WO2013157638A1 - HAp/Col複合体によって被覆された生体材料 - Google Patents
HAp/Col複合体によって被覆された生体材料 Download PDFInfo
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- WO2013157638A1 WO2013157638A1 PCT/JP2013/061666 JP2013061666W WO2013157638A1 WO 2013157638 A1 WO2013157638 A1 WO 2013157638A1 JP 2013061666 W JP2013061666 W JP 2013061666W WO 2013157638 A1 WO2013157638 A1 WO 2013157638A1
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61K6/831—Preparations for artificial teeth, for filling teeth or for capping teeth comprising non-metallic elements or compounds thereof, e.g. carbon
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Definitions
- the present invention relates to a biomaterial that is implanted in a living body.
- Patent Document 1 in biomaterials such as artificial root implants and artificial bone implants, titanium having a good biocompatibility or an alloy material thereof is used as a constituent metal material, and this metal substrate is used. It is known that the compatibility with a living body is improved by coating hydroxyapatite on the surface.
- Vertebrate bone is a complex composed of inorganic hydroxyapatite (HAp) and organic collagen, and forms a unique nanocomposite structure in which HAp is oriented along collagen fibers in the c-axis direction in living bones.
- HAp inorganic hydroxyapatite
- this structure imparts mechanical properties unique to bone. Therefore, for example, in the case of producing an artificial biomaterial, a structure and characteristics similar to those of a living bone cannot be obtained by simply combining hydroxyapatite (HAp) and collagen.
- HAp hydroxyapatite
- Col collagen
- Patent Document 2 discloses an apatite / organic compound complex in which a mixed solution of a collagen solution and phosphoric acid is gradually added to a calcium hydroxide suspension to obtain a molded body having a Young's modulus similar to that of living bone.
- a manufacturing method is disclosed.
- Patent Document 3 while controlling the pH and temperature during the reaction, an aqueous phosphoric acid solution containing collagen and an aqueous solution containing a calcium salt are simultaneously dropped into a reaction vessel, and the resulting coprecipitate is pressure-molded.
- Patent Document 4 discloses a technique for improving apatite formation on a collagen surface using an organic acid.
- Patent Document 5 includes an organic-inorganic composite biomaterial having a microporous structure in which a hydroxyapatite / collagen composite having an average fiber length of 60 ⁇ m or more is included and the c-axis of hydroxyapatite is oriented along the collagen fiber.
- a hydroxyapatite / collagen composite having an average fiber length of 60 ⁇ m or more is included and the c-axis of hydroxyapatite is oriented along the collagen fiber.
- JP 2006-314760 Japanese Unexamined Patent Publication No. 7-101708 Japanese Patent Laid-Open No. 11-199209 Japanese Unexamined Patent Publication No. 2000-5298 JP 2003-190271 A
- Patent Documents 2-5 only suggest the effectiveness of a bone-like complex containing hydroxyapatite and collagen. For example, a joint between a metal biomaterial implanted in a living body and bone is used. There is no specific study on the methods and issues to promote this.
- This invention is made
- the biomaterial of the present invention is a biomaterial in which the surface of a metal substrate is coated with a coating agent containing a complex of hydroxyapatite and collagen, and the hydroxyapatite in the complex is The c-axis is oriented along the collagen fiber.
- the weight ratio of hydroxyapatite to collagen in the complex is 3: 2 to 9: 1.
- the biomaterial is preferably an implant material or an on-plant material for oral surgery, orthopedic surgery, brain surgery, dental, ophthalmology, otolaryngology.
- the osteosynthesis-promoting coating agent for biomaterials of the present invention is characterized in that it contains a composite of hydroxyapatite and collagen in which the c-axis of hydroxyapatite is oriented along the collagen fibers.
- the method for producing a biomaterial according to the present invention includes a step of coating the surface of a metal substrate with the osteosynthesis promoting coating agent.
- the encapsulating of the biomaterial is suppressed and the bonding between the biomaterial and the bone is promoted by the coating agent containing the HAp / Col complex in which the c-axis of hydroxyapatite is oriented along the collagen fiber. be able to.
- the delay in the bonding between the biomaterial and the bone is that the implanted biomaterial is covered with a fibrous coating (encapsulation). They found that osteogenic cells are blocked from entering the surface of the biomaterial. Then, if the encapsulation of the biomaterial can be suppressed until the osteogenic cells proliferate and migrate, the present invention is completed under the assumption that the joining of the biomaterial and the bone can be promoted. It came.
- the surface of the metal substrate is coated with a coating agent containing a complex of hydroxyapatite (HAp) and collagen (Col) (HAp / Col complex).
- HAp hydroxyapatite
- Col collagen
- a coating agent containing a composite of hydroxyapatite (HAp) and collagen (Col) coated on the surface of the biomaterial of the present invention is, for example, a hydroxy described in Patent Document 5 (Japanese Patent Laid-Open No. 2003-190271).
- a fibrous composite of apatite (HAp) and collagen (Col) and a method for producing the same can be considered.
- Hydroxyapatite is a compound having a general composition of Ca 5 (PO 4 ) 3 OH, and CaHPO 4 , Ca 3 (PO 4 ) 2 , Ca 4 O (PO 4 ) depending on the non-stoichiometry of the reaction. 2 , Ca 10 (PO 4 ) 6 (OH) 2 , CaP 4 O 11 , Ca (PO 3 ) 2 , Ca 2 P 2 O 7 , Ca (H 2 PO 4 ) 2 ⁇ H 2 O, etc. A group of compounds.
- Hydroxyapatite is based on a compound represented by the composition formula of Ca 5 (PO 4 ) 3 OH or Ca 10 (PO 4 ) 6 (OH) 2 , and a part of the Ca component contains Sr, It may be substituted with one or more selected from Ba, MG, Fe, Al, Y, La, Na, K, H and the like. A part of the (PO 4 ) component may be substituted with one or more selected from VO 4 , BO 3 , SO 4 , CO 3 , SiO 4 and the like. Furthermore, a part of the (OH) component may be substituted with one or more selected from F, Cl, O, CO 3 and the like. Moreover, some of each of these components may be defective. Since some of the PO 4 and OH components of apatite in living bones are usually replaced by CO 3 , during the production of this composite biomaterial, CO 3 contamination from the atmosphere and partial replacement of each component ( 0 to 10% by mass) may be present.
- Hydroxyapatite may be the same solid solution, substitutional solid solution, interstitial solid solution, or non-quantitative defects, in addition to the usual microcrystalline / amorphous and crystalline materials.
- the atomic ratio of calcium and phosphorus (Ca / P) is preferably in the range of 1.3 to 1.8, more preferably 1.5 to 1.7.
- the composition and crystal structure of apatite (calcium phosphate compound) in the product can have a composition and structure similar to apatite present in vertebrate bones. This is because biocompatibility and bioabsorbability are increased.
- Collagen is now known to have about 20 different molecular species in biological tissues of a wide range of animals including fish, not limited to mammals, and is collectively called “collagens”. .
- the collagen used in the present invention is not particularly limited in the species, tissue site, age, etc. of the animal used as the starting material, and any can be used. Generally, however, mammals (for example, bovine, Collagen obtained from skin, bone, cartilage, tendon, organ, etc. of pigs, horses, rabbits, mice, etc.) and birds (eg, chickens, etc.) is used. In addition, collagen-like proteins obtained from the skin, bones, cartilage, fins, scales, organs, etc.
- fish eg cod, flounder, flounder, salmon, trout, tuna, mackerel, Thai, sardine, shark, etc.
- collagen obtained by gene recombination technology may be used instead of extraction from animal tissue.
- type I collagen is the most abundant and well-studied among the molecular species of collagen. Usually, collagen is often referred to as type I collagen.
- the molecular species of collagen used in the present invention is not particularly limited, but it is preferable that type I collagen is the main component.
- collagen may be used by appropriately chemically modifying amino acid residues of collagen protein such as acetylation, succination, maleylation, phthalation, benzoylation, esterification, amidation, guanidinolation and the like.
- a method for preparing collagen for example, a method of extracting from the above starting materials with a neutral buffer solution or a dilute acid such as hydrochloric acid, acetic acid or citric acid can be mentioned.
- the former is called neutral salt-soluble collagen, and the latter is called acid-soluble collagen.
- the amount of extracted collagen is small, and most remains as insoluble collagen.
- an enzyme solubilization method and an alkali solubilization method are known.
- the former is called enzyme-solubilized collagen and the latter is called alkali-solubilized collagen, both of which can be solubilized as molecular collagen in a yield of almost 100%.
- the collagen preparation method (extraction type) used in the present invention is not particularly limited, but if the molecular weight is large when the collagen is solubilized, the strength of the complex becomes insufficient due to steric hindrance, Monomeric (monomolecular) collagen is preferably used.
- Monomeric (monomolecular) collagen is preferably used.
- enzyme-solubilized collagen and alkali-solubilized collagen have a large amount of monomeric components, and non-helical portions (telopeptides) that have most of the antigenicity of collagen at the preparation stage are selectively degraded. -It is suitable because it is removed.
- the collagen from which the non-spiral portion is decomposed and removed is called atelocollagen.
- the isoionic point is the pH at which both positive and negative charges derived from the dissociation group unique to the protein molecule cancel each other.
- the isoionic point of enzyme-solubilized collagen is pH 8-9
- the isoionic point of alkali-solubilized collagen is pH 4-5.
- Examples of the enzyme for solubilization include pepsin, trypsin, chymotrypsin, papain, pronase and the like. Pepsin and pronase are preferably used because of the ease of treatment after the enzyme reaction.
- hydroxyapatite and collagen are oriented in a self-organizing manner to form a fibrous composite similar to living bone.
- Self-organization generally refers to “same or heterogeneous atoms, molecules, fine particles, etc., gather together by non-covalent interaction to form a specific organization (Tokyo Chemical Dojin” It means “from the Biochemical Dictionary”).
- calcium phosphate having an apatite structure (hydroxyapatite: HAp) has a peculiar orientation of living bone, that is, the c-axis of HAp (main axis in crystallography (vertical axis)). It shall mean a microporous structure oriented along collagen fibers.
- the metal base material is processed into an appropriate shape for, for example, an implant material or an on-plant material for oral surgery, orthopedic surgery, brain surgery, dental, ophthalmology, otolaryngology, Specifically, forms, such as a wire, a pin, a screw, a nail, a mesh, and a plate, can be illustrated, for example.
- the material of the metal substrate is not particularly limited, and a known metal material can be appropriately selected according to the use of the biomaterial. From the viewpoint of biocompatibility, titanium or a titanium alloy is preferably exemplified. be able to.
- the metal material may have a surface subjected to processing such as etching, sand blasting, machining, laser processing, and particle baking according to the application.
- the fibrous composite of hydroxyapatite and collagen can be produced using at least three kinds of components of collagen, phosphate and calcium salt as starting materials.
- phosphate includes phosphoric acid
- calcium salt includes calcium hydroxide.
- Examples of the phosphoric acid source of the aqueous phosphate solution used in the present invention include disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and phosphoric acid.
- the aqueous phosphate solution is used for the reaction after dissolving the collagen described above.
- Examples of the calcium source of the calcium salt aqueous solution used in the present invention include calcium carbonate, calcium acetate, calcium hydroxide and the like.
- the aqueous calcium salt solution may be a suspension as long as it is in a uniform state.
- calcium carbonate obtained by calcining calcium carbonate in a mortar or the like to obtain calcium hydroxide, and adding water thereto is obtained.
- an aqueous calcium salt solution and an aqueous phosphate solution containing collagen can be simultaneously dropped into a reaction vessel.
- “simultaneously” does not mean only the form of dripping at the same time, but also includes the form of dripping alternately in small amounts (about 0.01 to 5 ml). Both solutions may be dripped continuously as long as they are simultaneous or may be dropped intermittently.
- an appropriate amount of pure water can be previously placed in the reaction vessel.
- the amount of pure water is not particularly limited, but is preferably about the same as the amount of calcium salt aqueous solution used.
- the calcium ion concentration in the reaction vessel is maintained at 3.75 mM or less and the phosphate ion concentration is maintained at 2.25 mM or less. If the concentration of calcium ions or phosphate ions exceeds the above range, there is a risk that suitable self-assembly of the complex may be hindered. This is thought to be because spontaneous nucleation occurs when the concentration of ions convection in the reaction container exceeds those in the body fluid. If the calcium ion concentration is maintained at 2.5 mM and the phosphate ion concentration is maintained at 1.5 mM or less, a composite having an average fiber length of 1 mm or more can be obtained, which is more preferable.
- the hydroxyapatite and collagen produced in the reaction vessel are preferably present in a weight ratio of 3: 2 to 9: 1, preferably 70:30 to 85:15. This is because it is important for self-organization that the weight ratio of hydroxyapatite to collagen when an ideal reaction occurs is closer to the composition of living bone (75:25).
- the calcium ion concentration and the phosphate ion concentration in the reaction vessel are determined by the rate of feeding the calcium salt aqueous solution and the phosphate aqueous solution containing collagen to the reaction vessel and / or calcium. It is possible to maintain the desired range by controlling the concentration of the salt solution and the starting solution of the phosphate solution containing collagen.
- the “starting stage concentration” means the concentration of each component (such as a calcium salt aqueous solution and a phosphate aqueous solution containing collagen) individually adjusted before being supplied to the reaction vessel.
- the “liquid feeding speed” means the amount of each reaction liquid delivered into the reaction container per unit time. The setting of the liquid feeding speed can be easily achieved by using, for example, a commercially available tube pump.
- the average liquid feed rate of the calcium salt aqueous solution is set to 5 to 25 mM / min.
- the concentration of the calcium salt aqueous solution in the starting stage is 400 mM or less, preferably in the range of 50 to 200 mM.
- the concentration of the phosphoric acid aqueous solution containing collagen is 120 mM or less, preferably in the range of 15 to 96 mM.
- the “average liquid feeding speed” means an average value per minute of the amount of liquid delivered into the reaction container in consideration of pump on / off control and the like.
- the ratio of the phosphoric acid aqueous solution containing collagen and the calcium salt aqueous solution is preferably in the range of 3: 1 to 1: 3.
- the amount of the phosphoric acid aqueous solution containing collagen is small, the strength is reduced due to excessive calcium composition, and when the amount of the aqueous solution containing calcium salt is small, calcium deficiency occurs and Young's modulus This is because there is a possibility that the strength is lowered and the strength is lowered (see JP-A-11-199209).
- the pH of the reaction solution is in the range of 7 to 11 and the range of change is within one. More preferably, the pH is in the range of 7 to 9, and the range of change is 0.5 or less. This is because native collagen causes precipitation at the isoelectric point in the pH range of 7 to 11 and fibers regenerate, and calcium phosphate is also likely to precipitate in this pH range. This is because collagen self-organization is promoted. If the pH exceeds 11, water molecules are hydrated around the collagen molecules, making it difficult for the water molecules to leave, which increases the water content of the complex, hinders self-assembly, and may reduce strength. .
- a pH controller for suitable pH control.
- the pH controller is equipped with a means for measuring the pH of the reaction solution and a means for adjusting the dropping amount of both solutions to be dropped, and is within a certain range with respect to the pH (for example, 10) set as the initial value.
- the dripping amount of both solutions is adjusted based on the pH value of both solutions so as to maintain (for example, ⁇ 0.3).
- Examples of the pH controller include those manufactured by NISSIN. It is preferable to carry out the reaction while constantly stirring both solutions and the reaction solution so that the pH of the reaction solution is not biased.
- the temperature of the reaction solution is preferably maintained at 35 ° C. to 40 ° C. This is because the complex formation is expected to be performed under the same conditions as those in the living body if the temperature is within this range.
- the fibrous composite of hydroxyapatite and collagen preferably has an average fiber length of 60 ⁇ m or more.
- the average fiber length is more preferably 1 mm to 7 mm, and further preferably 3 mm to 7 mm.
- the “average fiber length” is an average value of the lengths of the composite fibers, and is measured by a specific device (for example, RapidVue manufactured by Beckman-Colter) or by visual observation.
- the fibrous composite of hydroxyapatite and collagen produced in this way is made into a fine fiber or granular form by performing, for example, a crushing process and a forming process before coating the surface of the metal substrate.
- a fibrous material having a fiber length in the above-mentioned range or processed into a fine fiber shape, granular shape, or the like, a “hydroxyapatite-collagen complex (HAp / Col complex)” Describe.
- a known coating method such as dip coating can be employed.
- the composite of hydroxyapatite and collagen HAp / Collagen
- a solution to which a complex of hydroxyapatite and collagen HAp / Col complex
- the solvent to which the hydroxyapatite-collagen complex (HAp / Col complex) is added is not particularly limited.
- pure water or a known pseudo body fluid for example, Li P.Biomimetic nano-apatitite coating capable of promoting bone ingrowth.
- dehydration treatment with ethanol or the like can be performed prior to air drying, vacuum drying or vacuum freeze drying in order to uniformly and quickly dry the water-containing coating layer immediately after coating.
- the number of immersions in the metal substrate can be adjusted in consideration of the coating state of the HAp / Col composite, the coating thickness, and the like.
- the thickness of the coating can be appropriately designed in the range of, for example, about 1 ⁇ m to 80 ⁇ m in consideration of the use of the biomaterial.
- the crosslinking may be performed by any method such as thermal crosslinking, chemical crosslinking using a crosslinking agent or a condensing agent, physical crosslinking using ⁇ rays, ultraviolet rays, thermal dehydration, electron beam, or the like.
- thermal crosslinking the collagen chains are crosslinked with each other by heating the material with sufficiently dried coating layer at a temperature of, for example, about 120 ° C. for 24 hours, thereby strengthening the coating.
- Examples of the chemical crosslinking agent include aldehyde-based crosslinking agents such as glutaraldehyde and formaldehyde; isocyanate-based crosslinking agents such as hexamethylene diisocyanate; 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Carbozide crosslinking agents; polyepoxy crosslinking agents such as ethylene glycol diethyl ether; transglutaminase and the like.
- the amount of these crosslinking agents used is preferably about 10 ⁇ mol to 10 mmol per 1 g of collagen.
- the cross-linking may be any cross-linking between collagens, but it is particularly preferable to cross-link carboxyl groups and hydroxyl groups, carboxyl groups and ⁇ -amino groups, and ⁇ -amino groups. In addition, it is preferable that at least 1% or more of the reactive functional groups are introduced with crosslinking, and more preferably 5% or more.
- hydroxyapatite and collagen composites (HAp / Col composites)
- these components can also be contained.
- examples of such components include inorganic salts such as Sr, Mg and CO 3 , organic substances such as citric acid and phospholipid, and drugs such as bone morphogenetic proteins.
- titanium and hydroxyapatite are said to be joined to bone, but depending on the implantation position and conditions, bone joining may not occur or bone joining may take time.
- the inventors of the present invention have a problem related to the osteosynthesis of the biomaterial in that the implanted biomaterial is covered (encapsulated) with a fibrous coating (fibroblast), and the osteogenic cells are It has been found that the entry to the surface of the biomaterial is hindered. That is, for example, in the case of a biomaterial coated with conventional hydroxyapatite, as a result of fibroblasts proliferating near the surface and forming a matrix early after implantation, encapsulation occurs, and the biomaterial and the bone It seems that osteosynthesis is inhibited.
- the surface of the metal substrate is coated with a coating agent containing a complex in which the c-axis of hydroxyapatite is oriented so as to follow the collagen fiber.
- a coating agent containing a complex in which the c-axis of hydroxyapatite is oriented so as to follow the collagen fiber for example, in the bone or under the periosteum
- the HAp / Col complex is absorbed at an appropriate speed while being phagocytosed. Encapsulation of the biomaterial is suppressed.
- the biomaterial of the present invention starts to absorb the HAp / Col complex immediately after implantation, but the HAp / Col complex remains until about 1 week after implantation. The HAp / Col complex is absorbed over 2 weeks.
- the coating agent containing the HAp / Col complex has a remarkable osteosynthesis promoting effect.
- the method for implanting and fixing the biomaterial of the present invention is not particularly limited.
- the biomaterial according to the present invention includes, for example, implant materials or on-plant materials for oral surgery, orthopedic surgery, brain surgery, dentistry, ophthalmology, and otolaryngology.
- the biomaterial of the present invention is, for example, a metal substrate having a form such as a wire, pin, screw, nail, mesh, plate, etc., coated with a coating agent containing a HAp / Col composite. These can be used for various medical purposes.
- the biomaterial of the present invention is not limited to the above form.
- the pre-treated wire is made up of three forms: (A) no coating, (B) hydroxyapatite (HAp) coating, and (C) HAp / Col composite coating. Divided into. Specifically, the wire processed with the following method was used.
- (C) HAp / Col composite coating A coating agent containing the HAp / Col composite was prepared according to the method described in Patent Document 5. Specifically, starting material (calcium hydroxide suspension, I derived from pig skin, adjusted to a mass ratio of HAp and Col of 80/20 in a reaction vessel controlled at a temperature of 40 ° C. and a pH of 9). Phosphoric acid solution containing type atelocollagen) was reacted by the simultaneous dropping method to obtain a fibrous HAp / Col composite having an average fiber length of 60 ⁇ m. This HAp / Col composite is oriented so that the c-axis of hydroxyapatite is along the collagen fibers.
- starting material calcium hydroxide suspension, I derived from pig skin, adjusted to a mass ratio of HAp and Col of 80/20 in a reaction vessel controlled at a temperature of 40 ° C. and a pH of 9
- Phosphoric acid solution containing type atelocollagen was reacted by the
- the wire After lifting the wire from the HAp / Col suspension, the wire was immersed in 100% ethanol for 20-30 seconds to dehydrate the coating layer. This was taken out and air-dried to evaporate ethanol and remaining water. If the HAp / Col composite coating on the wire surface is insufficient after air drying, the above operation can be repeated. Furthermore, after air-drying the wire surface, the collagen chains in the coating layer were thermally cross-linked by heating at 140 ° C. for 12 hours under vacuum in a vacuum oven.
- FIG. 1 The result of having observed the wire surface coat
- the sample is collected with the skull, fixed with 70% ethanol at room temperature for 1 week, embedded with an MMA resin-based embedding kit, and approximately 10 ⁇ m with a hard tissue microtome. After slicing to a thickness of 5 mm and staining with Vilanueva staining solution, histological observation with an optical microscope was performed. In addition, based on the tissue slice images, histomorphometric measurement was performed using image analysis software. First, the length of the bone contact site (L b ) and the length of the entire circumference of the wire (L f ) are measured, and the length of the bone contact site (L b ) is calculated as the total length of the wire (L f ).
- the joining force of the sample was evaluated by a shearing force test (FIG. 5). Specifically, in the shearing force test, the wire was sampled in a lump with the skull, and then the sample was stored in 4 ° C. physiological saline and tested within 1 hour. A sample was trimmed with a diamond disk so that both ends of the wire were exposed from the skull, leaving a range of 6.0 mm in the center of the wire. Set the sample on the jig prepared for mechanical testing so that the wire is positioned perpendicular to the movement direction of the jig, and apply a load in a certain direction to both ends of the wire (1.0 mm / min) The shear force was measured.
- ⁇ CT was taken and observed.
- the number of specimens in each group was 5, and the measurement results were statistically tested using Wilcoxon's multiple rank sum test with the significance level adjusted by Holm's method.
- the wire (Ti) is encapsulated by the fibrous tissue (Fi), and in the example shown in FIG. Not observed (contact rate with bone: 6.5%), and in the example shown in FIG. 7, contact between the wire and new bone was not observed (contact rate with bone: 0%).
- HAp hydroxyapatite
- the maximum strength determined by the shear force test is (A) No coating group, 3.46N in the example shown in FIG. 10, 2.8 ⁇ 0.9N in the example shown in FIG. 11, (B) Hydroxyapatite (HAp) coating In the group, 4.31N in the example shown in FIG. 10, 6.0 ⁇ 2.2N in the example shown in FIG. 11, and in the (C) HAp / Col composite coating group, 14.8N in the example shown in FIG. In the example shown, it was 16.4 ⁇ 3.0 N, and it was confirmed that the bonding force with the bone of the (C) HAp / Col composite coating group was remarkably large. Moreover, as shown in FIG.
- the (C) HAp / Col composite coating group showed the largest shearing force, and a significant difference was recognized between each group (P ⁇ 0.05). Furthermore, the observation result by ⁇ CT before and after the shearing force test is shown in FIG. In the specimens (A to C) before the shear force test, new bone was observed around the wire in any group. In the specimens (A 'to C') after the shear force test, fractures were not observed in the (A ') uncoated group, but (B') the HAp coated group and (C ') the HAp / Col composite coating. In the group, fracture findings (arrowheads in the figure) were observed.
- coating the surface of the metal substrate with the coating agent containing the HAp / Col complex suppresses the encapsulation of the biomaterial and promotes the bonding between the biomaterial (metal substrate) and the bone. It was confirmed that it was possible.
Abstract
Description
合体の好適な自己組織化が妨げられる恐れがある。これは、反応容器内に対流するイオン
の濃度が、体液中におけるそれらの濃度を超えると自発的な核形成を起こすためと考えら
れる。なお、カルシウムイオン濃度が2.5mM、リン酸イオン濃度が1.5mM以下に維持されれば、平均繊維長1mm以上の複合体を得ることができ、より好適である。
<1>生体材料の作製
(1)金属基材の事前処理
金属基材として、純チタン製のワイヤーを使用した。具体的には、径0.5mmの純チタン製のワイヤーを12.0mmに切断し、このワイヤー表面をエメリー紙で粗造化した。さらに、このワイヤーを、中性洗剤、純水、アセトン、エタノール、純水の順に、各30分間超音波洗浄した。
(2)ワイヤーの表面へのコーティング
動物実験に供するため、事前処理したワイヤーを、(A)コーティングなし、(B)ハイドロキシアパタイト(HAp)コーティング、(C)HAp/Col複合体コーティング、の3形態に分けた。具体的には、以下の方法で処理したワイヤーを使用した。
上記(1)で処理したワイヤーをそのまま使用した。
Li P.らの報告 (Li P. Biomimetic nano-apatite coating capable of promoting bone ingrowth. J Biomed Mater Res. 2003;66A:79.)を参考に疑似体液を調整し、45℃の条件下で3日間この疑似体液中にワイヤーを浸漬する操作を3回繰り返してコーティングした。
特許文献5に記載された方法に沿ってHAp/Col複合体を含むコーティング剤を作製した。具体的には、温度40℃、pHを9に制御した反応容器中で、HApとColの質量比が80/20になるよう調整した出発物質(水酸化カルシウム懸濁液、ブタ皮膚由来のI型アテロコラーゲンを含んだリン酸溶液)を同時滴下法により反応させ、平均繊維長さ60μmの繊維状のHAp/Col複合体を得た。このHAp/Col複合体は、ハイドロキシアパタイトのc軸がコラーゲン繊維に沿うように配向している。得られた繊維状のHAp/Col複合体0.1グラムに対して純水800μLを加え、細胞破砕用ペストルにてHAp/Col複合体を破砕することで均一にHAp/Col複合体が分散したゾル状の懸濁液を得た。その後、室温にてピンセットでワイヤーを把持して、このHAp/Col複合体を含む懸濁液に浸漬させ、2~3回溶液中で上下させた後、引き上げた。
HAp/Col複合体で被覆したワイヤー表面を走査型電子顕微鏡で観察した結果を図1、図2に示す。図1に示したように、ワイヤー表面には微小多孔質構造を有するHAp/Col複合体が被覆されていることが確認される。また、図2の弱拡大図でも、ワイヤー表面には微小多孔質構造を有するHAp/Col複合体が被覆されていることが確認される。さらに、図2の強拡大図(右下図)に示したように、ワイヤー表面は10μm程度のHAp由来と考えられる粒子(図2中矢頭部分)とCol由来と考えられる膜様構造(図2の強拡大図中*印部分)で被覆されていることが確認される。さらにHAp由来と考えられる粒子はナノサイズの多孔質構造を有していることが確認される。
上記の3形態のワイヤー、(A)コーティングなし、(B)ハイドロキシアパタイト(HAp)コーティング、(C)HAp/Col複合体コーティング、をそれぞれ、12週齢SD系雄ラットの頭蓋骨骨膜下に埋植した。以下、各ラット群を、(A)コーティングなし群、(B)ハイドロキシアパタイト(HAp)コーティング群、(C)HAp/Col複合体コーティング群と記載する。
なお、組織形態学的計測とせん断力試験において,各群の検体数は5とし,計測結果はHolmの方法で有意水準を調整したWilcoxonの多重順位和検定を用い統計検定を行った。
組織学的観察の結果を図6、図7に示す。
図7に示した例で観察された骨接触率の結果を図8に示す。(A)コーティングなし群と(C)HAp/Col複合体コーティング群との間でそれぞれ有意差が認められた(P < 0.05)。また、(B)HApコーティング群と(C)HAp/Col複合体コーティング群との間でそれぞれ有意差を認められた(P < 0.05)。
新生骨高さの結果を図9に示す。(A)コーティングなし群と(B)HApコーティング群との間でそれぞれ有意差が認められた(P < 0.05)。また、(A)コーティングなし群と(C)HAp/Col複合体コーティング群との間でそれぞれ有意差が認められた(P < 0.05)。
また、図11に示したように、(C)HAp/Col複合体コーティング群が最も大きなせん断力を示し、各群間で有意差を認めた(P < 0.05)。
さらに、せん断力試験の前後におけるμCTでの観察結果を図12に示す。
せん断力試験前の検体(A~C)ではいずれの群でもワイヤー周囲に新生骨を認めた。せん断力試験後の検体(A’~C’)では、(A’)コーティングなし群では骨折所見は認められなかったが、(B’)HApコーティング群と(C’)HAp/Col複合体コーティング群では、骨折所見(図中の矢頭部分)を認められた。また、(B)HApコーティング群よりも大きな骨折片が(C)HAp/Col複合体コーティング群では観察された。すなわち、(C)HAp/Col複合体コーティング群では、骨とワイヤーの接合力が顕著に大きいことが確認された。
Claims (5)
- ハイドロキシアパタイトとコラーゲンの複合体を含むコーティング剤によって金属基材の表面が被覆された生体材料であって、前記複合体中のハイドロキシアパタイトのc軸がコラーゲン繊維に沿うように配向していることを特徴とする生体材料。
- 複合体中のハイドロキシアパタイトとコラーゲンの重量比が、3:2~9:1であることを特徴とする請求項1の生体材料。
- 生体材料は、口腔外科用、整形外科用、脳外科用、歯科用、眼科用、耳鼻科用のインプラント材またはオンプラント材であることを特徴とする請求項1または2の生体材料。
- ハイドロキシアパタイトのc軸がコラーゲン繊維に沿うように配向している、ハイドロキシアパタイトとコラーゲンの複合体を含むことを特徴とする生体材料用の骨接合促進コーティング剤。
- 請求項4の骨接合促進コーティング剤によって、金属基材の表面を被覆する工程を含むことを特徴とする生体材料の製造方法。
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US14/394,807 US20150132353A1 (en) | 2012-04-19 | 2013-04-19 | BIOMATERIAL COATED WITH HAp/Col COMPOSITE |
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JP2020200529A (ja) * | 2019-06-13 | 2020-12-17 | 国立研究開発法人物質・材料研究機構 | 積層体の製造方法、及び積層体 |
US11234747B2 (en) | 2015-02-25 | 2022-02-01 | National University Corporation Tokyo Medical And Dental University | Medical device, device structures for dentistry, for head and neck surgery and for orthopedic surgery, and method for bonding medical device to bone |
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US10671485B2 (en) | 2017-03-31 | 2020-06-02 | Nutanix, Inc. | Image management for desktop virtualization |
CN107349472B (zh) * | 2017-06-30 | 2020-06-30 | 浙江德康医疗器械有限公司 | 一种促进骨融合的重复梯度多孔钛合金的制备方法 |
CN109079124A (zh) * | 2018-08-01 | 2018-12-25 | 郑州大学第附属医院 | 一种医用植入双金属材料及其制备方法 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US11234747B2 (en) | 2015-02-25 | 2022-02-01 | National University Corporation Tokyo Medical And Dental University | Medical device, device structures for dentistry, for head and neck surgery and for orthopedic surgery, and method for bonding medical device to bone |
JP2020200529A (ja) * | 2019-06-13 | 2020-12-17 | 国立研究開発法人物質・材料研究機構 | 積層体の製造方法、及び積層体 |
JP7340798B2 (ja) | 2019-06-13 | 2023-09-08 | 国立研究開発法人物質・材料研究機構 | 積層体の製造方法、及び積層体 |
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JPWO2013157638A1 (ja) | 2015-12-21 |
EP2839849A1 (en) | 2015-02-25 |
US20150132353A1 (en) | 2015-05-14 |
EP2839849A4 (en) | 2015-11-18 |
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