KR20030027943A - Porous synthetic bone graft and method of manufacture thereof - Google Patents

Abstract

(i) preparing a mixture of finely separated biocompatible ceramic powders, organic binders and pore formers in an inert liquid to form an object and to align at least some of the pore formers along the coaxial axis;

(ii) optionally shaping the resulting object;

(iii) allowing the pore former to form a porous structure in the object;

(iv) heating the shaped object to a temperature sufficient to fix the porous structure; And

(v) A method of making artificial bones is described that further includes heating the object to remove residues and pore formers from the organic binder and fuse them.

Description

POROUS SYNTHETIC BONE GRAFT AND METHOD OF MANUFACTURE THEREOF

Commercially available synthetic bone grafts are generally made of calcium phosphate ceramic (the main inorganic material of human bone) and have a porous structure similar to human porous bone. Many of them actually originate from animals (young cattle) or marine organisms (corals). They are intended to provide linked macroporous structures and provide intensive bone conduction to regenerate and heal host bone tissue. However, none of them provide biomechanical and bone integrity properties equivalent to good levels of grafts.

These synthetic bone grafts generally have linked macroporous structures, typically 100-500 μm in diameter, the pore size of the porous structure being important for bone conductivity. In vitro and in vivo experiments show that the appropriate pore size for bone tissue during growth is about 200-300 μm. If the pore size is less than 100 μm, bone tissue accumulates on the surface without bone growth. After transplantation, the bone graft should be replaced with slowly degrading and growing bone. It should result in bone restoration at the bone site damaged by the receptor's own bone formation activity. However, decomposition requires that the bone substitute material is microporous with a pore diameter of 1 to 5 mu m. The degradation of "degradable" bone grafts consists of two steps: extracellular degradation of the cervix in the sintered particles and intracellular phagocytosis of the particles separated in this way. The first step is impossible in annealed bioceramic bulk and very difficult in porous synthetic bone grafts with thick connecting walls because there is no small neck to which cells can attack.

Commercially available synthetic bone grafts generally have a random pore size distribution and lack the desired orientation of the connecting porous structures. The structure has the potential to interfere with angiogenesis in vivo after a period of time, and the center of the bone graft generally remains boneless. Although most commercial bone grafts have a similar chemical composition to the mineral state of living bones, grafts are not suitable for large-scale application or permanent replacement because post-operative nutrients cannot flow through synthetic porous bone grafts.

The present invention relates to the production of synthetic bone in the form of porous masses from calcium phosphate or other ceramic powders. More specifically, the present invention relates to a novel process for producing good synthetic bone grafts having a controllable porous structure. It can be used to replace autografts and allografts for orthopedic surgery, including spinal reconstruction, musculoskeletal reconstruction, fracture repair, hip and knee reconstruction, bone augmentation methods, and oral / chin face surgery.

The European bone graft market is currently dominated by grafts (bones taken from some of the body and then transplanted into another part of the same individual) and allografts (bones taken from one individual and then transplanted to different individuals). In the autograft method, the bone graft is taken from the patient, typically from the pelvis. Two surgeries must be performed at the same time. The patient is advantageous to have suitable, living, and working cells. However, disadvantages can also be noted. Among them are chronic, often debilitating pains following harvest surgery, blood loss, risk of infection, and long periods of hospitalization and recovery. Secondary surgery also substantially increases the economic burden.

Allografts generally use bones from corpses. This eliminates the need for secondary surgery, but the implanted bone may not be suitable for the host bone and ultimately may be rejected. Allografts, although unlikely, also present a significant risk of introducing various viruses into patients, including AIDS and hepatitis. Therefore, much effort has been put into developing synthetic bone grafts that are biocompatible.

(Summary of invention)

The present invention provides a novel method of manufacturing a unique and extremely flexible porous structure. No biological material needs to be included in the final product. It can mimic human spongy bone on a large scale, and the pore size can vary from a few microns to several millimeters. The method allows for controllable pore size, shape and pore direction. A number of different sizes of interconnected tubular-like pores (with preferred orientation) may be provided to quickly guide bone growth and angiogenesis through the entire structure. The porous structure may have a thin wall that facilitates the attachment of osteoblasts and promotes mineral deposition. The size and shape of the bone graft can be adjusted by the shaping method, or molded by tools such as a diamond wheel or a high speed drill during surgery by orthopedic surgery.

According to the invention:

(i) preparing a mixture of finely separated biocompatible ceramic powders, organic binders and pore formers in an inert liquid to form an object and to align at least some of the pore formers along the coaxial axis;

(ii) optionally shaping the resulting object;

(iii) allowing the pore former to form a porous structure in the object;

(iv) heating the shaped object to a temperature sufficient to fix the porous structure; And

(v) further heating the object to remove residues and pore formers of the organic binder and fusing them.

Detailed Description of the Invention

Having described the present invention in general terms, the present invention will now be described with reference to the accompanying drawings, in which the schemes represent flowcharts of typical methods of the invention.

Essential components of the process are biocompatible ceramic powders, organic binders and pore formers. The ceramic powder can be any ceramic material that is biocompatible. For example it may be a mechanical ceramic so that the resulting artificial bone graft has sufficient strength. Materials that can be used include zirconium and alumina. However, it is preferable to use calcium phosphate ceramics. All medical grade tricalcium phosphates including α-tricalcium phosphate (TCP), β-TCP and hydroxyapatite (HA) Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ can be used for this purpose, but large-scale production For this reason, it is preferable to use HA, because it is more stable. Mixtures of biocompatible materials can be used, for example calcium phosphate ceramics and mixtures of alumina or zirconia. In addition, small amounts, for example up to 5% by weight, of silica and organic zinc compounds can be mixed in the powder to increase bone conductivity.

The ceramic powder is preferably dispersed uniformly. The smaller the particles, the larger the surface area and thus the more likely the particles are wetted by the liquid; This also facilitates final sintering. In general, the powder does not exceed an average diameter of about 100 microns. Therefore, the powders preferred powder will have an average particle diameter of 1 nm to 50 μm, for example 0.1 to 10 μm.

The organic binder must bond the ceramic powders together to form a densely packed structure having a plurality of contact points between each ceramic particle having a gap of the hot electrode in which the inert liquid remains. The precise form of the organic binder is not important unless it leaves a residue after firing; It will generally be solid. Carbohydrate powders, especially corn flour or wheat flour, have been found to be particularly useful, but other organic materials such as natural extractive starch may also be used. Those skilled in the art will understand which alternative materials may be used. The binder must be inserted as a powder into the slurry.

Pore formers are present to form pores in objects formed from ceramic powders and binders. This is generally accomplished by gas evolution from pore formers. Stable pore-formers include microorganisms such as yeast cells, with phosphorus-containing and carbon-derived inorganic salts of acids, in particular alkali metal salts such as sodium salts of phosphoric acid and carbonic acid. Specific examples include disodium diphosphate and sodium bicarbonate.

Slurry is formed in the inert liquid, ie the liquid must not react with the pore-forming agent at room temperature and also with the ceramic binder. Although organic liquids such as ethanol can also be used, typically the inert liquid is water, especially deionized water.

In one embodiment of step (i) a slurry of ceramic powder is first prepared and then an organic binder and a pore former are added to it (steps 1 and 2 of FIG. 1). However, the ceramic powder, organic binder and pore former may also be mixed together and then a liquid solvent added. In a preferred embodiment, the calcium phosphate ceramic slurry is prepared by first mixing calcium phosphate with water or another inert liquid. In order to aid dispersion, it is desirable to add a dispersant to ensure uniform distribution of the ceramic powder throughout the slurry. Typical dispersants that can be used for this purpose include polymers and acid / base solutions such as phosphate and acrylate polymers. Preferred dispersants include ammonia, phosphoric acid such as orthophosphoric acid, or ammonium salts of acrylate or methacrylate polymers such as ammonium polyacrylate and ammonium polymethacrylate.

It is then desirable to optionally mill the slurry with a milling medium, such as beads or cylinders of alumina, stainless steel or tungsten carbide. Of course these milling media are removed after milling.

In a preferred embodiment, the milling is typically carried out in a cylinder mill of the rubber wall. Typically, a closed cylinder mill is allowed to rotate for several hours at low speed to form a high density, well dispersed ceramic slurry. In order to optimize the size of the powder, it is generally desirable to take at least 1 hour to about 50 hours for the milling operation. It will be appreciated that the effective pore structure is a series of densely irregular ceramic particles that diffuse to neighbors during the final stages of the process, so that the size of the powder in the slurry can determine the pore size.

Generally, carbohydrate powder and pore former are then slowly added to the slurry to form what is described as a high viscosity stretchable material. Preferably, mixing is performed in a closed oxygen chamber to ensure that the mixed material is oxygen rich in order for the pore-forming agent to react. It will be appreciated that the amount of pore-forming agent controls the overall porosity of the final product, but the quality of the binder determines the stretch properties of the mixture.

It will also be appreciated that the exact conditions used in step (iii) will depend on the type of pore former. Therefore, when yeast is used, it is generally necessary to have a small amount of sugar-like nutrients present to promote the mechanism for producing carbon dioxide. In general, an increase in body temperature will cause the pore-forming agent to react and result in gas evolution. It will be appreciated that the pore forming step may be accelerated by increasing the temperature and / or pressure, but care is required to ensure that the temperature is maintained below the temperature at which the yeast dies. Generally, a temperature of 28 to 30 ° C. will cause the yeast to form pores. However, it has been found that when a large amount of yeast is used, some of the yeast can survive and withstand higher temperatures, for example below 40 ° C. Pore size is roughly defined by temperature and pore former used. The use of a closed oxygen chamber assists in the reproducibility of the process but of course mixing can simply be carried out in air.

The amount of ceramic powder used should generally be as high as possible. Typically 80% of the total weight of ceramic powder, 19% carbohydrate and about 1% yeast are used. Therefore, generally 50 to 90 wt% ceramic, 5 to 50 wt% binder and 0.5 to 5 wt% pore former are used. Clearly, the exact amount of pore-forming agent used depends on the form of the medicament.

It will also be appreciated that if sufficient pore formers are present, the pore size will increase with time. Ideally, the pore size should be about 200 to 300 microns. If the pore size is significantly smaller than this, the osteoblasts will be insufficient to grow inwards. In addition, if it is desirable to fill the pores in any direction, it should be slightly larger than the ideal pore size, as will be described below, otherwise the molecules will not be retained by the pores.

It will be understood that at this time the object has a dough-like appearance, ie it does not take its specific shape.

Preferably, prior to the optional shaping step (ii) the product is transferred to an extruder or other device to provide the shape and size required for the shaping step (step 3 in FIG. 3). The purpose of the extrusion step is to produce the desired pore shape and orientation in the final porous structure. Using different extrusion forces and different forms of the front mold, the material can be formed into any geometric shape with the desired alignment, such as linear, hollow tube, crosslinked material, or spiral pores in a vertical or horizontal plane. The pore former will stretch along the extrusion direction and ultimately produce the desired pore direction, ie align along the coaxial axis. Obviously, the object must have a sufficient viscosity as in the dough-like to allow this alignment. Sometimes, this can be accomplished by simply stretching. It will be appreciated that a particular advantage of using microorganisms is that well connected pores can be formed. In contrast, chemical agents generally lead to poorly linked pores.

The extrusion step is essential for the manufacture of spongy or cortical bone mimetics, but it is generally necessary when artificial bone grafts are used in load bearing applications. This is because the mineral composition in the form of natural load-bearing bones, such as the femoral and hip joints, has a tube-like structure rather than a simple spongy bone structure. The direction of this tube-like porous structure will depend on the stress distribution load, which results in the load bearing bone being stronger than the rib bone.

The mixture is then optionally molded (step 4 of FIG.). Preferably it is molded in a mold. The three-dimensional form of the mold can be designed with computer-aided medical image analysis technology so that the shape can replicate the patient's missing bone structure. Once the object is closed in the mold, the temperature of the mold can be raised to allow the pore-forming agent to react and form pores. It will be appreciated that the force caused by the expansion of the pore-forming agent compresses the ceramic powder. The amount of pore former, together with process time and process temperature, determines the porosity density and mechanical strength of the final product. The total time required to complete the reaction at the optimized process temperature is typically 30 to 90 minutes, preferably 40 to 60 minutes, in particular about 45 minutes, depending on the size of the object.

Prior to step (iv), when water is used as the inert liquid, it is desirable to reduce the temperature of the object below the freezing point of water (step 5 in the figure). Preferably, the hermetic mold is reduced to a temperature of about −5 ° C. to liquid nitrogen. The freezing step can prevent the pore-forming agent from further reacting. The expansion resulting from the formation of ice from water further strengthens the porous structure of the object. The frozen sample can then be removed from the mold.

It is then generally necessary to remove some of the liquid from the object, typically by evaporation. This can be achieved in a vacuum chamber where water or other liquid is evaporated from the surface and a hydrostatic pressure gradient through the compact provides the driving force for the liquid to move. More uniform pressure occurs as fluid flows through the porous channel from the interior of the object to the surface. Naturally, process temperature, rate of temperature increase, vacuum pressure and duration of the sublimation process depend on the size and shape of the object and the type of liquid employed. These can be measured by routine experiments.

The purpose of step (iv) is to stabilize the article (step 6 of FIG.). For this purpose, it is generally desirable to pre-heat the air (where it can be dried or wet), typically an oven, which is preferably humidity controlled. Temperatures of 100, 130 or 150 to 230 ° C. are generally suitable for stabilization. In general, stabilization can be achieved in less than 1 hour, generally within 5 to 50 minutes, for example 15 to 45 minutes. It has been found that the use of steam is generally advantageous because it causes polymerization of the organic binder without microcracks formed on the sample surface which can be caused by the direct heating process. These cracks are retained and deepened during subsequent annealing processes, which can greatly reduce productivity.

Once the object has stabilized it may be standardized to remove any irregular flow and / or adjust the final geometry of the article, if desired, to correspond to the desired shape of the artificial bone graft.

In step (v) the article is heated or baked to remove the binder and any residual pore formers. Generally temperatures of 400 ° C. to 1000 ° C. are necessary for this purpose. This depends in part on the amount of binder used and the heating rate applied. As this heating step typically results in the generation of carbon-containing gases, it will be appreciated that the heating should be performed slowly so that these gases diffuse out of the artificial bone through the connected porous channels. If this is not done, the trapped gas may accumulate enough to cause internal damage to the dense porous structure. In general, the heating rate should not exceed 10 ° C. per minute, and typically should be less than 5 ° C. per minute, perhaps 1 or 2 ° C. per minute for large samples.

Removing the binder is generally completed when no more carbon gas appears from the article.

Preferably, following this heating step, the sample is annealed or calcined at high temperature, typically at about 1200 to about 1450 ° C. to achieve the required biomechanical strength and biocompatibility (step 7 of FIG. 7). Repeatedly described, the temperature and time of heating depend on the size of the sample and the initial ceramic concentration. Care should be taken not to use too high temperatures as small interconnected pores may fuse and result in macropores starting to become isolated.

In some cases, the product counts sufficiently for some purposes but insufficiently for some other purposes. It has been found that the strength of the product may be enhanced by immersing it in the formed ceramic slurry of apatite ceramic powder, although it does not need to be the same as originally used. The slurry should also contain a dispersant which may be in the same or different form as used initially. Preferably the slurry should be milled before use to reduce the particle size, for example from 5 μm on average to 1 μm on average. The slurry is left for about an hour and a half to allow large particles to decompose. Suitable average particle size, ie particles below 0.2 μm, may be poured from the formed suspension.

Immersion typically should be continued for at least 0.5 hours with continuous stirring of the slurry. After that, the slurry is preferably boiled until no more bubbles are generated from the sample. This typically takes 10 minutes to 1 hour depending on the size of the sample. This process ensures that the pores of the sample are packed with apatite particles. Any excess slurry and apatite particles may be removed by a centrifugation process (eg 2500-1500 rpm) through the interconnecting macropore structure. This immersion step can be repeated if necessary. The sample can then be received by repeating the annealing step.

Another way to improve the mechanical strength of a porous structure is to reinforce it with a polymer, preferably a biodegradable polymer such as polycaprolactone (PCL); The polymer acts as a filler. For this purpose, after the polymer is dissolved in a solvent to provide a concentration of about 10-50% by weight, typically 20-40% by weight, the object is immersed for about 5 minutes to 1 hour, for example 20 minutes. The object is then separated and centrifuged to remove any residual solution. It is then desirable to heat the sample to melt any polymer that blocks the pores. This process can be repeated if desired.

In an advantageous embodiment of the invention some or all of the pores of the artificial bone can be used as a drug delivery system with a controlled release mechanism. This can generally be accomplished by immersing the artificial bone in a solution of the desired cell growth factor or drug.

At present, there are no effective drug delivery mechanisms for delivering engineered high molecular weight proteins or enzymes into bone. This can be achieved according to the invention as the size of the bone graft can be adjusted to accommodate the molecule. Therefore, high molecular weight engineered proteins or enzymes inserted in this manner can be released from the bone graft to stimulate bone growth, and the porous matrix can guide the proliferation and differentiation of osteoblasts. Growth factors for bone growth, including transforming growth factor (TGF-β1), bone morphogenic genetic protein (BMP-2) and bone morphogenic protein (OP-1), can be inserted into the artificial bone of the present invention in this manner. have.

Other materials that can be inserted include vitamins such as vitamin D and trace minerals such as zinc that can be inserted in the form of salts.

In a preferred embodiment, these molecules are inserted into the pores together with the biodegradable polymer. Biodegradable polymers help to "fix" active molecules into the pores while improving the strength of artificial bones.

Suitable biodegradable polymers that can be used for this purpose include starch, typically corn starch, or other naturally occurring polymers or mixtures of such polymers with, for example, polyethylene or poly (lactic acid) or poly (glycolic acid). In general, the concentration of non-naturally occurring polymers should be kept low to avoid any possible biological side effects. It may be possible to use mixtures of starch and low density polyethylene up to about 50% by weight.

The active compound can be applied from a solution of the material by dipping if a biodegradable polymer is used. Application of a slight vacuum to the artificial bone graft may be useful because it will increase the absorption of the solution.

When this immersion step is carried out several times, the strength of the artificial bone can be increased significantly. Residual biodegradable polymers can generally be removed by centrifugation.

Therefore, it will be appreciated that the artificial bone graft of the present invention can be used as a 3-D scaffold for in vitro engineered magnetografts.

The manufacturing cost of the method is generally significantly lower than for existing methods, and the production time is generally faster than for other methods. Under normal circumstances, large samples with irregular forms can also be produced within 24 hours. Therefore, it can be customized. For example, the desired shape of the bone graft may be made according to a 3-D skeletal scan image of the patient prior to jaw face surgery. Therefore, bone grafts can be produced individually for each patient.

The following examples illustrate the invention.

Example 1

Commercial medical grade hydroxyapatite Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ powder (ASTM F118588) with a particle size of 0.6 μm to 1 μm was used to prepare synthetic porous bone grafts. The first step is to have the ingredients:

160 g of hydroxyapatite powder

70 ml of deionized water

A slurry of 2 g of ammonium polyacrylate is prepared.

These ingredients were first uniformly mixed in a plastic spoon in a plastic container. After the homogeneous solution was formed, it was mechanically stirred for 5 minutes at about 1200 rpm with a double blade stirrer. This became about 115 ml of slurry. The slurry was then poured into a cylinder mill, a polyethylene flask, cylinder containing 10 cm long, 6 cm diameter and 100 cm ³ high density small Al ₂ O ₃ for further dispersion of the aggregates. The cylinder mill was sealed and stirred at 120 rpm for 30 minutes to form a homogeneous slurry.

70 g of fine, sieved wheat flour and 7 g of yeast cells were then slowly added and then blown in a mixer to form a handleable and plastic mixture.

A. Sample not extruded

The mixture was then divided in equal amounts and placed without sealing in four Teflon coated petri dishes without extrusion. These petri dishes were then transferred to a temperature controlled incubator and maintained at 28-30 ° C. The incubator time was changed in four increments, 15 minutes to 1 hour, in 15 minute increments. At the end of each step, one of the Petri dishes was slowly cooled in liquid nitrogen to stop the biological reaction and prepare the next step process.

Excess water was then removed from the sample at 20 ° C. at a pressure of 10 ⁻¹ to 10 ⁻³ mmHg. The dried sample was then stabilized in the oven at 200 ° C. for 30 minutes. The formatted sample was then slowly heated in a furnace at a rate of 5 ° C. per minute and kept at 1000 ° C. to remove organic additives. The sample was then annealed at 1250 ° C. for 2 hours and slowly cooled to room temperature at 5 ° C. per minute.

Optimal microscopic examination of each porous structure of the calcined sample showed that they all exhibited nearly identical porous structures as the human spongy bone. As shown in Table 1, the size of the pores interconnected with the pores increased with increasing incubation time.

time Pore size Interconnected Pore Size 15 mins 50-100 μm Average diameter 40㎛ 30 minutes 300-500 μm Average diameter 200㎛ 45 mins 800-1000 μm Average diameter 400㎛ 60 mins 2000-3000 μm Average diameter 1000 ㎛

B. Extrusion

After the mixing process, the mixture was processed through an extrusion unit to form a cylindrical sample. The front mold of the extrusion unit was two connected cylinders and the diameters were 5 cm for the first step and 3 cm for the second step, respectively. Steel nets with a 3 mm mesh were attached to both ends of the second stage cylinder. The extruded mixture was then placed in a Teflon coated plate without being sealed. Thereafter, along with the mixture, the plates were transferred to a temperature controlled incubator and maintained at 28-30 ° C. Thereafter, the mixture was transferred to a refrigerator and kept at −5 ° C. for 2 hours, and the excess water was sublimed from the sample at 20 ° C. at a pressure of 10 ⁻¹ to 10 ⁻³ mmHg in a freeze drying chamber. The format, heating and annealing process was the same as described in section A. The sample exhibited a uniform tube-like porous structure with a pore size of 800 to 1000 μm in length and an average diameter of about 200 μm. Interconnected pores of about 200 μm average diameter were connected at the ends of these tube-like macropores. The structure is ideal for the introduction of bone growth and angiogenesis.

C. In case of hermetic molding

The extrusion process was the same as described in section B. However, the steel net was removed during the extrusion process. The extruded cylindrical sample was transferred into a closed cylindrical mold. Insertion method and sublimation process were the same as described in Section B, and format, heating and annealing processes were the same as described in Section A. The cross section of the sample showed a structure similar to that of human long bones. The dense structure formed the outer shell of the sample; It consisted of a solid substantially solid body made of Ca / P ceramic arranged in concentric layers. A porous structure similar to that found in spongy / sponge bones was found in the middle of the sample; The pore size gradually decreased, eventually leading to a dense structure.

Example 2

A sample of the porous HA product obtained in Example 1B was immersed in a boiling HA slurry having an average particle size of 0.2 μm. Immersion times were 30 to 90 minutes at 30 minute intervals and the slurry was continuously stirred. The remaining slurry was then removed by centrifugation process (2500-15000 rpm). The sample was subjected to an annealing process at 1280 ° C. for 5 hours.

Mechanical testing of the samples was performed using a Lloyd benchtop test machine fitted with a 2.5 kN load cell and a remote computer control unit. The rod was applied to the sample (average sample contact area 0.8 cm ² ) at a crosshead speed of 0.1 mm per minute until brittle fracture occurred. The obtained result is shown in FIG. It can be seen that the compressive strength of the porous HA sample increases with increasing immersion time.

Example 3

6 g of PCL was dissolved in a 60 ° C. oven in a 150 cc glass beaker. After the solid PCL is dissolved in a clear viscous liquid, 20 ml acetone is added to dissolve the PCl and form a flowable solution. The viscosity of the solution was 0.8835 ± 0.025 pas. The porous sample of Example 1B was then immersed in solution and placed on a hot plate to boil at a constant temperature of 57 ° C.

After 20 minutes, the sample was removed and subjected to a centrifugation process (2500-15000 rpm) to remove any residual solution from the interconnect macropore structure. The sample was then placed in a 60 ° C. oven to melt any blocking PCL in the macropore structure and the centrifugation process was repeated.

The mechanical test of Example 2 was performed. The obtained result is as showing in FIG. It can be seen that PCL reinforced porous HA samples have significantly increased compressive strength.

The porosity of the samples tested before the immersion process according to ASTMC134 standard was as follows.

Porosity of the Porous HA Samples Tested Total volume, cm ³ 1.06078 ± 0.01493 Volume of open pores, cm ³ 0.79737 ± 0.01935 Volume of impermeable pores, cm ³ 0.20262 ± 0.00596 Apparent porosity, P% 79.6589 ± 0.28677 Water absorbency, A% 133.81 ± 1.89755 Apparent specific gravity 2.93957 ± 0.03229 Bulk density, g / cm ³ 0.59597 ± 0.0074

Claims (27)

(i) preparing a mixture of finely separated biocompatible ceramic powders, organic binders and pore formers in an inert liquid to form an object and to align at least some of the pore formers along the coaxial axis; (ii) optionally shaping the resulting object; (iii) allowing the pore former to form a porous structure in the object; (iv) heating the shaped object to a temperature sufficient to fix the porous structure; And (v) further heating the object to remove residues and pore formers from the organic binder and fuse them. The method of claim 1 wherein the ceramic powder is of calcium phosphate. The method of claim 2 wherein the ceramic powder is α or β tricalcium phosphate. The method of claim 2 wherein the calcium phosphate is hydroxy apatite. 5. The method according to claim 1, wherein the powder has an average particle size not exceeding 100 microns. The method of claim 1, wherein the organic binder is a carbohydrate powder. 7. The method of claim 6, wherein the organic binder is corn flour or wheat flour. The method of claim 1, wherein the pore forming agent is yeast, disodium diphosphate or sodium bicarbonate. The method according to claim 1, wherein the inert liquid is water. The method according to any one of the preceding claims, characterized in that a slurry of ceramic powder is first obtained and an organic binder and a pore former are added thereto. The method of claim 10 wherein the slurry of ceramic powder is optionally obtained by milling together with the milling aid. The method according to claim 10 or 11, wherein the dispersant is mixed with the ceramic powder. 13. The method of claim 12 wherein the dispersant is an ammonia solution, orthophosphoric acid or an acrylic and / or methacrylic acid polymer. 13. The method of any of claims 10-12, wherein the organic binder and pore former are uniformly dispersed in the slurry in a closed oxygen-containing chamber. The method according to claim 1, wherein the pore formers are aligned in step (i) by extruding the object. The method of any one of the preceding claims, wherein the object is molded using a mold. 17. The method of claim 16, wherein the inert liquid is water and the hermetic mold is cooled below freezing to strengthen the porous structure of the object. The method of claim 1, wherein after step (ii) the inert liquid is removed from the object. The process according to any one of the preceding claims, wherein step (iv) is carried out at a temperature between 100 and 230 ° C. 19. The method of any of claims 1 to 18, wherein step (iv) comprises subjecting the article to steam. The process according to claim 1, wherein step (v) is carried out by heating to 400 to 1000 ° C. at a rate not exceeding 10 ° C. per minute. The method of claim 1, wherein after step (v) the object is annealed at a temperature of about 1450 ° C. or less. The method of any one of the preceding claims, wherein the product of step (v) is immersed in a ceramic slurry and then boiled to separate the resulting object by centrifugation. The method of claim 1, wherein substantially the same as described in any one of the embodiments. Artificial bone produced by the method as described in any one of the preceding paragraphs. 26. The artificial bone of claim 25 comprising one or more proteins, vitamins or trace elements or minerals. 27. The artificial bone of claim 26 further comprising a biodegradable polymer.