CN101401957B - Chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material, producing method and apparatus thereof - Google Patents
Chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material, producing method and apparatus thereof Download PDFInfo
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- CN101401957B CN101401957B CN2008102350767A CN200810235076A CN101401957B CN 101401957 B CN101401957 B CN 101401957B CN 2008102350767 A CN2008102350767 A CN 2008102350767A CN 200810235076 A CN200810235076 A CN 200810235076A CN 101401957 B CN101401957 B CN 101401957B
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Abstract
The invention relates to a chitosan-beta-tricalcium phosphate composite spherical particle, and a method and a device for preparing the same. The method comprises the following steps: preparing a chitosan acetic acid solution at first, and then adding beta-nano-tricalcium phosphate powders into the chitosan acetic acid solution to prepare a suspension liquid, wherein the mass ratio of the beta-tricalcium phosphate to the chitosan is (6-1) to (1-5). The prepared suspension liquid is added into a material storage tank from a feed opening, is forced to flow out of a liquid guiding tube evenly through controlling the pressure in the material storage tank, and is dripped into a condensate in a thermal insulation container to be condensed so as to form spherical particles. The condensed spherical particles are treated by freeze-drying at first, then are crosslinked by 2.5 percent of glutaraldehyde solution, and finally are washed by anhydrous ethanol to obtain the chitosan-beta-tricalcium phosphate composite spherical porous particle material. The spherical particle material has homogeneous particle diameter distribution, contains a large number of micropores communicated with one another therein, has higher specific surface area, and can be applied to tissue repair and medicament slow release.
Description
One, technical field
The invention belongs to a kind of spherical particle material that is applied to biomedical sector, be specifically related to a kind of chitosan-beta-tricalcium phosphate composite spherical granule and preparation method thereof and device.
Two, background technology
Prior art: chitin extensively is present in the cell wall of the arthropodan shell such as shrimp, Eriocheir sinensis and insecticide and the rudimentary plants such as bacterium, algae, is one of the abundantest biopolymer of occurring in nature, is a kind of very abundant natural regenerated resources.Chitosan be chitin take off the acetyl product, chitosan is nontoxic, good biocompatibility, biodegradable, in recent years, very noticeable in the research of the aspects such as medical absorbable suture, hemostatic material, wound dressing material and artificial skin as natural medical polymer materials.Simultaneously, chitosan also is a kind of good hard tissue repairing material, also is being applied aspect fracture absorbable fination material and the damaged packing material of bone.But because the mechanical property of chitosan is lower, its application in hard tissue repair is subject to certain restrictions.
(β-TCP) is one of biodegradation or bio-absorbable type biological active ceramic material to bata-tricalcium phosphate, behind its implanted human body, Ca, P that degraded produces can enter the live body blood circulation, help new bone formation, it can be used as the desirable substitution material of human body hard tissue such as tooth and bone, has good biodegradable, biocompatibility and biological nontoxic.Therefore, bata-tricalcium phosphate is a kind of comparatively desirable hard tissue repairing material.The bata-tricalcium phosphate of synthetic exists with Powdered usually, if with chitosan and the compound preparation composite of bata-tricalcium phosphate, the good biocompatibility of existing natural macromolecular material and biodegradability have again good mechanical property, and the performance of material will be very significantly improved.Chitosan-bata-tricalcium phosphate composite also can be used for preparing the packing material of particle shape except being used for preparing the block body stephanoporate support.
Micro-sphere material has the unexistent excellent properties of a lot of irregular particles, as being difficult for causing stress concentration etc. after high flowability, high bulk density, difficult reunion, the filling.At present, reparation, the alveolar ridge of frontal resorption increase due to the filling, periodontal disease of root canal and exodontia nest, the filling of jaw bones blister cavities, atrophic rhinitis's filling, mastoid cavity filling, shaping (such as the nasus incurvus beauty treatment) reach in the damaged filling of bone with other position of skeleton, and the microsphere particle packing material is used widely.The polymer-matrix microsphere particle has multiple preparation method, and commonly used have emulsifying-chemical crosslink technique, emulsion solvent evaporation technique and a spray drying method.The microsphere diameter distribution of using these method preparations is larger, and packed density is large, and when being applied to tissue filling, intergranular hole is very few, is unfavorable for growing into of cambium.
Three, summary of the invention
The present invention is directed to the large defective of microspherulite diameter distribution that prior art exists, a kind of chitosan-beta-tricalcium phosphate composite spherical granule and preparation method thereof and device are provided, the granule of preparation has the homogeneous distribution diameter.
Technical scheme of the present invention is: a kind of chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material, particle diameter is φ 0.8～4mm, the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore, the porosity of granular materials is 75～92%, and wherein quality is than bata-tricalcium phosphate: chitosan=(6～1): (1～5).
The preparation method of described chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material, step is: the first step, taking by weighing the chitosan that accounts for solution gross mass 5～25%, to be dissolved in mass concentration be to obtain chitosan-acetic acid solution in 1～5% the acetum; Then the mass ratio of pressing bata-tricalcium phosphate and chitosan is (6～1): (1～5), take by weighing the nanometer bata-tricalcium phosphate, will make chitosan-bata-tricalcium phosphate suspension in the nanometer bata-tricalcium phosphate adding chitosan-acetic acid solution;
Second step, with the first step prepare chitosan-the bata-tricalcium phosphate suspension is the pipe of φ 0.5～3mm from caliber, evenly flow out with the speed of 10～60/min, splash into temperature for condensation in the-condensed fluid of (10～20) ℃, form spheroidal particle; Described condensed fluid is dimethicone or vegetable oil.
The 3rd step is with the condensed spheroidal particle separation of second step, lyophilization; It is cross-linking agent solution crosslinking Treatment 3～24h of 0.25～2.5% that spheroidal particle after the lyophilization is put into mass concentration, then cleans with dehydrated alcohol, obtains chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material.Described cross-linking agent is any one in formaldehyde, glutaraldehyde, the Biformyl.
Adopt drop-condensation method of the present invention to prepare microsphere particle, the preparation facilities of chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material mainly is comprised of charge door, Pressure gauge, pressure-control valve, storage tank, flow control valve, catheter, condensed fluid and cool-bag.
The slurry for preparing adds storage tank from charge door, by the pressure in Pressure gauge and the pressure-control valve control storage tank, to guarantee that slurry evenly flows out from catheter.The slurry that flows out from catheter drips behind certain volume greatly mouth of pipe director, in dropping process, because that capillary effect forms is spherical, then enters the condensed fluid condensation in the cool-bag, forms spheroidal particle.According to the surface tension formula:
mg＝2πrσ
In the formula: m is drop mass; R is the extracapillary radius; σ is surface tension; G is acceleration of gravity.When density and viscosity one timing of chitosan solution, under the condition without external interference, this method can be prepared the spheroidal particle of good sphericity, uniform particle diameter.
Beneficial effect: the present invention preparation obtain chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material:
(1) contain a large amount of intercommunication micropores in the granule body interior, form three-dimensional netted stereochemical structure, this granule has higher specific surface area, is conducive to the Flow of tissue fluid of the adhesion of cell;
(2) chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material has the particle size distribution of homogeneous, does not need to carry out follow-up screening during use and processes; The present invention be the slurry that will configure by splashing in the freezing in advance liquid, the surface tension of using liquid is condensed into a kind of process of spheroidal particle.According to the surface tension formula:
mg＝2πrσ
In the formula: m is drop mass; R is the extracapillary radius; σ is surface tension; G is acceleration of gravity.When density and viscosity one timing of slurry, under the condition without external interference, this method can be prepared the microsphere particle of good sphericity, uniform particle diameter.
(3) because the narrow diameter distribution of the spheroidal particle of the present invention preparation, and the spherical granular material of same particle size can obtain maximum interparticle porosity after the filling, so when being applied to tissue filling, be conducive to growing into of cambium.
(4) granular materials is comprised of chitosan and nanometer bata-tricalcium phosphate, has both possessed good degradation capability, when being used for the bone reparation, can provide Ca, P ion for new bone formation again.
Four, description of drawings:
Fig. 1 spheroidal particle forming device schematic diagram.
Device mainly is comprised of charge door 1, Pressure gauge 2, pressure-control valve 3, storage tank 4, flow control valve 5, catheter 6, condensed fluid 7 and cool-bag 8.
Fig. 2 is the photo of chitosan-beta-tricalcium phosphate composite spherical honeycombed grain.
Fig. 3 is the internal void photo of chitosan-beta-tricalcium phosphate composite spherical honeycombed grain.
Five, the specific embodiment:
Embodiment 1:
(1) taking by weighing the chitosan that accounts for solution gross mass 5%, to be dissolved in mass concentration be in 1% the acetum, to make chitosan-acetic acid solution; Then be that the ratio of 2:1 takes by weighing the nanometer bata-tricalcium phosphate in the mass ratio of bata-tricalcium phosphate and chitosan;
(2) the nanometer bata-tricalcium phosphate is added chitosan-acetic acid solution, fully stir and obtain chitosan-bata-tricalcium phosphate acetic acid suspension;
(3) as shown in Figure 1, the suspension for preparing adds storage tank 4 from charge door 1, the pressure of controlling in the storage tanks 4 by Pressure gauge 2 and pressure-control valve 3 is 0.08MPa, to guarantee that the speed with 10/min evenly flows out the catheter 6 of chitosan-bata-tricalcium phosphate suspension from caliber as φ 0.5mm, flow velocity can be controlled by flow control valve 5, and solution splashes into condensation in the condensed fluid 7 in the cool-bag 8, and the temperature of condensed fluid is-10 ℃, condensed fluid is vegetable oil, forms spheroidal particle;
(4) condensed microsphere is separated, and process 8h-5 ℃ temperature lyophilization, it is 0.25% glutaraldehyde solution crosslinking Treatment 3h that spheroidal particle after the lyophilization is put into first mass concentration, clean with dehydrated alcohol again, obtain chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material, as shown in Figure 2, the good sphericity of granule, uniform particle diameter, particle diameter are φ 0.8mm, as shown in Figure 3, the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore, porosity is 75%, forms three-dimensional netted stereochemical structure.
Embodiment 2:
(1) taking by weighing the chitosan that accounts for solution gross mass 15%, to be dissolved in mass concentration be to make chitosan-acetic acid solution in 3% the acetum, is that 6:1 takes by weighing the nanometer bata-tricalcium phosphate by the mass ratio of bata-tricalcium phosphate and chitosan;
(2) the nanometer bata-tricalcium phosphate is added chitosan-acetic acid solution, fully stir and obtain chitosan-bata-tricalcium phosphate acetic acid suspension;
(3) chitosan for preparing-bata-tricalcium phosphate acetic acid suspension is added storage tank 4 from charge door 1, the pressure of controlling in the storage tanks 4 by Pressure gauge 2 and pressure-control valve 3 is 0.5MPa, to guarantee that the speed with 60/min evenly flows out the catheter 6 of chitosan-bata-tricalcium phosphate suspension from caliber as φ 3mm, flow velocity can be controlled by flow control valve 5, solution splashes into condensation in the condensed fluid 7 in the cool-bag 8, the temperature of condensed fluid is-20 ℃, condensed fluid is dimethicone, forms spheroidal particle;
(4) condensed microsphere is separated, and process 24h-10 ℃ temperature lyophilization, it is 2.5% glyoxal solution crosslinking Treatment 24h that spheroidal particle after the lyophilization is put into first mass concentration, clean with dehydrated alcohol again, obtain chitosan-beta-tricalcium phosphate composite spherical granule, particle diameter is φ 4mm, and the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore, porosity are 92%.
Embodiment 3:
(1) taking by weighing the chitosan that accounts for solution gross mass 25%, to be dissolved in mass concentration be that 5% acetum is made chitosan-acetic acid solution, is that 2:5 takes by weighing the nanometer bata-tricalcium phosphate by the mass ratio of bata-tricalcium phosphate and chitosan;
(2) the nanometer bata-tricalcium phosphate is added chitosan-acetic acid solution, fully stir and obtain chitosan-bata-tricalcium phosphate acetic acid suspension;
(3) chitosan for preparing-bata-tricalcium phosphate acetic acid suspension is added storage tank 4 from charge door 1, the pressure of controlling in the storage tanks 4 by Pressure gauge 2 and pressure-control valve 3 is 0.25MPa, to guarantee that the speed with 30/min evenly flows out the catheter 6 of chitosan-bata-tricalcium phosphate suspension from caliber as φ 2.3mm, flow velocity can be controlled by flow control valve 5, solution splashes into condensation in the condensed fluid 7 in the cool-bag 8, the temperature of condensed fluid is-15 ℃, condensed fluid is vegetable oil, forms spheroidal particle;
(4) condensed microsphere separates, and process 14h-8 ℃ temperature lyophilization, it is 1.5% formalin crosslinking Treatment 14h that spheroidal particle after the lyophilization is put into first mass concentration, clean with dehydrated alcohol again, obtain chitosan-beta-tricalcium phosphate composite spherical granule, particle diameter is φ 2.8mm, and the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore, porosity are 82%.
Claims (5)
1. chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material, the particle diameter that it is characterized in that described chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material is φ 0.8～4mm, the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore, the porosity of chitosan-beta-tricalcium phosphate composite spherical granule is 75～92%, and wherein quality is than bata-tricalcium phosphate: chitosan=(6～1): (1～5).
2. preparation method of chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material as claimed in claim 1 is characterized in that preparation process is:
The first step, taking by weighing the chitosan that accounts for solution gross mass 5～25%, to be dissolved in mass concentration be to obtain chitosan-acetic acid solution in 1～5% the acetum; Then the mass ratio by bata-tricalcium phosphate and chitosan is (6～1): (1～5) takes by weighing the nanometer bata-tricalcium phosphate, the nanometer bata-tricalcium phosphate is added in the chitosan-acetic acid solution make chitosan-bata-tricalcium phosphate suspension;
Second step, with the first step prepare chitosan-the bata-tricalcium phosphate suspension is the pipe of φ 0.5～3mm from caliber, evenly flow out with the speed of 10～60/min, splash into temperature for condensation in the-condensed fluid of (10～20) ℃, form spheroidal particle;
The 3rd step is with the condensed spheroidal particle separation of second step, lyophilization; It is cross-linking agent solution crosslinking Treatment 3～24h of 0.25%～2.5% that spheroidal particle after the lyophilization is put into mass concentration, then cleans with dehydrated alcohol, obtains chitosan-beta-tricalcium phosphate composite spherical granule.
3. the preparation method of chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material as claimed in claim 2 is characterized in that, described condensed fluid is dimethicone or vegetable oil.
4. the preparation method of chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material as claimed in claim 2 is characterized in that, described cross-linking agent is any one in formaldehyde, glutaraldehyde, the Biformyl.
5. the device for preparing chitosan-beta-tricalcium phosphate composite spherical honeycombed grain material as claimed in claim 1, it is characterized in that, described device is comprised of storage tank (4) and cool-bag (8), be provided with charge door (1) at storage tank (4) top, on storage tank (4), also be provided with Pressure gauge (2), Pressure gauge (2) is connected with pressure-control valve (3), be provided with catheter (6) in the bottom of storage tank (4), be provided with flow control valve (5) at catheter (6), below catheter, be provided with cool-bag (8).
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| US5810988A (en) * | 1994-09-19 | 1998-09-22 | Board Of Regents, University Of Texas System | Apparatus and method for generation of microspheres of metals and other materials |
| CN1546181A (en) * | 2003-12-12 | 2004-11-17 | 清华大学 | Degradable material capable of guiding the regeneration and renovation process of hard tissue and its preparation |
| CN1607033A (en) * | 2003-10-15 | 2005-04-20 | 中国科学院过程工程研究所 | Chitose microsphere and microcapsule with uniform size and its preparation method |
| CN1931378A (en) * | 2006-09-29 | 2007-03-21 | 清华大学 | Micro rack for bone tissue engineering and its prepn process and application |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5810988A (en) * | 1994-09-19 | 1998-09-22 | Board Of Regents, University Of Texas System | Apparatus and method for generation of microspheres of metals and other materials |
| CN1607033A (en) * | 2003-10-15 | 2005-04-20 | 中国科学院过程工程研究所 | Chitose microsphere and microcapsule with uniform size and its preparation method |
| CN1546181A (en) * | 2003-12-12 | 2004-11-17 | 清华大学 | Degradable material capable of guiding the regeneration and renovation process of hard tissue and its preparation |
| CN1931378A (en) * | 2006-09-29 | 2007-03-21 | 清华大学 | Micro rack for bone tissue engineering and its prepn process and application |
Non-Patent Citations (1)
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| 卢勰炜等.新型壳聚糖-海藻酸钠胃漂浮小丸的制备.《中国现代应用医学杂志》.2004,第21卷(第6期), * |
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