3D printing filament, artificial bone prosthesis, and preparation method therefor

Abstract

A 3D printing filament, an artificial bone prosthesis, and a preparation method therefor. The preparation method for the artificial bone prosthesis comprises the following steps: (1) uniformly mixing polycaprolactone and porous tricalcium phosphate powder material; (2) preparing the mixed material into a solid printing raw material; (3) according to a preset model, melting the solid printing raw material by means of a 3D printer, to print an artificial bone prosthesis. The porous tricalcium phosphate powder material is formed by drying a precipitate after a salt solution is mixed and reacted, the salt solution comprising a calcium salt and a phosphate solution. The artificial bone prosthesis has relatively good degradation performance, mechanical strength and biological activity, and avoids the problem of cytotoxicity caused by organic solvent residues.

Description

3D printing filament, artificial bone repair body and preparation method thereof Related applications

[0001] This application claims priority to Chinese patent application No. CN2023112007250 filed on September 18, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present disclosure relates to a 3D printing-based filament, an artificial bone prosthesis, and a preparation method thereof, in particular to a preparation method of a polycaprolactone / porous tricalcium phosphate composite artificial bone prosthesis. Background Art

[0003] Tumors, trauma, necrosis, congenital malformations, and other causes often lead to large-scale destruction of bone structures and bone defects. There is an urgent need to develop new artificial bone materials for bone defect repair. The pore structure of artificial bone materials has a crucial impact on their mechanical properties and biological functions. Excessively high porosity generally results in low mechanical strength, while too low a porosity will hinder the ingrowth of new bone tissue. To ensure bone tissue ingrowth, the pore diameter is generally greater than 100 microns, and the pores should be interconnected. The traditional manufacturing process of artificial bone materials has low precision, and the use of traditional pore-forming agents cannot obtain a special pore structure, which is not conducive to new bone ingrowth and angiogenesis. 3D printing technology constructs objects through layer-by-layer printing. The product has high precision, high material utilization, and can construct complex pore structures. Its application in the field of orthopedics is significantly advanced.

[0004] Currently, polyetheretherketone (PEEK) and polylactic acid (PLA) are the primary materials used in biomedical 3D printing. PEEK, formed through laser melting, exhibits high mechanical strength and chemical inertness, making it widely used in applications such as skull printing. However, PEEK is difficult to degrade in vivo and exhibits poor bioactivity (see Reference 1: Singh S., Prakash C. and et al. Plasma treatment of polyether-ether-ketone: A means of obtaining desirable biomedical characteristics. Eur. Polym. J. 2019, 118:561-577). PLA is formed by fused deposition modeling (FDM) by depositing filaments layer by layer. This method offers high precision, low cost, and repeatability in the printing process, resulting in PLA scaffolds with high mechanical strength. However, the degradation products of polylactic acid are acidic, hindering new bone growth, and they also have poor toughness (see Reference 2: Lipsa R., Tudorachi N. and et al. Biodegradation of poly(lactic acid) and some of its based systems with Trichoderma viride. Int. J. Biol. Macromol. 2016, 88:515-526). Researchers have tried to improve the biocompatibility of artificial bone scaffolds by adding calcium phosphate materials such as hydroxyapatite to printing materials. However, these materials still suffer from issues such as non-degradability in vivo, a mismatch between degradation rates and the osteogenesis cycle, and low bioactivity, making them difficult to meet the growing market demand (see Reference 3: Pan Y., Chen Y. and et al. Effect of notch sensitivity on the mechanical properties of HA / PEEK functional gradient biocomposites. J. Polym. Eng. 2016, 36:933-941). Studies have shown that the degradation cycle of hydroxyapatite can exceed ten years. After implantation, dense hydroxyapatite material only forms new bone tissue on the surface and lacks the ability to induce bone formation.

[0005] Therefore, there is an urgent need to develop 3D printed composite artificial bone materials with higher bioactivity and full degradation in vivo. Summary of the Invention

[0006] The present disclosure relates to a 3D printing filament, an artificial bone prosthesis based on 3D printing, and a preparation method thereof. The artificial bone prosthesis has excellent degradation performance, mechanical strength and biological activity, and avoids the cytotoxicity problem caused by residual organic solvents.

[0007] One aspect of the present disclosure provides a method for preparing an artificial bone prosthesis based on 3D printing, comprising the following steps:

[0008] (1) Mixing polycaprolactone and porous tricalcium phosphate powder materials uniformly;

[0009] (2) Making the mixed material into solid printing material;

[0010] (3) According to the preset model, the solid printing material is melted and printed into an artificial bone repair body by a 3D printer;

[0011] The porous tricalcium phosphate powder material is formed by drying a precipitate obtained after a mixed reaction of a salt solution, wherein the salt solution includes a calcium salt and a phosphate solution.

[0012] In one embodiment, in step (1), the polycaprolactone and porous tricalcium phosphate powder material are mixed uniformly by a mechanical method or a solvent dissolution method.

[0013] In one embodiment, polycaprolactone and porous tricalcium phosphate powder materials are added to an internal mixer and heated and mixed. The obtained mixed material is placed in a pelletizer for crushing, and then added to the internal mixer and mixed again.

[0014] In one embodiment, step (1) specifically includes: adding polycaprolactone and porous tricalcium phosphate powder materials into an internal mixer and heating and mixing them, the heating temperature is 30-200° C., and the mixing time is 0.5-12 hours; the obtained mixed material is placed into a pelletizer and crushed to form a granular material with a diameter of 0.1-10 mm; and then adding the mixed material into the internal mixer and mixing it again, the heating temperature is 50-150° C., and the mixing time is 0.5-12 hours, to obtain a uniformly mixed polycaprolactone / porous tricalcium phosphate powder material composite material.

[0015] In one embodiment, step (1) specifically includes: dissolving polycaprolactone and porous tricalcium phosphate powder materials in a solvent respectively, stirring them evenly and mixing them, and then injecting them into pure water; collecting the precipitated precipitate by filtration, and drying it for 6 to 24 hours to obtain a uniformly mixed polycaprolactone / porous tricalcium phosphate powder material composite fiber.

[0016] In one embodiment, the solvent includes a combination of one or more selected from N,N-dimethylformamide (DMF), chloroform, acetone, toluene, and carbon tetrachloride.

[0017] In one embodiment, the mass ratio of the solid material to the solvent is 0.01-0.2.

[0018] In one embodiment, the volume ratio of the mixed solvent to pure water is 0.05-0.2.

[0019] In one embodiment, the drying temperature is 30-100°C.

[0020] In one embodiment, the weight average molecular weight of the polycaprolactone is 50,000-200,000 Da.

[0021] In one embodiment, the mass content of the porous tricalcium phosphate powder material in the material after mixing in step (1) is less than 50%; more preferably, it is 10-50%; further, it is 10-40%; and further, it is 25-40%. Optionally, the mass content of the porous tricalcium phosphate powder material in the material after mixing is 10%, 15%, 20%, 25%, 30%, 40%, 45%, or 50%.

[0022] In one embodiment, in step (2), the solid printing material is a filament, and the filament is made by a screw extruder, the temperature of the screw extruder is set to 60~130℃, and the filament making speed is 0.1~5 m / min.

[0023] In one embodiment, in step (3), the parameters of the 3D printer are set as follows: printing temperature 120-250° C., printing speed 5-70 mm / s, filling rate 20-100%, and wire width 0.1-0.8 mm.

[0024] In one embodiment, the salt solution further comprises a magnesium salt, and the porous tricalcium phosphate powder material contains 1-3% by mass of magnesium. In another embodiment, the mass percentage of magnesium is 1.3-2%. Alternatively, the mass percentage of magnesium is 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.7%, 1.9%, 2%, 2.2%, 2.5%, 2.8%, or 3%.

[0025] In one embodiment, the porous tricalcium phosphate powder material is prepared by the following steps:

[0026] preparing a first solution containing calcium ions; preparing a phosphate solution and adjusting the pH to 9.5-10.5 with an alkaline solution to serve as a second solution;

[0027] heating and mixing the first solution and the second solution, and reacting them at 60-95° C. with stirring;

[0028] The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed. The washed precipitate is spray-dried to obtain the porous tricalcium phosphate powder material.

[0029] In one embodiment, the first solution further contains magnesium ions, and the molar ratio of calcium ions to magnesium ions in the first solution is 6-10; after the first solution and the second solution are mixed, the molar ratio of calcium ions to phosphate ions is 1.1-1.5; the calcium salt includes a combination of one or more selected from anhydrous calcium chloride, calcium chloride dihydrate and calcium nitrate tetrahydrate, the magnesium salt includes magnesium chloride hexahydrate and / or magnesium nitrate hexahydrate, the phosphate includes a combination of multiple selected from one of disodium hydrogen phosphate, diammonium hydrogen phosphate and sodium hydrogen phosphate, and the alkali solution is ammonia water or sodium hydroxide.

[0030] In one embodiment, the washed precipitate is spray-dried using a spray dryer, wherein the air inlet temperature of the spray dryer is 240-300° C., the air outlet temperature is 120-150° C., and the feed rate is 30-200 mL / min.

[0031] Another aspect of the present disclosure provides a 3D printing filament for an artificial bone repair body, wherein the filament is made of a uniformly mixed polycaprolactone and a magnesium-containing tricalcium phosphate powder material, wherein the magnesium-containing tricalcium phosphate content in the filament is 10-50 wt %. The magnesium-containing tricalcium phosphate powder material is formed by drying a precipitate obtained after a mixed reaction of multiple salt solutions, wherein the salt solutions include calcium salt, magnesium salt, and phosphate solution.

[0032] In one embodiment, the magnesium-containing tricalcium phosphate powder material is formed by spray-drying the precipitate, and has a particle size of 1-20 μm.

[0033] In one embodiment, the magnesium-containing tricalcium phosphate powder material contains 1-3% by mass of magnesium.

[0034] In one embodiment, the wire diameter of the wire is 0.1-0.8 mm.

[0035] In one embodiment, the filament is made by a screw extruder, the temperature of the screw extruder is set to 60-130° C., and the filament making speed is 0.1-5 m / min.

[0036] In one embodiment, polycaprolactone and magnesium-containing tricalcium phosphate powder materials are mixed by the following steps: polycaprolactone and magnesium-containing tricalcium phosphate powder materials are added to an internal mixer and heated and mixed, the heating temperature is 30~200°C, and the mixing time is 0.5~12 hours; the obtained mixed material is placed in a pelletizer and crushed to form a granular material with a diameter of 0.1~10 mm; then the mixed material is added to the internal mixer and mixed again, the heating temperature is 50~150°C, and the mixing time is 0.5~12 hours to obtain a uniformly mixed polycaprolactone / magnesium-containing tricalcium phosphate powder material composite material.

[0037] In one embodiment, the weight average molecular weight of the polycaprolactone is 50,000-200,000 Da.

[0038] In one embodiment, the magnesium-containing tricalcium phosphate powder material is prepared by the following steps:

[0039] preparing a first solution containing calcium ions and magnesium ions at a molar ratio of 6 to 10; preparing a phosphate solution and adjusting the pH to 9.5 to 10.5 with an alkaline solution to serve as a second solution;

[0040] The first solution and the second solution are heated and mixed, with the molar ratio of calcium ion to phosphate ion being 1.1 to 1.5, and reacted at 60 to 95° C. with stirring;

[0041] The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed. The washed precipitate is spray-dried to obtain the magnesium-containing tricalcium phosphate powder material.

[0042] In one embodiment, the calcium salt is a combination of one or more of anhydrous calcium chloride, calcium chloride dihydrate, and calcium nitrate tetrahydrate; the magnesium salt is selected from magnesium chloride hexahydrate and / or magnesium nitrate hexahydrate; the phosphate is selected from a combination of multiple of disodium hydrogen phosphate, diammonium hydrogen phosphate, and sodium hydrogen phosphate; and the alkali solution is ammonia water or sodium hydroxide.

[0043] In one embodiment, the washed precipitate is spray-dried using a spray dryer, wherein the air inlet temperature of the spray dryer is 240-300° C., the air outlet temperature is 120-150° C., and the feed rate is 30-200 mL / min.

[0044] Yet another aspect of the present disclosure provides an artificial bone prosthesis based on 3D printing, which is prepared by the preparation method.

[0045] In a preferred embodiment, the porosity of the artificial bone prosthesis is 30-70%, the maximum pore size is greater than 300 μm, and the mechanical strength is 2-20 MPa.

[0046] In the 3D-printed artificial bone prosthesis disclosed herein and its preparation method, a special porous tricalcium phosphate powder material is compounded into a degradable polycaprolactone material to obtain a solid printing raw material (e.g., filament), which is then melt-printed by a 3D printer to produce an artificial bone prosthesis. The artificial bone prosthesis has excellent degradation performance, mechanical properties, and biological activity, and in particular, can avoid the cytotoxicity problem of organic solvents. The internal pores formed are interconnected, thereby facilitating new bone ingrowth, material transport, and vascularization. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] In order to more clearly illustrate the technical solution of the present disclosure, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present disclosure. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0048] FIG1 is an XRD result of the porous tricalcium phosphate powder material prepared in Example 1.

[0049] FIG2 is a SEM microscopic morphology of the porous tricalcium phosphate powder material prepared in Example 1.

[0050] FIG3 is an EDS spectrum of the porous tricalcium phosphate powder material prepared in Example 1.

[0051] FIG4 is a photograph of the artificial bone prosthesis prepared in Example 1 of the present disclosure.

[0052] FIG5 is a SEM microscopic morphology of the artificial bone repair body prepared in Example 1 of the present disclosure.

[0053] Figures 6(a) and 6(c) are the microscopic observation results of MC3T3-E1 bone progenitor cells cultured with the artificial bone repair body extract prepared in Example 1 after 1 day and 3 days, respectively; Figures 6(b) and 6(d) are the microscopic observation results of MC3T3-E1 bone progenitor cells cultured in the blank control group after 1 day and 3 days, respectively. DETAILED DESCRIPTION

[0054] The preferred embodiments of the present disclosure are described in detail below with reference to the accompanying drawings to make the advantages and features of the present disclosure more easily understood by those skilled in the art. It should be noted that the descriptions of these embodiments are intended to facilitate understanding of the present disclosure and do not constitute a limitation of the present disclosure. In addition, the technical features involved in the various embodiments of the present disclosure described below may be combined with each other as long as they do not conflict with each other.

[0055] For 3D-printed products made of polycaprolactone and tricalcium phosphate, conventional calcined and ground tricalcium phosphate raw materials—calcined at 1200 degrees Celsius, then ground and sieved—result in micron-sized, hard tricalcium phosphate. This micron-sized, hard tricalcium phosphate material exhibits poor mixing properties in polycaprolactone. Therefore, a solvent method can be used to obtain a uniform composite material by mixing low-concentration solutions of polycaprolactone and tricalcium phosphate in organic solvents. However, this solvent method is plagued by toxic residual solvents, limiting its clinical application. Hydroxyapatite, a composite material in 3D-printed products, has a chemical composition identical to the inorganic components of human bone, promoting osteoblast adhesion and proliferation and exhibiting good biocompatibility after implantation. However, it degrades slowly in vivo. Studies have shown that the degradation cycle of hydroxyapatite can exceed ten years. After implantation, dense hydroxyapatite forms new bone tissue only on the surface and lacks the ability to induce bone formation.

[0056] Based on this, the inventors used a low-density porous tricalcium phosphate material obtained by a low-temperature wet chemical precipitation method, and doped it with active magnesium elements that are beneficial to osteogenesis. They can prepare a uniform composite material by mixing polycaprolactone through a solvent method or by a banbury mechanical mixing method to solve the following problems:

[0057] (1) Poor degradation performance

[0058] Common materials used in 3D-printed artificial bone prostheses are polyetheretherketone (PEEK) and polylactic acid (PLA). PEEK does not degrade in vivo and has poor adhesion to bone tissue. Polylactic acid degradation products are acidic and can easily trigger inflammation. This application utilizes a composite of polycaprolactone and tricalcium phosphate (preferably containing magnesium) to produce a fully biodegradable artificial bone prosthesis. The degradation products are neutral, promoting new bone formation.

[0059] (2) Organic solvent residue problem

[0060] If polycaprolactone is dissolved in an organic solvent and mixed with calcium phosphate powder, although the better fluidity of the solution helps the materials mix more evenly, the solvent cannot be completely removed in subsequent processes such as drying or filtration, resulting in greater cytotoxicity. The raw materials of this application can be completed by mechanical mixing using a banburying method to avoid solvent residue.

[0061] (3) Insufficient mechanical strength and biological activity

[0062] Polycaprolactone is dissolved in an organic solvent and mixed with calcium phosphate powder. The solvent components are freeze-dried after 3D printing, resulting in a scaffold material with a mechanical strength of only 1-2 MPa, which is not suitable for application in bone tissue. This application improves mixing performance by using a magnesium-containing tricalcium phosphate material, allowing the mixing process to be completed through a mechanical mixing method, significantly enhancing the material's mechanical strength and bioactivity.

[0063] The inventors proposed a 3D printed magnesium tricalcium phosphate polycaprolactone artificial bone repair body and a preparation method thereof, which specifically includes the following steps:

[0064] (1) Weigh polycaprolactone and tricalcium phosphate powder materials and mix the two materials evenly.

[0065] (2) The mixed material is passed through a screw extruder to form a filament.

[0066] (3) After importing the digital model and setting the parameters, a hot melt extrusion 3D printer was used to prepare tricalcium phosphate / polycaprolactone artificial bone repair.

[0067] A 3D printing filament for artificial bone repair and a preparation method thereof are also proposed, specifically comprising: being made from a mixed polycaprolactone and a magnesium-containing tricalcium phosphate powder material, wherein the magnesium-containing tricalcium phosphate content in the filament is 10-50 wt %. The magnesium-containing tricalcium phosphate powder material is formed by drying the precipitate after a mixed reaction of multiple salt solutions, wherein the salt solution includes calcium salt, magnesium salt and phosphate solution.

[0068] In step (1), the weight-average molecular weight of the polycaprolactone material used is 50,000 to 200,000 Da; the tricalcium phosphate powder material used is prepared by a low-temperature wet chemical method and has a particle size of 1 to 20 μm; the content of the tricalcium phosphate material in the polycaprolactone / tricalcium phosphate composite material is 0 to 50 wt.%. Furthermore, the tricalcium phosphate powder material contains magnesium, and the magnesium content is 1 to 3 wt.%, preferably 1.3 to 2 wt.%. The content of the tricalcium phosphate material in the polycaprolactone / tricalcium phosphate composite material is preferably 10 to 50 wt.%.

[0069] In step (1), the two materials can be mixed evenly using a mechanical mixing method. The specific process of mixing the two materials using the mechanical mixing method is as follows: polycaprolactone and magnesium tricalcium phosphate powder materials are added to an internal mixer and heated and mixed, the heating temperature is 30-200°C, and the mixing time is 0.5-12 hours. The obtained mixed material is placed in a pelletizer and crushed to form a granular material with a diameter of 0.1-10 mm. Then, the material is added to an internal mixer and mixed evenly again, the heating temperature is 50-150°C, and the mixing time is 0.5-12 hours to obtain a uniformly mixed polycaprolactone / magnesium tricalcium phosphate composite material.

[0070] In step (1), the two materials can also be mixed evenly using a solvent dissolution method. The specific process of mixing the two materials using the solvent dissolution method is as follows: polycaprolactone and magnesium-containing tricalcium phosphate materials are dissolved and stirred using a solvent respectively, and after stirring evenly, the two materials are mixed and then injected into pure water. The precipitated precipitate is collected by suction filtration and dried for 6 to 24 hours to obtain a uniformly mixed polycaprolactone / magnesium-containing tricalcium phosphate composite fiber. The solvents used include but are not limited to N,N~ dimethylformamide (DMF), chloroform, acetone, toluene and carbon tetrachloride, the mass ratio of solid material to solvent is 0.01 to 0.2, and the volume ratio of solvent to water after mixing is 0.05 to 0.2. The solvent dissolution stirring time is 10 to 60 minutes, and the drying temperature is 30 to 100°C.

[0071] In step (2), the temperature of the screw extruder used is set to 60-130°C, and the spinning speed is 0.1-5 m / min. The content of magnesium tricalcium phosphate in the obtained magnesium tricalcium phosphate polycaprolactone composite wire is 10-50 wt.%.

[0072] In step (3), the parameters of the 3D printer are set as follows: printing temperature 120~250℃, printing speed 5~70 mm / s, filling rate 20~100%, and wire diameter 0.1~0.8 mm.

[0073] The prepared 3D printed polycaprolactone / magnesium-containing tricalcium phosphate artificial bone repair body has a porosity of 30-70%, a maximum pore size greater than 300 μm, and a mechanical strength of 2-20 MPa.

[0074] The magnesium-containing tricalcium phosphate powder material is prepared by the following steps:

[0075] (1) Dissolving a calcium salt and a magnesium salt in water to obtain a first solution, wherein the concentration of the calcium salt is 1 to 100 g / L, and the concentration of the magnesium salt is 0.4 to 40 g / L. Furthermore, the molar ratio of calcium ions to magnesium ions is 6 to 10; the concentration of the calcium salt is more preferably 30 to 100 g / L, further 50 to 100 g / L, further 60 to 90 g / L, and particularly 80 to 90 g / L; for example, 80 g / L, 82 g / L, 84 g / L, 86 g / L, 88 g / L, or 90 g / L. Optionally, the concentration of the magnesium salt is more preferably 0.4-30 g / L, further 5-30 g / L, further 15-30 g / L, particularly 20-30 g / L; for example, 20 g / L, 22 g / L, 24 g / L, 25 g / L, 27 g / L or 29 g / L.

[0076] (2) Dissolve phosphate in water and adjust the pH to 9.5-10.5, or further to 9.8-10.0, using an alkali solution (preferably ammonia or sodium hydroxide) to obtain a second solution, wherein the concentration of phosphate is 1-100 g / L. The concentration of phosphate in the second solution is more preferably 30-100 g / L, or further 50-90 g / L, or further 70-90 g / L, or particularly 80-90 g / L; for example, 81 g / L, 83 g / L, 84 g / L, 85 g / L, 87 g / L, or 88 g / L. More preferably, the pH is adjusted to 9.8-10.2 using ammonia. The inventors have found that the pH value has an important influence on the preparation of porous magnesium-containing tricalcium phosphate powder. According to X-ray diffraction results, a pH value that is too high or too low will produce more impurity phases, resulting in the porous magnesium-containing tricalcium phosphate powder containing more calcium hydrogen phosphate impurity phases or hydroxyapatite.

[0077] (3) Equal volumes of the first solution and the second solution were heated to 60-95°C and then mixed, and a wet chemical reaction was carried out at 60-95°C under stirring conditions at normal pressure, wherein the stirring rate was 100-500 rpm and the molar ratio of calcium ion to phosphate ion was 1.1-1.5.

[0078] (4) The suspension after the wet chemical reaction is centrifuged to obtain a precipitate, which is then washed 4 to 8 times with water. The washed precipitate is added to 5 to 20 times the mass of water and stirred to form a slurry. The slurry is processed into a porous tricalcium phosphate powder using a spray dryer, wherein the inlet air temperature of the spray dryer is 240 to 300 °C, the outlet air temperature is 120 to 150 °C, and the feed rate is 30 to 200 mL / min.

[0079] The calcium salt is selected from a combination of one or more of anhydrous calcium chloride, calcium chloride dihydrate and calcium nitrate tetrahydrate; the magnesium salt is selected from magnesium chloride hexahydrate and / or magnesium nitrate hexahydrate; and the phosphate is selected from a combination of multiple of one of disodium hydrogen phosphate, diammonium hydrogen phosphate and sodium hydrogen phosphate.

[0080] The porous tricalcium phosphate powder has a porous structure, and the specific content of magnesium in it shows excellent biological activity, effectively promoting new bone formation. Compared with hydroxyapatite, the porous tricalcium phosphate powder material has better degradation performance, and therefore has significant advantages in the application of bone repair materials. Tricalcium phosphate materials usually need to be prepared by high-temperature calcination or solid-phase reaction at temperatures above 1000 degrees, which consumes a lot of energy and the product particles are micron-level, with high density and irregular surface. At present, although some manufacturers can stably produce tricalcium phosphate powder raw materials, most of them calcine the raw materials through solid-phase reaction method and crush the powder through mechanical grinding, which is expensive. After sintering, the grains are large and have irregular geometric shapes, and the fluidity is poor during the preparation of liquid-phase composite materials. The tricalcium phosphate powder of this application is prepared based on wet chemical reaction. It directly reacts with wet chemical reaction at 60~95℃ under normal pressure to generate a magnesium-containing tricalcium phosphate suspension, and obtains a low-density porous magnesium-containing tricalcium phosphate powder through a special molding method of spray drying.

[0081] Example 1: Preparation of porous tricalcium phosphate powder material

[0082] Weighing and dissolving: Weigh 900 g of anhydrous calcium chloride and 270 g of magnesium chloride hexahydrate, dissolve in 10 L of water to obtain solution A; weigh 830 g of diammonium hydrogen phosphate, dissolve in 10 L of water, and adjust the pH of the solution to 10.0 with ammonia water to obtain solution B.

[0083] Heat and mix: Heat solution A and solution B to 70°C and mix, stirring continuously at 100 rpm to form a suspension.

[0084] Wet chemical reaction: The mixed suspension was heated and stirred at 70°C and 100 rpm for 12 hours.

[0085] Centrifugal washing: The suspension after the wet chemical reaction was centrifuged at 2000 rpm for 3 minutes to obtain the precipitate, and water was added and centrifuged for washing 5 times.

[0086] Spray Drying: Add the cleaned precipitate to 10 L of water and stir to form a slurry. Set the spray dryer's inlet air temperature to 250°C and the outlet air temperature to 120°C. Spray dry the slurry at a rate of 50 mL / min to obtain a low-density porous tricalcium phosphate powder.

[0087] Test: The XRD results, SEM micromorphology, and EDS spectrum of the prepared porous tricalcium phosphate powder are shown in Figures 1 to 3, respectively. The magnesium content is 1.9%, and the particle size distribution is in the range of ~5~20 μm.

[0088] Example 2: Preparation of artificial bone prosthesis

[0089] Weighing and mixing: 180 g of polycaprolactone and 120 g of the porous tricalcium phosphate powder prepared in Example 1 were weighed and mixed in an internal mixer at 100°C for 1 hour. The resulting mixture was crushed in a pelletizer to form granules with a diameter of less than 5 mm. The mixture was then added to an internal mixer and mixed again at 100°C for 1 hour to obtain a uniformly mixed magnesium-containing tricalcium phosphate polycaprolactone composite material.

[0090] Filament Production: Using a screw extruder with a feed temperature set at 90°C and a process temperature controlled at 100°C, the uniformly mixed magnesium tricalcium phosphate-containing polycaprolactone composite was added to a twin-screw extruder. The extruded filament diameter was set to 2.85 mm and the production speed was set to 1 m / min. This yielded a 3D printing filament containing 40 wt% magnesium tricalcium phosphate.

[0091] 3D printing: The digital model was imported, the printing temperature was set to 180°C, the printing speed was 5 mm / s, the filling rate was 80%, and the wire width was 0.4 mm. A 3D-printed polycaprolactone / tricalcium phosphate artificial bone prosthesis was prepared, as shown in Figure 4.

[0092] [Corrected 15.10.2024 in accordance with Rule 91] Testing: The micromorphology of the 3D-printed polycaprolactone / tricalcium phosphate artificial bone prosthesis is shown in Figure 5. Figures 6(a) and 6(c) show the microscopic observations of MC3T3-E1 bone progenitor cells cultured with the extract of the 3D-printed polycaprolactone / tricalcium phosphate artificial bone prosthesis for one and three days, respectively; Figures 6(b) and 6(d) show the microscopic observations of MC3T3-E1 bone progenitor cells cultured in a blank control group for one and three days, respectively. Both extraction experiments used DMEM as the cell culture medium. Extraction cell experiments demonstrated healthy cell growth, and the resulting artificial bone prosthesis exhibited non-cytotoxicity and good biocompatibility.

[0093] Example 3: Preparation of artificial bone prosthesis

[0094] Weighing and mixing: 240 g of polycaprolactone and 60 g of the magnesium-containing tricalcium phosphate prepared in Example 1 were weighed and mixed in an internal mixer at 100°C for 1 hour. The resulting mixture was crushed in a pelletizer to form granules with a diameter of less than 5 mm. The mixture was then added to an internal mixer and mixed again at 80°C for 1 hour to obtain a uniformly mixed magnesium-containing tricalcium phosphate polycaprolactone composite material.

[0095] Filament production: Using a screw extruder with a feed temperature set at 80°C and a process temperature controlled at 90°C, the uniformly mixed magnesium tricalcium phosphate-containing polycaprolactone composite was added to a twin-screw extruder. The extruded filament diameter was set to 1.75 mm and the production speed was set to 1 m / min to produce 3D printing filament with a magnesium tricalcium phosphate content of 20 wt%.

[0096] 3D printing: A digital model was imported, and the printing temperature was set to 130°C, the printing speed to 20 mm / s, the fill factor to 30%, and the wire width to 0.4 mm. A 3D-printed magnesium-containing tricalcium phosphate polycaprolactone artificial bone was produced. Cell culture experiments with the extract showed good cell growth, demonstrating comparable biocompatibility to the artificial bone prosthesis in Example 2, with no cytotoxicity.

[0097] Example 4: Preparation of artificial bone prosthesis

[0098] Weighing and dissolving: Weigh 200 g of polycaprolactone and dissolve it in 4.0 kg of DMF reagent. Stir with a stirring paddle at 400 rpm for 30 min until the solution is uniform. Weigh 20 g of the porous magnesium-containing tricalcium phosphate powder prepared in Example 1 and dissolve it in 4.0 kg of DMF reagent. Stir with a stirring paddle at 400 rpm for 30 min until the solution is uniform.

[0099] Mixing: Combine the magnesium tricalcium phosphate and polycaprolactone solutions and stir at 400 rpm for 30 minutes until the solution is homogeneous. Pour the mixture into 100 L of pure water, resulting in a white, flocculent precipitate. Filter the mixture using a vacuum filter to obtain the polycaprolactone magnesium tricalcium phosphate composite fiber, which is then oven-dried at 60°C for 12 hours.

[0100] Filament production: Using a screw extruder with a feed temperature set at 90°C and a process temperature controlled at 100°C, the dried magnesium tricalcium phosphate and polycaprolactone composite was added to the screw extruder. The extruded filament diameter was set to 1.75 mm and the production speed was set to 1 m / min to produce filament for 3D printing.

[0101] 3D printing: A digital model was imported, and the printing temperature was set to 150°C, the printing speed to 10 mm / s, the fill factor to 50%, and the wire width to 0.4 mm. A 3D-printed magnesium-containing tricalcium phosphate polycaprolactone artificial bone was produced. Cell culture experiments with the extract showed good cell growth, demonstrating comparable biocompatibility to the artificial bone prosthesis in Example 2, with no cytotoxicity.

[0102] The above-mentioned artificial bone prosthesis based on 3D printing has the following characteristics:

[0103] (1) Connected pore structure

[0104] Hot-melt 3D printing technology is used to manufacture complex interconnected pore structures. The material is flexible and the composite material design overcomes the problems of traditional ceramic materials such as high brittleness and difficulty in processing. Compared with existing bone filling materials, the artificial bone repair material of this application can be individually customized and is easy to cut and process, making it easier for doctors to shape it during surgery. 3D-printed porous artificial bones promote the adhesion of osteoblasts and the deposition of bone tissue, thereby improving bone conductivity and bioactivity. The interconnected pores inside the 3D-printed porous scaffold are conducive to new bone growth, material transport and vascularization.

[0105] (2) Degradation performance

[0106] The degradation products of polycaprolactone are neutral and not likely to induce an inflammatory response. At the same time, when polycaprolactone is directly applied to bone tissue repair, its biological activity is insufficient, and the new bone tissue cannot form a tight bone bond with the polymer scaffold. This application uses tricalcium phosphate material to composite polycaprolactone. Compared with traditional hydroxyapatite materials, tricalcium phosphate (β-TCP) has a similar chemical composition but better degradation performance. It can produce bioactive ions Ca through degradation. 2+ and PO4 3- Ions. After being implanted in the body, tricalcium phosphate ceramics can form a strong chemical bond with bones.

[0107] (3) The internal mixing method has no solvent residue problem

[0108] The porous magnesium-containing tricalcium phosphate powder material of the present application has better fluidity in molten polycaprolactone. The porous magnesium-containing tricalcium phosphate powder material and polycaprolactone are mixed by a banburying mechanical mixing method, which improves the mixing performance. The mixing process can be completed by the banburying mechanical mixing method without the need to add organic solvents, thereby avoiding the cytotoxicity caused by organic reagents.

[0109] (4) Insufficient mechanical strength and biological activity

[0110] By adopting porous magnesium-containing tricalcium phosphate powder material, the mixing performance is improved, and the mixing process can be completed by a mixing mechanical mixing method, which significantly improves the mechanical strength and biological activity of the material.

[0111] In addition, the use of porous magnesium-containing tricalcium phosphate powder material as the main raw material has better biological activity than traditional calcium phosphate materials. The magnesium ions doped in the magnesium-containing tricalcium phosphate material can induce osteoblast differentiation and osteogenic expression after degradation and release in the body.

[0112] As used in this specification and claims, the terms "comprises" and "include" merely indicate the inclusion of the steps and elements specifically identified, and these steps and elements do not constitute an exclusive list; a method or apparatus may also include other steps or elements. The term "and / or" as used herein includes any combination of one or more of the associated listed items.

[0113] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0114] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In the event of any conflict or inconsistency between the definitions used herein and those in other published documents, the definitions used herein shall prevail.

[0115] The above embodiment is intended only to illustrate the technical concepts and features of the present disclosure and is a preferred embodiment. Its purpose is to enable those familiar with the art to understand the contents of the present disclosure and implement them accordingly. It is not intended to limit the scope of protection of the present disclosure. Any equivalent transformations or modifications made based on the principles of the present disclosure are intended to be included in the scope of protection of the present disclosure.

[0116] The above embodiments are only for illustrating the technical concepts and features of the present disclosure, and are intended to enable people familiar with this technology to understand the contents of the present disclosure and implement them, and are not intended to limit the scope of protection of the present disclosure.

Claims

1. A method for preparing an artificial bone prosthesis based on 3D printing, comprising the following steps: (1) Mixing polycaprolactone and porous tricalcium phosphate powder materials uniformly; (2) Making the mixed material into solid printing material; (3) According to a preset model, the solid printing material is melted and printed into an artificial bone repair body by a 3D printer; in, The porous tricalcium phosphate powder material is formed by drying the precipitate after a salt solution mixed reaction, wherein the salt solution includes a calcium salt and a phosphate solution.

2. The preparation method according to claim 1, characterized in that: In step (1), the polycaprolactone and porous tricalcium phosphate powder material are mixed evenly by a mechanical method or a solvent dissolution method.

3. The preparation method according to claim 2, characterized in that: The step (1) specifically comprises: adding polycaprolactone and porous tricalcium phosphate powder materials into an internal mixer and heating and mixing them, the heating temperature is 30-200° C., and the mixing time is 0.5-12 hours; the obtained mixed material is put into a pelletizer and crushed to form a granular material with a diameter of 0.1-10 mm; and then adding the mixed material into the internal mixer and mixing it again, the heating temperature is 50-150° C., and the mixing time is 0.5-12 hours, so as to obtain a uniformly mixed polycaprolactone / porous tricalcium phosphate powder material composite material.

4. The preparation method according to claim 2, characterized in that: Step (1) specifically comprises: dissolving polycaprolactone and porous tricalcium phosphate powder materials respectively using solvents, stirring and mixing them, and then injecting them into pure water; collecting the precipitated precipitate by suction filtration, and drying for 6 to 24 hours to obtain a uniformly mixed polycaprolactone / porous tricalcium phosphate powder material composite fiber; wherein the solvent comprises a combination of one or more selected from N,N-dimethylformamide, chloroform, acetone, toluene and carbon tetrachloride, the mass ratio of the solid material to the solvent is 0.01 to 0.2, the volume ratio of the solvent to pure water after mixing is 0.05 to 0.2, and the drying temperature is 30 to 100°C.

5. The method according to any of the preceding claims, characterized in that The weight average molecular weight of polycaprolactone is 50,000-200,000 Da, and the mass content of porous tricalcium phosphate powder material in the material after mixing in step (1) is less than 50%.

6. The method according to any of the preceding claims, characterized in that In step (2), the solid printing material is a filament, and the filament is made by a screw extruder. The temperature of the screw extruder is set to 60-130° C., and the filament making speed is 0.1-5 m / min.

7. A method according to any preceding claim, characterised in that In step (3), the parameters of the 3D printer are set as follows: printing temperature 120~250°C, printing speed 5~70 mm / s, filling rate 20~100%, and wire diameter 0.1~0.8 mm.

8. A method according to any preceding claim, characterised in that The porous tricalcium phosphate powder material is formed by spray drying the precipitate, and has a particle size of 1-20 μm.

9. The method according to any preceding claim, characterized in that The salt solution also includes magnesium salt, and the porous tricalcium phosphate powder material contains 1-3% by mass of magnesium element.

10. The method according to any preceding claim, characterized in that The porous tricalcium phosphate powder material is prepared by the following steps: A first solution is prepared, wherein the first solution contains calcium ions; a phosphate solution is prepared, and the pH value is adjusted to 9.5-10.5 with an alkali solution to serve as a second solution; The first solution and the second solution are heated and mixed, and reacted at 60-95° C. with stirring; The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed and spray-dried to obtain the porous tricalcium phosphate powder material.

11. The preparation method according to claim 10, characterized in that: The first solution further contains magnesium ions, and the molar ratio of calcium ions to magnesium ions in the first solution is 6-10; after the first solution and the second solution are mixed, the molar ratio of calcium ions to phosphate ions is 1.1-1.5; the calcium salt includes a combination of one or more selected from anhydrous calcium chloride, calcium chloride dihydrate and calcium nitrate tetrahydrate, the magnesium ions come from magnesium chloride hexahydrate and / or magnesium nitrate hexahydrate, the phosphate includes a combination of multiple selected from one of disodium hydrogen phosphate, diammonium hydrogen phosphate and sodium hydrogen phosphate, and the alkali solution is ammonia water or sodium hydroxide.

12. The preparation method according to claim 10 or 11, characterized in that: The washed precipitate is spray dried using a spray dryer, wherein the inlet air temperature of the spray dryer is 240-300°C, the outlet air temperature is 120-150°C, and the feed rate is 30-200 mL / min.

13. A 3D printing filament for an artificial bone repair body, characterized in that: The wire material is made of a uniformly mixed polycaprolactone and a magnesium-containing tricalcium phosphate powder material, the content of magnesium-containing tricalcium phosphate in the wire material is 10-50 wt %, and the magnesium-containing tricalcium phosphate powder material is formed by drying a precipitate after a mixed reaction of multiple salt solutions, and the salt solution includes a calcium salt, a magnesium salt and a phosphate solution.

14. The 3D printing filament according to claim 13, characterized in that: The magnesium-containing tricalcium phosphate powder material is formed by spray-drying the precipitate, and has a particle size of 1-20 μm.

15. The 3D printing filament according to claim 13 or 14, characterized in that: The magnesium-containing tricalcium phosphate powder material contains 1-3% by mass of magnesium element.

16. The 3D printing filament according to any one of claims 13 to 15, characterized in that: The wire diameter of the wire material is 0.1-0.8 mm.

17. The 3D printing filament according to any one of claims 13 to 16, characterized in that: The wire material is made by a screw extruder, the temperature of the screw extruder is set at 60-130° C., and the wire making speed is 0.1-5 m / min.

18. The 3D printing filament according to any one of claims 13 to 17, characterized in that: The polycaprolactone and magnesium-containing tricalcium phosphate powder materials are mixed by the following steps: the polycaprolactone and magnesium-containing tricalcium phosphate powder materials are added to an internal mixer for heating and mixing, the heating temperature is 30-200°C, and the mixing time is 0.5-12 hours; the obtained mixed material is put into a pelletizer for crushing to form a granular material with a diameter of 0.1-10 mm; and then added to the internal mixer for uniform mixing again, the heating temperature is 50-150°C, and the mixing time is 0.5-12 hours, so as to obtain a uniformly mixed polycaprolactone / magnesium-containing tricalcium phosphate powder material composite material.

19. The 3D printing filament according to any one of claims 13 to 18, characterized in that: The weight average molecular weight of polycaprolactone is 50000~200000 Da.

20. The 3D printing filament according to any one of claims 13 to 19, characterized in that: The magnesium-containing tricalcium phosphate powder material is prepared by the following steps: A first solution is prepared, wherein the first solution contains calcium ions and magnesium ions, and the molar ratio of the calcium ions to the magnesium ions is 6 to 10; a phosphate solution is prepared, and the pH value is adjusted to 9.5 to 10.5 with an alkali solution to serve as a second solution; The first solution and the second solution are heated and mixed, the molar ratio of calcium ions to phosphate ions is 1.1-1.5, and reacted at 60-95° C. with stirring; The suspension obtained after the reaction is centrifuged to obtain a precipitate, which is then washed and spray-dried to obtain the magnesium-containing tricalcium phosphate powder material.

21. The 3D printing filament according to claim 20, characterized in that: The calcium salt comprises a combination of one or more selected from anhydrous calcium chloride, calcium chloride dihydrate and calcium nitrate tetrahydrate, the magnesium salt comprises magnesium chloride hexahydrate and / or magnesium nitrate hexahydrate, the phosphate comprises a combination of multiple selected from disodium hydrogen phosphate, diammonium hydrogen phosphate and sodium hydrogen phosphate, and the alkali solution is ammonia water or sodium hydroxide; a spray dryer is used to spray dry the washed precipitate, the inlet air temperature of the spray dryer is 240-300°C, the outlet air temperature is 120-150°C, and the feed rate is 30-200 mL / min.

22. An artificial bone prosthesis based on 3D printing, prepared by the preparation method according to any one of claims 1 to 12, or printed by the 3D printing filament according to any one of claims 13 to 21.

23. The artificial bone prosthesis according to claim 22, characterized in that: The porosity of the artificial bone repair body is 30-70%, the maximum pore size is greater than 300 μm, and the mechanical strength is 2-20 MPa.

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