JPH07115972B2 - Method for producing porous ceramic material - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing a porous ceramic material. More specifically, the present invention has a number of specific sized spherical voids and a number of specific sized capillary void passages communicating with each other and the external space for bone regeneration, The present invention relates to a method for producing a porous ceramic material useful as a material used for other medical applications, or an electronic material, and a material for genetic engineering.

[0002]

Calcium phosphate compounds, such as hydroxyapatite, and solid solutions thereof have good affinity with living bodies and are useful as substitute materials or prosthetic materials for medical materials, for example, bones or roots. . For example, Japanese Patent Laid-Open No. 56-54841 discloses a bone defect filling material and a void filling material using a powdery apatite-type calcium phosphate compound crystal structure.

Further, JP-A-56-166843 discloses a filler for bone defects and voids, which is composed of a porous body of a calcium phosphate compound. The pores contained in the porous body of this calcium phosphate compound have a maximum pore diameter of 3.
It has a diameter of 00 mm and a minimum pore diameter of 0.05 mm, has a shape dimension that allows bone-forming components of a living body to easily enter, and forms a substantially continuous three-dimensional network structure.

[0004] As described above, the conventional calcium phosphate compound ceramic material is deformed with time after performing a surgical operation such as filling or prosthesis, or hard soft tissue near the filling or prosthetic portion. However, there is a problem in that the excised tissue of the abnormal portion is forced to be removed. In general, it is most preferable to promote natural healing in the treatment of a defect of a hard tissue of a living body, for example, a resection of a bone tumor part or a defect caused by an external damage of a bone, and an artificial substitute or a prosthesis is always preferable. Not that. Even if the artificial body is filled or prosthetic in the living body, such artificial body is eventually consumed in the living body, and instead, natural living tissue is regenerated to control the regeneration rate of bone. It is most desirable to control the resulting resorption of bone over time and to heal the defect. In this case, it is important that the replacement speed (turnover speed) of the artificial material by living tissue is appropriate, and when the turnover speed is excessively high, local damage such as inflammation is caused, and the resulting excess Diseases such as the occurrence of cancer may occur together. In addition, when the turnover speed is low and the artificial object is present in the living body for a long period of time, the local living tissue (bone) is deformed or the soft tissue in the vicinity thereof is hardened, which requires excision surgery. There are things.

In order to deal with the above problems, it is important that the filling material or prosthesis material to be inserted into the living body can satisfy the requirements for inducing and replacing the living tissue at the cell level. That is, osteophyte cells (osteolysis) to living tissues, osteoregenerative cells (osteoplast) are appropriately promoted to activate, bone destruction cells (octeoclast), and collagen fibers that promote hardening of soft tissues. It is important to suppress invasion, development, and hardening of bone tissue, and not inhibit the invasion of red blood cells and body fluids and the development of capillaries.

In order to meet the above requirements, the filler or prosthesis material to be inserted into the living body has a good affinity with the living body, in particular, biocompatibility (bioresponsibility). It is possible to provide a good habitation and growth space for the activation of desired cells, prevent the invasion of cells that should be repelled, and prevent the hardening of bone tissue due to the abnormal development of collagen fibers. It is necessary, and development of a method for efficiently producing such a porous material is strongly desired.

[0007]

SUMMARY OF THE INVENTION The object of the present invention is to provide a porous ceramic material useful for regeneration of bone tissue in a living body, that is, induction of new bone, other medical applications, electronic materials, genetic engineering materials and the like. Is to provide a method for manufacturing the same.

[0008]

The porous ceramic material produced by the method of the present invention comprises a sintered porous body of a calcium phosphate compound, and a large number of capillaries extending like channels in the porous body. Voids and a large number of spherical pores having a pore diameter of 30 to 600 μm are formed, and the diameter of the capillary void passage is in the range of 2 to 30 μm, provided that
Smaller than the diameter of the spherical pores, the spherical pores, the outer space of the porous body, and the spherical pores are communicated by the large number of capillary void passages. Is.

The above-mentioned porous ceramic material can be manufactured by the following method of the present invention. That is, in the method for producing a porous ceramic material of the present invention, 100 parts by weight of egg white is bubbled to form a large number of spherical bubbles having a pore size of 30 to 600 μm, and the egg white foam is added to 30 to 120 parts by weight of the calcium phosphate compound. The powder is mixed and shaped by pouring the mixture into a mold of desired shape and size, the shaped mixture is heated to a temperature of 120-150 ° C. to harden the egg white, then a temperature of 500-700 ° C. To carbonize egg white by heating to 800 ° C in an oxygen-containing atmosphere
Heating to a temperature of ˜1350 ° C. to burn off the carbide and sinter the calcium phosphate compound powder,
Whereby a plurality of spherical pores having a pore size of 30 ～600Myuemu, they mutually the and communicates with the outside space, 2
It is characterized in that it forms a large number of capillary void passages having a diameter of ˜30 μm, but smaller than the spherical holes.

In another method for producing the porous ceramic material of the present invention, 100 parts by weight of egg white is bubbled to obtain a pore size of 30.
A large number of spherical bubbles of up to 600 μm are formed, and the egg white foam is mixed with 30 to 120 parts by weight of calcium phosphate compound powder and 1 to 5 parts by weight of a length of 5 mm or less and 1 to 30 μm.
However , the mixture is molded with an organic fiber having a diameter smaller than the pore diameter of the bubbles, and the mixture is poured into a mold having a desired shape and dimension, and the molded mixture is
Heat to a temperature of ~ 150 ° C to harden the egg white, then 50
Heat to a temperature of 0-700 ° C to carbonize the egg whites and fibers, then 800 ° C-1350 ° C in an oxygen containing atmosphere.
To remove the carbides and sinter the calcium phosphate compound powder by heating to a temperature of
A large number of spherical pores having a pore diameter of 30 to 600 μm and communicating with each other and the external space, 2 to 30 μm
However, a large number of capillary void passages having a diameter smaller than the spherical hole are formed.

[0011]

The porous ceramic material produced by the method of the present invention comprises a sintered porous body of a calcium phosphate compound. Calcium phosphate compounds used in the present _{process, CaHPO 4 Ca 3 (PO 4} ) 2 Ca 5 (PO 4) 3 OH Ca 4 O (PO 4) 2 Ca 10 (PO 4) 6 (OH) 2 CaP 4 O ₁₁ Ca (PO ₃ ) ₂ Ca ₂ P ₂ O ₇ Ca (H ₂ PO ₄ ) ₂ · H ₂ O and the like as a main component, and includes a group of compounds called hydroxyapatite. Hydroxyapatite has the composition formula Ca ₅ (PO ₄ ) ₃ OH or Ca ₁₀ (PO
₄ ) ₆ (OH) ₂ is used as a basic component, and a part of Ca component is Sr, Ba, Mg, Fe, A
It may be substituted with one or more of 1, Y, La, Na, K, H and the like, and a part of the (PO ₄ ) component is V
It may be substituted with at least one of O ₄ , BO ₃ , SO ₄ , CO ₃ , and SiO _4, and a part of the (OH) component may be substituted with at least one of F, Cl, O, and CO _3. It may be substituted. The hydroxyapatite may be a normal crystal, or may be any of an isomorphic solid solution, a substitutional solid solution, and an interstitial solid solution, and may also include non-stoichiometric lattice defects.

Generally, the calcium phosphate compound used in the method of the present invention preferably has an atomic ratio of calcium (Ca) to phosphorus (P) in the range of 1.30 to 1.80, and 1.60 to 1.60. Those in the range of 1.67 are more preferable. Examples of the calcium phosphate compound used in the present invention include tricalcium phosphate [Ca ₃ (PO ₄ ) ₂ ], hydroxyapatite [Ca ₅ (PO ₄ ) ₃ OH], and C.
a ₁₀ (PO ₄ ) ₆ (OH) ₂ is preferable, and one synthesized by the sol-gel method and freeze-dried is particularly preferable. Further, the calcium phosphate compound is preferably one that is sintered at a temperature of 800 to 1350 ° C., and the sintering temperature is more preferably 850 to 1200 ° C.

In the porous ceramic material obtained by the method of the present invention, the calcium phosphate compound is sintered in the form of powder and, therefore, may have fine voids between the powder particles which are contact-sintered with each other. it can. The calcium phosphate porous body of the porous ceramic material obtained by the method of the present invention may have any shape and size, and inside thereof, a plurality of capillary voids extending in the shape of passages, 30 A large number of spherical pores having a pore diameter of ˜600 μm are formed, and the diameter of the capillary void passage is 2
It is within the range of -30 μm, and the spherical pores and the outer space of the porous body are communicated with each other through the large number of capillary void passages. Further, the spherical holes communicate with each other via a capillary void passage.

The sintered porous body preferably has a porosity of 40 to 90%, more preferably 60 to 70%. It is preferable that the pores in the sintered porous body have a spherical shape or a shape close thereto, and that they are evenly distributed in the porous body. This hole is
The ceramic material, when embedded in a living body, provides a living space for biologically activating bone phagocytic cells, bone regenerating cells and the like. Bone regeneration cells, etc.
In particular, they very much prefer to stay in spherical pores. The pore size of pores for this is required to be in the range of 30 ~600μm, preferably 30 ~300μm. Voids whose pore diameter is outside the range of 30 to 600 μm cannot give a good living space to the cells.

When the shape of the pores is a true sphere or a sphere close thereto, the mechanical strength of the obtained porous material is high.
Therefore, when this porous material is implanted in a living body, it can maintain high mechanical strength until it is returned over by new bone, and fractures during that period can be prevented. Capillary void passages in the sintered porous body are to communicate the spherical pores with each other, and to the external space of the porous body, through the passage, the bone phagocytes, bone regenerating cells, Erythrocyte fluid and the like can freely enter the porous body and promote the development of capillaries. However, the diameter of this capillary void passage is 2-3
Since it is within the range of 0 μm, it is difficult for bone-disrupting cells and collagen fibers to enter the capillary void passages in the porous body, and it is possible to prevent abnormal development of collagen fibers and hardening of bone tissue. That is, in the porous body of the present invention, the capillary void passages also have a function as a biofilter.

When the diameter of the capillary void passage is smaller than 2 μm, it becomes difficult for the bone phagocytic cells, bone regenerating cells, erythrocyte fluid and the like to enter into the porous body, and when it is larger than 30 μm, broken cells and collagen fibers are not formed. It allows invasion and development, which inhibits bone regeneration and leads to stiffening of regenerated bone tissue and its surrounding tissues. In the porous ceramic material obtained by the method of the present invention, the spherical pores in the porous body are communicated with each other through a large number of capillary void passages, whereby the exhaustion of the porous body and the biological tissue. Of bone destructive cells that occur after the completion of turnover of bone tissue, and the abnormally advanced bone erosion is predicted from the initial regeneration rate. The action (resorption of bone) can be controlled.

In the method of the present invention, the capillary void passage is
(1) Passages formed by combustion of organic fibers, and (2)
It is a passage formed by the gas generated by the combustion of hardened egg white. Above all, the passage formed by the combustion of the organic fiber is preferable because the diameter can be controlled well. The porous ceramic material obtained by the method of the present invention can be easily and freely processed into a shape corresponding to the shape of the defect or void to be filled or prosthetic. Also,
The ceramic material of the present invention may be formed into granules having a particle size of 0.05 to 5 mm.

When the porous ceramic material produced by the method of the present invention is embedded in a living body as a filling material or a prosthetic material, blood, body fluid, as well as bone phagocytic cells and bone regenerating cells enter through the capillary void passages. Then, it is consumed by the bone phagocytic cells grown in the pores, and at the same time, bone tissue is regenerated by the bone regenerating cells, so-called turnover is performed. At this time, since the capillary void passages communicating with the pores toward the outer space of the porous body have a diameter of 2 to 30 μm, the bone-disrupting cells and the collagen fibers are separated from the capillary tube in the porous body. It is difficult for the collagen fibers to enter into the void-like passages, and it is possible to prevent abnormal development of collagen fibers and their hardening. Therefore, the soft tissue of the regenerated bone is not destroyed or hardened by the collagen fiber. Therefore, the porous ceramic material of the present invention induces new bone and is replaced by normal bone tissue grown in vivo.

As mentioned above, porous ceramic materials which can be turned over by normal bone tissue are new and can only be realized by the method according to the invention.

The first method for producing the porous ceramic material of the present invention is to foam 100 parts by weight of egg white,
A large number of spherical bubbles having a pore size of 30 to 600 μm were formed, the egg white foam was mixed with 30 to 120 parts by weight of a calcium phosphate compound powder, and the mixture was cast into a mold having a desired shape and dimension, and molded. Mix the mixture at 120-150 ° C
To heat the egg white to a temperature of 500-700
Heating to a temperature of ° C to carbonize the egg white, and then to a temperature of 800 to 1350 ° C in an oxygen-containing atmosphere to burn off the carbide and sinter the calcium phosphate compound powder. Is included.

Generally, the calcium phosphate compound powder used in the method for producing a porous ceramic material of the present invention preferably has a particle size of 0.05 to 10 μm. Particularly preferred calcium phosphate compound powder preferably contains a plate-shaped crystal portion, and according to the observation result based on SEM (scanning electron microscope), 30% of the powder particles are contained.
Those having a particle size distribution in which the following have a particle size of 1 μm or more and 70% or more have a particle size of 1 μm or less are preferable.

In order to form air bubbles having a desired pore size in the egg white, the egg white is whipped using an emulsifying mixer, and the liquid surface thereof is gently stroked so that the egg white air bubbles are formed on the slide glass. A sample is taken and observed under a microscope to measure the pore size of the bubbles. This operation is repeated until the desired pore size is obtained. Next, a predetermined amount of calcium phosphate compound powder is added and the mixing is repeated again. At this time, a suitable porosity controlling agent, for example, a fatty acid such as oleic acid or maleic acid and / or an aliphatic alcohol such as isopropyl alcohol or isobutyl alcohol may be added in a small amount.

The obtained mixture is molded into a predetermined shape and size. Any molding method and apparatus used in the molding step for sintering can be used, but in general, casting molding using a mold is used. The obtained molded product is heated to a temperature of 120 to 150 ° C., preferably 6
Heat for 0 to 120 minutes to harden the egg whites. At this time, the relative humidity of the heating atmosphere is preferably adjusted to 30 to 70%, and the temperature rising rate is preferably regulated to 5 to 10 ° C./minute. This hardened egg white strengthens the cellular framework.

Next, the molded product is heated to a temperature of 500 to 700 ° C., preferably 120 to 180 minutes, to carbonize the egg white. Then, the molded product in an oxygen-containing atmosphere, for example, in air,
The mixture is heated to 800 to 1350 ° C., preferably 850 to 1200 ° C., the carbides are burned and removed, and the calcium phosphate compound powder is sintered. The heating time at this time is generally about 1 to 3 hours.

The gas generated during the above-mentioned egg white hardening, egg white carbonization, and carbide combustion escapes to the outside of the porous body,
At this time, a large number of capillary void passages are formed, and spherical voids are formed corresponding to the spherical bubbles of the egg white foam. The pores communicate with the outer space of the porous body through the capillary void passages, and the pores also communicate with each other through the capillary void passages. The diameter of the capillary void passage thus formed is smaller than the diameter of the spherical hole.

In the above production method, 1 to 5 parts by weight of 5 parts by weight of 5 parts by weight of calcium phosphate compound powder is added.
mm or less and 2 to 30 μm , but with pores of egg white bubbles
Organic fibers having a diameter smaller than the diameter can be added to and mixed with the egg white foam. In this case, the molded product is heated to a temperature of 500 to 700 ° C., preferably 1 after heating the egg white for curing.
It is heated for 20 to 180 minutes to carbonize the egg white and the organic fiber. These carbides are burned off during the sintering heating.

The organic fiber in the above method has a diameter of 2 to 30.
It has the effect of ensuring the formation of μm capillary passages. The organic fiber is not particularly limited as long as it has a length of 5 mm or less and a diameter of 2 to 30 μm and can be completely burned. In general, animal fibers such as cats, raccoon dogs and mice are used. Hair is preferred, or other natural organic fibers including silk fibers, cellulose fibers, and organic synthetic fibers such as polyester, polypropylene, polyacid, polyacrylic fibers and the like are preferred.

[0028]

The present invention will be further described with reference to the following examples.

Example 1 A mixture of 100 g of egg white and 3 g of oleic acid was whipped with an emulsifying mixer, and sometimes its liquid surface was gently stroked on the surface of a slide glass to sample, and this was observed under a microscope. Then, whipping was continued until the minimum bubble diameter of the egg white spherical bubbles became 30 μm. 90 g of synthetic hydroxyapatite (Ca ₅ (PO ₄ ) ₃ OH,
Ca / P atomic ratio = 1.67, particle size 0.05-10 μm)
Were mixed. This mixture was cast into a frame and molded. The molded product was heated to 150 ° C. at a temperature rising rate of 10 ° C./min in an atmosphere having a relative humidity of 30%, and heated at this temperature for 180 minutes to cure the egg white and form a framework of bubbles. Next, this molded product is gradually heated to 500 ° C. for 12 hours.
The egg white was carbonized by heating for 0 minutes. Finally, the molded product was heated in air at a temperature of 1000 ° C. for 1 hour to sinter the hydroxyapatite powder.

The obtained porous body had a porosity of 76%, and when observed under a microscope, the pore size was 30 to 500 μm.
A large number of spherical pores of m 2 and a large number of capillary void passages having a diameter of 12 μm were observed, and the voids communicated with the outside and between the pores by the capillary void passages. A 1 × 1 × 1 cm cube was cut out from the above porous molded article, and its uniaxial compressive strength was measured and found to be 12 kg / cm ² .

Example 2 The same operation as in Example 1 was performed. However, 5 g of polymethylmethacrylate fiber (length = 5 to 10 μm, diameter =
3-10 μm) was additionally mixed in the egg white whipping process.
The resulting hydroxyapatite porous material had spherical pores and capillary void passages similar to those in Example 2,
Many capillary passages having a diameter of 3 to 10 μm were recognized.

Example 3 The porous body obtained in each of Examples 1 and 2 was cut into a columnar shape having a diameter of 0.5 cm and a length of 1 cm, which was produced by a surgical operation on the femur of a beagle dog. The defect was filled. When incision was observed 2 weeks later, significant induction of new bone was observed in each of the spherical pores. In addition, after 2-3 months, the development of new bone is observed from the outer peripheral portion to the inner portion of the porous body, so-called turnover progresses smoothly, and phenomena such as abnormal growth of collagen fiber cells and hardening of tissue are observed. I was not able to admit.

[0033]

The porous ceramic material obtained by the method of the present invention has spherical pores having a pore size of 30 to 600 μm and capillary void passages having a diameter of 2 to 30 μm. -Like void passages can function as a biofilter, so abnormal development due to collagen fiber invasion, hardening of bone tissue due to the catalytic action of collagen fibers, and inhibition of new bone-induced capillary destruction of bone-destructing cells It makes it difficult for the cells to enter the void passages, prevents the collagen fibers themselves from hardening due to abnormal development of collagen fibers, and allows only bone phagocytic cells, bone regenerating cells, red blood cells, and body fluids to selectively pass through. Further, the spherical pores having a specific pore diameter can promote activation of osteophagocytic cells and bone regenerating cells at the cellular level. Therefore, by using the porous ceramic material of the present invention, it is possible to promote the induction of parent bone while maintaining a good affinity with the living body, and to regenerate the bone over time caused by controlling the bone regeneration rate. It can control resorption and promote bone turnover. INDUSTRIAL APPLICABILITY The method of the present invention enables efficient production of a porous ceramic material which is useful not only for the above-mentioned biomaterials but also for ICLSI electronic materials, genetic engineering medium materials and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location A61K 6/00 A A61L 27/00 J C04B 35/447 (56) Reference JP-A-51-116809 (JP, A) US Patent 3929971 (US, A) US Patent 3497455 (US, A) "CLINICAL ORTHOPEA DCS AND RELATED RES ERCH" No. 157, p.263, 12th line

Claims (14)

[Claims] 1. Bubbling 100 parts by weight of egg white to give a pore size of 3
Molded by forming a large number of spherical bubbles of 0 to 600 μm, mixing the egg white foam with 30 to 120 parts by weight of calcium phosphate compound powder, and pouring the mixture into a mold having a desired shape and size. 120 to 1 of the mixture
Heat to 50 ° C. to harden the egg white, then 500-
The egg white is carbonized by heating to a temperature of 700 ° C., and then heated to a temperature of 800 ° C. to 1350 ° C. in an oxygen-containing atmosphere to burn off the carbide and sinter the calcium phosphate compound powder. , thereby 30 ~600μ
a large number of spherical holes with a hole diameter of m and
A method for producing a porous ceramic material, characterized in that a large number of capillary void passages each having a diameter of 2 to 30 μm, but having a diameter smaller than that of the spherical holes are communicated with the external space. 2. The egg white hardening and heating step is 30 to 70%.
The method according to claim 1, wherein the method is performed in an atmosphere having relative humidity of 5 to 10 ° C./min at a heating rate. 3. The calcium phosphate compound powder is 0.0
A method according to claim 1 having a particle size of 5-10 µm. 4. The method according to claim 1, wherein the atomic ratio of calcium to phosphorus in the calcium phosphate compound is in the range of 1.30 to 1.80. 5. The method of claim 1, wherein the calcium phosphate compound is hydroxyapatite. 6. The method according to claim 1, wherein the porous body has a porosity of 40% to 90%. 7. 100 parts by weight of egg white is bubbled to obtain a pore size of 30.
A large number of spherical bubbles having a size of up to 600 μm are formed, and the egg white foam is mixed with 30 to 120 parts by weight of calcium phosphate compound powder and 1 to 5 parts by weight, a length of 5 mm or less , and 2 to 30 μm.
of m, provided that the than the diameter of a spherical bubble is mixed into an organic fiber having a small diameter, the mixture was molded into a desired shape and size, and heating the molded the mixture to a temperature of 120 to 150 ° C. Harden egg white, then 500-700 ° C
To carbonize the egg whites and fibers, and then
By heating in an oxygen containing atmosphere to a temperature of 800 ° C. to 1350 ° C., and sintering the calcium phosphate compound powder with burning off the carbide, thereby 30-600
a large number of spherical pores having a pore size of μm and communicating with each other and the external space, forming a large number of capillary void passages having a diameter of 2 to 30 μm, but having a smaller diameter than the spherical pores. A method for producing a porous ceramic material, comprising: 8. The organic fiber is animal fiber, silk fiber, cellulose fiber and / or organic synthetic fiber.
7. The method according to 7 . 9. The length of the organic fibers is 1 [mu] m to 5 mm, The method of claim 7. 10. The egg white hardening and heating step comprises 30 to 70.
5 to 10 ° C./in an atmosphere having a relative humidity of
The method according to claim 7 , wherein the method is performed at a heating rate of 1 minute. 11. The calcium phosphate compound powder is less than 0.1%.
The method according to claim 7 , which has a particle size of 05 to 10 μm. 12. atomic ratio of calcium to phosphorus in the calcium phosphate compound is in the range of 1.30 to 1.80, The method of claim 7. Wherein said calcium phosphate compound is hydroxyapatite, The method of claim 7. 14. The method according to claim 7 , wherein the porous body has a porosity of 40% to 90%.