JP5176096B2 - Bone affinity agent containing carbon nanotubes, and materials and preparations using the same - Google Patents

Description

  The present invention relates to a biocompatible bone substitute material that is implanted to repair, reinforce, or replace a damaged joint or bone of a patient, and a pharmaceutical preparation that forms new bone tissue from damaged bone. The present invention relates to a bone-affinity agent used by being incorporated in a material or formulation for orthopedic surgery.

  Patients who have had their bones damaged by a fracture undergo bone fixation surgery using a titanium alloy plate, an intramedullary nail, an osteosynthesis tool such as a screw or wire. Titanium alloy osteosynthesis fixtures are excellent in corrosion resistance, biocompatibility, and bone compatibility, but may be damaged by metal fatigue or may be damaged due to insufficient strength of thin plates, thin screws, or wires.

  In addition, orthopedic surgery for replacing the hip joint by a hip joint caused by diseases such as osteoarthritis and rheumatoid arthritis is performed. Such an artificial hip joint is, for example, a spherical joint made of a ceramic or metal head attached to the pelvis side and a polyethylene liner or metal socket covering it, and a femoral joint attached to the femoral side and inserted into the joint member. It consists of a metal stem. Several years after this hip replacement surgery, if the polyethylene liner is worn at the sliding part and wear powder causing osteolysis occurs, or if the hip joint is infected with bacteria, re-operation Is required. Even if the artificial hip joint is made of only alumina ceramics or zirconia ceramics, it generates wear powder even if not as much as polyethylene, and also causes phase transition and breakage or infection with bacteria.

  Bone cement such as polymethylmethacrylate used for fixing such an artificial hip joint to bone may cause cracks, loosening between the bone cement and bone, or insufficient fixing strength.

  In addition, bone augmentation materials such as hydroxyapatite used for bone transplantation to bone defects, bone fusion after fracture, and fracture fixation at the distal part of the spine or radius are hardened together with sodium chondroitin sulfate and are similar to bone. Although it forms a state, the fixing strength is insufficient.

  Patent Document 1 describes a bone regeneration base material in which a bioabsorbable organic porous material is combined with an osteophilic inorganic material such as calcium triphosphate or hydroxyapatite. On the other hand, Non-Patent Document 2 discloses a catheter for a medical instrument containing carbon nanotubes.

  There is no known bone affinity material for bone tissue replacement that is used for bone treatment, has bone affinity, promotes bone formation, and enables safe and early healing. Its development was desired.

JP-A-2005-52224 Morinobu Endo, et al., `` Nano Letters '', 2005, Vol. 5, No. 1, p. 101-105

  The present invention has been made to solve the above-mentioned problems, and provides a bone affinity agent that can be contained in a bone affinity material or a pharmaceutical preparation for replacement of a biological tissue used in the treatment of bone damaged by a patient. The purpose is to do. In addition, this bone-compatible agent contains bone-compatible materials that are highly safe for the body, durable and wear-resistant, and bone-compatible preparations that are safe and have drug transport properties and osteogenic properties. The purpose is to provide

The bone affinity agent according to claim 1, which has been made to achieve the above object, includes a bone affinity substance that promotes bone formation in a living body by being composed of carbon nanotubes and collagen. And

  A carbon nanotube is a kind of highly crystalline carbon nanofiber produced by, for example, a gas phase method, and is a substance having a fiber diameter of 1 to several 100 nm and a fiber length of 1 to several 1000 μm.

  The bone affinity agent according to claim 2 is the one according to claim 1, wherein the carbon nanotubes are suspended at a concentration of 0.01 to 500 mg / mL, or a concentration of 0.001 to 50% by weight. It is characterized by being distributed by.

A bone affinity agent according to a third aspect is the one according to any one of the first to second aspects, and includes a surfactant.
The bone-compatible material for substitute for biological tissue according to claim 4 , wherein the bone-compatible agent according to any one of claims 1 to 3 is an artificial joint, artificial bone, osteosynthesis fixture, artificial tooth, artificial skin, artificial blood vessel. And contained in or attached to a biomaterial selected from artificial body fluids.

The bone-compatible material for bone tissue replacement according to claim 5 is the bone affinity material according to claim 4 , wherein the biomaterial is the artificial joint, the artificial bone, or the artificial tooth, and includes polyethylene, alumina ceramics, It is formed of at least one selected from zirconia ceramics, titanium alloy, bone cement, hydroxyapatite, and calcium phosphate cement.

A preparation according to claim 6 is characterized by containing the bone affinity agent according to any one of claims 1 to 3 , a dispersing agent and / or a medium.

The formulation of claim 7, those described in claim 6, the bone affinity agent, BIOLOGICAL decomposable resin particles, synthetic resin particles, or is contained in a liposome, to be transported to the bone tissue It is characterized by.

The preparation according to claim 8 is the preparation according to any one of claims 6 to 7 , characterized by containing an osteogenic agent or osteogenesis-inducing cells together with the osteophilic agent.

  The bone-affinity agent of the present invention is highly safe in life and may be contained in a bone-affinity material or a drug transport formulation for replacement of a living tissue that is durable and wear-resistant and used in the treatment of bone damaged by a patient. it can.

  Materials and formulations containing it can promote the formation of damaged bone and can be quickly repaired, and will not loosen or break even after prolonged use.

  Examples of the present invention will be described in detail below, but the scope of the present invention is not limited to these examples.

  The bone affinity agent of the present invention is a dispersion containing a bone affinity substance composed of carbon nanotubes.

  The carbon nanotube preferably has an average fiber diameter of 80 to 150 nm and an average fiber length of 10 to 20 μm. Specifically, the carbon nanotube is a vapor grown carbon fiber having an average fiber diameter of 80 nm and an average fiber length of 10 to 20 μm. VGCF-H (all manufactured by Showa Denko KK; VGCF is a registered trademark of the same company) having an average fiber diameter of 150 nm and an average fiber length of 10 to 20 μm.

  Carbon nanotubes are fine and easily form aggregates. Therefore, the bone affinity agent should be a liquid in which carbon nanotubes are suspended in physiological saline containing a surfactant such as an ionic surfactant such as sodium carboxymethylcellulose or a nonionic surfactant. preferable. The concentration of the carbon nanotubes suspended in the bone affinity agent is more preferably 0.01 to 500 mg / mL. The surfactant is preferably 0.04-1.25 wt% sodium carboxymethylcellulose so as not to affect bacterial culture.

  The osteophilic agent may be a solid and may be a mixture of carbon nanotubes and a medium in which the carbon nanotubes are dispersed. The concentration of the carbon nanotubes dispersed in the bone affinity agent is preferably 0.01 to 50% by weight.

  Note that the bone affinity agent may consist only of a bone affinity substance that is a carbon nanotube.

  It may be a powder in which this bone affinity substance is dispersed in a medium, for example, a powder such as an excipient, or may be a molded body that is molded after being dispersed. In such a solid powder or molded body, the concentration of carbon nanotubes is preferably 0.001 to 50% by weight.

  The bone-compatible material for bone tissue replacement of the present invention is one in which this bone-compatible agent is contained in the biological material, partially exposed from the biological surface, or applied to the surface of the biological material.

  Biomaterials such as artificial joints, artificial bones, and artificial teeth are made of ultra-high-density polyethylene (UHMWPE) that is strong and resistant to wear powder, alumina ceramics and zirconia ceramics used for sliding surfaces of artificial joints, artificial joints Titanium alloys such as Ti-6A-4V for orthopedic treatment used as osteosynthesis materials and spinal fixation materials, bone cements such as polymethylmethacrylate cement that attaches artificial joints to bones, bulking materials for bone grafts, and substitute materials Hydroxyapatite, a calcium phosphate cement that hardens in a few minutes when placed in sodium chondroitin sulfate for use as a bulking material for fixation of fractures of the spine and distal radius. Examples of biomaterials include metals and resins used for artificial hearts exemplified by pacemakers, polyester fibers and polytetrafluoroethylene films used for artificial blood vessels, and polyvinyl alcohol and collagen used for artificial skin.

  The preparation of the present invention contains the above-mentioned bone affinity agent and a dispersant and / or medium, and may be a liquid, granule, tablet, or powder.

  This preparation is contained in collagen, biodegradable resin particles such as suspended polylactic acid, synthetic resin particles such as polyethylene beads, and liposomes made of fat and phospholipid. Or a partially exposed preparation that specifically transports the osteogenic agent to the site of bone injury to be treated.

  This preparation may contain an osteogenic agent such as a bone morphogenetic protein (BMP) and an osteogenesis-inducing cell such as a stem cell together with the bone affinity agent. Furthermore, you may have collagen. It may be liquid, or may be lyophilized to form a powder or pellet.

  Below, the bone affinity agent to which this invention is applied, the material and formulation which used it are demonstrated as an example.

  First, a bone affinity test solution, which is a solution containing carbon nanotubes to which the present invention is applied, and a comparison test solution of a formulation to which the present invention is not applied are prepared, and a biocompatibility test is performed in which the test solution is embedded in subcutaneous tissue An example is shown.

(Preparation example of bone affinity test solution and comparative test solution for biocompatibility test)
VGCF (manufactured by Showa Denko KK), which is a carbon nanotube having an average fiber diameter of 80 nm and an average fiber length of 10 to 20 μm, and physiological saline were mixed to prepare a test solution of 1% by volume of a bone affinity agent. Also, instead of carbon nanotubes, alumina ceramics (Tymicron; manufactured by Daimei Chemical Co., Ltd.), which is said to be about 100 nm in diameter and excellent in bone affinity, were used in the same manner. Thus, comparative test solutions for preparations other than the present invention were prepared.

  Each of the prepared solutions is sterilized by heating at 121 ° C. for 15 minutes by an autoclave, and is injected and injected through an 18 gauge (G) needle with a 1 mL syringe. The same applies to the following liquids.

(Biocompatibility test)
Six-week-old ddy mice were divided into three groups of 10 mice. A longitudinal incision of about 1 cm was made in the right back of the mouse, the subcutaneous tissue was exfoliated, and a pocket with a depth of about 3 mm was made to implant the test solution.

  A test group was prepared by injecting 5 μL of a bone affinity test solution containing carbon nanotubes into the pockets of the first group of mice. A control test group was prepared by injecting 5 μL of a comparative test solution of a preparation containing alumina ceramics into the pocket of the second group of mice. After creating a pocket in the third group of mice, the skin was sutured to form a sham operation group. In each group, subcutaneous tissues were removed together with the tissues around the pockets from 5 animals at 1 week and 4 weeks later. The excised subcutaneous tissue was fixed and embedded, and then stained with hematoxylin and eosin to prepare a tissue specimen and observed with an optical microscope. Furthermore, F4 / 80 immunostaining was performed on the sections prepared in the same manner, and accumulation of macrophages was observed.

  As a result, in the control group, due to the high biocompatibility of the alumina ceramics, almost no acute inflammatory cells were observed after one week, and only a few macrophages were observed around the alumina ceramics. Further, after 4 weeks, almost no inflammatory cells were observed.

  In the unadministered sham operation group, accumulation of neutrophils and lymphocytes showing acute inflammation after 1 week was hardly observed. In addition, accumulation of lymphocytes showing chronic inflammation was hardly observed after 4 weeks.

  On the other hand, in the test group using the bone affinity agent containing carbon nanotubes, as in the control group and the sham operation group, the acute inflammation in the subcutaneous tissue after 1 week and the chronic inflammatory reaction after 4 weeks were not induced. The foreign body reaction was weak. There are few macrophages in the same manner as in the control group. Therefore, this bone affinity agent has high safety.

  Next, in order to investigate the affinity between the carbon nanotubes in the bone affinity agent and the bone, an example of a bone affinity test in which the bone affinity agent is implanted under the periosteum of the skull of a mouse is shown.

(Bone affinity test)
A bone affinity test solution containing carbon nanotubes was prepared in the same manner as the biocompatible test bone affinity agent. Moreover, the negative comparison test liquid containing an alumina ceramic was prepared like the test liquid. Furthermore, a positive comparative test solution containing the same concentration of polystyrene beads, which are about the same size as that of latex bead polystyrene (manufactured by Sigma) and are said to have poor bone affinity, was prepared.

  Six-week-old ddy mice were divided into four groups of 10 mice. A 1 cm lateral incision was made at the top of the mouse to expose the skull, and the periosteum at the midline of the skull was peeled to create a pocket having a depth of about 5 mm.

  A test group was prepared by injecting 5 μL of a bone affinity test solution containing carbon nanotubes into the pockets of the first group of mice. A negative control group was injected by injecting 5 μL of a negative comparison test solution containing alumina ceramics into the pockets of the second group of mice. A positive control group was injected by injecting 5 μL of a positive comparison test solution containing polystyrene beads into the pocket of the third group of mice. After creating the pockets of the fourth group of mice, the skin was sutured to form a sham operation group. In each group, skulls were extracted from the 5 animals at 1 week and 4 weeks together with tissues around the pockets. The extracted skull was fixed and embedded, and then stained with hematoxylin and eosin to prepare a tissue specimen and observed with an optical microscope. Furthermore, F4 / 80 immunostaining was performed on the sections prepared in the same manner, and accumulation of macrophages was observed. The back was stained with hematoxylin.

  As a result, in the unadministered sham operation group, cortical bone was maintained, and the periosteal tissue was almost repaired in one week, and accumulation of neutrophils, lymphocytes and the like showing acute inflammation was hardly observed. In 4 weeks, the periosteal tissue was completely repaired.

  In the positive control group with a positive comparative test solution containing polystyrene beads, the bone formation layer of the periosteum was destroyed after 1 week, the surface of the cortical bone was already eroded, and the bone tissue that was the bone formation layer of the periosteum after 4 weeks. Osteoclasts and many inflammatory cells were found in the area where the surface of the cortical bone was eroded and was greatly destroyed.

  In the negative control group with a negative comparative test solution containing alumina ceramics, the cortical bone directly below was maintained, and after 1 and 4 weeks, the alumina ceramics remained under the periosteum and did not erode the bone formation layer or cortical bone. It was. Four weeks later, the periosteum was repaired with alumina ceramic inside.

  On the other hand, in the test group using the bone affinity agent containing carbon nanotubes, as in the case of alumina ceramics, after 1 week, the cortical bone immediately below was kept, and the carbon nanotubes remained under the periosteum, and in 4 weeks, the periosteal tissue Was repaired normally, carbon nanotubes entered under the periosteum and came into contact with the bone tissue, and did not erode the bone-forming layer or cortical bone, and had no effect on the bone tissue.

  Therefore, the carbon nanotube of this bone affinity agent has extremely good affinity with bone tissue.

  Next, in order to examine the effect of carbon nanotubes in a bone affinity agent on the repair of bone tissue, an example of a bone repairability test in which a bone affinity agent is implanted in a bone defect portion of a mouse tibia will be shown.

(Bone repair test)
A bone affinity test solution containing carbon nanotubes was prepared in the same manner as the biocompatible test bone affinity agent. Further, in the same manner as the comparative test solution, a negative comparative test solution containing alumina ceramics was prepared. Furthermore, a positive comparison test solution containing the same kind of polystyrene beads of the same size and concentration as described above was prepared.

  Six-week-old ddy mice were divided into four groups of 10 mice. A longitudinal incision of about 1 cm was made in the front surface of the right lower leg of the mouse, the front surface of the tibia was exposed, and a bone hole having a depth of 1.5 mm was opened in the diaphysis of the right tibia with a K-wire having a diameter of 0.7 mm.

  A test group was prepared by injecting 5 μL of the bone affinity test solution contained in the bone hole of the first group of mice. 5 μL of negative comparative test solution containing alumina ceramics was injected into the bone hole of the second group of mice to form a negative control group. A 5 μL positive comparison test solution containing polystyrene beads was injected into the bone hole of the third group of mice to form a positive control group. After making a bone hole in the fourth group of mice, the skin was sutured to form a sham operation group. In each group, the tibia was removed together with the surrounding tissue from 5 animals at 1 week and 4 weeks later. The excised tibia was fixed and embedded, and then stained with hematoxylin and eosin to prepare a tissue specimen and observed with an optical microscope. Furthermore, a specimen for an electron microscope of a bone repair part after 4 weeks was prepared, and a joint part of the bone tissue was observed with a transmission electron microscope.

  As a result, the untreated sham operation group showed vigorous bone formation in the defect after 1 week, and after 4 weeks, bone repair was completed, bone cortex was formed, and the bone marrow cavity was continuously normal. The tibia was repaired.

  In the positive control group with a positive comparative test solution containing polystyrene beads, after one week, many acute inflammatory cells such as lymphocytes were observed in the bone defect, there were few new bones, bone repair was delayed, and after 4 weeks, The bone hole was not repaired and bone formation was interrupted and buried with granulation tissue with inflammatory cells.

  In the negative control group with a negative comparison test solution containing alumina ceramics, bone repair was observed in the defect after one week, as in the sham operation group, bone repair progressed, and it joined directly to the new bone formed with alumina ceramics. Encapsulated in bone. Four weeks later, the bone repair of the defect was completed, and alumina ceramics entered the repaired bone cortex and was directly bonded to the bone tissue. Both the bone cortex and bone marrow cavity were formed continuously, and alumina ceramics were directly bound to the bone tissue of the formed cortical bone and enclosed in the bone.

  On the other hand, in the test group using the bone affinity agent containing carbon nanotubes, no inflammatory cells were observed after 1 week, and a vigorous bone repair image was observed, and the carbon nanotubes were taken into the new bone. The carbon nanotubes were directly bound to the formed bone tissue and enclosed in the bone. In 4 weeks, the cortical bone and bone marrow cavity were completely repaired, and carbon nanotubes were taken into the bone tissue. The carbon nanotubes were directly bonded to the bone tissue and encapsulated in the bone. Even when observed with an electron microscope, no gaps were observed between the carbon nanotubes and the bone tissue, and they were completely integrated.

  Therefore, the carbon nanotube of this bone affinity agent does not inhibit bone repair, but rather promotes bone repair. In addition, since the carbon nanotube of the bone affinity agent is directly bound to the bone tissue and taken into the bone, it has been shown that it is extremely effective for bone formation when included in a biomaterial fixed to the bone tissue.

  Next, a composite of a carbon nanotube and collagen in a bone affinity agent is prepared as a bone affinity agent transport formulation to bone tissue, and using this, an ectopic bone in the back muscle of the mouse by bone morphogenetic protein (BMP) is used. The example which performed the formation test is shown.

(Examples of preparation of bone affinity transport drug test preparation and comparative test preparation)
10 μL of 1% interface between 2 mg of liquid type I atelocollagen (cell matrix) (Nitta Gelatin Co., Ltd.) and 0.75 μg of carbon nanotube VGCF (Showa Denko Co., Ltd .; registered trademark) The mixture was mixed with physiological saline containing an active agent, and further 5 μg of the bone morphogenetic protein rhBMP-2 (BMP) (manufactured by Genetics) was mixed, followed by lyophilization to prepare a bone affinity transporting preparation as a pellet. A control preparation was prepared in the same manner except that no carbon nanotube was used.

(Ectopic bone formation test)
Six-week-old male ddy mice were divided into two groups of 10 mice. A longitudinal incision of about 1.5 cm was made in the middle of the back of the mouse, the left back fascia was incised, and a 6 mm long and 8 mm deep pocket was created under the fascia. The osteophilic agent transport preparation and the control preparation were embedded in the pockets of each group of mice, and 3 weeks later, the ectopic bone formed in the back muscle was removed together with the surrounding tissues.

  In the ectopic bone using the bone affinity transport preparation, bone having a larger particle diameter was formed than the ectopic bone using the control preparation. Further, the extracted ectopic bone was observed by observing a soft X-ray photograph image with a soft X-ray imaging apparatus (manufactured by SOFTEX, product number: Soflon SRO-M50). Further, the removed ectopic bone was fixed and embedded, and then stained with hematoxylin and eosin to prepare a tissue specimen and observed with an optical microscope. The histology shows that both groups of mice using a bone-affinity agent transport formulation containing carbon nanotubes and a control formulation not containing it have normal bone tissue consisting of normal trabecular bone and hematopoietic bone marrow. Was showing. The bone trabecula transported preparation was thicker and denser than the control preparation. In addition, when the bone affinity transporting preparation was used, an image in which the carbon nanotubes entered the trabecular bone and were integrated was observed. Moreover, no inflammation is observed.

  Further, the bone mineral content and bone density of the removed new bone of the ectopic bone were measured with a bone mineral meter (ALOKA, product number: DCS-600), and the bone area was measured by scanning area plotting. The result is shown in FIG.

  As is apparent from FIG. 1, the bone affinity transport composition containing carbon nanotubes showed higher values for bone mineral content, bone density, and bone area than the control preparation containing no carbon nanotube.

  From these facts, it has been clarified that carbon nanotubes promote ectopic bone formation by BMP and collagen and produce large and dense bones.

The details of the reason are not necessarily clear and should be further studied in the future. However, because carbon nanotubes have amplified the ability as a drug transporter to hold and release BMP of collagen, or the carbon nanotubes themselves It is inferred that it has the ability to retain and release BMP, or because the bone formation scaffold was strengthened by carbon nanotubes, or because it had a positive effect on angiogenesis that is important for bone formation.

  Next, in order to investigate the antibacterial properties of the bone affinity agent, an antibacterial property test was conducted by preparing a bone affinity agent test solution to which the present invention was applied and a bone affinity comparison test solution to which the present invention was not applied. Is shown.

  8 mg, 40 mg and 200 mg of carbon nanotube VGCF or VGCF-H (all manufactured by Showa Denko KK) were suspended in 10 mL of physiological saline, respectively, to prepare a test solution for carbon nanotube VGCF or VGCF-H.

  On the other hand, carbon nanotubes VGCF or VGCF- were used in the same manner as the test solution for VGCF or VGCF-H except that 10 mL of 0.05% by weight carboxymethylcellulose (CMC) -containing physiological saline was used instead of physiological saline. Test solutions for H and CMC were prepared. A comparative test solution for alumina ceramics was prepared in the same manner as the test solution for VGCF except that alumina ceramics (Tymicron; manufactured by Daimei Chemical Co., Ltd.) having an average particle size of 100 nm were used instead of VGCF. Further, a comparative test solution of alumina ceramics and CMC was obtained in the same manner as the test solution of VGCF except that 10 mL of 0.05% by weight carboxymethylcellulose-containing physiological saline was used instead of physiological saline. A control solution was obtained in the same manner as the VGCF test solution, except that Mueller Hinton broth (Eiken Chemical Co., Ltd.) was used instead of VGCF and physiological saline.

The obtained bone affinity test solution and control solution were added to the holes of the culture plate by 50 μL each. The bacteria Staphylococcus aureus was pre-cultured for 20 hours to 9.0 × 10 ⁸ cells / mL, then diluted to 2.0 × 10 ⁷ cells / mL with Mueller Hinton medium, A bacterial culture was used. 50 μL of the bacterial culture was added to each hole of the culture plate to make a total of 100 μL, followed by incubation for 8 hours. Furthermore, 100 μL of BacTiter-GLO (Promega Co., Ltd .; trade name), a drug that emits light depending on the concentration of ATP produced by living bacteria in proportion to the number of bacteria, was added to each hole of the culture plate. . After stirring, the mixture was centrifuged to precipitate carbon nanotubes or alumina ceramics and bacteria, and the luminescence of the supernatant was measured. Each was performed with the number of test samples n = 3. For comparison, the luminescence was measured in the same manner except that the control solution was used and no bacterial culture was added. The results are summarized in FIG.

  As is clear from FIG. 2, the test solution which is a bone affinity agent containing carbon nanotubes showed excellent antibacterial properties depending on the concentration of carbon nanotubes. In particular, the presence of sodium carboxymethylcellulose as a surfactant further enhances antibacterial properties. On the other hand, the comparative test solution containing alumina ceramics did not show antibacterial properties.

  Although the details of the mechanism of action of bone affinity agents are not always clear, carbon nanotubes adsorb bacteria and inactivate them, or adsorb nutrients necessary for bacterial growth and suppress bacterial growth It is guessed that it is to do.

  By each test as described above, the carbon nanotubes not only cause an inflammatory reaction in the living body, but also have little foreign body reaction, good compatibility with bone tissue and no adverse effects on bone such as osteolysis, It has been revealed that it has various pharmacological actions such as being directly incorporated into bone tissue without inhibiting bone repair, being taken into bone, promoting bone formation by BMP, and having antibacterial properties. It was.

  The bone affinity agent containing carbon nanotubes alone or in combination is a type of pacemaker implanted in the body, artificial joints, artificial bones, osteosynthesis fixtures, artificial bones, artificial skins, artificial blood vessels, and artificial body fluids. It can be used by being contained in a bone-compatible material for tissue replacement.

  This bone affinity agent has good compatibility between carbon nanotubes and bone tissue, and does not adversely affect bones such as osteolysis. Therefore, plates and screws for fracture treatment, which are biomaterials that come into contact with bone tissue, etc. It can be used by being incorporated in an osteosynthesis fixture, artificial joint, artificial bone, artificial bone or the like.

  In addition, the bone affinity agent is incorporated into these biomaterials because the carbon nanotubes are directly incorporated into the bone tissue without inhibiting the bone repair and are taken into the bone to promote the repair of the bone tissue and the formation of new bone. It can be used for plates and screws that accelerate fracture healing and artificial joints that do not loosen by firmly fixing the surrounding bone defect to the bone.

  Furthermore, since this bone affinity agent promotes ectopic bone formation by BMP, in order to perform bone regenerative medicine, bone regeneration by cytokines such as BMP, cell therapy using stem cells, etc., gene therapy, etc. When performing, carbon nanotubes can be used alone or in a complex with collagen or the like, and can be used as a pharmaceutical preparation for forming a scaffold for promoting bone formation or as a drug transporter.

  Bone-compatible materials and pharmaceutical preparations for replacement of biological tissues using functional materials and biomaterials containing this bone-compatible agent are used in regenerative medicine, especially bone tissue regeneration, which is performed during bone metabolism abnormalities and orthopedics. Useful for medical care.

It is a graph which shows the amount of bone minerals, a bone density, and a bone area in the ectopic bone formation test which used the test preparation of the bone affinity transport formulation to which this invention is applied, and the comparative test preparation which does not apply this invention.

It is a graph which shows the result of the antibacterial test of the test liquid of the bone affinity agent to which this invention is applied, and the comparison test liquid to which this invention is not applied.

Claims (8)

A bone affinity agent comprising a bone affinity substance that promotes bone formation in a living body by comprising carbon nanotubes and collagen .   The bone affinity agent according to claim 1, wherein the carbon nanotubes are suspended at a concentration of 0.01 to 500 mg / mL or dispersed at a concentration of 0.001 to 50% by weight. The bone affinity agent according to any one of claims 1 to 2, comprising a surfactant. The bone affinity agent according to any one of claims 1 to 3 is contained in or attached to a biomaterial selected from an artificial joint, an artificial bone, an osteosynthesis fixture, an artificial tooth, an artificial skin, an artificial blood vessel, and an artificial body fluid. A bone-compatible material for substituting for a living tissue, characterized in that The biomaterial is the artificial joint, the artificial bone, or the artificial tooth, and is formed of at least one selected from polyethylene, alumina ceramics, zirconia ceramics, titanium alloy, bone cement, hydroxyapatite, and calcium phosphate cement. The bone-compatible material for substituting for a living tissue according to claim 4 , wherein A preparation comprising the bone affinity agent according to any one of claims 1 to 3 , a dispersing agent and / or a medium. The bone affinity agent, BIOLOGICAL decomposable resin particles, synthetic resin particles, or is contained in a liposome formulation according to claim 6, characterized in that transport to the bone tissue. The preparation according to any one of claims 6 to 7, comprising an osteogenic agent or osteogenesis-inducing cells together with the osteophilic agent.

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