WO2003082366A1 - Materiau support d'ingenierie tissulaire, vaisseau artificiel, element de manchette et revetement destine a des implants - Google Patents

Materiau support d'ingenierie tissulaire, vaisseau artificiel, element de manchette et revetement destine a des implants Download PDF

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Publication number
WO2003082366A1
WO2003082366A1 PCT/JP2003/003594 JP0303594W WO03082366A1 WO 2003082366 A1 WO2003082366 A1 WO 2003082366A1 JP 0303594 W JP0303594 W JP 0303594W WO 03082366 A1 WO03082366 A1 WO 03082366A1
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WO
WIPO (PCT)
Prior art keywords
resin
porous
dimensional network
network structure
growth factor
Prior art date
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PCT/JP2003/003594
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English (en)
Japanese (ja)
Inventor
Yasuhide Nakayama
Eisuke Tatsumi
Yasushi Nemoto
Original Assignee
Japan As Represented By President Of National Cardiovascular Center
Bridgestone Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from JP2002091793A external-priority patent/JP2003284767A/ja
Priority claimed from JP2002259848A external-priority patent/JP2004097267A/ja
Priority claimed from JP2002259849A external-priority patent/JP2004097268A/ja
Application filed by Japan As Represented By President Of National Cardiovascular Center, Bridgestone Corporation filed Critical Japan As Represented By President Of National Cardiovascular Center
Priority to AU2003221090A priority Critical patent/AU2003221090C1/en
Priority to CA2484012A priority patent/CA2484012C/fr
Priority to DE10392444T priority patent/DE10392444T5/de
Publication of WO2003082366A1 publication Critical patent/WO2003082366A1/fr
Priority to US10/950,620 priority patent/US20050107868A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges

Definitions

  • Tissue engineering scaffold material artificial blood vessel, cuff member, and bioimplant member coating material
  • the present invention relates to a tissue engineering scan holder material, an artificial blood vessel, a cuff member, and a living body implanting member covering material.
  • the present invention firstly relates to a porous tissue engineering scaffold capable of easily engrafting and culturing cells and stably organizing cells, and an artificial blood vessel using this scaffold.
  • the scaffold material for tissue engineering and the artificial blood vessel of the present invention can be used not only in basic research in biotechnology, but also as a medical material used as an artificial skeleton base material in replacement medicine using artificial organs and regenerative medicine using tissue engineering. It is particularly useful for artificial blood vessels having a good patency rate even with a small diameter of 6 mm or less, utilizing the property that vascular endothelial cells take over the entire inner wall.
  • a material for tissue engineering there has been used a material such as a polystyrene Petri dish or a polyester mesh coated with an extracellular matrix such as collagen, which has been widely used mainly in monolayer culture.
  • Culture modes other than monolayer culture include spheroid morphology by shaking culture and embedded culture using collagen gel.
  • embedded culture using collagen gel is cultivated in vivo. In other words, it was possible to grow cells in a three-dimensional morphology, and it was also possible to conduct basic research on cell functions that were insufficient with monolayer culture.
  • tubes made of polyester resin or PTFE resin mesh have been put into practical use for a long time, and research is being conducted to reduce the diameter and improve the patency rate.
  • the mainstream technologies studied to date are those using segmented polyurethane tubing, which has a proven track record as an antithrombotic material, and an artificial vascular material in which an antithrombotic substance such as heparin is immobilized on the surface using a graft chain or the like. And so on.
  • Collagen gel for embedded culture is not a porous structure such as a three-dimensional network structure
  • a problem that cell engraftment cannot be obtained uniformly over the entire surface, or the distribution of engraftment cannot be adjusted.
  • a method for producing a porous material having a three-dimensional network structure a salt-containing method, a bubble method, and the like are known. There has not yet been obtained a hold member made of a three-dimensional network structure.
  • the cell engraftment structure obtained by collagen gel embedding culture has no physical strength in the collagen gel itself, which is the carrier material, and can be used to evaluate cell functions. However, it cannot be used for such uses, for example, for artificial blood vessels.
  • the present invention relates to a cuff member capable of invading cells from a living tissue and capable of firmly adhering to the living tissue, and more particularly to a therapy for subcutaneously inserting a force-Eureta catheter.
  • the present invention relates to cuff members useful for living skin insertion such as blood circulation using assisted heart, peritoneal dialysis, central parenteral nutrition, transcannula DDS and transcatheter DDS.
  • force-nucleating catheters used in therapies such as ventricular assist devices and peritoneal dialysis are used to perform subcutaneous puncture into the body. Need to be detained.
  • a force member also referred to as a skin cuff
  • the puncture area is sealed tightly.
  • a pliable velor made mainly of polyester fiber is wound around a puncture input neuron, and the pliable velor and the subcutaneous tissue are fixed at the insertion portion by fixing the force velore.
  • a fiber bur is made of polyester fiber, etc., as a force member, fixed at the skin insertion position of the catheter, and the catheter is indwelled by joining the subcutaneous tissue so as to press the cuff member.
  • Some of these fabric velours are impregnated with collagen or the like to achieve more robust adhesion.
  • a cuff member made of a member having excellent biocompatibility is fixed to the subcutaneous tissue at the puncture site.
  • the blood circulation method using a ventilator is a therapy that assists blood circulation with a pulsation pump installed outside the patient
  • the vibration of the pulsation pump equivalent to about 1.5 Hz is transmitted to the force neuron.
  • the insertion portion of the force neuron is always subjected to a mechanical load due to vibration.
  • stress is generated at the adhesive interface between the subcutaneous tissue and the cuff member in an attempt to remove it. .
  • a typical example of a problem that is considered to be due to a decrease in the adhesion between the cuff member and the subcutaneous tissue due to these stress loads is an infection problem such as a tunnel infection.
  • the number of experiences of troubles is very large.
  • the development of a cuff member that can prevent infection is an urgent issue in this therapy.
  • the present invention covers the surface of a living body-implanted member such as an artificial valve, an artificial valve ring, an artificial blood vessel, an artificial breast, an artificial bone, an artificial joint, an artificial heart and the like, and its accompanying components.
  • the present invention relates to a covering material for a living body implanted member for mitigating a foreign substance reaction from a living body.
  • bio-implantable members such as artificial valves, artificial valve rings, artificial blood vessels, artificial breasts, artificial bones, artificial joints and artificial hearts, and their accompanying components.
  • Investigations have been focused on materials that are chemically inert and do not or do not irritate surrounding tissues and are immunologically ignored by the living body. Examples of such materials include metal materials such as titanium, stainless steel, and platinum; ceramic materials such as hydroxyapatite; and polymer materials such as polytetrafluoroethylene, polyester, and polypropylene.
  • Has been Metallic materials are used, for example, for stents to be placed in blood vessels, bone fixation bolts, and artificial joints.
  • Ceramic materials are used, for example, as artificial joints and artificial bones for filling and replacing joint and bone defects.
  • High-molecular materials are used to secure blood flow after resection of an aneurysm, sutures used for suturing sutures that cannot be removed without re-incision, artificial trachea, breasts lost due to resection of breast cancer It has been put to practical use in artificial breasts used for prosthetic surgery and breast augmentation in plastic surgery.
  • Metal materials to be implanted in the living body are mainly composed of stainless steel, which has good protection against water, but contain various electrolytes, proteins, and lipids in long-term indwelling in blood vessels. ⁇ is generated by constant exposure to blood, which may also be a factor irritating surrounding tissues.
  • the mainstream of artificial breasts that are currently in practical use are silicone packs filled with saline, etc., which often contract and contract due to thickening of the encapsulated collagen tissue on the surface after subcutaneous implantation.
  • the silicone bag is deformed in the living body, and there is a problem that peripheral tissues are pressed, an inflammatory reaction is caused, and breast cancer is recurred.
  • an artificial trachea a tube made of a silicon tube has been put into practical use, but it has no affinity with the living trachea, and has a problem that it is detached by long-term implantation and causes infection at the interface. Was.
  • the invention according to the first aspect is a tissue engineering scan material comprising a homogeneous porous body having a three-dimensional network structure, wherein cells can be uniformly engrafted over the entire surface of the porous structure, Excellent physical strength, not only for basic research in the field of tissue engineering, but also for artificial blood vessels, especially when applied to small-diameter artificial blood vessels with an inner diameter of 6 mni or less, a high patency rate over a long period of time It is an object of the present invention to provide a tissue engineering scan hold material capable of forming an artificial blood vessel capable of maintaining the above condition, and an artificial blood vessel using the tissue engineering scan hold material.
  • the tissue engineering scan hold material of the present invention is a tissue engineering scan hold material made of a thermoplastic resin, wherein the thermoplastic resin has an average pore diameter of 100 to 65 ⁇ m and an apparent density of 0 to 0 1 to It is characterized by forming a porous three-dimensional network structure of 0.5 g Z cm 3 with communication.
  • the tissue engineering scan hold material of the present invention has a porous three-dimensional network structure of a thermoplastic resin having the above-mentioned specific average pore diameter and apparent density, so that cells and cells are transferred to the pores of the porous three-dimensional network structure.
  • the collagen suspension can easily penetrate. Therefore, cells can be seeded uniformly over the entire porous three-dimensional network structure.For example, it is possible to obtain an artificial peritoneum consisting of two layers of mesothelial cells and fibroblasts. It can also be used to analyze the mechanism of Dali cosulation and for basic studies on dialysis.
  • tissue engineering scaffold material when used as an artificial blood vessel, vascular endothelial cells can be present on the inner wall of the artificial blood vessel, and occlusion is unlikely to occur, resulting in the realization of a small-diameter artificial blood vessel. Is possible.
  • the artificial blood vessel of the present invention is made of the above-described carrier material of the present invention, and has a high patency rate even with a small bore of 6 mm or less in inner diameter, and is effective for coronary artery bypass surgery, peripheral artery reconstruction surgery, and the like. Can be applied.
  • the cells easily invade and engraft from the subcutaneous tissue of the living body and adhere to the subcutaneous tissue by constructing capillaries, and as a result, the downgrowth is achieved. Control the progress of infection and reduce the risk of various infection troubles including tunnel infection It is an object to provide a head member.
  • the cuff member of the present invention is formed of a base resin made of a thermoplastic resin or a thermosetting resin, has an average pore diameter of 100 ⁇ m to 100 ⁇ m, and an apparent density of 0.01 to 0.1 ⁇ m. It is characterized by having a porous three-dimensional network structure of 5 g Z cm 3 which is communicable.
  • the cuff member of the present invention has an interconnected porous three-dimensional network structure portion made of a thermoplastic resin or a thermosetting resin having the above-mentioned specific average pore diameter and apparent density, the porous three-dimensional Cells easily penetrate into the pores of the network and engraft them, resulting in strong adhesion to living tissue.
  • the cells easily invade from the subcutaneous tissue of the living body, adhere to the tissue, and are adhered to the tissue, whereby the adhesion with the living tissue can be obtained robustly. It is an object of the present invention to provide a living body implanting member covering material capable of preventing a bad effect on a living body by being implanted in a living body.
  • the covering material for a living body implanted member of the present invention is formed of a base resin made of a thermoplastic resin or a thermosetting resin, has an average pore diameter of 100 to 100 ⁇ m, and has an apparent density of 0 It is characterized by having a porous three-dimensional network structure having a communicability of 1 to 0.5 g Z cm 3 .
  • the coating material for a living body implanting member of the present invention has a continuous porous three-dimensional network structure portion made of a thermoplastic resin or a thermosetting resin having the above-mentioned specific average pore diameter and apparent density. Cells can easily invade and engraft into the pores of the three-dimensional reticulated network, and capillaries can be constructed, and robust adhesion to living tissue can be obtained.
  • the coating material for a living body implantation member of the present invention has a porous three-dimensional network structure layer capable of invasion and engraftment of cells and construction of capillaries.
  • the artificial implant, artificial valve ring, artificial blood vessel, artificial breast, artificial bone, artificial joint, artificial heart, and the like, and their accompanying parts are embedded in the living body using the biological implantable member covering material of the present invention.
  • the members to be treated it is possible to alleviate foreign body reaction from the surrounding tissue to these members.
  • a living body implanting member is one that is implanted in a living body, and includes a system constructed from various components.
  • the actuator Enoregergy converter
  • the left and right blood pumps as pumps, atrial cuffs, atrial connectors, arterial grafts and arterial connectors
  • Internal coil in the transcutaneous energy transmission system internal unit in the transcutaneous information transmission system, internal battery in the battery system, internal control unit in the control system, volume displacement (volume displacement)
  • the system has a compliance chamber, a displacement chamber, and a vent tube.
  • it consists of multiple parts such as internal unit connection cables and connectors. In the present invention, all of these are referred to as living body implanted members.
  • the implantable body covering material of the present invention can mitigate a foreign body reaction by coating the outer surface of the transmitter when implanting the transmitter into an animal body for an animal ecology survey in addition to a clinical purpose. It is also possible.
  • FIG. 1 is an SEM image (magnification: 20) of the entire tubular structure of the carrier material manufactured in Example 1.
  • FIG. 2 is a stereomicroscopic image (100 ⁇ magnification) of the microstructure inside the tubular structure of the carrier material manufactured in Example 1.
  • FIG. 3 is an SEM image (magnification: 20) of the surface layer of the inner wall of the tubular structure of the carrier material manufactured in Example 1.
  • FIG. 4 is an SEM image (at a magnification of 20) of the outer surface layer of the tubular structure of the carrier material manufactured in Example 1.
  • FIG. 5 is an optical microscope image ( ⁇ 10) of the porous three-dimensional network material containing cells produced in Example 2 after culturing for 3 days.
  • FIG. 6 is an optical micrograph ( ⁇ 10) showing that in Example 2, the internal tissue had survived over the entire surface even after one week of additional culture.
  • FIG. 7 is a photograph of a scene in Example 3 in which blood flow was secured by an artificial blood vessel and pulsation occurred.
  • FIG. 8 is a photograph showing that thrombus was not formed inside the artificial blood vessel one week after transplantation in Example 3.
  • FIG. 9 is a SEM image (magnification: 50) of the surface layer portion of the annular structure manufactured in Comparative Example 1.
  • FIG. 10 is an SEM image (50%) of the microstructure inside the annular structure manufactured in Comparative Example 1. Times).
  • FIG. 11 is an optical microscope cross-sectional image ( ⁇ 10) of the tubular structure material containing cells produced in Comparative Example 2 after culturing for 3 days.
  • FIG. 12 is a SEM image (magnification: 50) of the surface of the cuff member manufactured in Example 4 on the tissue contact side.
  • FIG. 13 is a SEM image (magnification: 50) of the internal cross section of the cuff member manufactured in Example 4.
  • FIG. 14 is a distribution diagram obtained by measuring the pore size distribution of the cuff member manufactured in Example 4.
  • FIG. 15 is a photograph immediately after the operation of embedding the cuff member manufactured in Example 4 into the incised area of the goat chest, suturing the subcutaneous tissue and penetrating and fixing it.
  • Fig. 16a is an enlarged photograph of the tissue around the test piece when the forceps member manufactured in Example 4 was implanted into the goat chest incision site for 2 weeks and extracted
  • Fig. 16b is the texture for comparison. It is an enlarged photograph of an enlarged photograph of a structure around a test piece when a test is similarly performed using a cloth.
  • tissue engineering scaffold and the artificial blood vessel of the present invention will be described in detail.
  • the three-dimensional network structure portion made of a thermoplastic resin constituting the tissue engineering skid holder of the present invention has an average pore diameter of 100 to 650 ⁇ m and an apparent density of 0.01 to 0.5 gZ cm 3 .
  • the structure be a porous three-dimensional network having a continuous pore structure.Even if the entire structure from the inner wall to the outer wall has a similar structure, there is a difference between the vicinity of the inner wall and the vicinity of the outer wall. Is also good.
  • the average pore diameter may be partially changed from the apparent density to the apparent density. For example, it may have so-called anisotropy in which the average pore diameter gradually changes from the inner wall toward the outer wall.
  • this average pore size of the porous three-dimensional network structure composed of the thermoplastic resin is 100 to 650 mu m, although the apparent density is 0. 01 ⁇ 0 5 gZ cm 3, preferably an average pore size 1 00 ⁇ 400;. Im And more preferably 100 to 300 / zm.
  • the apparent density is within the range of 0.01 to 0.5 gZ cm 3 , the cell viability is good and the physical properties are excellent.
  • Strength to maintain the force elastic characteristics approximate to a living body obtained preferably 0. 0 1 ⁇ 0. 2 g Z cm 3, more preferably 0. 0 1 ⁇ 0. Lg Z cm 3.
  • the pore size distribution is monodisperse, and it is desirable that pores having a pore size of 150 to 300 m, which is an important pore size for cell invasion, have a high contribution ratio.
  • the contribution ratio of pores having a pore diameter of 150 to 300 ⁇ m is 10% or more, preferably 20% or more, more preferably 30% or more, still more preferably 40% or more, and particularly preferably 50% or more. %, The cells easily invade, and the invaded cells easily adhere and grow, which is effective for use as a scaffold material and an artificial blood vessel.
  • the contribution ratio of pores having a pore diameter of 150 to 300 ⁇ in the average pore diameter of the porous three-dimensional network structure is based on the total number of pores in the method for measuring the average pore diameter in Example 1 described later. It refers to the ratio of the number of pores with a pore size of 150 to 300 ⁇ .
  • porous three-dimensional network structure having an average pore size, apparent density and pore size distribution, cells and collagen suspension culture solution easily penetrate into pores, and cells adhere to and grow on the porous structure layer. It is possible to obtain a good carrier material which is easy to perform. Therefore, when it is formed into a tubular shape, cells can be engrafted to the whole from the inner wall to the outer periphery, so that an artificial blood vessel with a low risk of occlusion and a high patency rate can be realized. .
  • thermoplastic resin constituting the tissue engineering carrier material of the present invention examples include a polyurethane resin, a polyamide resin, a polyacid resin, a polyolefin resin, a polyester resin, a fluorine resin, an acrylamide resin, a methacryl resin, and the like. Derivatives can be exemplified.One of these may be used alone, or two or more thereof may be used in combination.
  • the resin is a polyurethane resin. It is preferable because an artificial blood vessel having excellent properties and physical properties can be obtained.
  • the segmented polyurethane resin is synthesized from three components, polyol, diisocyanate, and chain extender, and has an elastomer characteristic of a block polymer structure having a so-called hard segment portion and a soft segment portion in a molecule.
  • the scaffold material and artificial blood vessel obtained by using polyurethane resin have an S—S curve that is elastically similar to a living blood vessel (higher compliance and lower elasticity in the low blood pressure region, and higher blood pressure in the high blood pressure region than in the low blood pressure region).
  • thermoplastic resin has a hydrolyzable or biodegradable property, it is gradually decomposed and absorbed after the transplantation of the artificial blood vessel into the living body, and finally, the resin base material with the engrafted cells remaining. It is also possible to exclude itself from the living body.
  • the porous three-dimensional network structure composed of such a thermoplastic resin includes collagen type I, collagen type II, collagen type III, collagen type IV, atherocollagen, fibronectin, gelatin, hyaluronic acid, and heparin.
  • One or more selected from the group consisting of polydimethylacrylamide and polyvinylpyrrolidone may be retained, and further, fibroblast growth factor, interleukin-1, tumor growth factor, epithelial growth Factor and double One or more cytokines selected from the group consisting of fibroblast growth factors may be retained, and furthermore, embryonic stem cells, vascular end
  • fine pores can be provided in the skeleton itself made of a thermoplastic resin for constructing the porous three-dimensional network structure layer.
  • Such micropores make the skeletal surface not a smooth surface but a complex uneven surface, and it is also effective for holding collagen and cell growth factors, etc., resulting in increased cell engraftment Is possible.
  • the micropores in this case are not introduced into the concept of calculating the average pore diameter of the porous three-dimensional network structure in the present invention.
  • the shape of the tissue engineering scaffold material of the present invention is not particularly limited.
  • it can be used as an artificial blood vessel.
  • this tubular structure has an inner diameter of 0.3 to 15 111111 and an outer diameter of 0.4 to 20 mm, preferably an inner diameter of 0.3 to: LO mm and an outer diameter of 0.4 to 15 mm. More preferably, the inner diameter is 0.3-6 mm and the outer diameter is 0.4-: L 0 mm, particularly preferably, the inner diameter is 0.3-2.5 mm, the outer diameter is 0.4-: L 0 mm, particularly preferably the inner diameter. 0.3-1.5 mm, outer diameter 0.4- 10 mm. Even with such a small-diameter artificial blood vessel, a high patency rate can be maintained over a long period of time.
  • the artificial blood vessel of the present invention comprising the scaffold material of the present invention may be one in which the outside is coated with another tubular structure.
  • the present invention provides When the density of impregnation of collagen or other material into the material is low, or when the thickness of the carrier material is thin, blood leakage is prevented for a certain period after transplantation, and cell adhesion and engraftment are sufficiently performed to prevent blood leakage. It can be absorbed by the living body when the possibility of bleeding is low, and can give a supplementary effect when it disappears.
  • tubular structure for coating for example, chitosan, polylactic acid resin, polyester resin, polyamide resin, polyurethane resin, fibronectin, gelatin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, Chondroitin Sulfate B, copolymer of hydroxymethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide, polybutylpyrroli And a tube formed from one or more selected from the group consisting of don, cross-linked collagen and fibrous mouth.
  • the thickness (outer diameter) of the tubular structure for coating such as the chitosan tube And the inner diameter is about 5 ⁇ 500 ⁇ It is preferable.
  • the artificial blood vessel of the present invention is novel in that it has a high patency and can secure a stable blood flow even if it has a small diameter that cannot be achieved by the conventional technology. There is no problem if it is applied to more than one.
  • thermoplastic resin structure having the structure is not limited to the following method. Further, according to the following method, it is possible to produce a thermoplastic resin substrate having a three-dimensional network structure of various shapes required as a carrier material for tissue engineering, such as a planar substrate.
  • a porous three-dimensional network structure made of a thermoplastic polyurethane resin first, a polyurethane resin, a water-soluble polymer compound described later as a pore-forming agent, and an organic solvent that is a good solvent for the polyurethane resin are used.
  • a polymer dope Concrete Specifically, after a polyurethane resin is mixed with an organic solvent to form a uniform solution, a water-soluble polymer compound is mixed and dispersed in this solution.
  • organic solvent examples include N, N-dimethylformamide, N-methyl-12-pyrrolidinone, tetrahydrofuran, and the like.However, this is not limited as long as the thermoplastic polyurethane resin can be dissolved, and the amount of the organic solvent is reduced. Alternatively or without use, it is also possible to melt the polyurethane resin by the action of heat and to mix the pore former there.
  • water-soluble polymer compound as a pore-forming agent examples include polyethylene glycol, polypropylene propylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, lipoxymethinoresenolellose, hydroxypropynolecellulose, and methyl cellulose paste.
  • examples thereof include cellulose and ethylcellulose, but are not limited as long as they are uniformly dispersed with a thermoplastic resin to form a polymer dope.
  • lipophilic compounds such as phthalic acid esters and paraffin, and inorganic salts such as lithium chloride and calcium carbonate can be used instead of the water-soluble polymer compound.
  • a crystal nucleating agent for a polymer to promote the formation of secondary particles during coagulation, that is, the formation of a skeleton of a porous body.
  • the polymer dope produced from a thermoplastic polyurethane resin, an organic solvent, and a water-soluble polymer compound is then immersed in a coagulation bath containing a poor solvent for the thermoplastic polyurethane resin, and the organic solvent and the water-soluble polymer are added to the coagulation bath. Extract and remove molecular compounds. By removing part or all of the organic solvent and the water-soluble polymer compound in this manner, a porous three-dimensional network structure material made of a polyurethane resin can be obtained.
  • the poor solvent used here include water, lower alcohols, and low carbon number ketones.
  • the solidified polyurethane resin may be finally washed with water or the like to remove the remaining organic solvent and pore-forming agent.
  • a tube molding jig consisting of a core rod with a diameter of 1.2 mm ⁇ and a cylindrical stopper made of medical polypropylene resin that can fix this core rod to the center of the paper tube, 23 g of the polymer dope was added.
  • the polyurethane resin is extracted by removing the internal NMP solvent from the paper tube surface by putting it into refluxing methanol and continuing refluxing for 72 hours. Coagulated.
  • the methanol was replaced with a new solution at any time while maintaining the reflux state.
  • methyl cellulose, methanol and residual NMP were extracted and removed.
  • Fresh water was supplied from time to time for washing. This was dried at room temperature under reduced pressure (20 mmHg (2.7 kPa)) for 24 hours to obtain a tubular porous three-dimensional network-shaped scan that can be used as an artificial blood vessel according to an embodiment of the present invention. Hold material was obtained.
  • Figures 1 to 4 show images of this carrier material taken with a scanning electron microscope (3)] manufactured by [011], JMS-5800 LV, or a stereo microscope (VH-6300, manufactured by KEYENCE).
  • the base material of the obtained skid holder material has a hole diameter of about 200 ⁇ m, an inner diameter of 1.2 mm ⁇ , an outer diameter of 3.2 mm ⁇ , and a structure It can be seen that the inside (Fig. 2), the inner wall surface layer (Fig. 3) and the outer surface layer (Fig. 4) have a porous three-dimensional network structure with almost the same structure, and that the whole is a homogeneous porous body.
  • the average pore diameter and the apparent density of the obtained carrier material were measured by the following methods. In the measurement of the average pore diameter and the apparent density, the sample was cut at room temperature using a double-blade razor (Feather, high stainless steel).
  • the three-dimensional network structure which is a feature of the present invention, is a structure that is excellent in continuity between holes.
  • the evaluation of water permeability as an index of the continuity was performed as follows.
  • Bovine blood vessel-derived smooth muscle cells (cell density: 6 ⁇ 10 6 ce 11 s ZmL) in DMEM (medium component) solution (containing 10% FCS (fetal calf serum)) and collagen type I solution (0.3% acidic Solution, manufactured by Koken Co., Ltd.) and mixed in equal amounts while cooling on ice. (Cell density: 3 ⁇ 10 6 ce 11 s / mL).
  • tubular porous three-dimensional network-structured carrier material (inner diameter: 1.2 ⁇ , outer diameter: 3.2 mm ⁇ , length: 2 cm) produced in Example 1 is bound by a clamp, and the other end is clamped.
  • the suspension (lmL) of the smooth muscle cells was injected until it oozed from the side wall of the tubular structure of the carrier material. All injection operations were performed on ice and repeated several times to fill the inside of the tubular structure with a collagen solution containing smooth muscle cells. Then, remove the clamp, pass a 1.2 mm mandrel made of SUS440 through the center of the tubular structure of the carrier material, and incubate at 37 ° C in an incubator at 37 ° C. A three-dimensional network structure material was obtained.
  • FIG. 5 shows a cross-sectional structure image obtained by culturing the porous three-dimensional network structure material containing cells obtained in this manner for 3 days and then observing the same with an optical microscope. From Fig. 5, it can be seen that cells are distributed all over the prepared structural material. It was observed that the structure containing these cells survived without necrosis even after additional culture for one week.
  • tubular porous three-dimensional network-structured scaffold material (inner diameter: 1.2 ⁇ , outer diameter: 3.2mm ⁇ i), length: 2cm) produced in Example 1,
  • a collagen type I aqueous solution (0.15% by weight) was injected from the other end, and the inside of the structure was filled with the collagen solution.
  • the clamp was removed, a 1.2 mm ⁇ mandrel made of S US440 was passed through the center of the tubular structure of the carrier material, and the collagen solution was gelled by holding it in the incubator at 37 ° C. Then, a tubular structure whose network structure was filled with collagen gel was produced.
  • the abdominal aorta of the rat was peeled off by about 3 cm, its ends were tied up with clamps to cut off the blood flow, then the central part of the artery was cut off, and the space between them was joined end-to-end with the tubular structure.
  • pulsation occurred and functioned as an artificial blood vessel (Figure 7).
  • the artificial blood vessel was excised, and the lumen surface of the tubular tissue was observed.
  • the thrombus was not adhered or formed on the lumen surface, it was extremely smooth (FIG. 8).
  • Thermoplastic polyurethane resin (Nippon Miractran Co., Ltd., Miractran E 980 PN AT) was dissolved by heating in tetrahydrafuran (manufactured by Wako Pure Chemical Industries, Ltd., THF) at 60 ° C. to obtain a 5.0% solution (weight / weight). 12 g of Na C in 16 mL of this THF solution
  • a suspension was prepared by dispersing one particle (the particle diameter was adjusted to 100 to 200 ⁇ by sieving).
  • a 1.2 mm ⁇ mandrel made of SUS440 was immersed in this suspension, dried, and a tube was formed around the mandrel with polyurethane containing NaC1 particles. After this was sufficiently dried, it was thoroughly washed with ion-exchanged water, and NaC1 embedded in the tube was dissolved and removed. Reduce the pressure at room temperature for 24 hours (20 mmHg (2.
  • Example 1 According to the appearance observation by SEM, the thing of Example 1 has a three-dimensional network structure in which the surface layer and the inside are the same, whereas in this comparative example, a dense layer is generated in the surface layer part ( (Fig. 9), the surface layer and the inside are completely different structures.
  • the internal structure is a three-dimensional net-like structure in which spherical holes are gathered and the wall of the hole penetrates where adjacent holes come into contact. was not ( Figure 10).
  • Example 2 The water permeability measured in the same manner as in Example 1 was 11.22 ⁇ 0.46 gZ60 seconds, and 20.08 ⁇ 0.96 g / 120 seconds, which were lower than those of Example 1. Indicated. This was presumed to be due to poor communication between the holes in the surface layer and the effect of the dense layer existing in the surface layer.
  • FIG. 11 shows a cross-sectional tissue image obtained by culturing the thus obtained tubular structural material containing cells for 3 days and then observing it with an optical microscope. From Fig. 11, the inside of the fabricated structural material Shows that almost no cells are present, but only on the inner wall.
  • a tissue engineering scan hold material comprising a homogeneous porous body having a three-dimensional network structure, and capable of uniformly engrafting cells throughout the inside of the porous structure.
  • Excellent physical strength not only for basic research in the field of biological tissue engineering, but also for artificial blood vessels, especially for artificial blood vessels with a small diameter of 6 mm or less
  • the present invention provides a tissue-engineering scaffold capable of forming an artificial blood vessel capable of maintaining the above conditions, and an artificial blood vessel using the tissue-engineering scaffold.
  • the communicating three-dimensional network structure portion made of a thermoplastic resin or a thermosetting resin constituting the force member of the present invention has an average pore diameter of 100 to 1000 / xm and an apparent density of 0.01 to 0.
  • a porous three-dimensional network structure of 5 g / cm 3 may be used, and even if the entire surface has a similar structure in the cross section in the thickness direction, it may be on one side and the other side. It may have a different structure.
  • the average pore diameter ⁇ apparent density may partially change.
  • the average pore diameter ⁇ apparent density gradually changes from one surface side to the other surface side. May be provided.
  • large pores that greatly deviate from the average pore diameter may exist on the contact surface side with the living tissue.
  • pores of about 500 to 2000 ⁇ are preferable, and since these pores are present near the surface layer on the side of the living tissue, it becomes easy to uniformly impregnate the extracellular matrix such as collagen to a deep part, and also from the tissue. It works in favor of cell invasion and the construction of capillaries. However, such pores having a large pore diameter are not introduced into the concept of calculating the average pore diameter of the porous three-dimensional network structure in the present invention.
  • the porous three-dimensional network has an average pore size of 100 to 1000 ⁇ m and an apparent density of 0.01 to 0.5 gZcm 3 , but the preferred average pore size is 200 to 600 ⁇ , more preferably 200 to 500 ⁇ . It is. If the apparent density within 0. 01 ⁇ 0. 5 g / cm 3 range, when a cellular engraftment properties good, maintaining excellent physical strength, cell invasion, engraft, and organized Although elastic properties similar to those of subcutaneous tissue can be obtained, it is preferably 0.05 to 0.3 g / cm 3 , more preferably 0.05 to 0.2 gZcm 3 .
  • the pore size distribution should be as high as 150 to 400 ⁇ , which is an important pore size for cell invasion.
  • the contribution rate of the pores of 100 ⁇ m is 10% or more, preferably 20% or more, more preferably 30% or more, still more preferably 40% or more, and particularly preferably 50% or more, This is preferable because it easily invades, and the invading cells easily adhere and grow.
  • the contribution ratio of pores having a pore diameter of 150 to 400 ⁇ in the average pore diameter of the porous three-dimensional network structure is defined as the pore diameter 15 to the total number of pores in the method for measuring the average pore diameter in Example 1 described later. Refers to the ratio of the number of pores of 0 to 400 ⁇ m.
  • porous three-dimensional network having an average pore size, apparent density, and pore size distribution, cells can easily penetrate into pores, and cells can easily adhere to and grow on the porous three-dimensional network.
  • the capillaries are constructed, and a good cuff member can be obtained in which the adhesion between the subcutaneous tissue and the catheter or force neur at the puncture site is strong and strong.
  • 0.2 to 500 mm can be used, preferably 0.2 to 100 mm, more preferably 0.2 to 50 mm, and particularly preferably.
  • the thickness is 0.2 to 10 mm, particularly preferably 0.2 to 5 mm. With such a thickness, the physical strength required for the cuff member, cell invasion, organization, and adhesion to the subcutaneous tissue Properties and bacterial barrier properties can be satisfied at a high level.
  • Resins, epoxy resins, polyimide resins, ataryl resins, methacrylic resins, and one or more of their derivatives can be exemplified, but a polyurethane resin is preferred, and a segmented polyurethane resin is particularly preferred.
  • the segmented polyurethane resin is synthesized from three components, a polyol, a diisocyanate, and a chain extender, and has an elastomer characteristic of a block polymer structure having a so-called hard segment portion and a soft segment portion in a molecule.
  • the elastic properties that can be obtained when resin is used are the stress generated at the interface between the subcutaneous tissue and the cuff member when the patient, catheter or force neurator moves, or when the skin around the insertion site is moved during disinfection or the like. Expected to have the effect of attenuating Wear.
  • a layer having the specific porous three-dimensional network structure as a first layer, and further laminate a second layer having a different structure on the first layer.
  • a fiber aggregate or a flexible film, or a porous three-dimensional network structure layer having an average pore diameter different from the porous three-dimensional network structure of the first layer and an apparent density can be used. It is.
  • the fiber aggregate examples include a nonwoven fabric and a woven fabric, and the thickness is 0.1 to: 100 mm, preferably 0.1 to 50 mm, more preferably 0.1 to 10 mm, Particularly preferably, the thickness is 0.1 to 5 mm. With such a thickness, good flexibility can be obtained when laminated with the porous three-dimensional network structure layer, and the bonding strength with the subcutaneous tissue is robust. And is preferred.
  • the non-woven fabric or the woven fabric preferably has a porosity in the range of 100 to 500 cc / cm 2 / min in terms of flexibility, suture strength with subcutaneous tissue, and the like.
  • the porosity is a value measured according to JISL 104, and may also be called air permeability or air permeability.
  • fiber aggregate one or more selected from the group consisting of polyurethane resin, polyamide resin, polylactic acid resin, polyolefin resin, polyester resin, fluororesin, acrylic resin, methacrylic resin and derivatives thereof
  • a synthetic resin consisting of fibers derived from natural products such as fibrous mouth, chitin, chitosan, cellulose, and one or more selected from these derivatives. Can also be used. Synthetic fibers and fibers derived from natural products may be used in combination.
  • the flexible film examples include a thermoplastic resin film, specifically, a polyurethane resin, a polyamide resin, a polylactic acid resin, a polyolefin resin, a polyester resin, a fluorine resin, a urea resin, a phenol resin, an epoxy resin, and a polyimide.
  • a thermoplastic resin film specifically, a polyurethane resin, a polyamide resin, a polylactic acid resin, a polyolefin resin, a polyester resin, a fluorine resin, a urea resin, a phenol resin, an epoxy resin, and a polyimide.
  • a thermoplastic resin film specifically, a polyurethane resin, a polyamide resin, a polylactic acid resin, a polyolefin resin, a polyester resin, a fluorine resin, a urea resin, a phenol resin, an epoxy resin, and a polyimide.
  • resins acrylic resins and methacrylic resins and derivatives thereof or
  • the film examples include two or more films, and preferably one or two or more films selected from the group consisting of polyester resin, fluorine resin, polyurethane resin, acrylic resin, vinyl chloride, fluorine resin, and silicon resin. Film.
  • an advantageous force member can be obtained in terms of flexibility and physical strength, and preferably 0.1 to 10 Omm. 0 mm, more preferably 0.1 mm to 5 O mm, even more preferably 0.1 mn! 110 mm.
  • the flexible film not only a solid film but also a porous film or a foam can be used.
  • a cuff member having a high bacterial barrier property and advantageous for infection control can be obtained.
  • the porous three-dimensional network When the second layer has a porous three-dimensional network having an average pore diameter and an apparent density different from the porous three-dimensional network of the first layer, the porous three-dimensional network has an average pore diameter of 0.1.
  • a porous three-dimensional network structure having an apparent density of about 0.01 to 1.0 g Z c ⁇ 3 at 2200 ⁇ can be used.
  • the thickness of the porous three-dimensional network structure layer as the second layer is preferably 0.2 to 2 Omm.
  • the second layer is an average of the fiber aggregate, the flexible film, and the porous three-dimensional network structure of the first layer.
  • a method of bonding using an adhesive especially laminating a hot melt nonwoven fabric between the first and second layers And a method of pressing under heating.
  • a hot-melt nonwoven fabric for example, a polyamide-type thermo-adhesive sheet such as PA101 manufactured by Nittobo Co., Ltd. can be used.
  • the polymer dope can be continuously laminated and formed by laminating and molding a fiber aggregate or a flexible film.
  • the second layer two or more layers of a fiber assembly, a flexible film, and a porous three-dimensional network structure layer may be provided, and the porosity of the first layer may be provided through the second layer. It may have a three-layer structure in which three-dimensional network structure layers are stacked.
  • collagen type I collagen type II, collagen type III, collagen type IV, atelocollagen, fibronectin, gelatin, hyaluronic acid, henolin, keratanic acid , Chondroitin, chondroitin sulphate, chondroitin sulphate B, elastin, heparan sulphate, laminin, tombospondin, vitronectin, osteonetatin, entacti Group consisting of methacrylate, hydroxymethacrylate and dimethylaminoethynolemethacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide and polybutylpyrrolidone
  • One or more selected from the group consisting of interferons, antivirals, antibacterials and antibiotics may be retained, and further, embryonic stem cells (which may be differentiated), One or more cells selected from the group consisting of vascular endothelial cells, mesodermal cells, smooth muscle cells, peripheral vascular cells, and mesothelial cells may be adhered.
  • fine holes can be provided in the skeleton itself made of a thermoplastic resin or a thermosetting resin constituting the porous three-dimensional network structure layer.
  • micropores make the skeletal surface not a smooth surface but a complex uneven surface, and it is also effective for holding collagen and cell growth factors, etc., and as a result, it is possible to increase cell engraftment is there.
  • the fine pores in this case are not included in the calculation of the average pore diameter of the porous three-dimensional network structure layer in the present invention.
  • thermoplastic polyurethane resin In order to produce a porous three-dimensional network made of a thermoplastic polyurethane resin, first, a polyurethane resin, a water-soluble polymer compound described later as a pore-forming agent, and an organic solvent which is a good solvent for the polyurethane resin are used. To produce a polymer dope. Specifically, after a polyurethane resin is mixed with an organic solvent to form a uniform solution, A water-soluble polymer compound is mixed and dispersed.
  • organic solvent examples include N, N-dimethylformamide, N-methyl-12-pyrrolidinone, tetrahydrofuran, and the like.However, this is not limited as long as the thermoplastic polyurethane resin can be dissolved, and the amount of the organic solvent is reduced. Alternatively or without use, it is also possible to melt the polyurethane resin by the action of heat and to mix the pore former there.
  • water-soluble polymer compound as a pore-forming agent examples include polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, canolepoxymethylcenorelose, hydroxypropinoresenorelose, methinoresenoleose, Ethyl cellulose and the like can be mentioned, but this is not limited as long as it is uniformly dispersed with a thermoplastic resin to form a polymer dope.
  • lipophilic compounds such as phthalic acid esters and paraffin, and inorganic salts such as lithium chloride and calcium carbonate can be used instead of the water-soluble polymer compound.
  • a crystal nucleating agent for a polymer to promote the formation of secondary particles during coagulation, that is, the formation of a skeleton of a porous body.
  • the polymer dope produced from a thermoplastic polyurethane resin, an organic solvent, and a water-soluble polymer compound is then immersed in a coagulation bath containing a poor solvent for the thermoplastic polyurethane resin, and the organic solvent and the water-soluble polymer are added to the coagulation bath. Extract and remove molecular compounds. By removing part or all of the organic solvent and the water-soluble polymer compound in this manner, a porous three-dimensional network structure material made of a polyurethane resin can be obtained.
  • the poor solvent used here include water, lower alcohols, and low carbon number ketones.
  • the solidified polyurethane resin may be finally washed with water or the like to remove the remaining organic solvent and pore-forming agent.
  • the communicating three-dimensional network structure portion made of a thermoplastic resin or a thermosetting resin constituting the covering material for a living body implantation member of the present invention has an average pore diameter of 100 to 100 ⁇ and an apparent density of A porous three-dimensional network structure of 0.01 to 0.5 g Z cm 3 may be used.
  • the other surface side may have a different structure.
  • the average pore diameter / apparent density may partially change.
  • the average pore diameter may be changed from one surface side to the other surface side. It may have a so-called anisotropy in which the soot diameter ⁇ the apparent density gradually changes.
  • a large-diameter hole that largely deviates from the average pore diameter may exist on the contact surface side with the living tissue.
  • pores having a size of about 500 to 2000 ⁇ are preferable, and since these pores are present near the surface layer on the side of the living tissue, it is easy to uniformly impregnate the extracellular matrix such as collagen to a deep portion. It is advantageous for the invasion of cells from the inside and the construction of capillaries. However, such large-diameter pores are not introduced into the concept of calculating the average pore diameter of the porous three-dimensional network structure in the present invention.
  • the average pore diameter of the porous three-dimensional network structure is 100 to 1000 m, an apparent density of 0.01 to 0.5 is a gZ cm 3, preferably an average pore size 200 to 600 mu m, more preferably 200 ⁇ 500 ⁇ m. If the apparent density within 0. 0 1 ⁇ 0. 5 g Roh cm 3 range, a cellular engraftment properties good, maintaining excellent physical strength, cell invasion, engraft, and organized In this case, elastic properties similar to those of the subcutaneous tissue can be obtained, but are preferably 0.05 to 0.3 g / cm 3 , more preferably 0.05 to 0.2 g / cm 3 .
  • the pore size distribution should be as high as 150 to 400 ⁇ m, which is an important pore size for cell invasion, and 150 to 400 ⁇ m.
  • the contribution ratio of the cells is 10% or more, preferably 20% or more, more preferably 30% or more, still more preferably 40% or more, and particularly preferably 50% or more, the cells can easily enter and Is preferred because it is easy to adhere and grow.
  • the contribution ratio of pores having a pore diameter of 150 to 400 / im in the average pore diameter of the porous three-dimensional network structure is a pore diameter of 150 to 400 m with respect to the total number of pores in the method for measuring the average pore diameter in Example 1 described later. Indicates the ratio of the number of holes.
  • porous three-dimensional network having an average pore size, apparent density, and pore size distribution, cells can easily penetrate into pores, and cells can easily adhere to and grow on the porous three-dimensional network.
  • a capillary is constructed, and a strong and good adhesion with the living body can be obtained in the portion where the living body implanting member is embedded.
  • the thickness of the porous three-dimensional network structure may be 0.5 to 50 Omm, preferably 0.5 to: L 00 mm, more preferably 0.5 to 50 mm, and particularly preferably 0.5 to 10 mm. , Particularly preferably 0.5 to 5 mm, such a thickness.
  • thermoplastic resin or thermosetting resin constituting such a porous three-dimensional network structure portion examples include polyurethane resin, polyamide resin, polylactic acid resin, polymalic acid resin, polyglycolic acid resin, polyolefin resin, and polyester. Resins, fluororesins, urine resins, phenolic resins, epoxy resins, polyimide resins, acrylic resins, methacrylic resins, and one or more of their derivatives can be exemplified, but polyurethane resins are preferred, and segmentation is particularly preferred. Polyurethane resins are preferred.
  • the segmented polyurethane resin is synthesized from three components of a polyol, a diisocyanate and a chain extender, and has an elastomer characteristic of a block polymer structure having a so-called hard segment portion and a soft segment portion in a molecule.
  • the elastic properties obtained when resin is used can be expected to have the effect of attenuating the stress generated at the interface between the living tissue and the living body implanted member.
  • a layer in which the specific porous three-dimensional network structure is formed is a first layer, and a second layer having a different structure is further laminated on the first layer. It is also possible.
  • a porous three-dimensional network structure layer having a different average pore size and apparent density from the porous three-dimensional network structure of the first layer can be used.
  • the porous three-dimensional network structure of the covering material for a living body implanted member of the present invention includes collagen type I, collagen type ⁇ , collagen type III, collagen type IV, athero-type collagen, fibronectin, gelatin, hyaluronic acid, heparin, Keratanic acid, chondroitin, chondroitin sulfate, chondroitin sulfate ⁇ , elastin, heparan sulfate, laminin, thrombospondin, vitronectin, osteonetatin, entactin, copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, hydroxyxetil Holds one or more selected from the group consisting of methacrylate and methacrylic acid copolymers, alginic acid, polyatarylamide, polydimethylacrylamide and polybutylpyrrolidone Platelet-derived growth factor, epidermal growth factor, transforming growth factor a
  • fine pores can be provided in a skeleton itself made of a thermoplastic resin or a thermosetting resin for constructing the porous three-dimensional network structure layer.
  • Such micropores make the skeletal surface not a smooth surface but a complex uneven surface, and it is also effective for retaining collagen and cell growth factors, etc., and as a result, it is possible to increase cell viability. is there.
  • the micropores in this case are not introduced into the concept of calculating the average pore diameter of the porous three-dimensional network structure layer in the present invention.
  • a porous three-dimensional network structure made of a thermoplastic polyurethane resin first, a polyurethane resin, a water-soluble polymer compound described later as a pore-forming agent, and an organic solvent that is a good solvent for the polyurethane resin are used.
  • a polymer dope Specifically, after a polyurethane resin is mixed with an organic solvent to form a uniform solution, a water-soluble polymer compound is mixed and dispersed in this solution.
  • the organic solvent include N, N-dimethylformamide, N-methyl-1-pyrrolidinone, tetrahydrofuran, and the like.
  • the organic solvent include N, N-dimethylformamide, N-methyl-1-pyrrolidinone, tetrahydrofuran, and the like.
  • the organic solvent include N, N-dimethylformamide, N-methyl-1-pyrrolidinone, tetrahydrofuran, and the like.
  • this does not apply as long as the thermoplastic polyurethan
  • Water-soluble polymer compounds as pore-forming agents include polyethylene glycol, poly Propylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, canolepoximethi / resenorelose, hydroxypropinoresenorelose, methylcellulose, ethylcellulose, etc. This does not apply as long as it forms a merdope.
  • lipophilic compounds such as phthalic acid esters and paraffin, and inorganic salts such as lithium chloride and calcium carbonate can be used instead of the water-soluble polymer compound. It is also possible to use a crystal nucleating agent for a polymer to promote the formation of secondary particles during coagulation, that is, the formation of a skeleton of a porous body.
  • the polymer dope produced from a thermoplastic polyurethane resin, an organic solvent, and a water-soluble polymer compound is then immersed in a coagulation bath containing a poor solvent for the thermoplastic polyurethane resin, and the organic solvent and the water-soluble polymer are added to the coagulation bath. Extract and remove molecular compounds. By removing part or all of the organic solvent and the water-soluble polymer compound in this manner, a porous three-dimensional network structure material made of a polyurethane resin can be obtained.
  • the poor solvent used here include water, lower alcohols, and low carbon number ketones.
  • the solidified polyurethane resin may be finally washed with water or the like to remove the remaining organic solvent and pore-forming agent.
  • the living body implantable member covering material of the present invention cells easily invade from living tissues, survive and become organized, so that adhesion to living tissues can be obtained robustly, As a result, it is possible to prevent adverse effects on the living body caused by embedding the living body implanting member in the living body.
  • the cuff member of the present invention and the bioimplant covering material constituting the surface thereof will be described more specifically with reference to examples.
  • the present invention is not limited to the following examples unless it exceeds the gist thereof. It is not limited in any way by the examples.
  • the polyurethane resin was coagulated by throwing it into refluxing methanol and continuing refluxing for 72 hours to extract and remove the NMP solvent from the upper and lower surfaces of the filter paper for chemical experiments.
  • the methanol was replaced with a new solution at any time while maintaining the reflux state.
  • the solidified polyurethane resin was removed from the Teflon frame, and washed with purified water for 72 hours in the Japanese Pharmacopoeia to extract and remove methylcellulose, methanol and remaining NMP. Fresh water was supplied as needed for washing water. This was dried under reduced pressure (20 mmHg) at room temperature for 24 hours to obtain a porous three-dimensional network structure material made of a thermoplastic polyurethane resin.
  • This porous three-dimensional network structure material is the bioimplant covering material of the present effort.
  • Figs. 1 and 2 are images of the covering member of the living body implanted member on the surface of the force-cuff member taken by a scanning electron microscope (SM200, manufactured by Topcon Corporation). It can be seen that the body implanting member covering material has a porous three-dimensional network structure with a pore diameter of about 35 ⁇ .
  • the average pore size and apparent density of the obtained cuff member with a thickness of 2.3 mm and a porous three-dimensional network structure (that is, the covering material for a bioimplant member) were measured by the following method, and the results are shown in Table 1.
  • Table 1 was measured in the following method, and the results are shown in Table 1.
  • the three-dimensional network structure manufactured in Example 4 and before the second layer was laminated was cut into a rectangular parallelepiped of about 10 mm ⁇ 10 mm ⁇ 3 mm using a double-edged razor.
  • the volume was determined from the dimensions obtained by measuring this sample with a projector (Nikon, V-12), and the weight was divided by the volume to determine the volume.
  • the first porous three-dimensional network structure layer is a porous three-dimensional network structure mainly composed of pores having a size effective for cell adhesion.
  • test piece was cut and used after ethylene oxide gas sterilization. After the operation, the test site was disinfected twice a day with acidic water or isodine. Samples were provided with free water, and an appropriate amount (approximately lkg) of Hay Cube was fed as feed 5 times a day. Two weeks after the operation, the previously implanted test piece and surrounding tissue were removed under general anesthesia. The test piece and the surrounding tissue adhered densely, and it was difficult to peel off each other. No findings such as infection or inflammation were observed in the surrounding area.
  • Fig. 5a shows a magnified photograph of the cuff member surface (that is, the covering material of the living body implanting member) that has been engrafted with a loupe.
  • An indistinct milky layer indicated by the arrow in Fig. 5a is also continuous inside the cuff member, and the inside of the cuff member is filled with transparent tissue, and the granulation tissue infiltrates. It was confirmed that.
  • Fig. 5b shows an enlarged photograph of the loupe when a test was performed in the same manner as above using a single woven fabric (the polyester fabric velor used in Example 4 (Pardy, Poveyy Double 'Velor Fabric)) alone.
  • a so-called down-growth phenomenon was observed in which the milky white layer infiltrated only from the epidermis in a deeper direction along the surface of the woven fabric.
  • the milky white layer was continuously present near the epidermis, and that the downgrowth was suppressed.
  • the porous three-dimensional network structure layer of the bioimplant member covering material on the surface of the forceps member of the present invention has extracellular matrices such as fibroblasts, macrophages, and collagen fibers extended from surrounding fibers.
  • the granulation tissue, mainly consisting of, was infiltrated, and angiogenesis was confirmed.
  • the cuff member of the present invention is organized by infiltration of living cells into the porous three-dimensional network structure layer, isolates the wound from the outside, and protects against exacerbation factors such as bacterial infection in the healing process. Was done.
  • the cuff member of the present invention As described in detail above, according to the cuff member of the present invention, cells easily invade and survive from the subcutaneous tissue of a living body, and a capillary is constructed, whereby adhesion to the subcutaneous tissue is obtained, and the As a result, the wound is isolated from the outside world, and exacerbated by factors such as bacterial infection during the healing process.
  • a cuff member that suppresses the progress of pengurose and is free from various troubles such as tunnel infection is provided.
  • Such a cuff member of the present invention can be used for a blood circulation method using an assisted artificial heart, which is a therapy for subcutaneously puncturing force-neutral catheters, peritoneal dialysis therapy, central parenteral nutrition, transcannula DDS and transcatheter DDS. It can be suitably used for a living skin penetration part such as.
  • an assisted artificial heart which is a therapy for subcutaneously puncturing force-neutral catheters, peritoneal dialysis therapy, central parenteral nutrition, transcannula DDS and transcatheter DDS. It can be suitably used for a living skin penetration part such as.

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Abstract

La présente invention concerne un matériau support destiné à des fins d'ingénierie tissulaire, un vaisseau artificiel, un élément de manchette et un revêtement destiné à des implants. Ledit matériau support destiné à des fins d'ingénierie tissulaire est constitué d'une résine thermoplastique et présente une structure réticulaire tridimensionnelle poreuse à cellules ouvertes, possédant une dimension des pores moyenne comprise entre 100 et 650 νm et une densité apparente comprise entre 0,01 et 0,5 g/cm3. Ledit vaisseau artificiel est constitué dudit matériau support. L'élément de manchette et le revêtement destiné à des implants sont chacun constitués d'une résine thermoplastique ou d'une résine thermodurcissable et présentent une partie d'une structure réticulaire tridimensionnelle poreuse à cellules ouvertes, possédant une dimension des pores moyenne comprise entre 100 et 1000 νm et une densité apparente comprise entre 0,01 et 0,5 g/cm3.
PCT/JP2003/003594 2002-03-28 2003-03-25 Materiau support d'ingenierie tissulaire, vaisseau artificiel, element de manchette et revetement destine a des implants WO2003082366A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU2003221090A AU2003221090C1 (en) 2002-03-28 2003-03-25 Tissue engineering scaffold material, artificial vessel, cuff member and coating for implants
CA2484012A CA2484012C (fr) 2002-03-28 2003-03-25 Materiau support d'ingenierie tissulaire, vaisseau artificiel, element de manchette et revetement destine a des implants
DE10392444T DE10392444T5 (de) 2002-03-28 2003-03-25 Stützgerüst für die Gewebsverarbeitung, künstliches Blutgefäß, Manschette und biologisches Implantat abdeckendes Glied
US10/950,620 US20050107868A1 (en) 2002-03-28 2004-09-28 Scaffold for tissue engineering, artificial blood vessel, cuff, and biological implant covering member

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP2002-91793 2002-03-28
JP2002091793A JP2003284767A (ja) 2002-03-28 2002-03-28 組織工学用スキャホールド材及び人工血管
JP2002-259849 2002-09-05
JP2002259848A JP2004097267A (ja) 2002-09-05 2002-09-05 カフ部材
JP2002-259848 2002-09-05
JP2002259849A JP2004097268A (ja) 2002-09-05 2002-09-05 生体埋込部材被覆材

Related Child Applications (1)

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US10/950,620 Continuation US20050107868A1 (en) 2002-03-28 2004-09-28 Scaffold for tissue engineering, artificial blood vessel, cuff, and biological implant covering member

Publications (1)

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WO2003082366A1 true WO2003082366A1 (fr) 2003-10-09

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Country Status (5)

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AU (1) AU2003221090C1 (fr)
CA (1) CA2484012C (fr)
DE (1) DE10392444T5 (fr)
TW (1) TW200400811A (fr)
WO (1) WO2003082366A1 (fr)

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WO2005084742A1 (fr) * 2004-03-08 2005-09-15 Japan As Represented By President Of National Cardiovascular Center Membre de brassard
WO2007124622A1 (fr) * 2006-04-28 2007-11-08 Wuhan University Of Technology Échafaudage stratifié poreux en 3d utilisé en ingénierie tissulaire et procédé de préparation de celui-ci
CN104841013A (zh) * 2015-05-04 2015-08-19 东华大学 一种复合材料纳米纤维/纳米纱双层血管支架及其制备方法
US10253615B2 (en) 2014-02-18 2019-04-09 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Method and a system for ultrasonic inspection of well bores

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WO2010005916A1 (fr) * 2008-07-06 2010-01-14 Mast Biosurgery Ag Procédés d'implantation d'une membrane résorbable à des fins de réduction des adhérences

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JPS6052851U (ja) * 1983-09-20 1985-04-13 日本バイリーン株式会社 腹膜透析用カテ−テル
JPH02265935A (ja) * 1989-04-06 1990-10-30 Nitta Gelatin Inc コラーゲンスポンジの製造方法
WO1990015636A1 (fr) * 1989-06-02 1990-12-27 Baxter International Inc. Dispositif poreux d'acces percutane
WO1996008222A1 (fr) * 1993-04-15 1996-03-21 Li Shu Tung Pansements resorbables pour lesions vasculaires
JPH0984871A (ja) * 1995-09-25 1997-03-31 Terumo Corp 医療用チューブおよびその製造方法
WO1999025391A2 (fr) * 1997-11-14 1999-05-27 Bonetec Corporation Squelette de polymere biodegradable
WO1999052356A1 (fr) * 1998-04-09 1999-10-21 Charlotte-Mecklenberg Hospital Authority Creation de tissus tridimensionnels
WO2000062829A1 (fr) * 1999-04-16 2000-10-26 Rutgers, The State University Echafaudages de polymere poreux pour genie tissulaire
EP1086664A2 (fr) * 1999-09-24 2001-03-28 World Medical Manufacturing Corporation Appareil de mise en place d'une prothèse endoluminale
JP2001129076A (ja) * 1999-11-01 2001-05-15 Terumo Corp 腹腔内留置カテーテル用カフ部材

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005084742A1 (fr) * 2004-03-08 2005-09-15 Japan As Represented By President Of National Cardiovascular Center Membre de brassard
JPWO2005084742A1 (ja) * 2004-03-08 2007-11-29 国立循環器病センター総長 カフ部材
JP4779968B2 (ja) * 2004-03-08 2011-09-28 独立行政法人国立循環器病研究センター カフ部材
WO2007124622A1 (fr) * 2006-04-28 2007-11-08 Wuhan University Of Technology Échafaudage stratifié poreux en 3d utilisé en ingénierie tissulaire et procédé de préparation de celui-ci
US10253615B2 (en) 2014-02-18 2019-04-09 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Method and a system for ultrasonic inspection of well bores
CN104841013A (zh) * 2015-05-04 2015-08-19 东华大学 一种复合材料纳米纤维/纳米纱双层血管支架及其制备方法

Also Published As

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CA2484012A1 (fr) 2003-10-09
TW200400811A (en) 2004-01-16
DE10392444T5 (de) 2005-05-25
AU2003221090C1 (en) 2009-11-05
AU2003221090B9 (en) 2009-05-21
AU2003221090B2 (en) 2008-11-20
AU2003221090A1 (en) 2003-10-13
CA2484012C (fr) 2012-06-26

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