JP2007229048A - Tricalcium phosphate-based bone substitute material - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a tricalcium phosphate-based bone substitute material having a sufficient strength, excellent bone affinity and osteoconducting property, and a good balance between osteogenetic rate and bioabsorption rate. <P>SOLUTION: The bone substitute material is made of a porous material consisting β-tricalcium phosphate and/or α-tricalcium phosphate. The porous material has a porous structure in which spherical pores communicate with each other over the whole, and has a porosity of ≥50% and ≤90%, an average pore diameter of ≥100 μm and ≤500 μm, a diameter of a communication section between respective pores of ≥20 μm and ≤100 μm, and a compressive strength of ≥5 MPa. Ca of ≥0.5 mol% and ≤3 mol% contained in the β-tricalcium phosphate and/or α-tricalcium phosphate is partially substituted by Mg. In the bone substitute material, phase transition temperature of β-tricalcium phosphate to α-tricalcium phosphate within a crystal phase of the porous material is ≥1,200°C and ≤1,350°C. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a bone prosthetic material comprising a porous body of tricalcium phosphate that can be suitably used for filling a bone defect in the field of orthopedics.

In recent years, in the field of orthopedics, bone defects due to trauma, bone tumor or artificial joint revision have been repaired using bone prosthetic materials.
As the material for the bone prosthetic material, since it has excellent biocompatibility and osteoconductivity, there are many calcium phosphate ceramics such as hydroxyapatite (HAp) and β-tricalcium phosphate (β-TCP). It is used.

For example, when the HAp is embedded in a living body as a bone grafting material, the bone is rapidly repaired using this as a scaffold, and exhibits excellent bone conduction ability to directly bond to new bone.
In addition, β-TCP has excellent bioresorbability that the material itself is absorbed as bone formation progresses after filling in the bone defect part, and the filling part is replaced with autologous bone. It is a material that is attracting attention.

  For this reason, in recent years, various calcium phosphate bone filling materials have been studied (see, for example, Patent Documents 1 and 2). In particular, a porous calcium phosphate compound can be easily penetrated by living tissues, cells, and the like into the pores, and is excellent in osteoconductivity.

However, the calcium phosphate-based porous body has problems such as difficulty in handling at the time of surgery because it is inferior in strength and fragile.
In particular, since the β-TCP porous body has a phase transition temperature from β-TCP to α-TCP of 1120 to 1180 ° C., the firing temperature at the time of producing the porous body must be lower than that. Commercially available β-TCP bone substitutes are usually manufactured at a firing temperature of around 1050 ° C. For this reason, the skeleton portion of the porous body did not sinter sufficiently, resulting in an immature sintered body, and the strength was very low compared to other calcium phosphate porous bodies.
JP 2001-259016 A Japanese Patent No. 3400740

  As mentioned above, since the conventional calcium phosphate-based bone grafting material has low strength, large-scale and complex-shaped bone grafting materials that are required in the medical field cause cracks and chips during production, Only small and simple shapes could be produced.

  On the other hand, in the case of the bioabsorbable material such as β-TCP, the bone filling material made of a porous material has various parameters such as porosity, pore diameter, pore structure, crystallinity, solubility, and particle size. However, this greatly affects the bone formation rate and the resorption rate of the bone filling material. For example, if the pore diameter is too large or the porosity is too high, the resorption rate of the bone grafting material is too high to provide a scaffold for forming new bone.

Therefore, the conventional bone prosthetic material made of β-TCP porous material is inferior in mechanical strength and has a high resorption rate in the living body, so that bone formation takes place at sites where bone formation is slow or large bone defects. The problem was that it was difficult to maintain a balance between the speed and the bioabsorption rate of β-TCP.
That is, it has been demanded that the bone grafting material composed of the β-TCP porous body can improve the strength and can maintain an appropriate balance between the bone formation rate and the bioresorption rate.

  The present invention has been made to solve the above technical problems, and is excellent in bone affinity and osteoconductivity, has a good balance between bone formation rate and bioresorption rate, and has sufficient strength. It is an object of the present invention to provide a tricalcium phosphate bone filling material.

The tricalcium phosphate bone filling material according to the present invention is a porous body made of β-tricalcium phosphate (β-TCP) and / or α-tricalcium phosphate (α-TCP), the porous body Has a porous structure in which spherical pores communicate with each other, with a porosity of 50% or more and 90% or less, an average pore size of 100 μm or more and 500 μm or less, and a diameter of a communication portion between each pore of 20 μm or more and 100 μm or less. And the compressive strength is 5 MPa or more, and 0.5 mol% or more and 3 mol% or less of Ca of the β-tricalcium phosphate (β-TCP) and / or α-tricalcium phosphate (α-TCP). The phase transition temperature from β-tricalcium phosphate (β-TCP) to α-tricalcium phosphate (α-TCP) in the crystalline phase of the porous body is 1200 ° C. or higher. Characterized in that at 350 ° C. or less.
By making the β-TCP porous body excellent in bone affinity and osteoconductivity as described above, the sinterability and mechanical strength can be improved, and the bone formation speed and It can be set as the bone grafting material by which the balance with a bioresorption rate is kept favorable.

As described above, according to the tricalcium phosphate bone substitute material according to the present invention, it is possible to improve the sinterability and improve the strength as compared with the conventional calcium phosphate bone substitute material. In addition, the balance between the bone formation rate and the bioresorption rate can be maintained well.
Accordingly, it can be suitably used as a bone prosthesis material that is excellent in bone affinity and osteoinductivity and easy to handle, and is expected to be used as a cell scaffold material (scaffold) for tissue engineering.

Hereinafter, the present invention will be described in more detail.
The tricalcium phosphate bone substitute material according to the present invention is a bone substitute material composed of β-TCP and / or α-TCP porous material. The porous body has a porous structure in which spherical pores communicate with each other, the porosity is 50% or more and 90% or less, the average pore diameter is 100 μm or more and 500 μm or less, and the diameter of the communication portion between the pores is It is 20 μm or more and 100 μm or less, and the compressive strength is 5 MPa or more.
That is, the bone grafting material according to the present invention is composed of a TCP porous body having a unique interpore communication structure, and has sufficient strength in handling.

Β-TCP used as the material for the bone prosthetic material according to the present invention has already been applied to the human body, and as described above, is a suitable material excellent in bone affinity and osteoinductivity.
On the other hand, α-TCP has high solubility and low mechanical strength, so it is difficult to use alone as a bone prosthesis, but it is effective for prevention of important infections and promotion of bone formation at the initial stage of implant. By loading the drug on α-TCP, the speed of solubility can be utilized.
Therefore, the bone grafting material according to the present invention has β-TCP as the main component from the viewpoint of strength improvement, and α-TCP can maintain the compressive strength of the porous body constituting the bone grafting material at 5 MPa or more. It can be contained as much as possible.

Further, the bone prosthetic material according to the present invention is a porous body having a unique inter-pore communication structure, in which a large number of spherical pores are distributed three-dimensionally throughout, and adjacent pores communicate with each other. By having, the penetration | invasion of the cell to the inside of this porous body is accelerated | stimulated, and formation of a bone can be aimed at.
The spherical pores are not limited to strictly spherical shapes, and include pores having a shape in which the true sphere is slightly flattened or distorted.

The porous body has a porosity of 50% or more and 90% or less and an average pore diameter of 100 μm or more and 500 μm from the viewpoints of surface area, permeability of blood, body fluids, etc., invasion and adhesion of cells, biological tissues, blood vessels and the like. The following.
When the average pore diameter is less than 100 μm, cells and tissues are less likely to enter the porous body, and bone formation inside the pores cannot be promoted sufficiently.
On the other hand, when the average pore diameter exceeds 500 μm, since the space is too large, the cells that have entered the pores are difficult to be anchored, and it is difficult to sufficiently settle them. In this case, too, bone formation inside the pores The promotion effect is insufficient.

Moreover, the diameter of the communication part between the said adjacent pores is 20 micrometers or more and 100 micrometers or less.
If it is a communication part which has the magnitude | size within the said range, a cell and a biological tissue can penetrate | invade and it can aim at formation promotion of the bone inside a porous body.
In addition, the diameter of the communicating part between the pores can be obtained from pore diameter distribution measurement using a mercury porosimeter.

The tricalcium phosphate bone prosthetic material according to the present invention having the above-described structure is produced by a manufacturing method as described in JP-A No. 2002-112888, that is, a slurry containing a calcium phosphate ceramic material is stirred. It can be produced by a foaming method.
The porous body in which pores are formed by stirring and foaming is dense in the skeleton itself defining the pores, is substantially spherical, has a high porosity, and has a relatively high strength. Due to the phenomenon, a property that allows easy penetration of cells, blood and the like can be obtained. Furthermore, it has excellent characteristics such as a large surface area per unit volume and a suitable property as a scaffold for invading cells.

Further, the bone prosthetic material according to the present invention is obtained by replacing 0.5 mol% or more and 3 mol% or less of Ca with Mg in β-TCP and / or α-TCP constituting the porous body. The phase transition temperature from β-TCP to α-TCP of the crystalline phase of the body is 1200 ° C. or higher and 1350 ° C. or lower.
By adding such Mg, the sinterability of the porous body can be improved and the strength can be improved.

As described above, β-TCP transitions to α-TCP at 1120 to 1180 ° C. Therefore, in order to maintain the β phase, it is usually necessary to lower the firing temperature.
On the other hand, the phase transition temperature can be shifted to a higher temperature side by replacing a part of Ca of TCP with any of Li, Na, K, Mg, or Zn.
In the present invention, among the above metal elements, in particular, substitution is made with Mg, which is dissolved in TCP.
Mg is one of the essential biological elements and is present in about 30 g in the adult body, of which about 60% is present in bone. Since the bone weight is about 1/5 of the body weight, the Mg content in the bone is about 2000 ppm. Also from such a point, addition of Mg to the bone grafting material is preferable.

The amount of substitution with Mg is 0.5 mol% or more and 3 mol% or less of Ca in TCP.
When the amount of Mg substitution is less than 0.5 mol% of Ca, the amount of phase transition from β-TCP to α-TCP exceeds 75%, and a porous TCP body having sufficient strength cannot be obtained.
On the other hand, when the amount of Mg substitution exceeds 3 mol% of Ca, the Mg content in the TCP porous body is 4000 ppm or more, which is not preferable because it is excessively higher than the Mg content in bone.

For example, when 2 mol% of Ca in β-TCP is partially substituted with Mg, the phase transition temperature from β-TCP to α-TCP rises to about 1300 ° C.
Therefore, since the firing temperature can be increased to the same level as HAp, the skeleton portion constituting the porous body is sufficiently sintered, and the mechanical strength of the β-TCP porous body can be improved.

It is preferable that the firing temperature for obtaining the above-described Mg-added TCP porous body is 1100 ° C. or more and 1200 ° C. or less.
When the firing temperature is less than 1100 ° C., the sintering becomes insufficient, and in particular, the sintering of the skeleton portion of the porous body becomes insufficient, the pores remain in the skeleton portion, and a sintered body with sufficient strength is obtained. I can't get it.
On the other hand, when the firing temperature exceeds 1200 ° C., the bioabsorption rate of the sintered body (porous body) becomes slow due to grain growth.

As described above, the particle diameter can be controlled by the firing temperature, and thereby the bioabsorption rate of the TCP porous body can be controlled, so that the physical property design of the TCP porous body can be freely designed according to the application. .
Further, by changing the amount of Mg substitution, the ratio and porosity of β-TCP and α-TCP constituting the TCP porous body can be controlled, thereby adjusting the bioabsorption rate of the porous body. It is also possible.

The raw material powder of TCP to which Mg is added as described above can be produced by a generally known method. Among these, an example of the synthesis method is described below.
A predetermined amount of calcium hydroxide, magnesium chloride, and water are stirred and mixed based on the desired amount of Mg substitution for Ca in TCP to prepare a calcium hydroxide slurry, and an aqueous phosphoric acid solution is gradually added thereto. Stir after the entire amount is dropped.
After aging, filtration, drying of the solid content, and calcination are performed to obtain a Mg-added TCP synthetic powder.
By using the TCP synthetic powder thus obtained as a raw material powder, a bone prosthetic material comprising the porous TCP according to the present invention can be produced by the stirring foaming method as described above.

EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not restrict | limited by the following Example.
[Example 1]
For each component in TCP, (Ca + Mg) /P=1.528, and β-TCP powder in which the Mg substitution amount of Ca was 2 mol% was prepared as follows.
First, calcium hydroxide slurry was prepared by stirring and mixing calcium hydroxide (Ca (OH) ₂ ) 13.4770 mol, magnesium chloride (MgCl ₂ ) 0.2750 mol, and pure water 15 dm ^{3 for} 30 minutes.
On the other hand, phosphoric acid (H ₃ PO ₄ ) 9.0 mol and pure water ³ dm ³ were stirred for 30 minutes to prepare an aqueous phosphoric acid solution.
The phosphoric acid aqueous solution was gradually added dropwise to the calcium hydroxide slurry at 20 to 25 cm ³ · min ⁻¹ and stirred for 4 hours.
The obtained slurry was aged for 24 hours and then filtered, and the solid content was dried at 80 ° C. in a dryer.
The obtained synthetic powder was calcined at 800 ° C. to obtain β-TCP powder to which Mg was added.

Next, a TCP porous body was produced as follows.
A slurry was prepared by adding 334.59 g of a 20 wt% polyethyleneimine aqueous solution as a dispersion medium to 500.00 g of the Mg-added β-TCP raw material powder (average particle diameter 1 μm) obtained as described above, and mixing the mixture with a ball mill for 48 hours.
1.40 g of polyoxyethylene lauryl ether was added as a foaming agent to 700.00 g of the obtained β-TCP slurry, and foamed to 1200 cm ³ by mechanical stirring to obtain a foamy slurry.
To this, 13.7 g of sorbitol polyglycidyl ether was added as a crosslinking agent, stirred, and cast into a mold.
The obtained gelled body was taken out from the mold and dried to obtain a molded body.
This was baked at 1050 ° C. to obtain a TCP porous body.

[Examples 2 to 6]
In Example 1, it was set as the calcination temperature shown in Examples 2-6 of Table 1, and it carried out similarly to Example 1, and obtained the porous TCP body.

About each TCP porous body obtained in the said Examples 1-6, the porosity, the compressive strength, the average pore diameter, and the average pore diameter of the communicating part between pores were calculated | required. These results are shown in Table 1.
The porosity was determined from the volume, weight, and true specific gravity.
The average pore diameter was determined by image analysis of the porous body embedded in a resin and the surface polished.
Moreover, the average pore diameter of the communicating part between pores was measured by a mercury intrusion method using a mercury porosimeter.

Furthermore, as a result of identifying the crystal phase of each obtained TCP porous body, all were β-TCP single phases.
As a result of TG-DTA from room temperature to 1400 ° C., the phase transition temperature from β-TCP to α-TCP was 1300 ° C.

In any of the TCP porous bodies, the pores communicate with each other over the whole body, and osteoblasts and the like can sufficiently enter in vivo, and have sufficient strength as a bone grafting material. Was recognized.
Moreover, as can be seen from Table 1, when the firing temperature is 1100 ° C. or higher (Examples 3 to 6), the strength is higher than that when the firing temperature is lower than 1100 ° C. (Examples 1 and 2), which is more preferable.

[Comparative Examples 1-6]
In Examples 1 to 6, β-TCP powder was prepared without adding Mg, and this was used as a raw material powder. Otherwise, a porous TCP was obtained in the same manner as in Examples 1 to 6.
About each obtained TCP porous body, the porosity, the compressive strength, the average pore diameter, and the average pore diameter of the communicating part between pores were calculated | required like Example 1. FIG. These results are shown in Table 2.

Furthermore, as a result of identifying the crystalline phase of each obtained TCP porous body, Comparative Examples 1 to 3 are β-TCP single phase, Comparative Examples 4 and 5 are α-TCP and β-TCP mixed phase, Comparative Example 6 was an α-TCP single phase.
As a result of TG-DTA from room temperature to 1400 ° C., the phase transition temperature from β-TCP to α-TCP was 1150 ° C.

The pore structure of the TCP porous body was almost the same as in the above example.
In addition, as shown in Table 2, when the firing temperature is 1130 ° C. or higher (Comparative Examples 4 to 6), a decrease in strength is observed. This is because the crystalline phase of the porous body is changed from β-TCP to α- When transitioning to TCP, the crystal structure is changed to cause volume expansion, which is considered to be due to defects in the porous structure.

  From the above results, it was confirmed that the tricalcium phosphate bone substitute material according to the present invention can be obtained as a porous body having higher strength than before by adding Mg at the time of TCP raw material powder synthesis.

Claims (1)

a porous body composed of β-tricalcium phosphate and / or α-tricalcium phosphate,
The porous body has a porous structure in which spherical pores communicate with each other, the porosity is 50% or more and 90% or less, the average pore diameter is 100 μm or more and 500 μm or less, and the diameter of the communication portion between each pore is 20 μm or more. 100 μm or less and the compressive strength is 5 MPa or more,
0.5 mol% or more and 3 mol% or less of Ca in the β-tricalcium phosphate and / or α-tricalcium phosphate is partially substituted with Mg,
A tricalcium phosphate-based bone grafting material characterized in that a phase transition temperature from β-tricalcium phosphate to α-tricalcium phosphate in a crystalline phase of the porous body is 1200 ° C. or higher and 1350 ° C. or lower.