JP2014111554A - Bone regeneration material for oral surgery - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a bone regeneration material for dentistry or oral surgery, capable of facilitating bone regeneration by being filled in a defective part or a damaged part of a bone in a dentistry or oral surgery region.SOLUTION: A bone regeneration material for dentistry or oral surgery, capable of facilitating bone regeneration by being filled in a defective part or a damaged part of a bone in a dentistry or oral surgery region is a pasty bone regeneration material for dentistry or oral surgery obtained by mixing a mixed fine particle containing a crosslinked gelatin fine particle and a fine particle consisting of a calcium phosphate-based compound at a weight ratio of 5:95 to 15:85 with an aqueous medium.

Description

The present invention relates to a bone regeneration material for dental or oral surgery that can promote bone regeneration by filling a bone defect or damage in a dental or oral surgery field.

In the field of dentistry or oral surgery, a method of reconstructing a bone defect or damage has been performed. For example, after losing teeth due to caries (cavities), periodontal disease, etc., so-called dental implant treatment is performed, in which a titanium or titanium alloy support is embedded in the jaw bone and the teeth are used as a foundation to restore the teeth. For this purpose, a certain amount of jawbone is required. Therefore, when there is a defect or damage in the jawbone, it is a precondition for performing dental implant treatment that the defect or damage is treated and reconstructed so that a certain amount of bone can be secured.

In order to treat such bone defects or injuries, paste-like bone filling materials in which calcium phosphate granules are suspended in an aqueous medium have been proposed (for example, Patent Documents 1 to 3). These bone filling materials can be filled into a bone defect or damage using an injector or the like, and are hardened after filling and fixed to the bone defect or damage. If a bone filling material is used, even a complicated defect or damaged part can be easily treated.

However, even if the paste-like bone filling materials described in Patent Documents 1 to 3 are used, bone regeneration is not promoted merely by compensating for a bone defect or damage. Indeed, bone regeneration is limited to the surface of the filled bone prosthetic material. In addition, although this bone prosthetic material has extremely high mechanical strength, it does not contain organic components such as collagen fibers of bone tissue, and therefore has a decisive disadvantage of being inferior in elastic modulus and toughness. In particular, in the field of dentistry or oral surgery, there have been problems such as destruction and exposure of the bone filling material due to the load of occlusal force, infection and dropping off due to oral resident bacteria. Therefore, in the field of dentistry or oral surgery, it is possible to secure bone mechanical strength by compensating for bone defects or damaged parts in the short term, and in the long term to promote regeneration of the patient's own bone. There was a need for surgical bone regeneration materials.

JP 2000-262609 A JP 2000-245823 A JP 2002-35106 A

An object of the present invention is to provide a bone regeneration material for dental or oral surgery that can promote bone regeneration by filling a bone defect or damage in a dental or oral surgery region.

The present invention relates to a bone regeneration material for dental or oral surgery that can promote bone regeneration by filling a bone defect or damage in a dental or oral surgery region, and comprises a crosslinked gelatin microparticle and a calcium phosphate compound. It is a bone regeneration material for dental or oral surgery that is a paste obtained by mixing mixed fine particles containing the fine particles with a weight ratio of 5:95 to 15:85 into an aqueous medium.
The present invention is described in detail below.

The bone regenerating material for dental or oral surgery of the present invention (hereinafter also simply referred to as “bone regenerating material”) is a paste prepared by mixing mixed fine particles containing fine particles of crosslinked gelatin and fine particles of a calcium phosphate compound in an aqueous medium. It is a shape.
As a result of intensive studies, the present inventors have found that such paste-like bone regeneration material can be easily filled into a bone defect or damaged part manually or by an injector, and can be cured in the body. It has been found that the cured product can secure the mechanical strength of the bone in the short term and can promote the regeneration of the patient's own bone in the long term, thereby completing the present invention.

Even a pasty bone prosthetic material composed of fine particles made of a conventional calcium phosphate compound and an aqueous medium can ensure the mechanical strength of the bone by filling and hardening. However, the calcium phosphate compound that constitutes the hardened bone filling material is hardly absorbed into the living body (even if it is absorbed into the living body, it is absorbed only at a very slow rate), so that osteoblasts enter. I can't. In order to regenerate the patient's own bone, osteoblasts and the like need to invade the artificial bone and proliferate.
On the other hand, in the present invention, by blending the crosslinked gelatin fine particles, the crosslinked gelatin fine particles are bioabsorbed to form continuous pores in the filling portion. Therefore, osteoblasts can enter and proliferate into the continuous pores. That is, the bone regeneration material of the present invention can serve as a scaffold material for the proliferation of osteoblasts as well as to supplement bone defects.

In the bone regeneration material of the present invention, the particles composed of the calcium phosphate compound become a paste when mixed with an aqueous medium and harden in the body to supplement the mechanical strength of the bone.
The calcium phosphate compound is not particularly limited, and examples thereof include tricalcium phosphate, tetracalcium phosphate, calcium hydrogen phosphate, hydroxyapatite, carbon-containing apatite, fluorapatite, amorphous calcium phosphate, and octacalcium phosphate. These calcium phosphate compounds may be used alone or in combination of two or more.

The preferable lower limit of the average particle diameter of the fine particles comprising the calcium phosphate compound is 5 μm, and the preferable upper limit is 100 μm. If the average particle size of the fine particles comprising the calcium phosphate compound is less than 5 μm, the mixture may be mixed with the aqueous medium to form a paste, which may increase the viscosity and make injection difficult. If it exceeds 100 μm, the strength of the cured product may be low and the mechanical strength of the bone may not be sufficiently compensated. A more preferable upper limit of the average particle size of the fine particles comprising the calcium phosphate compound is 50 μm.

The crosslinked gelatin fine particles are gradually absorbed in vivo after the treatment, and have a role of generating continuous pores into which osteoblasts can enter the filling portion. Further, since the crosslinked gelatin fine particles swell in the living body, the effect of improving the adhesion to the filled portion can be obtained. It is also expected that the cross-linked gelatin microparticles swell with moisture, so that the volume is increased after transplantation into the bone hole and the bone gelatin hole is in close contact with the bone hole. Further, by containing the crosslinked gelatin fine particles, a hemostatic effect can be expected, and it can also be used in a site with bleeding. In the conventional bone grafting material containing only the inorganic material, bleeding does not stop, and a large amount of blood is absorbed to reduce the strength, or it collapses and flows into the defect. In addition, the inclusion of the crosslinked gelatin fine particles also exhibits an effect that variation in time from preparation to curing is reduced. Further, by using the crosslinked gelatin fine particles, bone regeneration inside the hardened bone regeneration material is promoted particularly in bone regeneration in the dental or oral surgery region, and the waiting period until denture wearing or implant surgery is shortened. The effect that can be demonstrated.

The crosslinked gelatin fine particles can be obtained by subjecting uncrosslinked gelatin fine particles to crosslinking by a conventionally known crosslinking method such as thermal dehydration crosslinking, ultraviolet crosslinking, chemical crosslinking or ionic crosslinking. Water absorption and bioabsorbability can be controlled by the crosslinking method and degree. Preferably, when the cross-linked gelatin fine particles are mixed with the calcium phosphate compound and an aqueous medium to form a paste, the average particle size of the cross-linked gelatin fine particles absorbed and swollen in the paste is about 30 to 500 μm. It is preferable to perform crosslinking as described above. Specifically, for example, it can be considered that uncrosslinked gelatin fine particles are heat-treated at 110 to 170 ° C. for 5 minutes to 48 hours under vacuum.

The preferable lower limit of the average particle diameter of the crosslinked gelatin fine particles is 10 μm, and the preferable upper limit is 400 μm. If the average particle size of the crosslinked gelatin fine particles is less than 10 μm, continuous pores into which osteoblasts can invade may not be formed. If the average particle size exceeds 400 μm, the strength of the cured product is low and sufficiently compensates for the mechanical strength of bone. There may not be. The more preferable lower limit of the average particle diameter of the crosslinked gelatin fine particles is 20 μm, and the more preferable upper limit is 200 μm.

By adjusting the blending ratio of the fine particles of the calcium phosphate compound and the crosslinked gelatin fine particles, the porosity of the cured product can be adjusted, thereby controlling the strength of the cured product and the bone regeneration rate. it can. In the bone regeneration material of the present invention, the weight ratio of the crosslinked gelatin fine particles to the calcium phosphate compound in the mixed fine particles (hereinafter also simply referred to as “mixed fine particles”) composed of the crosslinked gelatin fine particles and the fine particles comprising the calcium phosphate compound is 5. : 95 to 15: 85. Within this range, it is possible to achieve both short-term bone mechanical strength and long-term bone regeneration. In particular, in bone regeneration in the dental or oral surgery field, a hardened bone regeneration material. Can withstand the occlusal pressure until it is completely replaced by regenerated bone. More preferably, it is in the range of 10:90 to 15:85 by weight ratio.

The aqueous medium is a medium for the bone regeneration material of the present invention.
Examples of the aqueous medium include water for injection. The aqueous medium may contain a buffer component for the purpose of adjusting pH. In addition, bone marrow fluid or cell suspension can also be used as the aqueous medium.
Further, the aqueous medium contains a small amount of a water-soluble polymer for the purpose of adjusting viscosity, contains an antibacterial agent for the purpose of preventing infection, and various growth factors for the purpose of promoting bone regeneration. You may contain.
Examples of the water-soluble polymer include polymers such as lactic acid, glycolic acid, succinic acid, maleic acid, fumaric acid and malic acid, chondroitin sulfate, hyaluronic acid, dextran sulfate, heparan sulfate, collagen, gelatin and the like.

The bone regeneration material of the present invention may further have various cell growth factors, antibacterial agents, antibiotics and other drugs. If bone regeneration material having these is used, bone defect or damage will be filled and cured, and then the cured product will be decomposed and the drug will be released gradually. can do. For example, early bone regeneration is expected by sustained release of cell growth factors. In addition, sustained release of antibacterial agents, antibiotics and the like is particularly effective for use in the oral cavity where many bacteria are present in the vicinity of the bone defect. Furthermore, when cell growth factors and bone marrow cells containing bone marrow mesenchymal cells are used in combination, there are few cells necessary for bone formation around the bone repair area, and it is effective for bone formation up to the center of the bone repair area. Even when cell invasion cannot be expected, a high healing effect can be expected. Note that the drug is not limited to a drug related to bone regeneration.

The bone regeneration material of the present invention can be produced by mixing the mixed fine particles with the aqueous medium to form a paste.
In preparing the bone regeneration material of the present invention, the ratio of mixing the mixed fine particles and the aqueous medium is not particularly limited. Ease of kneading operation, ease of injection using an injector, time to cure However, the lower limit of the blending amount of the aqueous medium with respect to 100 parts by weight of the mixed fine particles is preferably 5 parts by weight, and the preferable upper limit is 65 parts by weight. If the content of the aqueous medium is less than 5 parts by weight, the viscosity of the bone regeneration material may be high and injection may be difficult, and if it exceeds 65 parts by weight, it may shrink when cured. . The minimum with more preferable content of the said aqueous medium is 15 weight part, and a more preferable upper limit is 45 weight part.

The method of mixing the mixed fine particles and the aqueous medium is not particularly limited, but the mixed fine particles and the aqueous medium are put in a syringe and kneaded and mixed, or the mixed fine particles and the aqueous medium are kneaded and mixed in a plate shape. The method is preferred.
In preparing the bone regeneration material of the present invention, the procedure for blending the mixed fine particles and the aqueous medium is not particularly limited, and the total amount of the fine particles comprising the calcium phosphate compound, the crosslinked gelatin fine particles, and the aqueous medium are mixed simultaneously. It doesn't matter. However, after mixing the fine particles comprising the calcium phosphate compound and the crosslinked gelatin fine particles, a method of adding the aqueous medium to the mixed fine particles, or adding a partial amount of the aqueous medium to the fine particles comprising the calcium phosphate compound. After kneading and mixing, it is preferable to add and mix the cross-linked gelatin fine particles and the remaining amount of the aqueous medium. By preparing a bone regeneration material by such a method, it can adjust more uniformly and can obtain hardened | cured material with high intensity | strength.

The fine particles composed of the calcium phosphate compound become sol when mixed with an aqueous medium, gelate with time even at room temperature, and finally harden. Further, when the crosslinked gelatin fine particles are mixed with an aqueous medium, they dissolve or swell over time even at room temperature. Therefore, it is preferable to prepare the bone regeneration material as soon as possible at the operation site immediately before the operation.

The bone regeneration material of the present invention can be easily filled into a bone defect or damage using a manual or injector such as a syringe. The filled bone regeneration material hardens even at room temperature and complements the mechanical strength of the bone. Furthermore, continuous pores are formed by absorbing the crosslinked gelatin fine particles as time passes, and osteoblasts enter the continuous pores to regenerate the patient's own bone. The bone regenerating material of the present invention is excellent in forming until it hardens in vivo, can easily cope with complicated bone shapes, and from the penetration of osteoblasts into continuous pores and the absorption of bone regenerating material Since bone regeneration is promoted, it is possible to exert a high effect on bone regeneration of a bone defect or damaged part, particularly in the dental or oral surgery region.

ADVANTAGE OF THE INVENTION According to this invention, the bone regeneration material for dentistry or oral surgery which can accelerate | stimulate the bone reproduction | regeneration by filling the defect | deletion part or damaged part of a bone in a dentistry or oral surgery area | region can be provided.

It is a schematic diagram which shows the position of the saddle type | mold bone defect produced in the beagle adult dog jaw ridge in evaluation of an Example. It is a soft X-ray image of a beagle adult dog (No. 1, 2) mandible 6 months after operation in evaluation of an Example. It is a soft X-ray image of a beagle adult dog (No. 3, 4) mandible 6 months after operation in evaluation of an Example. It is an undecalcified ground specimen tissue image of A part of mandible beagle mandible 6 months after operation in evaluation of an example. It is an undecalcified ground specimen tissue image of B part of a beagle adult mandible 6 months after operation in evaluation of an example. It is an undemineralized grinding | polishing tissue image of the C site | part of the beagle adult mandible 6 months after operation in evaluation of an Example. It is a comparison of the ridge volume of each site | part of the beagle adult mandible 6 months after operation in evaluation of an Example. It is the comparison of the bone density of each site | part of the beagle adult mandible 6 months after operation in evaluation of an Example.

Hereinafter, embodiments of the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

Example 1
Uncrosslinked gelatin fine particles having an average particle size of 200 μm were heat-treated at 140 ° C. for 14 hours under vacuum to obtain thermally crosslinked gelatin particles.
Fine particles comprising the obtained heat-crosslinked gelatin fine particles and a calcium phosphate compound having an average particle size of 8 μm (α-TCP content is 75% by weight, tetracalcium phosphate content is 18% by weight, calcium hydrogen phosphate dihydrate 5% by weight and 2% by weight of hydroxyapatite) were mixed at a weight ratio of 5:95, 10:90 and 15:85 to obtain mixed fine particles. Next, 45 parts by weight of an aqueous medium (an aqueous solution containing 5.4% sodium chondroitin sulfate, 13% disodium succinate anhydrous, 0.3% sodium hydrogen sulfite) was added to 100 parts by weight of the obtained mixed fine particles. For 1 minute to obtain a pasty bone regeneration material.

(Comparative Example 1)
Fine particles made of a calcium phosphate compound having an average particle size of 8 μm (α-TCP content is 75% by weight, tetracalcium phosphate content is 18% by weight, calcium hydrogen phosphate dihydrate content is 5% by weight, hydroxy 30 parts by weight of an aqueous medium (aqueous solution containing 5.4% sodium chondroitin sulfate, 13% disodium succinate anhydrous, 0.3% sodium hydrogen sulfite) with respect to 100 parts by weight of apatite content 2% by weight) In addition, the mixture was mixed for 1 minute to obtain a paste-like bone regeneration material.

(Evaluation)
Using an adult canine mandible defect model, the effectiveness of applying the bone regeneration material of the present invention was examined by the following method.
Extract the premolars (P3, 4) and posterior molars (M1) of both lower jaws of 4 adult beagle dogs (No. 1 to 4) in advance, and after healing, place them on the left and right sides of the alveolar ridge (alveolar crest). A total of four saddle-type bone defects of height (5 mm) × near centrifugal width (10 mm) were produced (FIG. 1). Group A at each site; bone regeneration material containing no heat-crosslinked gelatin fine particles produced in Comparative Example 1, Group B; weight ratio of heat-crosslinked gelatin fine particles produced in Examples and fine particles comprising calcium phosphate compound is 10: The bone regeneration material which is 90, the bone regeneration material which is C group; 15:85 was filled. After each bone regeneration material hardened, the wound was closed with sutures. The remaining one site was closed with sutures without injecting bone regeneration material (control group).
Six months after the operation, the adult beagle was euthanized, the mandible was removed, and a soft X-ray was taken. A soft X-ray image is shown in FIGS.
In addition, histological observation was performed with an undecalcified polished specimen. The undecalcified polished specimen tissue images of each part are shown in FIGS.
Furthermore, the ridge volume (including material and new bone) and bone density at each site were analyzed based on micro CT imaging. FIG. 7 shows a comparison of the ridge volume at each site, and FIG. 8 shows a comparison of the bone density at each site.

From the above evaluation, it was shown that when the bone regeneration materials of Examples and Comparative Examples were filled, the bone volume was increased as compared with the control group in which nothing was injected into the defect and closed. Bone regeneration material group A (comparative example) that does not contain heat-crosslinked gelatin fine particles has the largest defect ridge volume at 6 months after surgery, and group B (weight ratio of gelatin fine particles to calcium phosphate compound 10:90) The average value of the defect ridge volume showed a tendency to decrease as the content of gelatin particles increased with the group C (weight ratio of gelatin fine particles to calcium phosphate compound 15:85). On the other hand, the bone density was the same as that of the adjacent bone in all. However, according to the histological observation, when the bone regeneration material of the comparative example was used, bone replacement occurred only from the marginal part of the graft, and a lot of massive material remained in the central part. Thus, it was found that the bone replacement progressed as a whole when the bone regeneration material of the example was used. In particular, most of the material was absorbed and replaced with bone at the C site filled with the bone regeneration material having a weight ratio of 15:85 between the heat-crosslinked gelatin fine particles and the fine particles comprising the calcium phosphate compound.

ADVANTAGE OF THE INVENTION According to this invention, the bone regeneration material of paste injection type dental or oral surgery which can accelerate | stimulate bone regeneration by adjusting the weight ratio of the heat-crosslinked gelatin fine particles and the fine particles comprising a calcium phosphate compound is provided. be able to.

Claims (2)

A bone regeneration material for dental or oral surgery that can promote bone regeneration by filling a bone defect or injury in a dental or oral surgery field,
Dental or oral surgery characterized in that mixed fine particles containing crosslinked gelatin fine particles and calcium phosphate-based compound fine particles in a weight ratio of 5:95 to 15:85 are mixed into an aqueous medium to form a paste. Bone regeneration material. The bone regeneration material for dental or oral surgery according to claim 1, wherein 5 to 65 parts by weight of an aqueous medium is mixed with 100 parts by weight of the mixed fine particles.