JPH04361757A - Bone filler - Google Patents

Abstract

PURPOSE:To provide a bone filler of calcium phosphate powder which is easy to handle and configurate when filling a subject and which is excellent in restoration of a bone-deficient part. CONSTITUTION:A bone filler in the form of a sheet (e.g. paper) or a lump wherein powders of calcium phosphate based material (esp. apatite hydroxide whisker) bond with one another via an organic macromolecular binder (esp. a cellulose binder such as cellulose pulp) in such a way as to form a porous structure.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to bone grafting materials using calcium phosphate materials.

0002

BACKGROUND OF THE INVENTION Bones and teeth of vertebrates are composed of about 70% by weight inorganic matter and about 30% by weight organic matter (substances mainly composed of collagen). This mineral is very similar to hydroxyapatite (Ca10(PO4)6(OH)2), and contains CO32-, Mg2+,
Contains Na+, Cl-, F-, etc.

In recent years, hydroxyapatite and tricalcium phosphate (Ca3 (PO
4) Calcium phosphate ceramics such as 2)
Because it has an excellent affinity for bone and tooth tissues,
It is attracting attention as a material for artificial bones, artificial tooth roots, etc. For example, sintered hydroxyapatite can be directly chemically bonded to bone (Hideki Aoki, Journal of Dental Science and Technology, 18, 41 (1)
977)) and that porous tricalcium phosphate is absorbed in vivo and replaced with bone (T.D. Driskell).
et al., J. et al. Dent. Res. ,52,123(
1973) ) has been reported.

[0004] When calcium phosphate ceramics are used as artificial bones, their field of use may be restricted due to their rather weak strength, and special consideration may be required when using them. However, as biomaterials, calcium phosphate ceramics have particularly excellent properties compared to other materials (they have excellent affinity for bones and teeth, and are not toxic), so calcium phosphate ceramics are used as porous blocks and It is also known that it can be used in powder form as a bone replacement material to be implanted into bone defects for repair. For example, in the field of oral surgery, bone defects in the stomatognathic region, such as cleft palate, cysts,
Various bone grafting materials are used for tooth extraction sockets, severe alveolar ridge resorption, bone fractures, etc.

However, when a porous block of calcium phosphate ceramics is used as a bone grafting material, it is difficult to form it during filling, a dead space is likely to be formed between the bone surface and the bone surface. There are problems such as difficulty in forming planar continuity. Furthermore, when calcium phosphate ceramic powder is used, it is difficult to give it a shape during filling (i.e., it takes time and effort to insert the powder, making efficient filling difficult), and it also tends to move after surgery. However, there are problems such as part of the powder leaking due to excessive packing.

As a type of calcium phosphate powder, a part of PO43- or OH- of hydroxyapatite is carbonated (
Carbonate-containing hydroxyapatite whiskers substituted by CO32-) and carbonate-free hydroxyapatite whiskers obtained by decarboxylating the carbonate-containing hydroxyapatite whiskers by heating are known ( (See Japanese Patent Application Laid-Open No. 2-141500). In this specification, the above carbonated hydroxyapatite whiskers and hydroxyapatite whiskers are collectively referred to as hydroxyapatite whiskers.

The above-mentioned hydroxyapatite whiskers have a length of 10 μm or more and an aspect ratio of 40 to 200. In this specification, the aspect ratio means a value expressed by the following formula. AsR=L/{(a+b)/2} (where AsR is the aspect ratio, L is the whisker length, a is the whisker thickness, and b is the whisker width).

The above-mentioned hydroxyapatite whiskers also have excellent properties as a bone grafting material;
As described above, since it has a very fine rod-like or needle-like shape, when it is used as a bone grafting material as it is, it scatters and is difficult to handle. Further, the above-mentioned problems also occur when hydroxyapatite whiskers are used as a bone grafting material by forming blocks.

[0009]

OBJECTS OF THE INVENTION It is an object of the invention to provide a bone grafting material using calcium phosphate powder that can be easily used and which solves the problems of the conventional calcium phosphate powder bone grafting material as described above. .

0010

[Means for Solving the Problems] The present invention is a sheet-like or block-like bone grafting material formed by combining powdered calcium phosphate materials to form a porous structure via an organic polymer binder.

The bone grafting material of the present invention is preferably in the form of paper sheets made from a powdered calcium phosphate material and a cellulose binder.

[0012] Furthermore, the bone grafting material of the present invention has a length of 10 μm.
The paper is made from 50 to 97 parts by weight of hydroxyapatite whiskers having an aspect ratio of 40 to 200 and 3 to 50 parts by weight of a cellulose binder (however, the total amount of whiskers and cellulose binder is 100 parts by weight). Preferably, it is in the form of a paper leaf.

Alternatively, the bone grafting material of the present invention is preferably in the form of a mass produced from a powdered calcium phosphate material and a cellulose binder to form a porous structure.

Preferred embodiments of the present invention are as follows. (1) A bone graft material in which the powdered calcium phosphate material is a powder of tricalcium phosphate, hydroxyapatite, and/or carbonate-containing hydroxyapatite.

(2) A bone grafting material in which the powdered calcium phosphate material is a spherical, needle-shaped, rod-shaped, plate-shaped, porous, or burr-shaped powder having a size of 10 microns to 5 mm.

(3) The weight ratio of the powdered calcium phosphate material and the organic polymer binder is from 50:50 to the powdered calcium phosphate material:organic polymer binder.
A bone substitute material with a ratio of 97:3.

(4) A bone grafting material in which 0.1 to 5 parts by weight of a paper strength enhancer is further added to 100 parts by weight of the total amount of the powdered calcium phosphate material and the organic polymer binder. .

(5) The organic polymer binder is pulp,
Bone replacement material that is microfibrillated cellulose or a mixture thereof.

The bone grafting material of the present invention is in the form of a sheet or a lump formed by combining powdered calcium phosphate materials to form a porous structure via an organic polymer binder.

Preferred examples of the above-mentioned powdered calcium phosphate materials include tricalcium phosphate, hydroxyapatite, and carbonic acid-containing hydroxyl, which have excellent affinity for bone and tooth tissues and are nontoxic. Mention may be made of apatite powder, as well as mixtures thereof.

[0021] The above powder material has a size of 10 microns to 5 mm.
spherical, needle-like, rod-like, plate-like, porous,
It is preferably a chestnut-like powder.

[0022] Preferred organic polymer binders used in the present invention are cellulosic binders, which are in the form of fibers, such as pulp, microfibrillated cellulose, or a mixture of both. However, the binder does not necessarily have to be in the form of fibers. As the cellulose binder, various derivatives including cellulose ester derivatives such as methylcellulose, ethylcellulose, benzylcellulose, carboxymethylcellulose, and carboxyethylcellulose, and regenerated cellulose can also be used. It is also possible to use protein binders such as gelatin and casein, or hydrophilic synthetic polymers such as polyvinyl alcohol. However, particularly preferred is a cellulose-based binder in which the pulp content is 50 to 100% by weight.

[0023] The pulp that is a preferred binder in the present invention is not particularly limited as long as it is a pulp that is normally used in the production of paper, and may be of any kind, such as softwood pulp, hardwood pulp, waste paper pulp, etc. , GP, three-pronged, hemp, cotton, gambi, and other cellulose fiber materials may be used. Among them, when increasing the content of hydroxyapatite whiskers, softwood bleached pulp (NBKP) is preferable in terms of suppressing a decrease in folding strength etc.
Moreover, it is preferable to use long fibers such as bark fibers such as hemp pulp.

The weight ratio of calcium phosphate powder to binder is: calcium phosphate powder: binder = 5
0:50-97:3, especially calcium phosphate powder:
Preferably, the binder ratio is 60:40 to 90:10. If the amount of calcium phosphate powder used is less than the above range, the content of binder in the produced filled paper will increase relatively, and the properties as a bone grafting material will deteriorate, which is not preferable. In addition, if the amount of hydroxyapatite whiskers used is greater than the above range, the self-supporting properties of paper sheets or lumps will decrease, and in actual use, after impregnating with physiological saline, bone defects will be When filling, etc.
It tends to become impossible to maintain the structure of paper sheets or lumps, which is disadvantageous in practical use.

[0025] In order to make a paper sheet (calcium phosphate powder-filled paper) which is advantageous as a bone grafting material of the present invention, a mixture (paper stock) containing calcium phosphate powder and a binder is first mixed with water. Mix to prepare stock solution. The procedure for preparing the paper stock solution is not particularly limited, but it can be carried out, for example, as follows.

[0026] An aqueous slurry of calcium phosphate powder (the concentration of solid content is generally preferably 5 to 20% by weight) and an aqueous slurry of a binder (the concentration of solid content is preferably 5 to 20% by weight).
(generally preferably 0.5 to 5% by weight) are prepared according to a conventional method, and the aqueous slurry is mixed (preferably slowly) so that the proportions of the calcium phosphate powder and the binder reach a predetermined value. Mix with stirring to prepare a mixed slurry. If necessary, water is added to prepare a stock liquid so that the concentration of solids in this mixed slurry is 0.2 to 0.4% by weight. When preparing this paper stock, a fixing agent and/or a paper strength enhancer may be added as necessary.

[0027] The fixing agent is not particularly limited as long as it is a fixing agent normally used for manufacturing filled paper, and any fixing agent may be used. For example, inorganic salts such as aluminum sulfate, cationic or anionic organic polymers (e.g. acrylamide, polyethyleneimine, epichlorohydrin, modified products thereof), natural polymers (e.g. cationic starch, sodium alginate) , chitosan) can be used as a fixing agent. When the amount of calcium phosphate powder is small, a fixing agent such as aluminum sulfate or cationic starch is sufficient, but when the amount of calcium phosphate powder is large, the above organic polymer substances alone or in mixtures, the above organic It is preferable to use a mixture of a polymeric substance and an inorganic salt such as aluminum sulfate, or a fixing agent such as chitosan or sodium alginate.

[0028] In preparing the above sample liquid, it is preferable to use 0.1 to 5 parts by weight of a fixing agent. If the amount of fixing agent used is less than the above range, the yield of hydroxyapatite whiskers will decrease, and if it is more than the above range, flocs will become large and papermaking will tend to become difficult.

The paper strength enhancer may be any substance used in paper manufacturing, such as starch, vegetable gum, PVA, CMC, polyacrylamide, and other dry paper strength enhancers; Surface paper strength enhancer with similar composition, urea-formalin resin, melamine-formalin resin,
Polyethyleneimine, dialdehyde starch, polyamine polyamide epichlorohydrin (e.g. Kaimen 557H・
・Product name). When a paper strength enhancer is used, the amount used is preferably 0.1 to 5 parts by weight.

[0030] The method for making paper filled with calcium phosphate powder from the paper stock liquid prepared as described above is not particularly limited, and conventional paper making methods (for example, cylinder method, Fourdrinier method) may be employed. can do. Although the thickness of this filled paper is not particularly limited, it is generally preferably 0.05 to 5 mm from the viewpoint of ease of handling.

[0031] The paper leaf-shaped bone grafting material is cut into an appropriate size at the treatment site (scissors etc. may be used, but generally it can be easily shredded by hand), and it can be used as is or rolled up with the fingertips. After forming into a mass, it is sterilized and then immersed in a body fluid-like fluid such as physiological saline, which can be easily applied to the target area. Other operations when using the bone graft material in the form of paper sheets or blocks are similar to those in the case of using conventional bone graft materials.

[0032] The bone grafting material in the form of paper sheets is obtained by cutting the above-mentioned calcium phosphate powder-filled paper (which may be in sheet form before dehydration) into small pieces using an appropriate cutter, and then cutting the small pieces into appropriate pieces. It may be a lump of a mixture containing a calcium phosphate powder and a binder obtained by molding into a lump using a granulator. Alternatively, it may be a lump obtained by dehydrating a paper stock liquid for producing calcium phosphate powder-filled paper and molding the resulting water-containing mixture into a lump.

[0033] The shape of the bulk bone grafting material is not particularly limited, but it is preferably spherical or spheroidal, and its size is preferably 3.5 to 400 mesh.

The bone graft material of the present invention contains 50 to 97 parts by weight of hydroxyapatite whiskers having a length of 10 μm or more and an aspect ratio of 40 to 200, and 3 to 97 parts by weight of an organic polymer binder (particularly a cellulose binder). 50 parts by weight (however, the total amount of the whisker and binder is 100 parts by weight)
It is preferable that the paper is made of hydroxyapatite-based whisker-filled paper obtained by forming a paper stock prepared by mixing 3 parts by weight with water.

[0035] The length of the hydroxyapatite whisker is 10
It has an aspect ratio (AsR) of 40 to 200, preferably 100 to 200, in terms of μm or more. In addition, hydroxyapatite whiskers have a flat strip-like or tape-like shape in which a/b is usually 0.7 or less and 0.1 or more in the formula defining AsR, and usually, Obtained as a single crystal.

[0036] Also, among the hydroxyapatite whiskers,
Carbonic acid-containing hydroxyapatite whiskers are PO43 of ordinary hydroxyapatite (Ca10(PO4)6(OH)2)
- or at least a part of OH- is carbonic acid (CO32
-) has a structure substituted with ). The above substitution with carbonic acid may have a structure in which either one of PO43- or OH- in each molecule is substituted, or a structure in which both are substituted. Carbonic acid-containing hydroxyapatite whiskers usually contain carbonic acid in the range of 2 to 7% by weight in the above-described bonded structure.

The above-mentioned hydroxyapatite whiskers can be produced by the method described in JP-A-2-141500.

That is, for example, the carbonic acid-containing hydroxyapatite whiskers described above can be directly produced by heating a solution containing a calcium salt and a phosphate in the presence of urea.

[0039] Examples of the calcium salt include calcium nitrate, calcium chloride, calcium hydroxide, calcium carbonate, calcium sulfate, etc., with calcium nitrate being particularly preferred. In addition, the above-mentioned phosphates include diammonium hydrogen phosphate, phosphoric acid, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate, ammonium dihydrogen phosphate, ammonium phosphate, phosphoric acid Potassium dihydrogen/dihydrate, dipotassium hydrogen phosphate/
Examples include dihydrate salts, and diammonium hydrogen phosphate is particularly preferred. The ratio of the amounts of calcium salt to phosphate used is the molar ratio of Ca to P (Ca/P), which is preferably in the range of usually 1.1 to 3.0, more preferably 1.67. It is preferable that there be.

The above urea acts as a precipitant, and ammonia generated by decomposition of urea adjusts the pH of the reaction solution to produce a uniform precipitate of hydroxyapatite or its precursor. In addition, carbonic acid generated at the same time as ammonia causes PO43- or OH- of the hydroxyapatite produced.
Replace with part of. The amount of urea used is 0.2 to 1 mole per 0.1 mole of phosphate of the hydroxyapatite raw material.
．． Preferably, the amount is in the range of 0 mol. If the amount of urea used is less than 0.2 mol per 0.1 mol of phosphate, pH adjustment may be insufficient and the desired product may not be obtained. Further, when the amount of urea used is more than 1.0 mol, the generated whiskers tend to further aggregate and take on a burr-like shape.

Next, the above calcium salt, phosphate and urea are dissolved in an acid aqueous solution. Examples of acids that can be used in the acid aqueous solution include nitric acid, hydrochloric acid, acetic acid, and sulfuric acid, with nitric acid being particularly preferred. The concentration of the nitric acid aqueous solution is usually in the range of 0.2 to 1.0 mol/l. After adjusting the pH of the above solution to a range of 0.7 to 3.3 with aqueous ammonia, the calcium salt and phosphate are reacted by heating and refluxing the solution at a constant temperature in an oil bath such as silicone oil. .

[0042] Also, among the hydroxyapatite whiskers,
Hydroxyapatite whiskers can be produced by heating the carbonic acid-containing hydroxyapatite whiskers described above to a temperature range of 800 to 1300°C, preferably to about 1200°C, and then rapidly cooling to decarboxylate. Although the hydroxyapatite obtained by the above decarboxylation tends to have a reduced weight compared to carbonic acid-containing hydroxyapatite whiskers, the shape of the whiskers is well maintained.

[0043]

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.

[Examples 1 to 8] Length 100 to 200 μm
Then, carbonic acid-containing hydroxyapatite whiskers having an aspect ratio of 100 to 200 were suspended in water to prepare a whisker water slurry having a solid content concentration of 12% by weight. Beaten pulp (NBK) is used as a cellulose binder.
P, freeness: 350c. s. f. ) was suspended in water to prepare a pulp slurry having a solid content of 1% by weight. In addition, microfibrillated cellulose (MFC) (manufactured by Daicel Corporation, MFC-100) as another cellulose-based binder is suspended in water to obtain a cellulose-based binder with a solid content of 4.5% by weight. A slurry was prepared.

[0045] The aqueous slurry of these three materials was charged into a paper stock preparation tank equipped with an agitator so that the weight proportions of carbonic acid-containing hydroxyapatite whiskers, pulp, and cellulose binder became the values shown in Table 1, and the mixture was stirred. A mixed slurry was prepared by mixing while stirring. Water was added to this mixed slurry to adjust the solid content concentration in the mixed slurry to 0.3% by weight.

Next, while slowly stirring this mixed slurry, 0.3 parts by weight of chitosan (Yaizu water) was added as a fixing agent (the total amount of carbonic acid-containing hydroxyapatite whiskers and cellulose binder is 100 parts by weight). Kaimen 557H (manufactured by Deck Hercules Co., Ltd.) and 0.2 parts by weight (the total amount of carbonic acid-containing hydroxyapatite whiskers and cellulose binder is 100 parts by weight) as a paper strength enhancer (manufactured by Deck Hercules Co., Ltd.). )
was added. Next, ammonia was added to the mixed slurry while stirring slowly to adjust the pH of the mixed slurry to 10.
The paper stock was prepared by adjusting the amount to 0.

The paper stock obtained as described above was dehydrated using a round sheet machine (dehydration conditions: pressure 3.5 kg/
cm2, time: 3 minutes, drying conditions: drum dryer temperature: 105°C, time: 3 minutes) A bone grafting material, which is a paper filled with carbonic acid-containing hydroxyapatite whiskers, was produced by hand papermaking.

Table 2 shows the physical properties of the obtained bone grafting material (paper filled with carbonic acid-containing hydroxyapatite whiskers). However, the physical property values shown in Table 2 are the average values of five bone grafting materials for each example.

[0049]

[Table 1]

[0050]

[Table 2]

[Example 9] The carbonic acid-containing hydroxyapatite whisker-filled paper produced in Example 3 was shredded by
After forming fine pieces with a side of 5 to 10 mm, water and a cellulose binder were added thereto, granulated in a pulverizer, and dried using a hot air drier to obtain a lump with a diameter of 1 to 15 mm.

[Reference Example] In the bone cortex of the lower edge of the mandible of a beagle dog, there are four holes on each side, each with a diameter of 3 mm and a depth of 1.5 mm (named from the center: A, B, C, D, Total 8
The bone replacement material prepared in Example 3 was sterilized in an autoclave at 130°C for 30 minutes, cut into small pieces, immersed in physiological saline to loosen it, and then The defect was filled. Add 6 m of bone substitute material to hole A.
Hole B was filled with 3 mg of bone grafting material, hole C was filled with 1.5 mg of bone grafting material, and hole D was filled with 6 mg of filter paper alone as a control. After 2 weeks, 4 weeks, and 12 weeks after the above treatment, the extracted decalcified specimens were stained with hematoxyeosin and examined histopathologically.

1) According to macroscopic findings, no inflammation of the gingiva was observed in either the site where the bone grafting material of the present invention was implanted or the site where the control sample was implanted, and the health status of the experimental animals was not observed. There were no abnormalities.

2) According to the X-ray progress findings, new bone formation was good in the areas where the bone graft material of the present invention was implanted after 2, 4, and 12 weeks, but when the control sample was implanted, Almost no bone formation was observed at the site of insertion.

3) After 2, 4, and 12 weeks, the compatibility of the implanted material with the surrounding bone tissue was examined histopathologically.
No inflammatory cells or new small blood vessels were observed around the site where the bone grafting material of the present invention was implanted at any time point, and new bone was well formed. Some giant cells were observed in the affected areas, and little new bone formation was observed.

[0056]

[Effects of the Invention] The bone replacement material of the present invention is easy to handle when filling a bone defect, and there is no scattering of calcium phosphate powder or leakage from the replacement site, and it can be easily used. It is a bone replacement material that has a remarkable effect in that the bone in the replacement site has good repairability.

Claims (4)

[Claims] 1. A sheet-like or block-like bone grafting material formed by combining powdered calcium phosphate-based materials to form a porous structure via an organic polymer binder. 2. The bone grafting material according to claim 1, which is in the form of paper sheets made from a powdered calcium phosphate material and a cellulose binder. 3. Hydroxyapatite whisker 50~ having a length of 10 μm or more and an aspect ratio of 40~200
2. The bone grafting material according to claim 1, which is in the form of a paper sheet made from 97 parts by weight and 3 to 50 parts by weight of a cellulose binder (provided that the total amount of whiskers and cellulose binder is 100 parts by weight). 4. A bone grafting material according to claim 1, in the form of a mass made of a powdered calcium phosphate material and a cellulosic binder to form a porous structure.