Patent Application
20180021479
The present invention relates to a material for filling a bone defect which is formed of biodegradable fibers in a cotton-like structure, and to a method of producing the material.
Recently, materials for filling a bone defect of a type which can rebuild the bone of a defect portion by utilizing a self-regenerating ability of bone has been developed. The bone filling material of this type for filling a bone defect promotes osteogenesis by osteocyte by supplying bone formation factor by implanting porous fibrous material containing ceramic which works as a bone formation factor.
The above-mentioned type of the material for filling a bone defect is produced by producing fibers by electrospinning or other method from a spinning solution which is produced by mixing a solution of a biodegradable polymer, such as poly L lactic acid (PLLA) or polylactic acid-polyglycclic acid copolymer (PLGA). After the material is implanted in a body, the matrix polymer of the biodegradable fiber works as a scaffold to maintain the three dimensional skeleton of the material in a defect portion. And, as the polymer is gradually absorbed and decomposed by contacting with biological fluids, bone forming factors, such as calcium phosphate, are exposed or released, and perform the biological activities of bone formation. Then, after the bone formation has been completed, the biodegradable polymer disappears by being decomposed and absorbed completely in the living body.
As a ceramic to be used as bone forming factors, bioabsorbable calcium phosphate, such as β-tricalcium phosphate (β-TCP), is used as a material having both biocompatibility and osteoconductivity. The mechanism of the biological activities of bioabsorbable calcium phosphate is not necessarily clear. However, it is thought that in a bone defect portion, bone forming cells attach well to the surface of calcium phosphate and proliferates and differentiates thereon, thereby becoming a scaffold (scaffold or substrate) for bone formation. It is known that calcium carbonate also shows the a function of attaching bone cell and proliferation.
While it is known that a bone is formed by a remodeling that is caused by coupling of osteoclasts and osteoblasts, it is experimentally confirmed and reported that if a small amount of silicon is supplied together with calcium during the above process, proliferation of osteoblasts is stimulated, and proliferation and differentiation are promoted. Based on above knowledge and understanding, a material for filling a bone defect in which a biodegradable polymer containing silicon-releasing vaterite phase calcium carbonate (SiV) particles has been proposed as a new type material for filling a bone defect (Patent literature 1). After the material is filled in a bone defect and is in contact with body fluids, a small amount of silicon is released gradually and stimulates osteoblasts as the calcium carbonate is being dissolved, thereby promoting proliferation and differentiation. Further, calcium ions released by decomposition of calcium carbonate are supplied to the vicinity of cells, whereby the activity of the cells is activated and high bioactivity is realized.
Patent literature 1: Japanese Patent No. 5179124
Non patent literature 1: Walsh et al. β-TCP bone graft substitutes in a bilateral rabbit tibial defect model. Biomaterials 29 (2008) 266-271)
Non Patent Literature 2: Obata et al. Electrospun microfiber meshes of silicon-doped vaterite/poly(lactic acid) hybrid for guided bone regeneration. Acta Biometatialla 6 (2010) 1248-1257.
Non patent Literature 3: Fujiwara et al. Guided bone regeneration membrane made of polycaprolactone/calcium carbonate composite nano-fibers. Biomaterials 26 (2005) 4139-4117).
Non patent literature 4: Hench L L. Polak J M: Third-generation biomedical materials. Science 2002, 295: 1014 -1017)
Rebuilding a lost bone by utilizing the self-regenerating ability of the bone is an excellent method by which permanent bone repair can be achieved. However, the self-regeneration of a bone needs a long period of time of at least three to six months after a material has been implanted. Therefore, the material for filling a bone defect used for such a method needs to initiate a bone regenerating activity as soon as possible after it was implanted, and also continue the activity of promoting bone formation by remaining in the defect portion until sufficient bone formation is achieved. However, until now, there has not been obtained any material for filling a bone defect that satisfies these contradicting requirements.
The material for filing a bone defect of the present invention is a material for filling a bone defect that includes biodegradable fibers produced by electrospinning in a cotton-like structure, and the biodegradable fibers contain calcium phosphate particles in an amount of 40% to 60% by weight, preferably 40% by weight, calcium carbonate particles in an amount of 10% by weight or more, preferably 30% by weight, and preferably a poly-L-lactic acid polymer in an amount of 30% by weight or more, preferably 30% by weight or all the remainder. Further, amount of an amorphous phase of the poly-L-lactic acid polymer is 75% to 98%, preferably 85% to 95%, more preferably 88% to 92%.
Because Polymer content of the biodegradable fibers used for the material for filling a bone defect of the present invention is limited as small as possible as far as fibers can be spun by electrospinning, exposure of calcium phosphate particles and calcium carbonate particles on the surface of a fiber is large, and the area which directly contacts with body fluids is large. As a result, high biological activity is achieved from the particles of calcium phosphate and the calcium carbonate.
The calcium carbonate contained in the material for filling a bone defect of the present invention is preferably a silicon-releasing calcium carbonate of a vaterite phase. Because such silicon-releasing calcium carbonate has a fast dissolution rate, calcium ions are released early after being implanted and create a calcium rich environment. On the other hand, silicon species doped in the calcium carbonate are released gradually and stimulate proliferation of osteoblasts and promotes bone formation.
The material for filling a bone defect of the present invention induces generation of bone-like apatite on a surface of a fiber by releasing a rich amount of calcium ions from the calcium carbonate. Polylactic acid which is a matrix polymer of the fiber has many carboxyl groups, and the polylactic acid is hydrolyzed by contacting with biological fluids, thereby forming a carboxyl group which induces nucleation of bone-like apatite.
As the calcium carbonate of the material for filling a bone defect of the present invention, calcium carbonate of vaterite phase is preferably used. Generally, based on the difference of crystal structure, calcium carbonate is classified into three types: a calcite phase, an aragonite phase, and a vaterite phase. Calcium carbonate of a vaterite phase has the highest solubility in the biological fluid of a human body. Therefore, PLA containing vaterite phase calcium carbonate has a high bone-like apatite forming ability.
Bioabsorbable calcium phosphate used for the material for filling a bone defect of the present invention is bioabsorbed slowly over time after being implanted in a defect and bone replaced. Because the material for filling a bone defect of the present invention contains 40% or more of bioabsorbable calcium phosphate, bone formation by absorption and replacement is performed effectively.
Biodegradable polymer used for the material for filling a bone defect of the present invention remains in a defect portion while maintaining a skeleton structure until calcium phosphate is absorbed and bone replaced, and works as a scaffold where bone cells perform their activity during formation of the bone. Because PLLA is not easily hydrolyzed, the concern that PLLA will disappear immediately after implantation by being decomposed and absorbed upon contacting with body fluid is small.
Outer diameter of the biodegradable fibers of the material for filling a bone defect of the present invention is preferably from 10 to 50 μm, more preferably from 30 to 50 μm.
A method of producing a material for filling a bone defect of the present invention includes the steps of: providing a mixture of calcium phosphate particles and SiV particles in a melted polymer solution in a kneader such that weight ratio of the three components are 40% to 60% by weight of calcium phosphate, 10% by weight or more of silicon-releasing calcium carbonate, and remainder is 30% by weight or more of poly L lactic acid; kneading the components in that state; cooling and solidifying the kneaded mixture to produce a composite body in which the molecular weight of the polymer is 200,000 to 250,000 and the amount of amorphous phase of the polymer is 755 or more, preferably 85% or more; producing a spinning solution by dissolving the composite by using a solvent; producing biodegradable fibers by spinning the spinning solution by using an electrospinning method; and producing the material for filling a bone defect in a cotton-like structure by receiving the biodegradable fibers in a collector filled with ethanol and accumulating the biodegradable fibers thereon.
The method of producing the material for filling a bone defect of the present invention includes the steps of kneading a solution containing silicon-releasing calcium carbonate particles, calcium phosphate particles, and melted poly lactic acid in a predetermined amounts respectively for a predetermined time at a predetermined temperature in a kneader by using the kneader; and during this process amino group portion of siloxane contained in the silicon-releasing calcium carbonate particles and a carboxy group at an end of the polylactic acid) structure is bonded (amino bonding). By using this process, the orderly structure of polylactic acid contained in the spinning solution is disturbed and the ratio of an amorphous phase of the polylactic acid becomes high, and solubility increases. As a result, the material for filling a bone defect produced by electrospinning method by using the spinning solution thus produced has a higher absorptivity in a living body. The amount of amorphous phase in the poly L lactic acid of the material for filling bone defect of the present invention is preferably from 75% to 98%, more preferably from 85% to 95%, further more preferably from 88% to 98%.
In the material for filling a bone defect of the present invention, approximately spherical TCP particles (preferable average particle diameter is about from 3 to 4 μm) and approximately spherical SiV particles (preferable average particle diameter is about 1 μm) are dispersed almost homogeneously in a matrix polymer in the composite fiber having a diameter of about 10 to 50 μm produced by electrospinning. Preferably, both the TCP particles and the SiV particles are dispersed almost homogeneously in the matrix polymer without being unevenly distributed in a specific portion. As a result, minute TCP particles and SiV particles are homogeneously dispersed widely near the surface of a fiber and over the vicinity of the center of the fiber. Because of that, after the material has been filled in a bone defect, as the biological absorption of the polymer proceeds, bone resorption of the TCP particles and silicon releasing from the SiV occurs uniformly in the bone defect portion for a comparatively long period of time.
Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings.
As a biodegradable polymer of a material for filling a bone defect of the present invention, poly L lactic acid (hereafter referred to as poly L lactic acid or PLLA) may be preferably used. Although PLLA is bioabsorbable, PLLA is more difficult to be hydrolyzed as compared to PLGA. Therefore, the biodegradable fiber formed of ELLA as a matrix polymer does not decompose easily when it is contacted with body fluids at a defect portion, and the biodegradable fiber remains for a long period of time without disappearing so that the skeleton of the material can be maintained.
On the other hand, in order for the bone growing factors contained in the matrix polymer, such as calcium phosphate and calcium carbonate to perform biological activities, these fine particles need to contact with body fluids. If the matrix polymer does not dissolve in human body fluids easily, bone forming factors may be prevented by the matrix polymer from performing sufficient osteogenic effect.
Because PLGA is easily decomposed and absorbed upon contacting with fluids, PLGA less prevents the bone forming factors contained therein from directly contacting with the biological fluids. However, because the decomposition/absorption rate of ALGA is fast, the skeleton of the material cannot be maintained for a long period of time to make a scaffold for bone formation. Because the rate of decomposition of PLLA when it contacted with biological fluids is considerably slow, PLLA remains in a body for a long period of time after being implanted in the body. Therefore, the problem that PLLA disappears before sufficient bone formation is completed is few. Conversely, because ELLA is not easily decomposed nor absorbed, there is a possibility that ELLA prevents bone forming factors contained therein from being exposed to the biological fluids or eluted outside. Further, even after the bone formation is completed, it is not desirable for the health of human body that ELLA remains in the body for a long period of time without disappearing.
If a melted PLA is mixed with silicon-releasing calcium carbonate (SiV) by kneading using the kneader, molecular weight of the PLA decreases. During that process of heat kneading, partial reaction occurs such that a bonding (an amide bond) takes place between an amino group portion of siloxane and a carboxy group at an end of a polylactic acid structure (Wakita et al, Dental Materials Journal 2011; 30(2): 232-238). Because of this, orderly structure of polylactic acid is disturbed and the ratio of amorphous phase of the polylactic acid becomes higher, which causes increase of solubility and fast absorption in a living body. However, in order to form a bone, it is desirable that a material itself is not absorbed and does not disappear for at least three to six months so that activity place for cells is secured. Because β-TCP does not have a silicic acid portion that is coupled to an amino group like that of SiV, heat kneading does not easily cause a change to PLA and, thus absorptivity of PLA is not likely to become high rapidly.
Inventors of the present invention found that, by mixing a substantial amount of calcium phosphate having no silicic acid portion coupled to amino group with a composite of SiV and PLLA, bio-absorptivity of the composite material becomes slower than that of the composite of SiV and PLLA. Therefore, it is possible to control the absorptivity of the composite material such that the composite material does not disappear before a bone is formed therein.
It is thought that other than a blending ratio of calcium carbonate and calcium phosphate at the time of kneading, ratio of amorphous phase of poly L lactic acid in the material for filling a bone defect of the present invention is greatly influenced by an amount of poly L lactic acid contained in a fiber. In the embodiment shown in
Calcium phosphate used for the material for filling a bone defect of the present invention may include bioabsorbable calcium phosphate, such as calcium hydrogen-phosphate, octacalcium phosphate, tetracalcium phosphate, tricalcium phosphate, and carbonic acid containing apatite. β-tricalcium phosphate is especially suitable as a material to make a scaffold for proliferation and differentiation of cells of an osteoblast system. Its appearance is powder-like. Diameter of particle constituting the powder is preferably 1 to 6 μm. In consideration of the fact that the outer diameter of a fiber constituting a filling material of the present invention is 10 to 50 μm, a particle diameter of 6 μm or less is preferable. In order to homogeneously disperse the calcium phosphate particles with silicon-releasing calcium carbonate particles which is mixed together at the time of kneading, outer diameter of the calcium phosphate particles should preferably be to about 1 to 2 μm which is equal to the diameter of the silicon-releasing calcium carbonate particles.
SiV used for the material for filling a bone defect of the present invention is a composite of siloxane and calcium carbonate, its appearance is powder-like, and the diameter of particles constituting the powder is suitably about 1 μm.
If SiV is implanted in a defect part and contacted with body fluids, vaterite phase calcium carbonate is hydrolyzed, and calcium ions are released in a short period of time. Silicon is gradually released. In Japanese Patent Application No. 2011-021790 filed before the present application, the inventors of the present invention disclosed releasing characteristics of calcium ions and silicon species in silicon-releasing calcium carbonate. PLLA in an amount of 42 g and 18 g of 2 SiV (vaterite phase calcium carbonate which contains 2% by weight of Si) were heated at 200° C. for 45 minutes by using a heating kneader to obtain a composite containing 30% by weight of 2 SiV. A spinning solution was prepared by mixing 9.3 g of CHCl3 with 1 g of the composite. By using this spinning solution, a cotton-like material was produced by an electrospinning method. The obtained cotton-like material was immersed in a tris buffer solution and was made to stand still in an incubator held at 37° C., and then, after having been immersed for a predetermined period, the solution was subjected to solid-liquid separation. Subsequently, the concentration of Si and Ca in the liquid was measured with an induction plasma-coupled spectrographic analysis (ICP).
Mixture of calcium phosphate particles and calcium carbonate particles is added to a biodegradable polymer melt that was produced by heating the polymer at a high temperature in a kneader, and then mixed and kneaded therein, and thereafter cooled under a room temperature to be solidified. Then, a composite body of silicon-releasing calcium carbonate, calcium phosphate, and biodegradable polymer is produced. Preferably, a weight ratio of the three components is made such that the ELLA is 30% by weight or more, the calcium phosphate is 40% to 60% by weight, and the silicon-releasing calcium carbonate is 10% by weight or more. More preferably, the PLLA is 30% by weight, the calcium phosphate is 40% by weight, and the silicon-releasing calcium carbonate is 30% by weight.
Next, a spinning solution is produced by dissolving the composite by chloroform. The spinning solution is spun by using an electrospinning method under a certain method/condition to produce a cotton-like material formed of biodegradable fibers. A collector container is filled with an ethanol liquid so that the electrospun fibers are received by the liquid and the electrospun fibers are accumulated in the collector container. The ethanol liquid filled in the collector container removes the chloroform remaining on a surface of fibers. As a result, it becomes possible to prevent fibers deposited on the collector plate from adhering each other, thereby forming a cotton-like material which has soft light feeling with low bulk density.
In order to promote the bone formation, it is desirable that content of inorganic particle (SiV, β-TCP) contained in the composite is high, because biological activities is increased. However, if the inorganic particles are increased beyond a certain limit, it becomes difficult to knead the particles with polymer. In an experiment conducted by the inventors of the present invention, kneading could not be conducted with 80% by weight of the entire inorganic particles and 20% by weight of PLLA. In the material for filling a bone defect of the present invention, it is preferable that PLLA content is 30% by weight or more and 40% by weight or less, and the remainder is constituted by bone forming inorganic ceramic particles (SiV, calcium phosphate).
The spinning solution of the electrospinning of the present invention is produced through the following two steps. In the first step, a solution produced by mixing inorganic particles to polymer melted at high temperature is kneaded in a kneader at a certain temperature for a certain time, and cooled and solidified so as to produce a composite. In the next step, the produced composite is dissolved by chloroform to produce the spinning solution.
Because PLLA has a highly orderly molecular arrangement, it is difficult to hydrolyze even if it is contacted with a body fluid. In order to produce a spinning solution, a PLLA melt is kneaded by using a kneader. In the mixing process (kneading while applying heat), it partially reacts with SiV particles such that bonding (an amide bond) takes place between an amino group portion of siloxane contained in SiV and a carboxy group at an end of polylactic acid (Wakita et al, Dental Materials Journal 2011; 30(2): 232-238). Accordingly, the orderly arrangement the polylactic acid is disturbed. As a result, a ratio of an amorphous phase of the polylactic acid becomes high, solubility of the material increases. Contrary, if inorganic material added to PLLA does not make amide bonds with polylactic acid, a ratio of an amorphous phase in the PLLA is not increased. Therefore, solubility does not become high rapidly.
In the material for filling a bone defect of the present invention, since kneading is performed with a blending ratio of 40% to 50% by weight of calcium phosphate, 10% by weight or more of silicon-releasing calcium carbonate, and the remainder of 30% by weight or more of PLLA, a ratio of amorphous in biodegradable fibers is controlled appropriately. As a result, the solubility of the PLLA matrix polymer to body fluids is controlled appropriately.
In an embodiment shown in
Outer diameter of the biodegradable fibers of the material for filling a bone defect of the present invention produced by using electrospinning is preferably 10 to 50 μm, more preferably 30 to 50 μl. In the spinning by electrospinning, outer diameter of a fiber generally tends to become several μm or less. As compared with it, the biodegradable fiber of the material for filling a bone defect of the present invention is thick. By making the outer diameter of a fiber to be 10 μm or more, it becomes possible to create a space (gap) between the fibers which is necessary for cells to enter into the inside of the cotton-like porous body of the present invention. It is difficult to make the outer diameter of a fiber spun by using electrospinning to be 50 μm or more.
As shown in
After the material for filling a bone defect of the present invention has been formed in cotton-like by electrospinning, the material is divided into a desired size and weight (for embodiment 2 g) by using a pair of tweezers and the like, packed with an aluminum package, and subjected to sterilization treatment. Embodiments of sterilization methods include radiation sterilization (γ rays, electron rays), oxidation ethylene gas sterilization, and high pressure steam sterilization. In the present invention, the radiation sterilization with γ rays is used suitably. In the case where the radiation sterilization with 25 kGy to 35 kGy of γ rays is applied to a sample of PLLA with a molecular weight of 200,000 to 250,000, the molecular weight decreases to 70,000 to 120,000.
The samples in the embodiment of the present invention were produced by using the materials shown below.
SiV particles and β-TCP particles were added to a polymer melt produced by melting PLLA at 180° C. in a kneader, and then kneaded in the kneader for 12 minutes, and thereafter, cooled and solidified therein to produce a composite of 30 SiV, 40β-TCP, and 30 PLLA.
A spinning solution was prepared by dissolving the above composite by chloroform, and then, a cotton-like material formed of biodegradable fibers was produced by spinning the spinning solution by electrospinning.
1) A method of electrospinning
10% concentration spinning solution for electrospinning was prepared by dissolving the composite with chloroform.
Thickness of a needle was set to 18 G, voltage was set to 25 kV, and a discharging rate of the spinning solution from the nozzle was set to 15 ml/hour. Flying distance from the nozzle to the collector was set to 25 cm. The collector container was filled with ethanol liquid and was configured to receive the electrospun fiber so that the fiber is deposited therein. As a result of filling the ethanol liquid in the collector, deposited fibers can be prevented from adhering to each other so that it becomes possible to form a cotton-like material with low bulk density.
2) The configuration of a fiber spun by the electrospinning is shown in
Bulk density, compression ratio, and compression recovery ratio of a sample of the cotton-like material of the embodiment were measured in accordance with JIS standard L 1927. Measurement result was that the bulk density was 0.01489 g/cm3, the compression ratio was 52.61%, and the compression recovery ratio was 31.10%.
If the material for filling a bone defect of the present invention is implanted in a body, the poly L lactic acid polymer constituting the fiber is dissolved and biologically absorbed. The rate differs depending on the difference of the content of the poly L lactic acid contained in the fibers, an amount of an amorphous phase, and the like. Thus, a plurality of samples in the embodiment of the present invention were prepared, and the crystallinity of the plurality of samples was measured by DSC. Further, the multiple samples were immersed in a sodium hydroxide solution. Evaluation and analysis were conducted by observing a change of an appearance and a decrease of molecular weight and a dry weight.
As experiment samples, [1] 30 SiV-70 PLLA, 70 SiV-30 PLLA, [3] 30 SiV-40 TCP-30 PLLA, [4] 10SiV-60 TCP-30 PLLA, and [5] 50 SiV-50 PLLA, each having a different composition weight ratio were produced. The preparation method followed the method described in paragraphs [0038] to [0040]. The crystallinity of the experiment samples [1] to [5] was measured by DSC. The measurement results are shown in
In the DSC measurement result shown in
As shown in the molecular weight measurement in
From the observation of a change of appearance, in the sample with a large PLLA content (the sample [1]), a large change was not found even after passing fourteen days since the sample has been immersed in the sodium hydroxide aqueous solution. Contrary, in the sample with a small PLLA content and a large Siv content(the samples [2] and [3]), a large shape change was observed when fourteen days have passed after the sample has been immersed in the sodium hydroxide aqueous solution. This result almost accords to the change of a molecular weight found at a time when fourteen days have passed after the sample has been immersed in the sodium hydroxide aqueous solution.
1) As a result of the observation of appearance, it was observed that the sample with a composition of 30 by weight of SiV and 70% by weight of PLLA (the sample [1]) was difficult to decompose in the sodium hydroxide aqueous solution. It is thought that this result comes from the fact that the molecular weight of PLLA of the sample [1] is high (about 270,000) and its crystallinity is high (21.8% according to DSC measurement shown in
In 30SiV/40TCP/30PLLA (the sample [3]) which was prepared by mixing 40% by weight of TOP to the composition of sample [1], upon passing one day after the sample has been immersed in the sodium hydroxide aqueous solution, a rapid decrease of molecular weight was observed. In the sample [3], molecular weight is 230,000 and the crystallinity is low (9.1% according to DSC measurement shown in
2) From the result of the observation of appearance, it was observed that the sample [2] with a composition of 70 SiV/30 PLLA was decomposed rapidly in the sodium hydroxide aqueous solution. It is thought that this result comes from the fact that in the sample [2], the molecular weight of PLLA is as low as about 200,000 and the crystallinity is low (7.5% according to the DSC measurement shown in
In 30 PLLA/40 TCP/30 SiV (sample [3]) which was prepared by mixing 40% by weight of TOP to the composition of sample [2], molecular weight of PLLA was about 230,000 and the crystallinity was 9.1% according to DSC measurement shown in
Samples of a cotton-like material for filling a bone defect produced in the above embodiment were subjected to sterilization treatment by irradiation of grays. Thereafter, the samples were implanted into a femur of a rabbit (sample alone), a spine (bone aspirate is mixed to the sample), and a spine (bone aspirate and an autologous bone are mixed to the sample), and bone formation was evaluated.
Evaluation of X ray visibility immediately after the embedding to the spine was conducted by radiography of a simple X-ray image. Evaluation of bone forming ability was conducted by a CT image and a dye slice. In the preparation method of a dye slice of the femur, a dye slice is prepared in a transverse direction to a bone hole, and a dye slice of a spine was prepared on a sagittal plane. Hematoxylin/eosin was conducted for dyeing.
From the CT image shown in
From the histological data and the organizational morphometrical data shown in
From the histological data and the organizational morphometrical data shown in
The material for filling bone defects of the present invention may be used in a manner that an autologous bone wrapped by the cotton material is filled in the bone defect, other than using the material alone. Because affinity with an autologous bone is high, if autologous bone is filled in a bone defect, bone formation is promoted.
The composite fibers of the material for filling a bone defect of the present invention are contacted with body fluids in a state where TOP particles and SiV particles are held such that both particles are closely positioned to each other in the matrix polymer. In this state, it is thought that bone formation by the absorption replacement of TCP and bone formation promotion by stimulation of osteoblast by a small amount of silicon are effectively performed in parallel.
A cotton-like material for filling a bone defect of the present invention formed by biodegradable fibers formed of a composite of poly L lactic acid, calcium phosphate, and silicon-releasing calcium carbonate can be used to fill in the bone defect in a human body such that filling position can be confirmed by X-rays.
In the invention of this application, a bioabsorbable compound such as β-TCP is used as the calcium phosphate. However, calcium phosphate having no bioabsorbability (for example: hydroxyapatite)is the same with β-TCP in a respect that it does not have a silicic acid portion coupled to an amino group. Thus, if a composite of Siv, PLLA, and HAp is prepared by adding a certain amount of hydroxyapatite (HAp) in place of β-TCP, an increase of the amount of amorphous phase caused by the disturbance in molecular order due to occurrence of an amide bond will be suppressed in a similar manner. Therefore, the bio-absorption of the thus-obtained composite can be delayed than a composite of Siv and PLLA. Therefore, it is thought that the invention described in the present application can be basically applied to the composite using HAp to that extent. Specifically, it is possible to prepare a same type of composition as that of the present invention by replacing β-TCP with HAp. For example, it is possible to prepare a composite of SiV of 30% by weight, HAp of 40% by weight, and PLLA of 30% by weight.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2014-014146 | Jan 2014 | JP | national |
| Number | Date | Country | |
|---|---|---|---|
| 61844305 | Jul 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14897296 | Dec 2015 | US |
| Child | 15686746 | US |
