CN110982335A - Preparation method of self-curing hydroxyapatite 3D printing ink - Google Patents
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Abstract
The invention relates to a preparation method of self-curing hydroxyapatite 3D printing ink, which utilizes the characteristics of plasticity and self-curing of calcium phosphate cement and takes temperature-sensitive PEG/polyester block copolymer solution as curing liquid and dispersing agent to prepare printing ink capable of being processed by 3D printing; by utilizing the gel characteristic of the temperature-sensitive PEG/polyester block copolymer solution, the printing ink is molded on a printing platform at 37 ℃ by a nozzle and naturally cured for 24 hours to form the hydroxyapatite bracket. The invention provides a novel preparation method for preparing a hydroxyapatite scaffold by 3D printing, provides a new idea for clinically and individually treating large-area bone defects, and has wide clinical application prospects.
Description
Technical Field
The invention relates to a method in the technical field of biomedical materials, in particular to a preparation method of self-curing hydroxyapatite 3D printing ink.
Background
The 3D printing technology is applied to clinic, a restoration model which accords with the wound shape of a patient is constructed through CT data reconstruction, and the application prospect in the aspect of clinical personalized treatment is proved to be good. Hydroxyapatite is a common bone tissue repair substitute material, and a hydroxyapatite scaffold is prepared by 3D printing, so that not only can a scaffold model matched with defects be constructed, but also the adhesive growth of cells and blood vessels can be promoted, the degradation time can be adjusted, and the healing capacity of wounds can be improved by adjusting the aperture and the porosity of the scaffold.
In past researches, as hydroxyapatite does not have fluidity and deposition molding capability, the method for preparing the hydroxyapatite scaffold by 3D printing mainly comprises the steps of carrying out 3D printing by using an adhesive, and removing the adhesive by high-temperature calcination in the later period; or prepared by phosphorylation of 3D printed calcium sulphate hemihydrate scaffolds [ J. Suwanprotateeb, J Mater Sci: Mater Med (2010) 21: 419-429 ]. The preparation processes of the two are complicated, and the water-soluble bioactive medicaments are not easy to load.
The temperature sensitive PEG/polyester block copolymer is an injectable thermotropic hydrogel, such as PLGA-PEG-PLGA triblock copolymer and the like, and the preparation raw materials (such as PEG and PLGA) of the thermotropic hydrogel are approved by FDA to be clinically applied. Its aqueous solution is in free-flowing sol state at low temp., and with the rise of temp., at a specific temp. the sol-to-gel phase transition can be produced, so that a compact gel network structure can be formed. The thermotropic hydrogel has good biocompatibility and degradability, and is commonly used for drug slow-release administration, cell culture scaffolds, surface wound repair materials and the like [ B, Jeong, Y.H. Bae, S.W. Kim, macromolecules, 1999 ].
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of self-curing hydroxyapatite 3D printing ink, and provides a new way for personalized preparation of hydroxyapatite supports.
The invention aims to realize the following scheme that the preparation method of the self-curing hydroxyapatite 3D printing ink is characterized in that a thermosensitive PEG/polyester block copolymer solution is used as a curing solution and a dispersing agent of α -TCP powder to prepare the gel-forming 3D printing processable printing ink at 37 ℃, the printing ink is formed on a printing platform at 37 ℃ through a nozzle and then naturally cured for 24 hours to form the hydroxyapatite bracket, and the preparation method comprises the following steps:
(1) mixing calcium hydrogen phosphate and calcium carbonate according to a molar ratio of 2:1, drying, calcining for 2-4h at 1250-;
(2) preparing a temperature-sensitive PEG/polyester block copolymer, preparing an aqueous solution according to the mass fraction of 10-20% (w (g)/v (mL)), so that the gel window of the aqueous solution is gel at 15-40 ℃, and mixing the aqueous solution and glycerol according to the volume ratio of 10:1, mixing;
(3) mixing α -TCP powder prepared in the step (1) with the mixed solution prepared in the step (2) according to a solid-to-liquid ratio of 0.6-1g/mL to obtain self-curing hydroxyapatite 3D printing ink, loading the ink into a printing cylinder, selecting a discharging needle with a diameter of 0.2-0.5mm, printing by using a vertical lamination 3D printer at the temperature of 25-30 ℃, setting a receiving platform at 37 ℃, and curing at room temperature for 24 hours after printing to obtain the self-curing hydroxyapatite support.
The temperature-sensitive PEG/polyester segmented copolymer in the step (2) comprises a triblock copolymer with the characteristics of reversed phase temperature-induced gel of PLGA-PEG-PLGA and PCLA-PEG-PCLA aqueous solution, wherein the aqueous solution is prepared by dissolving the copolymer by magnetic stirring at 4 ℃, and is mixed with glycerin by magnetic stirring at 4 ℃.
The solid-liquid mixing mode in the step (3) is magnetic stirring and mixing at the temperature of 4 ℃.
Mixing α -TCP powder prepared in the step (1) with the mixed solution prepared in the step (2) according to a solid-to-liquid ratio of 0.6-1g/mL to obtain self-curing hydroxyapatite 3D printing ink, loading the ink into a printing cylinder, selecting a discharging needle with a diameter of 0.2-0.5mm, printing by using a vertical lamination 3D printer at the temperature of 25-30 ℃, setting a receiving platform at 37 ℃, and curing at room temperature for 24 hours after printing to obtain the self-curing hydroxyapatite support.
The method comprises the steps of preparing α -TCP powder by a solid-phase reaction method, preparing ABA type PEG/polyester three-stage copolymer by bulk polymerization of polymer monomers, controlling the monomer input in raw materials, regulating and controlling the polymer structure to further control a phase transition window, enabling the copolymer to generate sol-gel transition at 37 ℃, mixing α -TCP powder and temperature-sensitive polyester solution at 4 ℃ to obtain self-curing hydroxyapatite 3D printing ink, printing and molding the self-curing hydroxyapatite 3D printing ink on a 37 ℃ printing platform by a 3D printer, and then naturally curing the self-curing hydroxyapatite for 24 hours.
The invention provides a preparation method of self-curing hydroxyapatite 3D printing ink by utilizing the characteristic that α -TCP is self-cured in aqueous solution with a proper proportion and according to the phase transition characteristic of temperature-sensitive PEG/polyester block copolymer, the printing ink is naturally cured to form a hydroxyapatite bracket after being printed and formed by using a 3D printer, the hydroxyapatite bracket has good mechanical strength and bone growth promoting capability, can be personally matched with the bone defect part of a patient, and has wide application prospect in the field of clinical personalized treatment of orthopedics.
The hydroxyapatite support is prepared by a 3D printing technology, the plasticity and the self-curing performance in the α -TCP hydration process are utilized to prepare the bone repair support matched with bone wounds, the bone repair support is suitable for clinical personalized treatment, the gel property of the thermosensitive PEG/polyester block copolymer aqueous solution is utilized to enable the printing ink to have proper fluidity and viscosity, the bone repair support is suitable for vertical deposition 3D printing, and the hydroxyapatite is formed by natural curing after printing and forming without other subsequent treatment.
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FIG. 1 is a schematic diagram of a self-curing hydroxyapatite scaffold prepared in the prior art.
Detailed Description
The following examples are carried out on the premise of the technical scheme of the invention, and detailed embodiments and specific operation procedures are given, but the scope of the invention is not limited to the following examples.
Example 1
A self-curing hydroxyapatite 3D printing ink is prepared by taking a temperature-sensitive polyethylene glycol (PEG)/polyester block copolymer solution as a curing solution and a dispersing agent of α -TCP powder to prepare a gel-forming 3D printing processable printing ink at 37 ℃, wherein the printing ink is formed on a printing platform at 37 ℃ through a nozzle, and is naturally cured for 24 hours to form a hydroxyapatite bracket, and the self-curing hydroxyapatite 3D printing ink is prepared according to the following steps:
(1) α -preparation of TCP:
mixing calcium hydrophosphate and calcium carbonate according to a molar ratio of 2:1, performing wet ball milling by taking ultrapure water of which the total mass is 1.5 times as a medium, rotating at 400rpm for 4 hours, performing ball milling, drying in a 130 ℃ oven, drying, calcining in a muffle furnace for 4 hours at 1400 ℃, taking out, rapidly cooling in a blast environment, performing absolute ethyl alcohol wet ball milling on cooled powder by using a zirconium oxide ball milling tank according to a ratio of 1g/mL, performing wet ball milling at 450rpm for 4 hours, removing ethanol from obtained powder suspension by using a rotary evaporator, and drying in a 60 ℃ oven to obtain α -TCP powder;
(2) preparing a temperature-sensitive PEG/polyester block copolymer:
adding 25 g of PEG with the molecular weight of 1000 into a 250mL three-neck flask, heating the mixture in an oil bath to 150 ℃ to melt the PEG, vacuumizing the mixture under stirring for 3 hours, cooling the system to room temperature, adding 50 g of lactide and 12.5 g of glycolide under the protection of argon gas, wherein the molar ratio is 3:1, heating the mixture under vacuum to melt the mixture and uniformly stirring the mixture, adding 75 mg of stannous octoate, finally controlling the temperature of the oil bath to be 150 ℃, the rotating speed of a stirrer to be about 60 r/min, continuing to react for 12 hours under the protection of argon gas, washing an initial product in hot water at 80 ℃ for three times after the reaction is finished, removing residual water through freeze drying for 48 hours, and preparing the PLGA-PEG-PLGA triblock copolymer; preparing 20% (w (g)/v (mL)) aqueous solution of PEG/block copolymer with a gel window of 15-40 ℃ as a gel, wherein the volume ratio of the aqueous solution to glycerol is 10:1, mixing in a magnetic stirring manner at the temperature of 4 ℃ to obtain a mixed solution;
(3) and (3) mixing the α -TCP powder prepared in the step (1) with the mixed solution prepared in the step (2) according to the solid-to-liquid ratio of 0.6g/mL to obtain the self-curing hydroxyapatite 3D printing ink.
The 'ink' is filled into a printing material cylinder, a discharging needle head is 0.5mm, a vertical lamination 3D printer is adopted to print in an environment of 25 ℃, a receiving platform is 37 ℃, and after printing is finished, the 'ink' is cured for 24 hours at room temperature to obtain the self-curing hydroxyapatite support. The compressive strength of the bracket is tested to be 4.66 +/-0.19 MPa.
Example 2
A self-curing hydroxyapatite 3D printing ink, similar to example 1, prepared by the following steps:
(1) α -TCP powder was prepared as in example 1;
(2) preparing a temperature-sensitive PEG/polyester block copolymer:
adding PEG with the molecular weight of 1500 into a 250mL three-neck flask, heating the mixture to 150 ℃ in an oil bath to melt the PEG, and vacuumizing for 3h under stirring; after the system is cooled to room temperature, lactide and glycolide are added according to the molar ratio of 10:1 under the protection of argon, the mass ratio of the total mass to PEG is 2.24:1, under the condition of vacuum heating, the lactide and glycolide are melted and uniformly stirred, and stannous octoate is added as a catalyst; finally, controlling the temperature of the oil bath at 150 ℃, controlling the rotating speed of a stirrer to be about 60 r/min, and continuously reacting for 12 hours under the protection of argon; after the reaction is finished, washing the primary product in hot water at 80 ℃ for three times, and removing residual water by freeze drying for 48 hours to prepare a PLGA-PEG-PLGA triblock copolymer; preparing PLGA-PEG-PLGA triblock copolymer aqueous solution according to the mass fraction of 10% (w (g)/v (mL)), leading the gel window to be gel at 15-40 ℃, wherein the volume ratio of the solution to glycerol is 10:1, mixing in a way of magnetic stirring at 4 ℃ to prepare a mixed solution;
(3) α -TCP powder prepared in the step (1) of example 1 and the mixed solution prepared in the step (2) are mixed according to the solid-to-liquid ratio of 0.6g/mL to obtain the self-curing hydroxyapatite 3D printing ink.
The 'ink' is filled into a printing cylinder, a discharging needle head is 0.5mm, a vertical lamination 3D printer is adopted to print in an environment of 25 ℃, a receiving platform is 37 ℃, and after printing is finished, the 'ink' is cured for 24 hours at room temperature to obtain a self-curing hydroxyapatite bracket, as shown in attached figure 1. The compressive strength of the bracket is tested to be 4.85 +/-0.97 MPa. .
Example 3
A self-curing hydroxyapatite 3D printing ink, similar to example 1, prepared by the following steps:
(1) α -TCP powder was prepared as in example 1;
(2) preparing a temperature-sensitive PEG/polyester block copolymer:
25 g of PEG having a molecular weight of 1000 was added to a 250mL three-necked flask, heated in an oil bath to 150 ℃ to melt the PEG, and evacuated under stirring for 3 hours. After the system is cooled to room temperature, 50 g of lactide and 12.5 g of glycolide are added under the protection of argon, and the molar ratio is 3: 1; heating under vacuum to melt and stir uniformly, and then adding 75 mg of stannous octoate; finally, controlling the temperature of the oil bath at 150 ℃, controlling the rotating speed of a stirrer to be about 60 r/min, and continuously reacting for 12 hours under the protection of argon; after the reaction is finished, washing the primary product in hot water at 80 ℃ for three times, and removing residual water by freeze drying for 48 hours to prepare a PLGA-PEG-PLGA triblock copolymer; preparing a block copolymer aqueous solution according to the mass fraction of 20% (w (g)/v (mL)), wherein the gel window of the block copolymer aqueous solution is gel at 15-40 ℃, and the volume ratio of the block copolymer aqueous solution to glycerol is 10:1, mixing in a way of magnetic stirring at 4 ℃ to prepare a mixed solution;
(3) α -TCP powder prepared in example (1) and the mixed solution prepared in example (2) were mixed according to a solid-to-liquid ratio of 1g/mL to obtain a self-curing hydroxyapatite 3D printing ink.
The 'ink' is filled into a printing material cylinder, a discharging needle head is 0.5mm, a vertical lamination 3D printer is adopted to print in an environment of 25 ℃, a receiving platform is 37 ℃, and after printing is finished, the 'ink' is cured for 24 hours at room temperature to obtain the self-curing hydroxyapatite support. The compressive strength of the bracket is tested to be 9.77 +/-0.54 MPa.
Claims (6)
1. A preparation method of self-curing hydroxyapatite 3D printing ink is characterized in that temperature-sensitive polyethylene glycol (PEG)/polyester block copolymer solution is used as a curing solution and a dispersing agent of α -TCP powder to prepare gel-forming 3D printing processable printing ink at 37 ℃, the printing ink is formed on a printing platform at 37 ℃ through a nozzle and then naturally cured for 24 hours to form a hydroxyapatite bracket, and the preparation method comprises the following steps:
(1) mixing calcium hydrogen phosphate and calcium carbonate according to a molar ratio of 2:1, drying, calcining for 2-4h at 1250-;
(2) preparing a temperature-sensitive PEG/polyester block copolymer, preparing an aqueous solution according to the mass fraction of 10-20% (w (g)/v (mL)), so that the gel window of the aqueous solution is gel at 15-40 ℃, and mixing the aqueous solution and glycerol according to the volume ratio of 10:1, mixing;
(3) mixing α -TCP powder prepared in the step (1) with the mixed solution prepared in the step (2) according to a solid-to-liquid ratio of 0.6-1g/mL to obtain self-curing hydroxyapatite 3D printing ink, loading the ink into a printing cylinder, selecting a discharging needle with a diameter of 0.2-0.5mm, printing by using a vertical lamination 3D printer at the temperature of 25-30 ℃, setting a receiving platform at 37 ℃, and curing at room temperature for 24 hours after printing to obtain the self-curing hydroxyapatite support.
2. The method for preparing self-curing hydroxyapatite 3D printing ink according to claim 1, wherein the temperature-sensitive PEG/polyester block copolymer in the step (2) comprises a triblock copolymer with reversed phase temperature-induced gel property in an aqueous solution of PLGA-PEG-PLGA and PCLA-PEG-PCLA, the aqueous solution is prepared by dissolving the block copolymer by magnetic stirring at 4 ℃, and the block copolymer and glycerol are mixed by magnetic stirring at 4 ℃.
3. The method for preparing the self-curing hydroxyapatite 3D printing ink according to claim 1, wherein the solid-liquid mixing manner in the step (3) is magnetic stirring mixing at 4 ℃.
4. The method for preparing the self-curing hydroxyapatite 3D printing ink according to any one of the claims 1 to 3, characterized by comprising the following steps:
(1) α -preparation of TCP:
mixing calcium hydrophosphate and calcium carbonate according to a molar ratio of 2:1, performing wet ball milling by taking ultrapure water of which the total mass is 1.5 times as a medium, rotating at 400rpm for 4 hours, performing ball milling, drying in a 130 ℃ oven, drying, calcining in a muffle furnace for 4 hours at 1400 ℃, taking out, rapidly cooling in a blast environment, performing absolute ethyl alcohol wet ball milling on cooled powder by using a zirconium oxide ball milling tank according to a ratio of 1g/mL, performing wet ball milling at 450rpm for 4 hours, removing ethanol from obtained powder suspension by using a rotary evaporator, and drying in a 60 ℃ oven to obtain α -TCP powder;
(2) preparing a temperature-sensitive PEG/polyester block copolymer:
adding 25 g of PEG with the molecular weight of 1000 into a 250mL three-neck flask, heating the mixture in an oil bath to 150 ℃ to melt the PEG, vacuumizing the mixture under stirring for 3 hours, cooling the system to room temperature, adding 50 g of lactide and 12.5 g of glycolide under the protection of argon gas, wherein the molar ratio is 3:1, heating the mixture under vacuum to melt the mixture and uniformly stirring the mixture, adding 75 mg of stannous octoate, finally controlling the temperature of the oil bath to be 150 ℃, the rotating speed of a stirrer to be about 60 r/min, continuing to react for 12 hours under the protection of argon gas, washing an initial product in hot water at 80 ℃ for three times after the reaction is finished, removing residual water through freeze drying for 48 hours, and preparing the PLGA-PEG-PLGA triblock copolymer; preparing 20% (w (g)/v (mL)) aqueous solution of PEG/block copolymer with a gel window of 15-40 ℃ as a gel, wherein the volume ratio of the aqueous solution to glycerol is 10:1, mixing in a magnetic stirring manner at the temperature of 4 ℃ to obtain a mixed solution;
(3) and (3) mixing the α -TCP powder prepared in the step (1) with the mixed solution prepared in the step (2) according to the solid-to-liquid ratio of 0.6g/mL to obtain the self-curing hydroxyapatite 3D printing ink.
5. The preparation method of the self-curing hydroxyapatite 3D printing ink according to claim 4, characterized by comprising the following steps:
preparing a temperature-sensitive PEG/polyester block copolymer in the step (2):
adding PEG with the molecular weight of 1500 into a 250mL three-neck flask, heating the mixture to 150 ℃ in an oil bath to melt the PEG, and vacuumizing for 3h under stirring; after the system is cooled to room temperature, lactide and glycolide are added according to the molar ratio of 10:1 under the protection of argon, the mass ratio of the total mass to PEG is 2.24:1, under the condition of vacuum heating, the lactide and glycolide are melted and uniformly stirred, and stannous octoate is added as a catalyst; finally, controlling the temperature of the oil bath at 150 ℃, controlling the rotating speed of a stirrer to be about 60 r/min, and continuously reacting for 12 hours under the protection of argon; after the reaction is finished, washing the primary product in hot water at 80 ℃ for three times, and removing residual water by freeze drying for 48 hours to prepare a PLGA-PEG-PLGA triblock copolymer; preparing PLGA-PEG-PLGA triblock copolymer aqueous solution according to the mass fraction of 10% (w (g)/v (mL)), leading the gel window to be gel at 15-40 ℃, wherein the volume ratio of the solution to glycerol is 10:1, mixing in a way of magnetic stirring at 4 ℃ to prepare a mixed solution;
(3) α -TCP powder prepared in the step (1) of example 1 and the mixed solution prepared in the step (2) are mixed according to the solid-to-liquid ratio of 0.6g/mL to obtain the self-curing hydroxyapatite 3D printing ink.
6. The preparation method of the self-curing hydroxyapatite 3D printing ink according to claim 4, characterized by comprising the following steps: (2) preparing a temperature-sensitive PEG/polyester block copolymer:
25 g of PEG having a molecular weight of 1000 was added to a 250mL three-necked flask, heated in an oil bath to 150 ℃ to melt the PEG, and evacuated under stirring for 3 hours. After the system is cooled to room temperature, 50 g of lactide and 12.5 g of glycolide are added under the protection of argon, and the molar ratio is 3: 1; heating under vacuum to melt and stir uniformly, and then adding 75 mg of stannous octoate; finally, controlling the temperature of the oil bath at 150 ℃, controlling the rotating speed of a stirrer to be about 60 r/min, and continuously reacting for 12 hours under the protection of argon; after the reaction is finished, washing the primary product in hot water at 80 ℃ for three times, and removing residual water by freeze drying for 48 hours to prepare a PLGA-PEG-PLGA triblock copolymer; preparing a block copolymer aqueous solution according to the mass fraction of 20% (w (g)/v (mL)), wherein the gel window of the block copolymer aqueous solution is gel at 15-40 ℃, and the volume ratio of the block copolymer aqueous solution to glycerol is 10:1, mixing in a way of magnetic stirring at 4 ℃ to obtain a mixed solution.
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| CN114099770A (en) * | 2021-11-02 | 2022-03-01 | 常州大学 | Self-curing 3D printing biological ink and preparation method and application thereof |
| CN114848898A (en) * | 2022-06-23 | 2022-08-05 | 点云生物(杭州)有限公司 | Artificial bone scaffold manufactured based on 3D printing process and method |
| CN115105644A (en) * | 2022-07-19 | 2022-09-27 | 南京屹特博医学科技发展有限公司 | 3D printing artificial bone repair material and preparation method thereof |
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| CN115105644A (en) * | 2022-07-19 | 2022-09-27 | 南京屹特博医学科技发展有限公司 | 3D printing artificial bone repair material and preparation method thereof |
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