JPH10167853A - Porous ceramic compact for artificial bone material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain porous ceramic used as a organic material for medicaluse. SOLUTION: This porous ceramic compact is made of a sintered porous body of a calcium phosphate compd. contg. spherical or cocoon-like secondary particles 1 consisting essentially of fibrous hydroxyapatite crystal grains as primary particles. Since the surface of each of the secondary particles 1 has echinulate fibers, the surfaces of the particles 1 are in contact with one another at many contact points and the particles 1 are deformed or overlapped with one another to form a three-dimensionally and tightly fixed matrix structure. Gaps 3 formed among the particles 1 in the matrix structure open to the outside.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a bio-permanent implantable bio-acceptable ceramic material having a hybrid structure and a method for producing the same. That is, the present invention provides a living body implant material in which new bone can grow in combination and has a novel tissue structure. The bioimplant material of the present invention can be used for orthopedic surgery, plastic surgery,
In the medical fields of neurosurgery, thoracic surgery, oral surgery, etc., it is suitably used as an artificial substitute, a supplementary material and a filling material necessary for performing an accurate operation or treatment. .

[0002]

2. Description of the Related Art Artificial bones made of conventional calcium phosphate ceramics have received attention from the standpoint of their biocompatibility, osteoinductive function, toxicological biostability, etc., and have already been put into practical use. I have. In particular, the hydroxyapatite composition is stable in the living body and has excellent biocompatibility, and the sintered body directly bonds to the mother bone without passing through soft tissues,
In new bone, it becomes a supplemental source of calcium and phosphorus ions,
It is known that living bone may be replaced.

The present inventors have invented a structure of a hydroxyapatite sintered body having high biocompatibility, high strength, and excellent shaping workability during surgery (Japanese Patent Application Laid-Open No. 60-1985). No. 16979, No. 60-18174, No. 6
2-158175, JP-A-5-246773, 5
-270940 and 5-270945).
In these inventions, the provision of a field capable of inducing osteogenesis is based on the idea that a field of recognition that osteoprogenitor cells form bone is necessary, and the curvature of the field is important here. He has proposed a hypothesis. The ultimate in the extension of the curvature is a circle, and since this three-dimensional expansion is a sphere, it provides a structure in which true spherical holes are provided in the material.

[0004] This spherical hole for a circle or a sphere is the most effective when a bone based on osteoclast origin is regenerated in an artificial bone material according to the above-mentioned prior art. by. In other words, this spherical occupancy indicates the optimal living space ratio for the osteogenic cells to mature and form new bone, and the occupation of the effective curvature field for new bone formation of the artificial bone material. It can be referred to as the rate. Japanese Patent Application Laid-Open No. Hei 7-291759 discloses that combustible spherical particles, that is, particles of polymethyl methacrylate are coated with a binder, and a calcium phosphate-based powder is filled in an interstitial space of a molded product. A method for producing porous ceramics, in which the dried and solidified product is fired, is disclosed. This is intended to place voids from which combustible spherical particles have escaped in the material.

[0005] The performance of the artificial bone material is confirmed through animal experiments. However, bone primordial cells have a lining cell structure on the wall surface in a spherical hole in the structure of the artificial bone material. It was confirmed that a layered new bone was formed toward the center of the vacancy, and that the rate of osteogenesis was also different due to the difference in vacancy diameter as well as toward maturation. However, in the case of the conventional artificial bone material, when the size of the mother bed material is 5 × 5 × 5 mm or more, it is fatal that bone formation is not recognized in pores existing deep in the artificial bone material. It had a defect.

The cause is apparently that the matrix structure itself remains in an obstructive structural environment with respect to transport of bone progenitor cells into the artificial bone material, exchange of blood and body fluid, nutrition supply, and the like. Although the environment for applying the artificial bone material in the prior art was said to have been improved, fenestration was performed on the metaphysis of the beagle dog femur, which is one of the optimally purified environments for causing bone formation. Seven years after the implantation period, this was excised and analyzed. As a result, bone formation and maturation around the artificial bone material were good. However, no bone formation was observed in the deep holes of the artificial bone material. In addition, the formation of new bone in such pores is inadequate and the maturation of bone is poor, which is frequently seen with the passage of time.

In the history of artificial bone research, artificial joint replacement has been introduced in Japan for more than 30 years.
Although the application of artificial joints has already become universal, the necessity of re-replacement is increasing due to the occurrence of defects based on temporal factors.

[0008] In the case of conventional artificial bone materials, in many cases, the bones are softly entangled in the soft tissue early and often fall off, and a slight amount of bone formation is observed only in the surface layer. It has been reported. Also, in conventional joint replacement surgery, the biggest obstacle is that the environment for joint reconstruction is poor, that is, a large amount of bone is required due to the necessity of filling due to skeletal bone defect. This is because it becomes insufficient.

[0009]

SUMMARY OF THE INVENTION In an artificial bone material,
By providing a special matrix structure, it allows bone progenitor cells to penetrate deep into the artificial bone material, exerts further functional effects as a nutrient supply channel for blood, body fluids, etc. It is an object of the present invention to provide an artificial bone material which also has a functional function. It is another object of the present invention to eliminate the factors inhibiting bone formation and its maturation that could not be overcome by the prior art.

That is, the conventional artificial bone material cannot function as a bone substitute, a bone substitute, or a bone filler, and overlooks the drawback that the artificial bone material is left unnecessarily placed in the artificial bone material or left in the dead space. In addition, when biocomplexation is not achieved, there is a drawback of destruction. For this reason, an object of the present invention is to provide an artificial bone material in which bone formation is fast and which is easy to handle at the time of processing, implantation, and the like.

The present invention solves the above-mentioned drawbacks of the conventional artificial bone material and further provides an artificial bone material having a function that can add and exhibit a new function. That is, the present inventors can clarify, through experiments, an environment that is optimal for osteogenesis, and provide the optimal environment. Provided is an artificial bone material having a matrix structure capable of preventing formation of an occluded structure in which bone progenitor cells, blood, bodily fluid, and the like invade into the artificial bone material and prevent exchange.

[0012]

Means for Solving the Problems The present invention has been made as a result of intensive studies to solve the above-mentioned problems, and as a result, has been found to be a molded article comprising a sintered porous body of a calcium phosphate compound. Inside, there are spherical or cocoon-shaped secondary particles consisting essentially of the primary particles of fibrous hydroxyapatite crystal particles, and the surface of each secondary particle is composed of chestnut iga fiber,
Therefore, the secondary particles are in contact with each other at a number of contact points on their surfaces, and have a configuration in which they can deform or overlap with each other, and can be firmly fixed three-dimensionally, and
In addition, the present invention provides a porous ceramic molded body for artificial bone material, characterized in that the hollow portion of the gap formed by the secondary particles has a matrix structure in which pores communicate with the outside.

That is, the primary particles are fibrous materials having a length of 10 to 200 μm, and the hollow portions of the gaps have a length of 10 to 50 μm.
It is preferable to use a structure consisting essentially of true spherical holes having a diameter in the range of 0 μm and a gap portion connecting the true spherical holes.
In addition, the spherical holes have chestnut ligament fiber crystals on the surface thereof to provide an optimal environment for bone formation, and the connecting gap connecting these spherical holes has a maximum diameter of 10 μm. A matrix structure having open pores is preferred. And the hydroxyapatite crystals formed therein,
It is important that thermodynamic stability with respect to the ionic composition in the body fluid is maintained even in the fluctuation of the body fluid composition due to acidosis or alkalidosis. In addition, the hydroxyapatite crystals may be prepared in a hot water reaction or in a high pressure autoclave with calcium hydroxide, phosphoric acid and pure water, and in a liquid phase dispersion system.
During the treatment, a spin force is generated in the solid phase to be formed while applying a rotational force to the liquid phase, and a self-granulated product can be used.

The self-granulated primary particles have a length of 1.
It is preferably a fibrous shape having a width of 0 μm to 1 mm and a width of 0.1 μm to 5 μm, a strip shape, or a foil shape having a width of 5 to 10 μm. Then, in order to form effective spherical holes, a sublimable substance, a flammable substance, or a transpirable substance having a size that can obtain a required pore diameter is added, or the raw material for crystal growth is added. The secondary particle hydroxyapatite crystal slurry is kneaded, and the resulting mixture is subjected to a mechanical dehydration process at a pressure of 100 to 500 kg / cm ² by a water-removing mold press to form a molded body, which is then calcined. It is preferable to use the step of performing the above.

It is preferable that the matrix structure has a communication gap portion having a size of 10 μm or less, so that it is possible to promote osteogenesis and maturation of new bone without forming a vegetative lumen. The filling rate of the fibrous primary particles of hydroxyapatite crystals into the molded body is preferably 10% or less by volume. Further, in the hydroxyapatite composition, Cl, CO ₂ ,
A structure in which an element ion selected from the group consisting of an alkali metal, an alkaline earth metal and a combination thereof is added and incorporated as a trace solid solution type is preferable.

To explain the matrix structure of the artificial bone material of the present invention, chestnut-like fibers are formed on the surface of each secondary particle, the chestnut-like fibers are entangled with each other, and the fibrous crystals are The load on the crystal surface is evenly distributed and the entanglement is even,
The stresses are naturally averaged out and the stress loads applied in the artificial bone material become non-deflective. Since the secondary particles are three-dimensionally configured so as to be deformed or overlapped with each other, their uniformity is guaranteed. That is, the secondary particles constituting the matrix structure of the artificial bone material of the present invention are spherical crystals composed of fibrous hydroxyapatite crystals, as observed by the electron microscope in FIG. 2, and are observed in FIG. Thus, it has a structure similar to "Marimo", its surface is chestnut bur-shaped, and is almost spherical with a flexible surface.

When the secondary particles are compressed during molding, come into contact with each other, and undergo deformation, the spherical secondary particles undergo deformation while being deformed, as observed in the electron micrograph of FIG. Surfaces can be brought into contact and formed. That is, in the artificial bone material of the present invention, the surface of the secondary particles is not fixed at one point, but is contacted by a large number, and is firmly fixed so that the chestnut-like crystals are in contact with each other, and is multipoint contact. Therefore, it is flexible and does not easily cause cracks or the like.

According to the present inventor, in order for bone progenitor cells to be implanted under self-recognition, to induce new bone, and for the new bone to mature normally, the structure and environment of the given field are required. I thought it was extremely important. For this purpose, a transfer microphotograph of an artificial bone material having a matrix structure as shown in FIG. 1 will be described with reference to a replica technique which is one of the electron microscope observation techniques. Since this transfer technique is close to so-called two-step transfer, it is faithful to the mother structure, and it is possible to measure the pore diameter without deformation even after firing shrinkage of the artificial bone material obtained by the present invention. it can.

That is, the surface of the spherical secondary particles (1) has a chestnut bur-like shape and forms a functional curvature field.
Gap or void formed by the aggregate of (1)
(3) is formed as a shell (2), on the surface of which provides a place for the formation of new cells or new bone. The holes (3) are substantially spherical holes (5) having a large diameter.
And a small-diameter communication gap portion (4) communicating with the spherical hole portion (5), and the hole portion (3) communicates with the outside. Small diameter communication gap (4)
Can form open pores and constitute a field through which blood vessels or body fluid tubes pass.

That is, the porous ceramic molded body for artificial bone material of the present invention can prevent osteogenic cells, blood, body fluids, and the like from entering the artificial bone material, thereby preventing the formation of a closed structure for preventing exchange. As described above, the matrix structure is a spherical or cocoon-like structure composed of hollow or coarse fibrous particles, and an aggregate of secondary particles whose surface is covered with chestnut burrs is sintered. It has been found that it can be obtained by doing. That is, as shown in FIG. 2, the secondary particles in a state in which the surfaces are in the shape of chestnut burrs and entangled with each other, even in the molded state, their surface chestnut burrs are intertwined with each other, so that the surfaces are firmly connected to each other Since they are combined, they are easy to fill, and the filling structure is easy to take.

Next, the sublimable substance, the transpirable substance or the flammable substance used in the present invention was confirmed by the above replica technology, and the sublimable substance and the transpirable substance were preferred. Is selected from those having a low combustion rate and no volume expansion or deformation during combustion, and those having no residual components. As the material applied for the purpose of remaining the form, spherical particles of polymethyl methacrylate having a controlled degree of polymerization are preferable, and the volume shrinks due to a slight increase in the degree of polymerization in a calcining furnace. Then, the matrix is left, and then, along with the thermal decomposition, transpiration is started through a matrix having a large porosity, and the residue is burned to leave no residual components. Therefore, a physical defect such as residual strain is not left in the artificial bone material through this process.

In the present invention, “calcium phosphate compound” means CaHPO ₄ , Ca ₂ (PO ₄ ) ₂ , Ca ₃ (PO ₄ ) ₃ OH, Ca ₄ O (P
O ₄ ) ₂ , Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , CaP ₄ O ₁₁ , Ca (PO ₃ ) ₂ , Ca ₂ P
It refers to a group of compounds called hydroxyapatite containing ₂ O ₇ , Ca (H ₂ PO ₄ ) ₂ .H ₂ O and a combination thereof as main components.
Hereinafter, in the present specification, the “occupancy of the curvature field” of the artificial bone material to be used is “the spherical occupancy as a field providing the bone regeneration”, and “the optimal habitation for the neoplastic cells” "Space ratio".

As described above, in the artificial bone material of the present invention,
Under specific design control, the structure between the curvature field occupancy indicating a true spherical occupancy and the pores having the distribution, the intervening matrix structure is a hollow part or a fibrous particle with a high porosity. This is a structure obtained by sintering the aggregate with secondary particles having a spherical or cocoon-like structure and the surface of which is covered with chestnut syrup-shaped crystals. This structure solves the above-mentioned problem. Things.

Further, the artificial bone material of the present invention has solved many more problems. For example, in the prior art, the matrix structure was constituted by pressure molding and sintering of fine powder or coarse powder and the degree thereof, but in this case, the interface between the sintered particles of the powder is surface contact, and If stress concentration occurs, cracks can easily grow, leading to destruction, which makes it difficult to apply it directly under the load. Fine processing was difficult. On the other hand, in the artificial bone material of the present invention, since the sintered particle interface is a limited point contact,
When stress concentration occurs in a specific part, it is partially destructive, but there is no growth of cracks penetrating the whole material, and the dispersion of stress occurs due to the formation of a bridge structure,
It has an apparently elastic behavior.

The primary particles in the porous ceramic molded article of the present invention are fibrous materials having a length of 10 to 200 μm. If the particle size is less than 10 μm, small particles are more tightly packed. The filling rate at the time is too high, which hinders the entanglement of the particles and causes trouble during molding.
In addition, a molding pressure based on a higher load is required, so that the secondary particles are broken and the molded body is accompanied by residual distortion. If it exceeds 200 μm, not only the shape of the secondary particles becomes irregular, but also the appearance of irregular shapes hinders the intended purpose.

The hollow portion is essentially composed of a true spherical hole having a diameter in the range of 10 to 500 μm and a hole connecting the holes. When the diameter of the true spherical hole is less than 10 μm, not only is the timing of new bone formation delayed, but also its maturation is delayed. And when it exceeds 500 μm, similarly,
A delay in bone formation is observed. When the new bone grows in the pores, the pore diameter of the hollow portion to be formed may not be too small, and if it is too large, the efficiency becomes poor.

A matrix composed of secondary particles is interposed between the pores forming the true spherical pores, and this matrix structure has open pores having a maximum diameter of 10 μm. In the case of pores having a diameter of more than 10 μm, bone formation is performed relatively early, and the function as a nutrition supply channel is lost. The diameter of the self-granulated secondary particles is 30 to 20.
It is in the range of 0 μm and is composed of fibrous or strip-shaped primary particles. The diameter of the secondary particles is necessary to form an appropriate interparticle gap. If the diameter exceeds 200 μm, the strength of the sintered body becomes too weak.

In the artificial bone material, bone can be regenerated at an early stage,
The fact that the aging can be promoted is considered to be based on a combination of the following organizational structure designs. Although this is not known academically, it can explain the experimental results well. That is, one of them is that it is important to provide a field that can induce osteogenesis. The other is, as the necessary and sufficient conditions, according to the present invention, as an environment maintenance that can make full use of the place set in the material.
The material design that the design of the matrix structure was brought in and its realization.

The performance of the artificial bone material has been confirmed through animal experiments.
It is confirmed that the inventors found that the bone progenitor cells were implanted on the wall surface of the artificial bone material with the lining cell structure in the spherical hole in the structure of the artificial bone material. The formation of a layered new bone is made towards, and at the same time towards the maturation, due to the difference in pore diameter, the rate of bone formation is also different,
("Apatite as a medical biomaterial and its application", written by Shigee Takagi, Industry and Products 339-347 (198
9)). However, when the size of the mother bed material was 5 × 5 × 5 mm or more, it was found that there was a fatal defect that bone formation was not recognized in the pores reaching the deep part of the artificial bone material. The experiment revealed this.

According to the present inventor, when forming a molded article of artificial bone material, the curvature of the formed pores set under the design management and the gaps between the pores having a specific distribution are formed. The matrix structure is obtained by sintering an aggregate of secondary particles, which are spherical or cocoon-shaped composed of hollow or coarse fibrous particles, and whose surface is covered with chestnut iga-like crystals It has been found that such a special matrix structure can solve the above-mentioned problems of the prior art artificial bone material.

In the artificial bone material of the present invention, since the secondary particles are filled and formed by controlling and producing a specific size and shape from the raw material of the hydroxyapatite solution, the interface between the sintered particles is limited. Point contact. For this reason, when stress concentration occurs in a specific portion, it is partially accompanied by destruction, but there is no crack growth penetrating the entire artificial bone material, and the stress is dispersed by the formation of a bridge structure, and apparently, It was found that the material exhibited elastic behavior.

Further, the secondary particles according to the present invention may be in the form of fibers,
Since it is composed of primary particles in the form of strips or foils, it has open pores of 10 μm or less at maximum, and in the filling structure of secondary particles, as a filling particle gap, a discontinuous 5-300 μm Due to the degree of open porosity, sufficient cell exchange, penetration of blood and body fluids, etc. can be achieved even inside the material. In addition, it has a function that bone maturation does not occur in the prior art.

The artificial bone material according to the present invention has excellent biocompatibility, has been proved to maintain toxicological biosafety based on ISO-10993, and has relatively high mechanical strength. In addition, the handleability is excellent through processing means such as processing.

[0034]

BEST MODE FOR CARRYING OUT THE INVENTION

Synthesis of Hydroxyapatite Crystal Particles It is known that the physical and chemical properties of synthetic hydroxyapatite vary depending on the characteristics of the packing structure of atoms. That is, it is based on the distribution structure of atoms on the crystal surface, that is, the distribution structure of Ca ^{2+ -sites} and PO ₄ ^3- -sites. That is, as a feature through the crystal structure, the fiber-like, needle-like or rod-like crystal with developed a-plane and the foil- or plate-like crystal with developed c-plane have different physicochemical properties. In addition, the development of a functional material with the addition of the defect structure described above.

On the other hand, it is known as a physicochemical property that the solubility of a calcium salt compound as an aqueous solution does not increase with an increase in temperature. Therefore, in the synthesis of hydroxyapatite, by conducting an aqueous solution reaction at a low temperature, hydroxyapatite in a fine and uniform form can be synthesized. This means that the form of the product in the production system can be controlled by controlling the speed of the reaction system by physical factors, and management and control of the environment in the aqueous solution reaction, that is, temperature and pressure. is important.

Hereinafter, conditions for synthesizing hydroxyapatite crystal particles will be discussed. The reactor has a two-tank structure with a stirrer, and the outer tank is for hot water bathing. In some cases, a high-pressure steam curing device with a stirrer and a reaction tank and a twin-body type may be used. As shown in the following examples, the chemical reaction and the phase inversion reaction are completed, and the obtained slurry-like product is subjected to a process of dehydration or the like, as a raw material of a predetermined molded body, and subjected to a water-removing die press. , To create a molded body.

Here, the stirring device is a three-plate flat plate three-stage system, the blade diameter used is 10 cm, the baffle plate can be mounted, the rotation speed is 50 to 300 rpm,
Both the shaft and the blades were coated with an epoxy resin and used after they were completely cured. The blade rotation speed during the reaction is a processing condition that determines the character as a raw material for a given molded body, that is, the concentration of the reaction system, the reaction temperature, the reaction time, and the environmental pressure in the reaction system are as important as Condition.

For this reason, the rotation speed of the blade is appropriately selected depending on the environmental conditions in the reaction system and the reaction time so as to fall within the range of the character of the raw material of the predetermined molded body. Further, the reason why the high-pressure steam curing device is a twin-body type is that the temperature and pressure of the reaction solution in the reaction tank can be instantaneously transferred. In addition, the blade rotation speed is appropriately selected.

According to the above-described production method, a hydroxyapatite slurry as a raw material for crystal formation is prepared. According to the present invention, a pure water-based slurry of hydroxyapatite particles having a spherical or cocoon-like shape filled with hollow or large porosity fibrous particles, and having a chestnut scallop-like fiber structure on a substantially spherical particle surface is provided. ,As below,
Through a dehydration process, a compact is formed. At that time, in consideration of the firing shrinkage accompanying the heat treatment of the molded body, 10 to 50
Sublimable, combustible or transpirable substances are added according to the material structure design so that 0 μm spherical holes remain as replicas in the material structure. Using a mold press, mold pressure 100 ~
While performing a mechanical dehydration process at 500 kg / cm ² , a green body is formed.

That is, after firing, a sublimable substance, a combustible substance or an evaporative substance having a particle size necessary to leave an effective spherical hole having a diameter of 10 to 500 μm as a shell is not added. Or after kneading in the state of being added, using a water-removing die press, 100 to 500
While performing a mechanical dehydration process at a pressure of kg / cm ² , a compact is formed. If the pressure is less than 100 kg / cm ² , the stability of the molded product is poor, and the occurrence rate of chipping and the like increases. Also,
At a pressure exceeding 500 kg / cm ² , breakage of the secondary particles and slipping based on the residual strain in the compact itself are observed, and the mechanical strength of the sintered compact decreases.

Here, the method of molding with a water-removing die press is a uniaxial load, and since the hydrostatic pressure is evenly distributed during the material molding due to the presence of fluid, the ordinary ceramic powder is uniformly molded. C used for molding into
There is no need to use a special molding method such as an IP method, a rubber press method, or an impact molding method, a molding apparatus, or a molding technique, which is economically advantageous in terms of equipment and investment.

That is, the feature of this process is that, based on the presence of a liquid under pressure, the internal stress applied to the material structure at the time of pressurization is equalized. In order to avoid the pressure non-uniformity, for example, it is not necessary to devise a mold or the like to cope with slipping failure based on the angle of repose as a powder characteristic. Therefore, under isotropic pressure, the chestnut-like particles as secondary particles composed of the primary particles of the hydroxyapatite crystal according to the present invention can be entangled with each other to prepare a uniform molded body. The density of the material compact, the physical properties or strength of the material function such as voids, etc., can also be adjusted by combining such processes.

[0043]

The matrix structure formed here is:
It has a significant feature that spherical and cocoon-shaped secondary particles with chestnut iga-like surface are introduced, and if the matrix structure is composed of only fibrous crystals,
Compared to those composed in powder form, during pressure molding, a compacted structure is formed by compression in the direction perpendicular to the fiber, the matrix structure is closed, and when applied as an artificial bone It has been found that the field of interaction with body fluids and the like is significantly impaired.

The material compact thus prepared is transferred to a calciner, subjected to a sublimation, combustion or transpiration process for forming a shell, and then placed in an electric furnace at 900 to 900 ° C.
Sintering is performed at 1250 ° C. to obtain a sintered sintered body.

A sublimable substance, a combustible substance, or a transpirable substance is used to form a shell. It is not limited as long as it is effective for forming pores having the above-mentioned curvature in the porous body. As one of them, spherical particles of a methyl methacrylate polymer are suitable. The reason is that, since this material has an appropriate hardness, it is not deformed or crushed by a mixing operation with the raw material of the molded body or a process such as compression molding, and also, when the molded body is calcined, Evaporation and combustion by thermal decomposition are easier than the matrix voids, and no residue is left, so that there is no contamination on the functional surface in the material structure. Therefore,
In consideration of firing shrinkage, it is possible to form pores having a size and shape exactly corresponding to the size and shape of the applied particles.

As described above, the present invention can provide an artificial bone material that is recognized by the bone progenitor cells itself and is an optimal site for implantation. And, for the growth and maturation of bone tissue, blood, due to the overall structure based on the design of the matrix structure that satisfies the interaction with bodily fluids, not only on the surface of the material, but also after the formation of bone deep in the material, Biocompatibility that can maintain the bone metabolic process normally and does not form a barrier site that hinders the quantitative increase of formed bone, especially high early osteogenesis,
The present invention also provides a biomaterial for medical use which is excellent in shaping workability, mechanical strength, and operability at the time of implantation, and which can absorb and absorb load stress concentration.

The material for artificial bone obtained according to the present invention is a porous hydroxyapatite ceramic material capable of inducing osteogenesis in defective bone tissue and promoting bone maturation with normal bone metabolism. It is completely new.

That is, osteonecrosis, bone defects after application of curettage to bone tumors, etc., reconstruction of the mother bed when artificial joints are inserted, orthopedic bone reconstruction including high energy trauma, osteoporosis, etc. For bone replacement, bone replacement or bone filling as a treatment for bone replacement for diseases of the disease, the application site is not always under the optimal environment for causing bone formation, It is often applied clinically in a poor environment where the source cells are implanted in a depleted bioactive mother bed.

On the other hand, in the case of the conventional artificial bone material, when applied in such a poor environment, a dead space is formed unnecessarily, or an obstacle that hinders an increase in bone mass is formed. Also, formation of an occluded structure and construction of a castle wall structure are often observed, or the composite of artificial bone material and new bone often fails. For this reason, it has been reported that the implant material cannot satisfy the physical characteristics of the bone, and also causes a problem that leads to a detachment or a fracture phenomenon.

An artificial bone material having such a problem can be easily determined by a short-term animal experiment. That is, a fenestration was performed to reach the medullary cavity in the long bone, which is one of the optimally purified environments for causing osteogenesis, and a material shaped and shaped in the same manner was implanted, and one week passed. Later, it can be determined by extracting and performing cell kinetic analysis. In particular, artificial bone materials currently on the market are porous materials, and the infiltration of body fluid into the pore structure and the behavior of cell components are important decisive factors.

According to the matrix structure of the artificial bone material of the present invention, since the tissue structure of the artificial bone material is not uniform and not an integral body, strain is not concentrated but concentrated when a load is applied or a stress is concentrated. Dynamic mechanical behavior and excellent early bone formation and maturation,
It is possible to cope with the applied load based on the composite function of the material and the new bone. As described above, by designing, managing and adjusting the tissue and structure of the artificial bone material, that is, the matrix structure, in addition to the function of promoting better new bone formation and bone maturation, the artificial bone material has The tissue and structure serve as a hybrid basic lattice induced by new bone, which exhibits physical and mechanical behavior similar to the stomach bone near the implant site.

Next, the artificial bone material of the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto.

[0053]

Example 1 [Preparation of Raw Material Calcium Phosphate] 0.15% calcium pyrophosphate was added as a buffer solution to a 10% solution of a phosphoric acid aqueous solution, and gradually added at room temperature (20 ° C.).
% While adding the aqueous dispersion of calcium hydroxide adjusted to
Stir at 10 to 20 rpm, start heating with hot water about 1 hour later, and adjust to 50 to 80 ° C 2 hours later. This temperature range should be appropriately selected because it varies depending on the properties of the starting material calcium hydroxide. During heating, the stirring speed is increased to 60-120 rpm. This increased stirring speed is preferably 80
-100 rpm is desirable. Meanwhile, the pH of the reaction system is maintained at 8 to 9 with a 5% ammonium aqueous solution using a micro burette.

Next, this slurry was directly transferred to a high-temperature steam curing reaction tank, and a temperature of 110 to 180 ° C. and a temperature of 2 to 2 hours.
After hydrothermal curing for 3 hours, the formation reaction and the phase inversion reaction are completely performed. This temperature range is preferably 130
~ 150 ° C is desirable. The blades of the high-temperature steam curing device used here are eccentrically designed. this is,
This is to make the flow of the fluid in the reaction tank a laminar flow.
The composition of the solid phase of the slurry before transferring to the high-temperature steam curing tank was a mixed phase of Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ and Ca (H ₂ PO ₄ ) ₂ . After the high-temperature steam curing, the slurry was completely converted into Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ as a slurry solid phase composition.
The ratio of P was 1.67.

As described above, the morphology of the generated solid phase is in a range that almost satisfies the purpose. According to microscopic observation, the particle size of the secondary particles having a chestnut-shaped surface is 80%.
２００200 μm, and the average particle size was 120 μm.

[0056]

[Example 2] [Preparation of raw material calcium phosphate] Calcium hydrogen phosphate Ca
10-15% by weight aqueous solution of HPO _4, adding excess phosphoric acid H ₃ PO _4, at room temperature with stirring (20 ° C.), slowly 5-1
A suspension of 0% by weight of calcium hydroxide Ca (OH) ₂ is added, until the hydroxyapatite stoichiometry is reached, and stirring is continued for about 2 hours. Next, while maintaining the pH of the reaction system at 8 to 9 by dropping a 5% by weight aqueous ammonium solution using a micro burette, the mixture is stirred for about 1 hour. Next, this slurry is directly transferred to a high-temperature steam curing reaction tank, and the same stirred water thermal curing as in Example 1 is performed at 110 to 150 ° C. for 2 hours. This is taken out and used as a forming raw material.

The composition of the solid phase of the slurry before it was transferred to the high-temperature steam curing tank was a mixed phase of Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ and Ca (H ₂ PO ₄ ) ₂ . After the high-temperature steam curing, the slurry was completely converted to Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ as a solid phase composition of slurry, and the ratio of Ca / P was 1.67. According to microscopic observation, the morphology of the generated phase is a fibrous crystal developed along the C-axis, having a size of 30 to 150 μm and an average of 9 μm.
The particles were secondary particles of 0 μm, and a fibrous structure having a high porosity was similarly observed inside the particles.

[0058]

Example 3 [Preparation of Raw Material Calcium Phosphate] Blades for stirring in a two-tank type reactor equipped with a stirrer have the center of the rotary blade eccentric as in the above-described embodiment. Next, about 1/4 of the total capacity of the tank is filled with pure water, and 100 to 150 rpm.
The mixture was heated to 70 to 80 ° C. while stirring at a rotation speed of 5% by weight while alternately adding a 10% Ca (OH) ₂ suspension and a 15% aqueous phosphoric acid solution little by little. Is added dropwise to adjust the pH to 8-9.
When the stoichiometric addition process is completed, the rotation speed of the stirring blade is reduced to 50 to 70 rpm, and stirring is continued for 24 hours for aging. Aging is good when stirring is stopped.
Since the crystal particles quickly settle out in the stirred suspension, the liquid is easily clarified, so that the determination is easy.

The composition of the solid phase of the obtained slurry is Ca ₁₀ (P
O ₄ ) ₆ (OH) ₂ , and its Ca / P ratio was 1.67. The morphology of the solid phase was relatively coarse spherical or egg-shaped, and the chestnut iga-like morph was relatively coarse.
If the bur is rough, it is coped with by adding a small amount of separately synthesized fibrous crystals and mixing them during molding.

[0060]

[Example 4] [Preparation of molded body and preparation of calcined body] The slurry synthesized in Examples 1 to 3 is washed by repeating inclined filtration when it is necessary to wash the slurry. In general, a filter cloth is laid in a box having a plastic net fixed to the bottom, a slurry is poured into the box, spontaneous dehydration is performed, and a water / solid ratio (at a drying temperature of 105 ° C.) of 25 to 30% is obtained. And drain water. This highly concentrated slurry is dried on a dry basis for 10
0 and 20 to 300 parts by weight of 30 to
A true spherical polymethyl methacrylate polymer (of sublimable, flammable or transpirable substance) having a particle size of 800 μm is added, mixed well, and the mixture is filled into a predetermined mold,
Molding pressure is 100 to 50 using a drain press.
While undergoing a mechanical dehydration process at a molding pressure of 0 kg / cm ² , a molded body was prepared and stored in a bench box.
This molding pressure is preferably about 300 kg / cm ² .
Next, if necessary, the formed body is taken out of the bench box, placed in a calciner, and gradually heated at a temperature gradient of 200 to 800 ° C. at a preset temperature gradient, so that the sublimation, flammability or By removing the transpirable substance through a process such as sublimation, thermal decomposition or combustion, pores having a predetermined range of curvature were formed, thereby forming a matrix rich in voids passing between these pores. A calcined body was obtained.

Next, the calcined body is placed in an electric furnace with a molybdenum silicide heating element adjusted to a temperature range of 900 to 1250 ° C. in an oxygen-containing atmosphere to form a molded calcined body of the hydroxyapatite composition. Sintered.

[0062]

Fifth Embodiment [Cleaning of Shells and Vacancies] The sublimable substance, flammable substance or transpirable substance described in the fourth embodiment forms pores having the above-mentioned curvature field occupancy in a porous body. Any type can be used as long as it is effective for the purpose. Here, the reason why the spherical particles of the methyl methacrylate polymer were selected is that this material has an appropriate hardness, so that it is deformed or crushed by a mixing operation with the raw material of the molded product or a process such as compression molding. Without sintering, and during calcination of the molded body, evaporation and combustion by thermal decomposition are easier than matrix voids,
In addition, since no residue is left, there is no contamination of a functional surface or the like in the material structure. Therefore, considering the firing shrinkage, the size and shape of the applied particles exactly correspond to the dimensions,
A void having a shape can be formed.

[0063]

Example 6 As discussed in Example 5, an average particle size of 100
From the slurry of hydroxyapatite particles granulated and synthesized to a size of μm, the occupancy rate of the functional curvature field of the prototype sample is converted to a volume of 300 μm so that the volume percentage of the functional curvature field of the prototype sample is 75% by volume, calculated from the drying basis at 105 ° C. Relatively uniform spherical particles of methyl methacrylate were blended and mixed with water and the material at a weight ratio of 50%. On the other hand, in the case of the functional curvature field occupancy of 0%, it is not necessary to perform mixing. However, for convenience of handling, the ratio of water and material when the occupancy of the functional curvature field is given is expressed by weight. 25 to 30% is better. When materials having different specific gravities are mixed, whether they are dry or wet, separation and layer separation can occur. The water / material ratio is determined from the standpoint of separation and handling. Selected.

This mold was uniaxially pressurized, the load speed was 1.6 kg / cm ² / sec, and 400 kg / cm ²
At which point the load was stopped for 60 seconds, followed by demolding to obtain the prescribed pellets. Through these operations, no abnormal findings such as collapse, cracks, and stratification on the pellet were observed.

The pellets were fired in a calcia crucible and slowly heated at a heating rate of 2 ° C./min up to 450 ° C. in an electric furnace with a heating element made of molybdenum silicide adjusted to 120 ° C. , After burning, temperature gradient 8.5
The temperature was raised at a rate of 1 ° C./min. At the stage where the temperature reached 1250 ° C., the temperature was maintained for 1 hour, allowed to cool, and then taken out. Each of the pellets after firing was obtained in a pure white stable shape, and no collapse, rupture, crack, or the like was observed.

Further, there was little firing shrinkage, and the material possessed a bending strength that could not be broken by fingers. FIG. 2 shows the results obtained by dividing the obtained material and sample into two parts by impact with a cutter knife and observing them with a scanning electron microscope. Based on these observation results, the tissue structure of the cut surface of the obtained artificial bone material is schematically shown in FIG.

From the above results, the artificial bone material according to the present invention is as described in claims 1 to 10, and can design a tissue structure capable of inducing osteogenesis and providing a field necessary for maturation. Technology and material settings were established. In addition, it was clarified that the mechanical strength of the fired body can be reliably improved by the distribution design of the functional curvature field and the particle size distribution of the hydroxyapatite secondary particles.

[0068]

Example 7 [Confirmation of Effect by Animal Experiment] With respect to the artificial bone material of the present invention, the function retention for a long period of time when the implant was applied was confirmed by an animal experiment. First, three commercially available artificial bone materials A, B, and C were used. An 8x15x5 mm fenestration was performed on the beagle dog just below the epiphysis of the tibia,
The same shaped and shaped material was implanted, and after one week, it was excised and compared. All of the extirpated sites were at the time when considerable hematomas were observed, but non-decalcified slices were prepared by a standard method. E. FIG. After staining and microscopic observation,
Compared.

The observation results are as follows. A shows no infiltration of body fluid or the like into the pores of the internal structure of the material.
In B, although infiltration of a bodily fluid component into pores in the material was observed, neither infiltration of cell components nor infiltration of blood components was observed. C shows infiltration of body fluid only in the surface layer,
In addition, infiltration of cell-like components was observed, but no such tissue was observed in the artificial bone material. That is, with the conventional artificial bone material, the closed structure could not be opened. Regarding the above A and B, bone was introduced into the artificial bone material through the implantation period of one year and seven years. No newborn or bone formation has been observed.

On the other hand, a similar animal experiment was performed on the artificial bone material of the present invention. One week after the implantation, this was excised and analyzed, and as a result of analysis, no portion of body fluid infiltrated into the voids and matrix voids was found at all, especially for the curvature space site . In many cases, infiltration of body fluid, infiltration of blood components, and invasion of precursor cell-like cell components were observed.

[0071]

Example 8 [Cell Dynamics Analysis] Age 15 years (estimated human equivalent age 90
), The tibia, the jawbone and the skull of an old beagle dog were selected as the application site, and each bone was partly extracted by fenestration.
Implanting and applying the artificial bone material of the present invention in a form to compensate for the defect site, cutting out the portion in contact with the artificial bone material and the mother bone over time, and continuing the experiment in a form to repair this Was used to perform cell kinetic analysis. For the tibia,
8 × 20 × 5mm, for the jawbone 10 × 30 × 5mm,
Implantation surgery was performed on the skull as a disk having a thickness of 8 mm and a diameter of 15 mm based on surgical procedures. 3
After a lapse of one week, the tibia site is filled with blood components throughout the cavities, and especially in the curvature site, the presence of progenitor cell-like cells and the implantation of osteoblasts are often observed. The formation of new bone in the lining shape was confirmed. Also,
In the jawbone region, similar tissue growth was observed at the site in contact with the bone marrow structure, and the bone tissue was diffusely introduced toward the deep portion of the artificial bone material. In addition, at the time of implantation into the cranial region, infiltration of fibroblasts and formation of soft tissue were observed in the region in contact with the cranial dura, and thereafter, new bone growth was observed in the tibia region and the jaw bone region. And normal bone maturation with lamellar structure had progressed.

On the other hand, the skull region has a tissue structure in which the artificial bone material is surrounded by soft tissue with the proliferation of fibroblasts. After 26 weeks, a new bone is observed in the site on the dura mater side, though it is dotted. This is presumed to be the formation of ectopic ossification, but the origin could not be clarified.

[0073]

Example 9 [Observation of New Bone Formation] Porosity (referred to as curvature field occupancy ) of 50% due to only pores (curvature sites) produced according to the present invention.
An artificial bone material of 10 × 20 × 5 mm in size reaching the bone marrow just below the epiphyseal line of the femur and tibia of a 6-month-old beagle dog Was implanted. At the time of sacrifice over time, blood biochemical observations were performed at the same time as bone kinetic analysis of the extirpated sites, mainly for changes in alkaline phosphatase and graprotein.

Regarding the change in the amount of alkaline phosphatase, the individual value itself was at a high level because the beagle dog was in the growth period, and it was difficult to test the difference in the significance test. The increase in protein is remarkable from 3 weeks to 9 weeks after implantation, indicating that new bone formation is vigorous. At the same time, the bone dynamics analysis revealed that new and rapid bone formation, bone mass increase and bone maturation could be achieved. That is, the formation of new bone in the artificial bone material and the like can be realized for the first time by the artificial bone material and the method for producing the same according to the present invention.

[0075]

Example 10 A material having a curvature field occupancy of 45% was implanted into spines of the goat by spinal process splitting C ₃ , C ₄ and C ₆ and secured with a non-absorbable suture. After a lapse of six months, the animals were sacrificed and dissected, and the fixed state was observed. Then, the cells were excised, subjected to cell kinetic analysis and observed, and subjected to bone histological analysis.

This application site has a relatively low blood flow rate, and is therefore judged to be an environment that is not very suitable as an extraction site for promoting the occurrence of bone formation. Conventionally, in clinical cases, there are cases in which the soft tissue is surrounded early and falls off, and although only a slight amount of bone formation is observed in the surface layer,
Some cases have been broken.

In the artificial bone material of the present invention, bone formation is clearly observed at the portion in contact with the cervical vertebrae as a mother bed, and at the portion where the upper spine and soft tissue are in contact, the fiber tissue is covered and the fiber tissue is It was confirmed that it had formed by penetrating to the inside and deep. In addition, the characteristics of new bone and the formation of new bone by excision into this site are more likely to remain in osteoid tissue compared to the site that is considered to be the optimally purified environment for causing new bone. This can be presumed to be a delay in calcification, probably due to the low site-specific blood flow and the effect of poor mechanical forces.

[0078]

Example 11 This example confirms applicability to bone, particularly applicability over time. Six mongrel dogs having a breeding history of 15 years or more were prepared, and hip replacement was performed using a small dog artificial bone hip joint manufactured by Richard, USA. That is, assuming that there is a large bone defect site on the back of the acetabulum, a bone defect of 20 × 30 × 40 mm is formed, and a curvature field occupancy of 25%, which is almost the same as that of the curvature field created by the present invention, is formed. After the artificial bone material was applied and dent processing was performed, the defect site was filled, the acetabular bone was fixed using two screws together, and the joint was reconstructed. The cast was not dared to protect the surgical site.

After the anesthesia was awake, the patient was left undisturbed. However, lameness was slightly observed up to about one week after the operation. I couldn't. Of these, 2 were 3 months and 6
A month later, the sacrifice site was removed and the remaining four animals were
Observation over a long period of time showed that the osteogenesis permeated into the artificial bone material after 3 months and 6 months showed good progress. No particular abnormality was observed in the acetabular shape, the surrounding bone tissue, its shape, and the like.

[0080]

The artificial bone material of the present invention has the following technical effects due to the constitution described in the claims. That is, the porous hydroxyapatite ceramic material according to the present invention can have a spherical structure of 10 to 500 μm as a functional curvature field and a matrix structure interposed between the holes, which can be obtained. The secondary particles that make up
Bone progenitor cell-like cells, which have open pores with a maximum value of 10 μm or less and have open pores with a diameter of 5 to 300 μm as packing particle gaps in the packing structure with secondary particles. Can be freely penetrated, and blood and body fluids can be easily infiltrated and exchanged. Therefore, maintenance of the nutrient lumen is not hindered, and growth and maturation of bone cells can be promoted. Directly joins the normal bone tissue of the mother bed, resulting in bone tissue similar to normal bone.

Furthermore, due to the special tissue structure of the artificial bone material of the present invention, the artificial bone material was directly connected to surrounding tissues without impairing the formation of vegetative blood vessels in the cavities and without recognizing foreign body reactions. A functional biomaterial having a biological production function has been realized. In addition, by dissolving a certain element or ion in a trace amount, characteristics such as polarity or dissociation of the interface of the artificial bone material can be improved. Not only can it be applied to many uses such as application to a carrier such as a forming factor agent or a bone growth factor agent, but also genetic engineering, such as cell culture,
It can be used for a cell growth reactor or the like. The functional porous ceramic material of the present invention has functionality and can be efficiently produced.

That is, the porous artificial bone material ceramic according to the present invention can provide an optimal environment in which the bone progenitor cells can be recognized and implanted, and can provide blood and bone for the growth and maturation of bone tissue. It can possess a matrix that facilitates interaction with body fluids, and the overall structure based on it allows bone metabolic processes to be normally maintained and formed not only on the surface of the artificial bone material but also after bone formation deep in the bone Biocompatibility with no formation of barriers that hinder the increase in bone mass, especially high early osteogenesis, and excellent shaping, mechanical strength, and operability during implantation Further, it is possible to provide a medical biomaterial capable of relaxing and absorbing the concentration of applied stress.

[Brief description of the drawings]

FIG. 1 is an explanatory diagram for schematically explaining a matrix structure of a porous artificial bone material ceramics of the present invention.

FIG. 2 is an electron micrograph showing the structure of secondary particles of hydroxyapatite as a raw material used in the porous artificial bone material ceramics of the present invention.

FIG. 3 is an electron micrograph (magnification: 9000) of a particle structure showing a bonding state of secondary particles of a porous ceramic formed at a pressure of 400 kg / cm ² .

[Explanation of symbols]

 1 secondary particles 2 shells 3 voids 4 small-diameter communicating gaps 5 large-diameter true spherical voids

Claims (10)

[Claims] 1. A molded body comprising a sintered porous body of a calcium phosphate compound, wherein said porous body comprises a spherical or cocoon essentially consisting of primary particles of fibrous hydroxyapatite crystal particles. The secondary particles have a shape of secondary particles, and the surface of each secondary particle is composed of chestnut iga fiber, so that the secondary particles come into contact with each other at many contact points on the surface,
It has a configuration in which it can be deformed or overlapped with each other so as to overlap and firmly fix three-dimensionally, and the hollow part of the gap formed by the secondary particles has a matrix structure communicating with pores to the outside. A porous ceramic molded body for an artificial bone material, comprising: 2. The primary particle is a fibrous material having a length of 10 to 200 μm, and the hollow portion of the gap is 10 to 500 μm.
The porous ceramic body for artificial bone material according to claim 1, characterized in that the ceramic body is essentially composed of true spherical holes having a diameter in the range of μm and a gap portion connecting the true spherical holes. 3. The spherical cavities have chestnut syrup-shaped fiber crystals on the surface thereof to provide an optimum environment for bone formation, and the connecting gap connecting the spherical cavities has a maximum size. Diameter 10
The porous ceramic molded body for artificial bone material according to claim 2, which has open pores of μm. 4. The hydroxyapatite crystal formed therein is thermodynamically stable with respect to the ionic composition in the body fluid even when the body fluid composition changes due to acidosis or alkalidosis. 4. A porous ceramic molded product for an artificial bone material according to any one of items 3 to 3. 5. The hydroxyapatite crystal is treated with calcium hydroxide, phosphoric acid and pure water in a hydrothermal reaction or in a high-pressure autoclave while performing pH treatment in a liquid phase dispersion system.
The artificial bone material according to any one of claims 1 to 4, wherein a spin force is generated in a solid phase to be formed while applying a rotating force to the liquid phase, and the solid phase is self-granulated. Porous ceramic molded body. 6. The self-granulated primary particles have a length of 10
6. The porous ceramic molded body for artificial bone material according to claim 5, which is in the form of a fiber having a width of 1 to 1 mm and a width of 0.1 to 5 m or a strip or a foil having a width of 5 to 10 m. 7. In order to form an effective spherical hole,
A secondary particle hydroxyapatite crystal slurry as a raw material for crystal growth is kneaded with or without the addition of a sublimable substance, a flammable substance, or a transpirable substance having a required pore size. Using a step of forming a molded body and performing calcination while performing a mechanical dewatering process at a pressure of 100 to 500 kg / cm ² by a water-removing mold press. 7. The porous ceramic molded article for an artificial bone material according to any one of 6. 8. The matrix structure has a communication gap portion having a size of 10 μm or less, so that bone formation and maturation of new bone can be promoted without forming a vegetative lumen. Item 8. A porous ceramic molded product for an artificial bone material according to any one of Items 1 to 7. 9. The filling rate of fibrous primary particles of hydroxyapatite crystals in a molded product is 10% by volume.
The porous ceramic molded product for an artificial bone material according to any one of claims 1 to 8, wherein: 10. An element ion selected from the group consisting of Cl, CO ₂ , an alkali metal, an alkaline earth metal and a combination thereof is added to the hydroxyapatite composition, and is incorporated as a trace solid solution type. The porous ceramic molded product for an artificial bone material according to any one of claims 1 to 9, wherein: