Porous hydroxyapatite particles, process for their preparation and use thereof
By preparing porous hydroxyapatite particles, the problem of slow degradation rate in existing hydroxyapatite medical aesthetic products has been solved, achieving rapid degradation and collagen regeneration, and reducing the risk of adverse reactions in the later stages of injection.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- CHANGZHOU INST OF MATERIA MEDICA
- Filing Date
- 2024-04-25
- Publication Date
- 2026-07-28
AI Technical Summary
Existing hydroxyapatite cosmetic products have a slow degradation rate, which may lead to adverse reactions such as granulomas and hard nodules in the later stages of injection.
A method for preparing porous hydroxyapatite particles was adopted, which involves cross-linking macromolecular polymers to form a gel, mineralizing and calcining at high temperature to form porous hydroxyapatite particles with a porosity of 30% to 70%.
Rapid degradation of porous hydroxyapatite particles was achieved, reducing the risk of adverse reactions in the later stages of injection and promoting collagen regeneration.
Smart Images
Figure CN118405671B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biomedical materials technology, specifically to a porous hydroxyapatite particle, its preparation method, and its application. Background Technology
[0002] Hydroxyapatite [Ca 10 [(PO4)6(OH)2] is a major component of human and animal bones, belonging to the most stable phase of calcium phosphate. It has a certain solubility in the body, and the calcium ions and phosphate released during degradation can participate in the body's metabolism. For a long time, hydroxyapatite has been widely used in orthopedic filling and repair due to its excellent biocompatibility and osteoconductivity. The product forms include bone powder, bone granules, and metal prosthesis coatings, which can effectively promote bone regeneration at bone defect sites.
[0003] In recent years, hydroxyapatite has not only been widely used in the medical field but has also gradually become a new favorite in cosmetic fillers. In 2003, a hydroxyapatite product for improving skin depressions appeared, in which the hydroxyapatite was in the form of solid microspheres, with a content of approximately 30%. In 2023, an improved hydroxyapatite product still contained solid microspheres, with a content of approximately 55.7%. In addition, many domestic manufacturers are also developing hydroxyapatite-based cosmetic filler products. Existing data indicates that hydroxyapatite is gradually becoming a new generation of regenerative material following dermal fillers and anti-aging injections.
[0004] It is evident that current development of hydroxyapatite mainly focuses on solid microspheres. However, solid hydroxyapatite microspheres have high crystallinity and a long degradation cycle, resulting in prolonged retention in the body. Literature reports that the metabolic time of hydroxyapatite in vivo can be as long as 3-5 years (Calcium hydroxylapatite (Radiesse) for correction of the mid-and lower face: consensus recommendations. Plast Reconstr Surg 120 (6Suppl): 55S-66S). This excessively long degradation time poses a higher risk to patients, such as the potential for adverse reactions like granulomas and hard nodules in the later stages of injection.
[0005] Given this risk, there is an urgent need for a rapidly degradable hydroxyapatite cosmetic filler product to reduce the risk of adverse reactions such as granulomas and hard nodules that may occur after injection. Summary of the Invention
[0006] This invention provides porous hydroxyapatite particles, their preparation method, and applications to solve the problem of slow degradation rate in existing hydroxyapatite medical aesthetic products.
[0007] To solve the above-mentioned technical problems, the present invention provides a method for preparing porous hydroxyapatite particles, comprising the following steps: Step S1, crosslinking a crosslinking agent with a macromolecular polymer to obtain a polymer gel; Step S2, granulating the polymer gel to obtain gel particles; Step S3, soaking the gel particles in a calcium ion solution, thoroughly washing them, then soaking them in a phosphate solution, thoroughly washing them, and repeating the above operation several times to mineralize them, thereby obtaining mineralized gel particles; Step S4, calcining the mineralized gel particles in a muffle furnace at high temperature to obtain porous hydroxyapatite particles.
[0008] Furthermore, the macromolecular polymer includes one or more of chitosan, carboxymethyl chitosan, chitosan hydrochloride, chitosan quaternary ammonium salt, hyaluronic acid or its salts, methylcellulose, carboxymethyl cellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.
[0009] Furthermore, the crosslinking agent includes one or more of glutaraldehyde, formaldehyde, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-hydroxysuccinimide, N-hydroxythiosuccinimide, butanediol glycidyl ether, divinyl sulfone, oxalic acid dihydrazide, and glycidyl methacrylate.
[0010] Furthermore, the molar ratio of reactive groups to crosslinking agents in the macromolecular polymer is 1:0.1 to 1:3; the concentration of the macromolecular polymer is 0.1% to 20%; and the reactive groups include carboxyl, amino, and hydroxyl groups.
[0011] Furthermore, the granulation method for the polymer gel granulation in step S3 includes homogenization granulation and extrusion granulation.
[0012] Furthermore, the particle size of the gel particles is 20–500 μm.
[0013] Furthermore, the calcium ion concentration in the calcium ion solution ranges from 0.01 to 7 mol / L; and the phosphate ion concentration in the phosphate ion solution ranges from 0.01 to 18 mol / L.
[0014] Furthermore, the reaction temperature range for mineralization in step S3 is 10–90°C; the calcination temperature in the muffle furnace in step S4 is 500–1500°C, and the calcination time is 1–24 h.
[0015] In another aspect, the present invention also provides porous hydroxyapatite particles, which are obtained by the preparation method described above, wherein the porosity of the porous hydroxyapatite is 30% to 70% and the particle size of the porous hydroxyapatite is 5 to 500 μm.
[0016] Thirdly, the present invention also provides the application of the porous hydroxyapatite particles as described above in the preparation of drug sustained-release carriers, medical aesthetic fillers or tissue engineering materials.
[0017] The beneficial effects of this invention are that the porous hydroxyapatite particles and their preparation method and application use polymer gel as a template for biomimetic mineralization, avoiding the introduction of oil phase solvents and organic solvents in the traditional emulsification method. At the same time, the pore density can be determined according to the degree of crosslinking of the polymer gel, effectively adapting to the degradation environment to achieve rapid and safe degradation without causing adverse reactions such as granulomas and hard nodules.
[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 The SEM image of the porous hydroxyapatite obtained after 2 hours of crosslinking as described in Example 1 is shown.
[0022] Figure 2 The XRD pattern of the porous hydroxyapatite involved in Example 1 is shown in comparison with that of the standard card.
[0023] Figure 3 The degradation comparison diagram of porous hydroxyapatite and solid hydroxyapatite involved in Example 1 is shown;
[0024] Figure 4 The image shows a comparison of porous hydroxyapatite and HA gel staining involved in Example 1;
[0025] Figure 5 The SEM image of the porous hydroxyapatite obtained after 12 hours of crosslinking as described in Example 4 is shown.
[0026] Figure 6 SEM images of the porous hydroxyapatite obtained by four mineralization processes as described in Example 5 are shown.
[0027] Figure 7 SEM images of porous hydroxyapatite obtained from seven mineralization processes as described in Example 6 are shown. Detailed Implementation
[0028] 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.
[0029] At least one embodiment provides a method for preparing porous hydroxyapatite particles, comprising the following steps: Step S1, crosslinking a crosslinking agent with a macromolecular polymer to obtain a polymer gel; Step S2, granulating the polymer gel to obtain gel particles; Step S3, soaking the gel particles in a calcium ion solution, thoroughly washing them, then soaking them in a phosphate solution, thoroughly washing them, repeating the above operation several times to mineralize them, obtaining mineralized gel particles; Step S4, calcining the mineralized gel particles in a muffle furnace at high temperature to obtain porous hydroxyapatite particles.
[0030] Specifically, the macromolecular polymer includes one or more of chitosan, carboxymethyl chitosan, chitosan hydrochloride, chitosan quaternary ammonium salt, hyaluronic acid or its salt, methylcellulose, carboxymethyl cellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropyl methylcellulose. The polymer template has excellent biocompatibility and will not affect the safety of injection.
[0031] Specifically, the crosslinking agent includes one or more of glutaraldehyde, formaldehyde, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-hydroxysuccinimide, N-hydroxythiosuccinimide, butanediol glycidyl ether, divinyl sulfone, oxalic acid dihydrazide, and glycidyl methacrylate. The pore density and size of the porous hydroxyapatite particles can be autonomously adjusted according to the degree of crosslinking of the polymer gel and the size of the gel particles.
[0032] Specifically, the molar ratio of reactive groups to crosslinking agents in the macromolecular polymer is 1:0.1 to 1:3; the concentration of the macromolecular polymer is 0.1% to 20%; and the reactive groups include carboxyl, amino, and hydroxyl groups.
[0033] Specifically, the granulation method for the polymer gel in step S3 includes homogenization granulation and extrusion granulation.
[0034] Specifically, the particle size of the gel particles is 20–500 μm.
[0035] Specifically, the calcium ion concentration in the calcium ion solution ranges from 0.01 to 7 mol / L; the phosphate ion concentration in the phosphate ion solution ranges from 0.01 to 18 mol / L.
[0036] Specifically, the reaction temperature range for mineralization in step S3 is 10–90°C; the calcination temperature in the muffle furnace in step S4 is 500–1500°C, and the calcination time is 1–24 h.
[0037] In another aspect, the present invention also provides porous hydroxyapatite particles, which are obtained by the preparation method described above, wherein the porosity of the porous hydroxyapatite is 30% to 70% and the particle size of the porous hydroxyapatite is 5 to 500 μm.
[0038] Thirdly, the present invention also provides the application of the porous hydroxyapatite particles as described above in the preparation of drug sustained-release carriers, medical aesthetic fillers or tissue engineering materials.
[0039] Example 1
[0040] Step S1: Add EDC / NHS with a carboxymethyl chitosan amino molar ratio of 1:2 and crosslink with 5% carboxymethyl chitosan concentration for 2 hours to form carboxymethyl chitosan gel.
[0041] Step S2: Granulate the above gel using a sieve to obtain carboxymethyl chitosan gel with a particle size of 50 μm;
[0042] Step S3: The calcium ion solution concentration is 1 mol / L, the soaking temperature is 50℃, and the soaking time is 1 h. After soaking, the gel particles are washed. The phosphate solution concentration is 0.6 mol / L, the soaking temperature is 50℃, and the soaking time is 1 h. The gel particles are washed again. The above operation is repeated 10 times to obtain mineralized gel particles.
[0043] Step S4: High-temperature calcination at 800℃ for 3 hours yields porous hydroxyapatite particles, such as... Figure 1 The resulting porous hydroxyapatite particles have a particle size of approximately 40 μm and a porosity of approximately 50%.
[0044] Specifically, the hydroxyapatite particles obtained above were subjected to X-ray diffraction (XRD) analysis, and the diffraction peaks are as follows: Figure 2 ,Depend on Figure 2 It can be seen that the prepared porous hydroxyapatite particles correspond completely with the characteristic peaks of the hydroxyapatite standard card, and the hydroxyapatite particles prepared by this method have high crystal phase content and good crystallinity.
[0045] Specifically, the same mass of porous hydroxyapatite and solid hydroxyapatite prepared above were weighed out, and the same volume of HCl was added. The reaction times were set to 0, 10, 30, 60, 120, 360, and 420 min, respectively. The difference in degradation residue between the two groups of hydroxyapatite samples was calculated, and the degradation residue rate was calculated according to the following formula:
[0046]
[0047] in,
[0048] P1 is the mass of the sample before the reaction;
[0049] P2 represents the residual mass of the sample after the reaction;
[0050] The porous structure of hydroxyapatite was investigated by acid hydrolysis experiments. In this experiment, the same mass of porous hydroxyapatite from Example 1 and solid hydroxyapatite from the comparative example were weighed and reacted in hydrochloric acid of the same concentration and volume. The mass of the remaining hydroxyapatite was recorded at the same time point. Theoretically, the more porous the hydroxyapatite, the larger its surface area, the larger the area in contact with the acid solution, and the shorter the time required for acid hydrolysis.
[0051] The results are as follows Figure 3 As shown, after 10 minutes of reaction, the amount of porous hydroxyapatite remaining was only 5.23%, while the amount of solid hydroxyapatite remaining was 44.54%. After 30 minutes of reaction, porous hydroxyapatite was completely decomposed, and solid hydroxyapatite was completely decomposed after 420 minutes of reaction.
[0052] The above data shows that the porous hydroxyapatite particles prepared by this method have a significantly faster degradation rate than solid hydroxyapatite under the same conditions. Therefore, it can be deduced that if both types of hydroxyapatite are implanted into skin tissue, the porous hydroxyapatite described in this invention, due to its larger surface area, can come into contact with more cells, and thus its overall degradation cycle will be shorter than that of solid hydroxyapatite.
[0053] Specifically, the porous hydroxyapatite prepared above was blended with sodium hyaluronate gel, with pure sodium hyaluronate gel serving as a control. 100 μL of the mixture was injected subcutaneously into mice, and tissue samples were harvested 3 months later for decalcification and staining. The staining results are as follows: Figure 4 .
[0054] Depend on Figure 4 It can be seen that three months after injection, the porous hydroxyapatite group had obvious collagen fiber encapsulation around the sample, while the HA gel group did not have this phenomenon, indicating that porous hydroxyapatite has the ability to promote collagen regeneration.
[0055] Example 2
[0056] Step S1: Add EDC / NHS with a carboxymethyl chitosan amino molar ratio of 1:0.1 to EDC / NHS, and crosslink with 0.1% carboxymethyl chitosan for 12 hours to form a carboxymethyl chitosan gel.
[0057] Step S2: Granulate the above gel using a sieve to obtain carboxymethyl chitosan gel with a particle size of 20 μm;
[0058] Step S3: The calcium ion solution concentration is 0.01 mol / L, the soaking temperature is 10℃, the soaking time is 1h, and then the gel particles are washed. The phosphate solution concentration is 0.01 mol / L, the soaking temperature is 10℃, the soaking time is 1h, and then the gel particles are washed. Repeat the above operation 10 times to obtain mineralized gel particles.
[0059] Step S4: The high-temperature calcination temperature is 500℃ and the calcination time is 24h to obtain porous hydroxyapatite particles. The obtained porous hydroxyapatite particles have a particle size of about 5μm and a porosity of about 30%.
[0060] Example 3
[0061] Step S1: Add EDC / NHS with a carboxymethyl chitosan amino molar ratio of 1:3 to EDC / NHS, and crosslink with 8% carboxymethyl chitosan concentration for 12 hours to form carboxymethyl chitosan gel.
[0062] Step S2: Granulate the above gel using a sieve to obtain carboxymethyl chitosan gel with a particle size of 500 μm;
[0063] Step S3: The calcium ion solution concentration is 7 mol / L, the soaking temperature is 90℃, the soaking time is 1h, and then the gel particles are washed. The phosphate solution concentration is 18 mol / L, the soaking temperature is 90℃, the soaking time is 1h, and then the gel particles are washed. Repeat the above operation 10 times to obtain mineralized gel particles.
[0064] Step S4: The high-temperature calcination temperature is 1500℃ and the calcination time is 1h to obtain porous hydroxyapatite particles. The obtained porous hydroxyapatite particles have a particle size of about 500μm and a porosity of about 70%.
[0065] Example 4
[0066] Step S1: Add EDC / NHS with a carboxymethyl chitosan amino molar ratio of 1:2 to EDC / NHS, and crosslink with 5% carboxymethyl chitosan concentration for 12 hours to form carboxymethyl chitosan gel.
[0067] Step S2: Granulate the above gel using a sieve to obtain carboxymethyl chitosan gel with a particle size of 50 μm;
[0068] Step S3: The calcium ion solution concentration is 1 mol / L, the soaking temperature is 50℃, the soaking time is 1 h, and then the gel particles are washed. The phosphate solution concentration is 0.6 mol / L, the soaking temperature is 50℃, the soaking time is 1 h, and then the gel particles are washed. Repeat the above operation 10 times to obtain mineralized gel particles.
[0069] Step S4: High-temperature calcination at 800℃ for 3 hours yields porous hydroxyapatite particles, such as... Figure 5 The resulting porous hydroxyapatite particles have a particle size of approximately 50 μm and a porosity of approximately 30%.
[0070] Example 5
[0071] Step S1: Add EDC / NHS with a carboxymethyl chitosan amino molar ratio of 1:2 to EDC / NHS, and crosslink with 5% carboxymethyl chitosan concentration for 12 hours to form carboxymethyl chitosan gel.
[0072] Step S2: Granulate the above gel using a sieve to obtain carboxymethyl chitosan gel with a particle size of 50 μm;
[0073] Step S3: The calcium ion solution concentration is 1 mol / L, the soaking temperature is 50℃, the soaking time is 1 h, and then the gel particles are washed. The phosphate solution concentration is 0.6 mol / L, the soaking temperature is 50℃, the soaking time is 1 h, and then the gel particles are washed. Repeat the above operation 4 times to obtain mineralized gel particles.
[0074] Step S4: High-temperature calcination at 800℃ for 3 hours yields porous hydroxyapatite particles, such as... Figure 6 The resulting porous hydroxyapatite particles have a particle size of approximately 10 μm and a porosity of approximately 40%.
[0075] Example 6
[0076] Step S1: Add EDC / NHS with a carboxymethyl chitosan amino molar ratio of 1:2 to EDC / NHS, and crosslink with 5% carboxymethyl chitosan concentration for 12 hours to form carboxymethyl chitosan gel.
[0077] Step S2: Granulate the above gel using a sieve to obtain carboxymethyl chitosan gel with a particle size of 50 μm;
[0078] Step S3: The calcium ion solution concentration is 1 mol / L, the soaking temperature is 50℃, the soaking time is 1 h, and then the gel particles are washed. The phosphate solution concentration is 0.6 mol / L, the soaking temperature is 50℃, the soaking time is 1 h, and then the gel particles are washed. Repeat the above operation 7 times to obtain mineralized gel particles.
[0079] Step S4: High-temperature calcination at 800℃ for 3 hours yields porous hydroxyapatite particles, such as... Figure 7 The resulting porous hydroxyapatite particles have a particle size of approximately 20 μm and a porosity of approximately 45%.
[0080] Example 7
[0081] Step S1: Add glutaraldehyde at a carboxymethyl chitosan amino molar ratio of 1:2 and crosslink with 5% carboxymethyl chitosan concentration for 12 hours to form carboxymethyl chitosan gel.
[0082] Step S2: Granulate the above gel using a sieve to obtain carboxymethyl chitosan gel with a particle size of 50 μm;
[0083] Step S3: The calcium ion solution concentration is 1 mol / L, the soaking temperature is 30℃, and the soaking time is 1 h. Then the gel particles are washed. The phosphate solution concentration is 0.6 mol / L, the soaking temperature is 30℃, and the soaking time is 1 h. Then the gel particles are washed. Repeat the above operation 7 times to obtain mineralized gel particles.
[0084] Step S4: The high-temperature calcination temperature is 800℃ and the calcination time is 3h to obtain porous hydroxyapatite particles. The obtained porous hydroxyapatite particles have a particle size of about 15μm and a porosity of about 30%.
[0085] Example 8
[0086] Step S1: Add butylene glycol glycidyl ether at a 1:1 molar ratio of sodium hyaluronate hydroxyl group to butylene glycol glycidyl ether, and crosslink with 20% sodium hyaluronate concentration for 2 hours to form sodium hyaluronate gel.
[0087] Step S2: Granulate the above gel using a sieve to obtain sodium hyaluronate gel with a particle size of 50 μm;
[0088] Step S3: The calcium ion solution concentration is 1 mol / L, the soaking temperature is 80℃, the soaking time is 1 h, and then the gel particles are washed. The phosphate solution concentration is 0.6 mol / L, the soaking temperature is 80℃, the soaking time is 1 h, and then the gel particles are washed. Repeat the above operation 7 times to obtain mineralized gel particles.
[0089] Step S4: The high-temperature calcination temperature is 700℃ and the calcination time is 15h to obtain porous hydroxyapatite particles. The obtained porous hydroxyapatite particles have a particle size of about 25μm and a porosity of about 60%.
[0090] Example 9
[0091] Step S1: Add EDC / NHS with a chitosan amino molar ratio of 1:2 and crosslink with 5% chitosan concentration for 12 hours to form chitosan gel.
[0092] Step S2: Granulate the above gel using a sieve to obtain chitosan gel with a particle size of 50 μm;
[0093] Step S3: The calcium ion solution concentration is 1 mol / L, the soaking temperature is 50℃, the soaking time is 1 h, and then the gel particles are washed. The phosphate solution concentration is 0.6 mol / L, the soaking temperature is 50℃, the soaking time is 1 h, and then the gel particles are washed. Repeat the above operation 7 times to obtain mineralized gel particles.
[0094] Step S4: The high-temperature calcination temperature is 1000℃ and the calcination time is 8h to obtain porous hydroxyapatite particles. The obtained porous hydroxyapatite particles have a particle size of about 20μm and a porosity of about 40%.
[0095] In summary, the porous hydroxyapatite particles, their preparation method, and their application of the present invention utilize polymer gel as a template for biomimetic mineralization, avoiding the introduction of oil-phase solvents and organic solvents in traditional emulsification methods. Furthermore, the pore density can be determined based on the degree of crosslinking of the polymer gel, effectively adapting to the degradation environment to achieve rapid and safe degradation without inducing adverse reactions such as granulomas or hard nodules.
[0096] 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 porous hydroxyapatite particles, characterized in that, Includes the following steps: Step S1: Crosslink the crosslinking agent with the macromolecular polymer to obtain a polymer gel; Step S2: Granulate the polymer gel to obtain gel particles; Step S3: Soak the gel particles in a calcium ion solution, wash them thoroughly, soak them in a phosphate solution, wash them thoroughly, and repeat the above operation several times to mineralize them and obtain mineralized gel particles. Step S4: The mineralized gel particles are placed in a muffle furnace and calcined at high temperature to obtain porous hydroxyapatite particles. The porosity of the porous hydroxyapatite is 30%–70%; The porous hydroxyapatite has a particle size of 5–500 μm; The macromolecular polymer includes one or more of chitosan, carboxymethyl chitosan, chitosan hydrochloride, chitosan quaternary ammonium salt, hyaluronic acid or its salts, methylcellulose, carboxymethyl cellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; The crosslinking agent includes one or more of glutaraldehyde, formaldehyde, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N-hydroxysuccinimide, N-hydroxythiosuccinimide, butylene glycol glycidyl ether, divinyl sulfone, oxalic acid dihydrazide, and glycidyl methacrylate.
2. The preparation method according to claim 1, characterized in that, The molar ratio of reactive groups to crosslinking agents in the macromolecular polymer is 1:0.1 to 1:3; The concentration of the macromolecular polymer is 0.1% to 20%; The reactive groups include carboxyl, amino, and hydroxyl groups.
3. The preparation method according to claim 1, characterized in that, The granulation method for granulating the polymer gel in step S2 includes homogenization granulation and extrusion granulation.
4. The preparation method according to claim 1, characterized in that, The particle size of the gel particles is 20–500 μm.
5. The preparation method according to claim 1, characterized in that, The calcium ion concentration range in the calcium ion solution is 0.01–7 mol / L; The phosphate concentration in the phosphate solution ranges from 0.01 to 18 mol / L.
6. The preparation method according to claim 1, characterized in that, The reaction temperature range for mineralization in step S3 is 10–90°C. In step S4, the calcination temperature in the muffle furnace is 500–1500℃, and the calcination time is 1–24h.
7. A porous hydroxyapatite particle, obtained by the preparation method according to any one of claims 1-6, characterized in that, The porosity of the porous hydroxyapatite is 30%–70%; The porous hydroxyapatite has a particle size of 5–500 μm.
8. The use of porous hydroxyapatite particles as described in claim 7 in the preparation of drug sustained-release carriers, medical aesthetic fillers, or tissue engineering materials.