CN101773683A - Chitosan modified alginate hydrogel three-dimensional porous bracket and preparation method thereof - Google Patents
Chitosan modified alginate hydrogel three-dimensional porous bracket and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a chitosan modified alginate hydrogel three-dimensional porous bracket with specific in-vitro degradability and a preparation method thereof. The method comprises the following steps: dissolving sodium alga acid serving as a raw material in phosphate buffer solution; performing amidation reaction of a carboxyl group in the sodium alga acid and an amino group in a cross-linking agent cystamine or dimethyl cystinate under the activation of water-soluble carbodiimide to form a chemically crosslinked hydrogel; performing freeze drying on the hydrogel to obtain a porous bracket material of the hydrogel; and performing surface modification on the porous bracket by using chitosan. In solution of a reducing agent such as cysteine with an appropriate concentration, a disulfide bond in a hydrogel cross-bridge is degraded through a disulfide bond-sulfydryl conversion reaction, so the porous bracket is decomposed and dissolved and disappears. Therefore, the porous bracket can be used as an in-vitro cell culture template material. The hydrogel porous bracket researched by the invention has the characteristics of simple preparation, rich raw material source, low cost and availability. Various physiochemical performances, mechanical strength, degradation rate and surface properties of the bracket material are controllable within a large range.
Description
Technical field
The present invention relates to the manufacturing of tissue construction with three-dimensional porous mould material, particularly a kind of chitosan-modified alginate hydrogel three-dimensional porous bracket and preparation method thereof is specially alginate hydrogel three-dimensional porous bracket of special external degradation and preparation method thereof.
Background technology
Organizational project is utilized the principle and the method for life sciences and engineering science, and research and development has the substituent of the clinical practice of new generation of gentrify tissue or organ dysfunction, is used for substituting part or all function of tissue or organ.The development of organizational project has proposed new challenge to biomaterial, the many chemistry of the research and development of biomaterial in the past, physics and processing characteristics design from material, cellular level and the molecular level from institute's implantable bioartificial material do not design, relevant cell can be grown on many biomaterials well, also relate to problems such as neural guiding, revascularization but be organized in intravital reconstruction, cell also is subjected to the regulation and control of the signaling molecule of host's damage location and surrounding health tissue's generation thereof.Therefore, ideal used in tissue engineering biomaterial should produce specific action with the special adhesion factor and the growth factor receptors that target cell is expressed, make target cell migrate to damage location, stimulate its growth and differentiation, and along with the reparation of tissue can be degraded fully by the relevant enzyme composition that cell discharges.This awaits from the molecular level design and prepares stimulating specific cell absorbable material reaction, biologically active.On the other hand, the classical way at external structure engineering three-dimensional tissue structures thing is the In vitro culture that cell seeding is carried out certain hour in porous support.Formed engineering tissue is made up of the synthetic extracellular matrix of timbering material, cell and cell usually, be that timbering material was not degraded usually in the cell culture stage, behind constructed three-dimensional tissue's implant into body, the timbering material of artificial preparation has potential danger [(a) the Kim M S that produces the immune inflammation reaction, Ahn H H, Shin Y N, et al.Biomaterials, 2008,28:5137-5143; (b) Williams D F, Biomaterials, 2008: 29:2941-2953].
The Okano seminar of Japan is in a creative way with the surface composition cultured cell that is grafted with temperature-responsive polymer such as PNIPAM (PIPAAm), and obtained the complete cell sheets of forming by cell and extracellular matrix by reducing temperature, this two-dimentional cell sheets can be directly used in tissue reconstruction, also can form the engineering three-dimensional tissue structures thing by the multilamellar stack, this technology is called the cell sheets engineering.By MOLECULE DESIGN and the new surface treatment method of research, the performance that is grafted with the cell culturing surfaces of temperature sensitive property PIPAAm base polymer be greatly improved [(a) Nishida K, Yamato M, Okano T, N Engl JMed, 2004,351:1187-1196; (b) Yamato M, Akiyama Y, Okano T, et al.Prog Polym Sci; 2007,32:1123-1133; (c) Idota N, Tsukahara T, Okano T, et al.Biomaterials, 2009,30:2095-2101].At present, the cell sheets technology has been applied to the reparation and the reconstruction of multiple tissue, comprises [Matsuda N such as anterior epithelium of cornea, epithelium of esophagus, urothelium, periodontal ligament, cardiac muscle and liver, Shimizu T, Okano T, et al.Adv Mater, 2007,19:3089-3099].Also can be at the cell sheets that protein-based hydrogel or cellulose family hydrogel surface are sticked and the back of increasing forms by enzymolysis process [(a) Nagai N under the culture plate sur-face peeling of protease or cellulase, Yunoki S, Satoh Y, et al.JBiosci Bioeng, 2004,98:493-496; (b) Sakai S, Ogushi Y, Kawakami K, Acta Biomaterialia, 2009,5:554-559].Under the action of a magnetic field, the magnetic cation liposome is adsorbed in the Tissue Culture Plate surface can form special magnetic field responsiveness decorative layer, plant in the fibroblast of this culture surface through stick, sprawl and breed after very fast formation cell sheets, and should be easy to strip down by the two dimension cell sheets after withdrawing magnetic field; After being marked as fibrocyte and hepatocyte with the magnetic cation liposome, under the magnetic field force effect, can directly form the cell sheets of two kinds of mixing with cells at hydrophilic surface, this type of technology is called magnetic field force cell sheets technology [(a) Ito A, Ino K, Kobayashi T, et al.Biomaterials, 2005,26:6185-6193; (b) Ito A, Jitsunobu H, Kawabe Y, et al.J Biosci Bioeng, 2007,104:371-378].
As previously mentioned, the cell sheets technology has obtained significant progress, the reparation of multiple tissue with rebuild in show potential application prospect.But can only make up two dimension or thickness is micron-sized three-dimensional engineering tissue by the cell sheets technology, can not provide required three dimensional growth microenvironment [(a) Ohashi K for relevant cell in the building process simultaneously, Yokoyama T, Yamato M, etal.Nature Med, 2007,13:880-885; (b) Zhang S, Gelain F, Zhao X, Semin Cancer Biol, 2005,15:413-420].The structure of the millimetre-sized bulk three-dimensional tissue that is made up of cell and extracellular matrix merely also needs further to explore additive method and technology, this will face a lot of difficulties and challenge, the survival of the intensity of constructed engineering tissue and shape hold facility, cell and function maintenance, metabolism etc. after degrading as mould material.Matsusaki seminar is incorporated into disulfide bond in the poly-gamma-glutamic acid hydrogel of chemical crosslinking, with its as mould material in external structure three-dimensional engineering tissue [the Matsusakia M that forms merely by cell and extracellular matrix, Yoshida H, Akashi M, Biomaterials, 2007,28:2729-2737].But the research major part for the poly-gamma-glutamic acid that is produced by microbial fermentation also is in laboratory stage, and its purity is still waiting further raising [Bajaj I B, Lele S S when using as biomaterial, Singhal R S, Biores Tech, 2009,100:826-832].
Summary of the invention
The object of the present invention is to provide a kind of chitosan-modified alginate hydrogel three-dimensional porous bracket and preparation method thereof.Employing is more prone to obtain, and the sodium alginate with good biocompatibility is as raw material, with cystamine or cystine dimethyl ester as cross-linking agent, under the activation of water-soluble carbodiimide, make sodium alginate generation chemical crosslink reaction, thereby obtain stable alginate covalent cross-linking hydrogel.Hydrogel can obtain the three-dimensional rack of loose structure after lyophilization.By surface modification and modification active substance is incorporated into material surface, has improved the mechanical strength and the cellular affinity of this type of alginate hydrogel.Cell seeding in porous support, can be formed three-dimensional cell/supporting structure thing behind the In vitro culture certain hour.The cell culture later stage is when adding the Reducing agent compositions such as aminothiopropionic acid, N-acetylcysteine, glutathion of suitable concentration to culture fluid; disulfide bond on the alginate hydrogel cross-bridge disconnects; disulfide bond-sulfydryl conversion reaction promptly takes place; thereby hydrogel is disintegrated; and the hydrogel catabolite after disintegrating is dissolvable in water in the cell culture fluid, obtains two-dimentional cell sheets or the engineering three-dimensional tissue structures thing be made up of cell and extracellular matrix fully.When the alginate hydrogel porous support is applied to organizational project as mould material, thickness, size, the shape of porous support can be transferred in the three-dimensional engineering tissue that is obtained fully, thus can be in the millimetre-sized bulk of external structure three-dimensional tissue.Because the disulfide bond in the cross-linking agent structure can be decomposed into sulfydryl with very fast speed under the effect of Reducing agents such as glutathion, so this type of chemical crosslinking alginate hydrogel three-dimensional porous bracket possesses special external degradation performance.
Preparation method of the present invention is simple, raw material sources abundant, every physicochemical property, mechanical strength, degradation rate and surface characteristic cheap and easy to get, hydrogel are in very large range controlled.By surface modification and modification bioactive substance is incorporated into material surface, can significantly improves the mechanical strength and the shape hold facility of three-dimensional porous rack, effectively improve the cellular affinity of timbering material, but limited to its degradation property influence.
A kind of chitosan-modified hydrogel three-dimensional porous bracket provided by the invention is to be raw material with the sodium alginate, sodium alginate is dissolved in the phosphate buffered solution, carboxyl in the sodium alginate can be under the activation of water-soluble carbodiimide with cross-linking agent cystamine or cystine dimethyl ester in amino generation amidation process form chemically crosslinked aquagel, the pre-freeze postlyophilization carries out finishing with chitosan to the porous support that obtains.
The sodium alginate unit: water-soluble carbodiimide=1: 2 (mol ratio), sodium alginate unit: cross-linking agent=2～2.5: 0.63～2.5 (mol ratio), chitosan is about 1～25 μ g/cm to the modification amount of alginate hydrogel porous support hole wall
2, the molecular weight of chitosan is selected 1～100k.
The preparation method of chitosan-modified alginate hydrogel three-dimensional porous bracket provided by the invention is through following step:
1) room temperature and stirring are down, in the phosphate buffered solution (pH=5) of sodium alginate, add water-soluble carbodiimide (EDC), stir and to add cystamine again behind the 30min or cystine dimethyl dissolves fully, pour in the plastic culture plate, place 0.1～10h under the room temperature and form hydrogel.Concentration 35～the 45mg/mL of sodium alginate.
Sodium alginate unit: EDC=1: 2, sodium alginate unit: cross-linking agent=2～2.5: 0.63～2.5, all are mol ratios.
2) above-mentioned hydrogel was put into the refrigerator precooling 24 hours, lyophilization 2d can obtain porous support materials.
3) in chitosan solution, soak 1～10h, it is modified thereby make constituent of chitosan be adsorbed onto the porous support pore surface.The porous support of surface modification soaked 24 hours in phosphate buffered solution (pH=7.4).
4) porous support after the surface treatment is put into refrigerator pre-freeze postlyophilization (method is with step 2) once more, can be obtained all good porous support materials of mechanical strength and cellular affinity.
Step 2) with step 4) in the precooling temperature be-20～-80 ℃, the lyophilization temperature is 0～20 ℃.
Chitosan solution concentration in the step 3) is selected 1～10mg/mL.
Among the present invention,, when excessive concentration, be difficult for dissolving, and the degradation time of prepared three-dimensional porous rack is long, is not suitable as cell in vitro and cultivates the mould material use because the sodium alginate molecular weight is bigger.In order to shorten degradation time, it is that the sodium alginate soln of 35～45mg/mL prepares hydrogel and three-dimensional porous rack thereof that the present invention has adopted concentration, but mechanical strength deficiency in the prerequisite sub-mount material that keeps certain degradation rate, particularly the mechanics intensity decreases is very fast under hydration, even has influence on the shape hold facility of porous material.On the other hand, when alginate hydrogel is applied to organizational project since strand too hydrophilic can not the active adsorption protein ingredient, lack the cell binding site, can not special interaction take place with cell.For these reasons, consider that simultaneously alginate is an anionic polyelectrolyte, by chemical crosslinking alginate hydrogel and porous support thereof having been carried out surface treatment, to improve mechanical strength and cellular affinity simultaneously with the electrostatic interaction of the good range of polycationic substances of cellular affinity.
The cross-linking agent that the present invention selects for use is cystamine or cystine dimethyl ester, discovers, when selecting cystine dimethyl as cross-linking agent for use, gained hydrogel intensity is very high, but is difficult for degraded; And when using cystamine as cross-linking agent, though hydrogel more easily degrade, because cystamine is crosslinked limited in one's ability, its intensity remains further raising, and the present invention selects to modify its surface with the range of polycationic substances chitosan solution and improves intensity.Swelling ratio when support is not modified is about 20～40g/g, and the swelling ratio after modified is about 5～10g/g.
The molecular weight of chitosan and solution concentration all produce material impact to surperficial modification effect.The concentration of chitosan solution is crossed not reach when low and is modified enhanced purpose, and the degradation time of hydrogel three-dimensional porous material obviously prolongs when excessive concentration, thus the present invention to have adopted concentration be the chitosan solution of 1～10mg/mL, preferred 2～7mg/mL.On the other hand, when adopting low or cross high-molecular weight chitosan as range of polycationic substances, finishing and reinforced effects to alginate hydrogel and porous support thereof are limited, therefore selected the chitosan of 1～100k molecular weight for use, wherein the chitosan-modified effect of 3～50k molecular weight is better.
Preparation method of the present invention is simple, raw material sources abundant, every physicochemical property, mechanical strength, degradation rate and surface characteristic cheap and easy to get, hydrogel are in very large range controlled.By surface modification and modification bioactive substance is incorporated into material surface, can significantly improves the mechanical strength and the shape hold facility of three-dimensional porous rack, can effectively improve the cellular affinity of timbering material, but limited to its degradation property influence.
The specific embodiment
Used primary raw material sodium alginate, EDC, cystamine or cystine dimethyl ester, the chitosan of the present invention is commercially available.
Embodiment 1:
(1) takes by weighing the 0.40g sodium alginate and be dissolved in the phosphate buffered solution (pH=5) of 10mL, be stirred to sodium alginate at ambient temperature and dissolve fully.
(2) EDC of adding 0.87g in solution (1) stirs 30min down at 4 ℃.
(3) in solution (2), add the 0.28g cystamine as cross-linking agent, after stirring abundant dissolving, reaction solution is poured in the plastic culture plate, and at room temperature place 3h formation hydrogel.
(4) hydrogel that step (3) is obtained is put into 24 hours postlyophilization 2d of refrigerator pre-freeze of-50 ℃, can obtain porous support materials.This not modified swelling ratio of three-dimensional porous rack in deionized water is about 35g/g, and the degradation time in the cysteine solution of 50mM concentration is about 15h.
(5) porous support that step (4) is obtained soaks 4h in 3mg/mL chitosan (molecular weight 5k) solution, thereby make chitosan solution be drawn into the porous support hole its hole wall surface is modified.
(6) (the same step 4) of method can obtain all good porous support materials of mechanical strength and cellular affinity in the hygrometric state porous support lyophilization once more that step (5) is obtained.The swelling ratio of modified three-dimensional porous rack in deionized water is about 7g/g, and the degradation time in the cysteine solution of 50mM concentration is about 16h.
Embodiment 2:
Raw material, preparation method are substantially the same manner as Example 1.It is 0.56g that step among the embodiment 1 (3) is adjusted into the cystamine addition, and the chitosan molecule amount in the step (5) is adjusted into 10k, and other step is identical.The not modified three-dimensional porous rack swelling ratio of this proportioning is about 24g/g.Three-dimensional porous rack swelling ratio after chitosan solution is modified is 6g/g.
Embodiment 3:
Raw material, preparation method are substantially the same manner as Example 1.It is 0.45g that step among the embodiment 1 (1) is adjusted into the sodium alginate addition, and it is 0.96g that step (2) is adjusted into the EDC addition.The three-dimensional porous rack intensity of unmodified is lower, can only keep its shape reluctantly, and swelling ratio is about 29g/g.And the three-dimensional porous rack compressive strength after modifying can reach 4.5 ± 1.3kPa, and modulus of compressibility is about 27.4 ± 6.1kPa, and swelling ratio is 8g/g.
Embodiment 4:
Raw material, preparation method are substantially the same manner as Example 3.It is 0.56g that step among the embodiment 3 (3) is adjusted into the cystamine addition, and other step is identical.The not modified three-dimensional porous rack swelling ratio of this proportioning is 24g/g.Three-dimensional porous rack swelling ratio after chitosan solution is modified is about 5g/g.
Embodiment 5:
Raw material, preparation method are substantially the same manner as Example 1.Cystamine in the step among the embodiment 1 (3) is adjusted into the cystine dimethyl ester, and its addition is 0.04g, is 8h with the chitosan solution modification time in the step (5).The three-dimensional porous rack of unmodified can be kept its shape reluctantly, can't measure its compressive strength, and the three-dimensional porous rack compressive strength after chitosan solution is modified can reach 11.2 ± 1.5kPa, and modulus of compressibility can reach 66.2 ± 8.4kPa.
Claims (8)
1. chitosan-modified hydrogel three-dimensional porous bracket, it is characterized in that it is is raw material with the sodium alginate, sodium alginate is dissolved in the phosphate buffered solution, carboxyl in the sodium alginate can be under the activation of water-soluble carbodiimide with cross-linking agent cystamine or cystine dimethyl ester in amino generation amidation process form chemically crosslinked aquagel, the pre-freeze postlyophilization obtains porous support, and the reuse chitosan carries out finishing to the porous support that obtains.
2. described alginate hydrogel three-dimensional porous bracket of claim 1, it is characterized in that the disulfide bond in the cross-linking agent structure can be decomposed into sulfydryl with very fast speed under the effect of Reducing agents such as cysteine, so this type of chemical crosslinking alginate hydrogel three-dimensional porous bracket possesses special external degradation performance.
3. according to the described chitosan-modified hydrogel three-dimensional porous bracket of claim 1, the molecular weight that it is characterized in that described chitosan is 1～100k.
4. the preparation method of the described chitosan-modified alginate hydrogel three-dimensional porous bracket of a claim 1 is characterized in that it is through following step:
1) in room temperature with under stirring, add water-soluble carbodiimide in the phosphate buffered solution of sodium alginate (pH=5), stir and to add cystamine again behind the 30min or cystine dimethyl dissolves fully, pour in the plastic culture plate, place 0.1～10h under the room temperature and form hydrogel; Concentration 35～the 45mg/mL of sodium alginate;
2) above-mentioned hydrogel was put into the refrigerator precooling 24 hours, lyophilization 2d obtains porous support materials;
3) in chitosan solution, soak, in phosphate buffered solution (pH=7.4), soaked 24 hours then;
4) put into refrigerator pre-freeze postlyophilization once more, method is with step 2), obtain final products.
5. in accordance with the method for claim 4, it is characterized in that described sodium alginate unit: water-soluble carbodiimide=1: 2 (mol ratio), sodium alginate unit: cross-linking agent=2～2.5: 0.63～2.5 (mol ratio), chitosan is about 1～25 μ g/cm to the modification amount of alginate hydrogel porous support hole wall
2
6. in accordance with the method for claim 4, it is characterized in that step 2) with step 4) described in the precooling temperature be-20～-80 ℃, the lyophilization temperature is 0～20 ℃.
7. in accordance with the method for claim 4, it is characterized in that the chitosan solution concentration described in the step 3) is 1～10mg/mL.
8. in accordance with the method for claim 4, it is characterized in that the soak time described in the step 3) is 1～10h.
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