CN112174152A - Multi-ion co-doped tetracalcium phosphate powder, and synthesis method and application thereof - Google Patents

Abstract

The invention relates to the field of biomedical materials, and particularly discloses multi-ion co-doped tetracalcium phosphate powder, a synthesis method and application; aiming at solving the problems that the pH value of the traditional tetracalcium phosphate hydrate is more than 12, which is not beneficial to bone cell proliferation, has no multiple biological properties such as bone conduction, bone induction, vascularization promotion and the like, and can not resist and inhibit bacteria in the prior art; the invention adopts an ultrasonic-assisted two-step liquid-phase chemical precipitation method to synthesize a multi-ion co-doped tetracalcium phosphate precursor in situThe composite powder is rapidly and circularly calcined and cooled under the assistance of ultrasonic wave to obtain the multi-ion co-doped tetracalcium phosphate powder, and the composition general formula of the multi-ion co-doped tetracalcium phosphate powder prepared by the method is Ca_{4‑ x} M _x (PO₄) _y‑z2‑(SiO₄) _y (BO₃) _z O, wherein (Ca + M)/(P + Si + B) =2 ± 0.2; according to the invention, the pH of the microenvironment of the tetra-calcium phosphate hydration product can be effectively regulated and controlled by doping boron ions, so that the proliferation of bone cells is facilitated; the obtained product has high phase purity, fine crystal grains, high hydration activity and controllable crystallinity, and is suitable for hard tissue repair.

Description

Multi-ion co-doped tetracalcium phosphate powder, and synthesis method and application thereof

Technical Field

The invention relates to the field of biomedical materials, in particular to multi-ion co-doped tetracalcium phosphate powder, a synthesis method and application.

Background

As is well known, tetracalcium phosphate Ca₄(PO₄)₂O (TTCP) is the main component of Calcium Phosphate Cement (CPC) and has obvious hydration property. The microstructure and chemical composition of the osteoid apatite formed by the hydration of TTCP are similar to the mineral composition of natural bone, and the osteoid apatite can be chemically bonded with the natural bone. Therefore, the CPC produced by using TTCP as a main raw material has good biocompatibility and osteoconductivity, is easy to mold or inject, can be accurately molded and filled or directly injected into a bone defect part in vivo according to the bone defect part, is quickly cured, has high application value for treating osteoporosis, bone joint replacement operation, fracture fixation, surgical plastic cosmetology, oral cavity, jaw and face bone filling repair and local drug release control, and is more and more popular among patients and clinicians.

At present, TTCP is synthesized by adopting a high-temperature solid-phase reaction method. SarginY et al (A New Method for the Solid-State Synthesis of Tetracalcium Phosphonates, a fractional centre: X-Ray Powder Diffraction and IR Studies, Journal of the European Central Society 17(1997)963-₄·2H₂O and CaCO₃Or CaCO₃And NH₄H₂PO₄Directly mixing the materials according to the ratio of Ca/P of 2, performing long-time ball milling and solid-phase reaction at 1500 ℃ for at least 24 hours, taking out the materials for 2-3 times in the reaction process, and performing intermediate reactionCrushing, then putting the mixture back to a high-temperature furnace for reaction, and then quickly cooling to obtain the TTCP. However, the above process not only has complex operation process, high calcination temperature, long calcination time, high energy consumption and unstable quality of coarse-grained products, but also needs rapid cooling to obtain high-purity TTCP, so that the service life of equipment is short, and industrial production cannot be realized. In order to solve the above problems, CN1106765A discloses a method for preparing high-purity tetracalcium phosphate. Firstly, liquid phase reaction is carried out for 20-24 hours, precipitation is carried out to prepare suspension liquid of hydroxyapatite micro-fine grains with low crystallinity, then proper amount of calcium salt and carbonate solution are dripped into the suspension liquid to lead CaCO₃The particles are deposited on the surface of hydroxyapatite to obtain uniform hydroxyapatite-calcium carbonate composition suspension, and then the uniform hydroxyapatite-calcium carbonate composition suspension is washed, dried, heated to 1500 ℃ and calcined for 4-6 hours, and then quenched to obtain high-purity tetracalcium phosphate powder. However, the hydroxyapatite-calcium carbonate composition obtained by the process has long reaction time, still needs high temperature and long time calcination, has coarse product grains, low hydration activity, rapid cooling, low phase purity and difficult satisfaction of CPC production requirements. For this reason, CN103922298A discloses a preparation process of rare earth yttrium ion doped tetracalcium phosphate, which is performed on calcium hydrogen phosphate (CaHPO)₄·2H₂O), calcium carbonate (CaCO)₃) Adding yttrium nitrate into the mixed raw materials, continuously ball-milling for 6 hours in a ball mill by taking water as a medium, drying, keeping the temperature at 1350-1500 ℃ for 1-6 hours, calcining, cooling along with the furnace, and thus obtaining the rare earth yttrium ion doped tetracalcium phosphate. Although the calcining temperature is reduced, the calcining time is shortened and the rapid cooling process is cancelled, the continuous material mixing and ball milling easily causes product pollution and cannot meet the production requirement of the orthopedic implant instrument.

Meanwhile, clinical studies show that the ideal CPC not only has good biocompatibility, injectable shapeability and hydration characteristics, but also needs good bone conduction, osteoinduction and vascularization capabilities, because only vascularization can provide sufficient nutrition for the functional activities of division, proliferation and the like of osteoblasts, and the CPC and natural bone tissues are evolved into a whole to exert a lasting physiological function in vivo. Moreover, the blood vessel growth can provide stable internal environment for cells, is more beneficial to bone cell attachment, promotes the growth and osteogenic differentiation of the induced bone cells, and the differentiation and gene expression of the formed bone cells can promote the growth and the stability of the blood vessel, and the two synergistically promote the generation and the repair of bones.

However, our earlier studies found that pH plays an important role in regulating osteoclast and osteoblast balance. However, the hydration product of conventional tetracalcium phosphate CPC has a pH greater than 12, which is not conducive to bone cell proliferation. So far, the research on the multi-ion co-doped tetracalcium phosphate powder which has the functions of promoting vascularization and the like and the hydration product with a moderate pH value has not been reported. Meanwhile, the prior art can not endow the tetracalcium phosphate powder with the functions of promoting new bone formation, reducing bone resorption, regulating calcium metabolism, reducing osteoclast activity and the like. Therefore, how to simulate the composition configuration of trace elements in natural bone, exert the synergistic biochemical effect of multiple ions in the bone regeneration and repair process, improve the microenvironment around bone filling, synthesize the multi-ion co-doped tetracalcium phosphate powder, enable the CPC and natural bone tissues to have similar biological performances of bone conduction, bone induction, vascularization and the like, and present multiple functions of antibiosis, bacteriostasis and the like, thereby having important clinical application value.

Disclosure of Invention

The invention discloses a multi-ion co-doped tetracalcium phosphate powder, which solves the problem that the pH of a hydration product of traditional tetracalcium phosphate (CPC) is more than 12 and is not beneficial to bone cell proliferation in the prior art.

The technical scheme of the invention is realized as follows: the invention provides a method for synthesizing multi-ion co-doped tetracalcium phosphate powder. The specific description is as follows:

firstly, synthesizing multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder by a liquid-phase chemical precipitation method through two-step reaction under the ultrasonic-assisted condition that the vibration frequency is 20-1000 kHz, wherein the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder is multi-ion co-doped hydroxyapatite and nano calcium carbonate two-phase in-situ composite powder, the multi-ion co-doped hydroxyapatite is located in the middle of composite powder particles, and the nano calcium carbonate powder is uniformly deposited and coated on the surfaces of the multi-ion co-doped hydroxyapatite particles. And then, under the ultrasonic wave auxiliary condition that the vibration frequency is 20-1000 kHz, putting the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder into a crucible, quickly and circularly calcining in a heat treatment furnace, and finally cooling to obtain the multi-ion co-doped tetracalcium phosphate powder.

The specific synthetic chemical reaction process is as follows:

ultrasonic-assisted liquid phase chemical precipitation step 1:

(10-3x)Ca²⁺+(6-3y-3z)PO₄ ^3-+3ySiO₄ ^4-+3zBO₃ ^3-+3xM^2+/3+→Ca _{- x103}M _x3(PO₄) _{y- z6-33}(SiO₄) _y3(BO₃) _z3(OH)₂↓

ultrasonic-assisted liquid phase chemical precipitation step 2:

Ca _{- x103}M _x3(PO₄) _{y- z6-33}(SiO₄) _y3(BO₃) _z3(OH)₂+2Ca²⁺+2CO₃ ^2-→Ca _{- x103}M _x3(PO₄) _{y- z6-33}(SiO₄) _y3(BO₃) _z3(OH)₂+2CaCO₃↓

ultrasonic-assisted rapid cycle calcination:

Ca _{- x103}M _x3(PO₄) _{y- z6-33}(SiO₄) _y3(BO₃) _z3(OH)₂+2CaCO₃→3Ca _x4-M _x (PO₄) _y-z2-(SiO₄) _y (BO₃) _z O

in order to achieve the purpose, the invention adopts the following technical scheme: respectively weighing calcium salt and a proper amount of metal salt containing M, phosphoric acid and/or phosphate, silicic acid and/or silicate, boric acid and/or borate; respectively preparing a multi-ion mixed suspension or solution L1 containing calcium salt and metal salt containing M, and a suspension or solution L2 containing phosphoric acid and/or phosphate, silicic acid and/or silicate and boric acid and/or borate; under the ultrasonic-assisted condition that the vibration frequency is 20-1000 kHz, slowly dropping suspension or solution L2 into suspension or solution L1 at the speed of 1-50 ml/min, controlling the stirring speed to be 10-300 rpm, the reaction temperature to be 40-90 ℃, and the reaction time to be 1-24 hours, finally obtaining multi-ion co-doped hydroxyapatite particle suspension L3 with fine particles and uniform size, wherein M is selected from one or more of alkali metal, alkaline earth metal, transition metal and rare earth metal ions, x is more than 0 and less than or equal to 1.5, y is more than 0 and less than or equal to 1, and z is more than or equal to 0 and less than or equal to 0.5.

Ultrasonic-assisted liquid phase chemical precipitation step 2: according to Ca _x4-M _x (PO₄) _y-z2-(SiO₄) _y (BO₃) _z Weighing appropriate amounts of calcium salt and carbonate according to a total molar ratio (Ca + M)/(P + Si + B) =2 +/-0.2 on the basis of deducting the molar amount of calcium in the multi-ion co-doped hydroxyapatite particles obtained in the step 1 of ultrasonic-assisted liquid-phase chemical precipitation, and respectively preparing into a suspension or a solution; under the ultrasonic-assisted condition with the vibration frequency of 20-1000 kHz, synchronously and respectively dropping prepared calcium salt and carbonate suspension or solution into the multi-ion co-doped hydroxyapatite particle suspension L3 obtained in the step 1 of liquid-phase chemical precipitation at the speed of 1-50 ml/min, controlling the reaction temperature to be 40-90 ℃, the stirring speed to be 10-300 rpm, reacting for 1-10 hours, aging for 5-24 hours, respectively washing for at least 3 times by using deionized water and/or ethanol, performing suction filtration, drying at 80-120 ℃ for 5-24 hours, and finally obtaining the multi-ion co-doped tetracalcium phosphate in-situ precursor powder of the nano calcium carbonate powder in-situ precipitated on the surface of the multi-ion co-doped hydroxyapatite particles.

Ultrasonic-assisted rapid cycle calcination: loading the multi-ion co-doped tetracalcium phosphate in-situ composite precursor powder obtained in the step 2 of ultrasonic-assisted liquid-phase chemical precipitation into a crucible, and vibrating at a vibration frequencyUnder the ultrasonic-assisted condition of 20-1000 kHz, rapidly heating to 1000-1400 ℃ at a speed of 20-1000 ℃/min, then cooling to 850-1250 ℃, rapidly heating to 1000-1400 ℃ at a speed of 20-1000 ℃/min, rapidly and circularly calcining for 1-8 times in sequence, wherein the cumulative time of a high-temperature section and a low-temperature section of the circular calcination is 0.1-10 hours respectively, and cooling to obtain multi-ion co-doped tetracalcium phosphate powder after the calcination is finished; the composition general formula of the multi-ion co-doped tetracalcium phosphate powder is Ca _x4-M _x (PO₄) _y-z2-(SiO₄)_y(BO₃)_zO。

Further, the M-doped alkali metal ions are sodium ions and potassium ions; the M-doped alkaline earth metal ions are magnesium ions, calcium ions, strontium ions and barium ions; the M-doped transition group metal ions are aluminum, zinc, manganese, cobalt, iron, copper and silver ions; the M-doped rare earth metal ions are europium, samarium, terbium, cerium, lanthanum and neodymium ions.

Further, the molar concentration of the multi-ion mixed suspension or solution L1 containing calcium salt and doped metal salt in the step 1 of ultrasonic-assisted liquid-phase chemical precipitation is 0.5-1M; the molar concentration of a suspension or solution L2 of phosphoric acid and/or phosphate, silicic acid and/or silicate, boric acid and/or borate in the step 1 of ultrasonic-assisted liquid-phase chemical precipitation is 0.5-1M; and the molar concentrations of the calcium salt and carbonate suspension or solution in the step 2 of ultrasonic-assisted liquid phase chemical precipitation are respectively 0.5-1M.

Further, the pH of the multi-ion mixed suspension or solution L1 containing calcium salt and M metal salt in the step S1 is 7-13.

Further, the calcium salt is one or more of calcium nitrate, calcium nitrite, calcium bicarbonate, calcium dihydrogen phosphate, calcium chloride, calcium chlorate, calcium perchlorate, calcium acetate, calcium citrate, calcium lactate and calcium glucose; the metal salt is one or more of nitrate, bicarbonate, chloride, chlorate, perchlorate, acetate, citrate, lactate and glucose salt; the phosphoric acid is one or more of orthophosphoric acid, metaphosphoric acid, pyrophosphoric acid, triphosphoric acid and polyphosphoric acid; the phosphate is one or more of potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, diammonium hydrogen phosphate and ammonium dihydrogen phosphate; the silicic acid or silicate is one or more of orthosilicic acid, metasilicic acid, disilicic acid, tetraethoxysilane, potassium silicate, sodium silicate and potassium sodium silicate; the boric acid or borate is one or more of orthoboric acid, sodium tetraborate, sodium borohydride, ammonium hydrogen borate and potassium borohydride; the carbonate is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate and ammonium bicarbonate.

Further, the multi-ion co-doped tetracalcium phosphate in-situ composite precursor powder can be cooled along with a furnace after being subjected to rapid circulating calcination or taken out from a heat treatment furnace for air cooling or quenched into a container filled with dry ice and liquid nitrogen auxiliary cooling medium in advance to realize rapid cooling, and finally the multi-ion co-doped tetracalcium phosphate powder with the grain size of 0.01-50 mu m, the phase purity higher than 98 percent, the crystallinity higher than 50 percent and good hydration activity is obtained.

Further, the high-temperature calcination can be heated by a traditional resistance furnace or microwave radiation, the microwave frequency is 0.915-2.45 GHz +/-25 MHz or the high-temperature calcination is heated by infrared radiation, and the infrared wavelength is 0.8-3.5 mu m.

Further, the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder is a composite powder formed by coating multi-ion co-doped hydroxyapatite particles through in-situ precipitation of nano calcium carbonate powder.

Furthermore, the multi-ion co-doped hydroxyapatite phase in the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder is positioned in the middle of composite powder particles, and the nano calcium carbonate powder is precipitated in situ on the surfaces of the multi-ion co-doped hydroxyapatite particles.

The invention also discloses multi-ion co-doped tetracalcium phosphate powder prepared by adopting the synthesis method, and the composition general formula of the multi-ion co-doped tetracalcium phosphate powder is Ca _x4-M _x (PO₄) _y-z2-(SiO₄) _y (BO₃) _z O, said M is selected from the group consisting of alkali metals, alkaline earth metals, transition group metals and rare earth metalsOne or more ions, wherein the cation molar ratio of the polyion co-doped tetracalcium phosphate powder is (Ca + M)/(P + Si + B) =2 ± 0.2.

In another aspect, the invention also provides an application of the multi-ion co-doped tetracalcium phosphate powder, wherein the pH of a microenvironment of the multi-ion co-doped tetracalcium phosphate hydration product is less than 12, and the multi-ion co-doped tetracalcium phosphate hydration product can be used for producing bone cement for repairing teeth, jaws, spines, joints and other hard tissues or dental root canal filling paste.

Compared with the prior art, the technical scheme of the invention has the advantages that:

(1) boron ion doping can effectively regulate and control the pH of the microenvironment of the tetra-calcium phosphate hydration product, so that the pH is less than 12, and the proliferation of bone cells is facilitated;

(2) the composite powder of the nano calcium carbonate powder in-situ precipitation and coating of the multi-ion co-doped hydroxyapatite particles is synthesized by two-step reaction of an ultrasonic-assisted liquid phase chemical precipitation method, the nucleation induction period of a product can be shortened in the chemical precipitation process, the size of crystal grains is reduced, the contact area of the multi-ion co-doped hydroxyapatite and the nano calcium carbonate is increased, the reaction activity is obviously increased, the solid phase reaction temperature of the multi-ion co-doped tetracalcium phosphate powder is reduced, the reaction time is shortened, and the production efficiency and the phase purity are improved.

(3) Under the auxiliary action of ultrasonic wave, the composite powder of the nano calcium carbonate powder in-situ precipitation and wrapping multi-ion co-doped hydroxyapatite particles is rapidly and circularly calcined, so that the method has the advantages of reducing reaction temperature, shortening reaction time, avoiding inconvenience caused by rapid cooling and the like, and the obtained multi-ion co-doped tetracalcium phosphate powder is small in grain size, high in phase purity, controllable in crystallinity, good in hydration activity and particularly suitable for CPC production and application.

(4) Based on the content of trace elements in a healthy bone specimen, multi-ion co-doping is carried out through simulation, so that the multi-ion co-doped tetracalcium phosphate powder has better biocompatibility and bioactivity, and has multiple biological functions of good bone cell conduction, vascularization promotion, osteogenesis performance and the like; the doping of rare earth ions can enable the tetracalcium phosphate to have the function of a fluorescent probe for tracing the phase change or hydration process; the addition of silver, zinc and copper ions can also obtain stronger antibacterial and bacteriostatic functions.

Drawings

FIG. 1 is a flow chart of a process for synthesizing multi-ion co-doped tetracalcium phosphate powder

FIG. 2 is a curve of an ultrasonic-assisted rapid cycle calcination process of multi-ion co-doped tetracalcium phosphate powder

FIG. 3 is a typical XRD spectrum of the in-situ composite powder of the multi-ion co-doped tetracalcium phosphate precursor prepared in example 1

FIG. 4 is a typical microscopic morphology photograph of the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder prepared in example 1

FIG. 5 is a typical microscopic morphology photograph of the nano calcium carbonate particles on the surface of the multi-ion co-doped hydroxyapatite particles in the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder prepared in example 1

FIG. 6 is a typical XRD spectrum of the multi-ion co-doped tetracalcium phosphate powder prepared in example 1

FIG. 7 is a typical microscopic morphology photograph of the multi-ion co-doped tetracalcium phosphate powder prepared in example 1

FIG. 8 is a typical XRD spectrum of the multi-ion co-doped tetracalcium phosphate powder hydration product prepared in example 1

FIG. 9 is a typical CIE chromaticity coordinate and fluorescence change photo of the product of the multi-ion co-doped tetracalcium phosphate powder prepared in example 1 after hydration for different times under 365nm excitation

FIG. 10 shows the pH value of 1wt% solution prepared from examples 9, 11 and 12 with different contents of boron ions and multi-ion co-doped tetracalcium phosphate and deionized water

Fig. 11 is a histological photograph obtained after filling a new zealand white rabbit bone defect with a mixture of bone morphogenetic protein and bone cement prepared from the multi-ion co-doped tetracalcium phosphate obtained in example 12 for 3 weeks.

Detailed Description

The present invention is described below by way of the following embodiments, which are to be understood as merely illustrative, and not restrictive.

The invention provides a multi-ion co-doped tetracalcium phosphate powder, which has a composition general formula of Ca _x4-M _x (PO₄) _y-z2-(SiO₄) _y (BO₃) _z O, wherein (Ca + M)/(P + Si + B) =2 ± 0.2.

M is selected from one or more of alkali metal, alkaline earth metal, transition metal and rare earth metal ions, and is doped by a suspension or solution of a metal salt, wherein 0 <x≤1.5；SiO₄ ^4-And/or BO₃ ^3-Partial replacement of PO by suspensions or solutions of silicic acid and/or silicates and/or boric acid and/or borates and/or phosphoric acid and/or phosphates₄ ^3-Wherein y is more than 0 and less than or equal to 1, and z is more than or equal to 0 and less than or equal to 0.5.

The alkali metal ions are sodium ions and potassium ions; the alkaline earth metal ions are magnesium, calcium, strontium and barium ions; the transition metal ions are aluminum, zinc, manganese, cobalt, iron, copper and silver ions; the rare earth metal ions are europium, samarium, terbium, cerium, lanthanum and neodymium ions.

In order to obtain the multi-ion co-doped tetracalcium phosphate powder with fine crystal grains, high phase purity and high hydration activity, the invention also provides a method for synthesizing the multi-ion co-doped tetracalcium phosphate powder.

FIG. 1 is a flow chart of a process for synthesizing multi-ion co-doped tetracalcium phosphate powder. The figure shows that under the auxiliary condition of ultrasonic wave, the composite powder of nano calcium carbonate powder in-situ precipitation coated with multi-ion co-doped hydroxyapatite particles is synthesized through two-step reaction by a liquid-phase chemical precipitation method; and then, under the auxiliary action of ultrasonic waves, carrying out rapid circulating calcination on the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder to obtain the multi-ion co-doped tetracalcium phosphate powder which has multiple biological functions of good osteocyte conduction, vascularization promotion, osteogenesis performance and the like and has strong antibacterial and bacteriostatic functions, and can meet the production requirement of CPC.

Fig. 2 is a curve of an ultrasonic-assisted rapid cycle calcination process of multi-ion co-doped tetracalcium phosphate powder. The figure shows that the multi-ion co-doped tetracalcium phosphate in-situ composite precursor powder is rapidly heated to a high temperature section (1000-1400 ℃) under the ultrasonic-assisted condition, then cooled to a low temperature section (850-1250 ℃), rapidly heated to the high temperature section, sequentially and rapidly and circularly calcined for 1-8 times, the cumulative time of the high temperature section and the low temperature section of circular calcination is 0.1-10 hours respectively, the heating rate is 20-1000 ℃/min, and finally, after calcination is completed, cooling is performed to obtain the multi-ion co-doped tetracalcium phosphate powder with the grain size of 0.01-50 mu m, the phase purity of more than 98%, the crystallinity of more than 50% and good hydration activity.

The present invention will be described in detail by way of examples. It is also to be understood that the following examples are illustrative of the present invention and are not to be construed as limiting the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art may be made in light of the above teachings. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.

Example 1Ca_3.2Sr_0.5Mg_0.2Zn_0.1(PO₄)_1.9(SiO₄)_0.1O powder

Weighing 5.631gCa (OH)₂、2.214gSrCO₃、0.890gMg(NO₃)₂And 0.892gZn (NO)₃)₂·6H₂Dissolving O in 100ml deionized water to obtain a multi-ion mixed solution L1, adding 30ml of concentrated ammonia water, controlling the pH value at about 8, and stirring in water bath at 40 ℃ for 30 min; take 5.586gH₃PO₄And 0.552gNa₄SiO₄Dissolving in 50ml deionized water to prepare a phosphorus-containing silicate mixed solution L2; dripping the L2 solution into the L1 solution at the speed of 2.5ml/min under the ultrasonic wave auxiliary condition of 25kHz and 500W, and mixing and stirring for 2 hours to obtain the multi-ion co-doped hydroxyapatite Ca_7.6Sr_1.5Mg_0.6Zn_0.3(PO₄)_5.7(SiO₄)_0.3(OH)₂Suspension L3. Then 4.723 were weighed separatelygCa(NO₃)₂

·4H₂O and 2.12gNa₂CO₃Adding 20ml of deionized water into each of the two solutions to prepare solutions, respectively adding a calcium nitrate solution and a sodium carbonate solution into the suspension L3 at the speed of 2.5ml/min under the ultrasonic wave auxiliary condition of 25kHz and 500W, and continuously mixing and stirring for 3 hours to obtain a white suspension of the composite powder containing the nano calcium carbonate powder in-situ precipitation and coating the multi-ion co-doped hydroxyapatite particles. And carrying out suction filtration on the white suspension, repeatedly washing the white suspension with deionized water and ethanol for 3-4 times, and removing various impurity ions to obtain the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder. Drying the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in an oven at 120 ℃ for 5 hours, and analyzing a microstructure. Fig. 3 shows typical XRD spectra of the in-situ composite powder of various ion co-doped tetracalcium phosphate precursors. Comparing the XRD spectrum of the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder with the hydroxyapatite standard spectrum (PDF # 09-0432) and the nano calcium carbonate powder standard spectrum (PDF # 76-0606), the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder contains two phases of hydroxyapatite and nano calcium carbonate, and has no other impurity phase. As can be seen from the typical microscopic morphology photograph of the multiple-ion co-doped tetracalcium phosphate precursor in-situ composite powder shown in fig. 4, the obtained composite powder is obtained by in-situ precipitation of nano calcium carbonate particles and wrapping the multiple-ion co-doped hydroxyapatite particles. Fig. 5 is a typical microscopic morphology high-magnification photograph of the surface of the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder, and it can be further seen that a large number of calcium carbonate particles with particle sizes smaller than 100 nm are in-situ deposited and wrapped on the surface of the multi-ion co-doped hydroxyapatite particles.

And then, under the ultrasonic wave auxiliary condition of 45kHz and 1500W, placing the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in a corundum crucible, quickly calcining for 0.5 hour in a microwave oven with 2.45GHz +/-25 MHz and 5kW at a high temperature section of 1400 ℃, then quickly cooling to 1000 ℃ and calcining for 0.5 hour at a low temperature section, repeatedly and circularly calcining for 3 times, and keeping the temperature rise speed at 120 ℃/min. Finally, the calcined product is taken out and then air-cooled to obtain 11.67g Ca with a phase purity higher than 98.5% and a grain size smaller than 5 μm_3.2Sr_0.5Mg_0.2Zn_0.1(PO₄)_1.9(SiO₄)_0.1And (3) O powder. Referring to FIG. 6, FIG. 6 is Ca_3.2Sr_0.5Mg_0.2Zn_0.1

(PO₄)_1.9(SiO₄)_0.1The typical XRD spectrum of O powder is compared with the standard spectrum (PDF # 70-1379) of tetracalcium phosphate to see that the final calcined product is Ca_3.2Sr_0.5Mg_0.2Zn_0.1(PO₄)_1.9(SiO₄)_0.1O (TTCP) pure phase, no impurity phase was found.

From Ca shown in FIG. 7_3.2Sr_0.5Mg_0.2Zn_0.1(PO₄)_1.9(SiO₄)_0.1The typical micro-morphology picture of the O powder can also see that the final calcined product has a particle size of 0.01-5 mu m.

Adding Ca_3.2Sr_0.5Mg_0.2Zn_0.1(PO₄)_1.9(SiO₄)_0.1Mixing O powder and deionized water to obtain bone cement slurry with liquid/solid ratio of 0.4ml/1g, injecting into a stainless steel mold with diameter of 5mm and height of 12mm, curing for 10-15min, maintaining in a constant temperature oven with humidity of 100% RH at 37 deg.C for 24 hr, and taking out to obtain compressive strength of 45MPa + -5 MPa. FIG. 8 shows Ca_3.2Sr_0.5Mg_0.2Zn_0.1(PO₄)_1.9(SiO₄)_0.1The comparative analysis of the XRD spectrum of the hydration product of O powder after being hydrated for 7 days and the hydroxyapatite standard spectrum (PDF # 09-0432) shows that the XRD diffraction peak of the hydration product is broadened, but the positions of all diffraction peaks coincide with the hydroxyapatite standard spectrum, namely the main crystalline phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity.

With the aid of a healthy adult male New Zealand white rabbit model of radius defects, Ca_3.2Sr_0.5Mg_0.2Zn_0.1(PO₄)_1.9(SiO₄)_0.1The O bone cement fills the defect of the radius. Histological observation showed 4 weeksNew bone formation begins, the bone defect part is repaired at 8 weeks, and obvious microvessel formation is seen around the new bone; imaging examination at week 12 post-implantation revealed almost complete repair of the defective area of bone. From this, Ca is known_3.2Sr_0.5Mg_0.2Zn_0.1(PO₄)_1.9(SiO₄)_0.1O can be used for CPC bone cement production and bone defect repair.

Example 2Ca_3.3Sr_0.2Mn_0.2Co_0.2Cu_0.1(PO₄)_1.8(SiO₄)_0.2O powder

Weighing 5.854gCa (OH)₂、0.886gSrCO₃、1.074gMn(NO₃)₂、0.563gCu(NO₃)₂And 1.746gCo (NO)₃)₂·

6H₂Dissolving O in 100ml deionized water to obtain polyion mixed solution L1, adding 30ml concentrated ammonia water, controlling pH at about 8, and stirring in 60 deg.C water bath for 30 min. Take 5.292gH₃PO₄And 0.732gNa₂SiO₃Dissolving in 46ml of deionized water to prepare a phosphorus and silicate ion mixed solution L2, dropwise adding the L2 solution into the L1 solution at a speed of 4ml/min under the ultrasonic wave assistance condition of 25kHz and 500W, and mixing and stirring for 3.5 hours to obtain the multi-ion co-doped hydroxyapatite Ca_7.9

Sr_0.6Mn_0.6Co_0.6Cu_0.3(PO₄)_5.4(SiO₄)_0.6(OH)₂Suspension L3. Separately weighing 4.723gCa (NO)₃)₂·4H₂O and 1.680g NaHCO₃Adding 20ml of deionized water into each of the two solutions to prepare solutions, respectively adding a calcium nitrate solution and a sodium bicarbonate solution into the suspension L3 at the speed of 3.5ml/min under the ultrasonic wave auxiliary condition of 25kHz and 500W, and continuously mixing and stirring for 5 hours to obtain a white suspension of the composite powder containing the nano calcium carbonate powder in-situ precipitation and coating the multi-ion co-doped hydroxyapatite particles. Carrying out suction filtration on the white suspension, repeatedly washing the precipitate for 3-4 times by using deionized water and ethanol, and removing various impurity ions to obtain the multi-ion co-doped tetracalcium phosphateAnd (3) driving body in-situ composite powder. And drying the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in an oven at 120 ℃ for 8 hours.

And then, under the ultrasonic wave auxiliary condition of 45kHz and 1500W, placing the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in a crucible, quickly calcining for 1.5 hours in a resistance furnace at a high temperature of 1350 ℃, then quickly cooling to 1000 ℃ and calcining for 2 hours at a low temperature, and repeating the cyclic calcination for 5 times at the temperature rise speed of 30 ℃/min. Finally, the calcined product is cooled along with the furnace to obtain 11.53g of Ca with the phase purity higher than 98%, the crystallinity of 95% and the grain size of 0.5-25 mu m_3.3Sr_0.2Mn_0.2Co_0.2Cu_0.1(PO₄)_1.8(SiO₄)_0.2And (3) O powder.

Adding Ca_3.3Sr_0.2Mn_0.2Co_0.2Cu_0.1(PO₄)_1.8(SiO₄)_0.2Mixing O powder and deionized water to obtain bone cement slurry with liquid/solid ratio of 0.5ml/1g, injecting into a stainless steel mold with diameter of 5mm and height of 12mm, curing for 10-12min, maintaining in a constant temperature oven with humidity of 100% RH at 37 deg.C for 24 hr, and taking out to obtain compressive strength of 55MPa + -7 MPa. XRD analysis shows that the main crystal phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity.

Ca is added by means of a bone defect model of the right femur end of a healthy adult male New Zealand white rabbit_3.3Sr_0.2Mn_0.2Co_0.2Cu_0.1(PO₄)_1.8(SiO₄)_0.2And filling the bone defect with the O-bone cement. Histological observation shows that after 12 weeks, a great amount of new bone tissue and microangiogenesis occur along with the degradation of bone cement, which can indicate that Ca is generated_3.3Sr_0.2Mn_0.2Co_0.2Cu_0.1(PO₄)_1.8(SiO₄)_0.2O has excellent biocompatibility, degradability, osteogenesis performance and vascularization capacity, can promote the regeneration of new bones, and is a potential bone repair material.

Example 3Ca_2.8Mg_0.5Fe_0.3Co_0.2Cu_0.1Zn_0.1(PO₄)_1.7(SiO₄)_0.3O powder

Weighing 4.742gCa (OH)₂、2.225gMg(NO₃)₂、1.619gFe(NO₃)₃、0.892gZn(NO₃)₂·6H₂O、1.746gCo(NO₃)₂·6H₂O and 0.563gCu (NO)₃)₂Dissolving the mixture in 100ml of deionized water to prepare a multi-ion mixed solution L1, adding 30ml of concentrated ammonia water, controlling the pH value to be 7-8, and stirring in a water bath at 50 ℃ for 30 min. Take 4.998gH₃PO₄And 1.099gNa₂SiO₃Dissolving in 48ml of deionized water to prepare a mixed solution L2 containing phosphorus and silicon ions, dripping the L2 solution into the L1 solution at the speed of 3ml/min under the ultrasonic wave assistance condition of 25kHz and 500W, and mixing and stirring for 4 hours to obtain the multi-ion co-doped hydroxyapatite Ca_6.4Mg_1.5Fe_0.9Co_0.6Cu_0.3Zn_0.3(PO₄)_5.1(SiO₄)_0.9(OH)₂Suspension L3. Separately weighing 3.1634gCa (CH)₃COO)₂And 1.92g (NH)₄)₂CO₃Adding 30ml of deionized water into each of the two solutions to prepare solutions, respectively adding a calcium acetate solution and an ammonia carbonate solution into the suspension L3 at the speed of 3ml/min, and mixing and stirring the solutions for 4 hours under the ultrasonic wave auxiliary conditions of 25kHz and 500W to obtain a white suspension of the composite powder containing the nano calcium carbonate powder in-situ precipitation and coated with the multi-ion co-doped hydroxyapatite particles. And carrying out suction filtration on the white suspension, repeatedly washing the precipitate for 3-4 times by using deionized water and ethanol, and removing various impurity ions to obtain the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder. And drying the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in an oven at 90 ℃ for 9 hours.

Under the ultrasonic wave auxiliary condition of 25kHz and 1500W, putting the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder into a crucible, quickly calcining for 0.05 h at a 1380 ℃ high-temperature section in an infrared radiation electric furnace with an infrared wavelength of 0.8-3.5 mu m and 5kW, then quickly cooling to 1100 ℃ low-temperature section for 0.05 h, and repeatedly and circularly calcining for 2 timesThe temperature rise rate is 500 ℃/min. Finally, the calcined product is taken out and put into liquid helium for quenching to obtain 11.13g of Ca with the phase purity higher than 99.6 percent_2.8Mg_0.5Fe_0.3Co_0.2Cu_0.1Zn_0.1(PO₄)_1.7(SiO₄)_0.3O powder, the crystallinity of the obtained powder is 51 percent, and the grain size is 0.05-5 mu m.

Adding Ca_2.8Mg_0.5Fe_0.3Co_0.2Cu_0.1Zn_0.1(PO₄)_1.7(SiO₄)_0.3Mixing the O powder and the citric acid aqueous solution to form the bone cement slurry, wherein the liquid/solid ratio is 0.45ml/1g, injecting the bone cement slurry into a stainless steel mould with the diameter of 5mm and the height of 12mm, curing for 8-10min, putting the bone cement slurry into a constant temperature box with the humidity of 100% RH, curing for 24 hours at 37 ℃, and taking out the bone cement slurry to obtain the bone cement slurry with the compressive strength of 58MPa +/-7 MPa. XRD analysis shows that the main crystal phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity.

With the aid of a healthy adult male New Zealand white rabbit model of radius defects, Ca_2.8Mg_0.5Fe_0.3Co_0.2Cu_0.1Zn_0.1(PO₄)_1.7

(SiO₄)_0.3The bone defect is filled with the O bone cement, and histological observation shows that a small amount of new bone is generated around the bone cement after 4 weeks, and no obvious inflammatory reaction exists; at 8 weeks, the bone defect part is repaired, and obvious microvascular network formation can be seen; imaging examination of the bone defect area at week 12 post-implantation almost completely repaired. From this, Ca is known_2.8Mg_0.5Fe_0.3Co_0.2Cu_0.1Zn_0.1(PO₄)_1.7(SiO₄)_0.3

The O has good biocompatibility, degradability, osteogenesis performance and vascularization capacity, can be used as a bone cement production raw material, and is a potential bone repair material.

Example 4Ca_2.9Sr_0.2Mg_0.2Fe_0.2Mn_0.2Co_0.2Ag_0.1(PO₄)_1.9(SiO₄)_0.1O powder

Weighing 4.964gCa (OH)₂、0.886gSrCO₃、0.890gMg(NO₃)₂、1.079gFe(NO₃)₃、1.074gMn(NO₃)₂、1.746gCo(NO₃)₂·6H₂O and 0.510gAgNO₃Dissolving the mixture in 100ml of deionized water to prepare a multi-ion mixed solution L1, adding 30ml of concentrated ammonia water, controlling the pH value to be 7-9, and stirring in a water bath at 50 ℃ for 30 min. Take 5.586gH₃PO₄And 0.5521gNa₄SiO₄Dissolving in 48ml deionized water to prepare phosphorus-containing silicate ion mixed solution L2; dripping the L2 solution into the L1 solution at the speed of 3ml/min under the ultrasonic wave auxiliary condition of 25kHz and 500W, and mixing and stirring for 6 hours to obtain the multi-ion co-doped hydroxyapatite Ca_6.7Sr_0.6Mg_0.6Fe_0.6Mn_0.6Co_0.6Ag_0.3(PO₄)_5.7(SiO₄)_0.3(OH)₂Suspension L3. Separately weighing 3.1634gCa (CH)₃COO)₂And 1.92g (NH)₄)₂CO₃30ml of deionized water is added to prepare solutions respectively, and the calcium acetate solution and the ammonium carbonate solution are added into the suspension L3 at the speed of 3ml/min respectively and simultaneously under the ultrasonic wave assistance condition of 25kHz and 500W, and simultaneously, the mixing and the stirring are continuously carried out for 8 hours. And carrying out suction filtration on the reacted solution to obtain a precipitate, and repeatedly washing the precipitate for 3-4 times by using deionized water and ethanol. The precipitate was dried at 90 ℃ for 9 hours.

And finally, under the ultrasonic wave auxiliary condition of 25kHz and 1500W, placing the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in a crucible, quickly calcining for 0.5 hour in an infrared radiation furnace with the infrared wavelength of 0.8-3.5 mu m and the infrared radiation furnace of 5kW at the high temperature of 1400 ℃, then quickly cooling to 900 ℃ and calcining for 1 hour at the low temperature, and repeatedly and circularly calcining for 2 times at the heating rate of 525 ℃/min. Finally, the calcined product is taken out and placed in liquid nitrogen for quenching to obtain 11.67g of Ca with the phase purity higher than 99.2%, the crystallinity of 75% and the grain size of 0.1-10 mu m_2.9Sr_0.2Mg_0.2Fe_0.2Mn_0.2Co_0.2Ag_0.1(PO₄)_1.9(SiO₄)_0.1And (3) O powder.

Adding Ca_2.9Sr_0.2Mg_0.2Fe_0.2Mn_0.2Co_0.2Ag_0.1(PO₄)_1.9(SiO₄)_0.1Mixing the O powder and the citric acid-removed aqueous solution to form slurry with the liquid/solid ratio of 0.46ml/1g, injecting the slurry into a stainless steel mold with the diameter of 5mm and the height of 12mm, curing for 5-8min, putting the mold into a constant temperature box with the humidity of 100% RH, curing for 24 hours at 37 ℃, and taking out the mold to obtain the compressive strength of 55MPa +/-8 MPa. XRD analysis shows that the main crystal phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity.

Selecting New Zealand white rabbit, inducing chronic periapical bone defect model by root tip operation, and adding Ca_2.9Sr_0.2Mg_0.2Fe_0.2Mn_0.2Co_0.2Ag_0.1(PO₄)_1.9(SiO₄)_0.1The bone defect part is filled with the O bone cement, histological observation shows that after the operation for 8 weeks, no inflammatory reaction exists, and the bone cement in the bone defect area is directly combined with the new bone and is gradually absorbed along with the growth of the new bone. After the operation, the X-ray film for half a year shows that new bone is formed in the bone defect area around the root tip, part of bone cement is degraded, and the bone cement is completely degraded and replaced by new bone after one year, so that the bone healing is realized.

From this, Ca is known_2.9Sr_0.2Mg_0.2Fe_0.2Mn_0.2Co_0.2Ag_0.1(PO₄)_1.9(SiO₄)_0.1O has good biocompatibility, degradation performance, vascularization capacity, osteogenesis performance and antibacterial and bacteriostatic performance, and can be used for repairing bone defects.

Example 5Ca_3.09K_0.2Sr_0.2Fe_0.1Mn_0.1Co_0.1Zn_0.1Cu_0.1Ag_0.01(PO₄)_1.9(SiO₄)_0.1O powder

Weighing 5.387gCa (OH)₂、0.6066gKNO₃、1.2698gSr(NO₃)₂、0.5396gFe(NO₃)₂、0.5369g

Mn(NO₃)₂、0.892gZn(NO₃)₂·6H₂O、0.5627gCu(NO₃)₂、0.8732gCo(NO₃)₂·6H₂O and 0.05096gAgNO₃Dissolving the mixture in 100ml of deionized water to prepare a multi-ion mixed solution L1, adding 50ml of concentrated ammonia water, controlling the pH value to be 9-10, and stirring in a water bath at 50 ℃ for 30 min. Take 5.586gH₃PO₄And 0.5521gNa₄SiO₄Dissolving in 48ml deionized water to prepare a mixed solution L2 containing phosphorus and silicate ions; dripping the L2 solution into the L1 solution at the speed of 3ml/min under the ultrasonic wave auxiliary condition of 1500W at 25kHz, mixing and stirring for 4 hours to obtain the polyion codoped hydroxyapatite Ca_7.27K_0.6Sr_0.6Fe_{0. 3}Mn_0.3Co_0.3Zn_0.3Cu_0.3Ag_0.03(PO₄)_5.7(SiO₄)_0.3(OH)₂Suspension L3. Separately weighing 3.1634gCa (CH)₃COO)₂And 1.92g (NH)₄)₂CO₃30ml of deionized water are respectively added to prepare solutions, and the calcium acetate solution and the ammonium carbonate solution are respectively added into the suspension L3 at the speed of 3ml/min under the ultrasonic wave assistance condition of 25kHz and 1500W, and are mixed and stirred for 2 hours. And carrying out suction filtration on the reacted solution to obtain a precipitate, and repeatedly washing the precipitate for 3-4 times by using deionized water and ethanol. The precipitate was dried at 90 ℃ for 9 hours.

And finally, under the ultrasonic wave auxiliary condition of 250kHz and 1500W, placing the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in a crucible, quickly calcining for 0.5 hour in a microwave electric furnace with 915MHz and 1500W at a high temperature of 1350 ℃, quickly cooling to 950 ℃ and calcining for 1 hour at a low temperature, and repeatedly and circularly calcining for 5 times at the temperature rise speed of 15 ℃/min. Finally, the calcined product is taken out for air cooling, and 11.57g of Ca with the phase purity higher than 99.0%, the crystallinity of 100% and the grain size of 0.05-10 mu m is obtained_3.09K_0.2Sr_0.2Fe_0.1Mn_0.1Co_0.1Zn_0.1Cu_0.1Ag_0.01(PO₄)_1.9(SiO₄)_0.1And (3) O powder.

Adding Ca_3.09K_0.2Sr_0.2Fe_0.1Mn_0.1Co_0.1Zn_0.1Cu_0.1Ag_0.01(PO₄)_1.9(SiO₄)_0.1Preparing bone cement slurry by using O powder and carboxymethyl chitosan aqueous solution, wherein the liquid/solid ratio is 0.45ml/1g, then injecting the bone cement slurry into a stainless steel mould with the diameter of 5mm and the height of 12mm, curing the bone cement slurry for 7-10min, putting the bone cement slurry into a constant temperature box with the humidity of 100% RH for curing for 24 hours at 37 ℃, and taking out the bone cement slurry to obtain the compressive strength of 51MPa +/-10 MPa. XRD analysis shows that the main crystal phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity.

Animal in vivo experiments show that Ca is adopted_3.09K_0.2Sr_0.2Fe_0.1Mn_0.1Co_0.1Zn_0.1Cu_0.1Ag_0.01(PO₄)_1.9(SiO₄)_0.1After the O-bone cement is implanted into the femoral condyle of the rabbit, the repair of the bone defect part is facilitated, no inflammatory reaction exists, the growth of new bones and the coverage rate of bones on the surface of an implant are obviously greater than those of the element-free doped tetracalcium phosphate cement, and Ca shows that_3.09K_{0. 2}Sr_0.2Fe_0.1Mn_0.1Co_0.1Zn_0.1Cu_0.1Ag_0.01(PO₄)_1.9(SiO₄)_0.1The O-bone cement has good biocompatibility, degradability, vascularization capacity, osteogenesis and antibacterial activity in vivo.

Example 6Ca_2.95Na_0.1Sr_0.2Mn_0.2Co_0.2Zn_0.2Cu_0.1Ag_0.05(PO₄)_1.5(SiO₄)_0.5O powder

Weighing 5.113gCa (OH)₂、0.2550gNaNO₃、1.2698gSr(NO₃)₂、1.0737gMn(NO₃)₂、0.375gCu(NO₃)₂、1.785gZn(NO₃)₂·6H₂O、1.7463gCo(NO₃)₂·6H₂O and 0.255gAgNO₃Dissolving in 100ml deionized water to obtain multi-ion mixed solution L1, adding 30ml concentrated ammonia water, controlling pH at 8-9 and 50 deg.CStirring in water bath for 30 min. Take 4.410gH₃PO₄And 2.7606gNa₄SiO₄Dissolving in 48ml deionized water to prepare mixed solution L2 containing phosphorus and silicate ions; dripping the L2 solution into the L1 solution at the speed of 3ml/min under the ultrasonic wave auxiliary condition of 25kHz and 500W, and mixing and stirring for 4 hours to obtain the polyion codoped hydroxyapatite Ca_6.85Na_0.3Sr_0.6Mn_0.6Co_0.6Zn_0.6Cu_0.2Ag_0.15(PO₄)_4.5(SiO₄)_1.5(OH)₂Suspension L3. Separately weighing 4.723gCa (NO)₃)₂·4H₂O and 1.58gNH₄HCO₃30ml of deionized water are respectively added to prepare solutions, and the calcium nitrate solution and the ammonium bicarbonate solution are respectively added into the suspension L3 at the speed of 3ml/min under the ultrasonic wave assistance condition of 25kHz and 500W, and are mixed and stirred for 2 hours. And carrying out suction filtration on the reacted solution to obtain a precipitate, and repeatedly washing the precipitate for 3-4 times by using deionized water and ethanol. The precipitate was dried at 90 ℃ for 9 hours.

And finally, under the ultrasonic wave auxiliary condition of 25kHz and 1500W, placing the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in a crucible, quickly calcining for 5 hours at 1400 ℃ in a resistance furnace at high temperature, then quickly cooling to 1250 ℃ for calcining for 1 hour at a low temperature section, and repeatedly and circularly calcining for 2 times at the temperature rise speed of 25 ℃/min. Finally, the calcined product is cooled along with the furnace to obtain 11.7g of Ca with the phase purity higher than 98.8%, the crystallinity of 90% and the grain size of 5-50 mu m_2.95Na_0.1Sr_0.2Mn_0.2Co_0.2

Zn_0.2Cu_0.1Ag_0.05(PO₄)_1.5(SiO₄)_0.5And (3) O powder.

Adding Ca_2.95Na_0.1Sr_0.2Mn_0.2Co_0.2Zn_0.2Cu_0.1Ag_0.05(PO₄)_1.5(SiO₄)_0.5Mixing O powder and alpha-tricalcium phosphate, blending with sodium carboxymethylcellulose water solution to obtain bone cement slurry with liquid/solid ratio of 0.55ml/1g, and injecting into a stainless steel container with diameter of 5mm and height of 12mmCuring for 8-12min in a steel mold, placing in a constant temperature box with humidity of 100% RH for curing at 37 deg.C for 24 hr, and taking out to obtain a compressive strength of 45MPa + -10 MPa. XRD analysis shows that the main crystal phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity.

Using Ca_2.95Na_0.1Sr_0.2Mn_0.2Co_0.2Zn_0.2Cu_0.1Ag_0.05(PO₄)_1.5(SiO₄)_0.5The O-bone cement is made into an implant with the diameter of 3mm and the length of 10mm, and the implant is implanted into the femoral defect part by means of a healthy adult New Zealand white rabbit femoral defect model. Histological observation shows that the material begins to degrade at 4 weeks, and osteoblasts are attached and new bones are formed at the junction of the material and bones; after implantation, the bone formation is active and new bone becomes compact in 12 weeks, haversian canals are obviously visible, small blood vessels in the lumen grow well, and no inflammatory reaction is caused, which indicates that Ca_2.95Na_0.1Sr_0.2Mn_0.2Co_0.2Zn_0.2Cu_0.1Ag_0.05(PO₄)_1.5(SiO₄)_0.5The O-bone cement has good biocompatibility, degradability, vascularization capacity, osteogenesis and antibacterial activity in vivo, and can be used for repairing bone defects.

Example 7Ca_2.53Na_0.1Sr_0.5Mn_0.2Co_0.5Al_0.1Cu_0.05Ag_0.02(PO₄)_1.5(SiO₄)_0.5O powder

Weighing 4.149gCa (OH)₂、0.2550gNaNO₃、2.214gSrCO₃、1.0737gMn(NO₃)₂、0.639gAl(NO₃)₃、0.2813gCu(NO₃)₂、4.3658gCo(NO₃)₂·6H₂O and 0.1019gAgNO₃Dissolving the mixture in 100ml of deionized water to prepare a multi-ion mixed solution L1, adding 30ml of concentrated ammonia water, controlling the pH to be 8-9, and stirring in a water bath at 50 ℃ for 30 min. Take 4.410gH₃PO₄And 2.760gNa₄SiO₄Dissolving in 48ml deionized water to obtain mixed solution L2 containing phosphorus and silicate ions at 35kHz and 1000WUnder the auxiliary condition of ultrasonic wave, the L2 solution is dripped into the L1 solution at the speed of 3ml/min, and is mixed and stirred for 4 hours to obtain the multi-ion co-doped hydroxyapatite Ca_5.59Na_0.3Sr_1.5Mn_0.6Co_1.5Al_0.3Cu_0.15Ag_0.06

(PO₄)_4.5(SiO₄)_1.5(OH)₂Suspension L3. Separately weighing 4.723gCa (NO)₃)₂·4H₂O and 1.58gNH₄HCO₃30ml of deionized water are respectively added to prepare solutions, and the calcium nitrate solution and the ammonium bicarbonate solution are respectively added into the suspension L3 at the speed of 3ml/min under the ultrasonic wave assistance condition of 35kHz and 1000W, and are mixed and stirred for 1 hour. And carrying out suction filtration on the reacted solution to obtain a precipitate, and repeatedly washing the precipitate for 3-4 times by using deionized water and ethanol. The precipitate was dried at 90 ℃ for 9 hours.

And finally, under the ultrasonic wave auxiliary condition of 25kHz and 2500W, placing the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in a crucible, quickly calcining at 1350 ℃ for 0.2h in a microwave oven of 2450MHz and 1500W, quickly cooling to 850 ℃ for calcining for 0.5h in a low-temperature section, and repeatedly and circularly calcining for 5 times at the temperature rise speed of 450 ℃/min. Finally, the calcined product is cooled along with the furnace to obtain 12.0g of Ca with the phase purity higher than 99.8 percent, the crystallinity of 95 percent and the grain size of 0.1-5 mu m_2.53Na_0.1Sr_0.5Mn_0.2Co_0.5Al_0.1Cu_0.05Ag_0.02(PO₄)_1.5(SiO₄)_0.5And (3) O powder.

Adding Ca_2.53Na_0.1Sr_0.5Mn_0.2Co_0.5Al_0.1Cu_0.05Ag_0.02(PO₄)_1.5(SiO₄)_0.5Mixing the O powder and the citric acid aqueous solution to form the bone cement slurry, wherein the liquid/solid ratio is 0.4ml/1g, injecting the bone cement slurry into a stainless steel mould with the diameter of 5mm and the height of 12mm, curing the bone cement slurry for 10 to 15min, putting the bone cement slurry into a constant temperature box with the humidity of 100 percent RH for curing at 37 ℃ for 24 hours, and taking out the bone cement slurry to obtain the bone cement slurry with the compressive strength of 65MPa +/-12 MPa. XRD analysis shows that the main crystal phase of the hydration product is lack of lower crystallinityCalcium hydroxyapatite.

Ca is added by means of an adult goat femoral condyle cancellous bone defect model_2.53Na_0.1Sr_0.5Mn_0.2Co_0.5Al_0.1Cu_0.05Ag_0.02

(PO₄)_1.5(SiO₄)_0.5The O bone cement fills the spongy bone defect, and histological observation shows that the bone cement is partially degraded when the implant is implanted for 12 weeks, part of newly-grown bone has a bone trabecular structure, and the bone cement is divided and wrapped to form a bone cement island; the bone cement is basically degraded at 24 weeks, is replaced by a large amount of mature trabeculae, lamellar bones and new trabeculae and forms osseous connection, the degradation speed and the bone repair capability of the bone cement are far greater than those of an undoped TTCP control group, and statistically significant differences (P) exist<0.01）。

Example 8Ca_2.65Na_0.1Sr_0.5Mn_0.1Fe_0.2Co_0.2Al_0.1Cu_0.05Zn_0.05Ag_0.05(PO₄)(SiO₄) O powder

Weighing 4.446gCa (OH)₂、0.2550gNaNO₃、2.214gSrCO₃、0.5369gMn(NO₃)₂、0.639gAl(NO₃)₃、1.0792gFe(NO₃)₂、0.2813gCu(NO₃)₂、0.4462gZn(NO₃)₂·6H₂O、1.7463gCo(NO₃)₂·6H₂O and 0.2548gAgNO₃Dissolving the mixture in 100ml of deionized water to prepare a multi-ion mixed solution L1, adding 70ml of concentrated ammonia water, controlling the pH value to be 10-13, and stirring in a water bath at 50 ℃ for 30 min. Take 2.940gH₃PO₄And 5.52gNa₄SiO₄Dissolving in 48ml deionized water to prepare mixed solution L2 containing phosphorus and silicate ions; dripping the L2 solution into the L1 solution at the speed of 3ml/min under the ultrasonic wave auxiliary condition of 25kHz and 500W, and mixing and stirring for 4 hours to obtain the polyion codoped hydroxyapatite Ca_5.95Na_0.3Sr_1.5Mn_0.3Fe_0.6Co_0.6Al_0.3Cu_0.15Zn_0.15Ag_0.15(PO₄)₃

(SiO₄)₃(OH)₂Suspension L3. Separately weighing 4.723gCa (NO)₃)₂·4H₂O and 1.6802gNaHCO₃30ml of deionized water are respectively added to prepare solutions, and a calcium nitrate solution and a sodium bicarbonate solution are respectively added into the suspension L3 at the speed of 3ml/min under the ultrasonic wave assistance condition of 25kHz and 500W, and are mixed and stirred for 2.5 hours. And (3) carrying out suction filtration on the solution after reaction to obtain a precipitate, and repeatedly washing the precipitate for 4 times by using deionized water and ethanol. The precipitate was dried at 90 ℃ for 9 hours.

And finally, under the ultrasonic wave auxiliary condition of 45kHz and 2500W, placing the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in a crucible, quickly calcining at 1350 ℃ for 0.5h in a microwave oven of 915MHz and 2500W, quickly cooling to 850 ℃ for 0.5h in a low-temperature section, and repeatedly and circularly calcining for 2 times at the temperature-rising speed of 500 ℃/min. Finally, the calcined product is cooled along with the furnace to obtain 11.95g of Ca with the phase purity higher than 99.8 percent, the crystallinity of 99 percent and the grain size of 0.1-5 mu m_2.65Na_0.1Sr_0.5Mn_0.1Fe_0.2Co_0.2Al_0.1Cu_0.05Zn_0.05Ag_0.05(PO₄)(SiO₄) And (3) O powder.

Adding Ca_2.65Na_0.1Sr_0.5Mn_0.1Fe_0.2Co_0.2Al_0.1Cu_0.05Zn_0.05Ag_0.05(PO₄)(SiO₄) Mixing O powder and deionized water to obtain bone cement slurry with liquid/solid ratio of 0.4ml/1g, injecting into a stainless steel mold with diameter of 5mm and height of 12mm, curing for 15-20min, maintaining in a constant temperature oven with humidity of 100% RH at 37 deg.C for 24 hr, and taking out to obtain compressive strength of 35MPa + -5 MPa. XRD analysis shows that the main crystal phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity.

Ca is added by means of a healthy adult male New Zealand white rabbit femur dry bone defect model_2.65Na_0.1Sr_0.5Mn_0.1Fe_0.2Co_0.2Al_0.1Cu_0.05Zn_0.05Ag_0.05(PO₄)(SiO₄) The O-bone cement is implanted into the rabbit bone defect, and histological observation shows that osteoclasts and osteoblasts appear after 2 weeks, the bone cement is replaced by new bones, and no inflammatory reaction exists; new bone replacement of the cortical bone region was seen to be essentially complete after 16 weeks. From this, Ca is known_2.65Na_0.1Sr_0.5Mn_0.1Fe_0.2Co_0.2Al_0.1

Cu_0.05Zn_0.05Ag_0.05(PO₄)(SiO₄) The O-bone cement can be used for repairing bone defects.

Example 9Ca_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.5(SiO₄)_0.5O powder

Weigh 4.075g Ca (OH)₂、0.2550gNaNO₃、0.3033gKNO₃、0.8858gSrCO₃、1.0738gMn(NO₃)₂、2.698gFe(NO₃)₂、1.785gZn(NO₃)₂·6H₂O and 1.7463gCo (NO)₃)₂·6H₂Dissolving O in 100ml of deionized water to prepare a multi-ion mixed solution L1, adding 50ml of concentrated ammonia water, controlling the pH value to be 9-12, and stirring in a water bath at 50 ℃ for 30 min. Take 4.410gH₃PO₄And 2.760gNa₄SiO₄Dissolving in 48ml deionized water to prepare mixed solution L2 containing phosphorus and silicate ions; dripping the L2 solution into the L1 solution at the speed of 3ml/min under the ultrasonic wave auxiliary condition of 25kHz and 500W, and mixing and stirring for 4 hours to obtain the polyion codoped hydroxyapatite Ca_5.5K_0.3Na_0.3Sr_0.6Mn_0.6Co_0.6Fe_1.5

Zn_0.6(PO₄)_4.5(SiO₄)_1.5(OH)₂Suspension L3. Separately weighing 4.723gCa (NO)₃)₂·4H₂O and 2.12gNa₂CO₃Adding 30ml of deionized water respectively to prepare solutions; under the ultrasonic wave auxiliary condition of 25kHz and 500W, calcium nitrate solution and sodium carbonate are mixedThe solutions were added simultaneously to suspension L3 at a rate of 3ml/min and mixed and stirred for 1.5 hours. And carrying out suction filtration on the reacted solution to obtain a precipitate, and repeatedly washing the precipitate for 3-4 times by using deionized water and ethanol. The precipitate was dried at 90 ℃ for 9 hours.

And finally, under the ultrasonic wave auxiliary condition of 25kHz and 2500W, placing the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in a crucible, quickly calcining for 0.5h at 1000 ℃ in a microwave oven of 2450MHz and 1500W, quickly cooling to 850 ℃ and calcining for 1.25 h at a low temperature section, and repeatedly and circularly calcining for 8 times at the temperature rise speed of 235 ℃/min. Finally, the calcined product is cooled along with the furnace to obtain 11.76g of Ca with the phase purity higher than 99.8 percent, the crystallinity of 80 percent and the grain size of 0.02-5.5 mu m_{2. 5}K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.5(SiO₄)_0.5And (3) O powder.

Adding Ca_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.5(SiO₄)_0.5Mixing O powder, calcium hydrogen phosphate mixed powder and citric acid aqueous solution to obtain bone cement slurry with liquid/solid ratio of 0.45ml/1g, injecting into a stainless steel mold with diameter of 5mm and height of 12mm, curing for 15-20min, placing into a constant temperature box with humidity of 100% RH at 37 deg.C for 24 hr, taking out, and measuring compressive strength to 65MPa + -10 MPa. XRD analysis shows that the main crystal phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity.

Ca was administered with the aid of a healthy adult male New Zealand white rabbit skull defect model_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.5(SiO₄)_0.5The histological observation shows that after 12 months of operation, the new bone replaces about 64% of the implanted volume of the bone cement, and the new bone grows from the surface of the bone cement and gradually advances to the deep layer, which is consistent with the replacement process of the autologous bone. From this, Ca is known_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.5(SiO₄)_0.5The O-bone cement can be used for repairing bone defects.

Example 10Ca_3.3Sr_0.2Mg_0.1Mn_0.1Co_0.1Eu_0.05Ce_0.05Sm_0.05La_0.05(PO₄)_1.8(SiO₄)_0.2O powder

Weighing 5.854gCa (OH)₂、0.8858gSrCO₃、0.445gMg(NO₃)₂、0.5369gMn(NO₃)₂、0.8732gCo(NO₃)₂·6H₂O、0.6691gEu(NO₃)₃·6H₂O、0.6512gCe(NO₃)₃·6H₂O、0.650gLa(NO₃)₃·6H₂O and 0.505gSm (NO)₃)₃Dissolving the mixture in 100ml of deionized water to prepare a multi-ion mixed solution L1, adding 30ml of concentrated ammonia water, controlling the pH value to be 7-9, and stirring in a water bath at 50 ℃ for 30 min. Take 5.292gH₃PO₄And 1.104gNa₄SiO₄Dissolving in 48ml deionized water to prepare phosphorus-containing silicate ion mixed solution L2; dripping the L2 solution into the L1 solution at the speed of 3ml/min under the ultrasonic wave auxiliary condition of 1500W at 25kHz, mixing and stirring for 6h to obtain the polyion codoped hydroxyapatite Ca_7.9Sr_0.6Mg_0.3Mn_0.3Co_0.3Eu_0.15Ce_0.15Sm_0.15La_0.15(PO₄)_5.4(SiO₄)_0.6(OH)₂Suspension L3. Separately weighing 3.1634gCa (CH)₃COO)₂And 1.92g (NH)₄)₂CO₃30ml of deionized water is added to prepare solutions respectively, and the calcium acetate solution and the ammonium carbonate solution are added into the suspension L3 at the speed of 3ml/min respectively and simultaneously under the ultrasonic wave assistance condition of 25kHz and 1500W, and simultaneously, the mixture is continuously mixed and stirred for 8 hours. And carrying out suction filtration on the reacted solution to obtain a precipitate, and repeatedly washing the precipitate for 3-4 times by using deionized water and ethanol. The precipitate was dried at 90 ℃ for 9 hours.

Finally, inUnder the ultrasonic wave auxiliary condition of 25kHz and 1500W, putting the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder into a crucible, quickly calcining for 0.5 hour at a high temperature section of 1400 ℃ in an infrared radiation furnace with an infrared wavelength of 0.8-3.5 mu m and 5kW, then quickly cooling to 850 ℃ and calcining for 1 hour at a low temperature section, and repeatedly and circularly calcining for 3 times at the temperature rise speed of 1000 ℃/min. Finally, the calcined product is taken out and placed in liquid nitrogen for quenching to obtain 11.94g of Ca with the phase purity higher than 98.5%, the crystallinity of 95% and the grain size of 0.5-10 mu m_3.3Sr_0.2Mg_0.1Mn_0.1Co_0.1Eu_0.05Ce_0.05Sm_0.05

La_0.05(PO₄)_1.8(SiO₄)_0.2And (3) O powder.

Adding Ca_3.3Sr_0.2Mg_0.1Mn_0.1Co_0.1Eu_0.05Ce_0.05Sm_0.05La_0.05(PO₄)_1.8(SiO₄)_0.2Mixing the O powder and the citric acid-removed aqueous solution to form bone cement slurry with the liquid/solid ratio of 0.5ml/1g, injecting the mixture into a stainless steel mold with the diameter of 5mm and the height of 12mm, curing for 10-12min, putting the mold into a constant temperature box with the humidity of 100% RH, curing for 24 hours at 37 ℃, and taking out the mold to obtain the bone cement slurry with the compressive strength of 45MPa +/-12 MPa. XRD analysis shows that the main crystal phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity. FIG. 9 shows Ca_3.3Sr_0.2Mg_0.1Mn_0.1Co_0.1Eu_0.05Ce_0.05Sm_0.05La_0.05(PO₄)_1.8(SiO₄)_0.2After the O powder is hydrated for different time, the typical CIE chromaticity coordinate and the fluorescence change photo of the product under the excitation of 365nm show that the color of the bone cement is gradually changed from white to orange along with the prolonging of the hydration time to 1 week, which shows that the bone cement is completely changed into hydroxyapatite and has the fluorescent tracing function in the hydration process.

Ca is added by means of a root periapical bone defect model of healthy adult male New Zealand white rabbits_3.3Sr_0.2Mg_0.1Mn_0.1Co_0.1Eu_0.05

Ce_0.05Sm_0.05La_0.05(PO₄)_1.8(SiO₄)_0.2The bone defect is filled with the O-bone cement, histological observation shows that no inflammatory reaction exists at 4 weeks, the bone cement is gradually absorbed along with the growth of new bones and is directly combined with the new bones, and a large number of capillaries are formed around the bone cement; micro-CT imaging observation shows that the bone cement is completely degraded and replaced by new bone after one year, and the aim of bone healing is achieved. From this, Ca is known_3.3Sr_0.2Mg_0.1Mn_0.1Co_0.1Eu_0.05Ce_0.05Sm_0.05La_0.05(PO₄)_1.8(SiO₄)_0.2O has good biocompatibility, degradation performance, vascularization capacity, osteogenesis performance and antibacterial and bacteriostatic performance, and can be used for repairing bone defects.

Example 11Ca_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.4(SiO₄)_0.5(BO₃)_0.1O powder

Weigh 4.075g Ca (OH)₂、0.2550gNaNO₃、0.3033gKNO₃、0.886gSrCO₃、1.0738gMn(NO₃)₂、2.698gFe(NO₃)₂、1.785gZn(NO₃)₂·6H₂O and 1.7463gCo (NO)₃)₂·6H₂Dissolving O in 100ml of deionized water to prepare a multi-ion mixed solution L1, adding 30ml of concentrated ammonia water, controlling the pH value to be 7.5-8, and stirring in a water bath at 50 ℃ for 30 min. Take 4.116gH₃PO₄、0.556gH₃BO₃And 2.760gNa₄SiO₄Dissolving in 48ml deionized water to prepare mixed solution L2 containing phosphorus and silicate ions; dripping the L2 solution into the L1 solution at the speed of 3ml/min under the ultrasonic wave auxiliary condition of 25kHz and 500W, and mixing and stirring for 4 hours to obtain the polyion codoped hydroxyapatite Ca_5.5K_0.3Na_0.3Sr_0.6Mn_0.6Co_0.6Fe_1.5Zn_0.6(PO₄)_4.2(SiO₄)_1.5(BO₃)_0.9(OH)₂Suspension L3. Separately weighing 4.723gCa (NO)₃)₂·4H₂O and 2.12gNa₂CO₃30ml of deionized water are respectively added to prepare solutions, and a calcium nitrate solution and a sodium carbonate solution are respectively added into the suspension L3 at the speed of 3ml/min under the ultrasonic wave assistance condition of 25kHz and 500W, and are mixed and stirred for 2 hours. And carrying out suction filtration on the reacted solution to obtain a precipitate, and repeatedly washing the precipitate for 3-4 times by using deionized water and ethanol. The precipitate was dried at 90 ℃ for 9 hours.

And finally, under the ultrasonic wave auxiliary condition of 25kHz and 2500W, placing the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in a crucible, quickly calcining for 1h at 1350 ℃ in a microwave oven of 2450MHz and 1500W, quickly cooling to 850 ℃ for 2h in a low-temperature section, and repeatedly and circularly calcining for 2 times at the temperature-rising speed of 950 ℃/min. Finally, the calcined product is cooled along with the furnace to obtain 11.48g of Ca with the phase purity higher than 99.8 percent, the crystallinity of 98 percent and the grain size of 0.2-5 mu m_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.4(SiO₄)_0.5(BO₃)_0.1And (3) O powder.

Adding Ca_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.4(SiO₄)_0.5(BO₃)_0.1Preparing bone cement slurry by the O powder and sodium carboxymethylcellulose aqueous solution, wherein the liquid/solid ratio is 0.55ml/1g, injecting the mixture into a stainless steel mould with the diameter of 5mm and the height of 12mm, curing the mixture for 18-25min, putting the stainless steel mould into a constant temperature box with the humidity of 100% RH, curing the mixture for 24 hours at 37 ℃, and taking out the stainless steel mould to obtain the bone cement slurry with the compressive strength of 45MPa +/-8 MPa. XRD analysis shows that the main crystal phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity.

By means of a healthy adult male New Zealand white rabbit femoral head ischemic necrosis bone defect model, bone morphogenetic protein and Ca are added_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.4(SiO₄)_0.5(BO₃)_0.1And mixing and filling the bone defect with O bone cement. Histological observations showed Ca obtained in example 9_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.5(SiO₄)_0.5Compared with O, a large amount of new bone is formed at 12 weeks, meanwhile, the degradation and the absorption are obvious, the volume of the bone cement is obviously reduced, a large amount of capillary vessels are seen to invade the inside of the bone cement, and no inflammatory reaction exists. From this, Ca is known_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.4

(SiO₄)_0.5(BO₃)_0.1The O-bone cement can be used for repairing bone defect and has antibacterial and bacteriostatic effects.

Example 12Ca_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.0(SiO₄)_0.5(BO₃)_0.5O powder

Weigh 4.075g Ca (OH)₂、0.2550gNaNO₃、0.3033gKNO₃、0.886gSrCO₃、1.0738gMn(NO₃)₂、2.698gFe(NO₃)₂、1.785gZn(NO₃)₂·6H₂O and 1.7463gCo (NO)₃)₂·6H₂Dissolving O in 100ml of deionized water to prepare a multi-ion mixed solution L1, adding 30ml of concentrated ammonia water, controlling the pH value to be 7.5-8, and stirring in a water bath at 50 ℃ for 30 min. Take 2.940gH₃PO₄、0.927gH₃BO₃And 2.760gNa₄SiO₄Dissolving in 48ml deionized water to prepare mixed solution L2 containing phosphorus and silicate ions; dripping the L2 solution into the L1 solution at the speed of 3.5ml/min under the ultrasonic wave auxiliary condition of 25kHz and 500W, and mixing and stirring for 6 hours to obtain the multi-ion co-doped hydroxyapatite Ca_5.5K_0.3Na_0.3Sr_0.6Mn_0.6Co_0.6Fe_1.5Zn_0.6(PO₄)_3.0(SiO₄)_1.5(BO₃)_1.5(OH)₂Suspension L3. Separately weighing 4.723gCa (NO)₃)₂·4H₂O and 2.12gNa₂CO₃30ml of deionized water are respectively added to prepare solutions, and a calcium nitrate solution and a sodium carbonate solution are respectively added into the suspension L3 at the speed of 3ml/min under the ultrasonic wave assistance condition of 25kHz and 500W, and are mixed and stirred for 5 hours. And (3) carrying out suction filtration on the solution after reaction to obtain a precipitate, and repeatedly washing the precipitate for 4 times by using deionized water and ethanol. The precipitate was dried at 90 ℃ for 12 hours.

And finally, under the ultrasonic wave auxiliary condition of 25kHz and 2500W, placing the multi-ion co-doped tetracalcium phosphate precursor in-situ composite powder in a crucible, quickly calcining for 1h at 1300 ℃ and high temperature in a microwave oven of 2450MHz and 1500W, then quickly cooling to 850 ℃ and calcining for 1h at a low temperature section, and repeating the cyclic calcination for 3 times, wherein the temperature rise speed is 950 ℃/min. Finally, the calcined product is cooled along with the furnace to obtain 10.34g of Ca with the phase purity higher than 99.8 percent, the crystallinity of 99 percent and the grain size of 0.1-10 mu m_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.0(SiO₄)_0.5(BO₃)_0.5And (3) O powder.

Adding Ca_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.0(SiO₄)_0.5(BO₃)_0.5Preparing bone cement slurry by the O powder and sodium carboxymethylcellulose aqueous solution, wherein the liquid/solid ratio is 0.6ml/1g, injecting the mixture into a stainless steel mould with the diameter of 5mm and the height of 12mm, curing for 22min, putting the stainless steel mould into a constant temperature box with the humidity of 100% RH at 37 ℃ for curing for 24 hours, and taking out the stainless steel mould to obtain the bone cement slurry with the compressive strength of 55MPa +/-10 MPa. XRD analysis shows that the main crystal phase of the hydration product is calcium-deficient hydroxyapatite with lower crystallinity.

Bone morphogenetic protein and Ca are mixed by means of a bone defect model of healthy adult male New Zealand white rabbits_2.5K_0.1Na_0.1Sr_0.2

Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.0(SiO₄)_0.5(BO₃)_0.5And mixing and filling the bone defect with O bone cement. Histological observations showed Ca obtained in example 9_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.5(SiO₄)_0.5Compared with O, new bone is formed around the bone cement at 8 weeks, a large amount of new bone is formed at 12 weeks, meanwhile, the degradation and absorption are more obvious, the volume of the bone cement is obviously reduced, a large amount of capillary vessels are formed in the bone cement, and no inflammatory reaction is seen. From this, Ca is known_2.5K_0.1Na_0.1

Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.0(SiO₄)_0.5(BO₃)_0.5The O-bone cement can be used for repairing bone defects, has rapid bone cell proliferation and antibacterial and bacteriostatic effects.

FIG. 10 shows the pH value of 1wt% solution prepared from different amounts of boron ions and multi-ion co-doped tetracalcium phosphate and deionized water with time. From this, it can be seen that Ca was obtained in example 9_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.5(SiO₄)_0.5Ca obtained in example 11 with O Final pH of 12.6_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_{0. 2}Fe_0.5Zn_0.2(PO₄)_1.4(SiO₄)_0.5(BO₃)_0.1O Final pH 9.6 and Ca obtained in example 12_2.5K_0.1Na_0.1Sr_0.2Mn_{0. 2}Co_0.2Fe_0.5Zn_0.2(PO₄)_1.0(SiO₄)_0.5(BO₃)_0.5O final pH 7.8, i.e. boron ion dopingThe impurity can obviously reduce the pH value of a hydration microenvironment around the multi-ion co-doped tetracalcium phosphate.

FIG. 11 shows Ca obtained in example 12_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.0(SiO₄)_0.5

(BO₃)_0.5Histological picture obtained after filling skull defect of New Zealand white rabbit with mixture of bone cement and bone morphogenetic protein for 3 weeks, showing that new bone formation around the bone cement occurred at 3 weeks, and Ca obtained in example 9_2.5K_0.1Na_0.1Sr_0.2Mn_0.2Co_0.2Fe_0.5Zn_0.2(PO₄)_1.5(SiO₄)_0.5Compared with the bone cement prepared by O, the bone cement is more beneficial to bone tissue proliferation.

Finally, it should be noted that: the above embodiments are only for illustrating the technical solutions of the present invention, and not for limiting the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may be modified or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims (9)

1. A synthesis method of multi-ion co-doped tetracalcium phosphate powder is characterized by comprising the following steps:

s1, according to Ca_10-xM_x(PO₄)_6-y-z(SiO₄)_y(BO₃)_z(OH)₂The molar amount of each element is shown, wherein, SiO₄ ^4-By introduction of silicic acid and/or suspensions or solutions of silicates, BO₃ ^3-By introducing boric acid and/or borate in suspension or solution, PO₄ ^3-Introduced by suspension or solution of phosphoric acid and/or phosphate to (Ca + M)/(P + Si +B) Respectively weighing calcium salt and a proper amount of metal salt containing M, phosphoric acid and/or phosphate, silicic acid and/or silicate and boric acid and/or borate with the molar ratio of 1.67 +/-0.2; respectively preparing a multi-ion mixed suspension or solution L1 containing calcium salt and metal salt containing M, and a suspension or solution L2 containing phosphoric acid and/or phosphate, silicic acid and/or silicate and boric acid and/or borate; slowly dropping suspension or solution L2 into suspension or solution L1 at a speed of 1-50 ml/min under the ultrasonic-assisted condition that the vibration frequency is 20-1000 kHz, controlling the stirring speed to be 10-300 rpm, the liquid-phase reaction temperature to be 40-90 ℃, and the reaction time to be 1-24 hours, and finally obtaining multi-ion co-doped hydroxyapatite particle suspension L3 with fine particles and uniform size, wherein M is selected from one or more of alkali metal, alkaline earth metal, transition metal and rare earth metal ions;

s2, according to Ca_4-xM_x(PO₄)_2-y-z(SiO₄)_y(BO₃)_zThe molar amount of each element shown as O is calculated, and based on the total molar ratio (Ca + M)/(P + Si + B) =2 +/-0.2, on the basis of deducting the molar amount of calcium in the polyion co-doped hydroxyapatite particles obtained in the step S1, appropriate amounts of calcium salt and carbonate are weighed and prepared into suspensions or solutions respectively; under the ultrasonic-assisted condition with the vibration frequency of 20-1000 kHz, synchronously and respectively dropping prepared calcium salt and carbonate suspension or solution into the multi-ion co-doped hydroxyapatite particle suspension L3 obtained in the step S1 at the speed of 1-50 ml/min, controlling the liquid phase reaction temperature to be 40-90 ℃, the stirring speed to be 10-300 rpm, reacting for 1-10 hours, aging for 5-24 hours, respectively washing for at least 3 times by using deionized water and/or ethanol, performing suction filtration, drying at 80-120 ℃ for 5-24 hours, and finally obtaining the multi-ion co-doped tetracalcium phosphate in-situ composite precursor powder of the in-situ precipitated nano calcium carbonate powder on the surface of the multi-ion co-doped hydroxyapatite particles;

s3, loading the multi-ion co-doped tetracalcium phosphate in-situ composite precursor powder obtained in the step S2 into a crucible, rapidly heating to 1000-1400 ℃ at a speed of 20-1000 ℃/min under the ultrasonic-assisted condition, then cooling to 850-1250 ℃, and rapidly heating to 1 ℃ at a speed of 20-1000 ℃/minSequentially and rapidly circulating and calcining for at least 1 time at 000-1400 ℃, wherein the accumulated time of the high-temperature section and the low-temperature section of the ultrasonic-assisted rapid circulating and calcining is 0.1-10 hours respectively, and cooling is carried out after the calcining is finished to obtain multi-ion co-doped tetracalcium phosphate powder; the composition general formula of the multi-ion co-doped tetracalcium phosphate powder is Ca _x4-M _x (PO₄) _y-z2-(SiO₄)_y(BO₃)_zO。

2. The method for synthesizing multi-ion co-doped tetracalcium phosphate powder according to claim 1, wherein the M-doped alkali metal ions are sodium and potassium ions; the M-doped alkaline earth metal ions are magnesium ions, calcium ions, strontium ions and barium ions; the M-doped transition group metal ions are aluminum, zinc, manganese, cobalt, iron, copper and silver ions; the M-doped rare earth metal ions are europium, samarium, terbium, cerium, lanthanum and neodymium ions.

3. The method for synthesizing multi-ion co-doped tetracalcium phosphate powder according to claim 1, wherein the phase purity of the multi-ion co-doped tetracalcium phosphate powder is greater than 98%, the crystallinity is greater than 50%, and the grain size is 0.01-50 μm.

4. The method for synthesizing multi-ion co-doped tetracalcium phosphate powder according to claim 1, wherein the molar concentration of the multi-ion mixed suspension or solution containing calcium salt and doped metal salt L1 in the S1 step is 0.5-1M; the molar concentration of the suspension or solution L2 of phosphoric acid and/or phosphate, silicic acid and/or silicate, boric acid and/or borate is 0.5-1M; and in the step S2, the molar concentrations of the calcium salt and the carbonate suspension or solution are respectively 0.5-1M.

5. The method for synthesizing multi-ion co-doped tetracalcium phosphate powder according to claim 1, wherein the pH of the multi-ion mixed suspension or solution L1 containing calcium salt and metal salt containing M in the step S1 is 7-13.

6. The method for synthesizing multi-ion co-doped tetracalcium phosphate powder according to claim 1, wherein the calcium salt is one or more of calcium nitrate, calcium nitrite, calcium bicarbonate, calcium dihydrogen phosphate, calcium chloride, calcium chlorate, calcium perchlorate, calcium acetate, calcium citrate, calcium lactate, and calcium glucose; the metal salt is one or more of nitrate, bicarbonate, chloride, chlorate, perchlorate, acetate, citrate, lactate and glucose salt; the phosphoric acid is one or more of orthophosphoric acid, metaphosphoric acid, pyrophosphoric acid, triphosphoric acid and polyphosphoric acid; the phosphate is one or more of potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, diammonium hydrogen phosphate and ammonium dihydrogen phosphate; the silicic acid or silicate is one or more of orthosilicic acid, metasilicic acid, disilicic acid, tetraethoxysilane, potassium silicate, sodium silicate and potassium sodium silicate; the boric acid or borate is one or more of orthoboric acid, sodium tetraborate, sodium borohydride, ammonium hydrogen borate and potassium borohydride; the carbonate is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate and ammonium bicarbonate.

7. The method for synthesizing multi-ion co-doped tetracalcium phosphate powder according to claim 1, wherein the rapid cyclic calcination can be performed by heating with a resistance furnace, microwave radiation heating with a frequency of 0.915-2.45 GHz ± 25MHz, or infrared radiation heating with a wavelength of 0.8-3.5 μm; after the rapid circulating calcination, the material can be cooled along with the furnace or taken out from a heat treatment furnace for air cooling or quenched into a container which is previously filled with dry ice and liquid nitrogen auxiliary cooling media for rapid cooling.

8. The multi-ion co-doped tetracalcium phosphate powder prepared by the method for synthesizing the multi-ion co-doped tetracalcium phosphate powder of any one of claims 1 to 7, wherein the composition general formula of the multi-ion co-doped tetracalcium phosphate powder is Ca_4-xM_x(PO₄)_2-y-z (SiO₄)_y(BO₃)_zO, wherein x is more than 0 and less than or equal to 1.5, y is more than 0 and less than or equal to 1, and z is more than or equal to 0 and less than or equal to 10.5, and the cation molar ratio of the polyion co-doped tetracalcium phosphate powder is (Ca + M)/(P + Si + B) =2 +/-0.2.

9. The application of the polyion codoped tetracalcium phosphate powder prepared by the polyion codoped tetracalcium phosphate powder synthesis method of any one of claims 1 to 7, wherein the pH of the microenvironment of the hydration product of the polyion codoped tetracalcium phosphate powder is less than 12, and the polyion codoped tetracalcium phosphate powder can be used for producing bone cement for tooth, jaw bone, spine, joint and other hard tissue restoration or dental root canal filling paste.

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