CN102070786A - Hyaluronic acid-sodium alginate composite hydrogel and preparation method thereof - Google Patents
Hyaluronic acid-sodium alginate composite hydrogel and preparation method thereof Download PDFInfo
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Abstract
The invention discloses hyaluronic acid-sodium alginate composite hydrogel and a preparation method thereof. The composite hydrogel is prepared from the following steps of: (1) dissolving hyaluronic acid and sodium alginate into water to obtain a solution 1; (2) adding a cross-linking agent to the solution 1, and regulating the pH value to be 4.0-5.5 with a buffer solution to obtain a solution 2; (3) adding a carboxyl activating agent to the solution 2 and stirring; and regulating and controlling the pH value of the solution 2 to be 2.0-5.5 in the stirring process until gel is formed to obtain the hyaluronic acid-sodium alginate composite hydrogenl. The invention provides a new approach for the modification of the hyaluronic acid, and the composite modified compound prepared by using the method has the advantages of higher mechanical property, capacity of resisting enzymatic degradation of the hyaluronic acid, biocompatibility, and the like and has potential application in the aspects of surgical operations and tissue engineering.
Description
Technical field
The present invention relates to a kind of hyaluronic acid-sodium alginate composite aquogel and preparation method thereof.
Background technology
Hyaluronic acid (hyaluronic acid HA) is a kind of linearity, unbranched acidic mucopolysaccharide, alternately forms repeatedly by N-acetylglucosamine and D-glucuronic acid, and be the very high medicine of a kind of value, cosmetic material.HA has good hydrophilicity, biocompatibility and moisture-keeping functions, is widely used in being described as natural moisturizing factor in the makeup.HA also has good biocompatibility, does not produce rejection in vivo.Because the physicochemical property such as rheological property, oilness and biocompatibility of HA uniqueness, HA can be used as resilient material and is applied to eye surgery, the treatment bone and joint diseases, and have the wound healing of promotion and certain anticancer effect.HA also has vital role in medicament slow release, post-operation adhesion preventing and organizational project.
But mechanical properties is relatively poor, in vivo easily by Unidasa fast drawbacks limit such as degraded hyaluronic acid in clinical application.For physics, the chemical stability of improving HA, keep not having in its natural biocompatibility, biodegradability and the body characteristic of rejection simultaneously, people adopt number of ways that its hydroxyl and carboxyl are carried out modifying and decorating.That chemical modification method comprises is crosslinked, grafting, esterification and composite modified etc.At present, owing to the composite modified initial characteristic of two kinds of raw materials that often can keep is subjected to people's attention.For composite modified, many macromolecular substance form crosslinked by the carboxyl of carboxyl or hydroxyl and HA.The material of success composite crosslinking comprises Xylo-Mucine, collagen, gelatin, poly(lactic acid), chitosan etc.Sodium alginate (sodium alginate, be called for short SAL) be a kind of by α-L-guluronic acid and beta-D-mannuronic acid by 1, the acidic mucopolysaccharide that the 4-glycosidic link is formed by connecting is widely used in food-processing, field of medicaments, comprises slow releasing carrier of medication, cell cultures etc.SAL has excellent biological compatibility, in case after forming gel, just have mechanical properties preferably.SAL and other polysaccharide have been seen in report as the mixture of chitosan, chondroitin sulfate etc., also have the people that the mixture of SAL-HA has been carried out rheol investigation, but this mixture only are the mixed solutions of two kinds of polymer substances.
Summary of the invention
The purpose of this invention is to provide a kind of hyaluronic acid-sodium alginate composite aquogel and preparation method thereof.
Hyaluronic acid provided by the present invention (HA) and sodium alginate (SAL) composite aquogel are to prepare according to the method that comprises the steps:
1) hyaluronic acid and sodium alginate is soluble in water, obtain solution 1,
2) linking agent is added in the described solution 1, and to regulate the pH value with buffered soln be 4.0-5.5, obtain solution 2;
3) add carboxyl activator and stirring in described solution 2, the pH value of regulating described solution 2 with buffered soln in the whipping process until the formation gel, promptly obtains hyaluronic acid and sodium alginate composite aquogel at 2.0-5.5.
In the above-mentioned solution 1, the mass ratio of hyaluronic acid and sodium alginate can be 1: 4-4: 1, and the preferred mass ratio is 1: 2.In the solution 1, the concentration sum of hyaluronic acid and sodium alginate can be 0.5-1.5g/100ml, is preferably 1.0g/100ml.
Above-mentioned steps 2) linking agent described in can be selected from following at least a: adipic dihydrazide (ADH), and polyoxyethylene glycol (PEG), glutaraldehyde and divinylsulfone (GTA) are preferably adipic dihydrazide (ADH); The proportioning of the add-on of described linking agent and described solution 1 can be 0.1g-1.0g: 100mL is preferably 0.52g: 100mL.
The activator of carboxyl described in the step 3) can be selected from following at least a: carbodiimide (EDC), N-hydroxy-succinamide (NHS) and N, N, N ", " Tetramethyl Ethylene Diamine (TEMED) is preferably carbodiimide to N; The proportioning of the addition of described carbonization imines and described solution 2 can be 10mmol-100mmol: 1L is preferably 50mmol: 1L.
Stir described in the step 3) and can under 15 ℃ of-40 ℃ of conditions, carry out, be preferably 20 ℃-30 ℃; Needing the pH value with buffered soln regulation and control solution 2 in the described whipping process is 2.0-5.5, and preferred pH value is 4.75.During stirring, the rotating speed of stirring should be unsuitable too fast, avoids causing forming behind the gel thinning.
Above-mentioned steps 2) identical with used buffered soln in the step 3), described buffered soln can be selected from following any one: phosphate buffer soln, citrate buffer solution and acetate buffer solution; The concentration of described buffered soln can be 0.01-0.5mol/L, and the pH value is 2.0-4.5, is preferably acetate buffer solution, and most preferable concentrations is 0.1mol/L, and the pH value is 3.6 acetate buffer solution.
Method of the present invention also comprises the step that hyaluronic acid that step 3) is obtained and sodium alginate composite aquogel wash.Washing times should not be less than 5 times, and the gel that slowly overturns during washing is removed so that residual reaction impurity is soluble in water.
The used hyaluronic molecular weight of the present invention can be 5.0 * 10
5Da-2.1 * 10
6Da, preferred molecular weight is 1.5 * 10
6Da; The granularity of used sodium alginate powder is 50 orders-300 orders, is preferably 200 orders.
The present invention is in the presence of carboxyl activator, and to carry out amidate action crosslinked and make hardness, visco-elasticity hyaluronic acid-sodium alginate composite cross-linked polymer preferably by having two or more amino superpolymer or oligopolymer (linking agent) and hyaluronic acid, sodium alginate in the molecular structure.The composite crosslinking hydrogel that obtains possesses the two-fold advantage of HA and SAL, and on the one hand, the ability of antienzyme degraded is improved, and on the other hand, the mechanical properties of hydrogel and matter structure feature improve.After the physicochemical property of composite crosslinking hydrogel are improved, have as the potential use of corium weighting material and tissue stent material and be used for surgical operation, field of tissue engineering technology.
Description of drawings
Fig. 1 prepares the process flow sheet of hyaluronic acid-sodium alginate composite aquogel for the present invention.
Fig. 2 is the infrared spectrogram of the hyaluronic acid-sodium alginate composite aquogel of embodiment 1 preparation.
Embodiment
Below by specific embodiment method of the present invention is described, but the present invention is not limited thereto.
Experimental technique described in the following embodiment if no special instructions, is ordinary method; Described reagent and material if no special instructions, all can obtain from commercial channels.
The preparation of embodiment 1, hyaluronic acid-sodium alginate hydrogel and physicochemical property checking thereof
Prepare hyaluronic acid-sodium alginate hydrogel according to process flow sheet shown in Figure 1, concrete steps are as follows:
1. polysaccharide dissolving: molecular weight is 1.5 * 10
6(particle diameter is 200 mesh sieves for the hyaluronic acid of Da (Furuida Biochemical Co., Ltd., Shandong) and sodium alginate, the aqueous solution of 10mg/ml, its viscosity is 205mPas in the time of 25 ℃, the brilliant rock bio tech ltd in Qingdao) soluble in water with 1: 2 ratio (mass ratio), make that its total concn is 1.0% (g/100ml), obtain solution 1.
2. add linking agent and regulator solution pH: after treating that polysaccharide during step 1. dissolves fully, linking agent ADH (Beijing JinYuan Chemical Group Co.,Ltd) is added in the described solution 1 with the proportioning of 0.52g: 100ml, mix.And above-mentioned mixing solutions is carried out pH adjust, adjust pH to 4.75 with the HAc-NaAc damping fluid (pH 3.6) of 0.1mol/L, obtain solution 2.
3. add the carboxyl activator: add EDC (Shanghai covalent chemical company limited) to solution 2, make its EDC concentration reach 50mmol/L.
4. stir and react and control pH: the reaction solution of step in 3. stirred and control pH, promptly begin to stir when adding EDC, stirring velocity should not be too fast, avoids the gel shear shinning that forms.At room temperature stir 4h, in the reaction process, make the pH value of reaction solution remain on 4.75, obtain hyaluronic acid and sodium alginate composite aquogel by the HAc-NaAc damping fluid that drips 0.1mol/L.
5. gel detergent: to the composite aquogel that 4. step forms, use the deionized water repetitive scrubbing, washing times should be no less than 5 times, washs more than 20 minutes at every turn, and the gel that slowly overturns during washing makes residual reaction impurity soluble in water and remove.
6. gel is preserved: the gel after 5. step is washed is preserved down at 4 ℃.
The hyaluronic acid that makes according to the method described above-sodium alginate composite aquogel is colourless, has certain rigidity and visco-elasticity.
Characteristic to hyaluronic acid-sodium alginate composite aquogel is measured: (Nicolet Nexus, Thermo Electron USA) measure whether form covalent linkage 1, to adopt the FT-IR spectrograph; 2, (Hitachi SEM-2500 Japan) observes the microstructure that forms gel to adopt scanning electron microscope; 3, adopt matter structure instrument that the matter structure feature of gel is measured (pre test speed 2.0mm/s, test speed 0.8mm/s, post test speed 2.0mm/s, rupture test distance 4.0%, distance 50%, 25 ℃ of temperature .).
Infrared spectrogram is seen Fig. 2, measurement result has shown gel formation new covalent linkage, and hyaluronic acid and sodium alginate are crosslinked together by adipic dihydrazide (ADH).Scanning electron microscope shows, forms in the gel evenly and the suitable reticulated structure in aperture.Matter structure instrument (Cns-Farnell, Britain) recording gel hardness is 357.06g, and cracked degree is 253.56g, and elasticity is 0.961.
Swell test:
Gel behind the vacuum-freeze-dry, weighing is placed on 12h in the deionized water, behind the water with filter paper removal surface, weighs, and the result shows that the gel suction can reach 40-50 times that self weighs.
Antienzyme degraded test:
It is the Unidasa liquid of 10U/ml that gel sample places the 10ml enzyme activity, and every interval 3h therefrom gets the 1ml supernatant liquor and measures, and the Unidasa liquid that replenishes the new preparation of 1ml then is to reaction system.Measuring method is as follows: the dense H of 5mL
2SO
4Place test tube and be cooled to 4 ℃, 1mL sample liquid or reference liquid place dense H carefully
2SO
4On the layer, begin jolting gently, violent then jolting, and make it constantly cooling in ice bath, next test tube is heated 10min in ebullient distilled water, be cooled to room temperature then, add 0.2mL carbazole test solution, shake up once more, and in boiling water bath, heat 15min, be cooled to room temperature, reaction solution is poured in the 1cm cuvette, under 530nm, measure absorbancy (A530).By hyaluronic acid contents in the standard curve determination solution.According to following formula calculated for gel by the zymolytic degree of hyaluronic acid:
Wi＝C
iV+∑C
i-1V
s
Wherein, C
iAnd C
I-1Be the HA concentration (mg/ml) of gel under i and i-1 are decomposed constantly, V is an enzyme liquid cumulative volume (10ml), and Vs is each sample volume (1ml) that takes out.
The result shows that along with the prolongation in treatment time, gel is decomposed by Unidasa gradually, when 9h, almost be decomposed fully, and the hyaluronic acid derivatives of control group promptly is decomposed behind 3h fully.
The preparation of embodiment 2, hyaluronic acid-sodium alginate hydrogel and physicochemical property checking thereof
Prepare hyaluronic acid-sodium alginate hydrogel according to process flow sheet shown in Figure 1, concrete steps are as follows:
1. polysaccharide dissolving: molecular weight is 5.0 * 10
5(particle diameter is 50 mesh sieves for the hyaluronic acid of Da (Furuida Biochemical Co., Ltd., Shandong) and sodium alginate, the aqueous solution of 10mg/ml, its viscosity is 100mPas in the time of 25 ℃, the brilliant rock bio tech ltd in Qingdao) soluble in water with 1: 4 ratio (mass ratio), make that its total concn is 0.5% (g/100ml), obtain solution 1.
2. add linking agent and regulator solution pH: after treating that polysaccharide during step 1. dissolves fully, linking agent ADH (Beijing JinYuan Chemical Group Co.,Ltd) is added in the described solution 1 with the proportioning of 0.1g: 100ml, mix.And above-mentioned mixing solutions is carried out pH adjust, adjust pH to 4.75 with the HAc-NaAc damping fluid (pH 3.6) of 0.1mol/L, obtain solution 2.
3. add the carboxyl activator: add EDC (Shanghai covalent chemical company limited) to solution 2, make its EDC concentration reach 10mmol/L.
4. stir and react and control pH: the reaction solution of step in 3. stirred and control pH, promptly begin to stir when adding EDC, stirring velocity should not be too fast, avoids the gel shear shinning that forms.At room temperature stir 4h, in the reaction process, make the pH value of reaction solution remain on 4.75, obtain hyaluronic acid and sodium alginate composite aquogel by the HAc-NaAc damping fluid that drips 0.1mol/L.
5. gel detergent: to the composite aquogel that 4. step forms, use the deionized water repetitive scrubbing, washing times should be no less than 5 times, washs more than 20 minutes at every turn, and the gel that slowly overturns during washing makes residual reaction impurity soluble in water and remove.
6. gel is preserved: the gel after 5. step is washed is preserved down at 4 ℃.
The hyaluronic acid that makes according to the method described above-sodium alginate composite aquogel is colourless, has certain rigidity and visco-elasticity.
Infrared measurement shows, gel formation new covalent linkage, hyaluronic acid and sodium alginate are crosslinked together by adipic dihydrazide (ADH).Scanning electron microscope shows, forms in the gel evenly and the suitable reticulated structure in aperture.Matter structure instrument (Cns-Farnell, Britain) recording gel hardness is 71.02g, and cracked degree is 66.89g, and elasticity is 0.97.
Swell test:
Gel behind the vacuum-freeze-dry, weighing is placed on 12h in the deionized water, remove the water on surface with filter paper after, weigh, the result shows, the gel suction can reach that self is heavy 55 times.
Antienzyme degraded test:
It is the Unidasa liquid of 10U/ml that gel sample places the 10ml enzyme activity, and every interval 3h therefrom gets the 1ml supernatant liquor and measures.
The result shows that along with the prolongation in treatment time, gel is decomposed by Unidasa gradually, when 6h, almost be decomposed fully, and the hyaluronic acid derivatives of control group promptly is decomposed behind 3h fully.
The preparation of embodiment 3, hyaluronic acid-sodium alginate hydrogel and physicochemical property checking thereof
Prepare hyaluronic acid-sodium alginate hydrogel according to process flow sheet shown in Figure 1, concrete steps are as follows:
1. polysaccharide dissolving: molecular weight is 2.1 * 10
6(particle diameter is 300 mesh sieves for the hyaluronic acid of Da (Furuida Biochemical Co., Ltd., Shandong) and sodium alginate, the aqueous solution of 10mg/ml, its viscosity is 300mPas in the time of 25 ℃, the brilliant rock bio tech ltd in Qingdao) soluble in water with 4: 1 ratios (mass ratio), make that its total concn is 1.5% (g/100ml), obtain solution 1.
2. add linking agent and regulator solution pH: after treating that polysaccharide during step 1. dissolves fully, linking agent ADH (Beijing JinYuan Chemical Group Co.,Ltd) is added in the described solution 1 with the proportioning of 1.0g: 100ml, mix.And above-mentioned mixing solutions is carried out pH adjust, adjust pH to 4.75 with the HAc-NaAc damping fluid (pH 3.6) of 0.1mol/L, obtain solution 2.
3. add the carboxyl activator: add EDC (Shanghai covalent chemical company limited) to solution 2, make its EDC concentration reach 100mmol/L.
4. stir and react and control pH: the reaction solution of step in 3. stirred and control pH, promptly begin to stir when adding EDC, stirring velocity should not be too fast, avoids the gel shear shinning that forms.At room temperature stir 4h, in the reaction process, make the pH value of reaction solution remain on 4.75, obtain hyaluronic acid and sodium alginate composite aquogel by the HAc-NaAc damping fluid that drips 0.1mol/L.
5. gel detergent: to the composite aquogel that 4. step forms, use the deionized water repetitive scrubbing, washing times should be no less than 5 times, washs more than 20 minutes at every turn, and the gel that slowly overturns during washing makes residual reaction impurity soluble in water and remove.
6. gel is preserved: the gel after 5. step is washed is preserved down at 4 ℃.
The hyaluronic acid that makes according to the method described above-sodium alginate composite aquogel is colourless, has certain rigidity and visco-elasticity.
Infrared measurement shows, gel formation new covalent linkage, hyaluronic acid and sodium alginate are crosslinked together by adipic dihydrazide (ADH).Scanning electron microscope shows, forms in the gel evenly and the suitable reticulated structure in aperture.Matter structure instrument (Cns-Farnell, Britain) recording gel hardness is 209.50g, and cracked degree is 190.28g, and elasticity is 1.14.
Swell test:
Gel behind the vacuum-freeze-dry, weighing is placed on 12h in the deionized water, remove the water on surface with filter paper after, weigh, the result shows, the gel suction can reach that self is heavy 20 times.
Antienzyme degraded test:
It is the Unidasa liquid of 10U/ml that gel sample places the 10ml enzyme activity, and every interval 3h therefrom gets the 1ml supernatant liquor and measures.
The result shows that along with the prolongation in treatment time, gel is decomposed by Unidasa gradually, when 8h, almost be decomposed fully, and the hyaluronic acid derivatives of control group promptly is decomposed behind 3h fully.
Claims (10)
1. the preparation method of hyaluronic acid and sodium alginate composite aquogel comprises the steps:
1) hyaluronic acid and sodium alginate is soluble in water, obtain solution 1,
2) linking agent is added in the described solution 1, and to regulate the pH value with buffered soln be 4.0-5.5, obtain solution 2;
3) add carboxyl activator and stirring in described solution 2, the pH value of regulating and control described solution 2 with buffered soln in the whipping process until forming gel, promptly obtains hyaluronic acid and sodium alginate composite aquogel at 2.0-5.5.
2. method according to claim 1 is characterized in that: the mass ratio of hyaluronic acid and sodium alginate is 1 in the described solution 1: 4-4: 1, and the preferred mass ratio is 1: 2; The concentration sum of hyaluronic acid and sodium alginate is 0.5-1.5g/100ml in the described solution 1, is preferably 1.0g/100ml.
3. method according to claim 1 and 2 is characterized in that: step 2) described in linking agent be selected from following at least a: adipic dihydrazide, polyoxyethylene glycol, glutaraldehyde and divinylsulfone are preferably adipic dihydrazide; The proportioning of the add-on of described linking agent and described solution 1 is 0.1g-1.0g: 100mL, is preferably 0.52g: 100mL.
4. according to arbitrary described method among the claim 1-3, it is characterized in that: the activator of carboxyl described in the step 3) is selected from following at least a: carbodiimide, N-hydroxy-succinamide and N, N, N ", " Tetramethyl Ethylene Diamine is preferably carbodiimide to N; The proportioning of the addition of described carbodiimide and described solution 2 is 10mmol-100mmol: 1L, is preferably 50mmol: 1L.
5. according to arbitrary described method among the claim 1-4, it is characterized in that: be stirred in described in the step 3) under 15 ℃ of-40 ℃ of conditions and carry out, be preferably 20 ℃-30 ℃; The pH value of regulation and control solution 2 is 4.75 in the described whipping process.
6. according to arbitrary described method among the claim 1-5, it is characterized in that: step 2) with step 3) in described in buffered soln identical, be selected from following any one: phosphate buffer soln, citrate buffer solution and acetate buffer solution, the concentration of described buffered soln is 0.01-0.5mol/L, and the pH value is 2.0-4.5.
7. method according to claim 6 is characterized in that: step 2) and step 3) in described in buffered soln be acetate buffer solution, being preferably concentration is that 0.1mol/L, pH value are 3.6 acetate buffer.
8. according to arbitrary described method among the claim 1-7, it is characterized in that: described hyaluronic molecular weight is 5.0 * 10
5-2.1 * 10
6Da, preferred molecular weight is 1.5 * 10
6Da; The granularity of described sodium alginate is 50 orders-300 orders, is preferably 200 orders.
9. according to arbitrary described method among the claim 1-8, it is characterized in that: described method also comprises the step that hyaluronic acid that step 3) is obtained and sodium alginate composite aquogel water wash.
10. hyaluronic acid that arbitrary described method prepares among the claim 1-9 and sodium alginate composite aquogel.
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