JP7424873B2 - Artificial lung and its manufacturing method - Google Patents

Description

The present invention relates to an artificial lung and a method for manufacturing the same.

Oxygenators having porous hollow fiber membranes may have reduced gas exchange performance after long-term use. Wet lungs and plasma leaks are said to be the main causes. The wet rung can restore gas exchange performance by blowing air at high pressure and removing condensed water from the hollow fiber membrane. On the other hand, plasma leak is said to cause an irreversible decline in the performance of oxygenators. In the long-term use of oxygenators, it is essential to solve problems caused by plasma leakage, and many studies have been made to date. Among these, as a means to improve plasma leak resistance, methods have been adopted in which the micropores present in the hollow fiber membrane are blocked or the micropores in the hollow fiber membrane are made extremely fine.

For example, Patent Document 1 describes that by applying a silicone coating to the outer surface of a porous hollow fiber membrane made of polypropylene, plasma leakage becomes less likely to occur and long-term use becomes possible.

Japanese Patent Application Publication No. 2002-035116

However, according to the method described in Patent Document 1, a continuous line of the hollow fiber membrane is moved at 0.5 to 50 m/min in the silicone monomer atmosphere during plasma discharge under high vacuum, and the silicone monomer is A silicone coating is produced by polymerization on the outer surface of the thread membrane. Therefore, there was a problem in that the coating process required complicated equipment and a long time.

Therefore, an object of the present invention is to provide a technique for manufacturing an artificial lung using a simpler method.

The present inventors conducted extensive research in order to solve the above problems. As a result, the inventors discovered that the above object can be achieved by bringing a porous hollow fiber membrane made of polypropylene into contact with a coating liquid containing dopamine (or its salt, oligomer), etc., and completed the present invention.

That is, the above object is a method for manufacturing an oxygenator having a plurality of porous hollow fiber membranes for gas exchange, at least a portion of which is formed of polypropylene, wherein the hollow fiber membranes have an inner surface forming a lumen and a plurality of porous hollow fiber membranes for gas exchange. , an outer surface, and containing at least one compound selected from the group consisting of dopamine, its salts, and oligomers, and coat the inner or outer surface of the hollow fiber membrane with the coating liquid. This can be achieved by a method comprising forming a polymer layer containing a polymer of the compound on the inner surface or outer surface by contacting for 16 hours or more.

According to the present invention, it is possible to provide an artificial lung using a simpler method.

FIG. 1 is a sectional view of a hollow fiber membrane external blood perfusion oxygenator according to an embodiment of the present invention. FIG. 2 is an enlarged sectional view of a porous hollow fiber membrane for gas exchange used in a hollow fiber membrane external blood perfusion oxygenator according to an embodiment of the present invention. FIG. 3 is a cross-sectional view of a hollow fiber membrane external blood perfusion oxygenator according to another embodiment of the present invention. FIG. 4 is a cross-sectional view taken along the line AA in FIG. 3. FIG. 5 is a front view showing an example of the inner cylindrical member used in the hollow fiber membrane external blood perfusion oxygenator according to the present invention. FIG. 6 is a central longitudinal sectional view of the inner cylindrical member shown in FIG. 5. FIG. FIG. 7 is a sectional view taken along line BB in FIG. FIG. 8 is a graph showing plasma leak resistance in Examples and Comparative Examples.

A first aspect of the present invention is a method for manufacturing an oxygenator having a plurality of porous hollow fiber membranes for gas exchange, at least a portion of which is formed of polypropylene, wherein the hollow fiber membranes have an inner surface forming a lumen. and an outer surface, and includes at least one compound selected from the group consisting of dopamine, its salts, and oligomers, and coats the inner or outer surface of the hollow fiber membrane with the coating liquid. and forming a polymer layer containing a polymer of the compound on the inner surface or outer surface by contacting the compound with the compound for 16 hours or more.

A second aspect of the present invention is an oxygenator having a plurality of porous hollow fiber membranes for gas exchange, at least a part of which is formed of polypropylene, wherein the hollow fiber membranes have an inner surface forming a lumen and a plurality of porous hollow fiber membranes for gas exchange. , an outer surface, and a polymer layer containing a polymer of at least one compound selected from the group consisting of dopamine, salts and oligomers thereof on either the inner surface or the outer surface; The present invention relates to an artificial lung in which an antithrombotic agent layer containing an antithrombotic agent is sequentially formed.

In this specification, at least one compound selected from the group consisting of dopamine, its salts, and oligomers is also simply referred to as a "polymer layer-forming compound."

According to the method for manufacturing an artificial lung according to the present invention, it is possible to provide an artificial lung using a simpler method compared to the manufacturing method described in Patent Document 1. The mechanism by which the structure of the present invention achieves the above-mentioned effects is presumed to be as follows. Note that the following mechanism is based on speculation, and the present invention is not limited to the following mechanism in any way.

In the method of the present invention, a coating liquid of a polymer layer-forming compound is brought into contact with the surface of the hollow fiber membrane for a predetermined period of time, the polymer layer-forming compound is polymerized on the surface of the hollow fiber membrane, and the polymer layer is formed on the surface of the hollow fiber membrane. Form. For example, dopamine is typically oxidized to produce 5,6-dihydroxyindole, which is polymerized to form and deposit a dopamine polymer (polydopamine) on a substrate to form a dopamine polymer layer. Therefore, according to the method of the present invention, an oxygenator can be manufactured by a simple operation of bringing a coating liquid containing a polymer layer-forming compound such as dopamine (or its salt, oligomer) into contact with the hollow fiber membrane surface. Here, if the contact time of the coating liquid and the hollow fiber membrane is less than 16 hours, the reaction of the polymer layer forming compound (for example, oxidation and polymerization of dopamine) will not proceed sufficiently, and the function of the polymer layer (for example, , plasma leak resistance, and adhesion with the antithrombotic agent layer). Therefore, the artificial lung manufactured by the method of the present invention has excellent plasma leak resistance and durability (antithrombotic maintenance property).

Furthermore, according to the method of the present invention, after assembling the oxygenator (or hollow fiber membrane bundle), it is possible to bring a coating liquid containing a compound such as dopamine (or a salt thereof) into contact with the surface of the hollow fiber membrane. . Therefore, the method of the present invention is preferable from the viewpoint of productivity/mass production.

In addition, the reactant of the polymer layer-forming compound according to the present invention (especially dopamine polymer (polydopamine)) has high reactivity with organic substances, and the polymer layer according to the present invention (especially dopamine polymer layer) Highly reactive. Therefore, the polymer layer has high adhesion to the polypropylene hollow fiber membrane. In addition, when an antithrombotic agent layer is formed on the polymer layer, the reactant of the polymer layer-forming compound in the polymer layer (especially polydopamine) is absorbed by the antithrombotic agent (for example, polymethoxy) in the antithrombotic agent layer. It also exhibits high reactivity with ethyl (meth)acrylate). Therefore, the polymer layer exhibits high reactivity with the antithrombotic agent and has high adhesion to the antithrombotic agent layer. That is, the antithrombotic agent layer can be firmly integrated with the hollow fiber membrane via the polymer layer. Therefore, the artificial lung produced by the method of the present invention has excellent antithrombotic effects (e.g., antithrombotic properties) and plasma leak resistance, and also has excellent resistance to plasma leakage even after long-term use, for example, for one month or more. Antithrombotic properties and plasma leak resistance can be maintained (that is, excellent antithrombotic properties, plasma leak resistance, antithrombotic maintenance properties, and plasma leak resistance maintenance properties).

Therefore, the artificial lung produced by the method of the present invention can be suitably used not only as an artificial lung used in ordinary surgeries, but also as a circulatory/pulmonary support device for patients with serious diseases.

Preferred embodiments of the present invention will be described below. Note that the present invention is not limited only to the following embodiments. Furthermore, the dimensional ratios in the drawings are exaggerated for convenience of explanation and may differ from the actual ratios.

In this specification, the range "X to Y" includes X and Y, and means "more than or equal to X and less than or equal to Y." Further, unless otherwise specified, operations and measurements of physical properties, etc. are performed under conditions of room temperature (20 to 25°C)/relative humidity of 40 to 50% RH.

Hereinafter, the manufacturing method of the oxygenator of the present invention will be explained in detail. For convenience, in this specification, the oxygenator of the present invention will be explained first, and then the manufacturing method of the present invention will be explained.

<Artificial lung>
An oxygenator according to one aspect of the present invention is an oxygenator having a plurality of porous hollow fiber membranes for gas exchange, at least a part of which is formed of polypropylene, the hollow fiber membranes having an internal cavity forming a lumen. a polymer layer and an antithrombotic agent layer formed by the method of the present invention on at least one of the inner surface and the outer surface in this order (i.e., a hollow fiber membrane, polymer layer and antithrombotic agent layer). The oxygenator of the present invention exhibits high plasma leak resistance and antithrombotic effects (e.g., antithrombotic properties), and even when used for a long period of time, for example, one month or more, its plasma leak resistance and Antithrombotic properties can be maintained (that is, excellent plasma leak resistance, antithrombotic properties, plasma leak resistance maintenance properties, and antithrombotic maintenance properties). Therefore, the artificial lung of the present invention uses ECMO (Extra Corporeal Membrane Oxygenation) or It can be particularly suitably used as an extracorporeal circulation device such as PCPS (Percutaneous Cardio Pulmonary Support). That is, the present invention provides an oxygenator having a plurality of porous hollow fiber membranes for gas exchange, at least a portion of which is formed of polypropylene, the hollow fiber membranes having an inner surface forming a lumen and an outer surface. and a polymer layer containing a polymer of at least one compound selected from the group consisting of dopamine and its salts and oligomers on either the inner surface or the outer surface, and an antithrombotic agent. an antithrombotic agent layer, and an antithrombotic agent layer are provided. Note that hereinafter, the polymer layer formed by the method of the present invention will also be simply referred to as a "polymer layer according to the present invention" or a "polymer layer."

Details of the oxygenator according to the invention will be explained below with reference to the drawings.

FIG. 1 is a sectional view of a hollow fiber membrane external blood perfusion oxygenator according to an embodiment of the present invention. FIG. 2 is an enlarged sectional view of a porous hollow fiber membrane for gas exchange used in a hollow fiber membrane external blood perfusion oxygenator according to an embodiment of the present invention.

In the embodiment shown in FIG. 1, a hollow fiber membrane external blood perfusion oxygenator 1 includes a housing 2 containing a large number of porous hollow fiber membranes 3 for gas exchange. As shown in FIG. 2, the hollow fiber membrane 3 includes a passageway (inner cavity) 3d forming a gas chamber in the center. Here, when oxygen-containing gas flows into the lumen 3d, blood flows outside the hollow fiber membrane (on the outer surface 3a' side) (hollow fiber membrane external blood perfusion oxygenator). Similarly, when blood flows into the lumen 3d, oxygen-containing gas flows outside the hollow fiber membrane (on the outer surface 3a' side) (hollow fiber membrane internal blood perfusion oxygenator). Although the present invention may take any of the forms described above, preferably, oxygen-containing gas flows in the inner cavity 3d, and blood flows outside the hollow fiber membrane (on the outer surface 3a' side). In addition, the hollow fiber membrane 3 has openings 3e and 3f that communicate its outer surface 3a' and inner surface 3c'. A polymer layer 16 and an antithrombotic agent layer 18 are provided on at least one of the inner surface 3c' and the outer surface 3a' of the hollow fiber membrane 3 in this order (i.e., the hollow fiber membrane, the polymer layer, and the antithrombotic agent layer in this order). ) is formed. Here, the polymer layer 16 and the antithrombotic agent layer 18 are preferably arranged at least on the side through which blood flows. That is, it is preferable that the polymer layer 16 and the antithrombotic agent layer 18 be formed at least on the outer surface 3a' of the hollow fiber membrane 3. More preferably, it is formed only at 3a'. In addition, although the polymer layer is arranged on the outer surface of the hollow fiber membrane in FIG. 2, the polymer layer may be arranged on the inner surface of the hollow fiber membrane. Further, in FIG. 2, the polymer layer is placed directly above the hollow fiber membrane, but the polymer layer may be placed on the hollow fiber membrane via another layer. Preferably, the polymer layer is disposed on the outer surface of the hollow fiber membrane, more preferably the polymer layer is disposed directly on the outer surface of the hollow fiber membrane.

The polymer layer 16 and the antithrombotic agent layer 18 according to the present invention may be formed on at least a portion of the inner surface 3c' and/or outer surface 3a' of the hollow fiber membrane 3, but the From the viewpoint of maintaining exchange performance (improving plasma leak resistance, suppressing wet rung), it is preferable to form on the entire inner surface 3c' and/or outer surface 3a', and on the entire outer surface 3a'. More preferably, it is formed. Further, the polymer layer 16 according to the present invention is preferably formed as a homogeneous membrane that closes the pores of the hollow fiber membrane 3, as shown in FIG. By adopting such a configuration, leakage of plasma through the pores of the hollow fiber membrane is suppressed, and the resistance to plasma leakage of the oxygenator can be further improved. Therefore, an oxygenator having such a structure can be used for a longer period of time. Note that even in the case of adopting this form, the polymer layer 16 and the antithrombotic agent layer 18 have high gas permeability, so that they can have sufficient gas exchange performance.

Further, the antithrombotic agent layer 18 containing an antithrombotic agent may be formed on at least a portion of the polymer layer 16, but may have antithrombotic properties (suppressing/preventing platelet adhesion/adhesion, and platelet activation). It is preferable to form the polymer layer over the entire polymer layer 16 from the viewpoints of antithrombotic maintenance (durability), plasma leak resistance, and the like. Note that in the embodiment shown in FIG. 2, the polymer layer 16 and the antithrombotic agent layer 18 may be present in the inner layer 3b (in some cases, the inner layer 3b and the inner layer 3c) of the hollow fiber membrane 3. However, it is preferable that it is substantially not present in the inner layer 3b (in some cases, the inner layer 3b and the inner layer 3c) of the hollow fiber membrane 3. When the antithrombotic agent is substantially absent, the inner layer 3b or inner layer 3c of the hollow fiber membrane retains the hydrophobic properties of the membrane base material itself, effectively preventing leakage of plasma components. can be prevented. In this specification, "the antithrombotic agent layer 18 containing an antithrombotic agent is substantially not present in the inner layer 3b (in some cases, the inner layer 3b and the inner surface layer 3c) of the hollow fiber membrane 3" means , means that no penetration of the antithrombotic agent is observed near the inner surface 3c' (the surface through which oxygen-containing gas flows) of the hollow fiber membrane 3. In addition, when forming a polymer layer as described in the preferred embodiment of the method for manufacturing an oxygenator described later, the polymer layer forming compound is substantially not added to the inner layer 3b or inner layer 3c of the hollow fiber membrane 3. It can be a form that does not exist in Similarly, as will be explained in the preferred embodiment of the method for manufacturing an oxygenator described below, by forming a film by applying a colloidal solution of an antithrombotic polymeric compound, the antithrombotic polymeric compound becomes hollow. It may be in a form in which it does not substantially exist in the inner layer 3b or inner layer 3c of the thread membrane 3.

That is, according to a particularly preferred embodiment of the present invention, oxygen-containing gas flows in the lumen of the hollow fiber membrane, blood flows in the outside (outer surface) of the hollow fiber membrane, and the polymer layer and the antithrombotic agent layer are connected to the hollow fiber membrane. They are formed in this order on the entire outer surface (blood contact area) of the membrane (external perfusion oxygenator).

Note that the polymer layer 16 may contain other components in addition to the dopamine polymer (polydopamine). Here, other components include, but are not particularly limited to, polyolefins, aliphatic hydrocarbons, inorganic fine particles, hydrophilic polymers, and the like. Preferably, the polymer layer 16 consists essentially of a dopamine polymer (polydopamine), more preferably only of a dopamine polymer (polydopamine). In addition, in this specification, "the polymer layer is substantially composed of a dopamine polymer (polydopamine)" means that the polymer layer is composed of a component other than the dopamine polymer (polydopamine) (for example, dopamine or its This means that it contains less than 5% by mass (calculated as solid content) of salt).

Similarly, the antithrombotic agent layer 18 may include other components in addition to the antithrombotic agent (eg, the antithrombotic polymeric compound of formula (1), heparin). Here, other components include, but are not particularly limited to, crosslinking agents, thickeners, preservatives, pH adjusters, amphiphilic substances, and the like. Preferably, the antithrombotic agent layer 18 consists essentially of an antithrombotic agent, and more preferably consists only of an antithrombotic agent. In addition, in this specification, "the antithrombotic agent layer is substantially composed of an antithrombotic agent" means that the antithrombotic agent layer contains components other than the antithrombotic agent at a ratio of less than 5% by mass (in terms of solid content). It means to include.

The hollow fiber membrane oxygenator 1 according to the present embodiment includes a housing 2 having a blood inlet 6 and a blood outlet 7, and a large number of porous hollow fiber membranes 3 for gas exchange housed in the housing 2. It has a hollow fiber membrane bundle and a pair of partition walls 4 and 5 that liquid-tightly support both ends of the hollow fiber membrane bundle in the housing 2, and between the partition walls 4 and 5 and the inner surface of the housing 2 and the outer surface of the hollow fiber membrane 3. It has a blood chamber 12 formed inside the hollow fiber membrane 3, a gas chamber formed inside the hollow fiber membrane 3, and a gas inlet 8 and a gas outlet 9 communicating with the gas chamber.

Specifically, the hollow fiber membrane oxygenator 1 of the present embodiment includes a cylindrical housing 2, an assembly of gas exchange hollow fiber membranes 3 housed in the cylindrical housing 2, and a hollow fiber membrane 3 assembly. It has partition walls 4 and 5 that hold both ends of the housing 2 in a fluid-tight manner, and the inside of the cylindrical housing 2 is divided into a blood chamber 12 which is a first fluid chamber and a gas chamber which is a second fluid chamber. The cylindrical housing 2 is provided with a blood inlet 6 and a blood outlet 7 that communicate with the blood chamber 12 .

Above the partition wall 4 which is the end of the cylindrical housing 2, there is a cap-shaped gas inlet having a gas inlet 8 which is a second fluid inlet that communicates with the gas chamber which is the internal space of the hollow fiber membrane 3. A side header 10 is attached. Therefore, a gas inflow chamber 13 is formed by the outer surface of the partition wall 4 and the inner surface of the gas inflow side header 10. This gas inflow chamber 13 communicates with a gas chamber formed by the internal space of the hollow fiber membrane 3.

Similarly, a cap-shaped gas outlet header 11 is attached below the partition wall 5 and has a gas outlet 9 which is a second fluid outlet communicating with the internal space of the hollow fiber membrane 3 . Therefore, the outer surface of the partition wall 5 and the inner surface of the gas outlet header 11 form a gas outlet chamber 14 .

The hollow fiber membrane 3 is a porous membrane at least partially made of polypropylene. Here, the hollow fiber membrane may be partially made of polypropylene and other parts made of a material other than polypropylene (other material), or partially or entirely made of polypropylene and other materials. good. Preferably, the hollow fiber membrane is composed solely of polypropylene. Note that the other materials mentioned above are not particularly limited and may be the same as hollow fiber membranes used in known oxygenators. When the hollow fiber membrane (particularly the inner surface of the hollow fiber membrane) is made of a hydrophobic polymer material, leakage of plasma components can be suppressed. As the material used for the porous membrane, hydrophobic polymeric materials similar to those of hollow fiber membranes used in known oxygenators can be used. Specific examples include polyolefin resins such as polyethylene and polymethylpentene, and polymeric materials such as polysulfone, polyacrylonitrile, polytetrafluoroethylene, and cellulose acetate. Among these, polyolefin resins are preferably used, and polymethylpentene is more preferred. In addition, when the hollow fiber membrane is composed of polypropylene and other materials as mentioned above, the content of polypropylene is usually 70% by mass (in terms of solid content) with respect to all the materials constituting the hollow fiber membrane. , preferably 80% by mass (in terms of solid content) or more, and more preferably 90% by mass (in terms of solid content) or more (upper limit: less than 100% by mass).

The inner diameter of the hollow fiber membrane is not particularly limited, but is preferably 50 to 300 μm, more preferably 80 to 200 μm. The outer diameter of the hollow fiber membrane is not particularly limited, but is preferably 100 to 400 μm, more preferably 130 to 200 μm. The wall thickness (membrane thickness) of the hollow fiber membrane is preferably 20 μm or more and less than 50 μm, more preferably 25 μm or more and less than 50 μm, even more preferably 25 to 45 μm, even more preferably 25 to 40 μm, even more preferably 25 to 35 μm, especially Preferably it is 25 to 30 μm. In addition, in this specification, "the wall thickness (membrane thickness) of a hollow fiber membrane" intends the wall thickness between the inner surface and the outer surface of the hollow fiber membrane, and the formula: [(outer surface of the hollow fiber membrane) diameter) - (inner diameter of hollow fiber membrane)]/2. By setting the lower limit of the thickness of the hollow fiber membrane as described above, sufficient strength of the hollow fiber membrane can be ensured. Moreover, it is satisfactory in terms of manufacturing time and cost, and is preferable from the viewpoint of mass production. Further, the porosity of the hollow fiber membrane is preferably 5 to 90% by volume, more preferably 10 to 80% by volume, particularly preferably 30 to 60% by volume. The pore diameter of the hollow fiber membrane is preferably 0.01 to 5 μm, more preferably 0.05 to 1 μm. The method for producing hollow fiber membranes is not particularly limited, and known methods for producing hollow fiber membranes can be applied in the same manner or with appropriate modification. For example, the hollow fiber membrane preferably has micropores formed in its walls by a stretching method or a solid-liquid phase separation method.

In addition, in this specification, "the pore diameter of a hollow fiber membrane" refers to the average diameter of the opening on the side coated with the antithrombotic agent (outer surface side). The pore diameter of the hollow fiber membrane is measured by the method described below.

First, the side (outer surface) of the hollow fiber membrane coated with the antithrombotic agent is photographed using a scanning electron microscope (SEM). Next, image processing is performed on the obtained SEM image to invert the pore portion (opening) to white and the other portion to black, and measure the number of pixels in the white portion. Note that the boundary level for binarization is set to a value midway between the difference between the whitest part and the blackest part.

Next, the number of pixels in the pores (openings) displayed in white is measured. The pore area is calculated based on the number of pixels of each pore determined in this way and the resolution (μm/pixel) of the SEM image. From the obtained pore area, the diameter of each pore is calculated assuming that the pore is circular, and a statistically significant number, for example, 500 pore diameters are randomly extracted. The arithmetic mean is defined as the "pore diameter of the hollow fiber membrane."

The material constituting the cylindrical housing 2 may also be the same as that used in known artificial lung housings. Specific examples include hydrophobic synthetic resins such as polycarbonate, acrylic-styrene copolymers, and acrylic-butylene-styrene copolymers. Although the shape of the housing 2 is not particularly limited, it is preferably, for example, cylindrical and transparent. By forming it from a transparent material, the inside can be easily checked.

The storage capacity of the hollow fiber membrane in this embodiment is not particularly limited, and the same capacity as that of a known oxygenator can be applied. For example, about 5,000 to 100,000 porous hollow fiber membranes 3 are housed in the housing 2 in parallel in the axial direction. Furthermore, the hollow fiber membrane 3 is fixed to both ends of the housing 2 in a liquid-tight manner by partition walls 4 and 5, with both ends of the hollow fiber membrane 3 open. The partition walls 4 and 5 are made of a potting agent such as polyurethane or silicone rubber. A portion of the housing 2 sandwiched between the partition walls 4 and 5 is partitioned into a gas chamber inside the hollow fiber membrane 3 and a blood chamber 12 outside the hollow fiber membrane 3.

In this embodiment, a gas inlet header 10 having a gas inlet 8 and a gas outlet header 11 having a gas outlet 9 are attached to the housing 2 in a liquid-tight manner. These headers may be made of any material, for example, the hydrophobic synthetic resin used for the above-mentioned housing. The header may be attached by any method, but for example, the header may be attached to the housing 2 by fusing using ultrasonic waves, high frequency, induction heating, etc., by bonding using an adhesive, or by mechanically fitting the header to the housing 2. can be attached to. Alternatively, a tightening ring (not shown) may be used. It is preferable that all blood contact parts (the inner surface of the housing 2 and the outer surface of the hollow fiber membrane 3) of the hollow fiber membrane oxygenator 1 be formed of a hydrophobic material.

In this embodiment, the antithrombotic agent layer is selectively formed on the outer surface of the hollow fiber membrane (external perfusion type). For this reason, blood (particularly plasma components) is difficult to penetrate or does not penetrate inside the pores of the hollow fiber membrane. Therefore, leakage of blood (particularly plasma components) from the hollow fiber membrane can be effectively suppressed and prevented. In particular, when the antithrombotic agent is substantially absent from the inner layer 3b of the hollow fiber membrane and the inner surface layer 3c of the hollow fiber membrane, the inner layer 3b of the hollow fiber membrane and the inner surface layer 3c of the hollow fiber membrane are Since the sexual state is maintained, leakage of high blood (particularly plasma components) can be more effectively suppressed and prevented. Therefore, the artificial lung obtained by the method of the present invention can maintain high gas exchange capacity for a long period of time.

The antithrombotic agent coating (formation of the antithrombotic agent layer) according to the present embodiment is formed on the polymer layer on the inner surface and/or outer surface of the hollow fiber membrane of the oxygenator, but in addition to the above, It may also be formed on other components (eg, the entire blood contacting part). By adopting this configuration, adhesion/adhesion and activation of platelets can be suppressed and prevented even more effectively in the entire blood contact portion of the oxygenator. Furthermore, since the contact angle of the blood contact surface is lowered, priming work becomes easier. In this case, it is preferable that the coating of the antithrombotic agent according to the present invention be formed on other structural members that come into contact with blood; (eg, the portion embedded in the septum) may not be coated with an antithrombotic agent. Since such parts do not come into contact with blood, there is no particular problem even if they are not coated with an antithrombotic agent.

Further, the artificial lung obtained by the method of the present invention may be of the type shown in FIG. 3. FIG. 3 is a sectional view showing another embodiment of an artificial lung obtained by the method of the present invention. Further, FIG. 4 is a cross-sectional view taken along the line AA in FIG. 3.

In FIG. 3, an oxygenator (hollow fiber membrane external blood perfusion type oxygenator) 20 includes an inner cylindrical member 31 having a blood circulation opening 32 on the side surface, and a large number of gases wrapped around the outer surface of the inner cylindrical member 31. A cylindrical hollow fiber membrane bundle 22 consisting of a replacement porous hollow fiber membrane 3, a housing 23 that accommodates the cylindrical hollow fiber membrane bundle 22 together with an inner cylindrical member 31, and a hollow fiber membrane 3 with both ends opened. , partition walls 25 and 26 that fix both ends of the cylindrical hollow fiber membrane bundle 22 to the housing, blood inlets 28 and blood outlets 29a and 29b communicating with the blood chamber 17 formed in the housing 23, and hollow fibers. It has a gas inlet 24 and a gas outlet 27 communicating with the inside of the membrane 3.

In the oxygenator 20 of this embodiment, as shown in FIGS. 3 and 4, the housing 23 includes an outer cylindrical member 33 that accommodates an inner cylindrical member 31, and the cylindrical hollow fiber membrane bundle 22 has an inner cylindrical member 31. The housing 23 is housed between the shaped member 31 and the outer cylindrical member 33, and the housing 23 further includes one of a blood inlet or a blood outlet that communicates with the inside of the inner cylindrical member, and a blood inlet that communicates with the inside of the outer cylindrical member. The blood inflow port and the other blood outflow port are provided.

Specifically, in the oxygenator 20 of this embodiment, the housing 23 has an inner cylindrical body 35 that is housed within the outer cylindrical member 33 and the inner cylindrical member 31, and whose tip is opened within the inner cylindrical member 31. Be prepared. A blood inlet 28 is formed at one end (lower end) of the inner cylindrical body 35, and two blood outlet ports 29a and 29b extending outward are formed at the side surface of the outer cylindrical member 33. Note that the number of blood outflow ports may be one or multiple.

The cylindrical hollow fiber membrane bundle 22 is wound around the outer surface of the inner cylindrical member 31. That is, the inner cylindrical member 31 serves as the core of the cylindrical hollow fiber membrane bundle 22. The inner cylindrical body 35 housed inside the inner cylindrical member 31 has an open end near the first partition wall 25 . Further, a blood inlet 28 is formed at the lower end portion protruding from the inner cylindrical member 31 .

The inner cylindrical body 35, the inner cylindrical member 31 around which the hollow fiber membrane bundle 22 is wound, and the outer cylindrical member 33 are each arranged substantially concentrically. One end (upper end) of the inner cylindrical member 31 and one end (upper end) of the outer cylindrical member 33, around which the hollow fiber membrane bundle 22 is wound around the outer surface, are kept in a concentric positional relationship by the first partition wall 25. At the same time, the space formed by the inside of the inner cylindrical member and between the outer cylindrical member 33 and the outer surface of the hollow fiber membrane is in a liquid-tight state in which the space is not communicated with the outside.

Additionally, a portion of the inner cylindrical body 35 slightly above the blood inlet 28, the other end (lower end) of the inner cylindrical member 31 around which the hollow fiber membrane bundle 22 is wound around the outer surface, and the other end (lower end) of the outer cylindrical member 33 ( The second partition wall 26 maintains the concentric positional relationship between the two, and the space formed between the inner cylindrical body 35 and the inner cylindrical member 31 and the outer cylindrical member 33 and the hollow fiber The space formed between the membrane and the outer surface is in a liquid-tight state where it does not communicate with the outside. Further, the partition walls 25 and 26 are formed of a potting agent such as polyurethane or silicone rubber.

Therefore, in the oxygenator 20 of this embodiment, the blood inlet 17a formed by the inside of the inner cylinder 35, the substantially cylindrical space formed between the inner cylinder 35 and the inner cylindrical member 31, The first blood chamber 17b has a cylindrical shape, and the second blood chamber 17c has a substantially cylindrical space formed between the hollow fiber membrane bundle 22 and the outer cylindrical member 33. A chamber 17 is formed.

The blood that has flowed in from the blood inflow port 28 flows into the blood inflow port 17a, rises within the inner cylinder body 35 (blood inflow port 17a), and flows out from the upper end 35a (open end) of the inner cylinder body 35. , flows into the first blood chamber 17b, passes through the opening 32 formed in the inner cylindrical member 31, contacts the hollow fiber membrane, performs gas exchange, and then flows into the second blood chamber 17c. The blood then flows out from the blood outflow ports 29a and 29b.

Further, a gas inflow member 41 having a gas inlet 24 is fixed to one end of the outer cylindrical member 33, and similarly, a gas inflow member 41 having a gas outlet 27 is fixed to the other end of the outer cylindrical member 33. An outflow member 42 is fixed. Note that the blood inlet 28 of the inner cylinder 35 penetrates this gas outlet member 42 and projects to the outside.

The outer cylindrical member 33 is not particularly limited, but a cylindrical body, a polygonal tube, a member having an elliptical cross section, etc. can be used. Preferably it is a cylindrical body. Further, the inner diameter of the outer cylindrical member is not particularly limited, and may be the same as the inner diameter of the outer cylindrical member used in known oxygenators, but is preferably about 32 to 164 mm. Further, the effective length of the outer cylindrical member (the length of the portion of the total length that is not buried in the partition wall) is also not particularly limited, and is similar to the effective length of the outer cylindrical member used in known oxygenators. However, it is preferably about 10 to 730 mm.

Further, the shape of the inner cylindrical member 31 is not particularly limited, but for example, a cylinder, a polygonal cylinder, an elliptical cross section, etc. can be used. Preferably it is a cylindrical body. Further, the outer diameter of the inner cylindrical member is not particularly limited, and may be the same as the outer diameter of the inner cylindrical member used in known oxygenators, but is preferably about 20 to 100 mm. Further, the effective length of the inner cylindrical member (the length of the portion of the total length that is not buried in the partition wall) is also not particularly limited, and is similar to the effective length of the inner cylindrical member used in known oxygenators. However, it is preferably about 10 to 730 mm.

The inner cylindrical member 31 is provided with a large number of blood circulation openings 32 on the side surface. As for the size of the opening 32, it is preferable that the total area is large as long as the necessary strength of the cylindrical member is maintained. For example, as shown in FIG. 5 which is a front view, FIG. 6 which is a longitudinal cross-sectional view at the center of FIG. 5, and FIG. 7 which is a cross-sectional view taken along the line BB in FIG. A plurality of annularly arranged openings 32 (for example, 4 to 24 openings, eight in the longitudinal direction in the figure) are provided on the outer peripheral surface of the cylindrical member at equal angular intervals. It is preferable to provide a plurality of sets (8 sets/round in the figure). Further, the opening shape may be round, polygonal, oval, etc., but an elliptical shape as shown in FIG. 5 is preferable.

Further, the shape of the inner cylinder 35 is not particularly limited, but for example, a cylinder, a polygonal cylinder, an elliptical cross section, etc. can be used. Preferably it is a cylindrical body. Further, the distance between the tip opening of the inner cylinder body 35 and the first partition wall 25 is not particularly limited, and a distance similar to that used in known oxygenators can be applied, but a distance of about 20 to 50 mm is preferable. be. The inner diameter of the inner cylinder 35 is also not particularly limited, and may be the same as the inner diameter of the inner cylinder used in known oxygenators, but is preferably about 10 to 30 mm.

The thickness of the cylindrical hollow fiber membrane bundle 22 is not particularly limited and may be similar to the thickness of cylindrical hollow fiber membrane bundles used in known oxygenators, but is preferably 5 to 35 mm, particularly 10 mm to 28 mm. It is preferable that Furthermore, the filling rate of the hollow fiber membranes in the cylindrical space formed between the outer and inner surfaces of the cylindrical hollow fiber membrane bundle 22 is not particularly limited, and the filling rate in a known oxygenator is similarly applied. However, it is preferably 40 to 85%, particularly 45 to 80%. The outer diameter of the hollow fiber membrane bundle 22 may be the same as the outer diameter of hollow fiber membrane bundles used in known oxygenators, but is preferably 30 to 170 mm, particularly preferably 70 to 130 mm. As the gas exchange membrane, those mentioned above are used.

The hollow fiber membrane bundle 22 is produced by winding the hollow fiber membranes around the inner cylindrical member 31, specifically, forming a hollow fiber membrane bobbin with the inner cylindrical member 31 as a core. Both ends of the bobbin can be formed by cutting both ends of the hollow fiber membrane bobbin together with the inner cylindrical member 31, which is the core, after fixing with the partition wall. Note that this cutting causes the hollow fiber membrane to open at the outer surface of the partition wall. Note that the method for forming the hollow fiber membrane is not limited to the above method, and other known methods for forming the hollow fiber membrane may be used in the same manner or with appropriate modification.

In particular, it is preferable that one or more hollow fiber membranes are wound around the inner cylindrical member 31 so that the hollow fiber membranes are substantially parallel and are spaced at a substantially constant interval. This makes it possible to more effectively suppress the drift of blood. Furthermore, the distance between the hollow fiber membranes and adjacent hollow fiber membranes is not limited to the following, but it is preferable that the distance be 1/10 to 1/1 of the outer diameter of the hollow fiber membranes. Further, the distance between the hollow fiber membranes and adjacent hollow fiber membranes is preferably 30 to 200 μm.

Further, the hollow fiber membrane bundle 22 is arranged such that one or more (preferably 2 to 16) hollow fiber membranes are arranged at the same time, and all adjacent hollow fiber membranes are arranged at substantially constant intervals on the inner side. It is formed by being wound around the cylindrical member 31, and when the hollow fiber membrane is wound on the inner cylindrical member, a rotating body and a hollow fiber membrane for rotating the inner cylindrical member 31 are used. It is preferable that the winder for knitting is formed by winding it around the inner cylindrical member 31 by moving under the conditions of the following formula (1).

By meeting the above conditions, the formation of blood drift can be further reduced. At this time, n, which is the relationship between the number of rotations of the winding rotating body and the number of reciprocations of the winder, is not particularly limited, but is usually 1 to 5, preferably 2 to 4.

Also, in the hollow fiber membrane type oxygenator 20, as shown in FIG. In some cases, at least one of the outer surface 3a' and the outer surface layer 3a) includes a polymeric layer and 16 and an antithrombotic agent layer 18 in this order (i.e. hollow fiber membrane, polymeric layer and antithrombotic agent layer in that order). )It is formed. Here, the polymer layer 16 and the antithrombotic agent layer 18 are preferably arranged at least on the side through which blood flows. That is, it is preferable that the polymer layer 16 and the antithrombotic agent layer 18 be formed at least on the outer surface 3a' of the hollow fiber membrane 3. More preferably, it is formed only at 3a'. Here, the preferred form of the hollow fiber membrane (inner diameter, outer diameter, wall thickness, porosity, pore diameter, etc.) is not particularly limited, but the same form as that described in FIG. 1 above can be adopted.

<Method for manufacturing artificial lungs>
Next, the method for manufacturing an oxygenator of the present invention will be explained in detail. The manufacturing method is a manufacturing method of an oxygenator having a plurality of porous hollow fiber membranes for gas exchange, at least a part of which is formed of polypropylene, the hollow fiber membranes having an inner surface forming a lumen; an outer surface;
A coating solution containing at least one compound selected from the group consisting of dopamine, salts and oligomers thereof is prepared, and the inner surface or outer surface of the hollow fiber membrane is brought into contact with the coating solution for 16 hours or more to coat the inner surface. Alternatively, a polymer layer containing a polymer of the above compound is formed on the outer surface.

In the manufacturing method of this embodiment, first, a coating liquid containing at least one compound selected from the group consisting of dopamine, its salt, its salt, and oligomer is prepared ((1) coating liquid preparation step). Then, the coating liquid prepared above is brought into contact with the inner surface or outer surface of the hollow fiber membrane for 16 hours or more ((2) coating liquid application step). Each step will be explained below.

(1) Coating liquid preparation step In this step, a coating liquid containing at least one compound (polymer layer forming compound) selected from the group consisting of dopamine, its salt (dopamine salt), and oligomer (dopamine oligomer) is prepared. Prepare. This coating liquid is used to coat the inner surface or outer surface of the hollow fiber membrane (hereinafter also simply referred to as "hollow fiber membrane surface"). The coating liquid contains at least one compound (polymer layer forming compound) selected from the group consisting of dopamine, its salts, and oligomers, and a solvent.

After the polymer layer-forming compound is applied to the surface of the hollow fiber membrane in this step, a polymer layer is formed as a homogeneous membrane in the coating liquid application step (2) below. This has the function of suppressing plasma leakage from one surface of the hollow fiber membrane to the other surface (from the outer surface side to the inner surface side or from the inner surface side to the outer surface side). (excellent in sex). It also has a function of improving adhesion with the antithrombotic agent layer, which will be described in detail below (therefore, antithrombotic properties and plasma leak resistance can be maintained even during long-term use). Here, the polymeric layer-forming compound is selected from the group consisting of dopamine and its salts and oligomers. The salt of dopamine is not particularly limited, and examples thereof include dopamine hydrochloride (2-(3,4-dihydroxyphenyl)ethylamine hydrochloride). As the dopamine oligomer, for example, a polymer in which about 2 to 50 5,6-dihydroxyindoles are repeated can be used. Among these, from the viewpoint of further improving plasma leak resistance and adhesion with the antithrombotic agent layer, it is preferable to use dopamine and dopamine salt, and it is more preferable to use dopamine and dopamine hydrochloride. Particular preference is given to using the hydrochloride of dopamine. That is, in a preferred form of the invention, the compound is dopamine or a dopamine salt. In a preferred form of the invention, the compound is dopamine or dopamine hydrochloride. In a particularly preferred form of the invention, the compound is dopamine hydrochloride.

The polymer layer-forming compound may be either a commercially available product or a synthetic product. The polymer layer forming compound can be purchased from Towa Pharmaceutical Co., Ltd., Nacalai Tesque Co., Ltd., Sigma-Aldrich Japan LLC, etc., for example.

One type of polymer layer forming compound may be used alone, or two or more types may be used in combination.

Further, the solvent used to prepare the coating liquid is not particularly limited as long as it can dissolve the polymer layer forming compound, and is appropriately selected depending on the type of the polymer layer forming compound. Specific examples include buffers such as phosphate buffer (PBS), carbonate buffer, Tris buffer, glycine buffer, and tricine buffer; HEPES buffer; and the like.

The concentration of the polymer layer-forming compound in the coating solution is not particularly limited, but is preferably 0.1 to 50 mg from the viewpoint of improving the permeability of the coating solution in the lumen of the hollow fiber membrane, cost, and polymerization rate. /mL, more preferably 0.5 to 10 mg/mL. In addition, the pH of the coating liquid is not particularly limited, but from the viewpoint of operability, reaction of the polymer layer forming compound (particularly the polymerization rate of dopamine), etc., the pH of the coating liquid is preferably 5.0 to 10.0, more preferably around neutrality ( For example, it is preferably 6.0 to 8.0, particularly 6.5 to 7.5).

The coating liquid may contain additives, if necessary, in addition to the polymer layer-forming compound and solvent. Examples of additives include polyolefins, aliphatic hydrocarbons, inorganic fine particles, and water-soluble polymers.

(2) Coating liquid application step In this step, the coating liquid prepared above is brought into contact with the inner or outer surface of the hollow fiber membrane for 16 hours or more, and the coating liquid is applied to the outer or inner surface of the hollow fiber membrane. Apply (coat). Here, the form of the hollow fiber membrane to which the coating liquid is applied (material, inner diameter, outer diameter, wall thickness, porosity, pore diameter)) was explained in the section of <Oxigenizer> above. , a detailed explanation will be omitted here.

Specifically, after assembling an oxygenator (for example, one with a structure as shown in FIG. 1 or FIG. 3), the coating liquid prepared as described above is applied directly or through the opening of the hollow fiber membrane. The polymer layer-forming compound or its polymer layer-forming compound or its Coat with polymer. As a result, the reaction of the polymer layer-forming compound (for example, oxidation/polymerization of dopamine) proceeds on the outer or inner surface of the hollow fiber membrane, and the coating film (polymer layer) containing the polymer of the polymer layer-forming compound progresses. ) is formed on the surface of the hollow fiber membrane. Further, the coating liquid may be applied to the hollow fiber membrane before the oxygenator is assembled. From the viewpoint of productivity/mass production, etc., after assembling the oxygenator (or hollow fiber membrane bundle), it is preferable that the coating liquid is brought into contact with (or circulated through) at least one of the outer surface and the inner surface of the hollow fiber membrane. .

As mentioned above, one preferred embodiment of the oxygenator produced by the method according to the invention is an externally perfused oxygenator. Therefore, it is preferable to apply the coating liquid to the outer surface of the hollow fiber membrane. That is, in a preferred embodiment of the present invention, the outer surface of the hollow fiber membrane is brought into contact with a coating liquid containing a polymer layer-forming compound.

It is preferable to encapsulate oxygen gas in the coating liquid before bringing the surface of the hollow fiber membrane into contact with the coating liquid. Thereby, the reaction of the polymer layer forming compound (for example, oxidation and polymerization of dopamine) can proceed sufficiently. Here, the conditions for sealing the oxygen gas are not particularly limited, but they should be such that the oxygen concentration (at 25°C) is about 0.5 to 1.5, especially about 0.8 to 1.2% by volume. preferable.

The hollow fiber membrane surface is brought into contact with the coating liquid for 16 hours or more. As a result, the polymer layer forming compound in the coating liquid is polymerized, and a polymer of the polymer layer forming compound (for example, dopamine is oxidized and polymerized to form polydopamine) is formed and deposited on the hollow fiber membrane surface. Form a polymer layer. Here, the contact time between the hollow fiber membrane surface and the coating liquid is 16 hours or more. If the contact time is less than 16 hours, the polymerization of the polymer layer-forming compound (e.g., oxidation/polymerization of dopamine) will not proceed sufficiently, and the functions of the polymer layer (e.g., plasma leak resistance, antithrombotic agent layer and The resulting hollow fiber membrane is not suitable for use in an oxygenator. From the viewpoint of plasma leak resistance, adhesion and gas exchange ability (gas permeation rate) with the hollow fiber membrane and the antithrombotic agent layer detailed below, and the balance of these, the hollow fiber membrane surface is coated with the coating liquid. The contact time is preferably 24 hours or more. In addition, the upper limit of the contact time of the hollow fiber membrane surface with the coating liquid is preferably 200 hours or less, more preferably 100 hours or less, from the viewpoint of gas exchange ability (gas permeation rate) and realization of practical production time. be. Therefore, the contact time of the hollow fiber membrane surface with the coating liquid is preferably 16 hours or more and 200 hours or less, more preferably 24 hours or more and 100 hours or less. With such a contact time, the hollow fiber membrane and the antithrombotic agent layer can be more tightly adhered to each other via the polymer layer while ensuring sufficient plasma leak resistance and gas exchange ability (gas permeation rate).

Furthermore, the method of bringing the hollow fiber membrane surface into contact with the coating liquid is not particularly limited. For example, a method of immersing the hollow fiber membrane in a coating solution; a method of flowing (filling) the coating solution into the inner cavity of the hollow fiber membrane; a method of applying the coating solution to the outer surface of the hollow fiber membrane can be used. Note that when the coating liquid is brought into contact with only one side of the hollow fiber membrane, for example, after immersing the hollow fiber membrane in the coating liquid, an appropriate gas (e.g., nitrogen gas, argon gas, etc.) is injected into the hollow fiber membrane cavity. gas, an inert gas such as helium gas, or oxygen gas) to replace the inner cavity of the hollow fiber membrane with the gas (according to this form, a polymer layer is selectively formed on the outer surface of the hollow fiber membrane). Coat the hollow fiber membrane after inserting a wire rod with approximately the same diameter as the inner diameter of the hollow fiber membrane into the hollow fiber membrane or closing both ends of the hollow fiber membrane to prevent the coating liquid from entering the inner cavity. (According to this form, a polymer layer can be selectively formed on the outer surface of the hollow fiber membrane); After the outer surface of the hollow fiber membrane is sealed with a film, etc., the hollow fiber membrane is brought into contact with the coating solution. (According to this form, it is possible to selectively form a polymer layer on the inner surface of the hollow fiber membrane); A method such as filling the inner cavity of the hollow fiber membrane with a non-polar solvent in advance and bringing it into contact with the coating liquid is carried out. Can be used.

Note that the surface of the hollow fiber membrane may be brought into contact with the coating liquid while the inner cavity of the hollow fiber membrane is under negative pressure. According to this method, the coating liquid can be brought into contact with the hollow fiber membrane surface (particularly the hollow fiber membrane lumen) more uniformly and reliably. In this embodiment, the degree of negative pressure is not particularly limited, but it is preferable that the inner cavity of the hollow fiber membrane is under a negative pressure of 50 hPa or more and 150 hPa or less, preferably 50 hPa or more and 100 hPa or less. Here, there are no particular restrictions on the method of applying negative pressure to the inner cavity of the hollow fiber membrane, but for example, a vacuum pump (e.g., a diaphragm pump) and one end of the hollow fiber membrane are airtightly connected, and the vacuum pump is operated. By doing so, negative pressure can be created. In addition, in this specification, the "degree of negative pressure (atmospheric pressure)" shall employ the value of the displayed pressure of the vacuum pump.

The contact conditions between the hollow fiber membrane surface and the coating liquid are not particularly limited. For example, the contact temperature is preferably 4 to 90°C, more preferably 25 to 40°C. Under such conditions, polymerization of the polymer layer-forming compound (for example, oxidation and polymerization of dopamine) can be sufficiently performed.

As a result, the polymer layer-forming compound is polymerized and a polymer layer is formed on the surface of the hollow fiber membrane, but if necessary, the hollow fiber membrane can be maintained in that state after being removed from the coating solution. good. By such an operation, the polymerization of the polymer layer-forming compound further progresses, and the polymer layer can be more efficiently formed on the surface of the hollow fiber membrane. Here, the holding conditions are not particularly limited. For example, the holding temperature is preferably 25 to 60°C, more preferably 35 to 40°C. Further, the holding time is preferably 16 to 100 hours, more preferably 24 to 80 hours. Under such conditions, the reaction of the polymer layer-forming compound will further proceed sufficiently, and the polymer layer can be formed on the surface of the hollow fiber membrane even more efficiently. Note that the above holding operation may be performed in an air atmosphere or an inert gas atmosphere.

Thereafter, the coating film is washed and dried as necessary. Although the cleaning method is not particularly limited, for example, cleaning may be performed with water, an alcoholic solvent (eg, ethanol), or the like. Thereby, unreacted polymer layer-forming compounds can be removed. Further, the drying method is not particularly limited, and examples thereof include methods such as natural drying, reduced pressure drying, and high temperature drying at normal pressure.

In this way, a polymer layer is formed on the hollow fiber membrane surface. The thickness (dry thickness) of the polymer layer is not particularly limited, but is preferably 10 to 500 nm, more preferably 100 to 400 nm, and still more preferably 150 to 300 nm. When the thickness of the polymer layer is 10 nm or more, sufficient adhesion to the hollow fiber membrane surface and antithrombotic agent layer and sufficient plasma leak resistance can be obtained. When the thickness of the polymer layer is 500 nm or less, deterioration in gas exchange performance can be prevented. In addition, in this specification, the film thickness of the polymer layer is calculated by dividing the mass of the coated polymer by the density of the polymer from the mass change by thermogravimetry (TG measurement), and calculating the volume. Adopt the value measured by dividing by the surface area. When the polymer layer is composed of polydopamine (PDA) (it is a polydopamine layer), the mass of the coated PDA is divided by the density of PDA (1.00 g/cm ³ ) from the mass change by TG measurement. The volume is calculated, and the value divided by the surface area is the thickness of the polymer layer.

Through the above steps (1) and (2), a polymer layer is formed on the surface of the hollow fiber membrane. In addition to steps (1) and (2), the method for manufacturing an oxygenator according to the present embodiment may optionally include other steps. Other steps include the following (3) antithrombotic agent layer forming step. This step is preferably performed after steps (1) and (2).

(3) Antithrombotic agent layer forming step In this step, a coating containing an antithrombotic agent (antithrombotic agent layer) is formed on the polymer layer. In one embodiment, an aqueous coating solution containing an antithrombotic agent is prepared, and the aqueous coating solution is applied to the polymer layer formed on the outer or inner surface of the hollow fiber membrane in (2) above. As mentioned above, the polymer layer and the antithrombotic agent layer are preferably formed on the outer surface of the hollow fiber membrane. That is, in a preferred embodiment of the present invention, the production method of the present invention includes forming a polymer layer on the outer surface of a hollow fiber membrane, and forming an antithrombotic agent layer containing an antithrombotic agent on the polymer layer. It also has. The method for forming the antithrombotic agent and the antithrombotic agent layer (coating) is not particularly limited, and any known method can be appropriately employed.

Antithrombotic agents are compounds that impart antithrombotic properties to oxygenators by being applied to the polymer layer formed on the hollow fiber membrane surface (e.g., the outer surface of the hollow fiber membrane), which is the part that comes into contact with blood. .

The antithrombotic agent can be used without particular limitation as long as it has antithrombotic properties and biocompatibility. Among these, from the viewpoint of having excellent properties, the antithrombotic agent preferably has a structural unit derived from an alkoxyalkyl (meth)acrylate represented by the following formula (1). That is, in a preferred embodiment of the present invention, the antithrombotic agent has a structural unit (1) represented by the following formula (1).

In the above formula (1), R ¹ represents an alkylene group having 1 to 4 carbon atoms; R ² represents an alkyl group having 1 to 4 carbon atoms; and R ³ represents a hydrogen atom or a methyl group. represent.

The compound having the structural unit represented by formula (1) has antithrombotic biocompatibility (suppressing/preventing effect on platelet adhesion/adhesion, and suppressing/preventing effect on platelet activation), especially platelet adhesion/adhesion. Excellent suppression and prevention effects. Therefore, by using a compound having the above-mentioned structural unit, antithrombotic biocompatibility (suppressing/preventing effect of platelet adhesion/adhesion, and suppressing/preventing effect of platelet activation), especially the effect of suppressing/preventing platelet adhesion/adhesion, can be improved. It becomes possible to manufacture an artificial lung with excellent suppression and prevention effects.

In addition, in this specification, "(meth)acrylate" means "acrylate and/or methacrylate." That is, "alkoxyalkyl (meth)acrylate" includes only alkoxyalkyl acrylate, only alkoxyalkyl methacrylate, and both alkoxyalkyl acrylate and alkoxyalkyl methacrylate.

In formula (1), R ¹ represents an alkylene group having 1 to 4 carbon atoms. Here, the alkylene group having 1 to 4 carbon atoms is not particularly limited, and includes linear or branched alkylene groups such as methylene group, ethylene group, trimethylene group, tetramethylene group, and propylene group. Among these, ethylene group and propylene group are preferable, and ethylene group is particularly preferable in view of the effect of further improving antithrombotic properties and biocompatibility. R ² represents an alkyl group having 1 to 4 carbon atoms. Here, the alkyl group having 1 to 4 carbon atoms is not particularly limited, and is a linear or It has a branched alkyl group. Among these, a methyl group and an ethyl group are preferable, and a methyl group is particularly preferable in view of the effect of further improving antithrombotic properties and biocompatibility. R ³ represents a hydrogen atom or a methyl group.

In addition, when the antithrombotic agent has two or more types of structural units derived from alkoxyalkyl (meth)acrylate, each structural unit may be the same or different.

Specifically, the alkoxyalkyl (meth)acrylates include methoxymethyl acrylate, methoxyethyl acrylate, methoxypropyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, Examples include methoxybutyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, propoxymethyl methacrylate, and butoxyethyl methacrylate. Among these, methoxyethyl (meth)acrylate and methoxybutyl acrylate are preferred, and methoxyethyl acrylate (MEA) is particularly preferred, from the viewpoint of further improving effects on antithrombotic properties and biocompatibility. That is, the antithrombotic agent is preferably polymethoxyethyl acrylate (PMEA). The above alkoxyalkyl (meth)acrylates may be used alone or in combination of two or more.

The antithrombotic agent according to the present invention preferably has a structural unit derived from alkoxyalkyl (meth)acrylate, and is a polymer composed of one or more structural units derived from alkoxyalkyl (meth)acrylate. (homopolymer) or a structural unit derived from one or more alkoxyalkyl (meth)acrylates and one or more monomers that can be copolymerized with the alkoxyalkyl (meth)acrylates. It may also be a polymer (copolymer) composed of structural units derived from the above (other structural units). In addition, when the antithrombotic agent according to the present invention is composed of two or more types of structural units, the structure of the polymer (copolymer) is not particularly limited, and may be a random copolymer, an alternating copolymer, a periodic copolymer, etc. It may be either a block copolymer or a block copolymer. Furthermore, the terminal end of the polymer is not particularly limited and is appropriately defined depending on the type of raw material used, but is usually a hydrogen atom.

Here, in the case where the antithrombotic agent according to the present invention has other structural units in addition to the structural units derived from alkoxyalkyl (meth)acrylate, monomers (copolymerizable There are no particular restrictions on the monomer. For example, methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, 2-ethylhexyl methacrylate, hexyl acrylate, hexyl methacrylate, ethylene, propylene, acrylamide, N, N-dimethylacrylamide, N,N-diethylacrylamide, aminomethyl acrylate, aminoethyl acrylate, aminoisopropyl acrylate, diaminomethyl acrylate, diaminoethyl acrylate, diaminobutyl acrylate, methacrylamide, N,N-dimethylmethacrylamide, N,N - Diethyl methacrylamide, aminomethyl methacrylate, aminoethyl methacrylate, diaminomethyl methacrylate, diaminoethyl methacrylate and the like. Among these copolymerizable monomers, those having no hydroxyl group or cationic group in the molecule are preferred. The copolymer may be a random copolymer, a block copolymer, or a graft copolymer, and can be synthesized by a known method such as radical polymerization, ionic polymerization, or polymerization using a macromer. Here, the proportion of the constituent units derived from the copolymerizable monomer in all the constituent units of the copolymer is not particularly limited, but considering antithrombotic properties and biocompatibility, the proportion of the constituent units derived from the copolymerizable monomer is It is preferable that the structural units derived from (other structural units) account for more than 0 mol% and 50 mol% or less of all the structural units of the copolymer. If it exceeds 50 mol%, the effect of the alkoxyalkyl (meth)acrylate may be reduced.

Here, the weight average molecular weight of the antithrombotic agent is not particularly limited, but is preferably 80,000 or more. In the method for manufacturing an oxygenator according to this embodiment, the antithrombotic agent is applied in the form of an aqueous coating liquid to the polymer layer formed on the outer surface or inner surface of the hollow fiber membrane. Therefore, from the viewpoint of ease of preparing a desired aqueous coating liquid, the weight average molecular weight of the antithrombotic agent is preferably less than 800,000. By setting it as the said range, it can suppress aggregation or precipitation of the said compound in the solution containing an antithrombotic agent, and can prepare a stable aqueous coating liquid. Furthermore, the weight average molecular weight of the antithrombotic agent is preferably more than 200,000 and less than 800,000, more preferably 210,000 or more and 600,000 or less, and more preferably 220,000 or more and 500,000 or less. It is even more preferable, and particularly preferably 230,000 or more and 450,000 or less.

As used herein, "weight average molecular weight" is measured by gel permeation chromatography (GPC) using polystyrene as a standard substance and tetrahydrofuran (THF) as a mobile phase. Specifically, a polymer to be analyzed is dissolved in THF to prepare a 10 mg/ml solution. Regarding the polymer solution prepared in this way, a GPC column LF-804 manufactured by Shodex was attached to a GPC system LC-20 manufactured by Shimadzu Corporation, THF was flowed as a mobile phase, polystyrene was used as a standard substance, and the target of analysis was analyzed. Measure GPC of the polymer. After creating a calibration curve using standard polystyrene, the weight average molecular weight of the polymer to be analyzed is calculated based on this curve.

By increasing the molecular weight of the antithrombotic agent, the content of polymers with relatively small molecular weights contained in the coating can be reduced, and as a result, the elution of relatively small polymers into the blood can be reduced. It is presumed that the effect of suppressing and preventing this phenomenon can also be obtained. Therefore, when the weight average molecular weight of the antithrombotic agent is within the above range, elution of the coating (particularly low molecular weight polymer) into the blood can be more effectively suppressed and prevented. It is also preferred from the standpoint of antithrombotic properties and biocompatibility. Furthermore, in this specification, "low molecular weight polymer" means a polymer having a weight average molecular weight of less than 60,000. The method for measuring the weight average molecular weight is as described above.

Further, an antithrombotic agent containing a structural unit derived from an alkoxyalkyl (meth)acrylate represented by the above formula (1) can be produced by a known method. Specifically, the alkoxyalkyl (meth)acrylate represented by the following formula (2) and a monomer (copolymerizable monomer ) are stirred together with a polymerization initiator in a polymerization solvent to prepare a monomer solution, and by heating the monomer solution, alkoxyalkyl (meth)acrylate or alkoxy A method of (co)polymerizing an alkyl (meth)acrylate and a copolymerizable monomer added as necessary is preferably used.

In addition, in the above formula (2), the substituents R ¹ , R ² and R ³ are the same as the definitions of the above formula (1), and therefore their explanations are omitted here.

The polymerization solvent that can be used in preparing the above monomer solution is particularly one that can dissolve the alkoxyalkyl (meth)acrylate of the above formula (2) used and the copolymerizable monomer added as necessary. Not restricted. For example, water, alcohols such as methanol, ethanol, propanol, and isopropanol; aqueous solvents such as polyethylene glycols; aromatic solvents such as toluene, xylene, and tetralin; and halogens such as chloroform, dichloroethane, chlorobenzene, dichlorobenzene, and trichlorobenzene. Examples include solvents. Among these, methanol is preferred in consideration of ease of dissolving alkoxyalkyl (meth)acrylate, ease of obtaining a polymer having the weight average molecular weight as described above, and the like.

The monomer concentration in the monomer solution is not particularly limited, but by setting the concentration relatively high, the weight average molecular weight of the obtained antithrombotic agent can be increased. Therefore, considering the ease of obtaining a polymer having the above-mentioned weight average molecular weight, the monomer concentration in the monomer solution is preferably less than 50% by mass, more preferably 15% by mass. The content is at least 50% by mass. Furthermore, the monomer concentration in the monomer solution is more preferably 20% by mass or more and 48% by mass or less, particularly preferably 25% by mass or more and 45% by mass or less. Note that, when two or more types of monomers are used, the above monomer concentration means the total concentration of these monomers.

The polymerization initiator is not particularly limited, and any known one may be used. Preferred are radical polymerization initiators because of their excellent polymerization stability, specifically persulfates such as potassium persulfate (KPS), sodium persulfate, and ammonium persulfate; hydrogen peroxide, t-butyl persulfate, etc. Peroxides such as oxide, methyl ethyl ketone peroxide; azobisisobutyronitrile (AIBN), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis(2, 4-dimethylvaleronitrile), 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride, 2,2'-azobis[2-(2-imidazolin-2-yl)propane] Disulfate dihydrate, 2,2'-azobis(2-methylpropionamidine) dihydrochloride, 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine)]hydrate, 3 -Hydroxy-1,1-dimethylbutylperoxyneodecanoate, α-cumylperoxyneodecanoate, 1,1,3,3-tetrabutylperoxyneodecanoate, t-butylperoxyneodecanoate Noate, t-butylperoxyneoheptanoate, t-butylperoxypivalate, t-amylperoxyneodecanoate, t-amylperoxypivalate, di(2-ethylhexyl)peroxydicarbonate, Examples include azo compounds such as di(secondary butyl) peroxydicarbonate and azobiscyanovaleric acid. Further, for example, the above radical polymerization initiator may be used in combination with a reducing agent such as sodium sulfite, sodium bisulfite, or ascorbic acid as a redox initiator. The amount of the polymerization initiator is 0.0001 to 1 mol based on the total amount of monomers (alkoxyalkyl (meth)acrylate and copolymerizable monomer added as necessary; the same applies hereinafter). %, more preferably 0.001 to 0.8 mol%, particularly preferably 0.01 to 0.5 mol%. Alternatively, the amount of the polymerization initiator to be blended is preferably 0.005 to 2 parts by mass, more preferably 0.005 to 2 parts by mass, based on 100 parts by mass of monomers (if multiple types of monomers are used, the entire monomer). is 0.05 to 0.5 parts by mass. With such a blending amount of the polymerization initiator, a polymer having a desired weight average molecular weight can be produced more efficiently.

The polymerization initiator may be mixed with the monomer and the polymerization solvent as it is, or may be mixed with the monomer and the polymerization solvent in the form of a solution that is previously dissolved in another solvent. In the latter case, the other solvent is not particularly limited as long as it can dissolve the polymerization initiator, and examples thereof include the same solvents as the above polymerization solvent. Further, the other solvent may be the same as or different from the above polymerization solvent, but in consideration of ease of controlling polymerization, etc., it is preferably the same solvent as the above polymerization solvent. In addition, the concentration of the polymerization initiator in the other solvent in this case is not particularly limited, but considering ease of mixing, etc., the amount of the polymerization initiator added is preferably set to 100 parts by mass of the other solvent. is 0.1 to 10 parts by weight, more preferably 0.15 to 5 parts by weight, even more preferably 0.2 to 1.8 parts by weight.

Next, by heating the monomer solution, alkoxyalkyl (meth)acrylate or alkoxyalkyl (meth)acrylate and other monomers are (co)polymerized. Here, as the polymerization method, for example, known polymerization methods such as radical polymerization, anionic polymerization, and cationic polymerization can be employed, and radical polymerization, which is easy to manufacture, is preferably used.

The polymerization conditions are not particularly limited as long as the above monomer (alkoxyalkyl (meth)acrylate or alkoxyalkyl (meth)acrylate and copolymerizable monomer) can be polymerized. Specifically, the polymerization temperature is preferably 30 to 60°C, more preferably 40 to 55°C. Further, the polymerization time is preferably 1 to 24 hours, preferably 3 to 12 hours. Under such conditions, high molecular weight polymers as described above can be produced more efficiently. In addition, gelation in the polymerization process can be effectively suppressed and prevented, and high production efficiency can be achieved.

Further, a chain transfer agent, a polymerization rate regulator, a surfactant, and other additives may be appropriately used during polymerization, if necessary.

The atmosphere in which the polymerization reaction is carried out is not particularly limited, and the polymerization reaction can be carried out in an atmosphere of air, an inert gas atmosphere such as nitrogen gas or argon gas, or the like. Further, during the polymerization reaction, the reaction solution may be stirred.

The polymer after polymerization can be purified by common purification methods such as reprecipitation, dialysis, ultrafiltration, and extraction. Among the above methods, purification by reprecipitation is preferred because it yields a (co)polymer suitable for preparing an aqueous coating solution. At this time, it is preferable to use ethanol as the poor solvent used for reprecipitation.

The purified polymer can be dried by any method such as freeze drying, vacuum drying, spray drying, or heat drying, but from the viewpoint of having little effect on the physical properties of the polymer, freeze drying or vacuum drying is preferred. is preferred.

As described above, in one embodiment of the present invention, an aqueous coating liquid containing an antithrombotic agent is prepared, and the aqueous coating liquid is applied to the outer surface or inner surface of the hollow fiber membrane formed in (2) above. By coating the polymer layer, a coating containing an antithrombotic agent (antithrombotic agent layer) is formed on the polymer layer.

(Preparation of aqueous coating liquid)
Here, a method for preparing an aqueous coating liquid according to the present invention will be explained.

The solvent used to prepare the solution containing the antithrombotic agent (aqueous coating liquid) is not particularly limited as long as it can appropriately disperse the antithrombotic agent and prepare the aqueous coating liquid. From the viewpoint of more effectively preventing the aqueous coating liquid from permeating to the outer surface or inner surface (the surface through which the oxygen-containing gas flows) of the pores of the hollow fiber membrane, it is preferable that the solvent contains water. Here, the water is preferably pure water, ion-exchanged water, or distilled water, and particularly preferably distilled water.

Further, the solvent other than water used to prepare the aqueous coating liquid is not particularly limited, but methanol and acetone are preferable in consideration of ease of controlling the dispersibility of the antithrombotic agent. The above-mentioned solvents other than water may be used alone or in the form of a mixture of two or more. Among these, methanol is preferred in view of ease of controlling the dispersibility of the antithrombotic agent. That is, the solvent is preferably composed of water and methanol. Here, the mixing ratio of water and methanol is not particularly limited, but considering the ease of controlling the dispersibility of the antithrombotic agent and the average particle size of the colloid, the mixing ratio (mass ratio) of water:methanol is , 6 to 32:1, more preferably 10 to 25:1. That is, the solvent is preferably composed of water and methanol at a mixing ratio (mass ratio) of 6 to 32:1, and preferably composed of water and methanol at a mixing ratio (mass ratio) of 10 to 25:1. is more preferable.

As mentioned above, when preparing an aqueous coating solution using a mixed solvent of water and a solvent other than water, the order in which the solvent (e.g., water and methanol) and antithrombotic agent are added is not particularly limited; It is preferable to prepare an aqueous coating solution using the following procedure. That is, an aqueous coating solution is prepared by adding an antithrombotic agent to a solvent other than water (preferably methanol) to prepare an antithrombotic agent-containing solution, and then adding the antithrombotic agent-containing solution to water. It is preferable to prepare According to such a method, it is easy to disperse the antithrombotic agent. Further, according to the above method, it is possible to form a colloid having a uniform particle size, and there is also an advantage that a uniform film can be easily formed.

In the above method, the rate of addition of the antithrombotic agent-containing solution to water is not particularly limited, but it is preferable to add the antithrombotic agent-containing solution to water at a rate of 5 to 100 g/min.

Although there are no particular restrictions on the stirring time or stirring temperature when preparing the aqueous coating solution, an antithrombotic agent-containing solution was added to water from the viewpoint of easily forming a colloid with a uniform particle size and dispersing the colloid uniformly. Afterwards, it is preferably stirred for 1 to 30 minutes, more preferably 5 to 15 minutes. Further, the stirring temperature is preferably 10 to 40°C, more preferably 20 to 30°C.

Although the concentration of the antithrombotic agent in the aqueous coating liquid is not particularly limited, it is preferably 0.01% by mass or more from the viewpoint of easily increasing the coating amount. Further, from the above viewpoint, the aqueous coating liquid preferably contains the antithrombotic agent at a concentration of 0.05% by mass or more, and particularly preferably at a concentration of 0.1% by mass or more. On the other hand, the upper limit of the concentration of the antithrombotic agent in the aqueous coating liquid is not particularly limited, but considering the ease of film formation and the effect of reducing coating unevenness, it is preferably 0.3% by mass or less; It is more preferable that the content is .2% by mass or less. In addition, within this range, deterioration in gas exchange ability due to an excessively thick coating of the antithrombotic agent is also suppressed.

(Aqueous coating liquid application process)
Next, the aqueous coating solution prepared as described above is applied (coated) to the polymer layer formed on the outer surface or inner surface of the hollow fiber membrane in (2) above. Specifically, after assembling an oxygenator (for example, one with a structure as shown in FIG. 1 or 3), a polymer layer is formed on the inner or outer surface of the hollow fiber membrane, and an aqueous coating liquid is applied to the polymer layer. A polymer layer (preferably a polymer layer formed on the outer surface of the hollow fiber membrane (i.e., the blood contacting part) ) is coated with an antithrombotic agent. This forms an antithrombotic agent layer on the polymer layer. The aqueous coating liquid may be applied to the hollow fiber membrane before the oxygenator is assembled.

The method of bringing the polymer layer into contact with the aqueous coating solution containing the antithrombotic agent is not particularly limited, but conventionally known methods such as filling and dip coating can be applied. Among these, filling is preferred in order to increase the amount of antithrombotic agent coated.

When filling is adopted as a method of bringing the polymer layer into contact with the aqueous coating liquid containing an antithrombotic agent, the filling amount of the aqueous coating liquid is 50 g/m ² with respect to the membrane area (m ² ) of the hollow fiber membrane. As mentioned above, it is preferable that the amount is more preferably 80 g/m ² or more. When the filling amount is 50 g/m ² or more, a coating (antithrombotic agent layer) containing a sufficient amount of antithrombotic agent can be formed on the surface of the hollow fiber membrane. On the other hand, the upper limit of the filling amount is not particularly limited, but the amount should be 200 g/m ² or less, more preferably 150 g/m ² or less, relative to the membrane area (m ² ) of the hollow fiber membrane. preferable.

In this specification, "membrane area" refers to the area of the outer surface of a hollow fiber membrane, and is calculated from the product of the outer diameter, pi, number, and effective length of the hollow fiber membrane.

The time period for which the polymer layer is brought into contact with the aqueous coating solution containing the antithrombotic agent is not particularly limited, but considering the amount of coating, ease of forming a coating film, and effect of reducing coating unevenness, it should be at least 0.5 minutes. The time is preferably at most 1 minute, and more preferably from 1 minute to 5 minutes. In addition, the contact temperature between the aqueous coating liquid and the polymer layer (the distribution temperature of the aqueous coating liquid) is preferably 5 to 40°C in consideration of the coating amount, ease of forming a coating film, and the effect of reducing coating unevenness. , 15 to 30°C is more preferable.

By drying the coating film after contact with the aqueous coating solution, a coating (antithrombotic agent layer) of the antithrombotic agent according to the present invention is formed on the polymer layer. Here, the drying conditions are not particularly limited as long as the polymer layer can be coated with an antithrombotic agent (an antithrombotic agent layer). Specifically, the drying temperature is preferably 5 to 50°C, more preferably 15 to 40°C. Further, the drying time is preferably 60 to 300 minutes, more preferably 120 to 240 minutes. Alternatively, the coating film may be dried by flowing a gas, preferably at 5 to 40°C, more preferably at 15 to 30°C, through the hollow fiber membrane continuously or stepwise. Here, the type of gas is not particularly limited as long as it does not affect the coating film and can dry the coating film. Specifically, air, and inert gases such as nitrogen gas and argon gas may be used. Further, the flow rate of gas is not particularly limited as long as it can sufficiently dry the coating film, but it is preferably 5 to 150 L, more preferably 30 to 100 L.

Through the above steps, an artificial lung in which a polymer layer and an antithrombotic agent layer are formed on the inner or outer surface of the hollow fiber membrane is obtained. Therefore, according to the manufacturing method according to the present embodiment, it is possible to provide an oxygenator having both desired antithrombotic properties and plasma leak resistance. Furthermore, the oxygenator manufactured by the method according to the present embodiment can maintain its antithrombotic properties and plasma leakage resistance even when used for a long period of time, for example, one month or more (i.e., durability (antithrombotic maintenance property). and plasma leak resistance). Therefore, the artificial lung manufactured by the method according to the present embodiment can be suitably used not only as an artificial lung used in normal surgery, but also as a lung support device for patients with serious diseases.

The effects of the present invention will be explained using the following examples. However, the technical scope of the present invention is not limited only to the following examples. In addition, in the following examples, unless otherwise specified, operations were performed at room temperature (25° C.). Furthermore, unless otherwise specified, "%" and "parts" mean "% by mass" and "parts by mass", respectively.

Examples 1 to 3
Dopamine hydrochloride (manufactured by Sigma-Aldrich Japan LLC) was added to a PBS solution (composition: 8 g/L NaCl, 0.2 g/L KCl, 1.15 g/L Na ₂ HPO ₄ , 0.2 g/L KH). _{2PO4 ,} pH 7.4) to a concentration of 2 mg/mL to prepare DA/PBS solution 1 (pH 7.4).

A porous hollow fiber membrane made of polypropylene (outer diameter: 170 μm, inner diameter: 112 μm, wall thickness: 29 μm, pore diameter: 0.05 μm, porosity: 30% by volume) was prepared in the DA/PBS solution 1 prepared above. The samples were immersed and held at 37° C. for 16 hours (Example 1), 24 hours (Example 2), and 100 hours (Example 3). Thereby, dopamine was oxidized and polymerized to form a dopamine polymer layer (polymer layer) on the surface of the hollow fiber membrane (retaining hollow fiber membranes 1 to 3). Note that in the above operations, operations other than immersion at 37°C for a predetermined time were performed at 25°C. Further, during the above immersion, oxygen gas was not blown. The retained hollow fiber membranes 1 to 3 were taken out from the DA/PBS solution 1, washed with RO water, and air dried at room temperature (25° C.) to obtain coated hollow fiber membranes 1 to 3.

Comparative example 1
Comparative coated hollow fiber membranes 1 were produced in the same manner as in Examples 1 to 3, except that the immersion time was changed to 1 hour.

That is, DA/PBS solution 1 (pH 7.4) was prepared in the same manner as in Examples 1 to 3.

A porous hollow fiber membrane made of polypropylene (outer diameter: 170 μm, inner diameter: 112 μm, wall thickness: 29 μm, pore diameter: 0.05 μm, porosity: 30% by volume) was prepared in the DA/PBS solution 1 prepared above. (Comparative retention hollow fiber membrane 1). Further, the comparison-retained hollow fiber membrane 1 was taken out from the DA/PBS solution 1, washed with RO water, and air-dried at room temperature (25° C.) to obtain a comparative coated hollow fiber membrane 1.

Comparative example 2
A porous hollow fiber membrane made of polypropylene (outer diameter: 170 μm, inner diameter: 112 μm, wall thickness: 29 μm, pore diameter: 0.05 μm, porosity: 30% by volume) was prepared as an uncoated hollow fiber membrane.

<Evaluation 1>
Regarding the coated hollow fiber membranes 1 to 3 obtained in Examples 1 to 3, the comparative coated hollow fiber membrane 1 obtained in Comparative Example 1, and the uncoated hollow fiber membrane of Comparative Example 2, plasma leak resistance and Gas permeability was evaluated.

[Plasma leak resistance]
The coated hollow fiber membrane was potted with epoxy resin, and sodium dodecyl sulfate (SDS) was dissolved in a 0.9 w/v% sodium chloride aqueous solution (saline solution) to a concentration of 1 mg/mL (SDS/saline solution). ) filled the outside of the hollow fiber membrane. A pressure of 760 mmHg was applied to the SDS/saline solution, and the amount of SDS/saline solution that permeated from the outside of the hollow fiber membrane into the lumen was measured to evaluate plasma leak resistance. In addition, the plasma leak resistance of the comparative coated hollow fiber membrane 1 and the uncoated hollow fiber membrane was evaluated in the same manner. The results are shown in FIG. FIG. 8 is a graph in which the vertical axis represents the amount of permeation of the SDS/saline solution per unit (area/time), and the horizontal axis represents time. The smaller the value on the vertical axis, the better the plasma leak resistance.

As shown in FIG. 8, the coated hollow fiber membranes 1 to 3 were shown to have significantly improved plasma leak resistance than the uncoated hollow fiber membranes and the comparative coated hollow fiber membrane 1.

[Gas permeability]
The coated hollow fiber membrane was potted with epoxy resin, and the outside of the hollow fiber membrane was filled with oxygen and nitrogen, respectively. A pressure of 50 mmHg was applied to the gas, and the amount of each gas flowing from the outside of the hollow fiber membrane to the inner cavity was measured to evaluate gas permeability. In addition, the gas permeability of the comparatively coated hollow fiber membrane 1 and the uncoated hollow fiber membrane was evaluated in the same manner. The results are shown in Table 1 below.

From Table 1 above, it was confirmed that coated hollow fiber membranes 1 to 3 had significantly higher gas permeability than comparative coated hollow fiber membrane 1. Although the coated hollow fiber membranes 1 to 3 have lower gas permeability than uncoated hollow fiber membranes, they still meet the gas permeability (1.0 mL/m ² · min · mmHg or more) required for an oxygenator. It was confirmed that sufficient preparations were made.

1, 20 Hollow fiber membrane external blood perfusion oxygenator,
2, 23 Housing,
3,50 Porous hollow fiber membrane for gas exchange,
3a outer layer,
3a' outer surface,
3b inner layer,
3c inner layer,
3c' inner surface,
3d passage (lumen),
3e Opening on the outer surface side,
3f Opening on the inner surface side,
4,5 Bulkhead,
6, 17a, 28 blood inlet,
7, 29a, 29b blood outflow port,
8, 24 gas inlet,
9,27 Gas outlet,
10 Gas inlet header,
11 Gas outlet header,
12, 17 blood chamber,
13 gas inflow chamber,
14 gas outflow chamber,
16 polymer layer,
17b first blood chamber,
17c first blood chamber,
18 antithrombotic agent layer,
22 cylindrical hollow fiber membrane bundle,
25 first bulkhead,
26 second bulkhead,
31 inner cylindrical member,
32 Blood circulation opening,
33 external cylindrical member,
35 inner cylinder body,
35a upper end,
41 Gas inflow member,
42 Gas outflow member.

Claims (4)

A method for producing an oxygenator having a plurality of porous hollow fiber membranes for gas exchange, at least a portion of which is formed of polypropylene, the method comprising:
The hollow fiber membrane has an inner surface forming a lumen and an outer surface,
preparing a coating liquid containing at least one compound selected from the group consisting of dopamine and its salts and oligomers;
A method comprising contacting the inner surface or outer surface of the hollow fiber membrane with the coating liquid for 16 hours or more to form a polymer layer containing a polymer of the compound on the inner surface or outer surface. 2. The method of claim 1, wherein the compound is dopamine or a dopamine salt. 3. The method according to claim 1, further comprising forming the polymer layer on the outer surface of the hollow fiber membrane, and forming an antithrombotic agent layer having an antithrombotic agent on the polymer layer. The antithrombotic agent has the following formula (1):

where R ¹ represents an alkylene group having 1 to 4 carbon atoms; R ² represents an alkyl group having 1 to 4 carbon atoms; and R ³ represents a hydrogen atom or a methyl group.
The method according to claim 3, having a structural unit (1) represented by: