JPH0359703B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to bone cement compositions. More specifically, the present invention relates to a cement composition for adhesion between bone and biomedical metal or ceramic materials such as artificial bones and artificial joints.

BACKGROUND OF THE INVENTION Calcium phosphate compounds, such as hydroxyapatite, and solid solutions thereof have good affinity with living organisms and are useful as medical materials, such as substitute materials for bones or tooth roots, or prosthetic materials.
For example, Japanese Unexamined Patent Publication No. 56-54841 discloses a bone defect and void filling material using a powdered calcium phosphate compound having an apatite crystal structure.

Furthermore, Japanese Patent Application Laid-Open No. 166843/1984 discloses a bone defect and cavity filler made of a porous body of a calcium phosphate compound. The pores contained in this porous body of calcium phosphate compound have a maximum pore diameter of 3.00 mm and a minimum pore diameter of 0.05 mm, and have a shape and size that allows the bone-forming components of the living body to easily enter, and are substantially continuous three-dimensional. It forms a network structure.

Conventional calcium phosphate compound ceramic materials, such as those described above, tend to deform over time after undergoing surgical procedures such as fillings and prosthetics, or promote hardening of soft tissue near the filling or prosthesis. Therefore, there were problems such as having to remove the tissue where the abnormality occurred.

In addition, methyl methacrylate-based adhesive cement has conventionally been used as bone cement to fix artificial bones or joints made of metal or ceramic materials in vivo; Cement contains a small amount of unreacted monomer, which dissolves in the living body and harms the living tissue, causing heat generation, loosening of the surgical site, and
Or, complications such as after-effects may occur, making it unsatisfactory.

In general, in the treatment of hard tissue defects in living organisms, such as the removal of bone tumors or defects caused by external bone damage, it is most preferable to promote natural healing, and replacement with artificial materials or prosthetics is not necessarily preferable. That's not the point. Even if it is filled in the living body or prosthesized using artificial bone cement,
It is most desirable that such bone cement is eventually consumed within the living body, and that natural living tissue regenerates in its place to complete the fixation. In this case, it is important that the rate at which bone cement is replaced by living tissue (turnover rate) is appropriate; if the turnover rate is excessively high, local inflammation and other disorders may occur, resulting in excess waste. Diseases, such as the development of cancer, may occur. In addition, if the bone cement exists in the body for a long time due to low tarsover rate,
This may cause deformation of local biological tissues (bones) and hardening of nearby soft tissues, which may require excision surgery.

In order to address the above-mentioned problems, it is important that bone cement inserted into a living body can satisfy the requirements for inducing and replacing living tissue at the cellular level. In other words, it appropriately promotes the activation of bone phagocytes (osteolysis) and bone regenerating cells (osteoplasts) in living tissues, and the invasion of bone destroying cells (osteocrusts) and collagen fibers that promote the hardening of soft tissues. It is important to suppress the development and hardening of bone tissue, and not to inhibit the entry of red blood cells, body fluids, etc., or the development of capillaries.

In order to meet the above requirements, the bone cement inserted into the living body must have good affinity for the living body, especially bioresponsibility, and be able to activate the desired cells. It is necessary to be able to provide a good space for the growth of bone tissue, to prevent the invasion of unwanted cells, and to prevent the hardening of bone tissue due to abnormal development of collagen fibers.

Purpose of the Invention The purpose of the present invention is to provide a material that is effective for adhering biological metals or ceramic materials such as artificial bones or artificial joints, and that is effective for regenerating bone tissue in a living body, that is, inducing new bone formation. An object of the present invention is to provide an effective bone cement composition.

Structure of the Invention The bone ceramic composition of the present invention comprises (1) a sintered body of a calcium phosphate compound, and has one or more pores formed in the sintered body with a diameter of 1 to 600 microns. A granule having a pore and a fine pore passage communicating the pore with an external space and having a size of 0.05 to 5 mm, and (2) water, physiological saline, blood, and artificial blood tissue. and at least one species selected from the group.

DETAILED DESCRIPTION OF THE INVENTION The bone cement composition of the present invention comprises sintered porous granules of a calcium phosphate compound, water, physiological saline, blood and/or artificial blood clot.

_The calcium _phosphate compounds used in the present invention are: _{CaHPO4Ca3 ( PO4 ) 2Ca5} ( _PO4 ) _3OHCa4O ( _{PO4 ) 2Ca10} ( _PO4 ) ₆ (OH) _{2CaP4O 11} Ca(PO ₃ ) ₂ Ca ₂ P ₂ O ₇ Ca(H ₂ PO ₄ ) ₂・H ₂ O, etc. are the main components, and it includes a group of compounds called hydroxyapatite. Hydroxyapatite has the composition formula Ca ₅ (PO ₄ ) ₃ OH or
The basic component is a compound containing Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , and a portion of the Ca component is Sr, Ba, Mg,
It may be substituted with one or more of Fe, Al, Y, La, Na, K, H, etc., and a part of the (PO ₄ ) component may be VO ₄ , BO ₃ , SO ₄ , CO ₃ , SiO ₄ Further, a portion of the (OH) component may be substituted with one or more of F, Cl, O, CO ₃ and the like. Hydroxyapatite may be a normal crystal, or a isomorphic solid solution,
It may be either a substitutional solid solution or an interstitial solid solution, and may also contain non-stoichiometric lattice defects.

Generally, the calcium phosphate compound used in the present invention preferably has an atomic ratio of calcium (Ca) to phosphorus (P) (Ca/P) in the range of 1.30 to 1.80, and preferably in the range of 1.60 to 1.67. Some are more preferable.

Calcium phosphate compounds used in the present invention include tricalcium phosphate [Ca ₃ (PO ₄ ) ₂ ], hydroxyapatite [Ca ₅ (PO ₄ ) ₃ OH], and Ca ₁₀
(PO ₄ ) ₆ (OH) ₂ is preferred, and one synthesized by a sol-gel method and freeze-dried is particularly preferred. Further, the calcium phosphate compound is preferably sintered at a temperature of 800 to 1450°C, and the sintering temperature is more preferably 850 to 1250°C.

In the granules of the present invention, the calcium phosphate compound is sintered in the form of powder, and therefore fine voids can be formed between the powder particles that are sintered in contact with each other.

The calcium phosphate porous granules of the present invention have a
5 mm in size, preferably 0.1 to 3 mm, and has at least one
pores having a pore size of 1 to 600 microns, preferably 10 to 300 microns, are formed, which communicate with the external space by means of microvoid passages. The diameter of this microvoid passage is preferably in the range of 1 to 30 microns, more preferably in the range of 1 to 20 microns. When the granule has a plurality of pores, it is preferable that these pores communicate with each other through fine pore passages having the same diameter as above.

The sintered porous granules preferably have a porosity of 40 to 90%, more preferably 60 to 70%.

It is preferable that the pores in the sintered porous granule have a true sphere or a shape close to a true sphere, and when a plurality of pores are present, it is preferable that they are uniformly distributed within the granule. These pores provide a living space for biologically activating bone phagocytes, bone regenerating cells, etc. when the ceramic material is implanted in a living body. Bone regeneration cells and the like very much prefer to stay in these pores, especially in the spherical pores. For this purpose, the pore diameter must be in the range of 1 to 600 microns, preferably 10 to 300 microns. Pores with a pore diameter outside the range of 1 to 600 microns cannot provide a good living space for the cells.

When the shape of the pores is a true sphere or a sphere close to this, the obtained porous material has high mechanical strength. Therefore, when this porous granular material is implanted in a living body, it can continue to maintain high mechanical strength and adhesive strength until it is returned over by new bone.

The microvoid passages in the sintered porous granules communicate at least the pores with the external space of the granules, and through these passages, the bone phagocytes, bone regenerating cells, red blood cell body fluid, etc. can freely enter the porous body, and the development of capillaries is promoted. Therefore, the diameter of this fine void passage is 1~
Preferably in the range of 30 microns, 1 to 20
More preferably, it is in the micron range. The micro-void passages as described above make it difficult for bone destruction cells and collagen fibers to enter the capillary-like cavity passages within the porous body, thereby preventing abnormal development of collagen fibers and hardening of bone tissue. That is, in the porous granule of the present invention, the fine void passages also function as a biofilter.

If the diameter of the micropore passage is smaller than 1 micron, it may be difficult for bone phagocytes, bone regenerating cells, red blood cell body fluid, etc. to enter the pores, and if it is larger than 30 microns, broken cells and collagen fibers may become difficult to enter. This may inhibit bone regeneration and may lead to hardening of the regenerated bone tissue and surrounding tissues.

In the porous granules of the present invention, when the granules include a plurality of pores, these pores may be interconnected by the above-mentioned fine pore passages, whereby the porous granules It can promote the exhaustion of the body and the regeneration (returnover) of living tissues.

It is preferable that the porous granules of the present invention have no acute angles.

An example of the porous granules used in the present invention is shown in FIG.

In the composition of the invention, water, saline, blood and/or artificial blood, such as polyvinylpyrrolidone, are preferably added to
By using it in an amount of ~200%, it is possible to promote the development of biological tissue on the surface and within the pores of porous granules used as bone cement.

If the amount of liquid components in the composition, such as water, physiological saline, blood or artificial blood serum, is less than 10%, the granules will tend to scatter when the composition is used, which may cause them to adhere to areas other than the affected area and cause negative effects. If the amount exceeds 200%, the granules and the liquid component tend to separate, which may make it difficult to fill the required amount of granules into the affected area.

The calcium phosphate compound sintered porous granules used in the present invention can be produced by various methods.

For example, the granules of the present invention may be prepared by mixing 30-90% by volume, preferably 30-60% by volume, of a sublimable solid material powder with a particle size of 1-600 microns into the remaining amount of calcium phosphate compound powder. This mixture is heated with an alcohol medium using a high-speed stirrer and stirred repeatedly to contain the sublimable solid substance.
Granules of 0.05 to 5 mm are formed, and then, depending on the case, they are granulated into granules of a predetermined size using a granulator, and after drying, the sublimable solid is heated at 300 to 500°C. It is produced by sublimating the material and then heating and sintering it to a temperature of 800-1450°C, preferably 850-1250°C.

The calcium phosphate compound powder used for producing the above granules preferably has a particle size of 0.05 to 10 microns. A particularly preferable calcium phosphate compound powder preferably includes a crystal part developed into a plate shape, and according to observation results based on an SEM (scanning electron microscope), 30% or less of the powder particles have a particle size of 1 μ or more, It is preferable to have a particle size distribution in which 70% or more has a particle size of 1 μ or less.

In addition, the sublimable solid substance powder is contained in the granules from 1 to 1.
If the material is for forming pores with the desired size of 600 microns, easily sublimes at temperatures between 200 and 800°C, and leaves virtually no residue;
There are no particular limitations on the type. Generally, the sublimable substance is selected from camphor, chlorine, naphthalene, and mixtures of two or more thereof. When the granulated mixture granules are heated to a temperature of 200 to 800°C, preferably for 120 to 180 minutes, the sublimable substance sublimates and escapes, forming pores. At this time, fine particles of the sublimable substance are removed from the pores. Fine pore passages communicating with the outside of the porous body are formed by the sublimation and escape of the powder. Furthermore, microscopic void spaces are also formed that communicate between the holes.

Next, the molded product is heated to 800-1450℃, preferably 850℃.
The calcium phosphate compound powder is sintered by heating to ~1200°C, preferably for 1 to 3 hours.

In the method using the above sublimable substance powder,
For 100 parts by weight of calcium phosphate compound powder,
1 to 5 parts by weight of organic fibers having a length of 1 to 5 mm and a diameter of 1 to 30 microns may be added. If such a mixture is heated to a temperature of 200 to 800° C., preferably for 120 to 180 minutes, the sublimable substance sublimates and escapes and the organic fibers are carbonized. Then 800
By heating to a temperature of ~1450° C., preferably for 1 to 3 hours, the carbide is burnt out and the calcium phosphate compound powder is sintered.

In this method, the incorporation of organic fibers is effective in ensuring the formation of capillary void channels having a diameter of 1 to 30 microns. This organic fiber is similar to that described above.

When mixing organic fibers or sublimable material powder with calcium phosphate compound powder, adding a volatile lower alcohol such as methanol or ethanol not only makes it easier to obtain a homogeneous mixture, but also reduces the particle size of the sublimable material particles. It is possible to control and improve the adhesion between the sublimable material particles and the organic fibers, thereby promoting the formation of microvoid passages communicating with the pores.

Another method for producing the porous granules of the present invention includes 30 to 90% by volume, preferably 30 to 60% by volume of
Organic synthetic resin particles having a particle size of 1 to 600 microns are mixed with 100 parts by weight of calcium phosphate compound powder, and this mixture is molded into a desired shape and size by a method similar to the method described above. The molded product is heated to a temperature of 200 to 800°C to thermally decompose and remove the organic synthetic resin particles, and then heated to a temperature of 800 to 1450°C in an oxygen-containing atmosphere to remove the calcium phosphate compound powder. This includes sintering.

The organic synthetic resin particles having a particle size of 1 to 600 microns used in the above method are contained in a porous body.
It is effective for forming pores of ~600 microns. There are no particular limitations on the type of organic synthetic resin, as long as it thermally decomposes at a temperature of 200 to 400°C and escapes from the porous body.
Generally, it is selected from thermoplastic synthetic resins such as methyl methacrylate, polypropylene, and polystyrene, with methyl methacrylate being particularly preferred. The organic synthetic resin described above has a certain hardness, so when the particles are mixed with calcium phosphate compound powder or when this mixture is press-molded, the spherical particles are not deformed or crushed. It is possible to form pores having a size and shape that exactly correspond to the size and shape of the particles used.

A mixture of organic synthetic resin spherical particles and calcium phosphate compound powder is formed into granules having desired dimensions and shape. The obtained granules are first
At a temperature of 200-500℃, preferably at 300-350℃
Heating is performed for 120 to 180 minutes to thermally decompose and remove the organic synthetic resin particles, forming corresponding pores and forming microporous passages extending from the pores.

Next, this molded product is heated to 800 ~
The calcium phosphate compound powder is sintered by heating at 1450°C, preferably 850-1250°C, preferably for 1-3 hours. At this time, even if there is a thermal decomposition residue of the organic synthetic resin particles, this is burned off during sintering and heating.

In the method using the above organic synthetic resin particles, 100 parts by weight of calcium phosphate powder is
~5 parts by weight of organic fibers having a length of 1 to 5 mm and a diameter of 1 to 30 microns can be added. The types and effects of this organic fiber are the same as described above.

Furthermore, in the method using the organic synthetic resin particles, 2 to 5 parts by weight of sublimable solid material particles having a particle size of 1 to 600 microns are additionally added to 100 parts by weight of the calcium phosphate compound powder. be able to. The type of this sublimable substance is the same as described above. In this method, the sublimable material particles have a particle size of 1 to 600 microns and are effective in forming capillary-like void passages.

Furthermore, in the method using the organic synthetic resin particles, 2 to 5 parts by weight of organic fibers having a length of 1 to 5 mm and a diameter of 1 to 30 microns are added to 100 parts by weight of the calcium phosphate compound powder. ,
2 to 5 parts by weight of sublimable solid particles having a particle size of 1 to 600 microns may be added. The types and effects of these organic fibers and sublimable solid particles are the same as described above.

The granules obtained by the above manufacturing method have pores of 1 to 600 μm in which bone cells can penetrate, and have an external shape with no acute angles, and the particle size of the granules is 0.05 to 600 μm.
Can be adjusted to any size of 5mm, and the firing temperature can be adjusted to 800℃.
Since any temperature between ~1450°C can be selected, it is possible to adjust the turnover rate. When using the above granules as a bone cement, water, physiological saline, patient's blood and/or artificial blood, such as polyvinylpyrrolidone, is used as a temporary fixing material until turnover occurs. .

The bone cement composition of the present invention can be used, for example, as described below.

In Fig. 2, the artificial bone cement plug 5 is inserted into the bottom of the femoral hip joint head which has been cut to form the medullary cavity, and then the stem of the alumina artificial hip joint 1 is inserted. Bone cement compositions 4, 3, and 2 are filled between the stem and the bone marrow. At this time, the sizes of the granules of bone cement compositions 4, 3, and 2 may be made smaller sequentially. The plug 5 is made of phosphoric acid, which has a large number of pores having a pore diameter of 1 to 600 microns, preferably 300 to 600 microns, and a microporous passage that communicates the pores with the external space, similar to the granules of the present invention. A material made of a sintered porous body of a calcium compound is used. The size and shape of the stopper may be any desired.

Further, the present invention will be explained in more detail with reference to examples, but the present invention is not limited to the examples.

Example By a known wet method, a phosphoric acid solution was added dropwise to a calcium hydroxide slurry to synthesize calcium phosphate with Ca/P=1.65, and after drying, a calcium phosphate powder of 150 μm or less was obtained. This calcium phosphate 100
37 g of polymethyl methacrylate resin with a particle size of 5 to 300 μm is mixed with 37 g of polymethyl methacrylate resin having a particle size of 5 to 300 μm, and this mixture is repeatedly heated and stirred using methanol as a medium using a high-speed stirrer, and then granulated by rolling. Using a machine, unfired granules having no acute angles of 0.1 to 3 mm were granulated. The granules were heated at 300°C for 24 hours to remove the organic synthetic resin particles by thermal decomposition, and
A porous body with pores of 300μ was obtained and further heated to 1000℃.
Sintered for 1 hour to form pores with a pore diameter of 5 to 300μ
Porous granules of 0.1 to 3 mm were obtained. This is a particle size of 0.1
It was divided into three types: ~0.15mm, 0.3~0.5mm, and 0.8~1.2mm. A microscopic photograph of the obtained granules is shown in FIG.

Separately, 300~ for 100g of calcium phosphate powder
40 g of polymethyl methacrylate resin having a particle size of 600 μm was added, mixed and dried using methanol as a medium, and the mixture was packed in a rubber balloon and subjected to isostatic pressing at 300 kg/cm ² to obtain a molded product. This molded body was gradually heated from room temperature to 300°C, the organic synthetic resin particles were removed by thermal decomposition, and a porous body having continuous pores of 300 to 600μ was obtained, which was then sintered at 1200°C for 1 hour in an electric furnace. After quenching, a cylindrical bone cement plug having continuous holes with a diameter of 5 mm and a length of 5 mm was obtained. The plug thus obtained had a porosity of 55%.

Figure 2 shows an example in which these granules and plugs were used to actually remove the hip joint of a dog, cut off the femoral head, replace it with an alumina artificial hip joint, and use the bone cement of the present invention at the same time. .

In FIG. 2, an alumina artificial hip joint 1 is inserted into the medullary cavity with a stem instead of the cut femoral head, and the bone cement of the present invention is used between the stem and the bone to induce new bone and The fixation of the artificial hip joint was observed. The plug 5 of the bone cement of the present invention is fixed under the stem, the granules of the present invention 0.8-1.2 mm, 4 are placed on top of it, then the granules 3 of 0.3-0.5 mm are placed on top of it, and finally the granules 3 of 0.1-1.2 mm are placed on top of the plug 5 of the bone cement of the present invention.
Granules 2 each having a diameter of 0.15 mm were injected together with physiological saline, and the artificial femoral head stem was immediately pushed into the diaphysis, and the stem was fixed and reduced. In addition, 6
is a dog's femur. Two weeks later, surgery was performed and the dog's femur was removed and its progress was observed. As a result, a large amount of new bone formation was observed especially in areas 7 and 8 where loads were applied, and a small amount of new bone formation was observed in other areas as well. From observation after 13 weeks,
The artificial hip joint is fixed to the dog's femur without coming off, and observation after the surgery shows that in areas 7 and 8 where the load is applied, most of the granules have been replaced by new bone, and granules in other areas have been replaced. The body was mostly covered with new bone, but the progress was good, with some new formation of the medullary cavity.

Effects of the Invention Since the granules used in the bone cement composition of the present invention are used with the addition of any one of water, physiological saline, patient's blood, and artificial blood plasma, the granules surface and The pores are covered with living tissue.
Furthermore, the granules of the present invention have pores and therefore have a large surface area. Therefore, in a short period of time, young granulation tissue covers the surface and the formation of new bone begins rapidly. After that, new bone is formed between the granules and begins to bridge, and as this develops, new bone including cancellous bone is formed. be done. In particular, in the case of an artificial hip joint, this phenomenon appears markedly in areas where loads are applied, and even in areas where no loads are applied, new bone formation occurs over the final period. Furthermore, in areas where loads are applied, all of the granules form dense cancellous bone connected by new bone, and the new bone continues to become denser, causing the artificial joint and surrounding bones to form. The artificial joint can be completely fixed by transitioning to compact bone with the same tissue. Thereafter, new bone is gradually formed even in areas where no load is applied, and eventually all of the granules are replaced by new bone. Furthermore, in order to increase the bone formation rate, it is preferable to increase the specific surface area of the granules and increase the number of granules, but for new bone formation, it is essential to supply osteogenic substances from within the body. Therefore, there is a limit naturally. Therefore, in the bone cement composition of the present invention, the bone formation rate can be adjusted by selecting the sintering temperature, pore size, and granule diameter during granule production. That is, the sintering temperature of the granules used in the bone cement composition of the present invention is 800 to 1350°C;
Preferably 850~1250℃, pore size 1~
600μ, preferably 5-300μ, granule size 0.05
~5 mm, preferably 0.1~3 mm.

Furthermore, by using a bone cement plug, the size of the granules can be further preferably adjusted to 0.1 to 0.15 mm.
By using three types of granules, 0.3 to 0.5 mm and 0.8 to 1.2 mm, and using larger granules from the bottom, it is possible to adjust the bone formation rate. In addition, since the bone cement plug has continuous holes, bone marrow flows through the bone cement plug filled in the bone marrow cavity.
The bone cement of the present invention can contact bone marrow and further promote the formation of new bone. Most of the bone cement composition of the present invention exists within the bone marrow cavity, and new bone is formed within the bone marrow cavity. However, unnecessary new bone within the bone marrow cavity is absorbed in vivo by osteoclasts. It is resorbed, leaving only new bone in the necessary areas. For the reasons mentioned above, the bone cement composition of the present invention can replace conventional bone cements, strengthen surrounding bone tissue, and completely fix artificial joints.

[Brief explanation of drawings]

FIG. 1 is a micrograph (500x magnification) of granule particles used in the bone cement composition of the present invention, and FIG. 2 is an explanatory diagram showing an example of the usage status of the bone cement composition of the present invention. 1... Artificial hip joint, 2... Granule layer with a particle size of 0.1 to 0.15 mm, 3... Granule layer with a particle size of 0.3 to 0.5 mm, 4
... Granule layer with a particle size of 0.8 to 1.2 mm, 5... Bone cement plug, 6... Femur, 7, 8... Load concentration area.

Claims (1)

[Scope of Claims] 1. Consisting of a sintered body of a calcium phosphate compound, one or more pores having a pore diameter of 1 to 600 microns are formed in the sintered body, and the pores are formed outside the sintered body. has a micro-void passage communicating with the space, and has a diameter of 0.05
A bone cement composition comprising granules having a size of ~5 mm and at least one selected from the group consisting of water, physiological saline, blood, and artificial blood tissue. 2. The atomic ratio of calcium to phosphorus in the calcium phosphate compound is within the range of 1.30 to 1.80.
A composition according to claim 1. 3. The composition of claim 1, wherein the calcium phosphate compound is hydroxyapatite. 4. The composition according to claim 1, wherein the pores have a pore diameter in the range of 3 to 300 microns. 5. The composition of claim 1, wherein the diameter of the microvoid passages is within the range of 1-30 microns. 6. The granules have a porosity of 40% to 90%.
A composition according to claim 1. 7. The composition according to claim 1, wherein the granules have a plurality of pores, and these pores communicate with each other through fine pore passages. 8 The calcium phosphate compound sintered body is 800~
A composition according to claim 1, which is sintered at a temperature of 1450°C. 9. The composition according to claim 1, wherein the amount of at least one of water, physiological saline, blood, and artificial blood is 10 to 200% of the weight of the granules.