CN110420357B - Drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing, and preparation method and application thereof - Google Patents
Drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing, and preparation method and application thereof Download PDFInfo
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
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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
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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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- 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
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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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 drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing, a preparation method and application thereof, and the preparation method comprises the following steps: firstly, preparing mesoporous hydroxyapatite with good biocompatibility by adopting a soft template method, and then modifying the mesoporous hydroxyapatite by using a coupling agent to prepare a drug-loaded modified nano microsphere with a loaded mesoporous material; the raw materials and the high molecular polymer are blended and stirred according to a certain proportion and a certain program, and finally the biomedical composite material suitable for 3D printing is obtained. The biomedical composite material has the characteristics of good mechanical property, high drug loading capacity, high encapsulation rate, good biocompatibility, convenient production and processing, easy preparation, capability of printing a bracket in a personalized manner and the like, can be widely applied to the field of biomedicine, particularly the field of bone repair, can induce the growth of bone tissues, promote the bone tissue repair and provide a new way for reducing the pain of patients and improving the success rate of operations.
Description
Technical Field
The invention belongs to the field of biomedicine and the technical field of novel material processing, and particularly relates to a drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing, a preparation method and application thereof.
Background
According to the IUPAC published report, when the diameter of the material is 2-50 nm, the material is called mesoporous material. Compared with other materials, the mesoporous material has the advantages of large specific surface area, regular pore channels, adjustable pore diameter and the like. Based on the advantages, the mesoporous material can be widely applied to the fields of biological materials, catalysis and the like. The structure and composition of the hydroxyapatite are similar to those of natural apatite, and the hydroxyapatite exists in human bones and teeth in large amount, respectively accounting for 60 percent and 97 percent, and has good biocompatibility. Meanwhile, the mesoporous hydroxyapatite has larger specific surface area and pore size, has higher drug loading rate and encapsulation rate when being used as a drug carrier, and can achieve the effect of slow release. Therefore, the mesoporous hydroxyapatite MHA has good application prospect in the fields of bone substitution and repair materials, drug carriers and the like.
In recent years, 3D printing technology has been rapidly developed, and is widely applied in the fields of education, medicine, furniture decoration, and the like, especially in the medicine field, such as preparation of personalized tablets, bone scaffolds, operation practice models, radiotherapy body and face fixing scaffolds, operation guide plates, and the like. The 3D printing technology is applied to a drug delivery system, so that not only can a three-dimensional drug carrier be printed, but also calcium and phosphorus can be dissociated from the surface of the material and absorbed by body tissues after the drug-loaded stent material is implanted into a human body, new tissues grow, and certain supporting and treating functions can be exerted.
Chinese patent 201410305882.2 describes a composite material of nano hydroxyapatite and polylactic acid, which is formed by blending calcium nitrate, calcium phosphate and gelatin solution and then injection molding. The method improves the dispersibility of the hydroxyapatite in the polylactic acid matrix and increases the interface bonding strength, but tetrahydrofuran introduced by the method has biotoxicity and increases potential safety hazards for materials. Chinese patent 201610835592.8 describes a method for preparing a stearic acid modified hydroxyapatite/poly (L-lactic acid) composite material by solution blending and hot pressing, which improves the interfacial bonding between the hydroxyapatite and the poly (lactic acid), but the used hydroxyapatite has a large particle diameter and is difficult to be dispersed in a matrix solution completely and uniformly by ultrasonic dispersion, thereby affecting the mechanical properties of the composite material. The Japanese apricot (university of Anhui academic thesis, 2015) introduces mesoporous nano Hydroxyapatite (HA) as a common drug carrier because of good biocompatibility and activity, no toxicity, large specific surface area, large pore volume and good degradation performance. Among the methods for synthesizing nano HA reported in the literature, the gas-liquid chemical precipitation method and the hydrothermal synthesis method are the simplest, environment-friendly and low-cost methods. The method successfully prepares the nanoscale spindle-shaped mesoporous HA particles and the magnetic HA composite particles by applying a gas-liquid chemical precipitation method; and an oscillation adsorption method is applied to discuss the adsorption and in-vitro slow release performance of the HA and the magnetic composite material thereof on the anti-cancer drugs and the protein drugs. Chinese patent CN105000569B discloses a mesoporous magnesium silicate/hydroxyapatite/polyetheretherketone composite material, a bone prosthesis, a preparation method and applications thereof, wherein the preparation method of the mesoporous magnesium silicate/hydroxyapatite/polyetheretherketone composite material comprises the following steps: uniformly mixing 15-20 wt% of mesoporous magnesium silicate, 10-15 wt% of hydroxyapatite and 65-75 wt% of polyether-ether-ketone to obtain mixed powder; then mixing the mixed powder with absolute ethyl alcohol, performing ultrasonic dispersion, evaporating the absolute ethyl alcohol at 65-80 ℃ to obtain composite powder, and processing and forming the composite powder by adopting a die pressing method, wherein the die pressing process is complex and is difficult to meet various individual application requirements in the field of biological medicines.
Therefore, in the prior art, although few researches on bone repair are carried out on mesoporous hydroxyapatite, the drug-loaded modified mesoporous hydroxyapatite biomedical composite material and wire suitable for 3D printing are not reported, the specific preparation method is few in reports, and the industrialization method is difficult.
Disclosure of Invention
Aiming at the individual requirements of bone defects of patients, a drug-loaded modified mesoporous hydroxyapatite composite material which has the characteristics of inducing bone tissue growth, biocompatibility and the like and is suitable for 3D printing is developed, and the defects of the existing research are overcome. The invention mainly aims to provide a drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing, a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
the biomedical composite material is characterized by comprising a high molecular polymer and drug-loaded modified mesoporous hydroxyapatite nano microspheres in parts by weight as follows:
high molecular weight Polymer: 70-95 parts of (A) a water-soluble polymer,
carrying medicine modified mesoporous hydroxyapatite nano-microspheres: 5-30 parts.
In a preferred embodiment, the high molecular polymer is at least one of polylactic acid, polyglycolic acid, polycaprolactone and copolymers thereof, wherein the molecular weight of the polylactic acid and the polyglycolic acid is 8 ten thousand or more, and the molecular weight of the polycaprolactone is 4 ten thousand or more; if the high molecular polymer is the copolymer of polylactic acid, polyglycolic acid or polycaprolactone, the molecular weight of the copolymer is more than 6 ten thousand.
In a preferred embodiment, the drug-loaded modified mesoporous hydroxyapatite nano microsphere is prepared by the following steps:
step 1), preparation of powder Mesoporous Hydroxyapatite (MHA):
dissolving calcium source and phosphorus source separatelyIn water with NH3·H2And O, adjusting the pH value of the solution to 9-12. Weighing a template agent, adding the template agent into the calcium source solution, and carrying out magnetic stirring in a water bath until the solution becomes a milky colloid;
dropping the phosphorus source solution slowly into the solution and using NH3·H2Adjusting the pH value to be 9-12, and stirring in a water bath for reaction;
thirdly, stopping stirring after the reaction is finished, aging in a water bath, then centrifugally pumping, washing, drying, grinding, and calcining in a muffle furnace to obtain powder Mesoporous Hydroxyapatite (MHA);
step 2), adding the powder mesoporous hydroxyapatite MHA obtained in the step 1) and a coupling agent into a beaker filled with deionized water and absolute ethyl alcohol respectively for ultrasonic treatment, then blending and refluxing, stirring and reacting in a water bath, performing suction filtration, washing, drying and grinding to obtain modified powder SMHA;
and 3), placing the modified powder SMHA prepared in the step 2) and a medicament in deionized water according to a certain ratio, performing ultrasonic treatment for 0.5-3 h, performing vacuum treatment for 5-60 min under magnetic stirring, oscillating for 20-48 h, performing suction filtration, washing, drying and grinding to finally obtain the medicament-loaded modified mesoporous hydroxyapatite nano-microsphere.
Wherein the calcium source in the step 1) is calcium nitrate (Ca (NO)3)2.4H2O), calcium ammonium nitrate (5Ca (NO)3)2·NH4NO3·10H2O), calcium phosphate (Ca)3(PO4)2·2H2At least one of O); the phosphorus source is ammonium dihydrogen phosphate (NH)4H2PO4) Diammonium hydrogen phosphate ((NH)4)2HPO4) Ammonium phosphate ((NH)4)3PO4) At least one of; the template agent is at least one of Cetyl Trimethyl Ammonium Bromide (CTAB), dodecyl phosphate (MAP), Sodium Dodecyl Sulfate (SDS), octadecylamine and citric acid; wherein the template agent: a calcium source: water (0.5-2 g): (0.1-0.8 g): (50-150 ml).
Wherein, the water bath temperature in the first step of the step 1) is 60-90 ℃, the magnetic stirring speed is 500-1000 rpm, and the stirring time is 0.5-2 h; the addition amount of the phosphorus source in the second step of the step 1) is 0.1-1 g, the water bath temperature is 80-100 ℃, the magnetic stirring rotating speed is 300-600 rpm, and the reaction time is 0.5-2 h; after the reaction in the step 1) and the step three is finished, the water bath temperature is 70-90 ℃, and the aging time is 40-48 h; washing conditions are as follows: washing with deionized water for three times, wherein the drying temperature of an oven is 60-80 ℃, and the drying time is 4-8 h; the muffle furnace calcining temperature is 400-700 ℃, and the calcining time is 2-6 h.
Wherein, MHA in the step 2): coupling agent: deionized water: absolute ethyl alcohol (0.2 to 1.5 g): (0.5-2 ml): (25-80 ml): (50-100 ml); wherein the coupling agent is at least one of silane coupling agent (KH550, KH560, KH570) and titanate coupling agent (NDZ-201, PU-801).
Wherein the ultrasonic temperature in the step 2) is 30-60 ℃, and the ultrasonic time is 0.5-2 h; after mixing, the water bath temperature is 60-80 ℃, the magnetic stirring rotating speed is 400-600 rpm, and the reflux time is 3-6 h; washing conditions are as follows: washing with absolute ethyl alcohol for three times, wherein the drying temperature of an oven is 70-80 ℃, and the drying time is 5-8 h.
Wherein, in the step 3), SMHA: medicine preparation: deionized water (0.1-1 g): (0.1-5 g): (25-50 ml); the medicine is at least one of vitamin E, nano-silver and curcumin; the magnetic stirring rotating speed is 200-400 rpm, and the washing conditions are as follows: washing with deionized water for three times, wherein the drying temperature of an oven is 50-80 ℃, and the drying time is 4-8 h.
In another aspect of the invention, a preparation method of any one of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material wires suitable for 3D printing comprises the following steps:
step 1), uniformly blending the prepared biomedical composite material under a high-speed mixer to obtain a uniform mixture; then adding the uniform mixture into a double-screw extruder, melting, mixing, extruding, cooling, granulating and drying to obtain a granular material of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing, and drying for later use;
and 2), adding the obtained granular material into a single-screw extruder for extrusion, and finally obtaining the drug-loaded modified mesoporous hydroxyapatite biomedical composite material wire rod suitable for 3D printing through extrusion, wire drawing, cooling and rolling.
In a preferred embodiment, the rotating speed of the high-speed mixer in the step 1) is 2000-4000 rpm, and the mixing time is 10-60 min; the cooling is at least one of water cooling and wind cooling; the temperature of the oven is 60-90 ℃, and the drying time is 6-16 h; the twin-screw temperature is set as follows: the first zone is 160-180 ℃, the second zone is 165-180 ℃, the third zone is 170-185 ℃, the fourth zone is 175-190 ℃, the fifth zone is 180-195 ℃, the head zone is 170-185 ℃, the melt temperature is 160-180 ℃, the rotation speed of the twin screw is 10-50 r/min, and the pelletizing speed is 4-30 r/min.
In a preferred embodiment, the cooling in step 2) is at least one of ice water cooling, water cooling and wind cooling; the single screw temperature in step 2) is set as: the first zone 165-.
On the other hand, any one of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing and the wire thereof are applied to the field of medicines, particularly the field of bone scaffolds and bone repair.
The technical scheme of the invention has the following technical characteristics:
(1) the biomedical composite material prepared by the method and suitable for 3D printing has the characteristics of good mechanical property, high drug loading capacity, high encapsulation efficiency, good biocompatibility and the like; in addition, the obtained biomedical composite material has a drug slow release function, can continuously release drugs to promote the bone tissue repair effect, induces the bone tissue to grow, improves the success rate of the operation and ensures that the operation is more accurate and safe;
(2) the invention adopts a soft template method to prepare mesoporous hydroxyapatite with good biocompatibility as a drug carrier to obtain a mesoporous material with uniform aperture and stable drug release. The mesoporous hydroxyapatite is modified by the coupling agent, so that the drug loading rate and the encapsulation rate of the drug are improved, and the interface compatibility of the hydroxyapatite and a polymer matrix material is improved.
(3) The invention combines the 3D printing technology, customizes a high-precision operation scheme and an implant for a patient, improves the success rate of complex operations, and ensures that the operations are more accurate, safer and the like; also meets various individual requirements in the biomedical field, and is easier to industrialize.
Drawings
Fig. 1 is a photograph of a biomedical composite material wire rod extruded by the 3D printing method of the present invention.
FIG. 2A is an infrared absorption spectrum of HA and MHA, and B is an infrared absorption spectrum of Enro @ SMHA, Enro @ MHA and enro.HCl.
Fig. 3 is a graph showing the sustained-release profile of the biomedical composite materials prepared in examples 1 to 4 in a phosphate buffer solution (pH 7.4).
Detailed Description
The present invention will be further described with reference to the following specific embodiments, but it should be noted that the drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing, the preparation method and the application thereof are not limited to this specific form or step. It will be apparent to those skilled in the art that the following description may be directly applicable, without any adjustment or modification, to the components or preparation of other similar composite materials not specified herein.
Example 1
The drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing is prepared from high molecular polymer polylactic acid and drug-loaded modified mesoporous hydroxyapatite nano microspheres according to the following components in parts by weight:
polylactic acid: 95 parts of (a) a reaction product of (B),
carrying medicine modified mesoporous hydroxyapatite nano-microspheres: 5 parts of a mixture;
the preparation method of the drug-loaded modified mesoporous hydroxyapatite nano microsphere comprises the following steps:
(1) firstly, calcium nitrate (Ca (NO))3)2.4H2O) and ammonium dihydrogen phosphate (NH)4H2PO4) Dissolving in water respectively, and adding NH3.H2And O, adjusting the pH value of the solution to be 9. Cetyl Trimethyl Ammonium Bromide (CTAB) is weighed and added to Ca (NO)3)2.4H2In O solution, CTAB: ca (NO)3)2.4H2O: water ═ 0.5 g: 0.2 g: 100ml, the water bath temperature is 90 ℃, the magnetic rotation speed is 500rpm, the stirring is carried out for 30min, and the solution becomes milk white colloid;
② will contain 0.1g of ammonium dihydrogen phosphate (NH)4H2PO4) The solution is slowly dropped into the above solution, and NH is used3.H2Adjusting the pH value to be 9, stirring and reacting at the water bath temperature of 90 ℃ and the rotating speed of 300rpm for 1 h;
thirdly, after the reaction is finished, stopping stirring, adjusting the temperature of the water bath to 90 ℃, aging in a water bath kettle for 48 hours, then carrying out centrifugal filtration, washing with deionized water for three times, drying in an oven at 60 ℃ for 6 hours, grinding, and calcining in a muffle furnace at 600 ℃ for 4 hours to obtain powder Mesoporous Hydroxyapatite (MHA);
(2) respectively adding the powder mesoporous hydroxyapatite MHA obtained in the step (1) and a silane coupling agent KH550 into a beaker filled with deionized water and absolute ethyl alcohol for ultrasonic treatment, wherein the weight ratio of MHA: KH 550: water: absolute ethanol ═ 0.2 g: 1 ml: 80 ml: 50ml, under the ultrasonic conditions: the temperature is 60 ℃, the time is 1h, then the mixture is mixed and refluxed for 3h, the mixture is stirred and reacted at the water bath temperature of 60 ℃ and the rotating speed of 400rpm, the filtration is carried out, the absolute ethyl alcohol is washed for three times, the mixture is dried for 5h in an oven at the temperature of 80 ℃, and the modified powder SMHA is obtained after grinding;
(3) placing the modified powder SMHA prepared in the step (2) and vitamin E into deionized water according to a certain ratio, wherein the ratio of SMHA: vitamin E: deionized water 1 g: 0.2 g: 50ml, performing ultrasonic treatment for 30min, performing vacuum treatment for 30min at a magnetic stirring rotating speed of 300rpm, oscillating for 48h, performing suction filtration, washing with deionized water for three times, drying for 6h at 60 ℃ in an oven, and grinding to finally obtain the drug-loaded modified mesoporous hydroxyapatite nano-microsphere.
On the other hand, the preparation method of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material wire rod suitable for 3D printing comprises the following steps:
(1) mixing the prepared biomedical composite material for 10min at the rotating speed of a high-speed mixer of 3000rpm to obtain a uniform mixture; then adding the uniform mixture into a double-screw extruder for melt mixing extrusion, water cooling, grain cutting and drying, wherein the temperature of the double screws is set as: the method comprises the following steps of firstly, carrying out primary zone 165 ℃, secondly, 170 ℃, thirdly 175 ℃, fourthly, 178 ℃, fifthly, 180 ℃, 170 ℃, fourthly, 160 ℃, rotating speed of a double screw rod is 10r/min, and granulating speed is 8r/min, finally obtaining granules of the drug-loaded modified mesoporous hydroxyapatite composite material suitable for 3D printing, and drying for 6 hours in an oven at 60 ℃;
(2) adding the obtained granular material into a single-screw extruder for extrusion, wherein the temperature of the single screw is set as follows: the first zone is 168 ℃, the second zone is 170 ℃, the third zone is 175 ℃, the fourth zone is 178 ℃, the die head zone is 175 ℃, the single screw rotating speed is 10r/min, the traction speed is 12r/min, and finally the drug-loaded modified mesoporous hydroxyapatite biomedical composite material wire rod suitable for 3D printing is obtained through extrusion, wire drawing, water cooling and rolling, and the product photo is shown in figure 1.
Example 2
The drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing is prepared from high molecular polymer polycaprolactone and drug-loaded modified mesoporous hydroxyapatite nano microspheres according to the following components in parts by weight:
polycaprolactone: 90 parts of (a) a mixture of (b),
carrying medicine modified mesoporous hydroxyapatite nano-microspheres: 10 parts of (A);
the preparation method of the drug-loaded modified mesoporous hydroxyapatite nano microsphere comprises the following steps:
(1) firstly, ammonium calcium nitrate (5Ca (NO))3)2·NH4NO3·10H2O) and ammonium dihydrogen phosphate (NH)4H2PO4) Dissolving in water respectively, and adding NH3.H2And O, adjusting the pH value of the solution to be 10. Dodecyl phosphate (MAP) is weighed and added to 5Ca (NO)3)2·NH4NO3·10H2In O solution, MAP: 5Ca (NO)3)2·NH4NO3·10H2O: water ═ 1 g: 0.5 g: 100ml, the water bath temperature is 90 ℃, the magnetic rotation speed is 300rpm, and the solution is stirred for 40min to become milk white colloid;
② will contain 0.5g of ammonium dihydrogen phosphate (NH)4H2PO4) The solution is slowly dropped into the above solution, and NH is used3.H2Adjusting the pH value to keep the pH value at 10, stirring and reacting at the water bath temperature of 90 ℃ and the rotating speed of 400rpm for 30 min;
thirdly, after the reaction is finished, stopping stirring, adjusting the temperature of the water bath to 90 ℃, aging in a water bath kettle for 40 hours, then carrying out centrifugal filtration, washing with deionized water for three times, drying in an oven at 70 ℃ for 4 hours, grinding, and calcining in a muffle furnace at 700 ℃ for 3 hours to obtain powder Mesoporous Hydroxyapatite (MHA);
(2) respectively adding the powder mesoporous hydroxyapatite MHA obtained in the step (1) and a silane coupling agent KH560 into a beaker filled with deionized water and absolute ethyl alcohol for ultrasonic treatment, wherein the weight ratio of MHA: KH 560: water: absolute ethanol ═ 0.5 g: 1.5 ml: 80 ml: 60ml, ultrasonic conditions are as follows: the temperature is 50 ℃ and the time is 1h, then blending and refluxing are carried out for 4h, stirring and reacting are carried out at the water bath temperature of 60 ℃ and the rotating speed of 500rpm, suction filtration is carried out, absolute ethyl alcohol is washed for three times, drying is carried out in an oven at the temperature of 80 ℃ for 6h, and grinding is carried out, so as to obtain modified powder SMHA;
(3) placing the modified powder SMHA prepared in the step (2) and curcumin into deionized water according to a certain ratio, wherein the ratio of SMHA: curcumin: deionized water 1 g: 0.2 g: 50ml, performing ultrasonic treatment for 40min, performing vacuum treatment for 40min at a magnetic stirring rotating speed of 400rpm, oscillating for 48h, performing suction filtration, washing with deionized water for three times, drying for 4h in an oven at 80 ℃, and grinding to finally obtain the drug-loaded modified mesoporous hydroxyapatite nano-microsphere.
On the other hand, the preparation method of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material wire rod suitable for 3D printing comprises the following steps:
(1) mixing the prepared biomedical composite material for 20min at the rotating speed of a high-speed mixer of 2500rpm to obtain a uniform mixture; then adding the uniform mixture into a double-screw extruder for melt mixing extrusion, water cooling, grain cutting and drying, wherein the temperature of the double screws is set as: the method comprises the steps of preparing a granular material of a drug-loaded modified mesoporous hydroxyapatite composite material suitable for 3D printing, wherein the first zone is 160 ℃, the second zone is 165 ℃, the third zone is 170 ℃, the fourth zone is 175 ℃, the fifth zone is 180 ℃, the head zone is 170 ℃, the melt temperature is 160 ℃, the rotating speed of a double screw is 15r/min, the grain cutting speed is 10r/min, and the granular material is dried for 6 hours in an oven at 80 ℃;
(2) adding the obtained granular material into a single-screw extruder for extrusion, wherein the temperature of the single screw is set as follows: the first zone is 165 ℃, the second zone is 168 ℃, the third zone is 170 ℃, the fourth zone is 174 ℃, the die head zone is 170 ℃, the single screw rotating speed is 12r/min, the traction speed is 15r/min, and finally the drug-loaded modified mesoporous hydroxyapatite composite material wire rod suitable for 3D printing is obtained through extrusion, wire drawing, water cooling and rolling.
Example 3
The drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing is prepared from high molecular polymer polylactic acid and drug-loaded modified mesoporous hydroxyapatite nano microspheres according to the following components in parts by weight:
polylactic acid: 85 parts of (A) and (B),
carrying medicine modified mesoporous hydroxyapatite nano-microspheres: 15 parts of (1);
the preparation method of the drug-loaded modified mesoporous hydroxyapatite nano microsphere comprises the following steps:
(1) calcium phosphate (Ca)3(PO4)2·2H2O) and ammonium phosphate ((NH)4)3PO4) Dissolving in water respectively, and adding NH3.H2And O, adjusting the pH value of the solution to be 10. Cetyl Trimethyl Ammonium Bromide (CTAB) is weighed and added to Ca3(PO4)2·2H2In O solution, CTAB: ca3(PO4)2·2H2O·10H2O: water ═ 1.5 g: 0.4 g: 100ml, the water bath temperature is 90 ℃, the magnetic rotation speed is 300rpm, and the solution is stirred for 40min to become milk white colloid;
② will contain 0.3g ammonium phosphate ((NH)4)3PO4) The solution is slowly added dropwise to the above solution with NH3.H2Adjusting the pH value to keep the pH value at 10, stirring and reacting at the water bath temperature of 90 ℃ and the rotating speed of 400rpm for 40 min;
thirdly, after the reaction is finished, stopping stirring, adjusting the temperature of the water bath to 90 ℃, aging in a water bath kettle for 48 hours, then carrying out centrifugal filtration, washing with deionized water for three times, drying in an oven at 80 ℃ for 4 hours, grinding, and calcining in a muffle furnace at 650 ℃ for 5 hours to obtain powder Mesoporous Hydroxyapatite (MHA);
(2) respectively adding the powder mesoporous hydroxyapatite MHA obtained in the step (1) and a silane coupling agent KH570 into a beaker filled with deionized water and absolute ethyl alcohol for ultrasonic treatment, wherein the ratio of MHA: KH 570: water: absolute ethanol ═ 0.4 g: 1.3 ml: 60 ml: 80ml, and the ultrasonic conditions are as follows: the temperature is 60 ℃, the time is 2 hours, then blending and refluxing are carried out for 6 hours, stirring and reacting are carried out at the water bath temperature of 80 ℃ and the rotating speed of 500rpm, suction filtration is carried out, absolute ethyl alcohol is washed for three times, drying is carried out for 8 hours at the temperature of 70 ℃ in an oven, and grinding is carried out, thus obtaining modified powder SMHA;
(3) placing the modified powder SMHA prepared in the step (2) and curcumin into deionized water according to a certain ratio, wherein the ratio of SMHA: curcumin: deionized water 1 g: 0.5 g: 50ml, performing ultrasonic treatment for 30min, performing vacuum treatment for 40min at a magnetic stirring rotating speed of 400rpm, oscillating for 48h, performing suction filtration, washing with deionized water for three times, drying in an oven at 80 ℃ for 8h, and grinding to finally obtain the drug-loaded modified mesoporous hydroxyapatite nano-microsphere.
On the other hand, the preparation method of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material wire rod suitable for 3D printing comprises the following steps:
(1) mixing the prepared biomedical composite material for 10min at the rotating speed of a high-speed mixer of 5000rpm to obtain a uniform mixture; then adding the uniform mixture into a double-screw extruder for melt mixing extrusion, water cooling, grain cutting and drying, wherein the temperature of the double screws is set as: the first zone is 170 ℃, the second zone is 175 ℃, the third zone is 178 ℃, the fourth zone is 180 ℃, the fifth zone is 185 ℃, the head zone is 175 ℃, the melt temperature is 165 ℃, the double-screw rotating speed is 25r/min, the granulating speed is 13r/min, and finally, the granular material of the drug-loaded modified mesoporous hydroxyapatite composite material suitable for 3D printing is obtained, and is dried for 6 hours in an oven at 80 ℃;
(2) adding the obtained granular material into a single-screw extruder for extrusion, wherein the temperature of the single screw is set as follows: the first zone is 170 ℃, the second zone is 175 ℃, the third zone is 178 ℃, the fourth zone is 180 ℃, the die head zone is 175 ℃, the single screw rotating speed is 20r/min, the traction speed is 25r/min, and finally the drug-loaded modified mesoporous hydroxyapatite composite material wire rod suitable for 3D printing is obtained through extrusion, wire drawing, air cooling and rolling.
Example 4
The drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing is prepared from high molecular polymer polyglycolic acid and drug-loaded modified mesoporous hydroxyapatite nano microspheres according to the following components in parts by weight:
polyglycolic acid: 80 parts of (a) a water-soluble polymer,
carrying medicine modified mesoporous hydroxyapatite nano-microspheres: 20 parts of (1);
the preparation method of the drug-loaded modified mesoporous hydroxyapatite nano microsphere comprises the following steps:
(1) firstly, calcium nitrate (Ca (NO))3)2.4H2O) and diammonium hydrogen phosphate ((NH)4)2HPO4) Dissolving in water respectively, and adding NH3.H2O adjusting the pH value of the solution to be 11. Cetyl Trimethyl Ammonium Bromide (CTAB) is weighed and added to Ca (NO)3)2.4H2In O solution, CTAB: ca (NO)3)2.4H2O·10H2O: 2g of water: 0.8 g: 100ml, the water bath temperature is 90 ℃, the magnetic rotation speed is 300rpm, and the solution is stirred for 40min to become milk white colloid;
(II) ammonium Hydrogen phosphate 1g ((NH)4)2HPO4) The solution is slowly dropped into the above solution, and NH is used3.H2Adjusting the pH value to be 11, stirring and reacting at the water bath temperature of 90 ℃ and the rotating speed of 600rpm for 30 min;
thirdly, after the reaction is finished, stopping stirring, adjusting the temperature of the water bath to 90 ℃, aging in a water bath kettle for 48 hours, then carrying out centrifugal filtration, washing with deionized water for three times, drying in an oven at 80 ℃ for 6 hours, grinding, and calcining in a muffle furnace at 700 ℃ for 3 hours to obtain powder Mesoporous Hydroxyapatite (MHA);
(2) respectively adding the powder mesoporous hydroxyapatite MHA obtained in the step (1) and a silane coupling agent KH550 into a beaker filled with deionized water and absolute ethyl alcohol for ultrasonic treatment, wherein the weight ratio of MHA: KH 550: water: absolute ethanol ═ 1 g: 1.8 ml: 80 ml: 100ml, ultrasonic conditions were: the temperature is 60 ℃, the time is 2 hours, then blending and refluxing are carried out for 6 hours, stirring and reacting are carried out at the water bath temperature of 80 ℃ and the rotating speed of 600rpm, suction filtration is carried out, absolute ethyl alcohol is washed for three times, drying is carried out for 8 hours at the oven temperature of 80 ℃, and grinding is carried out, thus obtaining modified powder SMHA;
(3) putting the modified powder SMHA prepared in the step (2) and vitamin E into deionized water according to a certain ratio, wherein the ratio of SMHA: vitamin E: deionized water 1 g: 5 g: 50ml, performing ultrasonic treatment for 60min, performing vacuum treatment for 50min at a magnetic stirring rotating speed of 400rpm, oscillating for 48h, performing suction filtration, washing with deionized water for three times, drying in an oven at 80 ℃ for 8h, and grinding to finally obtain the drug-loaded modified mesoporous hydroxyapatite nano-microsphere.
On the other hand, the preparation method of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material wire rod suitable for 3D printing comprises the following steps:
(1) mixing the prepared biomedical composite material for 15min at the rotating speed of a high-speed mixer of 3000rpm to obtain a uniform mixture; then adding the uniform mixture into a double-screw extruder for melt mixing extrusion, water cooling, grain cutting and drying, wherein the temperature of the double screws is set as: 175 ℃ in the first zone, 178 ℃ in the second zone, 180 ℃ in the third zone, 185 ℃ in the fourth zone, 190 ℃ in the fifth zone, 1785 ℃ in the machine head zone, 170 ℃ in the melt, 18r/min in the rotation speed of a double screw and 13r/min in the grain cutting speed, finally obtaining the granular material of the drug-loaded modified mesoporous hydroxyapatite composite material suitable for 3D printing, and drying the granular material in an oven at 80 ℃ for 8 hours;
(2) adding the obtained granular material into a single-screw extruder for extrusion, wherein the temperature of the single screw is set as follows: the first zone is 170 ℃, the second zone is 175 ℃, the third zone is 178 ℃, the fourth zone is 180 ℃, the die head zone is 175 ℃, the single screw rotating speed is 15r/min, the traction speed is 20r/min, and finally the drug-loaded modified mesoporous hydroxyapatite composite material wire rod suitable for 3D printing is obtained through extrusion, wire drawing, air cooling and rolling.
Comparative example 1
Polylactic acid: 90 portions of
Nano hydroxyapatite: 9 portions of
Silane coupling agent KH 550: 1 part of
(1) Mixing the prepared biomedical composite material for 15min at the rotating speed of a high-speed mixer of 3000rpm to obtain a uniform mixture; then adding the uniform mixture into a double-screw extruder for melt mixing extrusion, water cooling, grain cutting and drying, wherein the temperature of the double screws is set as: 175 ℃ in the first zone, 178 ℃ in the second zone, 180 ℃ in the third zone, 185 ℃ in the fourth zone, 190 ℃ in the fifth zone, 1785 ℃ in the machine head zone, 170 ℃ in the melt, 18r/min in the rotation speed of a double screw and 13r/min in the grain cutting speed, finally obtaining the granular material of the drug-loaded modified mesoporous hydroxyapatite composite material suitable for 3D printing, and drying the granular material in an oven at 80 ℃ for 8 hours;
(2) adding the obtained granular material into a single-screw extruder for extrusion, wherein the temperature of the single screw is set as follows: the first zone is 170 ℃, the second zone is 175 ℃, the third zone is 178 ℃, the fourth zone is 180 ℃, the die head zone is 175 ℃, the single screw rotating speed is 15r/min, the traction speed is 20r/min, and finally the drug-loaded modified mesoporous hydroxyapatite composite material wire rod suitable for 3D printing is obtained through extrusion, wire drawing, air cooling and rolling.
And (3) performance testing:
printing the composite materials prepared in the steps of examples 1-4 and comparative example 1 into standard sample strips by using an injection molding machine, and testing the mechanical properties of the prepared sample strips by respectively referring to GB 1040-; the biocompatibility of the composite was tested with reference to the MTT test in YY/T0993-2015, and the performance of the samples obtained in the above examples/comparative examples was compared as shown in tables 1 and 2.
TABLE 1 specific surface area, pore size and pore volume of MHA, SMHA, Enro @ SMHA
Table 2 results of performance tests of biomedical composites suitable for 3D printing according to the present invention
As can be seen from table 2, the biomedical composite material suitable for 3D printing has the characteristics of good mechanical properties, high drug loading capacity, high encapsulation efficiency, good biocompatibility, convenience in production and processing, easiness in preparation, capability of printing a stent in a personalized manner and the like, and can meet various personalized requirements in the biomedical field, particularly 3D printing of a bone stent and application in the bone repair field. As can be seen from the specific surface area, the average pore diameter and the pore volume in Table 1, the specific surface area, the average pore diameter and the pore volume of SMHA are all larger than the specific surface area, the average pore diameter and the pore volume of MHA, because the silane coupling agent is connected with MHA through-Si-O-Si-bonds, so that the pore channels are enlarged, and the average pore diameter, the pore volume and the specific surface area are enlarged; comparing the data before and after loading the drug, the specific surface area after loading the drug is 21.95cm2The/g drops to 9.16cm2Per g, the average pore diameter is reduced from 55.78nm to 49.22nm, and the pore volume is reduced from 0.15cm3The/g falls to 0.083cm3The result is that the specific surface area, the average pore diameter and the pore volume are all reduced. FIG. 2A is the infrared absorption spectra of HA (upper) and MHA (lower), and B is the infrared absorption spectra of Enro @ SMHA (upper), Enro @ MHA (middle) and enro.HCl (lower), which shows that the mesoporous hydroxyapatite of the present invention HAs reliable preparation and feasible drug-loading modification method. Fig. 3 is a slow release curve of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material prepared in examples 1 to 4 in a phosphate buffer solution (pH 7.4), which shows that the slow release effect is significant, and the drug-loaded modified mesoporous hydroxyapatite biomedical composite material can be used for slow release of drugs in the biomedical field, especially in the bone repair field, can induce bone tissue growth, promote bone tissue repair, and provide a new approach for reducing pain of patients and improving the success rate of surgery.
Although particular embodiments of the invention have been described and illustrated in detail, it should be understood that various equivalent changes and modifications could be made to the above-described embodiments in accordance with the spirit of the invention, and the resulting functional effects would still fall within the scope of the invention, without departing from the spirit of the description and the accompanying drawings.
Claims (7)
1. The biomedical composite material is characterized by comprising a high molecular polymer and drug-loaded modified mesoporous hydroxyapatite nano microspheres in parts by weight as follows:
high molecular weight Polymer: 70-95 parts of (A) a water-soluble polymer,
carrying medicine modified mesoporous hydroxyapatite nano-microspheres: 5-30 parts of a solvent;
the drug-loaded modified mesoporous hydroxyapatite nano microsphere is prepared by the following steps:
step 1), preparation of powder Mesoporous Hydroxyapatite (MHA):
dissolving calcium source and phosphorus source in water separately, and using NH3·H2O, adjusting the pH value of the solution to 9-12;
weighing a template agent, adding the template agent into the calcium source solution, and carrying out magnetic stirring in a water bath until the solution becomes a milky colloid;
dropping the phosphorus source solution slowly into the solution and using NH3·H2Adjusting the pH value to be 9-12, and stirring in a water bath for reaction;
thirdly, stopping stirring after the reaction is finished, aging in a water bath, then centrifugally pumping, washing, drying, grinding, and calcining in a muffle furnace to obtain powder Mesoporous Hydroxyapatite (MHA);
step 2), adding the powder mesoporous hydroxyapatite MHA obtained in the step 1) and a coupling agent into a beaker filled with deionized water and absolute ethyl alcohol respectively for ultrasonic treatment, then blending and refluxing, stirring and reacting in a water bath, performing suction filtration, washing, drying and grinding to obtain modified powder SMHA;
step 3), placing the modified powder SMHA prepared in the step 2) and a medicament in deionized water according to a certain ratio, performing ultrasonic treatment for 0.5-3 h, performing vacuum treatment for 5-60 min under magnetic stirring, oscillating for 20-48 h, performing suction filtration, washing, drying and grinding to finally obtain the medicament-loaded modified mesoporous hydroxyapatite nano-microspheres;
the calcium source in the step 1) is at least one of calcium nitrate, calcium ammonium nitrate and calcium phosphate; the phosphorus source is at least one of ammonium dihydrogen phosphate, diammonium hydrogen phosphate and ammonium phosphate; the template agent is at least one of cetyl trimethyl ammonium bromide, dodecyl phosphate, sodium dodecyl sulfonate, octadecylamine and citric acid; wherein the template agent: a calcium source: water = (0.5-2 g): (0.1-0.8 g): (50-150 mL);
the water bath temperature in the first step of the step 1) is 60-90 ℃, the magnetic stirring speed is 500-1000 rpm, and the stirring time is 0.5-2 h; the addition amount of the phosphorus source in the second step of the step 1) is 0.1-1 g, the water bath temperature is 80-100 ℃, the magnetic stirring rotating speed is 300-600 rpm, and the reaction time is 0.5-2 h; after the reaction in the step 1) and the step three is finished, the water bath temperature is 70-90 ℃, and the aging time is 40-48 h; washing conditions are as follows: washing with deionized water for three times, wherein the drying temperature of an oven is 60-80 ℃, and the drying time is 4-8 h; the muffle furnace calcining temperature is 400-700 ℃, and the calcining time is 2-6 h.
2. The drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing according to claim 1, characterized in that: the high molecular polymer is at least one of polylactic acid, polyglycolic acid, polycaprolactone and copolymers thereof, wherein the molecular weight of the polylactic acid and the polyglycolic acid is more than 8 ten thousand, the molecular weight of the polycaprolactone is more than 4 ten thousand, and the molecular weight of the copolymers is more than 6 ten thousand.
3. The biomedical composite material of the drug-loaded modified mesoporous hydroxyapatite suitable for 3D printing according to claim 1, wherein in the step 2), MHA: coupling agent: deionized water: absolute ethyl alcohol = (0.2-1.5 g): (0.5-2 mL): (25-80 mL): (50-100 mL); wherein the coupling agent is at least one of silane coupling agent and titanate coupling agent;
the ultrasonic temperature in the step 2) is 30-60 ℃, and the ultrasonic time is 0.5-2 h; after mixing, the water bath temperature is 60-80 ℃, the magnetic stirring rotating speed is 400-600 rpm, and the reflux time is 3-6 h; washing conditions are as follows: washing with absolute ethyl alcohol for three times, wherein the drying temperature of an oven is 70-80 ℃, and the drying time is 5-8 h.
4. The biomedical composite material of the drug-loaded modified mesoporous hydroxyapatite suitable for 3D printing according to claim 1, wherein in the step 3), SMHA: medicine preparation: deionized water = (0.1-1 g): (0.1-5 g): (25-50 mL); the medicine is at least one of vitamin E, nano-silver and curcumin; the magnetic stirring rotating speed is 200-400 rpm, and the washing conditions are as follows: washing with deionized water for three times, wherein the drying temperature of an oven is 50-80 ℃, and the drying time is 4-8 h.
5. The preparation method of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material wire rod suitable for 3D printing according to any one of claims 1 to 4, characterized by comprising the following steps:
step 1), uniformly blending the prepared biomedical composite material under a high-speed mixer to obtain a uniform mixture; then adding the uniform mixture into a double-screw extruder, melting, mixing, extruding, cooling, granulating and drying to obtain a granular material of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing, and drying for later use;
and 2) adding the obtained granular material into a single-screw extruder for extrusion, and finally obtaining the drug-loaded modified mesoporous hydroxyapatite biomedical composite material wire rod suitable for 3D printing through extrusion, wire drawing, cooling and rolling.
6. The preparation method of the drug-loaded modified mesoporous hydroxyapatite biomedical composite material wire rod suitable for 3D printing according to claim 5, wherein the rotating speed of the high-speed mixer in the step 1) is 2000-4000 rpm, and the mixing time is 10-60 min; the cooling is at least one of water cooling and wind cooling; the temperature of the oven is 60-90 ℃, and the drying time is 6-16 h; the twin-screw temperature is set as follows: the first zone is 160-180 ℃, the second zone is 165-180 ℃, the third zone is 170-185 ℃, the fourth zone is 175-190 ℃, the fifth zone is 180-195 ℃, the head zone is 170-185 ℃, the melt temperature is 160-180 ℃, the rotating speed of the twin screw is 10-50 r/min, and the pelletizing speed is 4-30 r/min;
the cooling in the step 2) is at least one of ice water cooling, water cooling and air cooling; the single screw temperature in step 2) is set as: the first zone 165-.
7. The drug-loaded modified mesoporous hydroxyapatite biomedical composite material suitable for 3D printing according to any one of claims 1 to 6 and application of a wire thereof in the field of stent printing.
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