JP2003159321A - Organic-inorganic compound porous body and manufacturing method thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide the organic-inorganic compound multiple porous bodies that make it possible to facilitate an immersion of a humor or the like, bonding with the bones of a living body and reconstruction of biological osteous tissues in an early stage and are practically used as a footing of tissue reconstructions, prosthetic material, bone filler, intervening substance between an implant and biological osteous tissues, substitute for cancellous bone, a carrier for sustained release of drugs or the like as well as the manufacturing method thereof. <P>SOLUTION: The organic-inorganic compound multiple porous bodies are composed of a structure in which inorganic particles such as the particles of biologically active bioceramics or the like are substantially and uniformly dispersed in organic polymers such as in vivo resolving absorptive polymers and have consecutive stomata of roughly 100-400 μm in inner diameter and the content of inorganic particles as much as 60-90 weight/%, leaving partially exposed inorganic particles on the surface and the inner surface of stomata. This multiple porous body can be obtained by manufacturing a fiber aggregate from a suspension of inorganic particles dissolved in a volatile solvent and dispersed thereon, which was heated and pressurized to be formed into a multiple porous fiber aggregate and immersed in a volatile solvent before the solvent was removed. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an organic-inorganic composite porous body, and more particularly to a scaffold for regenerating a living bone tissue,
Prosthesis, bone filler, inclusion between implant and living bone tissue, cancellous bone substitute, DDS (Drug Deliverl)
y System), an organic-inorganic composite porous material suitable for applications such as a drug sustained release carrier.

[0002]

2. Description of the Related Art As an inorganic porous material for medical purposes, for example, ceramics are calcined or sintered (Calcine
Porous ceramics obtained by d, Sintered) are known. However, such porous ceramics
Although it is hard to be used for applications such as scaffolds for reconstructing living bone tissue and prostheses, it has the drawback of being brittle, so damage due to slight post-surgery is always a concern. Further, it is also difficult to process and deform the shape of the porous ceramic so as to match the shape of the defect portion of the living bone tissue at the operation site.

On the other hand, as an organic porous material for medical purposes, for example, a sponge disclosed in Japanese Patent Publication No. 63-64988 is known. This sponge is usually used as a prosthetic material for hemostasis during surgery and for suturing soft tissues (eg, organs) of the living body, and is a sponge having continuous pores made of biodegradable and absorbable polylactic acid. . Such a sponge is produced by a method in which polylactic acid is dissolved in benzene or dioxane and the polymer solution is freeze-dried to sublimate the solvent.

However, the porous body produced by the freeze-drying method like the above sponge requires a long time for sublimation, and it is difficult to completely remove the solvent, and the thickness thereof is 1 mm or less ( Normally, it is as thin as a few hundred μm) and a few mm
It is practically difficult to manufacture the above thick porous body. As another method for producing a porous body having continuous pores,
Various methods other than the above freeze-drying method have been investigated, but it is difficult to obtain a thick porous body having a thickness of several mm. By applying such a thin porous body to a complicated and relatively large three-dimensional space of a tissue damage site, for example,
It is difficult to use it as a material for reconstructing the tissue of a three-dimensionally damaged site while exhibiting the function as a primary prosthetic material.
Therefore, a three-dimensional cube having a large thickness and having a free shape that can be worked before or after surgery is required.

As another effective method for producing a continuous porous body, a thin molded product such as a sheet is prepared by mixing a large amount of water-soluble soluble powder particles such as NaCl having a predetermined size with a polymer. An elution method of forming continuous pores having the same diameter as the powder particles by immersing the powder particles in water (solvent) and then eluting the powder particles is known. Since it is difficult to do so, it is limited to a thin continuous porous body. Further, if the ratio of water-soluble powder particles is high, it is difficult to form open cells. Moreover, when the porous body is used as an implantable material in a living body, there is a problem that the residual powder particles are toxic.

[0006] Like the above sponge, a porous body containing no inorganic powder particles such as bioactive bioceramics directly binds to a living bone tissue such as hard bone or cartilage.
dingability to bone), conductivity (osteoconductivit)
y), since bone tissue, which is not osteoblast, invades and intervenes due to lack of bone replacement, it takes a long time to completely replace and regenerate bone tissue in the living body. It takes or ends without being replaced.

[0007] Therefore, the Applicant of the present invention has a bioceramic powder grain inside which can be planted as a scaffold of a three-dimensional cube by being seeded with osteoblasts and can be planted for a bridge me in a large bone defect. We have already filed an application for a porous body having a large thickness and containing continuous biodegradable and absorbable polymer (Japanese Patent Application No. 8-229280).

This porous body is based on a method for producing a porous body called a solution precipitation method. That is, the biodegradable and absorbable polymer is dissolved in a mixed solvent of the solvent and a non-solvent having a higher boiling point than the solvent, and the bioceramic powder particles are dispersed to prepare a suspension, which is mixed from the suspension. This is a method in which the solvent is vaporized at a temperature lower than the boiling point of the solvent to precipitate the biodegradable and absorbable polymer containing the bioceramic powder particles.

The principle of forming a porous body by this solution precipitation method is as follows. That is, when the mixed solvent is vaporized at a temperature lower than the boiling point of the solvent from the suspension described above, the solvent having a low boiling point is vaporized preferentially and the ratio of the non-solvent having a high boiling point is gradually increased. When a certain ratio is reached, the solvent cannot dissolve the polymer. Therefore, the polymer begins to precipitate / precipitate, encloses the bioceramic powder particles that have started to settle from the beginning, and the precipitated / precipitated polymer shrinks and solidifies due to the high proportion of the non-solvent and contains the bioceramic powder particles. A cell structure is formed in which the mixed solvent is encapsulated in the thin cell wall of the polymer which is immobilized as it is. Then, the remaining solvent destroys a part of the cell wall to form pores and diffuses / disappears, and the non-solvent with a high boiling point gradually diffuses through the pores, and finally diffuses completely. Disappear. As a result, a bioceramic powder particle-containing porous body is formed in which the traces of the mixed solvent that are wrapped in the polymer cell wall are connected as continuous pores.

[0010]

The above solution precipitation method is
This is an epoch-making method of forming a porous body having a large expansion ratio from a low expansion ratio to a high expansion ratio, and it is possible to obtain a block-shaped three-dimensional porous body having a thickness of several mm to several tens of mm. Therefore, it is very useful as a scaffold for bone regeneration of a three-dimensional shape (three-dimensional structure).

However, the disadvantage of this method is that in a suspension containing a large amount of bioceramic powder particles, the bioceramic powder particles that belong to a relatively large particle size distribution among the average particle diameters initially start to volatilize the solvent. When the polymer starts to settle from the start of precipitation from the bottom, a considerable amount of bioceramic powder particles have already settled with a concentration gradient toward the bottom, so the resulting porous body has a content of bioceramic powder particles. The content is not partially uniform, and the content increases from the upper surface side to the bottom surface side of the porous body. Such a non-uniform porous material having a concentration gradient is difficult to be effectively used for scaffolds for bone tissue reconstruction, prostheses, bone fillers and the like. This problem can be improved to some extent by controlling the sedimentation rate of the bioceramic powder particles, but it cannot be completely solved. Especially 30% by weight
It is difficult to obtain a porous body for three-dimensional bone reconstruction containing the above-mentioned bioceramic powder particles and having a uniform and uniform concentration.

The porous body containing a small amount of bioceramic powder particles produced by the above-mentioned method has the majority of bioceramic powder particles enclosed in the polymer cell wall and is difficult to be exposed on the inner surface of the continuous pores. When embedded in a bioceramics powder, it is difficult for the bioceramics powder particles to exert the conductive action of the living bone tissue from the beginning of the implantation, and bioactivity along with the bioceramics powder particles exposed along with the decomposition of the polymer that forms the skin layer on the inner surface of the continuous pores causes bioactivity. There is a problem of being expressed.

Further, the porous body produced by the above method is
Even if ultrafine particles are selected, the content rate of bioceramics powder particles must be at most about 30% by weight. If the content is larger than this, the bioceramics powder particles are more likely to settle, and the obtained porosity is increased. There is a limit that the bottom side of the body contains a large amount of bioceramic powder particles and becomes extremely brittle.

Further, the porous body produced by the above method is
Usually, the proportion of the continuous pores (porosity) is as high as 80% or more, but generally speaking, since only relatively small continuous pores having a pore diameter of several μm to several tens of μm can be obtained,
It cannot be said that the pore diameter and pore morphology are ideal for the invasion and growth of osteoblasts inside the porous body.

An object of the present invention is to provide an organic-inorganic composite porous material which can solve these problems and a method for producing the same.

[0016]

The organic-inorganic composite porous material according to the present invention is a porous material in which inorganic powder particles are dispersed substantially uniformly in an organic polymer and which has continuous pores inside.
Part of the inorganic powder particles is exposed on the surface and the inner surface of the pores. And, in the continuous pores, osteoblasts invade and proliferate,
It is adjusted to a pore size of about 100 to 400 μm, which is suitable for stabilization, and the inorganic powder particles are contained in a large amount of 60 to 90% by weight. The porous body has a large thickness of 1 to 50 mm and has a three-dimensional solid shape.

Such an organic-inorganic composite porous material is a nonwoven fabric-like fiber aggregate from a suspension prepared by the method of the present invention, that is, by dissolving an organic polymer in a volatile solvent and dispersing inorganic powder particles. It can be produced by a method of forming a porous fiber aggregated compact by heating under pressure to form a porous fiber aggregated compact, and then immersing the fiber aggregated compact in a volatile solvent and then removing the solvent. . As a means for producing a nonwoven fabric-like fiber assembly from a suspension, a means for spraying while making the suspension into fibers is preferably adopted, and when the fiber assembly formed body is immersed in a volatile solvent, the fiber assembly is It is desirable to apply an external force so as to maintain the shape of the molded body, whereby a porous body having mechanical strength can be obtained.

As described above, when means for spraying the prepared suspension while fibrating the prepared suspension is adopted as means for forming the fiber aggregate, the fibers of the organic polymer containing the inorganic powder particles are entangled with each other and contacted with each other. And the fibers are aggregated and solidified by volatilization of the volatile solvent to form a thick non-woven fabric fiber aggregate having an arbitrary shape. This fiber assembly is
The inter-fiber void is not a round cell space, but it has a continuous space in which the welded and solidified fibers have a spacing of several hundreds of μm, and the inorganic powder particles are included in the fiber to form a fiber aggregate. It is evenly distributed throughout the body. When this fiber assembly is pressure-molded under heating to form a porous fiber assembly-molded body and is immersed in a volatile solvent while maintaining its shape while applying an external force, the fibers shrink and fuse. Then, the substantially fibrous morphology disappears, and a porous matrix is obtained in which the morphology is changed to a continuous pore body having a cell structure in which interfiber voids have a roundness. Along with this transformation, a part of the inorganic powder particles contained in a large amount is exposed on the inner surface of the pores and is also exposed on the surface to such an extent that the inorganic powder particles are not easily dropped. And organic-inorganic composite porous body, that is, inorganic powder particles are dispersed substantially uniformly at a high content, and a part of the organic material is exposed on the surface or inside the continuous pores.
An inorganic composite porous body is obtained. Of course, when the skin layer is formed on the surface depending on the conditions, the inorganic powder particles may be exposed by sanding. This composite porous body is suitable for infiltration and stabilization of osteoblasts by controlling the average pore size of continuous pores by adjusting the external pressure to maintain the shape of the fiber aggregated body when immersed in a volatile solvent. Good 10
It is desirable that the porosity be controlled so that the porosity can be controlled in the range of 0 to 400 μm and the porosity is in the desirable condition of 50 to 90%.

In the production method of the present invention, 60 to 90% by weight (41% when the average particle size is 3 μm) is used within the range where fiberization is possible.
(Corresponding to about 81% by volume) can be uniformly contained in the pore body. Even if contained in a large amount, the fibers are welded before the inorganic powder particles settle, so the inorganic powder particles are more evenly dispersed and the content is much higher than that of the porous body obtained by the solution precipitation method described above. The porous body can be finally obtained. However, if the content is too high, the amount of the polymer as the binder decreases, and the porous body becomes brittle and it becomes difficult to maintain its shape.

The present organic-inorganic composite porous material for medical use such as scaffolding for regeneration of living bone tissue has solvent characteristics suitable for the present production method as an organic polymer, and has already been put into practical use and its safety has been confirmed. Therefore, a polymer is selected that decomposes relatively quickly and is not brittle even when it becomes a porous body. That is, amorphous or poly-D, L-lactic acid in which crystalline and amorphous are mixed,
Block copolymer of L-lactic acid and D, L-lactic acid, copolymer of lactic acid and glycolic acid, copolymer of lactic acid and p-dioxanone, copolymer of lactic acid and caprolactone, copolymer of lactic acid and ethylene glycol, Alternatively, biodegradable and absorbable polymers such as mixtures thereof are used. Its viscosity average molecular weight is that it is easy to form a non-woven fiber aggregate,
Considering the period of decomposition and absorption in the living body, 50,000 to 1,000,000 are preferably used.

In particular, poly-D, L-lactic acid, which is amorphous due to the monomer ratio, a block copolymer of L-lactic acid and D, L lactic acid, a copolymer of lactic acid and glycolic acid, and lactic acid and p.
-A biodegradable total absorbable polymer such as a dioxanone copolymer is used to form a nonwoven fabric-like fiber assembly, and the fiber assembly-molded body which is pressure-molded under heating is treated with a volatile solvent. It is preferable in view of the solvent characteristics at that time,
When these polymers are used, they are not brittle even if they contain a large amount of inorganic powder particles, and have a compressive strength (1-5MP) similar to cancellous bone.
It has a compressive strength of about a) and can be thermally deformed at a relatively low temperature (about 70 ° C), unlike a porous body made of ceramics alone, and is rapidly hydrolyzed in vivo to 6-12.
It is possible to obtain an organic-inorganic composite porous body which is completely absorbed in a month. The composite porous body having such characteristics is extremely preferable as a biomaterial to be filled in a defect portion of a living bone. Since it is a composite, it also has the unique advantage of a thermoplastic polymer that, unlike a ceramic-only material, can be thermally deformed during surgery and shaped to match the defect.

The biodegradable total absorbable polymer has a molecular weight of
As described above, a polymer having a viscosity average molecular weight of 50,000 to 1,000,000 is used because it affects the time until hydrolysis and total absorption and the possibility of fiber formation. A polymer having a viscosity average molecular weight of less than 50,000 has a short time to be hydrolyzed to a low molecule of an oligomer or a monomer unit, but has insufficient spinnability, and thus is sprayed while forming a fiber to form a composite fiber aggregate. Is difficult. Further, a polymer having a viscosity average molecular weight of more than 1,000,000 requires a long period of time to be completely hydrolyzed, and is therefore unsuitable as a polymer of a composite porous body for the purpose of early replacement with biological tissue. . Although it depends on the polymer, the preferable viscosity average molecular weight is about 100,000 to 300,000. When a polymer having a molecular weight in this range is used, the formation of a fiber assembly is facilitated and the hydrolysis completion time is appropriate. The composite porous body of the present invention can be obtained.

In the above-mentioned organic-inorganic composite porous body intended for medical use, inorganic powder particles have bioactivity and have good osteoconductivity (sometimes said to show osteoinduction ability) and good organism. Bioceramics powder with affinity is used. As such bioceramic powder particles, for example, surface bioactive calcination, calcined hydroxyapatite, apatite wollastonite glass ceramics, bioactive and total bioabsorbable uncalcined, uncalcined hydroxyapatite, dicalcium. Powder particles of phosphate, tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcite, ceravital, diopsite, natural coral and the like can be mentioned. Further, it is also possible to use those in which an alkaline inorganic compound, a basic organic substance or the like is attached to the surface of these powder particles. Among them, it is ideal that total replacement is performed by one's own living tissue and tissue regeneration is performed. Among these, total absorbability in vivo is completely absorbed and completely replaced with bone tissue. Bioceramic powder of
In particular, uncalcined and uncalcined hydroxyapatite, tricalcium phosphate, and octacalcium phosphate have the highest activity, excellent osteoconductivity, excellent biocompatibility, low toxicity, and are absorbed into the body in a short period of time. So
Optimal.

It is preferable to use the above-mentioned bioceramic powder particles having a particle size of 10 μm or less, and if the bioceramic powder particles having a larger particle size are used,
When the suspension in which the powder particles are mixed is sprayed while forming fibers, the fibers are cut into short pieces, which makes it difficult to form fiber aggregates, and even if the fiber aggregates can be formed, the fibers solidify. By the time, the bioceramics powder particles may be slightly settled and dispersed unevenly. 20-30μ
If the size exceeds m, even if it is totally absorbable, it takes a long time for complete absorption, and a tissue reaction during that time sometimes appears, which is not preferable.

The more preferable particle size of the bioceramic powder particles is 0.2 to 5 μm. When such bioceramic powder particles are used, a suspension obtained by mixing the powder particles at a high concentration as in the present invention is used. Even when a fiber aggregate is formed by thinning the fiber to about 1 to 3 μm, the fiber is difficult to be cut, and when the concentration is high as in the present invention, the powder particles are included in the fiber in a state of being exposed from the fiber. After the fiber assembly is immersed in the volatile solvent, the powder particles become a composite porous body exposed from the surface and the inner surface of the continuous pores.

The content of the bioceramics powder particles is intended for medical applications such as scaffolds in regenerative medical engineering, carriers or bone fillers for DDS, substitutes for irregularly shaped cancellous bone (Allograft). In the case of the organic-inorganic composite porous body, it is preferable to set the content to 60 to 90% by weight in view of the bioactivity effect of bioceramics. In the case of forming a fiber aggregate containing inorganic powder particles as in the present invention, and immersing the fiber aggregate formed body which is pressure-molded under heating into a volatile solvent to obtain a composite porous body, it is formed into a fiber. Since a large amount of inorganic powder particles can be contained within the range where it is possible to achieve the above, the content rate of bioceramic powder particles is 60 to 9 as described above.
0% by weight (volume ratio when the average particle size is 3 μm is 41 to 8)
(Corresponding to a high ratio of 1%). When the content rate of bioceramic powder particles exceeds 90% by weight,
It becomes difficult to form a fiber aggregate because it does not become a satisfactory fiber when cut into fibers. On the other hand, when it is less than 60% by weight, bioceramic powder particles are insufficient and few are exposed on the surface. The bioactivity derived from the bioceramics powder is difficult to be expressed from the beginning when it is embedded in the.

Porous ceramics obtained by sintering ceramics such as hydroxyapatite are hard but brittle, so that a thin material is easily cracked or chipped by an external force, which is unsatisfactory as an implant.
On the other hand, the composite porous body containing the bioceramic powder in the biodegradable and absorbable polymer, which is particularly amorphous, has a high content of the bioceramic powder of 60 to 90% by weight. Due to the binding effect of the polymer, it has a compressive strength similar to that of cancellous bone that retains its flexibility and is not brittle, specifically, it has a compressive strength of about 1 MPa to 5 MPa, so it can replace cancellous bone (for allograft: Allograft
Substitute for bone), bone filler, prosthesis, scaffold for regeneration and carrier of DDS.

Another promising application is an inclusion with an artificial implant for living bone (hard bone, cartilage). For example, when implanting an artificial material with a high concentration made of polylactic acid-based polymer containing bioceramic powder, which is a bioactive and bioabsorbable bone cement, avoid creating a gap with the living body. Since it is difficult, direct contact with bone tissue with the present composite porous body interposed therebetween causes remarkable osteoconductivity. This works effectively in various parts of the living bone, but for example, in the case of median sternotomy, the sternum fixation pin that penetrates this porous body is embedded in the median bone to make the osteoporosis extremely hollow. It can bring osteoinduction (combination with cytokine) and bone conduction into bone. Alternatively, it can be used as an underlay of this type of plate to achieve close contact with bone. It has many uses as an intervening body and an artificial body, such as direct connection between an artificial intervertebral disc and a vertebral endplate.

The organic-inorganic composite porous body has a porosity (total porosity) of 50% or more, and technically, it is possible to reach up to about 90%. Considering both invasion and stabilization of cells, it is approximately 60 to 8
0% is good, and considering the efficiency of invasion of osteoblasts to the central part of the composite porous body, the number of continuous pores is 50 to 50%.
It is preferable to occupy 90%, especially 70 to 90%.

The continuous pores of this organic-inorganic composite porous material are
The pore diameter is adjusted to about 100 to 400 μm.
Studies on the pore size of porous ceramics and invasion and stabilization of osteoblasts have already been carried out many times. From the results, the pore size of 300 to 400 μm is the most effective for calcification, and the effect increases with increasing distance. It is known to fade. Therefore, the pore diameter of the composite porous body of the present invention is adjusted to about 100 to 400 μm as described above, but 50
Includes pores with diameters in the range of up to 500 μm and the center of distribution is 2
It may be from 00 to 400 μm.

By the way, when the diameter of continuous pores is larger than 400 μm and the porosity (total porosity) is higher than 90%,
Since the strength of the composite porous body is lowered, there is a high possibility that it will be easily broken during implantation in a living body. On the other hand, when the pore size is smaller than 100 μm and the porosity is lower than 50%, the strength of the composite porous body is improved, but the invasion of osteoblasts is difficult and the time required for complete hydrolysis and absorption Becomes longer. However, such a low-porosity composite porous body having a small pore size,
It can be optionally used as a carrier for DDS as a material that is desired to maintain sustained release for a relatively long period of time that accompanies degradation of a polymer. The more preferable pore diameter of the continuous pores is 150 to 350 μm, and the more preferable porosity (total porosity) is 70 to 80%. The pore diameter of the continuous pores and the ratio of the continuous pores to the entire pores are, as described above, the compression ratio when the fiber aggregate is pressure-molded to form the fiber aggregate molded body, and the fiber aggregate molded body. Can be controlled by adjusting the external pressure for maintaining the shape when the shape is retained and immersed in a volatile solvent.

The organic-inorganic composite porous material as described above can be used, for example, as an implant of various shapes by embedding it in a defective portion of a living bone. At that time, since the composite porous body is heated to about 70 ° C. by utilizing the thermoplasticity of the organic polymer and deformed so as to conform to the shape of the defect portion, the defect portion can be embedded without a gap. Can be performed easily and accurately. Further, due to the toughness of the organic polymer and the hardness of the ceramic powder particles, it can be used by cutting with a scalpel into a desired shape without being deformed during surgery.

When the composite porous body is embedded in the bone tissue of a living body as described above, for example, a body fluid rapidly penetrates from the surface of the composite porous body into the inside of the composite porous body through the continuous pores. Since the hydrolysis of the biodegradable and absorbable polymer progresses almost simultaneously from both the surface and inside of the continuous pores, the degradation progresses uniformly over the entire porous body (however, the wetting property with biological fluid is large. Due to the wetting property of the bioceramic powder particles that are contained and exposed on the surface, it is significantly improved as compared with the case of using only the polymer, or the property of improving the wetting property of the polymer is also intended to make the invasion and growth of cells to be proliferated more effective. With corona discharge, plasma treatment,
Oxidizing treatment such as hydrogen peroxide treatment may be performed). Then, the composite porous body in which bone cells are present or which is in contact with the bone cells, has a bone tissue in the surface layer portion of the composite porous body due to the osteoconductivity of the bioceramic powder particles exposed on the surface thereof. Propagation is quickly formed by trabeculae of trabecul
arbone), the composite porous body binds to the defect site of the living bone within a short period of time, and the bone conductivity of the bioceramic powder particles exposed on the inner surface of the pores causes bone tissue to form inside the composite porous body. It also penetrates into the bone and conducts and grows osteoblasts, so that it directly binds to the surrounding bone. This phenomenon becomes remarkable as the degradation of the biodegradable and absorbable polymer progresses, and gradually replaces the surrounding bone. And finally, the polymer is completely decomposed and absorbed, and when the bioceramic powder particles are bioabsorbable, the bioceramic powder particles are also completely absorbed and completely replaced by the grown bone tissue, Regeneration of the bone defect is complete.

Further, in consideration of the rate of decomposition and absorption as a scaffold for bioreconstruction which requires the above total replacement,
By gradually releasing various growth factors such as cytokines, various therapeutic agents, antibacterial agents, etc., which are pre-filled in the pores or dissolved in a polymer in advance and carried, it is possible to regenerate the living body or disease. It can accelerate or be effective in healing. It is obvious that the composite porous body can be used as a filling material or a prosthesis material for a defective tissue by itself or in combination with allograft bone as described above.

The above-mentioned organic-inorganic composite porous material is a scaffold for regenerating living tissue of total or partial replacement type, drug carrier, prosthesis, bone filler, inclusion between implant and living tissue, and sponge. Although intended for medical uses such as bone substitutes, in the case of organic-inorganic composite porous bodies intended for other purposes, polymethyl methacrylate, polyvinyl acetate, polyvinyl chloride, polyurethane as the organic polymer. , Polyalkylene oxide, and various general-purpose resins soluble in other volatile solvents are appropriately selected and used according to the application. As the inorganic powder particles, various industrial fillers, functional fillers, ceramics powder particles, carbon powders, carbon nanotubes and the like are appropriately selected and used according to the application.

Next, the manufacturing method of the present invention will be described.

According to the production method of the present invention, first, the above-mentioned organic polymer is dissolved in a volatile solvent and the above-mentioned inorganic powder particles are uniformly dispersed to prepare a suspension. As the volatile solvent, low boiling point dichloromethane, dichloroethane, methylene chloride, which easily volatilizes at a temperature slightly higher than room temperature,
A solvent such as chloroform is used. In addition, these solvents, non-solvents having a higher boiling point than these solvents, for example,
Volatility in which any one of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, ter-butanol, and ter-pentanol having a boiling point in the range of 60 to 110 ° C is used alone or in combination of two or more. A mixed solvent of is also used.

Next, the suspension is filled in a sprayer, and is sprayed from an injection hole of the sprayer with an inert high-pressure injection gas such as nitrogen gas while fiberizing the suspension onto an object to be injected.
When sprayed in this way, the volatile solvent is volatilized and the suspension is made into fibers and entangled with each other, and the fibers are solidified while being welded at their mutual contact points to form a non-woven fiber aggregate. 5 sometimes necessary as biomaterial for medical use
In order to obtain a composite porous body with a thickness of 50 mm, after forming this fiber assembly by spraying, wait for the solvent to evaporate and dry, and then spray it again to thicken it. It suffices to repeatedly obtain a predetermined wall thickness.

As the object to be ejected, a mesh or plate made of polyethylene or other olefin resin, fluororesin, silicon resin or the like having good peelability is used. In particular, when a sprayable body such as a mesh is used, the volatile solvent is volatilized through the mesh after the suspension is fibrillated by the spray and hits the mesh. There is an advantage that a fiber assembly can be formed which is easy to be permeated by a solvent without being fused to form a skin layer. The mesh is preferably 50-300 mesh, and the mesh having a mesh larger than 50 mesh has fibers wrapping around to the back side through the mesh, which makes it difficult to separate the formed fiber assembly from the mesh. , A mesh having a mesh smaller than 300 mesh is less likely to volatilize the volatile solvent smoothly, so that the fibers on the mesh side are fused and a skin layer is easily formed. The object to be ejected is not limited to a flat net body or a plate body, and a three-dimensional net body or a plate body having a convex curve and / or a concave curve may be used. The use of such a three-dimensional object to be ejected has an advantage that a thick fiber assembly having the three-dimensional shape can be formed.

In the fiber assembly formed by spraying the suspension while making it into fibers as described above, the size of inter-fiber voids is as large as several hundred μm, and the ratio of inter-fiber voids (porosity) is 60. It is about 90%. Then, the inorganic powder particles are included in the fiber and are dispersed uniformly throughout the entire fiber aggregate without settling.

The fiber length of this fiber assembly is 3 to 100 mm.
The fiber diameter is preferably 0.5 to 50 μm.
It is preferably about the same. A fiber aggregate having such a fiber length and a fiber diameter becomes a composite porous body in which the fibers are easily fused by the subsequent solvent permeation treatment and the fibers are substantially lost.

The fiber length is mainly the molecular weight of the organic polymer,
Depending on the polymer concentration of the suspension, the content and particle size of the inorganic powder, the higher the molecular weight, the higher the polymer concentration, the lower the content of the inorganic powder, the smaller the particle size of the inorganic powder. I see, it tends to be longer. On the other hand, the fiber diameter mainly depends on the polymer concentration of the suspension, the content ratio of the inorganic powder particles, the size of the injection hole of the sprayer, etc.
The higher the polymer concentration, the higher the content ratio of the inorganic powder particles, and the larger the injection hole, the larger the thickness tends to be. The fiber diameter also changes depending on the pressure of the jet gas. Therefore, it is necessary to adjust the molecular weight of the polymer, the concentration of the polymer, the content and particle size of the inorganic powder particles, the size of the injection hole, the gas pressure, etc. so that the fiber length and the fiber diameter described above are obtained.

The above fiber assembly is then pressure-molded under heating to form a porous fiber assembly molded body. At that time, first, the fiber aggregate was heated and solidified under pressure to form a preform having continuous voids, and then the preform was pressure-molded under a higher pressure to obtain a continuous void having a controlled strength. It is desirable to use a porous fiber aggregated molded body having a certain amount. When a porous fiber aggregated molded body is produced by pressure molding in this way, the pore size and porosity of the continuous pores of the finally obtained composite porous body can be adjusted, and the strength of the composite porous body is improved. You can also The heating at the time of pressure molding is sufficient to soften the fiber aggregate a little, and the pressure is adjusted so that the porosity of the finally obtained composite porous body is 50 to 90%. In addition, the pressure may be set so that the diameter of the continuous pores is approximately 100 to 400 μm.

Next, the fiber aggregated molded body is dipped in a volatile solvent to permeate the solvent into the molded body, and then the permeated solvent is removed. When immersing the fiber assembly formed body in a volatile solvent, the fiber assembly formed body is filled in a predetermined mold having a large number of pores, and the shape is maintained while pressure is applied to the fiber assembly formed body from the outside. It is preferable to soak while soaking. It should be noted that a solvent may be poured onto the upper surface of the fiber aggregated molded body so as to permeate the solvent. Further, as a method of removing the solvent, a method of vacuum suction of the solvent inside the fiber aggregated molded body or the like is adopted.

Examples of the volatile solvent include the above-mentioned solvents such as dichloromethane, dichloroethane, methylene chloride and chloroform, and these solvents including the above-mentioned methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, ter-butanol, One of alcohols such as ter-pentanol or a mixture of two or more thereof is preferably used.

As described above, when the fiber aggregate molded body is dipped in a volatile solvent and the solvent is permeated into the molded body, the fibers are dissolved in the solvent from the surface, and the fibers are fused with each other to substantially disappear the fibers. Then, the cell walls are formed in a state where the inter-fiber voids have rounded continuous pores having a pore diameter of about 100 to 400 μm. Then, some of the inorganic powder particles contained in the fibers are exposed to the inner surface of the pores (wall surface of the bubbles) without settling due to the fusion of the fibers, and are also exposed to the surface of the porous body. However, when the skin layer is formed on the surface, the skin layer may be removed by sanding to expose the inorganic powder particles existing in the surface layer. Due to the above, the pore size is 100 to 4
A target organic-inorganic composite porous body is obtained which has a large number of continuous pores of 00 μm, a large amount of inorganic powder particles are uniformly dispersed, and the inorganic powder particles are exposed on the surface and the inner surface of the pores. In that case, when the fiber aggregated molded body is immersed in a volatile solvent while being heated at 50 to 60 ° C., the fiber aggregated molded body is reduced to 5-1.
The fibers can be sufficiently fused with each other by leaving it for 0 minutes to efficiently obtain the desired composite porous body.

As described above, the organic-inorganic composite porous body obtained by the above-mentioned production method is a scaffold for reconstructing a living bone tissue, a prosthesis, a bone filler, an inclusion between an implant and a living bone tissue, Substitute for cancellous bone in bulk form, which is effectively used as a carrier for sustained drug release, etc., and therefore, a scaffold for reconstructing living bone tissue comprising this organic-inorganic composite porous material, a prosthesis material, a bone filler, Any inclusions between implants and living bone tissue, bulk-shaped cancellous bone substitutes, and sustained drug release carriers are included in the present invention.

[0048]

BEST MODE FOR CARRYING OUT THE INVENTION Next, specific examples of the present invention will be described.

Example 1 A polymer solution (concentration: poly-D, L-lactic acid (PDLLA) having a viscosity average molecular weight of 200,000 (molar ratio of D-lactic acid and L-lactic acid of 50/50) was dissolved in dichloromethane. PDLLA 4 g / dichloromethane 10
0 ml) and an unsintered hydroxyapatite powder (u-HA) having an average particle size of 3 μm are mixed with ethanol to homogenize them uniformly, thereby producing u-HA.
Was mixed in an amount of 230 parts by weight with respect to 100 parts by weight of PDLLA to prepare a suspension.

An HP-E air brush (manufactured by Anest Iwata Co., Ltd.) was used as a sprayer, and the above suspension was filled in the sprayer. The nitrogen gas was 1.6 kg / cm ² , and the separation was about 120 cm. The polyethylene net body (150 mesh) was sprayed to form a fiber aggregate, and the fiber aggregate was peeled from the mesh body. The fiber diameter of this fiber assembly is 1.0
The fiber length was about 10 μm, the apparent specific gravity was 0.2.

This fiber assembly was cut into an appropriate size and filled in a cylindrical female mold having a diameter of 30 mm and a depth of 30 mm,
A disk-shaped fiber aggregate molded body having a diameter of 30 mm and a thickness of 5 mm was obtained by compressing with a male mold so that the apparent specific gravity of the fiber aggregate was 0.5.

Next, the above fiber aggregate molded body is immersed in a solvent consisting of dichloromethane mixed with ethanol to allow the solvent to permeate the inside of the molded body and allowed to stand at 60 ° C. for 10 minutes, and then the solvent inside the molded body is vacuumed. After removal by suction, an organic-inorganic composite porous body having a diameter of 30 mm, a thickness of 5 mm and a u-HA content of 70% by weight was obtained.

When the partially cut surface of this composite porous body was observed with an electron microscope, fibers fused and disappeared, and 100 to 4
Continuous pores having a large pore size of about 00 μm are formed, u-HA is uniformly dispersed, and u-H is formed on the inner surface and the surface of the pores.
A was exposed. The apparent specific gravity of this composite porous body is 0.
5, the ratio of continuous pores to all pores (continuous porosity) is 7
The compression strength was 5% and the compression strength was 1.1 MPa.

Example 2 In the same manner as in Example 1, a disk-shaped fiber aggregate molded body having a diameter of 30 mm and a thickness of 5 mm was prepared as a preform, which was heated to 80 ° C. in a gear oven. Then, they were placed in a chamber having a reduced diameter portion having different diameters, and press-fitted into a cylinder having a lower diameter of 10.6 mm. The compressive strength of the cylindrical rod-shaped fiber aggregate molded body that was pressure-molded under heating in this manner was about 2.5 MPa.

Next, the cylindrical rod-shaped fiber aggregate molded body is filled in a syringe having holes of the same diameter and having the same diameter, and pressure is applied from the upper surface and the lower surface thereof to increase the height of the cylindrical rod-shaped fiber aggregate molded body. While squeezing to such an extent that it did not change, it was immersed in a solvent (60 ° C.) made of dichloromethane mixed with 15% by weight of methanol for 10 minutes, and then the solvent was removed to obtain a composite porous body.

An electron micrograph of the partially cut surface and the sanded surface of this composite porous body shows a porous form in which the fibers have disappeared, and is composed of mixed pores having a pore diameter of about 150 to 300 μm. Was exposed from the surface of the porous body and the inner surface of the pores. The apparent specific gravity of this composite porous body is about 0.5.
5, continuous porosity 70%, compressive strength about 3.5M
It had risen to Pa. This composite porous body has a viscosity average molecular weight of PDLLA and a ratio of the occupied amount, and an average particle size of 3 μm.
Based on the in vivo biodegradation and absorption characteristics of -HA, it is considered that complete absorption occurs in about 6 months, depending on the implantation site and size.

[Example 3] P having a viscosity average molecular weight of 100,000
DLLA (molar ratio of D-lactic acid and L-lactic acid 30/70) was synthesized, and β-tricalcium phosphate (β-TCP) having an average particle size of about 3 μm was mixed with 80 by the same method as in Example 1.
A suspension was prepared by uniformly mixing the mixture by weight%. This β-TC
It has been confirmed that P is bioactive and bioabsorbable, and although it has a different mechanism from u-HA, it is known to show osteoconductivity due to HA formation in vivo.

Using this suspension, a fiber assembly produced by the spray method in the same manner as in Example 2 was compression molded under heating to form a fiber assembly molded body, which was subjected to a solvent immersion treatment to give an apparent appearance. A composite porous body having a specific gravity of about 0.6, a continuous porosity of 75% and a compressive strength of 4.2 MPa was obtained. The volume ratio of β-TCP particles in this composite porous body was about 65% by volume, and u
Since the volume of the inorganic powder particles is considerably larger than that of the composite porous bodies of Examples 1 and 2 in which HA is 70% by weight (about 55% by volume),
Due to the exposure of β-TCP to the surface of the porous body and the inner surface of the pores,
The bioactivity is remarkably expressed.

In this composite porous body, the fibers in the non-woven fiber assembly disappeared and β-TCP was formed on the bulk cell wall.
Since the particles have changed into a buried form, they do not easily disintegrate even when immersed in body fluid in the living body and the powder particles do not easily disperse in the surroundings. It was confirmed that it was completely decomposed and absorbed while showing bioactivity. Therefore, this composite porous body is a good scaffold for hard tissues (bone, cartilage).

Example 4 D, L-lactic acid (D / L molar ratio 1) and glycolic acid (GA) were mixed at a molar ratio of 8: 2.
And a copolymer P (DLLA-GA) having a viscosity average molecular weight of 130,000 was synthesized by a known method.
In the same manner as in Example 1, a suspension was prepared by uniformly mixing this polymer with 60% by weight of octacalcium phosphate (OCP) and heating the fiber assembly produced by the spray method in the same manner as in Example 2. The mixture was compression-molded into a fiber aggregate molded body, which was then subjected to a solvent immersion treatment to finally obtain a composite porous body having an apparent specific gravity of 0.50. This composite porous body has a high OCP activity and the decomposition and absorption of the copolymer is GA.
Since it is fast due to the above, while most of the bone was absorbed and replaced with bone after 3 to 4 months, it showed good bone conduction (it is easily converted to new bone).

Example 5 D, L-lactide (lactid)
e) and para-dioxanone (p-DOX) were blended in a molar ratio of 8: 2 and copolymerized by a known method to obtain a copolymer having a viscosity average molecular weight of about 100,000. p-DO
The polymer of X is not found to be a volatile general-purpose good solvent, but since it becomes soluble in chloroform, dichloromethane, etc. at the above ratio, the target composite porous body can be obtained by the same method as in the above-mentioned examples. did it. Moreover, since the above-mentioned copolymer shows rubber-like properties having plasticity, which is more plastic than the copolymer P (DLLA-GA) of D, L-lactic acid and glycolic acid of Example 4, the particles of the inorganic powder particles are Since the volume ratio of the inorganic powder particles can be as high as 70% by volume (85% by weight) when the diameter is 3 μm, this composite porous body avoids biological reactions due to the decomposition products of the copolymer as much as possible and is bioactive. The activity of the inorganic powder is expressed very effectively. In particular, p-DOX has a higher hydrophilicity than PDLLA because of the characteristics of p-DOX. Therefore, it is considered that this composite porous body is effective as a scaffold for cartilage regeneration for cell growth in Ex vivo (in vitro petri dish).

[0062]

As is apparent from the above description, the organic-inorganic composite porous material of the present invention contains a large amount of inorganic powder particles in the organic polymer in a uniformly dispersed state and is formed inside. Bodily fluids quickly infiltrate through large pores with large pores, and inorganic powder particles such as bioceramics exposed on the surface and the inner surface of continuous pores early bond with biological bone and regenerate biological (bone) tissue. To provide a place where
It has an effect of having practical strength required for medical use. Therefore, a scaffold for living bone tissue reconstruction, a prosthesis, a bone filler, an inclusion between the implant and living bone tissue,
It is used as an alternative to cancellous bone and as a carrier for sustained drug release.

Claims (20)

[Claims] 1. An organic-inorganic composite porous structure in which inorganic powder particles are substantially uniformly dispersed in an organic polymer, continuous pores are formed inside, and a part of the inorganic powder particles is exposed on the surface and inside the pores. body. 2. A non-woven fabric-like fiber aggregate is prepared from a suspension prepared by dissolving an organic polymer in a volatile solvent and dispersing inorganic powder particles, and this is pressure-molded under heating to form a porous fiber. An aggregate molded body, which is a porous body obtained by immersing a fiber aggregated molded body in a volatile solvent and then removing the solvent, in which inorganic powder particles are substantially uniformly dispersed in an organic polymer, An organic-inorganic composite porous body having continuous pores, wherein a part of the inorganic powder particles is exposed on the surface and the inner surface of the pores. 3. The organic-inorganic composite porous body according to claim 1 or 2, wherein the porosity is 50 to 90%, and the continuous pores occupy 50 to 90% of all the pores. 4. The diameter of continuous pores is approximately 100 to 400 μm.
The organic-inorganic composite porous body according to any one of claims 1 to 3. 5. The organic-inorganic composite porous body according to claim 1, wherein the content of the inorganic powder particles is 60 to 90% by weight. 6. The organic-inorganic composite porous body according to claim 1, having a thickness of 1 to 50 mm and having a thick three-dimensional three-dimensional shape. 7. The organic polymer is a biodegradable and absorbable polymer, and the inorganic powder particles are bioactive bioceramic powder particles having an average particle size of 10 μm or less, according to any one of claims 1 to 6. The organic-inorganic composite porous body of. 8. The organic polymer according to any one of claims 1 to 6, wherein the organic polymer is a biodegradable total absorbable polymer, and the inorganic powder particles are bioabsorbable bioceramic powder particles having total absorbability. Inorganic composite porous body. 9. A biodegradable total absorbable polymer is a poly-
D, L-lactic acid, L-lactic acid and D, L-lactic acid block copolymers, lactic acid and glycolic acid copolymers, lactic acid and p-dioxanone copolymers, lactic acid and ethylene glycol block copolymers Either, the bioabsorbable bioceramic powder particles of total absorbability, uncalcined, unbaked hydroxyapatite, dicalcium phosphate, tricalcium phosphate, tetracalcium phosphate,
The organic-inorganic composite porous body according to claim 8, which is a powder particle of any one of octacalcium phosphate, calcite, ceravital, diopsite, and natural coral. 10. The organic-inorganic composite according to claim 7, which has a compressive strength of 1 to 5 MPa. 11. A oxidative treatment such as corona discharge or plasma treatment is performed, claim 8, claim 9, claim 1 or claim 1.
The organic-inorganic composite according to any one of 0. 12. A non-woven fabric-like fiber aggregate is prepared from a suspension prepared by dissolving an organic polymer in a volatile solvent and dispersing inorganic powder particles, and this is pressure-molded under heating to form a porous fiber. A method for producing an organic-inorganic composite porous body, which comprises forming an aggregated molded body, immersing the fiber aggregated molded body in a volatile solvent, and then removing the solvent. 13. When forming a porous fiber aggregated compact by heat-molding the fiber aggregate under heating, first, the fiber aggregate is heated and solidified under pressure to form a preform having continuous voids. 13. The method according to claim 12, wherein the preform is then pressure-molded under a higher pressure to obtain a porous fiber aggregate molded body having continuous voids adjusted and high strength. 14. A method of immersing a porous fiber aggregated molded body in a volatile solvent, wherein the fiber aggregated molded body is filled in a predetermined mold having a large number of pores and the shape is maintained. The manufacturing method according to claim 12. 15. A scaffold for regenerating biological bone or cartilage tissue, which comprises the organic-inorganic composite porous body according to any one of claims 7, 8, 9, 10, and 11. 16. A bioprosthesis material comprising the organic-inorganic composite porous body according to claim 7, claim 8, claim 9, claim 10, or claim 11. 17. A bone filler comprising the organic-inorganic composite porous material according to any one of claims 7, 8, 9, 10, and 11. 18. An interposition between an implant and a living bone tissue, which is composed of the organic-inorganic composite porous body according to any one of claims 7, 8, 9, 10 and 11. object. 19. A bulk-shaped cancellous bone substitute comprising the organic-inorganic composite porous material according to any one of claims 7, 8, 9, 10, and 11. 20. A sustained drug release carrier comprising the organic-inorganic composite porous material according to any one of claims 7, 8, 9, 10 and 11.