Preparation method for constructing piezoelectric bone scaffold for bone tumor repair through 3D printing

Abstract

The invention discloses a preparation method for constructing a piezoelectric bone scaffold for bone tumor repair through 3D printing, and belongs to the field of biomedical materials. The method constructs a piezoelectric bone scaffold material for bone tumor treatment and repair through 3D printing, and specifically comprises the following steps: uniformly mixing barium titanate (BTO) and hydroxyapatite (HA) in a fixed volume ratio, printing a green body with a specific pore structure through light-cured resin, and then performing degreasing, sintering, polarization and post-treatment to prepare the BTO / HA piezoelectric composite bone scaffold. The piezoelectric composite bone scaffold prepared by the invention has an accurate shape highly matched with a bone defect part, can catalyze and generate reactive oxygen free radicals through a piezoelectric effect, realizes efficient in-situ inactivation of residual bone tumor cells, integrates two major functions of bone tumor treatment (piezoelectric anti-tumor) and bone defect repair (HA ossification promotion), and has a good application prospect. The treatment and repair effects are improved and the life quality of patients is improved.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical materials, and specifically relates to a preparation method for constructing a piezoelectric bone scaffold using 3D printing technology, which is used for integrated treatment and repair of bone tumors. Background Art

[0002] The repair and functional reconstruction of bone defects caused by severe trauma, surgical resection, degenerative diseases and congenital deformities are common and difficult problems in orthopedic clinical treatment. Autologous and allogeneic bone transplantation is currently the best option for treating bone defects. However, this option is subject to problems such as donor shortage, site necrosis, and immune rejection. Bone tissue engineering has become a feasible option to guide bone tissue regeneration. At present, many limitations are exposed in the treatment of large-area bone defects caused by bone tumors. For example, the implant lacks local anti-tumor effect, has low osteogenic activity, and has a poor match between shape and defect site. Therefore, the development of bone graft scaffold materials with high bioactivity and certain anti-tumor properties is not only of scientific significance, but also of social and economic value.

[0003] Piezoelectric materials have piezoelectricity due to their non-centrosymmetry. They can be divided into piezoelectric ceramics and piezoelectric polymers. The electrical stimulation they generate can promote the growth and repair of biological tissues and play an important role in the biomedical field. Piezoelectric composites have the characteristics of simulating the piezoelectricity of natural bones and have received widespread attention in the field of bone tissue repair. Piezoelectric materials will polarize when subjected to mechanical stress such as ultrasound. This polarization causes the center of charge to shift, resulting in deformation. Subsequently, positive and negative charges are distributed at both ends of the piezoelectric material, generating an electric field and potential. This potential caused by the piezoelectric effect determines the energy levels of the valence band and conduction band of the piezoelectric material, thereby allowing charge exchange at the interface of the piezoelectric material and effectively catalyzing redox reactions. Under the action of ultrasound, the piezoelectric effect induces the generation of a large number of electron holes. The electrons enriched in the conduction band energy level segment and the holes enriched in the valence band energy level segment will further react with the surrounding water molecules and oxygen molecules to generate a large amount of ·OH and O2 - ·, to achieve the inactivation of tumor cells. Piezoelectric composite materials have the characteristics of simulating the piezoelectricity of natural bones and have received widespread attention in the field of bone tissue repair. Traditional piezoelectric materials are mainly prepared by injection molding, freeze drying and other methods. The processing of complex structural shapes of piezoelectric materials is not only costly, but also extremely difficult, or even impossible to process. With the development of 3D printing technology, piezoelectric composite materials with complex 3D structures have begun to emerge. The preparation of piezoelectric materials through 3D printing can not only effectively mix functional drug ingredients targeting lesions, but also carry out diversified structural designs such as geometric shape, connectivity and porosity according to treatment needs, which can achieve customized bone tissue repair. Therefore, the combination of 3D printing technology and piezoelectric composite materials has become an effective measure for bone repair. Summary of the Invention

[0004] Based on the existing technology, the purpose of the present invention is to provide a method for preparing a piezoelectric bone scaffold that uses 3D printing technology to construct an integrated piezoelectric bone scaffold for bone tumor treatment and repair. Piezoelectric ceramic bone scaffold materials with special structures are manufactured through 3D printing technology, and the influence of the slurry solid (barium titanate and hydroxyapatite) content on the ceramic crystal structure, pore structure and electrical properties is systematically studied. At the same time, for bone tissue repair, hydroxyapatite is added to the slurry to explore the effects of the prepared bone scaffold material on tumor inhibition and ossification promotion. The bone scaffold material prepared by this method has a precise shape that is highly matched with the traumatic bone part, and the introduction of hydroxyapatite can greatly promote ossification. Under the action of mechanical stress such as ultrasound, ·OH and 02 - Free radicals can achieve efficient tumor inactivation and can be used for effective reconstruction of bone defect areas after bone tumor surgery.

[0005] The specific steps include:

[0006] Step 1, Preparation of Resin Slurry: For the resin matrix, mix 1,6-hexanediol diacrylate (HDDA) and trimethylolpropane triacrylate (TMPTA) at a specific mass ratio and set aside. The solid components of the slurry consist of barium titanate (BTO) and hydroxyapatite (HA) ceramic powders. The ceramic powders are mixed uniformly at a volume ratio of 1:1.

[0007] Step 2: After all the raw materials are mixed, ball milling beads with a weight equivalent to the raw materials are introduced into the ball milling container. The resulting mixture is mixed evenly in a high-speed ball mill, and the resulting slurry is used for 3D printing.

[0008] Step 3: Create a model of the desired pore structure and import it into a 3D printer. Different volume ratios of BTO and HA require different UV exposure intensities and durations. The resulting green body is ultrasonically cleaned in anhydrous ethanol for 180 seconds and air-dried to obtain the final green body.

[0009] In step 4, the four green bodies were placed in a muffle furnace for comprehensive debinding and sintering. The sintering process was as follows: the temperature was raised to 550°C at a rate of 1°C / min and held for 2 hours to promote the removal of volatiles and binders. The temperature was then raised to a higher temperature at a rate of 2°C / min and held for a sufficient time to effectively sinter the ceramic powder. The ceramic powder was then cooled naturally to room temperature to produce a sintered body with a unique porous structure.

[0010] Step 5: Silver plating is performed on the upper and lower surfaces of the sintered body to enhance conductivity. The coated body is placed in a muffle furnace and heated to 650°C at a rate of 5°C / min. The temperature is maintained for 2 hours to ensure diffusion and adhesion of the silver layer, followed by natural cooling.

[0011] Step 6: polarize the sintered body using an oil bath polarization device, apply a certain polarization voltage at a constant temperature of 25° C. for a certain period of time, and then let it stand for 24 hours to obtain a BTO / HA piezoelectric composite bone scaffold.

[0012] Preferably, in step 1, the mass ratio of the resin matrix is ​​50 wt%, the volume ratio of BTO and HA is 5:5, 6:4, 7:3, 8:2, and the total solid loading is 30-50 vol%.

[0013] Preferably, the rotation speed of the ball mill in step 2 is 400-600 rpm, and the ball milling time is 12-24 h.

[0014] Preferably, the UV irradiation intensity in step 3 is 2.01, 2.32, 2.55 and 2.74 mW / cm 2 , the processing times are 5, 4, 4 and 4s.

[0015] Preferably, in step 4, the ceramic powder is sintered at a temperature of 800-1000° C. and kept at this temperature for 2-4 hours.

[0016] Preferably, in step 6, the polarization voltage is 4-8 kV / mm and the time is 30-60 min.

[0017] Compared with the prior art, the present invention has the following significant advantages:

[0018] (1) By adopting the present invention, the shape of the scaffold can be accurately manufactured according to the location of the bone defect through 3D printing technology, thereby achieving highly matched personalized repair.

[0019] (2) The present invention can generate active oxygen free radicals through piezoelectric effect catalysis, thereby achieving efficient in situ inactivation of residual bone tumor cells and preventing tumor recurrence.

[0020] (3) The present invention integrates two major functions: bone tumor treatment (piezoelectric anti-tumor) and bone defect repair (HA ossification promotion), achieving one-time implantation and dual effects, avoiding secondary surgery, and improving the treatment effect and the patient's quality of life. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The preparation process and mechanism of action of the piezoelectric ceramic bone scaffold material are shown in the schematic diagram of the integrated BTO / HA bone scaffold for treatment and repair. The BTO / HA bone scaffold prepared using this method, when implanted into a bone defect, promotes ossification and, under the influence of ultrasound, generates free radicals that inactivate tumor cells, achieving integrated tumor treatment and bone repair at the bone defect site. DETAILED DESCRIPTION

[0022] The present invention is further described in detail below with reference to the embodiments.

[0023] Example 1

[0024] In step 1, 50 wt% of 1,6-hexanediol diacrylate (HDDA) and 50 wt% of trimethylolpropane triacrylate (TMPTA) were mixed and set aside. The solid components of the slurry consisted of barium titanate (BTO) and hydroxyapatite (HA) ceramic powders. The ceramic powders were mixed in a volume ratio of 5:5, with a total solid loading of 30 vol%.

[0025] Step 2: After all the raw materials are mixed, ball milling beads of a weight equivalent to the raw materials are introduced into the ball milling container. The resulting mixture is mixed evenly in a high-speed ball mill (600 rpm, 24 hours), and the resulting slurry is used for 3D printing.

[0026] Step 3: Create a model of the desired pore structure and import it into the 3D printing equipment. Different volume ratios of BTO and HA require different UV exposure intensities (2.01mW / cm 2 The prepared embryos were ultrasonically cleaned with anhydrous ethanol for 180 seconds and air-dried to obtain the final embryos.

[0027] In step 4, the four green bodies were placed in a muffle furnace for comprehensive debinding and sintering. The sintering process was as follows: the temperature was raised to 550°C at a rate of 1°C / min and held for 2 hours to promote the removal of volatiles and binders. The temperature was then raised to 800°C at a rate of 2°C / min and held for 2 hours to effectively sinter the ceramic powder. The ceramic powder was then naturally cooled to room temperature to produce a sintered body with a unique porous structure.

[0028] Step 5: Silver plating is performed on the upper and lower surfaces of the sintered body to enhance conductivity. The coated body is placed in a muffle furnace and heated to 650°C at a rate of 5°C / min. The temperature is maintained for 2 hours to ensure diffusion and adhesion of the silver layer, followed by natural cooling.

[0029] Step 6: polarize the sintered body using an oil bath polarization device, apply a polarization voltage of 6 kV / mm at a constant temperature of 25° C. for 30 minutes, and then let it stand for 24 hours to obtain a BTO / HA piezoelectric composite bone scaffold.

[0030] Example 2

[0031] In step 1, 50 wt% of 1,6-hexanediol diacrylate (HDDA) and 50 wt% of trimethylolpropane triacrylate (TMPTA) were mixed and set aside. The solid components of the slurry consisted of barium titanate (BTO) and hydroxyapatite (HA) ceramic powders. The ceramic powders were mixed in a volume ratio of 6:4, with a total solid loading of 30 vol%.

[0032] Step 2: After all the raw materials are mixed, ball milling beads of a weight equivalent to the raw materials are introduced into the ball milling container. The resulting mixture is mixed evenly in a high-speed ball mill (600 rpm, 24 hours), and the resulting slurry is used for 3D printing.

[0033] Step 3: Create a model of the desired pore structure and import it into the 3D printing equipment. Different volume ratios of BTO and HA require different UV exposure intensities (2.32mW / cm 2 The prepared embryos were ultrasonically cleaned with anhydrous ethanol for 180 seconds and air-dried to obtain the final embryos.

[0034] In step 4, the four green bodies were placed in a muffle furnace for comprehensive debinding and sintering. The sintering process was as follows: the temperature was raised to 550°C at a rate of 1°C / min and held for 2 hours to promote the removal of volatiles and binders. The temperature was then raised to 800°C at a rate of 2°C / min and held for 2 hours to effectively sinter the ceramic powder. The ceramic powder was then naturally cooled to room temperature to produce a sintered body with a unique porous structure.

[0035] Step 5: Silver plating is performed on the upper and lower surfaces of the sintered body to enhance conductivity. The coated body is placed in a muffle furnace and heated to 650°C at a rate of 5°C / min. The temperature is maintained for 2 hours to ensure diffusion and adhesion of the silver layer, followed by natural cooling.

[0036] Step 6: polarize the sintered body using an oil bath polarization device, apply a polarization voltage of 6 kV / mm at a constant temperature of 25° C. for 30 h, and then let it stand for 24 h to obtain a BTO / HA piezoelectric composite bone scaffold.

[0037] Example 3

[0038] In step 1, 50 wt% of 1,6-hexanediol diacrylate (HDDA) and 50 wt% of trimethylolpropane triacrylate (TMPTA) were mixed and set aside. The solid components of the slurry consisted of barium titanate (BTO) and hydroxyapatite (HA) ceramic powders. The ceramic powders were mixed in a volume ratio of 7:3, with a total solid loading of 30 vol%.

[0039] Step 2: After all the raw materials are mixed, ball milling beads of a weight equivalent to the raw materials are introduced into the ball milling container. The resulting mixture is mixed evenly in a high-speed ball mill (400 rpm, 12 hours), and the resulting slurry is used for 3D printing.

[0040] Step 3: Create a model of the desired pore structure and import it into the 3D printing equipment. Different volume ratios of BTO and HA require different UV exposure intensities (2.55mW / cm 2 The prepared embryos were ultrasonically cleaned with anhydrous ethanol for 180 seconds and air-dried to obtain the final embryos.

[0041] In step 4, the four green bodies were placed in a muffle furnace for comprehensive debinding and sintering. The sintering process was as follows: the temperature was raised to 550°C at a rate of 1°C / min and held for 2 hours to promote the removal of volatiles and binders. The temperature was then raised to 800°C at a rate of 2°C / min and held for 2 hours to effectively sinter the ceramic powder. The ceramic powder was then naturally cooled to room temperature to produce a sintered body with a unique porous structure.

[0042] Step 5: Silver plating is performed on the upper and lower surfaces of the sintered body to enhance conductivity. The coated body is placed in a muffle furnace and heated to 650°C at a rate of 5°C / min. The temperature is maintained for 2 hours to ensure diffusion and adhesion of the silver layer, followed by natural cooling.

[0043] Step 6: polarize the sintered body using an oil bath polarization device, apply a polarization voltage of 4 kV / mm at a constant temperature of 25° C. for 60 min, and then let it stand for 24 h to obtain a BTO / HA piezoelectric composite bone scaffold.

[0044] Example 4

[0045] In step 1, 50 wt% of 1,6-hexanediol diacrylate (HDDA) and 50 wt% of trimethylolpropane triacrylate (TMPTA) were mixed and set aside. The solid components of the slurry consisted of barium titanate (BTO) and hydroxyapatite (HA) ceramic powders. The ceramic powders were mixed in a volume ratio of 8:2, resulting in a total solid loading of 50 vol%.

[0046] Step 2: After all the raw materials are mixed, ball milling beads of a weight equivalent to the raw materials are introduced into the ball milling container. The resulting mixture is mixed evenly in a high-speed ball mill (600 rpm, 24 hours), and the resulting slurry is used for 3D printing.

[0047] Step 3: Create a model of the desired pore structure and import it into the 3D printing equipment. Different volume ratios of BTO and HA require different UV exposure intensities (2.74mW / cm 2 The prepared embryos were ultrasonically cleaned with anhydrous ethanol for 180 seconds and air-dried to obtain the final embryos.

[0048] In step 4, the four green bodies were placed in a muffle furnace for comprehensive debinding and sintering. The sintering process was as follows: heating to 550°C at a rate of 1°C / min and holding for 2 hours to promote the removal of volatiles and binders; then heating to 1000°C at a rate of 2°C / min and holding for 4 hours to effectively sinter the ceramic powder. The ceramic powder was then naturally cooled to room temperature to produce a sintered body with a unique porous structure.

[0049] Step 5: Silver plating is performed on the upper and lower surfaces of the sintered body to enhance conductivity. The coated body is placed in a muffle furnace and heated to 650°C at a rate of 5°C / min. The temperature is maintained for 2 hours to ensure diffusion and adhesion of the silver layer, followed by natural cooling.

[0050] Step 6: polarize the sintered body using an oil bath polarization device, apply a polarization voltage of 8 kV / mm at a constant temperature of 25° C. for 30 h, and then let it stand for 24 h to obtain a BTO / HA piezoelectric composite bone scaffold.

[0051] Comparative Example 1

[0052] This comparative example is basically the same as the embodiment, except that the polarization treatment in step 6 is not performed.

[0053] The results showed that the BTO / HA piezoelectric composite bone scaffold prepared in this comparative example basically did not generate active oxygen free radicals under the action of ultrasound and could not inactivate tumor cells.

[0054] Comparative Example 2

[0055] This comparative example is basically the same as Example 4, except that no HA component is added during the preparation of the slurry in step 1.

[0056] The results showed that the BTO piezoelectric composite bone scaffold prepared in this comparative example had limited ossification-promoting effect, which was significantly weaker than that of the BTO / HA piezoelectric composite bone scaffold, and the interface tissue growth between the scaffold and the bone injury site was significantly slower than that of the BTO / HA piezoelectric composite bone scaffold.

Claims

1. A method for preparing a piezoelectric bone scaffold for 3D printing to repair bone tumors, characterized in that: The following steps are involved: Step 1, Preparation of Resin Slurry: For the resin matrix, mix 1,6-hexanediol diacrylate (HDDA) and trimethylolpropane triacrylate (TMPTA) at a specific mass ratio and set aside. The solid components of the slurry consist of barium titanate (BTO) and hydroxyapatite (HA) ceramic powders. The ceramic powders are mixed uniformly at a volume ratio of 1:

1. Step 2: After all the raw materials are mixed, ball milling beads with a weight equivalent to the raw materials are introduced into the ball milling container. The resulting mixture is mixed evenly in a high-speed ball mill, and the resulting slurry is used for 3D printing. Step 3: Create a model of the desired pore structure and import it into a 3D printer. Different volume ratios of BTO and HA require different UV exposure intensities and times. The resulting green body is ultrasonically cleaned with anhydrous ethanol for 180 seconds and air-dried to obtain the final green body. In step 4, the four green bodies were placed in a muffle furnace for comprehensive debinding and sintering. The sintering process was as follows: the temperature was raised to 550°C at a rate of 1°C / min and held for 2 hours to promote the removal of volatiles and binders. The temperature was then raised to a higher temperature at a rate of 2°C / min and held for a sufficient time to effectively sinter the ceramic powder. The ceramic powder was then cooled naturally to room temperature to produce a sintered body with a unique porous structure. Step 5: Silver is plated on the upper and lower surfaces of the sintered body to enhance conductivity. The plated body is placed in a muffle furnace and heated to 650°C at a rate of 5°C / min. The temperature is maintained for 2 hours to ensure diffusion and adhesion of the silver layer, followed by natural cooling. Step 6: polarize the sintered body using an oil bath polarization device, apply a certain polarization voltage at a constant temperature of 25° C. for a certain period of time, and then let it stand for 24 hours to obtain a BTO / HA piezoelectric composite bone scaffold.

2. The method according to claim 1, characterized in that In the step 1, the mass ratio of the resin matrix is ​​50 wt %, the volume ratio of BTO and HA is 5:5, 6:4, 7:3, 8:2, and the total solid loading is 30-50 vol %.

3. The method according to claim 1, characterized in that In the step 2, the rotation speed of the ball mill is 400-600 rpm, and the ball milling time is 12-24 hours.

4. The method according to claim 1, wherein In step 3, the ultraviolet irradiation intensity is 2.01, 2.32, 2.55 and 2.74 mW / cm 2 , the processing times are 5, 4, 4 and 4s.

5. The method according to claim 1, wherein In the step 4, the ceramic powder is sintered at a temperature of 800-1000° C. and kept at this temperature for 2-4 hours.

6. The method according to claim 1, characterized in that In step 6, the polarization voltage is 4-8 kV / mm and the time is 30-60 min.

7. The BTO / HA piezoelectric composite bone scaffold according to claim 1, characterized in that: The pore size of the scaffold is 100-200 μm.

8. The BTO / HA piezoelectric composite bone scaffold according to claim 1, characterized in that: The stent can effectively generate reactive oxygen free radicals when treated with ultrasound.

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