JP2008272385A - Biological implant material, its production method, and application - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a biological implant material, its production method, and application. <P>SOLUTION: A biomaterial having a surface structure having controlled size, shape and connection of surface microspaces, has (1) a surface structure in which spaces formed by connecting groove-like spaces or hole-like spaces are connected by grooves narrower than the hole-like spaces, and which has a recessed/projecting structure of not less than 50 μm and not more than 1000 μm for introducing bone tissue, and (2) an axial symmetric property of luminescent spots corresponding to a spatial frequency to the periodicity of the recessed/projecting structure to luminescent spots corresponding to a wave number 0 in a power spectrum of height information of the recessed/projecting structure of the surface relative to a binarized image of a two-dimensional map; and further its manufacturing method, and biological implant and a cell culture carrier as its applications are provided. Thus, biomaterials such as the biological implant having the surface structure suitable for the intrusion of osseous tissue and the blood vessel are provided. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a biological implant material and a method for producing the same, and more specifically, and more specifically, has a surface structure in which the size and shape of a surface microspace and the connection structure thereof are controlled. A biomaterial such as a bioimplant material having a specific surface structure capable of efficiently guiding the accompanying tissue into the surface fine space, and easily reproducing the designed surface structure as designed, and its production It relates to methods and applications.

  As a method of forming a surface structure for the purpose of bone penetration, for example, a method of spraying powders having different particle diameters to obtain a porous coating (see Patent Documents 1 and 2), or a method of obtaining a rough surface by arc spray ( Patent Document 3), a method using a titanium fiber non-woven material or sintered body (see Patent Document 4), a method in which titanium beads are diffused and fused to the artificial joint surface (see Patent Document 5), a calcium phosphate-based sintered body A method of fixing a porous material having spherical pores composed of the above to the surface of an artificial joint has been proposed (see Patent Document 6). However, these surface structures are formed by an indirect and stochastic structure control method. Therefore, it is very difficult to reproduce the designed surface structure as designed. A method of laminating meshes (see Patent Document 7) has also been proposed, but a designed hole can be formed on the surface, but a continuous groove structure cannot be formed on the surface.

  In addition, since the uneven shape on the surface is formed stochastically, a hole having a size suitable for tissue formation may be formed by chance, but many holes having a size not suitable for tissue formation are formed. There is a problem. In such a hole having a size unsuitable for tissue formation, a tissue with a blood vessel cannot enter into a small hole particularly unsuitable for tissue invasion, and there is a possibility that blood flow may decrease in this portion.

  There is a statistic that artificial joint replacement has an initial infection rate of about 2-4% even when a clean room is used. The cause of such infection is blood flow around the artificial object. This is also due to the lack of immune function. In addition, in the case of cementless without using bone cement, antibiotics cannot be injected together with bone cement, and it is necessary to rely on drug administration from blood vessels, but there is insufficient blood flow around the implant. In this case, the transport of the drug via the blood vessel does not function effectively, and the effect is limited.

  Thus, until now, biomaterials such as bioimplant materials that have a surface microstructure that is suitable for bone formation and invasion of biotissues with new blood vessels on the surface of biomaterials such as bioimplants have been The fact is that it was not known.

Japanese Patent No. 2710849 JP-A-5-056990 JP-A-5-146504 JP 2004-16398 A JP 2004-141234 A JP 2002-102329 A JP-A-6-7388

  In such a situation, in view of the above prior art, the present inventors have conducted extensive research with the goal of developing a biological implant material having a surface structure suitable for invasion of biological tissue. At least, in a biological implant material having a surface structure in which the size, shape and connection of the surface microspace are controlled, it has been found that a tissue with new blood vessels can be efficiently guided into the surface microspace, The present invention has been completed. The present invention provides a specific surface structure having a surface structure in which the size, shape, and continuous structure of the surface microspace are controlled, and can efficiently induce a tissue with new blood vessels into the surface microspace. It is an object of the present invention to provide a living body implant material and the like that can be easily reproduced as designed and have a designed surface structure.

The present invention for solving the above-described problems comprises the following technical means.
(1) A biomaterial having a surface structure in which the size, shape, and connection of a surface fine space are controlled, and 1) a groove-like space connected or a hole-like space It has a surface structure consisting of concavo-convex structures of 50 μm or more and 1000 μm or less for invasion of bone tissue connected by narrower grooves. 2) Binarization of a two-dimensional map of height information of the concavo-convex structure on the surface A biomaterial characterized in that, in a power spectrum for an image, a bright spot corresponding to a spatial frequency relative to the periodicity of the concavo-convex structure has symmetry with respect to a bright spot corresponding to a wave number of 0.
(2) The biomaterial according to (1), wherein the biomaterial has a plurality of surface structures having different power spectra with respect to a binarized image of a two-dimensional map of the height information of the uneven structure.
(3) A biomaterial having a continuous groove-like surface fine space structure, having a surface roughness of 0.05 μm to 30 μm, a width of 50 to 500 μm and a depth of 50 to 500 μm The biomaterial according to (1) or (2), wherein the biomaterial has a surface structure composed of an uneven structure in which spaces are connected.
(4) A biomaterial having a continuous groove-like surface fine space structure, having a surface roughness of 0.05 μm to 30 μm, a hole shape having a width of 50 to 1000 μm and a depth of 500 to 1000 μm. The biomaterial according to (1) or (2), wherein the space has a surface structure composed of a concavo-convex structure connected by grooves narrower than the width of the hole-shaped space.
(5) The biomaterial according to any one of (1) to (4), wherein the groove-like space is oriented and formed.
(6) The biomaterial according to any one of (1) to (5), wherein a groove-like space or a hole-like space at a dense bone level is oriented and formed.
(7) A biological implant comprising the biological material according to any one of (1) to (6).
(8) A cell culture carrier comprising the biomaterial according to any one of (1) to (6).
(9) A method for producing the biomaterial according to any one of (1) to (6) above, wherein a mask in which a slit having a predetermined width and length is formed on a coating layer forming surface of an implant base material A method for producing a biomaterial, characterized in that it is sprayed with titanium particles having an average particle diameter of 10 to 150 μm.
(10) The method for producing the biomaterial according to any one of (1) to (6) above, wherein a mask having a slit having a predetermined width and length is used as an uneven structure of an implant substrate or a coating layer A method for producing a biomaterial, characterized in that the biomaterial is placed on a forming surface and blasted.
(11) The method for producing a biomaterial according to (9) or (10), wherein the biomaterial is a bioimplant.
(12) The method for producing a biomaterial according to (9) or (10), wherein the biomaterial is a cell culture carrier.

Next, the present invention will be described in more detail.
The present invention relates to a biomaterial having a surface structure in which the size, shape, and connection of a surface fine space are controlled, and a groove-like space connected or a hole-like space has a width of the hole-like space. Power for the binarized image of the two-dimensional map of the height information of the concavo-convex structure on the surface, which has a concavo-convex structure of 50 μm or more and 1000 μm or less for invasion of bone tissue connected by a narrower groove The spectrum is characterized in that the bright spot corresponding to the spatial frequency with respect to the periodicity of the concavo-convex structure has symmetry with respect to the bright spot corresponding to wave number 0.

  In the present invention, the biomaterial has a plurality of surface structures having different power spectra with respect to a binarized image of the two-dimensional map of the height information of the concavo-convex structure, and a continuous groove-shaped surface fine space structure. And having a surface structure composed of a concavo-convex structure in which groove-like spaces having a surface roughness of 0.05 to 30 μm and a width of 50 to 300 μm and a depth of 50 to 300 μm are connected. A hole-shaped space having a groove-like surface fine space structure, having a surface roughness of 0.05 μm to 30 μm, a width of 50 to 1000 μm and a depth of 50 to 1000 μm, A preferred embodiment is to have a surface structure composed of an uneven structure connected by grooves narrower than the width of the space.

  In the present invention, the “surface fine space” means a fine space formed on the surface of the biomaterial implant of the biomaterial of the present invention. In the present invention, having a surface structure in which “groove-like spaces are connected” is defined as a structure in which groove-like recesses are formed on the surface and they are connected to each other. “Surface structure connected by grooves narrower than the width of the hole-shaped space” is defined as a structure in which hole-shaped recesses are formed on the surface and the hole-shaped structures are connected to each other by the groove-shaped structure. The In addition, the groove-like space means a shape sandwiched between a floor and two walls by an elongated depression, and the hole-like space means that all directions except the upward direction are not connected unless there is a connection. It means a shape surrounded by walls. In addition, the groove-shaped space connected is a shape formed by connecting elongated recesses, and the hole-shaped space is connected by a groove. Two or more hole-shaped spaces are groove-shaped spaces. It is the shape of the state connected by. The width of the hole-shaped space is larger than the width of the groove-shaped space.

  Further, the “grooved space at the level of the dense bone” means a grooved space on the surface in contact with the dense bone tissue. The “hole-like space at the compact bone level” means a hole-like space on the surface in contact with the dense bone tissue. In the manufacturing process, even when a groove width fluctuation or a structural defect is formed, the power spectrum corresponding to the height information of the surface structure is acceptable as long as the periodicity is not lost.

  In the present invention, in the above biomaterial, at least a part of the wall surface is calcium phosphate, titanium oxide, alkali titanate, polymer, silane coupling agent, compound formed by hydrolysis of metal alkoxide, mesoporous material, drug, or calcium Containing, or coated with, at least one of compounds containing at least one of magnesium, sodium, potassium, lithium, zinc, tin, tantalum, zirconium, silicon, niobium, aluminum, iron, phosphorus and carbon It is possible that

  In addition, the present invention provides, for example, as a representative application of the biomaterial of the present invention, as a typical example, a bioimplant containing the biomaterial as at least a part of the component, and the biomaterial described above at least as a component. Examples of the carrier for cell culture contained in part.

  In the present invention, the biomaterial can be applied to, for example, a dialysis component, a circulation device component, a filter, and the like in addition to a bioimplant material and a cell culture carrier, but is not limited thereto. Further, the biological implant material referred to in the present invention is a material in which a surface microstructure is formed on the outer side or the inner side of the whole or a part of the surface of the base material for a biological implant material. Or the molded object for using in vivo as an artificial tooth root etc. is meant.

  As long as the biological implant material has characteristics and safety necessary for use in vivo, its shape, usage pattern, and the like are not particularly limited. Examples of the shape of the biological implant material of the present invention include those having an arbitrary shape such as a block shape, a column shape, a plate shape, and an amorphous bulk shape. Examples of the use form of the biological implant material of the present invention include, for example, product forms such as an artificial hip joint stem, an artificial knee joint, an artificial vertebral body, an artificial intervertebral disc, a bone prosthetic material, a bone plate, a bone screw, and an artificial tooth root. Illustrated.

  The cell culture carrier referred to in the present invention means a molded body for culturing cells and tissues in cell engineering, tissue engineering, and regenerative medical engineering. There are no particular restrictions on the shape and usage as long as it has the characteristics necessary for use in cell culture. For example, the shape may be any shape such as a plate shape, a sheet shape, a block shape, a column shape, an indeterminate bulk shape, and a cup shape. Moreover, as a usage form, you may have product forms, such as a cell culture petri dish and a cell culture sheet.

  The metal used as the biomaterial in the present invention is preferably exemplified by pure titanium, titanium alloy, stainless steel, Co or an alloy thereof, Ta, Nb or an alloy thereof, Au, Ag, Cu, Pt and the like. . Further, as ceramics used as a biomaterial in the present invention, preferably, for example, calcium phosphate ceramics such as hydroxyapatite and calcium triphosphate, alumina ceramics, zirconia ceramics, Si ceramics, titania ceramics, at least calcium and Examples thereof include biomaterial glass containing phosphorous and crystallized glass for biomaterial.

  The polymer used as the biomaterial in the present invention is preferably a polyolefin (co) polymer, polystyrene polymer, polyvinyl chloride or polyvinylidene chloride polymer, polyvinyl alcohol, ester thereof or the like. Polyvinyl acetal polymer, polymer of unsaturated compound in which nitrogen atom of substituent is directly bonded to aliphatic chain, poly (meth) acrylic acid (ester) polymer, poly (meth) acrylonitrile polymer, Polymers of unsaturated compounds in which carbonyl groups or nitrile groups are directly bonded to aliphatic chains such as poly (meth) acrylamide polymers, polycyanoacrylate polymers, polydiene polymers, fluorine resins, polyester polymers Examples include coalescence.

  Furthermore, as a polymer used as a biomaterial in the present invention, for example, a hydroxycarboxylic acid polymer such as polylactic acid, a polyether or polyoxide polymer, a polyether polyester polymer, a polycarbonate polymer, a polyurethane ( (Urea) polymers, segmented polyurethane (urea) polymers, polyamide or polyimide polymers, polyamino acid polymers, polyacetal polymers, silicon-containing polymers, sulfur-containing polymers, etc. .

  Examples of the polymer include cellulose or derivatives thereof, starch or derivatives thereof, agarose or derivatives thereof, polysaccharides such as agar, alginic acid or gums, heparin or derivatives thereof, chondroitin or derivatives thereof, hyaluronic acid, chitin. , Mucopolysaccharides such as chitosans, collagens such as atelopeptide collagen and reconstituted collagen or derivatives thereof, gelatins, keratins, or copolymers comprising two or more of the above polymers, or block polymers, graft polymerization Or a crosslinked body, those composites, etc. are illustrated.

  In the present invention, a drug can be used. In the present invention, the agent used as an additive on or in the biomaterial is preferably, for example, an anti-inflammatory agent, fibronectin, albumin or laminin, clotting or anticoagulant (antithrombin, plasmin, urokinase, streptokinase). , Fibrinogen activator, thrombin, etc.), kallikrein, kinin, radikinin antagonists, enzymes that do not act on blood, hormones, growth factors such as bone morphogenetic and cell growth factors, proteinaceous bone growth factors, coagulation or anticoagulants Examples thereof include, but are not limited to, hemolysis inhibitors and osteoporosis therapeutic agents.

  In the present invention, the filler used as an additive on or in the biomaterial is preferably composed of, for example, one or more of metals, ceramics, polymers, carbon-based materials, or any composites thereof. . The composite is a material in which two or more kinds of materials different from each other are firmly bonded and integrated by physical, chemical or mechanical mixing and bonding, for example, Examples include a material obtained by compounding members of different materials by kneading, a material compounded by precipitation from a precursor solution, and the like.

  Moreover, the filling may hold | maintain a chemical | medical agent etc. inside. As the filler for holding the drug, preferably, for example, a hydrogel comprising any one or more of polyvinyl alcohol, collagen, gelatin, agar, hyaluronic acid, chitin / chitosan, polyvinyl acetate or the like Examples include dried products, biodegradable polymers such as polylactic acid polymers and polyethylene glycol polymers, and composites of these components and calcium phosphate ceramics.

  Next, the manufacturing method of the biological implant material in this invention is demonstrated. As a method for producing a living body implant material in the present invention, for example, a method of spraying titanium particles by installing a mask, a method of blasting a substrate by installing a mask, a thermoplastic polymer such as polylactic acid, etc. For example, a method of forming at a glass transition point (Tg) or higher or a temperature range in a molten state is exemplified.

  Further, as the above manufacturing method, for example, a method of forming a groove or hole-like structure by blasting, a molten metal of titanium or tantalum using a mold formed of dental wax, and casting by an investment molding method or a full molding method. A method of obtaining a metal molded body by casting, a ceramic slurry or a sol-gel precursor is cast and molded into a polymer mold such as gypsum or urethane, and then fired at 300-1650 ° C. to form a ceramic molded body The method etc. which are obtained are illustrated as a suitable thing. The production method of the present invention is not limited to these production methods, and the above-described materials, temperature, and pressure can be appropriately changed depending on the target product.

  In biomaterials such as artificial bones, it is important to form artificial bones that contribute to the formation of regular biological tissues and that are suitable for the orientation of the site to be implanted. It is important to control the direction of the groove in the minute space to be oriented in an arbitrary direction, and to form a groove that connects the alignment grooves to each other in order to enable introduction of blood vessels. However, there are no reports of biomaterials such as conventional artificial bones that have a structure in which the spatial arrangement of such oriented grooves is controlled and that are suitable for invasion of living tissue and introduction of cells. It was.

  On the other hand, the biomaterial of the present invention has a structure group of oriented groove-like spaces, and the oriented grooves are connected by a groove-like structure into which living tissue can invade and are implanted at a site to be implanted. It is a constituent element that it is spatially arranged so as to suitably match the orientation of the film. They are suitable for the formation of hard tissue and soft tissue that can sufficiently invade cells, tissues, blood vessels, etc., and promote tissue regeneration suitable for the orientation of the living tissue at the site of implantation. Construction of the structure becomes possible.

  The biomaterial of the present invention has a surface roughness of 0.05 μm to 30 μm for anchoring bone cells, a groove having a width of 50 to 500 μm and a depth of 50 to 500 μm for invasion of bone tissue Having a surface structure composed of a concavo-convex structure in which a plurality of spaces are connected, and a connected groove-like space at a dense bone level is oriented or formed, or 50 to 50 for invasion of bone tissue A hole-shaped space having a width of 1000 μm and a depth of 50-1000 μm has a surface structure composed of a concave-convex structure connected by grooves, and the hole-shaped space at the level of dense bone is oriented and formed. It is characterized by.

  In the present invention, the groove-shaped space or the hole-shaped space is formed to be oriented, for example, the groove-shaped space or the hole-shaped space is, for example, a bone unit in the cortical bone of the femoral shaft. It means having the same degree of orientation as that observed in a living tissue such as an array. In this case, even if the orientation of the bone tissue is not necessarily imitated as it is, it is easier to design and simplify the distribution of stress and the orientation direction of the tissue using the bone tissue as a model. It is desirable from the viewpoint of manufacturing ease and cost.

  In the present invention, it is desirable that the long direction of the groove-like space is oriented in the same direction as the orientation observed in the living tissue in the site where the groove is embedded, but here, it is oriented in the same direction as the orientation. The term “for example” means having the same orientation as that observed in living tissue such as an arrangement of bone units in the cortical bone of the femoral shaft. In this case, the present invention does not imitate the orientation of the bone tissue as it is, but it is easier to design by extracting the stress distribution and the orientation direction of the tissue as a model and simplifying this. It is desirable from the viewpoints of ease and manufacturing and cost.

  In the present invention, a structure in which groove-like spaces are connected or a structure in which hole-like spaces are connected by grooves is formed. However, in terms of ease of design, ease of manufacture, and cost, the structure is further simplified. It is desirable to have a structure in which similar convex portions are periodically arranged. In the periodicity, even if defects or fluctuations occur due to manufacturing, as long as the bright spot corresponding to the spatial frequency does not disappear in the power spectrum for the binary image of the two-dimensional map of the height information of the implant surface, Permissible.

  In the present invention, in an implant having a concavo-convex structure on the surface, a relative value with respect to the height of a reference point arbitrarily selected is calculated with respect to the height at each point on the surface, and the value is used as a color shading. The projection on the plane is defined as a two-dimensional map of the height information of the surface of the implant. In the two-dimensional map of the height information of the surface of the implant, for example, the average value of all points of the surface height is set as a threshold value, and a point having a height equal to or higher than the threshold value is set to “1”. The value less than “0” is assigned to “1” or “0” with “black” or “white” and plotted again. This is the binary value of the two-dimensional map of the height information of the implant surface. It is defined as a chemical image. In the present invention, the value used for the threshold value is not particularly limited.

  The power spectrum is a two-dimensional Fourier transform of the image, and the square of the absolute value is expressed in shades, and the position of the bright spot is the wave number with respect to the periodicity of the image (the reciprocal of the distance of the periodic structure, also referred to as spatial frequency) Indicates. In the present invention, since the power spectrum for the binarized image of the two-dimensional map of the height information on the surface of the implant is obtained, the meaning represents the spatial frequency with respect to the periodicity of the concavo-convex structure. In addition, in a random structure having no periodic structure, no clear bright spot appears in the power spectrum other than the central bright spot corresponding to the wave number 0 (the distance of the periodic structure is infinite). When the periodicity of the concavo-convex structure on the implant surface is different, the power spectrum is different. This is because, in the power spectrum of the binarized image of the two-dimensional map of the height information of the two implant surfaces having the same projected area, the wave number is 0. Means that at least a part of the bright spots of the spatial frequency with respect to the periodicity of the concavo-convex structure do not overlap when the positions of the bright spots are aligned.

  In the present invention, even when a plurality of surface structures are mixed, a luminescent spot having symmetry in the power spectrum is obtained, but in this case, a figure in which the luminescent spots of the individual power spectra are superimposed is obtained. . That is, even if there is a random surface structure, a bright spot having symmetry in the power spectrum corresponding to the periodic structure of the other part can be obtained. The present invention is suitable for bone tissue regeneration by constructing a biomaterial with controlled orientation in the simplified form as described above, and is easy to design and manufacture the biomaterial, and The greatest feature is that a new biomaterial capable of satisfying all cost rationality requirements has been created. Regarding the above-mentioned orientation, errors occur both in production and in use, but these are included in an allowable range that is regarded as having orientation in the present invention. However, it is desirable that the deviation in orientation due to manufacturing errors be within the range of the degree of orientation found in living tissue.

  The present invention makes it possible to control nutrient replenishment and oxygen replenishment by adjusting the surface structure of biomaterials with high accuracy as described above, and to suitably control tissue regeneration, hard tissue formation, and soft tissue formation. It is possible to construct and provide a simple biomaterial. In these, the biomaterial has a predetermined highly regular spatial arrangement composed of the orientation grooves with high orientation and the continuous grooves connecting the orientation grooves, and the desired shape is obtained. The space form can be quantitatively controlled and the design changes can be made arbitrarily and easily, and can be realized only when all the conditions are met.

The present invention has the following effects.
(1) It is possible to form a biomaterial having communication grooves in which the orientation, size and shape of the grooves of the biomaterial are directly controlled.
(2) Thereby, it is possible to provide only a scaffold structure suitable for the invasion of bone tissue and blood vessels, in which a shape unfavorable for the formation of bone tissue and blood vessels is eliminated.
(3) Thereby, it becomes possible to control the form of the biological tissue formed there by the geometric shape of the groove formed.
(4) The orientation and periodicity of the formed tissue can be controlled by controlling the geometric shape such as the shape and orientation of the grooves and the distribution thereof.

  EXAMPLES Next, although this invention is demonstrated concretely based on an Example, this invention is not limited at all by the following Examples.

(Preparation of implants with continuous groove-like surface fine space structure)
A mask in which slits having a width of 300 μm and a length of 1200 μm were arranged in a hexagonal close-packed pattern at intervals of 150 μm was placed on the coating layer forming surface of the implant substrate, and titanium particles having an average particle diameter of about 70 μm were sprayed. An implant having a surface structure (FIG. 1) in which groove-like spaces having an average width of about 180 μm and a depth of about 230 μm were connected could be formed. It was also possible to coat the surface with calcium phosphate-based bioactive ceramics such as hydroxyapatite using thermal spraying or the like.

(Manufacture of implants having a surface fine space structure in which hole-like spaces are connected)
A mask in which circular slits of φ300 μm were arranged in a square array at intervals of 150 μm was placed on the coating layer forming surface of the implant base material, and titanium particles having an average particle diameter of about 70 μm were sprayed. An implant having a surface structure (FIG. 2) in which hole-like spaces having an average width of about 390 μm and a depth of about 230 μm were connected by grooves having a width of about 200 μm and a depth of about 230 μm could be formed. It was also possible to coat the surface with calcium phosphate-based bioactive ceramics such as hydroxyapatite using thermal spraying or the like.

(Animal experiment of implant having continuous groove-like surface fine space structure)
The 4 × 3 mm implant prepared in Example 1 was implanted in a bone defect hole having a diameter of 5 mm and a depth of 5 mm prepared in the vicinity of the proximal tibia of a 12-week-old healthy male SPF rabbit, and the periosteum, subcutaneous tissue, and The skin was sutured. After 7 days, 2 weeks and 4 weeks after implant implantation, the animals were euthanized by exsanguination under an anesthesia of about 50 ml / kg (iv) of sodium pendbarbital, and the cervical implant was removed, Fixed in 10% neutral buffered formalin. After fixation, the implanted part was made into a semi-decalcified state by an ion exchange method, and then a section having a thickness of about 3 μm was prepared, and hematoxylin / eosin staining was performed, and morphological evaluation was performed.

  In the evaluation, granulation tissue with new blood vessels invaded into the connected groove-like space at the dense bone level on the seventh day of implantation (FIG. 3a), and along the groove-like structure wall at the second week. New bone formation occurred (FIG. 3b), and it was observed that bone tissue with blood vessels was formed inside the groove-like structure at 4 weeks (FIG. 3c). With respect to the formed bone tissue, an oriented tissue was formed using the orientation structure of the groove-like space of the implant as a template.

(Animal experiments of implants having a surface fine space structure in which hole-like spaces are connected)
The 4 × 3 mm implant prepared in Example 2 was implanted in a bone defect hole having a diameter of 5 mm and a depth of 5 mm prepared in the vicinity of the proximal tibia of a 12-week-old healthy male SPF rabbit, and the periosteum, subcutaneous tissue, and The skin was sutured. Four weeks after implant implantation, the animals were euthanized by exsanguination under an anesthesia of about 50 ml / kg (iv) of sodium pendant barbital, and the cervical implant was removed and fixed in 10% neutral buffered formalin. did. After fixation, the implanted part was made into a semi-decalcified state by an ion exchange method, and then a section having a thickness of about 3 μm was prepared, and hematoxylin / eosin staining was performed, and morphological evaluation was performed.

  In this evaluation, it was observed that bone tissue and bone marrow tissue with new blood vessels were formed in a hole-like space at a dense bone level and a groove-like space connecting the holes (FIG. 4). An oriented structure was not formed in the hole-like space having an isotropic structure and the groove-like space connecting the holes.

(Periodicity of implants with continuous groove-like surface microstructure)
6 to 11 show a binarized image of the height information of the surface of an implant having a surface structure in which groove-like spaces are connected and its power spectrum. Bright spots corresponding to the wave number of the repetition period can be seen in the repeating direction of the unevenness.

(Periodicity of implants having a surface fine spatial structure in which hole-like spaces are connected by grooves)
12 to 13 show a binarized image of the height information of the surface of an implant having a surface structure in which hole-like spaces are connected by grooves and its power spectrum. Bright spots corresponding to the wave number of the repetition period can be seen in the repeating direction of the unevenness.

(Periodicity with defects or fluctuations in the surface fine spatial structure)
FIGS. 14 to 19 are binary images of height information of the surface of an implant having a surface structure in which groove-like spaces with defects or fluctuations are connected or a surface structure in which hole-like spaces are connected by grooves. And its power spectrum. Regardless of the presence of defects and the fluctuation of the size of the groove-like space, bright spots corresponding to the wave number of the repetition period for the basic uneven structure are seen.

Comparative Example 1
(Preparation of an implant having a random surface structure)
Titanium particles having an average particle size of about 70 μm were sprayed on the implant base material, and further, hydroxyapatite particles having an average particle size of about 80 μm were sprayed. An irregular concavo-convex structure was formed on the surface.

Comparative Example 2
The 4 × 3 mm implant prepared in Comparative Example 1 was implanted in a bone defect hole having a diameter of 5 mm and a depth of 5 mm prepared in the vicinity of the proximal tibia of a 12-week-old healthy male SPF rabbit, and the periosteum, subcutaneous tissue, and The skin was sutured. Four weeks after implant implantation, the animals were euthanized by exsanguination under an anesthesia of about 50 ml / kg (iv) of sodium pendant barbital, and the cervical implant was removed and fixed in 10% neutral buffered formalin. did. After fixation, the implanted part was made into a semi-decalcified state by an ion exchange method, and then a section having a thickness of about 3 μm was prepared, and hematoxylin / eosin staining was performed, and morphological evaluation was performed.

  In the evaluation, it was observed that a bone tissue was formed in a minute space of an irregular depression-like structure formed by chance on the implant surface of the depression portion at the dense bone level (FIG. 5). Formation of new blood vessels was not observed in the formed tissue.

Comparative Example 3
(Random structure)
20 to 22 show a binarized image of the height information of the surface of an implant having a random spatial structure and its power spectrum. A thin halo pattern is seen around the bright spot corresponding to the central wave number of 0, and no obvious periodicity of the structure is seen.

  As described above in detail, the present invention relates to a bioimplant material, a method for producing the bioimplant material, and a use thereof. According to the present invention, the orientation, size, and shape of the groove of the biomaterial are directly controlled. A biomaterial in which grooves are formed can be formed. Further, according to the present invention, due to the formed groove, it is easy to conduct body fluids and bubbles, and can provide a scaffold suitable for invasion of bone tissue and blood vessels, and further, due to the geometric shape of the formed groove, A biological material such as a biological implant that can control the form of the biological tissue formed there can be produced and provided. The present invention provides a biomaterial having a specific surface structure suitable for invasion of bone tissue or blood vessels defined by a power spectrum for a binarized image of a two-dimensional map of height information of a surface uneven structure. Useful.

FIG. 1 shows a surface fine space structure according to the first embodiment. FIG. 2 shows a surface fine space structure according to the second embodiment. FIG. 3 shows the structure induced in the surface fine space structure according to Example 3. FIG. 4 shows the structure induced in the surface fine space structure according to Example 4. FIG. 5 shows a structure induced in a random surface fine space structure according to Comparative Example 2. FIG. 6 (a) shows a groove-like space formed by arranging convex portions of the surface uneven structure according to Example 5 in a hexagonal lattice. (B) shows a power spectrum. FIG. 7 (a) shows a groove-like space formed by arranging convex portions of the surface concavo-convex structure according to Example 5 in a face-centered lattice. (B) shows a power spectrum. FIG. 8 (a) shows a groove-like space formed by arranging the groove-like space domains formed by the convex portions of the surface concavo-convex structure according to Example 5 to form an angle of 90 degrees. is there. (B) shows a power spectrum. FIG. 9 (a) shows a groove-like space formed by projecting convex portions of the surface uneven structure according to Example 5 in a zigzag manner. (B) shows a power spectrum. FIG. 10 (a) shows the groove-like space formed by arranging the groove-like space domains formed by the convex portions of the surface uneven structure according to Example 5 to form an angle of 60 degrees. is there. (B) shows a power spectrum. FIG. 11 (a) shows a groove-like space formed by arranging convex portions of the surface concavo-convex structure according to Example 5 in a hexagonal lattice. (B) shows a power spectrum. FIG. 12 (a) shows a space in which hole-like spaces formed by arranging convex portions of the surface concavo-convex structure according to Example 6 in a cubic lattice are connected by grooves. (B) shows a power spectrum. FIG. 13 (a) shows a groove-like space and a hole-like shape formed by arranging the groove-like space domains formed by the convex portions of the surface concavo-convex structure according to Example 6 to form an angle of 60 degrees. The surface structure which consists of space is shown. (B) shows a power spectrum. FIG. 14A shows a structure in which a defect is formed in a groove-like space formed by arranging convex portions of the surface uneven structure according to Example 7 in a hexagonal lattice. (B) shows a power spectrum. FIG. 15 (a) shows a structure in which a defect is formed in a groove-like space formed by arranging convex portions of the surface uneven structure according to Example 7 in a hexagonal lattice. (B) shows a power spectrum. FIG. 16 (a) shows a structure in which the groove width fluctuates in a groove-like space formed by arranging convex portions of the surface uneven structure according to Example 7 in a hexagonal lattice. (B) shows a power spectrum. FIG. 17 (a) shows a structure in which a defect is formed in a space in which hole-like spaces formed by arranging convex portions of the surface concavo-convex structure according to Example 7 in a cubic lattice are connected by grooves. is there. (B) shows a power spectrum. FIG. 18 (a) shows a structure in which defects are formed in a space in which hole-like spaces formed by arranging convex portions of the surface concavo-convex structure according to Example 7 in a cubic lattice are connected by grooves. is there. (B) shows a power spectrum. FIG. 19 (a) shows the size of the recesses and the grooves for connecting the recesses in the space in which the hole-shaped spaces formed by arranging the convex portions of the surface uneven structure according to Example 7 in a cubic lattice are connected by the grooves. This shows a structure having fluctuations in the width. (B) shows a power spectrum. FIG. 20 (a) shows a space formed by randomly and randomly arranging convex portions of the surface uneven structure according to Comparative Example 3. (B) shows a power spectrum. FIG. 21 (a) shows a space formed by randomly arranging convex portions of the surface uneven structure according to Comparative Example 3 in a relatively dense manner. (B) shows a power spectrum. FIG. 22 (a) shows a space formed by randomly arranging wire-like convex portions according to Comparative Example 3. FIG. (B) shows a power spectrum.

Claims (12)

  A biomaterial having a surface structure in which the size, shape and connection of the surface fine space are controlled, and 1) the groove-like space is connected or the hole-like space is narrower than the width of the hole-like space. It has a surface structure composed of a concavo-convex structure of 50 μm or more and 1000 μm or less for invasion of bone tissue connected by a groove. A biomaterial characterized in that, in the spectrum, a bright spot corresponding to a spatial frequency relative to the periodicity of the concavo-convex structure has symmetry with respect to a bright spot corresponding to a wave number of 0.   The biomaterial according to claim 1, wherein the biomaterial has a plurality of surface structures having different power spectra with respect to a binarized image of a two-dimensional map of height information of the uneven structure.   A biomaterial having a continuous groove-like surface fine space structure, having a surface roughness of 0.05 μm to 30 μm, and a groove-like space having a width of 50 to 500 μm and a depth of 50 to 500 μm. The biomaterial according to claim 1, wherein the biomaterial has a surface structure composed of an uneven structure.   A biomaterial having a continuous groove-shaped surface fine space structure, having a surface roughness of 0.05 μm to 30 μm, a hole-shaped space having a width of 50 to 1000 μm and a depth of 500 to 1000 μm, The biomaterial according to claim 1, wherein the biomaterial has a surface structure composed of a concavo-convex structure connected by grooves narrower than the width of the hole-shaped space.   The biomaterial according to any one of claims 1 to 4, wherein the groove-like space is oriented.   The biomaterial according to any one of claims 1 to 5, wherein a groove-like space or a hole-like space at a compact bone level is oriented.   A living body implant comprising the living body material according to claim 1.   A cell culture carrier comprising the biomaterial according to any one of claims 1 to 6.   A method for producing the biomaterial according to any one of claims 1 to 6, wherein a mask having slits of a predetermined width and length is placed on the coating layer forming surface of the implant base material, A method for producing a biomaterial, comprising spraying titanium particles having a particle diameter of 10 to 150 μm.   A method for producing a biomaterial according to any one of claims 1 to 6, wherein a mask having a slit having a predetermined width and length is placed on the surface of the implant substrate or coating layer on which the concavo-convex structure is formed. And a blasting process for producing a biomaterial.   The method for producing a biomaterial according to claim 9 or 10, wherein the biomaterial is a bioimplant.   The method for producing a biomaterial according to claim 9 or 10, wherein the biomaterial is a cell culture carrier.