container 21 in this plasma purifier 7 can be synthetic resins such as polypropylene, polycarbonate, polystyrene, polymethyl methacrylate, glass, metals such as stainless steel, etc., but polypropylene, which can be autoclaved and is easy to handle, is used. The plasma purifier 7 is provided with a filter having a mesh that allows plasma components to pass through but not the adsorbent. It is preferable that
The material constituting this filter may be any physiologically inert and strong material, but polyester and polyamide are particularly preferred.

Next, the adsorbent 22 filled and housed in the plasma purifier 7 will be explained. The adsorbent 22 contains complex I on an insoluble carrier.
It is characterized by binding a compound of formula M or a dipeptide or a derivative thereof. ? i! As the elementary TTJ compound, monocyclic and fused ring heterocompounds having 1 or more oxygen, nitrogen or (and) nitrogen atoms as heteroatoms in the ring are preferable. Examples are as follows. Namely, furan and its derivatives, thiophene and its derivatives and dithiolane derivatives, virol and its derivatives, azoles, pyridine and its derivatives, quinoline and its related compounds, acridine and its related compounds, pyrimidine and its related compounds, pyrazine and its related compounds. Compounds, andran and pyrone and related compounds, phenoxazine, phenothiazine, pterin and alloxazine compounds, purine bases, nucleic acids, hemin, chlorophyll, vitamin B1. , phthalocyanine, alkaloid, etc. Among these many heterocyclic compounds, compounds called so-called sulfa drugs having a sulfonamide group in their molecules are preferred.

In addition, a dipeptide or a derivative thereof is a compound formed by dehydration of two amino acids of the same or different types to form an acid amide bond, that is, a peptide bond, between one carboxyl group and the other amino group, or a dipeptide or its derivative. It is a derivative. Such dipeptides or derivatives thereof are preferably acidic amino acids such as aspartic acid, glutamic acid, asparagine, glutamine, etc., aromatic amino acids such as phenylalanine, tyrosine, short tyrosine, surinamine, or tryptophan, proline, hydroxyproline, histidine, etc. Dipeptides with complex I-amino acids such as, or derivatives thereof, particularly preferred are dipeptides with aspartic acid or glutamic acid and phenylalanine, tyrosine, tryptophan, proline or hydroxyproline, or derivatives thereof. Among these, more preferred dipeptides or derivatives thereof include aspartyl phenylalanine, which is a dipeptide of aspartic acid and phenylalanine, and its derivatives, and aspartyl phenylalanine methyl ester is particularly preferred.

Furthermore, as an insoluble carrier constituting the adsorbent 22,
It may be hydrophilic or hydrophobic,
For example, agarose-based, dextran-based, cellulose-based, polyacrylamide-based, polyvinyl alcohol-based, polyvinylpyrrolidone-based, polyacrylonitrile-based, styrene-divinylbenzene copolymer, polystyrene-based, acrylic ester-based, methacrylic ester-based, polyethylene-based , polypropylene, poly(4-fluoroethylene), ethylene-vinyl acetate copolymer, polyamide,
Organic polymers such as polycarbonate, polyvinylidene fluoride, polyvinyl formal, polyarylate, polyethersulfone, glass, alumina,
Inorganic materials such as titanium-based, activated carbon-based, and ceramic-based materials, and natural organic polymers derived from living organisms such as collagen and chitosan may be used. Furthermore, immobilized enzymes and known carriers used in affinity chromatography can be used without any particular limitations. The form of such water-insoluble carrier is not particularly limited, and for example, particulate, u
Various shapes such as filamentous, hollow fiber, membrane, and flat plate shapes can be used, but from the viewpoint of fluid permeability for body fluids such as blood and plasma, and ease of handling when preparing the purification material, it is preferable. ,
Particulates, especially those with an average particle size of 0.05 to 5 mm are preferable, and the average particle size is J I 5-Z-880.
After classification using the sieve specified in 1, the intermediate value between the upper limit particle size and the lower limit particle size of each grade is taken as the particle size of each grade, and its ff1
It is calculated as an ffi average. Further, the particle shape is preferably spherical because it is difficult to cause physical damage to cells and it is easy to obtain uniform particles. In order to be able to retain a larger amount of the dipeptide or its derivative, and thereby exhibit even higher adsorption efficiency, it is preferable that the material has a porous structure, and the pores of the porous material can be further improved. It is desirable that the average pore diameter is in the range of 100 to 5,000 pores, particularly 200 to 3,000 pores. When the water-insoluble carrier has a porous structure, the average pore diameter of the pores is 100 to 500.
The reason why the average pore size is smaller than 100 is because if the average pore size is smaller than 100, the permeation and diffusion of pathogenic substances in body fluids into the pores may be inhibited and the amount of adsorbed pathogenic substances may be reduced. This is because if the number is larger than 5,000, the strength of the porous body decreases and the surface area decreases, making it impractical. Note that the average pore diameter referred to here refers to the value measured by a mercury intrusion porosimeter, which calculates the amount of pores by injecting mercury into a porous body and calculating the pore size from the amount of mercury that entered, and then the pore diameter from the pressure required for intrusion. It is.

Taking these points into consideration, particularly preferred water-insoluble carriers include porous acrylic ester particles and porous chitosan particles.

In the adsorbent 22 used in this example, methods for immobilizing the heterocyclic compound, dipeptide, or its derivative on the surface of the water-insoluble carrier include covalent bonding, ionic bonding, physical adsorption, embedding, or immobilization on the surface of the carrier. All known methods such as precipitation and insolubilization can be used, but in view of the elution properties of the immobilized ligand, it is preferable to use the immobilized ligand by covalent bonding and insolubilization.
In general, known methods for activating immobilized enzymes, insoluble carriers, and immobilization of ligands used in the field of affinity chromatography can be preferably used.

Next, the mixer 8 mentioned above is for mixing the purified plasma and the blood concentrated by the plasma separator 4. Although it is desirable to completely mix the mixture by stirring or the like, a chamber or a Y-tube where two different fluids meet can also sufficiently achieve the purpose.

Note that the pathogenic substance, which is the adsorbed substance targeted by the blood purification device of this embodiment, is a harmful protein contained in body fluids. .

IgE, IgG, rgM), rheumatoid factor, or anti-nuclear antibody, anti-DNA antibody, anti-lymphocyte antibody, anti-erythrocyte antibody, anti-platelet antibody, anti-acetylcholine receptor antibody, anti-colon antibody, anti-renal glomerulus antibody.

Autoantibodies such as lung basement membrane antibodies, anti-epidermal intercellular desmosomal antibodies, anti-insulin receptor antibodies, anti-minilin antibodies, anti-hemophilia factor II antibodies, reduction products of immunoglobulins, between immunoglobulins, or between immunoglobulins and others complexes with substances (especially antigens and antigen-like substances), lymphocytes, complements.

This includes fibrinogen and the like.

Next, the present invention will be explained in more detail by showing experimental examples.

(Experimental Example 1) The filtration membrane 17 used in the plasma separator 4 has an average pore diameter of 0-
06μm, film thickness 130μm polypropylene toneffQ
On the blood-contacting surface of the membrane, an ultraviolet curable resin (manufactured by Dainippon Ink Co., Ltd., product name: Guicure MV) is printed using a screen plate, and the filtration membrane is immediately irradiated with ultraviolet rays to cure the ultraviolet curable resin. By adhering and curing mold resin on the film surface, protrusions 17a having uniform height, bottom, diameter, gap, and occupied area as shown in Table 1 are formed.

The outer diameter of the filtration membrane 17 is 102 mm, and the central opening is 22 m.
As the plasma flow path forming body 16, two screen meshes made of polyester having an opening of 290 μm and a thickness of 135 μm were used. The lIl unit 18 can be formed using a heat sealing method (140°C, 2 seconds) or an ultrasonic welding method (Branlin, Ultrasonic Welter Model 870).
0 use), the outer diameter of the flow path regulator 20 is 102 mm.
The central opening diameter was 22 mm, and the materials and Brinell hardness were as shown in Table 1. Furthermore, as shown in FIG.
Hot melt adhesive (manufactured by Toagosei Kogyo Co., Ltd.: PP
ET-1009) and housed in a polycarbonate cylindrical container 2311, a polycarbonate pusher 12 is inserted through a silicone rubber O-ring 13.
was inserted and used as plasma separator 4 for the experiment.

Further, the adsorbent 22 used in the plasma purifier 7 was prepared as follows. First, 0.1M phosphate buffer (
Add 5% (W/V) glutaraldehyde to pH 7.4)
It was dissolved to give the same concentration.

Porous chitosan beads (manufactured by Fujibo Co., Ltd., Chitopearl BCW3003) were added to this glutaraldehyde aqueous solution from 0.2 to
0.4g (added at the rate of fi wet weight ff1/mI2,
After degassing, use a blood mixer (manufactured by Kayagaki Irika Kogyo,
Next, the resulting reaction product was washed with distilled water and mixed with dimethylformamide (DMF) and 0.1M carbonate buffer (PL-1).
A solution of 0.1 M sulfathiazole dissolved in a mixture (2:3) with 10) was degassed and stirred overnight at room temperature using a blood mixer. After washing with distilled water, 1
M monoethanolamine (pH 8, O) was added to degas the mixture, and the mixture was stirred overnight in a blood mixer. After washing this with distilled water, it was immersed in a 1 (W/V)% sodium borohydride solution in 0.1M phosphate buffer (pH 7,4) and allowed to react at room temperature for 3 hours with occasional stirring. Through this reaction, the aldehyde group of glutaraldehyde,
The azomethine bonds generated by the reaction with the amino groups of chitosan and sulfathiazole were reduced and stabilized. Additionally, distilled water, pH containing 0.5M sodium chloride
The adsorbent material 22 was prepared by washing with 4,0,0,02M acetate buffer and pH10,0,2M carbonate buffer.

After degassing 100 g of the adsorbent prepared as described above in physiological saline, polyester mesh (225
Polycarbonate cylindrical container 2 with mesh attached
Fill and store it in 1, and add 5r of blood! It was used as purifier 7 in a blood purification experiment.

The blood purification device shown in FIG. 1 was assembled using each of the devices described above. Using this device, blood to which anticoagulant CACD solution with a hematocrit value of 40% and a temperature of 37° C. was added was allowed to flow in at a flow rate of 50 mε per minute for 2 hours, and the plasma filtration flow filQ was measured. In addition, the plasma protein concentration before and after using one device was measured, and the adsorption rate of each plasma protein was calculated from the difference. In addition, as a numerical value indicating the size of the device, the blood side briming amount P of the plasma separator is
v was measured. These results are shown in Table 1.

(Experimental Example 2) In preparing the adsorbent 22, dimethylformamide (D
MF) and 0.1M carbonate buffer (pH 1O) (2
Except that instead of using a 0.1 M sulfathiazole solution dissolved in 3), a 0.05 M asbatyl phenylalanine methyl ester (manufactured by Ajinomoto Co., Ltd., aspartame) solution dissolved in a 0.1 M carbonate buffer (pH 10) was used. A blood purification experiment was conducted in the same manner as in Experimental Example 1. The results are shown in Table 1.

(Experimental Example 3) Instead of the plasma separator 4 used in Experimental Example 1, a membrane unit was formed using a filtration membrane 25 without protrusions as shown in FIG. 6, and a flow path regulating plate 26 made of polypropylene was used. (Protrusion height 85μm, protrusion bottom diameter 300μm, protrusion gap 750μm)
A blood purification experiment was conducted in the same manner as in Experimental Example 1, except that a plasma separator 27 was used. The results are shown in Table 1.

(Experimental Example 4) In place of the plasma separator 4 used in Experimental Example 1, a flow path is a membrane unit in which a filtration membrane 28 with protrusions and a filtration membrane 11129 without protrusions are joined as shown in FIG. A blood purification experiment was conducted in the same manner as in Experimental Example 1 except that a plasma separator 30 having a stacked structure was used without using a regulator.

The results are shown in Table 1.

As is clear from the results shown in Table 1, especially in Experimental Example 1.
The plasma separator 4 used in 2 has a stable and high plasma filtration rate Q.
, and as a result, IgG in the same processing time
It was shown that the adsorption rate of IgM and IgM was increased.

[Effects of the Invention] As explained above, according to the blood purification device of the present invention,
By downsizing the plasma separator, which is a component of the device, and bringing out high plasma separation performance, the entire blood purification device can be downsized, and the removal efficiency of pathogenic materials can be increased, resulting in a reduction in blood purification time. It became possible to shorten the As a result, the amount of extracorporeal circulation of blood is small and the extracorporeal circulation time is short, making it possible to provide a blood purification device that places less physical burden on the human body.

[Brief explanation of the drawing]

FIG. 1 is a diagram showing the overall configuration of a blood purification device according to an embodiment of the present invention, FIG. 2 is an exploded perspective view showing a plasma separator used in the present invention, and FIG. 3 is a side sectional view of the device. , FIG. 4 is a perspective view showing the blood flow path of the plasma separator used in the present invention, FIG. 5 is a sectional view of the plasma purifier used in the present invention, and FIGS. It is a side sectional view showing a separator. ■...Blood inlet, 2...Blood pump, 4...
・Plasma separator, 5. Plasma pump, 7. Plasma purifier, 8. Mixer, 10. Blood outlet Applicant Terumo Corporation Company Representative Patent Attorney Katsuzo Asakura Figure 1 Figure 4

Claims (8)

[Claims] (1) A blood purification device having a blood inlet port and a blood outlet port, purifying blood introduced from the blood inlet port and drawing it out from the blood outlet port, the blood purification device concentrating the blood introduced from the blood inlet port. a plasma separator that separates blood and plasma; a plasma purifier that purifies the plasma separated by the plasma separator; a mixer that mixes the concentrated blood and the plasma purified by the plasma purifier; a blood circulation circuit that leads blood from the blood inlet to the blood outlet via the plasma separator and the mixer; and a blood flow circuit that causes the plasma separated in the plasma separator to flow into the mixer via the plasma purifier. A blood purification device characterized by comprising a plasma separation circuit. (2) The plasma separator covers the entire surface of a plasma channel forming body forming a plasma channel with a filtration membrane, and at least one part of the filtration membrane
A plurality of membrane units each having a first plasma outflow port are stacked one on top of the other with a flat plate-like flow path regulating body in between, and these membrane units are connected to a blood inflow port and a blood outflow port communicating with the blood circulation circuit, and the blood plasma outflow port. The membrane unit is housed in a container having a second plasma outflow port communicating with the separation circuit, and the first plasma outflow port of each membrane unit is communicated with the second plasma outflow port of the container, and the filtration membrane has a projecting part integrally on the surface facing the flow path regulating body, and the projecting part forms a blood flow path between the filtration membrane and the flow path regulating body, and the container A blood path in which blood flows in from the blood inflow port passes through the blood flow path, is filtered by the filtration membrane, and reaches the blood outflow port; and a blood path through which the blood is filtered by the filtration membrane and passes through the filtration membrane to the membrane unit. 2. The blood purification device according to claim 1, further comprising a plasma path through which plasma flowing into the membrane unit passes through a plasma flow path in the membrane unit, passes through the first plasma outlet, and reaches the second plasma outlet. Device. (3) The blood purification device according to claim 2, wherein the protrusions of the filtration membrane are a number of independent protrusions. (4) The height of the protrusion of the protrusion is 20 to 200 μm, the bottom diameter is 100 to 1000 μm, and the interval between the apexes of the protrusion is 3
4. The blood purification device according to claim 3, wherein the protrusion has an area of 3 to 20% of the entire membrane surface. (5) The blood purification device according to claim 2, wherein the flow path regulator has a Brinell hardness of 10 or more and a thickness of 10 to 200 μm. (6) The blood purification device according to claim 2, wherein the filtration membrane is made of polyolefin. (7) Claim 1, wherein the plasma purifier is constructed by filling and storing an adsorbent formed by bonding a heterocyclic compound, a dipeptide, or a derivative thereof to an insoluble carrier in a container having an inlet and an outlet for plasma. Blood purification device as described. (8) The plasma purification device according to claim 1, wherein the plasma purification device is a plasma filter that fractionates plasma components using a membrane.