JP2004049355A - Bone prosthetic material and manufacturing method therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a bone prosthetic material which can further increase osteogenic property, and a manufacturing method therefor. <P>SOLUTION: A calcium phosphate containing slurry is prepared (S1), and an expanded slurry is prepared by adding a foaming agent in the calcium phosphate containing slurry (S2). Then, an organic porous element having continuous fine air spaces is impregnated with the expanded slurry (S3), and the organic porous element impregnated with the expanded slurry is dried (S4). Then, the organic porous element is resolve-extinguished by heating, and the remaining calcium phosphate is sintered (S5). At this time, the weight part of a liquid component based on 100 pts.wt. of calcium phosphate in the calcium phosphate containing slurry is set to be 55 to 75, and the viscosity of the calcium phosphate containing slurry is set to be 500 centipoise or lower. <P>COPYRIGHT: (C)2004,JPO

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a bone substitute and a method for producing the same.
[0002]
[Prior art]
Conventionally, for repair of bone defects and voids caused by treatment of diseases such as bone tumors and trauma such as fractures, a method of implanting autologous bone, or filling an artificial material as a bone replacement material The way has been done.
[0003]
As such a bone replacement material, a calcium phosphate-based ceramic (hereinafter, calcium phosphate) having excellent biocompatibility and osteoconductivity is often used. Hydroxyapatite (hereinafter, HAP) and β-tricalcium phosphate (hereinafter, β-TCP) are typical materials. This HAP has excellent osteoconductivity and directly binds to bone tissue, but is non-resorbable and will remain in the living body for a long time. On the other hand, β-TCP has excellent osteoconductivity, directly binds to bone tissue, is absorbed in bone tissue with time, and is replaced with autologous bone. These materials are properly used depending on the purpose of bone replacement.
[0004]
The osteoconductive ability of such a bone substitute requires a sufficient blood flow having many cells supplied from a living body. Therefore, it is made of a porous body having continuous pores. However, a porous body having a large number of continuous pores has low strength, making the operation difficult, and may not sufficiently serve as a scaffold for bone formation. Therefore, the following sponge method has been devised as a method for producing a porous body having continuous pores while maintaining strength.
[0005]
In the sponge method, a ceramic slurry is prepared by dissolving a ceramic powder in a solution such as water. At this time, a dispersant, a deflocculant, a surfactant and the like for improving the dispersion of the powder may be added. This ceramic slurry is impregnated into an organic porous material, typically a sponge. For impregnation, the sponge is repeatedly compressed in the slurry or the whole is depressurized and sucked. The sponge impregnated with the ceramic slurry is dried and then fired. The firing temperature is set to a temperature at which all the components other than the ceramic in the sponge and the slurry disappear. By doing so, only the ceramic remains after sintering, and its form is substantially similar to the original sponge.
[0006]
By the way, in the sponge method, the following various devices are devised.
In conventional example 1 (Japanese Patent Publication No. 63-27310), a foaming agent is added to a ceramic raw material slurry, and an organic porous material (eg, sponge) having continuous fine pores is added to the ceramic raw material slurry. The ceramic raw material slurry is adhered to the inner surface of the pores by immersion or foaming after foaming, and then the organic porous body to which the ceramic raw material slurry is adhered is decomposed and disappears. Then, the remaining ceramic skeleton is sintered to form a ceramic porous body having continuous fine pores and uniformly distributed pores throughout. Among them, the ceramic slurry has a viscosity coefficient of 0.5 to 1000 poise, particularly preferably a viscosity coefficient of 5 to 200 poise, and the pore diameter of the original organic porous body is 0.05 to 1.5 mm, It is particularly preferably 0.1 to 0.7 mm, using a surfactant having a foaming property to break bubbles to increase the adhesion to pores, and to break it before heating with ether vapor or ultrasonic waves. It foams and the ceramic raw material adheres continuously along the pores.If necessary, the viscosity modifier and dispersant can be added to change the properties of the slurry. It is desirable to reduce the volume, increase the bulk density of the ceramic porous body, and exhibit strength. Further, in the examples, only the case where the amount of the solution to the ceramic powder is 54% or less or 80% or more is described. To have.
[0007]
In Conventional Example 1, the viscosity of the slurry is 0.5 to 1000 poise, and 5 to 200 is particularly desirable. However, in practice, when the viscosity exceeds 5 poise, the viscosity is too high and it is difficult to sufficiently impregnate the sponge. In addition, the weight ratio of the liquid component to the ceramic powder is 54% or less and 80% or more. When the weight ratio is 54% or less, foaming is difficult and sponge is difficult to impregnate. On the other hand, if it is 80% or more, the resulting porous body does not have sufficient strength. The foaming agent is used to eliminate the slurry in each cell of the sponge and leave only the slurry attached to the sponge skeleton in the sponge.However, in such a method, only a porous material having an extremely high porosity is used. It cannot be obtained, and the porosity is 80% or more in all of the examples. It is also described that the foam caused by the foaming agent is broken, and that the foam is broken by applying ether vapor or ultrasonic waves. However, each of these methods extremely increases the porosity of the porous body. In addition, a dispersing agent for preparing a slurry is also described, but only mention is made to minimize the amount, but no specific example of an appropriate dispersing agent is mentioned.
[0008]
In Conventional Example 2 (Japanese Patent Publication No. 1-54308), the ceramic porous body produced in the same manner as in Conventional Example 1 is calcium phosphate having a molar ratio of calcium to phosphoric acid of 1.30 to 1.58. The case is described.
[0009]
In Conventional Example 2, the calcium phosphate used is amorphous calcium phosphate, which is expected to change to tricalcium phosphate after firing. However, the composition ratio of phosphorus to calcium is actually 1.30 to 1.58. It is not necessarily the whole tricalcium phosphate. Even if tricalcium phosphate is made, there is no mention of biocompatibility which is important as a bone substitute.
[0010]
Conventional example 3 (Japanese Patent Application Laid-Open No. 57-179063) describes a method of forcibly removing excess slurry with compressed air in order to prevent clogging after impregnation into a sponge.
[0011]
Conventional Example 4 (JP-A-59-3059) describes that for the same purpose, centrifugal force is applied after impregnation to forcibly drive out excess slurry.
[0012]
In Conventional Examples 3 and 4, there is a step of driving out excess slurry after impregnation, and as a result, the amount of slurry remaining in the sponge decreases, so that it is difficult to obtain a porous body having a low porosity.
[0013]
In the conventional example 5 (Japanese Patent Publication No. 6-33191), an organic porous material having a three-dimensional network structure or a sponge structure is brought into contact with a highly viscous liquid ceramic having a function of a foaming agent. A ceramic film is formed on a polyhedron constituting surface in a unit cell forming a three-dimensional network structure or a sponge-like structure of a porous body, and the organic porous body is dried without damaging the ceramic film. There is described a method for producing a ceramic having a high porosity, which comprises firing a dried product. It also describes that polyacrylic acid is used as a deflocculant when preparing a slurry.
[0014]
In the conventional example 5, since the ceramic film is left in each cell, the pores of the finally obtained ceramic porous body are independent from each other without communication, and are not suitable as bone replacement materials. Although polyacrylic acid and ammonium polyacrylate are used as a dispersing agent when preparing the slurry, the weight part in the slurry is 1% or less of the ceramic powder, and it is not possible to maintain the foaming state of the slurry. That is enough.
[0015]
In addition, in any of the above-mentioned conventional examples, there is no mention of pores much smaller than the sponge skeleton, that is, micropores associated with sintering of the ceramic powder. Further, in the conventional example described above, there is a problem associated with the sponge method, that is, excess slurry remains on both the upper and lower surfaces of the sponge impregnated with the slurry so that pores are easily blocked on the surface of the porous body after firing. No workaround was given.
[0016]
[Problems to be solved by the invention]
By the way, it has been confirmed that the osteogenic property largely depends on the stomatal properties of the bone replacement material.For example, as far as possible, stomatal properties that can ensure blood flow into the material, that is, hinder the entry of cells into the material. It has been recognized that it is preferable to have no porosity.
[0017]
However, it is required to further enhance osteogenesis, and it is necessary to further improve not only the stomatal property that can secure blood flow into the material, that is, the stomatal property that does not hinder the entry of cells into the material. Is emerging.
[0018]
The present invention has been made in order to solve the above-mentioned problems, and an object of the present invention is to provide a bone replacement material capable of further improving osteogenesis and a method for producing the same.
[0019]
[Means for Solving the Problems]
In order to achieve the above object, a first aspect of the present invention is to impregnate an organic porous material having continuous fine pores with a foaming slurry obtained by adding a foaming agent to a calcium phosphate-containing slurry and foaming the foamed slurry. After drying the impregnated organic porous body, the organic porous body is heated to decompose and disappear, and the remaining calcium phosphate is sintered, and the bone filling material made of the calcium phosphate porous body has pores having a size of 5 μm or less. It is characterized by.
[0020]
As described above, since the bone replacement material is made of a porous calcium phosphate and has pores having a size of 5 μm or less, absorption and replacement after implantation into a living body is accelerated.
[0021]
According to a second aspect of the present invention, an organic porous material having continuous fine pores is impregnated with a foaming slurry obtained by adding a foaming agent to a calcium phosphate-containing slurry and foaming the organic porous material, and then drying the organic porous material impregnated with the foaming slurry. Heating the organic porous material to decompose and disappear, and sintering the remaining calcium phosphate to produce a bone filling material made of the calcium phosphate porous material, wherein the calcium phosphate-containing slurry contains 100 parts by weight of calcium phosphate. And the viscosity of the slurry containing calcium phosphate is not more than 500 centipoise.
[0022]
By setting the weight part of the liquid component with respect to calcium phosphate to 55% or more, a sufficient amount of micropores having a size of 5 μm or less can be present in the completed bone replacement material, and the bone replacement material can be implanted into a living body. Subsequent absorption / replacement is faster. Also, when the content is set to 55% or more, it is easy to impregnate the organic porous material, for example, the sponge with the slurry, and as a result, it is possible to easily produce a bone replacement material having a high strength porous calcium phosphate. On the other hand, by setting the weight part to 75% or less, the disadvantage that the calcium phosphate content in the slurry is small and as a result, the strength of the bone replacement material is reduced is also prevented.
[0023]
A third invention relates to the second invention, characterized in that the foamed slurry is dried without forcibly expelling the foamed slurry from the organic porous body impregnated with the foamed slurry.
[0024]
As a result, the impregnated slurry is not only present on the organic porous material, such as a sponge skeleton, or is present not only as a curtain at a communication portion between cells defined by the sponge skeleton, but also in the sponge cells. The amount will remain. Therefore, the porosity of the porous body after sintering becomes low, and a bone substitute having high strength can be obtained. Also, according to this method, since the slurry is foamed before impregnation, there is no possibility that all the cells in the sponge will be completely filled with the slurry, and the pores corresponding to the cells will have an appropriate probability even after sintering. Remains. In addition, such pores are connected to each other with an appropriate probability, so that there is no danger of loss of communication.
[0025]
A fourth invention relates to the second or third invention, wherein an ammonium salt of polyacrylic acid is added as a deflocculant to the calcium phosphate-containing slurry, and the amount added is 2 to 10% by weight based on the weight of calcium phosphate. Features.
[0026]
The polyacrylic acid ammonium salt added by such a weight amount disperses calcium phosphate well as a deflocculant, and itself acts as a viscosity modifier to maintain a good foaming state after foaming and to form an organic porous material such as a sponge. Does not hinder the impregnation of If the weight percent of the ammonium polyacrylate is less than 2%, it is difficult to maintain the state after foaming, and if it exceeds 10%, the foam becomes too dense after foaming, and impregnation into a sponge becomes difficult.
[0027]
A fifth invention relates to any one of the second to fourth inventions, and when drying the organic porous material impregnated with the foamed slurry, the organic porous material is placed on another organic porous material, and the drying proceeds. Accordingly, the organic porous body impregnated with the foamed slurry is placed on another organic porous body while being turned upside down.
[0028]
The sponge method has a disadvantage that excess slurry remains on the surface of the organic porous body after impregnation, for example, the sponge, and a film is formed. As a result, pores are blocked on the surface of the porous body. For this reason, when drying the sponge impregnated with the foamed slurry, the sponge impregnated with the foamed slurry is placed on a second sponge different from the sponge, and the sponge impregnated with the foamed slurry is turned upside down as the drying proceeds. The sponge impregnated with the foamed slurry is placed on the fourth and subsequent sponges while being turned upside down, if necessary, until the drying is completed. By drying the sponge impregnated with the slurry on another sponge in this manner, excess slurry on the surface can be absorbed by the other sponge during drying. In addition, the sponge impregnated with the slurry is turned upside down during drying, and further dried on another sponge, so that excess slurry on both upper and lower surfaces of the sponge impregnated with the slurry can be removed.
[0029]
A sixth invention relates to any one of the second to fifth inventions, wherein the calcium phosphate is β-tricalcium phosphate powder produced by a mechanochemical method.
[0030]
Since the raw material is β-tricalcium phosphate (β-TCP), the porous body after sintering is also composed of only β-TCP. Further, β-TCP obtained by the mechanochemical method is suitable for use as a bone replacement material because of its good biocompatibility.
[0031]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, a porous material having high strength according to the present invention, the pores of which have appropriate communication properties obtained by copying the pores of an organic porous material such as a sponge, and the pores are not blocked on the surface of the porous material, and have a size of 5 μm or less. An embodiment of a method for producing a bone replacement material having both micropores and good biocompatibility will be described.
[0032]
The powder of β-tricalcium phosphate (β-TCP), which is a raw material of the bone replacement material, is produced by a mechanochemical method as described below.
[0033]
The calcium carbonate powder and the calcium hydrogen phosphate dihydrate powder are weighed so as to have a molar ratio of 1: 2, and pure water is added to adjust the slurry. This is subjected to a grinding reaction in a ball mill for about 24 hours, then dried and fired at 750 to 900 ° C. to obtain β-TCP powder.
[0034]
Β-TCP slurry (β-TCP slurry containing calcium phosphate) is prepared by adding water and ammonium polyacrylate as a deflocculant to the β-TCP powder produced by the above mechanochemical method and stirring the mixture with a ball mill or the like. A manufacturing process (step S1) is performed. The mixing ratio is such that the total weight of the water component and the deflocculant is 55 to 75 with respect to the weight of β-TCP of 100, and the amount of the deflocculant is 2 to 10 therein. I do. Since the porosity and the like of the resulting porous body can be controlled by the weight ratio, it is arbitrarily selected from the above range, but typically 300 g of β-TCP powder, 200 ml of water and 10 ml of deflocculant. At this time, the viscosity of the β-TCP slurry is set to 500 centipoise or less.
[0035]
Next, a small amount of a surfactant, which is a foaming agent for foaming the slurry, is added to β-TCP, and the mixture is stirred to form a foamed slurry (step S2). Although the type of the surfactant is not particularly limited, for example, polyoxyethylene alkyl ether or the like can be used.
[0036]
An impregnation step (step S3) of impregnating the sponge, which is an organic porous material, with the foamed slurry is performed. The type of sponge is not particularly limited. For example, a urethane sponge having about 40 to 60 cells per inch can be used. The impregnation method is as follows.
[0037]
The sponge is immersed in the foamed slurry, and the sponge is repeatedly compressed and restored in the slurry by hand or using a suitable tool. When the sponge has sufficiently impregnated the foamed slurry and restored to its original size, it is removed from the foamed slurry. When removing the sponge, carefully take care so that a part of the foamed slurry which is impregnated with the sponge is firmly gripped and does not flow out of the sponge. In this case, it is desirable to insert a spatula or the like under the sponge and take it out gently. That is, the foamed slurry is not forcibly expelled from the sponge.
[0038]
Next, a drying step (Step S4) of drying the sponge impregnated with the foamed slurry is performed as follows.
[0039]
The sponge taken out of the foamed slurry, that is, the sponge impregnated with the foamed slurry is placed on another drying sponge (dried) prepared in advance. The type of the sponge for drying is not particularly limited, but it is preferable to use the same type as the sponge for impregnating the slurry, for example, because it is easy to prepare.
[0040]
Next, drying is performed in this state, that is, while the sponge impregnated with the foamed slurry is placed on the drying sponge. Drying conditions such as a drying temperature and a drying time are not particularly limited, but if the drying is too slow, it may be difficult to maintain a foamed state. Therefore, a drying furnace usually heated to 50 to 80 ° C. Perform some rapid drying in the inside.
[0041]
After the start of drying, the sponge impregnated with the foamed slurry is replaced on another drying sponge at a timing after a predetermined time elapses (before the foamed slurry on the sponge surface is completely solidified). At this time, the sponge impregnated with the foam slurry is turned upside down and replaced. Since the newly formed upper surface was in contact with the drying sponge first, excess foaming slurry was removed, and the surface became a good surface reflecting the general sponge shape. Then, by being turned upside down as described above, the lower surface comes into contact with the drying sponge, and the surface becomes similarly favorable.
[0042]
As described above, in the sponge impregnated with the foamed slurry, excess foamed slurry is removed from both the upper and lower surfaces.
[0043]
If necessary, the sponge impregnated with the foamed slurry is repeatedly placed upside down on another drying sponge until the drying is completed. In addition, excess foaming slurry may remain on the side surface, but most of this can be removed by scraping off with a spatula at an appropriate timing at the beginning of drying. The end of the drying step is not particularly limited. For example, the sponge may be dried to such an extent that most of the moisture evaporates and the sponge is not significantly deformed even if it is held by hand. Typically, drying is performed for 24 hours.
[0044]
A firing step (step S5) of firing the dried sponge, that is, the sponge containing β-TCP, is performed. The firing conditions are not particularly limited, and may be any temperature as long as β-TCP sinters with sufficient strength (900 ° C.) or more and does not transition to αTCP (1150 ° C. or less). For example, baking is performed at 1050 to 1100 ° C. for 30 minutes or more. By this baking, the sponge, the deflocculant, the surfactant for foaming, and the like are all lost, and a porous body made of high-purity β-TCP is obtained. Since the initial concentration of the slurry is appropriate, the porous body thus obtained contains a sufficient amount of micropores of 5 μm or less. In addition, the entire surface up to the surface reflects the original sponge shape, and the pores are maintained in communication. On the other hand, since there is also a high probability that the cell is filled with β-TCP, this acts to lower the porosity of the porous body and increase its strength. Therefore, the bone replacement material has high strength and is easily replaced with autologous bone.
[0045]
In addition, cells may be added to the bone substitute prepared as described above. The cells to be added may be somatic cells such as ES cells, somatic stem cells, mesenchymal stem cells, bone cells and chondrocytes. Autologous cells or allogeneic cells may be used.
Further, a growth factor may be added to the bone replacement material. As the growth factor to be added, BMP, FGF, TGF-β, VEGF, IGF, PDGF, HGF and the like can be adopted. Of course, a growth factor may be added together with the cells.
[0046]
【The invention's effect】
As described above in detail, according to the first aspect, the bone replacement material is made of a porous calcium phosphate and has pores having a size of 5 μm or less, so that the absorption and replacement after implantation into a living body are fast. Become. Therefore, osteogenicity can be further enhanced.
[0047]
According to the second invention, by setting the weight part of the liquid component with respect to calcium phosphate to 55% or more, a sufficient amount of micropores having a size of 5 μm or less can be present in the completed bone replacement material, Absorption and replacement of the filler after implantation into the living body becomes faster. Therefore, osteogenicity can be further enhanced. Also, when the content is set to 55% or more, it is easy to impregnate the organic porous material, for example, the sponge with the slurry, and as a result, it is possible to easily produce a bone replacement material having a high strength porous calcium phosphate. On the other hand, by setting the weight part to 75% or less, the disadvantage that the calcium phosphate content in the slurry is small and as a result, the strength of the bone replacement material is reduced is also prevented.
[0048]
According to the third aspect of the present invention, the impregnated slurry is not only present as sticking to the organic porous body, for example, a sponge skeleton, or presenting a curtain at a communication portion between cells defined by the sponge skeleton, but also as a sponge. A considerable amount will also remain in the cell. Therefore, the porosity of the porous body after sintering becomes low, and a bone substitute having high strength can be obtained.
[0049]
According to the fourth invention, the ammonium polyacrylate added in an amount of 2 to 10% by weight based on the weight of calcium phosphate disperses calcium phosphate well as a deflocculant, and also acts as a viscosity modifier itself, and after foaming. It does not hinder the impregnation of the organic porous material, for example, sponge, while maintaining a good foaming state. Therefore, a bone substitute made of a porous material having good porosity can be obtained.
[0050]
According to the fifth aspect, by drying the sponge impregnated with the slurry on another sponge, excess slurry on the surface can be absorbed by the other sponge during drying. Therefore, a bone substitute having good porosity up to the surface can be obtained.
[0051]
According to the sixth aspect, since the raw material is β-tricalcium phosphate (β-TCP) obtained by the mechanochemical method, the porous body after sintering becomes a bone replacement material having good biocompatibility.
[Brief description of the drawings]
FIG. 1 is a flowchart illustrating a manufacturing process according to an embodiment of the present invention.
[Explanation of symbols]
S1 β-TCP slurry preparation step S2 Foamed slurry preparation step S3 Impregnation step S4 Drying step S5 Baking step

Claims (6)

An organic porous material having continuous fine pores is impregnated with a foamed slurry obtained by adding a foaming agent to a calcium phosphate-containing slurry and then foaming. The organic porous material impregnated with the foamed slurry is dried, and then heated to form the organic material. In the bone replacement material consisting of a porous calcium phosphate material that decomposes and disappears the porous material and sinters the remaining calcium phosphate,
A bone replacement material having pores having a size of 5 μm or less. An organic porous material having continuous fine pores is impregnated with a foaming slurry obtained by adding a foaming agent to a calcium phosphate-containing slurry and foaming the organic porous material, and after drying the organic porous material impregnated with the foaming slurry, the organic porous material is heated and heated. In the method of manufacturing a bone replacement material for decomposing and disappearing the porous body and sintering the remaining calcium phosphate to produce a bone replacement material composed of the calcium phosphate porous body,
A method for producing a bone replacement material, wherein the weight part of the liquid component relative to 100 parts by weight of calcium phosphate in the calcium phosphate-containing slurry is 55 to 75, and the viscosity of the calcium phosphate-containing slurry is 500 centipoise or less. The method according to claim 2, wherein the foamed slurry is dried without forcibly displacing the foamed slurry from the organic porous material impregnated with the foamed slurry. 4. The bone substitute material according to claim 2, wherein an ammonium salt of polyacrylic acid is added as a deflocculant to the calcium phosphate-containing slurry, and the added amount is 2 to 10% by weight based on the weight of calcium phosphate. Method. When drying the organic porous body impregnated with the foamed slurry, the organic porous body is placed on another organic porous body, and as the drying proceeds, the organic porous body impregnated with the foamed slurry is turned upside down. The method for producing a bone substitute according to any one of claims 2 to 4, wherein the bone substitute is placed on another organic porous material. The method for producing a bone replacement material according to any one of claims 2 to 5, wherein the calcium phosphate is β-tricalcium phosphate powder produced by a mechanochemical method.

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