WO2003082366A1

WO2003082366A1 - Tissue engineering scaffold material, aritficial vessel, cuff member and coating for implants

Info

Publication number: WO2003082366A1
Application number: PCT/JP2003/003594
Authority: WO
Inventors: Yasuhide Nakayama; Eisuke Tatsumi; Yasushi Nemoto
Original assignee: Japan As Represented By President Of National Cardiovascular Center; Bridgestone Corporation
Priority date: 2002-03-28
Filing date: 2003-03-25
Publication date: 2003-10-09
Also published as: DE10392444T5; AU2003221090A1; CA2484012C; AU2003221090C1; CA2484012A1; AU2003221090B2; AU2003221090B9; TW200400811A

Abstract

It is intended to provide a scaffold material for tissue engineering uses, an artificial vessel, a cuff member and a coating for implants. The scaffold material for tissue engineering uses is made of a thermoplastic resin and has an open cell porous three-dimensional network structure with an average pore size of 100 to 650 μm and an apparent density of 0.01 to 0.5 g/cm3. The artificial vessel is made of the scaffold material. The cuff member and the coating for implants are each made of a thermoplastic resin or a thermosetting resin and have a part of an open cell porous three-dimensional network structure with an average pore size of 100 to 1000 μm and an apparent density of 0.01 to 0.5 g/cm3.

Description

Description Tissue engineering scaffold material, artificial blood vessel, cuff member, and bioimplant member coating material

TECHNICAL FIELD 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. Background art

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.

Conventionally, as 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.Especially, 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.

For conventional artificial blood vessels, 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, There is a problem that cell engraftment cannot be obtained uniformly over the entire surface, or the distribution of engraftment cannot be adjusted. As 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.

Although artificial blood vessels as substitutes for autologous blood vessels have already been widely used in clinical applications, small-diameter artificial blood vessels have poor patency, so small-diameter blood vessels required for coronary artery bypass surgery and peripheral artery reconstruction At present, autologous vein transplantation has been adopted. Even if only antithrombotic properties are pursued as in the current mainstream technology for examining small diameters, these conventional human blood vessel linings only form a pseudo-intimal membrane made of fibrous collagen, leading to the formation of endothelium. As a result, the patency rate of a small-diameter artificial blood vessel is low. In addition, there are many cases in which pannus invades from the anastomosis part without adhering to the inner wall, which causes occlusion, because there is no hole in the inner wall through which cells can enter.

Secondly, 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.

Unlike recently developed urinary catheters, enteral feeding, and airway management, 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. When the indwelling in a living body is for a long period of time, a force member (also referred to as a skin cuff) is used to separate the inside of the living body from the outside world and prevent the invasion of bacteria into the living body and volatilization of body fluid moisture. The puncture area is sealed tightly. Conventionally, in a blood circulation method using an assisted artificial heart, 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. Has been detained. Also in peritoneal dialysis therapy, 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. I have. Some of these fabric velours are impregnated with collagen or the like to achieve more robust adhesion. There is also a method in which a cuff member made of a member having excellent biocompatibility is fixed to the subcutaneous tissue at the puncture site.

However, since 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. are doing. In other words, the insertion portion of the force neuron is always subjected to a mechanical load due to vibration. Furthermore, due to changes in the patient's own body position and the movement of the force neuron during disinfection of the puncture site, 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. With the current situation in which treatment must be discontinued due to bacterial infection rather than heart failure, the development of a cuff member that can prevent infection is an urgent issue in this therapy.

Even in peritoneal dialysis therapy, in which a catheter is placed for a long time by subcutaneous insertion, there is a major problem with the cuff material. In other words, in this therapy, a force table is placed in the abdominal cavity in order to inject and drain the dialysate, but when the living body recognizes the catheter as a foreign substance, it acts to remove the force table, and the subcutaneous tissue The catheter does not adhere and the epidermis enters the abdominal cavity along the catheter, causing a downgrowth phenomenon. These pockets of downgrowth make it difficult to reach the disinfectant solution, cause epidermal inflammation and tunnel infections, and ultimately also induce peritonitis. Considering that there is a report that the incidence of SEP (sclerosing cocoon peritonitis) is high in patients who frequently experience Pseudomonas aeruginosa peritonitis, the prevention of infection by improving cuff members is It can be said that this is a major issue.

As described above, cuff members and the like containing collagen as a main component have been developed.In such cuff members, the volume is reduced by absorbing liquids such as physiological saline, alcohol, isodine, blood, and body fluid. The subcutaneous tissue may grow at the catheter insertion site It is difficult, and as a result, the effect of suppressing downgrowth has not been obtained. Thirdly, 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. Conventionally, there are no or few eluting materials for the constituent materials of 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, for example, stents to be placed in blood vessels, 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.鲭 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. In this case, 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. As 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.

In the case of an implantable artificial heart, for example, Pocket infection, which causes inflammation and infection at the interface with tissues, has become a problem. Disclosure of the invention

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 μm 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. In addition, when this tissue engineering scaffold material is 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.

In the invention according to the second aspect, 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 μm to 100 μm, and an apparent density of 0.01 to 0.1 μm. It is characterized by having a porous three-dimensional network structure of 5 g Z cm ^{3 which} is communicable.

Since 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.

In the invention according to the third aspect, 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.

Therefore, 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. By covering 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. For example, when it comes to artificial heart systems, the actuator (Enoregergy converter) as an internal drive unit, 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. In addition, 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. BRIEF DESCRIPTION OF THE FIGURES

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, and 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. Preferred embodiments of the invention

Hereinafter, the forms of the 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 μm and an apparent density of 0.01 to 0.5 gZ cm ³ . In other words, it is only necessary that 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. Further, 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.

In 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. As long as 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.

In the concept of the average pore size, it is preferable that 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. No. The contribution ratio of pores having a pore diameter of 150 to 300 μm 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 μπι 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 μπι.

With such a 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. . Examples of the thermoplastic resin constituting the tissue engineering carrier material of the present invention 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.Preferably, 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). Low compliance

> Highly elastic properties). Also excellent in thrombotic and physical properties.

If the 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. Keratanic acid, chondroitin, chondroitin sulfate, chondroitin sulfate B, copolymer of hydroxymethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydridic xylethyl methacrylate and methacrylic acid, alginic acid, polyatarylamide, 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 endothelial cells, mesodermal cells, smooth muscle cells, peripheral vascular cells And one or more cells selected from the group consisting of mesothelial cells and mesothelial cells. Embryonic stem cells may be differentiated.

In the tissue engineering scan hold material of the present invention, 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. However, 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. For example, in the case of a tubular structure, it can be used as an artificial blood vessel.

In this case, 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. By providing such a coating layer, 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. Although there is no particular limitation on the 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 πι 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.

Hereinafter, an example of a method for producing a porous three-dimensional network structure made of a thermoplastic polyurethane resin constituting the tubular member of the scaffold material or the artificial blood vessel of the present invention will be described. The method for producing the 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.

To manufacture 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. To produce 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. Examples of the organic solvent 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.

Examples of the water-soluble polymer compound as a pore-forming agent 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. Depending on the type of thermoplastic resin, 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. Examples of 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.

Hereinafter, Examples and Comparative Examples will be described, but the present invention is not limited to the following Examples at all without departing from the gist thereof.

(Example 1)

Dissolver (approx. 200 O rpm) of thermoplastic polyurethane resin (Nippon Miractran Co., Ltd., Miractran E980PNAT) as N-methyl-2-pyrrolidinone (Kanto Chemical Co., Ltd., peptide synthesis reagent, NMP) And dissolve at room temperature 5.0% A solution (weight Z weight) was obtained. About 1.0 kg of this NMP solution

(Inoue Seisakusho, 2. OL preparation, PLM-2 type) weighed and mixed with the same weight of polyurethane resin as methyl cellulose (Kanto Chemical Co., reagent, 25 cp grade) at 40 ° C for 20 minutes. Then, while stirring was continued, the pressure was reduced to 2 OmmHg (2.7 kPa) for 10 minutes to remove bubbles, thereby obtaining a polymer dope.

A 3.5 mm inner diameter, 4.6 mm outer diameter, 6 Omm long cylindrical paper tube made with a filter paper for chemical experiments (manufactured by Toyo Roshi Kaisha, for qualitative analysis, No. 2) and a 3113440 In a tube molding jig consisting of a core rod with a diameter of 1.2 mm φ 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. After injecting and injecting using a needle, and then sealing, 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. At this time, the methanol was replaced with a new solution at any time while maintaining the reflux state. After 72 hours, transfer the tube-forming jig from the refluxed methanol to a methanol bath at room temperature without drying, remove the contents from the tube-forming jig in the bath, and place in purified water of Japanese Pharmacopoeia for 72 hours. By washing, 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). However, according to Figs. 1-4, the base material of the obtained skid holder material has a hole diameter of about 200 μm, an inner diameter of 1.2 mmφ, an outer diameter of 3.2 mmφ, 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).

[Measurement of average pore size] The plane (cut surface) of the sample cut with a double-edged razor is converted into a stereomicroscope (Keyence,

Using the photos taken with VH-6300), image processing of individual holes on the same plane as a figure surrounded by a skeleton of a three-dimensional network structure. (Image processing device uses NIRECO's LU ZEX AP.) The image was captured using a SONY LEN 50 CCD camera.) Then, the area of each figure was measured. This was defined as the true circle area, and the diameter of the corresponding circle was determined as the hole diameter. The average pore diameter was measured to be 169 ± 55; tm, ignoring the micropores drilled in the skeleton of the porous body and ignoring the micropores drilled in the same plane. At the same time, the contribution ratio of 150 to 300 μπι in the pore size distribution was measured to be 71.2%, confirming that the porous body was mainly composed of pores of a size effective for cell adhesion.

[Measurement of apparent density]

As a result of calculating the volume from the dimensions obtained by measuring a sample cut with a double-edge razor to a length of about 10 mm with a projector (Nikon, V-12), and dividing the weight by the volume, 0.077 ± 0.002 g / cm ³ was calculated.

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.

[Evaluation of water permeability]

First, seal the end of one side of the sample cut in the same way as above to a length of 10 mm, and insert a needle with an inner diameter of 0.3πιιηφ, an outer diameter of 1.2πιπιφ, and a length of 40mm from the opening at the other end. The tube was adjusted so that the effective transmission surface of the tubular structure was 0.50 mm in tube length. The needle was connected to a 50 mm long, 5πιπιφ diameter silicon tube and a 25 mm diameter water-filled, 2 mm diameter, 90 mm long girdle, and the permeability of distilled water was measured at 25 ° C. Permeability was 13.47 ± 0.33 gZ for 60 seconds and 24.64 ± 0.35 g / 120 seconds. Since the amount of water permeation under no load without this sample is 13.70Z60 seconds and 24.87 / 120 seconds, this carrier material has good water permeability and is highly tertiary. It was confirmed that it was an original network structure. (Example 2)

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).

One end of the tubular porous three-dimensional network-structured carrier material (inner diameter: 1.2ηιηιφ, outer diameter: 3.2 mm φ, 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.

(Figure 6).

(Example 3)

One end of the tubular porous three-dimensional network-structured scaffold material (inner diameter: 1.2πιπιφ, 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. After that, the clamp was removed, a 1.2 mm φ 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. When the blood flow was resumed after removal of the clamp, pulsation occurred and functioned as an artificial blood vessel (Figure 7). One week later, the artificial blood vessel was excised, and the lumen surface of the tubular tissue was observed. When the thrombus was not adhered or formed on the lumen surface, it was extremely smooth (FIG. 8).

(Comparative Example 1)

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 μπι by sieving). A 1.2 mm φ 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.

7 kP a)) After drying, a porous tubular structure having an inner diameter of 1.2πιπιφ and an outer diameter of 3.2 mmφ was obtained.

When the average pore size and apparent density of this porous tubular structure were measured in the same manner as in Example 1, the average pore size was 121 ± 65 μΐη, but the contribution ratio of pores with a pore size of 150 to 300 μπι was 31. 8%. The apparent density was 0.086 ± 0.004 g / cm ³ .

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).

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.

(Comparative Example 2)

A suspension of smooth muscle cells (cell density: 3 × 10 ⁶ ce 11 s / mL) prepared in the same manner as in Example 2 was used for the porous tubular structure (inner diameter: 1.2 mm < i), an outer diameter of 3.2 mm φ, and a length of 2 cm) was injected in the same manner as in Example 2, followed by culturing to obtain a tubular structural material containing cells.

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.

As described in detail above, according to the present invention, there is provided 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.

Hereinafter, preferred embodiments and configurations of the cuff member of the present invention will be described in detail.

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. Further, the average pore diameter ゃ apparent density may partially change. For example, the average pore diameter ゃ apparent density gradually changes from one surface side to the other surface side. May be provided. In addition, large pores that greatly deviate from the average pore diameter may exist on the contact surface side with the living tissue. As such pores, pores of about 500 to 2000 μπι 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 μm and an apparent density of 0.01 to 0.5 gZcm ³ , but the preferred average pore size is 200 to 600 μηι, more preferably 200 to 500 μπι. 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 . Even if the average pore size is the same, the pore size distribution should be as high as 150 to 400 μπι, which is an important pore size for cell invasion. When the contribution rate of the pores of 100 μm 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 μπι 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 μm.

With such a 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.

As the thickness of the porous three-dimensional network structure, 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.

Examples of the thermoplastic resin or the thermosetting resin that constitutes such a porous three-dimensional network structure portion include polyurethane resin, polyamide resin, polylactic acid resin, polyolefin resin, polyester resin, fluororesin, urea resin, and phenol. 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.

In the cuff member of the present invention, it is also possible to use 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. . As the second 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.

Examples of the fiber aggregate 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.

As the 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.

Examples of the flexible film 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. One selected from the group consisting of resins, acrylic resins and methacrylic resins and derivatives thereof or

Examples of the film 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. When the thickness of such a flexible film is 0.1 to 50 Omm, 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. As the flexible film, not only a solid film but also a porous film or a foam can be used. When laminated with a solid flexible film, a cuff member having a high bacterial barrier property and advantageous for infection control can be obtained.

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 πι ^{3 at} 2200 μππ can be used. The thickness of the porous three-dimensional network structure layer as the second layer is preferably 0.2 to 2 Omm.

As a method of laminating the second layer on the porous three-dimensional network structure layer, the second layer is an average of the fiber aggregate, the flexible film, and the porous three-dimensional network structure of the first layer. In the case of a porous three-dimensional network structure layer with different pore sizes and apparent densities, 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. As such a hot-melt nonwoven fabric, for example, a polyamide-type thermo-adhesive sheet such as PA101 manufactured by Nittobo Co., Ltd. can be used. Other examples include a method of dissolving and bonding the surface layer of the contact surface using a solvent, a method of melting and bonding the surface layer by heat, and a method of using ultrasonic waves or high frequency. Further, at the time of manufacturing the first layer, the polymer dope can be continuously laminated and formed by laminating and molding a fiber aggregate or a flexible film.

As 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.

In the porous three-dimensional network structure of the cuff member of the present invention, 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: platelet-derived growth factor, epidermal growth factor, transforming growth factor α, insulin-like growth factor, insulin-like growth factor binding protein, hepatocyte proliferation Factor, vascular endothelial growth factor, angiopoietin, nerve growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, transforming growth factor i3, latent transforming growth factor i3, activin, bone plasma protein, fiber Blast growth factor, tumor growth factor J3, diploid fibroblast growth factor, heparin binding Sexual epidermal growth factor-like growth factor, schwannoma-derived growth factor, amphiregulin, beta-cellulin, epigrelin, lymphotoxin, erythropoietin, tumor necrosis factor α, interleukin-1, interleukin-6, interleukin 1-8, Interleukin 1

17. 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. In the force member according to the present invention, 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. 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., and as a result, it is possible to increase cell engraftment is there. However, 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.

Hereinafter, an example of a method for producing a porous three-dimensional network structure made of a thermoplastic polyurethane resin constituting the cuff member of the present invention will be described, but the method for producing a cuff member of the present invention is not limited to the following method. Not something.

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. Examples of the organic solvent 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.

Examples of the water-soluble polymer compound as a pore-forming agent 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. Depending on the type of thermoplastic resin, 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.

Hereinafter, a preferred embodiment of the living body implantable member covering material of the present invention will be described in detail.

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 ιη 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. In addition, the average pore diameter / apparent density may partially change. For example, 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 孔 the apparent density gradually changes. Further, a large-diameter hole that largely deviates from the average pore diameter may exist on the contact surface side with the living tissue. As such pores, pores having a size of about 500 to 2000 μπι 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 .

Even if the average pore size is the same, the pore size distribution should be as high as 150 to 400 μm, which is an important pore size for cell invasion, and 150 to 400 μm. When 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.

With such a 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 Then, a high level of physical strength, cell invasion, organization, adhesion to biological tissue, and the like required as a covering material for a living body implanted member can be satisfied.

Examples of the thermoplastic resin or thermosetting resin constituting such a porous three-dimensional network structure portion 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.

In the covering material for a living body implanted member of the present invention, 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. As the second layer, 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 π, collagen type III, collagen type IV, athero-type collagen, fibronectin, gelatin, hyaluronic acid, heparin, Keratanic acid, chondroitin, chondroitin sulfate, chondroitin sulfate Β, 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, insulin-like growth factor, insulin-like growth factor binding protein, hepatocyte growth factor, vascular endothelial growth factor, angiopoietin, nerve growth Factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, trait Transforming growth factor J3, latent transforming growth factor, activin, bone plasma protein, fibroblast growth factor, tumor growth factor, diploid fibroblast growth factor, heparin-binding epidermal growth factor-like growth factor, schwanoma Derived growth factors, amphiregulin, beta-cellulin, epiglerin, lymphotoxin, erythropoietin, tumor necrosis factor α, interleukin-1 j3, interleukin-6, interleukin-18, interleukin-17, interferon , One or more selected from the group consisting of antiviral agents, antibacterial agents and antibiotics may be retained, and further, embryonic stem cells (which may be differentiated), blood vessels One or two selected from the group consisting of endothelial cells, mesodermal cells, smooth muscle cells, peripheral vascular cells, and mesothelial cells Or more of the cells may be bonded.

Further, in the covering material for a living body implanted member of the present invention, 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. However, 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.

Hereinafter, an example of a method for producing a porous three-dimensional network structure made of a thermoplastic polyurethane resin constituting the bioimplantable member covering material of the present invention will be described. The method is not limited to the following method.

To manufacture 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. 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 in this solution. Examples of the organic solvent include N, N-dimethylformamide, N-methyl-1-pyrrolidinone, tetrahydrofuran, and the like. However, this does not apply as long as the thermoplastic polyurethane resin can be dissolved. Alternatively, it is also possible to melt the polyurethane resin by the action of heat without using it, and to mix the pore-forming agent therein.

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. Depending on the type of thermoplastic resin, 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.

As described in detail above, according to 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.

Hereinafter, 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. However, 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.

(Example 4)

Dissolver (about 2000 rpm) was added to N-methyl-2-pyrrolidinone (Kanto Chemical Co., Ltd., peptide synthesis reagent, ΝMP) from thermoplastic polyurethane resin (Milactran E980 PNAT, manufactured by Nippon Milactran). This was used and dissolved at room temperature to obtain a 7.5% solution (weight Z weight). Approximately 1.0 kg of this NMP solution is weighed and placed in a planetary mixer (manufactured by Inoue Seisakusho, 2.0 L, PLM-2 type). Stir methyl cellulose (reagent, 50 cp grade, manufactured by Kanto Chemical Co., Ltd.) equivalent to half the weight of the resin at 40 ° C for 20 minutes, and reduce the pressure to 2 OmmHg (2.7 kPa) for 10 minutes while stirring is continued. An operation of defoaming was added to obtain a polymer dope.

Separately, two 15-mm X 15-Omm Teflon square frames with a thickness of 3 mm and punched out of the inner 14 Omm X 14 Omm section are stacked, and a 15-Omm X 150-mm square filter paper for chemical experiment ( Toyo Roshi Kaisha, for quantitative analysis, No. 1) was fixed. The polymer dope was cast here, drained with a glass rod, and fixed with a 15 Omm X 15 Omm square filter paper for chemical experiments (manufactured by Toyo Roshi Kaisha, for quantitative analysis, No. 1). . 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.

After 72 hours, 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.

Next, a 14 OmmX 140 mm polyester fabric velor (Bird, Poveyy Dubnore Velor Fabric, perforated 3800 cc / cm ² / min, thickness 1.5 mm) was added to tetrahydrofuran (Kanto Chemical Co., Ltd., special grade reagent). ) And squeezing with two rolls to obtain an impregnation amount of 0.104 ± 0.002 g / cm ^2, and superimposing the porous three-dimensional mesh structure material (covering material for living body embedded member) on this to obtain a cuff member of the present invention by compression under a load 1. 0 k gZcni ^2.

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 μμπι. 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. Was. In the measurement of average pore size and apparent density, the sample was cut The test was performed at room temperature using a double-edged power razor (Feather, high stainless steel).

[Measurement of average pore size]

Using a photo taken by an electron microscope (SM200, manufactured by Topcon) of a plane (cut surface) of a sample cut with a double-edged razor, individual holes on the same plane are surrounded by a skeleton of a three-dimensional network structure. The images were processed (using a Nireco LUZEX AP image processor and the SONY LE N50 CCD camera was used as the image processing device), and the area of each figure was measured. This was defined as the area of a perfect circle, and the diameter of the corresponding circle was determined as the hole diameter. Fine pores perforated in the skeleton of the porous body were ignored, and only the communicating holes on the same plane were measured. At the same time, the pore size distribution was measured for all the measured pores, and is shown in Fig. 3. In addition, the contribution ratio of 150 to 400 m pores was measured from the pore size distribution measurement results. -

[Measurement of apparent density]

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.

table 1

From Table 1, it is clear that 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.

(Example 5)

Adult goats (female, weighing 54 kg) were used as test samples, and the abdominal epidermis from the shaved left chest was used as the test site. At the time of surgery, the specimens were placed on the left side, and the endotracheal tube was quickly performed using normal procedures, and maintained under general anesthesia with isoflurane. After disinfection of the epidermis around the thorax and abdomen, the epidermis was incised by 2 Omm, half of the sample piece of the cuff member prepared in Example 4 was embedded, and the subcutaneous tissue was sutured and fixed through (Fig. 4). The cuff member is 1 OmmX

A 10 mm 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. As shown in the figure, 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.

On the other hand, in the cuff member of the present invention, it was confirmed that the milky white layer was continuously present near the epidermis, and that the downgrowth was suppressed.

After the above test, the extirpated sample pieces were immediately fixed in 10% neutral buffered formalin, and HE stained specimens were prepared in a conventional manner, and observed with an optical microscope. As a result, 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.

Four weeks later, a specimen obtained by the same procedure showed that a large amount of granulation tissue had spread within the buried test piece, and that a more mature connective tissue had been formed. It has been confirmed that the conversion is progressing.

The above suggests that 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.

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.

Claims

The scope of the claims

1. A tissue engineering scan holder made of a thermoplastic resin, wherein the thermoplastic resin has an average pore size of 100 to 650 m, an apparent density of 0.01 to 0.5 gZ cm ³ , and a continuous porous material. 1. A tissue-holding material for a tissue engineering, characterized by forming a conductive three-dimensional network structure.

2. The scaffold for tissue engineering according to claim 1, wherein the porous three-dimensional network structure has an average pore diameter of 100 to 400 μm and an apparent density of 0.01 to 0.5 gZcm ³ . Wood.

3. The scaffold for tissue engineering according to claim 2, wherein the porous three-dimensional network structure has an average pore diameter of 100 to 300 μm.

4. In any one of claims 1 to 3, the apparent only density of the porous three-dimensional network structure is 0. 01~0. 2 g / tissue engineering Sukiyaho Rudo, characterized in that cm is ³ Wood.

5. The scaffold for tissue engineering according to claim 4, wherein the apparent density of the porous three-dimensional network structure is 0.01 to 0.1 lgZcm ³ .

6. The tissue engineering according to any one of claims 1 to 5, wherein a contribution ratio of pores having a pore diameter of 150 to 300 μπι in the average pore diameter of the porous three-dimensional network structure is 10% or more. Scan hold material.

7. The carrier for tissue engineering according to claim 6, wherein a contribution ratio of pores having a pore diameter of 150 to 300 μπι in the average pore diameter of the porous three-dimensional network structure is 20% or more.

8. The carrier for tissue engineering according to claim 7, wherein a contribution ratio of pores having a pore diameter of 150 to 300 μπι in the average pore diameter of the porous three-dimensional network structure is 30% or more.

9. The scaffold for tissue engineering according to claim 8, wherein a 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 40% or more.

10. The pore size of the porous three-dimensional network structure at an average pore size of claim 9 A scaffold for tissue engineering, wherein the contribution of pores of 0 to 300 μπι is 50% or more.

11. The thermoplastic resin according to any one of claims 1 to 10, wherein the thermoplastic resin is a polyurethane resin, a polyamide resin, a polylactic acid resin, a polyolefin resin, a polyester resin, a fluororesin, an acrylic resin, and a methacrylic resin. A scan-holding material for tissue engineering, which is one or more selected from the group consisting of these derivatives.

12. The scaffold for tissue engineering according to claim 11, wherein the thermoplastic resin is a polyurethane resin.

13. The tissue engineering scan holder material according to claim 12, wherein the polyurethane resin is a segmented polyurethane resin.

14. The method according to any one of claims 1 to 13, wherein the porous three-dimensional network structure comprises collagen type I, collagen type II, collagen type III, collagen type IV, athero-type collagen, fibronectin, gelatin, Hyaluronic acid, heparin, keratanic acid, chondroitin, chondroitin sulfate, chondroitin sulfate Β, copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, A scaffold for tissue engineering, wherein one or more members selected from the group consisting of polyatarylamide, polydimethylacrylamide and polyvinylpyrrolidone are retained.

15. The method according to claim 14, wherein the porous three-dimensional network structure further comprises fibroblast growth factor, interleukin-1, tumor growth factor i3, epidermal growth factor, and diploid fibroblast growth factor. A tissue engineering scan material characterized in that one or more selected from the group consisting of:

16. The tissue engineering scan holder material according to claim 15, wherein cells are adhered to the porous three-dimensional network structure.

17. The cell of claim 16, wherein the cell is one or more selected from the group consisting of embryonic stem cells, vascular endothelial cells, mesodermal cells, smooth muscle cells, peripheral vascular cells, and mesothelial cells A material for a scaffold for tissue engineering, which is characterized by being above.

18. The tissue engineering scan material according to claim 17, wherein the embryonic stem cells are differentiated.

1 9. The scaffold for yarn and textile engineering according to any one of claims 1 to 18, wherein the shape is a tubular structure.

20. The tubular structure according to claim 19, wherein the inner diameter of the tubular structure is 0.3 to 15 mm and the outer diameter is

A scaffold for tissue engineering, which has a thickness of 0.4 to 2 Omm.

21. In Claim 20, the inner diameter of the tubular structure is 0.3 to 10 mm and the outer diameter is

A scaffold for tissue engineering, having a thickness of 0.4 to 15 mm.

22. The tubular structure according to claim 21, wherein the inner diameter of the tubular structure is 0.3 to 6 mm and the outer diameter is 0.3.

A scaffold for tissue engineering, which is 4 to 10 mm.

23. The tissue engineering scan holder material according to claim 22, wherein the tubular structure has an inner diameter of 0.3 to 2.5 mm and an outer diameter of 0.4 to 1 Omm.

24. The tissue engineering scan holder material according to claim 23, wherein the inner diameter of the tubular structure is 0.3 to 1.5 mm and the outer diameter is 0.4 to 1 Omm.

25. An artificial blood vessel characterized by being made of the carrier material according to any one of claims 1 to 24.

26. The artificial blood vessel according to claim 25, wherein the outside of the carrier is covered with another tubular structure.

27. The tubular structure according to claim 26, wherein the tubular structure covering the outside of the carrier material is chitosan, polylactic acid resin, polyester resin, polyamide resin, polyurethane resin, fibronectin, gelatin, hydranolonic acid, keratanic acid, chondroitin, and condon. Droitin sulfate, chondroitin sulfate B, copolymer of hydroxyxetyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyatarylamide, polydimethylacrylamide, An artificial blood vessel, which is a tube formed of one or more selected from the group consisting of polybulpyrrolidone, cross-linked collagen and fibrous mouth.

28. Made of a thermoplastic or thermosetting resin, with an average pore diameter of 100 to 1000 m and an apparent density of 0.01 to 0.5 g Z cm ³ A cuff member having a porous three-dimensional network structure.

29. The cuff member according to claim 28, wherein the porous three-dimensional network structure has an average pore diameter of 200 to 600 µιη and an apparent density of 0.01 to 0.5 gZcm ³ .

30. The cuff member according to claim 29, wherein the porous three-dimensional network structure has an average pore size of 200 to 500 μηι and an apparent density of 0.01 to 0.5 gZcm ³ .

31. In any one of claims 28 to 30, an apparent density of the porous three-dimensional network structure is 0. from 05 to 0. 3 g / cuff member characterized by cm ^3.

32. The cuff member according to claim 31, wherein the apparent density of the porous three-dimensional network structure is 0.05 to 0.2 gZcm ³ .

33. The cuff member according to any one of claims 28 to 32, wherein a contribution ratio of pores having a pore diameter of 150 to 400 μπι in the average pore diameter of the porous three-dimensional network structure is 10% or more.

34. The cuff member according to claim 33, wherein a contribution ratio of pores having a pore diameter of 150 to 400 µηι in the average pore diameter of the porous three-dimensional network structure is 20% or more.

35. The cuff member according to claim 34, wherein a contribution ratio of pores having a pore diameter of 150 to 400 μπι in the average pore diameter of the porous three-dimensional network structure is 30% or more.

36. The cuff member according to claim 35, wherein a contribution ratio of pores having a pore diameter of 150 to 400 zm in the average pore diameter of the porous three-dimensional network structure is 40% or more.

37. The cuff member according to claim 36, wherein a contribution ratio of pores having a pore diameter of 150 to 400 m in an average pore diameter of the porous three-dimensional network structure is 50% or more.

38. The cuff member according to any one of claims 28 to 37, wherein the thickness of the porous three-dimensional network structure is 0.2 to 50 Omm.

39. The force member according to claim 38, wherein the thickness of the porous three-dimensional network structure is 0.2 to 100 mm.

40. The cuff member according to claim 39, wherein the thickness of the porous three-dimensional network structure is 0.2 to 50 mm.

41. The method according to claim 40, wherein the thickness of the porous three-dimensional network structure is 0.2 to 10 m. A cuff member characterized by m.

42. The cuff member according to claim 41, wherein the thickness of the porous three-dimensional network structure is 0.2 to 5 mm.

43. The method according to any one of claims 28 to 42, wherein the base resin is a polyurethane resin, a polyamide resin, a polylactic acid resin, a polyolefin resin, a polyester resin, a fluororesin, a urea resin, a phenol resin, an epoxy resin, A force member comprising at least one member selected from the group consisting of a polyimide resin, an acrylic resin, a methacrylic resin, and derivatives thereof.

44. The cuff member according to claim 43, wherein the base resin is a polyurethane resin.

45. The cuff member according to claim 44, wherein the polyurethane resin is a segmented polyurethane resin.

46. The laminate according to any one of claims 28 to 45, wherein the laminate is a laminate of a first layer having the porous three-dimensional network structure and a second layer different from the first layer. Cuff member.

47. The porosity according to claim 46, wherein the second layer is a fiber aggregate, a flexible film, and a porous material having an average pore size and / or an apparent density different from the porous three-dimensional network structure of the first layer. A cuff member comprising one or more members selected from the group consisting of a three-dimensional network structure layer.

48. The cuff member according to claim 47, wherein the fiber aggregate is a nonwoven fabric or a woven fabric.

49. The cuff member according to claim 48, wherein the nonwoven fabric or the woven fabric has a thickness of 0.1 to 100 mm.

50. The cuff member according to claim 49, wherein said nonwoven fabric or woven fabric has a thickness of 0.1 to 50 mm.

51. The cuff member according to claim 50, wherein the nonwoven fabric or the woven fabric has a thickness of 0:!

52. The cuff member according to claim 51, wherein the nonwoven fabric or the woven fabric has a thickness of 0.1 to 5. Omm.

53. The cuff member according to any one of claims 48 to 52, wherein the nonwoven fabric or the woven fabric has a porosity of 100 to 5000 cc / cmVmin.

54. The fiber assembly according to any one of claims 46 to 53, wherein the fiber aggregate is made of a polyurethane resin, a polyamide resin, a polylactic acid resin, a polyolefin resin, a polyester resin, a fluororesin, an acrylic resin, a methacrylic resin, and derivatives thereof. A force member comprising one or more members selected from the group consisting of:

55. The fiber assembly according to any one of claims 46 to 53, wherein the fiber aggregate is composed of one or more selected from the group consisting of fiber mouth, chitin, chitosan, cellulose, and derivatives thereof. A cuff member characterized by the above-mentioned.

56. The force member according to any one of claims 46 to 55, wherein the flexible film is a thermoplastic resin film.

57. The thermoplastic resin according to claim 56, wherein the thermoplastic resin is a polyurethane resin, a polyamide resin, a polylactic acid resin, a polyolefin resin, a polyester resin, a fluororesin, a urea resin, a phenol resin, an epoxy resin, a polyimide resin, a silicone resin, or an acrylic resin. A force member comprising at least one member selected from the group consisting of a resin, a methacrylic resin, and a derivative thereof.

58. The cuff member according to claim 57, wherein the thermoplastic resin is at least one member selected from the group consisting of polyvinyl chloride, polyurethane resin, fluorine resin and silicone resin.

59. The cuff member according to any one of claims 46 to 58, wherein the thickness of the flexible film is 0.1 to 50 Oram.

60. The cuff member according to claim 59, wherein the thickness of the flexible film is 0.1 to 100 mm.

6 1. The cuff member according to claim 60, wherein the thickness of the flexible film is 0.1 to 50 mm.

62. The cuff member according to claim 61, wherein the thickness of the flexible film is 0.1 to 10 mm.

63. The method according to any one of claims 46 to 62, wherein the porous three-dimensional network structure layer of the second layer has an average pore size of 0.1 to 200 μπι and an apparent density of 0.01 to 1.0. cuff member which is a g / cm ^3.

64. The cuff member according to any one of claims 46 to 63, wherein the thickness of the porous three-dimensional network structure layer of the second layer is 0.2 to 2 Omm.

65. The method according to any one of claims 28 to 64, wherein the porous three-dimensional network structure comprises collagen type I, collagen type II, collagen type III, collagen type IV, athero-type collagen, fibronectin, Gelatin, hyaluronic acid, heparin, keratanic acid, chondroitin, chondroitin sulfate, chondroitin sulfate B, elastin, heparan sulfate, laminin, thrombospondin, vitronectin, osteonectin, gentactin, hydroxyxethyl methacrylate and dimethylethylamino One selected from the group consisting of a copolymer of ethyl methacrylate, a copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide and polyvinylpyrrolidone A cuff member characterized by holding two or more types.

66. The method of claim 65, wherein the porous three-dimensional network further comprises a platelet-derived growth factor, an epidermal growth factor, a transforming growth factor α, an insulin-like growth factor, an insulin-like growth factor-binding protein, and a hepatocyte. Growth factor, vascular endothelial growth factor, angiopoietin, nerve growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, transforming growth factor j3, latent transforming growth factor) 3, activin, bone plasma protein , Fibroblast growth factor, tumor growth factor, diploid fibroblast growth factor, heparin-binding epidermal growth factor-like growth factor, sphinoma-derived growth factor, amphiregulin, beta-senorellin, epigrelin, lymphotoxin, erythroe Poietin, tumor necrosis factor α, interleukin-1β, interleukin-6, interleukin-18, interleukin Ikin one 1 7, it centers Feron, antiviral agents, cuff member, characterized in that one selected from the group consisting of antimicrobial agents 及 Pi antibiotics or two or more are held.

67. The cuff member according to claim 66, wherein cells are adhered to the porous three-dimensional network structure.

68. The method of claim 67, wherein the cell is one or more selected from the group consisting of embryonic stem cells, vascular endothelial cells, mesodermal cells, smooth muscle cells, peripheral vascular cells, and mesothelial cells. A cuff member characterized by the following.

69. The cuff member according to claim 68, wherein the embryonic stem cells are differentiated.

70. Heat formed by thermoplastic resin or a base resin made of a thermosetting resin, an average pore diameter of 100 to 1000 Myupaiiota, apparent density 0.01 to 0. Of 5 g / cm ^3, porosity of communicability A bioimplantable member covering material having a three-dimensional network structure.

71. The living body implanting member according to claim 70, wherein the porous three-dimensional network structure has an average pore diameter of 200 to 60 μμπι and an apparent density of 0.01 to 0.5 g / cm ³ . Coating material.

72. The living body implanting member according to claim 71, wherein the porous three-dimensional network structure has an average pore size of 200 to 50 μμπι and an apparent density of 0.01 to 0.5 g / cm ³ . Coating material.

73. The covering material for living body implantation member according to any one of claims 70 to 72, wherein the apparent density of the porous three-dimensional network structure is 0.05 to 0.3 g / cm ³ .

74. The covering material for living body implantation member according to claim 73, wherein the apparent density of the porous three-dimensional network structure is 0.05 to 0.2 gZ cm ³ .

75. The bioimplant according to any one of claims 70 to 74, wherein the contribution of pores having a pore diameter of 150 to 400 / zm to the average pore diameter of the porous three-dimensional network structure is 10% or more. Included member covering material.

76. The coating material for living body implantation according to claim 75, wherein the contribution rate of pores having a pore diameter of 150 to 400 m in the average pore diameter of the porous three-dimensional network structure is 20% or more.

77. The coating material for living body implantation according to claim 76, wherein a contribution ratio of pores having a pore diameter of 150 to 400 m in the average pore diameter of the porous three-dimensional network structure is 30% or more.

78. The living body implanting member according to claim 77, wherein a contribution ratio of pores having a pore diameter of 150 to 400 m in an average pore diameter of the porous three-dimensional network structure is 40% or more.

79. The porous three-dimensional network structure of claim 78, wherein A coating material for a living body implanted member, wherein a contribution ratio of pores of 50 to 400 μηι is 50% or more.

80. The bioimplantable member covering material according to any one of claims 70 to 79, wherein the thickness of the porous three-dimensional network structure is 0.5 to 500 mm.

81. The covering material for living body implantation member according to claim 80, wherein the thickness of the porous three-dimensional network structure is 0.5 to 100 mm.

82. The covering material for living body implantation member according to claim 81, wherein the thickness of the porous three-dimensional network structure is 0.5 to 50 mm.

83. The covering material for living body implantation member according to claim 82, wherein the thickness of the porous three-dimensional network structure is 0.5 to 10 mm.

84. The covering material for living body implantation member according to claim 83, wherein the thickness of the porous three-dimensional network structure is 0.5 to 5 mm.

85. The method according to any one of claims 70 to 84, wherein the base resin is a polyurethane resin, a polyamide resin, a polylactic acid resin, a polymalic acid resin, a polyglycolic acid resin, a polyolefin resin, a polyester resin. Bioimplant characterized by one or more selected from the group consisting of fluororesin, urea resin, phenolic resin, epoxy resin, polyimide resin, acrylic resin, methacrylic resin and derivatives thereof Included member covering material.

86. The bioimplantable member covering material according to claim 85, wherein the base resin is a polyurethane resin.

87. The bioimplantable member covering material according to claim 86, wherein the polyurethane resin is a segmented polyurethane resin.

88. The laminate according to any one of claims 70 to 87, comprising a first layer comprising the porous three-dimensional network structure and a second layer different from the first layer. A covering material for a living body implanted member, characterized in that:

89. The method according to any one of claims 70 to 88, wherein the porous three-dimensional network has collagen type I, collagen type II, collagen type III, collagen type IV, athero-type collagen, fibronectin, Gelatin, hyaluronic acid, heparin, keratanic acid, chondroitin, chondroitin sulfate, chondroitin sulfate Acid B, elastin, heparan sulfate, laminin, thrompospondin, vitronectin, osteonectin, entactin, copolymer of hydroxyxetinole methacrylate and dimethylaminoethyl methacrylate, hydroxyxethyl methacrylate and methacrylic acid Characterized in that one or more members selected from the group consisting of copolymers of alginic acid, polyacrylamide, polydimethylacrylamide and polyvinylpyrrolidone are retained. .

90. The method of claim 89, wherein the porous three-dimensional network further comprises platelet-derived growth factor, epidermal growth factor, transforming growth factor, insulin-like growth factor, insulin-like growth factor binding protein, hepatocyte growth factor. , Vascular endothelial growth factor, angiopoietin, neuronal growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, transforming growth factor i3, latent transforming growth factor 3, activin, bone plasma protein, Fibroblast growth factor, tumor growth factor, diploid fibroblast growth factor, heparin-binding epidermal growth factor-like growth factor, sphinoma-derived growth factor, amphiregulin, beta-senorellin, epigrelin, lymphotoxin, Erythropoietin, tumor death factor Q ;, interleukin-1 1) 3, interleukin-1 6, interleukin-1 8, a A bioimplant coating material comprising one or more members selected from the group consisting of interleukin-17, interferon, antiviral agents, antibacterial agents and antibiotics.

91. The bioimplantable member covering material according to claim 90, wherein cells are adhered to the porous three-dimensional network structure.

92. In Claim 91, the cell is one or more selected from the group consisting of embryonic stem cells, vascular endothelial cells, mesodermal cells, smooth muscle cells, peripheral vascular cells, and mesothelial cells. A biological implantable member covering material, characterized in that:

93. The covering material according to claim 92, wherein the embryonic stem cells are differentiated.