CN113855861B - Low-temperature preparation method of high-strength HA-PLA composite material capable of carrying medicine in situ - Google Patents
Low-temperature preparation method of high-strength HA-PLA composite material capable of carrying medicine in situ Download PDFInfo
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
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- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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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
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- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
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- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B25/00—Phosphorus; Compounds thereof
- C01B25/16—Oxyacids of phosphorus; Salts thereof
- C01B25/26—Phosphates
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Abstract
The invention discloses a low-temperature preparation method of a high-strength HA-PLA composite material capable of carrying medicine in situ, which comprises the following steps: step one, preparing hydroxyapatite powder; and adding the dichloromethane solution and mixing with the polylactic acid particles, and stirring until the dichloromethane solution and the polylactic acid particles are completely dissolved to obtain a polylactic acid solution; step two, adding the hydroxyapatite powder into the polylactic acid solution, stirring, uniformly mixing, and standing to naturally volatilize dichloromethane to obtain a primary composite material; wherein the weight ratio of the hydroxyapatite powder to the polylactic acid solution is as follows: 8:2 to 7: 3; putting the primary composite material into a mold, performing cold sintering on the primary composite material, applying pressure to the mold, and preserving heat; and step four, demolding after the temperature of the mold is reduced to room temperature to obtain the high-strength HA-PLA composite material capable of carrying the medicine in situ.
Description
Technical Field
The invention belongs to the technical field of HA-PLA composite materials, and particularly relates to a low-temperature preparation method of a high-strength HA-PLA composite material capable of carrying medicine in situ.
Background
Hydroxyapatite (HA) is a common bioactive material that is widely used in the repair of human skeletal defects, injuries and enamel lesions. However, the HA itself HAs a large brittleness and a low fatigue strength, and it is difficult to meet the long-term service requirements of the implant after being implanted into the human body. In order to improve the mechanical property of HA, the traditional HA sintering process reaches a high temperature of more than 1000 ℃, which causes huge energy consumption and environmental pollution, and the high sintering temperature also greatly limits the drug loading function of the HA material. In 2016, Randall et al, inspired by natural mineralization, proposed a novel sintering process that can sinter powder materials into densified solid materials at temperatures below 300 ℃ with the addition of transient solvents, which they named cold sintering technology (CSP).
At present, most research directions are to dope certain substances or influence of synthesis temperature on HA performance, and research of uniaxial pressure on a material system is scarce. The cold sintering process combines temperature and pressure, has no influence on the performance of most dopants due to low sintering temperature, and is an excellent processing process.
Disclosure of Invention
The invention aims to provide a low-temperature preparation method of a high-strength HA-PLA composite material capable of carrying medicine in situ, polylactic acid is used for replacing an instantaneous solvent, high densification of Hydroxyapatite (HA) is realized through a cold sintering technology, and the prepared HA-PLA composite material HAs excellent biodegradability and medicine loading capacity.
The technical scheme provided by the invention is as follows:
a low-temperature preparation method of a high-strength in-situ drug-loaded HA-PLA composite material comprises the following steps:
step one, preparing hydroxyapatite powder; and adding the dichloromethane solution into the mixture to be mixed with the polylactic acid particles, and stirring the mixture until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution;
step two, adding the hydroxyapatite powder into the polylactic acid solution, stirring, uniformly mixing, and standing to naturally volatilize dichloromethane to obtain a primary composite material;
wherein the weight ratio of the hydroxyapatite powder to the polylactic acid solution is as follows: 8:2 to 7: 3;
putting the primary composite material into a mold, performing cold sintering on the primary composite material, applying pressure to the mold, and preserving heat;
and step four, demolding after the temperature of the mold is reduced to room temperature to obtain the HA-PLA composite material capable of carrying the medicine in situ.
Preferably, in the first step, the method for preparing hydroxyapatite powder comprises:
step a, mixing (NH) 4 ) 2 HPO 4 The solution is added to Ca (NO) 3 ) 2 Adding the solution into the solution and stirring, and dropwise adding ammonia water to keep the pH value of the solution at 10.5 +/-0.2 in the stirring process;
b, standing and aging the solution, and repeatedly washing the precipitate with deionized water until the pH value is neutral;
step c, drying the precipitate in a blast drying chamber to obtain the hydroxyapatite powder;
wherein, the (NH) 4 ) 2 HPO 4 Solution and Ca (NO) 3 ) 2 The Ca/P molar ratio in the solution was 1.67.
Preferably, in said step a, (NH) 4 ) 2 HPO 4 The concentration of the solution was 0.5mol/L, Ca (NO) 3 ) 2 The concentration of the solution was 0.3 mol/L.
Preferably, in step a, the magnetic stirring is carried out at a speed of 500r/min for 2 hours.
Preferably, in the step c, the precipitate is dried in a forced air drying chamber at 80 ℃ for 15 hours to obtain the hydroxyapatite powder.
Preferably, in the step one, the weight ratio of the polylactic acid particles to the dichloromethane is 1: 9.
Preferably, in the second step, after the hydroxyapatite powder is added into the polylactic acid solution, the mixture is magnetically stirred for 2 hours at 30 ℃ at 500 r/min.
Preferably, in the third step, the pressure applied to the mold ranges from: 300MPa to 500 MPa.
Preferably, in the third step, the heat preservation time is 30min to 40 min.
Preferably, in the third step, the temperature of cold sintering is: 80-100 ℃.
The beneficial effects of the invention are as follows:
1. the invention adopts a cold sintering technology, realizes the densification of the HA-PLA composite material at low temperature, obviously improves the mechanical property of the system, HAs obvious effect on improving the defects of poor toughness and high brittleness of the HA material, reduces energy consumption, saves cost, and HAs simple processing mode and easy operation.
2. Compared with a bracket made of a pure HA material, the bracket is added with a degradable material PLA; the addition of PLA replaces the instant solvent required to be added in the cold sintering process, the PLA is converted into a viscous state in the heating process, meanwhile, the PLA gradually permeates into gaps of HA particles under the action of uniaxial pressure, the HA particles are uniformly coated, crystal grains are refined, and the agglomeration phenomenon of HA is effectively reduced.
3. Compared with the simple mixing and dissolving of HA and PLA, the invention applies the property that PLA can be converted into viscous state at 55-155 ℃, and the temperature range is also within the effective temperature of most of common medicines for dentistry and orthopaedics, thereby not influencing the medicine carrying performance of a material system and not damaging the effective components of the medicines.
The HA is encapsulated by PLA, so that the drug loading capacity of the system is remarkably improved, the drug and HA-PLA powder are mixed before cold sintering, the physical state of the drug is not limited in the process, the drug and the HA-PLA can be uniformly mixed and then placed in a mould for sintering, and the ultrahigh drug loading rate can be obtained; both PLA and HA can be degraded and absorbed along with the process of wound healing, and do not produce substances harmful to the human body.
Drawings
FIG. 1 is a flow chart of a low-temperature preparation method of the high-strength HA-PLA composite material capable of carrying drugs in situ.
FIG. 2 is a schematic diagram of the HA-PLA cold sintering process according to the present invention.
Fig. 3 is an SEM image of a primary composite material of the present invention having a HA/PLA mass ratio of 8: 2.
FIG. 4 is an SEM image of a primary composite material of the present invention having a HA/PLA mass ratio of 7: 3.
FIG. 5 is an SEM photograph of the HA-PLA composite material prepared in example 1 of the present invention.
FIG. 6 is an SEM photograph of the HA-PLA composite material prepared in example 2 of the present invention.
FIG. 7 is an SEM image of a primary composite material of the present invention having a HA/PLA mass ratio of 10: 0.
FIG. 8 is an SEM image of a primary composite material of the present invention having a HA/PLA mass ratio of 9: 1.
FIG. 9 is an SEM image of the HA-PLA composite prepared in comparative example 1 of the present invention.
FIG. 10 is an SEM photograph of the HA-PLA composite prepared in comparative example 2 of the present invention.
FIG. 11 is an SEM image of a primary composite material of the present invention having a HA/PLA mass ratio of 6: 4.
FIG. 12 is an SEM image of a primary composite material of the present invention having a HA/PLA mass ratio of 5: 5.
FIG. 13 is an SEM image of the HA-PLA composite material prepared in comparative example 3 of the present invention.
FIG. 14 is an SEM photograph of the HA-PLA composite material prepared in comparative example 4 of the present invention.
FIG. 15 is a graph of the effect of mass ratio of HA/PLA in HA-PLA composite on the relative density of the sample.
FIG. 16 is a graph of flexural strength stress strain for composites of different HA/PLA mass ratios.
FIG. 17 is a graph of compressive strength stress strain for composites of different HA/PLA mass ratios.
FIG. 18 is a water absorption trend chart of composite materials with different HA/PLA mass ratios.
FIG. 19 is a graph showing the effect of the holding time after cold sintering on the relative compactness of the HA-PLA composite material.
FIG. 20 is a graph showing the effect of cold sintering soak temperature on relative densification of a sample.
Fig. 21 is a graph of the effect of pressure on relative density of a sample.
FIG. 22 is a graph of DOX release ratio over time for composites of different HA/PLA mass ratios.
Detailed Description
The present invention is further described in detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.
As shown in figure 1, the invention provides a low-temperature preparation method of a high-strength HA-PLA composite material capable of carrying medicine in situ, and the specific preparation process is as follows.
Firstly, preparing HA particles.
First, (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. Finally, the washed precipitate is dried in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
Secondly, preparing a primary composite material.
Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with the PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with the final concentration of 10%, adding weighed hydroxyapatite into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at the temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8: 2-7: 3 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
And thirdly, cold sintering.
As shown in FIG. 2, which is a schematic view of the cold sintering process of the primary composite of HA-PLA, the primary composite of HA-PLA is gradually densified at high temperature and high pressure. In the process of cold sintering and temperature rising, PLA is converted into a viscous state, the viscosity of a composite material system is increased, and the PLA slowly flows under the action of uniaxial pressure to gradually wrap HA particles, so that the high-densification HA-PLA material is obtained.
The melting point of the polylactic acid is 155 ℃, the glass transition temperature is 55 ℃, and the cold-burning temperature is selected to be between 55 ℃ and 155 ℃. In the invention, the primary composite material (powder) is heated at the temperature of 80-100 ℃, and the molds are applied with pressures of 300-500 MPa in different sizes and are kept warm for 30-40 min. After the cold sintering is finished, the mold is removed after the grinding tool is cooled to the room temperature, and the HA-PLA material sample with high densification is obtained. Meanwhile, experimental research shows that different process parameters have different influences on the densification of the HA-PLA composite material, and the strength sequence is approximately as follows: HA/PLA ratio, heat preservation time, cold sintering temperature and pressure.
The preparation of the primary composite of HA-PLA according to the present invention is further illustrated below with reference to the following specific examples.
Example 1
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8:2 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 80 ℃, applying 500MPa pressure to the die, and keeping the temperature for 30 min. After the cold sintering is finished, the mold is removed after the grinding tool is cooled to the room temperature, and the HA-PLA material sample with high densification is obtained.
Example 2
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 7:3 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at the temperature of 80 ℃, applying the pressure of 500MPa to the die, and keeping the temperature for 30 min. After the cold sintering is finished, the mold is removed after the grinding tool is cooled to the room temperature, and the HA-PLA material sample with high densification is obtained.
Example 3
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8:2 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 100 ℃, applying 500MPa pressure to the die, and keeping the temperature for 30 min. After the cold sintering is finished, the mold is removed after the grinding tool is cooled to the room temperature, and the HA-PLA material sample with high densification is obtained.
Example 4
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8:2 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at the temperature of 80 ℃, applying the pressure of 300MPa to the die, and keeping the temperature for 30 min. After the cold sintering is finished, the mold is removed after the grinding tool is cooled to the room temperature, and the HA-PLA material sample with high densification is obtained.
Example 5
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8:2 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 80 ℃, applying 500MPa pressure to the die, and keeping the temperature for 40 min. After the cold sintering is finished, the mold is removed after the grinding tool is cooled to the room temperature, and the HA-PLA material sample with high densification is obtained.
Comparative example 1
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the mixture is completely dissolved to obtain a polylactic acid solution with the final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a ratio, and magnetically stirring for two hours at the temperature of 30 ℃ at 500r/min to fully mix the hydroxyapatite powder and the polylactic acid solution; wherein, HA: the mass ratio of PLA is 10:0 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 80 ℃, applying 500MPa pressure to the die, and keeping the temperature for 30 min. And after the cold sintering is finished, cooling the grinding tool to room temperature, and demolding to obtain the HA-PLA material sample.
Comparative example 2
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 9:1 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 80 ℃, applying 500MPa pressure to the die, and keeping the temperature for 30 min. And after the cold sintering is finished, cooling the grinding tool to room temperature, and demolding to obtain the HA-PLA material sample.
Comparative example 3
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5 (+ -0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 6:4 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 80 ℃, applying 500MPa pressure to the die, and keeping the temperature for 30 min. And after the cold sintering is finished, cooling the grinding tool to room temperature, and demolding to obtain the HA-PLA material sample.
Comparative example 4
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 5:5 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 80 ℃, applying 500MPa pressure to the die, and keeping the temperature for 30 min. After the cold sintering is finished, the mold is removed after the grinding tool is cooled to room temperature, and the HA-PLA material sample is obtained.
Comparative example 5
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8:2 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 80 ℃, applying 500MPa pressure to the die, and keeping the temperature for 20 min. And after the cold sintering is finished, cooling the grinding tool to room temperature, and demolding to obtain the HA-PLA material sample.
Comparative example 6
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8:2 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 80 ℃, applying 500MPa pressure to the die, and keeping the temperature for 60 min. And after the cold sintering is finished, cooling the grinding tool to room temperature, and demolding to obtain the HA-PLA material sample.
Comparative example 7
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. Finally, the washed precipitate was dried in a forced air drying chamber at 80 ℃ for 15 hours,obtaining the hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8:2 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 60 ℃, applying 500MPa pressure to the die, and keeping the temperature for 30 min. And after the cold sintering is finished, cooling the grinding tool to room temperature, and demolding to obtain the HA-PLA material sample.
Comparative example 8
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8:2 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at 120 ℃, applying 500MPa pressure to the die, and keeping the temperature for 30 min. And after the cold sintering is finished, cooling the grinding tool to room temperature, and demolding to obtain the HA-PLA material sample.
Comparative example 9
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. And finally, drying the washed precipitate in a blast drying chamber at 80 ℃ for 15 hours to obtain hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8:2 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at the temperature of 80 ℃, applying the pressure of 100MPa to the die, and keeping the temperature for 30 min. And after the cold sintering is finished, cooling the grinding tool to room temperature, and demolding to obtain the HA-PLA material sample.
Comparative example 10
(1) HA granules were prepared. Will be (NH) 4 ) 2 HPO 4 The solution (0.5mol/L) was slowly added to Ca (NO) 3 ) 2 The solution (0.3mol/L) (Ca/P molar ratio 1.67) was magnetically stirred at 500r/min for 2 hours, and during the stirring, aqueous ammonia was added dropwise to maintain the pH of the solution at 10.5(± 0.2). The mixed solution was then aged for 5 hours at rest, and the precipitate was repeatedly washed with deionized water until the pH was neutral. Finally, the washed precipitate was placed on a drum at 80 deg.CDrying for 15 hours in an air drying chamber to obtain the hydroxyapatite powder.
(2) Preparing a primary composite material. Firstly, weighing PLA particles and a solvent dichloromethane according to a weight ratio of 1:9, adding a dichloromethane solution into a beaker filled with PLA, fully stirring until the dichloromethane solution is completely dissolved to obtain a polylactic acid solution with a final concentration of 10%, adding weighed hydroxyapatite powder into the polylactic acid solution according to a proportion, and magnetically stirring for two hours at a temperature of 30 ℃ at 500r/min to fully mix the two solutions; wherein, HA: the mass ratio of PLA is 8:2 respectively. And finally, standing to naturally volatilize the dichloromethane to obtain the primary composite material of the HA-PLA.
(3) And (5) cold sintering. Heating the primary composite material (powder) at the temperature of 80 ℃, applying the pressure of 700MPa to the die, and keeping the temperature for 30 min. And after the cold sintering is finished, cooling the grinding tool to room temperature, and demolding to obtain the HA-PLA material sample.
As shown in fig. 3-6, in the primary composite materials obtained in examples 1 and 2 (with a mass ratio of HA to PLA of 8:2 and 7:3), the HA is coated with PLA, the microstructure is in the form of a sheet with rounded boundaries, the PLA pores are fewer, the number of Hydroxyapatite (HA) particles exposed outside the polylactic acid layer is fewer, and the coating effect is better. By observing the exposed HA particles, the HA particle size is obviously refined, which shows that the agglomeration phenomenon can be well improved and the crystal grains are refined by adding PLA. The density of an HA-PLA composite material system obtained by cold-burning the primary composite material of HA-PLA is remarkably improved.
As shown in fig. 7-10, in comparative examples 1 and 2 (the mass ratio of HA to PLA is 10:0 and 9:1, respectively), the primary composite material before sintering had relatively coarse HA grains and serious agglomeration, and although the density after cold sintering treatment was improved, the primary composite material had relatively large pores and low density compared with 8:2 and 7:3 systems, and fig. 10 shows that the coarse HA grains exposed outside are not significantly improved.
As shown in fig. 11 to 14, in comparative examples 3 and 4, the primary composite materials obtained in the mass ratios of HA to PLA of 6:4 and 5:5, respectively, had a PLA-coated primary composite material, had a sheet-like microstructure with rounded boundaries, had fewer PLA pores, had fewer Hydroxyapatite (HA) particles exposed outside the polylactic acid layer, had a better coating effect, and had a better density of the HA-PLA composite material obtained after cold sintering. However, with the temperature increase during sintering, after reaching the glass transition temperature, PLA is converted into a viscous state, and for the samples of 5:5 and 6:4 (comparative examples 3 and 4), the content of PLA is too high, so that the humidity of the system is too high, and the overflow phenomenon of the material is caused under the action of pressure.
Relative density tests are carried out on the HA-PLA composite materials obtained after cold sintering in the examples 1-2 and the comparative examples 1-4, and the test results are shown in FIG. 15. As can be seen from FIG. 15, the relative compactness of the materials prepared in examples 1-2 and comparative examples 3-4 can reach more than 81.3%; the material HAs good compactness, while the materials prepared in comparative examples 1-2 (HA: PLA mass ratios of 10:0 and 9:1, respectively) have poor relative compactness.
The bending property test of the HA-PLA composite materials obtained after cold sintering in the examples 1-2 and the comparative examples 1-2 is carried out by using a universal testing machine, and the test result is shown in figure 16. Test procedure load rate: 0.5mm/min, the samples were processed to 4mm 3mm 20mm standards, and pure HA (comparative example 1) had very poor strength and high brittleness, and broke during cutting and grinding of the samples, so the curve of comparative example 1 is not shown in the figure, and the strength of HA was significantly improved after adding PLA. As can be seen from fig. 16, as the content of polylactic acid increases, the bending stress of the HA/PLA composite system is significantly increased, and the HA-PLA composites prepared in example 1 (corresponding to curve b) and example 2 (corresponding to curve c) have better bending stress; the most significant effect was 5.5 times that of the 9:1 (comparative example 2) when the PLA content was increased from 10% to 20% HA/PLA of 8:2 (example 1). The increase in flexural strength becomes progressively slower with increasing PLA content.
Further, the HA-PLA composite materials obtained in examples 1 to 2 and comparative examples 1 to 4 after cold sintering were subjected to a stress-strain curve in a compression test (a loading rate of 0.5mm/min) to each sample, as shown in FIG. 17. In FIG. 17, curve a corresponds to comparative example 1, curve b corresponds to comparative example 2, curve c corresponds to example 1, curve d corresponds to example 2, curve e corresponds to comparative example 3, and curve f corresponds to comparative example 4. As shown in fig. 17, all curves initially were elastically deformed, the stress rapidly increased, and the elastic modulus increased with the addition of polylactic acid, and the compressive strength increased to 2-3 times that of pure hydroxyapatite (comparative example 1). When the proportion of the polylactic acid is 10% -30%, the stress which can be borne by the sample is gradually increased along with the increase of the strain, but when the content of the polylactic acid is continuously increased, the stress value begins to be gradually weakened, and the highest point of the curve of FIG. 17 shows a platform, which shows that the yield strength is enhanced by adding the polylactic acid, and the variation trend of the strength is similar to that of the compressive strength. In addition, it can be found that the curves a and f in fig. 17 are obviously different, the curve a is a compression curve of pure hydroxyapatite (corresponding to comparative example 1), the value of the stress which can be borne by the curve a is small, cracks appear on the surface of the sample rapidly during the experiment, and the top of the curve is sharp and rapid fracture, which indicates that the material is brittle fracture; the composite material with the f-curve of 50% polylactic acid (corresponding to comparative example 4) has a fracture belonging to ductile fracture, and in the test, when the surface of the sample begins to crack, the fracture does not directly occur, and a tearing process exists, which is considered to have a direct relation with the added polylactic acid.
The results of water absorption tests of the HA-PLA composites obtained after cold sintering in examples 1 to 2 and comparative examples 1 to 4 are shown in fig. 18, where the weight of the material system after cold sintering is changed after being soaked in PBS, it can be shown that there is a change in the weight of the material system after cold sintering, and after loading a drug, the drug molecules can be released from the material system, thereby verifying the possibility of drug loading and drug release of the material system.
The comprehensive comparison between the examples 1-2 and the comparative examples 1-4 shows that the coating property of the polylactic acid on the hydroxyapatite is better along with the increase of the content of the polylactic acid, and the internal structure of the HA-PLA composite material sample obtained after cold sintering is more compact, so that the strength of the HA-PLA composite material sample is certainly better than that of a pure hydroxyapatite cold-sintered sample; the polylactic acid can improve the HA agglomeration phenomenon, so that the composite material with higher polylactic acid content HAs higher compressive strength; the pure hydroxyapatite is very brittle, and the polylactic acid has certain strength and toughness, so that the strength of a sample can be improved by adding the polylactic acid; the CSP process can promote high densification of the HA-PLA composite material; the addition of polylactic acid can obviously improve the compressive strength, but when the content of the polylactic acid is too high, the strength is reduced, because the coating particles of hydroxyapatite and polylactic acid are enlarged, the plasticity of the material is improved, but the strength is relatively weakened. The comprehensive description of the properties of the primary composite material and the HA-PLA composite material obtained after cold sintering and the existence of material overflow phenomenon in the preparation process is combined: HA: the mass ratio of PLA is the most appropriate ratio of 8: 2-7: 3.
As shown in fig. 19, when examples 1 and 5 and comparative examples 5 and 6 are compared, the ratio of HA: the mass ratio of PLA is 8:2, the cold sintering temperature is 80 ℃, and the pressure is 500MPa, the heat preservation time after cold sintering HAs certain influence on the compactness of the HA-PLA composite material. From FIG. 19, it can be seen that the HA-PLA composite materials prepared in examples 1 and 5 (the holding times are 30min and 40min, respectively) have better compactness, while the material prepared in the holding time of 20min (corresponding to comparative example 5) HAs poorer compactness; the material compactness is in an increasing trend within the heat preservation time of 20-40 min, and the heat preservation time of 30min and 40min respectively reaches 88.7% and 88.8% of high compactness. When the heat preservation time is longer than 40min, the compactness of the prepared HA-PLA composite material is in a descending trend. Therefore, the heat preservation time after cold sintering is 30-40 min, which is the most suitable heat preservation interval.
As shown in fig. 20, when examples 1 and 3 and comparative examples 7 and 8 are compared, the ratio of HA: the mass ratio of PLA is 8:2, the heat preservation time is 30min, and the pressure is 500MPa, the cold sintering temperature also HAs certain influence on the compactness of the HA-PLA composite material. As can be seen from FIG. 20, in examples 1 and 3, the HA-PLA composite material prepared HAs high compactness when the cold sintering temperature is 80-100 ℃. When the cold sintering temperature is 60 ℃ (corresponding to comparative example 7), the compactness of the prepared HA-PLA composite material is lower than that of the HA-PLA composite material when the compactness is 80 ℃; when the cold sintering temperature is higher than 100 ℃, the compactness of the prepared HA-PLA composite material is gradually improved, but the overflow phenomenon of the material occurs; the flooding phenomenon was severe at 120 c (corresponding to comparative example 8). Therefore, a cold sintering temperature of 80 ℃ to 100 ℃ is the most suitable cold sintering temperature.
As shown in fig. 21, when examples 1 and 4 and comparative examples 9 and 10 are compared, the ratio of HA: the mass ratio of PLA is 8:2, the cold sintering temperature is 80 ℃, and the heat preservation time is 30min, the applied pressure HAs certain influence on the compactness of the HA-PLA composite material. As can be seen from FIG. 19, in examples 1 and 5, the prepared HA-PLA composite material HAs high compactness when the corresponding pressure is 300 MPa-500 MPa. The compactness of the HA-PLA composite material prepared at a pressure of 100MPa (corresponding to comparative example 9) is lower than that of the HA-PLA composite material prepared at a pressure of 300MPa (corresponding to example 4); the HA-PLA composite material prepared under the pressure of 500MPa (corresponding to example 1) HAs the best compactness (the relative compactness can reach 88.8%); when the pressure is more than 500MPa, the compactness of the prepared HA-PLA composite material is in a descending trend, and the relative compactness of the material when the pressure is 700MPa (corresponding to comparative example 10) is approximately the same as that of the material when the pressure is 100MPa (corresponding to comparative example 9). Therefore, a pressure of 300MPa to 500MPa is most suitable in the cold sintering molding process.
Application test example
The HA-PLA composite materials prepared in examples 1 and 2 and comparative example 1 were subjected to drug loading test by using doxorubicin hydrochloride (DOX), which is a common cancer drug, and the processes of HA-PLA drug loading and drug release were explored to further illustrate the drug loading capacity of the HA-PLA composite materials.
The specific process is as follows:
before cold sintering, fully grinding the drug powder and the primary HA/PLA powder prepared in the comparative example 1 and the examples 1 and 2 respectively, uniformly mixing, sintering the powder into a round piece with the diameter of 6mm and the height of 2mm (+ -0.3 mm) by adopting a cold sintering method, and sintering at a low temperature of 80-100 ℃, wherein the round piece does not influence drug molecules, and the drug can be completely wrapped in a carrier, so that the drug loading rate is basically 100%, which is unprecedented.
The specific test method comprises the following steps: preparing a carrier: 10: 1, selecting HA/PLA as 10/0, 8/2 and 7/3 as carriers (corresponding to comparative example 1, example 1 and example 2 respectively), weighing 100mg of the carriers and DOX10mg, fully grinding the carriers, pouring the carriers into a grinding tool with the diameter of 6mm, and performing cold sintering treatment on the mixed powder under the conditions of uniaxial pressure of 500MPa, heat preservation temperature of 80 ℃ and heat preservation time of 30min to obtain wafers with the diameter of 6mm and the height of 2mm (+ -0.3 mm).
The obtained sample was immersed in a PBS solution having PH of 7.4, the temperature of the PBS solution was maintained at 37 ℃ in order to simulate the temperature of a human body, samples were taken at intervals, and the released DOX content in the PBS solution was measured by an ultraviolet spectrophotometer UV-1780, and the obtained curve is shown in fig. 22.
As can be seen from fig. 22, the DOX concentration gradually increased within the first 20 hours, and at 20 hours, the 8/2 (example 1) and 7/3 (example 2) samples could reach a drug release rate of 90% or more, and if they were placed close to the lesion, they could release a large amount of drug in a short time, effectively combating the virus. Whereas the pure HA (10/0) sample (comparative example 1) had less than 40% drug release within 20 h. In the interval of 20-30h, there is a stage of drug concentration reduction, because the drug concentration in the solution is high, the drug concentration in the sample is low, the whole solution system reaches the stage of diffusion equilibrium, after adding PLA, the density of the sample is high, and the longer the time required for reaching diffusion equilibrium is. After 30h, the drug concentration is basically maintained to be stable along with the increase of time, the whole system can stably release the drug for a long time to achieve the effect of continuously resisting viruses, the drug release rate of 8/2 (example 1) and 7/3 (example 2) samples can be stabilized to be about 60%, the drug utilization rate is high, the environment with high drug concentration can be maintained, the drug release rate of 10/0 (comparative example 1) samples is stabilized to be about 30%, a large amount of drug can not be released in the composite material system, and certain drug waste is caused.
The test proves that: the addition of PLA increases the binding sites of HA, HA and DOX can be uniformly coated together in the cold sintering process, the drug loading rate of the system is greatly improved, and DOX can be released at a stable rate along with the degradation and absorption of PLA-HA.
While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable in various fields of endeavor to which the invention pertains, and further modifications may readily be made by those skilled in the art, it being understood that the invention is not limited to the details shown and described herein without departing from the general concept defined by the appended claims and their equivalents.
Claims (7)
1. A low-temperature preparation method of a high-strength HA-PLA composite material capable of carrying medicine in situ is characterized by comprising the following steps:
step one, preparing hydroxyapatite powder; mixing the dichloromethane solution with the polylactic acid particles, and stirring until the dichloromethane solution and the polylactic acid particles are completely dissolved to obtain a polylactic acid solution;
step two, adding the hydroxyapatite powder into the polylactic acid solution, stirring, uniformly mixing, and standing to naturally volatilize dichloromethane to obtain a primary composite material;
wherein the weight ratio of the hydroxyapatite powder to the polylactic acid solution is as follows: 8:2 to 7: 3;
putting the primary composite material into a mold, performing cold sintering on the primary composite material, applying pressure to the mold, and preserving heat;
fourthly, demolding after the temperature of the mold is reduced to room temperature to obtain the HA-PLA composite material capable of carrying the medicine in situ;
in the third step, the value range of the pressure applied to the mold is as follows: 300MPa to 500 MPa; the heat preservation time is 30-40 min; the temperature of cold sintering is as follows: 80-100 ℃.
2. The low-temperature preparation method of the high-strength in-situ drug-loaded HA-PLA composite material according to claim 1, wherein in the first step, the method for preparing the hydroxyapatite powder comprises:
step a, mixing (NH) 4 ) 2 HPO 4 The solution is added to Ca (NO) 3 ) 2 Adding the solution into the solution and stirring, and dropwise adding ammonia water to keep the pH value of the solution at 10.5 +/-0.2 in the stirring process;
b, standing and aging the solution, and repeatedly washing the precipitate with deionized water until the pH value is neutral;
step c, drying the precipitate in a blast drying chamber to obtain the hydroxyapatite powder;
wherein, the (NH) 4 ) 2 HPO 4 Solution and Ca (NO) 3 ) 2 The Ca/P molar ratio in the solution was 1.67.
3. The low temperature preparation method of high strength in situ drug-loadable HA-PLA composite material according to claim 2, wherein in the step a, (NH) 4 ) 2 HPO 4 The concentration of the solution was 0.5mol/L, Ca (NO) 3 ) 2 The concentration of the solution was 0.3 mol/L.
4. The low-temperature preparation method of the high-strength in-situ drug-loadable HA-PLA composite material according to claim 3, wherein in the step a, the magnetic stirring is performed at a speed of 500r/min for 2 hours.
5. The low-temperature preparation method of the high-strength in-situ drug-loadable HA-PLA composite material according to claim 4, wherein in the step c, the precipitate is dried in a forced air drying chamber at 80 ℃ for 15 hours to obtain the hydroxyapatite powder.
6. The low-temperature preparation method of the high-strength in-situ drug-loadable HA-PLA composite material according to claim 4 or 5, wherein the weight ratio of the polylactic acid particles to the dichloromethane in the step one is 1: 9.
7. The low-temperature preparation method of the high-strength HA-PLA composite material capable of carrying drugs in situ according to claim 6, wherein in the second step, after hydroxyapatite powder is added into the polylactic acid solution, the mixture is magnetically stirred for 2 hours at 30 ℃ at 500 r/min.
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| CN109833513A (en) * | 2019-03-08 | 2019-06-04 | 华南理工大学 | A kind of hydroxyapatite scaffold and its preparation method and application of high degradability |
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| CN111286074A (en) * | 2020-01-20 | 2020-06-16 | 武汉理工大学 | Polylactic acid/nano hydroxyapatite composite material and preparation method and application thereof |
| CN111559852A (en) * | 2020-05-11 | 2020-08-21 | 西南交通大学 | Cold isostatic pressing sintering preparation method of bioglass |
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| JP3836444B2 (en) * | 2002-05-30 | 2006-10-25 | 独立行政法人科学技術振興機構 | Hydroxyapatite composite, method for producing the same, and medical material using the same |
| CA2996051A1 (en) * | 2015-09-29 | 2017-04-06 | The Penn State Research Foundation | Cold sintering ceramics and composites |
| JP2019524621A (en) * | 2016-07-05 | 2019-09-05 | イーティーエッチ チューリッヒ | High performance ceramics from cold sintered nanoscale powders |
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| CN110799473A (en) * | 2016-08-26 | 2020-02-14 | 沙特基础工业全球技术有限公司 | Ceramic-polymer composite obtained by cold sintering process using reactive monomer process |
| CN109833513A (en) * | 2019-03-08 | 2019-06-04 | 华南理工大学 | A kind of hydroxyapatite scaffold and its preparation method and application of high degradability |
| CN110078038A (en) * | 2019-05-27 | 2019-08-02 | 淄博新维陶瓷科技有限公司 | A kind of hydroxyapatite and the preparation method and application thereof |
| CN111286074A (en) * | 2020-01-20 | 2020-06-16 | 武汉理工大学 | Polylactic acid/nano hydroxyapatite composite material and preparation method and application thereof |
| CN111559852A (en) * | 2020-05-11 | 2020-08-21 | 西南交通大学 | Cold isostatic pressing sintering preparation method of bioglass |
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