WO2022185962A1 - 人工肺の製造方法 - Google Patents

人工肺の製造方法 Download PDF

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Publication number
WO2022185962A1
WO2022185962A1 PCT/JP2022/006838 JP2022006838W WO2022185962A1 WO 2022185962 A1 WO2022185962 A1 WO 2022185962A1 JP 2022006838 W JP2022006838 W JP 2022006838W WO 2022185962 A1 WO2022185962 A1 WO 2022185962A1
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WO
WIPO (PCT)
Prior art keywords
hollow fiber
fiber membrane
group
coating liquid
silicone compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2022/006838
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English (en)
French (fr)
Japanese (ja)
Inventor
蓮成 ▲高▼間
健 佐藤
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Terumo Corp
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Terumo Corp
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Priority to JP2023503716A priority Critical patent/JP7774037B2/ja
Publication of WO2022185962A1 publication Critical patent/WO2022185962A1/ja
Priority to US18/239,346 priority patent/US12544718B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0081—After-treatment of organic or inorganic membranes
    • B01D67/0088—Physical treatment with compounds, e.g. swelling, coating or impregnation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
    • B01D63/02—Hollow fibre modules
    • B01D63/021—Manufacturing thereof
    • B01D63/022—Encapsulating hollow fibres
    • B01D63/0223—Encapsulating hollow fibres by fixing the hollow fibres prior to encapsulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D53/00—Separation of gases or vapours; Recovering vapours of volatile solvents from gases; Chemical or biological purification of waste gases, e.g. engine exhaust gases, smoke, fumes, flue gases, aerosols
    • B01D53/22—Separation of gases or vapours; Recovering vapours of volatile solvents from gases; Chemical or biological purification of waste gases, e.g. engine exhaust gases, smoke, fumes, flue gases, aerosols by diffusion
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
    • B01D63/02—Hollow fibre modules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/08—Hollow fibre membranes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/26—Polyalkenes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/70—Polymers having silicon in the main chain, with or without sulfur, nitrogen, oxygen or carbon only
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/26—Polyalkenes
    • B01D71/262—Polypropylene

Definitions

  • the present invention relates to a method for manufacturing an oxygenator.
  • Oxygenators with porous hollow fiber membranes may lose gas exchange performance with long-term use. Wet rung and plasma leak are considered to be the main factors. The wet rung blows in air at high pressure to remove condensed water from the hollow fiber membrane, thereby recovering the gas exchange performance. On the other hand, plasma leakage is said to cause irreversible performance deterioration of oxygenators. In the long-term use of an oxygenator, it is essential to solve the problem of plasma leakage, and many studies have been made so far.
  • Japanese Patent Application Laid-Open No. 2002-035116 describes that by applying a silicone coating to the outer surface of a porous hollow fiber membrane made of polypropylene, plasma leakage is less likely to occur and long-term use becomes possible.
  • an object of the present invention is to provide means for forming a coating layer containing a silicone compound on a hollow fiber membrane by a simpler method.
  • the inventors have conducted intensive research to solve the above problems.
  • a silicone compound is dissolved in a specific organic solvent to prepare a coating liquid, and the inner surface of the hollow fiber membrane is brought into contact with the coating liquid while the outer surface of the hollow fiber membrane is in contact with water.
  • the above object is a method for producing an oxygenator having a plurality of porous hollow fiber membranes for gas exchange, wherein a silicone compound is dissolved in an organic solvent having a surface tension of less than 70 dyn/cm to form a coating liquid.
  • FIG. 1 is a cross-sectional view of a hollow fiber membrane external blood perfusion oxygenator according to one embodiment of the present invention.
  • 1 is a hollow fiber membrane external blood perfusion type oxygenator; 2 is a housing; 3 is a gas exchange porous hollow fiber membrane; 4 and 5 are partition walls; 8 gas inlet; 9 gas outlet; 10 gas inlet header; 11 gas outlet header; 12 blood chamber; indicate gas outflow chambers, respectively.
  • FIG. 2 is an enlarged cross-sectional view of a porous hollow fiber membrane for gas exchange used in a hollow fiber membrane external blood perfusion type oxygenator according to one embodiment of the present invention.
  • FIG. 1 is a hollow fiber membrane external blood perfusion type oxygenator
  • 2 is a housing
  • 3 is a gas exchange porous hollow fiber membrane
  • 4 and 5 are partition walls
  • FIG. 2 is an enlarged cross-sectional view of a porous
  • FIG. 3 is a cross-sectional view of a hollow fiber membrane external blood perfusion oxygenator according to another embodiment of the present invention.
  • 3a is an outer surface layer
  • 3a′ is an outer surface
  • 3b is an inner layer
  • 3c is an inner surface layer
  • 3e the opening on the outer surface
  • 3f the opening on the inner surface
  • 16 the coating layer
  • 18 the coating, respectively.
  • FIG. 3 is a cross-sectional view of a hollow fiber membrane external blood perfusion oxygenator according to another embodiment of the present invention.
  • 20 is a hollow fiber membrane external blood perfusion oxygenator; 3 is a porous hollow fiber membrane for gas exchange; 17 is a blood chamber; 17a and 28 are blood inlets; 22 a tubular hollow fiber membrane bundle; 23 a housing; 24 a gas inlet; 25 a first partition; 26 a second partition; 27 is a gas outlet; 29a and 29b are blood outlets; 31 is an inner tubular member; 32 is an opening for blood circulation; 33 is an outer tubular member; and 42 indicate the gas outflow member, respectively.
  • 4 is a cross-sectional view taken along line AA of FIG. 3. FIG. In FIG.
  • FIG. 5 is a front view showing an example of an inner tubular member used in the hollow fiber membrane external blood perfusion type oxygenator according to the present invention.
  • 31 denotes an inner tubular member
  • 32 denotes a blood flow opening
  • 6 is a central longitudinal sectional view of the inner tubular member shown in FIG. 5.
  • FIG. 6 31 denotes an inner tubular member; and 32 denotes a blood flow opening, respectively.
  • 7 is a cross-sectional view taken along the line BB of FIG. 5.
  • 31 denotes an inner tubular member; and 32 denotes a blood flow opening, respectively.
  • the present invention is a method for producing an oxygenator having a plurality of porous hollow fiber membranes for gas exchange, comprising dissolving a silicone compound in an organic solvent having a surface tension of less than 70 dyn/cm to prepare a coating liquid. , while the outer surface of the hollow fiber membrane is in contact with water, the inner surface of the hollow fiber membrane is brought into contact with the coating liquid, and the inner surface is coated with a silicone compound (a silicone compound used for preparing the coating liquid and / or a crosslinked product of the silicone compound).
  • a silicone compound a silicone compound used for preparing the coating liquid and / or a crosslinked product of the silicone compound.
  • a coating layer containing a silicone compound can be formed on a hollow fiber membrane by a simpler method than the production method described in JP-A-2002-035116. becomes possible.
  • the coating liquid can be easily passed through the lumen of the hollow fiber membrane.
  • the surface tension of the organic solvent is decreased, or as the time for which the inner surface of the hollow fiber membrane is brought into contact with the coating liquid is increased, It was found that the coating liquid easily leaked to the outer surface of the hollow fiber membrane.
  • the silicone compound appears on the outer surface of the hollow fiber membrane (a coating containing the silicone compound is formed on part of the outer surface), and the outer surface is highly antithrombotic.
  • a film containing a molecular compound in particular, a water-soluble antithrombotic polymer compound (for example, polymethoxyethyl acrylate (PMEA))
  • PMEA polymethoxyethyl acrylate
  • the present inventors brought the inner surface of the hollow fiber membrane into contact with the coating liquid while bringing the outer surface of the hollow fiber membrane into contact with water. It has been found that the coating liquid is less likely to leak out to the outer surface of the hollow fiber membrane through the hollow fiber membrane, and that the release of the silicone compound to the outer surface can be suppressed. As a result, the inventors have found that an oxygenator having desired plasma leak resistance and antithrombogenicity can be provided, and have completed the present invention.
  • X to Y includes X and Y and means “X or more and Y or less”.
  • measurements of operations and physical properties are performed under the conditions of room temperature (20 to 25° C.)/relative humidity of 40 to 50% RH.
  • a and/or B means both A and B or either A or B.
  • FIG. 1 is a cross-sectional view of a hollow fiber membrane external blood perfusion type oxygenator according to one 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 type oxygenator according to one embodiment of the present invention.
  • the hollow fiber membrane external blood perfusion oxygenator is also simply referred to as “hollow fiber membrane oxygenator” or “oxygenator”.
  • the porous hollow fiber membrane for gas exchange is also simply referred to as "porous hollow fiber membrane” or "hollow fiber membrane”.
  • the hollow fiber membrane external blood perfusion type oxygenator 1 has a large number of gas exchange porous hollow fiber membranes 3 housed in the housing 2 .
  • the hollow fiber membrane 3 has a passage (lumen) 3d forming a gas chamber in the center.
  • the hollow fiber membrane 3 has openings 3e and 3f that communicate between its outer surface 3a' and inner surface 3c'.
  • a coating layer 16 containing a silicone compound is formed on the inner surface 3c' of the hollow fiber membrane 3 through which the oxygen-containing gas flows.
  • a coating 18 containing an antithrombotic polymer compound is formed on the outer surface 3a' (the outer surface 3a' and the outer surface layer 3a in some cases) of the hollow fiber membrane 3, which is the blood contact portion.
  • Coat layer 16 may contain other components in addition to the silicone compound.
  • other components include, but are not particularly limited to, polyolefins, aliphatic hydrocarbons, inorganic fine particles, cross-linking agents, and the like.
  • coat layer 16 is composed only of a silicone compound.
  • coating 18 may contain other ingredients in addition to the antithrombotic polymeric compound.
  • other components include, but are not particularly limited to, other antithrombotic substances (eg, heparin), cross-linking agents, thickeners, preservatives, pH adjusters, and the like.
  • the coating layer 16 containing a silicone compound may be formed on at least a part of the inner surface 3c' of the hollow fiber membrane 3 through which the oxygen-containing gas flows. improvement effect, wet run suppression effect), etc., it is preferable that the groove is formed on the entire inner surface 3c′.
  • the coating layer 16 containing the silicone compound is formed over the entire inner surface 3c' so as to close the openings 3f of the pores on the inner surface 3c' side. Since the coating layer 16 containing a silicone compound has high gas permeability, it can have sufficient gas exchange performance.
  • the coat layer 16 containing the silicone compound may be present on the inner surface layer 3c (in some cases, the inner surface layer 3c and the inner layer 3b) of the hollow fiber membrane 3 .
  • the coating 18 containing an antithrombotic polymer compound may be formed on at least a portion of the outer surface 3a' of the hollow fiber membrane 3, which is the blood contacting portion. From the viewpoints of adhesion/attachment suppression/prevention effect and platelet activation suppression/prevention effect, it is preferable that the coating be formed on the entire outer surface 3a′.
  • the coating 18 containing the antithrombotic polymer compound may be present on the inner layer 3b (in some cases, the inner layer 3b and the inner surface layer 3c) of the hollow fiber membrane 3. is preferably not substantially present in the inner layer 3b of the hollow fiber membrane 3 (in some cases, the inner layer 3b and the inner layer 3c).
  • the inner layer 3b or the inner surface layer 3c of the hollow fiber membrane retains the hydrophobic properties of the membrane base material itself, preventing the leakage of plasma components. ) can be effectively prevented.
  • the coating 18 containing the antithrombotic polymer compound is substantially absent from the inner layer 3b (in some cases, the inner layer 3b and the inner surface layer 3c) of the hollow fiber membrane 3" , means that no permeation of the antithrombotic polymer compound is observed in the vicinity of the inner surface 3c′ of the hollow fiber membrane 3 (the surface on which the oxygen-containing gas flows).
  • the colloidal solution of the antithrombotic polymer compound is applied to form a film, whereby the antithrombotic polymer compound is applied to the hollow fiber membranes 3. It can be in a form in which it is not substantially present in the inner layer 3b or the inner surface layer 3c.
  • a hollow fiber membrane oxygenator 1 comprises 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 for liquid-tightly supporting both ends of the hollow fiber membrane bundle to 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. , 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.
  • the hollow fiber membrane oxygenator 1 of this embodiment includes a tubular housing 2, an assembly of gas exchange hollow fiber membranes 3 housed in the tubular housing 2, and a hollow fiber membrane 3 It has partition walls 4 and 5 that hold both ends to the housing 2 in a liquid-tight manner, and the interior of the cylindrical housing 2 is divided into a blood chamber 12 as a first fluid chamber and a gas chamber as a second fluid chamber.
  • the cylindrical housing 2 is provided with a blood inlet 6 and a blood outlet 7 communicating with the blood chamber 12 .
  • a gas inlet 8 which is a second fluid inlet communicating with the gas chamber, which is the internal space of the hollow fiber membrane 3.
  • a side header 10 is attached.
  • 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 .
  • a cap-shaped gas outflow side header 11 having a gas outflow port 9 which is a second fluid outflow port that is provided below the partition wall 5 and communicates with the internal space of the hollow fiber membrane 3 is attached. Therefore, the gas outflow chamber 14 is formed by the outer surface of the partition wall 5 and the inner surface of the gas outflow side header 11 .
  • the hollow fiber membrane 3 is a porous membrane made of a hydrophobic polymeric material, and the same hollow fiber membranes used in known artificial lungs are used, and are not particularly limited.
  • the hollow fiber membrane in particular, the inner surface of the hollow fiber membrane
  • a hydrophobic polymer material similar to a hollow fiber membrane used for a known oxygenator can be used.
  • Specific examples include polyolefin resins such as polypropylene, polyethylene, and polymethylpentene, and polymeric materials such as polysulfone, polyacrylonitrile, polytetrafluoroethylene, and cellulose acetate.
  • polyolefin resins are preferably used, more preferably polypropylene and polymethylpentene, and still more preferably polypropylene. That is, in a preferred embodiment of the present invention, at least part of the hollow fiber membrane (preferably, the entire hollow fiber membrane) is made of polyolefin resin. In a more preferred form of the present invention, at least part of the hollow fiber membrane (preferably the whole hollow fiber membrane) is made of polypropylene or polymethylpentene. In a further preferred form of the present invention, at least part of the hollow fiber membrane (preferably the whole hollow fiber membrane) is made of polypropylene.
  • the inner diameter of the hollow fiber membrane is not particularly limited, it is preferably 50-300 ⁇ m, more preferably 80-200 ⁇ m.
  • the outer diameter of the hollow fiber membrane is not particularly limited, but is preferably 100-400 ⁇ m, more preferably 130-200 ⁇ m.
  • the thickness (film thickness) of the hollow fiber membrane is preferably 20 ⁇ m or more and less than 50 ⁇ m, more preferably 25 ⁇ m or more and less than 50 ⁇ m, still more preferably 25 to 45 ⁇ m, still more preferably 25 to 40 ⁇ m, still more preferably 25 to 35 ⁇ m, especially It is preferably 25 to 30 ⁇ m.
  • the term “thickness (film thickness) of the hollow fiber membrane” means the thickness between the inner surface and the outer surface of the hollow fiber membrane, and is represented by the formula: [(the outer surface of the hollow fiber membrane diameter)-(inner diameter of hollow fiber membrane)]/2.
  • 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 size of the hollow fiber membrane is preferably 0.01-5 ⁇ m, more preferably 0.05-1 ⁇ m.
  • the method for producing the hollow fiber membrane is not particularly limited, and a known method for producing a hollow fiber membrane can be applied in the same manner or by appropriately modifying it.
  • the hollow fiber membrane has micropores formed in the wall thereof by a drawing method or a solid-liquid phase separation method.
  • the "hollow fiber membrane pore size” refers to the average diameter of the openings on the side (outer surface side) coated with the antithrombotic polymer compound.
  • the pore size of the hollow fiber membrane is measured by the method described below.
  • a scanning electron microscope (SEM) is used to photograph the side (outer surface) of the hollow fiber membrane that is coated with the antithrombotic polymer compound.
  • SEM scanning electron microscope
  • the obtained SEM image is subjected to image processing, the pore portion (opening portion) is reversed to white and the other portion to black, and the number of pixels in the white portion is measured.
  • the boundary level for binarization is set to an intermediate value between the differences between the whitest part and the blackest part.
  • the pore area is calculated based on the number of pixels of each pore thus determined and the resolution ( ⁇ m/pixel) of the SEM image. From the obtained pore area, the diameter of each pore is calculated by regarding the pore as circular, and a statistically significant number, for example, 500 pore diameters are randomly extracted, and the Let the arithmetic mean be the "pore size of the hollow fiber membrane".
  • the same material used for the housing of known artificial lungs can also be used for the material constituting the cylindrical housing 2 .
  • Specific examples include hydrophobic synthetic resins such as polycarbonate, acrylic/styrene copolymers, and acrylic/butylene/styrene copolymers.
  • the shape of the housing 2 is not particularly limited, it is preferably cylindrical and transparent, for example. By forming with a transparent body, it is possible to easily confirm the inside.
  • the storage amount of the hollow fiber membranes in this embodiment is not particularly limited, and the same amount as a known oxygenator can be applied.
  • about 5,000 to 100,000 porous hollow fiber membranes 3 are accommodated in parallel in the housing 2 in the axial direction.
  • the hollow fiber membranes 3 are fixed to both ends of the housing 2 in a liquid-tight state by partition walls 4 and 5 in a state in which both ends of the hollow fiber membranes 3 are open.
  • the partition walls 4 and 5 are made of a potting agent such as polyurethane or silicone rubber. The portion between the partition walls 4 and 5 in the housing 2 is partitioned into a gas chamber inside the hollow fiber membranes 3 and a blood chamber 12 outside the hollow fiber membranes 3 .
  • 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 also be made of any material, but may be made of, for example, the hydrophobic synthetic resin used for the housing described above.
  • 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 waves, induction heating, or the like, bonding with an adhesive, or mechanically fitting. can be attached to Alternatively, a clamping ring (not shown) may be used. All of the blood-contacting 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 are preferably made of a hydrophobic material.
  • the coating (coating) of the antithrombotic polymer compound is selectively formed on the outer surface of the hollow fiber membrane (external perfusion type). Therefore, blood (especially plasma components) hardly or does not permeate inside the pores of the hollow fiber membrane. Therefore, leakage of blood (especially plasma components) from the hollow fiber membrane can be effectively suppressed/prevented.
  • the antithrombotic polymer compound is substantially absent in the inner layer 3b of the hollow fiber membrane and the inner layer 3c of the hollow fiber membrane, the inner layer 3b of the hollow fiber membrane and the inner layer 3c of the hollow fiber membrane are Since the hydrophobic state of the material is maintained, it is possible to more effectively suppress and prevent leakage of high blood (especially plasma components). 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 coating of the antithrombotic polymer compound according to the present embodiment is essentially formed on the outer surface of the hollow fiber membrane of the oxygenator, but in addition to the outer surface, other constituent members (for example, the entire blood contact portion) may be formed in By adopting this configuration, adhesion/adhesion and activation of platelets can be more effectively suppressed/prevented in the entire blood-contacting part of the oxygenator. In addition, since the contact angle of the blood-contacting surface is low, the priming work is facilitated.
  • the coating of the antithrombotic polymer compound according to the present invention is preferably formed on other components that come into contact with blood. Other portions (for example, the portion embedded in the septum) may not be coated with the antithrombotic polymer compound. Since such portions do not come into contact with blood, there is no particular problem even if they are not coated with the antithrombotic polymer compound.
  • FIG. 3 is a cross-sectional view showing another embodiment of an artificial lung obtained by the method of the present invention.
  • 4 is a cross-sectional view taken along the line AA of FIG. 3.
  • an oxygenator (hollow fiber membrane external blood perfusion type oxygenator) 20 includes an inner cylindrical member 31 having blood circulation openings 32 on its side surface, and a large number of gases wrapped around the outer surface of the inner cylindrical member 31.
  • a tubular hollow fiber membrane bundle 22 made of the replacement porous hollow fiber membranes 3 a housing 23 for accommodating the tubular hollow fiber membrane bundle 22 together with an inner tubular member 31, and a state in which both ends of the hollow fiber membranes 3 are opened.
  • partition walls 25 and 26 fixing both ends of the tubular hollow fiber membrane bundle 22 to the housing, a blood inlet 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 interior of the membrane 3 .
  • the oxygenator 20 of this embodiment includes a housing 23 that includes an outer tubular member 33 that accommodates an inner tubular member 31, and a tubular hollow fiber membrane bundle 22 that accommodates the inner tubular member. Further, the housing 23 has either a blood inlet or a blood outlet communicating with the inside of the inner tubular member, and a blood tube communicating with the inside of the outer tubular member. and the other of an inlet or a blood outlet.
  • the housing 23 includes an inner cylindrical body 35 that is housed in an outer cylindrical member 33 and an inner cylindrical member 31 and whose tip is open within the inner cylindrical member 31 .
  • a blood inlet 28 is formed at one end (lower end) of the inner cylindrical body 35, and two blood outlets 29a and 29b extending outward are formed on a side surface of the outer cylindrical member 33. As shown in FIG. The number of blood outlets may be one or plural.
  • the tubular hollow fiber membrane bundle 22 is wound around the outer surface of the inner tubular member 31 . That is, the inner tubular member 31 serves as the core of the tubular hollow fiber membrane bundle 22 .
  • the inner cylindrical body 35 housed inside the inner cylindrical member 31 has an opening near the first partition wall 25 at its tip.
  • a blood inlet 28 is formed at the lower end protruding from the inner tubular member 31 .
  • the inner tubular body 35, the inner tubular member 31 around which the hollow fiber membrane bundle 22 is wound, and the outer tubular member 33 are arranged substantially concentrically.
  • One end (upper end) of the inner tubular member 31 around which the hollow fiber membrane bundle 22 is wound and one end (upper end) of the outer tubular member 33 are concentrically positioned by the first partition wall 25.
  • the space formed between the inside of the inner tubular member and between the outer tubular member 33 and the outer surface of the hollow fiber membrane is in a liquid-tight state that does not communicate with the outside.
  • the second partition wall 26 maintains the concentric positional relationship between the two, and the space formed between the inner cylindrical member 35 and the inner cylindrical member 31 and the outer cylindrical member 33 and the hollow fibers are separated from each other.
  • the space formed by the outer surface of the membrane is in a liquid-tight state that does not communicate with the outside.
  • the partitions 25 and 26 are made of a potting agent such as polyurethane or silicone rubber.
  • the blood inlet 17a formed by the interior of the inner cylindrical body 35, the substantially cylindrical space formed between the inner cylindrical body 35 and the inner cylindrical member 31, and the and a second blood chamber 17c, which is substantially a cylindrical space formed between the hollow fiber membrane bundle 22 and the outer cylindrical member 33.
  • a chamber 17 is formed.
  • the blood flowing in from the blood inlet 28 flows into the blood inlet 17a, rises in the inner cylindrical body 35 (blood inlet 17a), and flows out from the upper end 35a (open end) of the inner cylindrical 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, and after gas exchange is performed, flows into the second blood chamber 17c. and flows out from the blood outlets 29a and 29b.
  • a gas inlet member 41 having a gas inlet 24 is fixed to one end of the outer cylindrical member 33 , and similarly, a gas inlet 27 having a gas outlet 27 is fixed to the other end of the outer tubular member 33 .
  • An outflow member 42 is fixed.
  • the blood inlet 28 of the inner cylindrical body 35 protrudes outside through the gas outflow member 42 .
  • the outer tubular member 33 is not particularly limited, but a cylindrical body, a polygonal tube, or one having an elliptical cross section can be used. A cylindrical body is preferred.
  • the inner diameter of the outer tubular member is not particularly limited, and may be the same as the inner diameter of the outer tubular member used in known artificial lungs, but is preferably about 32 to 164 mm.
  • the effective length of the outer cylindrical member is not particularly limited, and is the same as the effective length of the outer cylindrical member used in known oxygenators. Although it is possible, it is preferably about 10 to 730 mm.
  • the shape of the inner tubular member 31 is not particularly limited, but for example, a cylindrical body, a polygonal cylinder, or one with an elliptical cross section can be used.
  • a cylindrical body is preferred.
  • 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 artificial lungs, but is preferably about 20 to 100 mm.
  • 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 not particularly limited, and is the same as the effective length of the inner cylindrical member used in known artificial lungs. Although it is possible, it is preferably about 10 to 730 mm.
  • the inner tubular member 31 has a large number of blood circulation openings 32 on its side surface. As for the size of the openings 32, it is preferable that the total area is large as long as the required strength of the tubular member is maintained. 5, which is a front view, FIG. 6, which is a central vertical cross-sectional view of FIG. 5, and FIG. 7, which is a cross-sectional view along the line BB of FIG.
  • a plurality of annularly arranged openings (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, and the openings are arranged at equal intervals in the axial direction of the cylindrical member. is preferably provided with a plurality of sets (8 sets/circumference in the figure).
  • the shape of the opening may be round, polygonal, elliptical, etc., but an oval shape as shown in FIG. 5 is preferable.
  • the shape of the inner cylindrical body 35 is not particularly limited, but for example, a cylindrical body, a polygonal cylinder, or one with an elliptical cross section can be used. A cylindrical body is preferred. Also, the distance between the tip opening of the inner cylindrical body 35 and the first partition wall 25 is not particularly limited, and the same distance as used in a known artificial lung can be applied, but about 20 to 50 mm is preferable. be. Also, the inner diameter of the inner cylinder 35 is not particularly limited, and may be the same as the inner diameter of the inner cylinder used in known artificial lungs, but is preferably about 10 to 30 mm.
  • the thickness of the tubular hollow fiber membrane bundle 22 is not particularly limited, and may be similar to the thickness of tubular hollow fiber membrane bundles used in known artificial lungs, preferably 5 to 35 mm, particularly 10 mm to 28 mm. is preferably
  • the filling rate of the hollow fiber membranes in the cylindrical space formed between the outer surface and the inner surface of the tubular hollow fiber membrane bundle 22 is not particularly limited, and the filling rate in a known artificial lung is applied in the same manner. Although it can be, 40 to 85% is preferable, and 45 to 80% is particularly preferable.
  • the outer diameter of the hollow fiber membrane bundle 22 may be similar to that of hollow fiber membrane bundles used in known artificial lungs, 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 formed by winding the hollow fiber membranes around the inner tubular member 31, specifically, forming a hollow fiber membrane bobbin using the inner tubular 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 tubular member 31 which is the core after fixing by the partition wall. This cutting opens the hollow fiber membrane on the outer surface of the partition wall.
  • the method for forming the hollow fiber membrane is not limited to the method described above, and other known hollow fiber membrane forming methods may be used in the same manner or modified as appropriate.
  • one or a plurality of hollow fiber membranes are wound around the inner cylindrical member 31 so that the hollow fiber membranes are substantially parallel and adjacent to each other are substantially at regular intervals.
  • the distance between the hollow fiber membranes adjacent to each other is preferably 1/10 to 1/1 of the outer diameter of the hollow fiber membrane, although not limited to the following.
  • the hollow fiber membranes have a distance of 30 to 200 ⁇ m between adjacent hollow fiber membranes.
  • the hollow fiber membrane bundle 22 has one or a plurality of hollow fiber membranes (preferably 2 to 16) at the same time, and all adjacent hollow fiber membranes are arranged at substantially constant intervals. It is formed by being wound around the tubular member 31, and when the hollow fiber membrane is wound on the inner tubular member, the rotating body and the hollow fiber membrane for rotating the inner tubular member 31 are combined. It is preferable that the winder for weaving is formed by winding around the inner cylindrical member 31 by moving under the condition of the following formula (1).
  • n which is the relationship between the number of revolutions of the winding rotor and the number of reciprocations of the winder, is not particularly limited, but is usually 1-5, preferably 2-4.
  • the inner surface 3c' of the hollow fiber membrane 3 through which the oxygen-containing gas flows is provided with a coating layer 16 containing a silicone compound.
  • a coating 18 containing an antithrombotic polymer compound is formed on the outer surface 3a' (the outer surface 3a' and the outer surface layer 3a in some cases) of the hollow fiber membrane 3, which is the blood contact portion.
  • the preferred form of the hollow fiber membrane is not particularly limited, but the same form as described in FIG. 1 above can be adopted.
  • the manufacturing method is a method for manufacturing an oxygenator having a plurality of porous hollow fiber membranes for gas exchange, wherein a silicone compound is dissolved in an organic solvent having a surface tension of less than 70 dyn/cm to prepare a coating liquid. Then, while the outer surface of the hollow fiber membrane is in contact with water, the inner surface of the hollow fiber membrane is brought into contact with the coating liquid, and the inner surface is coated with a silicone compound (a silicone compound used for preparing the coating liquid and and/or a coat layer containing a crosslinked product of the silicone compound).
  • a silicone compound a silicone compound used for preparing the coating liquid and and/or a coat layer containing a crosslinked product of the silicone compound.
  • a silicone compound is dissolved in an organic solvent having a surface tension of less than 70 dyn/cm to prepare a coating liquid (simply referred to as "(1) Coating liquid preparation step”, “Coating liquid preparation step” or “step (1)”). Then, the inner surface of the hollow fiber membrane is brought into contact with the coating liquid while the outer surface of the hollow fiber membrane is brought into contact with water (simply referred to as “(2) coating liquid application step”, “coating liquid application step” or “ (Also referred to as step (2)”). Each step will be described below.
  • a coating liquid to be applied to the inner surface of the hollow fiber membrane is prepared.
  • the coating liquid contains a silicone compound and an organic solvent with a specific surface tension.
  • the silicone compound has the function of suppressing plasma leakage from the outer surface side to the inner surface side of the hollow fiber membrane.
  • a phenomenon called wet rung in which water vaporized from blood accumulates in the lumen of the hollow fiber membrane, can cause a problem of reduced gas exchange performance. It also has the function of suppressing rungs.
  • Any silicone compound can be used without particular limitation as long as it is a polymer compound having a siloxane bond (Si--O--Si) in its main skeleton.
  • the silicone compound is preferably a silicone compound represented by the following formula (1) because it can form a coat layer having excellent resistance to plasma leakage. That is, according to a preferred embodiment of the present invention, there is provided a method for producing an artificial lung, wherein the silicone compound is represented by the following formula (1).
  • R 1 to R 8 each independently represent an alkyl group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 30 carbon atoms, or an aromatic hydrocarbon group having 1 to 6 carbon atoms.
  • Group consisting of ethylenically unsaturated bond-containing group, amino group-containing group, hydroxyl group-containing group, carboxy group-containing group, maleimide group-containing group, thiol group-containing group and halogen group (fluoro group, chloro group, bromo group, iodo group) represents a reactive group selected from n is 1 or more and 100,000 or less.
  • R 1 to R 8 are each independently an alkyl group having 1 to 6 carbon atoms or an aromatic hydrocarbon group having 6 to 30 carbon atoms, However, at least one of R 1 to R 8 is an ethylenically unsaturated bond-containing group having 1 to 6 carbon atoms, an amino group-containing group, a hydroxyl group-containing group, a carboxyl group-containing group, a maleimide group-containing group, A reactive group selected from the group consisting of a thiol group-containing group and a halogen group is preferred.
  • At least one of R 1 to R 3 and at least one of R 6 to R 8 are each independently an ethylenically unsaturated bond-containing group having 1 to 6 carbon atoms
  • one of R 1 to R 3 and one of R 6 to R 8 are each independently an ethylenically unsaturated bond-containing group having 1 to 6 carbon atoms, or an amino group-containing group, a hydroxyl group-containing group, a carboxy group-containing group, a maleimide group-containing group, a thiol group-containing group and a halogen group, and the remaining two of R 1 to R 3 and R 4 to R 5 and the remaining two of R 6 to R 8 each independently represent an alkyl group having 1 to 6 carbon atoms or an aromatic hydrocarbon group having 6 to 30 carbon atoms.
  • the silicone compound represented by formula (1) has a reactive group
  • a cross-linking reaction proceeds in the process of forming the coat layer (for example, in the process of drying the organic solvent) to form a cross-linked product of the silicone compound. sell. This can improve the adhesion and durability of the coat layer.
  • the silicone compound (preferably the silicone compound represented by formula (1)) used for preparing the coating liquid does not have a reactive group, the silicone compound is directly contained in the coating layer formed on the inner surface of the hollow fiber membrane.
  • the silicone compound (preferably the silicone compound represented by formula (1)) used for preparing the coating liquid has a reactive group
  • the coating layer formed on the inner surface of the hollow fiber membrane has , a silicone compound (that is, an uncrosslinked silicone compound) and/or a crosslinked product of the silicone compound used for preparing the coating liquid.
  • Examples of the alkyl group having 1 to 6 carbon atoms or the aromatic hydrocarbon group having 6 to 30 carbon atoms in formula (1) include methyl group, ethyl group, n-propyl group, phenyl group, fluorescein and derivatives thereof. derived groups.
  • Examples of fluorescein derivatives include fluorescein isothiocyanate, N-hydroxysuccinimide fluorescein, Oregon Green, Tokyo Green, SNAFL, carboxyfluorescein, carboxyfluorescein diacetate, and aminofluorescein. Among them, from the viewpoint of fluidity and Young's modulus after curing, a methyl group and an ethyl group are preferable, and a methyl group is more preferable.
  • Examples of the ethylenically unsaturated bond-containing group having 1 to 6 carbon atoms include vinyl group, vinyloxy group, allyl group, allyloxy group, propenyl group and propenyloxy group.
  • Functional groups containing an amino group include an amino group and an aminophenyl group.
  • Functional groups containing hydroxyl groups include hydroxyl groups, phenol groups, and catechol groups.
  • a carboxy group and a maleic acid group are mentioned as a functional group containing a carboxy group.
  • a maleimide group is mentioned as a functional group containing a maleimide group.
  • a thiol group and a thiophenol group are mentioned as a functional group containing a thiol group.
  • Halogen groups include fluoro, chloro, bromo, and iodo groups. Among them, a vinyloxy group, an allyloxy group, and an allyl group are preferable, and a vinyloxy group is more preferable, because of good cross-linking reactivity.
  • n in formula (1) is not particularly limited, it is preferably from 1 to 100,000, more preferably from 1 to 10,000. When n is within the above range, liquid can pass through the lumen of the fiber (hollow fiber membrane) under negative pressure.
  • Either a commercially available product or a synthetic product may be used as the silicone compound.
  • Commercially available products include, for example, SYLGARD (registered trademark) 184 and 186 manufactured by Dow Corning.
  • One of the silicone compounds may be used alone, or two or more may be used in combination.
  • the concentration of the silicone compound in the coating liquid is not particularly limited, it is preferably 10 mg/mL or more and less than 800 mg/mL from the viewpoint of improving the liquid permeability of the coating liquid in the lumen of the hollow fiber membrane. From the viewpoint of forming a sufficiently thick coat layer, the concentration is preferably 200 mg/mL or more and less than 800 mg/mL, more preferably more than 400 mg/mL and less than 800 mg/mL, and even more preferably 500 mg/mL. 750 mg/mL or less. That is, according to a preferred embodiment of the present invention, there is provided a method for manufacturing an oxygenator, wherein the concentration of the silicone compound in the coating liquid is more than 400 mg/mL and less than 800 mg/mL.
  • the concentration of the silicone compound in the coating liquid is 500 mg/mL or more and 750 mg/mL or less. With such a concentration, a coating layer having sufficient plasma leak resistance can be formed in one coating liquid application process. In addition, when the coating layer is formed in the coating liquid application process multiple times, it is possible to form a coating layer with a sufficient thickness even if the concentration is low. It is preferably 20 mg/mL or more and 70 mg/mL or less.
  • the sum of the concentration of the silicone compound in the coating liquid used in each step is preferably is 200 mg/mL or more and less than 800 mg/mL, more preferably more than 400 mg/mL and less than 800 mg/mL, still more preferably 500 mg/mL or more and 750 mg/mL or less. That is, in a preferred embodiment of the present invention, the total concentration of silicone compounds in the coating liquid used in each step is more than 400 mg/mL and less than 800 mg/mL. In a more preferred embodiment of the present invention, the total concentration of silicone compounds in the coating liquid used in each step is 500 mg/mL or more and 750 mg/mL or less.
  • organic solvent An organic solvent is used for the purpose of dissolving the silicone compound.
  • the organic solvent must have a surface tension of less than 70 dyn/cm in order to pass the coating liquid through the lumen of the hollow fiber membrane. If the surface tension of the organic solvent is 70 dyn/cm or more, the solubility of the silicone compound may be lowered, or the passage of the coating liquid may become difficult, so there is a possibility that the coating layer may not be formed satisfactorily.
  • the surface tension of the organic solvent is preferably 50 dyn/cm or less, more preferably 50 dyn/cm or less, from the viewpoint of improving the solubility of the silicone compound and the permeability of the coating liquid in the lumen of the hollow fiber membrane. It is 40 dyn/cm or less, more preferably 30 dyn/cm or less.
  • the lower limit of the surface tension is not particularly limited, but it is preferably 15 dyn/cm or more from the viewpoint of allowing the hollow fiber to flow without problems and from the viewpoint of preventing the coating liquid from permeating through the pores of the hollow fiber membrane. be.
  • the numerical range of the surface tension of the organic solvent is preferably 15 dyn/cm or more and less than 70 dyn/cm, more preferably 15 dyn/cm or more and 50 dyn/cm or less, and still more preferably 15 dyn/cm or more and 40 dyn/cm or less. and particularly preferably 15 dyn/cm or more and 30 dyn/cm or less. Note that 1 dyn/cm is 0.001 N/m.
  • the surface tension of an organic solvent (when using a mixture of two or more organic solvents, the surface tension of the mixed organic solvent) is measured at 20° C. using a Dunouy surface tensiometer (manufactured by Ito Seisakusho). Measured at Specifically, a platinum ring was suspended at the tip of a thin rod attached to the center of the steel wire, brought into contact with the liquid surface of the organic solvent at a horizontal position, and the platinum ring was pulled up by turning the knob and twisting the steel wire to remove the liquid. Read the moment when the sample is separated from the surface with the dial and pointer, and take the value as the surface tension (dyn/cm) of the organic solvent.
  • organic solvents examples include aromatic hydrocarbons such as toluene (28.5 dyn/cm) and xylene (28.4 dyn/cm), cyclohexane (25.3 dyn/cm), and n-hexane (18.4 dyn/cm).
  • aromatic hydrocarbons such as toluene (28.5 dyn/cm) and xylene (28.4 dyn/cm), cyclohexane (25.3 dyn/cm), and n-hexane (18.4 dyn/cm).
  • n-heptane (20.1 dyn/cm), diethyl ether (16.96 dyn/cm), diisopropyl ether (17.1 dyn/cm), methylhexyl ether (23.5 dyn/cm), ethyl acetate (24.0 dyn/ cm), butyl acetate (25.2 dyn/cm), isopropyl laurate (30.1 dyn/cm), isopropyl myristate (28.3 dyn/cm), methyl ethyl ketone (24.6 dyn/cm), methyl isobutyl ketone (23.
  • the organic solvent is selected from the group consisting of n-hexane, cyclohexane, acetone, butyl alcohol, 1-propanol, isopropanol, chloroform, diethyl ether, aromatic hydrocarbons and fluorine-based solvents.
  • a method for manufacturing an oxygenator is provided, which is at least one kind of oxygenator.
  • the organic solvent is n-hexane or acetone.
  • the surface tension of the solvent for dissolving the silicone compound is less than 70 dyn/cm, an organic solvent having a surface tension of 70 dyn/cm or more may be included.
  • the organic solvent preferably has low solubility in water.
  • the solubility of the organic solvent in 100 mL of water at 20° C. is preferably 10 mg/100 mL or less.
  • Organic solvents with low solubility in water include aromatic hydrocarbons such as toluene and xylene, cyclohexane, n-hexane, n-heptane, diethyl ether, diisopropyl ether, methylhexyl ether, ethyl acetate, butyl acetate, and isopropyl laurate.
  • aromatic hydrocarbons such as toluene and xylene, cyclohexane, n-hexane, n-heptane, diethyl ether, diisopropyl ether, methylhexyl ether, ethyl acetate, butyl acetate, and isopropyl laurate.
  • solvents may be used alone or in combination of two or more.
  • the coating liquid may contain additives, if necessary, in addition to the above silicone compound and organic solvent.
  • Additives include carnauba wax, PDMS-PEG, crosslinkers.
  • the configuration of the hollow fiber membrane (material, inner diameter, outer diameter, wall thickness, porosity, pore size) to which the coating liquid is to be applied can be the configuration described in the above description of the oxygenator. Therefore, detailed description is omitted here.
  • This process may be applied to the hollow fiber membranes before assembling the oxygenator, or may be applied to the hollow fiber membranes after assembling the oxygenator.
  • the specific operating method is not particularly limited.
  • the blood chamber of the hollow fiber membrane external blood perfusion type oxygenator shown in FIG. 1 or 3 is filled with water.
  • the coating liquid is passed from one end of the hollow fiber membrane (e.g., the gas inlet of the oxygenator) to the other end of the hollow fiber membrane (e.g., the gas outlet of the oxygenator). It can be performed.
  • the portion to be brought into contact with water may be at least a part of the outer surface of the hollow fiber membrane, but preferably the entire outer surface of the hollow fiber membrane.
  • exposure of the silicone compound can be suppressed over the entire outer surface of the hollow fiber membrane.
  • an oxygenator having excellent antithrombotic properties can be provided.
  • the portion to be brought into contact with the coating liquid may be at least a part of the inner surface of the hollow fiber membrane, but preferably the entire inner surface of the hollow fiber membrane.
  • a coat layer containing a silicone compound can be formed over the entire inner surface of the hollow fiber membrane. As a result, it is possible to provide an oxygenator having excellent resistance to plasma leakage.
  • the operation of bringing the inner surface of the hollow fiber membrane into contact with the coating liquid is carried out from one end of the hollow fiber membrane (for example, the gas inlet of the oxygenator) to the other end of the hollow fiber membrane (for example, the gas outlet of the oxygenator). ) by passing the coating liquid through.
  • Liquid passage can be performed by applying a negative pressure to the lumen of the hollow fiber membrane or by pressurizing the coating liquid.
  • the flow rate of the coating liquid during passage is preferably 0.001 to 1.0 m/sec, more preferably 0.1 to 1.0 m/sec. With such a flow rate, it is possible to apply a sufficient amount of the coating liquid to the inner surface of the hollow fiber membrane while preventing the coating liquid from leaking to the outer surface of the hollow fiber membrane.
  • the amount of the coating liquid to be passed is preferably 10 to 10,000 mL/m 2 , more preferably 30 to 1,000 mL/m 2 , and still more preferably 40 to 200 mL per membrane area (m 2 ). / m2 . With such an amount, it is possible to apply the coating liquid over the entire inner surface of the hollow fiber membrane.
  • the contact time between the inner surface of the hollow fiber membrane and the coating liquid is not particularly limited, but is preferably 1 to 10000 seconds, more preferably 1 to 100 seconds. With such a contact time, it is possible to apply a sufficient amount of the coating liquid to the inner surface of the hollow fiber membrane while preventing leakage of the coating liquid to the outer surface of the hollow fiber membrane.
  • Fluid circulation step The production method of the present invention includes a step of causing a fluid to circulate in the lumen of the hollow fiber membrane after the above "(2) Coating liquid application step” (simply “(3) Fluid circulation step", " It is preferable to further have a “fluid circulation step” or “step (3)”). That is, according to a preferred embodiment of the present invention, there is provided a method for manufacturing an oxygenator, comprising contacting the inner surface of the hollow fiber membrane with a coating liquid and then allowing the fluid to flow through the lumen of the hollow fiber membrane. Step (3) will be described below.
  • the fluid is passed through the lumen of the hollow fiber membrane.
  • excess coating liquid accumulated in the lumen of the hollow fiber membrane can be removed.
  • clogging can be prevented and the thickness of the coat layer can be made more uniform, so that the gas permeability of the artificial lung (especially gas flow in the lumen of the hollow fiber membrane) can be improved.
  • the fluid is not particularly limited as long as it is gas or liquid, but is preferably selected from the group consisting of air, inert gases (rare gases such as nitrogen and argon), water, and lower alcohols. That is, according to a preferred embodiment of the present invention, there is provided a method for manufacturing an artificial lung, wherein the fluid is selected from the group consisting of air, inert gas, water and lower alcohol. These fluids can remove excess coating liquid without adversely affecting the coating liquid (coating film). Air or water is more preferable from the viewpoint of cost and the like.
  • the operation of circulating the fluid is not particularly limited. For example, it can be performed by allowing a fluid to flow from one end of the hollow fiber membrane (eg, the gas inlet of the oxygenator) to the other end of the hollow fiber membrane (eg, the gas outlet of the oxygenator).
  • the flow can be achieved by applying a negative pressure to the lumen of the hollow fiber membrane or by pressurizing the fluid.
  • the flow velocity is preferably 0.5 to 10 m/sec, more preferably 1 to 10 m/sec. . With such a flow rate, excess coating liquid can be removed without adversely affecting the coating liquid (coating film).
  • the flow time is preferably 10 seconds or more, more preferably 3600 seconds or more, from the viewpoint of sufficiently removing excess coating liquid. Although the upper limit of the distribution time is not particularly limited, it is about 168 hours or less.
  • the fluid is a gas (e.g., air, inert gas (rare gases such as nitrogen and argon)
  • (3) the fluid circulation step and (4) the drying step described later may be performed separately. Alternatively, it may be the same step.
  • the flow velocity is preferably 0.01 to 1.0 m/sec, more preferably 0.1 to 1.0 m/sec.
  • the circulation time is preferably 1 to 100 seconds, more preferably 10 to 100 seconds. With such flow velocity and circulation time, excess coating liquid can be removed without adversely affecting the coating liquid (coating film).
  • the temperature of the fluid is not particularly limited, it is preferably 10 to 45°C, more preferably 20 to 40°C. At such a temperature, excess coating liquid can be removed without adversely affecting the coating liquid (coating film).
  • step (3) The water that has been in contact with the outer surface of the hollow fiber membrane in step (2) may be subjected to step (3) as it is, but preferably the water that has been in contact with the outer surface in advance is removed. After that, step (3) is performed.
  • step (4) Drying step
  • the step of drying the hollow fiber membrane may further have “(4) drying step”, “drying step” or “step (4)").
  • the step (4) will be described below.
  • the hollow fiber membrane that has undergone the (2) coating liquid application step (preferably (3) fluid flow step) is dried to remove water, organic solvent, etc. adhering to the surface of the hollow fiber membrane.
  • the silicone compound preferably the silicone compound represented by formula (1)
  • the silicone compound is crosslinked by this step, and the silicone compound (the silicone compound used for preparing the coating liquid and / Or a coat layer containing a crosslinked product of the silicone compound) is formed.
  • the drying method is not particularly limited as long as water, organic solvents, etc. can be removed, and known methods can be appropriately adopted. Specific examples include drying under reduced pressure, drying by heating, air drying (drying by exposing to gas), centrifugal drying, and the like, and two or more of them may be combined as appropriate.
  • the drying temperature is preferably 45 to 80°C, and the drying time is preferably 1 to 48 hours.
  • the (3) fluid circulating step may also serve as the (4) drying step.
  • the drying temperature (the temperature of the gas to be circulated) is preferably 10° C. or more and less than 45° C., more preferably 20° C. or more and 40° C. or less, and the drying time is preferably 12 to 60 hours.
  • the film thickness of the coating layer after drying is not particularly limited, it is preferably 0.1 to 10 ⁇ m, more preferably 0.5 to 7 ⁇ m, and even more preferably 1 to 5 ⁇ m.
  • the film thickness of the coat layer is 0.1 ⁇ m or more, sufficient plasma leak resistance can be obtained.
  • the film thickness of the coat layer is 10 ⁇ m or less, deterioration of gas exchange performance can be prevented.
  • a coating layer containing a silicone compound is formed on the inner surface of the hollow fiber membrane by the above steps (1) and (2) (optionally further including steps (3) and/or (4)).
  • the method for manufacturing an oxygenator according to this embodiment may optionally have other steps.
  • Other steps include the following (5) antithrombogenic coating formation step. Said step is preferably performed after steps (1) and (2) (optionally further comprising steps (3) and/or (4)).
  • Antithrombotic coating formation step In this step, a coating containing an antithrombotic polymer compound is formed on the outer surface of the hollow fiber membrane. That is, according to a preferred embodiment of the present invention, there is provided a method for producing an artificial lung, further comprising forming a coating containing an antithrombotic polymer compound on the outer surface of the hollow fiber membrane.
  • the method of forming the antithrombotic polymer compound and the film is not particularly limited, and known methods can be appropriately employed.
  • the antithrombotic polymer compound is a compound that imparts antithrombotic properties to the oxygenator by being applied to the outer surface of the hollow fiber membrane, which is the part that contacts blood.
  • the antithrombotic polymer compound can be used without any particular limitation as long as it has antithrombotic properties and biocompatibility. Among them, from the viewpoint of being excellent in the above properties, the antithrombotic polymer compound preferably has a constitutional unit derived from an alkoxyalkyl (meth)acrylate represented by the following formula (I).
  • R 3 represents a hydrogen atom or a methyl group
  • R 1 represents an alkylene group having 1 to 4 carbon atoms
  • R 2 represents an alkyl group having 1 to 4 carbon atoms.
  • the compound having the structural unit represented by formula (I) has antithrombotic properties and biocompatibility (platelet adhesion/adhesion suppression/prevention effect and platelet activation suppression/prevention effect), particularly platelet adhesion/ Excellent adhesion control and prevention effect. Therefore, by using a compound having the above structural unit, antithrombotic properties and biocompatibility (platelet adhesion/adhesion suppression/prevention effect and platelet activation suppression/prevention effect), particularly platelet adhesion/adhesion It is possible to manufacture an oxygenator that is excellent in the effect of suppressing and preventing
  • (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.
  • R 1 represents an alkylene group having 1 to 4 carbon atoms.
  • 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.
  • an ethylene group and a propylene group are preferable, and an ethylene group is particularly preferable in consideration of the effect of further improving antithrombogenicity and biocompatibility.
  • R 2 represents an alkyl group having 1 to 4 carbon atoms.
  • the alkyl group having 1 to 4 carbon atoms is not particularly limited, and is a straight chain of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or There are branched alkyl groups. Among these, a methyl group and an ethyl group are preferred, and a methyl group is particularly preferred in view of the effect of further improving antithrombotic properties and biocompatibility.
  • R3 represents a hydrogen atom or a methyl group.
  • alkoxyalkyl (meth)acrylates include methoxymethyl acrylate, methoxyethyl acrylate, methoxypropyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, Methoxybutyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate and the like.
  • the antithrombotic polymer compound is preferably polymethoxyethyl acrylate (PMEA).
  • PMEA polymethoxyethyl acrylate
  • the antithrombotic polymer compound according to the present invention preferably has structural units derived from alkoxyalkyl (meth)acrylates, and is composed of one or more structural units derived from alkoxyalkyl (meth)acrylates. Even if it is a polymer (homopolymer) or one or more alkoxyalkyl (meth)acrylate-derived structural units and one or more copolymerizable with the alkoxyalkyl (meth)acrylate It may be a polymer (copolymer) composed of structural units (other structural units) derived from monomers.
  • the structure of the polymer (copolymer) is not particularly limited. It may be a coalescence, a periodic copolymer, or a block copolymer.
  • the terminal 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.
  • the antithrombotic polymer compound according to the present invention has other structural units in addition to the structural units derived from the alkoxyalkyl (meth)acrylate, a monomer that can be copolymerized with the alkoxyalkyl (meth)acrylate (Copolymerizable monomer) is not particularly limited.
  • the copolymerizable monomer those having no hydroxyl group or cationic group in the molecule are preferable.
  • the copolymer may be a random copolymer, a block copolymer, or a graft copolymer, and can be synthesized by known methods such as radical polymerization, ionic polymerization, and polymerization using macromers.
  • the ratio of the structural units derived from the copolymerizable monomer in the total structural units of the copolymer is not particularly limited.
  • Structural units derived from (other structural units) are preferably more than 0 mol% and 50 mol% or less in all the structural units of the copolymer. If it exceeds 50 mol %, the effect of the alkoxyalkyl (meth)acrylate may decrease.
  • the weight-average molecular weight of the antithrombotic polymer compound is not particularly limited, but is preferably 80,000 or more.
  • the antithrombotic polymer compound is applied to the outer surface of the hollow fiber membrane in the form of an aqueous coating liquid. Therefore, the weight-average molecular weight of the antithrombotic polymer compound is preferably less than 800,000 from the viewpoint of facilitating the preparation of the desired aqueous coating liquid. Within the above range, aggregation or precipitation of the compound can be suppressed in the solution containing the antithrombotic polymer compound, and a stable aqueous coating liquid can be prepared.
  • the weight average molecular weight of the antithrombotic polymer compound is preferably more than 200,000 and less than 800,000, more preferably 210,000 or more and 600,000 or less, and 220,000 or more and 500,000. It is even more preferable when it is below, and it is especially preferable when it is 230,000 or more and 450,000 or less.
  • the "weight average molecular weight” is measured by gel permeation chromatography (GPC) using polystyrene as a standard and tetrahydrofuran (THF) as a mobile phase.
  • GPC gel permeation chromatography
  • a polymer to be analyzed is dissolved in THF to prepare a 10 mg/ml solution.
  • a GPC column LF-804 manufactured by Shodex was attached to a GPC system LC-20 manufactured by Shimadzu Corporation, THF was run as a mobile phase, and polystyrene was used as a standard substance. Measure the GPC of the polymer.
  • the weight average molecular weight of the polymer to be analyzed is calculated based on this curve.
  • the content of polymers with relatively small molecular weights contained in the film can be reduced, and as a result, polymers with relatively small molecular weights are eluted into the blood. It is presumed that the effect of suppressing/preventing Therefore, when the weight-average molecular weight of the antithrombotic polymer compound is within the above range, elution of the film (especially low-molecular weight polymer) into the blood can be more effectively suppressed/prevented. It is also preferable from the viewpoint of antithrombogenicity and biocompatibility.
  • the term "low molecular weight polymer" as used herein 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.
  • the antithrombotic polymer compound containing the structural unit derived from the alkoxyalkyl (meth)acrylate represented by the above formula (I) can be produced by a known method. Specifically, an alkoxyalkyl (meth)acrylate represented by the following formula (II), and a monomer copolymerizable with the alkoxyalkyl (meth)acrylate added as necessary (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 an optionally added copolymerizable monomer is preferably used.
  • the polymerization solvent that can be used in the preparation of the monomer solution is particularly capable of dissolving the alkoxyalkyl (meth)acrylate of formula (II) used and the optionally added copolymerizable monomer.
  • alcohols such as water, methanol, ethanol, propanol, and isopropanol
  • aqueous solvents such as polyethylene glycols
  • aromatic solvents such as toluene, xylene, and tetralin
  • halogens such as chloroform, dichloroethane, chlorobenzene, dichlorobenzene, and trichlorobenzene. system solvents and the like.
  • methanol is preferred in consideration of the ease of dissolving the alkoxyalkyl (meth)acrylate and the ease of obtaining a polymer having the weight average molecular weight as described above.
  • the concentration of the monomer in the monomer solution is not particularly limited, but by setting the concentration relatively high, the weight-average molecular weight of the resulting antithrombotic polymer compound can be increased. Therefore, considering the ease of obtaining a polymer having a weight average molecular weight as described above, the monomer concentration in the monomer solution is preferably less than 50% by mass, more preferably 15% by mass. It is more than 50% by mass and less than 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, and particularly preferably 25% by mass or more and 45% by mass or less. In addition, the said monomer concentration means the total concentration of these monomers, when using 2 or more types of monomers.
  • the polymerization initiator is not particularly limited, and any known one may be used. Radical polymerization initiators are preferred in terms of excellent polymerization stability, and specifically, persulfates such as potassium persulfate (KPS), sodium persulfate and ammonium persulfate; oxides, peroxides such as methyl ethyl ketone peroxide; 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-dimethylbutyl peroxyneodecanoate, ⁇ -cumyl peroxyneodecan
  • the radical polymerization initiator may be used in combination with a reducing agent such as sodium sulfite, sodium hydrogen sulfite, or ascorbic acid as a redox initiator.
  • the blending amount of the polymerization initiator is 0.0001 to 1 mol with respect to the total amount of the monomers (alkoxyalkyl (meth)acrylate and optionally added copolymerizable monomer; hereinafter the same).
  • % more preferably 0.001 to 0.8 mol %, particularly preferably 0.01 to 0.5 mol %.
  • the amount of the polymerization initiator is preferably 0.005 to 2 parts by mass, more preferably 0.005 to 2 parts by mass with respect to 100 parts by mass of the monomer (when using a plurality of types of monomers, the entire amount). 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 they are, or may be dissolved in another solvent in advance and mixed with the monomer and the polymerization solvent in the form of a solution.
  • 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 solvents.
  • the other solvent may be the same as or different from the polymerization solvent, but is preferably the same solvent as the polymerization solvent in consideration of ease of control of polymerization.
  • the concentration of the polymerization initiator in the other solvent is not particularly limited, but considering the ease of mixing, etc., the amount of the polymerization initiator added is preferably 100 parts by mass of the other solvent. is 0.1 to 10 parts by mass, more preferably 0.15 to 5 parts by mass, and even more preferably 0.2 to 1.8 parts by mass.
  • the alkoxyalkyl (meth)acrylate or the alkoxyalkyl (meth)acrylate and other monomer are (co)polymerized by heating the monomer solution.
  • 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 monomers (alkoxyalkyl (meth)acrylate or alkoxyalkyl (meth)acrylate and copolymerizable monomer) can be polymerized.
  • the polymerization temperature is preferably 30 to 60°C, more preferably 40 to 55°C.
  • the polymerization time is preferably 1 to 24 hours, preferably 3 to 12 hours. Under such conditions, the high-molecular-weight polymer as described above can be produced more efficiently. In addition, gelation in the polymerization process can be effectively suppressed/prevented, and high production efficiency can be achieved.
  • chain transfer agents may be used as appropriate during polymerization.
  • polymerization rate modifiers may be used as appropriate during polymerization.
  • surfactants may be used as appropriate during polymerization.
  • the atmosphere in which the polymerization reaction is carried out is not particularly limited, and it can be carried out in an air atmosphere, an inert gas atmosphere such as nitrogen gas or argon gas. Further, the reaction solution may be stirred during the polymerization reaction.
  • the polymer after polymerization can be purified by general purification methods such as reprecipitation, dialysis, ultrafiltration, and extraction.
  • purification by reprecipitation is preferable because a (co)polymer suitable for preparing an aqueous coating liquid can be obtained.
  • the polymer after purification can be dried by any method such as freeze drying, vacuum drying, spray drying, or heat drying. is preferred.
  • the solvent used for preparing the solution containing the antithrombotic polymer compound is particularly limited as long as it can appropriately disperse the antithrombotic polymer compound to prepare the aqueous coating liquid. not.
  • the solvent preferably contains water.
  • the water is preferably pure water, ion-exchanged water or distilled water, and particularly preferably distilled water.
  • the solvent other than water used for preparing the aqueous coating liquid is not particularly limited, but methanol and acetone are preferable in consideration of the ease of control such as the dispersibility of the antithrombotic polymer compound.
  • the solvents other than water may be used singly or in the form of a mixture of two or more.
  • methanol is preferred in consideration of the ease of further control such as the dispersibility of the antithrombotic polymer compound. That is, the solvent is preferably composed of water and methanol.
  • the mixing ratio of water and methanol is not particularly limited, but considering the dispersibility of the antithrombotic polymer compound and the ease of further control of the average particle size of the colloid, the mixing ratio of water:methanol (mass ratio) is preferably 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 is composed of water and methanol at a mixing ratio (mass ratio) of 10 to 25:1. is more preferred.
  • the order of adding the solvent (e.g., water and methanol) and the antithrombotic polymer compound is particularly limited.
  • aqueous coating liquid by a method of adding a solution. According to such a method, it is easy to disperse the antithrombotic polymer compound.
  • colloids having a uniform particle size can be formed, and there is the advantage that a uniform coating can be easily formed.
  • the addition rate of the antithrombotic polymer compound-containing solution to water is not particularly limited, but it is preferable to add the antithrombotic polymer compound-containing solution to water at a rate of 5 to 100 g/min.
  • stirring time and stirring temperature when preparing the aqueous coating solution. is preferably stirred for 1 to 30 minutes, more preferably 5 to 15 minutes.
  • the stirring temperature is preferably 10 to 40°C, more preferably 20 to 30°C.
  • the concentration of the antithrombotic polymer compound in the aqueous coating liquid is not particularly limited, it is preferably 0.01% by mass or more from the viewpoint of facilitating an increase in the coating amount. Furthermore, from the above viewpoint, the aqueous coating liquid preferably contains the antithrombotic polymer compound at a concentration of 0.05% by mass or more, and particularly preferably at a concentration of 0.1% by mass or more.
  • the upper limit of the concentration of the antithrombotic polymer compound in the aqueous coating liquid is not particularly limited, but considering the ease of forming the coating and the effect of reducing coating unevenness, it is 0.3% by mass or less. It is preferably 0.2% by mass or less, and more preferably 0.2% by mass or less. Moreover, within such a range, deterioration in gas exchange capacity due to excessive thickness of the coating of the antithrombotic polymer compound is suppressed.
  • the aqueous coating liquid prepared as described above is applied (coated) onto the outer surface of the hollow fiber membrane.
  • an oxygenator for example, one having a structure such as that shown in FIG. 1 or FIG. 3 described later
  • the aqueous coating liquid is brought into contact with (or circulated through) the outer surface of the hollow fiber membrane.
  • the outer surface of the hollow fiber membrane that is, the blood-contacting portion
  • an antithrombotic polymer compound As a result, a coating containing the antithrombotic polymer compound is formed on the outer surface of the hollow fiber membrane.
  • the application of the aqueous coating liquid to the hollow fiber membranes may be performed before the oxygenator is assembled as long as the aqueous coating liquid is brought into contact with (or flows through) the outer surface of the hollow fiber membranes.
  • the method of bringing the outer surface of the hollow fiber membrane into contact with the aqueous coating liquid containing the antithrombotic polymer compound is not particularly limited, but conventionally known methods such as filling and dip coating (immersion method) can be applied. . Among these, filling is preferable because it increases the coating amount of the antithrombotic polymer compound.
  • the filling amount of the aqueous coating liquid is relative to the membrane area (m 2 ) of the hollow fiber membrane.
  • the filling amount is 50 g/m 2 or more, a coating containing a sufficient amount of the antithrombotic polymer compound can be formed on the hollow fiber membrane surface.
  • the upper limit of the filling amount is not particularly limited, it is preferably 200 g/m 2 or less, more preferably 150 g/m 2 or less.
  • membrane area refers to the area of the outer surface of the hollow fiber membrane, and is calculated from the product of the outer diameter, circumference, number and effective length of the hollow fiber membrane.
  • the time for which the outer surface of the hollow fiber membrane is brought into contact with the aqueous coating solution containing the antithrombotic polymer is not particularly limited, but considering the amount of coating, the ease of forming the coating film, the effect of reducing coating unevenness, etc. It is preferably from 0.5 minutes to 100 minutes, more preferably from 1 minute to 70 minutes, and even more preferably from 1 minute to 30 minutes.
  • the contact temperature between the aqueous coating solution and the hollow fiber membrane takes into account factors such as the amount of coating, the ease with which the coating is formed, and the effect of reducing coating unevenness. Then, 5 to 40°C is preferable, and 15 to 30°C is more preferable.
  • the amount of the antithrombotic polymer compound to be applied to the outer surface of the hollow fiber membrane is not particularly limited, but it is preferably an amount such that the thickness of the coating after drying is about 5 nm to 20 ⁇ m. If the above thickness cannot be obtained by one application (contact), the application process may be repeated until the desired thickness is obtained.
  • a coating (coating) of the antithrombotic polymer compound according to the present invention is formed on the outer surface of the hollow fiber membrane.
  • the drying conditions are not particularly limited as long as the coating (coating) with the antithrombotic polymer compound can be formed on the outer surface (furthermore, the outer surface layer) of the hollow fiber membrane.
  • the drying temperature is preferably 5 to 50°C, more preferably 15 to 40°C.
  • the drying time is preferably 60 to 300 minutes, more preferably 120 to 240 minutes.
  • the coating film may be dried by passing a gas of preferably 5 to 40° C., more preferably 15 to 30° C. through the hollow fiber membrane continuously or stepwise.
  • the type of gas is not particularly limited as long as it does not affect the coating film and can dry the coating film.
  • Specific examples include air, and inert gases such as nitrogen gas and argon gas.
  • the gas flow rate is not particularly limited as long as it can sufficiently dry the coating film, but is preferably 5 to 150 L, more preferably 30 to 100 L.
  • an artificial lung in which a coat layer containing a silicone compound is formed on the inner surface of the hollow fiber membrane, and a coating containing an antithrombotic polymer compound is formed on the outer surface of the hollow fiber membrane. Therefore, according to the manufacturing method according to the present embodiment, it is possible to provide an oxygenator having desired antithrombotic properties and plasma leak resistance.
  • Porous hollow for gas exchange made of porous polypropylene having an inner diameter of 112 ⁇ m, an outer diameter of 170 ⁇ m, a wall thickness of 29 ⁇ m, a porosity of about 30% by volume, and a pore diameter of the outer surface (that is, the pore diameter of the opening) of 50 nm
  • a bundle of 20,000 fiber membranes (a) was wound around, and a blood external perfusion type hollow fiber membrane oxygenator (a) having a membrane area (area of the outer surface of the hollow fiber membrane) of 1.9 m 2 was produced. did.
  • Example 1 (Preparation of coating liquid) Polydimethylsiloxane (vinyl-terminated PDMS, SYLGARD (registered trademark) 184; hereinafter the same) was dissolved in n-hexane (surface tension: 18.4 dyn/cm; hereinafter the same) to a concentration of 600 mg/mL to obtain a coating solution ( 1) was prepared.
  • n-hexane surface tension: 18.4 dyn/cm; hereinafter the same
  • the blood channel of the external blood perfusion type hollow fiber membrane oxygenator (a) was filled with water, and the outer surface of the hollow fiber membrane was brought into contact with water.
  • the coating liquid (1) was passed from the gas inlet to the gas outlet at a flow rate of 0.1 m/sec for 10 seconds to bring the inner surface of the hollow fiber membrane into contact with the coating liquid.
  • the coating liquid amount at this time was 105 mL/m 2 per film area.
  • the water in the blood channel and the coating liquid (1) in the gas channel were removed, and air (25° C.) was passed from the gas inlet to the gas outlet at a flow rate of 1.7 m/sec for 48 hours.
  • a thread membrane oxygenator (1) (hereinafter also simply referred to as "oxygenator (1)") was manufactured.
  • a coating liquid (2) was prepared by dissolving polydimethylsiloxane in n-hexane to a concentration of 200 mg/mL.
  • a hollow fiber membrane (2 ) (hereinafter also simply referred to as “oxygenator (2)”).
  • Example 3 (Preparation of coating liquid) A coating liquid (2) was prepared by performing the same operation as in Example 2 (preparation of coating liquid).
  • the blood channel of the external blood perfusion type hollow fiber membrane oxygenator (a) was filled with water, and the outer surface of the hollow fiber membrane was brought into contact with water.
  • the coating liquid (2) was passed from the gas inlet to the gas outlet at a flow rate of 0.1 m/sec for 10 seconds to bring the inner surface of the hollow fiber membrane into contact with the coating liquid. Thereafter, the water in the blood channel and the coating liquid (2) in the gas channel were removed, and left in an oven at 60° C. for 12 hours.
  • the hollow fiber membrane is dried and the polydimethylsiloxane is crosslinked, resulting in a blood externally perfused hollow fiber membrane artificial lung having a hollow fiber membrane (3) with a coat layer (dry film thickness: 4 ⁇ m) formed on the inner surface.
  • (3) (hereinafter also simply referred to as “oxygenator (3)”) was manufactured.
  • Example 4 (Preparation of coating liquid) The same operation as in Example 1 (preparation of coating liquid) was performed to prepare coating liquid (1).
  • the blood channel of the external blood perfusion type hollow fiber membrane oxygenator (a) was filled with water, and the outer surface of the hollow fiber membrane was brought into contact with water.
  • the coating liquid (1) was passed from the gas inlet to the gas outlet at a flow rate of 0.1 m/sec for 10 seconds to bring the inner surface of the hollow fiber membrane into contact with the coating liquid.
  • the water in the blood channel and the coating liquid (1) in the gas channel were removed, and water (25° C.) was passed from the gas inlet to the gas outlet at a flow rate of 0.1 m/sec for 50 seconds. After that, the water in the gas flow path was removed and left in an oven at 60° C. for 12 hours.
  • the hollow fiber membrane is dried and the polydimethylsiloxane is crosslinked, resulting in a blood externally perfused hollow fiber membrane artificial lung having a hollow fiber membrane (4) with a coat layer (dry film thickness: 4 ⁇ m) formed on the inner surface.
  • (4) (hereinafter also simply referred to as "oxygenator (4)") was manufactured.
  • Each of the hollow fiber membranes (1) to (4) and the comparative hollow fiber membrane (1) was potted with an epoxy resin, and sodium dodecyl sulfate (SDS) was added to a 0.9 w/v% sodium chloride aqueous solution at a concentration of 1 mg/mL.
  • the outside of the hollow fiber membrane was filled with a solution (SDS/saline solution) dissolved so as to A pressure of 760 mmHg was applied to the SDS/saline solution, and the amount of the SDS/saline solution permeating from the outside of the hollow fiber membrane to the lumen for 600 seconds was measured to evaluate plasma leak resistance.
  • the plasma leak resistance of the hollow fiber membrane (a) was also evaluated in the same manner.
  • " ⁇ " indicates that the SDS/saline solution permeation amount is less than 0.2 mL/m 2 ⁇ min ⁇ mmHg, 0.2 mL / m 2 ⁇ min ⁇ mmHg or more and less than 0.4 mL / m 2 ⁇ min ⁇ mmHg
  • a value of 0.4 mL/m 2 ⁇ min ⁇ mmHg or more is represented as “x”. It means that the lower the SDS/saline solution permeation amount, the better the plasma leakage resistance.
  • the SDS/saline solution permeation amount is less than 0.4 mL/m 2 ⁇ min ⁇ mmHg ( ⁇ or ⁇ )
  • sufficient plasma leakage resistance suitable for long-term use is exhibited.
  • Example 1 is different from Example 1 in that the fluid to be circulated in the lumen is air
  • Example 4 is different from Example 1 in that the fluid is water, but the results of Example 1 and Example 4 are the same. Therefore, description of the results of Example 4 in Table 1 below is omitted.

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JPS57180405A (en) * 1981-04-28 1982-11-06 Kuraray Co Ltd Hollow yarn type treating device for body fluid
JPS5944267A (ja) * 1982-09-02 1984-03-12 テルモ株式会社 中空糸型人工肺
JPS6397172A (ja) * 1986-10-15 1988-04-27 株式会社ジェイ・エム・エス 抗血栓性の優れた中空繊維型人工肺
JP2015136383A (ja) * 2014-01-20 2015-07-30 テルモ株式会社 中空糸膜外部血液灌流型人工肺
WO2016143751A1 (ja) * 2015-03-10 2016-09-15 テルモ株式会社 人工肺および人工肺の製造方法

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JP2002035116A (ja) 2000-07-19 2002-02-05 Senko Medical Instr Mfg Co Ltd ハイブリッド型人工肺

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Publication number Priority date Publication date Assignee Title
JPS57180405A (en) * 1981-04-28 1982-11-06 Kuraray Co Ltd Hollow yarn type treating device for body fluid
JPS5944267A (ja) * 1982-09-02 1984-03-12 テルモ株式会社 中空糸型人工肺
JPS6397172A (ja) * 1986-10-15 1988-04-27 株式会社ジェイ・エム・エス 抗血栓性の優れた中空繊維型人工肺
JP2015136383A (ja) * 2014-01-20 2015-07-30 テルモ株式会社 中空糸膜外部血液灌流型人工肺
WO2016143751A1 (ja) * 2015-03-10 2016-09-15 テルモ株式会社 人工肺および人工肺の製造方法

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