CN111973811A - Zinc-containing artificial bone and preparation method thereof - Google Patents

Zinc-containing artificial bone and preparation method thereof Download PDF

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CN111973811A
CN111973811A CN202010888452.3A CN202010888452A CN111973811A CN 111973811 A CN111973811 A CN 111973811A CN 202010888452 A CN202010888452 A CN 202010888452A CN 111973811 A CN111973811 A CN 111973811A
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zinc
artificial bone
powder
bone
printing
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CN111973811B (en
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曾庆丰
益明星
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Xi'an Particle Cloud Biotechnology Co ltd
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Xi'an Particle Cloud Biotechnology Co ltd
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Abstract

The invention provides a zinc-containing artificial bone for bone tissue repair and a preparation method thereof, wherein the preparation raw materials comprise: zinc-containing powder, bioceramic powder and high-molecular polymer binder; the raw materials comprise the following components in percentage by mass: contains zinc powder 0.1-15 wt%, bioceramic powder 80-98 wt% and high molecular polymer adhesive 0.5-10 wt%. The preparation method of the zinc-containing artificial bone is prepared by a 3D printing process. The invention solves the problems of poor bone inductivity and poor bone performance of the traditional bioceramic artificial bone, and solves the problems of poor mechanical strength and difficulty in meeting the bone repair requirement of a bearing part of the traditional bioceramic artificial bone.

Description

Zinc-containing artificial bone and preparation method thereof
Technical Field
The invention belongs to the technical field of medical treatment, and relates to a zinc-containing artificial bone for clinical bone defect repair and a preparation method thereof.
Background
Bone defects are common clinical orthopedic diseases, and the defects are caused by various orthopedic diseases such as severe trauma, joint replacement, bone tumor excision, osteomyelitis, congenital deformity and the like. The most effective means for treating bone defects is to perform bone graft surgical repair. The development of clinical medicine and biological materials is always the direction of the adoption of the repair materials in the bone defect repair. Autologous bone grafting is always the most ideal bone grafting material, but the application of the autologous bone grafting is limited due to the defects of limited supply area, secondary operation, infection, supply area structure damage, residual pain and the like. Allogeneic bone has the advantages of tissue morphology, structure, strength, osteoinductive capacity and the like, but has potential risks of immunological rejection and disease transmission. The xenogeneic bone has the advantages similar to xenogeneic bone, but has the inevitable ethical problems, and the rejection reaction and the disease spread are more obvious. The above-mentioned shortcomings of the materials have made bone substitute materials a focus of research, and some new bone graft materials, including metals, organic materials, inorganic materials, etc., have been developed through long-term research and improvement. Among them, Hydroxyapatite (HA) and tricalcium phosphate (TCP) bioceramics are most similar in composition to human bone minerals. These two materials are most used in artificial bone implants for bone defect repair that are currently on the market. HA was first applied, but it degrades slowly or not substantially in the human body. Although beta-TCP has the advantage of biodegradability, the beta-TCP has poor mechanical strength and is difficult to meet the bone repair requirement of a load-bearing part. Therefore, the artificial bone prepared from the two materials singly or in combination has the defects of insufficient osteogenic performance and mechanical performance.
Chinese patent publication No. CN 103845762a discloses a method for preparing porous bone scaffold by laser and adding zinc oxide to improve performance, but it adopts laser sintering (SLS) process, where the temperature of laser spot irradiation is as high as 2000-3000 ℃, and the added zinc oxide is melted into liquid phase under high temperature condition to fill the gaps of ceramic powder to make it compact. While this is beneficial for improving mechanical properties, the biological activity of the zinc-containing component and the bioceramic material is sacrificed. The biological ceramic material and the zinc oxide are vitrified at high temperature by laser sintering, and the prepared artificial bone is difficult to biodegrade in vivo.
The chinese utility model patent document with publication number CN 210096010U discloses a bone tissue engineering scaffold, which is a main mesh scaffold made of metal titanium or zinc alloy and internally designed with metal support columns. Then zinc-based metal balls, fluffy balls rolled by metal wires and beta-TCP particles are filled on the metal main body grid support. Although the application is in the field of bone tissue engineering, the scaffold is a metal scaffold in essence. If titanium is used as the stent lattice body, it is known that titanium or titanium alloys are very stable and do not degrade. If zinc or zinc-based metal is completely used as the main body of the grid of the bracket, the whole bracket is almost completely made of zinc-based metal materials by adding the filled zinc-based metal balls. This has the problem that the cycle time is very long, in the short case of a few years and in the long case of a decade, in order to completely degrade the zinc. More seriously, the local zinc ion concentration is too high, and exceeds the safe concentration threshold (between 100 and 150 uM) of zinc ions, and the exceeding of the safe concentration threshold has toxicity and harm to the growth of cells around tissues. This is unacceptable as a medical implant.
Chinese patent publication No. CN 110508788A discloses a method for preparing a tissue engineering scaffold made of zinc or zinc alloy or composite material thereof, which comprises preparing a polylactic acid porous scaffold by 3D printing, and then coating the polylactic acid scaffold with gypsum and salt perfusion slurry by investment casting. Dissolving and removing the polylactic acid at 560-650 ℃, then casting zinc or zinc alloy molten metal liquid into the die turnover body, and finally washing off the wrapping material. Obtaining the zinc or zinc-based metal porous bracket. The principle is the principle of investment casting, and the obtained zinc or zinc-based metal bracket is also the principle of investment casting. The metal bracket is different from the biological ceramic bracket in main material.
In addition, chinese patent publication No. CN 111012949a discloses a method for preparing a zinc ion-containing tissue engineering scaffold with anti-inflammatory function. The patent skillfully applies the advantage of the anti-inflammatory function of zinc ions, but the patent discloses a cartilage tissue engineering scaffold which takes Wharton's jelly as a scaffold main body and induces the deposition of zinc ions, and is applied to the field of cartilage repair.
Disclosure of Invention
The invention aims to provide a zinc-containing artificial bone for bone tissue repair and a preparation method thereof, which solve the problems of poor bone inductivity and poor bone performance of the traditional bioceramic artificial bone and solve the problems of poor mechanical strength and difficulty in satisfying bone repair of a bearing part of the traditional bioceramic artificial bone.
The invention is realized by the following technical scheme:
a zinc-containing artificial bone is prepared from raw materials including: zinc-containing powder, bioceramic powder and high-molecular polymer binder; the raw materials comprise the following components in percentage by mass: contains zinc powder 0.1-15 wt%, bioceramic powder 80-98 wt% and high molecular polymer adhesive 0.5-10 wt%.
Preferably, the zinc-containing powder is any one or a mixture of more of pure zinc powder, zinc-based metal powder, zinc oxide, zinc hydroxide powder and zinc chloride powder.
Furthermore, the zinc-based metal powder contains zinc and alloy elements, and the alloy elements are any one or the combination of at least two of Mg, Li, Fe, Ag, Ca, Sr and Mn elements.
Preferably, the bioceramic powder is one or a combination of at least two of hydroxyapatite, tricalcium phosphate, calcium sulfate, calcium silicate, calcium carbonate, calcium magnesium silicate and bioactive glass.
Preferably, the high molecular polymer adhesive is one or more of polyvinyl alcohol, poly (D-lactic acid), poly (L-lactic acid), poly (racemic lactic acid-poly (glycolic acid)), poly (lactic acid-co-glycolic acid), polycaprolactone, phosphoric acid, photosensitive resin, chitosan, gelatin, hyaluronic acid and sodium alginate.
The preparation method of the zinc-containing artificial bone is prepared by a 3D printing process.
Preferably, the 3D printing process is a filament-free extrusion 3D printing process, a powder spreading 3D printing process or a photocuring 3D printing process.
Further, the filament-free extrusion 3D printing process comprises the following steps:
(1) preparing paste: uniformly mixing biological ceramic powder and zinc-containing powder to obtain a solid material, and adding water into a high-molecular polymer binder to dilute into an aqueous solution to obtain a liquid material; mixing the solid material and the liquid material, uniformly stirring, and performing defoaming treatment to obtain a paste body;
(2) artificial bone three-dimensional model: establishing a three-dimensional model of a standard part by using three-dimensional modeling CAD software or acquiring a three-dimensional model of a defect part by using CT data of a patient, and designing a G code file for printing the artificial bone by using the three-dimensional model by using 3D Slicer software and FreeCAD software;
(3) 3D printing without silk extrusion: printing the artificial bone according to the G code file by using a 3D biological ceramic printer;
(4) and (3) freeze drying: and (4) carrying out freeze drying on the artificial bone prepared by the filament-free extrusion 3D printing in the step (3) to obtain the zinc-containing artificial bone.
Preferably, the powder laying 3D printing process is as follows:
(1) preparing materials: mixing the biological ceramic powder and the zinc-containing powder, uniformly stirring, and then spreading the obtained powder in a printer bin; preparing a binder;
(2) artificial bone three-dimensional model: designing a porous artificial bone model by using three-dimensional modeling CAD software, and deriving STL format data;
(3) powder bonding three-dimensional printing: inputting STL format data derived in the step (2) into a 3D printer, reading the three-dimensional cross section information data of the artificial bone by using the 3D printer, spraying a binder according to the three-dimensional cross section information data of the artificial bone, and selectively bonding a biological ceramic material and a zinc powder-containing material in a printer bin together to obtain the artificial bone;
(4) and (3) drying: and (4) after the step (3) is finished, drying the artificial bone, and blowing off the non-bonded powder to obtain the zinc-containing artificial bone.
Preferably, the preparation method of the photocuring 3D printing zinc-containing artificial bone comprises the following steps:
(1) preparing the photocuring slurry: mixing the biological ceramic powder, the zinc-containing powder and the photosensitive resin, and uniformly stirring;
(2) artificial bone three-dimensional model: designing a three-dimensional model of the artificial bone by utilizing CAD software in a computer, connecting the computer with a DLP photocuring ceramic 3D printer in a data mode, and forming the three-dimensional model into a numerical control program by software matched with the DLP photocuring ceramic 3D printer;
(3) carrying out three-dimensional printing by using a DLP photocuring ceramic 3D printer, and taking out the molded artificial bone after printing is finished;
(4) cleaning: putting the artificial bone printed and formed in the step (3) into cleaning fluid for cleaning;
(5) and (3) sintering: and (4) placing the artificial bone cleaned in the step (4) into a sintering furnace for sintering, and then cooling along with the furnace to obtain the zinc-containing artificial bone.
Compared with the prior art, the invention has the following beneficial technical effects:
zinc (Zn) is an essential element for human body, 90% of zinc element in human body is stored in muscle and skeleton, is one of the most important elements in the processes of protein synthesis and energy metabolism, participates in a large amount of physiological reaction processes of human body cell development and growth, gene expression, immune system, nervous system and the like, has good effect of promoting osteogenesis, and can enrich mesenchymal stem cells. Zinc plays an important role in the normal development, metabolism and function of bones. Zinc can stimulate the growth of bone, has special direct stimulation effect on the proliferation of osteoblast, and has certain inhibition effect on osteoclast. Because the standard electrode potential (-0.763V) of zinc is lower, zinc can be electrochemically degraded in human body and release zinc ions, and the zinc ions can promote bone formation and mineralization, the zinc with excellent bone formation performance can be used as a beneficial component of an ideal artificial bone material. The artificial bone prepared by adding the zinc powder in the normal temperature environment has the advantages of good bone performance promotion and biodegradability, and the mechanical strength of the artificial bone is greatly improved, so that the requirement of bone defect repair of a bearing part can be met. According to the artificial bone provided by the invention, the beneficial element zinc is added, and the problem that the traditional bioceramic artificial bone has poor bone inductivity and poor bone performance due to the good bone performance promotion of zinc ions is solved. Meanwhile, zinc powder is used as a granular reinforcing phase, and the addition of the zinc powder brings dispersion strengthening of the artificial bone, so that the problems that the traditional bioceramic artificial bone is poor in mechanical strength and difficult to meet the bone repair requirement of a bearing part are solved.
Furthermore, the biological functionality of zinc-based metal is also worth paying attention, and after different alloy elements (such as Mg, Li, Fe, Ag, Ca, Sr and Mn) are endowed, the biological function of promoting bone to inhibit bone fracture can be further optimized, and the bone defect repairing material can be prepared on the basis of the biological function.
The artificial bone is prepared by adopting an additive manufacturing (3D printing) process. The porosity, the pore size, the pore spacing, the pore connectivity, the pore distribution characteristics and the like in the porous structure are accurately designed and manufactured, a channel for nutrition delivery and metabolic discharge and a microenvironment for cell adhesion and growth are provided for stem cell tissues around bone defects, and the growth and the regeneration repair of new bone tissues are facilitated.
Drawings
Fig. 1 is a diagram of a pure zinc-containing artificial bone object prepared by adopting filament-free extrusion 3D printing.
Fig. 2 is a scanning electron microscope photograph of a pure zinc-containing artificial bone prepared by filament-free extrusion 3D printing.
Fig. 3 is a photo-curing 3D printed zinc-containing artificial bone object diagram.
Fig. 4 is a zinc-containing artificial bone implanted in the medullary cavity of rabbit after 4 weeks of operation.
Fig. 5 is a diagram of a conventional artificial bone implanted in the medullary cavity of a rabbit after 4 weeks.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is illustrated by the following specific examples and drawings, but is by no means limited thereto. The following is a description of the preferred embodiments of the present invention, and should not be taken as limiting the invention, but rather as embodying the invention in its broadest form and as indicating any variations, equivalents and modifications within the spirit and scope of the present invention.
The zinc-containing artificial bone provided by the invention comprises raw materials of zinc-containing powder, biological ceramic powder and a high molecular polymer binder.
The raw material of the artificial bone comprises 0.1-15% of zinc powder by mass, such as 2%, 4%, 5%, 8%, 10%, 11%, 12%, 13%, 14% and the like, based on 100% of the total mass. The biological ceramic material accounts for 80-98% of the components of the artificial bone by mass percent. The high molecular polymer adhesive accounts for 0.5-10% of the artificial bone composition by mass.
The zinc-containing powder of the present invention refers to particles having a particle size of micro-or nano-scale and containing zinc element, which may include various forms such as pure zinc, zinc-based metal, zinc oxide, zinc chloride, zinc hydroxide, etc. The zinc-containing powder is selected from any one of pure zinc powder, zinc-based metal powder, zinc hydroxide powder or zinc chloride powder or the combination of at least two of the pure zinc powder, the zinc-based metal powder, the zinc hydroxide powder or the zinc chloride powder. The zinc-based metal contains small amounts of other alloying elements, such as any one or a combination of at least two of the elements Mg, Li, Fe, Ag, Ca, Sr, Mn. The zinc-based metal comprises the following components, by mass, 0.1-20% of alloy elements and the balance of zinc, wherein the total mass of the components is 100%.
The zinc-containing powder has a particle size of 10nm to 100 μm, for example, 20nm, 40nm, 50nm, 100nm, 500nm, 1 μm, 5 μm, 10 μm, 50 μm, 80 μm, etc.
The biological ceramic material comprises one or a combination of at least two of Hydroxyapatite (HA), tricalcium phosphate (TCP), calcium sulfate, calcium silicate, calcium carbonate, calcium magnesium silicate and bioactive glass.
The high molecular polymer adhesive comprises one or any combination of polyvinyl alcohol (PVA), dextrorotatory polylactic acid (PDLA), levorotatory polylactic acid (PLLA), racemic polylactic-co-glycolic acid (PDLLA), polylactic-co-glycolic acid (PLGA), Polycaprolactone (PCL), phosphoric acid, photosensitive resin, chitosan, gelatin, hyaluronic acid or sodium alginate. The high molecular polymer adhesive has good biocompatibility, is easy to process, and has elasticity and biodegradability.
The invention provides a preparation method of the zinc-containing artificial bone, which is prepared by an additive manufacturing (3D printing) process. The preparation method of additive manufacturing (3D printing) can be a filament-free extrusion 3D printing process, a powder spreading 3D printing process or a photocuring 3D printing process. All of which can prepare the zinc-containing artificial bone through proper binder selection and process adjustment.
The preparation method of the filament-free extrusion 3D printing zinc-containing artificial bone comprises the following steps:
(1) preparing paste: weighing the biological ceramic powder and the zinc-containing powder in proportion, uniformly mixing to obtain a solid material, and diluting the high-molecular polymer binder into a water solution with a certain concentration to obtain a liquid material. Mixing the solid material and the liquid material, uniformly stirring, and defoaming to obtain an extrudable paste;
(2) artificial bone three-dimensional model: establishing a three-dimensional model of a standard part by using three-dimensional modeling CAD software or acquiring a three-dimensional model of a defect part by using CT data of a patient, and designing a G code file for printing the artificial bone by using the three-dimensional model by using 3D Slicer software and FreeCAD software;
(3) 3D printing without silk extrusion: the artificial bone is printed by a 3D biological ceramic printer (Xian Point cloud Biotechnology Co., Ltd.). Firstly, filling the uniform paste in the step (1) into a charging barrel, then connecting the uniform paste into a printing head, then loading the artificial bone G code file designed in the step (2) into PC Printer software, setting printing parameters, and carrying out filament-free extrusion 3D printing to obtain the zinc-containing artificial bone with the porous structure;
(4) and (3) freeze drying: and (4) carrying out freeze drying on the artificial bone prepared by the filament-free extrusion 3D printing in the step (3) at-60 ℃ for 16-24 h to obtain a final zinc-containing artificial bone finished product.
The zinc-containing artificial bone prepared by the method. The preparation method has the advantages that the zinc-containing powder and the ceramic powder are uniformly mixed, and the 3D printing forming is carried out under the action of the high molecular polymer binder. The zinc-containing powder and the biological ceramic powder are physically mixed, so that the modification and denaturation of zinc-containing components caused by high-temperature sintering and other processes are avoided. Thereby ensuring the normal release and degradation of the zinc-containing component. In addition, the artificial bone containing zinc in the porous structure is prepared by the filament-free extrusion 3D printing, and the pore diameter, the pore spacing, the filament diameter, the pore connectivity and the like of the porous structure can be accurately designed and manufactured by a computer. The pore size requirement (about 200-. The hole connectivity is as high as more than 95%. The zinc-containing artificial bone prepared by the method not only has good bone conduction and bone inductivity, but also has excellent bone performance.
The preparation method of the powder-laying 3D printing zinc-containing artificial bone comprises the following steps:
(1) preparing a binder: for example, phosphoric acid is dissolved in pure water to obtain a diluted phosphoric acid solution. Or dissolving polylactic acid, polyglycolic acid, polycaprolactone and the like in an organic solvent to obtain a diluted macromolecular polymer binder with a certain proportion;
(2) artificial bone three-dimensional model: designing a porous artificial bone by using three-dimensional modeling CAD software (for example, setting geometric parameters such as length, width, height or diameter, and the like, setting parameters such as porosity, large pore diameter, pore spacing and the like, and deriving STL format data;
(3) powder spreading and printing: inputting the STL format data derived in the step (2) into a 3D printer (Zprinter250, 3D Systems, USA), reading the three-dimensional porous structure section information data of the artificial bone by the 3D printer, selectively adhering the biological ceramic material and the zinc powder-containing material together to form a section profile by controlling a nozzle and spraying a binder, and gradually advancing layer by layer to finally obtain a molded artificial bone; the powder spreading thickness is 0.1mm in the printing process, and the controlled dosage of the adhesive is 0.3L/m2。
(4) And (3) drying: and (4) after the printing in the step (3) is finished, drying the artificial bone in a drying oven for 2 hours (the drying temperature is maintained at 50 ℃), taking out the artificial bone, and blowing off the non-bonded powder by using compressed air to obtain a zinc-containing artificial bone finished product.
The zinc-containing artificial bone prepared by the method. The geometric dimension of the material is basically consistent with the design dimension. And uniformly mixing the powder. The zinc-containing powder is physically combined with the bioceramic powder without modification or denaturation reaction. Other process advantages are similar to the filament-free extrusion 3D printing method, and the description is not repeated.
The preparation method of the photocuring 3D printing zinc-containing artificial bone comprises the following steps:
(1) preparing the photocuring slurry: weighing the biological ceramic powder with the particle size smaller than the layer thickness (50 mu m), the zinc-containing powder and the photosensitive resin according to a certain proportion, mixing and stirring uniformly;
(2) artificial bone three-dimensional model: designing a three-dimensional model of the artificial bone by utilizing CAD software in a computer, connecting the computer with a DLP photocuring ceramic 3D printer in a data mode, and forming the three-dimensional model into a numerical control program by software matched with the DLP photocuring ceramic 3D printer;
(3) DLP photocuring ceramic 3D printer (Xian cloud biotechnology limited), carry out three-dimensional printing. The printing was carried out automatically layer by layer, the layer thickness being 50 μm. Taking out the molded artificial bone after printing;
(4) cleaning: putting the artificial bone printed and formed in the step (3) into cleaning fluid for cleaning;
(5) and (3) sintering: and (4) putting the artificial bone cleaned in the step (4) into a sintering furnace, keeping the temperature at 1150 ℃ for 2 hours, and cooling along with the furnace to obtain a zinc-containing artificial bone finished product.
The zinc-containing artificial bone prepared by the photocuring 3D printing method has the advantages that the photocuring process can manufacture extremely complex geometric shapes, and the geometric dimension precision is very high. Is particularly suitable for designing special hole patterns such as circles, ellipses, rhombuses and the like. And can accurately design and manufacture the artificial bone with the porous structure with the characteristic of complex pore distribution. Such as compact hole patterns of the outer cortical-bone-like layer and loose hole patterns of the inner cancellous bone-like layer, can only be realized by photocuring 3D printing. The strength of the artificial bone after sintering is very high, and the artificial bone is particularly suitable for repairing bone defects of load-bearing parts. Pure zinc or zinc-containing components are oxidized to zinc oxide, and both zinc hydroxide and zinc oxide can be dissolved in simulated body fluid to release zinc ions which are beneficial to bone function.
The zinc-containing artificial bone provided by the invention can achieve the purpose of regulating and controlling the release amount and release rate of zinc ions. Firstly, the zinc element accounts for the mass percentage of the artificial bone, and the zinc element content in the unit area of the artificial bone is determined, so that the zinc ion release amount of the artificial bone in unit time is directly influenced. Secondly, the high molecular polymer adhesive can interact with the free degraded zinc ions, and can successfully load the zinc ions and release the zinc ions through slow release. The zinc ion is induced to differentiate into osteoblasts in the whole bone repairing process, and the requirements of different implantation positions and different implantation time on the degradation rate of the zinc ion in the artificial bone are met.
When the artificial bone is applied to the focus part, the artificial bone is soaked by body fluid. The zinc containing component is soaked by surrounding body fluid and slowly degraded. Research shows that the degradation products of pure zinc in vivo are respectively the hydrozincite Zn5(OH)8Cl2·H2O, zinc oxide ZnO and hydrozincite Zn5(CO3)2(OH)6They are soluble salts and precipitate zinc ions. Since the high molecular polymer binder in the artificial bone contains functional groups capable of interacting with zinc ions, the functional groups of these organic substances include carboxyl, phosphate, phenolic hydroxyl, and the like. The functional group can produce interaction such as chelation, cross-linking or electrostatic binding with zinc ions to form a functional compound loaded with zinc ions. This slows the rate of zinc degradation in vivo, since the repair cycle of bone tissue is relatively long, typically taking 3 to 6 months. The mutual combination of the functional groups in the high molecular polymer binder and the zinc ions is helpful for regulating and controlling the degradation and release rate of the zinc ions. The concentration threshold of zinc ions is far lower than 100uM (the research shows that the concentration threshold of zinc ions with obvious cytotoxicity is between 100 and 150 uM).
The content of zinc element in the artificial bone is controlled, and the total release amount of zinc ions can be controlled. Meanwhile, the concentration or the content of the high molecular polymer binder is controlled, so that the amount of functional groups such as carboxyl, phosphate or phenolic hydroxyl in the organic matter is indirectly regulated and controlled. The quantity of functional groups is small, the quantity of loaded zinc ions is small, and the quantity of free zinc ions is large. On the contrary, the number of functional groups is large, the number of loaded zinc ions is large, the free zinc ions are reduced, and the release speed of the zinc ions is slowed down. In addition, the degradation cycles of different high molecular weight polymeric binders are different. For example, the complete degradation cycle of poly (L-lactic acid) (PLLA) is about 24 months, while the degradation cycle of poly (lactic-co-glycolic acid) (PLGA) is 6-12 months. Therefore, the release rate of zinc ions can be regulated by using different types of binders.
Realizes the regulation of the release amount and the release rate of the zinc ions, leads the zinc ions to be continuously and slowly released, induces the stem cells to be differentiated into osteoblasts, and is matched with the rate of new bone generation. After the bone tissue regeneration and repair are completed, the high molecular polymer binders are all biodegradable within one to two years, and zinc ions are finally released along with the degradation of the high molecular polymer binders. In addition to being absorbed by bone tissue and muscle tissue, the excess zinc ions are metabolized by body fluids and discharged from the body.
EXAMPLE 1 preparation of Artificial bone containing pure Zinc (extrusion without filaments)
(1) The biological ceramic material is selected to be mixed powder of beta-tricalcium phosphate (beta-TCP) and Hydroxyapatite (HA), and the mixing ratio of the beta-tricalcium phosphate (beta-TCP) to the Hydroxyapatite (HA) is 3.5: 1. The grain diameter of the powder is 10-20 μm. The zinc-containing component is selected to be pure zinc powder with the purity higher than 99 percent and the grain diameter of the pure zinc powder is 10-20 mu m. Selecting polyvinyl alcohol (PVA) as a high molecular polymer binder;
(2) preparing materials: according to the mass ratio, the pure zinc powder is 10 percent, the biological ceramic powder (mixed by beta-TCP and HA) is 84.5 percent, the polyvinyl alcohol is 5.5 percent, and the ingredients are mixed. The method comprises the specific steps of preparing 8g of polyvinyl alcohol and 92g of pure water into a polyvinyl alcohol aqueous solution with the mass fraction of 8%, placing the polyvinyl alcohol aqueous solution in a wide-mouth bottle with a cover, heating and swelling the wide-mouth bottle in a water bath at 60 ℃ for 2 hours, and then stirring the wide-mouth bottle in a magnetic stirrer at 96 ℃ at the rotating speed of 250r/min for 2 hours to completely dissolve the polyvinyl alcohol aqueous solution to form a uniform solution. 23.58 g of the aqueous polyvinyl alcohol solution was weighed out and used. 22.45 g of beta-tricalcium phosphate (beta-TCP), 6.41 g of Hydroxyapatite (HA) and 3.27 g of pure zinc powder are weighed.
(3) Preparing a printing paste: and (3) pouring all the solid powder and the solution weighed in the step (2) into a stainless steel stirring cup and tightly covering the stainless steel stirring cup. Stirring in vacuum stirrer at 2000r/min for 4 times (1 min each time), placing into charging barrel, defoaming in homogenizer at 3000r/min for 2 times (2.5 min each time) to obtain uniform printing paste;
(4) artificial bone three-dimensional model: establishing a standard part three-dimensional model by using three-dimensional modeling CAD software, and designing a G code file for printing the artificial bone by using 3D Slicer software and FreeCAD software;
(5) silkless 3D printing: the artificial bone is printed by a 3D biological ceramic printer (Xian Point cloud Biotechnology Co., Ltd.). Firstly, the uniformly mixed printing paste in the step (3) is loaded into a printing head, then the designed artificial bone G code file in the step (4) is loaded into PC Printer software, and the parameters of the printing process are set as follows: the printing speed is 10mm/s, the printing layer height is 0.3mm, the filling rate is 30%, the slurry is uniformly extruded 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) refrigerating: placing the printed biological ceramic artificial bone in the step (5) in a refrigerator at the temperature of minus 80 ℃ for storage;
(7) and (3) freeze drying: freeze-drying the refrigerated artificial bone of (6) at-60 deg.C for 16 h.
(8) And (3) sterilization: and (4) packaging the freeze-dried artificial bone in the step (7), and then performing irradiation sterilization treatment to obtain a zinc-containing artificial bone finished product.
The photo of the zinc-containing artificial bone material prepared in this example 1 is shown in fig. 1, and the scanning electron micrograph is shown in fig. 2.
EXAMPLE 2 preparation of Zinc-magnesium alloy-containing Artificial bone (powder-spreading and adhesive-spraying)
(1) In the embodiment, the selected biological ceramic material is a mixture of calcium magnesium silicate and calcium sulfate, the mixing ratio of the calcium magnesium silicate and the calcium sulfate is 1:1, and the particle size of the powder is 10 μm. Selecting zinc-containing component as zinc-magnesium binary alloy powder; the magnesium content in the zinc-magnesium alloy is 5 percent of the total mass fraction of the zinc-magnesium alloy, and the balance is zinc. The grain diameter of the zinc-magnesium alloy powder is 10 mu m. Selecting phosphoric acid as a binder;
(2) preparing materials: according to the mass ratio, 15 percent of zinc-containing magnesium alloy powder, 84.5 percent of mixture of calcium magnesium silicate and calcium sulfate and 0.5 percent of phosphoric acid are mixed. 150 g of zinc-magnesium alloy powder, 845 g of mixed powder of calcium magnesium silicate and calcium sulfate (the mixing ratio is 1:1) and 5 g of phosphoric acid in the above proportion are weighed by balance. After weighing, a binder is prepared, and 5 g of phosphoric acid is diluted by pure water to form a phosphoric acid solution with the mass fraction of 8.75% to be used as the binder for powder spreading and printing. Mixing calcium magnesium silicate, calcium sulfate and zinc-magnesium alloy powder, uniformly stirring, and then flatly paving the powder in a printer bin. The nozzle of the printer is adjusted to smoothly and continuously spray the adhesive.
(3) Designing a macroporous artificial bone model (with the height of 3mm, the diameter of 10mm, the porosity of 70% and the diameter of a macropore of 600 mu m) by using three-dimensional modeling CAD software, and deriving data in STL format;
(4) powder spreading and printing: inputting STL format data derived from the model designed in the step (3) into a 3D printer (Zprinter250, 3D Systems, USA), starting a printing instruction, reading the three-dimensional cross section information data of the artificial bone by the printer, selectively adhering powder in a material box together to form a cross section profile by controlling a nozzle and spraying an adhesive, wherein the powder laying thickness is 0.1mm in the printing process, and the control dosage of the adhesive is 0.3L/m2. And (5) progressing layer by layer to obtain the whole artificial bone.
(5) And (3) drying: after the printing in the step (4) is finished, the artificial bone is placed in a drying oven to be dried for 2 hours (the drying temperature is maintained at 50 ℃), then the artificial bone is taken out, and the non-bonded powder is removed by using compressed air.
(6) And (3) sterilization: and (5) packaging the dried and cleaned artificial bone obtained in the step (5), and performing irradiation sterilization treatment to obtain a zinc-containing artificial bone finished product.
Example 3 preparation of Zinc oxide-containing Artificial bone (photocured 3D printing)
(1) The biological ceramic material is selected to be tricalcium phosphate (TCP), the purity is higher than 95 percent, and the particle size of the powder is 20 mu m. The zinc-containing component is selected to be zinc oxide powder with the particle size of 20 μm. Selecting photosensitive resin as a high molecular polymer binder;
(2) preparing the photocuring slurry: according to the mass ratio, 0.1 percent of zinc oxide powder, 89.9 percent of beta-tricalcium phosphate and 10 percent of photosensitive resin. Weighing a mixture with the total mass of 2000 g according to the proportion, uniformly stirring, and pouring into a material box of a DLP photocuring ceramic 3D printer;
(3) artificial bone three-dimensional model: designing a three-dimensional model of the artificial bone by utilizing CAD software in a computer, connecting the computer with a DLP photocuring ceramic 3D printer in a data mode, and forming the three-dimensional model into a numerical control program by software matched with the DLP photocuring ceramic 3D printer;
(4) DLP photocuring ceramic 3D printer (Xian cloud biotechnology limited), carry out three-dimensional printing. The layer-by-layer ultraviolet irradiation printing is carried out, and the layer thickness is 50 micrometers. Taking out the molded artificial bone after printing;
(5) cleaning: putting the artificial bone printed and formed in the step (4) into 95% ethanol cleaning solution for cleaning;
(6) and (3) sintering: and (4) placing the artificial bone cleaned in the step (5) into a sintering furnace, sintering for 2h at the temperature of 1150 ℃, and cooling along with the furnace.
(7) And (3) sterilization: and (4) packaging the artificial bone sintered in the step (6) and performing irradiation sterilization treatment to obtain a zinc-containing artificial bone finished product.
The photograph of the zinc-containing artificial bone object prepared in this example 3 is shown in fig. 3, and the test results of the compressive load resistance are shown in table 2. The artificial bone of the embodiment has very high strength, and is particularly suitable for repairing bone defects of load-bearing parts.
Performance testing
The zinc-containing artificial bones provided in examples 1, 2 and 3 were subjected to performance tests by the following methods:
(1) zinc ion release amount: soaking artificial bone samples with the same size in phosphate buffer solution PBS with the same volume, placing the artificial bone samples in an incubator at 37 ℃, taking out all PBS soaking solutions after soaking for a period of time, adding a new PBS solution with the same volume, and measuring the total release amount of zinc ions at days 1, 3, 7, 14, 21 and 27.
The results of the tests on example 1, example 2 and example 3 are shown in table 1.
TABLE 1 table for measuring release amount of zinc ion
Figure BDA0002656236850000151
Table 1 shows the maximum zinc ion release, the maximum release in example 2, the moderate release in example 1, and the minimum release in example 3. This is due to a number of reasons. First, the pure zinc powder in example 1 accounted for 10% by mass, the zinc-magnesium alloy powder in example 2 accounted for 15% (the magnesium content was small), and the zinc oxide powder in example 3 accounted for 0.1% by mass. From the content of zinc, the zinc content is different by more than 100 times, the quantity of the zinc contained in the artificial bone per unit area is different, and the corresponding difference exists in the release amount of zinc ions through reaction. Furthermore, different types of binders and different binder contents also affect the release rate of zinc ions. Such as phosphoric acid in example 2, degrades faster than the polyvinyl alcohol in example 1. Indirectly affects the release rate of zinc ions, and example 2 is also faster than example 1. The release amount of zinc ions in example 3 was small, and in addition to the minimal zinc element content (0.1%) itself, the photosensitive resin was also an important factor affecting the low release rate of zinc ions.
(2) And (3) testing the compressive strength: samples of the zinc-containing artificial bones (cubes 10mm in length, 10mm in width and 10mm in height) provided in examples 1 and 3 were subjected to a maximum pressurizing load by a microcomputer-controlled electronic universal tester with a pressurized area of 10mm × 10mm at a rate of 1mm/min, according to GB/T1964-. The compression load was measured in N. Example 2 did not participate in the compressive strength test because of the inconsistent sample size.
The model of the microcomputer control electronic universal tester used for mechanical property test is RGM, and the manufacturer is manufactured by Shenzhen Riger apparatus Limited. The test method is GB/T1964-1996 test method for the compression strength of the porous ceramic.
Examples 1 and 3 each tested 4 samples and compared to a conventional artificial bone (HA + TCP) under the same conditions. The test results are shown in Table 2. The average compressive load of the zinc-containing artificial bone obtained in example 1 was measured to be 348.2N, which is more than 2 times that of the conventional artificial bone (HA + TCP). The pure zinc powder is used as a granular reinforcing phase, and the addition of the pure zinc powder brings about dispersion strengthening of the artificial bone, so that the mechanical strength of the zinc-containing artificial bone is improved by times. The average compressive load of the artificial bone containing zinc obtained in example 3 was 1175.5N. This is because the strength of tricalcium phosphate and zinc oxide is greatly enhanced after sintering, the melting point of zinc oxide is 1975 ℃, the sintering of the invention is carried out at 1150 ℃ and can not reach the melting point, thus the materials can not be vitrified and still can be degraded, and in order to consider the degradation performance of the artificial bone, the tricalcium phosphate and zinc oxide which are raw materials and can be dissolved in simulated body fluid are selected in the embodiment 3, and the zinc ions which are beneficial to promoting the bone formation are slowly released. The artificial bone of the embodiment 3 has very high strength, slow degradation speed, less zinc ion release amount and slow release rate, and is particularly suitable for repairing bone defects of load-bearing parts. Such as repairing and treating bone defects of cervical vertebra, spine, etc.
TABLE 2 comparative test results of compressive load resistance of artificial bone containing zinc and conventional artificial bone
Figure BDA0002656236850000161
Figure BDA0002656236850000171
The zinc-containing artificial bone prepared in this example 1 was subjected to an implantation test in an animal body, and compared with a conventional artificial bone (HA + TCP) as a control group to evaluate the osteoinductive property and bone-promoting property of the zinc-containing artificial bone. As shown in fig. 4 and 5. Experimental method, calcein is a calcium ion fluorescence indicator, and if newly deposited calcium element exists in tissues, green fluorescence is generated. The experimental results show that under the same environment, the artificial bone containing zinc implanted in fig. 4 has obvious new bone tissue generation around the bone, while the conventional artificial bone in fig. 5 has poor bone performance.

Claims (10)

1. The zinc-containing artificial bone is characterized by comprising the following raw materials: zinc-containing powder, bioceramic powder and high-molecular polymer binder; the raw materials comprise the following components in percentage by mass: contains zinc powder 0.1-15 wt%, bioceramic powder 80-98 wt% and high molecular polymer adhesive 0.5-10 wt%.
2. The artificial bone containing zinc according to claim 1, wherein the zinc-containing powder is a mixture of one or more of pure zinc powder, zinc-based metal powder, zinc oxide, zinc hydroxide powder and zinc chloride powder.
3. The artificial bone containing zinc according to claim 2, wherein the zinc-based metal powder contains zinc and an alloy element, and the alloy element is any one or a combination of at least two of Mg, Li, Fe, Ag, Ca, Sr and Mn elements.
4. The zinc-containing artificial bone according to claim 1, wherein the bioceramic powder is one or a combination of at least two of hydroxyapatite, tricalcium phosphate, calcium sulfate, calcium silicate, calcium carbonate, calcium magnesium silicate, and bioactive glass.
5. The artificial bone containing zinc according to claim 1, wherein the high molecular polymer binder is one or more of polyvinyl alcohol, poly (D-lactic acid), poly (L-lactic acid), poly (racemic lactic acid-co-glycolic acid), poly (lactic acid-co-glycolic acid), polycaprolactone, phosphoric acid, photosensitive resin, chitosan, gelatin, hyaluronic acid, and sodium alginate.
6. The method for preparing artificial bone containing zinc according to any one of claims 1 to 5, wherein the artificial bone is prepared by a 3D printing process.
7. The preparation method of the artificial bone containing zinc according to claim 6, wherein the 3D printing process is a filament-free extrusion 3D printing process, a powder-spreading 3D printing process or a photocuring 3D printing process.
8. The method for preparing artificial bone containing zinc according to claim 7, wherein the filament-free extrusion 3D printing process comprises the following steps:
(1) preparing paste: uniformly mixing biological ceramic powder and zinc-containing powder to obtain a solid material, and adding water into a high-molecular polymer binder to dilute into an aqueous solution to obtain a liquid material; mixing the solid material and the liquid material, uniformly stirring, and performing defoaming treatment to obtain a paste body;
(2) artificial bone three-dimensional model: establishing a three-dimensional model of a standard part by using three-dimensional modeling CAD software or acquiring a three-dimensional model of a defect part by using CT data of a patient, and designing a G code file for printing the artificial bone by using the three-dimensional model by using 3D Slicer software and FreeCAD software;
(3) 3D printing without silk extrusion: printing the artificial bone according to the G code file by using a 3D biological ceramic printer;
(4) and (3) freeze drying: and (4) carrying out freeze drying on the artificial bone prepared by the filament-free extrusion 3D printing in the step (3) to obtain the zinc-containing artificial bone.
9. The method for preparing artificial bone containing zinc according to claim 7, wherein the powder spreading 3D printing process comprises the following steps:
(1) preparing materials: mixing the biological ceramic powder and the zinc-containing powder, uniformly stirring, and then spreading the obtained powder in a printer bin; preparing a binder;
(2) artificial bone three-dimensional model: designing a porous artificial bone model by using three-dimensional modeling CAD software, and deriving STL format data;
(3) powder bonding three-dimensional printing: inputting STL format data derived in the step (2) into a 3D printer, reading the three-dimensional cross section information data of the artificial bone by using the 3D printer, spraying a binder according to the three-dimensional cross section information data of the artificial bone, and selectively bonding a biological ceramic material and a zinc powder-containing material in a printer bin together to obtain the artificial bone;
(4) and (3) drying: and (4) after the step (3) is finished, drying the artificial bone, and blowing off the non-bonded powder to obtain the zinc-containing artificial bone.
10. The method for preparing artificial bone containing zinc according to claim 7, wherein the method for preparing artificial bone containing zinc by photocuring 3D printing comprises the following steps:
(1) preparing the photocuring slurry: mixing the biological ceramic powder, the zinc-containing powder and the photosensitive resin, and uniformly stirring;
(2) artificial bone three-dimensional model: designing a three-dimensional model of the artificial bone by utilizing CAD software in a computer, connecting the computer with a DLP photocuring ceramic 3D printer in a data mode, and forming the three-dimensional model into a numerical control program by software matched with the DLP photocuring ceramic 3D printer;
(3) carrying out three-dimensional printing by using a DLP photocuring ceramic 3D printer, and taking out the molded artificial bone after printing is finished;
(4) cleaning: putting the artificial bone printed and formed in the step (3) into cleaning fluid for cleaning;
(5) and (3) sintering: and (4) placing the artificial bone cleaned in the step (4) into a sintering furnace for sintering, and then cooling along with the furnace to obtain the zinc-containing artificial bone.
CN202010888452.3A 2020-08-28 2020-08-28 Zinc-containing artificial bone and preparation method thereof Active CN111973811B (en)

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CN114560691A (en) * 2022-03-30 2022-05-31 佛山仙湖实验室 Antibacterial photocuring 3D printing biological ceramic material and preparation method and application thereof
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CN115591015A (en) * 2022-10-25 2023-01-13 季华实验室（Cn） Degradable metal/polymer composite bone fracture plate and preparation method thereof
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CN112916876A (en) * 2021-01-22 2021-06-08 暨南大学 Preparation method of degradable metal-based biological ceramic porous bone restoration
WO2022197859A1 (en) * 2021-03-16 2022-09-22 Orthomod Llc Bioceramic-containing thermoplastic extrusion and method of surgical implant manufacture
WO2022220766A1 (en) * 2021-04-17 2022-10-20 Bloocell Sağlik Teknoloji̇leri̇ Sanayi̇ Ve Ti̇caret Li̇mi̇ted Şi̇rketi̇ Hybrid, artificial bone tissue implant absorbing mechanical vibrations, whose architectural structure imitates trabecular bone, allowing the saturation of bone marrow, blood, and nutrients, supporting autological regeneration, which can be used with titanium structures
CN113290851A (en) * 2021-05-05 2021-08-24 西北工业大学 Forming process method of high-strength functional PCL/HA porous bone scaffold
CN113209376A (en) * 2021-05-05 2021-08-06 西北工业大学 Normal-temperature neutral preparation method of functional HA/CMCS composite biological ceramic bone scaffold with toughness
CN113290851B (en) * 2021-05-05 2023-02-28 西北工业大学 Forming process method of high-strength functional PCL/HA porous bone scaffold
CN113209376B (en) * 2021-05-05 2022-07-26 西北工业大学 Normal-temperature neutral preparation method of functional HA/CMCS composite biological ceramic bone scaffold with toughness
CN113230457B (en) * 2021-05-14 2022-07-05 太原理工大学 Degradable porous zinc-based composite material for bone repair and preparation method thereof
CN113230457A (en) * 2021-05-14 2021-08-10 太原理工大学 Degradable porous zinc-based composite material for bone repair and preparation method thereof
CN113262324B (en) * 2021-05-19 2022-01-18 辽宁工业大学 Multi-phase gradient-distributed porous Zn-Ag-TCP composite material and preparation method thereof
CN113262324A (en) * 2021-05-19 2021-08-17 辽宁工业大学 Multi-phase gradient-distributed porous Zn-Ag-TCP composite material and preparation method thereof
CN114014647A (en) * 2021-10-21 2022-02-08 华南理工大学 Zinc silicate composite tricalcium phosphate ceramic support and preparation method and application thereof
CN114315406A (en) * 2022-01-11 2022-04-12 无锡特科精细陶瓷有限公司 Method for preparing porous alumina ceramic by gel injection molding method
CN114560691A (en) * 2022-03-30 2022-05-31 佛山仙湖实验室 Antibacterial photocuring 3D printing biological ceramic material and preparation method and application thereof
CN115337451A (en) * 2022-08-05 2022-11-15 江苏迈伦医疗科技有限公司 Porous biological ceramic artificial bone and preparation method thereof
CN115252892A (en) * 2022-09-14 2022-11-01 点云生物(杭州)有限公司 Modified bioactive glass bone filling material and preparation method and application thereof
CN115591015A (en) * 2022-10-25 2023-01-13 季华实验室（Cn） Degradable metal/polymer composite bone fracture plate and preparation method thereof
CN115591015B (en) * 2022-10-25 2024-01-26 季华实验室 Degradable metal/polymer composite bone fracture plate and preparation method thereof
CN115957374A (en) * 2022-12-16 2023-04-14 吉林大学 Metal artificial bone implant with core-shell structure and preparation method thereof

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