Biphasic bioactive tissue repair scaffold and preparation method thereof

Abstract

The invention discloses a biphasic bioactive tissue repair scaffold and a preparation method thereof, and the preparation method comprises the following steps: step 1, carrying out surface modification on calcium phosphate ceramic powder to obtain modified calcium phosphate ceramic powder; 2, fully and uniformly mixing the modified calcium phosphate ceramic powder, potassium sodium niobate piezoelectric ceramic powder, a dispersing agent, a photoinitiator and photosensitive resin, and carrying out ball milling to obtain light-cured resin slurry; 3, constructing a 3D printing model according to design, and printing the light-cured resin slurry according to the 3D printing model to obtain a bracket blank; and 4, cleaning, degreasing and sintering the bracket blank to obtain the required bracket. According to the invention, the biphasic bioactive tissue repair scaffold with good mechanical properties, efficient anti-tumor ability and good bone regeneration promoting ability can be prepared, and technical support is provided for clinical repair of postoperative bone defects of bone tumors.

Description

Technical Field

[0001] The present invention relates to the technical field of bone tissue repair biomaterials, and in particular to a biphasic bioactive tissue repair scaffold and a preparation method thereof. Background Art

[0002] Bone tumors refer to tumors that occur in bones or their accessory tissues (such as bone marrow, cartilage, etc.). Currently, the main treatment strategies for bone tumors in clinical practice include surgical resection, chemotherapy, radiotherapy, etc. Surgical resection causes greater trauma and cannot completely eliminate tumor cells in the lesion site, while chemotherapy and radiotherapy can cause serious adverse reactions.

[0003] For local bone defects caused by bone tumor surgery, the current clinical treatment methods include autologous bone transplantation, allogeneic bone transplantation, and filling with synthetic bone repair materials. Although autologous bone transplantation is the gold standard for bone defect repair in clinical practice, its bone supply is limited and cannot meet the requirements of large-area repair. Although allogeneic bone can solve the problem of limited bone sources, it is prone to absorption and deformation after implantation and has strong antigenicity, which affects the treatment effect. Traditional calcium phosphate ceramic implants have poor mechanical properties and do not have anti-tumor ability.

[0004] Successful tissue regeneration requires the scaffold to have specific mechanical properties, appropriate size and porosity. The tissue regeneration repair scaffolds prepared by existing technologies do not have anti-tumor ability, and their ability to promote bone tissue regeneration is also limited.

[0005] 3D printing technology can precisely control the spatial distribution of printed slurry and prepare porous scaffolds with controllable size and complex structure. Using 3D printing technology to prepare biphasic bioactive tissue repair scaffolds with good mechanical properties, high anti-tumor ability and good bone regeneration ability is of great significance for the repair of bone defects after bone tumor surgery in clinical practice. Summary of the invention

[0006] The present invention provides a biphasic bioactive tissue repair scaffold and a preparation method thereof in view of the problems existing in the prior art.

[0007] The technical solution adopted by the present invention is: a method for preparing a biphasic bioactive tissue repair scaffold, comprising the following steps:

[0008] Step 1: Surface modification of calcium phosphate ceramic powder to obtain modified calcium phosphate ceramic powder;

[0009] Step 2: Fully mix the modified calcium phosphate ceramic powder, potassium sodium niobate piezoelectric ceramic powder, dispersant, photoinitiator and photosensitive resin, and obtain a photocurable resin slurry after ball milling;

[0010] The sodium potassium niobate piezoelectric ceramic is a sodium potassium niobate piezoelectric ceramic doped with manganese and cobalt;

[0011] The mass ratio of the calcium phosphate ceramic powder to the sodium potassium niobate piezoelectric ceramic powder is 16-19:1-4;

[0012] Step 3: Construct a 3D printing model according to the design, and print the photocurable resin slurry obtained in Step 2 according to the 3D printing model to obtain a scaffold blank;

[0013] Step 4: The scaffold blank obtained in Step 3 is washed, degreased and sintered to obtain the required scaffold.

[0014] Further, the calcium phosphate powder is composed of one or two or more of hydroxyapatite, β-tricalcium phosphate, and biphasic calcium phosphate in any proportion; the surface modifier of the calcium phosphate powder is composed of one or two or more of stearic acid, oleic acid, and fatty alcohol polyoxyethylene ether phosphate in any proportion; the addition amount of the surface modifier is 1 wt.% - 6 wt.% of the mass of the calcium phosphate ceramic powder.

[0015] Further, the contents of manganese and cobalt in the sodium potassium niobate piezoelectric ceramic are both 0.2 mol.%.

[0016] Further, the photoinitiator is composed of one or two or more of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide, 1-hydroxy-cyclohexyl-phenyl ketone, phenyl bis(phosphine oxide), methyl benzoylformate, isopropyl thioxanthone, or 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone in any proportion.

[0017] Further, the monomer of the photosensitive resin is composed of one or two or more of 1,6-hexanediol diacrylate, dipropylene glycol diacrylate, tripropylene glycol diacrylate, and 2-hydroxyethyl methacrylate in any proportion; the mass of the photosensitive resin is 50 wt.% - 70 wt.% of the mass of the photocurable resin slurry;

[0018] Further, in Step 3, the 3D printing is carried out using a digital light processing 3D printer;

[0019] The 3D printing exposure energy density is 6.20 Mj / cm 2 , and the exposure time is 2 s.

[0020] Further, the degreasing and sintering process in Step 4 is as follows:

[0021] First, heat up to 300 °C and hold for 1 h; then heat up to 600 °C and hold for 5 h; continue to heat up to 1100 °C and hold for 2 h; finally, cool naturally to room temperature; the heating rate is 1-2 °C / min.

[0022] A biphasic bioactive tissue repair scaffold, the scaffold has a biomimetic conch shell structure, and its porosity is 65%.

[0023] Furthermore, the scaffold is an initial layer composed of a cross-layered structure formed by horizontally and vertically rotating and splicing unit structures, and the initial layer forms a multi-layer structure through rotational stacking and mirror stacking.

[0024] Furthermore, the unit structure includes two connected sub-unit structures, and the sub-unit structure includes a first cylinder 1, a second cylinder 2, and a third cylinder 3;

[0025] The second cylinder 2 includes four semi-elliptical cylinders with the same structure, and the four second cylinders 2 are divided into two groups; for each group of second cylinders 2, the two semi-elliptical cylinders are perpendicular to each other, and their planar parts are located in the same plane, and the two formed planes are perpendicular to each other; the two planes and the outer extension vertices of the four second cylinders 2 form a cubic structure;

[0026] The sub-unit structure as a whole is located inside the cubic structure;

[0027] The first cylinder 1 is an elliptical cylinder and is arranged at the center of the cubic structure; the third cylinder 3 is two elliptical cylinders vertically arranged perpendicular to each other in the cubic space; the first cylinder 1 and the third cylinder 3 are perpendicular to each other in the cubic space;

[0028] One end of the first cylinder 1 is connected to one group of second cylinders 2, and the other end is connected to the other group of second cylinders 2 and the third cylinder 3;

[0029] The first cylinder 1 is connected to the second cylinder 2 and the third cylinder 3 by a 45° chamfer;

[0030] During the longitudinal and transverse splicing process of the unit structure, the first cylinders 1 in different unit structures are located on the same straight line to form a single-layer structure, and the single-layer structures are stacked to form a layered initial layer.

[0031] The beneficial effects of the present invention are:

[0032] (1) In the present invention, calcium phosphate ceramics and sodium potassium niobate are compounded to prepare a piezoelectric ceramic scaffold. Sodium potassium niobate can improve the mechanical properties of calcium phosphate ceramics, enhance their piezoelectric properties, and promote bone tissue regeneration; while the doping of manganese and cobalt elements can improve the piezoelectric catalytic properties of the ceramics, increase the ROS generation rate under ultrasonic stimulation, and show an obvious inhibitory effect on tumor cells;

[0033] (2) The present invention prepares a porous scaffold with a biomimetic conch shell structure through 3D printing technology. The soft-hard phase alternating cross-layered structure and appropriate porosity can prolong the residence time of blood and cells in the scaffold, promoting bone tissue regeneration. The longitudinal three-level stacked structure can break the overall periodicity of the scaffold, effectively limit the transmission of force, achieve layered deformation, inhibit the rapid expansion of shear bands, and improve the mechanical properties of the scaffold;

[0034] (3) The biphasic bioactive tissue repair scaffold prepared by the present invention has good mechanical properties, high anti-tumor ability and good bone regeneration promotion ability, and has important clinical significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 It is a schematic diagram of the initial layer structure in the scaffold of the present invention; a is a schematic diagram of the subunit structure, b is a schematic diagram of the unit structure, and c is a schematic diagram of the initial layer structure.

[0036] Figure 2 It is a schematic diagram of the structure of the scaffold of the present invention, a is a schematic diagram of the stacked structure, and b is a schematic diagram of the scaffold structure.

[0037] Figure 3 It is a schematic diagram of the mechanical properties of the scaffolds obtained in Example 1 and Comparative Example 2 of the present invention, a is a schematic diagram of the deformation behavior under a given strain, and b is a schematic diagram of the stress-strain curve during the compression process.

[0038] Figure 4 It is an SEM image of the scaffold obtained in Example 1 of the present invention, a is the result under a low magnification microscope, b is the result under a high magnification microscope, and c is the EDS energy spectrum analysis result.

[0039] Figure 5 It is an SEM image of the scaffold obtained in Comparative Example 3 of the present invention, a is the result under a low magnification microscope, b is the result under a high magnification microscope, and c is the EDS energy spectrum analysis result.

[0040] Figure 6 It is a schematic diagram of the transmission electron microscope result of the piezoelectric ceramic powder used in the examples of the present invention, a is the transmission electron microscope result of the sodium potassium niobate piezoelectric ceramic powder doped with manganese and cobalt used in Examples 1 and 2, and b is the transmission electron microscope result of the sodium potassium niobate piezoelectric ceramic powder used in Comparative Example 3.

[0041] Figure 7 It is a schematic diagram of the degradation results of the scaffold powders obtained in Examples 1, 2 and Comparative Examples 1, 3 of the present invention, a is the degradation efficiency curve, b is the statistical chart of the degradation rate k value, and c is the kinetic curve of degradation.

[0042] Figure 8 It is a schematic diagram of the anti-tumor and bone formation promotion results of the scaffolds obtained in Examples 1, 2 and Comparative Examples 1, 3 of the present invention.

[0043] In the figure, 1 is the first cylinder, 2 is the second cylinder, and 3 is the third cylinder. Specific implementation mode

[0044] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

[0045] A preparation method of a biphasic bioactive tissue repair scaffold includes the following steps:

[0046] Step 1: Surface modification of calcium phosphate ceramic powder to obtain modified calcium phosphate ceramic powder; the calcium phosphate powder is one or two or more of hydroxyapatite, β-tricalcium phosphate, and biphasic calcium phosphate mixed in any proportion. The surface modifier of the calcium phosphate powder is one or two or more of stearic acid, oleic acid, and fatty alcohol polyoxyethylene ether phosphate ester mixed in any proportion; the addition amount of the surface modifier is 1 wt.% to 6 wt.% of the mass of the calcium phosphate ceramic powder;

[0047] Step 2: Mix the modified calcium phosphate ceramic powder, sodium potassium niobate piezoelectric ceramic powder, dispersant, photoinitiator, and photosensitive resin evenly, and obtain a photocurable resin slurry after ball milling;

[0048] The photoinitiator is one or two or more of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide, 1-hydroxy-cyclohexyl-phenylmethanone, phenyl bis(phosphine oxide), methyl benzoylformate, isopropyl thioxanthone, or 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone mixed in any proportion.

[0049] The monomer of the photosensitive resin is one or two or more of 1,6-hexanediol diacrylate, dipropylene glycol diacrylate, tripropylene glycol diacrylate, and 2-hydroxyethyl methacrylate mixed in any proportion; the mass of the photosensitive resin is 50 wt.% to 70 wt.% of the mass of the photocurable resin slurry.

[0050] The sodium potassium niobate piezoelectric ceramic is a sodium potassium niobate piezoelectric ceramic doped with manganese and cobalt; the contents of manganese and cobalt in the sodium potassium niobate piezoelectric ceramic are both 0.2 mol.%. The mass ratio of the calcium phosphate ceramic powder to the sodium potassium niobate piezoelectric ceramic powder is 16-19:1-4.

[0051] Step 3: Construct a 3D printing model according to the design, and print the photocurable resin slurry obtained in Step 2 according to the 3D printing model to obtain a scaffold blank; 3D printing is carried out using a digital light processing 3D printer;

[0052] The 3D printing exposure energy density is 6.20 Mj / cm 2 , and the exposure time is 2 s.

[0053] Use Solidworks 3D modeling software to construct a 3D printing model.

[0054] Step 4: The bracket blank obtained in Step 3 can be cleaned, degreased and sintered to obtain the required bracket.

[0055] The degreasing and sintering process is as follows:

[0056] First, heat up to 300 °C and keep the temperature for 1 h; then heat up to 600 °C and keep the temperature for 5 h; continue to heat up to 1100 °C and keep the temperature for 2 h; finally, cool naturally to room temperature; the heating rate is 1-2 °C / min.

[0057] The bracket has a bionic conch shell structure with a porosity of 65%; it is an initial layer composed of a cross-layered structure formed by horizontally and vertically rotating and splicing unit cell structures, and the initial layer forms a multi-layer structure through rotational stacking and mirror stacking. As Figure 2 shown, in the following embodiments, a three-layer structure composed of an initial layer, a rotating layer, and a mirror layer is adopted, and the specific number of layers is selected according to actual conditions.

[0058] The unit cell structure is as Figure 1 shown, including two connected sub-unit cells, and the sub-unit cell includes a first cylinder 1, a second cylinder 2, and a third cylinder 3;

[0059] The second cylinder 2 includes four semi-elliptical cylinders with the same structure, and the four second cylinders 2 are divided into two groups; for each group of second cylinders 2, the two semi-elliptical cylinders are perpendicular to each other, and their flat parts are located in the same plane, and the two planes formed are perpendicular to each other; the two planes and the outer extension vertices of the four second cylinders 2 form a cubic structure;

[0060] The whole sub-unit cell is located inside the cubic structure;

[0061] The first cylinder 1 is an elliptical cylinder and is arranged at the center of the cubic structure; the third cylinder 3 is two elliptical cylinders arranged perpendicular to each other in the cubic space; the first cylinder 1 and the third cylinder 3 have the same structure and are perpendicular to each other in the cubic space;

[0062] One end of the first cylinder 1 is connected to one group of second cylinders 2, and the other end is connected to the other group of second cylinders 2 and the third cylinder 3;

[0063] The first cylinder 1 is connected to the second cylinder 2 and the third cylinder 3 by a 45° bevel angle;

[0064] During the longitudinal and transverse splicing of the unit cell structure, the first cylinders 1 in different unit cell structures are located on the same straight line to form a single-layer structure, and the single-layer structures are stacked to form a layered initial layer;

[0065] During the longitudinal and transverse splicing of the unit cell structure, the first cylinder 1 forms a support structure that penetrates the single-layer plane. Through 180° longitudinal rotation and replication splicing, the first cylinder 1 has different orientations on different planes, forming an initial cross-layered structure similar to a bionic conch shell. The cross-layered structure formed by rotation splicing has node connection heterogeneity, where the nodes at both ends of the first cylinder 1 have more spatial constraints and are regarded as the "soft phase"; while other nodes with fewer constraints are regarded as the "hard phase".

[0066] The cross-layered structure with alternating soft-hard phases can simulate the multi-material modulus difference in the natural conch shell structure. In the longitudinal stacking of the scaffold, 90° rotation stacking and mirror stacking are used. Adjust the parameters such as the diameter and length of the first cylinder, the second cylinder, and the third cylinder to ensure that its porosity is 65%. The scaffold is cut into a cylinder with a diameter of φ6mm and a length of 10mm by Boolean operation for the subsequent preparation of scaffolds for each example.

[0067] Longitudinal stacking is to further improve the mechanical properties of the scaffold. By mirror stacking and rotation stacking, the overall periodicity is broken, making the conduction of cross-layer forces more difficult, achieving layered deformation, and suppressing the rapid expansion of shear bands.

[0068] Example 1

[0069] A preparation method of a biphasic bioactive tissue repair scaffold includes the following steps:

[0070] Step 1: Place calcium phosphate powder in an anhydrous ethanol solution of fatty alcohol polyoxyethylene ether phosphate with a mass concentration of 6wt.%. Stir until evenly mixed; transfer to a ball mill tank, add ball mill beads with a ball-to-material ratio of 1:1, and ball mill for 4h. After completion, dry, grind, and sieve to obtain powder with good dispersibility and suspension stability.

[0071] Step 2: Weigh the modified calcium phosphate powder and sodium potassium niobate powder doped with manganese and cobalt according to a mass ratio of 18:2. The contents of manganese and cobalt in the sodium potassium niobate piezoelectric ceramic are both 0.2mol.%.

[0072] Weigh photosensitive resin (polymerized from 1,6-hexanediol diacrylate) according to 55wt.% of the total mass of the slurry, and add 3% of the dispersant and 2,4,6-trimethylbenzoyl-diphenylphosphine oxide based on the total mass of the slurry. Transfer to a ball mill tank, add ball mill beads with a ball-to-material ratio of 1:1, and ball mill for 8h to obtain a photocurable resin slurry with uniform distribution of ceramic particles.

[0073] Step 3: Use SolidWorks software to design the unit cell structure of the bionic conch shell, obtain the scaffold model through mirror stacking and rotation stacking, and adjust the parameters to make its porosity about 65%. The structure is as Figure 1 and Figure 2 shown.

[0074] Import the 3D printed model into a digital light processing 3D printer, adjust the height of the squeegee and the traveling speed, and set the exposure energy density to 6.20 Mj / cm 2 , with an exposure time of 2 s, to print out the blank of the stent. Remove the blank of the stent with a spatula, put it into absolute ethanol, and repeat ultrasonic cleaning 3 times, 10 minutes each time. After cleaning, put it into a muffle furnace for degreasing sintering. The steps are as follows: heat it up to 300 °C at a heating rate of 2 °C / min and keep it warm for 1 h; then heat it up to 600 °C at a heating rate of 1 °C / min and keep it warm for 5 h; then heat it up to 1100 °C at a heating rate of 2 °C / min, and then keep it warm for 2 h; finally, cool it naturally to room temperature to obtain the required stent.

[0075] Example 2

[0076] The other preparation steps of this example are the same as those of Example 1. The difference is that in step 2, the mass ratio of the modified calcium phosphate powder and the manganese- and cobalt-doped sodium potassium niobate powder is 19:1.

[0077] Comparative Example 1

[0078] A porous ceramic stent. The other preparation steps of this comparative example are the same as those of Example 1. The difference is that in step 2, only calcium phosphate ceramic powder is used.

[0079] Comparative Example 2

[0080] A porous ceramic stent. The other preparation steps of this comparative example are the same as those of Example 1. The difference is that in step 3, the 3D model uses square holes as the unit cell structure.

[0081] Comparative Example 3

[0082] A porous ceramic stent. The other preparation steps of this comparative example are the same as those of Example 1. The difference is that in step 2, the sodium potassium niobate powder is not doped with manganese and cobalt.

[0083] Mechanical property tests were carried out on Example 1 and Comparative Example 2, and the results are as Figure 3 shown. As can be seen from Figure 3 a in it, in Comparative Example 2, the overall structure collapsed at 6% strain, and the brittle characteristics of the fractured part were obvious; while in Example 1, the hierarchical dispersed shear band design achieved hierarchical failure, and the failure was limited within one layer at 6% strain, and the integrity of the remaining layers was kept good. Its rotating stacked cross-layered structure effectively inhibited the crack propagation across layers. From Figure 3As can be seen in b, the stress of comparative example 2 rises sharply at the initial stage of compression, reaches the stress peak at a strain of 1.5%, and then drops sharply to a low point, and the subsequent compression process cannot provide effective mechanical support; while the stress of embodiment 1 is relatively dispersed, the stress rises slowly at the initial stage of compression, and can quickly recover to the original stress level in the subsequent compression, providing relatively stable support. This shows that the conch shell bionic structure can effectively improve the mechanical properties of the bracket.

[0084] The stents obtained in Example 1 and Comparative Example 3 were subjected to electron microscopy analysis, wherein the scanning electron microscopy results and EDS energy spectrum analysis results of Example 1 and Comparative Example 3 are as follows: Figure 4 and Figure 5 As shown, the transmission electron microscopy results of the two piezoelectric powders used in Example 1 and Comparative Example 3 are as follows Figure 6 shown.

[0085] from Figure 4 and Figure 5 It can be seen that when potassium sodium niobate piezoelectric ceramic powder is added, a sparsely distributed lamellar grain structure appears on the surface of the bracket, and when manganese and cobalt-doped potassium sodium niobate piezoelectric ceramic powder is added, a high-density distributed rod-shaped grains appear on the surface of the bracket.

[0086] from Figure 6 It can be seen that pure potassium sodium niobate and manganese and cobalt doped potassium sodium niobate are both nanoscale. Pure potassium sodium niobate presents a typical irregular polyhedral structure, while manganese and cobalt doped potassium sodium niobate presents a uniform cubic structure.

[0087] The stents obtained in Examples 1, 2 and Comparative Examples 1, 3 were ground into powders for ultrasonic catalytic effect testing. The redox-resistant Rhodamine B dye solution was catalytically degraded by the powder with piezoelectric effect under ultrasound to evaluate the piezoelectric catalytic effect of the four stent powders under ultrasound. The dye solution concentration used was 5 mg / L, 50 mL was configured, the ceramic powder used was 0.2 g, and the ultrasonic conditions were 180 W, 40 kHz. The four powders were respectively mixed with Rhodamine B dye to the same concentration, and after continuous stirring for 30 minutes in a dark environment (generally, the powder itself adsorbs the dye to reach equilibrium after 30 minutes to avoid the influence of the powder itself on the adsorption of the dye color), the ultrasound was continued for 30 minutes under the same ultrasonic conditions, and the absorbance of the solution at the excitation wavelength of 553 nm was measured after stirring for 30 minutes when the powder reached adsorption equilibrium, and every 5 minutes after the start of ultrasound. The less the absorbance measured at the same excitation wavelength, the closer the liquid color is to transparency, that is, the better the degradation effect of the red Rhodamine B itself, and the better the piezoelectric catalytic effect of the stent powder. The comparison results are as follows: Figure 7 shown.

[0088] from Figure 7As can be seen from a, under the action of ultrasound, the rhodamine B solution itself will be slightly degraded; the degradation of the rhodamine B solution in Comparative Example 1 is almost the same as that under the condition of only ultrasound; while in Examples 1, 2 and Comparative Example 3 under ultrasound, a piezocatalytic effect is generated, making the rhodamine B solution gradually degrade almost into a transparent color, indicating that the addition of sodium potassium niobate can improve the piezocatalytic ability of the composite scaffold. From Figure 7 As can be seen from b and c, the degradation rate of the rhodamine B dye in Example 2 is much higher than that in Comparative Example 3, indicating that the doping of manganese and cobalt elements can further improve the piezocatalytic ability of sodium potassium niobate. And the degradation rate of the rhodamine B dye in Example 1 is higher than that in Example 2, indicating that the higher the content of manganese- and cobalt-doped sodium potassium niobate piezoelectric ceramics in the scaffold powder, the better the piezocatalytic ability.

[0089] The scaffolds obtained from the comparative examples and examples were placed in the bodies of animals with bone tumor models. After 4 weeks and 20 weeks (anti-tumor section tests were performed after 4 weeks, and osteogenic section staining was performed after 20 weeks), section staining was performed respectively, and the results are as Figure 8 shown. As can be seen from the figure, the anti-tumor effect and osteogenic effect of the composite ceramic scaffold are both better than those of the calcium phosphate ceramic scaffold, and the anti-tumor effect and osteogenic effect of the manganese- and cobalt-doped sodium potassium niobate composite ceramic are significantly better than those of the scaffold prepared from sodium potassium niobate ceramic powder. It shows that manganese- and cobalt-doped sodium potassium niobate can degrade into manganese and cobalt ions in the body to achieve the purpose of anti-tumor and osteogenesis.

[0090] The present invention adopts a porous scaffold structure of bionic conch shells, and by constructing a three-level structure stacked longitudinally, the overall periodicity of the scaffold is broken, making the conduction of cross-layer force more difficult, achieving layered deformation, suppressing the expansion speed of the shear band, and improving the mechanical properties of the scaffold, so that the scaffold can still effectively maintain the integrity of the structure under a certain load, and provide sufficient mechanical support in the early stage of implantation. In addition, this asymmetric cross-layered structure has node heterogeneity, and the structure of alternating soft and hard phases can effectively reduce the fluid velocity while simulating the natural conch shell structure, prolong the residence time of blood in the scaffold, promote the effective exchange of nutrients and metabolites, improve the adhesion efficiency of cells at the scaffold interface, and promote the growth of new bone tissue. At the same time, the porous structure of the scaffold allows cells to fully contact with potassium sodium niobate, which can inhibit tumor cells as much as possible under the action of ultrasound, and has efficient anti-tumor ability. By doping potassium sodium niobate with manganese and cobalt to improve the piezoelectric properties of calcium phosphate ceramics, piezoelectric biomaterials can be semiconductor functional materials that can realize the conversion between mechanical energy and electrical energy. Under the action of ultrasonic machinery, piezoelectric potential is generated, which is helpful for the generation, migration and separation of charge carriers in the material, and produces high-intensity reactive oxygen molecules, which have the potential to become a highly efficient sonosensitizer. Sonosensitizers are stimulated by ultrasound to produce high doses of cytotoxic reactive oxygen molecules, which then induce oxidative stress in tumor cells, destroy biological macromolecules, and ultimately lead to tumor cell apoptosis or necrosis. Compared with traditional chemotherapy, physical therapy, and photothermal therapy, sonosensitizers have the advantages of greater tissue penetration depth and higher safety. The doping of manganese and cobalt elements improves the piezoelectric catalytic properties of potassium sodium niobate, improves the efficiency of composite ceramic stents in generating ROS under ultrasound, and thus improves the anti-tumor ability of the composite stent.

[0091] In summary, the present invention constructs a porous scaffold of a bionic conch shell structure through 3D printing technology, which has good mechanical properties, and the appropriate porosity can promote the growth of new bone tissue. At the same time, a composite ceramic scaffold with integrated anti-tumor and osteogenic functions with ultrasonic piezoelectric catalytic effect is constructed using manganese and cobalt-doped potassium sodium niobate composite calcium phosphate ceramics, which uses enhanced acoustic power to resist tumors, and the doping of manganese and cobalt ions further enhances the anti-tumor performance of the scaffold and gives it angiogenic properties, thereby improving the osteogenic ability of the scaffold, and providing an effective strategy for the repair of bone defects after bone tumor surgery in clinical practice. Compared with the prior art, the present invention has significant progress.

Claims

1. A preparation method of a biphasic bioactive tissue repair scaffold, characterized in that, It includes the following steps: Step 1: The calcium phosphate ceramic powder is surface-modified to obtain the surface-modified calcium phosphate ceramic powder. Step 2: The surface-modified calcium phosphate ceramic powder, sodium potassium niobate piezoelectric ceramic powder, dispersant, photoinitiator, and photosensitive resin are fully mixed and homogenized, and after ball milling, a photocurable resin slurry is obtained. The sodium potassium niobate piezoelectric ceramic is a sodium potassium niobate piezoelectric ceramic doped with manganese and cobalt. The mass ratio of the calcium phosphate ceramic powder to the sodium potassium niobate piezoelectric ceramic powder is 16 - 19:1 - 4. Step 3: A 3D printing model is constructed according to the design, and the photocurable resin slurry obtained in Step 2 is printed according to the 3D printing model to obtain a scaffold blank. Step 4: The scaffold blank obtained in Step 3 is cleaned, degreased, and sintered to obtain the required scaffold.

2. The preparation method of a biphasic bioactive tissue repair scaffold according to claim 1, wherein, The calcium phosphate powder is composed of one or two or more of hydroxyapatite, β-tricalcium phosphate, and biphasic calcium phosphate in any proportion; the surface modifier of the calcium phosphate powder is composed of one or two or more of stearic acid, oleic acid, and fatty alcohol polyoxyethylene ether phosphate in any proportion; the addition amount of the surface modifier is 1 wt.% - 6 wt.% of the mass of the calcium phosphate ceramic powder.

3. The preparation method of a biphasic bioactive tissue repair scaffold according to claim 1, characterized in that, The contents of manganese and cobalt in the sodium potassium niobate piezoelectric ceramic are both 0.2 mol.%.

4. The preparation method of a biphasic bioactive tissue repair scaffold according to claim 1, characterized in that, The photoinitiator is composed of one or two or more of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide, 1-hydroxy-cyclohexyl-phenyl ketone, phenyl diphosphine oxide, methyl benzoylformate, isopropyl thioxanthone, or 2-hydroxy-2-methyl-1-[4(2-hydroxyethoxy)phenyl]-1-propanone in any proportion.

5. The preparation method of a biphasic bioactive tissue repair scaffold according to claim 1, characterized in that, The monomer of the photosensitive resin is composed of one or two or more of 1,6-hexanediol diacrylate, dipropylene glycol diacrylate, tripropylene glycol diacrylate, and 2-hydroxyethyl methacrylate in any proportion; the mass of the photosensitive resin is 50 wt.% - 70 wt.% of the mass of the photocurable resin slurry.

6. The preparation method of a biphasic bioactive tissue repair scaffold according to claim 1, characterized in that, In Step 3, 3D printing is carried out using a digital light processing 3D printer. The exposure energy density of 3D printing is 6.20 Mj / cm 2 , and the exposure time is 2 s.

7. The preparation method of a biphasic bioactive tissue repair scaffold according to claim 1, characterized in that, The degreasing and sintering process in Step 4 is as follows: First, heat up to 300 °C and keep it warm for 1 h; then heat up to 600 °C and keep it warm for 5 h; continue to heat up to 1100 °C and keep it warm for 2 h; finally, cool it naturally to room temperature; the heating rate is 1 - 2 °C / min.

8. The biphasic bioactive tissue repair scaffold obtained by using any one of the preparation methods according to claims 1 to 7, characterized in that, The scaffold has a bionic conch shell structure with a porosity of 65%.

9. The biphasic bioactive tissue repair scaffold according to claim 8, characterized in that, The scaffold is an initial layer composed of a cross-layered structure formed by the transverse and longitudinal rotation splicing of a unit structure, and the initial layer forms a multi-layer structure through rotational stacking and mirror stacking.

10. A biphasic bioactive tissue repair scaffold according to claim 9, characterized in that, The unit structure includes two connected sub-unit structures, and each sub-unit structure includes a first column (1), a second column (2), and a third column (3). The second column (2) includes four semi-elliptical cylinders with the same structure, and the four second columns (2) are divided into two groups; for each group of second columns (2), the two semi-elliptical cylinders are perpendicular to each other, and their planar parts are in the same plane, and the two planes formed are perpendicular to each other; the two planes and the outer extension vertices of the four second columns (2) form a cubic structure. The sub-unit structure as a whole is located inside the cubic structure. The first cylinder (1) is an elliptical cylinder and is arranged at the center of the cubic structure; the third cylinder (3) is two elliptical cylinders that are perpendicularly arranged to each other within the cubic space; the first cylinder (1) and the third cylinder (3) are perpendicular to each other within the cubic space. One end of the first cylinder (1) is connected to a group of second cylinders (2), and the other end is connected to another group of second cylinders (2) and the third cylinder (3). The first cylinder (1) is connected to the second cylinder (2) and the third cylinder (3) with a 45° chamfer. During the longitudinal and transverse splicing of the unit structure, the first cylinders (1) in different unit structures are located on the same straight line to form a single-layer structure, and this single-layer structure is stacked to form an initial layered layer.

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