CN101401972B - Collagen-chitosan spherical honeycombed grain material, producing method and apparatus thereof - Google Patents
Collagen-chitosan spherical honeycombed grain material, producing method and apparatus thereof Download PDFInfo
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- CN101401972B CN101401972B CN2008102350748A CN200810235074A CN101401972B CN 101401972 B CN101401972 B CN 101401972B CN 2008102350748 A CN2008102350748 A CN 2008102350748A CN 200810235074 A CN200810235074 A CN 200810235074A CN 101401972 B CN101401972 B CN 101401972B
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- honeycombed grain
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Abstract
The invention relates to a collagen-chitosan spherical porous granular material, a method and a device for preparing the same. The preparation method comprises the following steps: step one, the collagen and the chitosan are weighed according to the mass ratio of (1-9) to (9-1); step two, collagen-chitosan acetum solution is prepared; step three, the solution is added into a storage tank from a charging hole, uniformly flows out at a speed of 10 to 60 drops per minute under the condition of the pressure is controlled between 0.08 and 0.5 MPa, and then is dripped into a condensed fluid with a temperature below -(10-20) DEG C in an insulated container for condensation, so as to form the collagen-chitosan spherical porous granular material with good sphericity and homogeneous grain diameter;and step four, the spherical porous grains are separated, undergo freeze drying and then cross-linking treatment for 3 to 24 hours, and are washed, so as to obtain the collagen-chitosan spherical porous granular material. The spherical granular material has the homogeneous particle size distribution, contains a plurality of mutually communicated micropores, has high specific surface, and can be applied to tissue restoration and drug release.
Description
Technical field
The invention belongs to field of biomedical materials, be specifically related to a kind of natural polymer Collagen-Chitosan spherical honeycombed grain material and preparation method thereof.
Background technology
Collagen protein or claim that collagen is by the synthetic a kind of biological macromolecule of zooblast extensively is present in bone, tendon, cartilage and the skin and other connective tissue of animal, accounts for the about 30% of mammal total protein, is the extracellular matrix composition that body weight for humans is wanted.Collagen has good biological characteristics, can be used as the holder of tissue, and reparation has significant impact to cell, tissue and even organ enforcement normal function and to wound.A large amount of results of study show that the performance of collagen can satisfy for the culture matrix as epidermis cell, fibroblast, keratocyte, chondrocyte and osteocyte.In tissue repair, collagen can participate in the organization healing process and can guide, Promote cell's growth; Effect with remarkable guiding/induced tissue regeneration, make the healing of wound surface practical function, reproducibility, can be widely used in reparation soft, sclerous tissues's damage, such as the treatment of the department of stomatology, orthopaedics, plastic surgery, department of eye, neurosurgery and tendon rupture and viscera perforation etc.
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, 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 simple collagen or chitin carrier all are difficult to satisfy the needs of organizational project cell culture on intensity and the degradation speed, and after collagen and chitosan is compound, have increased the carrier mechanical strength.In addition, add chitosan in the collagen and can postpone time of beginning to degrade, will be conducive to growing into of cell and cambium.At present, the Collagen-Chitosan composite is used for artificial skin or wound dressing mainly with the form of film.The invention provides a kind of method for preparing the spherical porous particle of Collagen-Chitosan composite.
Summary of the invention
Bad for the honeycombed grain material sphericity that solves prior art preparation, the inhomogenous shortcoming of particle diameter the invention provides the Collagen-Chitosan spherical honeycombed grain material and preparation method thereof and the device that uses of a kind of uniform particle diameter, good sphericity.
Technical scheme of the present invention is a kind of Collagen-Chitosan spherical honeycombed grain material, the spheroidal particle of described Collagen-Chitosan 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 Collagen-Chitosan spherical honeycombed grain material is 80～95%, and the granulometric composition mass ratio is collagen: chitosan=(1～9): (9～1).
A kind of preparation method for preparing described Collagen-Chitosan spherical honeycombed grain material, preparation process is:
The first step, in mass ratio collagen: chitosan=(1～9): the ratio of (9～1) takes by weighing collagen and chitosan;
It is in 1～5% the acetum that second step, the collagen that the first step is taken by weighing and chitosan add mass concentration, and the gross mass that is formulated as Collagen-Chitosan accounts for 3～20% solution of Collagen-Chitosan acetum gross mass, stirs dissolving;
The 3rd step, the collagen-chitin acetum that second step is prepared adds storage tank from charge door, the pressure of controlling in the storage tank by Pressure gauge and pressure-control valve is 0.08～0.5MPa, evenly flows out with the speed of 10～60/min to guarantee the catheter of collagen-chitin acetum from caliber as φ 0.5～3mm.The collagen-chitin acetum that flows out from catheter drips behind the subsphaeroidal granule of about φ 0.8～4mm greatly mouth of pipe director, in dropping process, because capillary effect forms spherical, the temperature that then splashes in the cool-bag is condensation in the-condensed fluid of (10～20) ℃, forms the collagen-chitosan spherical honeycombed grain material of good sphericity, uniform particle diameter.
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 collagen-chitin liquid density and viscosity one timing, under the condition without external interference, this method can be prepared the spheroidal particle of good sphericity, uniform particle diameter.
The 4th step is with the condensed spheroidal particle separation of the 3rd 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 the Collagen-Chitosan spherical honeycombed grain material.Described condensed fluid is dimethicone or vegetable oil.Described cross-linking agent is any one in formaldehyde, glutaraldehyde, the Biformyl.
The device for preparing described Collagen-Chitosan spherical honeycombed grain material, described device is comprised of storage tank and cool-bag, be provided with charge door at the storage tank top, on storage tank, also be provided with Pressure gauge, Pressure gauge is connected with pressure-control valve, bottom at storage tank is provided with catheter, is provided with flow control valve at catheter, is provided with cool-bag below catheter.
Beneficial effect: the Collagen-Chitosan spherical honeycombed grain material of the present invention's preparation:
(1) contain a large amount of intercommunication micropores in the granule body interior, form the 3 D stereo network structure, this granule has higher specific surface area, is conducive to the Flow of tissue fluid of the adhesion of cell;
(2) the Collagen-Chitosan granule has the particle size distribution of homogeneous, does not need to sieve the granular materials that processing can obtain having same particle size; According to the surface tension formula: mg=2 π r σ
In the formula: m is drop mass; R is the extracapillary radius; σ is surface tension; G is acceleration of gravity.When Collagen-Chitosan liquid density and viscosity one timing, under the condition without external interference, this method can be prepared the spheroidal particle of good sphericity, uniform particle diameter.
(3) uniform particle diameter of the spheroidal particle of the present invention's preparation, and the spherical granular material of same particle size, the intergranular space rate is maximum after the filling, so the collagen-chitin granule of the present invention's preparation is conducive to the migration growth of Flow of tissue fluid and cell.
(4) can by changing the composition of material, regulate the degradation speed of spherical granular material.
Description of drawings:
Fig. 1 is the used device sketch map of the present invention.
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 collagen-chitosan spherical honeycombed grain.
Fig. 3 is the internal void photo of Collagen-Chitosan spherical honeycombed grain.
The specific embodiment:
Embodiment 1:
(1) by collagen: the mass ratio of chitosan is that 1:9 takes by weighing collagen and chitosan;
(2) it is in 3% the acetum that the collagen that the first step is taken by weighing and chitosan add mass concentration, and it is 20% Collagen-Chitosan acetum that the quality that is mixed with collagen and chitosan accounts for whole solution quality, stirs, fully dissolving;
(3) as shown in Figure 1, the Collagen-Chitosan acetum for preparing is added storage tank 4 from charge door 1, the pressure of controlling in the storage tank 4 by pressure-control valve and Pressure gauge is 0.08MPa, to guarantee that the speed with 10/min evenly flows out the catheter 6 of Collagen-Chitosan solution from caliber as φ 0.5mm, can come coutroi velocity by flow control valve 5.Splashing into condensation in the condensed fluid 7 in the cool-bag 8, the temperature of condensed fluid be-(10～20) ℃, and the formation spheroidal particle, as shown in Figure 2, the sphericity of the spheroidal particle that the present invention makes is fairly good, uniform particle diameter; Condensed fluid is vegetable oil.
(4) condensed microsphere separates, 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, cleans with dehydrated alcohol again, obtains collagen-chitosan spherical honeycombed grain material, as shown in Figure 3, particle diameter is φ 0.8mm, the granule body interior be the aperture less than the micropore of 150 μ m, intercommunication between the micropore, be tridimensional network, the porosity of Collagen-Chitosan spherical honeycombed grain material is 80%.
Embodiment 2:
(1) by collagen: the mass ratio of chitosan is that 9:1 takes by weighing collagen and chitosan;
(2) it is in 1% the acetum that the collagen that the first step is taken by weighing and chitosan add mass concentration, and it is 3% Collagen-Chitosan acetum that the quality that is mixed with collagen and chitosan accounts for whole solution quality, stirs, fully dissolving;
(3) the Collagen-Chitosan acetum for preparing is added storage tank 4 from charge door 1, be 0.5MPa by the pressure of control in the storage tank 4, to guarantee that the speed with 60/min evenly flows out the catheter 6 of Collagen-Chitosan solution from caliber as φ 3mm, splash 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 separates, 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 collagen-chitosan spherical honeycombed grain material, particle diameter is φ 0.8～4mm, and the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore, the porosity of Collagen-Chitosan spherical honeycombed grain material are 95%.
Embodiment 3:
(1) by collagen: the mass ratio of chitosan is that 5:4 takes by weighing collagen and chitosan;
(2) it is in 5% the acetum that the collagen that the first step is taken by weighing and chitosan add mass concentration, and it is 12% Collagen-Chitosan acetum that the quality that is mixed with collagen and chitosan accounts for whole solution quality, stirs, fully dissolving;
(3) the Collagen-Chitosan acetum for preparing is added storage tank 4 from charge door 1, be 20.5MPa by the pressure of control in the storage tank 4, to guarantee that the speed with 40/min evenly flows out the catheter 6 of Collagen-Chitosan solution from caliber as φ 1.5mm, splash into condensation in the condensed fluid 7 in the cool-bag 8, the temperature of condensed fluid is-(10～20) ℃, form spheroidal particle; Condensed fluid is dimethicone.
(4) condensed microsphere separates, and process 14h-7 ℃ temperature lyophilization, it is 1.5% formalin crosslinking Treatment 18h that spheroidal particle after the lyophilization is put into first mass concentration, clean with dehydrated alcohol again, obtain collagen-chitosan spherical honeycombed grain material, particle diameter is φ 1.8mm, and the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore, the porosity of Collagen-Chitosan spherical honeycombed grain material are 88%.
Claims (5)
1. collagen-chitosan spherical honeycombed grain material, it is characterized in that described collagen-chitosan 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 collagen-chitosan spherical honeycombed grain material is 80～95%, and the granulometric composition mass ratio is collagen: chitosan=(1～9): (9～1).
2. a preparation method for preparing collagen-chitosan spherical honeycombed grain material as claimed in claim 1 is characterized in that, preparation process is:
The first step, in mass ratio collagen: chitosan=(1～9): the ratio of (9～1) takes by weighing collagen and chitosan;
It is in 1～5% the acetum that second step, the collagen that the first step is taken by weighing and chitosan add mass concentration, and the gross mass that is formulated as collagen-chitin accounts for 3～20% solution of collagen-chitin acetum gross mass, stirs dissolving;
In the 3rd step, the collagen-chitin acetum that second step is prepared is the pipe of φ 0.5～3mm from caliber, evenly flows out with the speed of 10～60/min, splashes into temperature for condensation in the-condensed fluid of (10～20) ℃, forms spheroidal particle;
The 4th step is with the condensed spheroidal particle separation of the 3rd 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 collagen-chitosan spherical honeycombed grain material.
3. the preparation method of collagen-chitosan 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 collagen-chitosan 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 collagen-chitosan 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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Citations (5)
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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 |
| CN1272383A (en) * | 2000-05-19 | 2000-11-08 | 清华大学 | Preparation method of nanometer phase calcium-phosphorus salt/collagen/polylactic acid bone composite material |
| 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 (5)
| 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 |
| CN1272383A (en) * | 2000-05-19 | 2000-11-08 | 清华大学 | Preparation method of nanometer phase calcium-phosphorus salt/collagen/polylactic acid bone composite material |
| 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)
| Title |
|---|
| 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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