JP6294852B2 - Biological implant - Google Patents

Description

  The present invention relates to a biological implant. More specifically, the present invention includes a dense substantial part, a microporous layer provided on the surface thereof, and a protective layer provided on the surface thereof. The invention relates to a bioimplant having a void extending from the outer surface of the layer to the surface of the microporous layer.

  The treatment method in which an artificial bone is transplanted into a bone defect portion or the like in which the bone is deficient has a smaller physical burden on the patient than the treatment method in which a normal bone of the patient, that is, an autologous bone is transplanted into the bone defect portion or the like. In recent years, it has been attracting attention because there are no problems in preparation.

  Bioceramics such as hydroxyapatite are known as excellent artificial bone materials because they are chemically bonded to bone. However, bioceramics have a problem of low strength and weakness against impact.

  As materials for artificial bones, metal materials such as titanium alloys and cobalt chromium alloys having very high strength properties are also known. However, these metal materials have the possibility of causing metal allergies, etc., and also have an extremely large elastic modulus compared to living bones. When transplanted into a defect, etc., stress shielding (stress shielding) occurs due to the difference in mechanical properties between the living bone and the metal material, the stress acting on the surrounding bone is absorbed by the metal material, and the surrounding bone becomes brittle There is a possibility of becoming.

  Therefore, in recent years, resins such as engineering plastics have attracted attention as materials that can solve such problems and have mechanical properties similar to those of living bones. For example, high-density polyethylene resin is very low elastic and flexible, making it suitable as a material for artificial bones. Polyetheretherketone (PEEK) is close to the original bone and has excellent biocompatibility. Therefore, it is suitable as a material for artificial bones.

  By the way, it is well known that the structure of an artificial bone is an important factor in terms of the ability to bind to bone, and when it is embedded in a living body, it is resin molded so that the living tissue can easily enter the inside. A method of making the body surface or the entire structure porous has also been proposed.

  For example, Patent Document 1 discloses a surface foam comprising a substantial part and a surface layer having a small diameter pore and a large diameter pore formed on the surface thereof, wherein the surface foam is formed of plastic. The small pores and a part of the large pores form open pores that open on the surface of the surface layer, and the open pores are small pores having an average pore size of 5 μm or less and average pore pore sizes. Has a large-diameter open pore of 10 to 200 μm, and the large-diameter open pore opened to the surface of the surface layer has a small-diameter pore and a communication hole communicating with the large-diameter pore formed on the inner wall surface thereof. "Featured surface foam" (Claim 1).

  Patent Document 2 discloses a biological implant comprising a dense substantial portion made of plastic and a porous surface layer formed on the surface of the substantial portion, wherein the substantial portion has an uneven structure on the outermost surface. The surface layer is formed by three-dimensionally connecting pores, and the thickness of the surface layer formed in the concave portion of the concavo-convex structure is equal to the thickness of the surface layer formed in the convex portion of the concavo-convex structure. A biological implant characterized in that it is at least doubled. "(Claim 1).

  Patent Document 3 discloses a porous device for tissue manipulation formed by solid freeform fabrication. As a solid freeform fabrication method, stereolithography, selective laser sintering, ballistic particle modeling production method, and Fusion deposition modeling is disclosed (claims 1 and 62, columns 0020, etc.).

International Publication No. 2009/095960 JP 2010-253195 A JP-T-2002-527144

  Since the surface foam disclosed in Patent Document 1 is formed by foaming the surface of a substrate formed of plastic, a surface layer having small diameter pores and large diameter pores is formed (see Patent Document 1). (Claims 1 and 7, etc.), the skeleton that forms the outer shape of the small pores and the large pores becomes thin, and is inferior in strength compared to a dense body. Therefore, when the surface foam of Patent Document 1 is embedded in a site where the use conditions are severe such as a heavy load is concentrated, a part of the pores in the surface layer is crushed, and the surface layer is bonded to the living bone. May not contribute.

  Since the surface layer having pores is formed on the surface of the concavo-convex structure, the living body implant disclosed in Patent Document 2 has a surface layer formed on the convex portion when used between vertebral bodies. There is a risk that the pores will collapse.

  The porous device disclosed in Patent Document 3 is porous as a whole and does not have a dense portion having few pores. Since this porous device is not so strong, it is not suitable for use in a site where a large load is applied.

  Problems to be solved by the present invention include a surface structure in which a living tissue such as a bone tissue can easily enter when embedded in a living body, and a case where it is embedded in a site where a load is intensively applied and between vertebral bodies, etc. It is to provide a biological implant having connectivity with bones by maintaining the surface structure even when implanted by being embedded.

Means for solving the problems are as follows:
(1) A dense substantial portion made of engineering plastic, a microporous layer provided on the surface of the substantial portion, and a protective layer provided on the surface of the microporous layer, wherein the protective layer is the microporous layer provided at a part of the surface of, Ri Do from engineering plastics, organic and dense skeleton porosity Ru der 5%, and a gap extending from the outer surface of the protective layer to the surface of the microporous layer And the said microporous layer is a biological implant characterized by having the micro open pore opened on the surface of the said microporous layer.

The preferred embodiment of (1) is as follows.
(2) The living body implant according to (1), wherein the protective layer has a porosity of 10 to 90%.
(3) The ratio (S _m / S × 100) of the exposed area S _m exposed in the voids of the micro porous layer to the total area S of the interface between the micro porous layer and the protective layer is 10 to 90%. The living body implant according to (1) or (2), wherein the living body implant is characterized.
(4) The living body implant according to any one of (1) to (3), wherein the protective layer has a thickness of 100 to 10,000 μm.

Means for solving the another problem is as follows.
(5) The method for manufacturing a living body implant according to any one of (1) to (4), wherein the protective layer is formed by rapid prototyping. is there.

  The living body implant according to the present invention has a surface structure in which a living tissue such as a bone tissue can easily enter when embedded in a living body, and is embedded in a portion where a load is intensively applied or between vertebral bodies. Even in the case of embedment in the living body, it is possible to provide a biological implant having connectivity with bone by maintaining the surface structure.

  In particular, the bioimplant according to the present invention includes a microporous layer having micro-open pores on the surface of a dense substantial portion made of engineering plastic, and a protective layer having a void reaching from the outer surface to the surface of the microporous layer. Therefore, when it is embedded in a living body, a living tissue such as a bone tissue can easily enter, and a new living tissue is formed there, and the living tissue is immobilized inside the living body implant. The implant is firmly bonded.

  In addition, the living body implant according to the present invention includes a protective layer having a dense skeleton made of engineering plastic, so when embedding in a site where a load is intensively applied or when implanting between vertebral bodies or the like. In addition, it is possible to prevent the microporous layer from being crushed by the skeleton portion, thereby maintaining the bonding property with the bone.

  Furthermore, the bioimplant according to the present invention is not formed so that the whole bioimplant is porous, but the microporous layer and the protective layer are provided on the surface of a dense substantial portion made of engineering plastic. Therefore, the whole biological implant has higher strength than a material having a porous structure. Therefore, the biological implant according to the present invention can be applied to a site where a relatively high strength is required.

  According to the method for manufacturing a living body implant according to the present invention, since the protective layer is formed by rapid prototyping, protective layers having various structures according to the application site can be easily formed.

FIG. 1 is a schematic diagram showing an arbitrary cross section of a biological implant which is an example of a biological implant according to the present invention. FIG. 2 is a schematic view of the biological implant shown in FIG. 1 when viewed from above. FIG. 3 is a schematic view of a living body implant, which is another example of the living body implant according to the present invention, as viewed from above. FIG. 4 is a schematic view of a living body implant, which is still another example of the living body implant according to the present invention, as viewed from above. FIG. 5 is an enlarged schematic view showing the microporous layer in the biological implant shown in FIG. FIG. 6 is an image observed from above with a digital microscope before driving the microporous layer in the living body implant specimen manufactured in Example 1. FIG. 7 is an image obtained by observing the microporous layer from the upper surface with a digital microscope after implanting the biological implant specimen manufactured in Example 1. FIG. 8 is an image of the microporous layer in the living body implant specimen manufactured in Comparative Example 1 observed from the top surface with a digital microscope before being driven. FIG. 9 is an image obtained by observing the microporous layer from the upper surface with a digital microscope after implanting the living body implant specimen manufactured in Comparative Example 1.

  The biological implant according to the present invention comprises a dense substantial portion made of engineering plastic, a microporous layer provided on the surface of the substantial portion, and a protective layer provided on the surface of the microporous layer, A dense skeleton portion made of engineering plastic provided on a part of the surface of the microporous layer, and a void reaching from the outer surface of the protective layer to the surface of the microporous layer. Has micro-open pores that open to the surface of the microporous layer.

(First embodiment)
Hereinafter, the biological implant according to the present invention will be described in detail with reference to FIGS. 1 and 2. FIG. 1 is a schematic view showing an arbitrary cross section of a biological implant which is an example of a biological implant according to the present invention. FIG. 2 is a schematic view of the biological implant shown in FIG. 1 when viewed from above. As shown in FIGS. 1 and 2, the living body implant 1 of this embodiment includes a dense substantial portion 2 made of engineering plastic, a microporous layer 3 provided on the surface of the substantial portion 2, and the microporous layer 3. And a protective layer 4 provided on the surface.

  The living body implant 1 does not have the entire living body implant 1 formed porous, but has a dense substantial part 2 made of engineering plastic. Therefore, the biological implant 1 has higher strength than a material in which the entire biological implant has a porous structure. Therefore, the biological implant 1 can be applied to a site where a relatively high strength is required.

  The engineering plastic forming the substantial part 2 is preferably an engineering plastic having mechanical properties similar or close to those of living bones or teeth. Examples of such an engineering plastic include polyether ether ketone, polyether ether ketone ketone, and polyether. Aromatic polyether ketones such as ketone ketone, polyether ketone ether ketone ketone, polyamide, polyacetal, polycarbonate, polyphenylene ether, modified polyphenylene ether, polyester, polyphenylin oxide, polybutylene terephthalate, polyethylene terephthalate, polysulfone, syndiotactic polystyrene , Polyethersulfone, polyphenylene sulfide, polyarylate, polyetherimi , Polyamideimide, fluororesin, ethylene vinyl alcohol copolymer, polymethylpentene, diallyl phthalate resin, polyoxymethylene, polytetrafluoroethylene and other thermoplastic engineering plastics, phenol, urea, melamine, unsaturated polyester, epoxy, Examples include thermosetting engineering plastics such as diallyl phthalate, silicone, and polyurethane. An engineering plastic can also be used individually by 1 type, and can also use 2 or more types together. Among these, polyether ether ketone (PEEK) is particularly preferable as the material for forming the substantial part 2 because of its high mechanical compatibility, which is close to that of living bones.

  The engineering plastic forming the substantial part 2 may be a fiber reinforced engineering plastic mixed with fibers. Examples of the fibers contained in the fiber-reinforced engineering plastic include carbon fibers including carbon nanotubes, glass fibers, ceramic fibers, metal fibers, and organic fibers. Examples of the glass fibers include fibrous materials of borosilicate glass (E glass), fibrous materials of high strength glass (S glass), fibrous materials of high elasticity glass (YM-31A glass), and the like. Examples of the ceramic fiber include a silicon carbide fiber, a silicon nitride fiber, an alumina fiber, a potassium titanate fiber, a boron carbide fiber, a magnesium oxide fiber, Examples include zinc oxide fibrous materials, aluminum borate fibrous materials, boron fibrous materials, etc. Examples of the metal fibers include tungsten fibrous materials, molybdenum fibrous materials, and stainless steel fibrous materials. Steel fiber, tantalum fiber, and the like. Examples of the organic fiber include, for example, polyvinyl alcohol fiber, polyamide fiber, polyethylene, and the like. Fibrous material terephthalate, fibrous material of a polyester, a fibrous material aramid, and the like. The fibers can be used alone or in a mixture of two or more.

  The substantial part 2 includes, in addition to engineering plastics, an antistatic agent, an antioxidant, a light stabilizer such as a hindered amine compound, a lubricant, an antiblocking agent, an ultraviolet absorber, an inorganic filler, and a pigment as necessary. Various additives such as coloring agents may be contained.

  The substantial part 2 is densely formed. That is, the substantial part 2 is formed without positively containing pores. In the present invention, the fact that the substantial part 2 is dense means that the porosity is 5% or less. The porosity of the substantial part 2 can be calculated from the measured density obtained by measuring the volume and mass of the substantial part 2 and the theoretical density of the substantial part 2.

  The protective layer 4 has a dense skeleton 5 made of engineering plastic provided on a part of the surface of the microporous layer 3 and a void 6 reaching from the outer surface of the protective layer 4 to the surface of the microporous layer 3. . Since the living body implant 1 includes the protective layer 4 having the dense skeleton 5 made of engineering plastic, the skeleton is used when it is embedded in a site where loads are concentrated or when it is embedded between vertebral bodies. 5 can prevent the microporous layer 3 from being crushed, thereby maintaining the bondability with the bone. Moreover, since the biological implant 1 includes the microporous layer 3 on the surface of the substantial part 2 and the protective layer 4 having the void 6 reaching from the outer surface to the surface of the microporous layer 3, the living body implant 1 is embedded in the living body. A living tissue such as a bone tissue is easy to enter, and a new living tissue is formed there, and the living tissue is fixed inside the living implant 1, so that the living tissue and the living implant 1 are firmly coupled. .

  The engineering plastic forming the skeleton 5 is preferably an engineering plastic having mechanical properties similar to or similar to living bones or teeth. Examples of the engineering plastic include the engineering plastic mentioned as the material forming the substantial part 2. Can do.

  The skeleton 5 is densely formed. That is, the skeleton 5 is formed without positively containing pores. In the present invention, the fact that the skeleton 5 is dense means that the porosity is 5% or less. The porosity of the skeleton 5 can be obtained in the same manner as the substantial part 2.

  The void 6 is a space that extends from the outer surface of the protective layer 4, that is, the outer surface of the biological implant 1 to the surface of the microporous layer 3, and is a space formed between the skeleton 5 and the skeleton 5. The shape and size of the gap 6 are not particularly limited, but preferably have a width that allows a biological tissue such as a bone tissue to easily enter the microporous layer 3.

  The structure of the protective layer 4 can prevent the microporous layer 3 from being crushed when the living body implant 1 is embedded in the living body, and can also allow a living tissue such as a bone tissue to enter the microporous layer 3. As long as it is comprised so that it may have, it does not specifically limit. The protective layer 4 shown in FIG. 1 and FIG. 2 forms a striped pattern on the surface of the microporous layer 3 by arranging the fibrous skeleton parts 5 at equal intervals. The fibrous skeleton parts 5 are arranged at equal intervals so as to be orthogonal to each other to form a striped pattern, and when viewed from the upper surface, the lattice-like skeleton parts 5 are formed. The protective layer 4 shown in FIG. 1 and FIG. 2 is laminated in two layers so that the skeleton parts 5 arranged in a striped pattern are orthogonal to each other, and is configured in a lattice shape when viewed from the top. The patterned skeleton portions 5 may be laminated and configured in a lattice shape when viewed from the upper surface, or may be configured only by a single-layer striped skeleton portion 5. Further, like the biological implant 101 shown in FIG. 3, the protective layer 104 has a structure in which a plurality of columnar skeleton portions 105 are provided on the surface of the microporous layer 103 to form a mesh-like void 106. There may be. In the protective layer 104 of this embodiment, a plurality of columnar skeleton parts 105 are arranged in a staggered manner, but the columnar skeleton parts may be arranged randomly or in a grid pattern. . Further, like the living body implant 201 shown in FIG. 4, the protective layer 204 has a structure in which one fibrous skeleton 205 is spirally arranged on the surface of the microporous layer 203 to form a spiral void 206. It may be a structure. The protective layer may have a structure in which two or more layers having different structures are stacked. For example, the protective layer may have a skeleton portion arranged in a striped pattern on a skeleton portion arranged spirally on the surface of the microporous layer.

The skeleton 5 is provided on a part of the surface of the microporous layer 3, and the surface of the microporous layer 3 on which the skeleton 5 is not provided is exposed to the gap 6. The ratio (S _m / S × 100) of the exposed area S _m of the exposed surface 7 exposed in the void 6 of the micro porous layer 3 to the total area S of the interface between the micro porous layer 3 and the protective layer 4 is 10 to 90%. It is preferable that it is 30 to 70%. A biological tissue such as a bone tissue reaches the microporous layer 3 through the gap 6 and enters the interior of the biological implant 1 through a microopen hole opened on the surface of the microporous layer 3, that is, the exposed surface 7. Therefore, the larger the ratio (S _m / S × 100) of the exposed area S _m, the larger the area where the living tissue enters in the living implant 1 and the connectivity between the living implant 1 and the living bone is improved. Also, as the ratio of the exposed area _{S m (S m / S ×} 100) is small, the proportion of skeletal portion 5 becomes large, since compression loads is improved, when embedded in the site where the load is applied to the intensive and It is possible to further prevent the microporous layer 3 from being crushed by the skeletal part 5 when it is embedded between vertebral bodies or the like. When the ratio (S _m / S × 100) of the exposed area S _m is within the above range, the surface structure of the biological implant 1 is maintained when the implant is implanted between vertebral bodies, etc. It is possible to provide a biological implant 1 having the property.

  The porosity of the protective layer 4 is preferably 10 to 90%, and more preferably 30 to 70%. When the porosity of the protective layer 4 is less than 10%, the space into which the living tissue enters becomes small, and the connectivity between the living implant 1 and the living bone may be reduced. In addition, as the porosity of the protective layer 4 increases, the strength of the protective layer 4 tends to decrease, and when the porosity of the protective layer 4 exceeds 90%, it is microscopic when it is embedded between vertebral bodies or the like. There is a possibility that the porous layer 3 cannot be prevented from being crushed. When the porosity of the protective layer 4 is within the above range, the living body implant 1 having connectivity with living bones is provided by maintaining the surface structure of the living body implant 1 when embedded between vertebral bodies or the like. can do.

  The porosity of the protective layer 4 is calculated from the calculated density and the theoretical density of the protective layer by cutting out the protective layer 4 from the biological implant 1 and measuring the volume and mass of the cut out protective layer 4. can do.

  The thickness of the protective layer 4 is preferably 100 to 10,000 μm. When the thickness of the protective layer 4 is less than 100 μm, the microporous layer 3 cannot be prevented from being crushed when the living body implant 1 is implanted between vertebral bodies or the like, and a part of the micro-open pores is blocked. There is a risk that. Moreover, it exists in the tendency for the intensity | strength of the biological implant 1 whole to fall, so that the thickness of the protective layer 4 becomes large. Therefore, when the thickness of the protective layer 4 is within the above range, a desired strength can be maintained, and the microporous layer 3 can be prevented from being crushed when it is embedded between vertebral bodies or the like. As a result, the connectivity with the living bone can be maintained. Further, if the protective layer 4 is completely buried in the microporous layer 3 due to excessive load applied to the protective layer 4, the micro-open pores may be blocked. Therefore, the thickness of the protective layer 4 is preferably larger than the thickness of the microporous layer 3 so that even if the protective layer 4 is embedded in the microporous layer 3, the micro-open pores can be blocked.

  As shown in FIG. 5, the microporous layer 3 is provided on the surface of the substantial part 2, and the surface of the surface of the microporous layer 3 on which the skeleton part 5 is not formed is exposed in the void 6 of the protective layer 4. Thus, the exposed surface 7 is formed. The microporous layer 3 has a plurality of micropores 31. The micropores 31 preferably include small pores 32 having an average pore diameter of less than 10 μm and large pores 33 having an average pore diameter of 10 μm to 200 μm.

  The small-diameter pores 32 are classified into small-diameter open pores that open on the exposed surface 7 and small-diameter internal pores that exist inside the microporous layer 3 depending on the location of the small-diameter pores 32. The small-diameter independent pores that are the pores 32 and the small-diameter continuous ventilation holes that are the small-diameter pores 32 that communicate with the small-diameter pores 32 or communicate with the large-diameter pores 33 are classified. When the average pore diameter of the small-diameter pores 32 is less than 10 μm, the average pore diameter of the small-diameter open pores, the average pore diameter of the small-diameter inside pores and the small-diameter independent pores, and the communication that is the average of the diameters of the communication portions of the small-diameter continuous pores Each pore diameter is less than 10 μm.

  The large-diameter pores 33 are classified into large-diameter open pores that open on the exposed surface 7 and large-diameter internal pores that exist inside the microporous layer 3 depending on the position of the large-diameter pores. The large-diameter independent pores that exist, the large-diameter continuous vents communicating with the large-diameter open pores, and the large-diameter continuous closed pores communicating with the large-diameter pores but not communicating with the large-diameter open pores are classified. When the average pore diameter of the large-diameter pore 33 is 10 to 200 μm, the average open pore diameter of the large-diameter open pore, the average pore diameter of the large-diameter inner pore and the large-diameter independent pore, and the large-diameter continuous vent and the large-diameter communication The large-diameter communication hole diameter, which is the average of the diameters of the communication portions of the closed pores, is 10 to 200 μm.

  The microporous layer 3 has a plurality of micropores 31, and a part of the plurality of micropores 31 forms microopen pores that open to the exposed surface 7 of the microporous layer 3. The micro open pores preferably have small open pores having an average open pore size of less than 10 μm, which is an average value of the size of the micro open pores, and large open pores having an average open pore size of 10 to 200 μm. The microporous layer 3 is formed in a porous structure by a plurality of small-diameter pores 32 and a plurality of large-diameter pores 33. In particular, the microporous layer 3 has a network structure by large-diameter continuous air holes formed by a plurality of large-diameter pores 33 communicating with each other. Preferably it is. When the microporous layer 3 has a small-diameter open pore and a large-diameter open pore having the average open pore size, and has a mesh structure, a biological tissue such as a bone tissue that has entered through the void 6 can be obtained. It becomes easy to enter the inside of the microporous layer 3, and it becomes easy to bond firmly with a living tissue.

  The average open pore diameter of the small open pores and the average open pore size of the large open pores in the microporous layer 3 are obtained by, for example, an intercept method using an image obtained by observing the surface of the biological implant 1 with a scanning electron microscope (SEM). It can ask for. Specifically, for the average open pore diameter of the large-diameter open pores, first, an SEM image obtained by observing the surface of the biological implant 1 with a scanning electron microscope at a predetermined magnification, for example, 300 times is obtained. Randomly draw five straight lines across this image, and measure the length of the part where the straight line and large-diameter open pores overlap. Is the average open pore size of the large open pores. On the other hand, since the small-diameter open pores usually exist in the skeleton portion between the large-diameter open pores and the large-diameter open pores, when measuring the average open pore diameter of the small-diameter open pores, in order to reduce the measurement error It is preferable to increase the magnification of the scanning electron microscope. For example, the average open pore diameter of the small-diameter open pores is determined by the intercept method using an SEM image obtained by observing at 3000 times with a scanning electron microscope.

  In addition, when there are a small number of large-diameter open pores or small-diameter open pores confirmed in the SEM image, for example, 10 or less, the long-diameter and short-diameter pores with the large-diameter open pores or small-diameter open pores on the SEM image as measurement objects And the average open pore size of the large open pores and the small open pores can be obtained from these arithmetic average values.

  The average pore diameter of the large-diameter internal pore, the large-diameter independent pore, and the average pore diameter of the small-diameter internal pore and the small-diameter independent pore are determined by observing an arbitrary cross section of the biological implant 1 with a scanning electron microscope. It can obtain | require similarly to a hole diameter.

  The communication hole diameter of the large-diameter communication hole and the large-diameter communication closed hole and the communication hole diameter of the small-diameter communication hole can be obtained from SEM images taken at a predetermined magnification in the same manner as described above. As another method, a mercury porosimeter is used. You can ask for it.

The ratio (S _b / S _m × 100) of the area S _b of the large-diameter open pores to the exposed area S _m of the microporous layer 3 is preferably 10 to 95%. When the ratio (S _b / S _m × 100) is within the above range, it becomes easy for a living tissue to enter the living body implant 1 and thus exhibits a strong binding ability with the living tissue after being embedded in the living body. In addition, the strength according to the application site can be ensured.

The ratio (S _b / S _m × 100) is determined by the large-diameter pores 33 using an image analysis software such as a Scion Image manufactured by Scion or the like, which is an image obtained by photographing the surface of the microporous layer 3 with a scanning electron microscope. It can be obtained by binarizing the large-diameter open pores to be formed and other portions, and then calculating the area ratio of the large-diameter open pores with respect to the area of the entire image. Note that the scanning electron microscope displays at an appropriate magnification for measuring the area of the large-diameter open pores.

  The thickness of the microporous layer 3 may be set as appropriate according to the site to which it is applied, the binding ability and strength with the biological tissue required for the biological implant 1, and is within the range of 10 to 1000 μm. Is preferred. When the thickness of the microporous layer 3 is within the above range, the microporous layer 3 is likely to be a scaffold for living tissue that has entered through the gap 6 and exhibits high binding ability with the living tissue. The thickness of the microporous layer 3 is obtained as a distance from the deepest point of the micropore 31 to the exposed surface 7 in the obtained SEM image by observing an arbitrary cross section of the microporous layer 3 with a scanning electron microscope. The measured value is taken as the thickness of the microporous layer 3 at the measurement point.

  The material for forming the microporous layer 3 is not particularly limited, and examples thereof include plastic and ceramic. Examples of the plastic include engineering plastic and bioabsorbable plastic.

  The engineering plastic is preferably an engineering plastic having mechanical properties similar or close to those of living bones or teeth. Examples of the engineering plastic include the engineering plastics listed as materials for forming the substantial part 2.

  The bioabsorbable plastic is a plastic that can be gradually decomposed and / or absorbed by the living body after the living body implant 1 is embedded in the living body. Bioabsorbable plastics include polylactic acid, polyglycolic acid, poly-ε-caprolactone and polybutyl succinate polymers, and lactic acid, glycolic acid, ε-caprolactone, and combinations of succinic acid and butanediol. And a copolymer obtained by copolymerizing at least two kinds of monomers selected from the group consisting of the following monomers. Bioabsorbable plastics can be used alone or in combination of two or more. In this invention, polylactic acid includes poly-L-lactic acid, poly-D-lactic acid, and poly-DL-lactic acid, and lactic acid includes L-lactic acid, D-lactic acid, and DL-lactic acid. .

The ceramic is not particularly limited, and examples thereof include a bioactive ceramic and a bioactive glass. Examples of the bioactive ceramic include calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, α-type tricalcium phosphate, β-type tricalcium phosphate , Calcium phosphate compounds such as dolomite, tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, fluorapatite, carbonate apatite, and chlorapatite. As the bioactive glass, SiO ₂ —CaO—Na ₂ O—P ₂ O ₅ glass, SiO ₂ —CaO—Na ₂ O—P ₂ O ₅ —K ₂ O—MgO glass, SiO ₂ —CaO—Al ₂ Examples thereof include O ₃ —P ₂ O ₅ glass, SiO ₂ —CaO—MgO—P ₂ O ₅ glass, and the like.

  Among these, the material for forming the microporous layer 3 is preferably the same engineering plastic as that of the substantial part 2. When the substantial part 2 is formed of polyetheretherketone (PEEK), the microporous layer 3 is also Further, it is more preferably formed by PEEK.

  The microporous layer 3 is not formed later by coating the surface of the substantial portion 2 with the microporous layer 3, but as described later, a large number of micropores are formed on the surface portion of the solid base material made of engineering plastic. Preferably, it is formed by forming a porous structure 31. By forming the microporous layer 3 in this way, the microporous layer 3 and the substantial part 2 are integrally formed, and the microporous layer 3 is difficult to peel from the substantial part 2.

  The microporous layer 3 may be provided on the entire surface of the substantial part 2 or may be provided only on a part of the surface of the substantial part 2, that is, only on the surface that needs to be bonded to living bone.

  As described above, the biological implant 1 includes a dense substantial portion 2 made of engineering plastic, a microporous layer 3 provided on the surface of the substantial portion 2, and a protective layer 4 provided on the surface of the microporous layer 3. The protective layer 4 includes a dense skeleton 5 made of engineering plastic provided on a part of the surface of the microporous layer 3 and a gap 6 reaching from the outer surface of the protective layer 4 to the surface of the microporous layer 3. Since the microporous layer 3 has micro-open pores that open on the surface of the microporous layer 3, the microporous layer 3 has a surface structure in which a biological tissue such as a bone tissue can easily enter when embedded in a living body, and the load is concentrated. To provide a biological implant having connectivity with bone by maintaining the surface structure even when it is embedded in such a site and when it is embedded between vertebral bodies etc. It can be.

  This biological implant 1 is a biological implant that is embedded or supplemented in a bone defect or the like, specifically, a bone filling material, an artificial joint member, an osteosynthesis material, an artificial vertebral body, an intervertebral body spacer, a vertebral body cage, an artificial body It is suitably used as a tooth root and alveolar bone aggregate. In particular, the living body implant 1 is suitably used as a living body implant that is embedded by being driven into a portion where a load is concentrated and a space formed in a bone. Therefore, this biological implant 1 is suitable as an intervertebral body spacer.

  The living body implant 1 may be used by being manufactured in a desired shape, or by cutting or cutting into a desired shape in accordance with a portion to be applied after being manufactured in an appropriate shape. May be manufactured in a desired shape. Examples of the desired shape include a shape similar to the shape of the portion to be compensated, or a shape corresponding to this shape, such as a similar shape, and specifically, a granular shape, a fibrous shape, a block shape, a film shape, and the like. Can be mentioned.

  Next, an example of a method for manufacturing the living body implant 1 will be described.

  The manufacturing method of the biological implant 1 includes a step of forming a surface foamed base material having a microporous layer 3 on the surface of the substantial part 2 and a step of forming a protective layer 4 on the surface of the surface foamed base material.

  The step of forming the surface foamed substrate includes a swelling step of immersing in a swelling solution that swells the engineering plastic, and a solidification step of solidifying and washing with a solution that does not elute the engineering plastic. A first step of obtaining a microporous substrate by forming micropores on the surface of the foam, and a foaming agent holding substrate by immersing the microporous substrate obtained in the first step in a solution containing a foaming agent A foaming agent holding step to obtain a surface soft foaming base material by immersing the foaming agent holding substrate in a foaming solution that swells the engineering plastic and foams the foaming agent, and this The surface foamed substrate is immersed in a coagulation solution that solidifies the swollen engineering plastic. A second coagulation step to obtain, and a second step of forming a desired micro pores 31 further erode the microvoided substrate.

  In the first step, pores that are the same as or smaller than the small-diameter pores 32 in the micropores 31 are formed on the surface portion of the solid substrate made of engineering plastic to obtain a microporous substrate. First, the swelling process which immerses a solid base material in a swelling solution is implemented. Although this swelling solution is not specifically limited, Acid aqueous solution, such as a sulfuric acid, nitric acid, or chromic acid, is mentioned. In this swelling step, it is only necessary to appropriately set conditions that can swell the surface of the solid substrate, and the swelling step is appropriately set according to the required thickness and pore diameter of the microporous layer 3. For example, the concentration of the swelling solution affects the porosity and thickness of the microporous layer 3, and is usually preferably high, and concentrated sulfuric acid or concentrated nitric acid can be suitably used. The amount of the swelling solution used should be such that the portion to be eroded of the solid substrate is immersed, and when the pores are formed on the entire surface of the solid substrate, the entire solid substrate should be immersed. It should be the amount that can be. The immersion time is determined according to the amount of erosion. Further, the temperature of the swelling solution is usually set to about room temperature.

  Next, a solidification step is performed in which the solid substrate taken out of the swelling solution is solidified and washed with a solution from which the engineering plastic does not elute. In the solidification process, the solid substrate is washed until the solution obtained by washing the solid substrate becomes neutral, and the engineering plastic that has been softened into a gel state with the swelling solution (in some cases, partially dissolved) is solidified to form micropores. A base material is used. The liquid that does not elute the engineering plastic used in this coagulation step (coagulation solution) is usually set to about room temperature, and the solid substrate with the swollen surface is left in the immersed state or stirred, or defoamed. It is immersed for a predetermined time while performing. By appropriately setting the type, concentration, and temperature of the coagulation solution, the porosity and thickness of the microporous layer 3 can be adjusted. Examples of the liquid from which the engineering plastic does not elute include water and ethanol.

  The thickness of the region where the pores are formed in the microporous substrate may be equal to the thickness of the microporous layer 3 of the biological implant 1. In addition, the pore diameter of the pores in the microporous substrate may be appropriately set depending on the type of the foaming agent as long as it has a pore diameter that allows the foaming agent used in the second step to enter the pores. The thickness of the region where the pores are formed, the pore diameter of the pores, and the like can be adjusted by the time of immersion in the swelling solution, the time of immersion in the solution from which the engineering plastic does not elute, and / or the temperature.

  In the first step, a step of drying the obtained microporous substrate can be performed as desired. The drying may be carried out under conditions where the engineering plastic does not melt or the like. For example, the drying is carried out at a temperature below the melting point of the engineering plastic, preferably below the glass transition temperature.

  In the second step, the microporous substrate obtained in the first step is eroded again to form the desired micropores 31. First, the foaming agent holding process which obtains a foaming agent holding base material by immersing the microporous base material obtained in the first step in a solution containing a foaming agent is performed. The foaming agent used in this step may be a foaming agent that foams with a foaming solution to be described later. Examples thereof include inorganic foaming agents such as carbonate and aluminum powder, and organic foaming agents such as azo compounds and isocyanate compounds. be able to. This foaming agent is preferably a substance that does not adversely affect the living body when the living body implant 1 is embedded, and examples thereof include carbonates, and more specifically, sodium bicarbonate, sodium carbonate, potassium carbonate, and the like. Is mentioned. The solvent for dissolving the foaming agent is not particularly limited, and examples thereof include water. In this foaming agent holding step, the conditions under which the foaming agent can be held on the surface of the foaming agent holding substrate and the inner wall surfaces of the pores formed in the first step, for example, the concentration of the foaming agent and the amount of solution used are set appropriately. The The temperature of the solution containing the foaming agent is usually set to about room temperature. The immersion state of the microporous substrate in the solution containing the foaming agent may be allowed to stand, the foamed solution may be stirred, or defoamed. The immersion time is determined appropriately.

  Next, a surface soft foaming step is performed in which the foaming agent holding base material is immersed in a foaming solution that swells the engineering plastic and foams the foaming agent to obtain a surface soft foaming base material. This step is usually performed without drying the foaming agent holding substrate, but the foaming agent holding substrate can also be dried. When the foaming agent holding substrate is immersed in a foaming solution, the swelling of the engineering plastic and the foaming of the foaming agent proceed almost simultaneously to obtain a surface soft foamed substrate. Any foaming solution may be used as long as it has the above-mentioned characteristics, and examples thereof include acidic aqueous solutions such as concentrated sulfuric acid, hydrochloric acid, and nitric acid. When the engineering plastic is PEEK and the foaming agent is carbonate, the foaming solution is preferably concentrated sulfuric acid having a concentration of 90% or more. In the surface soft foaming step, dipping conditions are set so that the engineering plastic can swell and the foaming agent can be foamed. The temperature of the foaming solution is usually set to about room temperature. The immersion state of the foaming agent holding substrate in the foaming solution may be left still, the foaming solution may be stirred, or defoaming may be performed. The immersion time is determined appropriately.

  Next, a second solidification step is performed in which the surface soft foam base is immersed in a coagulation solution that solidifies the swollen engineering plastic to obtain a surface foam base. The surface soft foam base material taken out from the foaming solution in this second coagulation step may be solidified by flowing the coagulation solution after being immersed in the coagulation solution, and the coagulation solution is repeatedly solidified by repeating the immersion in the coagulation solution several times. Also good. The coagulation solution used in this step is a solution from which the engineering plastic does not elute, and includes, for example, an aqueous solution such as water and ethanol, a polar solution such as acetone, and the like, when the engineering plastic is PEEK. In addition, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid and other inorganic acid aqueous solutions having a concentration of less than 90%, water-soluble organic solvents, and the like can be mentioned. Examples of the water-soluble organic solvent include N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, ethylene glycol, diethylene glycol, trietylene glycol, propylene glycol, Alcohols such as dipropylene glycol, glycerin ethanol, propanol, butanol, pentanol, hexanole and their aqueous solutions, liquids such as polyethylene glycol, polypropylene glycol, polyvinylpyrrolidone Mention may be made of polymers or their aqueous solutions and mixtures thereof. In the second coagulation step, the surface soft foam base material is immersed in a coagulation solution under conditions that allow coagulation. For example, the temperature of the coagulation solution is usually set to about room temperature. The immersion state of the surface soft foam base material in the coagulation solution may be left still, the coagulation solution may be stirred, or defoaming may be performed. The immersion time is determined appropriately.

  In the second step, a cleaning step of cleaning the surface foamed substrate is performed as desired. This cleaning step is performed until the cleaning liquid that has cleaned the surface foamed substrate becomes neutral. In this cleaning step, the surface foamed substrate taken out from the coagulation solution may be cleaned by flowing the cleaning solution after being immersed in the cleaning solution, or may be cleaned by repeating the immersion in the cleaning solution a plurality of times. The cleaning liquid used in this cleaning step may be any liquid that does not elute the engineering plastic. Examples thereof include water and pure water. This cleaning step can be performed at room temperature, for example.

  In the first step, a drying step of drying the obtained surface foamed substrate can be performed as desired. The drying may be performed under conditions where the engineering plastic does not melt, for example, at a temperature below the melting point of the engineering plastic, preferably below the glass transition temperature. In this way, a surface foamed substrate is produced.

  Next, a process of forming the protective layer 4 on the surface of the manufactured surface foam base will be described. As a manufacturing method of the protective layer 4, the method of manufacturing by rapid protriping, the mesh lamination method, etc. can be mentioned.

  Rapid prototyping, sometimes referred to as additive manufacturing, divides the three-dimensional solid information stored in the computer into information obtained by cutting a three-dimensional solid into pieces, and is formed based on this information. This is a technique for manufacturing a three-dimensional three-dimensional object at a high speed by sequentially laminating shaped objects. According to rapid prototyping, the protective layer 4 having various structures according to the application site can be easily formed at high speed. Examples of rapid prototyping include a hot melt lamination method, an optical shaping method, a powder bonding method, and an ink jet method. The hot melt lamination method is a method of forming a desired shaped body by extruding a thermoplastic resin melted by heating from the tip of a thin nozzle. The optical modeling method is a method of selectively curing a photocurable resin by three-dimensionally irradiating a liquid photocurable resin with a laser beam or ultraviolet rays to form a desired modeled body. The powder bonding method is a method of forming a desired shaped body by spreading powders of resin and metal, etc., and directly sintering and hardening with a high-power laser beam or the like. The ink jet method is a method of forming a desired shaped body by spraying and laminating a liquid material.

  Of rapid prototyping, the hot melt lamination method will be described in detail below. In the hot melt laminating method, the engineering plastic for forming the protective layer 4 is put into a material container of a modeling apparatus, the inserted engineering plastic is pushed out from a nozzle, and an appropriate pattern is formed on the surface of the microporous layer 3 of the surface foam substrate. By drawing, the protective layer 4 having the skeleton 5 and the gap 6 is formed. The engineering plastic is heated so as to have fluidity that is easy to be extruded from a nozzle and easy to be molded, and is heated to a temperature range from the melting point of the engineering plastic to the decomposition temperature, for example. There may be one nozzle or two or more nozzles. As an example of the formation method of the protective layer 4, first, the engineering plastic is extruded while moving the nozzle or the modeling table, and the fibrous line that becomes the skeleton part 3 is drawn like a one-stroke drawing. A body is formed on the surface of the microporous layer 3. For example, in the case of the protective layer 4 shown in FIG. 2, the nozzle or the modeling table is moved, and the line formed by being pushed out of the nozzle on the surface of the microporous layer 3 is linearly formed from one side to the other side. Draw and fold back at the end of this straight line, and draw a straight line in a position parallel to the previously drawn straight line and at a predetermined distance from the straight line. By repeating such an operation, for example, a straight line is arranged at a predetermined interval, and the pattern is drawn with one line so that all the lines fit in a virtual space that is substantially rectangular in plan view. At this time, the end of the line is positioned on the diagonal line of the starting point. The second-layer shaped body is drawn by rotating the same pattern as the first-layer shaped body by 90 ° on the first-layer shaped body, with the end portion of the first-layer shaped body as the starting point. That is, the straight line is drawn so as to be orthogonal to the first layer and the second layer. In this way, the stripe-like line that becomes the skeleton part 5 is welded to the surface of the microporous layer 3, and the stripe-like line that becomes the skeleton part 5 is welded to each other in the form of a lattice to form the protective layer 4. As a result, a rectangular disk-shaped surface porous body is formed. The biological implant 1 shown in FIG. 2 can be obtained by cutting out a disk body from a surface porous body formed in a square disk shape. Here, the pattern of the protective layer 4 shown in FIG. 2 has been described, but the pattern is not particularly limited, and an appropriate pattern can be set, and each layer may be the same pattern or different. In addition, by appropriately setting the thickness of the engineering plastic extruded from the nozzle, it is possible to adjust the thickness of the skeleton 5 to be formed, and by appropriately setting the spacing between the lines, The width and the porosity of the protective layer 4 can be adjusted.

  The mesh lamination method is a method for producing the biological implant 1 by laminating a mesh made of engineering plastics produced in advance on a surface foamed substrate. Specifically, after a mesh made of engineering plastics manufactured in advance is laminated on the surface of the microporous layer 3, the laminated mesh is heated at a predetermined temperature to weld the mesh to the surface of the microporous layer 3. . The mesh pattern of the mesh is not particularly limited, and examples thereof include a lattice shape, a stripe shape, and a spiral shape. When a plurality of meshes are stacked, the mesh pattern of each mesh is the same. May be different. In the case where the meshes to be laminated are the same mesh pattern, by rotating or translating each mesh, the gap 6 is not in a column shape penetrating from the outer surface of the protective layer 4 to the surface of the microporous layer 3, You may form so that it may become a complicated path | route. By appropriately setting the thickness of the mesh, the thickness of the skeleton portion 5 to be formed can be adjusted, and by appropriately setting the mesh opening, the width of the gap and the porosity of the protective layer 4 Etc. can be adjusted.

  In this way, the surface porous body to be the biological implant 1 is manufactured.

  The biological implant 1 can be used in the obtained state, or can be used after being shaped or shaped into a desired shape. When the living body implant 1 is used in the obtained state, it is preferably molded into a desired shape when the solid base material is prepared.

  When the microporous layer 3 in the biological implant 1 is formed of a bioabsorbable plastic, for example, a surface porous body that becomes the biological implant 1 can be manufactured as follows.

The method for manufacturing the biological implant 1 is the same as the method for manufacturing the biological implant 1 described above except that the microporous layer 3 is formed on the surface of the substantial part 2.
First, a porous sheet made of a bioabsorbable plastic to be the microporous layer 3 is formed. The method for producing the porous sheet is not particularly limited. For example, a mixing step of mixing a granule made of a bioabsorbable plastic and a granule made of a soluble substance to obtain a granule mixture, and heating and pressurizing the granule mixture It has a shaping | molding process which forms a molded object, and the elution process which immerses a molded object in the solvent in which a soluble substance melt | dissolves, and elutes a soluble substance.

  The mixing method in a mixing process is not specifically limited, It can mix by dry blend etc. The soluble substance may be any substance that dissolves in the solvent used in the elution step, and the solvent is preferably water from the viewpoint of the implant used in the living body and the environment at the time of production. Therefore, the soluble substance is water-soluble. Preferably, it is a sex substance. Examples of water-soluble substances include salts (such as sodium chloride or potassium chloride and sodium sulfate), saccharides (polysaccharides such as α, β or γ-cyclodextrin, dextrin and starch, sucrose, lactose, and mannitol), celluloses (Hydroxypropylcellulose, methylcellulose, etc.), protein, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, polyacrylate, polyethylene oxide, sulfonated polyisoprene, sulfonated polyisoprene copolymer and the like. The average particle size of the granules made of bioabsorbable plastic and the granules made of a soluble substance and the mixing ratio thereof are appropriately set according to the required pore size and porosity.

  In the molding step, the granule mixture obtained in the mixing step is heated and pressed by a mold press or the like to form a molded body. The molding temperature is preferably a temperature equal to or higher than the melting point of the bioabsorbable plastic. The molding pressure is preferably 1 to 20 MPa.

  In the elution step, the molded body is immersed in a solvent in which the soluble substance dissolves to elute the soluble substance to obtain a porous body. As described above, it is preferable to use water as the solvent.

  The porous body is sliced to an appropriate thickness to obtain a porous sheet. The method for adhering the porous sheet to the surface of the substantial part 2 made of the engineering plastic prepared in advance is not particularly limited. For example, the porous sheet cut out to a desired size after applying a solvent to the surface of the substantial part 2 A method of sticking a porous sheet, a method of placing a porous sheet cut out to a desired size on the surface of the substantial part 2, and then heating the porous sheet to weld it to the surface of the substantial part 2 it can. In this way, a surface porous substrate in which the microporous layer 3 is formed on the surface of the substantial part 2 is manufactured. The porous body made of a bioabsorbable plastic may be pasted on the substantial part 2 as it is by forming it in a porous sheet of a desired size in advance. As a method for forming the protective layer 4 on the surface of the surface porous substrate, the method for producing the protective layer 4 described above can be adopted.

  When the microporous layer 3 in the biological implant 1 is formed of ceramic, for example, a surface porous body that becomes the biological implant 1 can be manufactured as follows.

  First, the substantial part 2 made of engineering plastic is prepared. Next, a microporous layer 3 made of ceramic is formed on the surface of the substantial part 2. As a method for forming the microporous layer 3, for example, flame spraying, plasma spraying, and other thermal spraying methods, physical vapor deposition methods such as sputtering, ion plating, ion beam vapor deposition, ion mixing methods, and the like, the substantial portion 2 is heated. Examples thereof include a method of coating the microporous layer 3 by welding a ceramic powder to an engineering plastic (for example, PEEK) having a surface dissolved. Examples of the ceramic include the above-described calcium phosphate compound and bioactive glass. As the method for forming the protective layer 4 on the surface of the surface porous substrate in which the microporous layer 3 made of ceramic is formed on the surface of the substantial part 2, the method for manufacturing the protective layer 4 described above can be adopted.

(Second Embodiment)
A biological implant which is another example of the biological implant according to the present invention will be described. The biological implant of this embodiment has a structure basically similar to that of the biological implant 1 of the first embodiment except that a bioactive substance and / or a drug is carried on the microporous layer.

  This bioimplant carries a bioactive substance, a drug, or a bioactive substance carrying a drug on all or a part of the exposed surface of the microporous layer and the inner wall surface of the micropore. The bioactive substance and the bioactive substance carrying the drug may be carried in the form of a film or layer on the inner wall surface of the micropores, or may be carried in a dispersed state. When the bioactive substance or the like is supported in a film or layer, the thickness of the bioactive substance or the like is preferably, for example, 0.1 to 100 μm, and particularly preferably 0.5 to 50 μm. preferable. When the bioactive substance or the like is supported in a dispersed state, the shape of the bioactive substance or the like may be granular, granular, or powdery that can be supported on the exposed surface of the microporous layer and the inner wall surface of the micropores. Aggregates may also be used, and examples thereof include a spherical shape, an elliptical spherical shape, a needle shape, a column shape, a rod shape, a plate shape, and a polygonal shape. In this case, the particle diameter of the bioactive substance or the like is preferably 0.001 to 10 μm, and particularly preferably 0.01 to 5 μm, for example. Note that “particle” and “particle diameter” described in the present specification are “primary particle” and “primary particle diameter”, respectively, unless otherwise specified, and are supported on the microporous layer. In the case where the bioactive substance is an aggregate, it is the primary particle that is the minimum unit constituting the aggregate and the diameter thereof. The particle diameter can be calculated by the intercept method. Specifically, a photograph can be taken with a scanning electron microscope, a straight line intersecting at least 15 particles can be drawn, and the average value of the length of the portion where the straight line and the particle intersect can be calculated. If the shape is other than spherical particles, the area-converted diameter is calculated.

A bioactive substance has a high affinity with a living body, and chemically reacts with a living tissue such as a bone tissue including a living bone or a tooth tissue including a living tooth (sometimes collectively referred to as a bone tissue). The substance is not particularly limited as long as it has a property, and examples thereof include a calcium phosphate compound, bioactive glass, and calcium carbonate. Examples of calcium phosphate compounds include calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, α-type tricalcium phosphate, β-type tricalcium phosphate, dolomite , Tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, fluorapatite, carbonate apatite, and chlorapatite. Examples of the bioactive glass include SiO ₂ —CaO—Na ₂ O—P ₂ O ₅ glass, SiO ₂ —CaO—Na ₂ O—P ₂ O ₅ —K ₂ O—MgO glass, and SiO ₂ —CaO. -Al ₂ O ₃ -P ₂ O ₅ -based _{glass, SiO 2 -CaO-MgO-P} 2 O 5 based glass (also called apatite wollastonite crystallized glass.), _{and, CaO-Al 2 O 3 -P} 2 O ₅ based glass. These calcium phosphate compounds and bioactive glasses are described in, for example, “Chemical Handbook Applied Chemistry 6th Edition” (The Chemical Society of Japan, published on January 30, 2003, Maruzen Co., Ltd.), “Development and Clinical of Bioceramics” (Edited by Hideki Aoki et al., April 10, 1987, Quintessence Publishing Co., Ltd.).

  Among these, the bioactive substance is preferably at least one of a calcium phosphate compound and bioactive glass from the viewpoint of excellent bioactivity. Furthermore, the bioactive substance is similar in composition, structure and properties to the living bone, and is stable in the body environment. Hydroxyapatite or tricalcium phosphate is particularly preferred in that it is excellent and does not show significant solubility in the body.

  Various drugs can be used depending on the functions required for the biological implant of the present invention. Examples of the drug include anti-inflammatory agents, antibiotics, antithrombotic agents, antitumor agents, anticoagulants, vascular cell growth promoters, vascular cell growth inhibitors, anticancer agents, vasodilators, and osteogenesis inducers. Can be mentioned. As an osteogenesis inducing factor, various osteogenesis-related proteins that are extracted from bone tissue can be used. For example, osteogenesis factor (BMP), transforming growth factor (TFG-β), cartilage-derived formation factor (CDMP), osteoinductive factor (OIF), insulin-like growth factor (IGF), platelet-derived growth factor (PDFG), fibroblast growth factor (FGF) and the like. As long as these drugs do not react with each other, two or more kinds of drugs selected from these may be supported on the surface layer 5.

  If the bioimplant has a bioactive substance, the bioactive substance has the property of binding to bone and adsorbing biomolecules, so this bioimplant needs to be bonded to living tissue such as bone and skin. This is particularly effective when used for various parts. For example, when a biological implant is used as an artificial bone, it becomes easy to bond with bone, and when used as a transdermal device, it becomes easy to adhere to the skin. Furthermore, when the biological implant has a drug, the drug is released over a long period of time, so that an effect corresponding to the type of the drug is obtained over a long period of time. When the bioimplant has a drug layer that is a bioactive substance carrying a drug, both of the effects exhibited by the above-described bioactive substance and drug can be obtained. In the case of facilitating the release of the drug, the drug is supported on the inner wall surface of the micropores as a drug layer by loading the drug on the bioactive substance rather than on the inner wall surface of the micropores. Better. The bioactive substance and / or drug layer is preferably supported on the exposed surface of the microporous layer and the inner wall surface of the micropore so as not to block the open pores of the micropore.

  Next, an example of the manufacturing method of the biological implant of the 2nd embodiment is demonstrated.

  The biological implant of the second embodiment is basically the same as the biological implant 1 of the first embodiment, except that the bioactive substance and / or the drug are supported on the exposed surface of the microporous layer and the inner wall surface of the micropores. Are the same. Therefore, the surface porous body having the substantial part, the microporous layer, and the protective layer can be manufactured basically in the same manner as the manufacturing method of the biological implant of the first embodiment. Below, an example of the method of carrying | supporting a bioactive substance, a chemical | medical agent, or a chemical | medical agent layer on the exposed surface of the microporous layer and the inner wall surface of a micropore in this surface porous body is demonstrated.

An example of a method for supporting a bioactive substance on a porous surface body manufactured in the same manner as the manufacturing method of the biological implant of the first embodiment will be described.
First, an ultrasonic irradiation process is performed in which ultrasonic waves are applied in a state where the surface porous body is immersed in a suspension of a bioactive substance. When this ultrasonic irradiation step is carried out, the suspension that has reached the microporous layer through the voids of the protective layer preferably bioactivates not only the exposed surface of the microporous layer but also the inner wall surface of the micropores, preferably uniformly. A bioactive substance-adhering substrate into which the substance has entered and is arranged can be obtained. Ultrasonic waves are irradiated on the surface porous body together with the suspension using, for example, an ultrasonic vibrator, an ultrasonic homogenizer, or the like. Conditions for irradiating ultrasonic waves are appropriately set according to the pore diameter, porosity, etc. of the pores, and for example, conditions for irradiating ultrasonic waves with an output of 200 W at a frequency of 20 to 38 kHz for 5 to 15 minutes are employed. In this ultrasonic irradiation step, the surface porous body may be immersed in the suspension, may be left in the suspension, or may be immersed in the stirred suspension. In this ultrasonic irradiation step, the suspension may be stirred for a while after the ultrasonic irradiation, or the bioactive substance-adhering substrate may be immersed in the same type of solvent after the ultrasonic irradiation and stirred for a while. Good. The liquid temperature of the suspension in the ultrasonic irradiation step, that is, the immersion temperature and the ultrasonic irradiation time are not particularly limited, and may be appropriately adjusted according to the amount of the bioactive substance disposed on the surface porous body.

  The suspension used in the ultrasonic irradiation step is a suspension of the bioactive substance described above, and the medium in which the bioactive substance is suspended is not particularly limited as long as it does not dissolve the engineering plastic. , Alcohols such as methanol, ethanol and propanol, water, acetone, hexane and the like. The bioactive substance is preferably a particle having a particle diameter in the above range and the above shape.

  In the manufacturing method of this embodiment, if desired, a washing step of washing the bioactive substance-adhered substrate after taking out from the suspension can be performed. The cleaning liquid for cleaning the bioactive substance-adhering substrate is not particularly limited as long as it is a medium that does not dissolve the engineering plastic. Examples thereof include water and the same medium as a suspension medium, preferably water or pure water. . In addition, a drying step for drying the bioactive substance-adhering substrate can be performed as desired following this washing step. As the drying method, a known drying method can be adopted without any particular limitation, and examples thereof include air drying, air drying, and heat drying.

  In the manufacturing method of this embodiment, the bioactive substance-adhering substrate is then heated to a glass transition temperature of the plastic forming the microporous layer at a heating temperature of −30 ° C. or higher and lower than the melting point to support and fix the bioactive substance. It is preferable to carry out an immobilization step. When this immobilization step is performed, the bioactive substance can be more firmly supported and fixed by the exposed surface of the microporous layer and the inner wall surface of the micropores. The heating temperature in this immobilization step is not less than the glass transition temperature (Tg) of the plastic of −30 ° C., that is, not less than 30 ° C. lower than the glass transition temperature (Tg−30) ° C. When the bioactive substance-adhering substrate is heated within this temperature range, a part of the bioactive substance-adhering substrate is softened, and the arranged bioactive substance is firmly supported, adhered, and fixed. The lower limit of the heating temperature is (Tg-30) ° C., and is preferably equal to or higher than the glass transition temperature (Tg) in that the bioactive substance-adhering substrate and the bioactive substance can be more firmly adhered to each other. The glass transition temperature (Tg) + 40 ° C. is particularly preferable. The upper limit of the heating temperature is less than the melting point of the plastic, and the glass transition temperature can be more firmly adhered to the surface porous body and the bioactive substance. (Tg) + 80 ° C. is preferable. In the present invention, the glass transition temperature (Tg) of the plastic is the lowest glass transition temperature when the plastic has a plurality of glass transition temperatures.

  In this immobilization step, the time for heating the bioactive substance-adhered substrate, that is, the time for maintaining the heating temperature may be a time that allows the vicinity of the exposed surface and the inner wall surface of the bioactive substance-attached substrate to be softened It is preferably 1 hour or longer, and particularly preferably 3 hours or longer, in that the bioactive substance-adhering substrate and the bioactive substance can be more firmly adhered to each other. The upper limit value of the heating time is not particularly limited, and even if it is significantly increased, improvement in the degree of adhesion of the bioactive substance cannot be expected. Therefore, considering economic or work efficiency, it can be set to, for example, 24 hours. As a heating method for the bioactive substance-adhering substrate, a known heating method can be appropriately employed. In this way, the bioactive substance disposed on the surface of the bioactive substance-adhering substrate can be immobilized.

  In this way, a bioimplant in which a bioactive substance is supported on the exposed surface of the microporous layer and the inner wall surface of the micropore is obtained. And this biological implant can be used with the obtained state, and can also be shape | molded or shaped and used for a desired shape similarly to the biological implant 1 of a 1st embodiment.

Next, an example of a method for supporting a drug on the surface porous body manufactured in the same manner as the manufacturing method of the biological implant of the first embodiment will be described.
The method for producing a biological implant carrying a drug has a step of immersing the porous surface in a solution containing the drug for a predetermined time. The drug can be appropriately selected depending on the required function. For example, at least one drug can be selected from the drugs described above. When the drug is a liquid drug, a diluted solution as it is or diluted is used. When the drug is a solid drug, a drug solution dissolved or suspended in an appropriate solvent is used. The concentration of the diluting solution and the chemical solution is appropriately adjusted in a range that is not less than the effective concentration of the drug to be used and does not harm the living body. The time for immersing the surface porous body in the solution containing the drug is not particularly limited as long as the drug is supported on the microporous layer in the surface porous body, and it is preferably immersed for 10 minutes or more.

  When the drug is supported on the surface porous body, it is preferable to perform a defoaming treatment while immersing the surface porous body in a solution containing the drug. By performing the defoaming treatment, the drug can enter into the micropores in the surface porous body. Moreover, the time for immersing the surface porous body in the solution containing the drug can also be shortened.

  After taking out the surface porous body from the solution containing the drug, it is preferable to dry it sufficiently at room temperature.

Next, an example of a method for supporting a drug layer, which is a bioactive substance containing a drug, on the surface porous body manufactured in the same manner as the method for manufacturing a biological implant of the first embodiment will be described.
A method for producing a biological implant carrying a drug layer includes a step of immersing a surface porous body in a calcium solution containing at least 10 mM calcium ions, and immersing the surface porous body in a phosphate solution containing at least 10 mM phosphate ions. Process. At least one of the calcium solution and the phosphoric acid solution contains a drug. Moreover, the surface porous body may be immersed first from any of the calcium solution and the phosphoric acid solution. Below, the case where a surface porous body is previously immersed in a calcium solution is demonstrated.

  First, the surface porous body is immersed in a calcium solution containing at least 10 mM calcium ions for a predetermined time. This calcium solution may contain at least calcium ions, and may contain sodium ions, potassium ions, magnesium ions, carbonate ions, silicate ions, sulfate ions, nitrate ions, chlorine ions, hydrogen ions, and the like. It is preferable that phosphate ions are not substantially contained. Examples of calcium solutions include aqueous solutions of compounds that are usually highly water-soluble and do not adversely affect the human body. Examples include calcium chloride, calcium hydroxide, calcium nitrate, calcium formate, calcium acetate, calcium propionate, and butyric acid. Examples thereof include calcium, calcium lactate, and a mixed solution thereof, and an aqueous solution of calcium chloride is preferable.

  After being immersed in the calcium solution for a predetermined time, the surface porous body is immersed in a phosphate solution containing at least 10 mM phosphate ions. This phosphate solution only needs to contain at least phosphate ions, and may contain sodium ions, potassium ions, magnesium ions, carbonate ions, silicate ions, sulfate ions, nitrate ions, chlorine ions, hydrogen ions, and the like. Although it is good, it is preferable that calcium ions are not substantially contained. Examples of the phosphoric acid solution include aqueous solutions of compounds that are usually highly water-soluble and do not adversely affect the human body. For example, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate , Potassium dihydrogen phosphate, and a mixed solution thereof, and an aqueous solution of dipotassium hydrogen phosphate is preferable.

  The drug is contained in at least one of a calcium solution and a phosphoric acid solution. The drug can be appropriately selected depending on the required function. For example, at least one drug can be selected from the drugs described above. The concentration of the drug is appropriately adjusted as long as it is not less than the effective concentration of the drug to be used and does not harm the living body.

  The order in which the surface porous body is immersed in the above two types of aqueous solutions is not particularly limited. For example, when hydroxyapatite is generated as a bioactive substance in the microporous layer, that is, in the porous structure, hydroxyapatite is used. From the viewpoint of the amount of production, it is preferable that the production reaction proceeds in an alkaline region where the solubility of is lower, and therefore the pH of the solution immersed in the latter half is preferably in the alkaline region of pH 8-10.

  The time for immersing the surface porous body in the calcium solution and the phosphoric acid solution is preferably immersed for 1 minute or more, particularly preferably 3 minutes or more. If it is within the above range, calcium ions, phosphate ions and the drug are sufficiently infiltrated into the surface porous body, and the bioactive substance and the drug are co-precipitated on the inner wall surface of the micropores in the microporous layer of the surface porous body. be able to. In addition, when it is desired to increase the production amount of the bioactive substance, the operation of immersing in each solution may be repeated a plurality of times.

  The biological implant of the second embodiment has various uses, and can be suitably used for, for example, a medical material that is required to be combined with a biological tissue. In particular, an artificial bone, an artificial tooth root, and an alveolar bone It can be used for bone-forming implants and transdermal devices. The artificial bone can be applied as, for example, a bone filling material, an artificial joint, an osteosynthesis material, an artificial vertebral body, an intervertebral body spacer, or a vertebral body cage. The alveolar bone-forming implant is embedded so as to compensate for the thin alveolar bone. A transdermal device is a medical device that penetrates the skin from the outside of the body into the body and is responsible for nutritional supplementation, drug solution injection, blood circulation, and the like, and is associated with any artificial organ.

  The biological implant according to the present invention is not limited to the above-described example, and various modifications can be made within a range in which the object of the present invention can be achieved.

Example 1
The surface of a square board (thickness 2 mm, made by Victrex 450 G) formed of polyether ether ketone (PEEK) (glass transition temperature 143 ° C., melting point 340 ° C., elastic modulus 4.2 GPa, flexural strength 170 MPa) is sandpaper. A solid substrate was prepared by polishing with (# 1000).

  The solid substrate was immersed in concentrated sulfuric acid (concentration: 98%) at room temperature for 5 minutes to perform a swelling process for swelling the solid substrate. Subsequently, the solid base material taken out from the concentrated sulfuric acid was immersed in pure water for 5 minutes. Thereafter, the solid water was repeatedly washed until the pH of the pure water became neutral, and a solid substrate having a swollen surface was solidified and washed. In this way, a microporous substrate was obtained.

  Next, a foaming agent holding step is performed in which the microporous substrate is immersed in an aqueous potassium carbonate solution (concentration: 3M) at room temperature for 4 hours to hold potassium carbonate on the surface of the microporous substrate and in the pores. A holding substrate was obtained.

  Next, this foaming agent holding base material is immersed in concentrated sulfuric acid (concentration: 95%) at room temperature for 1 minute to swell PEEK and foam potassium carbonate, and perform a surface soft foaming step. Obtained.

  The obtained soft surface foamed base material was solidified by dipping in dilute sulfuric acid (concentration: 86%) for 5 minutes at room temperature, and then taken out from dilute sulfuric acid (concentration: 86%) for 10 minutes in pure water at room temperature. A second solidification step for immersion was performed. Next, a cleaning process was repeatedly performed until the pH of pure water was neutralized. Subsequently, the drying process which dries for 12 hours at 80 degreeC was implemented, and the surface foaming base material by which the microporous layer which consists of PEEK was formed in the surface of the substantial part which consists of PEEK was obtained.

  A protective layer was formed on the surface of the obtained surface foamed substrate on which the microporous layer was formed using a direct modeling apparatus (IMC-1703, manufactured by Imoto Seisakusho Co., Ltd.). Specifically, PEEK powder (Daicel Evonik Co., Ltd., Vestakeep) is charged into a material container and heated to 420 ° C., and this is extruded from a nozzle (diameter 0.3 mm) to form a plurality of PEEK lines. Were formed on the surface of the microporous layer. The first shaped bodies were arranged in stripes with a pitch of 1.0 mm. By forming a second-layer shaped body in which the same pattern as the first-layer shaped body is rotated by 90 ° on the first-layer shaped body, the protective layer having a lattice shape in a plan view is formed on the surface foaming group. A surface foam formed on one side of the material was obtained. Subsequently, the biological implant test body 1 which has a structure shown in FIG.1 and FIG.2 was obtained by cutting out the disk body of diameter 10mm from a square disk-shaped surface foam.

  After the living body implant specimen 1 was embedded and fixed in an epoxy resin, it was cut in a direction including the axis of the disc body, the cut surface was polished, the polished surface was observed with a digital microscope, and the thickness of the protective layer was measured. 700 μm.

The living body implant specimen 1 fixed with the epoxy resin is cut slightly from the interface between the microporous layer and the protective layer at the protective layer side, and the area S of the interface between the microporous layer and the protective layer and the exposure of the microporous layer are exposed. the area _{S m} was measured. The ratio of the exposed area (S _m / S × 100) was 50%.

The volume of the protective layer 4 in the biological implant specimen 1 is measured, the protective layer is cut out from the biological implant specimen 1, and the mass of the cut out protective layer is measured to calculate the density, and the calculated density and protection The porosity of the protective layer was calculated based on the theoretical density of the layer (1.30 g / cm ³ ) and found to be 50%.

  An image obtained by photographing the surface of the microporous layer in the biological implant specimen 1 with a scanning electron microscope (300 times) is image-analysis software (Scion Image, manufactured by Scion), and the large-diameter opening formed by the large-diameter pores. When binarized into pores and other portions, and then the ratio of the area of the large-diameter open pores to the exposed area of the entire image was calculated, it was 78%. Moreover, when the average open pore diameter of the large diameter open pores and the small diameter open pores opened on the surface of the microporous layer was measured by the intercept method as described above, the average open pore diameter of the large open pores was 73 μm. The average open pore diameter of the small diameter open pores was 2 μm.

  The biological implant specimen 1 is cut in the thickness direction of the microporous layer, the cut surface is observed with a scanning electron microscope, and the distance from the deepest point of the micropores to the exposed surface in the obtained SEM image is determined as the microporous layer. As a result, the thickness of the microporous layer was in the range of 50 to 100 μm.

(Comparative Example 1)
A surface foamed substrate was formed in the same manner as in Example 1, and this was used as a biological implant specimen 2.

(Injection test)
An implantable material having a space slightly smaller than the living body implant specimen 1 of Example 1 was prepared. The space in the material to be driven has a width larger than the diameter of the biological implant specimen 1 and a height smaller by 0.1 mm than the thickness of the biological implant specimen 1. The living body implant test body 1 was driven into this space using a hammer, and the surface state of the living body implant test body 1 before and after driving was observed with a digital microscope. FIG. 6 shows an enlarged photograph (300 times) of the surface of the biological implant specimen 1 before being driven, and FIG. 7 shows an enlarged photograph (300 times) of the surface of the biological implant specimen 1 after being hammered.

  As shown in FIGS. 6 and 7, the structure of the microporous layer in the biological implant test body 1 did not change before and after implantation, and the micropores were not crushed by implantation. Since the living body implant test body 1 is provided with the protective layer on the microporous layer, it can be seen that the microporous layer was protected by the protective layer and the micropores were prevented from being crushed.

  For the living body implant test body 2 of Comparative Example 1 as well as the living body implant test body 2, a material to be driven having a space slightly smaller than that of the living body implant test body 2 is prepared, and the living body implant test body 2 is driven into the space. The surface state of the front and rear living body implant specimens 2 was observed with a digital microscope. FIG. 8 shows an enlarged photograph (300 times) of the surface of the biological implant specimen 2 before being driven, and FIG. 9 shows an enlarged photograph (300 times) of the surface of the biological implant specimen 2 after being hammered.

  As shown in FIGS. 8 and 9, a part of the micro-open holes was crushed by the driving, and a part of the micro-open holes was closed after the driving. Since the biological implant specimen 2 is not provided with a protective layer on the microporous layer, the microporous layer is compressed by the inner wall forming the space when driven into the space of the material to be driven, and the micro-open pores are formed. You can see that part of it was crushed.

1, 101, 201 Biological implant 2 Substrate 3, 103, 203 Microporous layer 4, 104, 204 Protective layer 5, 105, 205 Skeletal part 6, 106, 206 Void 7 Exposed surface 31 Micropore 32 Small diameter pore 33 Large diameter Pores

Claims (5)

A dense substantial part made of engineering plastic, a microporous layer provided on the surface of the substantial part, and a protective layer provided on the surface of the microporous layer,
The protective layer, the microporous layer disposed on part of the surface of, Ri Do from engineering plastics, and dense skeleton porosity Ru der 5%, the microporosity from the outer surface of the protective layer A void reaching the surface of the layer,
The bioimplant, wherein the microporous layer has microopen pores that open to the surface of the microporous layer.   The living body implant according to claim 1, wherein the porosity of the protective layer is 10 to 90%. The ratio (S _m / S × 100) of the exposed area S _m exposed in the voids of the micro porous layer to the total area S of the interface between the micro porous layer and the protective layer is 10 to 90%. The living body implant according to claim 1 or 2, characterized by the above.   The thickness of the said protective layer is 100-10000 micrometers, The biological implant as described in any one of Claims 1-3 characterized by the above-mentioned. It is a manufacturing method of the living body implant according to any one of claims 1 to 4,
A method for producing a biological implant, wherein the protective layer is formed by rapid prototyping.

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