JPWO2018115128A5 - - Google Patents

Description

The technical field to which the invention belongs The present invention relates to a porous implant mass composition for treating a defect in a living body such as a bone defect and a tooth extraction wound, and further relates to the production thereof. More specifically, the present invention relates to novel optimized shapes and pore structures that are mechanically stable but allow for highly porous bone graft substitutes.

Background Bone fillings are important in many areas such as orthopedics, dentistry, traumatology and orthodontics. Such bone filling materials are used, for example, to fill holes remaining after removal of bone tumors, to fill bone defects after fractures, to fill voids remaining after tooth extraction, and before implant placement for dental or orthopedic surgery. It is used to strengthen bones or to act as a carrier for antibiotics or bone-forming substances.

Bone grafts can be classified based on their origin, i.e., autologous materials in which the living body's own bone is used, and bone graft substitutes in which the material comes from another source. Specific bone graft substitutes include allogeneic transplant (human-derived) materials, xenograft (animal-derived) materials and synthetic materials.

Autologous transplant materials are bone-inducible, bone-conducting, and have excellent healing power, but the amount that can be collected is limited, and the morbidity of the donor site and the associated pain frequently occur in patients .

For these reasons, bone graft substitutes are commonly used. Bone from allogeneic and xenografts is osteoconducting and has a bone structure similar to that of natural bone. However, the disease can be transmitted. Synthetic bone grafts can avoid the risk of transmission of the disease and are available in unlimited amounts. They also provide greater freedom in designing and optimizing bone graft substitutes for good bone conduction.

For good bone conduction, it is important that the material of the graft is in close contact with the bone wall. To achieve this, it would be advantageous if the bone graft material could be formed directly into the required shape during surgery. For this reason, bone graft substitutes are best offered as loose granules that can adapt to the contours of any defect.

Allogeneic and heterologous implants usually consist of trabecular bone fragments, and many synthetic bone graft substitutes attempt to mimic the natural trabecular structure of bone fragments, which is the trabecular structure. This is because it provides a lot of space between bone fragments for inward bone growth. Unfortunately, these trabecular structures are so fragile that it is a major challenge to form them in the required shape with sufficient pressure without destroying them.

To increase the stability of the granules, the walls can be compressed or the porosity within the granules can be reduced. However, either method reduces or eliminates inward growth of bone tissue. It was found that the use of spherical granules with a homogeneous internal porosity increased resistance to breakage when placed in the defect. However, spherical granules do not provide much of the natural intergranular space desired for optimal inward bone growth. When round balls of the same size are densely arranged in a grid pattern, the porosity that can be calculated is only 26%. This can be further reduced by mixing small and large granules. As described in WO-A-2005 / 107826 (Maspero et al.), WO 2005/107826, 40% of spherical granules in the range of 500 μm to 1000 μm capable of adhering to each other. An intergranular space is obtained.

In U.S. Pat. No. 6,302,913 (US 6'302'913 B1) (Ripamonti et al.), We describe the advantages of implants with surface recesses accessible to surrounding tissue. .. Their study shows rapid bone formation in a cavity named "endogenous bone-inducing activity". They suggest that bone formation can be triggered simply by providing a specific surface shape (recess of size 300-3000 μm). However, all studies were performed using modifications to the surface of discs, rods or dental implants.

US Patent Application Publication No. 2016/018439 (US-2016 / 0184390) describes synthetic bone graft materials based on calcium ceramic granules, osteoconducting proteins, and biocompatibility matrices. The calcium ceramic granules are located in a biocompatible matrix and have a specific surface area greater than about 30 m ² / g.

Therefore, what is desired for optimal bone regeneration results is a granular material that allows contact with the surrounding bone wall when placed in the defect. The granules are preferably mechanically stable so that they do not break upon insertion. The granules are preferably microporous for moisture absorption. The mass preferably forms an interconnected, highly porous scaffold with large mesh pores between the granules. Ideally, the granules have surface recesses and preferably combine with each other to form a mechanically stable mass.

Outline of the Invention The implant according to the invention solves the above-mentioned problems by providing a bone conduction biocompatible bone graft substitute. Bone graft substitutes combine substantially high mechanical stability of spherical porous granules without the limitation of reduced intergranular space. The internal structure of the granules has a high porosity while maintaining high stability, allowing the granules to be pushed into the defect without causing significant damage to the granules, while at the same time the bone cells are the space between the granules. Can grow into.

In an exemplary embodiment of the invention, the surface of the granule has a dent when viewed from the outside of the granule. The depression significantly increases the porosity in the implanted mass, thus providing more space between the granules for the inward growth of the tissue. Due to the indentations on the granules, the granules have an irregular shape and thus an increase in intergranular space is achieved while maintaining mechanical stability.

In one embodiment of the invention, the granules are attached to each other. They are coated with a very thin layer of biocompatible and absorbent thermoplastic polymer. Bonding can be achieved by using a solvent or a plasticizer such as pressurized CO ₂ that lowers the glass transition temperature (Tg) of the coating. Subsequent condensation of the granular mass will result in the coatings abutting against each other, or the coating of one granule becoming a mass of another. When the granules are pushed into the defect, the mass can adapt to the shape of the defect and thus to the bone wall. When the plasticizer is removed from the mass and Tg rises again, the aforementioned mass hardening occurs, thus forming a stiff implant.

In one embodiment of the invention, the granules are bound together at several points of contact only to allow for the largest interconnected pores within the mass. Such implant compositions according to the invention form an open porous scaffold or composite matrix that allows inward growth and regeneration of bone tissue.

In one embodiment, the granules have a specific surface area of less than 20 m ² / g, preferably less than 10 m ² / g, more preferably less than 5 m ² / g, most preferably less than 3 m ² / g.

In one embodiment of the invention, the granules can withstand an average compressive force of at least 1N, ensuring that the granules do not break during insertion.

In an exemplary embodiment, the moldable implant composition of the invention comprises a plurality of biocompatible granules mixed with a biocompatible polymer and a plasticizer for the polymer. The plasticizer is contained in an amount sufficient to prepare at least a portion of the biocompatible polymer so that the implant mass can be molded (ie, plastically deformable). The implant mass can be inserted into the bone defect, where the implant mass can be deformed to take the shape of the defect. The moldable implant composition can be deformed, molded, and / or engraved to have a particular shape, either in situ or in situ.

In one embodiment of the invention, the plasticizer is selected to work with the curing agent. When the hardener is applied to a moldable implant composition, the effect of the plasticizer is neutralized and the implant composition hardens, thereby providing adequate structural support. In an exemplary embodiment, the plasticizer is partially soluble in an aqueous solution such as body fluid, so that the body fluid acts as a curing agent by extracting at least a portion of the plasticizer from the implant composition. Can be.

In one aspect of the invention, the softened implant composition is moldable but not flexible enough to flow like a liquid (ie, not fluid but plastically deformable). The advantage of a deformable implant is that its hardness allows the implant to remain in the desired shape until the hardener coagulates it.

In another embodiment of the invention, the implant composition is fluid and can take the form of an implant site or molding. This aspect of the invention may be advantageous when the desired implant shape is complex and / or difficult for the practitioner to form. By making the implant fluid, the implant mass can facilitate the shape of the implant site or molding.

The moldable implant composition can also be molded ex-site using a molding die. The moldable implant composition of the present invention can be easily transformed into a mold shape and then rapidly cured using a curing agent. Molding and curing the implant composition in a mold according to the method of the invention can save valuable time during surgery, thereby reducing costs and risks. For example, after tooth extraction, a mold can be used in Excitu to make a copy of the root. The implants of the present invention provide the practitioner with the ability to select the best method for a particular situation.

In another embodiment of the invention, the granules are formed from bone tissue compatible ceramic, mostly made of calcium phosphate or other calcium based minerals. Implants made of calcium phosphate ceramics according to the present invention have (i) the ability to develop direct adhesion and binding to existing bone tissue; (ii) the ability to promote cell function and expression; (iii) form new bone. The ability to prepare scaffolds or templates for the purpose; and (iv) show performance such as the ability to promote bone formation and act as a carrier for bioactive substances.

In another embodiment of the invention, the granules are formed from synthetic biomaterials such as β-tricalcium phosphate, hydroxyapatite, mixtures thereof, or other synthetically produced calcium phosphate phases.

These and other features of the invention will be more fully apparent from the claims and attachments below.

BRIEF DESCRIPTION OF THE DRAWINGS To further clarify the above and other advantages and features of the invention, a more detailed description of the invention is provided by reference to the particular embodiments shown in the accompanying drawings. Will be done. It should be understood that these drawings show only typical embodiments of the present invention and therefore should not be considered to limit their scope.

FIG. 1 shows a typical spherical granule containing calcium phosphate produced without modification as described in the present invention. Figures 2a-2c show exemplary implant compositions according to the invention with indentations of a size that increases relative to the size of the granules; the granules are made at constant pressure with pologens within various size ranges. .. FIGS. 3a and 3b illustrate more exemplary implant compositions according to the invention, in which the granules are made with porogen within a single size range and various pressures. FIGS. 4a-4d show samples made with cylindrical granules with indentations of a size that increases relative to the size of the granules, where the granules are at constant pressure with porogen within various size ranges. Manufactured. FIGS. 5a-5c illustrate the measurement of intergranular space. FIG. 6 shows the results of analyzed intergranular porosity of spherical granules without pits and granules with exemplary pits as described herein. FIG. 7 shows an applied test method in which the destructive force of granules according to the present invention is measured. FIG. 8 shows the results of a granule destructive force comparative test according to the present invention against commercially available granules. FIG. 9 shows that at least 75% of the pores between the sintered particles have a diameter of about 1 to about 10 μm, as measured by mercury intrusion porosymmetry.

Detailed Description of Drawings According to FIGS. 2a-2c, the granules according to FIG. 1 were modified by adding indentations from the outside. The porogen used was cellulose spheres. The applied pressure was 100 MPa. To make these exemplary embodiments, spherical porogens of different sizes, ie 100-200 μm as shown in FIG. 2a, 200-355 μm as shown in FIG. 2b, and 355-500 μm as shown in FIG. 2c. used.

According to FIGS. 3a and 3b, the granules according to FIG. 1 were modified by adding indentations from the outside. The porogen used was cellulose spheres. The size of the porogen was selected to be in the range of 355-500 μm. The applied pressure was either 10 MPa as shown in FIG. 3a or 26 MPa as shown in FIG. 3b.

Figures 4a-4d demonstrate the effect of different sized cellulose spheres on cylindrical granules, from small indentations to large strains in cylindrical granules. The applied pressure is 100 MPa and the size of the cellulose spheres used is 100-200 μm as shown in FIG. 4a, 200-355 μm as shown in FIG. 4b, 355-as shown in FIG. 4c. It was selected to be in the range of 500 μm, 710 to 1000 μm as shown in FIG. 4d.

According to FIGS. 5a-5c, the intergranular space was measured by image analysis of 3D reconstituted micro CT slices through a defined cylindrical volume filled with granules. Porosity inside the granules was not measured, only the pores between the granules were analyzed. a) Micro CT slices through the implant mass, b) Removal of pores in the granules by adjusting the contrast of the image, c) Generation of a 3D model. Intergranular porosity is calculated by volumetric measurement using a 3D model.

According to FIG. 7, a single granule of average size and average shape was selected and placed in a mechanical test device. A cell with a load of 10 N was used and the granules were loaded at a rate of 1 mm / min until the granules broke.

According to FIG. 8, the results show that the mechanically destructive force of the granules produced according to the present invention is a highly porous competing product (Bio-Oss® (Geistrich, Switzerland), Cerasorb® M. (Curasan AG, Germany), BoneCeramic ™ (Straumann, Switzerland)) is significantly higher , indicating no reduction compared to pitless spherical granules.

According to FIG. 9, mercury intrusion porosymmetry measurements were used to demonstrate that in the granules according to the invention, the pores between the sintered particles in the granules are homogeneous . That is, the average diameter of at least 75% of the pores is between about 1 and about 10 μm.

Description of Exemplary Embodiments Embodiments of the present invention include a formable implant composition for repairing a bone defect or wound. The moldable implant composition is formed from a plurality of particulate granules. The biocompatible polymer is placed around or coated on the granules. The granules and polymer are filled or aggregated to form an implant mass, and the polymer is softened with a plasticizer to make the implant mass formable or fluid. Implant mass is shaped or engraved to form a bone implant that fills a particular bone defect or structural void. The implant composition is then cured or caused to cure. As more fully described below, the order and timing of (i) softening the polymer, (ii) forming the implant mass, and (iii) forming the implant mass are various of the present invention. It can change according to various embodiments.

So far, such implant compositions have required constant mechanical strength granules to allow (i) non-destructive coatings and (ii) non-destructive insertion and condensation into the defect. The product can only be manufactured by using spherical granules. However, this limits the porosity between the granules and reduces the amount of open space available to the tissue after insertion of the implant mass. According to the present invention, the present inventors have found how the pores between particles can be increased by adding surface recesses without significantly reducing the mechanical properties.

I. Components of Implant Composition Here, various components of the implant according to the present invention will be described.

In an exemplary embodiment, the invention comprises biocompatible granules, which are hard materials that provide structural support or physiological benefits to the implant mass. Granules can be made of synthetic, natural, polymeric or non-polymeric materials. In one embodiment, the granules are also degradable so that the implant decomposes over time and / or replaces natural bone tissue.

The biocompatible granules of the present invention are synthetic biocompatible materials such as biopolymers, bioglasses, bioceramics, more preferably calcium sulfate, silicon oxide, calcium phosphate, such as monocalcium phosphate monohydrate, anhydrous. Monocalcium Phosphate, Dicalcium Phosphate Anhydride, Dicalcium Phosphate, Tetracalcium Phosphate, Calcium Orthorate, Calcium Pyrophosphate, α-Tricalcium Phosphate, β-Tricalcium Phosphate (β-TCP), Apatite, For example, hydroxyapatite (HA), or polymer, such as poly (α-hydroxyester), poly (orthoester), poly (ether ester), polyanhydride, poly (phosphazene), poly (propylene fumarate), poly. (Esteramide), Poly (ethylene fumate), Poly (amino acid), Polyhydride, Polypeptide, Poly (Hydroxybutyrate), Poly (Hydroxyvalerate), Polyurethane, Poly (Apple acid), Polylactide, Polyglycolide, It can be made from polycaprolactone, poly (glycolid-co-trimethylene carbonate), polydioxanone, or copolymers thereof , their terpolymers or blends of their polymers , or combinations of biocompatible and degradable materials.

The biocompatible granules of the present invention can be made of naturally occurring materials such as xenografts or allografts or other animal or human-derived hard materials. As will be apparent to those of skill in the art, such materials can be ground into small particles and then granules can be made using known granulation and sintering techniques.

Calcium phosphate ceramics are biocompatible and can be used in a variety of biomedical applications. Hydroxyapatite and β-TCP bioceramics and biphasic ceramics made from them are particularly useful materials because they are similar in ionicity to the mineral component of bone. In addition, their absorption rate can be controlled according to the needs of a specific treatment method. Furthermore, because β-TCP is degradable, it can be absorbed in vivo and replaced with newly formed bone.

In another embodiment of the invention, the granules have interstitial pores within the granules that allow the uptake of body fluids. Body fluids contain proteins and factors that help tissue regeneration. The use of porous granules reduces the amount of implantable material and allows for better in situ incorporation.

Thus, in one embodiment, the pores have an average homogeneous diameter of about 1 μm to about 10 μm. Homogeneity means that the granules have a homogeneous surface porosity defined by having a diameter of at least 75% of the pores having a diameter of about 1 to about 10 μm, as measured by mercury intrusion porosity. do.

In an exemplary embodiment, biocompatible granules with a ferret diameter of about 100 μm to about 4000 μm, preferably about 500 μm to about 1000 μm are selected.

The term ferret diameter indicates that the granules can be irregularly shaped, but it may be advantageous to use regularly shaped granules, such as spherical granules with indentations. For some applications, spherical granules are easier to handle and more easily estimate the amount required to fill a cavity of known volume. Granules of spherical or other regular shape and / or size form a more uniform pore structure or scaffold between adjacent particles. However, the drawback of the orderly structure is the low intergranular porosity. Therefore, this can be advantageous if the granules have an irregular shape. Irregular shape means that substantially any granule is not substantially spherical and has, for example, the shape of a rod, tip, tripod, or is distorted as described in detail by the present invention. It means that it is a granule.

Preferably, the granules have an irregular surface. This simulates the natural bone structure and helps bone cells grow more effectively in the matrix.

An example of how such granules can be produced is described below. 155 grams of β-TCP and a particle size of 1 μm to 30 μm to form spherical granules of biphasic calcium phosphate with a ratio of 60% hydroxyapatite (HA) and 40% β-tricalcium phosphate (β-TCP). 232.5 g of HA powder having the above was mixed with 112.5 g of cellulose in a powder mixer. 250 ml of deionized water was slowly added to the powder mixture with continuous stirring. The obtained mass was extruded through a multi-hole 800 μm nozzle and sphericalized in a pellet rounder for 3 minutes to obtain granules having an average diameter of about 350 μm to about 1000 μm. Then, the obtained green granules were sintered at 1100 ° C. for 8 hours.

Other methods such as high shear mixing and fluidized bed granulation may also be used to produce spherical granules. An example of how such granules can be produced by fluidized bed granulation is described below. In order to form β-TCP granules, 1.5 kg of β-TCP powder having a particle size of 1 μm to 30 μm was placed in a fluidized bed granulator together with 500 g of cellulose. The powder mixture was fluidized with a suction air stream of 160 cubic meters per hour and the polyvinylpyrrolidone solution was sprayed onto the vessel to agglomerate the particles at a spray rate of 50 grams per minute. After 25 minutes, granules with an average diameter of about 350 μm to about 1000 μm were obtained. The obtained β-TCP green granules were then sintered at 1100 ° C. for 8 hours.

Within the scope of the invention, the granules have a regular or irregular surface and shape, including pits. Preferably, the indentation is a recess or dimple. Indentations on the surface of the granules can be obtained by pushing the porogen into the surface of the granules in an uncured state (in the above example, this would mean before the sintering process). Depending on the shape of the porogen, dents of various shapes can be obtained. Preferably, the porogen is spherical to provide a concave depression. The concave feature preferably covers at least 25% of the surface of the granules. More preferably, the concave features preferably cover at least 50% of the surface of the granules (see FIGS. 2-4).

According to a preferred embodiment, a method for producing a porous implant composition used for repairing a defect in vivo, comprising a plurality of biocompatible granules, wherein at least a portion of the granules has a surface depression. ,
-Producing granules and mixing the granules with Porogen;
-Pushing porogen onto the surface of at least part of the granules;
-Contains to remove the porogen from the implant mass so that a dent remains on the surface where the porogen comes into contact with the granules.

An example of how such a depression can be formed on the surface of a spherical granule is described below. Green granules were used immediately after production. Cellulose spheres in the size range of 350-500 μm were mixed with the still wet spherical green body in a Turbula mixer at 25 rpm for 7 minutes.

The mixture thus obtained was filled in a cylindrical container and pressed with a hydraulic press at 16 to 24 MPa for 2 minutes. Cellulose spheres were thus pushed onto the surface of the green granules. The pitted granules were then dried overnight at 70 ° C. on a drying shelf. The obtained green granules were then sintered at 1100-1200 ° C. for 4-8 hours. After sintering, the granules were classified to obtain granules having an average diameter of about 500 to 1000 μm.

Further examples of how such depressions can occur on the surface of stick-shaped non-spherical granules are described below. Although not rounded but oven-dried, green granules as described above were used. Cellulose spheres of various sizes, about 100-1000 μm, were mixed with the greens. The mixture thus obtained was filled in a cylindrical container and pressed twice for 1 minute at 100 MPa with a hydraulic press. The recessed stick thus obtained was then dried overnight at 70 ° C. on a drying shelf. The obtained green body was then sintered at 1100-1200 ° C. for 4-8 hours.

Porogens that can be used in the present invention can be any natural or synthetic material that can be removed from the implant composition by burning, melting, dissolving, leaching or mechanical removal. The porogen residue in the final product should be low enough to allow for biocompatibility of the implant composition. Examples of porogens are polysaccharides and their derivatives such as cellulose, microcrystalline cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylmethyl cellulose acetate succinate (AQOAT), ethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate. , Hydroxypropylmethylcellulose phthalate, croscarmellose, starch, processed starch; sodium glycolate starch, pregelatinized starch. Examples may also be synthetic polymers and copolymers made thereof, such as polymethylmethacrylate, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylpyrrolidone, polyvinyl alcohol, silicones, polylactide and polyglycolide. Further examples may be salts such as sodium chloride, potassium chloride, sodium hydrogen carbonate. Further examples may be ice or frozen material.

Porogen can be used alone or in combination with two or more excipients, if desired. Preferably, the salt can be removed by leaching, the polymer and polysaccharide can be removed by burning, the frozen material can be removed by melting, and the polymer can be removed by melting.

To analyze the increase in intergranular porosity achieved by this novel method, intergranular porosity was measured by image analysis of 3D reconstituted micro CT slices through a defined cylindrical volume filled with granules ( FIG. 5). The implant composition containing spherical granules had an intergranular porosity of 40%, whereas the addition of pits using the above experiment resulted in a 51% intergranular porosity, which was 27.5%. Corresponds to an increase in intergranular porosity (Fig. 6).

To measure the mechanical stability of the granules, a single granule of average size and shape was selected and placed in a mechanical test device (FIG. 7). The mechanical destructive power of the granules according to the present invention was compared with that of commercially available granules. At least 20 granules were tested per product. The results were as follows: Competitive products such as Bio-Oss® (Registered Trademark) (Geistrich, Switzerland), Synthetic Porous Cerasorb® M (Curasan, Germany), a heterogeneous bone trabecular graft material. (Country) as well as the synthetic bone trabecular shape BoneCeramic ™ (Straumann, Switzerland) showed destructive power well below an average of 1N. Spherical granules with concentrated internal pores in the center of the granules showed an average destructive power of 1.5N. The method described in the present invention increased the intergranular porosity from 40% to 51% without reducing the force at break.

The results show that granules produced according to the present invention have significantly higher average mechanical destructive power, which is not significantly reduced compared to highly porous spherical granules compared to highly porous spherical granules. show.

The implant composition of the present invention may also include a biocompatible polymer placed around the granules to form an implant mass. In one embodiment, some or all of the granules are coated with a biocompatible polymer. In an exemplary embodiment, the biocompatible polymer is also degradable to facilitate absorption into the body when the implant is replaced by newly formed biological tissue.

Biocompatible and preferably absorbent polymers suitable for use in the present invention include poly (α-hydroxyester), poly (orthoester), poly (ether ester), polyanhydrous, poly (phosphazene), poly. (Protein fumarate), poly (esteramide), poly (ethylene fumarate), poly (amino acid), polysaccharide, polypeptide, poly (hydroxybutyrate), poly (hydroxyvalerate), polyurethane, poly (apple acid) ), Polylactide, polyglycolide, polycaprolactone, poly (glycolid-co-trimethylene carbonate), polydioxanone, or copolymers thereof, terpolymers, or blends of polymers thereof.

The synthetic biocompatible granules can preferably be spray coated with a fluidized bed device or dip coated with the desired biocompatible polymer. Both methods result in biocompatible granules with advantageous properties.

The spray coating process in the fluidized bed device allows the production of large numbers of biocompatible granules coated with nearly identical polymers in a very fast and economical manner. A fluidized bed process can be used to control the thickness of the coating layer to produce biocompatible granules with multiple coating layers that differ from each other. Coating with a fluidized bed device provides a homogeneous and continuous coating. During the coating process, the granules do not stick to each other, thus avoiding the formation of unwanted aggregates that can lead to a highly heterogeneous size distribution and coating thickness.

Incorporation of additives such as plasticizers or biologically active substances into the coating can be readily controlled by fluidized bed devices. Therefore, each granule is loaded with the same amount of biologically active substance. The thickness of the coating is also easily controlled. Therefore, the release of incorporated biologically active material is also predictable and well controlled.

The coating of biocompatible granules may include one or more layers of various average thicknesses. This embodiment of the invention makes it possible to provide biocompatible granules with several coatings for a particular purpose. The outermost degradable coating can be selected according to a certain desired degradability delay. This can delay, for example, the delivery of the biologically active substance. Thus, synthetic biocompatible granules can be coated with different coatings, each of which is degradable and exerts a particular effect.

The biocompatible polymer coating preferably has a thickness of about 1 μm to about 300 μm, preferably about 5 μm to about 30 μm. The coating thickness of the granules can also be expressed as a weight fraction of the coating material from about 4% to about 20% of the total weight of the implant mass, which can be loaded with additives such as plasticizers or biologically active substances. Those skilled in the art will recognize that different coating layers with different thicknesses can be applied to the granules by selecting different coating solutions and varying the coating time.

The mechanical stability of implants made from coated granules can depend on the thickness and homogeneity of the coating. If the coating thickness is insufficient, the granules may not stick to each other. On the other hand, if there is too much coating, the pH around the implant can drop as the implant deteriorates. Whether the thickness of the coating adversely affects the performance of the implant depends on the application of the implant.

As described above, it is beneficial to have a moldable mass in order for the implant mass to fit well into the defect. This can be achieved by adding a plasticizer to the biocompatible polymer and lowering the glass transition temperature (Tg) of the polymer. In one embodiment, the biocompatible polymer and plasticizer are selected to function in a polymer-solvent system. Biocompatible polymers are selected to have the desired flexibility and tackiness when partially dissolved or softened in a particular plasticizer. When the plasticizer is removed (eg, by evaporation or diffusion into the body), the biocompatible polymer cures to form a hard bone implant. Polymers and plasticizers are selected to give the implant a certain degree of rigidity when softened and cured. The plasticizer can be a liquid or a gas such as pressurized CO ₂ .

Plasticizers are preferably biocompatible or exhibit very low toxicity, so that the implant can be safely present in the bone implant once it is placed in the patient. Suitable plasticizers include n-methyl-2-pyrrolidone (NMP), acetone, ethyl lactate, ethyl acetate, ethyl formate, acetyltributyl citrate, triethyl citrate, tetrahydrofuran, toluene, alcohol, and carbon dioxide. , Not limited to these. Those skilled in the art will recognize that the plasticizers of the invention can be one or a combination of many other solvents that condition the biocompatible polymers of the invention.

In an exemplary embodiment, the plasticizer is a solvent that is soluble in an aqueous medium ranging from miscible to dispersible. Thus, the plasticizer can diffuse into aqueous media or body fluids such as tissue fluids such as serum, lymph, cerebrospinal fluid, and saliva. When the plasticizer diffuses from the implant mass, the bone implant hardens. In this way, the body fluid can be used as a sclerosing agent for in situ solidifying the bone implant site.

Bone implants can also be excitedly cured by withdrawing a plasticizer from the polymer. In one embodiment, the plasticizer is selected to be partially soluble in water. When the implant is molded in an exciter, such as in a mold, water is placed in the implant, thereby extracting the plasticizer and hardening the bone implant. Alternatively, the plasticizer can be removed by evaporation (eg, heating and / or application of vacuum).

Solubility or miscibility of a degradable polymer to a particular plasticizer can vary depending on factors such as crystallinity, hydrophilicity, hydrogen bonding ability, and molecular weight. As a result, the molecular weight and concentration of the biocompatible polymer can be adjusted to adjust the solubility of the plasticizer. As mentioned above, in order to form a formable implant, the polymer-plasticizer system is designed so that the plasticizer softens the polymer but does not liquefy the polymer, thereby creating a sticky, flexible mass. Has been done.

In one embodiment, the polymer-solvent system is designed to reduce the Tg of the biocompatible polymer to a temperature below room temperature. For example, acetone , NMP, or alcohol is added to the polylactic acid glycolic acid (PLGA) until the Tg of PLGA is from about 45-55 ° C to below room temperature. Similarly, other polylactides having a Tg in the range of 40-65 ° C. and their copolymers can be lowered to below room temperature with a plasticizer.

In another embodiment, the bone implant can be shaped and / or molded without a plasticizer if it is made above Tg. Thus, in this embodiment, the implant can be heated above Tg to allow the implant to be moldable for implantation in a person or mold without a plasticizer. Bone implants, when molded at temperatures above 37 ° C., harden as the temperature decreases. It is a prerequisite that the Tg of the polymer is higher than the body temperature (37 ° C.), which is the case with some of the above polymers.

According to one embodiment of the invention, the bone implant has macropores and / or micropores that form an open porous scaffold or composite matrix. The term "open porous scaffold" or "composite matrix" defines an open porous region containing a granular region containing solid or porous granules and a space or discontinuity between adjacent granules of the granular region. Refers to the structural matrix of granules bonded or joined together so as to. The open porous region can be at least initially filled with air or gas, or at least partially filled with liquids, solid particles, gels, etc.

Scaffolds or composite matrices can be obtained by fusing together granular biomaterials such as polymer granules and / or coated granules. Scaffolds or composite matrices for biocompatible implants can be made of indented granules with micropores with an average diameter of more than about 0 to about 10 μm . Fusion of the granules leaves micropores and / or forms macropores between the granules having an average diameter of more than about 10 μm to about 2000 μm, preferably about 100 μm to about 500 μm.

In some cases, it may be advantageous to provide a biocompatible scaffold or composite matrix containing both coated and uncoated granules. Coated and uncoated granules can be completely mixed so that they fuse together and still have the required stability. By providing a mixture of coated and uncoated granules for the manufacture of biocompatible implants, the amount of coating material that must be degraded can be further reduced.

A membrane can also be placed on the outer surface of the bone implant, which prevents inward growth and / or contamination of soft tissue and leaves space open for regeneration away from the outer surface. The biocompatible membrane can be a layer of degradable polymer film, polymer textile, polymer fleece, or interconnected fused polymer particles, or a combination thereof , sealed to the implant and thus against soft tissue and epithelial cells. To form at least one impermeable layer.

In one embodiment of the invention, the membrane is composed of poly (α-hydroxy ester), poly (orthoester), poly (ether ester), polyanhydride, poly (phosphazene), poly (propylene fumarate), poly (ester). Amid), Poly (ethylene fumarate), Poly (amino acid), Polysaccharide, Polypeptide, Poly (Hydroxybutyrate), Poly (Hydroxyvalerate), Polyurethane, Poly (Apple acid), Polylactide, Polyglycolide, Polycaprolactone , Poly (glycolid-co-trimethylene carbonate), polydioxanone, or copolymers thereof, terpolymers or synthetic biocompatible and degradable polymers selected from the group comprising blends of those polymers.

Cell obstruction can also be achieved by fusing granules or coated granules. When a large force is applied, the polymer particles that are coated or bonded can fill the pores between all the particles. Granules used for this purpose preferably have a size smaller than about 500 μm, more preferably between about 1 μm and 200 μm.

II. Implant Composition Formation As mentioned above, implant composition formation is (i) softening the polymer to form an implant mass that is formable (ie, plastically deformable); and (ii) formable. Includes shaping an implant mass (exciting or instituting) into the desired shape. In various embodiments of the invention, these steps are performed in different orders and / or simultaneously. Unless otherwise specified, the term "unmolded" means an implant mass that requires a significant amount of molding to reach its final shape in the patient. The term "molded" means an implant that is well shaped so that it requires little or no molding to function as an implant in the patient.

For example, an unformed implant mass is formed and then softened. The coated granules are packed to form an unformed implant mass. Implant mass is hard as it has little or no plasticizer . The unmolded implant mass can be easily stored or shipped without affecting the condition of the implant.

Alternatively, the implant mass is immersed in a liquid plasticizer. The biocompatible polymer and plasticizer of the implant mass are selected so that the biocompatible polymer absorbs the plasticizer. The unmolded implant mass remains in the plasticizer until it absorbs a sufficient amount of plasticizer to be fully moldable , but completely enough to produce a non- moldable soapy liquid. Does not dissolve or soften.

In an alternative embodiment, an initially hard, unmolded implant mass is conditioned with a plasticizer to give a softened (or moldable) implant mass. Next, the moldable implant mass is pushed into a molding die to form a molded implant mass. The mold may have any desired mold cavity (eg, extraction root shape, cylinder shape, or other regular or irregular shape).

The hardener is added to the molded implant mass in the mold, eg, using a syringe. The curing agent is the liquid selected to extract or neutralize the plasticizer. In one embodiment, the curing agent is a substance in which the plasticizer dissolves. Thus, the hardener pulls the plasticizer out of the molded implant mass, thereby forming a hardened implant composition. In an exemplary embodiment, the curing agent is water. Finally, the hardened implant mass is removed from the mold and placed in the defect in the bone.

In another embodiment, the implant is formed at least partially inside the bone defect. In this embodiment, polymer coated granules are placed in the bone defect before being softened with a plasticizer. After filling the bone defect or void with the required amount of polymer coated granules, the plasticizer is injected into the void. The plasticizer softens at least a portion of the polymer, whereby the granules can adhere to each other to form an implant mass.

In each of the above methods, the implant mass is finally inserted into the living body by a method known to those skilled in the art.

Therefore, according to the present invention, there is described a bone graft substitute that substantially combines the high mechanical stability of spherical porous granules without limiting the reduced intergranular space. The internal structure of the granules has a high porosity while maintaining high stability, allowing the granules to be pushed into the defect without causing significant damage to the granules, while at the same time the bone cells are the space between the granules. Can grow into. In an exemplary embodiment of the invention, the surface of the granule has a dent when viewed from the outside of the granule. The depression significantly increases the porosity in the implanted mass, thus providing more space between the granules for the inward growth of the tissue. Due to the indentations on the granules, the granules have an irregular shape and thus an increase in intergranular space is achieved while maintaining mechanical stability.

The invention is described above with reference to various embodiments. The description of these specific embodiments is only useful for the description and deeper understanding of the invention and should not be considered as limiting the scope of the invention. Rather, the invention is defined by the appended claims and equivalents that are obvious to those skilled in the art and follow the general concept of the invention.

Claims (10)

A method for producing a porous implant mass composition used for treating a defect in a living body, which comprises a plurality of biocompatible granules and at least a part of the granules has a surface depression.
Granules of synthetic biocompatible material, said synthetic biocompatible material
・ Bio-glass or
・ Calcium sulfate, silicon oxide, calcium phosphate, monocalcium phosphate monohydrate, anhydrous monocalcium phosphate, dicalcium phosphate anhydride, anhydrous dicalcium phosphate, tetracalcium phosphate, calcium ortholithate, calcium pyrophosphate, α- Bioceramics selected from the group of tricalcium phosphate, β-tricalcium phosphate (β-TCP) and apatite,
To produce the granules selected from a list containing ;
Mixing the granules with Porogen;
Pushing the porogen onto the surface of at least a portion of the granules;
A method for producing a porous implant mass composition comprising removing the pologene from an implant mass such that a depression is obtained on the surface of the pologene pressed into the granules. The method of claim 1 , wherein at least a portion of the granules is spherical. The method according to claim 1 or 2 , wherein the porogen is in the form of particles, and at least a part of the surface of the particles has a convex shape. The method according to any one of claims 1 to 3 , wherein the porogen is in the form of particles and at least a part of the particles is spherical. The method according to any one of claims 1 to 4 , wherein at least a part of the porogen has a diameter in the range of 10 to 250% of the diameter of the granules. The method according to any one of claims 1 to 5 , wherein the weight of the porogen used is in the range of 20% by weight to 80% by weight of the amount of granules. The method according to any one of claims 1 to 6 , wherein the porogen comprises at least one element selected from the group consisting of ice, salt, polyethylene, silicon, polystyrene and cellulose. The method according to any one of claims 1 to 7 , wherein the porogen contains cellulose. The method according to any one of claims 1 to 8 , wherein the step of removing the porogen comprises burning removal, sieving, dissolving, melting or evaporating. The method according to any one of claims 1 to 9 , wherein the step of removing the porogen comprises burning and removing the porogen.