WO2022252526A1 - 一种无机非金属纳米颗粒组装的水凝胶材料及其在增材制造技术中的应用 - Google Patents

一种无机非金属纳米颗粒组装的水凝胶材料及其在增材制造技术中的应用 Download PDF

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WO2022252526A1
WO2022252526A1 PCT/CN2021/134538 CN2021134538W WO2022252526A1 WO 2022252526 A1 WO2022252526 A1 WO 2022252526A1 CN 2021134538 W CN2021134538 W CN 2021134538W WO 2022252526 A1 WO2022252526 A1 WO 2022252526A1
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particles
inorganic non
metallic
gel
ink
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French (fr)
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王华楠
豆珍珍
陈楷文
李鑫
宫传波
孙凯
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大连理工大学
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    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/01—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics
    • C04B35/14—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on silica
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
    • B29C64/30—Auxiliary operations or equipment
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C67/00—Shaping techniques not covered by groups B29C39/00 - B29C65/00, B29C70/00 or B29C73/00
    • B29C67/02—Moulding by agglomerating
    • B29C67/04—Sintering
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00—Processes of additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y50/00—Data acquisition or data processing for additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
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    • C—CHEMISTRY; METALLURGY
    • C03—GLASS; MINERAL OR SLAG WOOL
    • C03B—MANUFACTURE, SHAPING, OR SUPPLEMENTARY PROCESSES
    • C03B19/00—Other methods of shaping glass
    • C03B19/06—Other methods of shaping glass by sintering, e.g. by cold isostatic pressing of powders and subsequent sintering, by hot pressing of powders, by sintering slurries or dispersions not undergoing a liquid phase reaction
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    • C04B2235/60—Aspects relating to the preparation, properties or mechanical treatment of green bodies or pre-forms
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Definitions

  • the invention belongs to the field of material science, nanomaterials, and biomedical engineering, and relates to a printable inorganic non-metallic gel ink raw material formed by biologically active inorganic non-metallic particles through electrostatic, hydrophobic, and magnetic effects, which is augmented by 3D printer technology. Fabrication and preparation of scaffolds and their applications.
  • tissue engineering dedicated to artificial tissues and organs has emerged as the times require.
  • tissue engineering has played an increasingly important role in tissue or organ repair.
  • Tissue engineering consists of three basic elements: scaffold materials, bioactive molecules and seed cells.
  • scaffold materials as an important part of tissue engineering, provide cells with a space structure and growth template for adhesion, proliferation, and differentiation, and can induce tissue regeneration.
  • the engineering must have good biological activity, compatibility, and inducibility. , At the same time, it is also necessary to provide temporary mechanical support for different parts or functions.
  • Additive manufacturing also known as rapid prototyping or solid form-free manufacturing or 3D printing, has emerged as a promising manufacturing technique in different fields including biomedical research.
  • Export the designed model as a standard 3D printing language file (stl. file) through the computer-aided design (CAD) model bracket, import the stl file into the slicing software to cut the model according to the route, and then use the 3D printer to additively manufacture the model stand.
  • CAD computer-aided design
  • the printed bracket is generally post-processed to remove excess material or Sintering treatment for higher mechanical strength.
  • the accurate three-dimensional defect model formed after CT scanning can print out the ideal scaffold that perfectly fits the specific defect, thus improving the great potential for personalized clinical medicine.
  • Additive manufacturing technology provides a high degree of control over the built structure, guarantees reproducibility, and supports scale and standardization.
  • metal materials there are metal materials, polymer materials, and inorganic non-metal materials on the scaffolds used for tissue engineering. Since metal materials are generally inert and non-degradable, they need to be taken out again after implantation in the human body, causing secondary damage to the patient.
  • the mechanical properties of polymer materials Weaker, it is difficult to support the repair of load-bearing damaged tissues and organs, while inorganic non-metallic materials can control the biological activity, mechanical properties, degradability and other characteristics of the scaffold by adjusting the composition and crystal state, and can be directly used in the human body or with the human body Directly related biology, application, biochemistry and other fields.
  • Inorganic non-metallic scaffolds can stimulate special cell responses at the molecular level in the physiological environment of the human body, can absorb active substances related to tissue repair, and release biologically active ions (for example, Ca, Mg, Sr, Si, B, Fe, Cu , Zn, Cr and other element ions) are used to induce changes in cell phenotypes or regulate the immune microenvironment to guide tissue healing and regeneration. It can also react with the host (cells, body fluids and tissues) through the surface microstructure, regulate the body's spontaneous repair function, induce and promote new bone formation, and is a kind of "adjustable biological response characteristics" and "active repair function”. Characteristic bioactive scaffold materials; using inorganic non-metallic material scaffolds as tissue engineering scaffolds has a more excellent tissue or organ repair effect.
  • biologically active ions for example, Ca, Mg, Sr, Si, B, Fe, Cu , Zn, Cr and other element ions
  • the current method of preparing inorganic non-metallic material scaffolds usually uses inorganic non-metallic particles and printable polymers to be mixed in a certain proportion to form a shear-thinning slurry, which is 3D printed to form a scaffold and then sintered at high temperature Remove plasticizers.
  • CN201710347623.X mixes bioceramic powder, degradable metal powder, bioglass sintering aid powder and binder solution to obtain a slurry that is degreased and sintered in an oxygen-free environment after 3D printing; the mixing of various components is done in the early stage It is very easy to have uneven mixing, which leads to low printing accuracy and uneven structure after sintering; Lei Chen et al.
  • the purpose of the present invention is to solve the shortcomings of the need for additives for plasticization when printing pure inorganic non-metallic materials.
  • Based on additive manufacturing technology a simple and effective method is used to prepare inorganic non-metallic materials with high strength and can be used for 3D printing. .
  • the strength of the gel ink is controllable in the range of 10Pa to 500kPa; the prepared gel ink has good printing Performance, through the integration of modeling software, slicing software and 3D printers to manufacture three-dimensional brackets.
  • the printed scaffold can be heat-treated according to the application requirements, and does not need to be processed above 1000°C.
  • the obtained scaffold structure is uniform, with adjustable macroscopic pores and microscopic pores, and the compressive strength can reach 70MPa.
  • the scaffold can be used in tissue engineering or in Applications in electronic devices and tissue engineering can be used as bone repair scaffolds, cartilage repair scaffolds, loaded with bioactive protein drugs, bioactive substance drug molecules or mesenchymal stem cells, endothelial cells, Schwann cell scaffolds; in electronic devices
  • the applications on it can be used as supercapacitors, batteries, solar cells, piezoelectric sensors, optoelectronic sensors, chemical sensing agents, biosensors, and electronic skin sensor devices, providing new design ideas for the additive manufacturing of inorganic non-metallic materials.
  • the present invention is realized by adopting the following technical solutions.
  • the invention provides a hydrogel material assembled with inorganic non-metallic nanoparticles, the hydrogel material is assembled from inorganic non-metallic particles to form a hydrogel network; the size of the inorganic non-metallic particles is 10nm-20um ; Inorganic non-metallic particles in the hydrogel material account for 2-80wt% of the total volume of the hydrogel; the hydrogel network has microscopic pores with a diameter of 0.1um-30um.
  • the mechanical support strength of the hydrogel material is 100kPa-400kPa
  • the viscosity is 2000-10000Pa.s
  • the damage recovery ability is 50%-100%.
  • the inorganic non-metallic particles are selected from silica particles, bioglass particles, clay particles, calcium sulfate particles, calcium carbonate particles, hydroxyapatite particles, iron oxide particles, zirconia particles , zinc oxide particles, titanium oxide particles, aluminum oxide particles, barium titanate particles, silicon carbide particles, graphene, graphene oxide, reduced graphene oxide, transition metal carbide or nitride (MXene), transition metal disulfide (TMD), hexagonal boron nitride and black phosphorus nanosheets or a combination of several; the transition metal dichalcogenide is preferably MoS 2 .
  • the preparation method of the hydrogel material is an electrostatic assembly method or a hydrophobic interaction assembly method or a magnetic interaction assembly method
  • the electrostatic assembly method comprises the following steps:
  • sol-gel method Use one or more of sol-gel method, chemical precipitation method, melting method, hydrothermal synthesis method, template method, chemical stripping method, electrochemical stripping method, and mechanical stripping method to prepare negatively charged inorganic non-metallic particles , dispersing the obtained negatively charged inorganic non-metallic particles in a liquid solvent containing deionized water, preparing a particle suspension with a mass volume fraction of 1%-80%, and fully stirring for 2-8h;
  • inorganic non-metallic nanoparticles to one or more combined solvents of methanol, ethanol, isopropanol, butanol, and acetone, and configure it into a 1%-50% suspension, stir for 20-60min and then add Water-soluble positively charged groups, the positively charged groups are amino groups in aliphatic amines, imines in nitrogen-nitrogen disubstituted amidino groups, imine compounds in tetrazole substituted guanidino groups, reaction 6- After 12 hours, centrifuge and wash to obtain positively charged inorganic nonmetallic particles; disperse positively charged inorganic nonmetallic particles in deionized water or in one or two liquid mixed solvents of methanol, ethanol, acetone, isopropanol, and configure the mass fraction 1%-80% particle suspension, fully stirred for 2-8h to obtain positively charged inorganic non-metallic particle suspension;
  • the particle number ratio of the negatively charged particle suspension to the positively charged particle suspension is 1:0-0:1, Preferably 10:1-1:50, more preferably 5:1-1:10, after stirring evenly, the precursor solution is obtained;
  • step S4 Add one or more combinations of 5mM-25mM acetic acid, phosphoric acid, hydrochloric acid, nitric acid acidic solution to the precursor solution obtained in step S3 while stirring, and after continuous stirring for 0.5-3h, pass through 2000g-10000g high-speed centrifugation for 20- 40min, remove the supernatant to obtain a gel ink raw material with a solid phase content of 2-80wt%, that is, the hydrogel material;
  • the hydrophobic interaction assembly method comprises the following steps:
  • sol-gel method chemical precipitation method, melting method, hydrothermal synthesis method, template method, chemical stripping method, electrochemical stripping method, and mechanical stripping method to prepare negatively charged inorganic non-metallic particles , disperse negatively charged inorganic non-metallic particles into absolute ethanol, prepare a suspension of inorganic non-metallic particles with a concentration of 1%-80%, stir for 20-60min, and then add silicon-halogen bond compounds containing hydrophobic groups, silane couples Joint agent, one or several combinations of stearic acid compounds, react for 6-12h, centrifuge and wash to obtain hydrophobic inorganic non-metallic particles, disperse hydrophobic inorganic non-metallic particles in deionized water or disperse in methanol, ethanol, In one or two liquid mixed solvents of acetone and isopropanol, a dispersion of hydrophobic inorganic non-metallic particles is obtained;
  • the hydrophobic inorganic non-metallic particle dispersion is centrifuged at 2000g-10000g high speed for 20-40min, and the supernatant is removed to obtain a gel ink raw material with a solid phase content of 2-80wt%, that is, the hydrogel material;
  • the magnetic interaction assembly method comprises the following steps:
  • the second aspect of the present invention provides an inorganic non-metallic nanoparticle-assembled hydrogel material used as a bone-filling biomedical material for injectable, shapeable, drug sustained-release carriers, wherein the inorganic non-metallic nanoparticles that make up the hydrogel are biological One or more combinations of glass particles, clay particles, calcium phosphate particles, and bioactive ceramic particles, the size of the inorganic non-metallic nanoparticles is 10nm-20um, and the inorganic non-metallic nanoparticles account for 2% of the total volume of the hydrogel -80wt%.
  • the third aspect of the present invention provides an inorganic non-metallic gel scaffold, the scaffold is a gel scaffold obtained by additively manufacturing the aforementioned hydrogel material, and the gel scaffold has interpenetrating pores formed by stacking fibers, The pore diameter is 50-1000 ⁇ m, and the porosity is 20%-80%.
  • the surface of the scaffold fiber has microscopic pores, the pore diameter is 3-80nm, the specific surface area is 50-500m 2 /g, and the fracture mechanical strength is 2-25MPa.
  • the preparation method of the gel scaffold comprises the following steps:
  • Design model establish a model through modeling software, and perform layered slicing processing on the established model in combination with slicing software;
  • (3) 3D printing target model body input the designed model into the printer, set the number of printing lines and printing speed of each layer of the model, and the number of printing layers, and put the gel ink raw material in the syringe of the printer for layer-by-layer printing. Finally, the gel model embryo body is formed;
  • the 3D printer described in step (3) prints fibers with a diameter ⁇ 160 ⁇ m, a printing layer height > 300 ⁇ m, and a printing speed of 0.5 mm/s-20 mm/s.
  • the treatment temperature is selected according to the properties of the bracket, and the procedure is to dry at 20-50°C for 8-24h, sinter at 300-1500°C for 2-72h, and heat up The rate is 0.5-10°C/min.
  • the fourth aspect of the present invention provides the application of inorganic non-metal gel scaffold in tissue engineering or in electronic devices.
  • the application of the inorganic non-metal gel scaffold in tissue engineering is as bone repair scaffold, cartilage repair scaffold, biological load Active protein drugs, bioactive substance drug molecules or mesenchymal stem cells, endothelial cells, Schwann cell scaffolds;
  • the application of inorganic non-metallic gel scaffolds in electronic devices is as supercapacitors, batteries, solar cells, piezoelectric sensors, optoelectronics Sensors, chemical sensing agents, biosensors, electronic skin sensing devices.
  • the present invention reports a process for customizing the preparation of inorganic non-metallic scaffolds using inorganic non-metallic particles as basic units.
  • the preparation method is simple and convenient, and has high application value for industrial mass production.
  • the present invention utilizes the electrostatic force, hydrophobic force and magnetic force between inorganic non-metallic particles to form inorganic non-metallic gel ink, and realizes the gelation of inorganic non-metallic materials under normal temperature conditions, with 10Pa-500kPa
  • the interval mechanical properties are precisely adjustable, and the viscosity range is controllable from 2000Pa.s to 10000Pa.s. It can be directly applied to inorganic non-metallic additive manufacturing technology without additives or crosslinking agents.
  • the invention uses the three-dimensional support prepared by inorganic non-metallic gel ink to realize the high-precision printing of inorganic non-metallic materials, and the aperture can reach 70um.
  • the fixing of the metal bracket realizes low-cost additive manufacturing.
  • the custom-made three-dimensional scaffold of the present invention has high strength, the compressive strength can reach 70MPa, and the compressive modulus can reach 500MPa, which fully meets the mechanical requirements for cell culture or tissue repair or tumor treatment or electronic devices.
  • the custom-made three-dimensional scaffold of the present invention has interconnected macroscopic macropores and a uniform surface microporous structure.
  • the macroscopic macropores are conducive to the growth of tissues and the production of blood vessels, and the uniform surface microporous structure is more conducive to cell growth. Adhesion, growth and differentiation.
  • Fig. 1 is a flow chart of the customized manufacturing of inorganic non-metallic stent according to the method of the present invention, and the illustration is a physical photo of the printed three-dimensional stent;
  • Fig. 3 is the potential test picture of the positively charged silica nanoparticles of the 50nm particle size prepared in embodiment 1;
  • Fig. 5 is the potential test picture of the positively charged silica nanoparticles of the 200-300nm particle size prepared in embodiment 4;
  • Fig. 7 is the potential test picture of the positively charged bioglass particle prepared in embodiment 6;
  • Figure 8 is a three-dimensional support and microscopic topography printed in Example 9;
  • picture A is an electron microscope picture of the whole support,
  • picture B is a surface topography picture of the scaffold fiber,
  • picture C is a further enlarged view of the surface topography of picture B, and
  • picture D The picture is a further enlarged view of the surface topography of Figure C;
  • Example 10 is a potential test picture of the positively charged mesoporous bioglass particles prepared in Example 10;
  • Figure 12 is the physical adsorption of the three-dimensional scaffold in Example 10;
  • Figure A is the nitrogen adsorption/desorption curve, and
  • Figure B is the pore size distribution curve;
  • Fig. 14 is a picture of three-dimensional scaffolds with different pores prepared in the method described in Example 24 and a Micro-CT reconstructed slice
  • A1-C1 are digital pictures of printed scaffolds with different pores
  • A2-C2 are Micro-CT images of scaffolds with different pores.
  • -CT pictures, A3-C3 are top views of scaffolds with different pores, A4-C4 are side views of scaffolds with different pores, A5-C5 are Micro-CT reconstruction images of scaffolds with different pores;
  • Figure 15 is the SEM electron microscope pictures of in vitro mineralization at different time points in Example 26, a1 in Figure A is the scanning electron microscope picture of the printed scaffold fiber, a2 is the scanning electron microscope picture of the mineralization of the scaffold on the 0th day, and a3 is the scaffold mineralized on the 28th day
  • the scanning electron microscope photo of , Figure B is the distribution of Si, O, Ca, P elements on the scaffold on the 28th day;
  • Figure 16 is an FTIR analysis chart of different time points of in vitro mineralization in Example 26;
  • Fig. 17 is the XRD analysis figure of different time points of mineralization in vitro in Example 26;
  • Figure 18 is the cell viability of MC3T3-E1 mouse embryonic osteoblast precursor cells cultured with the extract of the three-dimensional scaffold in Example 27;
  • Figure 19 is the ALP and alizarin red staining and quantification results of the MC3T3-E1 mouse embryonic osteoblast precursor cells cultured in contact with the three-dimensional scaffold in 7 days, A is the ALP of the SiO 2 and BG scaffold and ARS staining, B is the quantitative map of ALP staining, and C is the quantitative map of ARS staining;
  • Figure 20 is the CT scan and histological staining of the skull parietal bone repair using the inorganic scaffold in Example 28, which is used to investigate the in vivo osteogenic activity of the three-dimensional scaffold.
  • Figure A is a digital photo of an animal model
  • Figure B is SiO 2 , BG , Micro-CT images of the repair effect of the skull parietal bone model with Bioss scaffolds at 12 weeks
  • picture C shows the quantification of new bone volume of SiO 2 , BG, and skull parietal bone models with Bioss scaffolds at 4 weeks, 8 weeks, and 12 weeks
  • picture D shows SiO 2 , Quantification of new trabecular bone width in BG, Bioss scaffold cranial parietal bone model at 4 weeks, 8 weeks, and 12 weeks.
  • the flow chart of the customized manufacturing of inorganic non-metallic stents according to the method of the present invention is a physical photo of the nanostructured bio-ink and the extrusion-type three-dimensional stent.
  • silica particles with a particle diameter of 50 nm were prepared by a sol-gel method. First mix ethanol and water, then add 26.6mL of ammonia water (25%) and stir at 800rpm, add 38.7mL of tetraethyl orthosilicate in a water bath at 25°C, adjust the rotation speed to 500rpm and stir for 5 hours. The particles were centrifuged and washed with deionized water to obtain a particle suspension in which negatively charged silica particles were dispersed in deionized water to form a mass fraction of 10%. The results in Figure 2 show that the 50nm particle size silica particles were successfully synthesized, with good uniformity and uniform dispersion among the particles.
  • the negatively charged silica particle suspension prepared in step (1) of Example 1 was configured into a suspension with a mass fraction of 10%, then acetic acid was added, and after stirring for 2 hours, the supernatant was removed by high-speed centrifugation at 8000g for 25 minutes Obtain the gel ink raw material, the solid phase content is 40wt%, the mechanical support strength of ink is measured by rotational rheometer time scanning mode, and the recovery ability of ink is measured by multiple cycles between continuous strain scanning and time scanning, The viscosity of the ink was measured by changing the shear rate, where the frequency was 1 Hz and the strain was 0.5%, as shown in Table 3:
  • the positively charged silica particle suspension prepared in step (2) of Example 1 was configured into a suspension with a mass fraction of 10%, then acetic acid was added, and after stirring continuously for 2 hours, the supernatant was removed by centrifugation at 8000 g for 25 minutes Obtain the gel ink raw material, the solid phase content is 40wt%, the mechanical support strength of ink is measured by rotational rheometer time scanning mode, and the recovery ability of ink is measured by multiple cycles between continuous strain scanning and time scanning, Measure the viscosity of ink by changing the shear rate, as shown in Table 4:
  • Example 1 and Comparative Example 1 and Comparative Example 2 From Example 1 and Comparative Example 1 and Comparative Example 2, it can be obtained that the gel ink assembled with opposite charges has higher mechanical support strength, and at the same time has a recovery ability of more than 90% after destruction.
  • the negatively charged silica particles prepared in step (1) in Example 1 are configured into a suspension with a mass fraction of 10% and added to the positively charged silica particles with a mass fraction of 10% obtained in step (2) of Example 1.
  • the number ratio of the negatively charged particle suspension to the positively charged particle suspension is 3:1, 2:1, 1:1, 1:5, 1:10, and the precursor solution is obtained after stirring evenly;
  • the negatively charged silica particles prepared in step (1) in Example 1 are configured into a suspension with a mass fraction of 10% and added to the positively charged silica particles with a mass fraction of 10% obtained in step (2) of Example 1.
  • the number ratio of the negatively charged particle suspension to the positively charged particle suspension is 1:2, and the precursor solution is obtained after stirring evenly; add acetic acid to the precursor solution, continue stirring for 2 hours, and centrifuge at a high speed of 8000g for 25min , Remove the supernatant to obtain the raw material of gel ink, the solid content is 5wt%, 10%, 20%, 30%, 40%, 50%, 60%, and the mechanical support strength of the ink is measured by the time scanning mode of the rotational rheometer , the recovery ability of the ink is measured by multiple cycles between continuous strain scanning and time scanning, and the viscosity of the ink is measured by changing the shear rate, where the frequency is 1Hz and the strain is 0.5%, as shown in Table 6:
  • silica particles with a particle size of 300-400 nm were prepared by a sol-gel method. First mix ethanol and water, then add 35mL of ammonia water (25%) and stir at 900rpm, add 38.7mL of tetraethyl orthosilicate in a water bath at 25°C, adjust the speed to 500rpm, stir for 30min and put it in 4°C The reaction was continued in the refrigerator for 12 hours. After the reaction, the particles were centrifuged and washed with deionized water to obtain a suspension of negatively charged silica particles dispersed in deionized water to form a particle suspension with a mass fraction of 10%.
  • the results in Figure 4 show that silica particles with a particle size of 300-400nm were successfully synthesized, with good uniformity and uniform dispersion among the particles.
  • the number ratio of the negatively charged particle suspension to the positively charged particle suspension is 3:1, 2:1, 1:1, 1:5, 1:10, and the precursor is obtained after stirring solution; add acetic acid to the precursor solution, continue to stir for 2 hours, centrifuge at a high speed at 8000g for 25 minutes, remove the supernatant to obtain the gel ink raw material, the solid phase content is 5wt%, and measure the mechanical properties of the ink through the time scanning mode of the rotational rheometer Support strength, the recovery ability of the ink is measured by multiple cycles between continuous strain sweeps and time sweeps, and the viscosity of the ink is measured by changing the shear rate, where the frequency is 1Hz and the strain is 0.5%, as shown in Table 7 Show:
  • the negatively charged silica particle suspension of 10% of the mass fraction of 200-300nm particle size obtained in the step (1) of Example 4 to the 200-300nm of the mass fraction of 10% obtained in the step (2) of Example 4.
  • the number ratio of the negatively charged particle suspension to the positively charged particle suspension is 1:2, and the precursor solution is obtained after uniform stirring; acetic acid is added to the precursor solution, After continuous stirring for 2 hours, centrifuge at a high speed of 8000g for 25 minutes, remove the supernatant to obtain the gel ink raw material, the solid phase content is 5%, 10%, 20%, 30%, 40%, 50%, 60%, and the solid phase content is 5%, 10%, 50%, 60%.
  • the mechanical support strength of the ink is measured in the time scanning mode of the instrument, the recovery ability of the ink is measured by multiple cycles between continuous strain scanning and time scanning, and the viscosity of the ink is measured by changing the shear rate, where the frequency is 1Hz, the strain is 0.5%, as shown in Table 8:
  • negatively charged bioglass particles were prepared by the sol-gel method.
  • use deionized water to centrifuge and wash the particles to obtain a particle suspension with a mass fraction of 10% by dispersing negatively charged bioglass particles in deionized water.
  • the results in Figure 6 show that the bioglass particles were successfully synthesized, and the single particle size was 50nm.
  • the aqueous dispersion of biological glass particles prepared in (1) was centrifuged to remove the lower layer and the precipitate was dispersed in butanol to prepare 400 mL of a 10 mg/mL dispersion, and sonicated for 15 min.
  • deionized water to centrifuge the particles to obtain negatively charged silica particles.
  • the results in Figure 7 show that the surface of the bioglass particles has been successfully modified with a positive charge of +36mv.
  • Model support sintering put the cube model support in an oven, dry at 40°C for 12 hours, then raise the temperature to 700°C at a rate of 5°C/min, and keep the temperature for 4 hours to obtain a cured customized inorganic non-metallic support .
  • the compression test of the sintered three-dimensional support was carried out by a mechanical testing machine, and the compression rate was 1mm/min, as shown in Table 10:
  • Example 6 and Comparative Examples 3 and 4 can still form a gel ink with stronger mechanics through the mutual attraction of positive and negative charges.
  • the gel ink formed by separate positively charged particles and negatively charged particles is only the accumulation of particles, which cannot achieve both mechanical support strength and recovery ability after damage.
  • the mass fraction obtained in step (1) in Example 6 is 10% of the negatively charged bioglass suspension that is added to the 10% positively charged bioglass suspension obtained in step (2) in Example 6
  • the number ratio of negatively charged particle suspension to positively charged particle suspension is 1:3, 1:1, 1:3, and the precursor solution is obtained after stirring evenly; acetic acid is added to the precursor solution, and after continuous stirring for 2 hours, pass 6000g high-speed centrifugation for 20min, remove the supernatant to obtain the gel ink raw material, the solid phase content is 10wt%
  • the mechanical support strength of the ink is measured by the time scanning mode of the rotational rheometer, through multiple continuous strain scanning and time scanning Cycle to measure the recovery ability of the ink, and measure the viscosity of the ink by changing the shear rate, wherein the frequency is 1Hz, and the strain is 0.5%, as shown in Table 13:
  • the mass fraction obtained in step (1) in Example 6 is 10% of the negatively charged bioglass suspension that is added to the 10% positively charged bioglass suspension obtained in step (2) in Example 6
  • the number ratio of negatively charged particle suspension to positively charged particle suspension is 1:3, and the precursor solution is obtained after stirring evenly; acetic acid is added to the precursor solution, and after continuous stirring for 2 hours, the supernatant is removed by 6000g high-speed centrifugation for 20 minutes.
  • the raw material of gel ink was obtained from liquid, and the solid phase content was 10%, 20%, 30%, 40%, and 50%.
  • the mechanical support strength of the ink was measured by the time scanning mode of the rotational rheometer, and the continuous strain scanning and time scanning were used to measure the mechanical support strength of the ink.
  • the recovery ability of the ink is measured by multiple cycles between, and the viscosity of the ink is measured by changing the shear rate, wherein the frequency is 1Hz, and the strain is 0.5%, as shown in Table 14:
  • the solid phase content is 30wt%, using modeling software to build a 15 ⁇ 15 ⁇ 15mm cube three-dimensional bracket model, and combining the slicing software to slice the built cube three-dimensional bracket model and import it into the extrusion injection In the 3D printer; select the inner diameter of the needle to be 600 ⁇ m, and then put the obtained nanostructured bio-ink into the nozzle of the 3D printer to print the cube model bracket, print layer by layer, and finally form the target model embryo. Put the cube model bracket in an oven, dry at 40°C for 12 hours, then raise the temperature to 700°C at a rate of 5°C/min, and keep the temperature for 4 hours to obtain a cured customized inorganic non-metallic bracket.
  • Fig. 8 is a scanning electron micrograph of the sintered bioglass scaffold.
  • Figure A is the electron microscope image of the overall scaffold
  • Figure B is the surface topography of the scaffold fiber
  • C is a further enlarged view of the surface topography of B
  • D is a further enlarged view of the surface topography of C.
  • the printed bioglass scaffold has a regular structure.
  • Figure B it can be seen that the scaffold fibers are uniform and smooth, and the particles are evenly arranged.
  • the particles are closely connected to form a uniform structure.
  • mesoporous bioglass particles were prepared by template method. First, dissolve 24.1 cetyltrimethylammonium bromide in 1000ml of deionized water, add 3.2ml of ammonia water (35%) and stir at room temperature for 10min, then add 38.7mL of ethyl orthosilicate, 6.23g of calcium nitrate , 1.97ml triethyl phosphate, adjust the rotating speed to 500rpm and stir the reaction for 12h.
  • Fig. 9 is a transmission electron microscope picture of mesoporous bioglass. It can be seen from the figure that the particle size of mesoporous bioglass particles is about 100nm, and individual particles are well dispersed.
  • the aqueous dispersion of mesoporous bioglass particles prepared in (1) was centrifuged to remove the lower layer and the precipitate was dispersed in ethanol to prepare 400 mL of a 10 mg/mL dispersion system, and sonicated for 15 min. It was placed in a water bath at 40° C., 2 mM cyclopropylformamidine was added within 20 minutes using a syringe pump, the stirring speed was 1000 rpm, and the reaction was carried out at 40° C. for 5 hours.
  • the mass fraction obtained in step (1) is 10% negatively charged mesoporous bioglass suspension that is added to the mass fraction obtained in step (2) in the positively charged mesoporous bioglass suspension of 10%.
  • Negative charge The number ratio of particle suspension to positively charged particle suspension is 1:3, and the precursor solution is obtained after stirring evenly; hydrochloric acid is added to the precursor solution, and after continuous stirring for 2 hours, it is centrifuged at 9000g for 15 minutes at a high speed, and the supernatant is removed to obtain a gel Ink raw material, the solid phase content is 30%, the mechanical support strength of the ink is measured by the time scanning mode of the rotational rheometer, and the recovery ability of the ink is measured by multiple cycles between continuous strain scanning and time scanning. The viscosity of the ink was measured at the shear rate, where the frequency was 1 Hz and the strain was 0.5%, as shown in Table 15:
  • Model support sintering put the cube model support in an oven, dry at 40°C for 12 hours, then raise the temperature to 800°C at a rate of 5°C/min, and keep the temperature for 4 hours to obtain a cured customized inorganic non-metallic support , the mesoporous scaffold has through-through macroscopic macropores and microscopic small pores.
  • Figure 11 is the characterization diagram of the sintered cube scaffold. From Figure 11, it can be obtained that the pore size of the printed scaffold is 250 ⁇ m.
  • Figure A in Figure 12 is the nitrogen adsorption-desorption curve of the mesoporous scaffold after sintering, and the pore volume is 0.417cc/ g, the specific surface area is 86.59m 2 /g, Figure B is the distribution curve of the mesopore size of the scaffold, the microscopic pore diameter of the scaffold is 17.939nm; the compression test of the sintered three-dimensional scaffold is carried out by a mechanical testing machine, and the compression rate is 1mm/ min, as shown in Table 16:
  • the negatively charged mesoporous bioglass particle suspension prepared in step (1) of Example 10 was configured into a suspension with a mass fraction of 10%, then acetic acid was added, and after continuous stirring for 2 hours, the supernatant was removed by high-speed centrifugation at 9000 g for 15 minutes.
  • the raw material of gel ink is obtained from liquid, and the solid phase content is 30wt%.
  • the mechanical support strength of the ink is measured by the time scanning mode of the rotational rheometer, and the recovery ability of the ink is measured by multiple cycles between continuous strain scanning and time scanning. , the viscosity of the ink is measured by changing the shear rate, where the frequency is 1Hz and the strain is 0.5%, as shown in Table 17:
  • the monodisperse mesoporous particles obtained by Example 9 and Comparative Example 5 and Comparative Example 6 can still form a gel ink with stronger mechanics through the mutual attraction of positive and negative charges, which proves that the preparation method of gel ink formed by the mutual attraction of particles has the advantages universality.
  • Example 10 Adding the negatively charged mesoporous bioglass suspension obtained in step (1) in Example 10 with a mass fraction of 10% into the positively charged bioglass with a mass fraction obtained in step (2) in Example 10
  • the number ratio of negatively charged particle suspension to positively charged particle suspension is 1:3, 1:1, 3:1, and the precursor solution is obtained after stirring evenly; add acetic acid to the precursor solution, and continue stirring for 2 hours , through 5000g high-speed centrifugation for 10min, remove the supernatant to obtain the gel ink raw material, the solid phase content is 10%, measure the mechanical support strength of the ink through the time scanning mode of the rotational rheometer, through the continuous strain scanning and time scanning Multiple cycles are used to measure the recovery ability of the ink, and the viscosity of the ink is measured by changing the shear rate, wherein the frequency is 1Hz and the strain is 0.5%, as shown in Table 19:
  • Example 10 Adding the negatively charged mesoporous bioglass suspension obtained in step (1) in Example 10 with a mass fraction of 10% into the positively charged bioglass with a mass fraction obtained in step (2) in Example 10
  • the number ratio of negatively charged particle suspension to positively charged particle suspension is 1:3, and the precursor solution is obtained after stirring evenly; add acetic acid to the precursor solution, continue stirring for 2 hours, and centrifuge at 5000g for 10 minutes at a high speed to remove The supernatant was used to obtain the gel ink raw material, and the solid content was 10%, 20%, 30%, 40%, 50%.
  • the mechanical support strength of the ink was measured by the time scanning mode of the rotational rheometer, and the continuous strain scanning and time Multiple cycles between scans were used to measure the recovery ability of the ink, and the viscosity of the ink was measured by changing the shear rate, where the frequency was 1 Hz and the strain was 0.5%, as shown in Table 20:
  • Calcium phosphate particles were prepared using chemical precipitation. Add 100 mL H3PO4 solution (75 mM ) dropwise to 100 mL Ca(OH) 2 (125 mM) aqueous suspension, then adjust the pH to 7.0, and stir continuously at room temperature for 14-16 h. Centrifuge the CaP nanoparticles , and then washed three times with deionized water to obtain calcium phosphate nanoparticles. The transmission electron microscope picture of calcium phosphate nanoparticles is shown in Figure 13. The calcium phosphate particles are uniformly dispersed and have a single particle size.
  • Adsorb sodium citrate on the surface of calcium phosphate particles to make the surface negatively charged disperse the calcium phosphate particles prepared in (1) in 10mM sodium citrate aqueous solution at a concentration of 10mg/mL and stir for 14-16h, then centrifuge the particles , and washed three times with deionized water to obtain negatively charged calcium phosphate particles.
  • Use a Zeta potential meter to test the surface potential of the particles synthesized in (1)(2) under the condition of pH 7, the results are shown in Table 21
  • the mass fraction obtained in step (1) in Example 13 is 10% of the negatively charged calcium phosphate particle suspension that is added to the positively charged calcium phosphate particle of 10% in mass fraction obtained in step (2) in Example 13
  • the number ratio of the negatively charged particle suspension to the positively charged particle suspension is 30%, and the precursor solution is obtained after stirring evenly; nitric acid is added to the precursor solution, and after continuous stirring for 2 hours, it is centrifuged at 10000g for 10 minutes to remove the upper
  • the raw material of gel ink is obtained from the supernatant, and the solid phase content is 10%, 20%, 30%, 40%, 50%.
  • the mechanical support strength of the ink is measured by the time scanning mode of the rotational rheometer, and the continuous strain scanning and time scanning
  • the recovery ability of the ink is measured by multiple cycles between, and the viscosity of the ink is measured by changing the shear rate, wherein the frequency is 1Hz, and the strain is 0.5%, as shown in Table 23:
  • alumina particles were prepared by hydrothermal method. First, dissolve 0.16mol/LAl(NO3)3 ⁇ 9H2O in 100ml deionized water, add hydrazine hydrate solution dropwise at a rate of 0.5ml/min with a constant pressure funnel under stirring at 500 rap until the pH reaches 5.0, and react for 3 hours. The solution was transferred to a reaction kettle and reacted at 200°C for 12h. After cooling to room temperature, it was washed three times with a mixture of deionized water and absolute ethanol, and then dispersed in deionized water to form a particle suspension with a mass fraction of 10%.
  • the aqueous dispersion of alumina glass particles prepared in (1) was centrifuged to remove the lower layer and the precipitate was dispersed in ethanol to prepare 400 mL of a 10 mg/mL dispersion system, and sonicated for 15 min. Place it in a water bath at 40°C, add 2mL of 3-aminopropyltrimethoxysiloxane within 20 minutes using a syringe pump, stir at 1000rpm, and react at 40°C for 5h. After the reaction was completed, the dispersed and cleaned particles were washed three times with deionized water to prepare a positively charged alumina particle dispersion and set the particle suspension to a mass fraction of 10%.
  • Model support sintering put the cube model support in an oven, dry at 40°C for 12 hours, then raise the temperature to 1500°C at a rate of 5°C/min, and keep the temperature for 4 hours to obtain a cured customized inorganic non-metallic support .
  • the compression test of the sintered three-dimensional support was carried out by a mechanical testing machine, and the compression rate was 1mm/min, as shown in Table 25:
  • hydrophobic silica particles were obtained by modifying the silica particles with a diameter of 50 nm prepared in Example 1. Centrifuge the silica water dispersion with a particle size of 50nm to remove the lower layer and disperse it in absolute ethanol to form 400mL of a 20mg/mL dispersion system. After stirring for 30min, add 4mL of octadecylsiloxane within 20 minutes using a syringe pump Alkanes, the stirring speed was 600rpm, and the reaction was carried out at room temperature for 8h. After the reaction, the particles were washed with absolute ethanol to prepare hydrophobic silica particles.
  • hydrophobic silica particles were obtained by modifying positively charged silica particles with a diameter of 50 nm prepared in Example 1. Centrifuge the silica water dispersion with a particle size of 50nm to remove the lower layer and disperse it in acetone to form 400mL of a 20mg/mL dispersion system. After stirring for 30min, use a syringe pump to add 4mL of octadecanoic acid within 20 minutes. The stirring speed is 600rpm, react at room temperature for 8h. After the reaction, the particles were washed with absolute ethanol to prepare hydrophobic silica particles.
  • hydrophobic silica particles were obtained by modifying positively charged silica particles with a diameter of 50 nm prepared in Example 1. Centrifuge the silica water dispersion with a particle size of 50nm to remove the lower layer and disperse it in acetone to form 400mL of a 20mg/mL dispersion system. After stirring for 30min, add 4mL of triethoxy tridecafluoride within 20 minutes using a syringe pump n-octylsilane, the stirring speed is 600rpm, and the reaction is carried out at room temperature for 8h. After the reaction, the particles were washed with absolute ethanol to prepare hydrophobic silica particles.
  • step (1) Disperse the hydrophobic silica particles obtained in step (1) in deionized water, then remove the supernatant through 8000g high-speed centrifugation for 15min to obtain the gel ink raw material, the solid phase content is 30wt%, and it is measured by the time scanning mode of the rotational rheometer
  • the mechanical support strength of the ink, the recovery ability of the ink is measured by multiple cycles between continuous strain scanning and time scanning, and the viscosity of the ink is measured by changing the shear rate, where the frequency is 1Hz and the strain is 0.5%, such as Table 28 shows:
  • hydrophobic silica particles were obtained by modifying the silica particles with a diameter of 50 nm prepared in Example 1. Centrifuge the silica aqueous dispersion with a particle size of 50nm to remove the lower layer and disperse it in deionized water to form 400mL of a 20mg/mL dispersion system. After stirring for 30min, use a syringe pump to add 4mL of trimethylchlorosilane within 20 minutes and stir. The speed was 600 rpm, and the reaction was carried out for 8 hours at room temperature. After the reaction, the particles were washed with absolute ethanol to prepare hydrophobic silica particles.
  • ferric oxide particles were prepared by co-precipitation method. Add 50ml of deionized water into the round bottom flask, then connect the condenser, take over the nitrogen gas, and a thermometer. Purify the oxygen in the deionized water with nitrogen for about 10 minutes, then add 0.52mmol FeSO 4 .6H 2 O (0.7g), 1.08mmol FeCl 3 .6H 2 O (0.145g) ultrasonically dissolved in 2ml of hydrochloric acid, when the temperature reaches 100 Celsius was added. After 5 minutes, 30ml of ammonia water (25%) was quickly added and stirred at 600rpm. After condensing and refluxing for 2 hours, the ferric oxide particles were collected by centrifugation, and the ferric oxide after centrifugal washing was dispersed in deionized water to form a particle suspension with a mass fraction of 30%.
  • the iron ferric oxide dispersion obtained in step (1) is oriented to assemble magnetic particles to form a uniform network structure, and then the assembled suspension is centrifuged at a high speed of 8000g for 20min, and the supernatant is removed to obtain a coagulated Rubber ink raw material, solid phase content is 40wt%.
  • the mechanical support strength of the ink is measured by the time scanning mode of the magnetic field rotational rheometer, the recovery ability of the ink is measured by multiple cycles between continuous strain scanning and time scanning, and the viscosity of the ink is measured by changing the shear rate, The frequency is 1Hz, and the strain is 0.5%, as shown in Table 31:
  • the solution after the reaction was washed with deionized water and centrifuged at 8000 rpm for three times, and the obtained centrifuge was dispersed in deionized water and ultrasonicated for 10 minutes to obtain a dispersion of barium titanate particles with a mass fraction of 5%.
  • the barium titanate particle dispersion prepared in (1) was centrifuged to remove the lower layer and the precipitate was dispersed in ethanol to form a 10 mg/mL dispersion in 400 mL, and sonicated for 15 min. It was placed in a water bath at 40° C., 2 mM cyclopropylformamidine was added within 20 minutes using a syringe pump, the stirring speed was 1000 rpm, and the reaction was carried out at 40° C. for 5 hours. After the reaction was completed, the dispersed and cleaned particles were washed three times with deionized water to prepare a positively charged barium titanate particle dispersion and place it into a particle suspension with a mass fraction of 5%.
  • the negative charge The number ratio of the particle suspension to the positively charged particle suspension is 1:3, and the precursor solution is obtained after stirring evenly; phosphoric acid is added to the precursor solution, and after continuous stirring for 2 hours, it is centrifuged at 7000g for 20 minutes at a high speed, and the supernatant is removed to obtain a gel Ink raw material, the solid phase content is 35%, the mechanical support strength of the ink is measured by the time scanning mode of the rotational rheometer, and the recovery ability of the ink is measured by multiple cycles between continuous strain scanning and time scanning. The viscosity of the ink is measured at the shear rate, where the frequency is 1 Hz and the strain is 0.5%, as shown in Table 33:
  • Model support sintering Put the cube model support in an oven, dry at 40°C for 12 hours, then raise the temperature to 1200°C at a rate of 5°C/min, and keep the temperature constant for 4 hours to obtain cured customized barium titanate ceramics
  • the barium titanate stent was subjected to polarization treatment at 120 degrees Celsius with a DC voltage of 1 kV/mm for 30 minutes.
  • Use the piezoelectric constant tester to test the piezoelectric constant, and use the impedance analyzer to obtain the dielectric constant. The results are shown in Table 34:
  • the resulting gel ink has higher mechanical strength and higher viscosity, and at the same time It has a higher piezoelectric effect and has a better application prospect as a piezoelectric sensor.
  • 1 g of lithium fluoride is dissolved in 20 ml of concentrated hydrochloric acid solution and placed in a 250 ml Teflon beaker. Then add 1g Ti 3 AlC 2 to the above solution, stir magnetically at 35°C for 24h, wash with deionized water, and centrifuge at 3500rpm for 3 times until the pH of the supernatant is 6, and disperse the centrifuge in deionized water for 10 minutes. , the concentration of the obtained MXene nanosheet dispersion was 1 mg/mL.
  • the polydiallyldimethylammonium solution (10ml, 1wt%) was added dropwise to the MXene (100ml; 0.1mg/mL) obtained in step (1). Then the magnetic stirring speed was 4000rpm for 1 hour after magnetic stirring for 24 hours. The obtained precipitate was washed twice with deionized water, and then sonicated for 5 minutes to obtain a positively charged MXene nanosheet dispersion with a concentration of 1 mg/ml.
  • the resulting gel ink has a higher mechanical
  • the strength and viscosity are also higher, which is more suitable for the printing of gel ink, and the printed electronic devices have higher energy storage capacity.
  • inorganic non-metallic particles prepared in Examples 1-22 to disperse in absolute ethanol to form a particle suspension with a mass fraction of 10%, add octadecyl tetraethyl orthosilicate under stirring at 800 rpm, and react at room temperature After 8 hours, it was centrifuged and washed with deionized water three times, then dispersed into a mixture of water and ethanol (1:1), and stirred at 500 rpm for 30 minutes to obtain a precursor solution. The precursor solution was centrifuged at 10,000 rpm for 30 minutes to obtain gel ink.
  • the nanostructured bio-ink with a mass fraction of 20% obtained by centrifugal concentration using modeling software to establish a 15 ⁇ 15 ⁇ 15mm cube three-dimensional scaffold model, combined with slices
  • the three-dimensional scaffolds of 0-200 ⁇ m, 200-400 ⁇ m, and 400-600 ⁇ m are shown in Figure 14.
  • A1-C1 are digital images of printed scaffolds with different pores
  • A2-C2 are Micro-CT images of scaffolds with different pores
  • A3-C3 are top views of scaffolds with different pores
  • A4-C4 are side views of scaffolds with different pores
  • A5-C5 are Micro-CT reconstruction images of scaffolds with different pores.
  • the nanostructured bio-ink with a mass fraction of 20% obtained by centrifugal concentration using modeling software to establish a 15 ⁇ 15 ⁇ 15mm cube three-dimensional scaffold model, combined with slices
  • the sintering conditions of 800°C, 900°C, 1000°C, 1100°C, and 1200°C are sintered and fixed in a muffle furnace. Compression tests were performed on the sintered three-dimensional
  • a1 in Figure 15 is the scanning electron microscope photo of the printed scaffold fiber
  • a2 is the scanning electron microscope photo of the scaffold mineralization on day
  • a3 is the scaffold mineralization 28
  • the scanning electron microscope photo of the scaffold on day 28 and b3 is the distribution of Si, O, Ca, and P elements on the scaffold on day 28. The more points in the figure, the more deposition.
  • Figure 16 is the FTIR analysis chart of different time points of in vitro mineralization
  • Figure 17 is the XRD analysis chart of different time points of in vitro mineralization; the above data can be seen that with the increase of time points, amorphous calcium phosphate is formed on the surface of the scaffold, and there is an obvious mineralization.
  • the inorganic scaffold prepared in Examples 23-25 was used to investigate whether the material has cytotoxicity and in vitro osteogenic effect through contact culture cell experiments. Concrete implementation steps are as follows:
  • MC3T3-E1 mouse embryonic osteoblast precursor cells were cultured in proliferation medium (Dulbecco s modified Eagle medium, DMEM) for 7 days, adding 10% v/v fetal bovine serum (FBS) and 100 U/mL penicillin and 100 ⁇ g/mL streptomycin in ⁇ -MEM, 37°C, 95% relative humidity, 5% CO2 .
  • proliferation medium Dulbecco s modified Eagle medium, DMEM
  • FBS v/v fetal bovine serum
  • penicillin and 100 ⁇ g/mL streptomycin in ⁇ -MEM, 37°C, 95% relative humidity, 5% CO2 .
  • ⁇ -glycerophosphate (10 mM) L-ascorbic acid (50 ⁇ g/mL) and dexamethasone (10 nM) were added to the cell culture medium.
  • the medium was changed after 1 day of culture, and non-adherent cells were removed every 3 days. Replace it once.
  • the cells in the 24-well plate were washed 3 times with PBS solution, and 110 ⁇ L of the mixed solution was added to each well. Stored in the dark and incubated in an incubator for 3 hours, the OD value was detected at a wavelength of 450 nm and the cell proliferation rate was calculated.
  • the cell viability of the cells in the experimental group and the control group is shown in Figure 18. The results show that the cell viability in the scaffold extract is greater than or equal to 100%, and the inorganic scaffold has good biocompatibility.
  • ALP staining was performed using the BCIP/NBT method. Additionally, Alizarin Red (ARS) staining was performed to assess mineralization of the extracellular matrix (ECM). Briefly, after 3 weeks of culture, we removed the cell culture medium and added 100 ⁇ l of ARS solution to each well, followed by incubation at 37 °C for 1 h. After image acquisition, the stained cells were treated with 10% cetylpyridinium chloride for 30 minutes at room temperature and tested for absorbance at 630 nm using a multimode plate reader assay.
  • ARS Alizarin Red
  • Figure 19 The results of the mineralization of the extracellular matrix in the experimental group and the control group, including alizarin red and ALP staining and quantitative analysis, are shown in Figure 19.
  • Figure A shows the ALP and ARS staining of SiO 2 and BG scaffolds
  • Figure B shows the quantification of ALP staining
  • Panel C is a quantitative map of ARS staining. The results showed that the silica and bioglass scaffolds had the ability to significantly promote the osteogenesis of preosteogenic cells, and the inorganic ions released from the BG scaffolds were crucial for better osteogenesis and had better mineralization effects.
  • the in vivo osteogenesis of scaffolds was investigated by implanting inorganic scaffolds in animals.
  • a 3-month-old (2.5-3.0Kg) rabbit was selected, and the heat-treated inorganic stent prepared in Example 23-25 was sterilized by ultraviolet light for 2 hours.
  • two cylindrical bone defects (diameter 10 mm, height 2 mm) were made at the top of the skull, and then inorganic scaffolds were implanted.
  • the rats were given penicillin treatment and placed in cages alone.
  • the rabbits were sacrificed, and the cranial parietal bones were collected for subsequent experiments. Micro-CT and hematoxylin-eosin staining were further performed.
  • Fig. 20 is the scaffold prepared by using inorganic colloidal gel in Example 28 as the repairing of bone defect in rabbits.
  • Picture A is the digital photo of the animal model
  • picture B is the Micro-CT image of the repair effect of the cranial parietal bone model of SiO 2 , BG and Bioss scaffold at 12 weeks
  • picture C is the cranial parietal bone model of SiO 2 , BG and Bioss scaffold at 4 weeks and 8 weeks
  • figure D is the quantification of new bone trabecular width in SiO 2 , BG, and Bioss scaffold cranial parietal bone models at 4 weeks, 8 weeks, and 12 weeks.
  • the experimental operation process is shown in Figure A.
  • Fig. B After being implanted in the skull parietal defect, partial bone repair occurred at 12 weeks (Fig. B).
  • the reconstruction of the skull parietal defect by Micro-CT showed an obvious bone repair effect, and the bone volume and bone size of the new bone Quantitative analysis of the beam width confirmed the good in vivo bone repair ability of the inorganic colloid gel-prepared scaffolds.

Abstract

本发明属于材料科学领域、纳米材料领域、生物医学工程领域，具体是一种无机非金属纳米颗粒组装的水凝胶材料及其在增材制造技术中的应用。水凝胶材料由无机非金属颗粒组装而成形成水凝胶网络；无机非金属颗粒的尺寸10nm～20um；无机非金属颗粒占水凝胶总质量的2～80wt％；水凝胶网络具有微观小孔，孔径为0.1um-30um。无机非金属颗粒以静电组装方法或输水作用组装方法或磁性作用组装方法组装成水凝胶材料。水凝胶材料经增材制造得到凝胶支架，作为骨修复支架，软骨修复支架。本发明水凝胶材料无须添加剂或交联剂直接应用于无机非金属增材制造技术。

Description

一种无机非金属纳米颗粒组装的水凝胶材料及其在增材制造技术中的应用 技术领域
本发明属于材料科学领域、纳米材料领域、生物医学工程领域，涉及由生物活性无机非金属颗粒通过静电作用，疏水作用，磁力作用形成可打印的无机非金属凝胶墨水原料，经过3D打印机技术增材制造制备支架及其应用。
背景技术
组织、器官缺损或功能障碍等疾病已成为危害人类健康的主要病因之一，致力于人造组织器官的“组织工程”由此应运而生。经过30多年的发展，组织工程在组织或器官修复治疗中发挥了越来越重要的作用。组织工程包含3个基本要素：支架材料、生物活性分子和种子细胞。其中支架材料作为组织工程中重要的组成部分，为细胞提供粘附、增殖、分化的空间结构和生长模板，并且可以诱导组织再生，其工程上必须具备良好的生物活性、相容性和诱导性，同时在不同的部位或功能上，也需要提供临时的机械支撑。目前，传统的支架制备方法如造孔剂法、冷冻浇筑法、气体发泡法、有机泡沫浸渍法等方法存在：(i)制备工艺复杂、重现性差，(ⅱ)支架尺寸、形状和孔分布难以精确控制，(ⅲ)存在溶剂残留等缺点，降低了支架在后续实验中的应用价值。增材制造允许精确控制多孔结构的内部孔结构，从而允许制造具有可重复性的复杂几何形状，增材制造的支架在组织工程领域中引起了极大的兴趣。
增材制造也被称为快速原型制造或无固体形式的制造或3D打印，已成为包括生物医学研究在内的不同领域中一种有希望的制造技术。通过计算机辅助设计(CAD)模型支架并将设计的模型导出为标准3D打印语言文件(stl.文件)，将stl文件导入切片软件中将模型进行按照路线切割，然后使用3D打印机进行增材制造模型支架。根据原材料的不同，有光固化打印，激光选区烧结，挤注式打印，立体光刻打印技术，喷墨打印，激光熔融沉积等打印方式，打印后的支架一般经过后期处理将多余的材料去除或烧结处理获得更高的机械强度。经过CT扫描后形成的精确三维缺陷模型，可以打印出完美切合特定缺陷的理想支架，从而为个性化临床医学提高了巨大的潜力。增材制造技术提供了对构建结构的高度控制，保证了重现性，并支持规模化和标准化。
用于组织工程支架上有金属材料、高分子材料、无机非金属材料，由于金属材料一般呈现惰性，不可降解性，植入人体内需要再次取出给患者带来二次伤害，高分子材料力学性能较弱，难以支撑承重受损组织和器官的修复，而无机非金属材料可以通过调节组分和晶态从而控制支架的生物活性和力学性能，降解性等特性，可直接用于人体或与人体直接相关的生物、应用、生物化学等领域。无机非金属支架在人体生理环境中具有在分子水平上激发特殊的细胞响应，能吸附与组织修复有关的活性物质，释放生物活性离子(例如，Ca，Mg，Sr，Si，B，Fe，Cu，Zn，Cr等元素离子)用于诱导改变细胞表型或者调节免疫微环境以指导组织愈合和再生。也可通过表面微观结构与宿主(细胞、体液及组织)发生界面反应，调控机体的自发修复功能，诱导、促进新骨形成，是一种具有“可调控生物响应特性”和“主动修复功能”特征的生物活性支架材料；使用无机非金属材料支架作为组织工程支架，具有更优异的组织或器官的修复效果。
目前制备无机非金属材料支架的方法通常使用无机非金属颗粒与具有可打印性的聚合物按照一定的比例混合配置成具有剪切变稀性的浆料，经过3D打印制成支架后经过高温烧结去除增塑剂。例如CN201710347623.X将生物陶瓷粉末、可降解金属粉末、生物玻璃助烧剂粉末和粘结剂溶液混合得到浆料经过3D打印后在无氧环境下脱脂，烧结；多种组分的混合在前期极易出现混合不均匀从而导致打印精 度不高及烧结后结构不均匀等情况；Lei Chen等(Biomaterials,2019,196:138-150)利用含有硅酸钙锂元素的无机非金属粉末以海藻酸和普朗尼克为增塑剂进行打印墨水的配置，打印的支架具有良好的成骨性能，但是由于增塑剂的存在，打印后的支架烧结固化过程设置为1000℃以上。使用增塑剂作为无机非金属支架打印非添加剂会存在添加剂烧结不尽，孔结构不均匀，容易引起应力集中可能会导致力学性能急剧下降。因此需要从材料设计角度出发，设计出新的无机非金属材料的增材制造方法。
发明内容
本发明的目的是解决纯无机非金属材料打印时需要填加剂进行增塑的缺点，基于增材制造技术使用一种简单而有效的方法制备了具有高强度可用于3D打印的无机非金属材料。使用生物活性无机颗粒通过静电作用、疏水作用，磁力作用形成高强度凝胶墨水同时具备高的破坏后恢复能力，凝胶墨水强度在10Pa至500kPa区间可控；制备的凝胶墨水具有良好的打印性能，经过建模软件，切片软件与3D打印机一体化制造三维支架。打印的支架可以根据应用需求进行热处理，不需要经过1000℃以上处理，得到的支架结构均匀，具有可调节的宏观大孔和微观小孔，压缩强度可达到70MPa,该支架可在组织工程或在电子器件中的应用，在组织工程上的应用可作为骨修复支架，软骨修复支架，负载生物活性蛋白药物、生物活性物质药物分子或间充质干细胞、内皮细胞、雪旺细胞支架；在电子器件上的应用可作为超级电容器、电池、太阳能电池、压电传感器、光电子传感器、化学传感剂、生物传感器、电子皮肤传感器件，为无机非金属材料的增材制造提供了新的设计思路。
本发明是采用如下技术方案来实现的。
本发明提供了一种无机非金属纳米颗粒组装的水凝胶材料，所述水凝胶材料由无机非金属颗粒组装而成形成水凝胶网络；所述无机非金属颗粒的尺寸是10nm～20um；所述水凝胶材料中无机非金属颗粒占水凝胶总体积的2～80wt％；所述水凝胶网络具有微观小孔，孔径为0.1um-30um。
上述技术方案中，进一步地，所述水凝胶材料的力学支撑强度为100kPa-400kPa，粘度为2000-10000Pa.s，破坏恢复能力为50％-100％。
上述技术方案中，进一步地，所述的无机非金属颗粒选自二氧化硅颗粒、生物玻璃颗粒、粘土颗粒、硫酸钙颗粒、碳酸钙颗粒、羟基磷灰石颗粒、氧化铁颗粒、氧化锆颗粒、氧化锌颗粒、氧化钛颗粒、氧化铝颗粒、钛酸钡微颗粒、碳化硅颗粒、石墨烯、氧化石墨烯、还原氧化石墨烯、过渡金属碳化物或氮化物(MXene)、过渡金属二硫化物(TMD)、六方氮化硼和黑磷纳米片的一种或几种的组合；过渡金属二硫化物优选MoS 2。
上述技术方案中，进一步地，所述水凝胶材料的制备方法为静电组装方法或疏水作用组装方法或磁性作用组装方法；
所述静电组装方法包括以下步骤：
S1、使用溶胶凝胶法、化学沉淀法、熔融法、水热合成法，模板法、化学剥离法、电化学剥离、机械剥离法中的一种或几种制备带负电荷的无机非金属颗粒，将得到的负电荷的无机非金属颗粒分散在含有去离子水的液态溶剂中，配置质量体积分数为1％-80％的颗粒悬浮液，充分搅拌2-8h；
S2、将无机非金属纳米颗粒加入到甲醇、乙醇、异丙醇、丁醇、丙酮的一种或几种的组合溶剂中，配置成1％-50％的悬浮液，搅拌20-60min后加入水溶性带正电荷的基团，所述带正电荷的基团是脂肪胺中的氨基，氮-氮双取代脒基中的亚胺，四氮取代胍基中的亚胺化合物，反应6-12h，离心洗涤得到正电荷无机 非金属颗粒；将正电荷无机非金属颗粒分散在去离子水中或分散在甲醇、乙醇、丙酮、异丙醇的一种或两种液态混合溶剂中，配置质量分数为1％-80％的颗粒悬浮液，充分搅拌2-8h，得到带正电荷的无机非金属颗粒悬浮液；
S3、将带负电荷的无机非金属颗粒悬浮液加入到带正电荷的无机非金属颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液颗粒数量比为1:0-0:1，优选10:1-1:50，更优选5:1-1:10，搅拌均匀后得到前驱体溶液；
S4、将步骤S3所得前驱体溶液边搅拌边加入5mM-25mM的醋酸、磷酸、盐酸、硝酸的酸性溶液的一种或几种组合，持续搅拌0.5-3h后，通过2000g-10000g高速离心20-40min，去掉上清液得到固相含量为2～80wt％的凝胶墨水原料，即所述水凝胶材料；
所述疏水作用组装方法包括以下步骤：
S1、使用溶胶凝胶法、化学沉淀法、熔融法、水热合成法，模板法、化学剥离法、电化学剥离、机械剥离法中的一种或几种制备带负电荷的无机非金属颗粒，将负电荷无机非金属颗粒分散到无水乙醇中，配置浓度为1％-80％的无机非金属颗粒悬浮液，搅拌20-60min后加入含有疏水基团的硅-卤键化合物，硅烷偶联剂，硬脂酸化合物中的一种或几种组合，反应6-12h，离心洗涤得到疏水性无机非金属颗粒，将疏水性无机非金属颗粒分散在去离子水中或分散在甲醇、乙醇、丙酮、异丙醇的一种或两种液态混合溶剂中，得到疏水性无机非金属颗粒分散液；
S2、将疏水性无机非金属颗粒分散液通过2000g-10000g高速离心20-40min，去掉上清液得到固相含量为2～80wt％的凝胶墨水原料，即所述水凝胶材料；
所述磁性作用组装方法包括以下步骤：
利用铁钴镍中的一种或多种元素制备磁性颗粒，分散在在去离子水中或分散在甲醇、乙醇、丙酮、异丙醇的一种或两种液态混合溶剂中，配成浓度为1％-80％的无机非金属磁性颗粒悬浮液，在10-300A/m的磁场作用下，磁性颗粒定向组装成均匀网络结构，然后将组装后的悬浮液通过1000g-10000g高速离心20-40min，去掉上清液得到固相含量为2～80wt％的凝胶墨水原料。
本发明第二方面提供了无机非金属纳米颗粒组装水凝胶材料用于可注射、可塑形、药物缓释载体的骨填充生物医用材料，其中，组成水凝胶的无机非金属纳米颗粒为生物玻璃颗粒、粘土颗粒、磷酸钙颗粒，生物活性陶瓷颗粒的一种或几种组合，所述无机非金属纳米颗粒尺寸为10nm～20um，所述无机非金属纳米颗粒占水凝胶总体积的2-80wt％。
本发明第三方面提供了一种无机非金属凝胶支架，所述支架由前述水凝胶材料经增材制造得到的凝胶支架，所述凝胶支架具有纤维堆叠成的相互贯通的气孔，孔径为50-1000μm，孔隙率为20％-80％；支架纤维表面具有微观小孔，孔径为3-80nm，比表面积为50-500m 2/g，断裂力学强度为2-25MPa。
上述技术方案中，进一步地，所述凝胶支架的制备方法包括以下步骤：
(1)以前述方法得到的凝胶墨水原料作为3D打印墨水；
(2)设计模型：通过建模软件建立模型，结合切片软件对所建立的模型进行分层切片处理；
(3)3D打印目标模型坯体：将设计好的模型输入打印机中，设置模型每层打印行数和打印速度以及打印层数，把凝胶墨水原料装在打印机的针筒中进行层层打印，最终形成凝胶模型胚体；
(4)热处理：将凝胶模型胚体放入烧结炉中调节烧结温度得到相应的定制化的三维多孔无机非金属 支架。
上述技术方案中，进一步地，在步骤(3)中所述的3D打印机打印纤维直径≥160μm，打印层高＞300μm，打印速度为0.5mm/s-20mm/s。
上述技术方案中，进一步地，在步骤(4)中所述的热处理过程根据支架的性质选择处理温度，程序为20～50℃下干燥8～24h，300-1500℃下烧结2-72h，升温速率为0.5-10℃/min。
本发明第四方面提供了无机非金属凝胶支架在组织工程或在电子器件中的应用，所述无机非金属凝胶支架在组织工程上的应用为作为骨修复支架，软骨修复支架，负载生物活性蛋白药物、生物活性物质药物分子或间充质干细胞、内皮细胞、雪旺细胞支架；无机非金属凝胶支架在电子器件上的应用为作为超级电容器、电池、太阳能电池、压电传感器、光电子传感器、化学传感剂、生物传感器、电子皮肤传感器件。
发明有益效果
(1)本发明报道了使用无机非金属颗粒为基本单元定制化制备无机非金属支架工艺，制备方法简单便捷，对于工业化量产有很高的应用价值。
(2)本发明利用无机非金属颗粒间的静电作用力、疏水作用力、磁力作用力形成无机非金属凝胶墨水，实现了无机非金属材料在常温条件下的凝胶化，具有10Pa-500kPa区间力学性能精确可调较性，粘度2000Pa.s-10000Pa.s区间可控，无须添加剂或交联剂直接应用于无机非金属增材制造技术。
(3)本发明使用无机非金属凝胶墨水制备的三维支架实现了无机非金属材料高精度打印，孔径可达到70um，同时实现了复杂结构支架的打印，无需较高烧结温度就能实现无机非金属支架的固定，实现了低成本增材制造。
(4)本发明定制化制备的三维支架具有较高的强度，压缩强度可达到70MPa，压缩模量可达到500MPa，完全满足细胞培养或用于组织修复或肿瘤治疗或电子器件的力学要求。
(5)本发明定制化制备的三维支架具有相互连通的宏观大孔和均匀的表面微孔结构，宏观大孔有利于组织的长入和血管的生产，均匀的表面微孔结构更利于细胞的粘附、生长和分化。
附图说明
图1是本发明所述方法无机非金属支架定制化制造的流程图，插图为打印的三维支架的实物照片；
图2是实施例1中所制备的负电荷50nm粒径大小的二氧化硅纳米颗粒的透射电镜照片，标尺＝100nm；
图3是实施例1中所制备的50nm粒径大小的正电荷二氧化硅纳米颗粒的电位测试图片；
图4是实施例4中所制备的负电荷200-300nm粒径大小的二氧化硅纳米颗粒的透射电镜照片，标尺＝500nm；
图5是实施例4中所制备的200-300nm粒径大小的正电荷二氧化硅纳米颗粒的电位测试图片；
图6是实施例6中所制备的负电荷生物玻璃颗粒的透射电镜照片，标尺＝200nm；
图7是实施例6中所制备的正电荷生物玻璃颗粒的电位测试图片；
图8是实施例9中所打印的三维支架及微观形貌图；A图为整体支架电镜图，B图为支架纤维表面形貌图，C图为B图的表面形貌进一步放大图，D图为C图的表面形貌进一步放大图；
图9是实施例10中所制备的负电荷介孔生物玻璃颗粒的透射电镜照片，标尺＝100nm；
图10是实施例10中所制备的正电荷介孔生物玻璃颗粒的电位测试图片；
图11是实施例10中通过打印后得到的三维支架的图片，图B为图A支架的放大图，标尺＝500μm；
图12是实施例10中三维支架的物理吸附；A图为氮气吸附/脱附曲线，B图为孔尺寸分布曲线；
图13是实施例13中所制备的负电荷磷酸钙颗粒的透射电镜照片，标尺＝100nm；
图14是实施例24中所述方法中制备不同孔隙的三维支架的图片以及Micro-CT重建的片,A1-C1为不同孔隙的打印支架的数码图片，A2-C2为不同孔隙的支架的Micro-CT图片，A3-C3为不同孔隙的支架的俯视图，A4-C4为不同孔隙的支架的侧视图，A5-C5为不同孔隙的支架的Micro-CT重建图；
图15是实施例26中体外矿化不同时间点SEM电镜图片，图A中a1为打印支架纤维扫描电镜照片，a2为第0天支架矿化的扫描电镜照片，a3为支架矿化28天支架的扫描电镜照片，图B为第28天支架上Si,O,Ca,P元素分布图；
图16是实施例26中体外矿化不同时间点FTIR分析图；
图17是实施例26中体外矿化不同时间点XRD分析图；
图18是实施例27中使用三维支架的浸提液培养MC3T3-E1小鼠胚胎成骨细胞前体细胞的细胞活力；
图19是实施例27中使用三维支架的接触培养的MC3T3-E1小鼠胚胎成骨细胞前体细胞在7天内的ALP和茜素红染色及定量结果，A图为SiO 2和BG支架的ALP和ARS染色，B图为ALP染色的定量图，C图为ARS染色的定量图；
图20是实施例28中使用无机支架的作为颅顶骨修复的CT扫描和组织学染色，用来考察三维支架的的体内成骨活性，A图为动物模型数码照片，B图为SiO 2、BG、Bioss支架颅顶骨模型12周的修复效果Micro-CT图，C图为SiO 2、BG、Bioss支架颅顶骨模型在4周、8周、12周新生骨体积的定量，D图为SiO 2、BG、Bioss支架颅顶骨模型在4周、8周、12周新生骨小梁宽度的定量。
具体实施方式
以下结合具体实施例对本发明作进一步说明，但不以任何方式限制本发明。
如图1所示，本发明所述方法无机非金属支架定制化制造的流程图，插图为纳米结构生物墨水和挤注式三维支架的实物照片。
下面结合附图通过实施例对本发明所述的一种生物活性无机非金属支架定制化制造技术作进一步说明。
实施例1
(1)负电荷50nm的二氧化硅颗粒的制备
本实例通过溶胶凝胶法制备50nm粒径的二氧化硅颗粒。先将乙醇与水混匀，然后加入26.6mL氨水(25％)800rpm搅拌均匀，在25℃水浴的条件下加入38.7mL的正硅酸乙酯，将转速调节到500rpm搅拌反应5h，反应结束后使用去离子水离心清洗颗粒，得到负电荷二氧化硅颗粒分散在去离子水中配置成质量分数为10％的颗粒悬浮液。图2结果表明50nm粒径二氧化硅颗粒成功合成，均一度较好，颗粒之间均匀分散。
(2)正电荷50nm的二氧化硅颗粒的制备
将(1)中制备的50nm粒径的二氧化硅水分散液离心取下层沉淀分散于无水乙醇中配置成10mg/mL的分散系400mL，搅拌30min后，使用注射泵在20分钟内加入4mL 3-氨丙基三甲氧基硅氧烷，搅拌速度为600rpm，室温条件下反应8h。反应结束后，使用去离子水清洗颗粒，制备出带正电荷二氧化硅颗粒分散在去离子水中配置成质量分数为10％的颗粒悬浮液。图3结果表明50nm粒径二氧化硅颗粒表面成功被修饰 上正电荷，带电荷为+35mv。
(3)凝胶墨水的制备
将步骤(1)得到的质量分数10％的带负电荷的二氧化硅颗粒悬浮液加入步骤(2)得到的质量分数10％的带正电荷的二氧化硅颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:2,搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过8000g高速离心25min,去掉上清液得到凝胶墨水原料，固相含量为40wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表1所示：
表1
  力学支撑强度 粘度 恢复能力
凝胶墨水 119.7kPa 9000Pa.s 85％
(4)三维支架打印
使用CAD画出长宽高为15mm的正方体，将模型输入到挤出式打印机中，设置参数分别为每层打印行数为15行，打印速度为3mm/s,打印层高为15mm,选用针头内径为500μm，然后将步骤(3)制备的凝胶墨水原料装在打印机的针筒中进行正方体模型支架打印。层层打印，最终形成目标模型胚体；
(5)模型支架热处理：将正方体模型支架放入烧结炉中，在40℃下干燥12h后以5℃/min的升温速率升到700摄氏度，恒温4h,得到固化后的定制化的无机非金属支架。通过力学测试机对烧结后的三维支架进行压缩测试，压缩速率为1mm/min，如表2所示：
表2
  压缩强度 弹性模量
三维支架 12MPa 15.3MPa
对比例1纯负电荷二氧化硅颗粒墨水
将实施例1步骤(1)制备的带负电荷的二氧化硅颗粒悬浮液配置成质量分数为10％的悬浮液，然后加入醋酸，持续搅拌2h后，通过8000g高速离心25min,去掉上清液得到凝胶墨水原料，固相含量为40wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表3所示：
表3
  力学支撑强度 粘度 恢复能力
凝胶墨水 1018kPa 536Pa.s 101％
对比例2纯正电荷二氧化硅颗粒墨水
将实施例1步骤(2)制备的带正电荷的二氧化硅颗粒悬浮液配置成质量分数为10％的悬浮液，然后加入醋酸，持续搅拌2h后，通过8000g高速离心25min,去掉上清液得到凝胶墨水原料，固相含量为40wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，如表4所示：
表4
  力学支撑强度 粘度 恢复能力
凝胶墨水 3420kPa 2000Pa.s 78％
通过实施例1和对比例1和对比例2可以得到，通过带相反电荷组装的凝胶墨水具有更高的力学支撑强度，同时具有破坏后90％以上的恢复能力。
实施例2
将实施例1中步骤(1)制备的带负电荷的二氧化硅颗粒配置成质量分数10％的悬浮液加入到实施例1步骤(2)得到的质量分数10％的带正电荷的二氧化硅颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为3:1、2:1、1:1、1:5、1:10，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过8000g高速离心25min,去掉上清液得到凝胶墨水原料，固相含量为5wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度其中频率为1Hz,应变为0.5％，如表5所示：
表5
负/正二氧化硅颗粒数量比 3:1 2:1 1:1 1:5 1:10
力学支撑强度(Pa) 497±94 710±293 222±175 15.7±5 0.03±0.02
粘度(Pa.s) 356±15 582.6±7 134.7±3 2.3±0.1 0.005±0
恢复能力(％) 99.6 106.3 97.9 102.5 100.8
实施例3
(1)纳米结构生物墨水的制备
将实施例1中步骤(1)制备的带负电荷的二氧化硅颗粒配置成质量分数10％的悬浮液加入到实施例1步骤(2)得到的质量分数10％的带正电荷的二氧化硅颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:2,搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过8000g高速离心25min,去掉上清液得到凝胶墨水原料，固相含量为5wt％、10％、20％、30％、40％、50％、60％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表6所示：
表6
Figure PCTCN2021134538-appb-000001
实施例4
(1)负电荷200-300nm二氧化硅颗粒的制备
本实例通过溶胶凝胶法制备300-400nm粒径的二氧化硅颗粒。先将乙醇与水混匀，然后加入35mL氨水(25％)900rpm搅拌均匀，在25℃水浴的条件下加入38.7mL的正硅酸乙酯，将转速调节到500rpm搅拌反应30min后放入4度冰箱中继续反应12h，反应结束后使用去离子水离心清洗颗粒，得到负电荷二氧化硅颗粒分散在去离子水中配置成质量分数为10％的颗粒悬浮液。图4结果表明300-400nm粒径大小的二氧化硅颗粒成功合成，均一度较好，颗粒之间均匀分散。
(2)正电荷200-300nm二氧化硅颗粒的制备
将(1)中制备的300-400nm粒径大小的二氧化硅水分散液离心取下层沉淀分散于甲醇中配置成10mg/mL的分散系400mL，超声15min。将其置于40℃的水浴中，使用注射泵在20分钟内加入2mM的精氨酸，搅拌速度为600rpm，反应结束后，使用去离子水清洗颗粒，制备出带正电荷二氧化硅颗粒分散在去离子水中配置成质量分数为10％的颗粒悬浮液。图5结果表明300-400nm粒径大小的二氧化硅颗粒表面成功被修饰上正电荷，带电荷为+27mv。
(3)凝胶墨水的制备
将步骤(1)得到的质量分数10％的200-300nm粒径大小的带负电荷的二氧化硅悬浮液加入步骤(2)得到的质量分数10％的200-300nm粒径大小的带正电荷的二氧化硅颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液颗粒数量比为3:1、2:1、1:1、1:5、1:10，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过8000g高速离心25min，去掉上清液得到凝胶墨水原料，固相含量为5wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表7所示：
表7
Figure PCTCN2021134538-appb-000002
实施例5
(1)凝胶墨水的制备
将实施例4步骤(1)得到的质量分数10％的200-300nm粒径大小的带负电荷的二氧化硅颗粒悬浮液加入实施例4步骤(2)得到的质量分数10％的200-300nm粒径大小的带正电荷的二氧化硅颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:2,搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过8000g高速离心25min,去掉上清液得到凝胶墨水原料，固相含量为5％、10％、20％、30％、40％、50％、60％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表8所示：
表8
Figure PCTCN2021134538-appb-000003
实施例6
(1)负电荷生物玻璃颗粒的制备
本实例通过溶胶凝胶法制备带负电荷的生物玻璃颗粒。首先将300ml无水乙醇与20ml去离子水混匀，室温下搅拌10min后，加入17.5mL冰醋酸(25％)1500rpm搅拌均匀，分别依次加入38.7mL正硅酸乙酯，6.23g硝酸钙，1.97ml磷酸三乙酯，将转速调节到500rpm搅拌反应12h，反应结束后使用去离子水离心清洗颗粒，得到负电荷生物玻璃颗粒分散在去离子水中配置成质量分数为10％的颗粒悬浮液。图6结果表明生物玻璃颗粒成功合成，单个颗粒粒径为50nm。
(2)正电荷生物玻璃颗粒的制备
将(1)中制备的生物玻璃颗粒水分散液离心取下层沉淀分散于丁醇中配置成10mg/mL的分散系400mL，超声15min。使用注射泵在20分钟内加入4mL 3-氨丙基三甲氧基硅氧烷，搅拌速度为900rpm，室温下反应8h,反应结束后使用去离子水离心清洗颗粒，得到负电荷二氧化硅颗粒分散在去离子水中配置成质量分数为10％的颗粒悬浮液，。图7结果表明生物玻璃颗粒表面成功被修饰上正电荷，带电荷为+36mv。
(3)凝胶墨水的制备
将步骤(1)得到的质量分数10％的2带负电荷的生物玻璃颗粒悬浮液加入步骤(2)得到的质量分数10％的带正电荷的无生物玻璃颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:1,搅拌均匀后得到前驱体溶液；在前驱体溶液中加入磷酸，持续搅拌2h后，通过8000g高速离心25min,去掉上清液得到凝胶墨水原料，固相含量为40％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表9所示：
表9
  力学支撑强度 粘度 恢复能力
凝胶墨水 97.1kPa 8638Pa.s 91.7％
(4)三维支架打印
使用CAD画出长宽高为8mm的圆柱，将模型输入到挤出式打印机中，设置参数分别为每层打印行数为7行，打印速度为3mm/s,打印层高为15mm,选用针头内径为500μm，然后将步骤(3)制备的凝胶墨水原料装在打印机的针筒中进行正方体模型支架打印。层层打印，最终形成目标模型胚体；
(5)模型支架烧结：将正方体模型支架放入烘箱中，在40℃下干燥12h后以5℃/min的升温速率升到700摄氏度，恒温4h,得到固化后的定制化的无机非金属支架。通过力学测试机对烧结后的三维支架进行压缩测试，压缩速率为1mm/min，如表10所示：
表10
  压缩强度 弹性模量
三维支架 2.7MPa 4.3MPa
对比例3纯负电荷生物玻璃颗粒墨水
将实施例6步骤(1)制备的带负电荷的生物玻璃颗粒悬浮液配置成质量分数为10％的悬浮液，然后加入醋酸，持续搅拌2h后，通过8000g高速离心25min,去掉上清液得到凝胶墨水原料，固相含量为40wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表11所示：
表11
  力学支撑强度 粘度 恢复能力
凝胶墨水 2030kPa 967Pa.s 78％
对比例4纯正电荷生物玻璃颗粒墨水
将实施例6步骤(2)制备的带正电荷的生物玻璃颗粒悬浮液配置成质量分数为10％的悬浮液，然后加入醋酸，持续搅拌2h后，通过8000g高速离心25min,去掉上清液得到凝胶墨水原料，固相含量为40wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，如表12所示：
表12
  力学支撑强度 粘度 恢复能力
凝胶墨水 5437Pa 1717Pa.s 93％
通过实施例6和对比例3及对比例4得到非单分散的颗粒依然可以通过正负电荷的相互吸引形成力学更强的凝胶墨水。但是单独的正电荷颗粒和负电荷颗粒形成的凝胶墨水只是颗粒的堆积，不能兼顾实现力学支撑强度和破坏后的恢复能力。
实施例7
(1)凝胶墨水的制备
将实施例6中步骤(1)得到的质量分数为10％的带负电荷的生物玻璃悬浮液加入实施例6中步骤(2)得到的质量分数为10％的带正电荷的生物玻璃悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:3、1:1、1:3，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过6000g高速离心20min,去掉上清液得到凝胶墨水原料，固相含量为10wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表13所示：
表13
负/正生物玻璃颗粒数量比 1:3 1:1 1:3
力学支撑强度(Pa) 679±47 437±5.8 231±7
粘度(Pa) 316±2.4 343±12 155±0.8
恢复能力(％) 92.5 92.2 90.6
实施例8
(1)凝胶生物墨水的制备
将实施例6中步骤(1)得到的质量分数为10％的带负电荷的生物玻璃悬浮液加入实施例6中步骤(2)得到的质量分数为10％的带正电荷的生物玻璃悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:3，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过6000g高速离心20min,去掉上清液得到凝胶墨水原料，固相含量为10％、20％、30％、40％、50％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表14所示：
表14
Figure PCTCN2021134538-appb-000004
实施例9
使用实施例8制备的凝胶墨水，固相含量为30wt％,使用建模软件建立15×15×15mm正方体三维支架模型，结合切片软件对所建的正方体三维支架模型进行切片导入到挤注式3D打印机中；选用针头内径为600μm，然后将得到的纳米结构生物墨水放入到3D打印机喷头中进行正方体模型支架打印，层层打印，最终形成目标模型胚体。将正方体模型支架放入烘箱中，在40℃下干燥12h后以5℃/min的升温速率升到700摄氏度，恒温4h，得到固化后的定制化的无机非金属支架。图8为烧结后的生物玻璃支架的扫描电镜图。A图为整体支架电镜图，B图为支架纤维表面形貌图，C为B图的表面形貌进一步放大图，D为C图的表面形貌进一步放大图。从A图可以看到打印的生物玻璃支架具有规整的结构，B图可以看出支架纤维表现均匀光滑，颗粒均匀排布，从C图和D图来看，颗粒紧密连接形成均匀的结构，表面具有0.1μm的小孔。从图8可以得生物玻璃组装的凝胶墨水打印的支架具有良好的打印性，支架表面具有均匀的结构和孔隙。
实施例10
(1)负电荷介孔生物玻璃颗粒的制备
本实例通过模板法制备介孔生物玻璃颗粒。首先将24.1十六烷基三甲基溴化铵溶解于1000ml去离子水中，加入3.2ml氨水(35％)在室温下搅拌10min后，分别依次加入38.7mL正硅酸乙酯，6.23g硝酸钙，1.97ml磷酸三乙酯，将转速调节到500rpm搅拌反应12h，反应结束后分别使用乙醇(1次)、乙醇-水(1次)、水(4次)6次离心再分散清洗颗粒，得到负电荷介孔生物玻璃颗粒分散液置成质量分数为10％的颗粒悬浮 液。图9为介孔生物玻璃的透射电镜图片，从图中可以看出介孔生物玻璃颗粒粒径在100nm左右，单个颗粒分散良好。
(2)正电荷介孔生物玻璃颗粒的制备
将(1)中制备的介孔生物玻璃颗粒水分散液离心取下层沉淀分散于乙醇中配置成10mg/mL的分散系400mL，超声15min。将其置于40℃的水浴中，使用注射泵在20分钟内加入2mM环丙基甲脒，搅拌速度为1000rpm，在40℃条件下反应5h。反应结束后使用去离子水清洗三次分散清洗颗粒，制备出带正电荷介孔生物玻璃颗粒分散液置成质量分数为10％的颗粒悬浮液。图10为介孔生物玻璃表面被修饰上正电荷，带电荷为23mv。
(3)凝胶墨水的制备
将步骤(1)得到的质量分数为10％的带负电荷的介孔生物玻璃悬浮液加入步骤(2)得到的质量分数为10％的带正电荷的介孔生物玻璃悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1：3，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入盐酸，持续搅拌2h后，通过9000g高速离心15min,去掉上清液得到凝胶墨水原料，固相含量为30％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表15所示:
表15
  力学支撑强度 粘度 恢复能力
凝胶墨水 89437Pa 8914Pa.s 90％
(4)三维支架打印
使用CAD画出长宽高为12mm的圆柱，将模型输入到挤出式打印机中，设置参数分别为每层打印行数为9行，打印速度为4mm/s,打印层高为5mm,选用针头内径为600μm，然后将步骤(3)制备的凝胶墨水原料装在打印机的针筒中进行正方体模型支架打印。层层打印，最终形成目标模型胚体；
(5)模型支架烧结：将正方体模型支架放入烘箱中，在40℃下干燥12h后以5℃/min的升温速率升到800摄氏度，恒温4h，得到固化后的定制化的无机非金属支架，介孔支架具有贯通的宏观大孔及微观小孔。图11为烧结后的正方体支架表征图，从图11可以得到打印的支架大孔孔径在250μm，图12中图A为介孔支架烧结后的氮气吸附-脱附曲线，孔体积为0.417cc/g，比表面积为86.59m 2/g，图B为支架介孔尺寸分布曲线，支架的微观小孔孔径为17.939nm；通过力学测试机对烧结后的三维支架进行压缩测试，压缩速率为1mm/min，如表16所示：
表16
  压缩强度 弹性模量
三维支架 1.5MPa 2.3MPa
对比例5纯负电荷介孔生物玻璃颗粒支架
将实施例10步骤(1)制备的带负电荷的介孔生物玻璃颗粒悬浮液配置成质量分数为10％的悬浮液，然后加入醋酸，持续搅拌2h后，通过9000g高速离心15min,去掉上清液得到凝胶墨水原料，固相含量为30wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如 表17所示：
表17
  力学支撑强度 粘度 恢复能力
凝胶墨水 1014Pa 467Pa.s 80％
对比例6纯正电荷介孔生物玻璃颗粒支架
将实施例10步骤(2)制备的带正电荷的生物玻璃颗粒悬浮液配置成质量分数为10％的悬浮液，然后加入醋酸，持续搅拌2h后，通过9000g高速离心15min,去掉上清液得到凝胶墨水原料，固相含量为30wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，如表18所示：
表18
  力学支撑强度 粘度 恢复能力
凝胶墨水 3417Pa 1778Pa.s 82％
通过实施例9和对比例5及对比例6得到单分散的介孔颗粒依然可以通过正负电荷的相互吸引形成力学更强的凝胶墨水，证明依靠颗粒相互吸引形成的凝胶墨水制备方法具有普适性。
实施例11
(1)介孔生物玻璃凝胶墨水的制备
将实施例10中步骤(1)得到的质量分数为10％的带负电荷的介孔生物玻璃悬浮液加入实施例10中步骤(2)得到的质量分数为10％的带正电荷的生物玻璃悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:3、1:1、3:1，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过5000g高速离心10min,去掉上清液得到凝胶墨水原料，固相含量为10％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表19所示：
表19
负/正介孔生物玻璃颗粒数量比 1:3 1:1 3:1
力学支撑强度(Pa) 637±5.8 279±47 131±7
粘度(Pa.s) 316±2.4 143±12 95±0.8
恢复能力 93.7 87.5 83.9
实施例12
(1)纳米结构生物墨水的制备
将实施例10中步骤(1)得到的质量分数为10％的带负电荷的介孔生物玻璃悬浮液加入实施例10中步骤(2)得到的质量分数为10％的带正电荷的生物玻璃悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:3，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过5000g高速离心10min,去掉上清液得到凝胶墨水原料，固相含量为10％、20％、30％、40％、50％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表20所示：
表20
Figure PCTCN2021134538-appb-000005
实施例13
(1)正电荷磷酸钙颗粒的制备
使用化学沉淀法制备磷酸钙颗粒。将100mL H 3PO 4溶液(75mM)滴加到100mL Ca(OH) 2(125mM)的水性悬浮液中，然后将pH调节至7.0，在室温下连续搅拌14-16小时.将CaP纳米颗粒离心，然后使用去离子水清洗3次，即得到磷酸钙纳米颗粒，磷酸钙纳米颗粒的透射电镜图片如图13所示，磷酸钙颗粒均匀分散，颗粒尺寸单一。
(2)负电荷磷酸钙颗粒的制备
将磷酸钙颗粒表面吸附柠檬酸钠使其表面带负电，将(1)中制备好的磷酸钙颗粒以10mg/mL的浓度分散在10mM的柠檬酸钠水溶液中搅拌14-16h，然后将颗粒离心，并使用去离子水清洗三次，得到带负电荷的磷酸钙颗粒。使用Zeta电位仪测试(1)(2)合成的颗粒在pH＝7条件下的表面电位，结果如下表21
表21
  磷酸钙颗粒 负电荷磷酸钙颗粒
表面电位 3.0±0.3 -20.1±0.6
(3)凝胶墨水的制备
将步骤(1)得到的质量分数为10％的带负电荷的介孔生物玻璃悬浮液加入步骤(2)得到的质量分数为10％的带正电荷的生物玻璃悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:3、1:2、1:1、5:1、10:1，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过5000g高速离心10min,去掉上清液得到凝胶墨水原料，固相含量为10％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表22所示：
表22
负/正磷酸钙颗粒数量比 1:3 1:2 1:1 5:1 10:1
力学支撑强度(Pa) 122±23 318±13 109±34 13.5±5 0.02±0.01
粘度(Pa.s) 20±10.5 22.6±7 14.7±3 0.3±0.2 0.023±0.007
恢复能力(％) 97.9 96.7 92 89.4 87.9
实施例14
(1)纳米结构生物墨水的制备
将实施例13中步骤(1)得到的质量分数为10％的带负电荷的磷酸钙颗粒悬浮液加入实施例13中步骤 (2)得到的质量分数为10％的带正电荷的磷酸钙颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为30％，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入硝酸，持续搅拌2h后，通过10000g高速离心10min,去掉上清液得到凝胶墨水原料，固相含量为10％、20％、30％、40％、50％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表23所示：
表23
质量分数(％) 10 20 30 40 50
力学支撑强度(Pa) 122±23 1781±125 5234±1256 19103±3513 73691±13479
粘度(Pa.s) 20±10.5 851±121 4752±1561 12889±8153 54576±13612
恢复能力 97.9 94.7 86.8 86.7 84.9
实施例15
(1)负电荷氧化铝颗粒的制备
本实例通过水热法制备氧化铝颗粒。首先将0.16mol/LAl(NO3)3·9H2O溶解于100ml去离子水中，在500rap搅拌下用恒压漏斗以0.5ml/min的速度滴加水合肼溶液至pH到5.0，反应3h后，将反应溶液转移至反应釜中在200℃下反应12h。待冷却到室温后，用去离子水和无水乙醇混合液中清洗三次后分散到无离子水中配置成质量分数为10％的颗粒悬浮液。
(2)正电荷氧化铝颗粒的制备
将(1)中制备的氧化铝璃颗粒水分散液离心取下层沉淀分散于乙醇中配置成10mg/mL的分散系400mL，超声15min。将其置于40℃的水浴中，使用注射泵在20分钟内加入2mL 3-氨丙基三甲氧基硅氧烷，搅拌速度为1000rpm，在40℃条件下反应5h。反应结束后使用去离子水清洗三次分散清洗颗粒，制备出带正电荷氧化铝颗粒分散液置成质量分数为10％的颗粒悬浮液。
(3)凝胶墨水的制备
将步骤(1)得到的质量分数为10％的带负电荷的氧化铝悬浮液加入步骤(2)得到的质量分数为10％的带正电荷的氧化铝颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:3，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过4000g高速离心25min,去掉上清液得到凝胶墨水原料，固相含量为30％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表24所示:
表24
  力学支撑强度 粘度 恢复能力
凝胶墨水 19477Pa 5919Pa.s 80％
(4)三维支架打印
使用CAD画出长宽高为12mm的圆柱，将模型输入到挤出式打印机中，设置参数分别为每层打印行数为9行，打印速度为4mm/s,打印层高为5mm,选用针头内径为600μm，然后将步骤(3)制备的凝胶墨水原料装在打印机的针筒中进行正方体模型支架打印。层层打印，最终形成目标模型胚体；
(5)模型支架烧结：将正方体模型支架放入烘箱中，在40℃下干燥12h后以5℃/min的升温速率升 到1500摄氏度，恒温4h,得到固化后的定制化的无机非金属支架。通过力学测试机对烧结后的三维支架进行压缩测试，压缩速率为1mm/min，如表25所示：
表25
  压缩强度 弹性模量
三维支架 11.5MPa 15.2MPa
实施例16
(1)疏水二氧化硅颗粒的制备
本实例通过对实施例1中制备的50nm粒径的二氧化硅颗粒进行改性得到疏水性二氧化硅颗粒。将50nm粒径的二氧化硅水分散液离心取下层沉淀分散于无水乙醇中配置成20mg/mL的分散系400mL，搅拌30min后，使用注射泵在20分钟内加入4mL十八烷基硅氧烷，搅拌速度为600rpm，室温条件下反应8h。反应结束后，使用无水乙醇清洗颗粒，制备出疏水性二氧化硅颗粒。
(2)凝胶墨水的制备
将步骤(1)得到的疏水二氧化硅颗粒分散在去离子水中，然后经过8000g高速离心15min去除上清液得到得到凝胶墨水原料，固相含量为30wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表26所示：
表26
  力学支撑强度 粘度 恢复能力
凝胶墨水 89.7kPa 8000Pa.s 83％
实施例17
(1)疏水二氧化硅颗粒的制备
本实例通过对实施例1中制备的50nm粒径的正电荷二氧化硅颗粒进行改性得到疏水性二氧化硅颗粒。将50nm粒径的二氧化硅水分散液离心取下层沉淀分散于丙酮中配置成20mg/mL的分散系400mL，搅拌30min后，使用注射泵在20分钟内加入4mL十八烷酸，搅拌速度为600rpm，室温条件下反应8h。反应结束后，使用无水乙醇清洗颗粒，制备出疏水性二氧化硅颗粒。
(2)凝胶墨水的制备
将步骤(1)得到的疏水二氧化硅颗粒分散在去离子水中，然后经过8000g高速离心15min去除上清液得到得到凝胶墨水原料，固相含量为30wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表27所示：
表27
  力学支撑强度 粘度 恢复能力
凝胶墨水 85.3kPa 7859Pa.s 85％
实施例18
(1)疏水二氧化硅颗粒的制备
本实例通过对实施例1中制备的50nm粒径的正电荷二氧化硅颗粒进行改性得到疏水性二氧化硅颗粒。 将50nm粒径的二氧化硅水分散液离心取下层沉淀分散于丙酮中配成20mg/mL的分散系400mL，搅拌30min后，使用注射泵在20分钟内加入4mL三乙氧基十三氟代正辛基硅烷，搅拌速度为600rpm，室温条件下反应8h。反应结束后，使用无水乙醇清洗颗粒，制备出疏水性二氧化硅颗粒。
(2)凝胶墨水的制备
将步骤(1)得到的疏水二氧化硅颗粒分散在去离子水中，然后经过8000g高速离心15min去除上清液得到凝胶墨水原料，固相含量为30wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表28所示：
表28
  力学支撑强度 粘度 恢复能力
凝胶墨水 90.3kPa 8573Pa.s 75％
实施例19
(1)疏水二氧化硅颗粒的制备
本实例通过对实施例1中制备的50nm粒径的二氧化硅颗粒进行改性得到疏水性二氧化硅颗粒。将50nm粒径的二氧化硅水分散液离心取下层沉淀分散于去离子水中配置成20mg/mL的分散系400mL，搅拌30min后，使用注射泵在20分钟内加入4mL三甲基氯硅烷，搅拌速度为600rpm，室温条件下反应8h。反应结束后，使用无水乙醇清洗颗粒，制备出疏水性二氧化硅颗粒。
(2)凝胶墨水的制备
将步骤(1)得到的疏水二氧化硅颗粒分散在去离子水中，然后经过8000g高速离心15min去除上清液得到得到凝胶墨水原料，固相含量为30wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表29所示：
表29
  力学支撑强度 粘度 恢复能力
凝胶墨水 80kPa 7523Pa.s 86％
(3)三维支架打印
使用CAD画出长宽高为15mm的正方体，将模型输入到挤出式打印机中，设置参数分别为每层打印行数为15行，打印速度为3mm/s,打印层高为15mm,选用针头内径为500μm，然后将步骤(3)制备的凝胶墨水原料装在打印机的针筒中进行正方体模型支架打印。层层打印，最终形成目标模型胚体；
(4)模型支架热处理：将正方体模型支架放入烧结炉中，在40℃下干燥12h后以5℃/min的升温速率升到700摄氏度，恒温4h,得到固化后的定制化的无机非金属支架。通过力学测试机对烧结后的三维支架进行压缩测试，压缩速率为1mm/min，如表30所示：
表30
  压缩强度 弹性模量
三维支架 11.5MPa 13.8MPa
实施例20
(1)四氧化三铁颗粒的制备
本实例通过共沉淀法制备四氧化三铁颗粒。圆底烧瓶中加入50ml去离子水，然后接好冷凝器，氮气接管，温度计。用氮气净化去离子水中的氧气，约10min，然后加入0.52mmol FeSO 4.6H 2O(0.7g)，1.08mmol FeCl 3.6H 2O(0.145g)超声溶解在2ml盐酸中，当温度到达100摄氏度加入。5min后快速加入30ml氨水(25％)，600rpm搅拌。冷凝回流反应2h后使用离心分离方法收集四氧化三铁颗粒，经离心洗涤后的四氧化三铁分散在去离子水中置成质量分数为30％的颗粒悬浮液。
(2)凝胶墨水的制备
将步骤(1)得到的四氧化三铁分散液在150A/m的磁场作用下，定向组装磁性颗粒形成均匀网络结构，然后将组装后的悬浮液通过8000g高速离心20min,去掉上清液得到凝胶墨水原料，固相含量为40wt％。，通过磁场旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表31所示：
表31
  力学支撑强度 粘度 恢复能力
凝胶墨水 109.7kPa 1013Pa.s 92％
(3)三维支架打印
使用CAD画出长宽高为15mm的正方体，将模型输入到挤出式打印机中，设置参数分别为每层打印行数为15行，打印速度为3mm/s,打印层高为15mm,选用针头内径为500μm，然后将步骤(3)制备的凝胶墨水原料装在打印机的针筒中进行正方体模型支架打印。层层打印，最终形成目标模型胚体；
(4)模型支架热处理：将正方体模型支架放入烧结炉中，在40℃下干燥12h后以5℃/min的升温速率升到700摄氏度，恒温4h,得到固化后的定制化的无机非金属支架。通过力学测试机对烧结后的三维支架进行压缩测试，压缩速率为1mm/min，如表32所示：
表32
  压缩强度 弹性模量
三维支架 13.2MPa 17.3MPa
实施例21
(1)负电荷钛酸钡颗粒的制备
称取6.8g十六烷基三甲基溴化铵表面活性剂溶解到100ml去离子水中，以600rpm转速搅拌1h，然后在冰水浴环境中加入9.45g的TiCl 4溶液，搅拌30min后加入21.2g的BaCl 2·2H 2O，以600rpm转速搅拌1h后逐渐升温到35摄氏度，然后调节上述溶液的pH至7.2，在35摄氏度水浴环境，600rpm磁力搅拌10小时后结束合成反应。将反应结束后的溶液用去离子水洗涤，8000rpm离心洗涤3次，得到的离心物分散到去离子水中超声10分钟，得到质量分数为5％的钛酸钡颗粒分散液。
(2)正电荷钛酸钡颗粒的制备
将(1)中制备的钛酸钡颗粒分散液离心取下层沉淀分散于乙醇中配置成10mg/mL的分散系400mL，超声15min。将其置于40℃的水浴中，使用注射泵在20分钟内加入2mM环丙基甲脒，搅拌速度为1000rpm，在40℃条件下反应5h。反应结束后使用去离子水清洗三次分散清洗颗粒，制备出带正电荷钛酸钡颗粒分 散液置成质量分数为5％的颗粒悬浮液。
(3)凝胶墨水的制备
将步骤(1)得到的质量分数为5％的带负电荷的钛酸钡颗粒悬浮液加入步骤(2)得到的质量分数为5％的带正电荷的钛酸钡颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为1:3，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入磷酸，持续搅拌2h后，通过7000g高速离心20min,去掉上清液得到凝胶墨水原料，固相含量为35％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表33所示:
表33
  力学支撑强度 粘度 恢复能力
凝胶墨水 9836Pa 6385Pa.s 85％
(4)三维支架打印
使用CAD画出长宽高为12mm的圆柱，将模型输入到挤出式打印机中，设置参数分别为每层打印行数为9行，打印速度为4mm/s,打印层高为5mm,选用针头内径为600μm，然后将步骤(3)制备的凝胶墨水原料装在打印机的针筒中进行正方体模型支架打印。层层打印，最终形成目标模型胚体；
(5)模型支架烧结：将正方体模型支架放入烘箱中，在40℃下干燥12h后以5℃/min的升温速率升到1200摄氏度，恒温4h，得到固化后的定制化的钛酸钡陶瓷支架，为了表征支架的压电、介电性能，对钛酸钡支架进行在120摄氏度下施加1kV/mm的直流电压，30分钟的极化处理。利用压电常数测试仪测试压电常数，使用阻抗分析仪得到介电常数，结果如表34所示：
表34
  压电常数 介电常数
钛酸钡支架 404Pc/N 3740kHz
对比例7纯负电荷钛酸钡颗粒凝胶墨水的制备
(1)将实施例21步骤(1)制备的带负电荷的钛酸钡颗粒配置成质量分数为5％的悬浮液，然后加入磷酸，持续搅拌2h后，通过7000g高速离心20min,去掉上清液得到凝胶墨水原料，固相含量为35wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，如表35所示：
表35
  力学支撑强度 粘度 恢复能力
凝胶墨水 4562Pa 3571Pa.s 83％
(2)三维支架打印
使用CAD画出电路线模型，将模型输入到挤出式打印机中，设置参数分别为每层打印行数为5行，打印速度为4mm/s,打印层高为1mm,选用针头内径为400μm，然后将步骤(1)制备的凝胶墨水原料装在打印机的针筒中进行模型支架打印。层层打印，最终形成目标模型胚体；
(3)模型支架烧结：将钛酸钡支架放入烘箱中，在40℃下干燥12h后以5℃/min的升温速率升到1200摄氏度，恒温4h，得到固化后的定制化的钛酸钡陶瓷支架，为了表征支架的压电、介电性能，对钛酸钡支 架进行在120摄氏度下施加1kV/mm的直流电压，30分钟的极化处理。利用压电常数测试仪测试压电常数，使用阻抗分析仪得到介电常数，结果如表36所示：
表36
  压电常数 介电常数
钛酸钡支架 360Pc/N 2320kHz
通过实施例21和对比例7来看，通过调控带负电荷的钛酸钡颗粒和带正电荷的钛酸钡颗粒组装，得到的凝胶墨水具有更高的力学强度，粘度也更高，同时具有更高的压电效应，作为压电传感器具有更好的应用前景。
实施例22
(1)负电荷的Ti 3C 2Tx MXene纳米片的制备
本实施例中通过将1g氟化锂溶于20ml浓盐酸溶液中放置于250ml特氟隆烧杯中。然后将1g Ti 3AlC 2加入上述溶液中，35℃磁力搅拌24h后用去离子水洗涤，3500rpm离心清洗3次，直到上清液pH为6，得到的离心物分散到去离子水中超声10分钟，得到的MXene纳米片分散液浓度为1mg/mL。
(2)正电荷的Ti 3C 2Tx MXene纳米片的制备
将聚二烯丙基二甲基铵溶液(10ml,1wt％)滴加到步骤(1)中得到的MXene(100ml；0.1mg/mL。然后磁性搅拌24小时后转速为4000rpm离心1小时。，将得到的沉淀物用去离子水冲洗2次，然后超声处理5分钟，得到浓度为1mg/ml的带正电荷的MXene纳米片分散液。
(3)凝胶墨水的制备
将步骤(1)得到的质量分数为0.1％的带负电荷的MXene纳米片悬浮液加入步骤(2)得到的质量分数为0.1％的带正电荷的MXene纳米片悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液数量比为30％，搅拌均匀后得到前驱体溶液；在前驱体溶液中加入醋酸，持续搅拌2h后，通过10000g高速离心60min,去掉上清液得到凝胶墨水原料，固相含量为15％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，其中频率为1Hz,应变为0.5％，如表37所示:
表37
  力学支撑强度 粘度 恢复能力
凝胶墨水 2859Pa 1523Pa.s 96％
(4)三维支架打印
使用CAD画出电路线模型，将模型输入到挤出式打印机中，设置参数分别为每层打印行数为5行，打印速度为4mm/s,打印层高为1mm,选用针头内径为400μm，然后将步骤(3)制备的凝胶墨水原料装在打印机的针筒中进行模型支架打印。层层打印，最终形成目标模型胚体；
(5)模型支架热处理：将模型支架放入烘箱中，在30℃下干燥12h后得到固化后的定制化的无机非金属导电支架。通过电化学工作站对打印支架进行循环伏安，交流阻抗，恒流充放电测试，测试结果如表38所示：
表38
  电容 功率密度 储能密度
三维支架 685.4mF/cm -2 24.9W/cm -3 51.7μW/hcm -2
对比例8纯负电荷Ti 3C 2Tx MXene纳米片凝胶墨水的制备
(1)将实施例22步骤(1)制备的带负电荷的Ti 3C 2Tx MXene纳米片配置成质量分数为1％的悬浮液，然后加入醋酸，持续搅拌2h后，通过10000g高速离心60min,去掉上清液得到凝胶墨水原料，固相含量为5wt％，通过旋转流变仪时间扫描模式测量墨水的力学支撑强度，通过连续的应变扫描与时间扫描之间的多个循环来测得墨水的恢复能力，通过改变剪切速率测得墨水的粘度，如表39所示：
表39
  力学支撑强度 粘度 恢复能力
凝胶墨水 968Pa 631Pa.s 89％
(2)三维支架打印
使用CAD画出电路线模型，将模型输入到挤出式打印机中，设置参数分别为每层打印行数为5行，打印速度为4mm/s,打印层高为1mm,选用针头内径为400μm，然后将步骤(1)制备的凝胶墨水原料装在打印机的针筒中进行模型支架打印。层层打印，最终形成目标模型胚体；
(3)模型支架烧结：将模型支架放入烘箱中，在30℃下干燥12h后得到固化后的定制化的无机非金属导电支架。通过电化学工作站对打印支架进行循环伏安，交流阻抗，恒流充放电测试，测试结果如表40所示：
表40
  电容 功率密度 储能密度
三维支架 358mF/cm -2 16.9W/cm -3 40.1μW/hcm -2
通过实施例22和对比例8来看，通过调控带负电荷的Ti 3C 2Tx MXene纳米片和带正电荷的Ti 3C 2Tx MXene纳米片组装，得到的凝胶墨水具有更高的力学强度，粘度也更高，更加适合凝胶墨水的打印，打印的电子器件具有更高的储能能力。
实施例23
凝胶墨水的制备
使用实施例1-22中制备的无机非金属颗粒分散到无水乙醇中配置成质量分数为10％的颗粒悬浮液，在800rpm的搅拌下加入十八烷基正硅酸乙酯，室温下反应8h后经过三次去离子水离心清洗后分散到水和乙醇(1：1)混合液，500rpm搅拌30min得到前驱体溶液。将前驱体溶液使用10000rpm离心速度，30min离心得到凝胶墨水。
实施例24
使用实施例1-20中正/负颗粒为2:1的比例混合，通过离心浓缩得到的质量分数20％的纳米结构生物墨水，使用建模软件建立15×15×15mm正方体三维支架模型，结合切片软件对所建的正方体三维支架模型进行切片导入到挤注式3D打印机中；将得到的纳米结构生物墨水放入到挤注式3D打印机中进行三维支架的打印，设置纤维的间隙，得到孔径在0-200μm、200-400μm、400-600μm的三维支架如图14所示，A1-C1为不同孔隙的打印支架的数码图片，A2-C2为不同孔隙的支架的Micro-CT图片，A3-C3为不同孔隙的支架的俯视图，A4-C4为不同孔隙的支架的侧视图，A5-C5为不同孔隙的支架的Micro-CT重建图。 从图14可以得到打印的支架具有完整的结构和纤维走向，证明实施例1-20得到的凝胶墨水具有很好的打印性。将得到的三维支架在25℃干燥24h后,以升温速率设置为5℃/min，200℃、300℃、500℃、800℃各两小时的烧结条件在马弗炉中烧结固定。通过力学测试机对烧结后的不同孔径大小的三维支架进行压缩测试，压缩速率为1mm/min，如表41所示：
表41
孔径大小(μm) 0-200 200-400 400-600
压缩强度(MPa) 20±2 10±3 5±1
实施例25
使用实施例1-20中正/负颗粒为2:1的比例混合，通过离心浓缩得到的质量分数20％的纳米结构生物墨水，使用建模软件建立15×15×15mm正方体三维支架模型，结合切片软件对所建的正方体三维支架模型进行切片导入到挤注式3D打印机中；将得到的纳米结构生物墨水放入到挤注式3D打印机中进行三维支架的打印，设置纤维的间歇，得到孔径在400-600μm三维支架，将得到的三维支架在25℃干燥24h后,以升温速率设置为5℃/min，200℃、300℃各两小时，最终烧结温度为500℃、600℃、700℃、800℃、900℃、1000℃、1100℃、1200℃的烧结条件在马弗炉中烧结固定。通过力学测试机对烧结后的不同孔径大小的三维支架进行压缩测试，压缩速率为1mm/min，如表42所示：
表42
烧结温度(℃) 500 600 700 800 900 1000 1100 1200
压缩强度(MPa) 2±0.5 6±1 8±2 12±1 13±3 15±2 17±1 20±2
实施例26
使用实施例23-25中制备的无机支架通过模拟体液方法考察该支架材料是否矿化能力。具体实施步骤如下：
将烧结后的无机非金属支架浸泡在一倍SBF模拟体液(pH＝7.40)中，以评价其体外矿化性能。将制得的支架经多次清洗，烘干处理后，准确称量质量，按照缓冲溶液体积与支架质量之比为100mL/g的比例，置于塑料广口瓶中，在37℃恒温摇床中以90r/min的速率恒速摇动1、3、7、14、21d，每隔两天换一次SBF模拟体液，且换液前测其相应的pH值。到预定时间后，取出样品，用去离子水轻轻洗涤3次，然后置于120℃真空干燥烘箱充分干燥，通过扫描电镜(SEM)和红外测试检测体外矿化效果。如图15为体外矿化不同时间点SEM电镜图片和能谱扫描图，图15中a1为打印支架纤维扫描电镜照片，a2为第0天支架矿化的扫描电镜照片,a3为支架矿化28天支架的扫描电镜照片及b3是第28天支架上Si,O,Ca,P元素分布，图中点越多说明沉积的越多，从图中可以看出钙和磷元素沉积的多，钙和磷元素的堆积，证明无机非金属支架具有较好的体外矿化性能。图16为体外矿化不同时间点FTIR分析图，图17为体外矿化不同时间点XRD分析图；以上数据可以看出随着时间点的增加，支架表面形成无定型的磷酸钙，出现了明显的矿化。
实施例27
使用实施例23-25中制备的无机支架通过接触培养细胞实验考察该材料是否存在细胞毒性及体外成骨效果。具体实施步骤如下:
(1)以MC3T3-E1小鼠胚胎成骨细胞前体细胞培养为例
MC3T3-E1小鼠胚胎成骨细胞前体细胞在增殖培养基(Dulbecco s modified Eagle培养基，DMEM)中培养7天，加入10％v/v胎牛血清(FBS)和100U/mL的青霉素和100μg/mL的链霉素的α-MEM，37℃、95％相对湿度，5％CO 2。为了诱导成骨，细胞培养基中加入了β-甘油磷酸(10mM)，L-抗坏血酸(50μg/mL)和***(10nM).培养1天后更换培养基，去除无黏附细胞，每3天更换一次。融合时，用磷酸盐缓冲盐水(PBS)冲洗细胞两次，用胰蛋白酶/EDTA(0.25％w/v胰蛋白酶/0.02％EDTA)分离细胞5分钟，在培养基中复苏。
(2)将热处理过后的二氧化硅和生物玻璃支架使用紫外灯灭菌2h，灭菌后的支架按照10mg/mL配置支架浸提液，然后置于37℃环境下浸提24h。取生长状况良好的MC3T3-E1，消化计数，调整细胞浓度为5×10 4个/mL,在24孔板中每孔以1.25cm 2/mL的浓度接种细胞，并设置阴性对照组。每组设置6个平行组。24h后向其中加入0.25mg/mL的浸提液。继续培养1天、2天、3天后，从培养箱中取出。使用CCK-8检测细胞活性。将CCK-8检测液与新鲜培养基以1:10的比例混合后，将24孔板内的细胞用PBS溶液清洗3次，每孔内加入110μL混合液。避光保存放入恒温箱内孵育3h后在450nm的波长下检测OD值并计算细胞的增值率。实验组与对照组细胞的细胞活力如图18所示，结果表明支架浸提液内的细胞活力大于等于100％，无机支架具有良好的生物相容性。
(3)为了进一步评估二氧化硅和生物玻璃支架的骨诱导作用，使用BCIP/NBT方法进行了ALP染色。此外，进行了茜素红(ARS)染色以评估细胞外基质(ECM)的矿化。简而言之，在培养3周后，我们除去细胞培养基，并在每个孔中加入100μlARS溶液，然后在37℃下孵育1h。采集图像后，将染色的细胞在室温下用10％的十六烷基氯化吡啶处理30分钟，并使用多模式读板仪测试测试在630nm处的吸光度。实验组与对照组细胞外基质矿化包括茜素红和ALP染色和定量分析结果如图19所示，A图为SiO 2和BG支架的ALP和ARS染色，B图为ALP染色的定量图，C图为ARS染色的定量图。结果表明二氧化硅和生物玻璃支架具有显着促进成骨前细胞的成骨能力，BG支架释放的无机离子对于更好的成骨作用至关重要，具有更好的矿化效果。
实施例28
通过动物体内植入无机支架培养考察支架的体内成骨。选取3个月龄(2.5-3.0Kg)的家兔，将实施例23-25中制备的无机支架热处理后的支架紫外灭菌2h。在家兔全身麻醉诱导后，在颅顶处制造2个圆柱骨缺损(直径10mm，高度2mm)，然后植入无机支架。术后3天后给予青霉素治疗，单独置于笼中。4周后处死家兔，收集颅顶骨进行后续实验。进一步进行显微Micro-CT和苏木精-伊红染色法。
图20是实施例28中使用无机胶体凝胶制备的支架作为家兔体内骨缺损修复情况。A图为动物模型数码照片，B图为SiO 2、BG、Bioss支架颅顶骨模型12周的修复效果Micro-CT图，C图为SiO 2、BG、Bioss支架颅顶骨模型在4周、8周、12周新生骨体积的定量，D图为SiO 2、BG、Bioss支架颅顶骨模型在4周、8周、12周新生骨小梁宽度的定量。实验操作过程如A图所示。植入颅顶骨缺损部位，12周出现了部分的骨修复(图B)，通过Micro-CT对颅顶骨缺损部位的重建看出明显的骨修复效果，以及通过对新生骨的骨体积和骨小梁宽度定量分析证实了无机胶体凝胶制备的支架具有良好的体内骨修复能力。

Claims (10)

  1. 一种无机非金属纳米颗粒组装的水凝胶材料，其特征在于，所述水凝胶材料由无机非金属颗粒组装而成，形成水凝胶网络；所述无机非金属颗粒的尺寸是10nm～20um；所述水凝胶材料中无机非金属颗粒占水凝胶总质量的2～80wt％；所述水凝胶网络具有微观小孔，孔径为0.1um-30um。
  2. 根据权利要求1所述的无机非金属纳米颗粒组装的水凝胶材料，其特征在于，所述水凝胶材料的力学支撑强度为100kPa-400kPa，粘度为2000-10000Pa.s，破坏恢复能力为50％-100％。
  3. 根据权利要求1所述的无机非金属纳米颗粒组装的水凝胶材料，其特征在于，所述的无机非金属颗粒选自二氧化硅颗粒、生物玻璃颗粒、粘土颗粒、硫酸钙颗粒、碳酸钙颗粒、羟基磷灰石颗粒、氧化铁颗粒、氧化锆颗粒、氧化锌颗粒、氧化钛颗粒、氧化铝颗粒、钛酸钡微颗粒、碳化硅颗粒、石墨烯、氧化石墨烯、还原氧化石墨烯、过渡金属碳化物或氮化物(MXene)、过渡金属二硫化物(TMD)、六方氮化硼、黑磷纳米片的一种或几种的组合。
  4. 根据权利要求1所述的无机非金属纳米颗粒组装的水凝胶材料，其特征在于，所述水凝胶材料的制备方法为静电组装方法或输水作用组装方法或磁性作用组装方法；
    所述静电组装方法包括以下步骤：
    S1、使用溶胶凝胶法、化学沉淀法、熔融法、水热合成法、模板法、化学剥离法、电化学剥离、机械剥离法中的一种或几种制备带负电荷的无机非金属颗粒，将得到的负电荷的无机非金属颗粒分散在含有去离子水的液态溶剂中，配置质量体积分数为1％-80％的颗粒悬浮液，充分搅拌2-8h；
    S2、将无机非金属纳米颗粒加入到甲醇、乙醇、异丙醇、丁醇、丙酮的一种或几种的组合溶剂中，配置成1％-50％的悬浮液，搅拌20-60min后加入水溶性带正电荷的基团，所述带正电荷的基团是脂肪胺中的氨基，氮-氮双取代脒基中的亚胺，四氮取代胍基中的亚胺化合物，反应6-12h，离心洗涤得到正电荷无机非金属颗粒；将正电荷无机非金属颗粒分散在去离子水中或分散在甲醇、乙醇、丙酮、异丙醇的一种或两种液态混合溶剂中，配置质量分数为1％-80％的颗粒悬浮液，充分搅拌2-8h，得到带正电荷的无机非金属颗粒悬浮液；
    S3、将带负电荷的无机非金属颗粒悬浮液加入到带正电荷的无机非金属颗粒悬浮液中，负电荷颗粒悬浮液与正电荷颗粒悬浮液颗粒数量比为1:0-0:1，优选10:1-1:50，更优选5:1-1:10，搅拌均匀后得到前驱体溶液；
    S4、将步骤S3所得前驱体溶液边搅拌边加入5mM-25mM的醋酸、磷酸、盐酸、硝酸的酸性溶液的一种或几种组合，持续搅拌0.5-3h后，通过2000g-10000g高速离心20-40min，去掉上清液得到固相含量为2～80wt％的凝胶墨水原料，即所述水凝胶材料；
    所述疏水作用组装方法包括以下步骤：
    S1、使用溶胶凝胶法、化学沉淀法、熔融法、水热合成法，模板法、化学剥离法、电化学剥离、机械剥离法中的一种或几种制备带负电荷的无机非金属颗粒，将负电荷无机非金属颗粒分散到无水乙醇中，配 置浓度为1％-80％的无机非金属颗粒悬浮液，搅拌20-60min后加入含有疏水基团的硅-卤键化合物，硅烷偶联剂，硬脂酸化合物中的一种或几种组合，反应6-12h，离心洗涤得到疏水性无机非金属颗粒，将疏水性无机非金属颗粒分散在去离子水中或分散在甲醇、乙醇、丙酮、异丙醇的一种或两种液态混合溶剂中，得到疏水性无机非金属颗粒分散液；
    S2、将疏水性无机非金属颗粒分散液通过2000g-10000g高速离心20-40min，去掉上清液得到固相含量为2～80wt％的凝胶墨水原料，即所述水凝胶材料；
    所述磁性作用组装方法包括以下步骤：
    利用铁钴镍中的一种或多种元素制备磁性颗粒，分散在去离子水中或分散在甲醇、乙醇、丙酮、异丙醇的一种或两种液态混合溶剂中，配成浓度为1％-80％的无机非金属磁性颗粒悬浮液，在10-300A/m的磁场作用下，磁性颗粒定向组装成均匀网络结构，然后将组装后的悬浮液通过1000g-10000g高速离心20-40min，去掉上清液得到固相含量为2～80wt％的凝胶墨水原料。
  5. 根据权利要求1～4任一项所述的无机非金属纳米颗粒组装水凝胶材料用于可注射、可塑形、药物缓释载体的骨填充生物医用材料，其中，组成水凝胶的无机非金属纳米颗粒为生物玻璃颗粒、粘土颗粒、磷酸钙颗粒，生物活性陶瓷颗粒的一种或几种组合，所述无机非金属纳米颗粒尺寸为10nm～20um，所述无机非金属纳米颗粒占水凝胶总体积的15-30vol％。
  6. 一种无机非金属凝胶支架，其特征在于，所述支架由权利要求1～4任一项水凝胶材料经增材制造得到的凝胶支架，所述凝胶支架具有纤维堆叠成的相互贯通的气孔，孔径为50-1000μm，孔隙率为20％-80％；支架纤维表面具有微观小孔，孔径为3-80nm，比表面积为50-500m 2/g，断裂力学强度为2-25MPa。
  7. 根据权利要求6所述的凝胶支架，其特征在于，所述凝胶支架的制备方法包括以下步骤：
    (1)以权利要求4所述方法得到的凝胶墨水原料作为3D打印墨水；
    (2)设计模型：通过建模软件建立模型，结合切片软件对所建立的模型进行分层切片处理；
    (3)3D打印目标模型坯体：将设计好的模型输入打印机中，设置模型每层打印行数和打印速度以及打印层数，把凝胶墨水原料装在打印机的针筒中进行层层打印，最终形成凝胶模型胚体；
    (4)热处理：将凝胶模型胚体放入烧结炉中调节烧结温度得到相应的定制化的三维多孔无机非金属支架。
  8. 根据权利要求7所述的凝胶支架，其特征在于，在步骤(3)中所述的3D打印机打印纤维直径≥160μm，打印层高＞300μm，打印速度为0.5mm/s-20mm/s。
  9. 根据权利要求7所述的制备方法，其特征在于，在步骤(4)中热处理过程根据支架的性质选择处理温度，程序为20～50℃下干燥8～24h，300-1500℃下烧结2-72h，升温速率为0.5-10℃/min。
  10. 根据权利要求6-9任一项所述的无机非金属凝胶支架在组织工程或在电子器件中的应用，所述无机非金属凝胶支架在组织工程上的应用为作为骨修复支架，软骨修复支架，负载生物活性蛋白药物、生物活性物质药物分子或间充质干细胞、内皮细胞、雪旺细胞支架；无机非金属凝胶支架在电子器件上的应用为作为超级电容器、电池、太阳能电池、压电传感器、光电子传感器、化学传感剂、生物传感器、电子皮肤传感器件。
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