JP2017035644A - Hollow fiber membrane module and production method of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hollow fiber membrane which has a gradient structure so that a bore diameter becomes large from an internal surface side toward an external surface and where the occurrence of residence when blood is flown into a hollow fiber membrane from the internal space of a header is suppressed even when the flow rate of the blood is low and the adhesion of a blood cell component at the inflow port of the hollow fiber membrane is suppressed.SOLUTION: In a hollow fiber membrane module including a cylindrical container, the bundle of hollow fiber membranes 3, a potting resin part and a header: the hollow fiber membrane 3 has a gradient porous structure in which a bore diameter is extended from an inside toward an outside in a membrane thickness direction; an inclined surface 10 having an inclination angle to an opening end surface 3a of 10 to 70 degrees over the whole circumference of the opening end of the hollow fiber membrane 3 is formed; and the inclined surface 10 is formed from the whole circumference of the outer end 3e of a film thickness toward the inside.SELECTED DRAWING: Figure 3

Description

  The present invention relates to a hollow fiber membrane module in a hollow fiber membrane medical device and a method for producing the same.

  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 flow rate of 200 mL / min for 4 hours, while CRRT is performed at a flow rate of 100 mL / min for 8 to 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 end portions fixed to both ends of the cylindrical container. ing. Further, the hollow fiber membrane module has a potting resin portion for embedding and fixing the hollow fiber membrane bundle at both ends of the cylindrical container. Further, the hollow fiber membrane module is provided at both end portions of the cylindrical container so as to face both end surfaces of the hollow fiber membrane, and includes a header including a nozzle serving as a fluid inlet / outlet, and a tubular container. It is provided in the side part and has a port that serves as a fluid inlet / outlet port.

  In blood purification therapy, it is necessary to prevent blood coagulation in the hollow fiber membrane module. This is because if the blood coagulates, the treatment must be temporarily interrupted by replacing the hollow fiber membrane module and the blood remaining in the circuit is lost accordingly. Therefore, the more serious the patient's pathological condition is like CRRT, the more important it is to suppress blood coagulation.

  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 operation, but blood coagulation may still occur due to blood compatibility of a hollow fiber membrane or the like and 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.

  In order to make blood smoothly flow into the hollow fiber membrane, a method of constructing a curved surface or an inclined surface at the open end of the hollow fiber membrane is disclosed. 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 inside the film thickness, only the hollow fiber membrane can be melted by heating or the like to change the shape of the hollow fiber inlet.

On the other hand, a hollow fiber membrane such as a polysulfone membrane that has a dense layer on the inner surface side of the film thickness and that has a gradient structure in which the pore diameter increases from the inner surface side toward the outer surface, Gets into the film thickness. In this case, since there is a potting resin, it is impossible to melt only the hollow fiber membrane, so that an inclination is not established or a step is generated in the inclination even if heating or the like is attempted.
The gradient structure is a structure necessary 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 performs a substantial solute removal function, solute removal is performed throughout the film thickness portion. Since the resistance is lower than that of the film that performs, 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 for blood to smoothly flow into the hollow fiber membrane, it is important to allow blood to flow through an inclined surface or curved surface at an appropriate angle. Even if the inclined surface is not constructed, or even if the inclined surface is constructed at an optimum angle, if the length of the inclined surface is short or there is a step on the inclined surface, the effect of preventing blood retention is insufficient. turn into.

  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. If the angle of inclination constructed at the open end of the hollow fiber membrane is too shallow or too deep, the effect of preventing blood retention will be insufficient. When blood flows at a high flow rate, the influence of the inclination angle is small due to its high fluidity, but when the blood flows at a low flow rate, the inclination angle is important because the blood tends to stagnate.

  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 a potting resin enters a 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 in a hollow fiber membrane having a gradient structure in which the pore diameter increases from the inner surface side toward the outer surface, A hollow fiber membrane module capable of suppressing the occurrence of stagnation when blood flows into the hollow fiber membrane from the header inner space even when flowing at a low flow rate, and the adhesion of blood cell components at the hollow fiber membrane inlet, and its An object is to provide a manufacturing method.

  As a result of intensive studies to solve the above problems, the inventors of the present invention have been able to prevent the potting resin from entering the film thickness even in the case of a film having a gradient structure. The present invention has been completed by finding that the above problems can be solved by constructing a plane.

That is, the present invention is as follows.
(1) a cylindrical container;
A hollow fiber membrane bundle loaded into the cylindrical container along the longitudinal direction of the cylindrical container;
A potting resin part that embeds both ends of the hollow fiber membrane bundle inside both ends of the cylindrical container, and fixes both ends of the hollow fiber membrane bundle to both ends of the cylindrical container;
Having a nozzle serving as an inlet / outlet of a fluid flowing in the cylindrical container, and headers provided respectively at both ends of the cylindrical container;
A hollow fiber membrane module comprising:
The hollow fiber membrane has a gradient porous structure in which the pore diameter increases from the inside to the outside in the film thickness direction,
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 of the hollow fiber membrane,
The inclined surface is formed from the entire outer edge of the film thickness toward the inside.
A hollow fiber membrane module characterized by the above.

  According to the present invention, by optimizing the shape of the end of the hollow fiber membrane having a gradient porous structure, blood flows smoothly from the header internal space into the hollow fiber membrane. Phenomena that lead to blood coagulation such as activation of the coagulation reaction can be suppressed. Furthermore, since the inflow port expands and the flow resistance is reduced, damage to blood cells can be suppressed.

(2) In the hollow fiber membrane module of the above (1), it is preferable that the height difference of the unevenness of the end surface of the potting resin portion in the end surface of the hollow fiber membrane bundle is 10 μm or less. In this hollow fiber membrane module, it is easy to suppress the accumulation and damage of blood cell components, and it is easy to suppress blood turbulence and smoothly flow blood into the hollow fiber membrane to suppress blood coagulation.

(3) In the hollow fiber membrane module of the above (2), when 1/2 of the inner diameter of the header is a radius a, it is a / 3 away from the central portion of the header in a direction perpendicular to the axis of the cylindrical container When the height from the end surface of the potting resin part to the inner surface of the header at a position h1, the height from the end surface of the potting resin part to the inner surface of the header at a position away from h1, 2a / 3, It is preferable that 0.9h1 ≦ h2 ≦ 1.0h1. Further, according to the present invention, it is possible to achieve both the effect of suppressing the retention of blood in the header and the effect of suppressing the retention of blood at the inflow portion to the hollow fiber membrane by using a header having a flat header space. It becomes.

(4) In the hollow fiber membrane module of the above (3), it is preferable that h1 ≦ 2.5 mm. 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.

(5) In the hollow fiber membrane module of (1), the length from the end surface of one of the potting resin portions to the end surface of the other potting resin portion is the container length L, and the container inner diameter of the cylindrical container is D It is preferable that 3.5 ≦ L / D ≦ 5.5.

The manufacturing method of the hollow fiber membrane module according to the present invention is as follows.
(6) In the manufacturing method of the hollow fiber membrane module,
Including a sealing agent in at least a part of the end of the hollow fiber membrane bundle,
The both ends of the hollow fiber membrane bundle are embedded with potting resin inside the both ends of the cylindrical container, and the both ends of the hollow fiber membrane bundle are fixed to the both ends of the cylindrical container,
Cutting and removing excess potting resin, opening the end face of the hollow fiber membrane,
A method of manufacturing a hollow fiber membrane module, comprising: heating a bundle of hollow fiber membranes to melt a part of the bundle of hollow fiber membranes and constructing an inclined surface on an end surface of the hollow fiber membrane.

  According to the present invention, even when blood flows at a low flow rate, the occurrence of retention when blood flows from the header internal space into the hollow fiber membrane is suppressed, and adhesion of blood cell components at the hollow fiber membrane inlet is suppressed. Can do.

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. (A) is a schematic diagram showing an inclined structure of the end portion of the hollow fiber membrane in the present invention, (b) is a schematic diagram showing an inclination angle of the end portion of the hollow fiber membrane in the present invention, and (c) is a general hollow fiber membrane. It is a schematic diagram which shows the structure of an 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.

  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.

[1. Manufacturing method of hollow fiber membrane]
The shape, dimensions, and fractionation characteristics of the hollow fiber membrane 3 of the present embodiment are not particularly limited, and can be appropriately selected in light of the intended purpose.

  The material of the hollow fiber membrane 3 is not particularly limited, but a hydrophilizing agent such as polyvinylpyrrolidone is added to a polysulfone polymer such as polysulfone (hereinafter sometimes referred to as “PSf”) or polyethersulfone. The contained 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 use and it is easy to optimize blood compatibility. The hollow fiber membrane 3 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
(-?-SO2-?-OC (CH3) 2-?-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.

  The process for producing the hollow fiber membrane 3 is not limited to the following, but, for example, a tube-in-orifice type spinneret is used, and a membrane-forming stock solution is solidified from the spinneret orifice through a hollow interior for coagulating the membrane-forming stock solution. Simultaneously with the liquid, it is discharged from the tube into the air.

The film-forming stock solution can be adjusted 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 3 can be adjusted to desired values by adjusting the stock solution discharge amount and the hollow inner solution discharge amount.

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.

  Next, the hollow fiber membrane 3 can be obtained by washing, further attaching a pore diameter retaining agent such as glycerin or an aqueous polyethylene glycol solution, and performing a drying treatment. Although the hollow fiber membrane 3 can be obtained without using a pore diameter retainer, it is preferable to use it because it becomes easy to control the change in the pore diameter in the drying process or the like.

[2. Manufacturing method of 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 FIGS. 1 and 2, for convenience, only portions appearing in the cross section are shown in the diagram.
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, even if the total area of the inner surface of the hollow fiber membrane 3 is the same, the thickness of the module is larger, and the longitudinal direction of the module Since the linear velocity of the fluid is suppressed when the length is shorter, the pressure loss can be suppressed low. 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 3.5 ≦ L / D ≦ 5.5.

  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).

  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. A flat structure such that ≦ 1.0 h1 is preferable, and h1 = h2 is more preferable. 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.

  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, and silicon resin.

  Thereafter, excess potting resin is cut off and the end surface 3a of the hollow fiber membrane 3 is opened. It is preferable to cut the end surface 4b of the hollow fiber membrane bundle 4 so that the surface of the potting resin portion 5 (end surface made of a cut surface) is smooth, and the unevenness of the unevenness of the end surface (surface) of the potting resin portion 5 (later Describes the measurement method) from the viewpoint of suppressing the accumulation of blood cell components, the occurrence of damage, and also from the viewpoint of suppressing blood turbulence and smoothly flowing blood into the hollow fiber membrane 3 to suppress blood coagulation. It is preferable that it is 10 micrometers or less.

[3. Method for constructing inclined structure of hollow fiber membrane inlet]
Since the hollow fiber membrane 3 has a gradient structure, the pore diameter of the outer surface is relatively large. Therefore, in the potting process, the potting resin enters the film thickness to some extent. In particular, when the hole area ratio on the outer surface of the hollow fiber is 20% or more, the potting resin easily enters. If the potting resin enters, it becomes difficult to construct the inclined surface 10 on the end surface 3a that is an inlet of the fluid to the hollow fiber membrane 3. Alternatively, the inclined surface 10 can be formed only on a part of the film thickness. On the other hand, when the potting resin enters the film thickness, the adhesive strength between the potting resin and the hollow fiber membrane 3 increases.

  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. It is possible to prevent the potting resin from entering the film thickness only in the opening portion, and to stably manufacture the tapered surface (or funnel-shaped, trumpet-shaped, or mortar-shaped) inclined surface 10 that is uniform on the end surface 3a. On the other hand, since the potting resin enters the film thickness except for the opening, the adhesive strength between the potting resin and the hollow fiber membrane 3 can be maintained. The tapered inclined surfaces 10 are preferably formed on both end surfaces 3a of the hollow fiber membrane 3, but will be described later if at least one end surface (fluid inlet side) is formed. Thus, it becomes 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 void portions of the film thickness of all the hollow fiber membranes 3 to be immersed, the inclined surface 10 is constructed from the outer end of the film thickness in all the hollow fiber membranes 3. Is possible.

  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 10 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.
As shown in FIG. 3 b, the inclination angle α of the inclined surface 10 is an angle formed by the inclined surface 10 and a straight line connecting the outer end 3 e and the other outer end 3 e of the film thickness in the longitudinal section of the hollow fiber membrane 3. It shall be shown. In other words, the inclination angle α of the inclined surface 10 indicates an inclination with respect to the end surface 3a when the end surface 3a of the hollow fiber membrane 3 before the inclined surface 10 is formed is set to 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 10 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.

  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. Washing with water, application of 20% strength glycerin (Japanese Pharmacopoeia) aqueous solution, and drying were performed to obtain a blood treatment membrane. The obtained hollow fiber membrane 3 had an inner diameter of 210 to 240 μm and a film thickness of 20 to 75 μm.

  9100 hollow fiber membranes were bundled, and 10 mm on one side of the bundle end was immersed in glycerin (Japanese Pharmacopoeia) having a concentration of 85% for 5 seconds. Then, in order to impregnate the hollow fiber membrane 3 with glycerol by capillary action, it left still for 20 hours. At this time, 370% of glycerin was contained in the end 4a of the hollow fiber membrane bundle 4 with respect to the weight of the hollow fiber membrane. 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 700 ° heat source for 5 seconds, and the inclined surface 10 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. The height of the header inner space after mounting the header 7 was h1 = h2 = 1.8 mm.

[Observation of inclined structure]
In order to evaluate whether or not the inclined surface 10 is constructed from the entire outer edge of the hollow fiber membrane 3 toward the inside, the open end of the hollow fiber membrane bundle 4 of the hollow fiber membrane module 1 is sliced. They were observed with a scanning electron microscope (Hitachi, S-3000N) at a 150 × field of view, not from directly above, but obliquely from above.
The state of the opening end face was observed in a total of five areas divided into a concentric circle having a radius that is half the radius of the opening end face and an outer peripheral portion thereof divided into four at an angle of 90 degrees (see FIG. 5).

[Measurement of tilt angle]
The inclination angle α of the inclined surface 10 was measured with a laser microscope (KEYENCE, VK-8500). Similar to the observation method in the inclined state, the open end of the hollow fiber membrane bundle 4 of the hollow fiber membrane module 1 is sliced, and a concentric circle (see FIG. 5) having a radius of half the radius of the outer circumference of the open end, The inclining angle α of the inlet was measured for a total of 15 hollow fiber membranes 3 in each of the three areas divided into a total of five areas divided into four at 90 °. The inclination angle α can be calculated using known analysis software that performs image processing, calculation, and the like.
It is confirmed that the inclination is constructed from the outer end of the film thickness of the hollow fiber membrane 3, and the inclination angle α is measured by measuring the shape from one point on the inner peripheral surface of the film thickness to the outer end of the film thickness. Was calculated.

[Measurement of unevenness of unevenness of the end surface of the potting resin part at the opening end surface]
Using a laser microscope (KEYENCE, VK-9700), the maximum raised height in the area of only the potting resin not including the hollow fiber membrane 3 at the open end of the hollow fiber membrane bundle 4 was measured. When bumps are observed on the end surface of the potting resin part 5, the maximum bump height in the 250 μm square area including the bumps is taken as the measurement value. If no bumps are observed, the 250 μm square area is not specified unless otherwise specified. The maximum height in that area was taken as the measurement value.

(Measurement of blood cell adhesion)
In order to evaluate the accumulation of blood cell components in the flow into the hollow fiber membrane 3, the number of blood cell components attached to the inclined portion (that is, the inclined surface 10) 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 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 were extracted, one at each of the four areas on the four sides of the center and outer periphery of the open end of the hollow fiber membrane bundle, and used as observation targets.

[Measurement of hemolysis rate]
In order to evaluate the damage of blood cell components in the flow into the hollow fiber membrane, 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. The header column 11 was manufactured by pressing and fixing the sealing material 9 (see FIG. 4).

  After separating blood cell components and plasma from bovine blood (hematocrit value: 50%) added with CPD by centrifugation (3500 rpm, 20 minutes), 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) and connected to another empty blood bag of the same volume via a circuit and header column 11. In the closed circuit thus obtained, the operation of perfusing the erythrocyte concentrated solution into the header column 11 using the head 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 the table of FIG. 6 together with the measurement results of other examples and comparative examples.

(Example 2)
The same production method and measurement method as in Example 1 were carried out except that the cut surface of the polyurethane resin was brought close to a heat source of 710 degrees for 5 seconds.

(Example 3)
The same production method and measurement method as in Example 1 were carried out except that the cut surface of the polyurethane resin was brought close to a heat source at 725 degrees for 6 seconds.

Example 4
The same manufacturing method and measurement method as in Example 1 were carried out except that a header having an inner height of h1 = h2 = 4.2 mm was mounted.

(Example 5)
The same production method and measurement method as in Example 1 were carried out except that the cylindrical container 2 having 6300 hollow fibers, a container length (L) of 170 mm, and a container inner diameter (D) of 32 mm was used.

(Example 6)
The same production method and measurement method as in Example 1 were carried out except that a cylindrical container 2 having 11700 hollow fibers, a container length (L) of 170 mm, and a container inner diameter (D) of 44 mm was used.

(Comparative Example 1)
The same production method as in Example 1 was carried out except that the end of the hollow fiber membrane bundle was not immersed in the glycerin aqueous solution before the hollow fiber membrane bundle was inserted into the cylindrical container. The obtained hollow fiber membrane had an inner diameter of 210 to 240 μm, a film thickness of 20 to 75 μm, and a glycerol content of 75% at the end of the hollow fiber membrane bundle. The header height was h1 = h2 = 1.8 mm. The obtained hollow fiber membrane module 1 was subjected to the same measurement method as in Example 1.

(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. Washing with water, application of 72% glycerin (Japanese Pharmacopoeia) aqueous solution, and drying were performed to obtain a blood treatment membrane. The obtained hollow fiber membrane had an inner diameter of 210 to 240 μm and a film thickness of 20 to 75 μm. Moreover, 200% of glycerin was contained in the end portion of the hollow fiber membrane bundle with respect to the weight of the hollow fiber membrane.

  A bundle of 9100 hollow fiber membranes was inserted into a cylindrical container and potted with a polyurethane resin, and then the excess polyurethane resin was cut to open the hollow fiber membrane. The urethane surface was brought close to a heat source of 720 degrees for 5 seconds, and an inclined surface was constructed at the end of the hollow fiber membrane. Then, the hollow fiber membrane module was obtained by mounting | wearing with the header, filling the antioxidant containing sodium pyrosulfite aqueous solution, and sterilizing with a gamma ray. The height of the header inner space after mounting the header was h1 = h2 = 1.8 mm.

(Comparative Example 3)
The same production method and measurement method as in Example 1 were carried out except that the cut surface of the polyurethane resin was brought close to a heat source of 740 degrees for 6 seconds.

As shown in the table (see FIG. 6), the hollow fiber membrane in which glycerin is sufficiently contained at the end of the hollow fiber membrane bundle prevented the potting resin from entering the film thickness. A slope was built inward.
As a result, it was shown that the number of blood cells adhering to the inclined part to which an appropriate angle was given was greatly reduced, and blood smoothly flowed into the hollow fiber membrane without stagnation, thereby indicating that blood coagulation can be suppressed. Moreover, since the urethane surface was smooth, it was also shown that there is little adhesion of the blood cell component in a urethane part.
Furthermore, since the rate of hemolysis can be reduced by the construction of the inclined structure, it has been shown that damage to blood cell components and accompanying blood coagulation can be suppressed.

  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 3e of hollow fiber membrane Outer end 4 Hollow fiber membrane bundle 4a End part 4b of hollow fiber membrane bundle End surface 5 of hollow fiber membrane bundle 5 Potting resin part 6 Port 7 Header 7a Cover part 7b Fixing part 7c Inner surface 8 of nozzle 9 Sealing material 10 Inclined surface 11 Header column

Claims (6)

A cylindrical container;
A hollow fiber membrane bundle loaded into the cylindrical container along the longitudinal direction of the cylindrical container;
A potting resin part that embeds both ends of the hollow fiber membrane bundle inside both ends of the cylindrical container, and fixes both ends of the hollow fiber membrane bundle to both ends of the cylindrical container;
Having a nozzle serving as an inlet / outlet of a fluid flowing in the cylindrical container, and headers provided respectively at both ends of the cylindrical container;
A hollow fiber membrane module comprising:
The hollow fiber membrane has a gradient porous structure in which the pore diameter increases from the inside to the outside in the film thickness direction,
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 of the hollow fiber membrane,
The inclined surface is formed from the entire outer edge of the film thickness toward the inside.
A hollow fiber membrane module characterized by the above.   2. The hollow fiber membrane module according to claim 1, wherein the difference in height of the unevenness of the end surface of the potting resin portion at the end surface of the hollow fiber membrane bundle is 10 μm or less.   When the radius a is 1/2 of the inner diameter of the header, the inner surface of the header from the end surface of the potting resin portion at a position a / 3 away from the central portion of the header in a direction orthogonal to the axis of the cylindrical container 0.9h1 ≦ h2 ≦ 1.0h1, where h2 is the height from the end surface of the potting resin portion to the inner surface of the header at a position where the height is up to h1, 2a / 3. The hollow fiber membrane module according to claim 2.   The hollow fiber membrane module according to claim 3, wherein h1 ≦ 2.5 mm.   When the length from one end surface of the potting resin portion to the end surface of the other potting resin portion is a container length L and the inner diameter of the cylindrical container is D, 3.5 ≦ L / D ≦ 5. The hollow fiber membrane module according to claim 1, wherein In the method for producing a hollow fiber membrane module,
Including a sealing agent in at least a part of the end of the hollow fiber membrane bundle,
The both ends of the hollow fiber membrane bundle are embedded with potting resin inside the both ends of the cylindrical container, and the both ends of the hollow fiber membrane bundle are fixed to the both ends of the cylindrical container,
Cutting and removing excess potting resin, opening the end face of the hollow fiber membrane,
A method of manufacturing a hollow fiber membrane module, comprising: heating a bundle of hollow fiber membranes to melt a part of the bundle of hollow fiber membranes and constructing an inclined surface on an end surface of the hollow fiber membrane.

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