JP2018171080A - Substitute bone block and method for producing same - Google Patents

Abstract

A substitute bone block having excellent bioresorbability and sufficient mechanical strength is provided. A substitute bone block having bioresorbability and a plurality of through holes provided in one direction is provided. The surface roughness Ra in the through hole is preferably 1 μm to 100 μm. Further, the diameter of the through hole is preferably 20 to 2500 μmφ. Further, the ratio of the volume occupied by the through-holes to the volume of the entire block including the through-holes is preferably 25% or less or 50% or more. Moreover, the mark which shows the direction of a through-hole may be provided in the surface in which the through-hole of a block is not provided. [Selection] Figure 1

Description

  The present invention relates to a substitute bone block having bioresorbability, and relates to a substitute bone block having excellent bioresorbability and sufficient mechanical strength by providing a plurality of through holes in one direction.

  Conventionally, a substitute bone block has been used as a substitute material for living hard tissues such as teeth and bones that have been lost or lost due to an accident or illness. Some of these bone substitutes provide a scaffold for bone formation, while others substitute for new bone as it is resorbed by the bone itself. These materials are required not to have an adverse effect on living tissue, to be deteriorated by an action from a living body, and to function for a long period of time. In addition, when used as a substitute material for tissues that are subject to very high loads and are subject to friction and wear, a substitute bone block made of a material with high mechanical strength and high density and excellent friction and wear characteristics is desired. The

Currently, materials widely studied as substitute bone blocks include calcium phosphate ceramics such as hydroxyapatite (HAP) and tricalcium phosphate (TCP). For example, Patent Document 1 discloses that a calcium phosphate powder synthesized and calcined by a mechanochemical method as a tricalcium phosphate sintered body having a high strength and high toughness mainly composed of a calcium phosphate-based compound is mixed with silica (SiO ₂ ). A tricalcium phosphate sintered body obtained by mixing and sintering powder and alumina powder (Al ₂ O ₃ ) is disclosed. Patent Document 2 discloses a calcium phosphate porous sintered body having a porous structure in which the porosity of the sintered body is 55% to 90% as a calcium phosphate sintered body having a porous structure. Yes. Furthermore, in Patent Document 3, as a substitute bone material having excellent bioabsorbability and sufficient mechanical strength, 99.5% or more highly pure β-type tricalcium phosphate (β-TCP) is cylindrical. A method for producing a bone substitute with pores is disclosed.

Japanese Patent No. 2800829 Japanese Patent No. 3400740 Japanese Patent No. 5014544 Japanese Patent No. 5681968 JP 2014-036733 A

  However, the above-described prior art documents have the following problems. First, the tricalcium phosphate sintered body described in Patent Document 1 is a low-purity tricalcium phosphate sintered body containing a replica of α-TCP, β-TCP, HAP, and calcium pyrophosphate. If the porosity of the material is increased, the bioabsorbability is excellent, but the mechanical strength is lowered, so that there is a problem that it cannot be used in a place where a load is applied. Further, the calcium phosphate porous sintered body described in Patent Document 2 is also excellent in bioabsorbability by adjusting the porosity of the sintered body to 55% to 90%, as in Patent Document 1. Since the mechanical strength is small, there is a problem that it cannot be used in a place where a load is applied.

  The substitute bone produced by the method for producing a substitute bone described in Patent Document 3 uses high-purity β-TCP of 99.5% or more as a substitute bone material to increase mechanical strength, In order to improve the property, through holes of 100 to 2000 μmφ are provided in at least two directions orthogonal to each other, and the ratio of the volume occupied by the through holes to the total volume of the bone substitute including the through holes is set to 25 to 50%. Then, when compared with the calcium phosphate sintered body described in Patent Documents 1 and 2, although it is surely excellent in mechanical strength, it is still sufficient for use in a part where a load is applied in vivo. I could not say.

  Therefore, an object of the present invention is to provide a substitute bone block having excellent bioabsorbability and sufficient mechanical strength. Unlike the substitute bones described in Patent Documents 1 to 3, by providing a plurality of through holes only in one direction, excellent bioabsorbability and sufficient mechanical strength can be obtained.

Further, one of the inventors of the present invention described in Patent Document 4 that β-type tricalcium phosphate (β-TCP) in which 3 mol% or less of vanadate ion (VO ₄ ³⁻ ) is solid-solved has sufficient bioabsorbability and mechanical properties. It has been reported that it has high strength. Furthermore, Patent Document 5 reports that β-TCP in which silicate ions (SiO ₄ ⁴⁻ ) are dissolved has sufficient bioabsorbability and mechanical strength. Therefore, in the present invention, β-TCP described in Patent Document 4 or 5 is used, the through hole is provided only in one direction, and the ratio of the volume occupied by the through hole to the total volume of the bone substitute including the through hole is 25%. It was found that a substitute bone block having excellent bioresorbability and sufficient mechanical strength can be obtained by making the following.

  The present invention provides a bioresorbable bone substitute block having a plurality of through holes provided in one direction. The surface roughness Ra in the through hole is preferably 1 μm to 100 μm. Further, the diameter of the through hole is preferably 20 to 2500 μmφ. Further, the ratio of the volume occupied by the through-holes to the volume of the entire block including the through-holes is preferably 25% or less or 50% or more.

Moreover, the substitute bone block of this invention may be comprised from the following materials.
(1) β-type tricalcium phosphate in which 3 mol% or less of vanadate ion (VO ₄ ^3- ) is dissolved in the phosphate ion (PO ₄ ^3- ) of β-type tricalcium phosphate (2) β-type phosphorus acid vanadate ion (VO ₄ ^3-) dissolved below 3 mol% relative to the tricalcium phosphate ion (PO ₄ ^3-), in addition to the vanadate ion (VO ₄ ^3-), β-type phosphoric acid Β-type phosphoric acid in which sodium ion (Na ⁺ ) is 9.1 mol% or less and magnesium ion (Mg ²⁺ ) is 9.1 mol% or less of tricalcium calcium ion (Ca ²⁺ ) Tricalcium (3) Less than 4 mol% of silicate ion (SiO ₄ ^4- ) with respect to phosphate ion (PO ₄ ^3- ) of β-type tricalcium phosphate, and calcium ion of β-type tricalcium phosphate (Ca ²⁺ ) less than 9.1 mol% sodium ion (Na ⁺ ) and less than 9.1 mol% magnesium ion (Mg ²⁺ ) Β-type tricalcium phosphate in solid solution

  Moreover, the substitute bone block of this invention may be provided with the mark which shows the direction of a through-hole in the surface in which the through-hole of the block is not provided.

  The present invention also includes a mixing process for mixing starting materials, a first baking process for baking the mixture obtained in the mixing process, and a pulverizing process for pulverizing the fired product obtained in the first baking process; Obtained by a molding process in which the powder obtained in the pulverization process is pressure-molded to create a molded body, a second firing process in which the molded body obtained in the molding process is fired, and a second firing process. A substitute bone block manufacturing method comprising: a through-hole disposing process for providing a plurality of through-holes in one direction in a fired body; and an ultrasonic cleaning process for ultrasonically cleaning the fired body provided with the through-holes in a solvent. provide. The ultrasonic cleaning process preferably includes a sterilization / disinfection subprocess which is a sterilization or / and disinfection process. Moreover, it is preferable that the through holes are arranged by a drill in the through hole arranging process, and the material of the drill is mainly iron or titanium.

  In the method for producing a substitute bone block, diammonium hydrogen phosphate, calcium carbonate, vanadium oxide, magnesium oxide, sodium carbonate, or silicon dioxide may be used as a starting material.

  Since the substitute bone block of the present invention has excellent bioresorbability and sufficient mechanical strength, it is suitable as an alternative material for living hard tissues such as missing and lost teeth and bones.

Embodiments of the present invention will be described below with reference to the drawings. In addition, this invention is not limited to description of this specification at all, and can be implemented with various aspects within the range which does not deviate from the summary.
<Configuration>

  FIG. 1 is a schematic diagram illustrating an example of a substitute bone block, where (a) is a perspective view and (b) is a cross-sectional view. The substitute bone block (0101) of the present invention is provided with a plurality of through holes (0102) in one direction (0103). The shape of the substitute bone block can be any shape other than the cube shown in FIG. 1. For example, a substitute bone block having the same shape as the shape of a defect in a living body, a missing tooth or a bone defect site is produced. You may do it. However, the shape of the defect site is often complicated, and it takes time and effort to change the shape of the bone substitute block to the shape of the defect site. Therefore, as shown in FIG. 2, a plurality of substitute bone blocks (0201a to 0201e) may be combined to be used as a substitute bone having the same shape as the shape of the defect site. In that case, for example, on the surface where the through hole of the substitute bone block is not provided, a projection (0202) for connecting the substitute bone blocks to each other and a recess (0203) capable of receiving the projection inside are provided. It may be done.

  The substitute bone block of the present invention is provided with a plurality of through holes (0102) in one direction. “In one direction” indicates that the central axes of the through holes are parallel to each other. When the through-hole is provided in the substitute bone block, introduction of osteoclasts and osteoblasts into the through-hole can be promoted. Then, the replacement of the substitute bone block with autologous bone can be promoted by the action of osteoclasts and osteoblasts.

  Moreover, when it is set as the structure by which several through-holes are provided in one direction, the fall of the mechanical strength of the substitute bone block by arrangement | positioning of a through-hole can be reduced. In FIG. 3, a case is considered where the bone defect site (0302) of the autologous bone (0301) is replaced with a substitute bone block. For example, in the substitute bone block (0303a) described in Patent Document 3 shown in FIG. 3A, through holes are provided in at least two directions orthogonal to each other. Then, when a load is applied in one direction of the substitute bone block, the through hole having a central axis that is not parallel to the load application direction (0304) greatly reduces the mechanical strength of the substitute bone block. Therefore, as shown in FIG. 3 (b), by providing only a through hole having a central axis in a direction parallel to the direction in which the load is applied to the substitute bone block (0303b), A decrease in mechanical strength can be minimized.

  Note that the through holes may be provided at arbitrary arrangement intervals. That is, the arrangement interval of the through holes may be changed depending on the position of the substitute bone block. For example, shortening the interval between through holes at a specific position on the bone substitute block to increase the density of the through hole reduces the mechanical strength of the bone substitute block at that position, but promotes replacement with autologous bone can do. On the contrary, if the through hole arrangement interval is lengthened to reduce the density of the through holes, it is possible to reduce the decrease in mechanical strength of the substitute bone block at such positions, but the promotion of replacement with autologous bone is suppressed. Is done. Therefore, when the substitute bone block is implanted in the own bone, the interval between the through holes is shortened at a position where sufficient mechanical strength is required, and conversely, the interval between the through holes is not required at a position where mechanical strength is required so much. By making the length longer, a substitute bone block having excellent bioabsorbability and sufficient mechanical strength can be obtained.

  For example, when a substitute bone block that is a cylindrical substitute bone block and includes a plurality of through holes having a central axis perpendicular to the bottom surface and the top surface is viewed from the bottom surface or the top surface, as shown in FIG. Although all the through holes (0401) may be arranged at regular intervals, the through holes arranged near the center of the bottom surface of the substitute bone block are arranged as shown in FIG. 4 (b). The interval between the through holes disposed near the outer periphery of the bottom surface of the substitute bone block may be increased by shortening the interval. When the substitute bone block is configured as shown in FIG. 4 (b), a decrease in mechanical strength near the outer periphery of the substitute bone block due to the provision of the through hole can be minimized, and the bottom surface of the substitute bone block can be reduced. In the vicinity of the center, the bioabsorbability of the substitute bone block can be improved.

  Further, the diameter of the through hole may be changed depending on the position of the substitute bone block. For example, the diameter of the through-hole is made short at a position where sufficient mechanical strength is required when the substitute bone block is implanted in autologous bone, and conversely, the diameter of the through-hole is set at a position where mechanical strength is not so required. By making it long, a substitute bone block having excellent bioabsorbability and sufficient mechanical strength can be obtained. For example, as shown in FIG. 4 (c), the diameter of the through-hole disposed near the center of the bottom surface of the substitute bone block is long, and the through-hole disposed near the outer periphery of the bottom surface of the substitute bone block The diameter may be short. With this configuration, similarly to the substitute bone block shown in FIG. 4B, the mechanical strength near the outer periphery of the substitute bone block due to the through hole can be minimized, and the substitute bone block. The bioabsorbability of the substitute bone block can be improved near the center of the bottom surface.

  Furthermore, in addition to the through hole, a hole that does not penetrate may be provided. If a through hole is provided in the substitute bone block, osteoclasts and osteoblasts can be introduced from both openings of the through hole. However, if too many through holes are provided, the substitute bone block The mechanical strength may decrease. Therefore, if a hole that does not penetrate is provided in addition to the through hole, introduction of osteoclasts and osteoblasts can be promoted while maintaining the mechanical strength of the substitute bone block. An example is shown in FIG. For example, as shown in FIGS. 4-2 (a) and (b), when the substitute bone block has a cylindrical shape, the substitute bone block has a through hole (0411) penetrating the bottom surface and the top surface of the cylinder, and penetrates the substitute bone block. A through hole (0412) may be provided. With this configuration, the mechanical strength of the substitute bone block can be increased as compared with the case where all the holes are through holes. Incidentally, FIG. 4B shows a cross-sectional view taken along the line A-B in FIG. In addition, as shown in FIGS. 4-2 (c) and (d), when the substitute bone block has a cylindrical shape, the hole near the center of the bottom and top surfaces of the cylinder is defined as a through hole (0145), and the distance from the center. It is good also as a structure which provides the hole (0414, 0413) which has not made the depth of a hole shallow as the distance leaves. With such a configuration, when the substitute bone block is viewed from above, the mechanical strength in the vicinity of the outer periphery of the substitute bone block can be increased, and the bioabsorbability near the center of the substitute bone block can be improved. Incidentally, FIG. 4-2 (d) is a cross-sectional view taken along the line CD of FIG. 4-2 (c).

  The surface roughness Ra of the through hole is preferably 1 μm to 100 μm. The surface roughness Ra is a straight line connecting two points (A, B) as a center line (0501), and the surface curve (0502) is folded in one direction along the center line (folded curve: 0503). It is a value obtained by dividing the area obtained by the curve and the center line by the distance between the two points. For example, if the surface roughness is small, that is, the surface is too smooth, osteoclasts and osteoblasts cannot be fixed on the surface of the through-hole, and replacement of the substitute bone block with autologous bone is difficult to be performed. . On the other hand, if the surface roughness is large, that is, the surface is too uneven, osteoclasts and osteoblasts are less likely to enter the through-hole, and replacement of the substitute bone block with autogenous bone is difficult.

  Further, the diameter of the through hole is preferably 20 to 2500 μmφ. As will be described later, since the substitute bone block is basically made of ceramics, it is difficult to make a through hole having a diameter of 20 μmφ in the ceramics. Also, if the diameter of the through hole is too small, the size of the osteoclast is said to be 20-100 μm, so it is not possible to introduce the osteoclast inside the through hole, and therefore the substitute bone block Cannot promote replacement with autologous bone. Conversely, if the diameter of the through hole is too large, it is not preferable because sufficient mechanical strength of the substitute bone block cannot be obtained.

  Moreover, it is preferable that the ratio of the volume which a through-hole occupies with respect to the volume of the whole block also including a through-hole is 25% or less. For example, Patent Document 3 describes that the ratio of the volume occupied by the through hole to the volume of the entire bone substitute is preferably 25 to 50%. By adopting such a configuration, it is said that excellent bioabsorbability can be obtained, but since sufficient mechanical strength cannot be obtained if the volume occupied by the through-hole is 25% or more, the part where the load is large Can not be used.

  The ratio of the volume occupied by the through hole to the volume of the entire block including the through hole may be 50% or more. By increasing the proportion of the volume occupied by the through-hole, the bioabsorbability of the bone substitute block can be improved. On the other hand, the mechanical strength decreases, but the mechanical strength is not required. There is no problem even if the volume occupied by the holes is increased. Examples of the site that does not require mechanical strength include the extracted mandible.

One of the inventors of the present invention has been researching by paying attention to β-tricalcium phosphate (β-TCP) among materials widely studied as a substitute bone block. β-TCP is superior in bioabsorbability compared to other calcium phosphate ceramics, and phosphate ions (PO ₄ ³⁻ ) and calcium ions (Ca ²⁺ ) in β-TCP can be ^combined with other ions. By replacing it, it is possible to control the mechanical strength and to promote the replacement of the substitute bone block with the autologous bone.

FIG. 6 shows the crystal structure of β-TCP. FIG. 6 (a) shows a planar structure composed of a-axis and b-axis of β-TCP, which is crystallographically independent of Ca and PO ₄ tetrahedra. Two columns A and B exist parallel to the c-axis. Note that β-TCP belongs to the rhombohedral system, and the lattice constant is a hexagonal lattice setting: a = b = 1.0439 nm, c = 3.7375 nm. FIG. 6B shows the crystal structures of the c-axis structures of the A column and B column of β-TCP. The A column has a repeating structure of PO ₄ (1) -Ca (4) -Ca (5) -PO ₄ (1) -vacancy-Ca (5). The B column is PO ₄ (3) -Ca (1) -Ca (2) -Ca (3) -PO ₄ (2) -PO ₄ (3) -Ca (1) -Ca (2) -Ca (3)-PO ₄ (2) is repeated, and the three Ca sites in the B column (Ca (1), Ca (2), Ca (3)) do not fall on the c-axis and form a broken line To do. Therefore, there are three types of crystallographically independent PO ₄ sites and five types of Ca sites in the unit cell in β-TCP. Table 1 shows the ratio of each PO ₄ site in the β-TCP unit cell, and Table 2 shows the ratio of each Ca site in the β-TCP unit cell.

Here, as an example of a bioabsorbable material used for a substitute bone block, vanadate ion (VO ₄ ³⁻ ) is 3 mol% or less with respect to β-type tricalcium phosphate phosphate ion (PO ₄ ³⁻ ). Solid β-tricalcium phosphate may be used. One of the inventors of the present invention can obtain β-TCP having excellent mechanical strength by dissolving 3 mol% or less of vanadate ions with respect to phosphate ions of β-TCP in Japanese Patent No. 5681968. Has been reported. In β-TCP, vanadate ions are substituted at the PO ₄ sites (PO ₄ (1), PO ₄ (2), and PO ₄ (3)) in FIG. Vanadium is one of the vital elements and is known to promote calcification of bones and teeth. Therefore, the vanadium in the substitute bone block is dissolved by the osteoblasts, so that the replacement of the substitute bone block with the autologous bone is promoted.

Another example of a bioabsorbable material used for a bone substitute is 3 mol% of vanadate ion (VO ₄ ³⁻ ) with respect to β-type tricalcium phosphate phosphate (PO ₄ ³⁻ ). Solid solution below, in addition to vanadate (VO ₄ ³⁻ ), β-type tricalcium phosphate calcium ion (Ca ²⁺ ), sodium ion (Na ⁺ ) 9.1 mol% or less, magnesium ion ( Β-type tricalcium phosphate in which any one or more of Mg ²⁺ ) is 9.1 mol% or less may be used. Magnesium is also contained in bones in the living body and plays a role in regulating the deposition action of calcium (calcium phosphate) on the bone. Sodium is also a substance involved in bone formation, which is contained in bones in the living body. Therefore, replacement of the substitute bone block with the autogenous bone is promoted by dissolving magnesium and sodium in the substitute bone block by the osteoblast.

FIG. 7 shows solid solution forms of monovalent and divalent metal ions in β-TCP. Here, the sodium ion is a monovalent metal ion, and the magnesium ion is a divalent metal ion. As shown in FIG. 7A, the monovalent metal ions are dissolved in Ca (4) sites and vacancies. That is, it dissolves in the form of Ca ²⁺ + □ (□: vacancy) → 2M ⁺ (M ⁺ : monovalent metal ion). The solid solubility limit of monovalent metal ions is 9.09 mol%, similar to the proportion of Ca (4) sites. In addition, as shown in FIG. 7B, the divalent metal ion is first solid-dissolved in the Ca (5) site up to 9.09 mol%, and when the Ca (5) site is filled with the divalent metal ion, the Ca (4 ) Solubility to 13.64mol% at the site. That is, it dissolves in the form of Ca ²⁺ → M ²⁺ (M ²⁺ : divalent metal ion).

As another example of a bioabsorbable material used for a substitute bone block, 4 mol% of silicate ion (SiO ₄ ^4- ) is added to phosphate ion (PO ₄ ^3- ) of β-type tricalcium phosphate. In the following, both 9.1 mol% or less of sodium ion (Na ⁺ ) and 9.1 mol% or less of magnesium ion (Mg ²⁺ ) were dissolved in the calcium ion (Ca ²⁺ ) of β-type tricalcium phosphate. β-type tricalcium phosphate may be used. One of the inventors of the present invention has reported in JP-A-2014-036733 about β-TCP in which the phosphate ions of β-TCP are replaced with silicate ions and simultaneously calcium ions and magnesium ions are dissolved. Replacing phosphate ions with silicate ions not only improves the mechanical strength and sinterability of β-TCP, but also has the effect of promoting bone formation. Can be used as a substitute bone block. When silicate ions are dissolved in β-TCP, the silicate ions are substituted with phosphate ions at PO ₄ (1) sites in the A column shown in FIG.

  In addition, as another example of a bioabsorbable material used for a substitute bone block, silicon is substituted at the phosphorous position of phosphoric acid in the crystal structure of β-type tricalcium phosphate to change the valence number of the substituting element. Β-type phosphate in which vacancies in the same crystal structure are substituted for monovalent cations for charge compensation, and divalent cations are substituted in the calcium position to stabilize the structure of the substituted solid solution. Tricalcium may be used. In the Japanese Patent Application No. 2014-051459, one of the present inventors discloses a method for producing a biomaterial ceramic obtained by sintering a biomaterial ceramic made of such β-type tricalcium phosphate. That is, the raw material phosphorus ion source material, silicon ion source material, calcium ion source material, the monovalent cation source material and the divalent cation source material are blended, and the blending ratio of the silicon ion source material is In the mixing step of mixing as less than 4.0 mol%, the calcination step of calcining the mixture obtained in the mixing step, the molding step of molding the calcined body obtained in the calcination step, and the molding step A method for producing a biomaterial ceramic sintered body having a firing step in which the obtained molded body is fired at a temperature higher than 1000 ° C. and lower than 1150 ° C. is disclosed, and the biomaterial manufactured using such a manufacturing method is disclosed Ceramics may be used as a material for the substitute bone block of the present invention because it is excellent in mechanical strength and bioabsorbability.

  In the case of the substitute bone described in Patent Document 3, it is described that the ratio of the volume occupied by the through hole to the volume of the entire substitute bone is preferably 25 to 50%, and the ratio of the volume occupied by the through hole is 25%. It is said that excellent bioabsorbability can be obtained by setting it to -50%, but if the proportion of the volume occupied by the through-hole is 25% or more as described above, sufficient mechanical strength can be obtained. Therefore, it cannot be used for parts with a large load. Therefore, in the substitute bone described in Patent Document 3, the mechanical strength of the substitute bone can be improved by setting the volume ratio of the through hole to 25% or less. The bioabsorbability cannot be obtained. On the other hand, β-TCP with improved mechanical strength and bioabsorbability can be obtained by using the above-mentioned material as the bioabsorbable material used in the substitute bone block of the present invention. Even when the volume ratio is 25% or less, a substitute bone block having sufficient mechanical strength and excellent bioabsorbability can be obtained.

FIG. 8 is a schematic diagram showing another example of a substitute bone block. The substitute bone block of the present invention may be provided with a mark indicating the direction of the through hole on the surface of the block where the through hole is not provided. As described above, when the substitute bone block is implanted in the living body, the direction of the through hole is preferably implanted so as to be the same direction as the direction in which the load is most applied to the substitute bone block. However, if the shape of the substitute bone block is complicated, it is difficult to confirm the direction of the through hole from the surface where the through hole is not provided. Therefore, by providing a mark on the surface where the through hole is not provided, the direction of the through hole can be easily confirmed by looking at the surface where the through hole is not provided. As the “mark”, for example, as shown in (a), a recess (0801a) in a direction substantially parallel to the direction of the through hole may be provided on the surface where the through hole is not provided. Moreover, as shown in (b), you may provide a marker (0801b) in the surface in which the through-hole is not provided.
<Manufacturing method>

  FIG. 9 shows an example of a method for manufacturing a substitute bone block. In the present invention, the method for producing a substitute bone block is not particularly limited. For example, the substitute bone block of the present invention includes a mixing process (S0901), a first firing process (S0902), a grinding process (S0903), and a molding process. (S0904), a second firing process (S0905), a through-hole arrangement process (S0906), and an ultrasonic cleaning process (S0907).

In the mixing process (S0901), the starting materials are mixed. As a starting material, for example, diammonium hydrogen phosphate ((NH ₄ ) ₂ HPO ₄ ) and calcium carbonate are used as a phosphoric acid source and a calcium source, and wet mixed in a ball mill for a predetermined time (for example, 48 hours). In addition, after finishing wet mixing, the solvent is removed using an evaporator or the like. In the wet mixing, an organic solvent such as ethanol is used as a solvent. When diammonium hydrogen phosphate is used as the phosphoric acid source, ammonia gas is generated in the first firing process compared to using ammonium dihydrogen phosphate ((NH ₄ ) H ₂ PO ₄ ) as a raw material. And the quality of the substitute bone block can be improved.

  In addition, when using β-TCP in which vanadate ions are dissolved as a substitute bone block, vanadium oxide may be further used as a starting material. When β-TCP in which magnesium ions are dissolved is used, magnesium oxide may be further used as a starting material. When β-TCP in which sodium ions are dissolved is used, sodium carbonate may be further used as a starting material. Further, when β-TCP in which silicate ions are dissolved is used, silicon dioxide may be further used as a starting material.

  In the first firing process (S0902), the mixture obtained in the mixing process is fired. For example, the powder obtained in the mixing process is uniaxially pressed to create a molded body, and the formed molded body is fired. Here, the first firing process is a step of calcining the material. By performing calcining, the sinterability of the substitute bone block can be increased, and therefore the mechanical strength of the substitute bone block can be increased. Since the first firing process is a pre-baking step, the shape of the molded body is not particularly limited.

  In the grinding process (S0903), the fired product obtained in the first firing process is ground. The fired product can be pulverized using a ball mill or the like.

  In the molding process (S0904), the powder obtained in the pulverization process is pressure-molded to form a molded body. The molded body molded in the molding process may have the shape of an actual substitute bone block. However, since the shape of the molded body slightly changes due to the second firing process described later, the fired body is ground after the second firing process. And it is good also as a desired shape.

  In the second firing process (S0905), the molded body obtained by the molding process is fired. The firing method is not particularly limited. For example, the firing can be performed in an air atmosphere at a temperature rising temperature of 3 ° C./min, a firing temperature of 1100 ° C., a holding time of 24 hours.

  In the through hole arrangement process (S0906), a plurality of through holes are provided in one direction in the fired body obtained in the second firing process. Although there is no particular limitation on the arrangement method of the through holes, for example, the arrangement of the through holes is preferably performed by a drill. Laser processing or water jet processing may be used, but it is difficult to perform through holes well in both laser processing and water jet processing.

  In addition, when the through-hole arrangement | positioning in a through-hole arrangement | positioning process is performed with a drill, it is preferable that the material of a drill is iron or titanium as a main component. For example, if the drill used for arranging the through holes contains a substance harmful to the living body, the substance may adversely affect the living body. Iron and titanium are essential elements of the human body, and even when dissolved in the living body, there is little risk of adverse effects on the living body.

  Further, the order of the second firing process and the through hole disposing process may be reversed. That is, the through-hole disposing process may be performed after the second firing process, or the second firing process may be performed after the through-hole disposing process. When the through-hole disposing process is performed after the second firing process, the through-holes are provided in the sintered body. Since the sintered body has a very high hardness, it is not easy to arrange the through holes. However, when the through-hole arrangement process is performed before the second firing process, the through-holes can be easily arranged because the through-holes are provided in the molded body, not the sintered body.

  In the ultrasonic cleaning process (S0907), the fired body provided with the through holes is ultrasonically cleaned in a solvent. That is, shavings of the fired body mainly present on the surface in the through hole in the through hole disposing process are removed in the ultrasonic cleaning process. Since the shavings of the fired body are sharp, if left in the substitute bone block, there is a risk of adverse effects in vivo.

  Note that the ultrasonic cleaning process may include a sterilization / disinfection subprocess (S0908) which is a sterilization or / and disinfection process. For example, it is preferable to use an organic solvent such as ethanol or acetone as the solvent used for ultrasonic cleaning because the bone substitute can be sterilized or / and disinfected.

In this example, a test was conducted in which a substitute bone block was implanted in the rabbit femur and the effect of the substitute bone block on bone formation was confirmed.
<Experiment method>

(Test substance)
FIG. 10 shows a test substance (substitute bone block) used in this example. FIG. 11 shows the shape of the test substance used in the examples. The test was performed using six kinds of materials from A to F as test substances. Each test substance was processed into a cylindrical shape having a diameter of 4 mm and a height of 5 mm, and a through hole having a diameter of 0.3 mm was provided in one direction on the side surface of the cylindrical shape. For comparison, each test substance without a through hole was also prepared and tested. Each test substance was heated at 1100 ° C. to 1150 ° C. for 24 hours in order to perform sterilization treatment. Since test substance F has high hygroscopicity, it was heated under 1250 ° C. water vapor for 5 hours.

  In addition, the line shown with the dotted line of FIG. 11 has shown the size of the test substance after the 2nd baking process in the manufacturing method of a substitute bone. As already described above, the shape of the molded body slightly changes due to the second firing process. Therefore, after the second firing process and before the through holes are disposed in the through hole placement process, the fired body is ground. A test substance of the desired size was obtained. At that time, in order to accurately grind the test substance to a desired size and provide a through hole at a desired position, the fired body was subjected to two step hole processing.

(Animals used and breeding conditions)
20-22 weeks old Japanese white (Kbs: JW) healthy animals Rabbits, males, 15 animals were obtained from Kitayama Labes Co., Ltd. on December 19, 2014 and acclimatized and quarantined for 7 days or longer. Each test substance was implanted into the left and right femoral shaft ends one by one in all surviving animals confirmed to be normal by observation of body weight and general condition during the period. The weight range at the time of arrival was 2.94 to 3.44 kg and at the time of implantation was 2.96 to 3.42 kg.

  Animal temperature 19 ± 3 ℃, humidity 50 ± 15%, ventilation rate 10-15 times / hour (all fresh air supply) and lighting time 12 hours / day (8:00 on, 20:00 off), illuminance Reared in a room set to 150-300 Lux.

  For animal breeding, an aluminum cage (350W × 527D × 350H mm, Tokiwa Scientific Instruments Co., Ltd.) was used in an automatic water-washing stainless steel fixed rack (Tokiwa Scientific Instruments Co., Ltd.). In addition, the feed used the solid feed feeder made from stainless steel. Weakly acidic water (Ecoprowater, Hamley stockholder) was used to disinfect each equipment.

  During the acclimatization / quarantine period and during the test period, the animal feed was sterilized for laboratory animals (RC-4, Lot No. 140911, 141113, 141211, Oriental Yeast Co., Ltd.), and the drinking water was filtered through a 5 μm filter. Tap water was freely taken from the automatic water supply device. Regarding pollutants in feed, we obtain the analysis results for each lot conducted by Oriental Yeast Co., Ltd., and confirm that the concentration of pollutants such as residual agricultural chemicals conforms to the standards established by our laboratory. did. Drinking water is tested once a year by the Waterworks Law, Ministry of Health, Labor and Welfare Ordinance No. 101, twice a year to check whether drinking is possible or not at the Koto Institute for Microbial Research, Ltd. It was confirmed that it complies with the standards defined in.

(Individual and cage identification)
Each animal was individually identified by attaching a serial number to the auricle using oil-based ink at the time of arrival. Cages are labeled with the test number, strain and animal species, individual number, sex, date of arrival, acclimatization period until grouping, and the test number, strain and animal species, animal number (individual number) after grouping, A label describing the sex and duration of administration was attached.

(Production of bone defect model)
Mix equal amounts of ketamine hydrochloride (ketalal 500 mg, Lot No. GYA0028, GYA0030, Daiichi Sankyo Propharma Co., Ltd.) and xylazine (Seractal 2% injection, Lot No. KP09G51, Bayer Medical Co., Ltd.) , 0.4 mL / kg is introduced intramuscularly, followed by induction anesthesia and maintenance anesthesia with Japanese Pharmacopoeia Isoflurane (Elcaine, Lot No.124ATA, Mylan Pharmaceutical Co., Ltd.) using an inhalation anesthesia device IMPAC6 (VetEquip Inc) A bone defect model was made by drilling a Φ4 mm hole at one location at 1.5 mm from the knee joint and 1.2 mm from the knee pulley.

  A wide range from the left and right knee joints to the femur is shaved with an electric clipper (THRIVE Model6000AD, Natsume Seisakusho Co., Ltd.), and isodine for animals (Lot No.ADDL706, ADDL704, Meiji Seika Co., Ltd.) and ethanol for disinfection (Lot) No.KPK6570, Wako Pure Chemical Industries, Ltd.) was thoroughly disinfected and then cut and exposed from the fascia part to expose the femoral shaft and epiphyseal part so as not to damage the muscle as much as possible. The diameter was gradually increased using an electric drill (Nagata Kikai Co., Ltd. and Ryobi Co., Ltd.), and finally a hole with a diameter of 4 mm was formed in one place. At the time of preparation, Japanese Pharmacopoeia physiological saline solution (Lot No.13I30C, 14B17C, Fuso Pharmaceutical Co., Ltd.) containing antibiotics (enrofloxacin for injection, Lot No. KP09G55, KP08SP3, Bayer Yakuhin Co., Ltd.) While dripping, the bone fragments were washed away and the bone cells were prevented from being killed by heat. After thoroughly washing the surgical site, excess water was removed and the test substance was implanted in the bone resection site. The bone was not fixed with an instrument. After confirming that the test substance was left at the site of the bone defect, the muscle, connective tissue, and skin were sutured, and the surgical site was disinfected with isodine for animals. The surgical instrument was disinfected with 5% Hibiten solution (Lot No.3355C, Dainippon Sumitomo Pharma Co., Ltd.).

  After the operation, disinfection and antibiotics (enrofloxacin, Lot No. KP09G55, KP08SP3, Bayer Yakuhin Co., Ltd.) were administered with animal isodine (Lot No. ADDL706, ADDL704, Meiji Seika Co., Ltd.) to prevent suppuration. In addition, an analgesic (Pubrenorphine, Lot No. 3B88L2, Otsuka Pharmaceutical Co., Ltd.) was administered for 3 days.

(contents of the test)
The test substance was implanted in holes made in the left and right femurs of one individual. Two samples were provided at each point for communication holes, and one sample was obtained for each week without communication holes. X-rays were taken at the time of implantation and planned killing. The test substance was administered once at the time of defect site preparation, and specimens were collected after completion of observation for 4 and 12 weeks. The sample was fixed for 1 day with a 10% neutral buffered formalin fixative and immediately changed to a 70% alcohol solution and fixed. Two non-decalcified polished specimens were prepared, one was confirmed for fluorescence and one was HE stained.

(Bone marking)
To analyze bone tissue dynamics, calcein (Lot No. CW071, Dojindo Laboratories, Inc.) 10 mg / 0.4 ml / kg on the back 7 days before and 3 days after autopsy for non-decalcified specimens Double labeling was performed by subcutaneous administration. The values for body weight used were the latest values (administration schedule 1-3-1-2). Calcein was dissolved in 2% sodium hydrogen carbonate solution (distilled water (Lot No. K4E81, Otsuka Pharmaceutical Factory Co., Ltd.) added with sodium hydrogen carbonate (Lot No. 509H1500, Kanto Chemical Co., Inc.)).
<Observation / measurement items>

(General condition)
All survivors were observed at least once daily and observed for abnormalities. Observation points were observed such as food intake, urination / feces, activity and appearance. The state of feeding was described as leaving food when 1/3 or more of the food fed 120 g was left. The state of urine / feces was described as abnormal if urine / feces were reduced or not observed. As for activity, the state in which the activity increased or decreased from the normal state was described as abnormal. Appearance was described as abnormal findings such as the presence of eyelids, such as the condition of hair being rough and hair loss, mucosal hyperemia.

(body weight)
All survivors were measured with an electronic balance SK-10KWP (A & D Co., Ltd.) at the time of arrival, at the time of implantation, and at the time of necropsy.

(X-ray photography)
All survivors were taken immediately after implantation and at necropsy. After necropsy, the test substance was removed and soft X-ray was taken. Immediately after implantation, an X-ray photograph of the implanted part was taken from one direction to confirm the implanted state of the test substance and the healing state of the bone. The X-ray diagnostic device VPX-40A (Toshiba Medical Supplies Co., Ltd.) dedicated to small animals was used for photographing, and the film was HR-S30 (Lot No. 87401C, 87403C, Fuji Film Co., Ltd.) at 46 KV and 3.00 mAs. The sample after extraction was performed under conditions of 3.5 KV, 3.5 mA, and 230 seconds using a soft X-ray imaging apparatus (M-60 type, Softex Corporation). FR (Lot No.33934F, FUJIFILM Corporation) was used as the film. High Ren Doll (Lot No. 4AB1, 4JB1, FUJIFILM Corporation) was used as the developer, and High Ren Fix (Lot No. 4CC1, 4GC1, FUJIFILM Corporation) was used as the fixing.

(Sample collection)
At the time of planned killing, blood was lethal and lethal under anesthesia with pentobarbital acid Na (Lot No. 4005101, Kyoritsu Pharmaceutical Co., Ltd.), and the femur at the site of implantation was collected. It was immersed and fixed in a 10% neutral buffered formalin solution (Lot No. KPJ4123, Wako Pure Chemical Industries, Ltd.), and fixed the next day with a 70% alcohol solution.
<Tissue preparation>

(Resin embedding)
After trimming the test substance and the surrounding mother bone with a band saw (Hozan Co., Ltd.), dehydrating with an alcohol dehydration column and replacing with acetone, and passing through acetone, monomer, and monomer, according to a conventional method Resin embedding was performed. In order to evacuate the air in the tissue and in order to accelerate the penetration of each solution, the air was appropriately evacuated. The embedding MMA resin was used as the resin. In addition, an additional MMA was added as appropriate so that the tissue was sufficiently embedded in the resin, and the polymer was completely polymerized in an incubator at about 35 ° C to prepare a polished specimen of about 20 µm.

  The MMA resin is prepared by adding 40 g of MMA polymer (Wako Pure Chemical Industries, Ltd.) to 100 mL of MMA monomer (Wako Pure Chemical Industries, Ltd.) and completely dissolving the MMA for embedding. Thereafter, 1 g of Benzoyl peroxide (Nacalai Tesque Co., Ltd.) was added and completely dissolved. For MMA for addition, 40 g of MMA polymer (Wako Pure Chemical Industries, Ltd.) was added to 100 mL of MMA monomer (Wako Pure Chemical Industries, Ltd.) and completely dissolved. Thereafter, Benzoyl peroxide (Nacalai Tesque Co., Ltd.) was added at a rate of 1.5 g and completely dissolved.

(Polished specimen)
It was produced on a plane as parallel as possible to the long axis surface of the produced small hole. Polishing using a micro-cutting machine (BS-3000N, EXAKT GmbH, Germany) and a micro-grounding machine (MG-4000N, EXAKT GmbH, Germany) One sheet was produced. Staining was performed with toluidine blue staining and HE staining.
<Test results>

(General condition)
There were no deaths in the study. In addition, food leftovers occurred frequently in all individuals until the 4th day after implantation, and then sporadically in some individuals, but this was caused by implanting the test substance into the bone by surgery under anesthesia. Judged to be. There were no abnormal findings in other general conditions. In all cases, body weight recovered at 4 weeks after model preparation, and no abnormal increase or decrease was observed.

(Fluorescent label)
FIG. 12 shows the results of observation of the fluorescent label after 4 weeks from the implantation of each test substance. The part surrounded by white is each test substance, and the high-intensity part shows the state of regenerating bone. In addition, the shape of the through hole is different in each figure because the surface observed as a fluorescent label is different in each test substance. In test substances A and B, slight bone regeneration is observed on the surface of the through-hole. In Test Substances C and D, bone regeneration was clearly observed on the surface of the through-hole, and the bone was regenerated but was thicker than Test Substances A and B. That is, the test substances C and D are superior in bioabsorbability compared to the test substances A and B. For Test Substances D and F, bone regeneration was observed on the surface of the through hole.

  FIG. 13 shows the observation results of the fluorescent label 12 weeks after each test substance was implanted. In the test substances A and B, the entire surface of the through hole shines brightly, that is, bone regeneration is observed on the entire surface of the through hole. Further, in the test substances C and D, the entire inside of the through hole is shining thinly, that is, bone formation occurs not only on the surface of the through hole but also the entire inside of the through hole.

  In addition, in FIG. 14, each test substance which does not provide the through-hole is implanted, and the observation result of the fluorescent label 12 weeks after is shown. In each of the test substances a to d, it can be seen that the surface of the test substance is slightly shining, that is, bone regeneration is performed on the surface of the test substance, but no particular change was observed inside each test substance. . Therefore, compared with each test substance provided with the through-hole shown in FIGS.

(HE staining)
FIG. 15 shows the observation results of the specimen after HE staining (hematoxylin / eosin staining) 4 weeks after each test substance was implanted. In addition, the part enclosed in white is each test substance, and it is a bone cell that shows the dark color outside the test substance. In test substances A and B, no invasion of bone cells was observed inside the through-hole, whereas in test substance C, invasion of bone cells was slightly observed on the surface of the through-hole. In addition, regarding the test substances D to F, it was clearly confirmed that bone cells had invaded the inside of the through-hole, and it was found that bone formation was progressing.

  FIG. 16 shows the observation result of the specimen after H.E. staining 12 weeks after each test substance was implanted. In each test substance, invasion of bone cells into the inside of the through-hole was confirmed, but test substances C and D were compared with test substances A and B in a manner corresponding to the experimental results shown in FIG. The amount of bone cells invading into the through hole was large. In the figure of the test substance C, the surface of the through hole is uneven, which indicates that the test substance is dissolved in the living body by osteoclasts.

  In addition, in FIG. 17, each test substance which does not provide the through-hole is implanted, and the observation result of the specimen after 12 weeks of H.E. staining is shown. It can be seen that any test substance has bone cells attached to the surface of the test substance.

Schematic diagram showing an example of a bone substitute block Outline diagram showing another example of bone substitute block The figure which shows the relationship between the mechanical strength of a substitute bone block and the direction of a through-hole Outline diagram showing another example of bone substitute block Outline diagram showing another example of bone substitute block Diagram showing surface roughness of through-hole Diagram showing the crystal structure of β-TCP Diagram showing solid solution form of monovalent and divalent metal ions in β-TCP Outline diagram showing another example of bone substitute block The figure which shows an example of the manufacturing method of a substitute bone block The figure which shows the test substance used in the Example The figure which shows the shape of each test substance used in the Example The figure which shows the observation result of the fluorescent label 4 weeks after implanting the test substance The figure which shows the observation result of the fluorescent label 12 weeks after implanting the test substance The figure which shows the observation result of the fluorescent label 12 weeks after implanting each test substance which does not provide the through hole The figure which shows the observation result of the specimen after H.E. dyeing 4 weeks after implanting the test substance The figure which shows the observation result of the specimen after H.E. dyeing 12 weeks after implanting the test substance The figure which shows the observation result of the specimen after implanting each test substance which does not have a through-hole, and 12 weeks later H.E.

0101: Substitute bone block, 0102: Through hole, 0103, one direction

Claims (13)

  A substitute bone block having bioabsorbability provided with a plurality of through holes in one direction.   The substitute bone block according to claim 1, wherein the surface roughness Ra in the through hole is 1 μm to 100 μm.   The substitute bone block according to claim 1 or 2, wherein the diameter of the through hole is 20 to 2500 µmφ.   The substitute bone block according to any one of claims 1 to 3, wherein a ratio of a volume occupied by the through hole to a volume of the entire block including the through hole is 25% or less.   The substitute bone block according to any one of claims 1 to 3, wherein a ratio of a volume occupied by the through hole to a volume of the entire block including the through hole is 50% or more. 6. The β-type tricalcium phosphate in which 3 mol% or less of vanadate ion (VO ₄ ³⁻ ) is solid-solved with respect to the phosphate ion (PO ₄ ³⁻ ) of β-type tricalcium phosphate. A substitute bone block according to any one of the above. In addition to vanadate ion (VO ₄ ^3- ), 9.1 mol% or less of sodium ion (Na ⁺ ) and magnesium ion (Mg ²⁺ ) with respect to calcium ion (Ca ²⁺ ) of β-type tricalcium phosphate The substitute bone block according to claim 6, wherein any one or more of 9.1 mol% or less is dissolved. Less than 4 mol% of silicate ion (SiO ₄ ^4- ) with respect to phosphate ion (PO ₄ ^3- ) of β-type tricalcium phosphate, and further against calcium ion (Ca ²⁺ ) of β-type tricalcium phosphate The sodium ion (Na ⁺ ) is 9.1 mol% or less and the magnesium ion (Mg ²⁺ ) is 9.1 mol% or less of β-type tricalcium phosphate. Substitute bone block.   The substitute bone block according to any one of claims 1 to 8, wherein a mark indicating a direction of the through hole is provided on a surface of the block where the through hole is not provided. A mixing process to mix the starting materials;
A first firing process for firing the mixture obtained in the mixing process;
A pulverization process for pulverizing the fired product obtained in the first firing process;
A molding process in which the powder obtained in the pulverization process is pressure-molded to create a molded body;
A second firing process for firing the molded body obtained in the molding process;
A through-hole arrangement process in which a plurality of through-holes are provided in one direction in the fired body obtained by the second firing process;
An ultrasonic cleaning process for ultrasonically cleaning the fired body provided with through holes in a solvent;
A method of manufacturing a substitute bone block having   The method of manufacturing a substitute bone block according to claim 10, wherein the ultrasonic cleaning process includes a sterilization / disinfection subprocess which is a sterilization or / and disinfection process. Through hole placement in the through hole placement process is done with a drill,
The method for manufacturing a substitute bone block according to claim 10 or 11, wherein a material of the drill is iron or titanium as a main component.   The method for producing a substitute bone block according to any one of claims 10 to 12, wherein diammonium hydrogen phosphate, calcium carbonate, vanadium oxide, magnesium oxide, sodium carbonate, or silicon dioxide is used as a starting material.