JPH05277174A - Living transplant material - Google Patents

Abstract

(57) [Summary] [Structure] The biological transplant material of the present invention is obtained by subjecting a gelatin solution containing a powder of a calcium phosphate compound to vacuum heat drying or the like to obtain a complex in which gelatin in a crosslinked state carries particles of the calcium phosphate compound. After being formed, the surface of the composite is coated with uncrosslinked gelatin so that the bioimplant material is kneaded with a liquid such as physiological saline so as to have an appropriate tackiness. [Effect] In the bioimplant of the present invention, since the film made of uncrosslinked gelatin is water-soluble, it has a proper viscosity when kneaded with a liquid such as physiological saline, and further gelatin is crosslinked to give a calcium phosphate compound. Since the complex carrying the particles of is insoluble in water, even if the particles are firmly carried in the complex and filled in the bone defect,
It does not fall off, the bone regenerates and grows in the bone defect at an early stage, and it has a great therapeutic effect.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a living body transplant material, and more particularly to a living body transplant material for filling a bone defect portion in the fields of oral surgery and orthopedic surgery.

[0002]

2. Description of the Related Art Mucoid, a mucoid glycoprotein contained in saliva, covers teeth in plaques that cause gingivitis. , Formed by precipitation. This plaque attaches to the gingival sulcus, becomes drainage, and causes gingivitis. Further, pockets are formed under the rim of the bone, and alveolar bone resorption occurs at this portion.

Even if alveolar bone resorption occurs due to gingivitis, if it is mild, it can be healed only by treatment for removing plaque, but if it is severe, the bone defect part where bone is absorbed is filled with a bioimplant. However, it is necessary to allow the bone to regenerate at the bone defect portion. However, if this treatment fails, you will have to extract your teeth.

As such a bioimplant, conventionally, calcium phosphate, which has excellent biocompatibility such as hydroxyapatite and tricalcium phosphate as described in JP-A-56-54841, and induces bone regenerative proliferation, is used. Granules of the system compound are used, and as a method for producing the same, the dry or wet-synthesized calcium phosphate compound described above is used.
It is fired at 00 ° C to 1300 ° C and has an average particle size of 200 to
It was classified into granules with a size of 1000 μm. And
The bioimplant material thus obtained was mixed with a liquid such as physiological saline and filled in the bone defect portion so that new bone was generated therein.

Further, the above-mentioned bioimplant is not only used for the bone defect part of the alveolar bone as described above, but also in oral surgery in general,
It has also been used in the field of orthopedics to repair bone defects.

[0006]

However, the above-mentioned conventional bioimplant materials do not become sticky even when mixed with a solution such as physiological saline, so that they do not move even when they are filled in a bone defect. However, there is a problem in that new bones are difficult to generate because they sometimes protrude outside.

[0007]

In order to solve the above-mentioned problems, the biological transplant material of the present invention is obtained by subjecting a gelatin solution containing powder of a calcium phosphate compound to vacuum heat drying or the like,
Cross-linked gelatin forms a complex that carries the particles of the calcium phosphate-based compound, and the surface of the complex is further coated with uncross-linked gelatin. This bioimplant material is kneaded with a liquid such as physiological saline. It is designed to have appropriate tackiness.

[0008]

Embodiments of the present invention will be described below with reference to the drawings. FIG. 1 is an enlarged cross-sectional view of a living body transplant material 1 of the present invention,
2 is a particle made of a calcium phosphate-based compound,
By subjecting the particles 2 to vacuum heat drying or the like, a complex 4 supported by gelatin 3 in a crosslinked state is formed, and a film 5 of uncrosslinked gelatin is further formed on the surface of the complex 4 to aggregate them. The granular material becomes the bioimplant 1.

The average particle size of the above-mentioned bioimplant 1 is 200 to 200 in consideration of the ease of use when filling the bone defect portion.
The particle size is preferably 1000 μm, and the size of the particles 2 is 100 μm or less so that the gelatin 3 in a crosslinked state can be sufficiently carried. Further, when the thickness of the film 5 is large, the bioimplant 1 carries the film. Since the amount of the particles 2 is reduced, the average thickness is preferably about 5 to 20 μm.

In the living transplant material 1 thus constructed, the film 5 is water-soluble, so that it is kneaded with a liquid such as physiological saline to give an appropriate tackiness, while the composite 4 is water-soluble. On the other hand, since it is insoluble, the particles 2 are firmly supported in the complex 4, do not move or fall off even when filled in the bone defect portion, and the bone regenerates and grows in the bone defect portion early. Has a great therapeutic effect. Further, as is apparent from the fact that gelatin is used for drug capsules, gelatin does not cause any harm to the living body, and even if the living body implant 1 is made of gelatin, it does not cause any damage to the living body.

Next, the method for producing this living body transplant material 1 will be described. First, commercially available gelatin or gelatin obtained by heat-treating collagen at a temperature of 80 ° C. or lower for several hours is prepared. Hydroxyapatite synthesized by a wet method or a solid phase method, a compound containing a calcium phosphate-based material such as powder obtained by crushing tricalcium phosphate or calcium phosphate-based crystallized glass, and the like, having a good affinity with a living body. In order to do so, the powder is fired at a temperature of 900 to 1300 ° C., pulverized and classified to have an average particle size of 100 μm or less.

Next, the above powder is mixed with pure water (or distilled water may be used) in a gelatin solution in which 1 wt% or more of gelatin is dissolved, and then air dried. Then, the air-dried mixture of gelatin and the powder is vacuum-heat dried at a temperature of 120 to 180 ° C.

By subjecting the above mixture to vacuum heat drying or the like, gelatin contained in the mixture undergoes a chemical bond to crosslink, and the gelatin 3 in the crosslinked state carries the particles 2 and is insoluble in water. Further, the composite body 4 has infusibility and non-thermoplasticity. Then, the composite 4 thus obtained is classified to obtain an average particle size of 50
Keep the size of ~ 500 μm.

Finally, the above gelatin solution and the average particle size of 5
The composite 4 classified to 0 to 500 μm was mixed, air-dried, and the mixture thus obtained had an average particle size of 200
By classifying to ~ 1000 μm, the coating 5 made of uncrosslinked gelatin and covering the surface of the composite 4 is collected to obtain a granular bioimplant 1 of the present invention.

Crosslinking by using a chemical agent is preferable because of problems such as toxicity of the chemical agent to be used.

Example 1 Hydroxyapatite was synthesized by a wet method using calcium nitrate and diammonium phosphate. This hydroxyapatite was calcined at 900 ° C. and then pulverized to prepare a powder having an average particle size of 3.1 μm.

Next, 0.5 wt% and 1 wt% of pure water as a solvent
%, 5% by weight, 10% by weight, 20% by weight, 30% by weight, 10 g of each of the above powders was mixed in 10 ml of the above solution, air-dried, and then vacuum-heat dried at 160 ° C. for 24 hours to cross-link the gelatin, and then average grain size. Six kinds of composites 4 were obtained in which the gelatin 3 in the crosslinked state was classified to have a diameter of 50 μm and the particles 2 of the calcium phosphate compound were carried.

Next, 10 g of each of the above-mentioned 6 kinds of composites 4 was separately mixed into the 10 wt% gelatin solution, air-dried, and then classified to an average particle size of 250 μm to form uncrosslinked gelatin. Six kinds of samples of the bioimplant 1 of the present invention in the form of granules were obtained by collecting the composites 4 with the coating 5 covering the surface thereof.

These samples were mixed in physiological saline at 37 ° C., and the suspended state of the liquid was observed. This is to confirm whether or not the bioimplant 1 is disintegrated and the particles 2 are not dissolved, in other words, whether or not the particles 2 are firmly supported in the composite body 4. The suspension means that the particles 2 are not sufficiently supported by the gelatin 3 in the crosslinked state and are thus eluted. Furthermore, the stickiness of the liquid was confirmed by touching with a finger.
The results are shown in Table 1.

[0020]

[Table 1]

As is clear from Table 1, the concentration of the gelatin solution in which the powder of the calcium phosphate compound is kneaded is 1% by weight.
The above was found to be good.

Example 2 90% tricalcium phosphate synthesized by the solid phase method using calcium carbonate and calcium pyrophosphate
After firing at 0 ° C., it was pulverized to prepare a powder having a particle diameter of 85 μm.

Next, 10 g of the above powder was mixed with 10 ml of a gelatin solution having a concentration of 10 wt% using pure water as a solvent, air-dried, and then vacuum-heat dried at 140 ° C. for 24 hours to cross-link the gelatin, and then the average particle size was obtained. A composite 4 was obtained in which gelatin 3 in a crosslinked state carried powder of a calcium phosphate compound 2 after being classified to 250 μm.

Next, 0.5 g, 1 wt%, 5 wt%, 10 wt%, 2 wt.
After mixing with 0 wt% gelatin solution of each concentration, air-dry,
Further, the mixture thus obtained has an average particle size of 250 μm.
Five kinds of samples of the bioimplant 1 of the present invention in the form of granules were obtained by assembling the composite 4 with the coating 5 made of uncrosslinked gelatin coating the surface of the composite 4 by classification.

These samples were mixed in 37 ° C. physiological saline, and the suspended state of the liquid and the tackiness of the liquid were confirmed by the method of Example 1. The results are shown in Table 1.

[0026]

[Table 2]

As is clear from Table 2, it was found that the concentration of the gelatin solution containing the composite 4 is preferably 1 wt% or more.

Example 3 Hydroxyapatite was synthesized by a wet method using calcium nitrate and diammonium phosphate. This hydroxyapatite was calcined at 900 ° C. and then pulverized to prepare a powder having an average particle size of 2.6 μm.

Next, 50 g of the hydroxyapatite powder was mixed with 50 ml of a gelatin solution having a concentration of 10 wt% using pure water as a solvent, air-dried, and then divided into 5 equal parts.
100 ℃, 120 ℃, 140 ℃, 160 ℃, 1
Vacuum heat drying at 80 ° C for 24 hours to cross-link the gelatin,
Then, the gelatin 3 in a crosslinked state is classified to have an average particle size of 100 μm and carries the particles 2 of the calcium phosphate-based compound 5
A kind of complex 4 was obtained.

Next, 10 g of each of the above-mentioned 5 kinds of composites 4 was separately mixed into the 10 wt% gelatin solution, air-dried, and the mixture thus obtained had an average particle size of 300.
Five kinds of samples of the bioimplant 1 of the present invention in the form of granules were obtained by classifying the composite 4 with the film 5 made of uncrosslinked gelatin covering the surface of the composite 4 by classifying the composite to 4 μm.

These samples were mixed in physiological saline at 37 ° C., and the suspended state of the liquid and the tackiness of the liquid were confirmed by the method of Example 1. The results are shown in Table 3.

[0032]

[Table 3]

As is apparent from Table 3, it was found that the temperature condition for vacuum heat drying is preferably 120 ° C. or higher.

Example 4 Calcium phosphate-based crystallized glass was pulverized to prepare powders having five kinds of average particle diameters as shown in Table 4.

[0035]

[Table 4]

Next, 5 gelatin solutions each having a concentration of 10 wt% and using pure water as a solvent were prepared in 5 ml, 10 g each of the above 5 kinds of powders were mixed, and after air-drying, they were dried at 140 ° C. for 24 hours.
The gelatin was cross-linked by vacuum heat drying for a period of time and then classified to an average particle size of 100 μm to obtain five kinds of composites 4 in which the cross-linked gelatin 3 carries the particles 2 of the calcium phosphate compound.

Next, 10 g of each of the above-mentioned five kinds of composites 4 was separately mixed into the above 10 wt% gelatin solution, air-dried, and the mixture thus obtained had an average particle size of 300.
Five kinds of samples of the bioimplant 1 of the present invention in the form of granules were obtained by classifying the composite 4 with the film 5 made of uncrosslinked gelatin covering the surface of the composite 4 by classifying the composite to 4 μm.

These samples were mixed in 37 ° C. physiological saline, and the suspended state of the liquid and the tackiness of the liquid were confirmed by the method of Example 1. The results are shown in Table 4.

As is apparent from Table 4, it was found that the average pore diameter of the above powder is preferably 100 μm or less.

Example 5 90% of tricalcium phosphate synthesized by the solid phase method using calcium carbonate and calcium pyrophosphate was used.
After firing at 0 ° C., it was pulverized to prepare a powder having a particle size of 10 μm.

Further, the calcium phosphate-based crystallized glass was pulverized to prepare a powder having an average particle size of 10 μm, which was mixed with a powder of tricalcium phosphate to obtain a mixed powder.

Next, the above mixed powder was mixed in a gelatin solution having a concentration of 10 wt% using pure water as a solvent, air-dried, and then 140
Gelatin is crosslinked by vacuum heat drying at 24 ° C. for 24 hours, and then the gelatin 3 in the crosslinked state is classified into the average particle size as shown in Table 5 to prepare 6 kinds of composites 4 carrying the particles 2 of the calcium phosphate compound. Obtained.

[0043]

[Table 5]

Next, 10 g of each of the above-mentioned 6 kinds of composites 4 was separately mixed into the 10 wt% gelatin solution, air-dried, and further classified by the thus obtained average particle size of 1000 μm. Film 5 made of cross-linked gelatin
Were collected to cover the surface of the composite 4, and six types of samples of the bioimplant 1 of the present invention in the form of granules were obtained.

These samples were mixed in 37 ° C. physiological saline and the tackiness of the solution was confirmed by touching with a finger. The results are shown in Table 5.
Shown in.

As is clear from Table 5, it was found that the average pore size of the composite 4 is preferably 50 to 500 μm.

Example 6 90% tricalcium phosphate synthesized by the solid phase method using calcium carbonate and calcium pyrophosphate
After firing at 0 ° C., it was pulverized to prepare a powder having a particle size of 60 μm.

Next, the above powder was mixed in a gelatin solution having a concentration of 10 wt% using pure water as a solvent, air-dried and then vacuum-heat dried at 140 ° C. for 24 hours to cross-link the gelatin, and then an average particle diameter of 300 μm was obtained. A complex 4 in which the gelatin 3 in the crosslinked state carries the particles 2 of the calcium phosphate-based compound by classification is obtained.

Next, the above composite 4 was divided into 10 g each, mixed in different amounts of 5 kinds of the 10 wt% gelatin solution, air-dried, and the mixture thus obtained had an average particle size of 1000 μm. Five kinds of samples of the bioimplant 1 of the present invention in the form of granules were obtained by assembling the composite 4 with the coating 5 made of uncrosslinked gelatin coating the surface of the composite 4 by classification.

When these samples were observed with an electron microscope, the average film thickness of the film 5 of the living implant 1 of each sample was as shown in Table 6. Furthermore, these samples were mixed in a physiological saline solution at 37 ° C., and the tackiness of the solution was confirmed by touching with a finger. The results are shown in Table 6.

[0051]

[Table 6]

As is clear from Table 6, it was found that the average film thickness of the film 5 is preferably 5 to 20 μm.

Animal Experiment Hydroxyapatite was synthesized by a wet method using calcium nitrate and diammonium phosphate. This hydroxyapatite was calcined at 900 ° C. and then pulverized to prepare hydroxyapatite powder having an average particle diameter of 3.1 μm.

Next, 10 g of the above powder was mixed in 10 ml of a gelatin solution having a concentration of 10 wt% using pure water as a solvent, air-dried and then vacuum heat-dried at 160 ° C. for 24 hours to cross-link the gelatin, followed by averaging the average particles. A composite 4 was obtained in which the gelatin 3 in a crosslinked state was classified to have a diameter of 300 μm and the particles 2 of the calcium phosphate compound were carried.

Next, 10 g of the above composite 4 was added to a concentration of 10 wt.
% Of the above gelatin solution, air-dry, and further classify the mixture thus obtained to an average particle size of 500 μm to coat the surface of the complex 4 with a film 5 of uncrosslinked gelatin. A biological transplant material 1 was obtained.

This bioimplant material 1 and hydroxyapatite granules having an average particle diameter of 450 μm used in general clinical practice as a comparative example were implanted in the femur of a rabbit for 1 week or 4 weeks.
After 8 weeks, the animals were sacrificed, the surrounding tissues were detected, and then fixed with formalin solution. This was decalcified and then resin-embedded / stained to prepare a pathological specimen.

One week after the implantation, generation of new bone and osteoblasts was observed around the bioimplant 1 of the present invention. On the other hand, some osteoblasts were found around the hydroxyapatite granules.

Four weeks after the implantation, active new bone formation was observed around the above-mentioned bioimplant 1. On the other hand, some new bone formation was observed around the hydroxyapatite granules.

Eight weeks after the implantation, the periphery of the above-mentioned living body transplant material 1 was mostly surrounded by new bone. On the other hand, the hydroxyapatite granules were also surrounded by new bone, but some fibrous tissue formation was observed.

[0060]

In the living transplant material of the present invention, since the film made of uncrosslinked gelatin is water-soluble, it is kneaded with a liquid such as physiological saline to give an appropriate tackiness, while gelatin is crosslinked. Since the complex carrying the particles of the calcium phosphate-based compound is insoluble in water, it does not move or fall off even when the particles are firmly carried in the complex and filled in the bone defect, and the Bone regenerates and grows in the bone defect, which has a great therapeutic effect.

[Brief description of drawings]

FIG. 1 is an enlarged cross-sectional view showing a living transplant material of the present invention.

[Explanation of symbols]

 1 Bioimplant 2 Particles 3 Crosslinked gelatin 4 Complex 5 Film

Claims (1)

[Claims] 1. A biological transplant material comprising an uncrosslinked gelatin film formed on the surface of a complex in which crosslinked gelatin carries particles of a calcium phosphate compound.