JP6963966B2 - Porous ceramic material and its manufacturing method - Google Patents

Description

The present invention relates to a porous ceramic material and a method for producing the same.

Among ceramic materials, calcium phosphate-based ceramic materials are the main components of bones and teeth, have excellent biocompatibility, and are also excellent in safety. Therefore, implant materials such as artificial bones and regenerative medicine It has been widely studied as a biomaterial such as a scaffold material for cell culture used in the above and a drug-carrying material for a drug delivery system (DDS).

Artificial bones made of calcium phosphate-based ceramic materials are used in the treatment of fractures, bone tumors, and degenerative diseases of bone. Bone conduction (providing an environment suitable for bone formation, migrating and fixing bone-forming cells, and in-situ bone formation) is particularly important as the performance required for calcium phosphate-based ceramic materials as artificial bone. The property of forming) and the strength to withstand intraoperative handling.

However, bone conductivity and strength are contradictory performances. In order to ensure bone conductivity, it is preferable to make the calcium phosphate-based ceramic material porous so that it has abundant pores that serve as entry paths for cells, bone and vascular tissues. On the other hand, in order to secure the strength, it is preferable that the pores are not included as much as possible. Therefore, in order to solve this dilemma, many studies have been conducted on the porous structure (amount and shape of pores) of calcium phosphate-based ceramic materials.

Porous calcium phosphate ceramic materials include (1) a large number of pores are densely distributed three-dimensionally, and adjacent pores have spherical open pores that communicate with each other in the skeletal wall that separates them. Sintered bodies (see Patent Document 1), (2) bead aggregates constructed by connecting bead-shaped porous ceramic materials having pores with nylon wires or the like (see Patent Document 2) have been proposed.

Further, it is disclosed that a sintered body having a diameter of 10 to 500 μm and having pores oriented in one direction and penetrating is a calcium phosphate-based ceramic material suitable as an artificial bone (Patent Documents 3 and 4). reference).

Japanese Patent No. 3470759 Japanese Unexamined Patent Publication No. 2003-335574 Japanese Unexamined Patent Publication No. 2004-275202 Japanese Unexamined Patent Publication No. 2005-1943

However, in the proposal according to Patent Document 1, since the pore diameter of the communicating portion formed by the open pores of the continuous ball is small and the pores do not have orientation, there may be pores in which the new bone does not easily penetrate into the material or cannot penetrate. Further, in the proposal of Patent Document 2, since a large number of beads are connected by a nylon wire or the like, the practicality is low.

Further, in the proposals described in Patent Documents 3 and 4, when the present inventors retested, it became clear that the invasion of cells and tissues was inferior in the direction perpendicular to the orientation direction of the pores.

The present invention has been made in view of the above circumstances, and an object of the present invention is a porous ceramic material having both good bone conductivity and practical strength, and an efficient manufacturing method thereof. Is to provide.

In order to solve the above problems, the present inventors have completed the present invention having the following features.
That is, the present invention is as follows.
[1] A porous ceramic material having pores that are substantially oriented in one direction and penetrate and granular pores formed in a ceramic region between the pores.
[2] The porous ceramic material according to the above [1], which comprises a sintered body having a pore diameter of 10 μm or more and less than 30 μm and a pore floor area ratio of 10% or more.
[3] The above-mentioned [1] or [2], wherein the granular pores formed in the ceramic region are spherical pores, and the pore diameter of the spherical pores is 3 to 40 μm. Porous ceramic material.
[4] Step A: A step of preparing a slurry by dispersing a ceramic raw material and organic beads in a medium.
Step B: A step of filling a predetermined container with a slurry and freezing the slurry in one direction.
Step C: Porous having pores that are substantially unidirectionally oriented and penetrate, including a step of drying the frozen slurry to obtain a molded product, and a step D: a step of firing the dried molded product. Method for manufacturing quality ceramic materials.
[5] The method according to the above [4], wherein the organic beads are organic spherical beads.
[6] The method according to [4] or [5] above, wherein the content of the organic beads in the slurry is 2 to 6% by weight based on the total weight of the slurry.
[7] The method according to any one of the above [4] to [6], wherein the average particle size of the organic beads is 3 to 40 μm.

According to the present invention, cells and tissues can invade not only in the orientation direction of pores oriented in one direction and penetrating, but also in the direction perpendicular to the orientation direction of the pores, resulting in good osteoconductivity and practicality. To provide a method for producing a porous ceramic material, which can realize a porous ceramic material having a high strength and particularly suitable for artificial bones, and can easily and efficiently produce such a porous ceramic material. Can be done.

It is a perspective view which showed typically an example of the porous ceramic material of this invention. It is a schematic cross-sectional view which expanded and showed the space between the adjacent pores of the pores which are oriented substantially in one direction and penetrate in the porous ceramic material of FIG. It is a figure which showed typically an example of the manufacturing method of the porous ceramic material of this invention. It is a schematic diagram of an example of a freezing apparatus used in a slurry freezing step in the method for producing a porous ceramic material of the present invention. A schematic cross-sectional view of the frozen slurry (FIG. 5 (A)), a schematic cross-sectional view of the molded body after drying of the frozen slurry (FIG. 5 (B)), and a sintered body obtained by firing the molded body. It is a schematic cross-sectional view (FIG. 5 (C)). 6 is an SEM observation image of a cross section of the ceramic material produced in Example 2. It is an SEM observation image of the cross section of the ceramic material produced in Comparative Example 2. It is a micro CT observation image after an animal experiment of the ceramic material produced in Example 2. It is a microscopic observation image (central part of the cortical bone part) of the tissue sample after the animal experiment of the ceramic material produced in Example 2.

Hereinafter, the present invention will be described according to its preferred embodiment.
FIG. 1 is a schematic perspective view of an example of the porous ceramic material of the present invention.
The porous ceramic material of the present invention has pores 12 that are substantially oriented in one direction and penetrate as shown in the porous ceramic material 11 (FIG. 1) of the example. Here, the individual pores of the pores 12 that are substantially oriented in one direction and penetrate are regions that are spaces inside the ceramic material 11 without the presence of the ceramic substance. In the present invention, "the pores are substantially oriented in one direction" means that there are a plurality of pores 12 extending in the uniaxial direction, and the direction of the long axis of the plurality of pores is substantially one direction. It means that it is aligned with. More specifically, the major axis directions of, for example, half or more, preferably 80% or more of the uniaxially extending pores in the ceramic material are aligned within a range of, for example, an angle of 30 ° or less. The "angle" here is the intersection angle of the normal projection of the long axis of the pores on an arbitrary plane. Further, "penetration" means that the pores penetrate the ceramic material in the direction of the long axis thereof.

The area of the cross section perpendicular to the orientation direction of each pore of the pore 12 (hereinafter, also referred to as “alignment penetration pore 12”) that is substantially oriented and penetrates in one direction is preferably 0.05 × 10 ^{−. It is 3 to} 100 × 10 ^-3 mm ² , and more preferably 0.05 × 10 ^-3 to 50 × 10 ^-3 mm ² . The "orientation direction" as used in the present invention is the direction of the long axis of the pores having the same number of pores and having the same number of long axes among the pores 12 that are substantially oriented and penetrate in one direction. .. When the area of the cross section is within the above range, the size is sufficient for cells, bones, and vascular tissues to invade, and the capillary phenomenon facilitates the passage of body fluids such as blood. However, in order to solve the problem of the present invention, it is not always necessary that the cross sections of all the pores of the oriented through pores 12 have exactly the above area. The shape (planar shape) of the cross section perpendicular to the orientation direction of each pore of the alignment through pore 12 is not particularly limited as long as the area of the cross section is within the above range.

To determine the cross-sectional area of the individual pores of the oriented through-pores 12, embed the porous ceramic material to be measured in a resin, slice it perpendicular to the orientation direction, and use an electron microscope or the like to slice it. It can be obtained by observing and measuring the opening area derived from the pores of interest in order. At this time, by cutting out the material to be measured every 1 mm and measuring the opening area in each cross section, the transition of the cross-sectional area of the pores over the length direction of the orientation of the pores can be measured with an accuracy suitable for the object of the present invention. Can be evaluated.

The length of the individual pores of the oriented through pores 12 in the major axis direction is preferably 5 mm or more, more preferably 10 mm or more, still more preferably 20 mm or more, and particularly preferably 30 mm or more. The upper limit of the length is not particularly limited. If the pores have a sufficient length, it becomes easy to obtain an implant material or the like by processing such as cutting. However, in order to solve the problem of the present invention, it is not necessary that all the pores of the oriented through pores 12 have the above length.

FIG. 2 is a schematic cross-sectional view showing an enlarged space between adjacent pores in the oriented through pores 12 formed in the porous ceramic material 11 of FIG. That is, as shown in FIG. 2, the porous ceramic material of the present invention has pores adjacent to the oriented through-pores 12 in order to ensure cell invasion even in the direction perpendicular to the orientation of the oriented through-pores 12. Granular pores 14 are also present in the ceramic region 13 (hereinafter, also referred to as “ceramic wall”) between 12A and 12B. The granular pores 14 may exist in a state in which a plurality of pores are connected to each other and penetrate the ceramic wall 13.

In the porous ceramic material of the present invention, since granular pores 14 are present in the ceramic region 13 between the adjacent pores of the oriented through-pores 12, cells and bones that have invaded the porous ceramic material through the oriented through-pores 12. -The vascular tissue can easily move and extend between the adjacent pores in the oriented penetrating pores 12 via the granular pores 14.

The granular pores 14 are preferably spherical pores. As shown in a specific example of the method for producing a porous ceramic material of the present invention described later, the granular pores 14 are usually pores (removal marks of organic beads) formed from organic beads.

The "spherical shape" of the "spherical pore" means, for example, an image of a cross section of the pore using a scanning electron microscope (SEM), and the measured pore area (S) based on the image. ) And the peripheral length (L), the circularity calculated based on the following formula expressing the circularity (the perfect circle is 1.0, and the more indefinite it becomes, the closer it is to 0.0) is 0.8 or more. It means that there is.
Circularity = 4π × S / L ²

The pore size of the granular pores 14 is not particularly limited, but is preferably 3 to 40 μm, more preferably 10 to 30 μm, and even more preferably 10 μm or more and less than 30 μm. Within the above range, movement and extension between adjacent pores 12A and 12B in the oriented penetrating pores 12 via the pores 14 of cells and bone / vascular tissues that have invaded the porous ceramic material through the oriented penetrating pores 12. Can proceed more easily.

The pore diameter of the granular pores 14 is determined by, for example, embedding a porous ceramic material to be measured in a resin, slicing it, observing it with a scanning electron microscope (SEM) or the like, and observing the area of the pores of interest. It is measured by measuring the equivalent circle diameter. Specifically, the following method was adopted.
For the cross-sectional area of the pore with the largest cross-sectional area in the sliced sample, the equivalent circle diameter is calculated by the following formula, and this is used as the pore diameter of the pore 14.
Circle equivalent diameter = {4 x (cross-sectional area) ÷ π} positive square root

Further, the abundance of the granular pores 14 in the ceramic wall 13 is preferably such that the area ratio (%) of the granular pores 14 in the cross section of the ceramic wall 13 is about 5 to 40%. If the area ratio (%) is less than 5%, the effect of cell or tissue invasion in the direction perpendicular to the orientation direction of the stomata cannot be expected, and if it exceeds 40%, it is possible that the strength to withstand intraoperative handling cannot be secured. There is sex. The area ratio referred to here is calculated by the following formula from a scanning electron microscope (SEM) observation image of a cross section of a ceramic material.
Area ratio (%) = [total area of granular pores / (total area of granular pores + area of ceramic region)] x 100

The "area of the ceramics region" in the above formula also includes the area of the sintered particle gaps (pores at the 1 μm level) of the ceramic raw material particles (inorganic particles).

In the calcium phosphate-based ceramic materials described in Patent Documents 3 and 4, when transplanted so that the orientation direction of the pores that are substantially oriented in one direction and the long axis direction of the mother bed bone are "parallel". , Cells and tissues efficiently invade the inside of the material from the stump of the mother bed bone through the entrance of the stomata. On the other hand, when transplantation is performed so that the orientation direction of the pores that penetrate substantially in one direction and the long axis direction of the mother bed bone are "vertical", the entrance of the pores is the stump of the mother bed bone. Since it does not come into contact with the cells, the invasiveness of cells and tissues is slightly reduced as compared with the case of transplanting so as to be "parallel". For this reason, in clinical use, it is recommended to transplant so that the orientation direction of the pores that penetrate in substantially one direction and the long axis direction of the mother bed bone are "parallel". ..

However, in actual clinical practice, it may be difficult to implant by arranging the orientation direction of the pores that are substantially oriented in one direction and the longitudinal direction of the mother bed bone in "parallel". In the porous ceramic material of the present invention, since the ceramic wall 13 between the adjacent pores of the oriented through-pores 12 also has pores 14, the orientation direction of the pores of the oriented through-pores 12 and the longitudinal direction of the mother bed bone It is possible to ensure good stomata of cells and tissues even when the ceramics are arranged "parallel" and cannot be transplanted.

The porosity of the porous ceramic material of the present invention is preferably 40 to 90%, more preferably 50 to 80%. When the porosity is 40% or more, sufficient tissue, for example, bone / vascular tissue is expected to be formed in the material after in vivo transplantation. On the other hand, if the porosity is 90% or less, practical strength is secured.

The "porosity" referred to here is measured in accordance with JIS R 1634. Specifically, it is as follows. A columnar test piece having a diameter of 6 mm and a height of 7 mm is cut out from the porous ceramic material to be evaluated. The weight and volume of the test piece are measured, and the porosity is calculated from the following formula.
Bulk density = (weight of test piece) / (volume of test piece)
Porosity (%) = (1-bulk density / theoretical density) x 100

As will be described later, the porous ceramic material of the present invention is typically a sintered body obtained by firing a molded product obtained by freezing and drying a slurry containing inorganic particles and organic beads, which are ceramic raw materials. A viewpoint that enables tissue fluid such as blood and bone marrow fluid that has invaded the ceramic wall between adjacent pores 12A and 12B of the oriented penetrating pore 12 and cells contained in body fluid to move more easily between the adjacent pores. Therefore, it is a sintered body in which the porosity of pores (macropores) having a pore diameter of 10 μm or more and less than 30 μm, which is obtained by measuring the integrated pore volume distribution by the mercury intrusion method, is 10% or more of the total pore volume. preferable. The pore volume ratio of the pores (macropores) having a pore diameter of 10 μm or more and less than 30 μm is preferably 11% or more, more preferably 12% or more. Further, it is preferable to have macropores having a relatively small pore size corresponding to the sintered particle gaps, and the pore size of the macropores having a relatively small pore size is preferably 0.1 to 5 μm. Having such macropores having a relatively small pore diameter has an advantageous effect on absorption of the porous ceramic material and bone formation as the surface area increases. Further, from the viewpoint of the balance between the rapid invasion of tissue fluid such as blood and bone marrow fluid into the porous ceramic material and the cells contained in the body fluid and the strength of the porous ceramic material, pores having a pore diameter of 30 μm or more (pores having a pore diameter of 30 μm or more). The porosity of the macropores) is preferably in the range of 30-99% of the total pore volume, more preferably in the range of 70-95%. Normally, the pores (macropores) having a pore diameter of 10 μm or more and less than 30 μm mainly reflect the pore diameter of the granular pores 14 in the ceramic wall 13, and the pores (macro pores) having a pore diameter of 30 μm or more are oriented and penetrated. The minor diameter of the pores (ie, the pore diameter perpendicular to the major axis of the oriented through-stomata) is reflected.

Further, the porous ceramic material of the present invention is preferably a porous calcium phosphate-based ceramic material using a calcium phosphate-based ceramic raw material as a ceramic raw material from the viewpoint of bone formation.

Next, a method for producing a porous ceramic material having pores that are substantially oriented in one direction and penetrate through the present invention will be described.
The method for producing a porous ceramic material having pores that are oriented and penetrates substantially in one direction of the present invention is typically produced by the following method, but is not limited thereto.

FIG. 3 is a diagram schematically showing an example of a method for producing a porous ceramic material having pores that are substantially oriented in one direction and penetrate through the present invention.
After the slurry preparation step (step A: FIG. 3 (A)) in which the ceramic raw material and the organic beads are dispersed in the medium to prepare the slurry 21, the obtained slurry 21 is filled in the container 31 (FIG. 3 (B)). , The container 31 is inserted into a refrigerant below the freezing point of the slurry in a certain direction (the direction of the arrow in FIG. 3C), and the slurry is frozen in one direction from one end side (step B). A step of drying the slurry to obtain a molded body (step C), and a step of firing the dried molded body to obtain a porous ceramic material 11 having pores that are substantially oriented in one direction and penetrate through (step C). Step D: FIG. 3 (D))).

Hereinafter, the production method of the present invention will be described in more detail according to each step.
FIG. 3 (A) schematically represents the preparation of the slurry. The slurry 21 used in the step A can be prepared by dispersing the ceramic raw material and the organic beads in a medium. Here, the "ceramic raw material" is an inorganic particle for producing the porous ceramic material of the present invention, and is preferably an inorganic particle for producing a calcium phosphate-based ceramic material. Further, the slurry 21 is preferably dissolved or dispersed with an additive described later.

Examples of the calcium phosphate-based ceramic raw material include hydroxyapatite, fluorine apatite, chlorine apatite, tricalcium phosphate, calcium metaphosphate, tetracalcium phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate and the like. , Or a mixture of any two or more of these. In addition, some of the Ca components in the calcium phosphate-based ceramic raw material are Sr, Ba, Mg, Fe, Al, Y, La, Na, K, Ag, Pd, Zn, Pb, Cd, H, and these exemplified elements. It may be replaced with one or more selected from other rare earth elements other than the rare earth elements contained therein. Further, a part of the (PO ₄ ) component may be replaced with one or more selected from _{VO 4} , BO ₃ , SO ₄ , CO ₃ and SiO _4. Further, a part of the (OH) component may be replaced with one or more selected from _{F, Cl, O, CO 3, I, and Br.}

From the viewpoint of bone formation, the calcium phosphate-based ceramic raw material is preferably hydroxyapatite, fluorine apatite, chlorine apatite, or tricalcium phosphate, and more preferably hydroxyapatite or tricalcium phosphate. The calcium phosphate-based ceramic raw material may be derived from a natural mineral or chemically synthesized by various wet methods, dry methods, or the like.

The content of the ceramic raw material in the slurry 21 is preferably in the range of 10 to 60% by weight, more preferably in the range of 20 to 50% by weight, based on the total weight of the slurry.

As the medium used for dispersing the ceramic raw material, one having a sublimation property that can be removed by freeze-drying, which will be described later, is preferable. For example, water, tert-butyl alcohol, benzene and the like can be mentioned, and water is preferable. Further, the water preferably has a high degree of purification, and distilled water, ion-exchanged water, purified water, sterilized purified water, water for injection and the like are preferable.

The organic beads may be generally called plastics, preferably those that do not melt at room temperature (25 ° C.), are unnecessary for water, and do not contain contamination with inorganic substances. Specifically, plastic beads selected from (meth) acrylic acid ester polymers, phenol resins, epoxy resins, polyethylene glycol and the like are exemplified. Of these, polymethyl methacrylate beads are preferable.

The content of the organic beads in the slurry is preferably in the range of 2 to 6% by weight, more preferably in the range of 2 to 5.5% by weight, based on the total weight of the slurry. If the content of the organic beads exceeds 6% by weight based on the total weight of the slurry, it becomes difficult for the crystals 61 of the frost columnar medium to grow in step B, and if it is less than 2% by weight, the cells in the direction perpendicular to the orientation direction of the pores 12 and the cells It may not be possible to secure a sufficient amount of granular pores to ensure tissue permeability. The weight ratio of the organic beads to the ceramic raw material (organic beads: ceramic raw material) is preferably 0.03: 1 to 0.6: 1, more preferably 0.05: 1 to 0.15: 1.

The organic beads may be either spherical particles or non-spherical particles, but spherical particles (organic spherical beads) are preferable from the viewpoint that the pore diameter of the pores 14 can be controlled relatively uniformly. Further, when the organic beads are measured by a laser diffraction method, the average particle size is preferably in the range of 3 to 40 μm, more preferably in the range of 10 to 40 μm. The average particle size referred to here can be measured by creating a particle size distribution of organic beads on a volume basis with a laser diffraction / scattering type particle size distribution measuring device and using the median size as the average particle size. As the measurement sample, organic beads dispersed in a dispersion medium such as purified water by ultrasonic waves can be preferably used.

The "spherical particles" are those having a sphericity in the range of 0.8 or more and 1.0 or less, and the "non-spherical particles" are those having a sphericity of 0.8 or more and 1.0 or less. It means particles that do not correspond to spherical particles in the following range. The shape of the non-spherical particles means that they are not substantially spherical, and examples thereof include flakes, needles, plates, lumps, and fibers. Here, the sphericity is the ratio (DS / DL) of the maximum diameter (DL) of a particle in a photographic projection drawing obtained by taking a photograph with a scanning electron microscope and the minor diameter (DS) orthogonal to this. means.

The slurry 21 is formed into a slurry for the purpose of increasing the viscosity of the slurry to improve the dispersibility of the slurry, maintaining the shape of the ceramic porous molded product before firing, and further controlling the growth of crystal particles during sintering. It is preferable to dissolve or disperse the additive. The additive is not particularly limited as long as it is a compound or composition that can achieve the above object, but a condensed polymer which is an organic substance that burns and burns during sintering is preferable. In this case, since the components derived from the additives do not substantially remain in the ceramic material obtained after firing, it is excellent in safety to living organisms. Examples of such additives include polyvinyl alcohol, polyacrylamide, ammonium polyacrylate, polyglycolic acid, polylactic acid, polyhydroxybutyrate, agarose, collagen, gelatin and the like. These additives may be used alone or in combination of two or more. If necessary, components other than the above-mentioned components may be added to the slurry 21 as long as the object of the present invention is not impaired.

When additives are added to the slurry, the amount of the additives to be added is preferably 0.1 to 20% by weight, more preferably 3 to 10% by weight, and ranges from 5 to 8% by weight, based on the total weight of the slurry. Is more preferable.

The slurry 21 can be prepared by a known method. Typically, the slurry 21 is prepared by adding ceramic raw materials, organic beads and, if necessary, additives to the medium with stirring. It is preferable to perform the defoaming treatment of the slurry 21. In this case, it is possible to prevent bubbles from remaining in the slurry and, as a result, undesired holes (defects) due to bubbles in the sintered body. As a method of defoaming treatment, a known method may be used, and examples thereof include a method of defoaming while stirring in a vacuum, a method of defoaming by planetary kneading and the like.

FIG. 3C schematically shows a step (step B) of freezing the slurry 21 in the container 31. In step B, the slurry 21 freezes in one direction from one end side, so that crystals of the frost columnar medium grow. Specifically, the slurry 21 obtained in step A is filled in a container 31, and the container 31 is inserted (immersed) in a refrigerant 41 cooled below the freezing point of the slurry 21 to insert (immerse) the slurry 21 in the container. Is frozen in one direction from one end side (that is, the end side on the tip side in the insertion direction of the container 31) to obtain a molded slurry. As a result of such freezing, crystals of the solidified medium having frost columns grow in the molded product and are oriented in one direction.

FIG. 4 is a schematic diagram of an example of a freezing device that can be used for freezing.
In the freezing device 71, a cylindrical container 31 containing the slurry 21 is connected to an appropriate power source 70 such as a constant speed motor, and the container 31 is cooled from above the freezing point of the slurry 41. Using the power source 70, it descends toward the refrigerant 41 and is inserted (immersed) into the refrigerant 41.

The speed at which the container 31 is inserted into the refrigerant 41, that is, the speed at which the container 31 is immersed in the refrigerant 41, is determined in the slurry 21 from the viewpoint that a porous ceramic material having high strength and communication holes having an appropriate pore diameter can be obtained. It is preferable to control the growth rate of the crystal by freezing the medium and the immersion rate so as to be substantially equal to each other. The "crystal growth rate" referred to here can be obtained, for example, by adding a scale to the side wall of the container 31 and calculating the moving speed of the frozen surface of the medium in the slurry 21 in the container. ..

By using the freezing device 71, the freezing of the slurry 21 can proceed substantially uniformly in a planar shape in the container 31, and the crystals of the medium can also be grown in a planar shape. At this point, temperature sensors are installed in the central portion (axis portion) and the vicinity of the side wall at a plurality of heights of the container 31, and at the same height of the container, the central portion (axis portion) and the vicinity of the side wall in the container are installed. It is confirmed that the temperature of the slurry in the part is almost the same.

Generally, when water is used as the medium in the slurry 21, the immersion speed of the container 31 is preferably in the range of 1 to 200 mm / h, more preferably in the range of 5 to 100 mm / h, and most preferably in the range of 10 to 50 mm / h. .. When the immersion rate of the container 31 and the crystal growth rate due to freezing of the medium in the slurry 21 are significantly different, for example, when the immersion rate is significantly higher than the crystal growth rate, the slurry 21 is irregular from the side surface, the upper surface, and the like. Freezing progresses, and a unidirectional frozen body of the medium cannot be obtained. On the other hand, when the immersion rate is significantly lower than the crystal growth rate, the medium is solidified due to fusion of the crystals of the medium toward the upper part of the container 31 (that is, the end opposite to the end on the tip side in the insertion direction of the container 31). It is not preferable because the shape of the component becomes a non-uniform frozen body in the direction of immersion. In the present invention, "the immersion rate of the container and the growth rate of crystals due to freezing of the medium in the slurry are substantially equal" means that one rate is in the range of approximately 50 to 150% of the other rate. , Preferably in the range of 80-120%.

In the freezing device 71, the container 31 is submerged in the refrigerant 41 in the upward direction (that is, the direction from the end of the container 31 in the insertion direction into the refrigerant 41 toward the other end of the container 31). The slurry is frozen in one direction. The temperature of the refrigerant needs to be lower than the freezing point of the slurry, but the temperature of the refrigerant 41 is 100 ° C. lower than the melting point of the medium used for the slurry (that is, the melting point to (melting point -100 ° C.)). Preferably, it is more preferably in the range of a temperature 15 ° C. lower than the melting point of the medium to a temperature 50 ° C. lower than the melting point of the medium (that is, a range of (melting point −15 ° C.) to (melting point −50 ° C.)). For example, when water is used as the medium, the range of 0 ° C. to −100 ° C. is preferable, and the range of −15 ° C. to −50 ° C. is more preferable. Further, the crystal growth rate depends on the temperature of the refrigerant, and the lower the temperature of the refrigerant 41, the higher the crystal growth rate, the higher the immersion speed, and the case where crystals of a medium having the same shape are formed. Productivity can be improved. The freezing point of the slurry can be easily measured by using differential scanning calorimetry (DSC).

In this way, by freezing the slurry in one direction (particularly by controlling the immersion rate of the container so that the growth rate of crystals due to freezing of the medium in the slurry and the immersion rate of the container are equal), the slurry The medium contained in is a long, unidirectionally oriented columnar solidified medium component (frost columnar solidified medium component), and as a result, it extends long in one direction and has pores with little change in cross-sectional area over the longitudinal direction. You can get a unity.

The refrigerant 41 is not particularly limited as long as it is a medium capable of cooling the slurry below the freezing point, and is not particularly limited. Liquid helium, liquid nitrogen, liquid oxygen, alcohols such as methanol and ethanol, ketones such as acetone, and hexane. Hydrocarbons such as, ionic liquid and the like can be used. However, if the refrigerant vaporizes or the temperature rises due to heat exchange, it is preferable to add or cool the refrigerant as appropriate to control the liquid level position and temperature of the refrigerant, and minimize these fluctuations. In order to do so, it is preferable to use a sufficient amount of refrigerant with respect to the slurry to be immersed.

The side wall of the container 31 is preferably made of a material having a higher specific heat than the medium in which the slurry is dispersed so that the slurry does not freeze from the side wall direction that is not immersed in the refrigerant of the container 31 due to the atmosphere on the refrigerant cooled by the refrigerant. For example, it is desirable that the material is formed of a heat insulating material such as polyethylene, polypropylene, vinyl chloride resin, silicone resin, fluororesin, and styrene resin. The thickness of the side wall of the container is preferably 0.5 mm or more. In this case, the contained slurry is less likely to freeze from the portion in contact with the side wall, and as intended, the structure of the solidified medium component of the frost columnar oriented in one direction becomes more easily aligned. The material of the bottom portion and the side wall of the container 31 may be the same, or may be different materials. When another material is used, the bottom of the container 31 is preferably made of a material such as a metal having a lower specific heat and higher thermal conductivity (for example, iron, copper, brass, stainless steel, etc.) than a medium in which the slurry is dispersed.

The shape of the container 31 is not particularly limited, but a cylindrical container as shown in FIGS. 3 and 4 is preferably used from the viewpoint of more uniform heat conduction. Further, as described above, in the present invention, it is important that the freezing of the slurry proceeds almost uniformly in a planar manner in the container and the crystal of the medium grows in a planar manner, but the diameter (inner diameter) of the container (inner diameter) of the container. ) Is too large, the degree of cooling of the slurry in the central portion (axis portion) in the container and the vicinity of the side wall differs, and freezing may not proceed almost uniformly in a planar shape. In the case of a cylindrical container, the diameter is preferably 200 mm or less, more preferably 150 mm or less. The lower limit of the inner diameter of the container is not particularly limited, but a molded product having oriented through pores having an area (opening area) of a cross section perpendicular to the orientation direction of 0.05 × 10 ^{-3 to} 100 × 10 ^-3 mm ^{2 is obtained.} From this point of view, 1 mm or more is preferable, and 2 mm or more is more preferable.

In the above-mentioned freezing device 71 (FIG. 4), the container 31 filled with the slurry 21 is moved to insert (immerse) the container 31 into the refrigerant 41, but in the present invention, the container filled with the slurry is fixed. Then, by moving the refrigerant (refrigerant storage container), the container filled with the slurry is inserted (immersed) into the refrigerant, and both the container filled with the slurry and the refrigerant (refrigerant storage container) are moved. Then, the container filled with the slurry may be inserted (immersed) in the refrigerant.

In step C, the frozen slurry is dried to obtain a molded product. Typically, the container containing the slurry is freeze-dried as it is under reduced pressure. By this operation, the solidified medium component of the frost column is sublimated, and the portion where the solidified medium component was present becomes macropores as sublimation marks, and as a result, the pores 62 that are substantially oriented in one direction in the molded body. Is formed. FIG. 5 (A) is a schematic cross-sectional view of the frozen slurry, and FIG. 5 (B) is a schematic cross-sectional view of the molded product obtained by drying the slurry. The frozen slurry contains the particles 51 of the ceramic raw material and the solidified medium component 61 oriented substantially in one direction, and after drying, substantially one in the region where the solidified medium component 61 was present. Directionally oriented pores (macropores) 62 are formed.

In step D, the obtained molded product is fired (FIG. 3 (D)). Typically, the molded product obtained in step C is withdrawn from the container 31, appropriately molded if necessary, and fired at a temperature suitable for each ceramic and a sintering time. In the case of sintering (baking), the mechanical strength of the obtained sintered body is such that the strength is suitable for implantation in the living body, that is, it can be processed at the surgical site and is embedded in the living body. It is desirable to determine the sintering conditions so that damage does not occur after loading. Such sintering conditions can be appropriately determined in consideration of the type of ceramics, the porosity of the porous body, the pore diameter, the orientation of the pores, and the like. The energy source used for firing is not particularly limited, but heat, microwaves, and the like are generally used. The firing temperature varies depending on the type of ceramic raw material, but is generally preferably 1000 to 1800 ° C, more preferably 1100 to 1600 ° C. If the firing temperature is less than 1000 ° C., densification by sintering does not proceed sufficiently and the strength tends to decrease, and if it exceeds 1800 ° C., it tends to change to another crystalline state due to melting or phase transition. The firing time is generally about 1 to 4 hours.

The molded body (FIG. 5 (C)) fired in step D has organic beads in addition to pores (macropores) 62 that are substantially unidirectionally oriented, which correspond to sublimation marks of the solidified medium component 61 in the frost column. A ceramic sintered body having pores (macropores) 82 corresponding to the combustion marks of the above, preferably macropores having a relatively small pore diameter (macropores having a pore diameter of 0.1 to 5 μm) corresponding to the interstitial particles of the sintered particles. The ceramic sintered body having the same material is produced, and a porous ceramic material having pores penetrating in substantially one direction of the present invention is produced. That is, the pores (macro pores) 62 in FIG. 5 (C) correspond to the pores 12 in FIGS. 1 and 2 that are substantially oriented in one direction, and the pores (macro pores) 82 in FIG. 5 (C). Corresponds to the granular pores 14 in FIG.

When the porous ceramic material of the present invention is used as an artificial bone, it is preferably formed into a desired shape and sterilized.

The method for forming the porous ceramic material into a block shape is not particularly limited, and a known method may be used. Specifically, a molding method by machining can be mentioned. Since the ceramic material is generally a hard and brittle material, the conventional porous ceramic material having a non-uniform thickness of the ceramic layer has extremely low machinability. As described above, in the porous ceramic material of the present invention, the pores are substantially oriented in one direction and the pore diameters are substantially uniform, so that the thickness of the ceramic layer between the through pores is also high. It is almost uniform. Therefore, it exhibits excellent machinability as compared with the conventional porous ceramic materials.

Further, the method for forming the porous ceramic material into granules is not particularly limited, and a known method may be used. Specific examples include mechanical crushing of a mold grinder, ball mill, jaw crusher, hammer crusher, etc., crushing with a mortar and the like. Further, the particle size may be made uniform by sieving the crushed porous ceramic material.

The method for sterilizing the porous ceramic material is also not particularly limited, and a known method may be used. Specific examples thereof include high-pressure steam sterilization (autoclave), γ-ray sterilization, EOG sterilization, and electron beam sterilization. Among them, the high-pressure steam sterilization method is widely used as the most common sterilization method.

The porous ceramic material of the present invention (preferably a porous calcium phosphate-based ceramic material) is an implant material such as the above-mentioned artificial bone, a scaffold material for cell culture used in regenerative medicine, and a drug for a drug delivery system (DDS). It is useful as a supporting material.

In addition, tissues such as transforming growth factor (TGF-β1), bone morphogenetic factor (BMP-2 or BMP-7), eg bone tissue, for the purpose of inducing higher levels of tissue, eg bone tissue. The porous ceramic material of the present invention may be impregnated, adsorbed, or immobilized with a substance having an action of promoting growth.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited by the following examples, and is appropriately modified to the extent that it can be adapted to the above and the following objectives. Of course, it is possible to carry out, and all of them are included in the technical scope of the present invention.

[Measurement method of crystal growth rate by freezing the medium in the slurry]
By calculating the moving speed of the frozen surface of the medium in the slurry from the scale attached to the container filled with the slurry, the growth rate of crystals due to freezing of the medium in the slurry was obtained. At the same time, at the same time, temperature sensors were installed near the center (axis) and the side wall of the container at a plurality of heights of the container filled with the slurry, and it was confirmed that the respective temperatures were almost the same.

[Measurement method of porosity]
Porosity was measured according to JIS R 1634. Specifically, it is as follows. A columnar test piece having a diameter of 6 mm and a height of 7 mm is cut out from the porous ceramic material to be evaluated. The weight and volume of the test piece were measured, and the porosity was calculated from the following formula.
Bulk density = (weight of test piece) / (volume of test piece)
Porosity (%) = (1-bulk density / theoretical density) x 100

[Measuring method of compressive strength]
Compliant with JIS R 1608. However, as the test piece, a columnar test piece having a diameter of 6 mm and a height of 7 mm was used.

[Measurement method of stomatal floor area ratio]
The pore size distribution was measured by the mercury press-fitting method (measurement range: 4 × 10 ^-3 to 4 × 10 ² μm). However, as the test piece, a columnar test piece having a diameter of 6 mm and a height of 7 mm was used. The pore floor area ratio is calculated from the pore size distribution obtained by the mercury intrusion method, and is the ratio of the pore volume of the pore diameter of 10 μm or more and less than 30 μm and the ratio of the pore volume of the pore diameter of 30 μm or more to the total pore volume in the measurement range. Was measured as the stomatal floor area ratio. The contact angle between mercury and β-tricalcium phosphate was 130 °, and the surface tension was 485 mN / m.

[Examples 1 and 2]
A container was filled with 40 g of a slurry in which β-tricalcium phosphate (β-TCP), additives, and polymethylmethacrylate beads (average particle size 20 μm) were dispersed and dissolved according to the composition shown in Table 1 in distilled water. It was cooled in a refrigerator maintained at 4 ° C. for 3 hours. The container was immersed in an ethyl alcohol bath cooled to −25 ° C. at 15 mm / h to form frost columnar ice in the slurry. The frozen body thus obtained was sublimated and dried in vacuum, and then the dried body was sintered at 1120 ° C. for 5 hours to obtain a porous ceramics sintered body.

[Comparative Example 1]
It was carried out under each condition shown in Table 1 according to the method of Example 1 except that the beads made of polymethyl methacrylate were adjusted to 7% by weight.

[Comparative Example 2]
It was carried out under each condition shown in Table 1 according to the method of Example 1 except that the beads made of polymethyl methacrylate were not used.

Porosity (porosity, pore volume ratio, presence or absence of granular pores, pore diameter of granular pores, etc.) and compressive strength of the materials (ceramic sintered body) prepared according to Examples 1 and 2 and Comparative Examples 1 and 2. It is shown in Table 1. Properties other than porosity, porosity, and compressive strength were measured by the methods described in the text of the specification.

* 1: In the ceramic sintered body obtained in Comparative Example 1, orientation through pores were not formed, pores and skeleton existed in a random shape, and granular pores derived from organic beads were randomly present in the skeleton portion. Was.

FIG. 6 is an SEM observation image of a cross section (cross section parallel to the orientation direction of the pores) of the test piece in which the material prepared in Example 2 is impregnated with the epoxy resin (magnification: 150 times).

FIG. 7 is an SEM observation image of a cross section (cross section parallel to the orientation direction of the pores) of the test piece in which the material prepared in Comparative Example 2 is impregnated with the epoxy resin (magnification: 150 times).

[Evaluation by animal experiments]
A φ4 mm bone hole was prepared in the femur diaphysis of a beagle dog, and the material of Example 2 formed into a columnar shape (φ4 mm × 10 mm; the orientation direction of the pores was the height direction of the column) was transplanted. The direction of the stomata is orthogonal to the long axis direction of the bone, and since the opening of the stomata is not in contact with the stump of the bone, it is relatively disadvantageous for the invasion of cells and tissues. be.

FIG. 8 is a micro X-ray CT image 6 weeks after transplantation of the material of Example 2. It was confirmed that the material was fused with the bone.

FIG. 9 is a microscopic image of a non-decalcified specimen 6 weeks after transplanting the material of Example 2. Bone formation was also confirmed in the central part of the material.

According to the present invention, macropores corresponding to sublimation marks of solidified medium components in frost columns, spherical macropores corresponding to combustion marks of organic beads, and macros having a relatively small pore size corresponding to sintered particle gaps. A porous ceramic material having pores is produced.
The porous ceramic material can be used as an implant material, a scaffold material for cell culture used in regenerative medicine, a drug-carrying material for a drug delivery system (DDS), and the like.

11 Porous ceramic material 12 Pore that is substantially oriented in one direction and penetrates 13 Ceramic region (ceramic wall)
14 Granular pores 21 Slurry 31 Container 41 Refrigerant 51 Ceramics raw material particles 61 Medium crystal 62 Pore that penetrates substantially in one direction 70 Power source 71 Freezing device 81 Organic beads 82 Granular pores (approximately spherical shape) Pore)

Claims (6)

A multi-porous ceramic material that have a substantially pores of the formed granular ceramics area between orientation to penetrate to have pores and the gas holes in one direction,
A porous ceramic material comprising a sintered body having a pore volume ratio of 10 μm or more and less than 30 μm of 10% or more and a pore volume ratio of 30 μm or more and less than 90% . Pores of particulate formed in said ceramics region is characterized pores der Rukoto spherical, porous ceramic material according to claim 1. Step A: A step of preparing a slurry by dispersing a ceramic raw material and organic beads in a medium.
Step B: A step of filling a predetermined container with a slurry and freezing the slurry in one direction.
Step C: A step of drying the frozen slurry to obtain a molded product, and a step D: a step of firing the dried molded product, which are substantially unidirectionally oriented and penetrating the pores and the pores. have a porosity of granular formed in the ceramic region between, pore volume of less than a pore size of 10μm or 30μm is 10% or more, and a pore size of 30μm or more pore volume of less than 30% or more 90% Oh Ru method of manufacturing a porous ceramic material. The method according to claim 3 , wherein the organic beads are organic spherical beads. The method according to claim 3 or 4 , wherein the content of the organic beads in the slurry is 2 to 6% by weight of the total weight of the slurry. The method according to any one of claims 3 to 5 , wherein the average particle size of the organic beads is 3 to 40 μm.

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