JP2001206787A - Calcium phosphate porous sintered compact and method of producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a porous body characterized in that the mechanical strength is high and cells and/or tissues can enter into the porous body. SOLUTION: In a calcium phosphate porous sintered compact, the porosity is continuously distributed in the range from 5% or less to 85% or more in a gradient manner. A method of producing the calcium phosphate porous sintered body includes the process of controlling a slurry obtained by dispersing or dissolving a calcium phosphate powder and an organic substance capable of curing by crosslinking polymerization into a solvent, the process of adding a foaming agent to the slurry and foaming the slurry to a prescribed volume by either stirring or introducing a gas in order to obtain a slurry in the bubbled state, and the process of adding and mixing at least one of a crosslinking agent and a crosslinking initiator to the slurry in the bubbled state, further introducing the slurry into a mold and curing the slurry by the crosslinking polymerization to obtain a formed body.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a calcium phosphate-based porous sintered body that can be used as a bone filling material and a method for producing the same.

[0002]

2. Description of the Related Art At present, various porous materials are used as bone filling materials. A porous body made of alumina or the like, which can be a dead tissue in a living body, can be considered, but a calcium phosphate-based porous body that is generally replaced by bone is known to be a preferable material as a bone replacement material. For example, Japanese Patent No. 29513
See No. 42.

[0003] Dense bodies are also used as bone substitutes.

[0004]

Since the conventional calcium phosphate-based porous body has low mechanical strength, it is difficult to replace it with a living tissue which is subjected to a large mechanical load, such as a vertebral body.

[0005] In addition, the dense body is used as a bone filling material. However, although the dense body has high mechanical strength, cells and tissues cannot penetrate into the inside. Therefore, there is a problem that the surrounding bone is biomechanically absorbed, or the material is deteriorated and destroyed in a high electrolyte environment in the living body. In particular, the vertebral body that supports the upper body and the cervical vertebra that supports the head are under heavy load. is there.
Therefore, it is important to secure material strength.

An object of the present invention is to provide a calcium phosphate-based porous sintered body having high mechanical strength and having the characteristics of a porous body through which cells and tissues can enter, and a method for producing the same. .

[0007]

A preferred solution of the present invention is a calcium phosphate-based porous sintered body according to claims 1 to 16 and a method for producing the same.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The calcium phosphate-based porous sintered body according to the present invention can be used as a bone filling material, has high mechanical strength, and has a porous structure capable of invading cells and tissues. Has the characteristics of the body.

[0009] The porosity of the calcium phosphate-based porous sintered body according to the present invention is substantially continuously and inclinedly distributed from 5% or less to 85% or more.

[0010] Preferably, the porosity of the calcium phosphate-based porous sintered body according to the present invention is substantially continuously and inclinedly distributed from 1% or less to 90% or more.

In any case, in a region having a high porosity (for example, a region of 75% or more), the average diameter of the communicating portion between the pores is 50 μm or more, and the pore diameter is 150 μm or more; And its three-point bending strength is 5M
It is preferably Pa or more. In addition, “substantially continuously” means that the porosity changes without boundaries, but also includes a case where the porosity is gradually changed by a layer structure of five or more layers.

In a region having a low porosity (for example, a region of 10% or less), the three-point bending strength is preferably 30 MPa or more. It is particularly preferable if the pressure is 50 MPa or more.

[0013] The porosity may be inclined in such a manner that the outside is rough and the inside is dense or vice versa. Alternatively, the porosity may be inclined from one side in the opposite direction. May be alternated.

The preferred structure of the porous ceramic sintered body is CaHPO ₄ , Ca ₃ (PO ₄ ) ₂ , Ca ₅ (PO ₄ ) ₃
OH, Ca ₄ O (PO ₄ ) ₂ , Ca ₁₀ (PO ₄ ) ₆ (O
H) ₂ , CaP ₄ O ₁₁ , Ca (PO ₃ ) ₂ , Ca ₂ P ₂ O ₇ ,
_{Ca (H 2 PO 4) 2} , Ca 2 P 2 O 7, Ca (H 2 PO 4) 2
· The main component of H ₂ O or the like, comprising a compound of a group called calcium phosphate. Part of the Ca component is Sr, B
a, Mg, Zn, Fe, Al, Y, La, Na, K, H
It may be substituted with one or more kinds selected from such as. Also,
Part of the (PO ₄ ) component is VO ₄ , BO ₃ , SO ₄ , C
It may be substituted by one or more selected from O ₃ and SiO ₄ . Further, part of the (OH) component is F, Cl, O,
It may be substituted by one or more selected from CO _{3 and the} like.

The calcium phosphate may be not only a normal crystal but also a solid solution of the same type, a solid solution of a substitution type, or a solid solution of an interstitial type, and may further contain a non-stoichiometric defect.

A preferred method for producing a calcium phosphate-based porous sintered body according to the present invention comprises the steps of: preparing a slurry in which a calcium phosphate-based powder and an organic substance curable by cross-linking polymerization are dispersed or dissolved in a solvent; A step of adding a foaming agent and foaming to a predetermined volume by stirring and / or introducing gas to form a foamed slurry; and adding a crosslinking agent and / or a crosslinking initiator (curing agent) to the foamed slurry. Mixing, introducing into a mold, and curing by cross-linking polymerization to form a molded article. At this time, it is preferable that the rotation is carried out in a rotating device or the like so that the density is coarse at the center of rotation and a dense gradient distribution is obtained at the outer edge of the rotation. In addition, a gradient distribution can be provided by another method.

In a preferred method for producing a calcium phosphate-based porous sintered body according to the present invention, the obtained molded body is dried,
And a sintering step.

According to a preferred embodiment of the present invention, the calcium phosphate-based porous ceramic sintered body is obtained by stacking a plurality of slurries or powders having different contents of beads for baking on a dense body. It may be obtained by molding, drying and baking, or by stacking and controlling the amount of foaming and changing the pore diameter and amount, and drying and baking. In this case, the latter method is more preferable.

The type of calcium phosphate may be changed depending on the direction of inclination.
The whole is preferably made of hydroxyapatite. In particular, the three-point bending strength of the dense body is preferably 50 MPa or more, and it is preferable that the body can be applied to a vertebral body or the like.

In practice, it is not a one-way tilt,
It is better to incline in two directions, three directions or more. The vertebral body or the like preferably has a structure in which the central portion is dense and porous toward the surface.

Preferred examples of application of the calcium phosphate-based porous sintered body according to the present invention are as follows.

(1) Use as a living bone replacement type bone reconstruction material having osteoconductive ability.

(2) Use as a filler for osteoporosis and bone defects.

(3) An artificial dura that can be used on the skull as a countermeasure for diseases such as prions (Jakob's disease caused by low molecular weight proteins).

(4) A bioactive substrate containing amino acids, carbohydrates and cytokines and used for tissue engineering.

(5) Biocompatible drug sustained release base such as anticancer drug.

(6) Culture vessels for stem cells, liver tissue, etc.

(7) Use as a filter for drinking water or fermented drinks.

(8) Column material used for adsorption / separation.

The present invention will be further described from another viewpoint.

A calcium phosphate-based porous sintered body having a porosity of 0.1% or more and 99.9% or less and having a gradient distribution is preferred. In areas with high porosity, pores (150 μm or more, conduction diameter 50 μm or more) into which cells and biological tissues can easily enter
The three-point bending strength is preferably 5 MPa or more. In areas with low porosity, the outside is rough,
It is preferable that the strength is high and the three-point bending strength is 30 MPa or more. The slope of the porosity may be coarse on the outside and dense on the inside, or vice versa, or may be sloped in the opposite direction from one side, and the dense and dense parts are alternated. Is also good.

In the present invention, since the porosity is inclinedly distributed, the mechanical strength is high in a region where the porosity is dense, and it is possible to support the load applied to the material in the initial period of 2 to 3 months after the operation. it can. In the region where the porosity is coarse,
Since the cells and tissues penetrate into the interior, it becomes very close to the living tissue from 3 months after the operation, and the strength is increased and the load can be supported.

The main uses are a bone-replacement material for living bone having osteoinductive and osteoconductive capabilities, a material for filling in osteoporosis and bone defects, and a physiologically active group used for tissue engineering, including amino acids, carbohydrates and cytokines. Materials, sustained-release base materials for anticancer agents and the like, and culture vessels for stem cells and liver tissues. It is also used as a filter for drinking water and fermented drinks.
It can also be used as a column material for adsorption and separation.

In a typical production method, hydroxyapatite powder (100 g) as a raw material is mixed with ion-exchanged water (80 g).
And a cross-linking polymerizing agent (polyethyleneimine: number average molecular weight: 8000-10500) is added and mixed by a ball mill for 5 hours. A foaming agent (polyoxyethylene lauryl ether: a nonionic surfactant, O.D.) was added to the obtained slurry (192 g).
Add 8 g) and stir mechanically until foam to 300 cm ³ . To this, a crosslinking agent (epoxy compound: sorbitol polyglycidyl ether, 4 g) is added, thoroughly stirred, and introduced into a cylindrical mold. 60rpm on the turntable
By rotating at m, the distribution of bubbles is made sloping. When the fluidity is lost due to the cross-linking polymerization and the strength at which bundling can be obtained is obtained, the mold is released, sufficiently dried with a humidifier and a dryer, and sintered at 1200 ° C.

The obtained hydroxyapatite porous sintered body is
The inside of the cylinder has a porosity of 60%, an average pore diameter of 200 μm, an average communicating diameter of 70 μm, and a three-point bending strength of 15 MPa. In the peripheral portion, a porosity of 20%, an average pore diameter of 50 μm, an average communicating diameter of 20 μm, and a three-point bending strength It is 45 MPa.

[0036]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of the present invention will be described below.

Example 1 (Utilizing centrifugal force) Hydroxyapatite powder 100 parts by weight, ion-exchanged water
0 parts by weight, cross-linking polymerization agent (polyethyleneimine)
8.7 parts by weight were mixed and mixed and ground with a ball mill for 24 hours to prepare a slurry. 195 g of this slurry was taken out, 1.5 g of polyoxyethylene lauryl ether was added as a foaming agent, and the mixture was foamed by stirring to reduce the volume to 20%.
0 cm ³ . Here, 2.9 g of sorbitol polyglycidyl ether as a curing agent was added and mixed well, and then cast into a mold having an inner diameter of 46 mm and a length of 100 mm.
With the mold longitudinal direction horizontal, 40 around the cylindrical rotation axis
It was rotated at a rotation speed of 0 rpm, left for 1 hour in this state, and stopped. After leaving still for 1 hour, it was removed from the mold, dried slowly, and sintered at 1200 ° C. for 2 hours to obtain a cylindrical sintered body having a diameter of 30 mm and a length of 65 mm.

The relationship between the distance from the center of the circle of the obtained sintered body and the porosity is shown in the table. The porosity was determined by observing the polished portion of the sample after embedding it in a resin, using a microscope, and using the area ratio of the resin portion, that is, the pore portion, in the observation range.

[0039]

[Table 1] Furthermore, in a portion at a distance of 6 mm or less from the center of the circle showing a porosity of 72% by microscopic observation, the average diameter of the communicating portion between the pores exceeded 50 μm, and the pore diameter exceeded 150 μm. In addition, a test piece for measuring three-point bending strength having a thickness of 3 mm, a width of 4 mm, and a length of 40 mm was prepared from the surface of the cylinder having a low porosity, and the measurement was performed under the measurement conditions of a span of 30 mm and a crosshead speed of 0.5 mm / min. When the point bending strength was measured, n = 5 average three-point bending strength was:
It was 80.5 MPa.

Example 2 (Lamination Method) A slurry A was prepared by mixing 100 parts by weight of hydroxyapatite powder, 58 parts by weight of ion-exchanged water, and 8.7 parts by weight of polyethyleneimine, and mixing and pulverizing the mixture all day and night with a ball mill. A curing agent was added to the slurry A in the same manner as in Example 1, mixed, and then cast into a mold having an inner diameter of 16 mm to obtain a columnar molded body A. Next, a foaming agent was added to the slurry A, and the mixture was stirred and foamed, and then a curing agent was added and mixed to prepare a slurry B. This slurry was cast between the mold A having an inner diameter of 22 mm and the center of the above-mentioned cylindrical compact A, and the slurry B was solidified and adhered to the cylindrical surface of the compact A at a thickness of 3 mm. A cylindrical molded body was obtained.
Further, the operation of casting another foamed slurry in the same manner on the surface of the columnar molded body, solidifying and bonding the same was repeated. Finally, 5 concentrically around the molded body A
A molded product having an outer diameter of 46 mm was obtained by laminating the molded products of the layers. The porosity of the sintered body is 10%, 30%, and 50%, respectively, in the order from the molded body A toward the outer peripheral direction.
%, 70% and 90%. After slowly drying the laminated columnar molded body, it is sintered at 1200 ° C. for 2 hours, and has a diameter of 30 m.
With m, a columnar sintered body having an integrated laminated structure was obtained. The obtained columnar sintered body is a dense body having a porosity of 0% at the center with a diameter of about 10 mm, and the porosity of the laminated portion obtained in the same manner as in Example 1 is from the center toward the outer periphery. 12 each
%, 33%, 52%, 71%, and 91%.

[0041]

According to the present invention, the porosity is inclinedly distributed,
The portion with coarse pores has high mechanical strength and can support a load applied in a living body in an early stage of two to three months after the operation.

Further, cells and tissues can penetrate into the parts having dense pores and become very close to living tissues, and the strength can be gradually increased after the operation to support the load.

Bone tissue penetrates into the porous body within a period of two to three months after the operation to improve the strength.

In particular, when the porosity of apatite alone changes gradually from dense to porous, the following remarkable effects can be obtained by gradually changing the porosity.

When the porosity gradually changes, when used as an artificial bone, when it is gradually replaced with its own bone from the surface,
The porosity is replaced from a place with a large porosity (a weak place), and the porosity proceeds in a denser direction. Therefore, the strength is improved every day. On the other hand, when the whole is made of a porous material having a constant porosity, the strength cannot be improved unless the entire part of the fixed pores is replaced.

When the porosity is gradually changed, the outermost (surface) porosity can be sufficiently increased.
Therefore, the bone is quickly replaced and the bone is fixed quickly.

 ──────────────────────────────────────────────────続 き Continued on the front page (71) Applicant 000221122 Toshiba Ceramics Co., Ltd. 7-25-5 Nishi Shinjuku, Shinjuku-ku, Tokyo (71) Applicant 591121410 Toshiba Denko Co., Ltd. 5--22-10 Shimbashi, Minato-ku, Tokyo No. Matsuokadamura-cho Building (72) Inventor Junzo Tanaka 1-1-1 Namiki, Tsukuba City, Ibaraki Prefecture Inorganic Materials Research Laboratory (72) Inventor Masaki Kikuchi 1-1-1 Namiki Tsukuba City, Ibaraki Prefecture Inorganic Materials Research Laboratory (72 Inventor Akimichi Hojo 30 Soya, Hadano-shi, Kanagawa Prefecture, Toshiba Ceramics Co., Ltd. (72) Inventor Koichi Imura 30-Soya, Hadano-shi, Kanagawa Toshiba Ceramics Co., Ltd. (72) Inventor Uemoto The hero 30 Soya, Hadano-shi, Kanagawa Toshiba Ceramics Co., Ltd. 5-22-22 Shimbashi, Minato-ku, Kyoto Toshiba Denko Kogyo Co., Ltd. (72) Inventor Masami Kinoshita 5-22-10 Shimbashi, Minato-ku, Tokyo Toshiba Denko Kogyo Co., Ltd. (72) Nobuaki Minowa Inventor 5-22-22 Shimbashi-ku, Tokyo Toshiba Denko Kogyo Co., Ltd. F-term (reference) 4C081 AB04 BA13 BB06 BB08 CE02 CF011 CF22 CF24 DA01 DA11 DB03 DB05 DB06 DC02 EA04

Claims (16)

[Claims] 1. A calcium phosphate-based porous sintered body having a porosity substantially continuously and gradiently distributed from 5% or less to 85% or more. 2. A calcium phosphate-based porous sintered body having a porosity continuously and gradiently distributed from 1% or less to 90% or more. 3. An area having a high porosity, wherein an average diameter of a communicating portion between pores is 50 μm or more, and a pore diameter is 150 μm or more.
3. The calcium phosphate-based porous sintered body according to any one of items 1 to 2. 4. A three-point bending strength of 5 MPa or more in a region having a high porosity.
The calcium phosphate-based porous sintered body according to any one of the above. 5. The method according to claim 1, wherein the three-point bending strength is 30 MPa or more in a region having a low porosity.
5. The calcium phosphate-based porous sintered body according to any one of 4. 6. The calcium phosphate-based porous sintered body according to claim 5, wherein the three-point bending strength is 50 MPa or more in a region having a low porosity. 7. The calcium phosphate-based porous sintered body according to claim 1, wherein the slope of the porosity is rough on the outside and dense on the inside. 8. The calcium phosphate-based porous sintered body according to any one of claims 1 to 6, wherein the slope of the porosity is such that the outside is dense and the inside is coarse. 9. The calcium phosphate-based porous sintered body according to any one of claims 1 to 6, wherein portions having a porosity of alternating density are alternated. 10. A calcium phosphate-based porous sintered body,
CaHPO_Four, Ca_Three(PO_Four)_Two, Ca_Five(PO_Four)_ThreeO
H, Ca_FourO (PO_Four)_Two, Ca_Ten(PO_Four)₆(OH)_Two,
CaP_FourO₁₁, Ca (PO_Three)_Two, Ca_TwoP_TwoO₇, Ca (H
_TwoPO_Four)_Two, Ca _TwoP_TwoO₇, Ca (H_TwoPO_Four)_Two・ H_TwoO's
A contractor characterized by comprising at least one component as a main component.
10. The calcium phosphate according to any one of claims 1 to 9
Porous sintered body. 11. A part of the Ca component is Sr, Ba, M
The calcium phosphate porous sinter according to any one of claims 1 to 10, wherein the sinter is substituted with at least one selected from g, Zn, Fe, Al, Y, La, Na, K, and H. Union. 12. Part of the component (PO ₄ ) is VO ₄ , B
_{O 3, SO 4, CO 3} , calcium phosphate porous sintered body according to any one of claims 1 to 1 1, characterized in that it is substituted with SiO ₄ from one or more selected. 13. Part of the (OH) component is F, Cl,
O, calcium phosphate porous sintered body according to any one of claims 1 to 12, characterized in that they have been substituted with one or more kinds selected from CO _3. 14. A step of preparing a slurry in which a calcium phosphate-based powder and an organic substance curable by cross-linking polymerization are dispersed or dissolved in a solvent, adding a foaming agent to the slurry, and performing at least one of stirring and gas introduction. Foaming to a predetermined volume, a step of forming a slurry in a foam state, adding and mixing at least one of a crosslinking agent and a crosslinking initiator to the slurry in the foam state, introducing into a mold, and curing by crosslinking polymerization. A method for producing a calcium phosphate-based porous sintered body, comprising a step of forming a molded body in which porosity is continuously and inclinedly distributed. 15. The calcium phosphate-based porous sintered body according to claim 14, wherein the pores are coarsened at the center of rotation and dense at the outer edge of the rotation to obtain a gradient distribution. Production method. 16. The method for producing a calcium phosphate-based porous sintered body according to any one of claims 14 to 15, further comprising a step of drying and sintering the molded body.