JP2006130007A - Hybrid complex and manufacturing method thereof, and medical material using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a complex of calcium phosphate and a polymeric base and a complex of titanium oxide and a polymeric base, the complexes each having a property of quickly adhering to biological tissues, soft tissues in particular, and to provide a manufacturing method thereof and medical material using the complexes. <P>SOLUTION: The surface of a transdermal terminal is coated with the complex manufactured by chemically combining hydroxyapatite sintered compact particles to fibrous silk fibroin having an alkoxyl group introduced to its surface, and the surface of the complex is coated with periodontal membrane cells or marrow cells. When the thus manufactured transdermal terminal is implanted into a rat, early extension of connective tissues is confirmed three days after the implantation. This shows that the transdermal terminal is adhered to the biological tissues (soft tissues) at an early stage. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a composite that can be used as a medical material for an in-dwelling medical device, a hybrid complex that has both rapid cell affinity and long-term cell adhesion stability, a method for producing the same, and The present invention relates to a medical material using.

  Polymeric base materials such as silicone rubber and polyurethane have characteristics such as biological inertness, long-term stability, strength and flexibility, and are widely used as medical materials for, for example, percutaneous catheters. However, since the exemplified polymer base material is inactive in the living body, when the exemplified polymer base material is used as a medical material, adhesion to a living tissue does not occur in the percutaneous part, and Downgrowth (a phenomenon in which epithelial tissue invades along the catheter surface) and the risk of bacterial infection at the invading site has always been a problem.

  On the other hand, calcium phosphate such as hydroxyapatite is widely used in the medical field as a bioactive material. The calcium phosphate is used in the medical field alone or in combination with an inorganic material or an organic material. The calcium phosphate is used as a member such as a percutaneous catheter.

  However, the calcium phosphate is brittle, has poor moldability, and does not have a binding property with a metal member. Therefore, for example, when the calcium phosphate is used as a percutaneous catheter, there is a problem that bacterial infection may occur from the gap between the metallic member and the calcium phosphate terminal.

  Thus, as one of the techniques for solving such a problem, for example, it has been proposed to use a calcium phosphate complex in which the surface of the polymer base material is modified with calcium phosphate such as hydroxyapatite.

  And as a method of modifying calcium phosphate on the surface of the polymer substrate, specifically, for example, a modification method by compounding with glass (see Patent Document 1), a modification using a biomimetic reaction The method (refer patent document 2) to perform, the modification method using the alternate dipping method (refer patent document 3), etc. are performed. These calcium phosphates have a problem that their crystal structure is amosphas (amorphous), they are easily dissolved in the living body, and their bioactivity is not sufficiently sustained.

  In addition, as a method for modifying the highly crystalline calcium phosphate ramix to the surface of the polymer substrate, a manufacturing method (see Patent Document 4) in which an adhesive or a polymer substrate is combined by melting, or a sputtering ion beam is used. There are a method of modifying using a method (see Patent Document 5), a method of modifying using a plasma treatment (see Patent Documents 6 and 7), a method of modifying using a laser ablation (see Patent Document 5), etc. This may impair the physical properties of the polymer substrate, and those performed by the sputtering ion beam method, plasma treatment method, and laser ablation method are based on the fact that the calcium phosphate particles are not uniform and are simply adsorbed. The bonding force between the material and the particles is not sufficient, and the calcium phosphate particles may peel off from the polymer substrate.

  On the other hand, titanium oxide is mixed and composited in paints, synthetic resins, inks, papermaking, chemical fibers, etc., utilizing the characteristics as a white pigment. Titanium oxide is used as a photocatalyst for deodorizing materials, antifouling materials, antibacterial / antiviral / antifungal materials, antifogging materials, water treatment materials, anticancer agents (materials) and the like. The titanium oxide is known as a chemically very stable and non-toxic substance. Specifically, for example, in an animal test (see Non-Patent Document 1) given by adding titanium oxide to feed for 16 months, an animal test (see Non-Patent Document 2) in which subcutaneous injection or powder inhalation was performed. No toxic symptoms have been reported. Furthermore, it has been reported that there is no carcinogenicity even when administered orally (see Non-Patent Document 3).

  Examples of such a material using titanium oxide as a medical material include a dental resin composite filler with high hiding power (see Non-Patent Document 4), an anticancer agent with a photocatalytic effect (see Non-Patent Document 5), and liquid containing Non-adhesive catheters have been proposed.

  And the titanium oxide composite which compounded these titanium oxides and the said polymer base material suitable as a medical material is proposed.

  As a method for producing the titanium oxide composite, specifically, for example, there is mixing by melting or melting. Examples of the method of coating the surface of the polymer substrate with titanium oxide include a dipping method, a spin coating method, a spray method, and a screen printing method.

  However, the titanium oxide composite produced by the above production method has a problem in that the properties inherent to the polymer substrate and titanium oxide are changed, or the titanium oxide is peeled off from the polymer substrate.

  Specifically, in the case of a titanium oxide composite produced by squeezing or melting, the physical properties inherently possessed by the titanium oxide or the polymer base material are impaired in the production process, or the physical properties are changed. End up.

  In addition, for example, a titanium oxide composite produced by the above-described method of coating titanium oxide on the surface of a polymer base material is obtained by simply applying titanium oxide to the surface of the polymer base material. It is physically bonded or adsorbed. Accordingly, the titanium oxide is easily peeled off from the surface of the polymer base material. Thus, if the titanium oxide is easily peeled off from the polymer base material, the function as the titanium oxide composite cannot be exhibited.

  Therefore, there is a need for a titanium oxide composite and a method for producing the same, in which titanium oxide is firmly bonded to the surface of the polymer substrate without impairing the original physical properties of the titanium oxide and the polymer substrate. ing.

In order to solve the above problems, methods developed by the present inventors are disclosed in, for example, Patent Documents 8 to 10. These technologies are based on chemical modification of the surface of a polymer substrate with a low molecular weight or polymer chain having an active group that chemically binds to calcium phosphate or titanium oxide, thereby forming a polymer with calcium phosphate or titanium oxide via a chemical bond. This is a method of forming a complex with a substrate. By these methods, the above problems have been solved.
JP 63-270061 A (publication date; November 8, 1988) JP 7-303691 A (publication date; November 21, 1995) JP 2000-342676 A (publication date: December 12, 2000) Japanese Laid-Open Patent Publication No. 10-15061 (Publication Date: January 10, 1998) JP 2003-52805 A (publication date; February 25, 2003) JP-A-8-56963 (Publication date; March 5, 1996) JP 2001-190653 A (publication date: July 17, 2001) JP 2001-172511 A (publication date; June 26, 2001) JP 2004-51954 A (publication date: February 19, 2004) JP 2004-143417 A (publication date: May 20, 2004) L.Herget, Chem.Ztg., 82,793 (1929) L. Vernettiblinate, Riforma. Med. Naples, 44, 15, 16 (1928) Manabu Kiyono, "Titanium oxide-physical properties and applied technology", Engineering Hall Publishing Co., Ltd. K. Yoshida, et al., J. Biomed. Mater. Res. Appl. Biomater., 58, 525 (2001) R. Cai, et al., Cancer Res., 52, 2346 (1992)

  By the way, in-vivo medical devices such as percutaneous catheters, particularly medical devices used for soft biological tissues such as subcutaneous tissues, muscles, blood vessels, etc., the affinity at the time of implantation of the medical devices is rapidly performed. It is particularly important. This is because infection due to bacteria or the like and deviation of the medical device occur during the period from the implantation of the medical device to the adhesion to the soft tissue. Therefore, as the composite of calcium phosphate and polymer base material and the composite of titanium oxide and base material used for the medical material of the medical device, those having a property of quickly adhering to soft tissue are preferable. I can say that.

  Therefore, the present invention relates to a composite of calcium phosphate and a base material having a property of rapidly adhering to a living tissue, particularly soft tissue, a composite of titanium oxide and a base material, a method for producing the composite, and the composite It aims at providing the medical material using this.

  As a result of intensive studies to solve the above problems, the present inventors have completed the present invention.

  That is, in order to solve the above-described problems, the hybrid complex according to the present invention has at least a part of the surface of the complex formed by chemically bonding calcium phosphate or titanium oxide and the base material further having an affinity for soft tissue. It is characterized by being covered with a soft tissue affinity improving material.

  The soft tissue affinity-improving substance has affinity for soft tissue and is a substance that quickly adheres to soft tissue. Therefore, by coating the surface of the complex formed by chemically bonding calcium phosphate or titanium oxide with high biocompatibility and the base material with the soft tissue affinity-improving substance, the affinity to biological tissue, particularly soft tissue, can be further increased. Improve and quickly bond with soft tissue. Therefore, there is an effect that it is possible to prevent infection caused by bacteria or the like that occurs in the initial stage of implantation of the medical device and displacement of the medical device. In the hybrid complex according to the present invention, since calcium phosphate or titanium oxide and the base material form a complex by chemical bonding, it can be said that the stability after implantation is extremely high.

  In order to solve the above problems, the hybrid complex according to the present invention is selected from the group consisting of autologous cells, ES cells, cell growth factors, adhesive proteins, and adhesive polysaccharides. Or a combination thereof.

  Autologous cells are cells collected from a living body in which a medical material is implanted, and have a particularly high affinity with the living tissue (soft tissue). Since ES cells have the property of transforming into cells suitable for ecologically transplanted environments, they have an affinity for transplanted sites as well as autologous cells, so when implanted in soft tissue, the cells are considered soft tissue. Shows good affinity. In addition, since cell growth factor has an effect of promoting cell adhesion and proliferation, it exhibits a more effective affinity promoting effect. Therefore, when implanted in soft tissue, the growth factor has good affinity with soft tissue. Indicates. Furthermore, since the adhesive protein and the adhesive polysaccharide have an effect of directly adhering to cells, they exhibit a more effective cell affinity promoting effect. Therefore, the medical device comprising the hybrid complex according to the present invention has improved affinity with a living tissue, particularly soft tissue, and can quickly adhere to the soft tissue. Therefore, there is an effect that it is possible to prevent infection caused by bacteria or the like that occurs in the initial stage of implantation of the medical device and displacement of the medical device.

  In order to solve the above problems, the hybrid complex according to the present invention is a substance in which the autologous cells are selected from the group consisting of periodontal ligament cells, bone marrow cells, fibroblasts, vascular endothelial cells, and ES cells, or A combination of these may also be used.

  The periodontal ligament cells, fibroblasts, or vascular endothelial cells are cells that form soft tissue, and bone marrow cells or ES cells are transformed into cells that are compatible with the environment transplanted into the living body and are therefore embedded in the soft tissue. It is a cell that has an affinity for soft tissue when grown. Therefore, it has a high affinity with soft tissues. For the above reasons, the medical device comprising the hybrid complex according to the present invention has improved affinity with living tissue, particularly soft tissue, and can be quickly bonded to soft tissue. Therefore, there is an effect that it is possible to prevent infection caused by bacteria or the like that occurs in the initial stage of implantation of the medical device and displacement of the medical device.

  In order to solve the above-mentioned problems, the hybrid complex according to the present invention is characterized in that the cell growth factor is fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), And a substance selected from the group consisting of epidermal growth factor (EGF), or a combination thereof.

  The fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), or epidermal growth factor (EGF) has an effect of promoting cell adhesion / proliferation. Since it is a substance that expresses a more effective affinity promoting effect, it has a particularly high affinity for soft tissue when embedded in soft tissue. Therefore, the medical device comprising the hybrid complex according to the present invention has an improved affinity with living tissue, particularly soft tissue, and can quickly become compatible with soft tissue. Therefore, there is an effect that it is possible to prevent infection caused by bacteria or the like that occurs in the initial stage of implantation of the medical device and displacement of the medical device.

  In the hybrid complex according to the present invention, in order to solve the above problems, the adhesive protein may be a substance selected from the group consisting of collagen, gelatin, fibrin, and fibroin, or a combination thereof.

  The above collagen, or gelatin or fibrin, or fibroin, or glycosaminoglycan, or pectin, or hyaluronic acid, or chondroitin, or hyaluronic acid, or chondroitin, or chitin, or chitosan, or alginic acid can directly adhere to cells. Therefore, a more effective cell affinity promoting effect is expressed. Therefore, it can be said that the affinity with the soft tissue is increased particularly when it is embedded in the soft tissue. Therefore, the medical device comprising the hybrid complex according to the present invention has improved affinity with a living tissue, particularly soft tissue, and can quickly adhere to the soft tissue. Therefore, there is an effect that it is possible to prevent infection caused by bacteria or the like that occurs in the initial stage of implantation of the medical device and displacement of the medical device.

  On the other hand, the method for producing a hybrid complex according to the present invention has a soft tissue affinity in which at least a part of the surface of the complex formed by chemically bonding calcium phosphate or titanium oxide and a substrate further has an affinity for soft tissue. A method for producing a hybrid complex formed by coating with an improving substance, the method comprising a coating step of coating the complex with the soft tissue affinity improving substance.

  As the coating step, for example, the above-mentioned hybrid complex is added to a solution of a soft tissue affinity improving substance (autologous cell, ES cell, cell growth factor, adhesive protein, adhesive polysaccharide) and stirred, When the body is recovered, a soft tissue affinity-improving substance (autologous cells, ES cells, cell growth factors, adhesive proteins, adhesive properties, etc.) is further added to the surface of the complex formed by chemically bonding the calcium phosphate or titanium oxide and the base material. A hybrid complex formed by coating a saccharide) can be produced. In the coating step, a solution containing a soft tissue affinity improving substance (autologous cells, ES cells, cell growth factors, adhesive proteins, adhesive polysaccharides) may be sprayed on the surface of the complex.

  In addition, the method for producing a hybrid complex according to the present invention is such that at least a part of the surface of the complex formed by chemically bonding calcium phosphate or titanium oxide and a substrate is further coated with autologous cells and / or ES cells. A method for producing a hybrid complex is characterized by comprising a culture step of inoculating and culturing the autologous cells and / or ES cells in a liquid medium containing the complex.

  By culturing autologous cells in a medium containing the complex, the autologous cells grown on the surface of the complex are adsorbed on the surface of the complex. Therefore, it is possible to produce a hybrid complex obtained by further coating autologous cells and / or ES cells on the surface of a complex formed by chemically bonding a calcium phosphate or titanium oxide and a base material.

  On the other hand, the medical material according to the present invention is a medical material using any one of the above hybrid complexes.

  Therefore, when a medical device is manufactured using a medical material, there is an effect that it is possible to prevent infection due to bacteria or the like that occurs in the initial stage of implantation of the medical device and deviation from the implanted portion. In the hybrid complex constituting the medical material according to the present invention, since calcium phosphate or titanium oxide and the base material form a complex by chemical bonding, it can be said that the stability after implantation of the medical device is extremely high. .

  As described above, according to the present invention, a complex of calcium phosphate and a substrate, and a complex of titanium oxide and a substrate, which have high in vivo stability and have a property of rapidly adhering to a living tissue, particularly soft tissue. In addition, a method for producing the composite and a medical material using the composite can be provided.

  Therefore, the somatic cell affinity is improved by using it as a medical material such as a transdermal device, and the transdermal device and the living body are brought into close contact with each other in a short period of time, thereby reducing the possibility of infection by bacteria. be able to. Further, by using the hybrid complex according to the present invention in an artificial blood vessel, somatic cell affinity is improved and the artificial blood vessel adheres in a short period of time, so that the probability of deviation from the artificial blood vessel placement portion can be reduced. Furthermore, by covering autologous cells such as periodontal ligament cells and bone marrow cells on the medical device, the medical device can be prevented from being displaced and wound healing can be achieved early in the implant.

  The embodiment of the present invention will be described as follows. Note that the present invention is not limited to this.

[Hybrid complex according to the present invention]
The hybrid complex according to the present invention is characterized in that at least a part of the surface of the complex formed by chemically bonding calcium phosphate or titanium oxide and a substrate is further coated with a soft tissue affinity improving substance. In the following description, “1. soft tissue affinity-improving substance”, “2. a complex formed by chemically bonding calcium phosphate and a substrate”, “3. a complex formed by chemically bonding titanium oxide and a substrate”, The description will be divided into “4. Method for producing hybrid complex according to the present invention” and “5. Utilization of hybrid complex according to the present invention”.

  In the description of the present invention, the term “hybrid complex” means that at least a part of the surface of a complex formed by chemically bonding calcium phosphate or titanium oxide and a substrate is further coated with a soft tissue affinity improving substance. Means a substance.

<1. Soft tissue affinity improving substance>
Here, the “soft tissue affinity-improving substance” is made of a substance having affinity for living tissue, particularly soft tissue. “Soft tissue” refers to body tissues other than bones, teeth, and various organs, including supportive tissue and motor organs, and includes subcutaneous tissue, muscle, fascia, tendon, synovium, dermis, and serosa. It consists of mesenchymal tissue. Hematopoietic organs such as bone marrow, lymph nodes, and blood cells are excluded, but peripheral nerves, sympathetic nerves, paraganglia, etc. are included in the outer lung lobe tissue. Soft tissue-forming cells include fibroblasts, histosphere, adipocytes, vascular and lymphatic endothelial cells, vascular epithelial cells smooth muscle cells, striated muscle cells, synovial cells, undifferentiated mesenchymal cells, peripheral nerve cells Such as Schwann cells.

  The “soft tissue affinity-improving substance” is not particularly limited, and examples thereof include autologous cells, ES cells, cell growth factors, adhesive proteins, adhesive polysaccharides, and the like.

  Here, the “autologous cell” means a cell collected from a living body in which a medical device is implanted. For example, when used in the hybrid complex according to the present invention, the cell is collected from the subject (may be an animal) and the cell cultured in vitro is returned to the subject. There are no particular limitations on the culture conditions and the like, and conditions that are suitable for the cells may be selected as appropriate. A medical device whose surface is coated with the cells is preferable because of its high affinity with a living tissue (soft tissue) and no immune reaction. Examples of cells that can be used as autologous cells include periodontal ligament cells, bone marrow cells, fibroblasts, vascular endothelial cells, ES cells (embryonic stem cell lines), and the like. Since the cells described above are cells that form soft tissue or cells that differentiate into soft tissue when implanted in soft tissue, the affinity for soft tissue is particularly high. Therefore, the medical material having the cells coated on the surface thereof quickly adheres to the living tissue (soft tissue).

  In addition, ES cells that are not autologous cells (cloned embryos: cloned embryos mean that the nuclei of the patient's own somatic cells have been removed and replaced with the nuclei of the egg. HYPERLINK "http: //www.trc-net. ne.jp/basics/i-02.html "(see http://www.trc-net.ne.jp/basics/i-02.html)) can also be used as a“ soft tissue affinity-improving substance ”. An ES cell is an undifferentiated cell that can be differentiated into various cells, and when the cell is implanted, the soft tissue bisects. Therefore, it can be said that the affinity with soft tissue is particularly high. Further, since it has a high proliferation ability and it is easy to prepare cells in vitro, it can be said to be particularly preferable as a “soft tissue affinity-improving substance” constituting the hybrid complex according to the present invention. Such ES cells must be derived from a living body in which a medical device is implanted. In other words, human-derived ES cells are used when the finally manufactured medical device is implanted in a human. ES cells can be obtained from WiCell, Inc. (see the article on November 30, 2001 in the Yomiuri Shimbun).

  Examples of the “cell growth factor” that can be used as the “soft tissue affinity improving substance” include, for example, fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), or hepatocyte growth factor (HGF). Or epidermal growth factor (EGF). For example, vascular endothelial cell growth factor (VEGF) has the property that, when the vascular endothelium is damaged, it adheres to the tissue and repairs the damaged site. Therefore, since the cell growth factor has an effect of promoting adhesion / proliferation of soft tissue cells, it is a substance that expresses a more effective affinity promoting effect and has a particularly high affinity with soft tissue. Therefore, it is suitable as a “soft tissue affinity improving substance”.

  Examples of the “adhesive protein” that can be used as the “soft tissue affinity-improving substance” include collagen, gelatin, fibrin, fibroin, and the like, and the “adhesive polysaccharide” includes glycosaminoglycan. Or pectin, hyaluronic acid, chondroitin, chitin, chitosan, alginic acid, or the like. Moreover, the partial decomposition product of the said substance, an oxide, an alkylene oxide addition product, a carboxymethylated product, and a crosslinked body may be sufficient. The adhesive protein and adhesive polysaccharide are proteins and polysaccharides secreted when cells adhere to a living body. Therefore, the adhesive proteins and polysaccharides are suitable as “soft tissue affinity improving substances” because of their high affinity with living tissues, particularly soft tissues. The “adhesive protein” and “adhesive polysaccharide” may be obtained by using commercially available products. Moreover, you may use after performing decomposition | disassembly, chemical modification, etc. as needed.

  The hybrid complex according to the present invention is such that at least a part of the surface of the complex formed by chemically bonding calcium phosphate or titanium oxide and a base material is further coated with the “soft tissue affinity-improving substance”. However, the “soft tissue affinity-improving substance substance” to be coated on the surface of the composite is not limited to one of the various substances exemplified above, and may be an aspect in which various combinations are coated. A method of coating the soft tissue affinity improving substance on the surface of the complex formed by chemically bonding the calcium phosphate or titanium oxide and the base material will be described later.

<2. Complex formed by chemical bonding of calcium phosphate and base material>
Below, the composite_body | complex (henceforth a calcium-phosphate composite) formed by a chemical bond of a calcium phosphate and a base material is demonstrated. In the following explanation, among calcium phosphates, the case where the calcium phosphate sintered body and the substrate are chemically bonded will be described. However, in the present invention, calcium phosphate is amorphous (amorphous) even if it is a sintered body. There may be. However, it can be said that the sintered body is preferable because of its high in vivo stability.

First, a calcium phosphate sintered body that forms a composite with a base material will be described. The calcium phosphate sintered body (also referred to as calcium phosphate ceramics) indicates calcium phosphate having high crystallinity when compared with amorphous (amorphous) calcium phosphate. Specifically, the calcium phosphate sintered body is obtained by sintering amorphous (amorphous) calcium phosphate. The calcium phosphate sintered body has at least one of calcium ions (Ca ²⁺ ), phosphate ions (PO ₄ ²⁻ ), and hydroxide ions (OH ⁻ ) on the surface of the calcium phosphate sintered body itself. Has two ions.

  Further, at least phosphate ions or calcium ions are present on one crystal face of the calcium phosphate sintered body. Specifically, the ions present depend on the crystal plane of calcium phosphate, and calcium ions and phosphate ions exist on different crystal planes. In addition, when the calcium phosphate sintered body contains hydroxide ions, the hydroxide ions are present on at least one crystal face where the calcium ions or phosphate ions are present. Will be.

Specific examples of the calcium phosphate sintered body include, for example, a hydroxyapatite sintered body (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ), calcium triphosphate (β (α) -calcium triphosphate (Ca ₃ (PO _{4 2} )), calcium metaphosphate (Ca (PO ₃ ) ₂ ), Ca ₁₀ (PO ₄ ) ₆ F ₂ , Ca ₁₀ (PO ₄ ) ₆ Cl _{2 and the} like. The calcium phosphate may be artificially produced by a known production method such as a wet method, a dry method, a hydrolysis method, or a hydrothermal method, and is obtained from bone, teeth, and the like. It may be naturally derived. In addition, the calcium phosphate sintered body may include a calcium phosphate hydroxide ion and / or a compound in which a part of the phosphate ion is substituted with carbonate ion, chloride ion, fluoride ion, or the like.

  Here, the manufacturing method of the said calcium phosphate sintered compact is demonstrated. The calcium phosphate sintered body according to the present embodiment can be obtained by sintering amorphous calcium phosphate. Specifically, a calcium phosphate sintered body can be obtained by sintering the above-exemplified calcium phosphate within a temperature range of 800 ° C. to 1300 ° C. for a predetermined time. By sintering the calcium phosphate, the crystallinity can be increased, and for example, the solubility when introduced into a living body can be reduced. The degree of crystallization of this calcium phosphate sintered body can be measured by X-ray diffraction (XRD). Specifically, the narrower the half width of the peak showing each crystal plane of the calcium phosphate complex, the higher the crystallinity.

  The lower limit of the sintering temperature at which the calcium phosphate is sintered is more preferably 650 ° C. or higher, further preferably 800 ° C. or higher, and particularly preferably 1000 ° C. or higher. If the sintering temperature is lower than 650 ° C., the sintering may not be sufficient. On the other hand, as an upper limit of sintering temperature, 1300 degreeC or less is more preferable, 1250 degreeC or less is further more preferable, and 1200 degreeC or less is especially preferable. When the sintering temperature is higher than 1300 ° C., it may be difficult to directly chemically bond with the functional group of the base material described later. Therefore, by setting the sintering temperature within the above range, a calcium phosphate sintered body that is difficult to dissolve in the living body (high crystallinity) and can be directly chemically bonded to the functional group of the substrate is manufactured. can do. In addition, the sintering time is not particularly limited, and may be set as appropriate.

  In addition, for example, when a hydroxyapatite sintered body or β-tricalcium phosphate is used as a material constituting the calcium phosphate sintered body, the hydroxyapatite sintered body or β-tricalcium phosphate has an affinity for living tissue and a living environment. Is excellent as a medical material because of its excellent stability. Further, the hydroxyapatite sintered body is difficult to dissolve in vivo. Therefore, for example, when a calcium phosphate complex is produced using the hydroxyapatite sintered body, the biological activity can be maintained for a long period in vivo.

  The calcium phosphate sintered body according to the present embodiment is more preferably particulate. More specifically, the lower limit of the particle diameter of the calcium phosphate is more preferably 0.001 μm or more, and further preferably 0.01 μm or more. When the particle diameter is smaller than 0.001 μm, when the complex of calcium phosphate and the base material is embedded in the living body, the calcium phosphate bound to the surface of the base material is eluted and the biocompatibility is impaired. There is a fear.

  On the other hand, the upper limit of the particle diameter of the calcium phosphate is more preferably 1000 μm or less, and even more preferably 100 μm or less. When the particle diameter is larger than 1000 μm, the bond between the calcium phosphate and the base material becomes relatively weak, and there is a risk of damage when the complex of calcium phosphate and the base material is embedded in a living body.

  Further, the calcium phosphate sintered body is obtained by controlling the sintering temperature of the calcium phosphate and the particle diameter of the calcium phosphate sintered body, for example, when the obtained calcium phosphate composite is embedded in a living body. The elution rate of can be controlled. That is, by controlling the sintering temperature and the particle size, the physical properties of the composite of calcium phosphate and the substrate can be designed according to the application.

(Base material)
As the substrate according to the present embodiment, a polymer substrate is preferable, a medical polymer is more preferable, and an organic polymer is particularly preferable. Specific examples of the base material include silicone polymer (which may be silicone rubber), polyethylene glycol, polyalkylene glycol, polyglycolic acid, polylactic acid, polyamide, polyurethane, polysulfone, polyether, and poly Synthetic polymers such as ether ketone, polyamine, polyurea, polyimide, polyester, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid, polymethacrylic acid, polymethyl methacrylate, polyacrylonitrile, polystyrene, polyvinyl alcohol, polyvinyl chloride; Polysaccharides such as cellulose, amylose, amylopectin, chitin and chitosan, polypeptides such as collagen, mucopolysaccharides such as hyaluronic acid and chondroitin, natural such as silk fibroin Molecule, and the like. Of the above-exemplified base materials, silicone polymer, polyurethane, polytetrafluoroethylene, or silk fibroin is preferably used because it has excellent properties such as long-term stability, strength, and flexibility.

  Further, in place of the exemplified base material, specifically, for example, a base material made of an inorganic material such as titanium oxide which can be suitably used as a medical material can be used. Therefore, the base material in the present invention includes a base material made of an inorganic material such as titanium oxide.

  Further, for example, the organic polymer and the inorganic material may be combined to form a base material.

  The surface of the base material according to the present embodiment has a functional group that can be chemically bonded to calcium phosphate.

In the case of hydroxyapatite or a sintered body thereof, the hydroxyapatite or the sintered body thereof can be chemically bonded to at least one functional group selected from the group consisting of an isocyanate group and an alkoxysilyl group. That is, when the substrate has at least one functional group selected from the group consisting of an isocyanate group and an alkoxysilyl group, the substrate and the hydroxyapatite sintered body are chemically bonded. be able to. In addition, the said alkoxysilyl group has shown group containing Si-OR. That is, in this embodiment, the alkoxysilyl group includes ≡Si—OR, ═Si— (OR) ₂ , —Si— (OR) _{3, and the} like. The above ≡ and ═ do not indicate only a triple bond or a double bond, and each bond may be bonded to a different group. Therefore, for example, —SiH— (OR) ₂ , —SiH ₂ — (OR) and the like are also included in the alkoxysilyl group. Further, R in the Si-OR represents an alkyl group or hydrogen.

  The functional group on the substrate surface may be a functional group possessed by the substrate itself, and the substrate surface may be treated by known means such as acid / alkali treatment, corona discharge, plasma irradiation, surface graft polymerization, etc. May be introduced by modifying the base material.

  Moreover, in order to introduce | transduce the said functional group, an active group may be introduce | transduced into a base material and a functional group may be introduce | transduced using this active group.

  And the calcium-phosphate composite can be obtained by making the base material which has the said functional group react with a calcium-phosphate sintered compact. In addition, the manufacturing method of a calcium phosphate complex is mentioned later.

When the calcium phosphate complex according to the present embodiment is, for example, a hydroxyapatite complex, the hydroxyapatite sintered body is chemically bonded to the surface of the base material. Specifically, the hydroxyl group (—OH) present in the hydroxyapatite sintered body is directly chemically bonded to the isocyanate group (—NCO) or alkoxysilyl group possessed by the substrate or the surface-modified linker. . When the alkoxysilyl group of the substrate is —Si≡ (OR) ₃ , a bond represented by the chemical formula (1) exists between the hydroxyapatite sintered body and the substrate.

(However, X represents a base material, and Y represents a hydroxyapatite sintered body)
In the above case, three hydroxyl groups of the hydroxyapatite sintered body are reacted with one (—Si≡ (OR) ₃ ) of the base material. Therefore, for example, even a substrate having a small number of alkoxysilyl groups can bond a large amount of hydroxyapatite sintered bodies. Therefore, when introducing an alkoxysilyl group into the substrate, the number of alkoxysilyl groups to be introduced can be reduced as compared with the conventional case. In addition, the silicon atom (Si) of the said Chemical formula (1) is a part of alkoxysilyl group which a base material has. Specifically, the silicon atom may be a part of the surface-modified graft chain or a part of the alkoxysilyl group of the polymer chain. Moreover, the oxygen atom (O) of the said Chemical formula (1) is a part of alkoxysilyl group which a base material has, or a part of hydroxyl group which a hydroxyapatite sintered compact has. Further, X and Si in the chemical formula (1) may be bonded by a polymer chain, may be bonded by a low molecular chain, or may be directly bonded.

  When the functional group is an isocyanate group, the hydroxyapatite sintered body and the base material are chemically bonded by a urethane bond.

  In the calcium phosphate complex, the binding amount (adsorption rate) of calcium phosphate on the substrate is preferably 5% by weight or more. Furthermore, the amount of the bond is more preferably 7% by weight or more, further preferably 10% by weight or more, and particularly preferably 12% by weight or more. When the binding amount is 5% by weight or more, when the calcium phosphate complex is used for a medical material such as a percutaneous terminal, high biocompatibility can be exhibited.

(Method for producing calcium phosphate complex)
Here, the manufacturing method of the calcium phosphate composite concerning this Embodiment is demonstrated. The method for producing a calcium phosphate complex according to the present embodiment is a method for producing a calcium phosphate complex in which calcium phosphate is chemically bonded to the functional group of the base particle, and the functional group capable of being chemically bonded to the calcium phosphate is provided. And introducing a functional group into the base particle by reacting the functional group-containing compound that can be reacted with the base particle with the base particle, and a functional group in the introduction step. Is a method including a separation step of separating the base particles into which the base material is introduced and an unreacted functional group compound, and a reaction step of reacting the functional groups introduced into the base particles with the calcium phosphate. Moreover, in the said manufacturing method, you may perform the formation process which forms a base material in a particle form before the said introduction | transduction process. This will be described below. In the following description, the case where calcium phosphate is a hydroxyapatite sintered body, the base material is silk fibroin, and an isocyanate group and / or an alkoxysilyl group is introduced into the base material will be described.

(Formation process)
In the forming step, the base material is formed into particles. Specifically, the base material is formed into a columnar or spherical particle shape having a length in the major axis direction of 1 cm to 1 μm and a length in the minor axis direction of 1 mm to 1 nm. As a method of forming the base material into particles, for example, when the base material is silk fibroin fiber, the fiber may be cut so as to be within the above range.

(Introduction process)
In the introduction step, a functional group capable of reacting with calcium phosphate (functional group capable of chemical bonding) is introduced into the base particle (hereinafter sometimes simply referred to as a base). In this introduction step, the reaction conditions and the like differ depending on the type of calcium phosphate and the type of chemical bond generated between the calcium phosphate and the substrate.

  A method for introducing an isocyanate group and / or an alkoxysilyl group (functional group) into the substrate is not particularly limited, and may be, for example, a reactive functional group at a molecular end. By using a silane coupling agent having a group, the functional group can be introduced into the substrate.

  Here, as one method for introducing an alkoxysilyl group into the substrate, a method for introducing it using a silane coupling agent will be described. In addition, the method of introduce | transducing an alkoxy silyl group into a base material is not limited to this method, A various method is employable.

The silane coupling agent has a chemical structure as shown in chemical formula [2].
[Chemical formula 2]
Z-Si≡ (OR) ₃ (2)
Z may be any reactive functional group that can be chemically bonded to an organic material (base material) such as various synthetic resins. Specifically, for example, vinyl group, epoxy group, amino group, (meth) An acryloxy group, a mercapto group, etc. are mentioned. The OR may be any one that can be chemically bonded to the hydroxyapatite sintered body. Specific examples include a methoxy group and an ethoxy group. In addition, Z and Si, which are reactive functional groups in the chemical formula (2), may be bonded by a high molecular chain, may be bonded by a low molecular chain, or may be directly bonded. .

  That is, as the silane coupling agent, specifically, for example, vinyl silane coupling agents such as vinyltrichlorosilane, vinyltrimethoxysilane, vinyltriethoxysilane; β- (3,4 epoxycyclohexyl) ethyltri Epoxy silane coupling agents such as methoxysilane, γ-glycidoxypropyltrimethoxysilane, γ-glycidoxypropylmethyldiethoxysilane, γ-glycidoxypropyltriethoxysilane; p-styryltrimethoxysilane, etc. Stylyl-based silane coupling agents; methacrylic compounds such as γ-methacryloxypropylmethyldimethoxysilane, γ-methacryloxypropyltrimethoxysilane, γ-methacryloxypropylmethyldiethoxysilane, γ-methacryloxypropyltriethoxysilane Roxy-based silane coupling agents; acryloxy-based silane coupling agents such as γ-acryloxypropyltrimethoxysilane; N-β (aminoethyl) γ-aminopropyltrimethoxysilane, N-β (aminoethyl) γ-aminopropyl Methyldimethoxymethoxysilane, N-β (aminoethyl) γ-aminopropyltriethoxysilane, γ-aminopropyltrimethoxysilane, γ-aminopropyltriethoxysilane, γ-triethoxy-N- (1,3-dimethyl-butylidene ) Amino-based silane coupling agents such as propylamine, N-phenyl-γ-aminopropyltrimethoxysilane, N- (vinylbenzyl) -β-aminoethyl-γ-aminopropyltrimethoxysilane hydrochloride, special aminosilane; γ-ureidopropyltriethoxysila Ureido silane coupling agents such as chlorosilanes; Chloropropyl silane coupling agents such as γ-chloropropyltrimethoxysilane; Mercapto silane coupling agents such as γ-mercaptopropyltrimethoxysilane and γ-mercaptopropylmethyldimethoxysilane A sulfide-based silane coupling agent such as bis (triethoxypropyl) tetrasulfide; an isocyanate-based silane coupling agent such as γ-isocyanatopropyltriethoxysilane; Of the above-exemplified silane coupling agents, γ-methacryloxypropyltrimethoxysilane is more preferable because it is a polymerizable monomer. What is necessary is just to select the said silane coupling agent suitably according to the kind of this active group, etc., when the kind of base material and the active group (after-mentioned) are introduce | transduced into the base-material surface.

  As a method for introducing an alkoxysilyl group into a substrate using the silane coupling agent, specifically, for example, a silane coupling agent having a reactive functional group at the terminal on a substrate subjected to corona treatment May be introduced directly. In addition, by drawing a proton (hydrogen atom) from the base material using a surfactant and a peroxide-based initiator to generate radicals, the water-insoluble monomer having the above functional group is directly grafted onto the base material. It can be polymerized. By using this method, the functional group can be directly introduced into the substrate.

  Moreover, as a method for introducing an alkoxysilyl group into a substrate, for example, an active group capable of reacting with the reactive functional group of the silane coupling agent is introduced into the substrate in advance, and this active group is introduced. An alkoxysilyl group may be introduced into the substrate by reacting the silane coupling agent with a reactive functional group of the silane coupling agent. Specific examples of the active group include a vinyl group and an amino group, but are not particularly limited. The reactive functional group of the silane coupling agent (the chemical formula (2)) is not particularly limited. May be set as appropriate according to the type of Z).

  Here, silk fibroin (fiber) is used as a base material, a vinyl group that is an active group is introduced into this silk fibroin, and by reacting this vinyl group with a reactive functional group of a silane coupling agent, Specific conditions of the method for introducing an alkoxysilyl group into the substrate will be described.

  First, the step of introducing an active group into the substrate (active group introduction step) will be described. In order to introduce a vinyl group into the substrate, for example, the substrate and the active group-containing compound may be reacted in a mixed solution of a catalyst, a polymerization inhibitor and a solvent.

  Specific examples of the active group-containing compound include 2-methacryloyloxyethyl isocyanate and hexamethylene diisocyanate. The solvent is preferably a polar solvent, and for example, dehydrated dimethyl sulfoxide, dehydrated dimethylformamide and the like are preferably used. The polymerization inhibitor is added so that active groups introduced into the base material and active group-containing compounds do not polymerize. Examples of the polymerization inhibitor include hydroquinone. Examples of the catalyst include dibutyltin (IV) dilaurate.

  The lower limit of the amount of the active group-containing compound added is preferably 10% by weight or more, more preferably 50% by weight or more, and particularly preferably 100% by weight or more based on the base material. If the amount added is less than 10% by weight, a sufficient amount of active groups may not be introduced into the substrate. On the other hand, the upper limit value of the addition amount is more preferably 500% by weight or less, still more preferably 400% by weight or less, and particularly preferably 300% by weight or less based on the base material. When the added amount is more than 500% by weight, it is not economical.

  And as a lower limit of reaction temperature, 30 degreeC or more is more preferable, 40 degreeC or more is further more preferable, and 45 degreeC or more is especially preferable. If the said reaction temperature is lower than 30 degreeC, reaction may not fully occur and an active group may not be introduce | transduced into a base material. On the other hand, as an upper limit of reaction temperature, 100 degrees C or less is more preferable, 80 degrees C or less is further more preferable, and 60 degrees C or less is especially preferable. When the reaction temperature is higher than 100 ° C, the active groups introduced into the substrate may react with each other. In addition, the substrate may be deteriorated. In addition, what is necessary is just to set reaction time suitably by reaction temperature etc. By making it react on the above conditions, an active group can be easily introduce | transduced into a base material.

  The lower limit of the active group introduction rate (% by weight) relative to the substrate is more preferably 0.1% by weight or more, still more preferably 1.0% by weight or more, and particularly preferably 2.0% by weight or more. When the introduction rate is less than 0.1% by weight, the number of alkoxysilyl groups introduced into the base material is reduced, which may make it impossible to produce a hydroxyapatite composite. On the other hand, the upper limit of the introduction rate is more preferably 30% by weight or less, further preferably 25% by weight or less, and particularly preferably 20% by weight or less. When the introduction ratio is more than 30% by weight, the number of active groups introduced into the substrate increases, and the active groups may react with each other.

  Next, an alkoxysilyl group is introduced into the base material by polymerizing an active group of the base material and a silane coupling agent having a reactive functional group at the terminal.

  The silane coupling agent is not particularly limited as long as the reactive functional group at the end can be polymerized with the active group introduced into the base material. When is introduced, for example, γ-methacryloxypropyltrimethoxysilane, which is the methacryloxy-based silane coupling agent, can be suitably used.

  And the alkoxy silyl group can be introduce | transduced into a base material by superposing | polymerizing the said silane coupling agent and the base material in which the active group was introduce | transduced in presence of a polymerization initiator and a solvent.

  As said solvent, nonpolar organic solvents, such as hydrocarbon solvents, such as toluene and hexane, are used suitably.

  As the polymerization initiator, for example, azobisisobutyronitrile, benzoyl peroxide, or the like may be used.

  The lower limit of the amount (addition amount) of the silane coupling agent used is preferably 10% by weight or more, more preferably 50% by weight or more, and more preferably 100% by weight with respect to the base material into which the active group has been introduced. The above is particularly preferable. If the amount used is less than 10% by weight, it may not be possible to introduce an alkoxysilyl group sufficient to react with a sufficient hydroxyapatite sintered body. On the other hand, the upper limit of the amount used is more preferably 500% by weight or less, further preferably 400% by weight or less, and particularly preferably 300% by weight or less. If the amount used is more than 500% by weight, it is not economical.

  The polymerization is more preferably performed in a nitrogen atmosphere. As a lower limit of polymerization temperature, 40 degreeC or more is more preferable, 45 degreeC or more is further more preferable, and 50 degreeC or more is especially preferable. When the polymerization temperature is lower than 40 ° C., the polymerization does not occur sufficiently and the functional group may not be introduced into the substrate. On the other hand, the upper limit of the polymerization temperature is more preferably 80 ° C. or less, further preferably 75 ° C. or less, and particularly preferably 70 ° C. or less. If the polymerization temperature is higher than 80 ° C, the substrate may be deteriorated. In addition, what is necessary is just to set suitably as polymerization time so that it may become a desired introduction rate (ratio in which a functional group is introduce | transduced into a base material).

  Further, the lower limit of the introduction ratio (% by weight) of the functional group with respect to the substrate is more preferably 0.1% by weight or more, and further preferably 1% by weight or more. Here, the introduction rate is the ratio of the weight of the silane coupling agent introduced per unit weight of the substrate. When the introduction ratio is 0.1% by weight or more, a sufficient amount of a hydroxyapatite sintered body capable of expressing biocompatibility can be bonded to the base material. On the other hand, the upper limit of the introduction rate is not particularly limited. However, if the introduction rate is higher than 100% by weight, the amount of the hydroxyapatite sintered body bonded to the base material is excessively increased. May not be right.

  The method for introducing an alkoxysilyl group into the substrate is not limited to the method described above, and various methods can be used. The reaction conditions are appropriately set depending on the base material, the active group-containing compound, the type of the silane coupling agent, and the like, and are not particularly limited. In this way, functional groups can be introduced on the surface of the substrate.

  Here, another method for introducing the alkoxysilyl group will be described. Specifically, it is a method in which an alkoxysilyl group is directly introduced into a substrate by reacting the silane coupling agent having an alkoxysilyl group with the substrate.

  First, the silane coupling agent and the surfactant are mixed. Then, this mixture is added to an aqueous solution containing a base material and an initiator and reacted. Thereby, an alkoxysilyl group can be directly introduced into the substrate. When an alkoxyl group is introduced into a substrate by the above method, the reaction can be carried out in an aqueous solution, so that the safety of the substrate into which the alkoxysilyl group has been introduced can be further improved.

  Specific examples of the surfactant used in the method for directly introducing the alkoxysilyl group into the base material include pentaethylene glycol dodecyl ether, hexaethylene glycol monododecyl ether, nonylphenyl polyoxyethylene, and polyoxyethylene. (10) Nonionic surfactants such as octylphenyl ether and dodecyl-β-glucoside are exemplified. Specific examples of the initiator include ammonium persulfate and potassium persulfate (potassium peroxodioate). Moreover, as a reaction solvent, water, alcohol, etc. are used suitably.

  In the method of directly introducing the alkoxysilyl group, the amount of the surfactant used is more preferably in the range of 1.0 to 50.0% by weight relative to the silane coupling agent, and 10.0. More preferably within the range of ˜25.0% by weight. By using the surfactant within the above range, the alkoxysilyl group of the silane coupling agent can be protected from water and alcohol.

  That is, in the method of directly introducing the alkoxysilyl group, the alkoxysilyl group is temporarily protected with a surfactant, and the protected alkoxysilyl group and the substrate are reacted to form a substrate. Alkoxysilyl groups can be introduced directly.

  The other reaction conditions (for example, the amount added to the substrate) in the method for directly introducing the alkoxysilyl group are the same as in the case where the functional group is an alkoxysilyl group, and detailed description thereof is omitted. .

  Next, the case where the functional group is an isocyanate group will be described. When the isocyanate group is polymerized with a monomer having an isocyanate group at the terminal and the base material is introduced into the base material, the isocyanate group may react with active hydrogen in the reaction solvent and be deactivated. The reaction is preferably carried out in a dehydrating solvent such as dimethyl sulfoxide or dehydrated dimethylformamide.

  In addition, when the monomer having an isocyanate group at the terminal is reacted with the substrate in water or alcohol having active hydrogen, the isocyanate group needs to be protected because the isocyanate group reacts with the active hydrogen. Specifically, for example, polymerization can be carried out by protecting the isocyanate group with a blocking agent such as phenol, imidazole, oxime, N-hydroxyimide, alcohol, lactam, or active methylene complex. The blocking agent protecting the isocyanate group can be removed by heating. Therefore, the isocyanate group can be introduced into the base material by heating after the monomer having an isocyanate group is protected with a blocking agent and polymerized with the base material.

  For example, when phenol is used as the blocking agent, the blocking agent protecting the isocyanate group can be eliminated by heating within a range of 110 to 120 ° C. Further, as the blocking agent, for example, when imidazole is used, heating is performed within a range of 110 to 130 ° C., and when oxime is used, heating is performed within a range of 130 to 150 ° C., thereby removing the blocking agent. be able to. Specific examples of the blocking agent include phenol-containing compounds such as methyl salicylate and methyl-p-hydroxybenzoate; imidazole; oxime-containing compounds such as methyl ethyl ketoxime and acetone oxime. Depending on the type of substrate, for example, N-hydroxyimide-containing compounds such as N-hydroxyphthalimide and N-hydroxysuccinimide; alcohol-containing compounds such as methoxypropanol, ethylhexanol, pentol, and ethyl lactate; caprolactam, pyrrolidinone, and the like Lactam-containing compounds; active methylene compounds such as ethyl acetoacetate may be used.

  In addition, about other reaction conditions (for example, the addition amount with respect to a base material), etc. in the case of using isocyanate as the said functional group, it is the same as that of the case of the method of introduce | transducing the said alkoxysilyl group directly into a base material, and details The detailed explanation is omitted.

  Moreover, when the said inorganic compound is a titanium oxide and introduce | transduces an alkoxy silyl group and / or an isocyanate group into a base material, a functional group should just be introduce | transduced according to the said reaction conditions, and detailed description is abbreviate | omitted.

(Separation process)
In the separation step, the base particle into which the functional group has been introduced in the introduction step and the unreacted functional group-containing compound are separated. Since the functional group-containing compound has a highly reactive functional group and a reactive group capable of reacting with the substrate, for example, the functional groups or reactive groups may react with each other. That is, some of the functional group-containing compounds used in the introduction step are introduced into the base particles, and the rest remain without reacting, or the functional group-containing compounds react with each other. There is. That is, after the introduction step, by-products are present in the reaction solution (dispersion liquid after the introduction step). Therefore, in the separation step, these by-products are separated.

  Specifically, first, the reaction solution is filtered using a filter (filter paper). At this time, the aperture of the filter (filter paper) to be used is preferably smaller than the base particle. It is more preferable to use a qualitative filter paper having a constant mesh opening. Thereby, the base material into which the functional group is introduced remains on the filter paper. And the functional group containing compound which is unreacted with a base material turns into a filtrate.

  And when filtering using the said qualitative filter paper, about the opening of a filter paper, for example, base material particle length is in the range of 1 cm to 1 μm, and length in the short axis direction is 1 mm to 1 nm. In the case of a columnar or spherical particle shape within the range, it may be set according to the size of the substrate particle, and may be about 100 nm to 10 μm.

  Thereafter, the functional group-containing compound that has been polymerized can be separated by irradiating the substrate remaining on the filter paper with ultrasonic waves.

  In addition, the said separation process should just be able to isolate | separate the base particle in which the functional group was introduce | transduced in the introduction process, and an unreacted functional group containing compound, and if both can be isolate | separated by another method, the details Such a method is not particularly limited.

(Reaction process)
In the reaction step, the functional group (isocyanate group and / or alkoxysilyl group) introduced into the substrate by the introduction step and the separation step is reacted with the hydroxyapatite sintered body. Specifically, the hydroxyapatite sintered body is adsorbed on the surface of the base material by immersing the base material in a dispersion in which the hydroxyapatite sintered body is dispersed. Then, the hydroxyl group of the hydroxyapatite sintered body adsorbed on the surface is reacted with the functional group.

  Specific examples of the dispersion medium for dispersing the hydroxyapatite sintered body include water; hydrocarbon solvents such as toluene and hexane; alcohols; ether solvents such as tetrahydrofuran and diethyl ether; acetone, methyl ethyl ketone, and the like. And organic solvents such as ketone solvents. Among the above-exemplified solvents, alcohols are preferably used in that the hydroxyapatite sintered body is well dispersed. For example, when using a hydrocarbon solvent such as hexane or toluene, in order to disperse the hydroxyapatite sintered body satisfactorily, for example, (1) Stir vigorously with a stirrer such as a stirrer, (2) A method of dispersing using an ultrasonic device, (3) using the stirring device and the ultrasonic device in combination, or the like may be used.

  In the preparation of the dispersion, the lower limit of the added amount of the hydroxyapatite sintered body is more preferably 0.01% by weight or more, further preferably 0.02% by weight or more with respect to the dispersion medium. 05% by weight or more is particularly preferable. When the added amount of the hydroxyapatite sintered body is less than 0.01% by weight, the hydroxyapatite sintered body may not be uniformly adsorbed on the surface of the substrate, and a uniform coated surface may not be formed. On the other hand, the upper limit of the added amount of the hydroxyapatite sintered body is more preferably 5.0% by weight or less, further preferably 4.0% by weight or less, and more preferably 3.0% by weight or less with respect to the dispersion medium. Is particularly preferred. When the amount added is more than 5.0% by weight, the amount of the hydroxyapatite sintered body remaining in the dispersion becomes significantly larger than the amount of the hydroxyapatite sintered body adsorbed on the surface of the substrate. Not economical.

  When the base material having a functional group is introduced into the dispersion in which the hydroxyapatite sintered body is dispersed, it is preferably introduced gently. Further, it is more preferable that the dispersion is gently stirred after the base material is charged. When stirring vigorously, the sintered hydroxyapatite particles may aggregate.

  Furthermore, after adsorbing the hydroxyapatite sintered body to the base material, the base material is separated from the dispersion. At this time, it is more preferable to separate using a qualitative filter paper. More preferably, the qualitative filter paper has the same opening as the qualitative filter paper used in the separation step. Specifically, as a separation method, it is efficient to first filter the supernatant hydroxyapatite sintered body of the dispersion once and then recover the precipitated substrate.

  The lower limit of the reaction temperature at which the hydroxyl group of the hydroxyapatite sintered body adsorbed on the surface of the substrate reacts with the functional group is more preferably 25 ° C. or more, more preferably 50 ° C. or more, and particularly preferably 80 ° C. or more. preferable. If the reaction temperature is lower than 25 ° C., the hydroxyapatite sintered body and the functional group may not react. On the other hand, the upper limit of the reaction temperature is more preferably 200 ° C. or less, further preferably 175 ° C. or less, and particularly preferably 150 ° C. or less. When the said reaction temperature is higher than 200 degreeC, a base material may decompose | disassemble.

  Further, after adsorbing the hydroxyapatite sintered body on the surface of the base material, the reaction may be performed under vacuum conditions as necessary. By reacting a hydroxyapatite sintered body with a functional group under vacuum conditions, a hydroxyapatite composite can be produced more quickly. In addition, when making it react under vacuum conditions, as a pressure which performs reaction, the inside of the range of 0.01 mmHg (1.33 kPa)-10 mmHg (13.3 kPa) is preferable. When the functional group is an alkoxysilyl group, by setting the pressure within the above range, methanol (ethanol) generated when the hydroxyl group of the hydroxyapatite sintered body is reacted with the alkoxysilyl group as the functional group is removed. be able to. Moreover, when the said functional group is a blocked isocyanate group (protected isocyanate group), when making the hydroxyl group of a hydroxyapatite sintered compact and the isocyanate group which is a functional group react by making pressure into the said range. Can be removed efficiently (for example, phenol, imidazole, oxime, etc.).

  In addition, what is necessary is just to change suitably the reaction conditions of the said introduction process and reaction process, the kind of solvent, etc. according to the kind of base material and the kind of functional group.

  In addition, the method for producing a calcium phosphate composite according to the present embodiment is a method for producing a hydroxyapatite composite in which a hydroxyapatite sintered body and a base material are bonded through a chemical bond, and a major axis of 1 cm to At least one functional group selected from the group consisting of an isocyanate group, an alkoxysilyl group, and a 4-methacryloxyethyl trimerlate anhydride (4META) group is introduced into the substrate surface cut to 1 μm and a minor axis of 1 mm to 1 nm. A separating step of separating the base material from the functional group-containing polymer not bonded to the base material surface, which is a byproduct, synthesized in the introducing step, and a functional group of the base material And a reaction step of forming a chemical bond by reacting with the hydroxyapatite sintered body. .

  In the calcium phosphate complex according to the present embodiment, it is more preferable that the calcium phosphate is a hydroxyapatite sintered body and the base material is silk fibroin. The hydroxyapatite sintered body has higher crystallinity than amorphous hydroxyapatite, and can be implanted in a living body for a long period of time, for example. Moreover, since both the hydroxyapatite sintered body and silk fibroin have high biological activity, the hydroxyapatite composite (inorganic compound composite) which is a composite of these has high biocompatibility.

  Next, the calcium phosphate complex in which the calcium phosphate and the base material are chemically bonded by ionic interaction will be described.

  In the calcium phosphate complex in the present embodiment, when the calcium phosphate is a calcium phosphate sintered body and the calcium phosphate sintered body and the base material are chemically bonded by ionic interaction, the surface of the base material has the functional group. Are ionized functional groups. When an ionic functional group is present on the surface of the base material, the ionic functional group and the ions of the calcium phosphate sintered body itself are chemically bonded by an ionic interaction, so that the calcium phosphate complex is formed. Will be formed.

  The ionic functional group is classified as an acidic functional group or a basic functional group.

Specific examples of the acidic functional group include —COO ⁻ , —SO ₃ ²⁻ , —SO ₃ ⁻ , —O ⁻ , R ₂ NC (S) ₂ ^{—, and the} like. Specific examples of the basic functional group include —NH ³⁺ , ethylenediamine, pyridine and the like. That is, the acidic functional group or basic functional group exemplified above is present on the surface of the substrate. In the above R ₂ NC (S) ₂ ^— , R represents an alkyl group.

  In addition, the ionic functional group may be any one that can be ionized by chemical treatment such as acid treatment or alkali treatment. Specifically, for example, carboxyl group, dicarboxyl group, dithiocarbamate ion, amine, ethylenediamine , Pyridine and the like.

  The functional group may be, for example, a nonionic functional group (neutral functional group) or the like that can bind the functional group and the calcium phosphate sintered body itself by a coordinate bond.

  Examples of a method for introducing an ionic functional group onto the surface of the substrate include a method of graft-polymerizing a vinyl polymerizable monomer having a carboxyl group, a dicarboxyl group, or a basic functional group at the terminal to the substrate. Is mentioned. Details will be described later.

  The bond by the ionic interaction is a chemical bond between ions present on the surface of the substrate and ions present on the surface of the calcium phosphate sintered body. Therefore, examples of the bond due to the ionic interaction include an ionic bond and a coordinate bond. In addition, the ionic bond in this embodiment includes a bond including both an ionic bond and a covalent bond. Similarly, the coordination bond in this embodiment includes a bond including both coordination bondability and covalent bondability. Note that in the case of a bond that includes both the above-described ionic bondability or coordination bondability and covalent bondability, it is assumed that the ionic bondability or coordination bondability is 50% or more.

  In addition to the above, the bond due to the ionic interaction may further include a bond due to a hydrogen bond, a dipole interaction, a van der Waals force, or the like.

  That is, in the case of the calcium phosphate composite according to the present embodiment, most of the calcium phosphate sintered body and the ionic functional group of the base material are bonded by ionic bonds or coordinate bonds.

  Here, the relationship between ions present on the surface of calcium phosphate and ionic functional groups present on the surface of the substrate will be described.

  When the ionic functional group present on the surface of the substrate is a basic functional group (a functional group having a positive charge), the basic functional group, phosphate ions present on the surface of calcium phosphate, and / or Or a calcium phosphate complex will be comprised by a chemical bond with a hydroxide ion directly.

  On the other hand, when the ionic functional group present on the surface of the substrate is an acidic functional group (functional group having a negative charge), the acidic functional group and the calcium ion present on the surface of calcium phosphate are directly The calcium phosphate complex is formed by chemical bonding.

  Here, the manufacturing method of the calcium phosphate composite concerning this Embodiment is demonstrated. The formation process and the separation process are the same as those described above, and detailed description thereof is omitted.

(Introduction process)
In the case of a calcium phosphate composite in which a calcium phosphate sintered body and a base material are bonded by ionic interaction, the functional group itself can be ionized by an ionization step described later.

  Here, a method of reacting a functional group-containing compound having a functional group with the substrate will be described as one method for introducing a functional group into the substrate. In addition, the method of introduce | transducing a functional group into a base material is not limited to this method, A various method is employable. In the following explanation, silk fibroin is used as a substrate, and the functional group (ionic functional group) is a carboxyl group (including a dicarboxyl group).

  The functional group-containing compound having a functional group is not particularly limited as long as it is a compound having a carboxyl group at the terminal, but a compound having a carboxyl group and a reactive group capable of reacting with a substrate is preferably used. used. Specific examples of the functional group-containing compound include 4-methacryloxyethyl trimellitate anhydride (hereinafter referred to as 4-META), succinic acid, succinic anhydride, and acrylic. An acid etc. are mentioned.

  Of the functional group-containing compounds exemplified above, 4-META is more preferably used because it is already commonly used as a dental material and can be suitably used as a medical material.

  And a functional group is introduce | transduced into the surface of a base material by making these functional group containing compounds and a base material react. Specifically, by using a surfactant and a peroxide-based initiator to extract protons (hydrogen atoms) from the substrate and generating radicals, the functional group-containing compound is directly grafted onto the substrate. Can be made. By using this method, the functional group can be directly introduced into the substrate. This reaction will be described below.

  Specific examples of the surfactant include pentaethylene glycol dodecyl ether, hexaethylene glycol monododecyl ether, nonylphenyl polyethylene, polyoxyethylene (10) octylphenyl ether, dodecyl-β-glucoside, and the like. .

  Specific examples of the peroxide initiator include ammonium peroxodisulfate and potassium persulfate (potassium peroxodisulfate).

  And a functional group can be introduce | transduced into a base material by adding the said base material, surfactant, a peroxide type initiator, and a functional group containing compound to a polymerization solvent, and making it polymerize.

  Specific examples of the polymerization solvent include water, methanol, dimethylformamide, and dimethyl sulfoxide. Of the polymerization solvents exemplified above, water is more preferable from the viewpoint of economics and safety when used as a medical material.

  The lower limit of the addition amount of the functional group-containing compound in the reaction system is more preferably 10% by weight or more, further preferably 50% by weight or more, and particularly preferably 100% by weight or more based on the base material. If the amount added is less than 10% by weight, a sufficient amount of functional groups may not be introduced into the substrate. On the other hand, the upper limit value of the addition amount is more preferably 500% by weight or less, still more preferably 400% by weight or less, and particularly preferably 300% by weight or less based on the base material. When the added amount is more than 500% by weight, it is not economical.

  Moreover, as a lower limit of superposition | polymerization temperature, 30 degreeC or more is more preferable, 35 degreeC or more is further more preferable, and 40 degreeC or more is especially preferable. If the polymerization temperature is lower than 30 ° C., the polymerization does not occur sufficiently and the functional group may not be introduced into the substrate. On the other hand, the upper limit of the polymerization temperature is more preferably 80 ° C. or less, further preferably 75 ° C. or less, and particularly preferably 70 ° C. or less. When the polymerization temperature is higher than 80 ° C., the introduction of the functional group proceeds so much that the substrate may be deteriorated. In addition, the substrate may be deteriorated. In addition, although superposition | polymerization time changes with superposition | polymerization temperature etc., what is necessary is just to set suitably so that it may become a desired introduction rate (ratio in which a functional group is introduce | transduced into a base material). By polymerizing under the above conditions, a functional group can be easily introduced into the substrate.

  Moreover, as a lower limit of the introduction ratio (% by weight) of the functional group with respect to the substrate, 0.1% by weight or more is more preferable, and 1.0% by weight or more is more preferable. Here, the introduction rate is the ratio of the weight of the functional group-containing compound introduced per unit weight of the substrate. If the introduction ratio is 0.1% by weight or more, a sufficient amount of calcium phosphate sintered body capable of expressing biocompatibility can be bonded to the substrate. On the other hand, the upper limit of the introduction rate is not particularly limited. However, if the introduction rate is higher than 100% by weight, the amount of the calcium phosphate sintered body bonded to the base material becomes excessive, which is economical. It may not be.

  The polymerization is more preferably performed in a nitrogen atmosphere. In this way, functional groups can be introduced on the surface of the substrate.

  For example, when succinic acid is used as the functional group-containing compound, a carboxyl group can be introduced onto the surface of the base material by refluxing the base material and succinic acid in a reflux solvent, for example. it can. Specific examples of the reflux solvent include polar solvents such as dehydrated dimethylformamide and dimethyl sulfoxide. In this case, the use ratio of succinic acid to the substrate is the same as described above.

  And when bonding a calcium-phosphate sintered compact and a base material by an ionic interaction, it is necessary to perform the ionization process which ionizes the introduce | transduced functional group. This ionization step may be performed after a separation step described later, or may be performed after the introduction step (before the separation step). The ionization process will be described below.

  In the ionization step, the functional group introduced into the substrate is ionized. Specifically, for example, the functional group can be ionized by subjecting the base material into which the functional group has been introduced to an alkali treatment or an acid treatment.

  When the said functional group is a carboxyl group, a carboxyl group can be ionized by immersing the base material which has this carboxyl group in alkaline solutions, such as potassium hydroxide, for example.

  That is, an acidic functional group can be obtained by treating the functional group with an alkali. On the other hand, the functional group can be converted to a basic functional group by acid treatment.

  When performing the alkali treatment, for example, it is more preferable to use a strongly basic aqueous solution such as potassium hydroxide or lithium hydroxide. On the other hand, when acid treatment is performed, it is more preferable to use a strongly acidic aqueous solution such as hydrochloric acid, sulfuric acid, and perchloric acid. Thus, the functional group of a base material can be ionized by performing an ionization process. That is, an ionic functional group can be present on the surface of the substrate.

(Reaction process)
In the reaction step, the ionic functional group ionized by the ionization step is reacted with ions present on the surface of the hydroxyapatite sintered body. Specifically, the hydroxyapatite sintered body is adsorbed on the surface of the base material by immersing the base material in a dispersion in which the hydroxyapatite sintered body is dispersed. Then, ions (calcium ions) present on the surface of the hydroxyapatite sintered body adsorbed on the surface are reacted with the ionic functional groups (—COO ⁻ ).

  Specific examples of the dispersion medium for dispersing the hydroxyapatite sintered body include, for example, water or hydrocarbon solvents such as toluene and hexane; alcohols; ether solvents such as tetrahydrofuran and diethyl ether; acetone, Organic solvents such as ketone solvents such as methyl ethyl ketone; Among the above-exemplified solvents, alcohols are preferably used in that the hydroxyapatite sintered body is well dispersed. Among the above-exemplified dispersion media, when the obtained calcium phosphate complex is used as a medical material, alcohols are more preferable, and a mixed solvent of alcohols and toluene is particularly preferable in order to obtain higher dispersibility. . The amount of the hydroxyapatite sintered body added in the preparation of the dispersion is the same as described above, and a detailed description thereof is omitted.

  In this reaction step, the reaction temperature for bonding the ionic functional group and the hydroxyapatite sintered body is not particularly limited, and can be performed at room temperature. That is, in this Embodiment, both are couple | bonded by ionic interaction and both can be couple | bonded more easily compared with the past.

  Moreover, what is necessary is just to change suitably the reaction conditions of the said introduction | transduction process, an ionization process, and a reaction process, the kind of solvent, etc. according to the kind of base material and the kind of functional group.

  In the above description, an example in which a hydroxyapatite sintered body is used as the calcium phosphate sintered body is described. However, the present invention is not limited to the above. For example, as the calcium phosphate sintered body, β-calcium triphosphate, etc. Even in the case of using a calcium phosphate complex, it can be suitably produced by using the above production method.

Moreover, in said description, although the carboxyl group containing compound is demonstrated as a functional group containing compound, as a functional group, it is not limited to a carboxyl group. Specific examples of the functional group-containing compound having another functional group include compounds having a functional group such as —SO ₃ ⁻ , —SO ₂ ⁻ , and —O ⁻ . R ₂ NC (S) ₂ ⁻ , NH ₃ ⁺ , pyridine, ⁺ H ₃ N—CH ₂ —CH ₂ —NH ₃ ^{+ and the} like. The functional group-containing compound may be appropriately selected depending on the type of substrate. In the above R ₂ NC (S) ₂ ^— , R represents an alkyl group.

<3. Complex formed by chemical bonding of titanium oxide and polymer substrate>
Below, the composite_body | complex (henceforth a titanium oxide composite) formed by a titanium oxide and a base material chemically bonding is demonstrated.

  The titanium oxide composite according to this embodiment has a structure in which titanium oxide is chemically bonded to a base material. More specifically, a titanium oxide composite comprising a substrate having an active group and titanium oxide having a reactive functional group capable of reacting with the active group, wherein the active group and the reactive functional group are chemically This is a combined configuration.

(Titanium oxide)
The titanium oxide according to the present embodiment is, for example, a compound represented by the chemical formula: TiO ₂ or the like, and has a hydroxyl group on the surface of this compound. That is, the titanium oxide according to the present embodiment refers to titanium oxide having a hydroxyl group on the surface.

Specifically, in the case of TiO ₂ , there are two kinds of hydroxyl groups on the crystal plane that occupies the most surface of titanium oxide, that is, the anatase type (001) plane and the rutile type (110) plane. Is present. One is a terminal OH group bonded to Ti ⁴⁺ , and the other is a bridged OH group bonded to two Ti ⁴⁺ (by Kiyono Manabu, titanium oxide properties and applications). , Technical Hall Publishing, 2000).

  The titanium oxide according to the present embodiment is suitable as a medical material because of its excellent affinity with living tissue and stability in the living environment.

  The titanium oxide is more preferably particulate. In the case of particles, the shape and particle diameter of the titanium oxide particles should be such that the titanium oxide and the substrate described later are chemically bonded to each other so that they can be fixed to the surface of the substrate. That's fine. Specifically, the lower limit of the particle diameter is more preferably 0.001 μm or more, and further preferably 0.01 μm or more. On the other hand, the upper limit of the particle diameter is more preferably 1000 μm or less, and even more preferably 100 μm or less. When the particle diameter is larger than 1000 μm or smaller than 0.001 μm, the bond between titanium oxide and the polymer base material described later becomes relatively weak, and when it is embedded in a living body, the titanium oxide composite Your body may be damaged.

(Base material)
As the substrate according to the present embodiment, a polymer substrate is preferable, a medical polymer material is more preferable, and an organic polymer is further preferable. Specific examples of the base material include silicone polymer (which may be silicone rubber), polyethylene glycol, polyalkylene glycol, polyglycolic acid, polylactic acid, polyamide, polyurethane, polysulfone, polyether, and poly Synthetic polymers such as ether ketone, polyamine, polyurea, polyimide, polyester, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid, polymethacrylic acid, polymethyl methacrylate, polyacrylonitrile, polystyrene, polyvinyl alcohol, polyvinyl chloride; Polysaccharides such as cellulose, amylose, amylopectin, chitin and chitosan, polypeptides such as collagen, mucopolysaccharides such as hyaluronic acid and chondroitin, natural such as silk fibroin Molecule, and the like. Of the above-exemplified base materials, silicone polymer, polyurethane, polytetrafluoroethylene, or silk fibroin is preferably used because it has excellent properties such as long-term stability, strength, and flexibility.

  Further, instead of the above-exemplified base materials, specifically, for example, a base material of an inorganic material such as a titanium alloy that can be suitably used as a medical material can be used. Therefore, the base material according to the present embodiment includes a base material made of an inorganic material such as the titanium alloy.

  In addition, the shape of the polymer substrate may be, for example, a sheet shape, a fiber shape, a tube shape, or a porous body, and may be appropriately selected depending on the application.

(Method for producing titanium oxide composite)
Here, the manufacturing method of the titanium oxide composite concerning this Embodiment is demonstrated.

  The manufacturing method of the titanium oxide composite according to the present embodiment is roughly divided into two methods. That is, (1) the surface of the substrate and / or titanium oxide is modified and then both are chemically bonded. (2) Both the titanium oxide and the substrate are chemically bonded without surface treatment.

  In the present embodiment, among the methods of (1) above, titanium oxide is a method for producing a titanium oxide composite formed by chemically bonding to a base material, and an active group introduction for introducing an active group into the base material is performed. A method including a step, a reactive functional group introduction step of introducing a reactive functional group capable of reacting with the active group into titanium oxide, and a reaction step of reacting the active group with the reactive functional group will be described.

  More specifically, for example, as a base material having an active group, a silicone rubber obtained by graft polymerization of a vinyl polymerizable monomer having a carboxyl group on the surface, and a titanium oxide having a reactive functional group introduced on the surface are used. An example of producing a titanium oxide composite according to the present embodiment by using titanium oxide introduced with amino groups as particles and reacting both will be described.

  That is, by reacting the active group with the reactive functional group, a chemical bond for bonding the titanium oxide and the base material is formed.

  The chemical bond possessed by the titanium oxide composite according to the present embodiment, that is, the chemical bond that binds the titanium oxide and the base material, as long as the bond strength between the titanium oxide and the base material is sufficiently obtained. Although not particularly limited, the chemical bonds shown below can be given as an example.

  These chemical bonds are obtained by a reaction between a reactive functional group introduced into titanium oxide and an active group introduced into the substrate.

  Hereinafter, the amide group represented by the chemical formula (3) among the above exemplified chemical bonds will be specifically described. The amide bond is a reaction between an amino group and a carboxyl group, an azidocarbonyl group, a chlorocarbonyl group, an N-hydroxysuccinimide carboxylate and / or an acid anhydride; a carboxyl group and an N-acetylamino group and / or N- It can be obtained by a reaction with a trimethylsilylamino group; a reaction between an isocyanate group and a carboxyl group; Appropriate reaction conditions vary depending on each combination, and the reaction conditions are not particularly limited as long as the reaction proceeds.

  For example, in the case of a combination of an amino group and a carboxyl group, first, titanium oxide is added to a solvent and stirred to disperse the titanium oxide, and then the substrate is immersed in the titanium oxide. And after raising the said base material from a solvent, it wash | cleans and reacts (condensation reaction) the active group which a base material has, and the reactive functional group which a titanium oxide has on specific reaction conditions.

  At this time, the lower limit of the amount of titanium oxide used is more preferably 0.001 part by weight or more, and still more preferably 0.01 part by weight or more with respect to 1 part by weight of the base material having an active group. On the other hand, the upper limit of the amount of titanium oxide used is more preferably 100 parts by weight or less, and still more preferably 50 parts by weight or less with respect to 1 part by weight of the base material having an active group. If the lower limit is less than 0.001 part by weight, the titanium oxide particles may not be uniformly adsorbed on the surface of the substrate, and a uniform coating surface may not be formed. On the other hand, when the upper limit is more than 100 parts by weight, it is not economical.

  Specific examples of the solvent for dispersing titanium oxide include water; hydrocarbon solvents such as toluene and hexane; alcohols; ether solvents such as tetrahydrofuran and diethyl ether; ketones such as acetone and methyl ethyl ketone. Solvent; and the like. As a lower limit of the usage-amount of the said solvent, 0.1 weight part or more is more preferable with respect to 1 weight part of said base materials, and 1.0 weight part or more is further more preferable. When the lower limit is less than 0.1 parts by weight, the titanium oxide particles may not be uniformly adsorbed on the surface of the substrate, and a uniform coating surface may not be formed. On the other hand, as an upper limit of the usage-amount of the said solvent, 1000 weight part or less is more preferable with respect to 1 weight part of said base materials, and 500 weight part or less is still more preferable. When the upper limit is more than 1000 parts by weight, it is not economical.

  And after raising a base material from a solvent, as a lower limit of the reaction temperature made to react with the active functional group which a base material has, and the reactive functional group which a titanium oxide has, 120 degreeC or more is more preferable, and 140 degreeC or more is more preferable 160 ° C. or higher is particularly preferable. When the said reaction temperature is lower than 120 degreeC, there exists a possibility that a condensation reaction may not fully advance. On the other hand, the upper limit of the reaction temperature is more preferably 200 ° C. or less, and further preferably 180 ° C. or less. When the said reaction temperature is higher than 200 degreeC, a base material may deteriorate.

  The condensation reaction is more preferably performed under reduced pressure. The lower limit of the degree of vacuum is more preferably 0.01 mmHg (1.33 Pa) or more, and further preferably 0.1 mmHg or more. When the lower limit of the degree of decompression is lower than 0.01 mmHg, it is not economical in terms of equipment such as an apparatus. On the other hand, the upper limit of the degree of vacuum is more preferably 10 mmHg (1.33 kPa) or less, and further preferably 5.0 mmHg or less. When the upper limit of the degree of decompression is higher than 10 mmHg, the condensation reaction hardly occurs and the reaction time becomes long. Moreover, when forming an amide bond with an amino group and a carboxyl group, it can be synthesized at a low temperature by using a condensing agent such as carbodiimide. Specifically, for example, the amide bond is formed by reacting at 4 ° C. to room temperature (25 ° C.) for 1 to 6 hours.

  In addition, the ester bond represented by the chemical formula (4) is obtained by a reaction of a carboxyl group with a hydroxyl group, a diazocarbonyl group and / or a diazoalkyl group. Appropriate reaction conditions vary depending on the combination and are not particularly limited. Specifically, for example, in the case of a combination of a carboxyl group and a hydroxyl group, a method of reacting a carboxyl group and a hydroxyl group in an organic solvent can be mentioned.

  The urea bond represented by the chemical formula (5) is obtained by reacting an amino group with an isocyanate group. The reaction conditions are not particularly limited, and examples thereof include a method of reacting an amino group and an isocyanate group in an organic solvent at room temperature.

  The thiourea bond represented by the chemical formula (6) can be obtained by reacting an amino group and an isothiocyanate group. The reaction conditions are not particularly limited. For example, a method of reacting an amino group and an isothiocyanate group in a sodium carbonate buffer solution at pH 9 within a temperature range of 0 ° C. to room temperature for 1 to 24 hours. Etc.

  The β-ketothioether bond represented by the chemical formula (7) is obtained by reaction of a mercapto group and an α-haloacetyl group. Although it does not specifically limit as reaction conditions, For example, the method etc. with which a mercapto group and (alpha) -haloacetyl group are made to react on the conditions of the weak alkali of water, room temperature, and pH 7-8 are mentioned.

  The Schiff base structure represented by the chemical formula (8) can be obtained by reacting an amino group with a moiety that can function as an aldehyde or a ketone. The reaction conditions include, for example, a method of reacting both at room temperature in an alkaline aqueous solution. Further, by reducing the above Schiff base structure using a known reducing agent such as sodium borohydride or sodium cyanoborohydride, the secondary or tertiary amine structure represented by the chemical formula (9) can be obtained. Obtainable.

  The sulfamide bond represented by the chemical formula (10) can be obtained by reacting an amino group with a sulfonyl chloride group and / or a sulfonic group. Appropriate reaction conditions vary depending on the combination and are not particularly limited.Specifically, for example, in the case of a combination of an amino group and a sulfonyl group, (1) an amino group at room temperature in an organic solvent. And (2) a method of reacting in water under alkaline conditions of pH 9-10.

  The hydroxy-secondary amine structure represented by the chemical formula (11) is obtained by a reaction between an amino group and an epoxy group. There are no particular limitations on the reaction conditions, and examples include a method of reacting in water at room temperature and pH 8-10.

  The carbamate bond represented by the chemical formula (12) can be obtained by reaction of a hydroxyl group with an isocyanate group and / or a carbonic acid diester. Appropriate reaction conditions vary depending on the combination and are not particularly limited. For example, in the case of a combination of a hydroxyl group and an isocyanate group, there is a method of reacting a hydroxyl group and an isocyanate group in a toluene solvent under reflux.

The arylamine structure represented by the chemical formula (13) is obtained by reacting an amino group with a halogenated aryl group and / or a sulfonated aryl group. Appropriate reaction conditions vary depending on the combination and are not particularly limited. Specifically, for example, in the case of an amino group and an aryl halide group, the amino group and There is a method of reacting with a halogenated aryl group. Ar ¹ in the chemical formula (13) represents an aryl group.

The aryl thioether bond represented by the chemical formula (14) is obtained by reacting a mercapto group with a halogenated aryl group and / or a sulfonated aryl group. Appropriate reaction conditions vary depending on the combination and are not particularly limited. Specifically, for example, in the case of a mercapto group and an aryl halide group, piperidine is catalyzed at 0 ° C. in a methanol solvent. And a method of reacting a mercapto group and a halogenated aryl group. In the chemical formula (14), Ar ² represents an aryl group.

  The sulfide bond represented by the chemical formula (15) is obtained by an exchange reaction between a mercapto group and a sulfide bond. Appropriate reaction conditions are not particularly limited and include, for example, a method of reacting a mercapto group with a sulfide bond at room temperature in an aqueous solution of pH 7-8.

  The thioether bond represented by the chemical formula (16) is obtained by reaction of a mercapto group with an acryloyl group and / or maleic imide. Appropriate reaction conditions vary depending on the combination and are not particularly limited. Specifically, for example, in the case of a mercapto group and an acryloyl group, in a neutral to alkaline solution, the mercapto group and acryloyl There is a method of reacting with a group.

  The β-aminothioether bond represented by the chemical formula (17) is obtained by reaction of a mercapto group with aziridine and / or imine. Appropriate reaction conditions vary depending on the combination and are not particularly limited. Specifically, for example, in the case of a mercapto group and an aziridine group, a method of reacting in an aqueous solution under weak alkaline conditions, etc. There is.

The vinyl bond represented by the chemical formula (18) is obtained by a vinyl polymerization reaction or the like. Appropriate reaction conditions differ depending on the combination, and are not particularly limited. Specifically, for example, for the TiO ₂ particles (titanium oxide particles) into which vinyl groups are introduced, the vinyl from the substrate is used. There is a method of bonding the two by graft polymerization of the base compound.

  These chemical bonds are obtained by a reaction between reactive functional groups on the titanium oxide particle surface and active groups on the substrate surface. Therefore, it is sufficient that one of the combinations exemplified above is a reactive functional group and the other is an active group. Specifically, for example, when an amide bond as shown in chemical formula (3) is obtained by a reaction between an amino group and a carboxyl group, the amino group may be the above active group, or a reactive functional group. It may be. Similarly, the carboxyl group may be a reactive functional group or an active group.

(Active group introduction process)
Here, the step of introducing an active group into the substrate (active group introduction step) will be described.

  As a method for introducing an active group into a substrate, for example, the surface of the substrate is introduced by, for example, acid / alkali treatment, corona discharge and / or plasma irradiation, and then performing a surface graft polymerization method or the like. And the like.

  Here, an example of a method for introducing an active group in the case of using a surface graft polymerization method and a polydimethylcyclohexane-based silicone rubber as a substrate will be described.

  When introducing an active group into a polydimethylsiloxane silicone rubber as a base material by graft polymerization, first, the surface of the base material is treated by corona treatment or plasma irradiation, and then the treated base material and the polymerizable single polymer are polymerized. The polymer is charged into a solvent and polymerized under an inert gas atmosphere and under reduced pressure.

  Examples of the solvent include water; hydrocarbon solvents such as toluene and hexane; alcohols; ether solvents such as tetrahydrofuran and diethyl ether; ketone solvents such as acetone and methyl ethyl ketone; As a lower limit of the usage-amount of the said solvent, 0.1 weight part or more is more preferable with respect to 1 weight part of the said processed base materials, and 1.0 weight part or more is further more preferable. When the amount of the solvent used is less than 0.1 parts by weight, it becomes difficult to uniformly introduce the active groups on the surface of the substrate. On the other hand, the upper limit of the amount of the solvent used is preferably 1000 parts by weight or less, more preferably 500 parts by weight or less, with respect to 1 part by weight of the treated base material. When the usage-amount of the said solvent is more than 1000 weight part, it is not economical.

  In addition, the polymerizable monomer used for the graft polymerization particularly has an active group at the terminal (or side chain) that reacts with a reactive functional group on the surface of the titanium oxide particles to form a chemical bond. It is not limited. In other words, the polymerizable monomer has, for example, an active group for forming a chemical bond represented by the chemical formulas (3) to (18). Specific examples of the polymerizable monomer include (meth) acrylic acid, aconitic acid, itaconic acid, mesaconic acid, citraconic acid, fumaric acid, maleic acid, vinyl sulfonic acid, and acrylamido-2-methylpropane. Sulfonic acid, vinyl sulfonic acid, and various metal salts or halides thereof; (meth) acrylamide, 2-hydroxyethyl (meth) acrylate, monoglycerol (meth) acrylate, N- [tris (hydroxymethyl) methyl] Acrylamide, N-vinylpyrrolidone, N- (meth) acryloylpyrrolidone, acryloylmorpholine, maleic imide, maleic anhydride; styrene monomers such as aminostyrene and carboxystyrene; glycidyl (meth) acrylate, (meth) acryloyloxy Ethyltri Tokishishiran, and vinyl benzyl amine and the like.

  As a lower limit of the addition amount of the polymerizable monomer, 0.001 part by weight or more is more preferable, and 0.01 part by weight or more is more preferable with respect to 1 part by weight of titanium oxide particles. When the addition amount of the polymerizable monomer is less than 0.001 part by weight, it becomes difficult to introduce a sufficient amount of active groups on the surface of the substrate. On the other hand, as an upper limit of the addition amount of the polymerizable monomer, 100 parts by weight or less is more preferable, and 50 parts by weight or less is more preferable with respect to 1 part by weight of the titanium oxide particles. When the addition amount of the polymerizable monomer is more than 100 parts by weight, it is not economical.

  Moreover, as a lower limit of the polymerization temperature which superposes | polymerizes the said base material and a polymerizable monomer, 40 degreeC or more is more preferable, and 50 degreeC or more is further more preferable. When the polymerization temperature is lower than 40 ° C., graft polymerization may not be sufficiently performed. On the other hand, the upper limit of the polymerization temperature is more preferably 100 ° C. or less, and further preferably 80 ° C. or less. When the polymerization temperature is higher than 100 ° C., the graft efficiency may decrease.

  In order to introduce, for example, a vinyl group as an active group into the base material, the base material and the active group-containing compound may be reacted in a mixed solution of a catalyst, a polymerization inhibitor and a solvent.

  Specific examples of the active group-containing compound include 2-methacryloyloxyethyl isocyanate and hexamethylene diisocyanate. The solvent is preferably a polar solvent, and for example, dehydrated dimethyl sulfoxide, dehydrated dimethylformamide and the like are preferably used. The polymerization inhibitor is added so that active groups introduced into the base material and active group-containing compounds do not polymerize. Examples of the polymerization inhibitor include hydroquinone. Examples of the catalyst include dibutyltin (IV) dilaurate.

  The lower limit of the amount of the active group-containing compound added is preferably 10% by weight or more, more preferably 50% by weight or more, and particularly preferably 100% by weight or more based on the base material. If the amount added is less than 10% by weight, a sufficient amount of active groups may not be introduced into the substrate. On the other hand, the upper limit value of the addition amount is more preferably 500% by weight or less, still more preferably 400% by weight or less, and particularly preferably 300% by weight or less based on the base material. When the added amount is more than 500% by weight, it is not economical.

  And as a lower limit of reaction temperature, 30 degreeC or more is more preferable, 40 degreeC or more is further more preferable, and 45 degreeC or more is especially preferable. If the said reaction temperature is lower than 30 degreeC, reaction may not fully occur and an active group may not be introduce | transduced into a base material. On the other hand, as an upper limit of reaction temperature, 100 degrees C or less is more preferable, 80 degrees C or less is further more preferable, and 60 degrees C or less is especially preferable. When the reaction temperature is higher than 100 ° C, the active groups introduced into the substrate may react with each other. In addition, the substrate may be deteriorated. In addition, what is necessary is just to set reaction time suitably by reaction temperature etc. By making it react on the above conditions, an active group can be easily introduce | transduced into a base material.

  The lower limit of the active group introduction rate (% by weight) relative to the substrate is more preferably 0.1% by weight or more, still more preferably 1.0% by weight or more, and particularly preferably 2.0% by weight or more. When the introduction rate is less than 0.1% by weight, the number of alkoxysilyl groups introduced into the substrate is reduced, and there is a possibility that the titanium oxide composite cannot be produced. On the other hand, the upper limit of the introduction rate is more preferably 30% by weight or less, further preferably 25% by weight or less, and particularly preferably 20% by weight or less. When the introduction ratio is more than 30% by weight, the number of active groups introduced into the substrate increases, and the active groups may react with each other.

  The active group may be an active group possessed by the polymer on the surface of the substrate.

(Reactive functional group introduction process)
The step of introducing a reactive functional group into the titanium oxide (reactive functional group introduction step) will be described below. As a method for introducing a reactive functional group into titanium oxide, specifically, for example, a silane coupling agent having a reactive functional group may be reacted with titanium oxide.

  Here, the silane coupling agent will be described. The silane coupling agent has a chemical structure as shown in chemical formula (19).

Z-Si- (OR) ₃ (19)
The Z may be any reactive functional group that can chemically bond with organic materials (base materials or active groups possessed by the base materials) such as various synthetic resins. Specifically, for example, vinyl groups, epoxy groups, and the like. , Amino groups, (meth) acryloxy groups, mercapto groups, and the like groups that can form chemical bonds represented by the above chemical formulas (3) to (18). That is, the silane coupling agent used in the present embodiment has at least a reactive functional group. The Si— (OR) ₃ may be any functional group that can be chemically bonded to titanium oxide. Specifically, examples of the OR include a methoxy group and an ethoxy group. In addition, the reactive functional group Z and Si in the chemical formula (19) may be bonded with a high molecular chain, may be bonded with a low molecular chain, or may be directly bonded.

  That is, as the silane coupling agent, specifically, for example, vinyl silane coupling agents such as vinyltrichlorosilane, vinyltrimethoxysilane, vinyltriethoxysilane; β- (3,4 epoxycyclohexyl) ethyltri Epoxy silane coupling agents such as methoxysilane, γ-glycidoxypropyltrimethoxysilane, γ-glycidoxypropylmethyldiethoxysilane, γ-glycidoxypropyltriethoxysilane; p-styryltrimethoxysilane, etc. Stylyl-based silane coupling agents; methacrylic compounds such as γ-methacryloxypropylmethyldimethoxysilane, γ-methacryloxypropyltrimethoxysilane, γ-methacryloxypropylmethyldiethoxysilane, γ-methacryloxypropyltriethoxysilane Roxy-based silane coupling agents; acryloxy-based silane coupling agents such as γ-acryloxypropyltrimethoxysilane; N-β (aminoethyl) γ-aminopropyltrimethoxysilane, N-β (aminoethyl) γ-aminopropyl Methyldimethoxymethoxysilane, N-β (aminoethyl) γ-aminopropyltriethoxysilane, γ-aminopropyltrimethoxysilane, γ-aminopropyltriethoxysilane, γ-triethoxy-N- (1,3-dimethyl-butylidene ) Amino-based silane coupling agents such as propylamine, N-phenyl-γ-aminopropyltrimethoxysilane, N- (vinylbenzyl) -β-aminoethyl-γ-aminopropyltrimethoxysilane hydrochloride, special aminosilane; γ-ureidopropyltriethoxysila Ureido silane coupling agents such as chlorosilanes; Chloropropyl silane coupling agents such as γ-chloropropyltrimethoxysilane; Mercapto silane coupling agents such as γ-mercaptopropyltrimethoxysilane and γ-mercaptopropylmethyldimethoxysilane A sulfide-based silane coupling agent such as bis (triethoxypropyl) tetrasulfide; an isocyanate-based silane coupling agent such as γ-isocyanatopropyltriethoxysilane; Of the above-exemplified silane coupling agents, γ-methacryloxypropyltrimethoxysilane is more preferable because it is a polymerizable monomer. What is necessary is just to select the said silane coupling agent suitably by the kind of base material, the kind of active group which a base material has, etc.

  As described above, since the silane coupling agent has a reactive functional group at one end and a functional group at the other end, it can be suitably used. In addition, the said reactive functional group can react with an active group. Moreover, a functional group is a thing which can react with a titanium oxide. In the following description, an example in which an active group is introduced into titanium oxide using a silane coupling agent will be described.

  The reaction conditions for reacting the silane coupling agent having a reactive functional group with titanium oxide vary depending on the type of reaction, the type of silane coupling agent used, and the like, and are not particularly limited. Moreover, as a kind of said reaction, a dry method, a wet method, etc. are suitable, for example.

  In the case of the dry method, titanium oxide particles are put into a high-speed stirrer, and a silane coupling agent having a functional group at one end and a reactive functional group at the other end is added dropwise or by spraying. It is made to dry after stirring uniformly. At this time, the addition amount of the silane coupling agent is more preferably in the range of 0.0001 to 10 parts by weight with respect to 1 part by weight of the titanium oxide particles.

  On the other hand, in the case of a wet method, titanium oxide particles and a silane coupling agent are added to an organic solvent, and the mixture is allowed to react for 10 minutes to 10 days in a temperature range of room temperature to 150 ° C. with stirring. After that, the solvent and unreacted silane coupling agent are removed and dried.

  Examples of the organic solvent used here include hydrocarbon solvents such as toluene and hexane; ether solvents such as tetrahydrofuran and diethyl ether; ketone solvents such as acetone and methyl ethyl ketone; The lower limit of the amount of the organic solvent used is preferably 0.1 parts by weight or more, more preferably 0.5 parts by weight or more with respect to 1 part by weight of titanium oxide particles (titanium oxide particles). When the amount of the organic solvent used is less than 0.1 parts by weight, the reaction system is difficult to be uniform, and the surface of the titanium oxide particles may not be uniformly modified. On the other hand, as an upper limit of the usage-amount of the said organic solvent, 1000 weight part or less is more preferable with respect to 1 weight part of titanium oxide particles, and 50 weight part or less is further more preferable. When the usage-amount of the said organic solvent is more than 1000 weight part, it is not economical.

  The lower limit of the addition amount of the silane coupling agent is more preferably 0.0001 part by weight or more and further preferably 0.001 part by weight or more with respect to 1 part by weight of the titanium oxide particles. When the addition amount of the silane coupling agent is less than 0.0001 parts by weight, the amount of the reactive functional group introduced into the surface of the titanium oxide particles may not be sufficient. On the other hand, the upper limit of the addition amount of the silane coupling agent is more preferably 10 parts by weight or less, and still more preferably 5 parts by weight or less with respect to 1 part by weight of the titanium oxide particles. When the addition amount of the silane coupling agent is more than 10 parts by weight, it is not economical. This reason is the same in the case of the dry method.

  Moreover, as a lower limit of reaction temperature, room temperature (25 degreeC) or more is more preferable. When the reaction temperature is lower than room temperature, the reaction may take a long time. On the other hand, as an upper limit of reaction temperature, 150 degrees C or less is more preferable, and 100 degrees C or less is further more preferable. When the reaction temperature is higher than 150 ° C., the reactive functional group and / or the functional group at the terminal of the silane coupling agent may cause an undesirable side reaction.

  Moreover, in order to maintain the photocatalytic activity of the titanium oxide into which the reactive functional group is introduced by the reactive functional group introduction step, the reaction temperature is preferably about 80 ° C.

(Reaction process)
In the reaction step, the active group introduced into the substrate by the active group introduction step is reacted with the reactive functional group introduced into the titanium oxide by the reactive functional group introduction step. Specifically, titanium oxide is adsorbed on the surface of the substrate by immersing the substrate in a dispersion in which the titanium oxide is dispersed. Then, the reactive functional group and the active group are reacted. In the following description, an example will be described in which silicone rubber is used as the base material and the base material and titanium oxide are bonded by an amide bond.

  Specific examples of the dispersion medium for dispersing the titanium oxide include water; hydrocarbon solvents such as toluene and hexane; alcohols; ether solvents such as tetrahydrofuran and diethyl ether; ketones such as acetone and methyl ethyl ketone. Organic solvents such as solvents; and the like. Of the above-exemplified solvents, water and alcohols are preferably used in that titanium oxide is well dispersed. Also, for example, when using a hydrocarbon solvent such as hexane or toluene, in order to disperse titanium oxide satisfactorily, for example, (1) stirring strongly with a stirrer such as a stirrer, (2) ultrasonic device (3) The above stirring device and ultrasonic device may be used in combination.

  In the preparation of the dispersion, the lower limit of the amount of titanium oxide added is preferably 0.1% by weight or more, more preferably 0.2% by weight or more, and more preferably 0.5% by weight with respect to the dispersion medium. The above is particularly preferable. If the amount of titanium oxide added is less than 0.1% by weight, titanium oxide may not be uniformly adsorbed on the surface of the base material, and a uniform coated surface may not be formed. On the other hand, the upper limit of the amount of titanium oxide added is more preferably 5.0% by weight or less, still more preferably 4.0% by weight or less, and particularly preferably 3.0% by weight or less with respect to the dispersion medium. . When the amount added is more than 5.0% by weight, the amount of titanium oxide remaining in the dispersion is remarkably larger than the amount of titanium oxide adsorbed on the surface of the substrate, which is not economical.

  The lower limit of the reaction temperature for reacting the reactive functional group of titanium oxide adsorbed on the surface of the substrate with the active group is more preferably 25 ° C. or more, further preferably 50 ° C. or more, and particularly preferably 80 ° C. or more. preferable. When the reaction temperature is lower than 25 ° C., the reactive functional group and the active group may not react. On the other hand, the upper limit of the reaction temperature is more preferably 200 ° C. or less, further preferably 175 ° C. or less, and particularly preferably 150 ° C. or less. When the said reaction temperature is higher than 200 degreeC, a base material may decompose | disassemble.

  In addition, it is more preferable that the substrate is washed with the same solvent as the dispersion medium before the reaction is performed after the substrate is immersed in the dispersion. Titanium oxide is laminated on the surface of the base material after the substrate is immersed, and when reacted without washing, the titanium oxide is laminated and remains in a composite state. It may be damaged or the strength may be insufficient.

  Moreover, you may make it react on vacuum conditions as needed. By reacting the reactive functional group of titanium oxide with the active group of the base material under vacuum conditions, the titanium oxide composite can be produced more quickly. In addition, when making it react on vacuum conditions, as a pressure which performs reaction, the inside of the range of 0.01 mmHg (1.33 Pa)-10 mmHg (1.33 kPa) is preferable.

  In addition, what is necessary is just to change suitably the reaction conditions of the said reaction process, the kind of solvent, etc. according to the kind of base material, the reactive functional group, and / or the kind of active group.

(Titanium oxide composite)
In the titanium oxide composite according to the present embodiment obtained by the above manufacturing method, titanium oxide is chemically bonded to the surface of the base material. Specifically, the reactive functional group introduced into titanium oxide and the active group possessed by the substrate are chemically bonded. Thereby, compared with the conventional titanium oxide composite, titanium oxide becomes difficult to peel from a base material. In other words, it becomes possible to fix titanium oxide on the surface of the base material for a long period of time. Therefore, it is possible to provide a titanium oxide composite capable of maintaining the function of titanium oxide for a long period of time.

  Further, the thickness of the titanium oxide layer of the obtained titanium oxide composite varies depending on the thickness of the base material and the application to be used. For example, in the case of a percutaneous catheter application, the thickness of the base material In the range of 0.0001% to 100%, more preferably in the range of 0.001% to 10%. By setting the thickness of the titanium oxide layer in the above range, a titanium oxide composite having excellent biocompatibility can be obtained without impairing the properties of the substrate. The obtained titanium oxide composite has excellent flexibility because titanium oxide is bonded to the surface of the substrate.

  Thus, since the titanium oxide composite according to the present embodiment is excellent in flexibility, strength, adhesion to a living body, and biocompatibility, a percutaneous medical device such as a percutaneous catheter or a percutaneous terminal; It can be suitably used as a medical material for artificial organs such as artificial organs. Moreover, in the manufacturing method according to the present embodiment, it is possible to manufacture a titanium oxide composite having a simpler and more complicated shape than the conventional method.

  Titanium oxide is excellent in bactericidal properties. Specifically, the sterilizing effect can be exhibited by irradiating ultraviolet light photocatalytic titanium oxide with ultraviolet light or visible light in the case of visible light photocatalytic titanium oxide. Therefore, when the titanium oxide composite according to the present embodiment is implanted in a living body as a transdermal device (for example, a catheter), it harms various living bodies that proliferate near the junction of the transdermal device. It is easy to sterilize bacteria and prevent infection by the bacteria. Specifically, sterilization can be easily performed by irradiating the titanium oxide complex with ultraviolet rays from outside the living body. This makes it possible to prevent infection. Therefore, the titanium oxide complex according to the present embodiment is a living body that can suppress in vivo exclusion, for example, when a transdermal device associated with an artificial organ is created or implanted in a living body for a long period of time. It is particularly suitable for medical polymers such as the creation of implant materials in the body, infusion in home treatment, and the creation of biological devices attached to nutrition.

  Moreover, in order to control the activity as a photocatalyst, titanium oxide particles coated with an organic substance or an inorganic substance can also be used for the composite. Examples of the inorganic substance that can be used for the surface coating include hydroxyapatite, and examples of the organic substance include a methacrylate compound, but are not limited thereto.

  In addition, since the titanium oxide complex according to the present embodiment can control the adsorption / desorption of cells by light, it can be applied to a cell dish for culturing regenerative medical cells.

  Titanium oxide can be fixed (fixed) on the surface of the base material for a long time, making it suitable as a deodorant, antibacterial / antifungal material, water treatment material, antifogging material, and antifouling material. Can be used for

  Moreover, the novel surface modification method of the base material by a titanium oxide can be provided.

  Moreover, the above-mentioned calcium phosphate can also be laminated | stacked on the titanium oxide composite concerning this Embodiment as needed, for example. Since calcium phosphate is excellent in biostability as described above, it can be suitably used as a biomaterial by laminating it on the titanium oxide composite according to this embodiment.

  As a method of further laminating calcium phosphate on the titanium oxide, specifically, for example, (1) particles of a mixture comprising a polymerizable monomer and calcium phosphate are mixed with the titanium oxide composite, that is, a substrate. (2) A method of polymerizing a polymerizable monomer by heat, light, radiation, or the like, and then solidifying the titanium oxide composite with calcium ions. A method of precipitating calcium phosphate by immersing it in a solution containing phosphate ions; and (3) alternately immersing the above titanium oxide complex in a solution containing calcium ions and a solution containing phosphate ions. The method of making it precipitate etc. is mentioned. In the case of the method (1), calcium phosphate can be laminated in a desired shape by using a mold having an appropriate shape.

  Next, titanium oxide is a titanium oxide composite formed by chemically bonding to a base material having a functional group capable of chemically bonding with titanium oxide, and the titanium oxide and the functional group are directly chemically bonded. The aspect which becomes will be described.

  The surface of the base material according to the present embodiment has a functional group capable of chemically bonding with the titanium oxide. “Titanium oxide and a functional group capable of reacting with titanium oxide of the substrate are chemically bonded directly” means that titanium oxide and the functional group are directly chemically bonded. is there. That is, in the titanium oxide composite according to the present embodiment, the base material and titanium oxide are chemically bonded. Specific examples of the functional group include at least one functional group selected from the group consisting of an alkoxysilyl group and an isocyanate group. The functional group on the substrate surface may be a functional group possessed by a polymer on the substrate surface, and the substrate surface may be subjected to, for example, acid / alkali treatment, corona discharge, plasma irradiation, surface graft polymerization, etc. It may be introduced by modifying the substrate by a known means.

  In addition, the method for producing a titanium oxide composite according to the present embodiment is a method for producing a titanium oxide composite in which titanium oxide is chemically bonded to a substrate, and the titanium oxide is chemically bonded to titanium oxide. The method includes a functional group reaction step of performing an introduction step of introducing a possible functional group and reacting the functional group of the substrate with the titanium oxide.

(Introduction process)
In the introduction step, a functional group that can be chemically bonded to titanium oxide is introduced into the base material. In the following description, a case where an alkoxysilyl group is introduced as a functional group capable of being chemically bonded to titanium oxide will be described.

  The method for introducing a functional group into the substrate, that is, the introduction step may be performed by a known method, and is not particularly limited. For example, a silane coupling agent having a functional group at the molecular end. Etc. can be used to introduce the functional group into the substrate.

  Here, as one method for introducing an alkoxysilyl group into the substrate, a method for introducing it using a silane coupling agent will be described. In addition, the method of introduce | transducing an alkoxy silyl group into a base material is not limited to this method, A various method is employable.

  As a method of introducing an alkoxysilyl group into a substrate using the silane coupling agent, specifically, for example, a silane coupling agent having a functional group at the terminal is directly applied to a substrate subjected to corona treatment. It may be introduced. In addition, by drawing a proton (hydrogen atom) from the base material using a surfactant and a peroxide-based initiator to generate radicals, the water-insoluble monomer having the above functional group is directly grafted onto the base material. It can be polymerized. By using this method, a functional group capable of chemically bonding with titanium oxide can be directly introduced into the substrate.

  Moreover, as a method for introducing an alkoxysilyl group into a substrate, for example, an active group capable of reacting with the reactive functional group of the silane coupling agent is introduced into the substrate in advance, and this active group is introduced. An alkoxysilyl group may be introduced into the substrate by reacting the silane coupling agent with a reactive functional group of the silane coupling agent. Specific examples of the active group include a vinyl group and an amino group, but are not particularly limited. The reactive functional group of the silane coupling agent (the chemical formula (19) It may be set as appropriate according to the type of Z). Therefore, the silane coupling agent used in the present embodiment only needs to have at least a functional group, and more preferably has a functional group and a reactive functional group. The functional group can be chemically bonded to titanium oxide, and the reactive functional group can be chemically bonded to the active group.

  Here, silk fibroin is used as a base material, a vinyl group which is an active group is introduced into the silk fibroin, and the base group is reacted with the reactive functional group of the silane coupling agent. The specific conditions of the method for introducing an alkoxysilyl group into are described.

  The step of introducing an active group into the substrate is the same as the above-described active group introduction step, and detailed description thereof is omitted.

  Next, an alkoxysilyl group, which is a functional group, is introduced into the base material by polymerizing an active group introduced into the base material and a silane coupling agent having a reactive functional group and a functional group at each end. To do.

  The silane coupling agent is not particularly limited as long as it has a functional group and the reactive functional group at the terminal can be polymerized with the active group introduced into the substrate. However, when a vinyl group is introduced as an active group, for example, γ-methacryloxypropyltrimethoxysilane, which is a methacryloxy silane coupling agent, can be preferably used.

  And the alkoxy silyl group which is a functional group can be introduce | transduced into a base material by polymerizing the base material in which the said silane coupling agent and the active group were introduce | transduced in presence of a polymerization initiator and a solvent.

  As said solvent, nonpolar organic solvents, such as hydrocarbon solvents, such as toluene and hexane, are used suitably.

  As the polymerization initiator, for example, azobisisobutyronitrile, benzoyl peroxide, or the like may be used.

  The lower limit of the amount (addition amount) of the silane coupling agent used is preferably 10% by weight or more, more preferably 50% by weight or more, and more preferably 100% by weight with respect to the base material into which the active group has been introduced. The above is particularly preferable. If the amount used is less than 10% by weight, it may not be possible to introduce an alkoxysilyl group sufficient to react with sufficient titanium oxide. On the other hand, the upper limit of the amount used is more preferably 500% by weight or less, further preferably 400% by weight or less, and particularly preferably 300% by weight or less. If the amount used is more than 500% by weight, it is not economical.

  The polymerization is more preferably performed in a nitrogen atmosphere. As a lower limit of polymerization temperature, 40 degreeC or more is more preferable, 45 degreeC or more is further more preferable, and 50 degreeC or more is especially preferable. When the polymerization temperature is lower than 40 ° C., the polymerization does not occur sufficiently and the functional group may not be introduced into the substrate. On the other hand, the upper limit of the polymerization temperature is more preferably 80 ° C. or less, further preferably 75 ° C. or less, and particularly preferably 70 ° C. or less. If the polymerization temperature is higher than 80 ° C, the substrate may be deteriorated. In addition, what is necessary is just to set suitably as polymerization time so that it may become a desired introduction rate (ratio in which a functional group is introduce | transduced into a base material).

  Further, the lower limit of the introduction ratio (% by weight) of the functional group with respect to the substrate is more preferably 0.1% by weight or more, and further preferably 1% by weight or more. Here, the introduction rate is the ratio of the weight of the silane coupling agent introduced per unit weight of the substrate. When the introduction ratio is 0.1% by weight or more, a sufficient amount of titanium oxide capable of expressing biocompatibility can be bound to the base material. On the other hand, the upper limit of the introduction rate is not particularly limited, but if the introduction rate is higher than 100% by weight, the amount of titanium oxide bonded to the base material is too large, which is not economical. There is.

  The method for introducing an alkoxysilyl group into the substrate is not limited to the method described above, and various methods can be used. The reaction conditions are appropriately set depending on the base material, the active group-containing compound, the type of the silane coupling agent, and the like, and are not particularly limited. In this way, functional groups can be introduced on the surface of the substrate.

  In the case where the functional group is an isocyanate group and the isocyanate group is introduced into the base material by polymerizing a monomer having an isocyanate group at the terminal with the base material, the isocyanate group is in the reaction solvent. The reaction is preferably carried out in a dehydrating solvent such as dehydrated dimethyl sulfoxide and dehydrated dimethylformamide.

  In addition, when the monomer having an isocyanate group at the terminal is reacted (polymerized) in water or alcohol having active hydrogen, the isocyanate group reacts with the active hydrogen, and thus the isocyanate group needs to be protected. There is. Specifically, for example, polymerization can be carried out by protecting the isocyanate group with a blocking agent such as phenol, imidazole, oxime, N-hydroxyimide, alcohol, lactam, or active methylene complex. The blocking agent protecting the isocyanate group can be removed by heating. Therefore, the isocyanate group can be introduced into the base material by heating after the isocyanate group is protected with the blocking agent and polymerized with the monomer present at the other end and the base material. That is, a substrate having an isocyanate group on the surface can be obtained.

  For example, when phenol is used as the blocking agent, the blocking agent protecting the isocyanate group can be eliminated by heating within a range of 110 to 120 ° C. Further, as the blocking agent, for example, when imidazole is used, heating is performed within a range of 110 to 130 ° C., and when oxime is used, heating is performed within a range of 130 to 150 ° C., thereby removing the blocking agent. be able to. Specific examples of the blocking agent include phenol-containing compounds such as methyl salicylate and methyl-p-hydroxybenzoate; imidazole; oxime-containing compounds such as methyl ethyl ketoxime and acetone oxime. Depending on the type of substrate, for example, N-hydroxyimide-containing compounds such as N-hydroxyphthalimide and N-hydroxysuccinimide; alcohol-containing compounds such as methoxypropanol, ethylhexanol, pentol, and ethyl lactate; caprolactam, pyrrolidinone, and the like Lactam-containing compounds; active methylene compounds such as ethyl acetoacetate may be used.

  In addition, about other reaction conditions (for example, the addition amount with respect to a base material), etc. when using isocyanate as said functional group, it is the same as that of the said functional group being an alkoxy silyl group, and detailed description is abbreviate | omitted. .

(Functional group reaction process)
In the functional group reaction step, a functional group (for example, an isocyanate group or an alkoxysilyl group) introduced into the substrate is reacted with the titanium oxide. This functional group reaction step may be performed under the same conditions as the above-described reaction step, and detailed description thereof is omitted.

(Titanium oxide composite)
The titanium oxide composite according to the present embodiment is a titanium oxide composite in which titanium oxide is chemically bonded to a base material having a functional group that can be chemically bonded to titanium oxide, and the titanium oxide and the group This is a structure in which the functional group of the material is chemically bonded.

  The titanium oxide composite obtained as described above can be further manufactured without modifying the titanium oxide surface (without requiring pretreatment).

  The method for producing a titanium oxide composite according to the present embodiment is a method for producing a titanium oxide composite in which titanium oxide is chemically bonded to a base material having a functional group capable of chemically bonding with titanium oxide. The method may include an introduction step of introducing a functional group capable of chemically bonding with titanium oxide into the base material, and a reaction step of reacting the functional group of the base material with the titanium oxide.

  Moreover, it is more preferable that the titanium oxide composite according to the present embodiment is manufactured by the above-described method for manufacturing a titanium oxide composite.

  Further, the method for producing a titanium oxide composite according to the present embodiment further includes an active group introduction step for introducing an active group into the base material before the introduction step, and in the introduction step, the reactive functional group and A method of reacting the reactive functional group with the active group using a compound containing a functional group capable of chemically bonding with titanium oxide is more preferable.

  According to said structure, since the active group which can react with the said reactive functional group is introduce | transduced into a base material, a various reactive functional group can be selected. Thereby, the said functional group can be introduce | transduced more easily.

  Moreover, the manufacturing method of the titanium oxide composite concerning this Embodiment is a manufacturing method of the titanium oxide composite formed by a titanium oxide chemically bonding to a base material, Comprising: A titanium oxide and a base material are chemically bonded. It may be a method including a reaction step.

  According to the above configuration, since the titanium oxide and the base material are chemically bonded, it is possible to provide a titanium oxide composite in which the titanium oxide and the base material are firmly bonded as compared with the conventional case.

  Further, the method for producing a titanium oxide composite according to the present embodiment is a method for producing a titanium oxide composite in which titanium oxide and a base material are bonded by chemical bonding, and can react with the base material in titanium oxide. It may be a method including a reactive group introducing step for introducing a reactive group and a bonding step for reacting the reactive group with a substrate.

  At this time, a titanium oxide composite can be more easily produced by using a silane coupling agent having a reactive group at one end and a reactive functional group at the other end.

<4. Method for producing hybrid composite material according to the present invention>
The hybrid complex according to the present invention may be produced by coating the calcium phosphate complex or titanium oxide complex described above with a soft tissue affinity improving substance. In other words, the hybrid complex according to the present invention includes a coating step of coating a calcium phosphate complex or a titanium oxide complex with a soft tissue affinity improving substance. In addition, the method for producing a hybrid complex according to the present invention may include each step of the method for producing a calcium phosphate complex and each step of a method for producing a titanium oxide complex as described above.

  The coating step may be performed in the state of the calcium phosphate complex or the titanium oxide complex, or after molding a medical device or the like using the calcium phosphate complex or the titanium oxide complex, the molded medical device. For example, a soft tissue affinity improving substance may be coated. Moreover, after adsorbing the calcium phosphate complex or the titanium oxide complex to the base material of a medical device such as a percutaneous terminal, the soft tissue affinity improving substance may be coated together with the medical device.

  The specific method of the coating step is not particularly limited as long as the soft tissue affinity improving material is coated on a calcium phosphate complex or a titanium oxide complex (hereinafter, appropriately referred to as calcium phosphate or the like). For example, a calcium phosphate complex or a titanium oxide complex is placed in a solution (suspension) of a soft tissue affinity improving substance and stirred, and then the calcium phosphate complex or the like may be recovered. In this case, the coating process can be carried out more easily by using a conventionally known automatic culture apparatus. Further, a solution (suspension) of a soft tissue affinity improving substance may be sprayed on the calcium phosphate complex or the like.

  When the soft tissue affinity improving substance is an autologous cell cell (periodontal ligament cell, bone marrow cell, fibroblast, vascular endothelial cell, ES cell) or ES cell, calcium phosphate is added to the cell suspension as described above. A method of adding a complex or the like and stirring, or a method of spraying a cell suspension may be used, but a method of inoculating and culturing the autologous cells or the like in a liquid medium containing a calcium phosphate complex or the like Method).

  By using the above culture step, autologous cells and the like grown by culture are adsorbed to the calcium phosphate complex and the like, and as a result, the autologous cell and the like can be coated on the calcium phosphate complex. Further, by including the above culture step, it is possible to simultaneously prepare a large amount of autologous cells to be coated and to coat a calcium phosphate complex, etc., and to omit the step of preculturing autologous cells and the like to prepare a large amount. It can be said that it is preferable.

Here, as conditions for culturing the autologous cells and the like, conditions that are favorable for the cells to be cultured may be appropriately selected and adopted. As a medium that can be used for the culture step, for example, α-MEM medium (containing 10% bovine serum, 50 IU penicillin, 50 μg / ml streptomycin, 2.550 μg / ml amphotericin B) and the like can be used. For other media, see the Functional Peptide Institute website (HYPERLINK "http://www.func-p.co.jp/hito.html" http://www.func-p.co.jp/hito.html The culture medium for human somatic cell culture disclosed in (2) above may be selected as appropriate and employed. The culture temperature may be appropriately optimized depending on the cells to be cultured. For example, the culture is preferably performed in the range of 28 ° C to 40 ° C, more preferably 37 ° C. The culture may be performed using a conventionally known CO ₂ incubator. The CO ₂ concentration may be 0 to 25%.

  In particular, during culture, it is preferable to rotate (invert) the culture vessel at arbitrary time intervals. This is because the proliferated cells can be prevented from collecting in a part of the culture vessel and can be uniformly coated with the calcium phosphate complex or the like. The interval for rotating the culture vessel is not limited, but is preferably 5 minutes to 2 hours, more preferably 10 minutes to 1 hour, and most preferably about 30 minutes. If the rotation interval is too short, there will be no time for the cells to settle and adhere to the calcium phosphate complex, etc., and the cells will float again in the culture medium, and they are rotated frequently and wasteful labor. Will end up. On the other hand, if the rotation interval is too long, cells and the like are accumulated at the bottom of the culture container, and the adhesion efficiency is lowered.

  In addition, for example, when a medical device or the like is molded using a calcium phosphate complex or a titanium oxide complex, the molded medical device or the like is coated with a soft tissue affinity improving substance, or a calcium phosphate complex or a titanium oxide complex is used. In the case of coating after adsorbing to a base material of a medical device such as a transdermal terminal, the culture device may be cultured while rotating the medical device in a culture container.

  The culture container or medical device may be rotated not only by 180 ° but also by appropriately setting a suitable rotation angle such as 90 ° or 45 ° according to the shape of the medical device. Depending on the shape of the medical device, there is a portion that is difficult to cover, and the cell is covered with the medical device by rotating at an angle that makes it easy for the cell to come into contact therewith.

  The coverage of the soft tissue affinity improving substance in the hybrid complex according to the present invention (the ratio of the soft tissue affinity improving substance covering the complex such as calcium phosphate) is most preferably 100%, but at least 80%. As long as it is covered, it is more preferably 50% or more. However, it is desirable that the soft tissue affinity improving material is not layered as much as possible. This is because if they are layered, there is a problem in the adhesion between cells, the adhesion is lowered, and a problem arises in the affinity for somatic cells when transplanted into a complex.

  Furthermore, it can be said that the coating layer of the soft tissue affinity-improving substance in the hybrid complex according to the present invention is preferably covered uniformly. This is because there is no unevenness in the coating layer of the soft tissue affinity improving substance, and it becomes easier to adhere to the surrounding soft tissue when implanted, and the affinity is further improved.

<5. Utilization of Hybrid Complex According to the Present Invention>
The hybrid complex according to the present invention is particularly suitable as a medical material used for manufacturing a medical device. When used as a medical material, the above-mentioned calcium phosphate complex may be used alone, or the hybrid complex in which a soft tissue affinity improving substance is coated and the hybrid complex in which a titanium oxide complex is coated with a soft tissue affinity improving substance. Further, a mixture thereof may be used. In addition, a medical material may be mixed with a material preferable as a medical material.

  Examples of the application of the medical material comprising the hybrid material according to the present invention include transcutaneous devices (pulmonary hypertension treatment catheter (long-term indwelling central vein catheter), peritoneal dialysis catheter, auxiliary artificial heart (VAS) blood supply tube・ Application of devascularization to the skin insertion site), application to colostomy, artificial bladder, stents and stent grafts, application to artificial blood vessels, shunts (external shunts, internal shunts), and in-vivo immobilization artificial hearts (Artificial heart, pacemaker, etc.).

In addition to the above, coronary stent, metallic stent, thrombus removal stent, ureteral stent, metallic stent for BMP treatment, biliary stent, esophageal stent, tracheal / bronchial stent, high calorie catheter, blood access, supplemental materials The present invention can also be used for artificial ligaments and the like. Embodiments of the present invention will be described in more detail with reference to the accompanying drawings. Of course, the present invention is not limited to the following examples, and it goes without saying that various aspects are possible in detail. Further, the present invention is not limited to the above-described embodiments, and various modifications can be made within the scope shown in the claims, and the present invention is also applied to the embodiments obtained by appropriately combining the disclosed technical means. It is included in the technical scope of the invention.

  Although the example which manufactured the hydroxyapatite (HAp) sintered compact particle group as an Example of this invention is shown, this invention is not limited to a following example.

[Example 1] Animal implantation test of percutaneous terminal coated with periodontal ligament cells (Production method of sintered hydroxyapatite particles)
First, a method for producing a hydroxyapatite sintered body according to this example will be described.

Using dodecane as a continuous oil phase and pentaethylene glycol dodecyl ether at 31 ° C. as a nonionic surfactant as a nonionic surfactant, 40 ml of a continuous oil layer containing 0.5 g of the nonionic surfactant was prepared. Next, 10 ml of a Ca (OH) ₂ dispersed aqueous solution (2.5 mol%) was added to the prepared continuous oil layer. Then, after sufficiently stirring the obtained dispersion, 10 ml of a 1.5 mol% KH ₂ PO ₄ solution was added to the water / oil (W / O) emulsion, and the reaction temperature was 50 ° C. The reaction was allowed to stir for 24 hours. Hydroxyapatite was obtained by separating the obtained reaction product by centrifugation. And the particle | grains (henceforth HAp particle | grains) of the hydroxyapatite sintered compact were obtained by heating the said hydroxyapatite on 800 degreeC conditions for 1 hour. This hydroxyapatite sintered body was a single crystal and had a major axis of 100 to 400 nm.

(Method for producing hydroxyapatite composite particles (composite))
First, fibrous silk fibroin (manufactured by Fujimura Yarn Co., Ltd., hereinafter referred to as SF fiber), which is a polymer substrate, was cut into an average length in the long axis direction of 100 μm and an average length in the short axis direction of 10 μm. The obtained SF fibers (hereinafter referred to as cutSF) were subjected to extraction / removal of non-volatile components with a Soxhlet extractor. A scanning electron microscope image of the obtained cutSF is shown in FIG.

  Next, 600 mg of soxhlet-extracted cutSF was put into a doctor test tube. Then, 82 mg of ammonium peroxodisulfate (APS) dissolved in 18 ml of pure water and 1088 μl of γ-methacryloxypropyltriethoxysilane (KBE503) were added. A well-stirred mixture was added to 292 μl of pentaethylene glycol dodecyl ether. The operations of freezing, degassing, thawing, and nitrogen replacement with liquid nitrogen were repeated twice.

  Next, the reaction was performed by heating the reaction solution in a 50 ° C. hot water bath for 60 minutes. Thereafter, the reaction solution was filtered using qualitative filter paper (retained particle diameter: 5 μm). As a result, SF fibers (filter cake) having alkoxysilyl groups introduced on the surface of cutSF were separated from the polymerized KBE and molecules esterified with silyl groups (filtrate). Further, in order to separate the polymerized KBE, the SF fiber having an alkoxysilyl group introduced on the surface of cutSF was treated with ultrasound (20 kHz, 35 W) for 1 minute in ethanol, and further stirred for 2 hours. After washing, the mixture was filtered with qualitative filter paper. Thereafter, vacuum drying was performed to obtain an SF fiber in which a polymer chain having a terminal alkoxysilyl group was graft-polymerized, that is, an alkoxysilyl group-introduced SF fiber (hereinafter referred to as KBE-cutSF). A scanning electron microscope image of the obtained KBE-cutSF is shown in FIG.

  In addition, the alkoxysilyl group introduction rate during the reaction time was 8.3% by weight. The introduction rate was determined by the following formula (1), where Ag is the weight of untreated cutSF and Bg is the weight of cutSF after the reaction (KBE-cutSF).

Introduction rate (% by weight) = ((B−A) / A) × 100 (1)
Table 1 and FIG. 3 show the introduction rate of alkoxysilyl groups in each reaction time (15 minutes, 60 minutes, 75 minutes, 90 minutes, 120 minutes).

  On the other hand, 300 mg of the HAp particles were added to 15 ml of a solution (toluene: methanol = 8.6: 1), dispersed by sonication for 20 seconds, and allowed to stand for 30 minutes to 1 hour.

  While the HAp particles were allowed to stand, about 300 mg of KBE-cutSF was dispersed in 15 ml of a solvent (toluene: methanol = 8.6: 1) in 30 ml of Erlenmeyer.

  Then, the supernatant solvent in which the HAp particles were dispersed was gently transferred to an Ellenmeyer in which KBE-cutSF was dispersed with a Pasteur pipette. Thereafter, the dispersion solvent in which KBE-cutSF and HAp particles were mixed every minute was gently stirred with a dropper.

  The stirring operation was repeated 10 times, and then the qualitative filter paper separated KBE-cutSF (hereinafter referred to as KBE-cutSF-HAp) on which HAp particles were adsorbed and HAp particles that were not adsorbed. Specifically, supernatant HAp particles were filtered, and then precipitated KBE-cutSF-HAp was recovered.

  Thereafter, the filtered KBE-cutSF-HAp was stirred and washed in ethanol for 2 hours, subjected to ultrasonic treatment for 1 minute, and then filtered through the qualitative filter paper.

  The filtered KBE-cutSF-HAp was dried at 60 ° C. and then treated at 120 ° C. and 1 mmHg for 2 hours. In this way, KBE-cutSF-HAp particles were synthesized. FIG. 4 shows a scanning electron microscope image of the KBE-cutSF-HAp particles.

Moreover, the result analyzed using FT-IR (diffuse reflection method) of the synthesized KBE-cutSF-HAp is shown in FIG. Fig. 5 (a) shows the results of FT-IR analysis of cutSF, Fig. 5 (b) shows the results of FT-IR analysis of KBE-cutSF, and (c) shows the FT-IR analysis of KBE-cutSF-HAp. It is a result. In FIG. 5 (c), there was a new absorption around 1050 cm ⁻¹ attributed to PO ₄ ³⁻ , indicating that the HAp particles were bound to the polymer substrate.

(Transdermal terminal manufacturing method)
Hereinafter, a method for producing a transdermal terminal by coating KBE-cutSF-HAp particles on a substrate will be described. The percutaneous terminal is an instrument used for preventing the downgrowth of the percutaneous device with the catheter. For example, a percutaneous terminal made of hydroxyapatite ceramics with high biocompatibility is known (H. AOKI, in “Medical Applications of Hydroxyapatite” (see Ishiyaku EuroAmerica Inc., 1994) p. 133).

  First, a cover tape was wound around a portion of the surface of the silicone rubber substrate of the percutaneous terminal that was not covered with the KBE-cutSF-HAp particles (other than the covered portion).

  Next, a silicone adhesive (GE Toshiba Silicone Co., Ltd .: non-corrosive quick-drying adhesive sealant TSE-399) is applied to the substrate while rotating at 360 rpm with the silicone rubber substrate catheter inserted as the axis. After that, the excess adhesive was removed by rotating at 5600 rpm for 10 seconds.

  Then, while rotating the substrate on which the adhesive was applied at 360 rpm, the KBE-cutSF-HAp particles were evenly attached, and then the excess KBE-cutSF-HAp particles were removed. The cover tape was peeled off from the substrate after this operation.

  Thereafter, the substrate coated with KBE-cutSF-HAp particles was dried at 85 ° C. for 5 minutes and removed from the rotating rod after 5 minutes. And it dried at 120 degreeC under reduced pressure (133 Pa (1 mmHg)) for 2 hours.

  Next, the substrate was immersed in pure water and subjected to ultrasonic treatment (output 20 kHz, 35 W) for 3 minutes to clean the substrate. Further, after the ultrasonic irradiation was completed, the substrate was stirred for 1 hour in pure water, washed, dried, and left for 24 hours to produce a transdermal terminal according to the present invention. An overall photograph of the percutaneous terminal thus obtained is shown in FIG. 6 (a), and a scanning electron microscope image of the percutaneous terminal is shown in FIG. 6 (b). According to FIG.6 (b), it turned out that KBE-cutSF-HAp particle | grains are coat | covered evenly on the transdermal terminal surface.

(Cell coating method for transdermal terminals)
The percutaneous terminal obtained as described above was placed in a microtube (2 ml), 2 ml of α-MEM medium was injected, and ultrasonic treatment (120 W, 1 minute) was performed.

The percutaneous terminal was replaced with a new microtube (2 ml), and 2 ml of periodontal ligament cells (2.5 × 10 ⁵ cells / ml) were inoculated there. The periodontal ligament cells were collected in advance from rats used in the animal implantation test described later and cultured in α-MEM medium.

  The microtube lid was left open for incubation. Incubation was performed at 37 ° C. in air. When incubating, the microtube was rotated at 20-30 minute intervals. This prevents periodontal ligament cells from accumulating on the bottom of the microtube and allows the periodontal ligament cells to be evenly coated on the surface of the percutaneous terminal.

About 2 days after the start of incubation (about 48 hours), the cultured percutaneous device complex was further replaced with a new microtube (2 ml), and 2 ml of new periodontal ligament cells (2.5 × 10 ⁵ cells / ml) were added there. Inoculation was carried out while rotating the microtube at intervals of 20 to 30 minutes.

  About 2 days (about 48 hours later) after the above incubation, incubation was further performed for about 8 hours, and a transdermal terminal having periodontal ligament cells adsorbed on the surface was finally produced.

  A scanning electron microscope image of the percutaneous terminal is shown in FIG. FIG. 7 shows that periodontal ligament cells are evenly coated on the percutaneous terminal.

(Animal implantation test)
The percutaneous terminal coated with periodontal ligament cells obtained by the above operation was implanted subcutaneously in a rat that was the same as the rat from which the periodontal ligament cells were removed, and after 3 days, the percutaneous terminal was removed from the implanted portion and stained by HE. Evaluation was performed.

[Example 2] Animal implantation test of percutaneous terminal coated with bone marrow cells A percutaneous terminal coated with bone marrow cells was prepared in the same manner as in Example 1 except that bone marrow cells were used as the cells to be coated. An animal implantation test was also performed according to Example 1.

[Comparative Example] Animal Implantation Test of Transcutaneous Terminal without Covering Cells Using the transdermal terminal before coating each cell of Examples 1 and 2, animal implantation as in Examples 1 and 2 A test was conducted.

[Results of Examples 1 and 2 and Comparative Example]
A scanning electron microscope image of the surface of the transdermal terminal taken out from the animal in Example 1 is shown in FIG. 8A, and a scanning electron microscope image of the surface of the transdermal terminal taken out from the animal in Example 2 is shown in FIG. FIG. 8 (c) shows a scanning electron microscope image of the surface of the transdermal terminal shown in (b) and taken out from the animal in the comparative example.

  In addition, the schematic of the percutaneous device 3 which consists of the percutaneous terminal 1 and the catheter 2 was shown in FIG. In the figure, a percutaneous terminal 1 is implanted in a living body, a catheter 2 exists outside the living body, and a drug is administered through the catheter 2. The percutaneous terminal 1 is for preventing the catheter 2 from down-growing. In addition, the area | region which performed the said electron microscope observation was enclosed with the circle in the same figure.

  As can be seen from FIGS. 8 (a) to (c), the percutaneous terminals coated with cells showed early extension of the connective tissue as compared with the comparative example. This indicates that the percutaneous terminal and the living tissue (soft tissue) are bonded early.

  Therefore, the medical material such as a transdermal terminal manufactured by the hybrid complex according to the present invention in which the hydroxyapatite complex is further coated with cells (periodontal ligament cells and bone marrow cells) has an affinity for living tissue, particularly soft tissue. Improve and can quickly bond with soft tissue. Therefore, it is possible to prevent infection caused by bacteria or the like that occurs in the initial stage of implantation of the medical material and displacement of the medical material and to expect an effect of promoting wound healing.

  The hybrid complex according to the present invention has a property of adhering to a living tissue (soft tissue) at an early stage. Therefore, it can be used as a medical material for various indwelling medical devices. For example, transcutaneous devices (pulmonary hypertension treatment catheter (long-term indwelling central venous catheter), peritoneal dialysis catheter, use of auxiliary artificial heart (VAS) for blood transfusion and devascularization at the skin insertion site), colostomy Application to artificial bladders, stents and stent grafts, artificial blood vessels, shunts (external shunts, internal shunts), and indwelling artificial heart internal fixation techniques (artificial hearts, pacemakers, etc.).

  In addition to the above, coronary stent, metallic stent, thrombus removal stent, ureteral stent, metallic stent for BMP treatment, biliary stent, esophageal stent, tracheal / bronchial stent, high calorie catheter, blood access, supplemental materials It can also be used for artificial ligaments.

  Therefore, according to the present invention, it can be favorably used in a wide variety of medical materials (medical devices).

2 is a diagram showing a scanning electron microscope image of cutSF in Example 1. FIG. 2 is a diagram showing a scanning electron microscope image of KBE-cutSF in Example 1. FIG. 4 is a graph showing the introduction rate of alkoxysilyl groups in the reaction time in Example 1. 2 is a diagram showing a scanning electron microscope image of KBE-cutSF-HAp particles in Example 1. FIG. 3 is a graph showing the results of FT-IR (diffuse reflection method) analysis in Example 1. FIG. 6A is an overall photograph of the transcutaneous terminal in which the surface produced in Example 1 is coated with KBE-cutSF-HAp particles, and FIG. 6B is a scanning type of a part of the transdermal terminal. It is a figure which shows an electron microscope image. It is a figure which shows the scanning electron microscope image of the percutaneous terminal which coat | covered the surface produced in Example 1 with KBE-cutSF-HAp particle | grains, and also coat | covered the periodontal ligament cell. FIG. 8A is a view showing a scanning electron microscope image of the surface of the transcutaneous terminal taken out from the animal in the animal implantation test of Example 1, and FIG. 8B is the animal of Example 2. FIG. 8C is a diagram showing a scanning electron microscope image of the surface of the transdermal terminal taken out from the animal in the implantation test, and FIG. 8C is the surface of the transdermal terminal taken out from the animal in the animal implantation test of the comparative example. It is a figure which shows the scanning electron microscope image of. It is the schematic of the percutaneous device which consists of a percutaneous terminal and a catheter.

Explanation of symbols

1 Percutaneous terminal 2 Catheter 3 Percutaneous device

Claims (9)

  A hybrid characterized in that at least a part of the surface of a complex formed by chemically bonding calcium phosphate or titanium oxide and a base material is further coated with a soft tissue affinity-improving substance having affinity for soft tissue. Complex.   2. The soft tissue affinity improving substance is a substance selected from the group consisting of autologous cells, ES cells, cell growth factors, adhesive proteins, and adhesive polysaccharides, or a combination thereof. The hybrid complex described.   2. The hybrid complex according to claim 1, wherein the autologous cell is a substance selected from the group consisting of periodontal ligament cells, bone marrow cells, fibroblasts, vascular endothelial cells, and ES cells, or a combination thereof. body.   A substance selected from the group consisting of fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and epidermal growth factor (EGF), or these The hybrid complex according to claim 1, which is a combination.   A hybrid complex, wherein the adhesive protein is a substance selected from the group consisting of collagen, gelatin, fibrin, and fibroin, or a combination thereof.   A hybrid complex, wherein the adhesive polysaccharide is a substance selected from the group consisting of glycosaminoglycan, pectin, hyaluronic acid, chondroitin, chitin, chitosan, and alginic acid, or a combination thereof. A method for producing a hybrid complex, wherein at least part of the surface of a complex formed by chemically bonding calcium phosphate or titanium oxide and a base material is further coated with a soft tissue affinity improving substance having affinity for soft tissue Because
A method for producing a hybrid complex, comprising a coating step of coating the complex with the soft tissue affinity-improving substance. A method for producing a hybrid complex in which at least part of the surface of a complex formed by chemically bonding calcium phosphate or titanium oxide and a base material is further coated with autologous cells and / or ES cells,
A method for producing a hybrid complex, comprising a culture step of seeding and culturing the autologous cells and / or ES cells in a liquid medium containing the complex.   A medical material using the hybrid complex according to any one of claims 1 to 5.