JPS6315861B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel blood processing device. More specifically, it is a porous hollow fiber made of polyethylene with a special membrane structure that particularly damages blood cells.
The present invention relates to a blood processing device comprising a plasma separation device that efficiently separates plasma components from blood without leakage, and a plasma filtration device that can separately remove high-molecular protein components such as immune complexes from the plasma separated by the device.

BACKGROUND ART The effectiveness of separating blood into blood cell components and plasma components has been proposed, and various separation techniques have been devised. For example, it has been suggested that separation of blood cells and plasma is preferred for preparing plasma preparations for component transfusions and for pretreatment of artificial kidneys. Additionally, an innovative technology called plasma exchange therapy has been shown to be effective against autoimmune diseases such as liver failure, myasthenia gravis, rheumatoid arthritis, and systemic lupus erythematosus. In order to effectively utilize this plasma exchange therapy, it is essential to first separate blood into blood cells and plasma components. Thereafter, the plasma containing the pathogenic substance is discarded and healthy human plasma or plasma preparations are added. However, due to problems such as securing plasma preparations, infection, and side effects, it is considered desirable to purify the separated own plasma and then mix it with blood cell components, and there is a desire for the development of an apparatus for this purpose.

Centrifugation has conventionally been widely used as a plasma separation method. However, although various improvements have been made to this centrifugal separation method, various drawbacks have been pointed out as shown below. (1) Expenses are high. (2) The device is large and cannot be carried. (3)It is expensive. (4) Easily contaminated with platelets. (5) There is no means to perform plasma purification continuously. etc.

It has recently been recognized that separation methods using membranes are very effective in solving these problems. The advantages of the membrane method can be summarized as follows: (1) No platelets are mixed. (2) Large quantities can be processed in a short time. (3) Can be incorporated into a plasma purification system. etc. In addition, the form of the membrane requires less blood filling,
It is clear that hollow fibers with compressive strength are preferred. Cellulose acetate membranes, polyvinyl alcohol membranes, polysulfone membranes, polymethyl methacrylate membranes, and the like are known as such hollow fiber membranes for separating blood cells and plasma, and for separating various solutes in plasma. These polymer films cannot be shaped without using a solvent or plasticizer. Therefore, even if a sufficient cleaning process is performed after the hollow fibers are formed, it is necessary to constantly check the amount of solvents and plasticizers that are harmful to living organisms remaining in the membrane. Furthermore, in order to separate blood cells and plasma at a practical speed, it is necessary to increase the pore size and porosity of the membrane, which inevitably reduces the mechanical strength of the hollow fibers. In particular, the mechanical strength of a membrane obtained by a method of forming a membrane by coagulating a solution consisting of a polymer and a solvent in a coagulating liquid becomes low. Therefore, when producing hollow fibers or processing them into modules, etc., they tend to break easily, which not only makes processing difficult, but also increases the incidence of pinholes, which can lead to a fatal lack of reliability as a medical device. water. Therefore, the current situation is that the film thickness must be increased to increase mechanical strength. On the other hand, increasing the film thickness reduces the overvelocity of blood and plasma. In order to obtain a sufficient overspeed, the transmembrane differential pressure may be increased, but if the transmembrane differential pressure is large, leakage or clogging of blood cells, or hemolysis of red blood cells is likely to occur. Therefore, in order to obtain sufficient overspeed with a low transmembrane differential pressure, it is necessary to increase the membrane area of the entire module. This increases the internal volume of the hollow fiber, in other words, increases the amount of blood filled, which inevitably increases the amount of residual blood, which is undesirable.

The drawbacks seen in these conventional plasma separation devices using hollow fiber membranes also apply to plasma separation devices that separate harmful substances from plasma. Plasma contains large amounts of proteins such as albumin, γ-globulin, and fibrinogen, and toxins such as bilirubin are bound to specific proteins. Therefore, it is desirable to remove this specific protein and return the remaining useful proteins to the body. Centrifugation is not practical for separating and fractionating these proteins, and ultrafiltration using hollow fiber membranes is advantageous. Conventional hollow fiber membranes are not satisfactory as mentioned above, and because the membranes are made porous using a coagulation method or a soluble material extraction method, the pores of the membrane are close to circular in shape and are not suitable for blood cells. The membrane was easily clogged with particles and proteins.

In view of the current situation, the present inventors conducted research on hollow fiber membranes that are highly safe and less likely to be clogged with solutes or blood cells, and as a result, were able to complete the present invention. That is, the present invention provides a plasma separation device that separates blood into components including blood cells and plasma, a plasma separation device that ultrafiltrates solutes in the plasma, and a plasma separation device that passes the plasma separated by the plasma separation device into the plasma separation device. In a blood processing device including a circuit for introducing a blood cell and a circuit for mixing the liquid passed through the plasma filtration device with the blood cell-containing component, a high-density device having a density of at least 0.955, preferably 0.960 (g/cm ³ ) or more is used. A longitudinally oriented porous hollow fiber membrane made of polyethylene and having a large number of micropores penetrating from the inner wall surface of the hollow fiber to the outer wall surface in the peripheral wall portion, the hollow fiber membrane having a porosity of 30 to 30. A 90vol% porous polyethylene hollow fiber membrane is used in the plasma separation device and the plasma filtration device, and the porous hollow fiber membrane used in the plasma separation device has a pure water filtration rate of 0.2 to 20/m ² . hr.mmHg,
Transmittance of human serum albumin is 80% or more,
It has the structure shown in (a) and (b) below, and the porous hollow fiber membrane used in the plasma filtration device has a permeability of human serum albumin of 40% or less and a rejection rate of bovine serum γ-globulin of 60%. % or more of the porous hollow fiber membrane.

(a) There are many strip-shaped micropores with an average width of 300 to 5000 Å and a length-to-width ratio of 2 to 50, oriented in the fiber length direction, and the micropores extend outward from the inner wall surface. They are continuous to the wall.

(b) The hollow fiber membrane has a thickness of 5 to 100 μm.

If the porosity of the hollow fiber membrane for plasma separation and plasma filtration used in the present invention is less than 30%, the permeation rate will be insufficient, and if it exceeds 90%, the strength of the hollow fiber membrane will be insufficient to handle it. becomes difficult.

The polyethylene hollow fiber membrane used in the blood treatment device of the present invention differs from conventionally known hollow fiber membranes in that
Manufactured using a melt-spinning method without the use of plasticizers or solvents. That is, by melt-spinning crystalline high-density polyethylene and stretching it to an appropriate ratio, the membrane is made porous. In this porous membrane, fine pores and polymer microfibrils are oriented in the stretching direction, that is, in the fiber axis direction, and the pores have a rectangular shape. The cause is unknown, but if blood or plasma is allowed to flow through the hollow part of a hollow fiber with such a membrane structure, clogging of blood cells and plasma proteins will not occur, and the overflow can be maintained at a high level. I found out. In particular, hollow fiber membranes having the following membrane permeability and membrane structure are preferred as membranes for use in plasma separation devices that effectively separate blood into components including blood cells and plasma. That is, when measured with pure water, the overrate is in the range of 0.2 to 20 (/m ² , hr, mmHg), the permeability of human serum albumin is 80% or more, and the pore structure has an average Width 300-5000
Å, and there are many strip-shaped micropores oriented in the fiber length direction with an average length-to-width ratio of 2 to 50, and the micropores mutually extend from the inner wall surface to the outer wall surface of the hollow fiber. It has a continuous structure and a film thickness of 5~
It is a hollow fiber membrane in the range of 100μm. The filtration rate of pure water is a guideline when filtering plasma, and if you try to define it by the filtration rate of plasma, the filtration rate may differ even if the same membrane is used depending on the purity of the plasma, so use this guideline. If the filtration rate is within the above range, a balance between a fine and appropriate filtration rate for plasma filtration, completeness of blood cell inhibition, and membrane strength can be obtained. That is, below the lower limit, the plasma filtration rate is too low, and above the upper limit, leakage of blood cells occurs or the membrane becomes too thin and lacks strength. If the average width of the pore structure is less than 300 Å, albumin permeability will be insufficient, and if it exceeds 5000 Å, blood cells may leak. If the pore length to width ratio is less than 2, the permeation rate will be insufficient for the rejection rate, and if it exceeds 50, the permeation rate will increase accordingly, but the microfibrils will deform when the transmembrane pressure increases. This is undesirable because it makes it easier for things that would normally be blocked to pass through. The film thickness also needs to be within the above range in view of the balance between strength and permeation rate. Further, as a membrane used in a plasma filtration device for over-fractionating plasma, a polyethylene hollow fiber membrane is preferably used, which has a permeability of human serum albumin of 40% or more and a rejection rate of bovine serum γ-globulin of 60% or more. As a result, useful albumin proteins are recovered and returned to components including blood cells, and γ-
Globulin proteins can be selectively removed. When explaining a specific method for producing a porous hollow fiber membrane by melt-forming for polyethylene, the following method is effective. i.e. 1 to 15
and a melt index value of at least 0.955.
g/cm ³ , preferably 0.960 g/cm ³ or more, in an essentially unbranched high-density polyethylene having a density of at least about 10°C above the melting point of the polymer and not exceeding about 80°C above the melting point of the polymer. Spinning draft 100-10000 using a nozzle for hollow fiber production in the temperature range
After melt-spinning the obtained highly oriented crystalline undrawn hollow fibers, if necessary, annealing the fibers at a temperature below the melting point of the polymer, cold stretching 5 to 200% at a temperature of 70°C or below, and then 70°C. Hot stretching is carried out in one stage or in multiple stages in a temperature range of ~125°C, and the total stretching amount of cold stretching and hot stretching is within the range of 50 to 1000%, and then 110 ± Ten
Manufactured by heat setting in the temperature range of °C.

The hollow fibers used in the blood processing device of the present invention must be made of high-density polyethylene with a density of at least 0.955 g/cm ³ or higher, and 0.960 g/cm ³
It is preferable that the density is higher than that. Such high-density polyethylene inherently has less branching, and this density limitation means that when made porous by melt spinning, cold stretching, or hot stretching, it becomes hollow with the above characteristics suitable for plasma separation or plasma filtration. Necessary to obtain thread. Density is measured by the method specified by ASTM D-1505 after heat treatment at 120° C. until density is substantially constant. Being made of such high-density polyethylene is a desirable condition for obtaining a porous hollow fiber with a special structure that maintains a practical overrate for plasma separation and plasma filtration membranes, and at the same time it is suitable for conventional plasma separation and plasma filtration membranes. This is also a condition for solving the lack of mechanical strength inherent in the plasma membrane. In other words, the hollow fibers of the present invention are dense and have high strength because they essentially have a highly crystalline structure, but as mentioned above, hollow fibers made porous by drawing heat treatment under appropriate conditions after melt spinning have no hollow fibers. Since the polymer portion forming the pores is highly crystalline and oriented in the fiber axis direction, it exhibits even higher mechanical strength. That is, the hollow fiber of the present invention exhibits significantly stronger properties than the conventional hollow fiber in which a pore structure is formed by coagulating and precipitating a solution of a solvent and a polymer in a coagulant. Therefore, it is a highly reliable hollow fiber with almost no damage during processing into modules, easy handling, and no pinholes, which are fatal defects for medical separation membranes.

In addition, medical separation membranes such as artificial kidneys are sterilized by ethylene oxide gas, γ rays, high pressure steam, etc. before use, but the plasma separation and plasma filtration membranes of the present invention can also be sterilized by the above-mentioned sterilization process. be. However, since the membrane of the present invention is made of polyethylene, its heat resistance is not necessarily high. Therefore, in the case of high-pressure steam sterilization, when the treatment temperature becomes high, the membrane structure changes. Therefore, it is necessary to adequately control the processing temperature, but if hollow fibers that have been sufficiently heat-set are used, high-pressure steam sterilization can be performed within the temperature range of 110°C ± 10°C.

The high-density polyethylene hollow fiber membrane used in the present invention is chemically inert and stable against various drugs. It also has excellent compatibility with living organisms and has little coagulant effect even when it comes into contact with blood. Although high-density polyethylene is essentially hydrophobic, this does not pose any problem since it can be easily made hydrophilic by passing it through with ethanol or the like before use.

The hollow fiber of the present invention has a very high porosity of 0 to 90 vol%, and a very thin membrane thickness of 5 to 100 microns. The porosity here is the volumetric porosity measured by a mercury intrusion porosimeter.

In the case of separation of blood cells and plasma, the higher the overvelocity of the plasma, the less favorable it is. If it is made larger than necessary, only blood cells will remain inside the hollow fiber and fluidity will be lost, resulting in blood clots, making it completely impractical. In short, blood must be processed at an appropriate overspeed. Preferred overspeed is 30-80ml/min per module
It is said that. If the water permeation rate (water overspeed) of the hollow fiber is large, it is possible to reduce the membrane area of the module, the transmembrane pressure difference can also be reduced, and the amount of blood filled can be reduced, which is a preferable direction. However, if the amount of water permeation is larger than necessary, the pore size will inevitably become larger, and blood cells and bacteria will leak out. According to the inventors' study, the overspeed of pure water is
It has been found that blood cells do not leak under normal blood processing conditions if it falls within the range of 0.2 to 20/m ² ·hr · mmHg.

When separating blood cells and plasma, it is preferable that the permeability of plasma proteins is high. However, it is recognized that sufficient therapeutic effects do not necessarily have to be transmitted through all proteins (Medical Science vol50No.1P14~
P20 (1980)).

If the permeability of human serum albumin is 80% or more, the plasma separation membrane of the present invention can be used. Useful as a membrane. Here, the permeability of human serum albumin is defined as the transmembrane pressure difference using a hollow fiber with an effective length of 7 cm.
When a physiological saline solution containing 0.1% human serum albumin was circulated inside the hollow space under conditions of 50 mmHg,
The concentration of human serum albumin contained in the liquid is 280m
It is calculated from the following equation by determining the absorbance at μ.

Transmittance = (concentration of human serum albumin in transfection/concentration of human serum albumin in stock solution) x 100 In addition, γ-globulin inhibition rate refers to bovine serum γ-globulin (manufactured by Sigma) 0.1wt% physiological saline solution. It was measured using the same method as human serum albumin permeability and calculated from the following formula.

Rejection rate = Solute concentration in the undiluted solution - Solute concentration in the permeated solution / Solute concentration in the undiluted solution x 100% Figure 1 is a scanning electron micrograph (10,000x magnification) of the inner wall of a porous polyethylene hollow fiber used in the plasma separation device of the present invention. As is clear from the photograph, the microfibrils are oriented in the fiber axis direction, and strip-shaped micropores that are also oriented in the fiber axis direction are observed between the microfibrils. Since this structure is similarly observed on the outer wall surface of the hollow fiber, it is thought that the structure shown in FIG. 1 is laminated in the film thickness direction. The size and morphology of micropores can be measured by electron microscopic observation. Preferred observation conditions are 5000
It is ~10,000 times larger, and it is possible to arbitrarily extract 30 or more items from a photo, measure their average width and length, and calculate the ratio of length to width.

When hard spheres are placed in the flow in a capillary, it is observed that the hard spheres gather in the center of the capillary. This phenomenon is called axial concentration, and a similar phenomenon is observed in hemocytes in the blood and cancer cells and bacteria in ascites. The effect of axial concentration becomes more significant as the inner diameter of the tube becomes smaller and as the average flow velocity of the tube increases. If this axial concentration effect is utilized during plasma separation, damage and leakage of blood cells can be reduced. For these reasons, the preferred shape of the hollow fiber is one with an inner diameter of 50 to 500 μm.

FIG. 2 is a schematic diagram showing the basic structure of the blood processing apparatus of the present invention. Blood from conduit 1 is sent to plasma separation device 3 by pump 2, where it is separated into component 5 containing blood cells and plasma 4. Separated plasma 4 is sent to plasma filtration device 6, and filtered plasma 7 is separated from blood cells. is mixed into component 5 containing. Plasma 8 containing a large amount of high molecular weight proteins such as γ-globulin is separated and removed.
Although only one pump is shown in FIG. 2, a pump can be provided between the plasma flow path 4 and the liquid flow path 7 as required.

Any type of device may be used as the plasma separation device and plasma filtration device used in the present invention, and for example, devices having a modular structure similar to those used in hemodialysis can be used. FIG. 3 is an example of such a plasma separation and plasma filtration device. Such a module generally includes a hollow fiber bundle 12 cut to an appropriate length in a cylindrical outer tube 14 made of plastic.
It is manufactured by filling it with adhesive, distributing the adhesive evenly to both ends using a centrifugal method, and allowing it to solidify. In this case, when filling the hollow fibers, it is important that the hollow fibers are fixed in a uniformly dispersed state inside the cylinder. It is preferable to temporarily fix the hollow fiber ends. Any method may be used for temporary fixing, but in order to prevent the adhesive from entering inside the hollow fibers when the adhesive is injected, temporary fixing using a fast-curing adhesive or heat fusion may be used to simultaneously fix the hollow fibers. A preferred example is a method in which the thread opening is closed. In FIG. 3, 9 and 10 are blood or plasma inlets or outlets, and 11 is a plasma or liquid outlet. The end portion of the hollow fiber bundle 12 filled inside is adhesively fixed to the module outer cylinder 14 by an adhesive part 13. The nozzle 15 is tightened with a cap 16 that screws into the threaded portion of the outer cylinder 14. 17 is gas venting. In the apparatus shown in FIG. 3, blood introduced from the blood inlet 9 passes through the hollow portion of the hollow fiber membrane, and blood enriched in blood cell components is taken out from the blood outlet 10. On the other hand, the filtered plasma component is taken out from 11 and sent to the next plasma filtering device.

[Brief explanation of the drawing]

FIG. 1 shows a scanning electron micrograph of a polyethylene hollow fiber incorporated into the blood processing device of the present invention, FIG. 2 is a schematic diagram showing the basic configuration of the blood processing device of the present invention, and FIG. This is a hollow fiber membrane separation or filtration device used in blood processing equipment. 1... Conduit, 2... Pump, 3... Plasma separation device, 4
... Plasma flow path, 5... Blood cell-containing component flow path, 6... Plasma filtration device, 7... Plasma fluid flow path, 8... High molecular weight protein-containing plasma flow path, 9, 10... Blood (plasma) inlet/outlet, 1
1... Plasma outlet, 12... Hollow fiber bundle, 13... Adhesive part,
14...Module outer cylinder, 15...Nozzle, 16...Cap, 17...Gas vent.

Claims (1)

[Scope of Claims] 1. A plasma separation device that separates blood into components including blood cells and plasma, a plasma filtration device that ultrafilters solutes in the plasma, and a plasma separation device that separates the plasma by the plasma separation device. A blood processing device including a circuit for introducing the blood into the plasma filtration device and a circuit for mixing the filtrate filtered by the plasma filtration device with the blood cell-containing component, which is made of high-density polyethylene having a density of at least 0.955 g/cm ³ or more. A longitudinally oriented porous hollow fiber membrane having a large number of micropores penetrating from the inner wall surface of the hollow fiber to the outer wall surface in the peripheral wall, the hollow fiber membrane having a porosity of 30 to 90 vol%. The porous hollow fiber membrane used in plasma separators and plasma filtration devices has a pure water filtration rate of 0.2 to 20/
^m2 ． hr.mmHg, human serum albumin permeability is 80
% or more, and has the structure shown in (a) and (b) below, and the porous hollow fiber membrane used in the plasma filtration device has a permeability of human serum albumin of 40% or less, and has a permeability of bovine serum γ-globulin. A blood processing device characterized by a porous hollow fiber membrane having a rejection rate of 60% or more. (a) There are many strip-shaped micropores with an average width of 300 to 5000 Å and a length-to-width ratio of 2 to 50, oriented in the fiber length direction, and the micropores extend outward from the inner wall surface. They are continuous to the wall. (b) The thickness of the hollow fiber membrane is 5 to 100 μm.