JP2017177084A - Hollow fiber membrane module - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hollow fiber module suppressing pressure loss for preventing the interruption of treatment accompanying pressure rise during CRRT operation and suppressing the adhesion of blood cell components at a hollow fiber membrane inflow port by suppressing the occurrence of residence when flowing from a header interior space into a hollow fiber membrane.SOLUTION: A hollow fiber module includes: a cylindrical container; a bundle of hollow fiber membranes 3 installed within the cylindrical container; a potting resin part fixing both end parts of the bundle of the hollow fiber membranes 3 to both end parts of the cylindrical container; and headers disposed at both end parts of the cylindrical container respectively. A ratio (Ri/Re) of the inside diameter (Ri) of the hollow fiber membrane 3 to the inside diameter (Re) of the opening end part of the hollow fiber membrane 3 of the entrance side of a fluid is exhibited as Ri/Re<1 and a ratio (Re/Ro) of Re to the outside diameter (Ro) of the hollow fiber membrane 3 is exhibited as 0.5≤Re/Ro<1.SELECTED DRAWING: Figure 4

Description

  The present invention relates to a hollow fiber membrane module in a hollow fiber membrane medical device.

  Many blood purification therapies using hollow fiber membrane separation techniques such as hemodialysis, blood filtration, and hemofiltration dialysis have been devised. Among them, there is continuous renal replacement therapy (CRRT) that supports renal function for patients with acute renal failure, which is different from general hemodialysis for chronic renal failure patients. Widely enforced.

  CRRT has a aspects of renal indication intended to replace renal function, and a non-renal indication aspect intended to remove humoral mediators such as cytokines. All of them are mainly for serious patients such as acute renal failure, and are often performed for a long time under conditions where the circulation flow rate is lower than that of normal hemodialysis in consideration of the influence on hemodynamics. For example, normal hemodialysis is performed at a blood flow rate of 200 mL / min for 4 hours, whereas CRRT is performed at a blood flow rate of 100 mL / min for 8 to 24 hours, or more than 24 hours.

  A hollow fiber membrane module for purifying blood has a cylindrical container and a hollow fiber membrane bundle loaded along the longitudinal direction of the cylindrical container and having both ends fixed to both ends of the cylindrical container. Yes. Further, the hollow fiber membrane module has a potting resin portion that embeds and fixes the hollow fiber membrane bundle at both ends of the cylindrical container. Further, the hollow fiber membrane module is provided at both ends of the cylindrical container so as to face both end surfaces of the hollow fiber membrane bundle, and includes a header having a nozzle serving as a fluid inlet / outlet, and a side surface of the cylindrical container. And a port serving as a fluid inlet / outlet port.

  In blood purification therapy, there are cases where the treatment must be interrupted during the operation, and examples thereof include increased pressure in the blood flow path, hemolysis, blood leak, and the like. The main factors causing the pressure increase are pressure loss when blood passes through the hollow fiber membrane module and blood coagulation occurring in the blood channel. In addition, increased pressure increases the risk of hemolysis and blood leaks. If pressure rises, it will be necessary to interrupt the treatment and replace the hollow fiber membrane module or blood circuit. Such replacement work hinders smooth treatment, and only the amount remaining in the flow path is the patient. It leads to loss of blood. Therefore, the more serious the patient's pathological condition is like CRRT, the more important it is to prevent an increase in pressure.

  The pressure loss of the hollow fiber membrane module is mainly determined by the blood flow rate, the hollow fiber membrane module channel cross-sectional area and the channel length. Therefore, in designing the hollow fiber membrane module, if the membrane area is the same, the cross-sectional area of the flow path is large and the flow path length is preferably as short as possible. Problems arise from a viewpoint other than pressure loss, such as manufacturing process and ease of handling.

  Blood clotting is caused by deposition of blood cell components such as platelets or activation of a clotting reaction. In many cases, an anticoagulant is administered at the time of administration, but blood coagulation may still occur due to the blood compatibility of the material that comes into contact with blood, such as a hollow fiber membrane, and the influence of blood retention in the module.

  When circulating blood at a low flow rate like CRRT, it is necessary to be careful because the blood flow tends to stagnate. Examples of the place where blood stays easily in the hollow fiber membrane module include the header internal space and the inflow portion into the hollow fiber membrane. Since the flow path suddenly expands from the header nozzle to the header internal space, if there is a dead space in the header internal space, blood stays there for a long time and causes coagulation. On the other hand, a header having a shape that narrows the root of the nozzle (see Patent Document 1) and a header that has a thin and flat internal space (see Patent Document 2) have been proposed.

  On the other hand, the inflow part to the hollow fiber membrane is also a region that tends to stay. Since a flow like a vortex is likely to be formed in a region flowing from a large space such as in the header into the thin duct of the hollow fiber membrane, this becomes a staying region.

  In addition, in the headers such as Patent Documents 1 and 2, since the header internal space is thin and flat, blood flowing from the nozzle strongly flows in a direction perpendicular to the opening of the hollow fiber. Therefore, when the flow direction changes by 90 degrees and flows into the hollow fiber membrane, stagnation is likely to occur in the region immediately after flowing into the hollow fiber.

  A method of constructing a curved surface or an inclined surface at the open end of the hollow fiber membrane is disclosed in order to allow blood to smoothly flow into the hollow fiber membrane from the header inner space. For example, there are a method of coating a resin (see Patent Documents 3 and 4) and a method of melting a hollow fiber membrane (see Patent Documents 5, 6, 7, and 8).

JP 09-108338 A Japanese Patent No. 2554958 Japanese Patent Publication No. 4-9423 JP 58-175567 A Japanese Patent Publication No.59-32142 JP 58-12655 A Japanese Patent No. 3084529 JP-A-7-255839 Japanese Patent No. 4311051 JP 2004-290670 A

  As described in Patent Documents 3 and 4, the method of forming the flow path by covering the open end of the hollow fiber with a resin requires selection of a resin that has good blood compatibility and is unlikely to change its shape. In this case, it is difficult to uniformly coat all the hollow fibers, which is not a practical method. In this respect, it is simple and preferable to directly melt the hollow fiber membrane and change the shape of the hollow fiber inlet as in Patent Documents 5, 6, 7, and 8.

  Patent Documents 5, 6, 7, and 8 exemplify polyacrylonitrile hollow fiber membranes, cellulose-based hollow fiber membranes, and the like. These are characterized by small pore diameters on both the inner surface side and the outer surface side of the hollow fiber membranes. It is a simple film. In such a hollow fiber membrane, since the potting resin does not enter the porous film thickness portion (the porous membrane wall of the hollow fiber membrane), the hollow fiber is compared with the case where the potting resin enters the film thickness portion. Although the adhesive strength between the membrane and the potting resin is weakened, it becomes possible to change the shape of the hollow fiber inlet by melting only the hollow fiber membrane by heating or the like. However, since the adhesive strength is relatively weak, the film thickness portion itself may collapse depending on the melting conditions, and there is a concern that the function as a hollow fiber membrane module may be lost. For this reason, an optimal shape is not necessarily obtained.

  On the other hand, for hollow fiber membranes such as polysulfone membranes, which have a dense structure with a dense layer on the inner surface side of the film thickness and the pore diameter increases from the inner surface side toward the outer surface, potting is performed during molding. The resin enters the inside of the film thickness portion. In this case, since there is a potting resin, it is impossible to melt only the hollow fiber membrane, and even if heating or the like is attempted, the inclination is not constructed or a step is generated in the inclination.

  The gradient structure is an important structure for improving the solute removal performance of the hollow fiber membrane. In other words, the solute removal performance is affected by the resistance of the hollow fiber membrane. In the case of a membrane having a gradient structure in which the dense layer on the inner surface side is responsible for the substantial solute removal function, the solute is removed throughout the film thickness portion. Since the resistance is lower than that of the film to be removed, high solute removal performance is exhibited. In particular, CRRT often requires removal of substances having a relatively large molecular weight, such as cytokines, and high solute removal performance is desired. Therefore, a membrane having the above gradient structure is suitable for that purpose. Yes.

  In addition, in order to smoothly flow blood into the hollow fiber membrane, it is important to flow in an inclined surface or a curved surface.

  In the above prior art documents and the like, the optimum shape of the inclined structure at the end of the hollow fiber membrane has never been required.

  In Patent Document 9 and Patent Document 10, it is proposed to melt the end portion of the hollow fiber membrane as a method of eliminating the burr on the cut surface of the hollow fiber membrane that occurs after the cutting step. It is not described that a slope structure is imparted to a hollow fiber membrane of a type in which potting resin enters the film thickness portion during molding, such as a yarn membrane.

  The present invention has been made in view of the above-described problems of the prior art, and suppresses pressure loss and prevents the treatment from being interrupted due to an increase in pressure during CRRT, and from the header inner space into the hollow fiber membrane. It is an object of the present invention to provide a hollow fiber membrane module that can suppress the occurrence of stagnation at the time of flow and suppress the adhesion of blood cell components at the hollow fiber membrane inlet.

  The inventors of the present invention have completed the present invention as a result of intensive studies to solve the above problems. That is, the present invention is as follows.

(1) a cylindrical container;
A bundle of hollow fiber membranes loaded into the cylindrical container along the longitudinal direction of the cylindrical container;
A potting resin portion that surrounds and embeds both ends of the bundle of hollow fiber membranes inside both ends of the cylindrical container, and fixes both ends of the bundle of hollow fiber membranes to both ends of the cylindrical container; ,
Having nozzles that serve as inlets and outlets for fluid flowing in the cylindrical container, and provided with headers provided at both ends of the cylindrical container,
The ratio (Ri / Re) of the inner diameter (Ri) of the hollow fiber membrane and the inner diameter (Re) of the open end of the hollow fiber membrane on the fluid inlet side is Ri / Re <1.
Because
The ratio (Re / Ro) between Re and the outer diameter (Ro) of the hollow fiber membrane is:
0.5 ≦ Re / Ro <1
A hollow fiber membrane module.

(2) a cylindrical container;
A bundle of hollow fiber membranes loaded into the cylindrical container along the longitudinal direction of the cylindrical container;
A potting resin portion that surrounds and embeds both ends of the bundle of hollow fiber membranes inside both ends of the cylindrical container, and fixes both ends of the bundle of hollow fiber membranes to both ends of the cylindrical container; ,
Having nozzles that serve as inlets and outlets for fluid flowing in the cylindrical container, and provided with headers provided at both ends of the cylindrical container,
The ratio (Ri / Re) of the inner diameter (Ri) of the hollow fiber membrane and the inner diameter (Re) of the open end of the hollow fiber membrane on the fluid inlet side is Ri / Re <1.
Because
When the dispersion diameter, which is the diameter of the hollow fiber membrane bundle dispersed in a circular shape on the end face of the hollow fiber membrane bundle, is Rb, it occupies the dispersion area (Ab), which is the area of the circle having the dispersion diameter Rb as the diameter. The ratio of the sum (At) of the end opening area on the fluid inlet side of the hollow fiber membrane is:
0.10 ≦ At / Ab ≦ 0.64
A hollow fiber membrane module.

(3) The film thickness (Rt) of the hollow fiber membrane is
30 μm ≦ Rt ≦ 45 μm
The hollow fiber membrane module according to (1) or (2).

(4) The inner diameter (Ri) of the hollow fiber membrane is
190μm ≦ Ri ≦ 240μm
The hollow fiber membrane module according to any one of (1) to (3), wherein

(5) The hollow fiber membrane module according to any one of (1) to (4), wherein the porous film thickness portion of the hollow fiber membrane has a gradient structure.

(6) Any one of (1) to (5), wherein an inclined surface of 10 degrees to 70 degrees with respect to the opening end surface is formed over the entire circumference of the opening end portion of the hollow fiber membrane. The hollow fiber membrane module described in 1.

(7) The hollow fiber membrane module according to any one of (1) to (6), wherein the hollow fiber membrane is composed of a hydrophobic polymer and a hydrophilic polymer.

(8) The hollow fiber membrane module according to (7), wherein the hydrophobic polymer is polysulfone and the hydrophilic polymer is polyvinylpyrrolidone.

(9) When the total module length is L and the inner diameter of the container is D,
3.5 ≦ L / D ≦ 5.5
The hollow fiber membrane module according to any one of (1) to (8).

  According to the present invention, pressure loss of the hollow fiber membrane module is suppressed, and even when blood flows at a low flow rate, occurrence of retention when blood flows from the header inner space into the hollow fiber membrane is suppressed, Adherence of blood cell components at the hollow fiber membrane inlet is suppressed. Furthermore, since the risk of hemolysis can also be reduced, as a result, it is possible to prevent an increase in pressure or interruption of treatment due to hemolysis. Furthermore, according to the present invention, it is possible to prevent the retention of blood caused by residual air in the circuit and air mixed at the time of priming or enforcement, and as a result, secondary pressure increase and hemolysis can be prevented. The interruption of the accompanying treatment can be prevented.

It is a schematic diagram which shows the structure of a hollow fiber membrane module. It is the schematic diagram which expanded the header site | part in a hollow fiber membrane module. It is a perspective view explaining the dispersion diameter of the edge part of a hollow fiber membrane bundle. (A) Schematic diagram showing an example of the inclined structure of the hollow fiber membrane end, (b) Schematic diagram showing the inclined structure of the hollow fiber membrane end according to the present invention, (c) of a general hollow fiber membrane end It is a schematic diagram which shows a structure. (A) The figure showing the longitudinal cross-section which shows an example of the inclination structure of a hollow fiber membrane edge part, (b) The figure showing the longitudinal cross-section which shows the inclination structure of the hollow fiber membrane edge part which concerns on this invention, (c) General It is a figure showing the longitudinal cross-section which shows the structure of a hollow fiber membrane edge part. It is a schematic diagram of the header column used in order to evaluate a hemolysis rate. In the Example of this invention, it is a figure which shows the outline of the observation area of the opening end surface of a hollow fiber membrane. It is a table | surface which shows the measurement result of each Example and a comparative example. It is a figure which shows the outline of the closed circuit which connected two blood bags through the circuit and the header column.

  Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. The embodiments described below are not intended to limit the present invention, and various modifications can be made within the scope of the invention.

[Production method of hollow fiber membrane]
The shape, dimensions, and fractionation characteristics of the hollow fiber membrane of the present embodiment are not particularly limited, and can be appropriately selected in light of the purpose of use.

  The material of the hollow fiber membrane is not particularly limited, but a polysulfone polymer such as polysulfone (hereinafter sometimes referred to as “PSf”) or polyethersulfone contains a hydrophilizing agent such as polyvinylpyrrolidone. The porous hollow fiber membrane is widely used as a hollow fiber membrane for blood purification because it is suitable for controlling the fractionation property according to the application and can easily optimize blood compatibility. The hollow fiber membrane may further contain a second hydrophilizing agent such as glycerin or polyethylene glycol, other additives, a surface modifier, and the like.

The polysulfone-based polymer is a general term for bisphenol-type polysulfone, which is a polymer having a repeating unit represented by the formula (1), and polyethersulfone, which is a polymer having a repeating unit represented by the formula (2). Widely used as a material for
(-Φ-SO2-Φ-O-Φ-C (CH3) 2-Φ-O-) n (1)
(-Φ-SO2-Φ-O-) n (2)
Here, Φ represents a benzene ring, and n represents a repetition of the polymer.

  Polyvinyl pyrrolidone (hereinafter referred to as PVP) is a water-soluble polymer compound obtained by vinyl polymerization of N-vinyl pyrrolidone, and is widely used as a material for hollow fiber membranes as a hydrophilizing agent or a pore-forming agent.

  In the process for producing the hollow fiber membrane, although not limited to the following, for example, a tube-in-orifice type spinneret is used, and a hollow inner liquid for coagulating the membrane-forming stock solution from the orifice of the spinneret. At the same time, the tube is discharged into the air.

The film-forming stock solution can be prepared by dissolving the polysulfone polymer and PVP in a common solvent.
Examples of the common solvent include solvents such as dimethylacetamide (hereinafter referred to as DMAc), dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, and dioxane, or a solvent composed of a mixture of two or more of the above. . Additives such as water may be added to the film-forming stock solution, but it is preferable not to add water as much as possible because water tends to impair the stability of the film-forming stock solution.

  As the hollow inner liquid, water or a coagulating liquid mainly composed of water can be used. In general, a mixed solution of a solvent and water used for the film-forming stock solution is preferably used. At this time, the inner diameter and the film thickness of the hollow fiber membrane can be adjusted to desired values by adjusting the stock solution discharge amount and the hollow inner solution discharge amount. The inner diameter (Ri) of the hollow fiber membrane is preferably 190 μm or more and 240 μm or less, more preferably 195 μm or more and 210 μm or less. More preferably, it is 197 μm or more and 205 μm or less, and particularly preferably 203 μm or less. If it is less than 190 μm, there is an increased risk of pressure increase due to shrinkage of the flow path, and if it is greater than 240 μm, the risk of blood coagulation increases due to an increase in the tendency of blood retention due to a decrease in linear velocity. The film thickness (Rt) is preferably 30 μm or more and 45 μm or less, more preferably 35 μm or more and 45 μm or less. More preferably, it is 38 micrometers or more, Most preferably, it is 40 micrometers or more. If it is less than 30 μm, the mechanical strength is lowered, and if it is more than 45 μm, the solute removal efficiency is lowered.

  The film-forming stock solution discharged from the spinneret together with the hollow inner liquid travels through the air gap part, is introduced into a coagulation bath mainly composed of water installed at the lower part of the spinneret, and is immersed for a predetermined time to complete coagulation. This is a so-called dry and wet spinning method. An air gap part means the space between a spinneret and a coagulation bath.

  The film-forming stock solution begins to solidify from the inner surface side due to the poor solvent component in the hollow inner liquid discharged simultaneously from the spinneret, and the solidification proceeds toward the outer surface side of the film while traveling through the air gap. To do. The poor solvent supplied from the hollow inner liquid penetrates into the membrane-forming stock solution mainly by diffusion to form the structure of the hollow fiber membrane, but the concentration of the poor solvent becomes thinner as it goes to the outer surface side. . Therefore, the hollow fiber membrane has a gradient porous structure in which the pore diameter increases from the inside to the outside of the film thickness portion.

  Next, the hollow fiber membrane can be obtained by washing, further attaching a pore size retaining agent such as glycerin or an aqueous polyethylene glycol solution, and performing a drying treatment. A hollow fiber membrane can be obtained without using a pore diameter retaining agent.

[Method of manufacturing hollow fiber membrane module]
FIG. 1 is a schematic diagram showing the structure of the hollow fiber membrane module 1, and FIG. 2 is an enlarged schematic diagram showing a portion of the header 7 in the hollow fiber membrane module 1. In FIG. 1 and FIG. 2, only the portions that appear in the cross section are shown in the diagrams for convenience.

  As shown in FIG. 1, a hollow fiber membrane module 1 according to the present embodiment is loaded along a substantially cylindrical tubular container 2 and the longitudinal direction of the tubular container 2, and both ends 4 a are tubular containers. A bundle of hollow fiber membranes 3 (hereinafter referred to as “hollow fiber membrane bundle”) 4 fixed inside the two end portions 2a of the two, and both end portions of the hollow fiber membrane bundle 4 inside the two end portions 2a of the cylindrical container 2 A potting resin portion 5 that surrounds 4a and has both ends 4a of the hollow fiber membrane bundle 4 embedded therein and fixed thereto. Further, the side portion 2b of the cylindrical container 2 is provided with a port 6 serving as a fluid inlet / outlet, and headers 7 are attached to the outer sides of both end portions 2a of the cylindrical container 2, respectively.

  In the hollow fiber membrane module 1 composed of hollow fibers having the same dimensions, the total area of the inner surface of the hollow fiber membrane 3 (the total area of all the hollow fiber membranes 3 constituting the hollow fiber membrane bundle 4) is the same. Even if the hollow fiber membrane module 1 is thicker and the hollow fiber membrane module 1 is shorter in the longitudinal direction, the linear velocity of the fluid is suppressed, so that the pressure loss is kept low. It is done. From this point of view, the total module length (or container length, which is the length from the end surface of one potting resin portion 5 to the end surface of the other potting resin portion 5) is L, and the inner diameter of the container is When D (see FIG. 2), it is preferable that L / D is small, but since it is substantially restricted by the size of the hollow fiber membrane bundle 4 to be filled, 3.5 ≦ L / D ≦ 5. 5 is preferable.

  As shown in FIGS. 1 and 2, the header 7 is a circular cap-shaped member disposed so as to face one end surface 3 a (for example, the upper side shown in FIG. 1) of the hollow fiber membrane 3. The header 7 is provided in a cylindrical shape along the peripheral edge of the cover portion 7 a and a substantially circular cover portion 7 a that covers the opening of the one end portion 2 a of the cylindrical container 2, and circumscribes the end portion 2 a of the cylindrical container 2. And a fixing portion 7b fixed to the cylindrical container 2.

  A nozzle 8 serving as a liquid inlet / outlet is provided in the central portion of the cover portion 7a (the central portion of the header 7). In a general case, the nozzle 8 extends along the axis C (see FIG. 2) of the cylindrical container 2. Further, an annular sealing material 9 for securing airtightness may be sandwiched between the end surface of the potting resin portion 5 on the cover portion 7a side and the peripheral edge of the cover portion 7a. In addition, the cap covered with the port 6 and the header 7 is shown by the code | symbol 12 (refer FIG. 1).

  The hollow fiber membrane bundle 4 is loaded along the longitudinal direction of the cylindrical container 2, and both end portions 4 a are fixed to the both end portions 2 a of the cylindrical container 2 via the potting resin portion 5.

  In order to fix the hollow fiber membrane bundle 4 to both ends 2a of the cylindrical container 2, for example, the hollow fiber membrane bundle 4 is inserted into the cylindrical container 2, and potting resin is applied to both ends 4a of the hollow fiber membrane bundle 4. By injecting and centrifugally rotating around the longitudinal center of the cylindrical container 2, forming a potting layer (potting resin portion 5) at both ends 4a of the hollow fiber membrane bundle 4 and sealing both ends, Can be fixed. Examples of the material of the potting resin include, but are not limited to, polyurethane resin, epoxy resin, silicon resin, and the like.

  Thereafter, excess potting resin is cut off and the end surface 3a of the hollow fiber membrane 3 is opened. The end surface 4b of the hollow fiber membrane bundle 4 is preferably cut so that the surface of the potting resin portion 5 (end surface made of a cut surface) is smooth.

The hollow fiber membrane bundle 4 is dispersed in a circular shape on the end face 4b made of the cut surface. When the dispersion diameter is Rb, the area of the circle having the dispersion diameter (also referred to as “dispersion area” in this specification). ) (Ab) is represented by Ab = π × (Rb / 2) ² (see FIG. 3).

[Construction method of inclined structure of hollow fiber membrane inlet]
Since the hollow fiber membrane 3 of the present embodiment has a gradient structure, the outer surface has a relatively large hole diameter. Therefore, in the potting process, the potting resin enters the film thickness portion 3T (see FIG. 4C) not a little. In particular, when the hole area ratio of the outer surface of the hollow fiber is 20% or more, the potting resin easily enters (refer to the potting resin portion indicated by reference numeral 5 in FIG. 5). If the potting resin enters, it may be difficult to construct an inclined surface on the end surface 3a that is the fluid inlet to the hollow fiber membrane 3 (see FIG. 4 (c)), or the film thickness portion 3T An inclined surface 3b is formed on a part of the inner side (near the center) (see FIG. 4B). That is, the melting temperature and decomposition temperature of the potting resin are generally higher than the melting temperature of the hollow fiber membrane 3, and the hollow fiber membrane 3 is melted so as to melt the film thickness portion 3T of the hollow fiber membrane 3 into which the potting resin has entered. Even if the treatment is performed at a temperature, the structure is supported by the potting resin, so that it cannot be uniformly melted. Conversely, when the treatment is performed at the melting temperature of the potting resin, the entire end surface is melted regardless of the presence or absence of the hollow fiber membrane 3, so that it is difficult to construct the inclined surface 3b on the end surface 3a of the hollow fiber membrane 3. Therefore, when the potting resin enters the entire film thickness portion 3T of the hollow fiber membrane 3, it becomes difficult to construct the inclined surface 3b over the entire film thickness portion 3T, and the potting resin enters a part of the film thickness portion 3T. In this case, only the portion where the potting resin does not enter is melted to form the inclined surface 3b. On the other hand, the bonding strength between the potting resin and the hollow fiber membrane 3 increases as the potting resin enters the film thickness portion 3T.

  Therefore, before the hollow fiber membrane bundle 4 is inserted into the cylindrical container 2, if a sealing agent is temporarily included in at least a part of the end portion 4a of the hollow fiber membrane bundle 4, the end surface 3a of the hollow fiber membrane 3 is removed. Only the opening portion prevents the potting resin from entering the film thickness portion 3T, and it is possible to stably manufacture the tapered surface (or funnel-shaped, trumpet-shaped, or mortar-shaped) inclined surface 3b on the end surface 3a (FIG. 4). (Refer to (a) and (b)). On the other hand, since the potting resin enters the film thickness portion 3T except for the opening, the adhesive strength between the potting resin and the hollow fiber membrane 3 can be maintained. The tapered inclined surface 3b is preferably formed on both end surfaces of the hollow fiber membrane 3, but will be described later if it is formed on at least one of the end surfaces 3a (fluid inlet side). In addition, it is possible to improve the flow of fluid (suppress blood retention).

  Including a sealing agent only in a necessary portion of the end portion 4a of the hollow fiber membrane bundle 4 utilizes a capillary phenomenon, and controls the time during which the end portion 4a of the hollow fiber membrane bundle 4 is immersed in the sealing agent. It becomes possible. In this method, since the sealing agent can be surely included in the gap portions of the film thickness portions 3T of all the hollow fiber membranes 3 to be immersed, it is possible to construct the inclined surfaces 3b in all the hollow fiber membranes 3. It is.

  The form of the hollow fiber membrane 3 included in the hollow fiber membrane bundle 4 is not limited, and may be straight yarn, wave yarn, or a mixture thereof, and the hollow fiber membrane bundle 4 may contain a spacer yarn. . Further, the hollow fiber membrane 3 may be coated with an additive such as polyethylene glycol or a vitamin agent.

  The sealing agent is not particularly limited as long as it is non-volatile, has a viscosity enough to remain in the pores, and does not dissolve the hollow fiber. For example, an aqueous solution of polyvinyl pyrrolidone, glycerin, or polyethylene glycol is suitable because it satisfies the above conditions and has conventionally been a constituent of the hollow fiber membrane module 1, but is not limited thereto.

  The inclined surface 3b shown in FIGS. 4 (a) to 4 (b) can be constructed by partial melting of the hollow fiber membrane 3 by heating. Examples of the heating means include a heat source such as a heater and light irradiation. At this time, if the hollow fiber membrane module 1 is rotated together with the cylindrical container 2 around the axis C of the cylindrical container 2 while being heated from the longitudinal direction side, even if there is temperature unevenness in the heat source itself, several thousand It is possible to uniformly heat tens of thousands of hollow fiber membranes 3 in the radial direction and in the circumferential direction.

  The opening diameter (inner diameter) Re in the end face 3a of the hollow fiber membrane 3 provided with the inclined surface 3b is Ri ≦ Re ≦ Ro in relation to the inner diameter (Ri) of the hollow fiber and the outer diameter (Ro) of the hollow fiber. (See FIG. 4). That is, when an inclination is given from the outer periphery (outer end 3e) of the hollow fiber membrane 3, Re = Ro (see FIG. 4A), and an inclination is given to a part of the film thickness portion 3T. In this case, Ri <Re <Ro (see FIG. 4B), and when no inclination is given, Re = Ri (see FIG. 4C). When the same hollow fiber membrane is used, Ri / Re <1 is preferable in order to suppress an increase in pressure. Furthermore, in order to suppress a phenomenon that leads to blood coagulation such as deposition of blood cell components and activation of a coagulation reaction, 0.5 ≦ Re / Ro <1 is preferable, and more preferably 0.6 ≦ Re / Ro <1, more preferably 0.65 ≦ Re / Ro <1.

On the other hand, the total opening area of the hollow fiber membrane 3 at the end face 4b with respect to the dispersion area (Ab) calculated from the dispersion diameter (Rb) of the hollow fiber membrane bundle 4 at the end face 4b (At = π × (Re / 2) ^2. The pressure loss can be suppressed as the ratio (At / Ab) of (× hollow fiber number) increases. Practically, it is preferable that 0.10 ≦ At / Ab ≦ 0.64, more preferably 0.25 ≦ At / Ab ≦ 0.62, due to the dispersion state of the hollow fiber and restrictions on the manufacturing process. is there. If it is less than 0.1, the effect of suppressing the pressure loss becomes insufficient. If it is larger than 0.64, the distribution state of the potting resin is deteriorated, and as a result, there is a portion where the potting resin does not exist locally. It is formed and becomes a factor of promoting blood retention.

  As shown in FIG. 5, the inclination angle α of the inclined surface 3 b is an angle formed by the opening surface (end surface 3 a) and the inclined surface 3 b in the longitudinal section of the hollow fiber membrane 3. In other words, the inclination angle α indicates the inclination with respect to the end face 3a when the end face angle of the hollow fiber membrane 3 before the inclined face 3b is formed is 0 degree.

  When the inclination angle α is less than 10 degrees or more than 70 degrees, there is a possibility that blood stays in the hollow fiber membrane inlet when blood flows into the hollow fiber membrane 3 from the internal space S of the header 7. Since adhesion of components may not be sufficiently suppressed, it is preferably in the range of 10 to 70 degrees. In order to further improve the effect of suppressing the adhesion of blood cell components, the inclination angle α is more preferably 15 to 65 degrees.

  After the inclined surface 3b is formed on the hollow fiber membrane 3, the header 7 having the nozzle 8 is attached and sterilized, whereby the hollow fiber membrane module 1 in which the hollow fiber membrane bundle 4 is filled in the cylindrical container 2 can be manufactured. The hollow fiber membrane module 1 may be filled with an aqueous solution such as an antioxidant.

  1 of the inner diameter of the header 7 in the internal space formed in the header 7 (that is, the space formed between the header 7 and the end surface 3a of the hollow fiber membrane 3 and indicated by S in FIG. 2). Let / 2 be the radius a. The radius a is a radius of the header 7 on the cylindrical container 2 side. More specifically, the radius a is 1 / of the inner diameter of the portion of the inner space S where the inner surface of the cover portion 7a is close to the urethane surface of the potting resin portion 5. 2. In addition, the height of the header 7 at a position a / 3 away from the center of the header 7 (the position where the axis C of the cylindrical container 2 passes) in the direction orthogonal to the axis C of the cylindrical container 2 (that is, potting resin) 0.9h1 ≦ h2 when the height of the header 7 at a position h1, 2a / 3 away from the end surface (surface) of the portion 5 and the inner surface 7c of the header 7 is h1, 2a / 3. It is preferably a flat structure such that ≦ h1, and more preferably h1 = h2. The height h of the internal space S of the header 7 is preferably 2.5 mm or less, more preferably 2.0 mm or less. By making such a space, it is possible to eliminate a dead space that causes stagnation even when blood flows at a low flow rate.

  It is desirable for the internal space S of the header 7 to minimize the dead space where blood stays. In order to distribute the blood flowing from the nozzle 8 to the hollow fiber membrane 3 without waste, it is necessary to make the inner space S of the header 7 flat. That is, it is preferable that the height (h) of the header 7 is substantially the same in the entire range of the cover portion 7a. Furthermore, it is more preferable if the value is 2.5 mm or less. Here, the height (h) of the header 7 is set such that the header 7 is attached to both end portions 2a of the cylindrical container 2 from the end surface of the potting resin portion 5 to the inner surface 7c of the cover portion 7a (the ceiling surface of the header 7). It was set as the distance to.

  Examples of the material for the cylindrical container 2 and the header 7 include polypropylene resin, polystyrene resin, polymethyl methacrylate resin, polyethylene terephthalate resin, nylon 6 resin, polysulfone resin, polyacrylonitrile resin, polycarbonate resin, ABS resin, and styrene / butadiene. Polymer resin etc. are mentioned.

  In particular, polypropylene resin, polystyrene resin, polyacrylonitrile resin, and styrene / butadiene copolymer resin are preferable because the resin cost is low, the versatility in the field of medical members is high, and high safety is confirmed. A styrene / butadiene copolymer resin is particularly preferred, but it is not particularly limited thereto.

  Hereinafter, although an embodiment and a comparative example explain this embodiment still in detail, this embodiment is not limited to the following examples.

Example 1
A film forming stock solution comprising 19 parts by weight of PSf (manufactured by Solvay), 7 parts by weight of PVP (manufactured by Nippon Shokubai Co., Ltd., K-90) and 74 parts by weight of DMAc (manufactured by Mitsubishi Gas Chemical Company) was prepared. A DMAc 60% by weight aqueous solution was used as the hollow inner liquid. The production stock solution and the hollow inner solution were discharged from the spinneret, and were immersed in a 60 ° C. coagulation bath made of water through a falling part covered with a hood to be solidified. The hollow fiber membrane obtained by washing with water and drying had an inner diameter of 200 μm and a thickness of 45 μm.

  10400 hollow fiber membranes were bundled, and 10 mm on one side of the bundle end was immersed in 55% glycerin (Japanese Pharmacopoeia) for 5 seconds. Then, in order to impregnate the hollow fiber membrane 3 with glycerol by capillary action, it left still for 20 hours. Thereafter, the hollow fiber membrane bundle 4 is inserted into a cylindrical container 2 having a container length (L) of 170 mm and a container inner diameter (D) of 39 mm, potted with polyurethane resin, and then excess polyurethane resin is cut. The hollow fiber membrane 3 was opened.

  The urethane surface was brought close to a heat source of 700 degrees for 5 seconds, and an inclined surface 3 b was constructed at the end of the hollow fiber membrane 3. Then, the hollow fiber membrane module 1 was obtained by attaching the header 7 to the cylindrical container 2, filling the antioxidant containing sodium pyrosulfite aqueous solution, and sterilizing by the gamma ray.

[Dispersion diameter of hollow fiber bundle at the open end]
About the circular form in which the hollow fiber membrane bundle 4 is formed on the heat treatment end face of the obtained hollow fiber membrane module 1 (see FIG. 3), the diameter of the bundle (hollow) with a microscope (KEYENCE, VHX-900) The dispersion diameter (Rb) of the yarn membrane bundle 4 was measured and found to be 38 mm.

[Measurement of hollow fiber opening diameter at the open end]
The opening diameter (Re) at the opening end face of the hollow fiber membrane 3 was measured with a laser microscope (KEYENCE, VK-8500). Similar to the observation method in the inclined state, the open end 4a of the hollow fiber membrane bundle 4 of the hollow fiber membrane module 1 is sliced, and a concentric circle whose radius is half the radius of the outer circumference of the open end 4a (see FIG. 7). Then, the opening diameter of the open end 4a was measured for a total of 15 hollow fiber membranes, each of which is an arbitrary three out of a total of five divided areas obtained by dividing the outer circumferential annular portion into four at 90 degrees. The average value of 15 was calculated. 8 together with the measurement results of other examples and comparative examples.

[Measurement of tilt angle]
The inclination angle α of the inclined surface 3b was measured with a laser microscope (KEYENCE, VK-8500). Similarly to the observation method of the inclined state and the measurement of the hollow fiber opening diameter, the open end portion 4a of the hollow fiber membrane bundle 4 of the hollow fiber membrane module is sliced, and half the radius of the outer circumference circle of the open end portion 4a is set as the radius. A total of 15 hollow fiber membranes 3 in each of a total of 5 areas divided into a concentric circle (see FIG. 7) and an annular part of the outer periphery thereof divided into four at an angle of 90 degrees, a total of 15 hollow fiber membranes 3 The inclination angle α was measured, and the average value of 15 was calculated. FIG. 8 shows a table together with the measurement results of other examples and comparative examples. The inclination angle α can be calculated using known analysis software that performs image processing, calculation, and the like.

[Measurement of blood cell count]
In order to evaluate the accumulation of blood cell components during the inflow into the hollow fiber membrane 3, the number of blood cell components deposited at the blood inflow site of the hollow fiber membrane 3 was measured.

  90 mL of healthy donor blood to which heparin was added to 2000 U / L was circulated through the hollow fiber membrane module 1 at a flow rate of 100 mL / min for 4 hours. Thereafter, the inside of the hollow fiber membrane module 1 was replaced with physiological saline and washed, and blood cells remaining in the hollow fiber were fixed with glutaraldehyde. After the cell fixation, the hollow fiber membrane module 1 was washed with distilled water, and then the module was disassembled to cut out a hollow fiber membrane inlet portion made of a hollow fiber and a potting resin, and freeze-dried.

  A sample for observation was prepared by cutting from the hollow fiber membrane inlet after lyophilization so that the longitudinal cross section of the hollow fiber membrane opening could be observed, and 300 times with a scanning electron microscope (Hitachi, S-3000N). From the field of view, the number of blood cells in an area of 200 μm from the end of the inflow portion of the hollow fiber in the direction of the long axis of the hollow fiber was measured.

  A total of five hollow fiber membranes 3 are extracted and observed, one in each of the four areas on the four sides of the open end 4a of the hollow fiber membrane bundle 4, and the number of blood cells in the five specimens to be observed is determined. Totaled. 8 together with the measurement results of other examples and comparative examples.

[Measurement of hemolysis rate]
In order to evaluate the damage of blood cell components in the flow into the hollow fiber membrane 3, the hemolysis rate of erythrocytes was measured.

  A portion comprising the potting resin portion 5 and the end portion 4a of the hollow fiber membrane bundle 4 embedded in the potting resin portion 5 is cut out from the hollow fiber membrane module 1, and the cover portion 7a of the header 7 is annularly formed from both sides of the cut portion. A header column 10 was manufactured by pressing and fixing the sealing material 9 (see FIG. 6).

  After separating blood cell components and plasma from bovine blood (hematocrit value: 50%) added with CPD (Citrate Phosphate Dextrose) by centrifugation (3500 rpm, 20 minutes), the plasma and buffy coat were removed. After adding the same volume of physiological saline to the obtained blood cell component and separating the blood cell component again by centrifugation (3500 rpm, 20 minutes), the supernatant was removed to obtain a concentrated erythrocyte solution.

  The obtained erythrocyte concentrate was transferred to an empty blood bag (volume: 200 mL) B, and connected to another empty blood bag B of the same volume via a circuit and header column 10 (see FIG. 9). In the closed circuit thus obtained, the operation of allowing the erythrocyte concentrated solution to perfuse the header column 10 using a drop and then returning to the original blood bag B was repeated 50 times in total.

  The concentrated erythrocyte solution after perfusion was collected, and the absorbance at a wavelength of 576 nm of the supernatant after centrifugation (3500 rpm, 20 minutes) was measured.

  The measurement results obtained as described above are shown in FIG. 8 together with the measurement results of other examples and comparative examples.

(Example 2)
The same manufacturing method and measurement method as in Example 1 were carried out except that the film thickness of the hollow fiber was 40 μm and that the cut surface of the polyurethane resin was treated at 710 ° C. for 5 seconds.

(Example 3)
The same production method and measurement method as in Example 1 were performed except that the inner diameter of the hollow fiber was 205 μm and that the cut surface of the polyurethane resin was treated at 710 ° C. for 5 seconds.

Example 4
The inside diameter of the hollow fiber was 210 μm, the number of hollow fibers was 6900, the container length (L) was 170 mm, the container inside diameter (D) was 32 mm, and the cut surface of the polyurethane resin was 690 The same manufacturing method and measurement method as in Example 1 were carried out except that the treatment was carried out at 5 ° C. for 5 seconds.

(Example 5)
Except that the inside diameter of the hollow fiber was 195 μm and the film thickness was 40 μm, and the cylindrical container 2 having a hollow fiber number of 13000, a container length (L) of 170 mm and a container inner diameter (D) of 44 mm was used. The same production method and measurement method as in Example 1 were carried out.

(Comparative Example 1)
Example 1 except that the cylindrical container 2 having a hollow fiber inner diameter of 205 μm, a film thickness of 50 μm, a hollow fiber number of 13,000, a container length (L) of 170 mm and a container inner diameter (D) of 44 mm was used. The manufacturing method and measuring method of were carried out.

(Comparative Example 2)
A film forming stock solution comprising 19 parts by weight of PSf (manufactured by Solvay), 7 parts by weight of PVP (manufactured by Nippon Shokubai Co., Ltd., K-90) and 74 parts by weight of DMAc (manufactured by Mitsubishi Gas Chemical Company) was prepared. A DMAc 60% by weight aqueous solution was used as the hollow inner liquid. The production stock solution and the hollow inner solution were discharged from the spinneret, and were immersed in a 60 ° C. coagulation bath made of water through a falling part covered with a hood to be solidified. The hollow fiber membrane obtained by washing with water and drying had an inner diameter of 195 μm and a thickness of 45 μm.

  7100 hollow fiber membranes were bundled and inserted into a cylindrical container 2 having a container length (L) of 170 mm and a container inner diameter (D) of 32 mm. After potting using polyurethane resin, excess polyurethane resin was cut to open the hollow fiber membrane 3. Thereafter, a header 7 was attached to the cylindrical container 2, filled with an antioxidant containing an aqueous sodium pyrosulfite solution, and sterilized by γ rays to obtain a hollow fiber membrane module. About the obtained hollow fiber membrane module, the same measuring method as Example 1 was implemented.

(Comparative Example 3)
The same manufacturing method and measurement method as in Example 1 were carried out except that the inner diameter of the hollow fiber was 225 μm, the film thickness was 45 μm, the number of hollow fibers was 9100, and the cut surface of the polyurethane resin was treated at 690 ° C. for 2 seconds. did.

  The hollow fiber membrane module of the present invention has a low risk of blood coagulation during operation when used for blood purification therapy that circulates blood at a low flow rate like CRRT, and can be used for treatment stably for a long time. .

DESCRIPTION OF SYMBOLS 1 Hollow fiber membrane module 2 Cylindrical container 2a End part 2b of cylindrical container Side part 3 of cylindrical container Hollow fiber membrane 3a End surface 3b Inclined surface 3T Film thickness part (porous film thickness part)
4 Hollow fiber membrane bundle 4a End (open end) of hollow fiber membrane bundle
4b End surface of hollow fiber membrane bundle 5 Potting resin part 6 Port 7 Header 7a Cover part 7b Fixing part 7c Inner face 8 Nozzle 9 Sealing material 10 Header column Ab Dispersion area D Container inner diameter L Module total length Rb Dispersion diameter of hollow fiber membrane bundle Ri Inside diameter of hollow fiber membrane Re Opening diameter of hollow fiber membrane (inner diameter at opening end face)
Ro Outer diameter of hollow fiber membrane Rt Thickness of hollow fiber membrane

Claims (9)

A cylindrical container;
A bundle of hollow fiber membranes loaded into the cylindrical container along the longitudinal direction of the cylindrical container;
A potting resin portion that surrounds and embeds both ends of the bundle of hollow fiber membranes inside both ends of the cylindrical container, and fixes both ends of the bundle of hollow fiber membranes to both ends of the cylindrical container; ,
Having nozzles that serve as inlets and outlets for fluid flowing in the cylindrical container, and provided with headers provided at both ends of the cylindrical container,
The ratio (Ri / Re) of the inner diameter (Ri) of the hollow fiber membrane and the inner diameter (Re) of the open end of the hollow fiber membrane on the fluid inlet side is Ri / Re <1.
Because
The ratio (Re / Ro) between Re and the outer diameter (Ro) of the hollow fiber membrane is:
0.5 ≦ Re / Ro <1
A hollow fiber membrane module. A cylindrical container;
A bundle of hollow fiber membranes loaded into the cylindrical container along the longitudinal direction of the cylindrical container;
A potting resin portion that surrounds and embeds both ends of the bundle of hollow fiber membranes inside both ends of the cylindrical container, and fixes both ends of the bundle of hollow fiber membranes to both ends of the cylindrical container; ,
Having nozzles that serve as inlets and outlets for fluid flowing in the cylindrical container, and provided with headers provided at both ends of the cylindrical container,
The ratio (Ri / Re) of the inner diameter (Ri) of the hollow fiber membrane and the inner diameter (Re) of the open end of the hollow fiber membrane on the fluid inlet side is Ri / Re <1.
Because
When the dispersion diameter, which is the diameter of the hollow fiber membrane bundle dispersed in a circular shape on the end face of the hollow fiber membrane bundle, is Rb, it occupies the dispersion area (Ab), which is the area of the circle having the dispersion diameter Rb as the diameter. The ratio of the sum (At) of the end opening area on the fluid inlet side of the hollow fiber membrane is:
0.10 ≦ At / Ab ≦ 0.64
A hollow fiber membrane module. The film thickness (Rt) of the hollow fiber membrane is
30 μm ≦ Rt ≦ 45 μm
The hollow fiber membrane module according to claim 1 or 2. The inner diameter (Ri) of the hollow fiber membrane is
190μm ≦ Ri ≦ 240μm
The hollow fiber membrane module according to any one of claims 1 to 3, wherein   The hollow fiber membrane module according to any one of claims 1 to 4, wherein the porous film thickness portion of the hollow fiber membrane has a gradient structure.   The inclined surface of 10 degrees to 70 degrees with respect to the opening end face is formed over the entire circumference of the opening end portion of the hollow fiber membrane, according to any one of claims 1 to 5. Hollow fiber membrane module.   The hollow fiber membrane module according to any one of claims 1 to 6, wherein the hollow fiber membrane comprises a hydrophobic polymer and a hydrophilic polymer.   The hollow fiber membrane module according to claim 7, wherein the hydrophobic polymer is polysulfone, and the hydrophilic polymer is polyvinylpyrrolidone. When the total module length is L and the inner diameter of the container is D,
3.5 ≦ L / D ≦ 5.5
The hollow fiber membrane module according to any one of claims 1 to 8, wherein

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