CN112618789A - Preparation method of temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement - Google Patents
Preparation method of temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement Download PDFInfo
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Abstract
The invention discloses a preparation method of calcium phosphate-based bone cement with temperature-magnetic field cooperative response drug release, which comprises the steps of firstly preparing modified Fe3O4Particles and forming SiO loaded with medicine on the surface2Coating; in Fe3O4@SiO2Forming polyelectrolyte shell on the surface of microsphere, liquid etching SiO2Forming a temperature-magnetic field double-response microcapsule after layering; coating P (NIPAM-AA) temperature sensitive hydrogel layer, and finally coating P (N)IPAM-AA) coated temperature-magnetic field dual-response microcapsules are mixed with a calcium phosphate bone cement solid phase, then mixed with a curing liquid, and added with a hydrogen peroxide blending liquid to form pores. When slight inflammation occurs, the calcium phosphate-based bone cement can release drugs autonomously and slowly, and when the inflammation is aggravated, the calcium phosphate-based bone cement can release drugs autonomously and quickly and can also control magnetic field response drugs manually; the magnetic field disappears, and the drug release speed is reduced; the inflammation disappears, the medicine stops releasing, and the medicine can be released in multiple responses.
Description
Technical Field
The invention belongs to the technical field of preparation of biomedical materials, and particularly relates to a preparation method of temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement.
Background
The bone implant can form a fibrous inflammation area due to the immunosuppression effect locally, the local body temperature can change along with the change of environmental conditions and diseases, the local temperature of slight inflammation is increased to 37-38 ℃, and the local temperature of severe inflammation is increased to 38-39 ℃. Drug-loaded Calcium Phosphate Cement (CPC) as a bone implant is currently the trend for local drug delivery studies at the surgical site. At present, the research on medicine-carrying CPC mainly focuses on a medicine slow-release system, the medicine slow-release system cannot achieve a timely treatment effect on infection or inflammation generated after being implanted into a human body for a period of time, and the problem that an implant can resist inflammation of different degrees cannot be completely solved. Therefore, the development of bone cement which can autonomously and slowly release drugs during light inflammation and autonomously accelerate and artificially regulate and control during heavy inflammation and can release drugs in a multi-response mode is one of the research focuses in the field at present.
Chinese patent 'calcium phosphate ceramic material carrying nano silver/berberine slow release coating and preparation method' (application number: CN109550078A, publication number: 109550078A) discloses a calcium phosphate ceramic material carrying nano silver/berberine slow release coating and a preparation method thereof, which comprises calcium phosphate ceramic and a nano silver/berberine composite slow release coating loaded on the surface of the calcium phosphate ceramic. The berberine is combined with the antibacterial effect of the nano-silver particles, the potential effect of the berberine in promoting cell osteogenic differentiation is fully exerted, the berberine and the nano-silver have a synergistic antibacterial effect, but the method cannot automatically release medicines in different inflammations.
Chinese patent "medicine microcapsule composite calcium-deficient calcium phosphate bone cement and use, preparation method and application" (application number: CN101905033A, publication number: 101905033B) discloses medicine microcapsule composite calcium-deficient calcium phosphate bone cement and use, preparation method and application. The bone cement is used by mixing the medicine microcapsule composite calcium-deficient calcium phosphate bone cement with the curing liquid physiological saline or other salt solutions uniformly and implanting the bone cement into a body. After the bone cement is implanted into a human body and cured, the drug is slowly released through the microstructure of a cured body; however, this method cannot achieve precise drug release when the implant is inflamed.
Chinese patent "intelligent controlled release bone cement with medicine carrying, its preparation method and application" (application No. CN111729131A, publication No. 111729131A) provides an intelligent controlled release bone cement with medicine carrying, its preparation method and application, the bone cement with medicine carrying comprises powder and liquid; the liquid-solid ratio of the powder and the liquid is 1 ml: 2-2.2 g. By adding the hollow polydopamine nano-particle/antibiotic drug-loaded microsphere, the drug loading is high and stable, the premature release of the drug is prevented, and the microsphere has pH responsiveness, can control the release of the drug according to the change of pH, but cannot control the release amount of the drug during slight inflammation and severe inflammation, and cannot realize the multi-response drug release.
Chinese patent "preparation method of gelatin microsphere/calcium phosphate cement composite multistage drug release carrier" (application No: CN200910068886.2, publication No: CN101564556A) discloses a preparation method of gelatin microsphere/calcium phosphate cement composite multistage drug release carrier, which obtains gelatin microspheres with different particle sizes by controlling the temperature and stirring time of vegetable oil, designs the type of encapsulated drugs according to the different degradation rates of the gelatin microspheres, thereby realizing the release of different drugs; but can not realize autonomous drug release according to the inflammation condition and can not respond to drug release for many times.
Chinese patent "preparation method of a drug-releasing calcium phosphate-based bone cement" (application No. CN202010391218.X, publication No. CN 111632191A) discloses a temperature-responsive drug-releasing calcium phosphate-based bone cement, which utilizes the characteristic that a phase-change material can be dissolved at 39 ℃, when local temperature rises to 39 ℃ when inflammation occurs, the phase-change material can be dissolved so as to release antibiotic, and the antibiotic enters an inflammation part through a network to diminish inflammation; the bone metabolism regulator in the mesoporous silicon dioxide can be slowly released through mesopores to promote bone ingrowth; antibiotics can be released automatically to diminish inflammation when inflammation occurs. But the response temperature is 39 ℃ of severe inflammation, and autonomous drug release in low inflammation cannot be realized.
Therefore, the development of bone cement which can autonomously and slowly release drugs during light inflammation and autonomously accelerate and artificially regulate and control drug release during heavy inflammation and can respond to drug release for many times is one of the important research points in the field at present.
Disclosure of Invention
The invention aims to provide a calcium phosphate-based bone cement with temperature-magnetic field cooperative response to release a drug, and solves the problems that the existing bone cement cannot release the drug autonomously in slight inflammation, cannot release the drug rapidly in severe inflammation and cannot respond to the drug release for many times.
The technical scheme adopted by the invention is as follows: a preparation method of temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement specifically comprises the following steps:
step 1, preparing PEG (polyethylene glycol) modified Fe3O4Particles;
step 2, modifying Fe with PEG3O4Preparation of Fe from particles3O4@SiO2Microspheres;
step 3, adding Fe3O4@SiO2Adding the microspheres into deionized water, adding the medicament, stirring, and drying in vacuum to obtain the Fe carrying the medicament3O4@SiO2Microspheres;
step 4, carrying the medicine Fe3O4@SiO2Dispersing the microspheres in a PU (polyurethane) aqueous solution, and collecting the microspheres by using a magnet for ultrasonic treatment; dispersing the microspheres in phospholipid aqueous solution, performing ultrasonic treatment, washing with deionized water, collecting magnetic spheres with magnet, and repeating the adsorption process for 3-10 times to obtain the carrierA drug temperature-magnetic field dual-response microcapsule precursor;
step 5, adding the drug-loading temperature-magnetic field double-response microcapsule precursor into a sodium hydroxide aqueous solution, stirring and drying to obtain a drug-loading temperature-magnetic field double-response microcapsule;
step 6, adding a mixed monomer of PNIPAM and AA into the drug-loading temperature-magnetic field dual-response microcapsule, then adding an MBA solution, stirring, adding an initiator, stirring for 30-120 s, and standing at room temperature for 6-24 h; washing and drying to obtain P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsules;
step 7, uniformly mixing the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule with the calcium phosphate bone cement solid phase to obtain calcium phosphate-based bone cement precursor solid phase powder;
and 8, stirring the calcium phosphate-based bone cement precursor solid phase powder and the curing liquid, adding the hydrogen peroxide blending liquid, stirring and injecting to obtain the calcium phosphate-based bone cement.
The present invention is also characterized in that,
in the step 1, the method specifically comprises the following steps: mixing Fe3O4Washing with a mixture of ethanol and water, and washing with Fe3O4Adding the particles into PEG aqueous solution, and stirring to obtain PEG modified Fe3O4Particles;
the mass ratio of ethanol to water is 1: 1; fe3O4The solid-to-liquid ratio of the particles to the PEG aqueous solution is 1: 100-300 g/ml; the mass fraction of the PEG aqueous solution is 2-8%; stirring for 12-36 h; PEG-modified Fe3O4The average particle diameter of the particles is 100 to 500 nm.
In the step 2, the method specifically comprises the following steps: modification of PEG with Fe3O4Adding the particles into the mixed solution A, stirring, and precipitating CTAB and SiO2And a n-hexane shell layer; collecting microspheres, refluxing in acetone solution to remove CTAB and n-hexane, washing to obtain Fe3O4@SiO2Microspheres;
PEG-modified Fe3O4The solid-liquid ratio of the particles to the mixed solution A is 1: 3-5 g/ml; the mixed solution A comprises the following components in percentage by massTetraethyl orthosilicate with the ratio of 2.5-4.5%, CTAB with the mass percent of 1.7-1.9% and n-hexane with the mass percent of 0.6-0.8%; fe3O4@SiO2The thickness of the silicon dioxide layer of the microsphere is 30-70 nm.
In the step 3, the medicine is an antibiotic medicine; the drug loading rate of the drug is 30-50%; the antibiotic medicine is any one of gentamicin, vancomycin hydrochloride, tobramycin sulfate, ciprofloxacin hydrochloride, nafcillin, linezolid, ceftriaxone, ampicillin trihydrate and amoxicillin; the stirring time is 6-48 h.
In step 4, carrying Fe3O4@SiO2The solid-liquid ratio of the microspheres to the PU aqueous solution is as follows: 1: 45-60 g/ml; fe3O4@SiO2The solid-liquid ratio of the microspheres to the phospholipid aqueous solution is 1: 45-60 g/ml; the mass fraction of the PU aqueous solution is 1.5-3.5%; the mass fraction of the phospholipid aqueous solution is 1.5-3.5%; the ultrasonic treatment time is 3-6 min.
In the step 5, the solid-to-liquid ratio of the drug-loading temperature-magnetic field double-response microcapsules to the sodium hydroxide aqueous solution is 1: 10-17 g/ml; the mass fraction of the sodium hydroxide aqueous solution is 20-60%; the average particle size of the drug-loading temperature-magnetic field dual-response microcapsule is 130-600 nm.
In step 6, the mass ratio of PNIPAM to AA is 92: 8; the mass percentage of MBA in the MBA solution in the mixed monomer is 5-10%; the initiator accounts for 0.5-2% of the total mixed monomers by mass; the initiator is any one of tetramethylethylenediamine, ammonium persulfate and azobisisobutyronitrile.
In the step 7, the mass percentage of the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 5-50%, the mass percentage of the calcium phosphate bone cement solid phase is 50-95%, and the sum of the mass percentages of the components is 100%; the calcium phosphate cement solid phase component consists of tetracalcium phosphate and calcium bicarbonate, wherein the weight percentage of the tetracalcium phosphate is 40-60%, and the weight percentage of the calcium bicarbonate is 40-60%.
In step 8, the solidifying liquid is any one of distilled water, blood, normal saline, dilute acid, serum and phosphate solution; the solid-liquid ratio of the calcium phosphate-based bone cement precursor solid-phase powder to the curing liquid is 1: 0.3-2.5 g/ml; the hydrogen peroxide blending liquid accounts for 6-10% of the total mass of the bone cement; the stirring time is 5-30 min.
The invention has the beneficial effects that:
the calcium phosphate-based bone cement with the temperature-magnetic field cooperative response drug release prepared by the method can realize the autonomous slow drug release when slight inflammation occurs, can further autonomously accelerate the drug release and can also manually control the magnetic field response drug when the inflammation is aggravated; the magnetic field disappears, and the drug release speed is reduced; the inflammation disappears, the medicine stops releasing, and can release medicine in response for many times, and simultaneously, the calcium phosphate-based bone cement prepared by the invention has better mechanical property than the traditional calcium phosphate bone cement, and has better application prospect in clinic.
Detailed Description
The present invention will be described in detail with reference to the following embodiments.
The invention relates to a preparation method of calcium phosphate-based bone cement with temperature-magnetic field cooperative response drug release, which is implemented according to the following steps:
step 1, preparation of modified Fe3O4Particle: mixing Fe3O4Washing with a mixture of ethanol and water, and washing with Fe3O4Adding the particles into PEG aqueous solution, and stirring to obtain PEG modified Fe3O4Particles; obtaining PEG modified Fe3O4Particles;
the mass ratio of the ethanol to the water is 1: 1; fe3O4The solid-liquid ratio of the particles to the aqueous solution of polyethylene glycol (PEG) is as follows: 1: 100-300 g/ml; the mass fraction of the PEG aqueous solution is 2-8%; stirring for 12-36 h;
PEG-modified Fe3O4The average particle diameter of the particles is 100 to 500 nm;
step 2, preparation of Fe3O4@SiO2Microsphere preparation: adding PEG modified Fe obtained in step 13O4Adding the particles into the mixed solution A, stirring, and precipitating Cetyl Trimethyl Ammonium Bromide (CTAB) and silicon dioxide (SiO)2) And isA hexane shell layer; collecting microspheres, refluxing in acetone solution to remove Cetyl Trimethyl Ammonium Bromide (CTAB) and n-hexane, and washing with ethanol to obtain Fe3O4@SiO2Microspheres;
PEG-modified Fe3O4The solid-liquid ratio of the particles to the mixed solution A is 1: 3-5 g/ml; the mixed solution A comprises tetraethyl orthosilicate of 2.5-4.5% by mass, Cetyl Trimethyl Ammonium Bromide (CTAB) of 1.7-1.9% by mass and n-hexane of 0.6-0.8% by mass;
prepared Fe3O4@SiO2The thickness of the silicon dioxide layer of the microsphere is 30-70 nm;
step 3, preparing drug-loaded Fe3O4@SiO2Microsphere preparation: mixing the Fe prepared in the step 23O4@SiO2Adding the microspheres into deionized water, adding the medicine, stirring for 6-48 h, and then drying in vacuum at normal temperature to obtain the Fe carrying medicine3O4@SiO2Microspheres;
the medicine is antibiotic medicine; the drug loading rate of the drug is 30-50%;
the antibiotic medicine is any one of gentamicin, vancomycin hydrochloride, tobramycin sulfate, ciprofloxacin hydrochloride, nafcillin, linezolid, ceftriaxone, ampicillin trihydrate and amoxicillin;
step 4, preparing a drug-loading temperature-magnetic field dual-response microcapsule precursor: carrying Fe3O4@SiO2Dispersing the microspheres in a Polyurethane (PU) aqueous solution, carrying out ultrasonic treatment for 3-6 min, and collecting the microspheres by using a magnet; dispersing the microspheres in a phospholipid aqueous solution, carrying out ultrasonic treatment for 3-6 min, washing with deionized water, collecting the magnetic spheres with a magnet, and repeating the adsorption process for 3-10 times to obtain a drug-loading temperature-magnetic field dual-response microcapsule precursor;
drug-loaded Fe3O4@SiO2The solid-liquid ratio of the microspheres to the Polyurethane (PU) aqueous solution is as follows: 1: 45-60 g/ml; fe3O4@SiO2The solid-liquid ratio of the microspheres to the phospholipid aqueous solution is 1: 45-60 g/ml;
the mass fraction of the Polyurethane (PU) aqueous solution is 1.5-3.5%; the mass fraction of the phospholipid aqueous solution is 1.5-3.5%;
step 5, preparing a drug-loading temperature-magnetic field double-response microcapsule: adding the drug-loading temperature-magnetic field double-response microcapsule precursor prepared in the step 4 into a sodium hydroxide aqueous solution, and stirring; then drying at normal temperature to obtain a drug-loading temperature-magnetic field double-response microcapsule;
the solid-liquid ratio of the drug-loading temperature-magnetic field double-response microcapsule to the sodium hydroxide aqueous solution is 1: 10-17 g/ml; the mass fraction of the sodium hydroxide aqueous solution is 20-60%;
the average particle size of the drug-loading temperature-magnetic field dual-response microcapsule is 130-600 nm;
step 6, adding a mixed monomer of poly (N-isopropylacrylamide) (PNIPAM) and Acrylic Acid (AA) into the drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 5, then adding an NN-Methylene Bisacrylamide (MBA) solution, fully stirring, then adding an initiator into the reacted solution, stirring for 30-120 s, and standing at room temperature for 6-24 h; washing and drying to obtain P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsules;
the mass ratio of the poly (N-isopropyl acrylamide) (PNIPAM) to the Acrylic Acid (AA) is 92: 8; the mass percent of MBA in the NN-Methylene Bisacrylamide (MBA) solution is 5-10% of that of the mixed monomer; the initiator accounts for 0.5-2% of the total mixed monomers by mass;
the initiator is any one of Tetramethylethylenediamine (TEMED), Ammonium Persulfate (AP) and azodiisobutyronitrile;
the average particle size of the prepared P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 140-650 nm;
step 7, preparing calcium phosphate-based bone cement precursor solid phase powder, and uniformly mixing the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 6 with a calcium phosphate bone cement solid phase to obtain the calcium phosphate-based bone cement precursor solid phase powder;
the mass percentage of the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 5-50%, the mass percentage of the calcium phosphate bone cement solid phase is 50-95%, and the sum of the mass percentages of the components is 100%;
the calcium phosphate cement solid phase component consists of tetracalcium phosphate and calcium bicarbonate, wherein the weight percentage of the tetracalcium phosphate is 40-60%, and the weight percentage of the calcium bicarbonate is 40-60%;
step 8, preparing calcium phosphate-based bone cement: and stirring the calcium phosphate-based bone cement precursor solid phase powder and the curing liquid, adding the hydrogen peroxide blending liquid, stirring and injecting to obtain the calcium phosphate-based bone cement.
The solidifying solution is any one of distilled water, blood, normal saline, dilute acid, serum and phosphate solution;
the solid-liquid ratio of the calcium phosphate-based bone cement precursor solid-phase powder to the curing liquid is 1: 0.3-2.5 g/ml;
the hydrogen peroxide blending liquid accounts for 6-10% of the total mass of the bone cement; the stirring time is 5-30 min.
The invention relates to a preparation method of calcium phosphate-based bone cement with temperature-magnetic field cooperative response drug release, which firstly prepares Fe modified by polyethylene glycol (PEG)3O4Particles; and in modifying Fe3O4SiO is formed on the surface of the particles2Coating to obtain Fe3O4@SiO2Microspheres, followed by Fe3O4@SiO2The microspheres load the drug; obtaining the drug-loaded Fe3O4@SiO2Microspheres; secondly, a layer-by-layer self-assembly method is adopted to carry out the preparation of Fe3O4@SiO2The surface of the microsphere adopts a material with opposite charges and temperature sensitivity to form a polyelectrolyte shell layer, and then SiO is etched by using a sodium hydroxide aqueous solution2A layer forming a temperature-magnetic field dual response microcapsule; and then coating a P (NIPAM-AA) temperature-sensitive hydrogel layer outside the temperature-magnetic field double-response microcapsule, finally uniformly mixing the P (NIPAM-AA) coated temperature-magnetic field double-response microcapsule with the calcium phosphate bone cement solid phase to obtain calcium phosphate-based bone cement precursor solid phase powder, mixing the calcium phosphate-based bone cement precursor solid phase powder with a curing solution, adding a hydrogen peroxide blending solution for pore forming, stirring and injecting to obtain the temperature-magnetic field synergistic response drug release porous calcium phosphate-based bone cement.
The advantages are that: 1. blending by adopting hydrogen peroxide blending liquid to ensure that the prepared calcium phosphate-based bone cement is porous calcium phosphate-based bone cement; 2. by utilizing the characteristic that the P (NIPAM-AA) temperature-sensitive hydrogel layer can be dissolved at 37 ℃, when slight inflammation occurs, the coated P (NIPAM-AA) temperature-sensitive hydrogel layer can be dissolved to promote the slow release of antibiotics; 3. by utilizing the characteristic that phospholipid in the polyelectrolyte layer is dissolved at 39-40 ℃, when local inflammation is aggravated to 39 ℃, the phospholipid is dissolved to further promote the release of antibiotics; 4. the magnetic field intensity can be artificially regulated and controlled, so that the magnetic particle core promotes the polyelectrolyte shell layer to deform in different degrees, thereby releasing the antibiotic in the middle layer in different degrees and further promoting the treatment of severe inflammation; 5. when the magnetic field is removed, the drug release speed is slow, when the inflammation disappears, the temperature sensitive layer is closed, the drug is not released any more, and the drug release can be realized by multiple responses; 6. the magnetic nano particles have the function of improving the mechanical property of calcium phosphate cement; therefore, the temperature-magnetic field cooperative response drug release reduces the drug resistance problem of the drug release system to a certain extent, realizes intelligent drug release when inflammation occurs, and has better application prospect clinically.
Example 1
The invention relates to a preparation method of calcium phosphate-based bone cement with temperature-magnetic field cooperative response drug release, which is implemented according to the following steps:
step 1, preparation of modified Fe3O4Particle: mixing Fe3O4Washing with a mixture of ethanol and water, and washing with Fe3O4Adding the particles into PEG aqueous solution, and stirring to obtain PEG modified Fe3O4Particles;
the mass ratio of the mixed solution of ethanol and water is 1: 1; fe3O4The solid-liquid ratio of the particles to the aqueous solution of polyethylene glycol (PEG) is as follows: 1:100 g/ml; the mass fraction of the PEG aqueous solution is 2 percent; the stirring time is 12 h;
PEG-modified Fe3O4The average particle size of the particles is 500 nm;
step 2, preparation of Fe3O4@SiO2Microsphere preparation: adding PEG modified Fe obtained in step 13O4Adding the particles into the mixed solution A, stirring, and precipitatingHexaalkyltrimethylammonium bromide (CTAB), Silica (SiO)2) And a n-hexane shell layer; collecting microspheres, refluxing in acetone solution to remove Cetyl Trimethyl Ammonium Bromide (CTAB) and n-hexane, and washing with ethanol to obtain Fe3O4@SiO2Microspheres;
PEG-modified Fe3O4The solid-to-liquid ratio of the particles to the mixed solution A is 1:3 g/ml; the mixed solution A contains tetraethyl orthosilicate with the mass percent of 2.5%, hexadecyl trimethyl ammonium bromide (CTAB) with the mass percent of 1.7% and n-hexane with the mass percent of 0.6%;
prepared Fe3O4@SiO2The thickness of the silicon dioxide layer of the microsphere is 30 nm;
step 3, preparing drug-loaded Fe3O4@SiO2Microsphere preparation: mixing the Fe prepared in the step 23O4@SiO2Adding the granules into deionized water, adding gentamicin (with a drug loading rate of 30%), stirring for 6h, and then drying in vacuum at normal temperature to obtain drug-loaded Fe3O4@SiO2Microspheres;
step 4, preparing a drug-loading temperature-magnetic field dual-response microcapsule precursor: carrying Fe3O4@SiO2Dispersing the microspheres in a Polyurethane (PU) aqueous solution, carrying out ultrasonic treatment for 3min, and collecting the microspheres by using a magnet; the microspheres were then dispersed in aqueous phospholipid solution, sonicated for 3min, washed with deionized water and the magnetic spheres were collected with a magnet. Repeating the adsorption process for 3 times to obtain a drug-loading temperature-magnetic field dual-response microcapsule precursor;
drug-loaded Fe3O4@SiO2The solid-liquid ratio of the microspheres to the Polyurethane (PU) aqueous solution is 1: 45-60 g/ml; fe3O4@SiO2The solid-to-liquid ratio of the microspheres to the phospholipid aqueous solution is 1:45 g/ml;
the mass fraction of the Polyurethane (PU) aqueous solution is 1.5 percent; the mass fraction of the phospholipid aqueous solution is 1.5%;
step 5, preparing a drug-loading temperature-magnetic field double-response microcapsule: adding the drug-loaded magnetic response microcapsule precursor prepared in the step 4 into a sodium hydroxide aqueous solution and stirring; then drying at normal temperature to obtain a drug-loading temperature-magnetic field double-response microcapsule;
the solid-liquid ratio of the drug-loading temperature-magnetic field double-response microcapsules to the sodium hydroxide aqueous solution is 1:10 g/ml; the mass fraction of the sodium hydroxide aqueous solution is 20 percent; the average grain diameter of the drug-loading temperature-magnetic field dual-response microcapsule is 600 nm;
step 6, adding a poly (N-isopropylacrylamide) (PNIPAM) and Acrylic Acid (AA) mixed monomer into the drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 5, then adding an NN-Methylene Bisacrylamide (MBA) solution, fully stirring, then adding an initiator into the reacted solution, stirring for 30s, and standing at room temperature for 6 h; washing and drying to obtain P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsules;
the mass ratio of the poly (N-isopropylacrylamide) (PNIPAM) to the Acrylic Acid (AA) is 92: 8; the mass percent of MBA in the NN-Methylene Bisacrylamide (MBA) solution is 5 percent of that of the mixed monomer; the initiator accounts for 0.5 percent of the total monomer by mass; the initiator is Ammonium Persulfate (AP); the average particle size of the prepared P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 650 nm;
step 7, preparing calcium phosphate-based bone cement precursor solid phase powder, and uniformly mixing the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 6 with a calcium phosphate bone cement solid phase to obtain the calcium phosphate-based bone cement precursor solid phase powder;
the mass percentage of the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 5 percent, the mass percentage of the calcium phosphate bone cement solid phase is 95 percent, and the sum of the mass percentages of the components is 100 percent;
the calcium phosphate bone cement solid phase component consists of tetracalcium phosphate with the mass percentage of 40% and calcium bicarbonate with the mass percentage of 60%;
step 8, preparing calcium phosphate-based bone cement: and stirring the calcium phosphate-based bone cement precursor solid phase powder and distilled water, adding the hydrogen peroxide blending solution, stirring and injecting to obtain the calcium phosphate-based bone cement.
The solid-to-liquid ratio of the calcium phosphate-based bone cement precursor solid-phase powder to the curing liquid is 1:0.3 g/ml; the hydrogen peroxide blending liquid accounts for 6 percent of the total mass of the bone cement; the stirring time was 5 min.
Example 2
The invention relates to a preparation method of calcium phosphate-based bone cement with temperature-magnetic field cooperative response drug release, which is implemented according to the following steps:
step 1, preparation of modified Fe3O4Particle: mixing Fe3O4Washing with a mixture of ethanol and water, and washing with Fe3O4Adding the particles into PEG aqueous solution, and stirring to obtain PEG modified Fe3O4Particles;
the mass ratio of the mixed solution of ethanol and water is 1: 1; fe3O4The solid-liquid ratio of the particles to the aqueous solution of polyethylene glycol (PEG) is as follows: 1:150 g/ml; the mass fraction of the PEG aqueous solution is 4 percent; the stirring time is 18 h;
PEG-modified Fe3O4The average particle size of the particles is 200 nm;
step 2, preparation of Fe3O4@SiO2Microsphere preparation: adding PEG modified Fe obtained in step 13O4Adding the particles into the mixed solution A, stirring, and precipitating Cetyl Trimethyl Ammonium Bromide (CTAB) and silicon dioxide (SiO)2) And a n-hexane shell layer; collecting microspheres, refluxing in acetone solution to remove Cetyl Trimethyl Ammonium Bromide (CTAB) and n-hexane, and washing with ethanol to obtain Fe3O4@SiO2Microspheres;
PEG-modified Fe3O4The solid-to-liquid ratio of the particles to the mixed solution A is 1:3.5 g/ml; the mixed solution A comprises tetraethyl orthosilicate with the mass percentage of 3%, hexadecyl trimethyl ammonium bromide (CTAB) with the mass percentage of 1.75% and n-hexane with the mass percentage of 0.65%;
prepared Fe3O4@SiO2The thickness of the silicon dioxide layer of the microsphere is 40 nm;
step 3, preparing drug-loaded Fe3O4@SiO2Microsphere preparation: mixing the Fe prepared in the step 23O4@SiO2Adding the granules into deionized water, adding nafcillin, stirring for 20h with the drug loading rate of 35%, and then drying in vacuum at normal temperature to obtain the carrierMedicine Fe3O4@SiO2Microspheres;
step 4, preparing a drug-loading temperature-magnetic field dual-response microcapsule precursor: carrying Fe3O4@SiO2Dispersing the microspheres in a Polyurethane (PU) aqueous solution, carrying out ultrasonic treatment for 4min, and collecting the microspheres by using a magnet; the microspheres were then dispersed in aqueous phospholipid solution, sonicated for 4min, washed with deionized water and the magnetic spheres were collected with a magnet. Repeating the adsorption process for 4 times to obtain a drug-loading temperature-magnetic field dual-response microcapsule precursor;
step 4 carrying Fe3O4@SiO2The solid-liquid ratio of the microspheres to the Polyurethane (PU) aqueous solution is as follows: 1:50 g/ml; fe3O4@SiO2The solid-to-liquid ratio of the microspheres to the phospholipid aqueous solution is 1:50 g/ml;
the mass fraction of the Polyurethane (PU) aqueous solution is 2 percent; the mass fraction of the phospholipid aqueous solution is 2 percent;
step 5, preparing a drug-loading temperature-magnetic field double-response microcapsule: adding the drug-loaded magnetic response microcapsule precursor prepared in the step 4 into a sodium hydroxide aqueous solution and stirring; then drying at normal temperature to obtain a drug-loading temperature-magnetic field double-response microcapsule;
the solid-liquid ratio of the drug-loading temperature-magnetic field double-response microcapsules to the sodium hydroxide aqueous solution is 1:13 g/ml; the mass fraction of the sodium hydroxide aqueous solution is 30 percent; the average grain diameter of the drug-loading temperature-magnetic field dual-response microcapsule is 240 nm;
step 6, adding a poly (N-isopropylacrylamide) (PNIPAM) and Acrylic Acid (AA) mixed monomer into the drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 5, then adding an NN-Methylene Bisacrylamide (MBA) solution, fully stirring, then adding an initiator into the reacted solution, stirring for 50s, and standing at room temperature for 10 h; washing and drying to obtain P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsules;
the mass ratio of the poly (N-isopropylacrylamide) (PNIPAM) to the Acrylic Acid (AA) is 92: 8; the mass percent of MBA in the NN-Methylene Bisacrylamide (MBA) solution is 6 percent of that of the mixed monomer; the initiator accounts for 0.6 percent of the total monomer by mass; the initiator is Tetramethylethylenediamine (TEMED); the average particle size of the prepared P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 260 nm;
step 7, preparing calcium phosphate-based bone cement precursor solid phase powder, and uniformly mixing the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 6 with a calcium phosphate bone cement solid phase to obtain the calcium phosphate-based bone cement precursor solid phase powder;
the mass percentage of the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 25 percent, the mass percentage of the calcium phosphate bone cement solid phase is 75 percent, and the sum of the mass percentages of the components is 100 percent;
the calcium phosphate bone cement solid phase component consists of 45 mass percent of tetracalcium phosphate and 55 mass percent of calcium bicarbonate;
step 8, preparing calcium phosphate-based bone cement: stirring the calcium phosphate-based bone cement precursor solid phase powder and blood, adding the hydrogen peroxide blending solution, stirring and injecting to obtain the calcium phosphate-based bone cement.
The solid-to-liquid ratio of the calcium phosphate-based bone cement precursor solid-phase powder to the curing liquid is 1:0.65 g/ml; the hydrogen peroxide blending liquid accounts for 7 percent of the total mass of the bone cement; the stirring time was 15 min.
Example 3
The invention relates to a preparation method of calcium phosphate-based bone cement with temperature-magnetic field cooperative response drug release, which is implemented according to the following steps:
step 1, preparation of modified Fe3O4Particle: mixing Fe3O4Washing with a mixture of ethanol and water, and washing with Fe3O4Adding the particles into PEG aqueous solution, and stirring to obtain PEG modified Fe3O4Particles;
the mass ratio of the mixed solution of ethanol and water is 1: 1; fe3O4The solid-liquid ratio of the particles to the aqueous solution of polyethylene glycol (PEG) is as follows: 1:200 g/ml; the mass fraction of the PEG aqueous solution is 5 percent; stirring for 24 h;
PEG-modified Fe3O4The average particle size of the particles is 300 nm;
step 2, preparation of Fe3O4@SiO2Microsphere preparation: adding PEG modified Fe obtained in step 13O4Adding the particles into the mixed solution A, stirring, and precipitating Cetyl Trimethyl Ammonium Bromide (CTAB) and silicon dioxide (SiO)2) And a n-hexane shell layer; collecting microspheres, refluxing in acetone solution to remove Cetyl Trimethyl Ammonium Bromide (CTAB) and n-hexane, and washing with ethanol to obtain Fe3O4@SiO2Microspheres;
PEG-modified Fe3O4The solid-to-liquid ratio of the particles to the mixed solution A is 1:4 g/ml; the mixed solution a contained 3.5% by mass of tetraethyl orthosilicate, 1.8% by mass of cetyltrimethylammonium bromide (CTAB), and 0.7% by mass of n-hexane;
prepared Fe3O4@SiO2The thickness of the silicon dioxide layer of the microsphere is 50 nm;
step 3, preparing drug-loaded Fe3O4@SiO2Microsphere preparation: mixing the Fe prepared in the step 23O4@SiO2Adding the particles into deionized water, and then adding ciprofloxacin hydrochloride, wherein the drug loading rate of the drug is 40%; stirring for 27h, and then drying in vacuum at normal temperature to obtain the drug-loaded Fe3O4@SiO2Microspheres;
step 4, preparing a drug-loading temperature-magnetic field dual-response microcapsule precursor: carrying Fe3O4@SiO2Dispersing the microspheres in a Polyurethane (PU) aqueous solution, carrying out ultrasonic treatment for 4.5min, and collecting the microspheres by using a magnet; the microspheres were then dispersed in aqueous phospholipid solution, sonicated for 4.5min, washed with deionized water and the magnetic spheres were collected with a magnet. Repeating the adsorption process for 6 times to obtain a drug-loading temperature-magnetic field dual-response microcapsule precursor;
drug-loaded Fe3O4@SiO2The solid-liquid ratio of the microspheres to the Polyurethane (PU) aqueous solution is as follows: 1:53 g/ml; fe3O4@SiO2The solid-to-liquid ratio of the microspheres to the phospholipid aqueous solution is 1:53 g/ml;
the mass fraction of the Polyurethane (PU) aqueous solution is 2.5 percent; the mass fraction of the phospholipid aqueous solution is 2.5 percent;
step 5, preparing a drug-loading temperature-magnetic field double-response microcapsule: adding the drug-loaded magnetic response microcapsule precursor prepared in the step 4 into a sodium hydroxide aqueous solution and stirring; then drying at normal temperature to obtain a drug-loading temperature-magnetic field double-response microcapsule;
the solid-liquid ratio of the drug-loading temperature-magnetic field double-response microcapsules to the sodium hydroxide aqueous solution is 1:13.5 g/ml; the mass fraction of the sodium hydroxide aqueous solution is 40 percent; the average particle size of the drug-loading temperature-magnetic field dual-response microcapsule is 365 nm;
step 6, adding a poly (N-isopropylacrylamide) (PNIPAM) and Acrylic Acid (AA) mixed monomer into the drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 5, fully stirring NN-Methylene Bisacrylamide (MBA) solution, then adding an initiator into the reacted solution, stirring for 80s, and standing at room temperature for 15 h; washing and drying to obtain P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsules;
the mass ratio of the poly (N-isopropylacrylamide) (PNIPAM) to the Acrylic Acid (AA) is 92: 8; the mass percent of MBA in the NN-Methylene Bisacrylamide (MBA) solution is 7 percent of that of the mixed monomer; the initiator accounts for 1.25 percent of the total monomer by mass; the initiator is azobisisobutyronitrile; the average particle size of the prepared P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 405 nm;
step 7, preparing calcium phosphate-based bone cement precursor solid phase powder, and uniformly mixing the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 6 with a calcium phosphate bone cement solid phase to obtain the calcium phosphate-based bone cement precursor solid phase powder;
the mass percentage of the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 27.5 percent, the mass percentage of the calcium phosphate bone cement solid phase is 72.5 percent, and the sum of the mass percentages of the components is 100 percent;
the calcium phosphate bone cement solid phase component consists of 50 percent by mass of tetracalcium phosphate and 50 percent by mass of calcium bicarbonate;
step 8, preparing calcium phosphate-based bone cement: stirring the calcium phosphate-based bone cement precursor solid powder and dilute acid, adding the hydrogen peroxide blending solution, stirring and injecting to obtain the calcium phosphate-based bone cement.
The solid-to-liquid ratio of the calcium phosphate-based bone cement precursor solid-phase powder to the curing liquid is 1:1.4 g/ml; the hydrogen peroxide blending liquid accounts for 8 percent of the total mass of the bone cement; the stirring time was 17.5 min.
Example 4
The invention relates to a preparation method of calcium phosphate-based bone cement with temperature-magnetic field cooperative response drug release, which is implemented according to the following steps:
step 1, preparation of modified Fe3O4Particle: mixing Fe3O4Washing with a mixture of ethanol and water, and washing with Fe3O4Adding the particles into PEG aqueous solution, and stirring to obtain PEG modified Fe3O4Particles;
the mass ratio of the ethanol to the water is 1: 1; fe3O4The solid-liquid ratio of the particles to the aqueous solution of polyethylene glycol (PEG) is as follows: 1:250 g/ml; the mass fraction of the PEG aqueous solution is 6 percent; the stirring time is 30 h;
PEG-modified Fe3O4The average particle size of the particles is 400 nm;
step 2, preparation of Fe3O4@SiO2Microsphere preparation: adding PEG modified Fe obtained in step 13O4Adding the particles into the mixed solution A, stirring, and precipitating Cetyl Trimethyl Ammonium Bromide (CTAB) and silicon dioxide (SiO)2) And a n-hexane shell layer; collecting microspheres, refluxing in acetone solution to remove Cetyl Trimethyl Ammonium Bromide (CTAB) and n-hexane, and washing with ethanol to obtain Fe3O4@SiO2Microspheres;
PEG-modified Fe3O4The solid-to-liquid ratio of the particles to the mixed solution A is 1:4.5 g/ml; the mixed solution A comprises tetraethyl orthosilicate with the mass percent of 4%, hexadecyl trimethyl ammonium bromide (CTAB) with the mass percent of 1.85% and n-hexane with the mass percent of 0.75%;
prepared Fe3O4@SiO2The thickness of the silicon dioxide layer of the microsphere is 60 nm;
step 3, preparing drug-loaded Fe3O4@SiO2Microsphere preparation: mixing the Fe prepared in the step 23O4@SiO2Adding the granules into deionized water, and then adding ampicillin trihydrate, wherein the drug loading rate of the drug is 45%; stirring for 36h, and then drying in vacuum at normal temperature to obtain the drug-loaded Fe3O4@SiO2Microspheres;
step 4, preparing a drug-loading temperature-magnetic field dual-response microcapsule precursor: carrying Fe3O4@SiO2Dispersing the microspheres in a Polyurethane (PU) aqueous solution, carrying out ultrasonic treatment for 5min, and collecting the microspheres by using a magnet; the microspheres were then dispersed in an aqueous phospholipid solution, sonicated for 5min, washed with deionized water and the magnetic spheres were collected with a magnet. Repeating the adsorption process for 8 times to obtain a drug-loading temperature-magnetic field dual-response microcapsule precursor;
drug-loaded Fe3O4@SiO2The solid-liquid ratio of the microspheres to the Polyurethane (PU) aqueous solution is 1:55 g/ml; fe3O4@SiO2The solid-to-liquid ratio of the microspheres to the phospholipid aqueous solution is 1:55 g/ml;
the mass fraction of the Polyurethane (PU) aqueous solution is 3 percent; the mass fraction of the phospholipid aqueous solution is 3 percent;
step 5, preparing a drug-loading temperature-magnetic field double-response microcapsule: adding the drug-loaded magnetic response microcapsule precursor prepared in the step 4 into a sodium hydroxide aqueous solution and stirring; then drying at normal temperature to obtain a drug-loading temperature-magnetic field double-response microcapsule;
the solid-liquid ratio of the drug-loading temperature-magnetic field double-response microcapsules to the sodium hydroxide aqueous solution is 1:15 g/ml; the mass fraction of the sodium hydroxide aqueous solution is 50 percent;
the average grain diameter of the drug-loading temperature-magnetic field dual-response microcapsule is 500 nm;
step 6, adding a poly (N-isopropylacrylamide) (PNIPAM) and Acrylic Acid (AA) mixed monomer into the drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 5, fully stirring NN-Methylene Bisacrylamide (MBA) solution, then adding an initiator into the reacted solution, stirring for 100s, and standing at room temperature for 20 h; washing and drying to obtain P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsules;
the mass ratio of the poly (N-isopropyl acrylamide) (PNIPAM) to the Acrylic Acid (AA) is 92: 8; the mass percent of MBA in the NN-Methylene Bisacrylamide (MBA) solution is 9 percent of that of the mixed monomer; the initiator accounts for 1.5 percent of the total monomer by mass; the initiator is azobisisobutyronitrile; the average particle size of the prepared P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 540 nm;
step 7, preparing calcium phosphate-based bone cement precursor solid phase powder, and uniformly mixing the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 6 with a calcium phosphate bone cement solid phase to obtain the calcium phosphate-based bone cement precursor solid phase powder;
the mass percentage of the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 35 percent, the mass percentage of the calcium phosphate bone cement solid phase is 65 percent, and the sum of the mass percentages of the components is 100 percent;
the calcium phosphate bone cement solid phase component consists of 45 mass percent of tetracalcium phosphate and 55 mass percent of calcium bicarbonate;
step 8, preparing calcium phosphate-based bone cement: stirring the calcium phosphate-based bone cement precursor solid powder and dilute acid, adding the hydrogen peroxide blending solution, stirring and injecting to obtain the calcium phosphate-based bone cement.
The solid-liquid ratio of the calcium phosphate-based bone cement precursor solid-phase powder to the curing liquid is 1: 2.2 g/ml; the hydrogen peroxide blending liquid accounts for 9 percent of the total mass of the bone cement; the stirring time was 25 min.
Example 5
The invention relates to a preparation method of calcium phosphate-based bone cement with temperature-magnetic field cooperative response drug release, which is implemented according to the following steps:
step 1, preparation of modified Fe3O4Particle: mixing Fe3O4Washing with a mixture of ethanol and water, and washing with Fe3O4Adding the particles into PEG aqueous solution, and stirring to obtain PEG modified Fe3O4Particles;
the mass ratio of the ethanol to the water is 1: 1; fe3O4The solid-liquid ratio of the particles to the aqueous solution of polyethylene glycol (PEG) is as follows: 1:300 g/ml; the mass fraction of the PEG aqueous solution is 8 percent; stirring for 36 h;
PEG-modified Fe3O4The average particle size of the particles is 100 nm;
step 2, preparation of Fe3O4@SiO2Microsphere preparation: adding PEG modified Fe obtained in step 13O4Adding the particles into the mixed solution A, stirring, and precipitating Cetyl Trimethyl Ammonium Bromide (CTAB) and silicon dioxide (SiO)2) And a n-hexane shell layer; collecting microspheres, refluxing in acetone solution to remove Cetyl Trimethyl Ammonium Bromide (CTAB) and n-hexane, and washing with ethanol to obtain Fe3O4@SiO2Microspheres;
PEG-modified Fe3O4The solid-to-liquid ratio of the particles to the mixed solution A is 1:5 g/ml; the mixed solution A contains tetraethyl orthosilicate with the mass percent of 4.5%, hexadecyl trimethyl ammonium bromide (CTAB) with the mass percent of 1.9% and n-hexane with the mass percent of 0.8%;
Fe3O4@SiO2the thickness of the silicon dioxide layer of the microsphere is 70 nm;
step 3, preparing drug-loaded Fe3O4@SiO2Microsphere preparation: mixing the Fe prepared in the step 23O4@SiO2Adding the granules into deionized water, adding amoxicillin, stirring for 48h with the drug loading rate of 50%, and vacuum drying at normal temperature to obtain Fe loaded with drug3O4@SiO2Microspheres;
step 4, preparing a drug-loading temperature-magnetic field dual-response microcapsule precursor: carrying Fe3O4@SiO2Dispersing the microspheres in a Polyurethane (PU) aqueous solution, carrying out ultrasonic treatment for 6min, and collecting the microspheres by using a magnet; the microspheres were then dispersed in aqueous phospholipid solution, sonicated for 6min, washed with deionized water and the magnetic spheres were collected with a magnet. Repeating the adsorption process for 10 times to obtain a drug-loading temperature-magnetic field dual-response microcapsule precursor;
drug-loaded Fe3O4@SiO2The solid-liquid ratio of the microspheres to the Polyurethane (PU) aqueous solution is 1: 45-60 g/ml; fe3O4@SiO2The solid-to-liquid ratio of the microspheres to the phospholipid aqueous solution is 1:60 g/ml;
the mass fraction of the Polyurethane (PU) aqueous solution is 3.5 percent; the mass fraction of the phospholipid aqueous solution is 3.5%;
step 5, preparing a drug-loading temperature-magnetic field double-response microcapsule: adding the drug-loaded magnetic response microcapsule precursor prepared in the step 4 into a sodium hydroxide aqueous solution and stirring; then drying at normal temperature to obtain a drug-loading temperature-magnetic field double-response microcapsule;
the solid-liquid ratio of the drug-loading temperature-magnetic field double-response microcapsules to the sodium hydroxide aqueous solution is 1:17 g/ml; the mass fraction of the sodium hydroxide aqueous solution is 60 percent;
the average particle size of the drug-loading temperature-magnetic field dual-response microcapsule is 130 nm;
step 6, adding a poly (N-isopropylacrylamide) (PNIPAM) and Acrylic Acid (AA) mixed monomer into the drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 5, then adding an NN-Methylene Bisacrylamide (MBA) solution, fully stirring, then adding an initiator into the reacted solution, stirring for 120s, and standing at room temperature for 24 h; washing and drying to obtain P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsules;
the mass ratio of the poly (N-isopropylacrylamide) (PNIPAM) to the Acrylic Acid (AA) is 92: 8; the mass percent of MBA in the NN-Methylene Bisacrylamide (MBA) solution is 10 percent of that of the mixed monomer; the initiator accounts for 2 percent of the total monomer by mass; the initiator is Ammonium Persulfate (AP); the average particle size of the prepared P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 140 nm;
step 7, preparing calcium phosphate-based bone cement precursor solid phase powder, and uniformly mixing the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule obtained in the step 6 with a calcium phosphate bone cement solid phase to obtain the calcium phosphate-based bone cement precursor solid phase powder;
the mass percent of the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule is 50 percent, the mass percent of the calcium phosphate bone cement solid phase is 50 percent, and the sum of the mass percent of the components is 100 percent;
the calcium phosphate bone cement solid phase component consists of 60 percent by mass of tetracalcium phosphate and 40 percent by mass of calcium bicarbonate;
step 8, preparing calcium phosphate-based bone cement: and stirring the calcium phosphate-based bone cement precursor solid phase powder and the phosphate solution, adding the hydrogen peroxide blending solution, stirring and injecting to obtain the calcium phosphate-based bone cement.
The solid-to-liquid ratio of the calcium phosphate-based bone cement precursor solid-phase powder to the curing liquid is 1:2.5 g/ml; the hydrogen peroxide blending liquid accounts for 10 percent of the total mass of the bone cement; the stirring time was 30 min.
The release rates of antibiotics at normal and low inflammation temperatures and high inflammation and with magnetic field control of a calcium phosphate-based bone cement prepared in examples 1, 2, 3, 4 and 5 of the present invention and a conventional calcium phosphate bone cement are shown in tables 1 and 2:
TABLE 1 antibiotic Release Rate at Normal and Low inflammation temperatures
As can be seen from Table 1, the bone cement prepared by the invention does not release drug when inflammation does not occur; when slight inflammation occurs, the bone cement prepared by the invention is subjected to drug sustained release, the maximum drug release amount in 30 days reaches 40.4%, and the maximum drug release amount in 60 days reaches 51.3%; and it can be seen from examples 1 to 5 that: with the content of the hydrogen peroxide foaming agent from 6% to 10%, the drug release amount is continuously increased from 16.8% to 40.4%, because the hydrogen peroxide foaming agent promotes the calcium phosphate cement to become porous calcium phosphate cement, antibiotics can be released through the pore channels, the more pores are formed, and the faster the drug is released.
TABLE 2 Low and high inflammation and antibiotic release rates with magnetic field control
It can be seen from table 2 that the drug release amount is increased at high inflammation without application of a magnetic field, because the phospholipid melting at 39 ℃ further promotes the drug release; when a low magnetic field strength is applied, the release rate of the bone cement is increased, and when a high magnetic field strength is applied, the release rate is further increased, so that when inflammation is serious, the release amount of the bone cement can be controlled by manually regulating different magnetic field strengths; examples 1-5, the drug release rate increased with increasing proportion of the added magnetically responsive microcapsules. Compared with the traditional medicine-releasing bone cement, the bone cement prepared by the invention can automatically release medicine in low inflammation, can be only regulated and artificially promoted in high inflammation, can control the medicine release according to the magnetic field intensity and the content of the magnetic response microcapsule, and is expected to become a promising clinical application bone cement.
The calcium phosphate-based bone cement prepared in examples 1, 2, 3, 4 and 5 of the present invention and the conventional calcium phosphate bone cement were immersed in the simulated body fluid at normal temperature for 0, 30 and 60 days to observe the change in compressive strength, as shown in table 3;
TABLE 3 comparison of the compressive strengths of the present invention and conventional CPC at room temperature for 0d, 30d, and 60d
As can be seen from Table 3, the mechanical properties of the temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement prepared by the invention are increased along with the increase of the magnetic response microcapsules; and the compressive strength is not changed basically along with the change of the soaking time, thereby laying a foundation for clinical application.
In order to test the drug release conditions when different inflammations occur, the test drug rates of the calcium phosphate-based bone cement prepared in examples 1, 2, 3, 4 and 5 and the traditional calcium phosphate bone cement are respectively measured in simulated body fluids under different inflammations at 37.5 ℃ and 39 ℃, meanwhile, the magnetic field strength is respectively applied for 0 and 0.5T for 10min under high inflammation at 39 ℃, the release is recorded as first response release, then the calcium phosphate-based bone cement is placed for 24h at normal temperature and then placed in the simulated body fluids at different temperatures, the samples are applied with stimuli with the magnetic field strength of 0 and 0.5T for 10min, the test drug rates are measured and recorded as second response release, and the first and second response release antibiotic release rates of the calcium phosphate-based bone cement and the traditional CPC are shown in Table 4;
TABLE 4 first and second response to conventional CPC for antibiotic release rates of the present invention
It can be seen from table 4 that the calcium phosphate-based bone cement prepared by the invention can autonomously release drugs in low inflammation, can further autonomously accelerate drug release in severe inflammation, can artificially regulate and control further drug release under different magnetic fields, can release drugs under different inflammation conditions and different magnetic field stimulations at least twice, has a drug release rate which does not change along with the change of times, and can realize the controlled drug release; along with the increase of the content of the magnetic particles in the bone cement, the release rate of the magnetic response drug-releasing bone cement is increased under the stimulation of different magnetic fields.
Claims (9)
1. A preparation method of temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement is characterized by comprising the following steps:
step 1, preparation of PEG-modified Fe3O4Particles;
step 2, modifying Fe with PEG3O4Preparation of Fe from particles3O4@SiO2Microspheres;
step 3, adding Fe3O4@SiO2Adding the microspheres into deionized water, adding the medicament, stirring, and drying in vacuum to obtain the Fe carrying the medicament3O4@SiO2Microspheres;
step 4, carrying the medicine Fe3O4@SiO2Dispersing the microspheres in a PU aqueous solution, and collecting the microspheres by using a magnet for ultrasonic treatment; dispersing the microspheres in a phospholipid aqueous solution, carrying out ultrasonic treatment, washing with deionized water, collecting the magnetic spheres with a magnet, and repeating the adsorption process for 3-10 times to obtain a drug-loading temperature-magnetic field dual-response microcapsule precursor;
step 5, adding the drug-loading temperature-magnetic field double-response microcapsule precursor into a sodium hydroxide aqueous solution, stirring and drying to obtain a drug-loading temperature-magnetic field double-response microcapsule;
step 6, adding a mixed monomer of PNIPAM and AA into the drug-loading temperature-magnetic field dual-response microcapsule, then adding an MBA solution, stirring, adding an initiator, stirring for 30-120 s, and standing at room temperature for 6-24 h; washing and drying to obtain P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsules;
step 7, uniformly mixing the P (NIPAM-AA) coated drug-loading temperature-magnetic field dual-response microcapsule with the calcium phosphate bone cement solid phase to obtain calcium phosphate-based bone cement precursor solid phase powder;
and 8, stirring the calcium phosphate-based bone cement precursor solid phase powder and the curing liquid, adding the hydrogen peroxide blending liquid, stirring and injecting to obtain the calcium phosphate-based bone cement.
2. The method for preparing the temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement according to claim 1, wherein in the step 1, the method specifically comprises the following steps: mixing Fe3O4Washing with a mixture of ethanol and water, and washing with Fe3O4Adding the particles into PEG aqueous solution, and stirring to obtain PEG modified Fe3O4Particles;
the mass ratio of ethanol to water is 1: 1; fe3O4The solid-liquid ratio of the particles to the PEG aqueous solution is as follows: 1: 100-300 g/ml; the mass fraction of the PEG aqueous solution is 2-8%; stirring for 12-36 h; PEG-modified Fe3O4The average particle diameter of the particles is 100 to 500 nm.
3. The method for preparing the temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement as claimed in claim 1, wherein in the step 2, specifically: modification of PEG with Fe3O4Adding the particles into the mixed solution A, stirring, and precipitating CTAB and SiO2And a n-hexane shell layer; collecting microspheres, refluxing in acetone solution to remove CTAB and n-hexane, washing to obtain Fe3O4@SiO2Microspheres;
PEG-modified Fe3O4The solid-liquid ratio of the particles to the mixed solution A is 1: 3-5 g/ml; mixingThe solution A comprises tetraethyl orthosilicate with the mass percent of 2.5-4.5%, CTAB with the mass percent of 1.7-1.9% and n-hexane with the mass percent of 0.6-0.8%; fe3O4@SiO2The thickness of the silicon dioxide layer of the microsphere is 30-70 nm.
4. The method for preparing the calcium phosphate-based bone cement with the temperature-magnetic field cooperative response to release the medicine according to the claim 1, wherein in the step 3, the medicine is an antibiotic medicine; the drug loading rate of the drug is 30-50%; the antibiotic medicine is any one of gentamicin, vancomycin hydrochloride, tobramycin sulfate, ciprofloxacin hydrochloride, nafcillin, linezolid, ceftriaxone, ampicillin trihydrate and amoxicillin; the stirring time is 6-48 h.
5. The method for preparing the temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement as claimed in claim 1, wherein in the step 4, the drug is loaded with Fe3O4@SiO2The solid-liquid ratio of the microspheres to the PU aqueous solution is as follows: 1: 45-60 g/ml; fe3O4@SiO2The solid-liquid ratio of the microspheres to the phospholipid aqueous solution is 1: 45-60 g/ml; the mass fraction of the PU aqueous solution is 1.5-3.5%; the mass fraction of the phospholipid aqueous solution is 1.5-3.5%; the ultrasonic treatment time is 3-6 min.
6. The method for preparing the temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement as claimed in claim 1, wherein in the step 5, the solid-to-liquid ratio of the drug-loaded temperature-magnetic field dual-response microcapsule to the sodium hydroxide aqueous solution is 1: 10-17 g/ml; the mass fraction of the sodium hydroxide aqueous solution is 20-60%; the average particle size of the drug-loading temperature-magnetic field dual-response microcapsule is 130-600 nm.
7. The method for preparing the temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement as claimed in claim 1, wherein in the step 6, the mass ratio of PNIPAM to AA is 92: 8; the mass percentage of MBA in the MBA solution in the mixed monomer is 5-10%; the initiator accounts for 0.5-2% of the total mixed monomers by mass; the initiator is any one of tetramethylethylenediamine, ammonium persulfate and azobisisobutyronitrile.
8. The method for preparing the temperature-magnetic field cooperative response drug release calcium phosphate-based bone cement according to claim 1, wherein in the step 7, the mass percentage of the P (NIPAM-AA) coated drug-loaded temperature-magnetic field dual-response microcapsule is 5-50%, the mass percentage of the calcium phosphate bone cement solid phase is 50-95%, and the sum of the mass percentages of the above components is 100%; the calcium phosphate cement solid phase component consists of tetracalcium phosphate and calcium bicarbonate, wherein the weight percentage of the tetracalcium phosphate is 40-60%, and the weight percentage of the calcium bicarbonate is 40-60%.
9. The method for preparing a calcium phosphate-based bone cement with a temperature-magnetic field cooperative response function for releasing a drug, according to claim 1, wherein in the step 8, the solidifying fluid is any one of distilled water, blood, normal saline, diluted acid, serum and phosphate solution; the solid-liquid ratio of the calcium phosphate-based bone cement precursor solid-phase powder to the curing liquid is 1: 0.3-2.5 g/ml; the hydrogen peroxide blending liquid accounts for 6-10% of the total mass of the bone cement; the stirring time is 5-30 min.
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