JP2005066354A - Composite osteosynthesis material - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a more ideal biomaterial which has decomposition absorbability in the living body, can be replaced by the living body, and is concurrently useful for application such as an artificial bone, an artificial joint, an artificial dental root, a bone filling material, an osteosynthesis material, and a bone prosthetic material which are equipped with association with the living body and the inductivity of tissue, and are bioactive, new and useful. <P>SOLUTION: (1) A bioresorbable bio-ceramic powder of 10-60 wt.% of 0.2-50 μm diameter is dispersed evenly in a biodegradable absorbable crystalline thermoplastic polymer matrix. A composite implant material consists of a high-density oriented shaped article which has a degree of crystallinity of 10-70%. (2) A compound material described in (1) is oriented by the crystallized matrix polymer under pressure and consists of the high-strength pressurized oriented shaped article which has a degree of crystallinity of 10-70%. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to an extremely high-strength implant comprising a novel particle and matrix polymer-reinforced composite material of a bioactive bioceramic having bioactivity and a crystalline thermoplastic polymer that is biodegradable and absorbable. The present invention relates to a material and a manufacturing method thereof.
More specifically, the present invention is a novel and useful artificial bone or joint that is biodegradable and absorbable and can be replaced with a living body, and at the same time has bioactivity and tissue inductivity. The present invention relates to a more ideal biomaterial useful for applications such as artificial tooth roots, bone fillers, bone cements, and bone prostheses.

It is non-toxic and safe, and is temporarily present in the living body. During the period until healing, it achieves its function and purpose mechanically and physiologically, and then gradually decomposes and disintegrates itself and is absorbed into the living body. An implant that is made from a material excreted outside the body through the metabolic circuit of the living body, and ultimately the site where it is embedded is replaced by the living body, and the original living state is reconstructed is an ideal biological material It can be said that.

In recent years, artificial bones, artificial joints, artificial tooth roots, bone filling materials, bone prosthetic materials intended to replace living bones and cartilage, which are hard tissues, or bone joints aimed at fixing fractures of cartilage or bone in each part Materials are made using various metals, ceramics, and polymers.
Among these, the metal osteosynthesis has a problem that the mechanical strength and the elastic modulus are much higher than those of living bones, resulting in a phenomenon that the strength of the surrounding bone is reduced by stress protection after treatment. In addition, the ceramic bone bonding material is excellent in hardness and rigidity, but has a fatal defect that it easily breaks due to its brittleness. Also, since polymers are usually less strong than bone, efforts are being made to increase strength.
On the other hand, bioactive bioceramics that can be directly bonded to bone are increasingly used for direct implantation or contact with the human body for the purpose of recovery or enhancement of biological functions.

Further, since bioceramics that are directly and strongly bonded to a living body and that are gradually replaced by the living body have the possibility of being unknown, further research is continued.
However, although bioceramics generally have high rigidity and hardness, they have the brittle nature of being easily chipped or cracked by an impact force, which is an instantaneous force, compared to metals, so there are limits to their use as implants. Development of a material having toughness without brittleness is desired.

On the other hand, polymers used for implants around hard tissues of living bodies are currently silicone resins used as a substitute for cartilage, curable acrylic resins as dental cement, polyesters for ligaments Or some examples, such as a braid of a polypropylene fiber, are known.
However, inactive and high-strength ultrahigh molecular weight polyethylene, polypropylene, polytetrafluoroethylene, and the like that are used to replace hard tissues in living bodies, are insufficient in strength to replace living bones by themselves. Therefore, if these are used alone as a substitute bone or a screw, a pin, or a plate for the purpose of joining bones, they are easily broken, broken or twisted to break.

Therefore, attempts have been made to make high-strength implants using plastics composite technology.
For example, carbon fiber reinforced plastic is an example of this, and when it is embedded in a living body for a long time, peeling occurs between the fiber and the matrix plastic, or the peeled carbon fiber breaks and the living body is broken. It is not practical because it can irritate and cause inflammation.
In recent years, polyorthoesters (butylene terephthalate-polyethylene glycol copolymer), which are said to bind to bone, have begun to attract attention, but the strength of this polymer itself is lower than that of living bone, and after bonding to bone The question remains whether the physical behavior of the body can be synchronized with the living bone.
Unlike the above polymers that are non-absorbable in vivo, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, and polydioxanone, which are biodegradable and absorbable, have been used as absorbable sutures for a long time. It is clinically used.
If each polymer used in this suture can be used as an osteosynthesis material, it does not require re-operation after healing, and it is excellent in that the tissue is reconstructed after the polymer is absorbed and lost The idea that an osteosynthesis material having the following can be obtained has been quite long.
Under such circumstances, research using the above-described biodegradable absorbable polymer as an osteosynthesis material has been actively conducted.

For example, a self-reinforced osteosynthesis device fused with polyglycolic acid fibers has been proposed (US Pat. No. 4,968,317) and used clinically, but it is rapidly degraded and fused. It was pointed out that the separation between the fibers and the disintegrated fibrous strips rarely stimulate the surrounding living body to cause inflammation. JP-A-59-97654 discloses a method for synthesizing polylactic acid and lactic acid-glycolic acid copolymer that can be used as a biodegradable and resorbable osteosynthesis device. It is the polymerization product itself that is mentioned as an osteosynthesis material, nothing is described about the molding process of this material, and no attempt is made to increase its strength to the level of human bones.

Therefore, in order to increase the strength, a biodegradable / absorbable polymer material such as polylactic acid containing a small amount of hydroxyapatite (hereinafter simply referred to as HA) is molded, and then stretched under heating in the major axis direction. A method for producing an oriented osteosynthesis pin (Japanese Patent Laid-Open No. 63-68155), and a molded article of high molecular weight polylactic acid or lactic acid-glycolic acid copolymer having a viscosity average molecular weight of 200,000 or more after melt molding Has been proposed (Japanese Patent Laid-Open No. 1-198553).
The bone bonding materials or pins obtained by these manufacturing methods are essentially improved in bending strength and tensile strength in the long axis direction because the crystal axis (molecular axis) of the polymer material is uniaxially oriented in the long axis direction. To do. In particular, in the latter case, in the case of an osteosynthesis having a viscosity average molecular weight of 200,000 or more after melt molding, it is practical because the strength is high even at a low magnification that does not cause fibrillation.

However, the bone cement obtained by essentially stretching only in the major axis direction is basically oriented only in the major axis direction where the molecule (crystal) is the molecular chain axis (crystal axis). The anisotropy of orientation with the transverse direction, which is a direction perpendicular to the axial direction, is large, and the transverse strength is relatively weak.
Further, according to the above-mentioned JP-A-63-68155, the maximum bending strength of 162 MPa is gradually obtained by stretching a mixture containing 5% by weight of HA. The strength decreases to 74 MPa, which is slightly higher than 63 MPa which is a value when the strength is not stretched.

However, this maximum strength value also does not sufficiently exceed that of cortical bone, and voids generated by stretching become porous heterogeneous bodies that exist at the interface between the filler and the matrix polymer. However, it cannot be used for implants that require high strength such as bone substitutes or osteosynthesis.
The publication also describes a method for producing a plate obtained by press-molding a biodegradable and absorbable polymer material powder such as polylactic acid containing a small amount of HA. The lactic acid mixture is merely melt-pressed, and there is no concept for increasing the strength in consideration of the orientation.

An object of this invention is to provide the implant material which can solve these subjects at once.

As a result of various studies on the above problems, the present inventors have found that (1) the size of primary particles or aggregates of primary particles in a polylactic acid (hereinafter simply referred to as polymer) matrix that is biodegradable and absorbable. 10 to 60% by weight of non-fired hydroxyapatite powder, which is a bioabsorbable bioceramic of 0.2 to 10 μm, is dispersed substantially uniformly and has a crystallinity of 10 to 70%. And (2) a non-fired hydroxyapatite powder that is a bioresorbable bioceramic, which is a high-density pressure-oriented molded body in which the matrix polymer is crystallized and oriented by pressurization, and We found that the above problems can be solved by creating a new composite material with matrix polymer reinforcement and using it as an implant material. The has been completed.

That is, the present invention provides:
(1) An unsintered hydroxyapatite powder 10 which is a bioabsorbable bioceramic having a primary particle or an aggregate size of primary particles of 0.2 to 10 μm in a polylactic acid matrix which is biodegradable and absorbable Provided is a composite osteosynthesis having a crystallinity of 10-70% with approximately 60% by weight dispersed substantially uniformly. Also,
(2) Unsintered hydroxyapatite powder 20 which is a bioabsorbable bioceramic having a primary particle or an aggregate size of primary particles of 0.2 to 10 μm in a polylactic acid matrix which is biodegradable and absorbable A composite osteosynthesis is provided in which ~ 50 wt% is dispersed substantially uniformly, the crystallinity is 10-70%, and the density is 1.4-1.8. Also,
(3) It is also characterized in that the bone bonding material has a bending strength of 150 to 320 MPa and a bending elastic modulus of 6 to 15 GPa. Also,
(4) The bone bonding material is characterized in that the tensile strength is 80 to 180 MPa, the shear strength is 100 to 150 MPa, and the compressive strength is 100 to 150 MPa. Also,
(5) It is also characterized in that the bone cement does not have voids. Also,
(6) The present invention is also characterized in that the amount of residual monomer in the bone cement is 0.5% by weight or less.

Hereinafter, the present invention will be described in detail, but before that, it will be clarified from the aspect of the composite material that the present invention is a composite material by a novel reinforcing system.
<Characteristics of composite material of the present invention>
1) For the purpose of improving the characteristics of a certain material, when many fine materials are dispersed therein, the former is called a base material (matrix) and the latter is called a dispersion material. A composite material is created by mixing these two types of substances in a macro, rather than at a molecular level, so that they have excellent properties not found in a single substance.

The method of making a material having a better property (higher strength) by compounding different kinds of materials in this way can be classified as follows according to the form of the dispersing material (reinforcing material) to be put in the matrix.
(1) Dispersion-strengthened
composite materials),
(2) Particle-reinforced composite material
composite materials),
(3) Fiber-reinforced composite material
composite materials).
The implant material of the present invention belongs to the composite material (2). The polymer as the matrix is polylactic acid or a copolymer thereof which is a thermoplastic and crystalline biodegradable and absorbable polymer, and the dispersing material is the bioceramics described above in the form of fine particles.

2) By the way, from the viewpoint of material engineering, implants, which are composite materials made from the combination of (3), have been considered promising, and many such studies have been tried for a period of time. However, for example, the method of filling and reinforcing bioceramics short fibers as a dispersion material did not give good results because the fiber pieces stimulated the living body and caused inflammation. In addition, the above-mentioned self-reinforcing method in which fibers of polylactic acid or polyglycolic acid having the same form as those reinforced with fibers is surface-fused has been considered. Since it is homogeneous and easily peels between the fibers, there is a drawback that the decomposed strip rarely causes irritation to the living body. Biomaterials are disqualified in this respect because they must be non-toxic (harmful) and safe and biocompatible.

3) Now, even if it is the filler-filled composite material of (2), the composite material with the high strength to the extent desired by the present invention can be obtained by simply mixing the bioceramics powder and the matrix polymer according to a conventional method. Is not easy to obtain.
In general, the properties of filler-filled composite materials include the form of the filler [shape (powder, sphere, plate, etc.), particle size, surface area] and functionality (in this case, bone binding, bone Inducibility, hard tissue inducing ability such as osteoconductivity and bioresorbability), and essentially the nature of the polymer. The mechanical properties greatly depend on factors such as the content, morphology, orientation, and interfacial force of the polymer and filler that are the matrix. Many of these factors are intricately intertwined with each other, so in order to develop the desired structural and functional properties, it is necessary to understand the effects of a single factor on the overall properties.

4) Describe this point in a little more detail.
In the composite material filled with the filler, the properties exhibiting remarkable effects are elastic modulus, tensile strength, elongation properties, toughness, hardness and the like. In the case of the filler-filled composite material in the case of the present invention, particles having extremely small L / D (length / particle size) of bioabsorbable bioceramics are selected. The elastic modulus of the reflecting composite material can be increased more effectively than the strength of the matrix polymer itself by increasing the filler loading.
However, the tensile strength, elongation, toughness, etc. tend to decrease as the filling amount increases. Therefore, the problem is how to increase the modulus of elasticity and make other properties more than the strength of the original matrix polymer.
In other words, the compounding can be said to be a technique for synergistically drawing out the excellent properties of the dispersion material and the matrix and how to offset the defects. The elastic modulus is a value in a region where the degree of deformation is small, whereas mechanical properties such as tensile strength, bending strength, torsional strength, elongation, and toughness are expressed in a region where the degree of deformation is relatively large.
Therefore, the elastic modulus is basically less affected by the interfacial adhesion between the particles and the matrix, and the latter properties are greatly affected. Therefore, it will be noticed that better latter physical properties can be obtained by increasing the interfacial adhesion.

5) An active method for increasing the interfacial adhesion is to bond a polymer as a matrix and a bioceramic as a dispersion material with a coupling agent. Several coupling agents represented by silicone and titanium are used in composite materials for industrial purposes. Therefore, these may be used.
However, at present, it is hard to say that the safety of this type of compound to the living body has been deeply studied. These coupling agents are used in non-absorbable dental bone cement, which is a highly filled material, but safety has not been known because no examples have been applied to biodegradable biomaterials. Currently unknown, it should be avoided to use in the present invention.
That is, the method of chemically bonding the matrix polymer and the bioceramic fine particles to increase the interfacial force is a non-absorbable method for hard tissue implants that are decomposed and absorbed in the living body as in the present invention. Unlike the case of implants, the coupling agent is gradually exposed during the degradation process, so it should not be used at the moment when safety issues are still unresolved. Moreover, it is not desirable because the surface activity of the bioceramics is impaired.

6) By the way, in a system in which fine particles of the same concentration are mixed with a thermoplastic crystalline polymer, it is generally known that if the dispersibility of the fine particles is improved, impact strength, tensile strength and elongation at break are relatively improved. It has been.
Similarly, the size of the fine particles greatly affects the physical properties of the composite material. When the size is reduced at the same concentration, generally the impact strength, tensile strength, compressive strength, elastic modulus and the like are relatively increased.
Since the surface area is relatively increased by reducing the size, the surface energy is relatively increased, the contact area with the polymer is also increased, and it effectively functions as a nucleating agent for polymer crystallization. As a result, the physical bond between the dispersant and the matrix is strengthened.
Considering the above facts, it is only necessary to mix as small a ceramic fine powder as possible within a certain concentration range and in a state of good dispersion as much as possible.

7) However, as in the present invention, bioabsorbable bioceramics are mixed with a thermoplastic and crystalline biodegradable absorbable polymer so as to have an extremely high strength equal to or higher than that of cortical bone, and When seeking a composite material with a complex function that enables early healing and replacement of living bone by bone induction and conduction, these problems cannot be easily solved by only simple mixing as described above. Absent.

8) Hereinafter, specific measures for solving the problems of the present invention will be described.
As the particle size of the inorganic fine powder decreases, the surface area of the particle increases with it, and the particles easily secondary agglomerate even with the generation of small charges on the surface, much larger than the diameter of a single particle It is usual to form a clump.
Therefore, it is not technically easy to obtain a uniform dispersion system in which large aggregates of fine particles are not present in a particle-reinforced composite material having a relatively high filler concentration. The ease of formation of secondary aggregates varies depending on the chemical structure of the microparticles, but the bioabsorbable bioceramic microparticles used in the present invention form aggregates relatively easily in a well-dried state. To do. It is common to see particles having an average particle size of several μm agglomerate with a diameter of 100 μm or more.

9) By the way, it is known that the strength without large deformation such as notch Charpy impact does not depend on the size of the aggregate, but depends on the maximum diameter of each particle.
Also, when subjected to forces such as bending, pulling, and twisting that cause large deformation and eventually breakage, the composite material is at a point of small deformation than the matrix polymer itself deforms and breaks. It is normal to destroy.
These phenomena are caused by the fact that relatively large particles or aggregates different from the polymer present in the matrix behave differently from the matrix upon deformation.
That is, the interface between the matrix and the particles is a discontinuous portion where the external deformation energy propagating in the matrix cannot be transferred as it is, and therefore, the destruction occurs with the interface between the two as a base point.

10) However, when the particles are finely and uniformly dispersed, unlike the case where large particles and aggregates are present, the barrier for this energy propagation is small, so that the deformation energy has little resistance and the system The matrix polymer of the composite material breaks at a deformation amount closer to the point at which the polymer deforms and breaks.
In other words, large filler-filled composites with large particles are present (even if they are uniformly dispersed) or poorly dispersed such that small particles form large aggregates. It can be said that the strength at the time of breaking due to deformation is rather smaller than the strength at the time of breaking only of the matrix polymer containing no dispersed particles.

11) For this reason, it is highly possible to create a uniform dispersion system consisting only of particles having a small particle size that does not significantly affect the amount and strength of deformation at the time of deformation and destruction so as not to form a large aggregate. It is absolutely necessary to obtain the desired strength.
That is, the bioabsorbable bioceramics (that is, unfired hydroxyapatite) used in the present invention is selected from 0.2 to 10 μm, more preferably 1 to several μm, and the aggregate is also 50 μm. It is necessary to use a system that is uniformly dispersed so as to have the following diameter.
The bioabsorbable bioceramics are typically non-fired wet HA (wet HA).
In the case of the non-fired wet HA, it is not necessary to fire and pulverize, and crystal particles in this range obtained by precipitation during synthesis can be used as they are. The size of the particles is not only necessary for satisfying the above-described physical strength, but also has an important relationship with the reactivity exhibited by surrounding osteoblasts, as will be described later. A system that satisfies such conditions has improved impact strength, surface hardness, elastic modulus, etc., which are strength when subjected to small deformation, and bending, tension, which is strength when subjected to large deformation. Further, the strength of torsion or the like maintains the matrix polymer itself and is a composite material with increased rigidity.

12) For the same purpose as in the present invention, surface bioactive bioceramics can also be used. However, since this bioceramic is not absorbed and disappears in vivo, bioabsorbable bioceramics are preferably used. It is done.
As the surface bioactive bioceramics, fine particles of the bioceramics are suitable temperature (hydroxyapatite (HA) is 600 to 1250 ° C., apatite wollastonite glass ceramics (AW) is 1500 ° C., tricalcium phosphate (TCP) is 1250 ° C., 1400 ° C.] and then mechanically pulverized and sectioned, and a particle size of approximately 0.2 to 50 μm, more preferably 1 to several tens μm, is selected. A system that is uniformly dispersed so as to have the following diameter is used.

13) Here, the bioceramic / polymer weight ratio can be mixed from a low ratio of 10% or less to a high ratio exceeding 60%.
When the amount of bioceramics added is less than 10%, the volume ratio occupied by bioceramics is small, so that direct bonding with bones and bone conduction properties that are expected of bioceramics are difficult to be exhibited, and replacement with living bones is slow. .
On the other hand, if it exceeds 60%, the fluidity at the time of thermoforming of the mixed system is insufficient, so that molding becomes difficult. Further, since the amount of the polymer in the molded product is insufficient and the binder effect does not reach, the filler and the polymer are easily separated, so that the strength becomes brittle.
Therefore, the preferred mixing ratio is 20 to 50% by weight, but most preferably 30 to 40% by weight. Within this range, the desirable properties of both the dispersion material and the polymer matrix as a composite material are structural and functional. It is remarkably expressed on both sides.
One effective strategy for mixing bioceramics such as HA relatively easily aggregated into the matrix without secondary aggregation is to add the bioceramics to a polymer dissolved in a solvent and disperse well. This dispersion is precipitated with a non-solvent.

The conditions, purpose, and method for obtaining uniform dispersion have been described above from the viewpoint of obtaining a mixed system of bioceramics and polymer.
14) However, even if the polymer-filler composite material uniformly dispersed in this way is processed by the usual thermoforming method, it exceeds the strength of high-strength plastic, and further, the strength of cortical bone (bending strength 150 ~ Biomaterials exceeding 200 MPa) are not obtained.
Generally, a polymer containing a large amount of filler is difficult to be thermoformed because of poor fluidity. In addition, in consideration of safety to living bodies as in the present invention, thermoforming when a titanium coupling agent that is extremely effective in improving fluidity cannot be used is more difficult.
Kneading the composite of this poorly fluid polymer and ceramic powder, and thermoforming by extrusion, which is a molding method that applies a shearing force when melted, the polymer itself deforms and flows with its original flow characteristics, Since the filled inorganic filler does not have the property of plasticizing and flowing due to heat, a boundary is formed at the interface between the polymer and the filler particles due to fluid deformation, and voids are interposed, resulting in a rough density. Can be formed.
The strength of a porous molded product containing a lot of voids is low. Therefore, in order to prevent the formation of voids, a pressure type molding method such as injection molding or press molding is generally used for molding such a polymer filled with a large amount of filler.

15) However, in such a normal molding method, the polylactic acid and the copolymer thereof of the present invention are easily thermally deteriorated by shearing force, or significantly hydrolyzed and deteriorated by a small amount of water contained therein. A molded product with high strength cannot be obtained at all.
Even so, if the heating conditions, drying conditions, and molding conditions of press molding are strictly adjusted, it may be possible to mold a plate with little degradation of the polymer, but the polymer itself has a molecular structure and higher order. Since it is not reinforced at the level of structure, it is still impossible to obtain strength exceeding the cortical bone.

16) One method of increasing the strength of a polymer that is crystalline and thermoplastic, such as poly L-lactic acid and its copolymer, is stretching. This means that at a specific temperature (temperature Tm or less at which the polymer melts and flows), both ends of the rod, which is the primary molded product, or the other end with one end fixed is pulled outward from the molded product. In the plastic processing, the uniaxial stretching is performed in the major axis direction, and the molecular chain and the resulting crystal phase are oriented in the tensile direction (MD) to obtain a secondary molded product having higher strength.

Although the purpose and the method are different from those of the present invention, a method of mixing a small amount of HA of 1 to 15% and uniaxially stretching the primary molded body in the major axis direction is disclosed in the aforementioned Japanese Patent Publication No. 3-63901. ing. However, when the polymer filled with the filler is stretched in this way, as described above, the polymer itself moves in the machine direction along with the plastic deformation of the polymer, but the filler particles themselves do not undergo plastic deformation of the polymer. Since they do not move completely in synchronism, it is inevitable that a boundary is formed at the interface between the particle and the polymer during stretching and voids are generated there. In particular, in the above-described free-width uniaxial stretching, which is a method in which an external force is not applied from the direction perpendicular to the stretching direction in the stretching process, a movement in which the material per unit volume is diluted by the force acting by stretching occurs.
When the draw ratio increases, the polymer changes from microfibrils to fibrillated states, but in this state, micro discontinuous spaces are formed between the fibrils, and the density of the material is further reduced.

17) From this fact, the stretched composite material in which filler is dispersed in a large amount has a larger filler filling amount, a larger number of voids, and a larger deformation amount due to stretching (stretching). The higher the magnification), the larger the void.
In addition, the number and size of voids are even more uneven in systems where the filler particle size is not adjusted, dispersion is poor, and the system contains large agglomerates.
In fact, a composite material having such voids is easily cut during stretching, so that the intended stretched product cannot be obtained.
Thus, the stretched composite material including the voids cannot provide the molded article having high strength required by the present invention.

18) Accordingly, the present inventor has earnestly achieved the object by the following molding method. This is because the billet of the polymer containing a large amount of the bio-absorbable bioceramics uniformly dispersed as described above is melt-molded by a method such as extrusion or compression molding and the thermal deterioration is suppressed as much as possible. This is a method in which the matrix polymer inside is crystallized and oriented by pressurization, for example, compression molding or forging, to obtain a high-density pressurized orientation product.
According to this method, the external force at the time of orientation molding acts inward toward the material body opposite to stretching, so that the material is in a dense state. For this reason, the interface between the particles and the matrix is changed to a more closely-contacted state, and even micro voids intervening in the air existing at the interface during the mixing process disappear, so that a high density can be obtained. That is, both are further integrated.

In addition, since the polymer of the matrix is oriented with the molecular chain axis and the crystalline phase, the resulting composite material exhibits significantly higher strength.
In this case, the orientation of the crystal obtained by press-filling the billet, which is the primary molding, particularly into the cavity of a mold having a partial or entire cross-sectional area smaller than the cross-sectional area of the billet is gold Because force is applied by “shearing” from the mold surface, it is considered that the surface has a strong tendency to be oriented parallel to a certain reference axis, unlike uniaxial orientation by simply stretching in the major axis direction. It is done.
Therefore, the characteristics that there is little anisotropy due to orientation and resistance to deformation such as twisting are manifested. However, the degree of orientation is essentially limited to such an extent that the molecular chain lamella is oriented, and is not so high that voids are generated due to the microfibril and fibril structure seen when the draw ratio is high.

19) The method of strengthening the composite material of the present invention has been described above. When this is compared with that of the conventional composite material, the difference in form is clear as shown in FIG.
In other words, the conventional particle-reinforced type (a) and fiber-reinforced type (b) each exhibit the physical strength of the filled particles and the fiber itself in those systems by increasing the packing rate as much as possible. This method aims to increase the strength essentially depending on the chemical and physical bonding strength with the matrix polymer.
In the fiber reinforced type (b), the entanglement of the fibers works effectively to improve the strength.
In this case, if a matrix polymer having a relatively high strength is used, a higher strength can be obtained.

20) However, as in the present invention, an example in which the matrix of this system is strengthened by performing a secondary processing (for example, pressure orientation) for crystal (molecular chain) orientation has not been seen conventionally.
In the present invention, in addition to the particle strengthening type (a), the matrix polymer is oriented by pressurizing the matrix polymer as described above, and the interface between the particles and the matrix polymer is more closely adhered. To strengthen by creating a denser system [particle reinforcement + matrix reinforcement type] (c)
This is a strengthening method.
That is, the present invention relates to a novel method for physically strengthening a matrix polymer that has not been conventionally performed by secondary molding processing (for example, pressure orientation) in cold, and a composite system obtained thereby. The difference is clear.

(A)
High-strength implant material The high-strength implant material of the present invention basically has (i) the size of primary particles or aggregates of primary particles is 0 in a crystalline thermoplastic polymer matrix that is biodegradable and absorbable. .High-density orientation molding having a crystallinity of 10 to 70%, in which 10 to 60% by weight of a non-fired hydroxyapatite powder, which is a bio-absorbable bioceramic of 2 to 10 μm, is dispersed substantially uniformly It is a composite high-strength implant material composed of a body.
(ii) In addition, a bioabsorbable bioceramic powder having a primary particle or aggregate size of primary particles of 0.2 to 10 μm in a crystalline thermoplastic polymer matrix that is biodegradable and absorbable. A high-density pressure-oriented molding which is a composite material composed of a molded product substantially uniformly dispersed, wherein the matrix polymer is crystallized and oriented by pressing, and the crystallinity is 10 to 70%. It is a composite high-strength implant material composed of a body.
Here, as is clear from the terminology, the “pressure-oriented molded article” refers to a high-density oriented molded article obtained by crystallizing and orienting a matrix polymer (in a billet) under pressure. “A high-density oriented molded body obtained by compression molding or forging molding oriented by press-fitting into a closed mold” described in detail in the section of (B) Implant production ”is included.

The details will be described below.
(a)
Bioceramics 1) The bioceramic used in the present invention is a bioceramic that is absorbable in vivo.
Examples of the bioceramics include unsintered hydroxyapatite (unsintered HA), dicalcium phosphate, tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcite, etc., either alone or as a mixture of two or more. Can do.
Specific bioabsorbable bioceramics include unfired HA (unfired HA), dicalcium phosphate, α-tricalcium phosphate (α-TCP), β-tricalcium phosphate. -To (β-TCP), tetracalcium phosphate (TeCP), octacalcium phosphate (OCP), dicalcium phosphate, hydrate, octacalcium phosphate (DCPD · OCP) , Dicalcium phosphate, anhydride, tetracalcium phosphate (DCPA · TeCP), calcite and the like.
In particular, unsintered hydroxyapatite is suitable.

2) Other bioceramics The bioceramics used in the present invention are limited to the above-described bioabsorbable bioceramics. Of course, other bioceramics such as surface bioactive bioceramics can be used as well. The bioabsorbable bioceramic used in the present invention is preferable in that it is absorbed into the living body and disappears.
Examples of the surface bioactive bioceramics include sintered hydroxyapatite, bioglass-based or crystallized glass-based biological glass alone, or a mixture of two or more thereof.
Specifically, calcined hydroxyapatite (HA), bioglass-based bioglass, cerabital, crystallized glass-based AW glass ceramics, crystallized glass-based bioberit-1, implant-1, Any one of β-crystallized glass and diopside, or a mixture of two or more thereof can be mentioned.

3) The bioceramics of 1) and 2) above differ in the degree of biological activity, resulting in differences in the speed and form of formation of new bone, so that they have the necessary biological activity alone or in combination of two or more. Mix and use as appropriate.
Therefore, the term “bioabsorbable bioceramics” herein refers to bioabsorbable bioceramics alone or a small amount of bioactive ceramics mainly composed of the bioabsorbable bioceramics. Mixtures are also included.
Of these, unfired HA, which is a bioabsorbable bioceramic of 1) according to the present invention, is different from the fired HA of 2) and is very similar to HA in the living body, and is completely in vivo. It is one of the most effective bioabsorbable active powders in the system of the present invention because it is absorbed and lost, has high activity, is safe, and has a track record of actual use.

(b) Particle size of bioceramic powder Here, bioabsorbable bioceramic powder is a general term for primary particles of bioabsorbable bioceramics or secondary particles that are aggregates (aggregates) of the particles. Point to it.
1) The particle size of the bioabsorbable bioceramic powder is the particle size of primary particles or secondary aggregates (aggregates) of 0.2 to 10 μm in order to obtain a high-strength composite material based on the above reasons. Is used. From the viewpoint of uniform dispersion with a crystalline thermoplastic polymer that is biodegradable and absorbable, those having the above-mentioned particle sizes are also preferable.
When the particle size of the bioabsorbable bioceramic powder is an upper limit close to 50 μm, it is desirable that the aggregate size is when the primary particles of about 10 μm are secondary aggregated.
When the independent primary particles have a size close to 50 μm, it is not desirable because the composite material breaks (breaks) when it yields.
The molded body and the oriented molded body are finally finished into an implant material having various fine shapes by a method such as cutting.
When the particle size is large, a fine and fine shape is chipped or broken at the interface of the powder, making it difficult to process. Therefore, it can be said that the particle size of 50 μm is the upper limit for determining the precision of the shape of the implant material.

2) The lower limit particle size of 0.2 μm corresponds to, for example, the size of primary particles of unfired HA.
Usually, the fine particles aggregate to form secondary agglomerated particles of several μm to several tens μm. By obtaining a system in which bioabsorbable bioceramic particles or aggregates having an apparent average particle size within such a range are uniformly dispersed in a polymer matrix, high strength can be obtained. Both properties of rapid replacement of the implant with living bone are satisfied at the same time. An implant composite material having a precise shape can be obtained.

3) When an implant material containing such bioabsorbable bioceramics is implanted in a living body, the bioceramic powder that appears on the surface is directly transferred without surrounding living bones and fibrous connective tissue. Or indirectly through HA deposited on the surface, early fixation between the two can be obtained at an early stage. This characteristic is preferable for implant materials such as pins and screws for the purpose of joining and fixing fractures.
In addition, the plate, the bone substitute having a different shape, and the bone joint material that could not be used due to the lack of strength in the past can also be applied because of the bonding with the bone.

4) Implant materials used as bone fracture fixing materials in bone maintain the strength required for fixation for at least 2 to 4 months required for bone fusion, and then gradually add water from the surface in contact with body fluids. Take the process of degradation as degradation progresses.
In this process, the bioabsorbable bioceramic powder contained inside is gradually exposed to the body fluid. Thereafter, the body fluid further penetrates into the interior of the implant through the interface between the bioceramic powder and the polymer. As a result, the hydrolysis of the polymer and the absorption of the degradation product into the living body are faster than in the case of the polymer alone system not containing the bioabsorbable bioceramics.
In this process, the exposed bioresorbable bioceramic powder promotes the invasion of new bone and sometimes forms a trabecular bone as a nucleus of bone formation. And it is absorbed by osteoclasts. In this way, the invasion / replacement of the living bone into the bone hole in which the implant material has disappeared is effectively performed.

5) The process and form in which the bone hole is replaced with living bone by the implant material of the present invention varies considerably depending on the type of bioabsorbable bioceramics it contains and the shape, size, or content of the granules. Compared to implant material made of bioabsorbable polymer alone, the amount of polymer in the implant material of the present invention is smaller than the amount filled with bioabsorbable bioceramics powder. The risk of an inflammatory reaction due to a foreign body reaction due to temporary occurrence of polymer strips can be avoided.
It is particularly effective in the case of fully absorbable bioactive particles such as unfired HA which is the bioabsorbable bioceramics of the present invention.
In addition, the speed of bone hole repair can be arbitrarily adjusted by selecting the type, size, and amount of bioresorbable bioceramics.

(c) Polymer composition The polymer is not particularly limited as long as it is a crystalline thermoplastic polymer that is biodegradable and absorbable, but among them, biosafety and biocompatibility have been confirmed, and polymers already in practical use have been confirmed. Lactic acid and various polylactic acid copolymers (for example, lactic acid-glycolic acid copolymer) are preferably used.
The polylactic acid is preferably a homopolymer of L-lactic acid or D-lactic acid, and the lactic acid-glycolic acid copolymer is a glycol having a molar ratio in the range of 99: 1 to 75:25. It has better hydrolysis resistance than acid homopolymers.
In addition, amorphous D, L-polylactic acid or a lactic acid-glycolic acid copolymer thereof, a lactic acid-caprolactone copolymer, or other polymers that are compatible with the homopolymer and the copolymer are biodegradable and absorbable. A small amount may be mixed in order to facilitate plastic deformation or in order to impart toughness to the oriented molded product obtained by pressure orientation.
Of course, in consideration of the reaction with the living body or the decomposition rate, unreacted monomers and catalyst residues are removed and purified, and a small amount of polymer is preferable.

(d) Raw material polymer and molecular weight of preformed body 1) The above polymer must have at least a certain property such as strength as an osteosynthesis material, but the molecular weight of the polymer melts into a preformed body such as billet. When the polymer is a polylactic acid or a lactic acid-glycolic acid copolymer, the initial viscosity average molecular weight is 150,000 to 700,000, preferably 250,000 to 550,000. is important.
When a polymer having a molecular weight in this range is used, a preform having a viscosity average molecular weight of 100,000 to 600,000 can be finally obtained by melt molding under heating.

2) The polymer can be made into a composite material for a high-strength implant material by cold plastic deformation for the orientation of molecular chains (crystals) by subsequent pressure orientation. If you set the conditions well in the process, you can minimize the decrease in molecular weight.
The range of the viscosity average molecular weight of the polymer constituting the implant material containing the bioresorbable bioceramics is different from the range of an implant obtained by molding only a polymer by the same method. This is because there is a difference in the apparent melt viscosity and the degree of deterioration during the process because the bioabsorbable bioceramic powder is contained in a large amount.
When the polymer according to the present invention has a molecular weight within this range, and a molded body in which molecular chains (crystals) are oriented by a pressing operation is actually used in vivo, for example, as an osteosynthesis material, For at least 2 to 4 months, which is the average period required for bone, the strength is at least as high as that of living bones. It slowly degrades at a rate that does not exhibit an inflammatory response. In this process, the bioactive properties of bioabsorbable bioceramics are expressed, so that initial bonding with bone is obtained, and then the bioceramics are absorbed into the living body and the replacement with living bone progresses moderately. To do.

3) When the initial viscosity average molecular weight of the polymer is less than 150,000, the melt viscosity is low, so that there is an advantage that molding is easy, but high initial strength cannot be obtained. In addition, since the strength decreases rapidly in the living body, the strength maintenance period becomes shorter than the period necessary for bone fusion. And since there is a possibility that a small amount of low molecular weight fragments are generated in a short time within 1.5 to 2 years after implantation in a living body, there is a risk of inflammation due to the foreign body reaction.
Also, if the initial viscosity average molecular weight of the polymer exceeds 700,000, it becomes difficult for the polymer to flow during heating, and high temperature and high pressure are required when preparing a preform by melt molding. Due to the heat generated by the high shear stress and frictional force at the time, the molecular weight is greatly reduced, and the molecular weight of the finally obtained implant material is lower than that of using 700,000 or less. Is smaller than expected.

A polymer having a low initial viscosity average molecular weight of 150,000 to 200,000 can be filled with a relatively large amount of 30 to 60% by weight of bioabsorbable bioceramic powder, but the molecular weight is higher after melt molding. When it is low, it is easy to break (yield fracture) when it yields due to external force such as bending deformation, so it is good to keep it to a low filling amount of 10 to 30% by weight, and the degree of deformation R described later is also kept relatively small. Is good.
On the other hand, a polymer having a high viscosity average molecular weight of 550,000 to 700,000 is relatively difficult to melt mold, so a large amount of bioabsorbable bioceramic powder of 40 to 60% by weight is filled and melt molded. Is even more difficult. Therefore, the bioabsorbable bioceramic powder should be 20% by weight or less, and the degree of deformation R must be kept small.
In short, if the initial viscosity average molecular weight is about 200,000 to 550,000, a relatively wide filling amount and degree of deformation R can be selected. Moreover, the strength maintenance period in the living body is appropriate, and the rate of decomposition / absorption is also moderate.

4) Since the fluidity of the mixture is poor when the filler filling amount is large, the viscosity average molecular weight is 100,000 or less, and in some cases, the low molecular weight is 10,000 or less so that the melt viscosity is lowered to facilitate molding. A small amount of polymer may be added as a lubricant so as not to affect the physical properties of the final implant.
If the amount of the residual monomer in the polymer used is large, the molecular weight is lowered during the processing, and the degradation in vivo is accelerated. Therefore, the amount is preferably suppressed to about 0.5% by weight or less.

When the filler is highly filled at 40% by weight or more, a soft bioabsorbable polymer or a complex composed of polylactic acid D-form and L-form optical isomer is used as a filler in order to increase the interfacial bond strength between them. The surface treatment may be used.
By subsequently manipulating the molecular (crystal) orientation by press-fitting into the mold, a high-strength pressure-oriented molded product, that is, a material for an implant can be obtained without substantially reducing the molecular weight.
Next, high strength screw-shaped, pin-shaped, rod-shaped, disk-shaped, button-shaped, cylindrical, and other desired bone joint materials are manufactured by secondary processing such as cutting, milling, punching, and drilling. To do.

(e) Crystallinity The pressure-oriented molded article of the present invention has a crystallinity range of 10 to 10 in consideration of the balance of two required factors of high mechanical strength and moderate hydrolysis rate. It is necessary to select 70%, preferably 20 to 50%.
When the degree of crystallinity exceeds 70%, the apparent rigidity is high, but it becomes brittle because it lacks toughness, and easily breaks when stress is applied in the body. Moreover, decomposition | degradation becomes slow more than necessary, and since it takes a long time for absorption and disappearance in the living body, it is not desirable.
Conversely, when the degree of crystallinity is as low as less than 10%, improvement in strength due to crystal orientation cannot be expected.
Considering the mechanical strength, the speed of annihilation due to decomposition and absorption, or the less irritation to the living body, the appropriate crystallinity is 10 to 70%, preferably 20 to 50%.
Even with a low crystallinity of 10 to 20%, the strength is improved by the effect of the filler as compared with the case of non-filling.
Even if the crystallinity is 50 to 70%, microcrystals are hardly generated in the process of plastic deformation due to pressurization, and adversely affect decomposition and absorption in vivo.

(f) Density The implant material of the present invention has (i) a high density and high mechanical properties compared with a conventional stretch-oriented molded article (i) which is not secondary molded and non-oriented. (Refer to NO3 ′ in Table 1 of Reference Example 1), or (ii) a three-dimensionally press-molded molded body, so that the density is higher than that of a conventional stretch-oriented molded body. Although it depends on the degree of deformation, the molded body obtained by mixing 20% of the bioabsorbable bioceramics of the present invention is 1.4 to 1.5 g / cm 3.
The molded body mixed in the 30% range is 1.5 to 1.6 g / cm 3, the molded body mixed in the 40% range is 1.6 to 1.7 g / cm 3, and the molded body mixed in the 50% range is 1.7 to 1 .8 g / cm @ 3. Therefore, the density of the compact in which 20 to 50% by weight of bioceramics is mixed is 1.4 to 1.8. This high density is also an index indicating the density of the material and is one of the important factors supporting high strength.

(G) Crystal Form Since the implant material of the present invention is made by pressure orientation, crystals (molecular chains) of the molded body are oriented.
In particular, in the case of press-fitting such as compression molding or forging, the orientation is essentially parallel to a plurality of reference axes.
In general, as the reference axis increases, the strength anisotropy of the molded body decreases, so that it is less likely to break with a relatively weak force from a certain direction like a directional material.
In particular, in the case of press-fitting, the fact that the crystals of the molded body are essentially oriented parallel to a plurality of reference axes in the implant material of the present invention will be explained with reference to FIGS. To do.
That is, FIGS. 1A and 1B are a longitudinal sectional view and a plan view showing a crystal state when a round rod is pressure-oriented by a press-fitting method as a representative example of pressure orientation.

As shown in FIGS. 1 (a) and 1 (b), the crystal form of the press-oriented molded body by press-fitting is basically an axis L (simply referred to as a central axis) L as a dynamic core of the molded body. That is, along a number of reference axes N inclined obliquely from the outer peripheral surface toward the central axis L where the mechanical points where external forces are concentrated during molding are continuous.
They are oriented in parallel continuously from the top to the bottom of (a).
In other words, a large number of reference axes N taking a radially oblique orientation around the central axis L form a substantially conical shape continuously in the circumferential direction as shown in FIG. Thus, a continuous phase of a substantially conical surface is formed by being oriented in the vertical direction and parallel to the reference axis N.
That is, it can be regarded as an oriented structure in which the conical crystal plane is continuous in the vertical direction of the central axis L and the crystal plane from the outer periphery toward the center is oriented in the direction of the central axis.

Such a crystalline state is achieved by the fact that the billet 1 is subjected to large shear due to friction during press-fitting, for example, compression molding, and is oriented obliquely from the outer peripheral surface toward the central axis L as crystallization proceeds.
In FIGS. 1 (a) and (b), a cylinder such as a round rod has been described. However, a pressure-oriented molded body by press-fitting and filling such as a flat plate instead of a cylinder is shown in FIG. 2 (a),
(B) As shown in (b), the axis that becomes a dynamic core by receiving a large shearing force from both side surfaces thereof is not a center line, and is parallel to and equidistant to both opposite side surfaces of the plate including this axis. A plane M in the middle) is formed.
Therefore, the crystals of the plate-like pressure-oriented molded body by press-fitting are oriented parallel to the oblique reference axis N from the opposite side surfaces of the plate toward the surface M.
Further, since the axis L or the surface M including the axis L that is the dynamic core of the molded body is a point where the force from the outside is concentrated, the force from the surrounding or both sides is adjusted during the pressurizing orientation by press-fitting and filling. By doing so, the point where the force from the outside is concentrated is off the center or the center, and the crystal is in the state of the crystal oriented toward the axis L off the center or the surface M deviated from the center to the left or right. .

(B) Production of implant material Production of the implant material of the present invention basically consists of (i) a crystalline thermoplastic polymer that is previously biodegradable and absorbable and a bioabsorbable bioceramic powder. A uniformly dispersed mixture is prepared, then the mixture is melt-molded to prepare a preform, and the preform is secondarily molded and plastically deformed to obtain an oriented molded body.
(1) The secondary molding is also characterized in that the preform is cold-pressed into a closed mold cavity and plastically deformed to form an oriented molded body.
(2) A mixture of the polymer and the bioabsorbable bioceramic powder mixes and disperses the bioceramic powder substantially uniformly in a solvent solution of the polymer, and this is mixed with the non-solvent of the polymer. It is also characterized by the fact that it is created by sedimentation.
(3) It is also characterized in that the pressure-oriented molded body is further cut.

(a) Preparation of mixture of polymer and bioabsorbable bioceramic powder 1) Bioabsorbable bioceramic powder that aggregates relatively easily is mixed and dispersed substantially uniformly in the matrix polymer. For example, bio-absorbable bioceramics powder is added to a matrix polymer dissolved in a solvent such as dichloromethane or chloroform and dispersed well. The dispersion is precipitated by adding a non-solvent such as ethanol or methanol. It is desirable to adopt a method of making a mixture. In this case, the polymer dissolution concentration and the ratio of solvent to non-solvent may be adjusted in accordance with the type of polymer and the degree of polymerization.

2) The bioabsorbable bioceramic powder / matrix polymer mixing ratio is 10 to 60% by weight, preferably 20 to 50% by weight, more preferably 30 to 40% by weight.
When the mixing ratio is less than 10% by weight, the volume ratio of the bioresorbable bioceramic powder is small, so that direct binding to bone, bone conduction, and bone induction are expected for the bioresorbable bioceramic powder. These properties are difficult to express, and the replacement with living bone is relatively slow, much like the polymer alone.
On the other hand, if it exceeds 60% by weight, the fluidity at the time of thermoforming of the mixed system is insufficient, so that molding becomes difficult, and the amount of polymer in the molded product is insufficient and the binder effect does not reach. Since − and polymer are easily separated, they become brittle in strength.
In addition, since the bioresorbable bioceramic powder is rapidly exposed from the surface of the bone-bonding material during the decomposition process in the living body, there is a concern that it may be harmful to the living body.
When the mixing ratio is within this range, desirable characteristics of both the bioabsorbable bioceramic powder and the polymer matrix can be remarkably exhibited in both the structure and function of the composite material.

(b) Melt molding 1) Although the composite material of the present invention belongs to a particle-reinforced composite material, a polymer system containing a large amount of bioceramic powder that is bioabsorbable like an implant material of the present invention is generally used. Thermoforming is difficult because of poor fluidity.
In addition, the safety in the living body must be taken into consideration for the implant, and it is further difficult to mold the titanium-based coupling agent that is extremely effective for improving the fluidity.
When this composite material with poor fluidity is kneaded and thermoformed by general extrusion molding, where shearing force is applied at the time of melting, the polymer itself deforms and flows with its original flow characteristics, but the filled bioabsorbable biomaterial Since ceramic powder does not have the property of plasticizing and flowing due to heat, the density of density increases as a result of the formation of a void at the interface between the polymer and the bioabsorbable bioceramic particles due to fluid deformation accompanying molding and the inclusion of voids. It is inevitable that a rough molded body is formed and the strength of the molded body is lowered.

2) A ram (plunger) is used to perform primary molding (melt molding to form a preformed body) of a polymer system containing a filler such as a bioceramic powder that is absorbed in a large amount of living body as in the present invention. ) Type melt extrusion molding method is advantageous, but it is also possible to use a pressure type molding method such as special injection molding or compression molding in consideration of the above problems so that voids are not easily formed.
In short, melt molding to obtain a billet may be performed under a temperature condition equal to or higher than the melting point of the polymer. However, if the temperature is too high, the molecular weight is significantly reduced. It is desirable to perform melt molding without interposing voids.

For example, when the polylactic acid having an initial viscosity average molecular weight of about 150,000 to 700,000 is used as the polymer, a temperature condition of not less than the melting point and not more than 200 ° C., preferably about 190 ° C. is selected, If drying is performed sufficiently, the viscosity average molecular weight after melt molding can be maintained at 100,000 to 600,000.
Similarly, as for the pressure condition, in order to prevent the molecular weight from decreasing due to heat generated by friction, the minimum pressure capable of melt molding, for example, 300 kg / cm 2 or less, preferably 150 to 250 kg / cm 2 is adopted. Is desirable. However, since this is considerably different depending on the composition and size (thickness, diameter, length) of the preform (billet), it may be changed depending on the situation.

3) It is desirable that the billet is melt-molded so as to have a cross-sectional shape similar to the cross-sectional shape of the cavity of the mold for pressure-oriented molding, and if the cavity has a circular cross-sectional shape, a larger circular cross-section The billet is melt-molded to form a cylindrical body having a shape.
When the cross-sectional shape of the billet is similar to the cross-sectional shape of the cavity in this way, the billet can be plastically deformed while being uniformly compressed from the periphery, and can be press-fitted into the cavity, so that a homogeneous pressure-oriented molded product can be obtained Can do.

4) At that time, the billet is preferably melt-molded so that the cross-sectional area thereof is 1.5 to 5.0 times the cross-sectional area of the cavity. Thus, after passing through the secondary process by pressure orientation, a desired shape is cut out by tertiary processing such as cutting.
5) In addition, the billet which is a preformed body may have a desired shape suitable for secondary forming by pressure orientation which is the next step, for example, forging orientation or compression orientation, in some cases (particularly in the case of a complicated cross-sectional shape). Cutting may be performed.

(c) Pressure molding to closed mold
(i) A billet, which is a primary molded product, is pressure-molded with a closed mold for secondary molding to obtain a multi-axis oriented molded body.
That is, for example, basically using the technique of the ram extrusion method or the compression molding method, the billet is formed into a closed mold having a cross-sectional area 2/3 to 1/5 of the cross-sectional area (however, 2/3 to 3/3 If you have any single value of 1/5 over the entire mold, if you have partial cross-sections of any value in this range partially in multiple parts of the mold, or before (Including the mold where the rest of the two have the same cross-sectional area as the billet), while cold or continuous pressurization (glass transition point (Tg) and melting temperature (Tm) An appropriate temperature (Tc) at which an interstitial crystal is formed may be plastically deformed and press-fitted into the cavity for orientation.

(1) Compression molding FIGS. 3 and 4 are longitudinal sectional views schematically showing a molding model by compression molding as an example of pressure molding, and FIG. 3 is a diagram before press-filling a billet into a cavity of a molding die. FIG. 4 shows the state after press-fitting.
Such a mold 2 comprises a thick cylindrical housing cylinder portion 2a for housing the billet 1 and a thin cylindrical molding cavity 2c into which the billet 1 is press-fitted and filled by the pressurizing means 2b. Are connected coaxially up and down via a reduced diameter portion 20a having a taper.
A pressurizing unit 2b is provided on the upper portion of the housing cylinder 2a, and the billet 1 is pressurized continuously or intermittently by a pressurizing unit 2b such as a piston (ram). An extremely minute air vent or gap (not shown) is formed at the bottom of the cavity 2c.

Using such a mold 2, as shown in FIG. 3, the billet 1 is accommodated in the accommodating cylinder portion 2a, and the billet 1 is continuously or intermittently pressurized by the pressurizing means 2b to enter the cavity 2c. If it is press-fitted while plastically deforming in the cold state to obtain the state shown in FIG. 4, a large shear due to friction occurs between the inner surface of the reduced diameter portion 20a and the inner surface of the cavity 2c during the press-fitting, and this orients the polymer. Acts as a lateral or diagonal external force (vector force).
For this reason, the polymer is essentially oriented along the inner surface of the reduced diameter portion 20a and crystallization proceeds. At the same time, since the press-fitting speed into the central portion of the molding cavity 2c is faster than the surroundings, the crystal axis of the compression-oriented molded body 10 molded according to the shape of the cavity 2c is the central axis in the longitudinal direction as shown in FIG. Oriented obliquely with respect to L, the crystal is oriented parallel to many reference axes from the circumference toward the central axis L. That is, the compression oriented molded body 10 that is oriented concentrically along the inner peripheral surface of the cavity 2c is obtained.
At the same time, since the polymer is compressed in the machine direction (machine direction), it also shows orientation in this direction. Thus, a qualitatively dense thin cylindrical compression-oriented molded body 10 is obtained.

In such press-fitting and molding, various shapes of compression-oriented moldings can be obtained by changing the shape of the housing cylinder portion 2a of the molding die 2 and the cavity 2c having a small cross section similar to this.
For example, as shown in FIG. 2, in order to obtain a plate-like compression-oriented molded body such as an osteosynthesis plate, the accommodation cylinder portion having a rectangular cross section and the cavity are reduced in diameter (tapered only on two sides in the long side direction). It is only necessary to perform pressure orientation in the same manner using a molding die that is coaxially connected in the vertical direction via a shape attached thereto or a shape provided with four sides tapered.
Further, by changing the inclination angle θ of the reduced diameter portion 20a of the mold 2 over the entire circumference or partially, the axis L or the surface M, which serves as the dynamic core of the molded body, deviates from the center or the middle. A compression-oriented molded body having a crystal state that is oriented obliquely toward the deviated axis L or the plane M can be obtained.

(2) Forging Molding FIG. 5 is a longitudinal sectional view schematically showing a molding model by forging molding as another example of pressure molding.
The molding die 2 shown in FIG. 5 has a cylindrical or (multi-) square tube-shaped accommodation tube portion 2a having a hollow disk shape or a hollow (multi-) angle having a projection plane area larger than the cross-sectional area of the tube portion 2a. It is provided at the center of the cylindrical cavity 2c, and a pressurizing means such as a piston (ram) is provided at the upper part of the accommodating cylinder 2a.
Using such a mold, the billet 1 made of the above-mentioned polymer is accommodated in the accommodating cylinder 2a and continuously or intermittently pressurized by the pressurizing means 2b, so that the billet 1 is cold on the projection plane. A forged oriented molded body having a cylindrical shape or a (multi-) square tube shape is obtained by press-fitting and filling the cavity 2c having a large area from the center to the periphery.

The forged oriented molded body obtained in this embodiment is different from the compression oriented molded body in that many molecular axes and crystals are radially oriented with many axes from the central part to the peripheral part of the molding cavity 2c. This is a forged oriented molded product that is oriented parallel to the reference axis, and is a molded product having a different orientation form from a simple uniaxially stretched product.
The method of such an embodiment is particularly effective when manufacturing an osteosynthesis or an accessory having a hole in a cylindrical shape, a (multi) rectangular tube shape, a button shape, or the like.
In the case of forging, the pressurizing action of cold-pressing and filling the billet into the cavity of the mold is basically due to drawing, but the orientation mechanism is basically the same as in the case of compression molding. .

(ii) According to the pressure orientation method as in (1) and (2), the external force at the time of orientation molding acts inwardly toward the material body opposite to stretching, so that the material is in a dense state. .
For this reason, the interface between bioabsorbable bioceramic powder and matrix polymer changes to a more tightly bonded state, and even micro voids intervening in the air that existed at the interface during the mixing process disappear, resulting in high density. can get. That is, both are further integrated.
In addition, since the polymer of the matrix is oriented with the molecular chain axis and the crystalline phase, the resulting composite material exhibits significantly higher strength.
The form is shown in FIG. 6 [Particle Strengthening + Matrix Strengthening] (c) as described above, and the difference from the conventional strengthening method by combining materials is clear.
In the case of pressure orientation molding, particularly compression orientation molding, as shown in FIG. 1, since a vector force is applied by “shear” from the mold surface (mold surface), it is uniaxial by simply stretching in the major axis direction. Unlike the orientation, it has a strong tendency to be oriented parallel to a certain reference axis.
Therefore, the characteristics that there is little anisotropy due to orientation and resistance to deformation such as twisting are manifested.

(iii) By the pressure molding according to the present invention, a secondary molded body having a block shape, a plate shape, a pin shape, a rod shape, a disk shape, or the like, in which molecular chain axes or crystal phases are selectively selectively oriented. obtain.
After that, it is further milled, cut, threaded, drilled, etc. as necessary, and has the desired shape such as screw, pin, rod, disk, button, and cylinder. Finished.
However, the method for obtaining an oriented molded body by pressure orientation such as compression molding or forging as used herein typically means that a billet, which is a melt-formed product, has any diameter, thickness, or width rather than itself. It means a molding method in which the pressure is forced and pressed continuously or intermittently into a narrow space of a molding die that is partially or entirely small.
Therefore, the method and the molded product obtained are essentially different from the orientation molding by stretching which stretches the material.

(iv) Deformation degree Deformation degree R = So / S (where So is the cross-sectional area of the billet, S is the cross-sectional area of the pressure-oriented molded article) is in the range of 3/2 to 5/1. Just do it.
If the degree of deformation is less than 3/2, the degree of pressure orientation is low and high strength cannot be obtained. If the degree of deformation is greater than 5/1, deformation is not easy, and cracks may occur during molding, or fibrillation may occur. It is not desirable because the directivity increases. The range of R that can be molded most stably is 2/1 to 4/1.

(v) Plastic deformation temperature Plastic deformation temperature is cold, in other words, [appropriate temperature (Tc) at which a crystal having a glass transition point (Tg) or higher and a melting temperature (Tm) or lower is generated]. Tg (60-65 ° C)
And a temperature (Tc) suitable for crystallization between Tm and Tm (175 to 185 ° C.).
Empirically, molecular slip occurs at a high temperature of 120 ° C. or higher, so that it is difficult to obtain a good pressure orientation state, and the ratio of the amorphous phase becomes considerably large at 80 ° C. or lower, so that it is as strong as cortical bone. It is difficult to obtain a highly oriented molded product.
Therefore, the preferable temperature range is 80 to 120 ° C, more preferably 90 to 110 ° C. The Tg of the lactic acid-glycol copolymer having the monomer ratio in the above range is 50 to 55 ° C., but the preferable plastic deformation temperature is almost the same as that of the single polymer.

(Vi) The pressure applied during plastic deformation, such as plastic deformation pressure, is the degree of deformation R, the time required for pressure orientation (deformation speed and heating time), and the cavity of the mold having the So cross section that accommodates the preform. , Which is determined by the relationship with the throttle angle (θ) of the path (which can be arbitrarily selected within the range of 10 ° to 60 °) when compressed into the cavity of the mold having an S cross-sectional area smaller than So. It is 10,000 kg / cm @ 2, preferably 500 to 5000 kg / cm @ 2.
The heating time is 1 to 5 minutes considering the crystallization and the growth rate.

(Vii) Action of pressure orientation When plastically deformed under such conditions, for example, in the case of forging, when press-filling a mold having a narrow cavity having a smaller diameter, thickness or width than a billet, In the meantime, a large shear is generated due to friction, and this acts as an external force (vector force) in the lateral and oblique directions for the orientation of the polymer to selectively orient the crystal. Then, the compact is compressed in the direction of the orientation axis, and the interface between the polymer and the bioceramic powder becomes more closely attached, so that it becomes qualitatively dense and high strength is obtained.
However, when the polymer system is simply extruded, drawn, and oriented in the machine direction by stretching, the lateral direction (side surface) is free (free width), and the thickness becomes thin during the stretching process. No external force is applied. Therefore, it becomes a uniaxially oriented molded body in which molecular chains and crystals are oriented only in the uniaxial (long axis) direction. Since the molded body is stretched in the direction of the orientation axis, the material is qualitatively thinner than that before stretching (voids are also formed), so it is mechanically weak and the molding of the present invention. The anisotropy is greater than the body, and the mechanical strength is also low.
When the billet is subjected to pressure orientation molding, crystallization proceeds during orientation during molding. The degree of crystallinity varies depending on the molding time and temperature. However, in the case of a composite material containing a large amount of bioabsorbable bioceramic powder as a filler as in the present invention, the growth of the matrix polymer crystals does not occur. The crystallinity is somewhat lower than when the matrix polymer alone is molded for the same orientation because it is hindered by the bioabsorbable bioceramics and tends to break the crystals finely by the pressure during plastic deformation. Get smaller. This is a preferable phenomenon from the viewpoint of degradation speed and tissue reaction in the living body.

(C) Features such as physical properties of implant materials
(i) The pressure-oriented molded article of the present invention is compressed and compacted by the pressure at the time of molding, but in some cases, the more the standard axis in which the crystals are oriented, the more the strength anisotropy decreases. doing.
On the other hand, when the reference axis is uniaxial, the crystals (molecular chains) are uniformly arranged in parallel with the reference axis direction. Therefore, since the pressure-oriented molded article of the present invention has many reference axes, the mechanical properties such as bending strength, flexural modulus, tensile strength, tear strength, shear strength, torsion strength, surface hardness are improved in a well-balanced manner, Destruction is unlikely to occur.

(ii) Physical properties The implant material of the present invention, in particular, an oriented molded body, has a bending strength of 150 to 320 MPa and a bending elastic modulus of 6 to 15 GPa. Depending on the degree and molecular weight. In addition, other physical strength ranges are obtained with a tensile strength of 80-180 MPa, a shear strength of 100-150 MPa, and a compressive strength of 100-150 MPa, which are generally similar to the strength of human cortical bone. Therefore, it can be said that it is close to an ideal as an implant.

For example, when L-lactic acid homopolymer having the above initial viscosity average molecular weight range is uniformly mixed and dispersed with 30% by weight of HA having an average particle size of 5 μm, billet is used and the degree of deformation R = So / S is 1.5. A pressure-oriented molded product obtained by pressure-oriented molding in the cold so as to achieve the above can be obtained with a bending strength of 250 MPa or more, sufficiently exceeding the bending strength of cortical bone.
Increasing the degree of deformation R that changes the degree of orientation increases the mechanical strength of the composite material in the machine direction. At the same time, if the filling amount of the bioabsorbable bioceramic powder is large, a high elastic modulus can be obtained.
Then, a bending strength exceeding 300 MPa and a modulus of elasticity close to 15 GPa of cortical bone are obtained.
The range of this elastic modulus of 6 to 15 GPa does not seem to be much different on the numerical value, but it is less likely to bend and bend at the time of insertion in practical use than it is below about 10 GPa or more. Since there is a large difference in the difficulty of deformation or rigidity, a difference of more than a numerical value is recognized in physical usefulness when used as an osteosynthesis material.
(iii) The pressure-oriented high-strength composite rod-shaped molded product of the present invention can be further cut into a final molded product by a method such as cutting to obtain a medical implant.

(iv) Features of the implant material The implant material of the present invention is:
(1) Since the primary particles or the aggregates (clusters) of primary particles having a size of 0.2 to 10 μm are included in a large amount and in a large amount of 10 to 60% by weight, Many unburned hydroxyapatite particles, which are bioabsorbable bioceramics, are evident on the surface, and at the initial stage after implantation, biocompatibility is good, and bioceramics directly bind to living bones, so that they are fixed in the initial stage. Increases nature.
(2) Since a polymer matrix in which molecular chains or crystals of a polymer having an appropriate molecular weight and its molecular weight distribution are oriented at a crystallinity of 10 to 70% is made by a new composite strengthening method strengthened by orientation. It can be designed such that initial high strength is imparted, and strength close to that is maintained for at least 2 to 4 months necessary for bone fusion, and then gradually decomposed at a rate that does not cause tissue reaction.
(3) Unburned hydroxyapatite powder, which is a bioabsorbable bioceramic, exists continuously up to the inside of the composite material, so it must be gradually decomposed and exposed to the surface to bond with living bone. Contribute to. In addition, the non-fired hydroxyapatite powder, which is a bioresorbable bioceramic, promotes bone induction and conduction, and quickly fills the void where the polymer has finally disappeared. Done.
(4) Since the composite material contains a large amount of unburned hydroxyapatite fine particles, which are bio-absorbable bioceramics, it can be copied well on simple X-ray photographs, which is impossible only with polymers. It is possible to effectively observe X-rays during the treatment process. Furthermore, unsintered hydroxyapatite, which is a matrix polymer and bioabsorbable bioceramics, has been used in clinical practice in the past, and is safe for the living body and excellent in biocompatibility. Therefore, this composite material for implants can be said to be one of ideal biomaterials.

As is clear from the above description, the composite high-strength implant material of the present invention has mechanical strength equal to or higher than that of cortical bone, has rigidity and toughness, and does not easily break in the initial stage. The period from the time when hard bone is healed by taking advantage of the properties of bone binding, bone conduction, bone induction and in vivo degradation / resorption by resorbable bioceramics, and efficient replacement with living bone Maintains strength, but then gradually decomposes and absorbs at a rate that does not cause harm to the surrounding bones, and the disappeared trace is immediately reconstructed by the living body, and a simple radiograph after surgery It is an ideal biomaterial that can be projected by
In addition, the method of the present invention can easily produce the above-described implant material without employing a special apparatus or harsh conditions.

EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, these do not restrict | limit the scope of the present invention.
Measurement methods for various physical property values will be described below.
(1) Compressive bending strength, compressive bending elastic modulus: measured according to JIS-K-7203 (1982).
(2) Tensile strength: Measured according to JIS-K-7113 (1981).
(3) Shear strength: R.SUURONEN et al. [R.SUURONEN, T.POHJONEN et al
, J. Mater. Med, (1992) 426].
(4) Density: Measured according to JIS-K-7112 (1980).
(5) Crystallinity: Calculated from the enthalpy of melting peak by differential scanning calorimeter (DSC) measurement.

(Reference Example 1) <Compression molding; Example 1>
Hydroxyapatite (HA) having a maximum particle size of 31.0 μm, a minimum particle size of 0.2 μm, and an average particle size of 1.84 μm in a solution of 4% by weight of poly L-lactic acid (PLLA) having a viscosity average molecular weight of 400,000 in dichloromethane. ) (Fired at 900 ° C.) was added and stirred to uniformly disperse HA without causing secondary aggregation. Further, ethyl alcohol was added with stirring to coprecipitate PLLA and HA. Next, this is filtered and completely dried to obtain PLLA granules in which HA having the above particle diameter is uniformly dispersed at a ratio of 20, 30, 40, 50, and 60% by weight, respectively. It was.
This was melt extruded at 185 ° C. with an extruder to obtain a cylindrical billet having a diameter of 13.0 mm, a length of 40 mm, and a viscosity average molecular weight of 250,000.

Next, as shown in FIGS. 3 and 4, the billet is heated to 110 ° C. in a housing cylinder portion having a hole with a diameter of 13.0 mm, and the diameter 7 is connected to the housing cylinder portion through a reduced diameter portion. By compressing and molding into a cavity having a hole having a length of .8 mm and a length of 90 mm, a compression oriented molded body in which the same shape as that of the cavity and PLLA and HA in which HA is uniformly dispersed is combined is formed. Obtained. However, θ = 15 °.
When the cross-sectional area of the molded body obtained here is S and the cross-sectional area of the billet before plastic deformation is So, the degree of deformation is R = So / S = 2.8.
Table 1 shows the obtained composite HA / PLLA compression-oriented molding (sample Nos. 2, 3, 4, 5, 6; reference examples) and PLLA compression-oriented with a deformation degree of 2.8 consisting only of PLLA. The physical properties of the molded body (Sample No. 1: Control Example 1) and the non-oriented molded body containing 30% by weight of HA particles but not subjected to compression orientation molding (Sample No. 3 ′; Comparative Example) were compared.

As shown in Table 1, the mechanical properties of the compression-oriented molded article of PLLA combined with HA, which is a surface bioactive bioceramic, are remarkably improved. Further, as another control example, a stretching force is applied by a conventional general uniaxial stretching method in which a force for orientation is applied in a direction away from the material opposite to the compression orientation of the present invention, and the orientation form is different. The physical properties of the molded product (Sample No. 7; Control Example 2) are shown in Table 1. Stretching was performed after heating in 110 ° C. liquid paraffin.
The mechanical properties of the non-oriented molded article (sample No. 3 ′) of PLLA combined with the above HA are the same as those of the compression oriented molded article (sample No. 1 to 6) containing or not containing the HA. Although it was inferior when compared, it was found to be superior to that of the stretch-oriented molded article (Sample No. 7).
In addition, it was confirmed that the non-oriented molded article of PLLA in which unfired HA was oriented and combined instead of the above HA had mechanical properties equal to or higher than those in the above case.

This sample No. In the molded product of No. 7, since the materials are shifted from each other at the interface between the filler and the polymer when deformed by stretching, the surface of the material is torn like a fiber, and the inside is infinitely large and small at the interface between the two It was an inferior substance forming a void. Therefore, reproducible physical property values could not be obtained and the values were low. No. in Table 1 7 showed the best value among them.
In addition, since innumerable voids are formed, it is a dilute substance with a low density of 0.924, it is easy for biological fluids to enter from the outside, and the hydrolysis rate seems to be high.
From this, it was proved that it is impossible to obtain an osteosynthesis having physical properties intended by the present invention by uniaxial stretching. Moreover, it was the intensity | strength which cannot be used as an osteosynthesis.

(Reference Comparative Example 1) <Compression molding>
Using PLLA having a viscosity average molecular weight of 400,000 and HA (calcined at 900 ° C.) having a maximum particle size of 100 μm and an average particle size of 60 μm, 30% by weight of HA is uniformly dispersed under the same method and conditions as in Reference Example 1. PLLA granules were obtained.
This was melt-extruded with an extruder in the same manner as in Reference Example 1 to obtain a cylindrical billet having a diameter of 13.0 mm, a length of 40 mm, and a viscosity average molecular weight of 250,000.
Next, this billet is press-fitted into the mold hole by the same method and conditions as in Reference Example 1, so that HA is uniformly dispersed and R = 2.8 combined HA / PLLA compression orientation. A molded body was obtained.
In Table 2, the physical properties of the obtained molded body and the molded body (sample No. 3) containing 30% by weight of HA of Reference Example 1 were compared.

Reference Comparative Example 1 in which the average particle size of HA was 60 μm was lower in strength than Reference Example 1 (Sample No. 3) in which the average particle size was 1.84 μm. Further, in the bending strength test, Reference Comparative Example 1 reached the yield point and broke when it showed the maximum load, but Reference Example 1 (Sample No. 3) did not break.
This is because even though PLLA is highly oriented, a large number of large HA particles or brittle HA aggregates are distributed, so that the matrix of PLLA orientation is interrupted by HA, and its strength is not utilized. It is thought that it was because of.
On the other hand, even in the case of Reference Example 1 (sample No. 3) containing HA which is an aggregate of 31.0 μm even with the maximum particle size, it was not broken even when the maximum load was shown.
Similarly, there was no breakage in the case of a compression-oriented molded body which is a composite material of particles having a maximum particle size of 45 μm in Example 2 described later or unfired hydroxyapatite containing aggregates thereof.

(Reference Example 2) <Compression molding; Example 2>
Using PLLA having a viscosity average molecular weight of 220,000 and 180,000 and the same HA as in Reference Example 1, a PLLA granule in which 30% by weight of HA is uniformly dispersed under the same method and conditions as in Reference Example 1 Obtained and extruded with an extruder, cylindrical billets having a diameter of 13.0 mm, a length of 40 mm, and viscosity average molecular weights of 150,000 and 100,000, respectively, were obtained.
Next, this billet is press-fitted in the same mold as in Reference Example 1 by the same method, so that HA / PLLA composite compression-oriented molded body of R = 2.8 in which HA is uniformly dispersed. Got.
Table 3 compares the physical properties of the obtained compression-oriented molded article and a compression-oriented molded article having the same molecular weight as each of the PLLA-only molded article as a control example.

The molded body from the billet having a viscosity average molecular weight of 150,000 is slightly lower in strength than the reference example 1, but the bending strength is sufficiently resistant to use as an osteosynthesis material. In addition, the strength and elastic modulus increased as compared with the comparatively oriented molded body containing only PLLA.
In contrast, a molded body from a billet having a viscosity average molecular weight of 100,000 had a bending strength increased more than that of PLLA alone, but broke at the yield point.
However, when the filling amount of the bioceramic particles is 10% by weight, a material that does not break during the falling is obtained depending on conditions. Polymers generally have a lower strength as their molecular weight decreases. The molded article having a viscosity average molecular weight of 100,000 is considered to have broken because the toughness as a composite material was lowered by the mixing of a large amount of HA.
Therefore, even if HA is mixed, it is determined that the lower limit of the viscosity average molecular weight of the billet necessary to have both sufficient strength (rigidity) and toughness is 100,000.

(Reference Example 3) <Compression molding; Example 3>
Using PLLA having a viscosity average molecular weight of 400,000 and the same HA as in Reference Example 1, a PLLA granule in which 15% by weight of HA is uniformly dispersed by the same method and conditions as in Reference Example 1 is obtained. Extrusion was performed using a machine to obtain a cylindrical billet having a diameter of 13.0 mm, a length of 40 mm, and a viscosity average molecular weight of 250,000.
Next, as shown in FIG. 3, the billet is formed by connecting a housing cylinder portion having a diameter of 13.0 mm and a cavity having a diameter of 7.0 mm and a length of 113 mm, or a housing cylinder portion having a diameter of 14.5 mm and a diameter. In a mold in which cavities having a length of 11.8 mm and a length of 57 mm are connected, HA is uniformly dispersed by the same method and conditions as in Reference Example 1, R = 3.5 and R = 1.5, respectively. A HA / PLLA composite compression-oriented molded body was obtained. However, θ = 15 °.
Table 4 compares the physical properties of the obtained molded body and the compression-oriented molded body of R = 3.5 and R = 1.5 only composed of PLLA as a control example.

From this result, the molded product of R = 3.5 had high strength (rigidity) and high toughness, which exceeded the bending strength of the compression-oriented molded product composed only of PLLA highly oriented to the same extent. . Since the degree of crystallinity is lower than that of a molded article made only of PLLA, it is a material that is less irritating and less irritating to surrounding tissues in vivo. This is presumably because the HA particles inhibited the crystal growth of PLLA and acted on microcrystallization.
The molded product of R = 1.5 has a slightly higher bending strength than the molded product of PLLA alone, but is an implant material that can be used sufficiently depending on the application.

(Reference Example 4) <Compression molding; Example 4>
Using PLLA having a viscosity average molecular weight of 400,000 and apatite wollastonite glass ceramics (AW-GC) having an average particle size of 2.7 μm, 35% by weight of AW-GC was obtained under the same method and conditions as in Reference Example 1. Uniformly dispersed PLLA granules were obtained and melt-extruded by an extruder to obtain a cylindrical billet having a diameter of 14.5 mm, a length of 45 mm, and a viscosity average molecular weight of 220,000.
Next, as shown in FIG. 3, the same method and conditions as in Reference Example 1 were placed in a molding die in which the billet was connected to a housing cylinder having a diameter of 14.5 mm and a cavity having a diameter of 9.6 mm and a length of 83 mm. Then, a compression-oriented molded body in which AW-GC / PLLA was composited with R = 2.3 in which AW-GC was uniformly dispersed was obtained. However, θ = 20 °.
Table 5 compares the physical properties of the obtained compression-oriented molded article and a PLLA compression-oriented molded article of R = 2.3 consisting only of PLLA as a control example.

The obtained molded body has improved bending strength as compared with a molded body only of PLLA. When this material is cut and AW-GC is exposed on the surface, AW-GC vigorously forms an HA layer on the surface several weeks after bone induction. It can be.

Example 1 <Compression Molding; Example 5>
Using PLLA having a viscosity average molecular weight of 400,000 and alpha-type tricalcium phosphate (α-TCP) having a maximum particle size of 22.0 μm and an average particle size of 7.7 μm, PLLA granules in which 25% by weight of α-TCP is uniformly dispersed are obtained under the conditions, and are melt-extruded by an extruder to form a cylindrical shape having a diameter of 13.0 mm, a length of 40 mm, and a viscosity average molecular weight of 250,000. I got a billet.
Next, as shown in FIG. 3, the billet is placed in a molding die in which a housing cylinder having a diameter of 13.0 mm and a cavity having a diameter of 7.5 mm and a length of 96 mm are connected. Press-filling was carried out under the conditions, and an R-3.0 α-TCP / PLLA composite compression-oriented molded body in which α-TCP was uniformly dispersed was obtained. However, θ = 15 ° C.
Table 6 compares the physical properties of the obtained compression-oriented molded product and a molded product of R = 3.0 consisting only of PLLA as a control example.

The obtained molded body has high strength like the HA composite molded body, and its bending strength and elastic modulus are higher than those of the PLLA-only molded body. Since α-TCP is bioabsorbable and has higher bioactivity than sintered HA, it can be a high-strength implant effective for bone replacement.

(Example 2) <Compression molding; Example 6>
Using a PLLA having a viscosity average molecular weight of 360,000 and uncalcined hydroxyapatite (wet-HA) having a maximum particle size of 45 μm and an average particle size of 3.39 μm, 40 wt% HA in the same manner and under the same conditions as in Reference Example 1. Were uniformly dispersed and melt-extruded by an extruder to obtain a cylindrical billet having a diameter of 10.0 mm, a length of 40 mm, and a viscosity average molecular weight of 200,000.

<Measurement of activity>
In order to check whether the activity is higher, two billets each containing 40% by weight of fired HA and unfired HA were prepared in the PLLA used in Example 2 above, and small pieces (10 × 10 × 2 mm), and both were immersed in the coagulant fluid, and the amount of calcium phosphate component deposited on the surface was observed. As a result, unsintered HA / PLLA began to deposit a large amount of crystals after 3 days, and the crystal layer covered the entire surface after 6 days, whereas that of sintered HA / PLLA did not cover the entire surface even after 6 days. It was.
The calcined HA powder is absorbed by bone cells and does not disappear. In some cases, it has been confirmed that the cells exhale again after eating poorly, and the risk of the powder causing a tissue reaction has been pointed out.
However, unsintered HA has a complete absorbability that it is absorbed and disappears by the living body, and is not the same problem because it is chemically the same substance as HA in the living body. To date no unfired HA / PLLA high-strength implants have been developed and this example forms the basis of the novelty, significance and inventiveness of the present invention.
Next, as shown in FIG. 3, the same method and conditions as in Reference Example 1 were placed in a molding die in which this billet was connected to a housing cylinder having a diameter of 10.0 mm and a cavity having a diameter of 7.0 mm and a length of 76 mm. Then, an R = 2.0 compression-oriented molded body in which the unfired HA was uniformly dispersed was obtained. However, θ = 30 °.
Table 7 compares the physical properties of the obtained compression-oriented molded body and an R = 2.0 molded body composed only of PLLA as a control example.

The bending strength of the uncompressed HA / PLLA composite compression-oriented molded body is higher than the strength of the molded body composed only of PLLA, as in the case of the fired HA-composite compressed alignment molded body of Reference Example 1. The value is shown. Since the unfired HA has a much higher bioactivity than the fired HA, a highly bioactive composite high strength implant material was obtained.
Since unsintered HA is not sintered, it is itself an inorganic chemical substance, and it is not a high-strength powder like ceramics. However, since it is not chemically modified by sintering, it is closer to living body hydroxyapatite. It is a substance. In the present invention, since the matrix polymer was reinforced, the unfired HA could also be made into a composite material having the same strength as that of the fired HA.

(Example 3) <Compression molding; Example 7>
The same method and conditions as in Reference Example 1 using PLLA having a viscosity average molecular weight of 400,000 and a solid type tricalcium phosphate (β-TCP) having a maximum particle diameter of 45 μm and an average particle diameter of 2.91 μm To obtain a PLLA granule in which 30% by weight of β-TCP is uniformly dispersed, melt-extruded by an extruder, and a cylindrical billet having a diameter of 13.0 mm, a length of 40 mm, and a viscosity average molecular weight of 250,000 Got.
Next, as shown in FIG. 3, the billet is placed in a molding die in which a housing cylinder portion having a diameter of 13.0 mm and a cavity having a diameter of 8.6 mm and a length of 74 mm, or a diameter of 7.8 mm and a length of 90 mm are connected. In addition, press-filling was performed under the same method and conditions as in Reference Example 1, and β-TCP / PLLA in which β-TCP was uniformly dispersed and R was 2.3 and 2.8 were combined in a compressed orientation. A molded body was obtained. However, θ = 15 °.
Table 8 shows the compression oriented molded product obtained and the composite HA / PLLA compressed oriented product of R = 2.8 in which HA of Reference Example 1 (fired at 900 ° C.) is dispersed by 30% by weight. The physical properties of were compared.

The obtained molded body has a R shown in Table 5 and Table 1 larger than the bending strength of the molded body of only PLLA having 2.3 and 2.8, respectively. Moreover, since the thing of R = 2.8 has a bending strength comparable as the compression orientation molded object of the same R, a high intensity | strength compression orientation molded object is obtained also by combining (beta) -TCP. It became clear that

(Example 4) <Compression molding; Example 8>
Using PLLA having a viscosity average molecular weight of 400,000 and tetracalcium phosphate (TeCP) having a maximum particle size of 30.0 μm and an average particle size of 10.0 μm, the same method and conditions as in Reference Example 15 were used, and the weight was 15% by weight. And 25% by weight of TeCP are uniformly dispersed and melted in a compression molding machine to obtain a cylindrical billet having a diameter of 13.0 mm, a length of 40 mm, and a viscosity average molecular weight of 250,000. It was.
Next, as shown in FIG. 3, the billet containing TeCP at 15% by weight is in the same mold as in Reference Example 3, and the one containing 25% by weight of TeCP is the same as in Example 5. Inside, press-fitting was performed under the same method and conditions as in Reference Example 1 to obtain TeCP / PLLA compression-oriented molded bodies in which Te is uniformly dispersed and R is 3.5 and 3.0, respectively. However, θ = 15 °.
Table 9 shows the obtained TeCP / PLLA composite compression-oriented molded body and HA / PLLA of R = 3.5 in which HA of Reference Example 3 (fired at 900 ° C.) is dispersed by 15% by weight. The physical properties of the composite compression-oriented molded product of No. 5 and the compression-oriented molded product of R = 3.0 in which α-TCP of Example 5 is dispersed by 25% by weight were compared.

The obtained molded body is different in the type of bioceramics from those of Reference Example 3 and Example 1, but the content rate and R are the same. However, each molded body had almost the same strength. When R was 3.5, it exceeded 300 MPa, indicating extremely high bending strength.

(Example 5) <Compression molding; Example 9>
Using PLLA having a viscosity average molecular weight of 600,000 and anhydrous dicalcium phosphate (anhydrous calcium phosphate-DCPA) having a maximum particle size of 40.0 μm and an average particle size of 5.60 μm, the same method as in Reference Example 1 PLLA granules in which 45% by weight of DCPA is uniformly dispersed under the conditions are obtained and melted in a compression molding machine to obtain a cylindrical billet having a diameter of 8.0 mm, a length of 40 mm, and a viscosity average molecular weight of 460,000. Obtained.
Next, as shown in FIG. 3, the same method and conditions as in Reference Example 1 were placed in a molding die in which this billet was connected to a housing cylinder having a diameter of 8.0 mm and a cavity having a diameter of 5.7 mm and a length of 76 mm. Then, a DCPA / PLLA composite compression oriented molded body of R = 2.0 in which DCPA was uniformly dispersed was obtained. However, θ = 45 °.
Table 10 shows the physical properties of the obtained compression-oriented molded body.

Although this molded article has a high viscosity average molecular weight, it can be plastically deformed by press fitting, has high bending strength and elastic modulus, and has high strength and toughness.

(Example 6) <Compression molding; Example 10>
Using PLLA having a viscosity average molecular weight of 400,000 and octacalcium phosphate (OCP) having a maximum particle size of 22.0 μm and an average particle size of 8.35 μm, 10 wt% and 20 wt% in the same manner as in Reference Example 1. PLLA granules in which weight percent OCP was uniformly dispersed were obtained and melted by a compression molding machine to obtain a cylindrical billet having a diameter of 13.0 mm, a length of 40 mm, and a viscosity average molecular weight of 250,000.
Next, a billet containing 10% by weight of OCP is placed in a molding die in which a housing cylinder having a diameter of 13.0 mm and a cavity having a diameter of 6.1 mm are connected, and a billet containing 20% by weight of OCP is contained in a housing cylinder having a diameter of 13.0 mm. And a mold having a diameter of 6.5 mm connected to each other by press-fitting in the same manner and conditions as in Reference Example 1, and OCP having uniformly dispersed R is 4.5 and 4.0, respectively. / PLLA composite compression oriented molded body was obtained. However, θ = 15 °.
Table 11 shows the physical properties of the obtained compression-oriented molded body.

All the molded bodies were high-strength molded bodies having a bending strength of 300 MPa or more. The OCP 20 wt% molded body had a lower R than the OCP 10 wt% molded body, but exceeded both strength and elastic modulus. However, since the pressure at the time of press-fitting is large, a pressure of about 10,000 kg / cm @ 2 was required.
As a control example, an OCP 10 wt% billet, which is relatively easy to press-fit, was press-fitted into a mold such that R = 5.5. However, the pressure at the time of press-fitting required a pressure higher than 10,000 kg / cm @ 2, and the obtained molded product had many cracks. From this, it can be said that the degree of deformation R for compressive orientation of PLLA containing bioabsorbable bioceramics is desirably 5 or less.

(Reference Example 5) <Compression molding; Example 12>
Copolymer of lactic acid-glycolic acid [P (LA-GA)] (molar ratio 90:10) having a viscosity average molecular weight of 380,000 and HA (900 (900)) having a maximum particle size of 31.0 μm and an average particle size of 1.84 μm (Combined compression of R = 2.8 HA / P (LA-GA) in which 30% by weight of HA is uniformly dispersed under the same method and conditions as in Reference Example 1). An oriented molded body was obtained. However, θ = 15 °.
Table 12 compares the physical properties of the obtained molded body and a compression-oriented molded body of only P (LA-GA) as a comparative example.

The obtained molded product was slightly lower in strength than the PLLA shown in Reference Example 1. However, it is sufficiently useful as an implant material.

(Reference Example 6) <Forging molding;>
Hydroxyapatite (HA) having a maximum particle size of 31.0 μm, a minimum particle size of 0.2 μm, and an average particle size of 1.84 μm in a solution of 4% by weight of poly L-lactic acid (PLLA) having a viscosity average molecular weight of 400,000 in dichloromethane. ) (Fired at 900 ° C.) was added and stirred to uniformly disperse HA without causing secondary aggregation. Further, ethyl alcohol was added with stirring to coprecipitate PLLA and HA. Then, this was filtered and completely dried to obtain PLLA granules in which HA having the above particle diameter was uniformly dispersed at a ratio of 30 to 40% by weight.
This was melt extruded at 185 ° C. with an extruder to obtain a cylindrical billet having a diameter of 13.0 mm, a length of 40 mm, and a viscosity average molecular weight of 250,000.
Next, as shown in FIG. 5, this billet is put into a receiving cylinder portion of a disk-shaped molding die having a diameter of 100 mm and a thickness of 10 mm, and a cylinder having a diameter of 50 mm protrudes from the center, heated to 100 ° C. Was subjected to intermittent forging at a pressure of 3,000 kg / cm @ 2 to obtain a molded body by HA / PLLA combined forging pressure orientation having the same size as the disk-shaped portion of the mold.
A test piece was cut out from the molded body in the radial direction excluding the cylindrical portion, and the physical properties were measured. As a result, the bending strength was 220 MPa, the bending elastic modulus was 7.4 GPa, the density was 1.505 g / cm @ 3, and the crystallinity was 43.0%.
The formed body by this forging orientation is considered to be an oriented body in which the crystal planes are different from those in the above embodiments, and the orientation axes are oriented in multiple axes from the disk-shaped central portion toward the outer peripheral direction.

(Reference Example 7) <Example of cutting: surface observation and change over time>
Each HA / PLLA composite compression-oriented molded body obtained in Reference Example 1 was cut with a lathe, a screw having an outer diameter of 4.5 mm, a valley diameter of 3.2 mm, a length of 50 mm, and a diameter of 3 Processed into a pin with a length of 2 mm and a length of 40 mm.
Moreover, using the PLLA granule in which 30% by weight of HA of Reference Example 1 is dispersed, a billet extruded into a plate shape by an extruder is obtained, and an accommodating cylinder portion having a rectangular cross section (plate shape) and A plate-shaped molded body with R = 2.8 was obtained by press-fitting into a mold having a cross-sectional rectangular cavity with a smaller cross-sectional area connected in the same manner and under the same conditions as in Reference Example 1. The surface of this molded body was cut with a slicing machine to obtain a plate having a thickness of 2.0 mm, a length of 20 mm, and a width of 5 mm.

The surfaces of the screw, pin, and plate were observed with a scanning electron microscope. All of the cut processed products were exposed in a state where fine particles were uniformly dispersed without forming HA on the surface to form a large aggregate. In addition, it was observed that the inside was similarly uniformly dispersed. And as these HA contents increased, more HA appeared on the surface.
It was also confirmed that such an implant was dense and free of voids, and that the bioceramics and the polymer were in good physical contact with each other. This is because the material of the present invention has high mechanical strength, and the living bone is bonded to the bone by direct contact with the bioceramics, maintaining it for the period necessary for bone healing, and bone conduction or bone replacement is effective. Indicates the basis for what is being done.
In addition, the pressure-oriented molded body in which the high-strength polymer / bioceramics obtained in the examples or the reference examples are composited in an aggregate liquid at 37 ° C. for 2 to 4 months has almost the same strength. It was confirmed that it was maintained. After that, although the degradation behavior differs depending on the composition and structure of the material, it is possible that after bone fusion, the bone is replaced and bone-removed faster than the polymer alone.
It was confirmed in vivo.

It is a schematic diagram which shows the crystal state of the cylindrical implant material of this invention. FIG. 1 (a) shows a longitudinal sectional view, and FIG. 1 (b) shows a plan view. It is a schematic diagram which shows the crystal state of the plate-shaped implant material of this invention. FIG. 2 (a) shows a longitudinal sectional view, and FIG. 2 (b) shows a plan view. It is the longitudinal cross-sectional view which showed typically the shaping | molding model by the compression orientation which is an example of press molding, and shows the state before press-filling a billet. It is the longitudinal cross-sectional view which showed typically the shaping | molding model by the compression orientation shaping | molding which is an example of pressure forming, and shows the state after press-filling a billet. It is the longitudinal cross-sectional view which showed typically the shaping | molding model by forge orientation shaping | molding which is another example of pressure forming. It is a schematic diagram which shows the internal structure which compared the composite material of this invention and the conventional composite material about the reinforcement | strengthening system of a composite material.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Billet 2 Mold 2a Accommodating cylinder part 2b Pressurizing means 2c Cavity 20a Reduced diameter part 3 Implant material

Claims (6)

In a polylactic acid matrix that is biodegradable and absorbable, unburned hydroxyapatite powder that is a bioabsorbable bioceramic having a primary particle or aggregate size of primary particles of 0.2 to 10 μm is 10 to 60 wt. % Is substantially uniformly dispersed, and the degree of crystallinity is 10 to 70%. In a polylactic acid matrix that is biodegradable and absorbable, unburned hydroxyapatite powder, which is a bioabsorbable bioceramic having a primary particle or aggregate size of primary particles of 0.2 to 10 μm, is 20 to 50 weights. % Is uniformly dispersed, the crystallinity is 10 to 70%, and the density is 1.4 to 1.8. The composite osteosynthesis material according to claim 1 or 2, wherein the osteosynthesis material has a bending strength of 150 to 320 MPa and a flexural modulus of 6 to 15 GPa. The composite bone bonding material according to claim 1 or 2, wherein the bone bonding material has a tensile strength of 80 to 180 MPa, a shear strength of 100 to 150 MPa, and a compression strength of 100 to 150 MPa. . The composite osteosynthesis material according to any one of claims 1 to 4, wherein the osteosynthesis material does not have a void. The composite osteosynthesis material according to any one of claims 1 to 5, wherein the residual monomer amount of the osteosynthesis material is 0.5% by weight or less.