CN103467756A - Method for preparing chitosan/hydroxyapatite composite microspheres - Google Patents
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Abstract
The invention relates to a method for preparing chitosan/hydroxyapatite composite microspheres, and belongs to the field of preparation technologies of biomedical materials. According to the method, chitosan, calcium nitrate and disodium hydrogen phosphate are taken as raw materials, and an in-situ synthesis technology is adopted for preparing the chitosan/hydroxyapatite (HA) composite microspheres. The method comprises the following steps: dropping a prepared calcium nitrate/chitosan solution into an oil phase containing Span 85 to form a water-in-oil type emulsion; adding a disodium hydrogen phosphate solution and uniformly stirring; dropping a glutaraldehyde water solution for cross-linking; finally regulating the pH value of a system through sodium hydroxide; performing dehydration, centrifugation, washing and drying to get a composite microsphere product. The chitosan/HA composite microspheres prepared by the method disclosed by the invention have the advantages of regular sphericity, narrow particle size distribution and high dispersivity, and can be used for effectively avoiding the problem of agglomeration of nano-HA particles during the preparation process of a traditional emulsification method, and be used as a medicine carrier or an injectable bone tissue repair material.
Description
Technical field
The present invention relates to a kind of technology of preparing of biomedical material, specifically a kind of method for preparing chitosan/hydroxyapatite composite microspheres.
Background technology
Matrix material is a field the most active in biomaterial research.Up to the present, the existing matrix material that comprises the various ways such as porous support, film, fiber, coating and microballoon successfully prepared and for bone damaged reparation study.Wherein, micro-sphere material has advantages of the uniquenesses such as granularity is little, specific surface area large, good fluidity.The injection-type artificial bone repair materials of being made by microballoon has very strong clinical operability, be not subject to the restriction of the damaged scope of bone during use, and be expected to change traditional bone grafting pattern of operating on, security is good, wound is little, thereby shows the application prospect more tempting than other form matrix materials.In addition, microballoon has low toxicity, efficient, slowly-releasing, the characteristic such as long-acting aspect drug release, has become the ideal carrier of somatomedin, microbiotic, the medicine such as anticancer at present.
Chitosan has good biocompatibility, biodegradability and antibiotic, anticorrosion, hemostasis and promotes the biological nature such as wound healing, thereby is widely used in the biomedical sectors such as artificial skin, wound dressing, bone tissue restoration and medicament slow release.But study, show, simple chitosan material lacks biological activity, can not form biological combination with osseous tissue, can't realize fixing with the permanent of bone.If chitosan and nanometer HA material are carried out to effective combination by the method for physics or chemistry, biological activity and bone connectivity that chitosan is good both can have been given, can effectively improve intensity, toughness and the machining property of HA material again, thereby make chitosan/HA matrix material become a kind of have several functions and desirable osseous tissue renovating material.
The dispersion and emulsion method is the traditional method for preparing chitosan/HA complex microsphere, the micron soon made or nanometer HA powder with carry out again emulsification after chitosan solution directly mixes.For example, the preparation method of patent hydroxy apatite/polylactic acid/chitosan composite microballoon (patent No. CN 102489231 A) and bibliographical information " preparation and property of nano-hydroxyapatite/chitosan medicine carrying microballoons " (Li Xiangnan etc., Central South University's journal (natural science edition) 2001, 42 (5): 1232-1237) and Preparation, characterization and in-vitro release of gentamicin from coralline hydroxyapatite-chitosan composite microspheres (Sivakumar M. etc., Carbohydrate Polymers 2002, 49 (3): 281-288).Yet, in the standby process of this legal system, because the reunion of nanometer HA particle makes it be difficult to be distributed to equably in glycan substrate, therefore can't reach nano combined between two kinds of components.In addition, this by the mixture microballoon simply be mixed, chitosan just, as the molding bonded agent of HA particle, lacks effective chemical bonding between two-phase.Defect on these preparation methods will certainly have influence on performance and the application of material.
In-situ synthesis refers under certain condition, by chemical reaction, inorganic particle is generated at the organic radical internal in-situ, thereby reaches evenly compound effect.With the dispersion and emulsion method, compare, in-situ synthesis has its unique advantage preparing aspect the mixture microballoon.At first, the preparation process of the generative process of HA and mixture microballoon completes in same reaction system, and preparation process one step completes, and energy consumption is low, simple to operate, is applicable to producing in enormous quantities.Secondly, nanometer HA crystal is nucleation and growth equably in chitosan basal body, can effectively avoid the reunion of HA particle, is conducive to prepare that interface bond strength is high, the complex microsphere of even structure and excellent performance.Yet, go back at present few people both at home and abroad and adopt the original position synthetic technology to prepare chitosan/HA mixture microballoon.
Summary of the invention
The objective of the invention is provides a kind of method for preparing the chitosan/hydroxyapatite composite microspheres of even structure, excellent property in order to overcome above-mentioned the deficiencies in the prior art.
Implementation procedure of the present invention is as follows: in water-in-oil (W/O) type reversed-phase emulsion system, take chitosan, nitrocalcite and Sodium phosphate dibasic as raw material, by the pH value in the conditioned reaction system, HA nanoparticle original position is created in the matrix of chitosan, thereby makes the chitosan of spherical rule, narrow diameter distribution, dispersed high and even structure/HA complex microsphere;
The preparation method of above-mentioned chitosan/HA complex microsphere comprises the steps:
(1) chitosan and calcium salt are dissolved in 2% acetum, obtain the chitosan solution that contains calcium ion;
(2) above-mentioned solution is joined in the oil phase that contains emulsifying agent, after stirring 0.5 h under room temperature, then add wherein phosphate solution, and at room temperature stir, make it to mix;
(3) crosslinked to adding glutaraldehyde solution to carry out in above-mentioned emulsion system;
(4) under constantly stirring, NaOH solution slowly being added drop-wise to emulsion system, the pH value of regulator solution is to alkalescence, and long-time the stirring, and chitosan and HA are deposited simultaneously;
(5) after adding acetone and stirring, that products therefrom is centrifugal, with acetone and water repetitive scrubbing, and be placed under room temperature and dry, finally obtain chitosan/HA complex microsphere.
In step (1) and (2), calcium salt used is nitrocalcite, calcium chloride, calcium hydroxide or calcium acetate; Phosphoric acid salt used is Sodium phosphate dibasic, diammonium hydrogen phosphate or phosphoric acid.
In step (2), oil phase used is vegetables oil or whiteruss, and the 5-20 that the oil phase volume is the water volume doubly.
In step (2), emulsifying agent used is Span-80, Span-85 or potassium sorbate; 0.1% ~ 3% (w/v) that emulsifier is the oil phase volume.
In step (2), add phosphatic amount to calculate than 1.67 by the Ca/P theoretical molar of HA.
In step (3), to adding the concentration of 1 mL glutaraldehyde water solution in the reaction system that contains 0.1 g chitosan, be 1 ~ 20 wt%.
In step (4), to adding the amount of NaOH in the reaction system that contains 0.1 g chitosan, be 0.01 ~ 0.3 g.
In gained chitosan/HA complex microsphere, chitosan is 1/1 ~ 20/1 with the Theoretical Mass ratio of HA.
The size of gained chitosan/HA complex microsphere can be controlled by regulating stirring velocity, and its particle size range is between 1 ~ 500 micron.
The form rule of gained chitosan/HA complex microsphere, dispersity is high, the grain size homogeneous, and nanometer HA particle in chitosan basal body without agglomeration.
Beneficial effect, owing to having adopted such scheme, the present invention has advantages of many uniquenesses with respect to prior art:
(1) preparation process of microballoon adopts single stage method to complete, and that is to say, the preparation process of the generative process of HA nano particle and mixture microballoon completes in same reaction system, can greatly reduce energy consumption, simplification of flowsheet and operation steps like this.And whole preparation technology is not high to equipment requirements, easy to implement and popularization, environmentally safe, be convenient to suitability for industrialized production.
(2) in position in building-up process, the chitosan macromole by with the interaction of mineral ion in interface, can control from molecular level nucleation and the growth of HA inorganic phase, and it is finally deposited in polymeric matrix equably, thereby effectively avoided the reunion of nano particle in microballoon inside.
(3), from composition principle and process, the synthetic biomineralization process that is similar to of original position, therefore be expected to obtain structure and performance closer to the chitosan of body bone tissue/HA complex microsphere.
(4) in-situ synthesis can obtain spherical rule, dispersity is high, particle diameter is little, interface bond strength is high, the chitosan of even structure and excellent performance/HA complex microsphere.
(5) gained chitosan/HA complex microsphere, by after soaking medicine carrying mode carrying medicament, can obtain the micro-sphere material that has bone reparation and the dual biological function of medicament slow release concurrently.This microballoon directly is filled into to the bone defect, is expected to both greatly shorten operating process, can utilize again the medicine fixed point to discharge and improve result for the treatment of.
(6) in prepared chitosan/HA complex microsphere, the effect that two kinds of components of chitosan and hydroxyapatite all have Adsorption of Heavy Metal Ions, so it also has potential application prospect in wastewater treatment.
(7) this method is equally applicable to prepare other inorganic-organic composites microballoons.
The accompanying drawing explanation
The stereoscan photograph of the microballoon that Fig. 1 is the embodiment of the present invention 1 preparation.
The stereoscan photograph of the microballoon that Fig. 2 is the embodiment of the present invention 2 preparations.
The surface topography of the microballoon that Fig. 3 is the embodiment of the present invention 2 preparations.
The size distribution figure of the microballoon that Fig. 4 is the embodiment of the present invention 2 preparations.
Embodiment
Below in conjunction with specific examples, technical scheme of the present invention is further described.
Embodiment 1: by 0.1 g chitosan and 0.029 g Ca (NO
3)
2.4H
2o is dissolved in 5 mL, in 2% acetic acid, obtains the chitosan solution that contains calcium ion.This solution is joined in the 100 mL soybean oil that contain span-85, stir under room temperature.Subsequently, in above-mentioned system, add by 0.027 g Na
2hPO
4.12H
2the aqueous solution (calculating than 1.67 by Ca/P theoretical molar in HA) of O preparation.After stirring makes it to mix, then add 1 mL glutaraldehyde solution to carry out crosslinked.After crosslinked 4 h, the NaOH solution of 1M slowly is added drop-wise in emulsion system, with the pH value of regulator solution, chitosan and HA is deposited simultaneously.After continuing under room temperature to stir 24 h, add 20 mL acetone, stir 30 min.Products therefrom is centrifugal, acetone and water repetitive scrubbing, and be placed under room temperature and dry, the complex microsphere that the mass ratio that finally obtains chitosan and HA is 8/1.
Embodiment 2: by 0.1 g chitosan and 0.059 g Ca (NO
3)
2.4H
2o is dissolved in 5 mL, in 2% acetic acid, obtains the chitosan solution that contains calcium ion.This solution is joined in the 100 mL soybean oil that contain span-85, stir under room temperature.Subsequently, in above-mentioned system, add by 0.053 g Na
2hPO
4.12H
2the aqueous solution (calculating than 1.67 by Ca/P theoretical molar in HA) of O preparation.Operation steps is with embodiment 1 afterwards.The complex microsphere that the mass ratio that finally obtains chitosan and HA is 4/1.
Embodiment 3: by 0.1 g chitosan and the anhydrous CaCl of 0.028 g
2be dissolved in 5 mL, in 2% acetic acid, obtain the chitosan solution that contains calcium ion.This solution is joined in the 150 mL soybean oil that contain span-80, stir under room temperature.Subsequently, in above-mentioned system, add by 0.020 g (NH
4)
2hPO
4the aqueous solution (calculating than 1.67 by Ca/P theoretical molar in HA) of preparation.Operation steps is with embodiment 1 afterwards.The complex microsphere that the mass ratio that finally obtains chitosan and HA is 4/1.
Embodiment 4: the chitosan of embodiment 2 preparations/HA complex microsphere is carried out to medicine carrying, release detection.Take (pH=7.4 in the PBS buffered soln that a certain amount of sample is immersed in 1 mg/mL tetracycline hydrochloride (TCH), 0.1M), centrifugal after immersion 48 h in the constant temperature oscillator of 37oC, the gained supernatant liquor is carried out to detection of drug concentration, and calculate thus entrapment efficiency and the drug loading of sample.The gained medicine carrying microballoons is joined in PBS solution, after ultrasonic dispersion, be placed in the constant temperature oscillation case of 37oC.After the certain hour of interval, take out, centrifugal, from supernatant liquor, draw solution is carried out the concentration detection, and adds the PBS solution of equal volume.Test result shows, this complex microsphere has certain slow release effect to medicine.
Claims (8)
1. a method for preparing chitosan/hydroxyapatite composite microspheres, it is characterized in that: in water-in-oil (W/O) type reversed-phase emulsion system, take chitosan, nitrocalcite and Sodium phosphate dibasic as raw material, by the pH value in the conditioned reaction system, HA nanoparticle original position is created in the matrix of chitosan, thereby makes the chitosan of spherical rule, narrow diameter distribution, dispersed high and even structure/HA complex microsphere;
The preparation method of above-mentioned chitosan/HA complex microsphere comprises the steps:
(1) chitosan and calcium salt are dissolved in 2% acetum, obtain the chitosan solution that contains calcium ion;
(2) above-mentioned solution is joined in the oil phase that contains emulsifying agent, after stirring 0.5 h under room temperature, then add wherein phosphate solution, and at room temperature stir, make it to mix;
(3) crosslinked to adding glutaraldehyde solution to carry out in above-mentioned emulsion system;
(4) under constantly stirring, NaOH solution slowly being added drop-wise to emulsion system, the pH value of regulator solution is to alkalescence, and long-time the stirring, and chitosan and HA are deposited simultaneously;
(5) after adding acetone and stirring, that products therefrom is centrifugal, with acetone and water repetitive scrubbing, and be placed under room temperature and dry, finally obtain chitosan/HA complex microsphere.
2. a kind of method for preparing chitosan/hydroxyapatite composite microspheres according to claim 1, it is characterized in that: in step (1) and (2), calcium salt used is nitrocalcite, calcium chloride, calcium hydroxide or calcium acetate; Phosphoric acid salt used is Sodium phosphate dibasic, diammonium hydrogen phosphate or phosphoric acid.
3. a kind of method for preparing chitosan/hydroxyapatite composite microspheres according to claim 1, it is characterized in that: in step (2), oil phase used is vegetables oil or whiteruss, the 5-20 that the oil phase volume is the water volume is doubly;
In step (2), emulsifying agent used is Span-80, Span-85 or potassium sorbate; 0.1% ~ 3% (w/v) that emulsifier is the oil phase volume;
In step (2), add phosphatic amount to calculate than 1.67 by the Ca/P theoretical molar of HA.
4. a kind of method for preparing chitosan/hydroxyapatite composite microspheres according to claim 1 is characterized in that: in step (3), to adding the concentration of 1 mL glutaraldehyde water solution in the reaction system that contains 0.1 g chitosan, be 1 ~ 20 wt%.
5. a kind of method for preparing chitosan/hydroxyapatite composite microspheres according to claim 1 is characterized in that: in step (4), to adding the amount of NaOH in the reaction system that contains 0.1 g chitosan, be 0.01 ~ 0.3 g.
6. a kind of method for preparing chitosan/hydroxyapatite composite microspheres according to claim 1, it is characterized in that: in gained chitosan/HA complex microsphere, chitosan is 1/1 ~ 20/1 with the Theoretical Mass ratio of HA.
7. a kind of method for preparing chitosan/hydroxyapatite composite microspheres according to claim 1 is characterized in that: the size of gained chitosan/HA complex microsphere can be controlled by regulating stirring velocity, and its particle size range is between 1 ~ 500 micron.
8. a kind of method for preparing chitosan/hydroxyapatite composite microspheres according to claim 1, it is characterized in that: the form rule of gained chitosan/HA complex microsphere, dispersity is high, the grain size homogeneous, and nanometer HA particle in chitosan basal body without agglomeration.
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103923355A (en) * | 2014-04-09 | 2014-07-16 | 无锡百运纳米科技有限公司 | Method for preparing agarose-hydroxyapatite composite microsphere |
| CN105315478A (en) * | 2014-11-07 | 2016-02-10 | 纳米及先进材料研发院有限公司 | Copolymer using nano calcium phosphate coated polymethyl methacrylate as substrate and coating method thereof |
| CN106178100A (en) * | 2016-07-20 | 2016-12-07 | 太原理工大学 | Carbon Nanotubes/Chitosan complex microsphere surface forms the preparation method of orientation nano-apatite |
| CN106178125A (en) * | 2016-07-20 | 2016-12-07 | 太原理工大学 | A kind of preparation method of nanometer hydroxyapatite chitosan compound microsphere |
| CN107376795A (en) * | 2017-07-18 | 2017-11-24 | 中国矿业大学 | A kind of preparation method of polyvinyl alcohol/hydroxyapatite composite microspheres |
| CN107579247A (en) * | 2017-09-17 | 2018-01-12 | 长沙仲善新能源科技有限公司 | Compound lithium cobaltate cathode material of a kind of graphene and preparation method thereof |
| CN107768627A (en) * | 2017-10-03 | 2018-03-06 | 长沙仲善新能源科技有限公司 | A kind of high-temperature stability nickle cobalt lithium manganate combination electrode and preparation method and application |
| CN107983766A (en) * | 2017-12-20 | 2018-05-04 | 华南师范大学 | A kind of preparation method and application of heavy metal cadmium soil remediation material |
| CN109549928A (en) * | 2017-09-26 | 2019-04-02 | 清华大学深圳研究生院 | A kind of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate and preparation method thereof |
| CN110354818A (en) * | 2019-08-05 | 2019-10-22 | 泰州禾益新材料科技有限公司 | The hydroxy apatite-base composite material and preparation method of arsenic, fluorine in a kind of absorption water |
| CN113599535A (en) * | 2021-07-21 | 2021-11-05 | 深圳大学 | nHA/GO/CS composite microspheres and preparation method and application thereof |
| CN116199800A (en) * | 2023-02-08 | 2023-06-02 | 中国林业科学研究院林产化学工业研究所 | Preparation method of chitosan-citral-calcium salt compound with vibrio resistance activity |
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Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103923355A (en) * | 2014-04-09 | 2014-07-16 | 无锡百运纳米科技有限公司 | Method for preparing agarose-hydroxyapatite composite microsphere |
| CN103923355B (en) * | 2014-04-09 | 2016-03-09 | 无锡百运纳米科技有限公司 | A kind of preparation method of agarose-hydroxyapatite composite microspheres |
| CN105315478A (en) * | 2014-11-07 | 2016-02-10 | 纳米及先进材料研发院有限公司 | Copolymer using nano calcium phosphate coated polymethyl methacrylate as substrate and coating method thereof |
| CN106178100A (en) * | 2016-07-20 | 2016-12-07 | 太原理工大学 | Carbon Nanotubes/Chitosan complex microsphere surface forms the preparation method of orientation nano-apatite |
| CN106178125A (en) * | 2016-07-20 | 2016-12-07 | 太原理工大学 | A kind of preparation method of nanometer hydroxyapatite chitosan compound microsphere |
| CN107376795A (en) * | 2017-07-18 | 2017-11-24 | 中国矿业大学 | A kind of preparation method of polyvinyl alcohol/hydroxyapatite composite microspheres |
| CN107579247A (en) * | 2017-09-17 | 2018-01-12 | 长沙仲善新能源科技有限公司 | Compound lithium cobaltate cathode material of a kind of graphene and preparation method thereof |
| CN109549928A (en) * | 2017-09-26 | 2019-04-02 | 清华大学深圳研究生院 | A kind of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate and preparation method thereof |
| CN107768627A (en) * | 2017-10-03 | 2018-03-06 | 长沙仲善新能源科技有限公司 | A kind of high-temperature stability nickle cobalt lithium manganate combination electrode and preparation method and application |
| CN107983766A (en) * | 2017-12-20 | 2018-05-04 | 华南师范大学 | A kind of preparation method and application of heavy metal cadmium soil remediation material |
| CN110354818A (en) * | 2019-08-05 | 2019-10-22 | 泰州禾益新材料科技有限公司 | The hydroxy apatite-base composite material and preparation method of arsenic, fluorine in a kind of absorption water |
| CN110354818B (en) * | 2019-08-05 | 2020-07-03 | 泰州禾益新材料科技有限公司 | Hydroxyapatite-based composite material for adsorbing arsenic and fluorine in water and preparation method thereof |
| CN113599535A (en) * | 2021-07-21 | 2021-11-05 | 深圳大学 | nHA/GO/CS composite microspheres and preparation method and application thereof |
| CN116199800A (en) * | 2023-02-08 | 2023-06-02 | 中国林业科学研究院林产化学工业研究所 | Preparation method of chitosan-citral-calcium salt compound with vibrio resistance activity |
| CN116199800B (en) * | 2023-02-08 | 2024-02-27 | 中国林业科学研究院林产化学工业研究所 | Preparation method of chitosan-citral-calcium salt compound with vibrio resistance activity |
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Application publication date: 20131225 |