High-crystallinity spherical beta-tricalcium phosphate material, and preparation method and application thereof

Abstract

This invention belongs to the field of biomedical materials technology, specifically relating to a highly crystalline spherical β-tricalcium phosphate material, its preparation method, and its application. The method includes the following steps: S1, weighing a calcium source compound and a phosphorus source compound into purified water, adding a slow-release alkali source and an ion chelating agent to obtain a mixed solution; S2, adjusting the pH of the mixed solution to 1.0–3.0, stirring until the solution is clear and transparent to obtain a transparent liquid; S3, transferring the transparent liquid to a reaction vessel and carrying out a hydrothermal reaction at 120–200°C, washing and filtering after the reaction to obtain microspheres; S4, drying the microspheres, calcining them at 800–1100°C, and cooling them in the furnace to obtain the highly crystalline spherical β-tricalcium phosphate material.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a highly crystalline spherical β-tricalcium phosphate material, its preparation method, and its application. Background Technology

[0002] β-Tricalcium phosphate (chemical formula β-Ca3(PO4)2, abbreviated as β-TCP) is a low-temperature stable crystalline form of tricalcium phosphate. Its chemical composition and crystal structure are similar to natural bone minerals, exhibiting excellent biocompatibility and bioactivity. After implantation, it can form direct chemical bonds with host bone tissue, thereby accelerating the bone healing process, and has been widely used in the biomedical field. In contrast, hydroxyapatite (chemical formula Ca...) has a slow degradation rate, significant brittleness, and poor mechanical properties. 10 Compared to (PO4)6(OH)2 (HAp), β-TCP not only has the characteristics of being non-cytotoxic and not causing adverse tissue reactions, but also can promote angiogenesis and new bone formation, showing good osteoconductivity, osteointegration and controllable biodegradability, and is considered to be a more ideal material in the field of bone defect filling and repair.

[0003] Porous microspheres, with their high specific surface area, excellent drug loading capacity, and easily manipulated physical form, have shown great potential in biomedical applications. They not only provide three-dimensional space for cell adhesion and tissue ingrowth but also facilitate nutrient transport and the removal of metabolic waste products.

[0004] However, the preparation of β-TCP microspheres with controllable pore size, high porosity, good mechanical strength and phase purity remains a challenge for current technology.

[0005] It should be noted that the information disclosed in this background section is only for understanding the background technology of the present application concept, and therefore, the above description is not considered to constitute prior art information. Summary of the Invention

[0006] This disclosure provides at least one highly crystalline spherical β-tricalcium phosphate material, its preparation method, and its application.

[0007] In a first aspect, embodiments of this disclosure provide a method for preparing highly crystalline spherical β-tricalcium phosphate material, comprising the following steps: S1, weighing a calcium source compound and a phosphorus source compound into purified water, adding a slow-release alkali source and an ion chelating agent to obtain a mixed solution; S2, adjusting the pH value of the mixed solution to 1.0–3.0, stirring until the solution is clear and transparent to obtain a transparent liquid; S3, transferring the transparent liquid into a reaction vessel and carrying out a hydrothermal reaction at 120–200°C, washing and filtering after the reaction is completed to obtain microspheres; S4, drying the microspheres, calcining them at a high temperature of 800–1100°C, and cooling them in the furnace to obtain highly crystalline spherical β-tricalcium phosphate material.

[0008] In one optional embodiment, the calcium source compound includes any one or more combinations of calcium chloride, calcium nitrate, calcium acetate, calcium carbonate, and calcium hydroxide; the phosphorus source compound includes any one or more combinations of diammonium hydrogen phosphate, ammonium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0009] In one optional embodiment, the slow-release alkaline source includes any one or more combinations of urea, ammonium carbonate, ammonium bicarbonate, and ammonia water; the ion chelating agent includes any one or more combinations of monosodium glutamate, sodium citrate, disodium succinate, L-tartaric acid, glycolic acid, and disodium ethylenediaminetetraacetate.

[0010] In one optional embodiment, the molar concentration of the calcium source compound is 0.015–0.3 mol / L; the molar concentration of the phosphorus source compound is 0.01–0.2 mol / L; the molar ratio of the calcium source compound to the phosphorus source compound is 1.5–2:1; the molar concentration of the slow-release alkali source is 0.2–1.0 mol / L; and the molar concentration of the ion chelating agent is 0.001–0.15 mol / L.

[0011] In one optional embodiment, the pH adjuster in S2 includes any one of hydrochloric acid, sulfuric acid, and nitric acid; the stirring time is 10 to 30 minutes.

[0012] In one optional embodiment, the hydrothermal reaction in S3 lasts for 1 to 4 hours; the washing specifically includes washing multiple times with purified water until the supernatant is neutral; the filtration collection method includes centrifugal filtration or sieve filtration collection.

[0013] In one optional embodiment, the drying in S4 specifically includes drying treatment at an environment of 60 to 100°C; the heating rate of the calcination is 0.5 to 10°C / min, and the calcination time is 2 to 8 hours.

[0014] Secondly, this disclosure also provides a highly crystalline spherical β-tricalcium phosphate material, prepared by the method described above, wherein the morphology of the highly crystalline spherical β-tricalcium phosphate material is a three-dimensional interconnected porous structure or a smooth solid structure.

[0015] In one optional embodiment, the particle size range of the highly crystalline spherical β-tricalcium phosphate material is 5–40 μm.

[0016] Thirdly, embodiments of this disclosure also provide an application of the highly crystalline spherical β-tricalcium phosphate material as described above in the fields of drug sustained release, bone tissue repair, and regenerative filler materials.

[0017] The beneficial effects of this invention are that the highly crystalline spherical β-tricalcium phosphate material, its preparation method, and its application utilize a hydrothermal template method to synthesize a hydroxyapatite (CDHA) microsphere precursor with ideal morphology and calcium deficiency characteristics. Then, through a precisely controlled calcination process, the CDHA precursor undergoes a phase transition, transforming into pure-phase β-TCP microspheres with a porous structure. The hierarchical porous structure imparted by the template can be retained by adjusting the calcination regime. This preparation method effectively combines the advantages of controllable morphology of the hydrothermal method and the good crystallinity and easy pore formation of the calcination method. It is expected to prepare porous β-TCP microspheres with good bioactivity, degradability, and suitable porosity and pore size to meet the needs of soft and hard tissue defect repair materials and drug carrier applications.

[0018] Other features and advantages of the invention will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the invention. The objects and other advantages of the invention are realized and obtained through the structures particularly pointed out in the description and the drawings.

[0019] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, preferred embodiments are described below in detail with reference to the accompanying drawings. Attached Figure Description

[0020] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0021] Figure 1 Fourier transform infrared spectrum of β-TCP material prepared in Example 1 provided for embodiments of this disclosure; Figure 2Optical micrograph and X-ray diffraction pattern of β-TCP material prepared in Example 1 provided for the embodiments of this disclosure, with a scale bar of 100 μm; Figure 3 Scanning electron micrograph of β-TCP material prepared in Example 1, which is provided as an embodiment of this disclosure; Figure 4 The calcium, phosphorus, and oxygen elemental distribution diagram of the β-TCP material prepared in Example 1 provided for the present disclosure; Figure 5 Optical micrograph and X-ray diffraction pattern of β-TCP material prepared in Example 2 provided for the present disclosure, scale bar is 100 μm; Figure 6 Scanning electron micrograph of β-TCP material obtained in Example 2, which is provided as an embodiment of this disclosure; Figure 7 The calcium, phosphorus, and oxygen elemental distribution diagram of the β-TCP material prepared in Example 2 provided for the present disclosure; Figure 8 Optical micrograph and X-ray diffraction pattern of β-TCP material prepared in Example 3 provided for the present disclosure, scale bar is 100 μm; Figure 9 Scanning electron microscope image of β-TCP material prepared in Example 3, which is provided as an embodiment of this disclosure; Figure 10 Optical micrograph and X-ray diffraction pattern of β-TCP material prepared in Example 4 provided for the present disclosure, scale bar is 100 μm; Figure 11 Scanning electron microscope image of β-TCP material prepared in Example 4, which is provided as an embodiment of this disclosure; Figure 12 Optical micrographs and X-ray diffraction patterns of β-TCP material prepared in Comparative Example 1 provided for embodiments of this disclosure, with a scale bar of 100 μm; Figure 13 Optical micrographs and X-ray diffraction patterns of β-TCP material prepared in Comparative Example 2 provided for embodiments of this disclosure, scale bar 100 μm; Figure 14 The optical micrograph and X-ray diffraction pattern of the β-TCP material prepared in Comparative Example 3 are provided for the embodiments of this disclosure. The scale bar is 100 μm. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] The terminology used herein is for the purpose of describing specific exemplary configurations only and is not intended to be limiting. As used herein, the singular articles “a,” “an,” and “the” may also be intended to include plural forms unless otherwise clearly stated herein. The terms “comprising,” “including,” and “having” are inclusive and thus specify the presence of features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or combinations thereof. The method steps, processes, and operations described herein should not be construed as requiring them to be performed in the specific order discussed or shown, unless specifically identified as such. Additional or alternative steps may be employed.

[0024] Currently, the preparation technology of porous β-TCP microspheres still faces a number of problems. For example, patent number CN101759169A discloses hollow microspheres of calcium phosphate nanostructures and their preparation method. This patent uses a microwave-hydrothermal method combined with organic template-guided self-assembly technology to prepare lamellar calcium phosphate microspheres with a particle size range of 1-5 μm. However, the product has low crystallinity, the hollow structure is prone to collapse, and the microsphere particle size is relatively small.

[0025] Patent CN101804206A discloses a porous calcium phosphate microsphere with drug controlled release function, its preparation method and its application. It utilizes a specific component glass to form β-TCP microspheres through low-temperature chemical conversion in a phosphate solution. However, the presence of lithium in the raw material system raises regulatory issues, and the microspheres are not highly pure and are doped with a small amount of hydroxyapatite microspheres.

[0026] Patent No. CN105056298A discloses a method for preparing porous calcium phosphate microspheres with large surface pores. The method uses a low-temperature emulsion-liquid nitrogen freezing technology to freeze a bubble-rich slurry to form calcium phosphate microspheres while retaining the large pore structure formed by the bubbles. However, the low-temperature preparation process results in low crystallinity of the calcium phosphate microspheres, and the uneven freezing rate of the droplets can easily lead to cracks inside the microspheres.

[0027] Patent No. CN108178656A discloses a high-porosity porous ceramic microsphere and its preparation method. The porous ceramic microsphere is prepared by mixing ceramic powder, pore-forming agent and wax slurry and then curing and calcining. However, the pore-forming agent used, polystyrene microspheres, may decompose and produce toxic gases such as benzene during high-temperature dewaxing. The use of wax slurry leads to poor stability of the microsphere mass production process, and the prepared α-TCP microspheres degrade too quickly, which can easily lead to insufficient mechanical support.

[0028] Patent No. CN113135769A discloses surface-coated modified porous calcium phosphate ceramic microspheres, their preparation method and application. The method involves uniformly mixing β-calcium phosphate ceramic powder, excipients and pore-forming agents, extruding and spherifying the powder, coating the surface with bioactive powder (magnesium phosphate / calcium silicate), and then calcining at high temperature to prepare porous calcium phosphate ceramic microspheres. However, the safety of the pore-forming agent and the excessively large size of the microspheres (0.5-3 mm) limit their application range.

[0029] The shortcomings of the above solutions are the result of the inventor's practical experience and careful research. Therefore, the discovery process of the above problems and the solutions proposed in this disclosure below should be considered as the inventor's contribution to this disclosure.

[0030] It should be noted that similar labels and letters in the following figures indicate similar items. Therefore, once an item is defined in one figure, it does not need to be further defined and explained in subsequent figures.

[0031] The following detailed description of some embodiments of the present invention is provided in conjunction with the accompanying drawings. Unless otherwise specified, the following embodiments and features can be combined with each other.

[0032] This disclosure provides a method for preparing highly crystalline spherical β-tricalcium phosphate material, comprising the following steps: S1, weighing calcium source compound and phosphorus source compound into purified water, adding slow-release alkali source and ion chelating agent to obtain a mixed solution; S2, adjusting the pH value of the mixed solution to 1.0-3.0, stirring until the solution is clear and transparent to obtain a transparent liquid; S3, transferring the transparent liquid into a reaction vessel and carrying out a hydrothermal reaction at 120-200℃, washing and filtering after the reaction is completed to obtain microspheres; S4, drying the microspheres, calcining them at 800-1100℃, and cooling them in the furnace to obtain highly crystalline spherical β-tricalcium phosphate material.

[0033] Specifically, compared with the traditional hydrothermal direct reaction of calcium and phosphorus, the introduction of an ion chelating agent to slowly release calcium ions results in more ordered and complete crystal growth, forming a uniform mesoporous microsphere structure. The ion chelating agent maintains a relatively stable calcium ion concentration throughout the reaction process, ensuring that the degree of calcium deficiency (Ca / P ratio) within all microspheres and even in different parts of a single microsphere is highly consistent and precisely close to 1.5, laying the foundation for subsequent conversion to high-purity β-TCP. In addition, the particle size and sphericity of CDHA precursor microspheres can be precisely controlled by hydrothermal parameters (temperature, time, concentration) and the type of calcium ion chelating agent.

[0034] Specifically, through high-temperature calcination, thermodynamically unstable calcium-deficient hydroxyapatite (CDHA) autonomously transforms into β-TCP. During the phase transition, the internal structure further evolves due to dehydration and atomic rearrangement, while the basic spherical morphology of the microspheres is maintained. In the high-temperature calcination process, the organic template agent (ion chelating agent) introduced by the hydrothermal reaction can be completely decomposed, and the generated gaseous products are completely volatilized, resulting in more complete crystal transformation and significantly improved phase purity.

[0035] In some embodiments, specifically, the calcium source compound includes any one or more combinations of calcium chloride, calcium nitrate, calcium acetate, calcium carbonate, and calcium hydroxide; the phosphorus source compound includes any one or more combinations of diammonium hydrogen phosphate, ammonium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0036] In some embodiments, specifically, the slow-release alkaline source includes any one or more combinations of urea, ammonium carbonate, ammonium bicarbonate, and ammonia water; the ion chelating agent includes any one or more combinations of monosodium glutamate, sodium citrate, disodium succinate, L-tartaric acid, glycolic acid, and disodium ethylenediaminetetraacetate.

[0037] In some embodiments, specifically, the molar concentration of the calcium source compound is 0.015–0.3 mol / L; the molar concentration of the phosphorus source compound is 0.01–0.2 mol / L; the molar ratio of the calcium source compound to the phosphorus source compound is 1.5–2:1; the molar concentration of the slow-release alkali source is 0.2–1.0 mol / L; and the molar concentration of the ion chelating agent is 0.001–0.15 mol / L.

[0038] In some embodiments, specifically, the pH adjuster in S2 includes any one of hydrochloric acid, sulfuric acid, and nitric acid; the stirring time is 10 to 30 minutes.

[0039] In some embodiments, specifically, the duration of the hydrothermal reaction in S3 is 1 to 4 hours; the washing specifically includes washing multiple times with purified water until the supernatant is neutral; the filtration collection method includes centrifugal filtration or sieve filtration collection.

[0040] In some embodiments, specifically, the drying in S4 includes drying treatment at an environment of 60 to 100°C; the heating rate of the calcination is 0.5 to 10°C / min, and the calcination time is 2 to 8 hours.

[0041] This disclosure also provides a highly crystalline spherical β-tricalcium phosphate material, prepared by the method described above, wherein the morphology of the highly crystalline spherical β-tricalcium phosphate material is a three-dimensional interconnected porous structure or a smooth solid structure.

[0042] In some embodiments, specifically, the particle size range of the highly crystalline spherical β-tricalcium phosphate material is 5–40 μm.

[0043] This disclosure also provides an application of the highly crystalline spherical β-tricalcium phosphate material as described above in the fields of drug sustained release, bone tissue repair, and regenerative filler materials.

[0044] Example 1: A highly crystalline spherical β-tricalcium phosphate material, comprising the following steps: S1: Weigh 1.264g of calcium chloride and 0.9g of diammonium hydrogen phosphate into 60mL of purified water, and add 3.6g of urea and 0.42g of glycolic acid; S2: Adjust the pH of the system to 2.5 and stir for 30 min until the solution is clear and transparent; S3: Transfer the above solution to a reaction vessel, the hydrothermal reaction temperature is 120℃, the reaction time is 2 h, wash the product five or more times with purified water until the supernatant is neutral, and collect it by filtration through a 1000-mesh sieve. S4: Vacuum drying at 80℃ removes free moisture from the material surface, followed by high-temperature calcination at 1100℃ for 2 hours at a heating rate of 5℃ / min, and then furnace cooling to obtain a highly crystalline β-tricalcium phosphate material.

[0045] The infrared spectrum of the β-TCP material prepared in this embodiment is as follows: Figure 1 As shown in the figure, PO4 can be seen 3- Characteristic vibrational peaks (signature functional groups of calcium phosphate materials): 1012.07 cm -1 The nearby strong peak corresponds to PO4 3- The asymmetric stretching vibration is a typical peak of tricalcium phosphate; 970.96 and 940.72 cm⁻¹. -1 The nearby peak corresponds to PO4 3-Symmetric stretching vibrations, with 563.83 and 494.09 cm⁻¹. -1 The nearby peak corresponds to PO4 3- Bending vibration; in addition, no hydroxyl (OH) - Characteristic peaks (3570, 630 cm⁻¹) -1 ), excludes hydroxyapatite (HAp); no HPO4 2- Characteristic peak (870 cm⁻¹) -1 This can eliminate impurities such as dicalcium phosphate.

[0046] The crystallinity of the β-TCP material prepared in this embodiment is as follows: Figure 2 As shown, the crystallinity calculated using the peak area ratio method in Jade software is 98.46%. XRD results show that the diffraction peaks of Example 1 correspond completely to the characteristic peaks of the β-TCP standard card (JCPDS NO.09-0169), and the characteristic peaks are sharp, narrow at half maximum, and without any impurity peaks, indicating that the sample is a single-phase, highly crystalline β-TCP substance, consistent with the previous infrared conclusions.

[0047] The optical micrographs and scanning electron micrographs of the β-TCP material prepared in this embodiment are as follows: Figure 2 and Figure 3 As shown, a porous tricalcium phosphate microsphere structure was prepared by hydrothermal template method combined with high-temperature calcination. The microspheres had a particle size of approximately 20–40 μm. Figure 5 The three constituent elements calcium, phosphorus, and oxygen are uniformly distributed on the sample surface. The calcium-to-phosphorus ratio, as determined by energy dispersive spectroscopy (EDS), is 1.53, which is close to the theoretical calcium-to-phosphorus ratio of 1.5 for tricalcium phosphate.

[0048] Example 2, a highly crystalline spherical β-tricalcium phosphate material, comprising the following steps: S1: Weigh 1.264g of calcium chloride and 0.9g of diammonium hydrogen phosphate into 60mL of purified water, and add 3.6g of urea, 0.28g of glycolic acid and 0.28g of tartaric acid; S2: Adjust the pH of the system to 3 and stir for 30 min until the solution is clear and transparent; S3: Transfer the above solution to a reaction vessel, and perform a hydrothermal reaction at 120°C for 4 hours. Wash the product five or more times with purified water until the supernatant is neutral, and then filter and collect it through a 1000-mesh sieve. S4: Vacuum drying at 80℃ removes free moisture from the material surface, followed by high-temperature calcination at 1100℃ for 2 hours at a heating rate of 10℃ / min, followed by furnace cooling to obtain a highly crystalline β-tricalcium phosphate material.

[0049] The crystallinity of the β-TCP material prepared in this embodiment is as follows: Figure 5As shown, the crystallinity calculated using the peak area ratio method in Jade software is 95.44%. XRD results show that the diffraction peaks of Example 2 almost completely correspond to the characteristic peaks of the β-TCP standard card (JCPDS NO.09-0169), and the characteristic peaks are sharper, with narrower half-widths and no impurity peaks, indicating that the sample is a single-phase, highly crystalline β-TCP substance.

[0050] The optical micrographs and scanning electron micrographs of the β-TCP material prepared in this embodiment are as follows: Figure 5 and Figure 6 As shown, unlike Example 1, a smooth, solid tricalcium phosphate microsphere structure was prepared. This may be due to the varying adsorption and binding abilities of different ion chelating agents (glycolic acid and tartaric acid) on different crystal planes of calcium-deficient hydroxyapatite (CDHA) during the hydrothermal reaction. The solid microspheres have a particle size of approximately 25–40 μm. Figure 7 The three constituent elements calcium, phosphorus, and oxygen are uniformly distributed on the sample surface. The calcium-to-phosphorus ratio, as determined by energy dispersive spectroscopy (EDS), is 1.41, which is close to the theoretical calcium-to-phosphorus ratio of 1.5 for tricalcium phosphate.

[0051] Example 3, a highly crystalline spherical β-tricalcium phosphate material, comprising the following steps: S1: Weigh 3.3g of calcium chloride and 2.64g of diammonium hydrogen phosphate into 100mL of purified water, and add 1.8g of urea, 1.5g of tartaric acid and 200mg of disodium ethylenediaminetetraacetate; S2: Adjust the pH of the system to 1.0 and stir for 10 min until the solution is clear and transparent; S3: Transfer the above solution to a reaction vessel, perform a hydrothermal reaction at 200℃ for 1 h; wash the product five or more times with purified water until the supernatant is neutral, and collect it by filtration through a 600-mesh sieve. Step S4: Vacuum drying at 80℃ removes free moisture from the material surface. Then, calcination at 1100℃ for 4 hours with a heating rate of 5℃ / min is performed, followed by furnace cooling to obtain a highly crystalline β-tricalcium phosphate material.

[0052] The crystallinity of the β-TCP material prepared in this embodiment is as follows: Figure 8As shown, the crystallinity calculated using the peak area ratio method in Jade software is 95.56%. The position of the main diffraction peak corresponds completely to the standard peak of β-TCP. The diffraction peaks are sharp and have a narrow half-width at half-maximum, indicating a relatively simple phase. However, there are typical strong main peaks of hydroxyapatite in the 31.8° to 32.9° range, which are much lower than the main peak of β-TCP and have a very small peak area ratio. This reflects that the sample prepared in Example 3 is a highly crystalline β-TCP material dominated by β-TCP and doped with a small amount of hydroxyapatite. This is mainly due to the excessively high hydrothermal reaction temperature (200°C), which generates highly regular hexagonal lattice hydroxyapatite (HAp). Since the atoms of the highly crystalline HAp are bound to fixed lattice sites, the calcination energy cannot fully penetrate the interior of the particles, and the final product is a calcium phosphate composite phase.

[0053] The optical micrographs and scanning electron micrographs of the β-TCP material prepared in this embodiment are as follows: Figure 8 and Figure 9 As shown, the microspheres are uniformly distributed in size, with particle sizes generally ranging from 5 to 20 μm. The microspheres are composed of a composite structure of smooth solid microspheres and interconnected porous microspheres.

[0054] Example 4, a highly crystalline spherical β-tricalcium phosphate material, comprising the following steps: S1: Weigh 0.82g of calcium nitrate and 0.64g of potassium phosphate into 300mL of purified water, and add 3.6g of urea and 0.3g of sodium citrate; S2: Adjust the pH of the system to 2.5 and stir for 30 min until the solution is clear and transparent; S3: Transfer the above solution to a reaction vessel, the hydrothermal reaction temperature is 200℃, the reaction time is 1 h, wash the product with purified water five or more times until the supernatant is neutral, centrifuge and filter to collect; S4: Vacuum drying at 100℃ removes free moisture from the material surface, followed by high-temperature calcination at 1100℃ for 8 hours at a heating rate of 10℃ / min, followed by furnace cooling to obtain a highly crystalline β-tricalcium phosphate material.

[0055] The crystallinity of the β-TCP material prepared in this embodiment is as follows: Figure 10 As shown, the crystallinity calculated using the peak area ratio method in Jade software is 98.21%. The XRD results are similar to those of Example 3, showing a highly crystalline β-TCP material dominated by β-TCP characteristic diffraction peaks and with a small amount of HAp doping; optical micrographs and scanning electron micrographs are shown below. Figure 10 and Figure 11 As shown, the microspheres are uniformly distributed in size, with a particle size generally ranging from 5 to 10 μm, and the microspheres are composed of a smooth, solid microsphere structure.

[0056] Comparative Example 1, a highly crystalline spherical β-tricalcium phosphate material, includes the following steps: S1: Weigh 0.58g of calcium chloride and 0.41g of disodium hydrogen phosphate into 120mL of purified water, and add 1.8g of urea and 40mg of disodium ethylenediaminetetraacetate; S2: Adjust the pH of the system to 2.0 and stir for 30 min until the solution is clear and transparent; S3: Transfer the above solution to a reaction vessel, the hydrothermal reaction temperature is 120℃, the reaction time is 2 h, wash the product with purified water five or more times until the supernatant is neutral, centrifuge and filter to collect; S4: Vacuum drying at 60℃ removes free moisture from the material surface, followed by high-temperature calcination at 1100℃ for 8 hours at a heating rate of 2℃ / min, and then furnace cooling to obtain a highly crystalline β-tricalcium phosphate material.

[0057] The crystallinity of the β-TCP material prepared in this embodiment is as follows: Figure 12 As shown, the crystallinity calculated using the peak area ratio method in Jade software is 95.81%. The XRD results are similar to those of Example 1, with sharp β-TCP characteristic peaks, narrow half-maximum widths, and no impurity peaks. The sample prepared in Comparative Example 1 is a single-phase, highly crystalline β-TCP material. However, combined with the optical microscopic images on the left, the β-TCP material prepared in Comparative Example 1 failed to maintain a complete microsphere morphology after high-temperature calcination. Under microscopic observation, it consisted of broken particles. This indicates that the amount of ion chelating agent added was too small. During the hydrothermal reaction, the CDHA crystal nuclei lacked the guiding force for directional assembly and would randomly agglomerate to form a loosely packed "pseudo-spherical" structure (only appearing spherical in appearance, with weak interparticle bonding and disordered pore distribution). It lacked structural stability and could not resist the shrinkage stress during calcination and the impact of gas escape (small molecule gas generated by the decomposition of the template agent), ultimately resulting in structural collapse and breakage into particles.

[0058] Comparative Example 2, a highly crystalline spherical β-tricalcium phosphate material, includes the following steps: S1: Weigh 1.33g of calcium chloride and 0.79g of diammonium hydrogen phosphate into 120mL of purified water, and add 1.8g of urea, 2.03g of sodium glutamate and 160mg of disodium ethylenediaminetetraacetate; S2: Adjust the pH of the system to 2.5 and stir for 30 min until the solution is clear and transparent; S3: Transfer the above solution to a reaction vessel, the hydrothermal reaction temperature is 120℃, the reaction time is 2 h, wash the product with purified water five or more times until the supernatant is neutral, centrifuge and filter to collect; S4: Vacuum drying at 100℃ removes free moisture from the material surface, followed by high-temperature calcination at 800℃ for 8 hours with a heating rate of 0.5℃ / min, followed by furnace cooling to obtain a highly crystalline β-tricalcium phosphate material.

[0059] The crystallinity of the β-TCP material prepared in this embodiment is as follows: Figure 13 As shown, the crystallinity calculated using the peak area ratio method in Jade software is 82.06%. XRD results indicate that this substance is composed of β-TCP (characteristic peaks are sharp, with narrow half-maximum width at half-maximum) and HAp, suggesting that subsequent calcination failed to completely convert the initial CDHA precursor microspheres into β-TCP. The CDHA precursor has a hexagonal crystal system (HAp), while β-TCP has a trigonal crystal system; the difference in their crystal structures is reflected in the PO4 content. 3- Coordination environment, Ca 2+ The crystal form transformation reaction requires high temperature to provide energy and drive the rearrangement to the trigonal coordination state of β-TCP. When the temperature is insufficient (800℃), atomic diffusion is slow, and the β-TCP crystal nuclei are mainly formed locally, which cannot completely replace the original crystal phase of HAp, and finally a composite phase of β-TCP and HAp is formed.

[0060] Comparative Example 3, a highly crystalline spherical β-tricalcium phosphate material, includes the following steps: S1: Weigh 1.0g of calcium carbonate and 1.05g of dipotassium hydrogen phosphate into 60mL of purified water, and add 0.9g of urea, 1.145g of sodium glutamate and 40mg of disodium ethylenediaminetetraacetate; S2: Adjust the pH of the system to 2.5 and stir for 30 min until the solution is clear and transparent; S3: Transfer the above solution to a reaction vessel, the hydrothermal reaction temperature is 180℃, the reaction time is 2 h, wash the product five or more times with purified water until the supernatant is neutral, and filter and collect it through a 1000-mesh sieve. S4: Vacuum drying at 60℃ removes free moisture from the material surface, followed by high-temperature calcination at 1000℃ for 4 hours at a heating rate of 10℃ / min, followed by furnace cooling to obtain a highly crystalline β-tricalcium phosphate material.

[0061] The crystallinity of the β-TCP material prepared in this embodiment is as follows: Figure 14 As shown, the crystallinity calculated using the peak area ratio method in Jade software is 94.75%. The characteristic XRD peak positions are similar to those in Example 3. Due to the excessively high hydrothermal reaction temperature (180°C), the Ca in the reaction system... 2+ PO4 3- OH -The diffusion rate is significantly improved, the crystal nuclei grow rapidly and directionally, are closely coordinated, and the atoms are arranged in an orderly manner to form a highly crystalline HAp with no obvious defects in the overall structure; the thermodynamic energy provided by calcination at 1000℃ is still insufficient to break the coordination bond network of the highly crystalline HAp and cannot fully trigger lattice reconstruction. Therefore, the core characteristic peak structure of HAp is clearly visible in the X-ray diffraction results.

[0062] In summary, this highly crystalline spherical β-tricalcium phosphate material, its preparation method, and its application utilize a hydrothermal template method to synthesize a hydroxyapatite (CDHA) microsphere precursor with ideal morphology and calcium deficiency characteristics. Then, through a precisely controlled calcination process, the CDHA precursor undergoes a phase transition, transforming into pure-phase β-TCP microspheres with a porous structure. The hierarchical porous structure imparted by the template can be preserved by adjusting the calcination regime. This preparation method effectively combines the advantages of controllable morphology of the hydrothermal method and the good crystallinity and easy pore formation of the calcination method. It is expected to produce porous β-TCP microspheres with good bioactivity, degradability, and suitable porosity and pore size to meet the needs of soft and hard tissue defect repair materials and drug carrier applications.

[0063] Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for preparing a highly crystalline spherical β-tricalcium phosphate material, characterized in that, Includes the following steps: S1, Weigh the calcium source compound and phosphorus source compound into purified water, add the slow-release alkali source and ion chelating agent to obtain a mixed solution; S2, adjust the pH of the mixture to 1.0-3.0, stir until the solution is clear and transparent to obtain a transparent liquid; S3, the transparent liquid was transferred to a reaction vessel and subjected to a hydrothermal reaction at 120-200℃. After the reaction was completed, the microspheres were obtained by washing and filtering. S4. After drying the microspheres, they are calcined at a high temperature of 800-1100℃ and cooled in the furnace to obtain highly crystalline spherical β-tricalcium phosphate material.

2. The preparation method according to claim 1, characterized in that, The calcium source compound includes any one or more combinations of calcium chloride, calcium nitrate, calcium acetate, calcium carbonate, and calcium hydroxide; The phosphorus source compound includes any one or more combinations of diammonium hydrogen phosphate, ammonium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate.

3. The preparation method according to claim 1, characterized in that, The slow-release alkaline source includes any one or more combinations of urea, ammonium carbonate, ammonium bicarbonate, and ammonia water; The ion chelating agent includes any one or a combination of monosodium glutamate, sodium citrate, disodium succinate, L-tartaric acid, glycolic acid, and disodium ethylenediaminetetraacetate.

4. The preparation method according to claim 1, characterized in that, The molar concentration of the calcium source compound is 0.015–0.3 mol / L; The molar concentration of the phosphorus source compound is 0.01–0.2 mol / L; The molar ratio of the calcium source compound to the phosphorus source compound is 1.5 to 2:1; The molar concentration of the slow-release alkali source is 0.2–1.0 mol / L; The molar concentration of the ion chelating agent is 0.001–0.15 mol / L.

5. The preparation method according to claim 1, characterized in that, The pH adjuster in S2 includes any one of hydrochloric acid, sulfuric acid, and nitric acid; The stirring time is 10 to 30 minutes.

6. The preparation method according to claim 1, characterized in that, The duration of the hydrothermal reaction in S3 is 1 to 4 hours; The washing process specifically includes washing multiple times with purified water until the supernatant is neutral. The collection methods for the filtration include centrifugal filtration or sieve filtration.

7. The preparation method according to claim 1, characterized in that, The drying process in S4 specifically includes drying treatment at an environment of 60–100°C. The calcination heating rate is 0.5–10 °C / min, and the calcination time is 2–8 h.

8. A highly crystalline spherical β-tricalcium phosphate material, characterized in that, The highly crystalline spherical β-tricalcium phosphate material prepared by the method described in any one of claims 1-7 has a morphology of a three-dimensional interconnected porous structure or a smooth solid structure.

9. The highly crystalline spherical β-tricalcium phosphate material as described in claim 8, characterized in that, The particle size range of the highly crystalline spherical β-tricalcium phosphate material is 5–40 μm.

10. The application of the highly crystalline spherical β-tricalcium phosphate material as described in claim 8 in the fields of drug sustained release, bone tissue repair and regeneration filler materials.

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