CN112220964A - Composite biological ceramic powder, composite biological ceramic artificial bone prepared from composite biological ceramic powder and preparation method of composite biological ceramic artificial bone - Google Patents
Composite biological ceramic powder, composite biological ceramic artificial bone prepared from composite biological ceramic powder and preparation method of composite biological ceramic artificial bone Download PDFInfo
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Abstract
The invention provides a composite biological ceramic powder, a composite biological ceramic artificial bone prepared from the composite biological ceramic powder and a preparation method of the composite biological ceramic artificial bone, wherein the composite biological ceramic powder comprises calcined bone powder and biological ceramic powder, the mass ratio of the calcined bone powder to the biological ceramic powder is 1 (0.8-3), the biological ceramic powder is one or more of beta-tricalcium phosphate, calcium carbonate, calcium sulfate and bioactive glass, and the composite biological ceramic artificial bone is prepared by adopting the composite biological ceramic powder through 3D printing. The outer surface of the composite bioceramic artificial bone can be coated with a guided bone regeneration membrane. The artificial bone prepared from the composite biological ceramic powder has good biocompatibility, can effectively promote bone healing, has certain hardness and strength, and is easy to shape.
Description
Technical Field
The invention belongs to the technical field of medical treatment, and relates to composite biological ceramic powder, a composite biological ceramic artificial bone prepared from the composite biological ceramic powder and a preparation method of the composite biological ceramic artificial bone.
Background
At present, the repair and reconstruction of large bone defects caused by the problems of tumors, disabilities, defects and the like are always a difficult problem in orthopedics, and autologous bones with good transplanting effect have the defects of limited material availability, secondary wound of patients and the like; allograft bone transplantation is accompanied by rejection and infection problems, and allograft bone has many limitations; the fibula transplantation with vascular pedicle is suitable for treating large bone defects, but has higher requirements on the source, the operation of operators and the postoperative management.
The hydroxyapatite prepared by chemical processing has similar composition with human bone minerals, and the prepared artificial bone is widely applied to bone defect repair. But the inside of the cell is usually free of a network porous structure, so that the cell is not beneficial to growth and proliferation, and the biocompatibility of the cell is poor.
The calcined bone is also used for preparing artificial bone for repairing bone defect, but the strength is lower. For example, CN1644221 discloses a composite material of a porous material and gel and an application thereof, but the prepared composite material is an injectable gel product, has no supporting strength, and cannot satisfy defect repair of a large bone. CN101954122A discloses a preparation method of a natural bone repair material with pre-plasticity, which is prepared by uniformly mixing calcined bone particles and a collagen solution and freeze-drying at a low temperature, wherein the internal pore structure cannot be regulated and controlled, the pore communication rate is low, the strength is low, and the clinical application is limited. CN103920193B discloses a preparation method of a bone-like ceramic composite material carrying bioactive factors, which is characterized in that bioactive factors are added, plastic drying is carried out to form a bone repair material, the internal pore structure cannot be regulated and controlled, the strength is low, and the clinical use effect of the product is influenced.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides the composite biological ceramic powder, the composite biological ceramic artificial bone prepared from the composite biological ceramic powder and the preparation method of the composite biological ceramic artificial bone, solves the problem of low strength of the existing calcined bone powder composite artificial bone, and effectively controls the internal pore structure of the artificial bone, so that the porosity of the artificial bone can reach more than 98%.
The invention is realized by the following technical scheme:
the composite biological ceramic powder comprises, by mass, calcined bone powder and biological ceramic powder, wherein the mass ratio of the calcined bone powder to the biological ceramic powder is 1 (0.8-3), and the biological ceramic powder is one or more of beta-tricalcium phosphate, calcium carbonate, calcium sulfate, calcium silicate and bioactive glass.
A composite biological ceramic artificial bone is prepared by adopting the composite biological ceramic powder.
Preferably, the method comprises the following steps:
(1) uniformly mixing the calcined bone powder, the biological ceramic powder and the binder to obtain slurry, then filling the slurry into a charging barrel, and defoaming to obtain uniform printing slurry; obtaining an artificial bone three-dimensional model according to CT data of a bone defect part of a patient;
(2) printing the slurry by using a biological ceramic 3D printer according to the three-dimensional model of the artificial bone to obtain the composite biological ceramic artificial bone, and performing freeze-drying treatment on the printed composite biological ceramic artificial bone.
Further, in the step (1), the binder is polyvinyl alcohol, polylactic acid, polycaprolactone, polylactic-glycolic acid, polyethylene glycol or collagen.
The tectorial membrane composite bioceramic artificial bone comprises the composite bioceramic artificial bone and a guide bone regeneration membrane coated on the outer surface of the composite bioceramic artificial bone.
Preferably, the raw material for preparing the guided bone regeneration membrane comprises chitosan, silk fibroin, collagen, polylactic acid or sodium alginate.
The preparation method of the film-coated composite biological ceramic artificial bone comprises the following steps:
(1) uniformly mixing the calcined bone powder, the biological ceramic powder and the binder to obtain slurry, then filling the slurry into a dispensing syringe, and defoaming to obtain uniform printing slurry; obtaining an artificial bone three-dimensional model according to CT data of a bone defect part of a patient;
(2) printing the printing slurry by using a biological ceramic 3D printer according to the three-dimensional model of the artificial bone to obtain a composite biological ceramic artificial bone, and performing freeze-drying treatment on the printed composite biological ceramic artificial bone;
(3) soaking the freeze-dried composite bioceramic artificial bone in the step (2) in a soaking solution prepared from raw materials for preparing a guide bone regeneration membrane, and soaking and laminating;
(4) crosslinking the composite bioceramic artificial bone subjected to the infiltration and film covering treatment by using a crosslinking agent;
(5) and (3) freeze-drying the composite bioceramic artificial bone after the crosslinking treatment to obtain the film-coated composite bioceramic artificial bone.
Preferably, in the step (3), the preparation method of the impregnating solution comprises the following steps: dissolving chitosan, chitin and collagen in glacial acetic acid solution, and stirring to obtain the soaking solution.
Preferably, in the step (4), the crosslinking treatment specifically comprises: placing the composite biological ceramic artificial bone subjected to the infiltration and film covering treatment in a genipin acetic acid aqueous solution for crosslinking treatment; then washed with water to neutrality.
Compared with the prior art, the invention has the following beneficial technical effects:
the composite biological ceramic powder combines calcined bone powder and biological ceramic powder, the calcined bone powder retains inorganic calcium-phosphorus mineral substances and porous structure of bone tissue, and can enhance adhesion of cells to the biological ceramic powder to ensure that the biological ceramic powder has excellent biocompatibility, and the addition of the biological ceramic powder can enhance the strength of the calcined bone powder and adjust the degradation performance of the calcined bone powder. The artificial bone prepared from the composite biological ceramic powder has good biocompatibility, can effectively promote bone healing, has certain hardness and strength, and is easy to shape.
The invention can prepare the artificial bone with any aperture, porosity and appearance by adopting a 3D biological ceramic extrusion deposition molding technology, thereby truly realizing the personalized accurate treatment of patients with bone defect. The prepared biological ceramic artificial bone has a multi-layer pore structure combining macro pores and micro pores, is favorable for cell adhesion, promotes the transportation of nutrient substances and enables the growth of new bone tissues. Meanwhile, the 3D biological ceramic extrusion deposition molding technology is adopted, the internal pore structure of the artificial bone is effectively controlled, and the porosity can reach more than 98%.
By adopting a bone guiding membrane regeneration technology, the composite bioceramic artificial bone is coated with the membrane outside, so that the composite bioceramic artificial bone can effectively prevent fibrous soft tissue at the defect part from being embedded, guide bone regeneration at the bone defect part in a closed environment, strengthen bone healing, avoid repair obstacles caused by periosteal defect and effectively improve the repair effect of the artificial bone.
Furthermore, the bone guiding regeneration membrane is formed on the outer surface of the composite bioceramic artificial bone by an infiltration membrane covering method, the infiltration membrane covering is easier to operate and more efficient than electrostatic spinning membrane covering, and the possible nano harm of the electrostatic spinning membrane covering to cells is avoided. In addition, the infiltration coating can form an interwoven microporous structure after freeze drying treatment, which is beneficial to the adhesion and proliferation of cells.
Drawings
FIG. 1 is a flow chart of the preparation of a bioceramic artificial bone according to example 1;
FIG. 2 is a calcined bone powder XRD pattern;
FIG. 3 shows the particle size detection results of calcined bone powder;
FIG. 4 is a flow chart of the preparation of the bioceramic artificial bone according to example 2.
Detailed Description
The present invention will now be described in further detail with reference to specific examples, which are intended to be illustrative, but not limiting, of the invention.
The invention provides composite biological ceramic powder which comprises, by mass, calcined bone powder and biological ceramic powder, wherein the mass ratio of the calcined bone powder to the biological ceramic powder is 1 (0.8-3), and the biological ceramic powder is one or more of beta-tricalcium phosphate, calcium carbonate, calcium sulfate, calcium silicate and bioactive glass.
Biological hydroxyl radicalThe chemical structural formula of apatite (hydroxyapatite HA) is Ca10(PO4)6(OH)2Is the main inorganic component of natural calcined bone and is also an active biological ceramic material.
The ideal bone repair material preferably has a continuous microporous structure resembling natural bone. The calcined bone treated at high temperature has obvious advantages as a bone repair material: the calcined bone has bone trabecula of original bone, trabecula gap and intraosseous cavity system, the continuous porous structure of the original natural bone is reserved, the size and the shape of micropores are suitable for the composition of cell regulatory factors and the growth of granulation tissues and new bone tissue cells, and the bone conduction is facilitated; secondly, the main component of the calcined bone is biological hydroxyapatite which is superior to artificially synthesized ceramic materials in the aspects of biocompatibility, physicochemical property, osteoconductivity and the like; the calcined bone can completely eliminate the antigenicity after being calcined at high temperature, does not generate immune rejection, has good biocompatibility, inhibits the immune response of a receptor, and prevents the spread of viruses; compared with the chemically synthesized hydroxyapatite, the calcined bone also contains other components, such as carbonate ions, magnesium, sodium, hydrogen phosphate composition ions and other trace elements, and particularly various trace elements play an important role in the bone repair and integration process. Therefore, the calcined bone powder is used as the raw material, and the prepared bioceramic artificial bone has better biocompatibility.
Beta-tricalcium phosphate (beta-TCP) is used as bioactive ceramics, is similar to minerals in natural bone matrixes in structure and composition, is a good bionic material, has high thermal stability, strong hardness and compressive strength and good bone conduction and biocompatibility, and is widely applied to bone repair materials.
The method for preparing the artificial bone by adopting the composite biological ceramic powder comprises the following steps:
(1) preparing calcined bone powder:
1) the method comprises the steps of taking limb bones of fresh and healthy adult animals (such as cattle, pigs, sheep and the like) as raw materials, cutting the limb bones into bone blocks with basically consistent sizes, soaking the bone blocks in cold water for 2 hours to remove blood water and impurities, washing the bone blocks for 3 times by running water, boiling the bone blocks in clear water for 90-150 min, and then removing tissues except the bones by using a bone knife to reduce the impurities and pollution as much as possible.
2) And (3) putting the treated bone blocks into a corundum crucible, calcining for 2h at 600 ℃ in a high-temperature box type furnace at the heating rate of 10 ℃/min, cooling along with the furnace, and forming the animal limb bones in the furnace into carbon black after calcining.
3) And putting the primarily calcined animal limb bones into a high-speed crusher to be crushed into powder, putting the powder into a high-temperature furnace to be secondarily calcined for 2 hours at 1000 ℃, wherein the heating rate is 10 ℃/min, and then cooling along with the furnace to form bone powder.
4) And (3) placing the calcined bone powder on a ball mill for grinding for 20 hours to prepare calcined bone powder with the particle size of about 1 mu m for later use.
(2) Composite biological ceramic powder: uniformly mixing the calcined bone powder and the biological ceramic powder in a certain proportion to form composite biological ceramic powder, wherein the biological ceramic powder is one or more of beta-tricalcium phosphate, calcium carbonate, calcium sulfate and calcium silicate;
(3) preparing printing slurry: uniformly mixing the composite biological ceramic powder and a binder to obtain printing slurry, then filling the printing slurry into a charging barrel, and defoaming to obtain uniform printable slurry, wherein the binder is polyvinyl alcohol, polylactic acid, polycaprolactone, polylactic acid-glycolic acid, polyethylene glycol or collagen;
(4) artificial bone three-dimensional model: CT data of a bone defect part of a patient are obtained, the data are processed by using 3D Slicer and three-dimensional CAD software, and an STL file of an artificial bone three-dimensional model suitable for a bone defect anatomical structure or special requirements is designed by the host bone prototype model.
(5)3D biological ceramic printing: the printing of the bioceramic artificial bone is carried out by using a 3D bioceramic printer (Xian Point cloud Biotechnology Co., Ltd.). Fixing a charging barrel filled with printable slurry on a 3D biological ceramic Printer, then loading the three-dimensional model artificial bone STL file designed in the step (4) into PC Printer software, setting printing parameters, and carrying out 3D printing, extrusion, deposition and molding to obtain a biological ceramic artificial bone primary blank.
(6) And (3) freeze drying: and (3) performing freeze-drying treatment on the printed bioceramic artificial bone blank by adopting a freeze-drying technology to obtain the composite bioceramic artificial bone.
The structure of artificial bone is usually porous to improve the rate of repair of artificial bone, reduce complications, and provide mechanical support for cell growth and function as well as physical and biochemical stimulation. In terms of the production process of artificial bones, the conventional methods for preparing artificial bones at present mainly include: although these conventional methods can produce porous scaffolds having different pore sizes and porosities, they are not capable of controlling the pore sizes, the interconnectivity of pores, the spatial orientation of pores, and the like, and are also difficult to produce porous scaffolds having arbitrary complex shapes. The 3D biological ceramic printer of the Xian point cloud biological technology limited company can solve the forming problem of the three-dimensional fine structure of the artificial bone by using an extrusion deposition forming technology. The extrusion deposition molding technology is a molding mode based on a continuous flow-state direct writing technology, and the working principle of the extrusion deposition molding technology is that fluid materials (ink or slurry) are extruded from a material pipe or a storage hopper by using pressure generated by compressed air, and the fluid materials are deposited in a continuous filament mode according to a designed path. The 3D bioceramic printing, extruding, depositing and forming technology is applied to the manufacturing process of artificial bones, can provide bone substitutes which are more inosculated with bone defect positions for patients, can provide more accurate and more intuitive bone substitute manufacturing conditions for doctors, and can enable artificial bone to form macro pores with 100% communication rate.
The freeze drying process can sublimate the water contained in the artificial bone of the biological ceramic from solid state to gas state directly, so that a large amount of micropore structures are formed on the surface and inside of the artificial bone, and the micropores are favorable for exchanging nutrient substances and ions, can effectively promote the growth of cells and improve the repair effect of the artificial bone.
The invention also carries out film covering on the surface of the prepared artificial bone to prepare the film-covered composite biological ceramic artificial bone, and the preparation method comprises the following steps:
(1) preparing the composite biological ceramic artificial bone according to the method;
(2) preparing an impregnating solution: the coating material is prepared into a uniform immersion liquid.
(3) Infiltrating and laminating: and (3) placing the composite biological ceramic artificial bone in a container filled with the impregnating solution, ensuring that the impregnating solution submerges the composite biological ceramic artificial bone, and carrying out infiltration and film coating.
(4) And (3) crosslinking treatment: and (3) crosslinking the composite bioceramic artificial bone subjected to the infiltration and film covering treatment by using a crosslinking agent, wherein the crosslinking agent can be genipin.
(5) And (3) freeze drying: and (3) freeze-drying the composite bioceramic artificial bone subjected to crosslinking treatment, removing water to form a microporous structure, and thus obtaining the coated composite bioceramic artificial bone.
(6) Packaging and sterilizing: and packaging the freeze-dried laminated composite bioceramic artificial bone, and performing irradiation sterilization treatment to obtain a finished product.
Polyvinyl alcohol belongs to water-soluble polymer, and can be dissolved in water together with silk fibroin to form a mixed system.
Common coating materials include chitosan, collagen, silk fibroin, polylactic acid and sodium alginate.
The chitosan is a linear polysaccharide from chitin partial deacetylation, has a chemical name of polyglucosamine (1-4) -2-amino-B-D glucose, has good biocompatibility, low toxicity, antibacterial property, immunoregulation activity, anticoagulation effect and biodegradability, and has biological functions of hemostasis, anti-inflammation, sterilization, wound healing promotion and organism immunity regulation.
The silk fibroin is a natural high molecular protein which is originated from silk and has high purity, easy purification and separation, no toxic and harmful effects on human bodies, good cell adhesion performance, excellent biocompatibility, capability of being hydrolyzed and degraded by protease and no toxic or side effect on tissues of degradation products.
By applying the bone guide membrane regeneration technology, the outer layer of the artificial bone can be coated with a membrane, so that a relatively closed environment is provided for bone formation, the embedding of fibrous soft tissue at the bone defect position is effectively prevented, and the bone regeneration is guided to accelerate bone repair. The method can be used for the large-segment bone defect, is not only beneficial to the repair of irregular bone defect, but also is not limited by the supply and demand of materials, and avoids secondary operation. At present, the bone-guiding regeneration membrane is widely applied, and the used materials mainly comprise terylene, polytetrafluoroethylene, titanium alloy, polyacetal and the like. The material has biological inertia and strong stability, does not react with the organism, can not be absorbed in the human body, needs to be taken out by a secondary operation, and increases the pain of a patient and the treatment time. The invention adopts chitosan, chitin and collagen to form the covering film, has good biocompatibility, biodegradability, and the time of film degradation is balanced with the time of tissue healing, when the tissue healing is finished, the film is degraded, the occupying effect can not be formed locally, the covering film can directly participate in tissue repair, the covering film does not need to be taken out after a secondary operation, and the covering film has remarkable advantages.
The bone guiding membrane can not only prevent connective tissue cells and epithelial cells from entering in the early stage of bone healing, avoid the competitive inhibition of the cells and cells with osteogenesis capacity, protect the stability of blood clots, but also create a bone growth space and allow osteoblasts to migrate and grow preferentially.
The bone guiding membrane isolates the contact of blood flow and blood vessel injury parts, prevents the formation of thrombus, simultaneously makes the surface of the artificial bone smoother, and reduces the adhesion and aggregation of blood platelets and the formation of acute thrombus. The film-coated artificial bone not only has the supporting function of common artificial bones, but also has the functions of preventing and treating thrombosis and intimal hyperplasia through mechanical barrier of the film and material products on the surface of the film.
Therefore, the invention combines the bone guiding membrane with the artificial bone, can effectively improve the bone repairing efficacy and simultaneously reduces the postoperative complications to a certain extent.
The laminated composite biological ceramic artificial bone can be prepared by the method. The artificial bone not only has good biocompatibility, bone conduction and bone induction, but also has the effects of preventing thrombosis and promoting wound healing.
Example 1: referring to fig. 1, the preparation method of the composite bioceramic artificial bone of the invention comprises the following steps:
(1) preparing calcined bone powder:
1) taking fresh and healthy adult calf bones as raw materials, cutting the adult calf bones into bone blocks with basically consistent sizes, soaking in cold water for 2h to remove blood water and impurities, washing for 3 times by running water, boiling in clear water for 90min, and removing tissues except the bones by using a boning knife to reduce the impurities and pollution as much as possible.
2) And (3) putting the treated bone blocks into a corundum crucible, calcining for 2 hours at 600 ℃ in a high-temperature box type furnace at the heating rate of 10 ℃/min, cooling along with the furnace, and enabling the ox leg bones in the furnace to be in a carbon black state after calcining.
3) Putting the primarily calcined bracket bones into a high-speed crusher for crushing treatment to form powder, then putting the powder into a high-temperature furnace for secondary calcination at 1000 ℃ for 2h, wherein the heating rate is 10 ℃/min, and then cooling along with the furnace to prepare calcined bone powder.
(2) Preparing a binder: mixing 4g of polyvinyl alcohol and 46g of water for injection, placing the mixture in a solvent bottle with a cover, heating and swelling the mixture in a water bath at 60 ℃ for 3h, and then stirring the mixture in a magnetic stirrer at 96 ℃ for 2.5h at the rotating speed of 130r/min to completely dissolve the mixture to prepare the adhesive.
(3) Mixing the prepared calcined bone meal and beta-tricalcium phosphate in a mass ratio of 1:1 to form composite biological ceramic powder, mixing the composite biological ceramic powder and a binder in a mass ratio of 1:1.07, placing the mixture in a homogenizer at a rotating speed of 1600r/min for 10min to form uniform printing slurry, then filling the printing slurry into a charging barrel, and defoaming to obtain the uniform printable slurry.
(4) Artificial bone three-dimensional model: acquiring image data of a bone defect part of a patient, processing the data by using 3D Slicer and three-dimensional CAD software to acquire a host bone prototype model, and designing an artificial bone three-dimensional model STL file suitable for a bone defect anatomical structure by using three-dimensional modeling software.
(5) Printing, extruding, depositing and forming the 3D biological ceramic: the printing of the bioceramic artificial bone is carried out by using a 3D bioceramic printer (Xian Point cloud Biotechnology Co., Ltd.). Firstly, fixing the charging barrel filled with printable slurry in the step (3) on a 3D biological ceramic Printer, then loading the STL file of the artificial bone three-dimensional model formed in the step (4) into PC Printer software, and setting the printing process parameters as follows: the printing speed is 9mm/s, the printing layer thickness is 120 microns, the average pore diameter is 430 microns, the printing slurry is extruded out at a constant speed through a spiral propeller, the workbench performs synthetic motion along the x-y axis, the printing head moves along the z axis, and the printing is sequentially performed layer by layer, so that the printing of the bioceramic artificial bone is finally completed.
(6) And (3) freeze drying: and (4) placing the bioceramic artificial bone formed in the step (5) in a freeze drying oven for cold drying for 24 hours to obtain an initial blank of the bioceramic artificial bone.
(7) Preparing an impregnating solution: 1.5g of chitosan was dissolved in 50ml of 2% glacial acetic acid solution, and the solution was magnetically stirred at room temperature to prepare a uniform wetting solution.
(8) And (4) placing the bioceramic artificial bone blank obtained in the step (6) in a container filled with an infiltration solution, ensuring that the artificial bone blank is completely in the infiltration solution, and infiltrating for 30min to coat a membrane.
(9) And (3) crosslinking treatment: firstly, placing the artificial bone subjected to the infiltration and film covering treatment in the step (8) in a genipin acetic acid aqueous solution with the mass ratio of 1%, and performing crosslinking treatment for 1 h; then washed to neutrality with copious amounts of deionized water.
(10) And (3) freeze drying: and (3) freeze-drying the biological ceramic artificial bone subjected to the cross-linking treatment for 36 hours by using a freeze dryer, and removing water to form a microporous structure.
(11) Packaging and sterilizing: and packaging the freeze-dried biological ceramic artificial bone, and performing irradiation sterilization treatment to obtain a finished product.
Example 2: see fig. 4
(1) Preparing calcined bone powder:
1) the method comprises the steps of taking fresh and healthy adult pig spinal bones as raw materials, cutting the adult pig spinal bones into bone blocks with basically the same size, soaking the bone blocks in cold water for 2 hours to remove blood water and impurities, washing the bone blocks for 3 times by running water, boiling the bone blocks in clear water for 90-150 min, and removing tissues except the bones by using a boning knife, so that the impurities and the pollution are reduced as much as possible.
2) And (3) putting the treated bone blocks into a corundum crucible, calcining for 2 hours at 600 ℃ in a high-temperature box type furnace at the heating rate of 10 ℃/min, cooling along with the furnace, and enabling the pig spinal bones in the furnace to be carbon black after calcining.
3) And putting the primarily calcined pig spinal bone into a high-speed crusher for crushing to form powder, putting the powder into a high-temperature furnace for secondary calcination at 1000 ℃ for 2 hours at the heating rate of 10 ℃/min, and then cooling along with the furnace to prepare calcined bone powder.
(2) Preparing a binder: dissolving 3g of collagen in 47g of 0.05mol/L acetic acid solution, placing on a magnetic stirrer, and stirring at the rotating speed of 220r/min for 60min to obtain a binder;
(3) mixing the prepared calcined bone meal, beta-tricalcium phosphate and calcium carbonate in a mass ratio of 1:1:1 to form composite biological ceramic powder, then mixing the composite biological ceramic powder and an adhesive in a mass ratio of 1:1.2, placing the mixture in a homogenizer at a rotating speed of 1800r/min for mixing for 8min to form uniform printing slurry, then filling the printing slurry into a charging barrel, and defoaming to obtain the uniform printable slurry.
(4) Artificial bone three-dimensional model: acquiring image data of a bone defect part of a patient, processing the data by using 3D Slicer and three-dimensional CAD software to acquire a host bone prototype model, and designing an artificial bone three-dimensional model STL file suitable for a bone defect anatomical structure by using three-dimensional modeling software.
(5) Printing, extruding, depositing and forming the 3D biological ceramic: the printing of the bioceramic artificial bone is carried out by using a 3D bioceramic printer (Xian Point cloud Biotechnology Co., Ltd.). Firstly, fixing the charging barrel filled with printable slurry in the step (3) on a 3D biological ceramic Printer, then loading the STL file of the artificial bone three-dimensional model formed in the step (4) into PC Printer software, and setting the printing process parameters as follows: the printing speed is 9mm/s, the printing layer thickness is 120 microns, the average pore diameter is 430 microns, the printing slurry is extruded out at a constant speed through a spiral propeller, the workbench performs synthetic motion along the x-y axis, the printing head moves along the z axis, and the printing is sequentially performed layer by layer, so that the printing of the bioceramic artificial bone is finally completed.
(6) And (3) freeze drying: and (4) placing the bioceramic artificial bone formed in the step (5) in a freeze drying oven for cold drying for 24 hours to obtain an initial blank of the bioceramic artificial bone.
(7) Preparing an impregnating solution: dissolving 2g of silk fibroin in 25g of formic acid solution, and magnetically stirring at normal temperature to prepare uniform soaking liquid.
(8) And (4) placing the bioceramic artificial bone blank obtained in the step (6) in a container filled with an infiltration solution, ensuring that the artificial bone blank is completely in the infiltration solution, and infiltrating for 30min to coat a membrane.
(9) And (3) crosslinking treatment: firstly, placing the artificial bone subjected to the infiltration and film covering treatment in the step (8) in a genipin acetic acid aqueous solution with the mass ratio of 1%, and performing crosslinking treatment for 1 h; then washed to neutrality with copious amounts of deionized water.
(10) And (3) freeze drying: and (3) freeze-drying the biological ceramic artificial bone subjected to the cross-linking treatment for 36 hours by using a freeze dryer, and removing water to form a microporous structure.
(11) Packaging and sterilizing: and packaging the freeze-dried biological ceramic artificial bone, and performing irradiation sterilization treatment to obtain a finished product.
Example 3:
(1) preparing calcined bone powder:
1) the method comprises the steps of taking fresh and healthy adult sheep chest bones as raw materials, cutting the fresh and healthy adult sheep chest bones into bone blocks with basically consistent sizes, soaking the bone blocks in cold water for 2 hours to remove blood water and impurities, washing the bone blocks for 3 times by running water, boiling the bone blocks in clear water for 90-150 min, and removing tissues except the bones by using a boning knife, so that the impurities and pollution are reduced as much as possible.
2) And (3) putting the treated bone blocks into a corundum crucible, calcining for 2 hours at 600 ℃ in a high-temperature box type furnace at the heating rate of 10 ℃/min, cooling along with the furnace, and calcining to form carbon black in the sheep thoracic cavity bone in the furnace.
3) Putting the primarily calcined sheep thoracic bones into a high-speed crusher for crushing to form powder, putting the powder into a high-temperature furnace for secondary calcination at 1000 ℃ for 2 hours at the heating rate of 10 ℃/min, and then cooling along with the furnace to prepare calcined bone powder.
(2) Preparing a binder: dissolving 9g of collagen in 42g of formic acid solution, placing on a magnetic stirrer, and stirring at a rotating speed of 220r/min for 60min to obtain a binder;
(3) mixing the prepared calcined bone meal, beta-tricalcium phosphate, calcium silicate and bioactive glass in a mass ratio of 4:1:1:1 to form composite biological ceramic powder, then mixing the composite biological ceramic powder and an adhesive in a mass ratio of 1:1.2, placing the mixture in a homogenizer at a rotating speed of 1800r/min for mixing for 8min to form uniform printing slurry, then filling the printing slurry into a charging barrel, and defoaming to obtain the uniform printable slurry.
(4) Artificial bone three-dimensional model: acquiring image data of a bone defect part of a patient, processing the data by using 3D Slicer and three-dimensional CAD software to acquire a host bone prototype model, and designing an artificial bone three-dimensional model STL file suitable for a bone defect anatomical structure by using three-dimensional modeling software.
(5) Printing, extruding, depositing and forming the 3D biological ceramic: the printing of the bioceramic artificial bone is carried out by using a 3D bioceramic printer (Xian Point cloud Biotechnology Co., Ltd.). Firstly, fixing the dispensing syringe filled with printable slurry in the step (3) on a 3D biological ceramic Printer, then loading the STL file of the artificial bone three-dimensional model formed in the step (4) into PC Printer software, and setting the printing process parameters as follows: the printing speed is 9mm/s, the printing layer thickness is 120 microns, the average pore diameter is 430 microns, the printing slurry is extruded out at a constant speed through a spiral propeller, the workbench performs synthetic motion along the x-y axis, the printing head moves along the z axis, and the printing is sequentially performed layer by layer, so that the printing of the bioceramic artificial bone is finally completed.
(6) And (3) freeze drying: placing the bioceramic artificial bone formed in the step (5) in a freeze drying oven for cold drying for 24 hours to obtain a primary blank of the bioceramic artificial bone;
(7) preparing an impregnating solution: 6g of sodium alginate is dissolved in 44ml of deionized water, and the mixture is magnetically stirred at normal temperature to prepare uniform soaking liquid.
(8) And (4) placing the bioceramic artificial bone blank obtained in the step (6) in a container filled with an infiltration solution, ensuring that the artificial bone blank is completely in the infiltration solution, infiltrating for 30min, covering a film, and then placing the blank in a ventilated and dry place for 2 d.
(9) And (3) crosslinking treatment: firstly, placing the artificial bone subjected to the infiltration and film covering treatment in the step (8) in a genipin acetic acid aqueous solution with the mass ratio of 1%, and performing crosslinking treatment for 1 h; then washed to neutrality with copious amounts of deionized water.
(10) And (3) freeze drying: and (3) freeze-drying the biological ceramic artificial bone subjected to the cross-linking treatment for 36 hours by using a freeze dryer, and removing water to form a microporous structure.
(11) Packaging and sterilizing: and packaging the freeze-dried biological ceramic artificial bone, and performing irradiation sterilization treatment to obtain a finished product.
X-ray diffraction of calcined bone powder prepared in example 1 confirmed that Ca was the main component10(PO4)6(OH)2Namely, the hydroxyapatite is biological hydroxyapatite, and is shown in figure 2.
The particle size of the calcined bone powder prepared in example 1 was measured, and the results are shown in FIG. 3. Particle size detection of the calcined bone powder shows that the content of the bone powder with the particle size within 10 mu m is 96.2 percent, the micron level can be achieved, and the 3D biological ceramic printing requirement can be met.
Calcined bone powder used alone has large brittleness and weak bone induction capability, and has small bone formation amount in the repair process. The strength of the artificial bone prepared by compounding the bone calcined bone powder and the biological ceramic powder is effectively improved compared with the strength of the artificial bone prepared by only using the calcined bone powder. The artificial bone prepared by calcined bone powder has the compression strength of 1.6 MPa. The compression strength of the artificial bone prepared by compounding the calcined bone powder and the biological ceramic powder is distributed between 3.7MPa and 7.6MPa, and the requirement on the mechanical property of the human cancellous bone with the compression strength of 2.6 to 4.1MPa can be met.
The separately applied membrane material has the disadvantages of poor mechanical property, high degradation speed, weak bone bonding force and the like, so that the combination of the guide membrane technology and the ceramic powder is a new way for treating bone defects. The infiltration coating method is simple, the hydrophilicity of the artificial bone is enhanced, and the adhesion rate of the artificial bone to cells can also reach 53 percent, so that the bone repair effect is effectively improved.
Claims (9)
1. The composite biological ceramic powder is characterized by comprising calcined bone powder and biological ceramic powder in parts by mass, wherein the mass ratio of the calcined bone powder to the biological ceramic powder is 1 (0.8-3), and the biological ceramic powder is one or more of beta-tricalcium phosphate, calcium carbonate, calcium sulfate, calcium silicate and bioactive glass.
2. A composite bioceramic artificial bone, prepared from the composite bioceramic powder of claim 1.
3. The method for preparing the composite bioceramic artificial bone according to claim 2, comprising:
(1) uniformly mixing the calcined bone powder, the biological ceramic powder and the binder to obtain slurry, then filling the slurry into a charging barrel, and defoaming to obtain uniform printing slurry; obtaining an artificial bone three-dimensional model according to CT data of a bone defect part of a patient;
(2) printing the slurry by using a biological ceramic 3D printer according to the three-dimensional model of the artificial bone to obtain the composite biological ceramic artificial bone, and performing freeze-drying treatment on the printed composite biological ceramic artificial bone.
4. The method for preparing the composite bioceramic artificial bone according to claim 3, wherein in the step (1), the binder is polyvinyl alcohol, polylactic acid, polycaprolactone, polylactic-glycolic acid, polyethylene glycol or collagen.
5. A coated composite bioceramic artificial bone, comprising the composite bioceramic artificial bone according to claim 2 and a guided bone regeneration coating on an outer surface of the composite bioceramic artificial bone.
6. The film-covered composite bioceramic artificial bone according to claim 5, wherein the raw materials for preparing the guided bone regeneration film comprise chitosan, silk fibroin, collagen, polylactic acid or sodium alginate.
7. The method for preparing the coated composite bioceramic artificial bone according to claim 5 or 6, comprising the following steps:
(1) uniformly mixing the calcined bone powder, the biological ceramic powder and the binder to obtain slurry, then filling the slurry into a charging barrel, and defoaming to obtain uniform printing slurry; obtaining an artificial bone three-dimensional model according to CT data of a bone defect part of a patient;
(2) printing the printing slurry by using a biological ceramic 3D printer according to the three-dimensional model of the artificial bone to obtain a composite biological ceramic artificial bone, and performing freeze-drying treatment on the printed composite biological ceramic artificial bone;
(3) soaking the freeze-dried composite bioceramic artificial bone in the step (2) in a soaking solution prepared from raw materials for preparing a guide bone regeneration membrane, and soaking and laminating;
(4) crosslinking the composite bioceramic artificial bone subjected to the infiltration and film covering treatment by using a crosslinking agent;
(5) and (3) freeze-drying the composite bioceramic artificial bone after the crosslinking treatment to obtain the film-coated composite bioceramic artificial bone.
8. The method for preparing the coated composite bioceramic artificial bone according to claim 7, wherein in the step (3), the preparation method of the impregnating solution comprises the following steps: dissolving chitosan, chitin and collagen in glacial acetic acid solution, and stirring to obtain the soaking solution.
9. The method for preparing the coated composite bioceramic artificial bone according to claim 8, wherein in the step (4), the crosslinking treatment specifically comprises: placing the composite biological ceramic artificial bone subjected to the infiltration and film covering treatment in a genipin acetic acid aqueous solution for crosslinking treatment; then washed with deionized water to neutrality.
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