JP5634042B2 - Bone regenerative medical material - Google Patents

Description

  The bone regenerative medical material of the present invention relates to a structure such as a living body transplant material used for a defect part such as a tooth or a bone. The artificial bone regeneration material of the present invention, particularly the artificial tooth root, shows a good bond with bone at an early stage. The artificial bone regenerated material of the present invention is useful as a regenerated material when joining not only artificial tooth roots but also other bones.

  Conventionally, a tissue excision defect part associated with a surgical operation is often transplanted with surrounding tissue, and a bone defect due to an operation involving bone excision has a mechanical strength (medical material), a so-called structure. A body is needed. Bone tissue-compatible fillers such as calcium phosphate and hydroxyapatite are used to treat the defect.

  From the viewpoint of regenerative medicine, not only affinity for bone tissue but also adhesion of bone-forming cells to a filling material and integration with surrounding bone tissue has been studied. In addition, the structure is made porous so that cells are attached or entangled, or the cell is invaded from the surface of the structure by a culture technique. As a specific prior art, Patent Document 1 can be cited.

  According to this document, a rectangular parallelepiped having a porosity of 20 to 97% for the purpose of providing a medical material having a structure capable of uniformly diffusing and distributing a sufficient amount of a substance necessary for treatment inside the material. A medical material composed of a three-dimensional structure and a hollow hole formed inside the main body is described. In addition, substances such as calcium phosphate and ceramic apatite, cells and tissues having physiological activity, proteins, and substances suitable for exerting their functions are introduced from the hollow holes.

International Publication WO2006 / 090777

  When conventional medical materials are used for bone regeneration, there is a problem that bone does not enter the porous three-dimensional structure. An object of the present invention is to provide a bone regenerative medical material in which bone grows inside a porous body and can be easily joined to the bone.

In the present invention (1), a prepolymer having a terminal isocyanate group obtained by reacting a polyol having active hydrogen with a polyisocyanate and a slurry obtained by suspending titanium powder in an aqueous dispersion medium are mixed and reacted. According to the above, after obtaining a polyurethane foam intermediate containing titanium powder, the intermediate is subjected to a heat treatment, and the intermediate is manufactured by degreasing and sintering,
It is composed of a foamed titanium fired body material obtained by sintering the titanium powder , including open cells in which a plurality of bubbles are connected to each other , and the foamed titanium fired body material has an average flow pore size of 20 to 20 Bone regenerative medical material characterized by being 80 μm .

The present invention (2) is the bone regenerative medical material according to the invention (1), wherein the titanium foam fired body material has a maximum pore diameter of 80 to 180 μm.

The present invention (3) is characterized in that the cell skeleton shape of the titanium foam fired body material is substantially triangular, and the cell skeleton surface is uneven in a particle shape, according to the invention (1) or (2) Bone regenerative medical material.

The present invention (4) is characterized in that the titanium foam fired body material is formed by connecting particles of the titanium powder to form a three-dimensional network structure. The bone regenerative medical material according to any one of 3).

In the present invention (5), the slurry comprises water as a dispersion medium, and the titanium powder having an average particle size of 0.5 to 30 μm is suspended in the dispersion medium.
The content of the isocyanate group in the prepolymer is 3 to 26% by mass,
The bone regenerative medical material according to any one of the inventions (1) to (4), wherein the polyol in the prepolymer is a polyether-based polyol containing at least 60 mol% of ethylene oxide units.

  The present invention (6) is the bone regenerative medical material according to any one of the inventions (1) to (5), wherein the titanium powder is produced by an atomizing method.

The present invention (7) is characterized in that the expanded titanium fired body material is formed into a sheet shape having a thickness of 0.1 to 10 mm, and ceramic apatite is coated on the outer periphery of the expanded titanium fired body material. The bone regenerative medical material according to any one of the inventions (1) to (6).

In the present invention (8), the substance injected into the foamed titanium fired body material has a physiological function,
Various cells, bone marrow cells, bone marrow fluid, stem cells isolated from bone marrow fluid, cord blood-derived cells, peripheral blood-derived cells, tissue subsections, various proteins, lipids, polysaccharides, enzymes, antibiotics, antibacterial substances, hormones, cytokines Blood coagulation promoters, cell growth factors, extracts from genetically engineered cells, substances produced from genetically engineered cells, vascular endothelial growth factor (VEGF), platelet-
inducedgrowthfactor (PIGF), therapeutic effect factor beta 1 (TGF.beta.1), acidic fibroblasts (aFGF), basic fibroblasts (bFGF), therapeutic effect factor alpha (TGF.alpha.), epidermal growth factor , Osteonectin, antipoietin (ANG1)
, ANG2, platelet-derived growth factor AB, platelet-derived growth factor BB, bone morphogenetic protein (BMP)
), At least one selected from the group of hepatocyte growth factor (HGF), extracellular matrix, collagen or any complex or derivative thereof, from the invention (1) The bone regeneration medical material according to any one of (7).

The present invention (9) comprises a substrate,
Artificial bone regeneration comprising a titanium porous sheet layer made of the bone regenerative medical material according to any one of the inventions (1) to (8) formed by firing and connecting titanium powder to the outer periphery of the base material It is a material.

The present invention (10) is characterized in that the artificial bone regeneration material is an artificial tooth root (
9) The artificial bone regenerated material.
In the present invention (11), a prepolymer having an isocyanate group at the terminal obtained by reacting a polyol having active hydrogen with a polyisocyanate is mixed with a slurry obtained by suspending titanium powder in an aqueous dispersion medium and reacted. An intermediate production process for obtaining a polyurethane foam intermediate containing titanium powder, and a degreasing process for obtaining a degreased body by degreasing the intermediate by applying heat treatment to the intermediate of the foamed titanium material; It is a manufacturing method of the bone regenerative medical material characterized by having a sintering process which sinters a degreased body.
The present invention (12) is the method for producing a bone regenerative medical material according to the invention (11), wherein the foamed titanium material has an average flow pore size of 20 to 80 μm.

  According to the present invention (1), when used as a bone regenerative medical material, there is an effect that the bone grows inside the porous body and is easily joined to the bone.

  According to the present invention (2), the substance to be injected can be filled up to the inside of the structure, and the excellent inductivity and implantability of various cells can be maintained.

  According to the present invention (3), there is an effect that the surface area of the porous body is increased, and the chance of living bone living cells is increased.

  According to the present invention (4), since the titanium powder particles are connected to each other and have a three-dimensional network structure, the three-dimensional network structure prevents local concentration of stress even if an external force is applied from any direction. be able to. In addition, since the cell skeleton surface has irregularities due to the particle shape, there is an effect that biological cells of the bone are easily attached.

  According to the present invention (5), when the prepolymer comes into contact with the slurry in the intermediate production process, the prepolymer has sufficient reactivity with respect to water in the slurry. It has moderate mechanical strength and flexibility, and finally produces an effect of obtaining a foamed titanium material that achieves both high mechanical strength and high porosity.

  According to the present invention (6), a slurry in which the titanium powder is uniformly suspended can be obtained, and further, a titanium powder having a more spherical shape can be obtained. High fluidity. As a result, the workability at the time of mixing the prepolymer and the slurry can be improved, and the entire polyurethane foam intermediate can be obtained.

  According to the present invention (7), there is an effect that the affinity with bone cells can be increased.

  According to the present invention (8), there is an effect that a substance having a physiological function can coexist.

  According to the present invention (9), there is an effect that it is possible to provide an artificial bone regenerated material in which bone grows inside the porous body and can be easily joined to other bones.

  According to the present invention (10), there is an effect that it is possible to provide an artificial tooth root in which bone grows inside the porous body and can be easily joined to other bone.

FIG. 1 is a schematic configuration diagram (a) and a schematic sectional view (b) of an artificial tooth root according to the best mode. FIG. 2 is an SEM photograph (300 times) of an intermediate of the expanded titanium material according to the best mode. FIG. 3 is an SEM photograph {(a) 100 times, (b) 300 times} of the expanded titanium material according to the best mode. FIG. 4 is an SEM photograph (200 ×) of the fiber porous body of the comparative example. FIG. 5 is a photograph showing the appearance of a tissue image 6 weeks after the metal foam according to the best mode was implanted under the periosteum of a rat skull. FIG. 6 is a photograph showing the appearance of a tissue image after 6 weeks after the porous fiber of the comparative example was implanted under the periosteum of a rat skull.

<Composition of expanded titanium material>
The bone regenerative medical material according to the present invention is a polyurethane foam intermediate containing titanium powder by mixing and reacting a prepolymer having a terminal isocyanate group and a slurry obtained by suspending titanium powder in an aqueous dispersion medium. The intermediate body is manufactured by subjecting the intermediate body to heat treatment, and degreasing and sintering the intermediate body, and is composed of a foamed titanium material containing open cells in which a plurality of bubbles are connected to each other. ing. In the bone regenerative medical material of the present invention, it is preferable that these pores are continuous. The bone regenerative medical material according to the best mode is a foamed titanium material, and basically has a hollow hole and a hollow part inside the material. Therefore, the inducibility and implantation of various cells including anchorage-dependent cells such as osteoblasts are excellent, and the cell growth is remarkably high. Moreover, it is preferable that the titanium foam material is formed into a sheet shape having a thickness of 0.1 to 10 mm.

The average flow pore size is preferably 20 to 80 μm (preferably 30 to 70 μm).
The average flow pore size is measured by the half dry method (ASTM E1294-89). The smaller the average flow pore size, the larger the surface area of the porous body, and the more the chance that the living cells of the bone are implanted increases. As the cell diameter of the urethane foam decreases in the manufacturing process, the surface area of the foam increases, and when the foam is fired, the average flow pore diameter of the titanium porous body after firing becomes small.

  The maximum pore diameter of the pores is preferably 80 to 180 μm (preferably 100 to 160 μm). The maximum pore diameter is measured by a bubble point method (ASTM F316-86, JIS K3832). That is, the fact that a value can be obtained by the measurement method is based on the assumption that the object is an open-celled object. Further, the value of the maximum pore diameter can be interpreted as a value reflecting the degree of pore communication in the foam. Injecting and filling a necessary and sufficient amount of substance into the expanded titanium material is convenient for promoting tissue formation by cells, but the porous titanium material constituting the expanded titanium material has a maximum pore diameter in the above range. Thus, it is clear that the structure has an open cell structure, and the injected substance can be injected as homogeneously as possible inside the structure. Thereby, the substance to be injected can be filled up to the inside of the structure, and excellent inductivity and implantation of various cells can be maintained.

  The hollow holes and hollow parts provided in the expanded titanium material are not simple single holes, but are branched and winding channels. Therefore, a sufficient amount of cells necessary for treatment can be obtained through the hollow holes and hollow parts. Growth factors such as growth substances can be uniformly diffused and distributed in the structure, and bones can be regenerated and grown.

  It is preferable that the above-mentioned foamed titanium material has a structure having a shape matched to a use site. It is preferable to appropriately set the shape of the structure, the material constituting the structure, and the porosity according to the mechanical strength applied to the site to be used and the necessity of cell distribution. Although not particularly limited, it is generally preferable that the mechanical strength is designed to have low strength at the front teeth and high strength at the molars. In the case of occlusion with a molar, it is said to be 60 kg vertically and a maximum of 100 kg, and although it is not particularly limited, it is preferable that the strength can withstand this. However, it is only necessary to be able to withstand the load when the inside of the expanded titanium material is filled with bone. Also, when filled with bone, titanium foam is stronger than bone.

  The tensile strength of the foamed titanium material is not particularly limited, but is preferably 2 MPa or more. Although the upper limit of tensile strength is not specifically limited, For example, it is 300 MPa or less. Further, the tensile elongation of the foamed titanium material is not particularly limited, but 0.5% or more is preferable. Although the upper limit of tensile elongation is not specifically limited, For example, it is 40% or less. The compressive strength (25%) is not particularly limited, but is preferably 2 to 300 MPa. The bending strength is not particularly limited, but is preferably 2 to 300 MPa. The bending elastic modulus is not particularly limited, but 100 to 10,000 MPa is preferable. In addition, the measuring method of these numerical values is based on the method of an Example description.

  In addition, it is advantageous that the affinity for bone cells can be increased by including at least a part of calcium phosphate or ceramic apatite as a substance to be injected into the expanded titanium material.

  It is preferable to inject a substance having a physiological function inside the titanium foam material. Here, the substances include various cells, bone marrow cells, bone marrow fluid, stem cells separated from bone marrow fluid, cord blood-derived cells, peripheral blood-derived cells, tissue subsections, various proteins, lipids, polysaccharides, enzymes, antibiotics Substances, antibacterial substances, hormones, cytokines, blood coagulation promoters, cell growth factors, extracts from genetically engineered cells, substances produced from genetically engineered cells, vascular endothelial growth factor (VEGF), platelet- inducedgrowthfactor (PIGF), therapeutic effect factor beta 1 (TGF.beta.1), acidic fibroblasts (aFGF), basic fibroblasts (bFGF), therapeutic effect factor alpha (TGF.alpha.), epidermal growth factor , Osteonectin, antipoietin (ANG1), ANG2, platelet-derived growth factor AB, platelet-derived growth factor BB, bone morphogenetic protein (BMP), hepatocytes殖因Ko (HGF), extracellular matrix, collagen or any complex or derivative thereof, at least one can be cited selected from the group of an equal.

<< Production Method of Titanium Foam Material >>
Hereinafter, the manufacturing method of the foamed titanium material (foamed titanium sintered body) of the present invention will be described in detail based on preferred embodiments. In the present embodiment, a method for producing a porous titanium material called “titanium foam” will be described.

  A method for producing a foamed titanium material is obtained by mixing and reacting a prepolymer having an isocyanate group at the terminal and a slurry obtained by suspending titanium powder in an aqueous dispersion medium, thereby reacting a polyurethane foam intermediate containing titanium powder. The intermediate manufacturing process to be obtained, the degreasing process of degreasing the intermediate to obtain a degreased body by subjecting the intermediate of the foamed titanium material to heat treatment, and the sintering process of sintering the degreased body. Thereby, the foamed titanium material according to the best mode is obtained. Hereinafter, each process will be described sequentially.

Intermediate production process First, a prepolymer and a slurry are used as raw materials for an intermediate of a foamed titanium material. Among these, a prepolymer has an isocyanate group at the terminal.

  Such a prepolymer may be any prepolymer having an isocyanate group at the terminal, but for example, a prepolymer produced by reaction with a polyisocyanate (polyfunctional isocyanate) exceeding a chemical equivalent with a polyol can be used. is there. Such a prepolymer has both excellent reactivity and excellent mechanical properties (flexibility and elasticity). Therefore, in the intermediate production process, the reactivity between the prepolymer and the moisture contained in the slurry can be increased, and a polyurethane foam intermediate having excellent mechanical properties can be obtained. Finally, excellent mechanical properties can be obtained. A foamed titanium material is obtained.

  Polyisocyanate is a compound having two or more isocyanate groups (—NCO) in one molecule. On the other hand, polyol is a compound having two or more active hydrogen groups (hydroxyl group, amino group, thiol group, carboxyl group, etc.) in one molecule. When these polyisocyanate and polyol are mixed, the isocyanate group in the polyisocyanate reacts with the active hydrogen group in the polyol to form a prepolymer.

  Here, examples of the polyisocyanate used in the present invention include toluene diisocyanate (TDI), triphenyl-methane-4,4 ′, 4 ″ -triisocyanate, benzene-1,3,5-triisocyanate, toluene- 2,4,6-triisocyanate, diphenyl-2,4,4′-triisocyanate, hexamethylene diisocyanate (HDI), xylene diisocyanate, chlorophenylene diisocyanate, diphenylmethane-4,4′-diisocyanate, naphthalene-1,5- Diisocyanate, xylene-α, α ′ diisocyanate, 3,3′-dimethyl-4,4′-biphenylene-diisocyanate, 3,3′-dimethoxy-4,4′-sulfonylbis (phenyl isocyanate), 4,4′- Methylenedio Luso-triisocyanate, ethylene diisocyanate, ethylene diisothiocyanate, trimethylene diisocyanate, dicyclohexylmethane-4,4′-diisocyanate, isophorone diisocyanate, 1,6-hexamethylene diisocyanate, 2,2,4-trimethyl-1,6- Hexane diisocyanate and the like can be mentioned, and one or more of these can be used in combination.

These polyisocyanates are classified into aromatic polyisocyanates and aliphatic polyisocyanates.
Of these, the polyisocyanate is preferably an aromatic polyisocyanate. Aromatic polyisocyanates are particularly highly reactive, and compounds having excellent mechanical properties can be obtained by reacting with polyols. For this reason, the mechanical characteristics and shape retention of the intermediate body of a foam titanium material can be improved, and finally the foam titanium material excellent in mechanical strength and dimensional accuracy is obtained. Aromatic polyisocyanates also have the advantage of being inexpensive and readily available.

  Examples of the polyol used in the present invention include polyether-based polyols such as polyoxyethine diol, polyoxyethylene triol, polyoxyethylene tetrol, polyoxyethylene hexol, polyoxyethylene octol, poly ( Butylene adipate) diol such as adipate polyol, polyester polyol such as caprolactone polyol such as poly-ε-caprolactone diol, polycarbonate polyol such as poly (hexamethylene carbonate) diol, etc. These may be used alone or in combination of two or more.

Among these, the polyol is preferably a polyether-based polyol containing at least 50 mol%, more preferably 60 mol%, of an ethylene oxide unit. Since the polyether polyol contains an ether chain, it is rich in flexibility and excellent in low temperature characteristics. In addition, polyether polyols containing at least 50 mol% of ethylene oxide units contain hydrophilic ethylene oxide units, so that the resulting prepolymer is hydrophilic and can be easily mixed with a slurry containing a large amount of moisture. Moreover, it is excellent in reaction with water and foaming stability. If the ethylene oxide unit is 60 mol%, it is more preferable because it becomes more hydrophilic. Furthermore, the polyether-based polyol can be easily removed by thermal decomposition because the molecular chain is easily broken by oxidation. Thereby, the intermediate body of the foaming titanium material in which quick degreasing is possible can be obtained.
Moreover, the weight average molecular weight of such a polyol is not particularly limited, but is preferably about 200 to 20000, and more preferably about 600 to 6000.

  Furthermore, in order to allow the intermediate of the foamed titanium material to form a foam having a three-dimensional network structure, the production of the isocyanate group-terminated prepolymer is a multifunctional and reactive with isocyanate group as a crosslinking agent. Those having properties may be used. As such crosslinking agents, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, polyethyleneimine, glycerin, trimethylolpropane, tolylene-2,4,6-triamine, ethylenediamine, trimethylenediamine, tetramethylenediamine, pentamethylenediamine , Hexamethylenediamine, ethanolamine, diethanolamine, hydrazine triethanolamine, benzene-1,2,4-tricarboxylic acid, nitrilotriacetic acid, citric acid, 4,4′-methylenebis (o-chloroaniline), and the like. So-called polyols may be used to react with isocyanate groups. Among these, glycerin and trimethylolpropane are preferable.

  In the prepolymer, the number of moles of isocyanate groups in the polyisocyanate is preferably about 1.1 to 10 times, and about 1.5 to 5 times the number of moles of active hydrogen groups in the polyol. It is more preferable that This ensures that the isocyanate group is in excess of the active hydrogen group in the prepolymer. As a result, the prepolymer can be a prepolymer having an isocyanate group at the terminal, and can reliably react with water in the slurry in the intermediate production process. As described above, examples of the active hydrogen group in the polyol include a hydroxyl group, an amino group, a thiol group, and a carboxyl group. A prepolymer is produced by reacting such a polyisocyanate and a polyol, but this reaction is preferably performed in an inert gas atmosphere so that the isocyanate group does not react with moisture in the air, Specifically, it is preferably performed in an atmosphere of nitrogen gas or argon gas.

  The mixing / reaction of the polyisocyanate and the polyol is carried out by charging the polyisocyanate and the polyol into various mixers, various stirrers and the like, and mixing and stirring them.

In addition, although the temperature at the time of mixing polyisocyanate and a polyol is not specifically limited, Preferably, it is about 40-140 degreeC, More preferably, it is about 50-120 degreeC. The mixing time is not particularly limited, but is preferably about 0.1 to 10 hours, more preferably about 1 to 5 hours.
A prepolymer is obtained as described above.

  The prepolymer used in the present invention may have a terminal isocyanate group as described above, but the ratio of this isocyanate group (NCO%) is 3 to 3 on the basis of the total mass of the prepolymer. It is preferably about 26% by mass, and more preferably about 5-15% by mass. Thereby, a prepolymer will have sufficient reactivity with respect to the water in a slurry, when it contacts with a slurry in an intermediate body manufacturing process. Moreover, the intermediate of the expanded titanium material produced by the reaction between this prepolymer and the water in the slurry has both moderate mechanical strength and flexibility, and finally high mechanical strength and high porosity. A foamed titanium material that achieves both a good rate is obtained.

On the other hand, the slurry is a liquid containing titanium powder and water, in other words, a dispersion obtained by suspending (dispersing) titanium powder in an aqueous dispersion medium.
Among these, the titanium powder is a powder that finally becomes a raw material of the titanium material constituting the foamed titanium material. Here, titanium includes not only pure titanium but also titanium oxide and titanium alloys.

  Here, in the present invention, since water is used as a dispersion medium for dispersing the metal powder, it is preferable that the metal powder to be used is not easily altered by ionization or oxidation by water. Specifically, even if the metal powder is made of a metal material having a relatively low ionization tendency rather than a metal having a relatively high ionization tendency such as K, Ca, Na, etc. The metal powder is less likely to be ionized, and as a result, the metal powder can be prevented from generating heat due to oxidation, and as a result, the reaction between the prepolymer and the slurry can be prevented from becoming unstable. In this respect, titanium is preferable because it has a small ionization tendency and is about the same as aluminum. Titanium has an extremely strong corrosion resistance equivalent to that of platinum (platinum) or gold in the air whose surface is protected by an oxide film because the oxide is very stable and hardly attacked. It is preferable to use an aqueous dispersion of titanium because it hardly reacts with acid or saline (seawater) at room temperature. Therefore, even when titanium is used as an aqueous dispersion, it is possible to suppress deterioration of the properties (chemical properties, mechanical properties and electrical properties) of the titanium powder due to oxidation, and the desired properties. A polyurethane foam intermediate having the following can be obtained.

  The metal material constituting the metal powder preferably has a specific gravity of 10 or less, and more preferably 8 or less. If the powder is composed of such a metal material having a relatively low specific gravity, it can be easily suspended in the aqueous dispersion medium in the slurry. Thereby, it is possible to obtain a slurry in which separation / sedimentation of the metal powder hardly occurs. As a result, in the intermediate manufacturing process, when the prepolymer and the slurry are mixed, the prepolymer and the slurry can be mixed evenly, and the intermediate of the metal foam material that is homogeneous as a whole, and consequently the metal foam material, can be obtained. Can be obtained. In addition, since the whole is homogeneous, the opportunity for contact between the metal powder particles is sufficiently increased, and a polyurethane foam intermediate in which the metal powder is closely connected can be obtained, and the melting point is high during the subsequent sintering. Even if the metal is difficult to heat and melt, it is easy to ensure that the particles are bonded to each other, so that the mechanical strength of the metal foam material can be improved. In this respect, the specific gravity of titanium is 4.5 and the specific gravity of titanium oxide is 4.23, which satisfies the above requirements.

  Moreover, it is preferable that the average particle diameter of the titanium powder used for this invention is about 0.5-60 micrometers, and it is more preferable that it is about 1-30 micrometers. The average particle size of the titanium powder is measured by a laser diffraction / scattering method. If the titanium powder has an average particle size set in the above range, it can be easily suspended in the aqueous dispersion medium in the slurry. As a result, a slurry in which separation and sedimentation of titanium powder is not particularly likely to occur can be obtained. As a result, when the prepolymer and the slurry are mixed in the intermediate production process, the prepolymer and the slurry can be mixed evenly, and an intermediate of a foamed titanium material that is homogeneous as a whole can be obtained. Moreover, the intermediate body which can construct | assemble a more fine three-dimensional network structure can be obtained, raising mechanical strength. In addition, if the titanium powder has an average particle diameter set in the above range, a finer three-dimensional network structure can be formed, so that the titanium powder has a particularly large surface area and is particularly excellent in flexibility and elasticity. A containing polyurethane foam intermediate can be obtained. Furthermore, by setting the average particle diameter of the powder within the above range, the number of opportunities for contact between the titanium powder particles increases, so that the strength of the expanded titanium material of the present invention can be further improved. Moreover, the surface area of the titanium foam material after sintering can be increased, and bone cells are easily attached. In addition, when the average particle diameter of titanium powder is less than the said lower limit, not only the handling of titanium powder becomes very difficult, but aggregation of particles becomes obvious and it becomes difficult to obtain a uniform slurry. On the other hand, when the average particle diameter of the titanium powder exceeds the upper limit value, the titanium powder is remarkably easily settled in the slurry. This again makes it difficult to obtain a uniform slurry.

  For such titanium powder, water atomization method, gas atomization method, atomization method such as high-speed rotating water atomization method, reduction method, carbonyl method, pulverization method, etc. can be used. In particular, those produced by the atomizing method are preferably used. According to the atomization method, titanium powder having a fine and narrow particle size distribution (uniform particle size) can be obtained efficiently. Therefore, the slurry in which the titanium powder is uniformly suspended is obtained by including the titanium powder manufactured by the atomizing method.

Moreover, according to the atomizing method, titanium powder having a more spherical shape can be obtained. Thereby, the fluidity | liquidity of titanium powder improves and a slurry becomes a thing with high fluidity | liquidity. As a result, it is possible to improve workability when mixing the prepolymer and the slurry, and to obtain a polyurethane foam intermediate that is homogeneous throughout.
Specifically, the average value of the aspect ratio of each particle of the titanium powder is preferably 0.5 to 1, and more preferably 0.7 to 1. Thereby, the fluidity of the titanium powder is particularly improved and the filling property between the particles is also particularly high. As a result, finally, the mechanical properties of the expanded titanium material can be particularly enhanced. The aspect ratio of each particle is a value obtained by dividing the minor axis of each particle by the major axis.

On the other hand, water reacts with an isocyanate group in the prepolymer to generate a gas such as oxygen dioxide. This gas causes the mixture of the prepolymer and the slurry to foam, and voids communicating with the external space are generated in the mixture. In addition, the mixture is crosslinked by the action of the reaction product generated by the reaction between the prepolymer and the slurry.
It does not specifically limit as water used for this invention, Pure water, ion-exchange water, tap water, RO water is mentioned.
In addition to the titanium powder and water, the slurry may contain other components.
Specifically, it is a water emulsion or the like. That is, the slurry may be mixed with a water emulsion in which a resin having a softening point of 20 to 100 ° C. is dispersed.

  Specific examples of the resin contained in the water emulsion include acrylic acid ester polymer, polyester, and polyethylene. In particular, the acrylate polymer is suitable as a resin contained in the water emulsion. By including these resins, it becomes difficult for the metal powder to fall off from the skeleton of the polyurethane foam by the resin in the emulsion, and the metal powder can be prevented from falling off. Furthermore, since the resin is contained in the polyurethane raw material as a water emulsion in which the resin is dispersed, the resin is easily uniformly dispersed in the polyurethane raw material, and the metal powder is effectively fixed to the polyurethane foam skeleton with the resin. Can do.

  Next, the prepolymer and the slurry are mixed. Thereby, as mentioned above, the isocyanate group in the prepolymer and the water in the slurry react to generate a gas such as carbon dioxide, and the resinification reaction also proceeds. As this gas escapes from the mixture of prepolymer and slurry to the external space, bubbles are generated in the mixture. As the resinification reaction proceeds with the foaming reaction, the mixture foams. Further, due to the action of a reaction product (for example, primary amine) generated by the reaction between the prepolymer and the slurry, (urethane bond), urea (urea) bond, burette bond, ( Allophanate bonds) and the like are generated, and these bonds cross-link three-dimensionally. Thereby, the mixture of a prepolymer and a slurry bridge | crosslinks, a three-dimensional network structure is formed, and the intermediate body of a foaming titanium material is manufactured.

As shown in FIG. 3, the intermediate body of the foamed titanium material is a so-called sponge-like form in which a resin material containing titanium powder constructs a three-dimensional network structure. Further, as shown in FIG. 3, the polyurethane foam intermediate body incorporates titanium powder particles in a network structure. For this reason, even if an external force is repeatedly applied to the polyurethane foam intermediate, the titanium powder particles are reliably prevented from falling off from the network structure. Thereby, the polyurethane foam intermediate can maintain the state in which the particles of the titanium powder are closely connected to the inside of the urethane polymer until the next step. And by using the intermediate body which has such a network structure, it has the three-dimensional network structure which the particle | grains of titanium powder connected finally, and the excellent foamed titanium which has an isotropic mechanical characteristic A material is obtained.
Here, mixing of the prepolymer and the slurry can be performed by charging the prepolymer and the slurry into various mixers, various agitators, and the like.

When mixing the prepolymer and the slurry, the mixing ratio of the prepolymer and the slurry is n ₂ when the number of moles of isocyanate groups in the prepolymer is n ₁ and the number of moles of water in the slurry is n _2. / N ₁ is preferably a ratio satisfying 6.5 to 390, more preferably a ratio satisfying 20 to 200. By setting the mixing ratio of the prepolymer and the slurry within the above range, the isocyanate group and water react necessary and sufficiently, and finally, foaming with excellent flexibility and elasticity and excellent mechanical strength. A titanium material is obtained.

  Moreover, an isocyanate group shows high reactivity also with respect to titanium material. This is considered to be caused by the fact that hydroxyl groups (OH groups) are exposed at a higher density on the surface of the titanium material than ceramic materials and glass materials. That is, when hydroxyl groups are present at a high density on the surface of the titanium powder, the affinity between the prepolymer and the titanium powder increases when the prepolymer and the slurry are mixed. For this reason, the resin component produced | generated by reaction of a prepolymer and a slurry and the particle | grains of titanium powder are tied together firmly, and these adhesive strength becomes especially high. As a result, the adhesive interface between the resin component and the titanium powder becomes difficult to peel, and a polyurethane foam intermediate having excellent flexibility and elasticity can be obtained.

  Furthermore, the prepolymer having an isocyanate group and the titanium powder can be mixed uniformly and sufficiently, and a polyurethane foam intermediate in which bubbles are almost uniformly distributed can be obtained. And the polyurethane foam intermediate body in which air bubbles are distributed almost uniformly in this way exhibits excellent elasticity.

  Moreover, when preparing the mixture which mixed the prepolymer and the slurry, it is preferable that the ratio of the mass of the titanium powder to the mass excluding water of the mixture is about 50 to 90% by mass, and about 70 to 85% by mass. More preferably. In the intermediate of the expanded titanium material, the titanium powder is adjusted by adjusting the ratio of the titanium powder in the slurry or adjusting the mixing ratio of the prepolymer and the slurry so that the ratio of the titanium powder is within the above range. The content of is optimized. Thereby, the intermediate body of the foamed titanium material becomes excellent in shape retention and mechanical strength after molding. As a result, a foamed titanium material obtained by subjecting such an intermediate to a degreasing process and a sintering process described later is excellent in dimensional accuracy and mechanical strength.

In addition, although the temperature at the time of mixing a prepolymer and slurry is not specifically limited, Preferably it is about 10-140 degreeC, More preferably, it is about 15-120 degreeC.
In addition, the prepolymer used may react part of the polyisocyanate with part of the polyol, and react the remaining polyisocyanate with the polyol in the intermediate production step.

In this intermediate production process, it is preferable to further mix a surfactant when mixing the prepolymer and the slurry. Thereby, the void | hole produced | generated in the intermediate body of a foaming titanium material becomes a finer and uniform thing. That is, the surfactant functions as a foam stabilizer.
As such a surfactant, any surfactant can be used. For example, various anionic (anionic) surfactants, various cationic (cationic) surfactants, various amphoteric surfactants. Various nonionic (nonionic) surfactants can be used.

  Of these, nonionic surfactants are particularly preferably used. Specific examples include ester types such as glycerin fatty acid esters, sorbitan fatty acid esters, and sucrose fatty acid esters, and ether types such as polyoxyethylene alkyl ether and polyoxyethylene alkyl phenyl ether, as well as esters and ethers combining these. Various types of nonionic surfactants and the like can be mentioned, and one or more of these can be used in combination.

Further, the surfactant is preferably a polypropylene glycol ethylene oxide adduct surfactant. Thereby, by adjusting the presence or absence and mixing amount of the surfactant, the pores generated in the intermediate of the expanded titanium material become further fine and uniform.
Examples of such a polypropylene glycol ethylene oxide adduct surfactant include Pluronic L-62 (manufactured by BASF).

  Moreover, in this intermediate manufacturing process, when mixing the prepolymer and the slurry, it is preferable to further mix a catalyst that promotes the reaction between the prepolymer and the slurry. As a result, the reaction between the prepolymer and the slurry proceeds more rapidly, and the time required for the reaction can be shortened. Further, even at a low temperature, the prepolymer and the slurry can be reliably reacted.

Furthermore, in the intermediate production process, additives such as a chain extender, a crosslinking agent, a plasticizer, and a release agent may be mixed in addition to the surfactant and the catalyst.
In addition, although said surfactant and various additives may be mixed in this intermediate body manufacturing process, you may add to any one or both of a prepolymer and a slurry previously.

  Moreover, when shape | molding the intermediate body of the foaming titanium material obtained by this intermediate body manufacturing process in a desired shape, a prepolymer and slurry are mixed in a shaping | molding die. Thereby, an intermediate is obtained in the mold. Next, the molded intermediate is removed from the mold (released). Thereby, the intermediate body of the foaming titanium material shape | molded by the desired magnitude | size and shape can be obtained. As a result, finally, foamed titanium materials of various sizes and shapes can be easily obtained.

  Note that the mold used for molding the intermediate body may be a mold in which a part of the cavity is opened. However, if the mold has a closed cavity, it is possible to reliably obtain the intermediate body to be formed. Can do. Further, the volume of the mixture of the prepolymer and the slurry increases with the foaming of the prepolymer. However, since the cavity is a closed space, the intermediate body crosslinks in a state where a pressure is applied so as to be compressed from the surroundings. This slightly increases the density of the intermediate. Therefore, by appropriately setting the volume of the cavity, it becomes easier to finally adjust the density and porosity of the titanium foam material.

In addition, when shape | molding the intermediate body of a titanium foam material, the shaping | molding dimension is determined considering the shrinkage | contraction part of the intermediate body in the degreasing process and sintering process mentioned later.
Moreover, the intermediate body of a foaming titanium material is dried as needed. Thereby, the water | moisture content which remained in the intermediate body is removed.
This drying can be performed by a method of heating the intermediate, a method of injecting gas, a method of irradiating infrared rays, or the like.

Among these, when the intermediate is heated, the heating condition is preferably a temperature of 30 to 100 ° C. × 0.1 hour to 2 weeks, and a temperature of 50 to 80 ° C. × 0.2 hours to 3 days. More preferably. The heating atmosphere is not particularly limited, but is preferably an inert gas atmosphere or a reducing gas atmosphere.
Moreover, when injecting gas, it is preferable that the gas to be used is an inert gas or a reducing gas.

  Further, before or after the intermediate body of the expanded titanium material is dried, the intermediate body may be subjected to post-processing such as cutting, cutting, cutting, grinding, and polishing, as necessary. The intermediate is superior in flexibility and toughness and has low hardness as compared with a degreased body obtained by degreasing an intermediate described later and a foamed titanium material obtained by sintering the degreased body. For this reason, by performing post-processing on the intermediate body, it is possible to easily and highly accurately process the desired shape as compared with the case of performing post-processing on the degreased body and the foamed titanium material.

For example, when the mold used for molding the intermediate is a cavity in which a part of the cavity is opened, when the prepolymer is foamed, the mixture of the prepolymer and the slurry may overflow from the opened part. There is. Therefore, by removing the overflowed portion by post-processing, an intermediate body having a shape to be formed can be easily obtained.
Incidentally, the apparent density of the intermediate foam titanium material is slightly different depending constituent material of the titanium powder is preferably in the range of about 300~800kg / ^{m 3,} more preferably about 500~700kg / ^{m 3.}

  Moreover, in the intermediate body of the expanded titanium material thus manufactured, the content of titanium powder is preferably about 50 to 90% by mass. As a result, the intermediate includes a resin component necessary for maintaining the shape retaining property, and the content of the titanium powder is sufficiently high, so that the sinterability is high. Therefore, by subjecting such an intermediate to a degreasing and firing step described later, a foamed titanium material that can be degreased and sintered in a short time and has sufficient mechanical strength as a structural member can be obtained.

Degreasing process Next, heat treatment is applied to the intermediate of the expanded titanium material. Thereby, an intermediate is degreased and a degreased body is obtained.
The heat treatment conditions in this degreasing are preferably about 300 to 700 ° C. for about 0.1 to 20 hours, more preferably about 400 to 600 ° C. for about 1 to 5 hours. Thereby, the resin component (organic component) can be reliably decomposed and removed from the intermediate without sintering the titanium powder. As a result, the resin component can be reliably prevented from remaining in the degreased body, and the resin component can be reliably prevented from remaining in the foamed titanium material.

That is, when the heat treatment conditions in the degreasing are below the lower limit, the intermediate may be insufficiently degreased. On the other hand, when the heat treatment conditions in degreasing exceed the upper limit, the titanium powder in the intermediate may be sintered.
In addition, you may make it perform a degreasing process in multiple steps. In that case, degreasing can be further promoted by gradually increasing the heat treatment temperature.
The atmosphere for performing the heat treatment may be any atmosphere, but is preferably an inert gas atmosphere such as nitrogen gas or argon gas. According to the inert gas atmosphere, it is possible to decompose and remove the resin component in the intermediate while reliably preventing the titanium powder from being oxidized, and the intermediate is reliably degreased.

Sintering step Next, the degreased body is heat treated. Thereby, the titanium powder in the degreased body is sintered to form a sintered body, and a foamed titanium material (foamed titanium material of the present invention) is obtained.
FIG. 3 is a diagram schematically showing an example of an observation image of the foamed titanium material of the present invention by a scanning electron microscope, and this observation image.

  In the foamed titanium material, particles of titanium powder diffuse to each other by sintering, and the particles of titanium powder are connected (necked) as shown in FIG. Moreover, the connected particle | grains are constructing the network structure which spreads in three dimensions (three dimensions). In the foamed titanium material having such a network structure, the network structure spreading in three dimensions can prevent local concentration of stress regardless of the external force applied from any direction. As a result, the foamed titanium material becomes a material exhibiting high mechanical characteristics, conductivity and thermal conductivity unique to the titanium material, despite its low density (light weight).

  In addition, voids are formed between the network structures of the expanded titanium material. A plurality of the voids are connected to each other, forming a so-called “continuous hole”. That is, according to the method for producing a foamed titanium material of the present invention, it is possible to efficiently produce a foamed titanium material having such continuous pores, an extremely large surface area, and excellent air permeability and liquid permeability. .

Furthermore, the shape of the gap is a spherical shape or a shape similar to a spherical shape. For this reason, the network structure necessarily has a highly isotropic structure, in other words, a structure having low anisotropy. As a result, the isotropy in mechanical properties of the foamed titanium material becomes higher.
Although the heat treatment conditions in this sintering differ slightly depending on the structural material of the titanium powder, the temperature is preferably about 800 to 1500 ° C. × 0.1 to 20 hours, and the temperature is about 1100 to 1500 ° C. × 1 to 5 hours. It is more preferable that Thereby, it is possible to reliably sinter the titanium powder and to prevent oversintering.

That is, when the heat treatment conditions in sintering are lower than the lower limit, sintering of the degreased body becomes insufficient and the mechanical strength may be reduced. On the other hand, when the heat treatment temperature exceeds 1500 ° C., the heat treatment apparatus (such as a firing furnace) may be significantly deteriorated due to the high temperature. Further, at a high temperature exceeding 1500 ° C., the activity of a gas (for example, amine-based gas) generated with degreasing becomes particularly high, and this gas may cause alteration or deterioration of the foamed titanium material or the heat treatment apparatus. In particular, in the method for producing a foamed titanium material of the present invention, a large amount of resin component may remain in the degreased body, so that a large amount of gas is generated by decomposition of this resin component during the sintering process. And it will be released for a long time. Since this gas may adhere to the inside of a heat treatment apparatus such as a firing furnace or accelerate the deterioration of the apparatus, the heat treatment on the degreased body is performed at 1500 ° C. or less from the viewpoint of minimizing these problems. Preferably it is done. Furthermore, when the heat treatment conditions in the sintering exceed the upper limit (1500 ° C.), depending on the titanium powder constituent material, sintering of the degreased body proceeds excessively, and the degreased body can maintain a three-dimensional network structure. There is a risk of collapse.
In addition, you may make it perform a sintering process in multiple times.

The atmosphere for performing the heat treatment may be any atmosphere, but it may be an inert gas atmosphere such as nitrogen gas or argon gas or a non-reduced atmosphere (vacuum atmosphere) formed by decompressing these atmospheres. An oxidizing atmosphere is preferred. According to the non-oxidizing atmosphere, the titanium powder can be sintered while reliably preventing the titanium powder from being oxidized.
Note that a reducing gas atmosphere such as hydrogen gas has a risk of hydrogen embrittlement, and sintering proceeds but may become brittle in strength.

Moreover, you may make it perform a degreasing process and a sintering process continuously, without reducing temperature on the way.
In addition, as described above, the expanded titanium material is constructed by connecting particles of titanium powder, but the titanium material generally has superior toughness compared to brittle materials such as ceramic materials and glass materials. have. On the other hand, since brittle materials such as ceramic materials and glass materials have low toughness, even if foam materials are produced using powders of these brittle materials, such foam materials are very brittle. Therefore, when a part of the three-dimensional network structure in the foamed material breaks, the impact easily propagates to another network structure, and the breakage progresses in a chain. As a result, the foam material using the powder of the brittle material has extremely low mechanical properties.

On the other hand, in the foamed titanium material of the present invention, even if a part of the three-dimensional network structure breaks, the excellent toughness of the titanium material affects the other network structure due to the excellent toughness of the titanium material. Is reliably prevented. Accordingly, the foamed titanium material has excellent mechanical properties.
The compressive strength of such a foamed titanium material is preferably 1 MPa or more, more preferably 2 MPa or more, although it varies slightly depending on the constituent material and porosity of the titanium powder. Such a foamed titanium material has sufficient mechanical strength as a structural member. Moreover, according to the manufacturing method of the foamed titanium material of the present invention, such a high strength expanded titanium material can be manufactured easily and reliably.

The porosity of the foamed titanium material is preferably about 70 to 99.5%, more preferably about 80 to 99%. Thereby, coexistence with the increase in the surface area in a foaming titanium material and the improvement of mechanical strength can be aimed at.
The density of the foam metal material can be calculated from the porosity and the composition of the metal powder used to produce the foam metal material. For example, SUS-316L (true density: 7950 kg / In the case of a foam metal material having a porosity of 88.3% and produced using a powder of m ³ ), the apparent density of the foam metal material is 930 kg / m ³ {= 7950 × (1−0.883)}. Become.

As mentioned above, although the manufacturing method of the foaming titanium material and foaming titanium material of this invention were demonstrated based on suitable embodiment, this invention is not limited to this.
For example, in the method for producing a foamed titanium material of the present invention, an optional step can be added as necessary.

Bone regeneration medical materials according to the dental implant present invention can be used in the artificial tooth root. An artificial tooth root 100 according to the present invention shown in FIG. 1 includes a base material 101 and a titanium porous sheet layer 102 made of a foamed titanium material provided on the outer periphery of the base material. The artificial tooth root is used in combination with the abutment 200 and the artificial tooth 300 that can be screwed with the artificial tooth root.

  The base material 101 is a columnar metal rod having a diameter of 1 to 5 mm and a length of 5 to 20 mm. This metal substrate is made of a metal having high biocompatibility, and in particular, titanium, titanium alloy, gold, and gold alloy can be mentioned. It is preferable to form a helical groove on the outer surface of the base material and firmly fix it to the titanium porous sheet layer 102. A screwing hole 101b for screwing with the abutment 200 is formed in the upper part 101a of the base material. The upper part 101a of the base material protrudes from the gums and engages the abutment 200 and the artificial tooth 300.

The titanium porous sheet layer 102 is formed by making a hole in the center of a cylindrical foamed titanium material, inserting a titanium rod, and vacuum sintering. This titanium porous sheet is a foamed titanium material according to the best mode. Such a foamed titanium material has a three-dimensional structure in which osteoblasts are preferably fixed, and the titanium porous sheet layer 102 made of the foamed titanium material functions as a hard tissue formation inducing layer for inducing osteoblasts.
That is, osteoblasts induced in the titanium porous sheet layer are induced to differentiate in the titanium porous sheet layer (foamed titanium material) to form a hard tissue layer. Here, the osteoblasts forming the hard tissue layer and the titanium porous sheet layer (foamed titanium sheet) are three-dimensionally physically bonded, and thus firmly bond the artificial tooth root and the living body.

The artificial tooth root 100 is manufactured as follows.
After drilling a screw-type or flat hole in a cylindrical or tapered foamed titanium material and inserting a screw-type or flat titanium rod in the bottom, vacuum baking is performed under strong pressure in a mold of an appropriate material. Conclude. In addition, the foamed titanium material may be formed into a foamed titanium material having a hole in the center of a columnar shape or a taper shape in advance by using a mold at the stage of the intermediate manufacturing process, or around the base material. A foamed titanium material intermediate may be formed and then vacuum-sintered after passing through a degreasing process and a sintering process. The vacuum sintering can be performed by a known method. Furthermore, it is preferable to carry out under a normal maximum vacuum.

  Alternatively, these cytokines may be supported by immersing the porous titanium sheet layer 102 in a solution containing cytokines such as bone morphogenetic protein (BMP) and fibroblast growth factor (FGF). Furthermore, the carbonate apatite may be supported by using a solution containing carbonate apatite on the outer periphery of the absorbent polymer film. These supporting methods are not particularly limited.

Example 1
2 mol of polyethylene glycol (Daiichi Kogyo Seiyaku, average molecular weight 1000), 1 mol of trimethylolpropane, and 80/20 mixture of 2,4- and 2,6-toluene diisocyanate (manufactured by Nippon Polyurethane Industry Co., Ltd., T-80 ) After mixing 7.7 moles, the mixture was stirred for 2 hours to make an isocyanate-terminated polyurethane prepolymer with 11% NCO%.

  Next, titanium powder produced by the gas atomization method was prepared. The titanium powder had an average particle size of 23 μm and a specific gravity of 4.6. Furthermore, a slurry obtained by mixing 600 parts by weight of titanium powder and 100 parts by weight of a water emulsion resin (manufactured by Nippon Zeon Co., Ltd., LX852) in 100 parts by weight of pure water was obtained. A prepolymer, a slurry, and Pluronic L-62 (polypropylene glycol ethylene oxide adduct, manufactured by BASF) were mixed and stirred in a mold having a cavity having a height of 200 mm × length of 200 mm × width of 200 mm. This allowed the mixture to foam and crosslink. Thereafter, the cross-linked product was taken out from the mold, and an intermediate body of the cubic shaped metal foam sintered body was obtained. The mixing ratio of the prepolymer, titanium powder, pure water, water emulsion resin, and L-62 was 100: 600: 100: 100: 1 by weight.

The intermediate thus obtained was put in a drying furnace and dried at a temperature of 70 ° C. for 2 days. When the density of the intermediate after drying was measured according to the method specified in JIS K 6400, the density was 452 kg / m ³ . In addition, the photograph at this time is shown in FIG. 2 (SEM, 300 times). The cross section of the cell skeleton has a triangular cross section that is recessed inward. When the prepolymer mixture is foamed, bubbles in each cell (hole) are pressed against each other, and the remaining (urethane generated by synthesis) resin component forms a cell skeleton, resulting in a triangular cross-sectional shape.

Next, the intermediate was placed in a degreasing sintering furnace and degreased under the following degreasing conditions. This obtained the defatted body.
<Degreasing conditions>
・ Degreasing temperature: 500 ° C
・ Degreasing time: Temperature rise 0.5 ° C./min Holding time 1 hour

Subsequently, the degreased body was sintered under the following sintering conditions. Thereby, the metal foam sintered body was obtained.
<Sintering conditions>
・ Sintering temperature: 1135 ° C
・ Sintering time: 2 hours ・ Sintering atmosphere: Vacuum

The cross-sectional photograph of the titanium foam sintered by the above method is shown in FIG. 3 {SEM, (a) 100 times, (b) 300 times}. It can be seen that the titanium particles are bonded in a state where the titanium particles are connected in a form close to rhombohedral filling such as hexagonal close-packed packing or cubic close-packed packing. Titanium particles are connected in a shape close to a triangle, which is the cross-sectional shape of the cell skeleton in the intermediate. This is because (1) the melting temperature of titanium is very high, and (2) the titanium-containing urethane foam (intermediate body) is formed by well dispersing and foaming titanium from a high-concentration slurry of titanium. It was because it was able to be obtained.

Thus, the cross-sectional shape of the cell skeleton of the intermediate body is a substantially triangular shape, and the cell skeleton has a triangular prism shape, so that the titanium particles are spread according to the shape of the cell skeleton of the urethane foam, It is possible to obtain a cell structure of a sintered body in which the titanium particles as described above are connected.
Thereby, since the cell skeleton shape (substantially triangular) of the sintered body and the surface of the cell skeleton are uneven due to the particle shape, the surface structure is easy for bone ecological cells to adhere to.
From the above, it brings about the effect of excellent bone cell growth.

  For reference, the strength properties of the sintered titanium foam are shown below. Thereby, it has the intensity | strength of the grade which can be used as an artificial tooth root.

<Conditions> Test environment temperature and humidity: 23 ° C 50% RH
Compression test: Test piece 10 × 10 × 1.6 mmt Compression speed 1 mm / min Up to 4000 N Compression tensile test: Test piece 5.5 × 53 × 1.6 mmt Speed 1 mm / min Distance between grips 40 mm
Bending test: Test piece 13 or 5.5 × 53 × 1.6 mmt Speed 2 mm / min Distance between fulcrums 40 mm Jig tip R5 mm (* measured in each test N = 3)

In addition, using an automatic pore size distribution measuring instrument (Perm-Prometer manufactured by POROUS MATERIALS), based on the bubble point method (ASTM F316-86, JIS K 3832) and the half dry method (ASTM E1294-89), the maximum The pore diameter and average flow pore diameter were measured.
Maximum pore size: 127.7 microns Average flow pore size: 53.9 microns

(Example 2)
A foam metal sintered body was obtained in the same manner as in Example 1 except that Brij58 (addition amount was the same) was used instead of L-62. (The mixing ratio of prepolymer, titanium powder, pure water, water emulsion resin, and Brij58 was set to 100: 600: 100: 100: 1 by weight.) Brij58 is an ICI Americas. It is a polyethylene glycol monocetyl ether manufactured by Inc. The maximum pore size was 176.8 microns and the average flow pore size was 77.3 microns.

Example 3
Foam metal by the same method as in Example 1 except that the mixing ratio of prepolymer, titanium powder, pure water, water emulsion resin, and L-62 is 100: 600: 70: 70: 0.5 by weight. A sintered body was obtained. The maximum pore size was 83.4 microns and the average flow pore size was 22.4 microns.

(Comparative example)
Fiber porous body fiber diameter: 50 μm, density (weight): 900 g / m ² ,
Thickness: 1.5mm, porosity: 87%
Maximum pore size: 202.6 microns Average flow pore size: 106.4 microns

A 200 times SEM photograph is shown in FIG. The cross section of the titanium fiber is not circular but rectangular, and is devised. Moreover, the numerical value itself called porosity has taken the value approximated with the titanium foam obtained from this invention.
However, according to the above electron micrograph, the voids are very loose and the surface shape is less uneven. Therefore, it seems that bone cells are difficult to be implanted.

(Reference example)
A foamed ceramic sintered body was obtained in the same manner as in the above example except that the metal powder was replaced with ceramic powder (alumina) having an average particle size of 4.0 μm.

<< Evaluation of sintered metal foam >>
When the compressive strength of the metal foam sintered body obtained in the example was measured, it had excellent strength that could be used as an artificial tooth root. Here, the external appearance photograph by the scanning electron microscope of the foam metal sintered compact obtained in the Example is shown in FIG.

As is clear from these figures, in the metal foam sintered body obtained in the example, a network structure spreading like a network three-dimensionally (three dimensions) was observed. In addition, a large number of voids were formed between the network structures. Moreover, it was recognized that the adjacent space | gap part is connected. Further, the shape of each gap portion has a spherical shape or a shape similar thereto.
Such a network structure characteristic of the present invention was observed. The shape of the cell skeleton forming this network structure is considered to contribute to the improvement of bone formation and growth.

《Rat skull implantation test》
A 12-week old Wistar male rat was incised subcutaneously in the head under complete anesthesia by intraperitoneal injection of Nembutal (0.71 ml / kg body weight), and a thickness of 1.5 mm was placed under the periosteum of the skull. mm Titanium foam molded into a disk shape with a diameter of 4 mm was implanted parallel to the bone surface. As a target, the fiber porous body of Comparative Example 1 (thickness disks of 0.5 mm and 4 mm) was embedded. Six weeks after implantation, the mice were euthanized by deep ether anesthesia, and the skull was removed and fixed with 10% neutral formalin.
The fixed sample was dehydrated in ethanol series according to a conventional method. Next, a block was prepared by embedding with Rigolac (Showa High Polymer), cut to a thickness of 0.4-0.5 mm, and then polished to a thickness of 150 μm. Further, Rigolac was coated on both sides of the thin piece to a thickness of 5 μm, and one side was polished to a thickness of 80 μm. After final polishing with water-resistant abrasive paper (# 1200), Cole's hematoxylin and eosin (HE) staining was performed and observed with an optical microscope. Similarly, the metal foam materials of Examples 1 to 3 were also tested.

  The results of the culture test are shown in FIGS. FIG. 6 shows a fiber porous body of Comparative Example 1, and FIG. 5 shows a state of a tissue image 6 weeks after implantation of the metal foam of Example 1 under the periosteum of a rat skull. Due to the effect of the geometric structure, bone is ingrowth in the foamed titanium sintered body, but the fiber porous body of the comparative example clearly shows that the bone does not enter the fiber porous body. As shown in FIG. 5, in the enlarged image of titanium foam, the size of the three-dimensional space formed by the fused titanium particles (average diameter 30 μm), that is, the three-dimensional space surrounded by the walls formed by the titanium particles, is vertical and horizontal. The spread of the height is 200 to 400 microns, and it is clear that the bone is standing up and ingrowth in the optimum space. In FIGS. 5 and 6, the part that appears in black is a titanium foam skeleton (1 in the figure, appears in black in the color photograph), and the part brighter than the titanium foam skeleton is a pore part (in the figure). 2, appearing in gray in a color photograph), and a portion darker than the bubble portion and brighter than black is a bone portion (3 in the figure, appearing red in the color photograph). In the tests of Examples 2 and 3, bone ingrowth was also observed.

Claims (12)

It contains titanium powder by mixing and reacting a prepolymer having a terminal isocyanate group obtained by reacting a polyol having active hydrogen with a polyisocyanate and a slurry obtained by suspending titanium powder in an aqueous dispersion medium. After obtaining the polyurethane foam intermediate,
It is manufactured by subjecting the intermediate to heat treatment, and degreasing and sintering the intermediate,
It is composed of a foamed titanium fired body material obtained by sintering the titanium powder , including open cells in which a plurality of bubbles are connected to each other , and the foamed titanium fired body material has an average flow pore size of 20 to 20 Bone regenerative medical material characterized by being 80 μm . The bone regenerative medical material according to claim 1, wherein the foamed titanium fired body material has a maximum pore diameter of 80 to 180 µm. The bone regenerative medical material according to claim 1 or 2, wherein the cell skeleton shape of the titanium foam fired body material is substantially triangular, and the cell skeleton surface is uneven in a particle shape. The bone regenerative medicine according to any one of claims 1 to 3, wherein the titanium foam fired body material is formed by connecting particles of the titanium powder to form a three-dimensional network structure. material. The slurry comprises water as a dispersion medium, and the titanium powder having an average particle size of 0.5 to 30 μm is suspended in the dispersion medium.
The content of the isocyanate group in the prepolymer is 3 to 26% by mass,
The bone regenerative medical material according to any one of claims 1 to 4, wherein the polyol in the prepolymer is a polyether-based polyol containing at least 60 mol% of ethylene oxide units.   The bone regenerative medical material according to any one of claims 1 to 5, wherein the titanium powder is manufactured by an atomizing method. 7. The titanium foam fired body material is formed into a sheet shape having a thickness of 0.1 to 10 mm, and ceramic apatite is coated on an outer periphery of the foamed titanium fired body material. The bone regenerative medical material according to any one of the above. The substance injected into the fired titanium foam material has a physiological function,
Various cells, bone marrow cells, bone marrow fluid, stem cells isolated from bone marrow fluid, cord blood-derived cells, peripheral blood-derived cells, tissue subsections, various proteins, lipids, polysaccharides, enzymes, antibiotics, antibacterial substances, hormones, cytokines , Blood coagulation promoters, cell growth factors, extracts from genetically engineered cells, substances produced from genetically engineered cells, vascular endothelial growth factor (VEGF), platelet-induced growth factor (PIGF), therapeutic effect factors Beta 1 (TGF.beta.1), acidic fibroblasts (aFGF), basic fibroblasts (bFGF), therapeutic effect factor alpha (TGF.alph.), Epithelial cell growth factor, osteonectin, antipoietin ( ANG1), ANG2, platelet-derived growth factor AB, platelet-derived growth factor BB, bone morphogenetic protein (BMP), hepatocyte growth factor (HGF), extracellular matrix Helix, collagen or bone regeneration medicine material according to any one of claims 1 to 7, characterized in that either a complex or derivative thereof, at least one selected from the group of an equal. A substrate;
An artificial bone regenerative material comprising a titanium porous sheet layer made of a bone regenerative medical material according to any one of claims 1 to 8, formed by firing and connecting titanium powder to the outer periphery of the base material. .   The artificial bone regeneration material according to claim 9, wherein the artificial bone regeneration material is an artificial tooth root. Contains titanium powder by mixing and reacting a prepolymer having an isocyanate group at the end obtained by reacting a polyol having active hydrogen with a polyisocyanate and a slurry obtained by suspending titanium powder in an aqueous dispersion medium. An intermediate manufacturing process for obtaining a polyurethane foam intermediate to be performed, a degreasing process for degreasing the intermediate by subjecting the intermediate of the titanium foam material to heat treatment, and a sintering for sintering the degreased body. A method for producing a bone regenerative medical material, comprising a ligation step. The method for producing a bone regenerative medical material according to claim 11, wherein the foamed titanium material has an average flow pore size of 20 to 80 µm.