CN115850734B - Cationic crosslinked thiourea grafted polymer hydrogel and preparation method and application thereof - Google Patents
Cationic crosslinked thiourea grafted polymer hydrogel and preparation method and application thereof Download PDFInfo
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- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 title claims abstract description 286
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title claims abstract description 142
- 239000000017 hydrogel Substances 0.000 title claims abstract description 115
- 125000002091 cationic group Chemical group 0.000 title claims abstract description 53
- 229920000578 graft copolymer Polymers 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000007864 aqueous solution Substances 0.000 claims abstract description 90
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 238000002156 mixing Methods 0.000 claims abstract description 17
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 95
- 229920002674 hyaluronan Polymers 0.000 claims description 94
- 229960003160 hyaluronic acid Drugs 0.000 claims description 94
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 150000001768 cations Chemical class 0.000 claims description 24
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 12
- 239000007795 chemical reaction product Substances 0.000 claims description 12
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 12
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 12
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 9
- IBVAQQYNSHJXBV-UHFFFAOYSA-N adipic acid dihydrazide Chemical compound NNC(=O)CCCCC(=O)NN IBVAQQYNSHJXBV-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 7
- 239000003446 ligand Substances 0.000 abstract description 11
- 230000007613 environmental effect Effects 0.000 abstract description 6
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- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- FOIXSVOLVBLSDH-UHFFFAOYSA-N Silver ion Chemical compound [Ag+] FOIXSVOLVBLSDH-UHFFFAOYSA-N 0.000 description 44
- 229920001661 Chitosan Polymers 0.000 description 37
- 238000012512 characterization method Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000004132 cross linking Methods 0.000 description 12
- 230000001070 adhesive effect Effects 0.000 description 9
- PUVAFTRIIUSGLK-UHFFFAOYSA-M trimethyl(oxiran-2-ylmethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1CO1 PUVAFTRIIUSGLK-UHFFFAOYSA-M 0.000 description 7
- 238000010586 diagram Methods 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 229910052709 silver Inorganic materials 0.000 description 6
- 239000000853 adhesive Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
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- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
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Abstract
The application discloses cationic crosslinked thiourea grafted polymer hydrogel and a preparation method and application thereof, and belongs to the technical field of cationic-ligand coordination crosslinked hydrogels. The preparation method of the application comprises the following steps: and mixing the thiourea grafted polymer aqueous solution with the cationic aqueous solution in a volume ratio of 1-9:1 for reaction to obtain the cationic crosslinked thiourea grafted polymer hydrogel. The preparation method is simple, mild in reaction, easy to operate, environment-friendly and beneficial to industrial production, and meanwhile, the formed cationic crosslinked thiourea grafted polymer hydrogel has excellent swelling performance, adhesion performance, rheological property and good biocompatibility, is wide in application range, meets the environmental protection requirement, has excellent biomedical application value, can be used as a skin dressing to be fixed on the skin surface under the condition of not needing an adhesion medium, and can maintain the moist environment of the skin surface.
Description
Technical Field
The application belongs to the technical field of cation-ligand coordination crosslinked hydrogel, and particularly relates to cation crosslinked thiourea grafted polymer hydrogel, and a preparation method and application thereof.
Background
Hydrogel formation is associated with its crosslinked network, which is generally divided into two types: firstly, forming chemical cross-links by forming covalent bonds between molecules; secondly, physical cross-linking is formed by hydrogen bonding, van der Waals forces, hydrophobic interactions, and the like. Among them, chemically crosslinked hydrogels are generally irreversible, but metal ion coordination bonds are a special covalent bond, and since the bond energy of coordination bonds is large and dynamic reversible, the preparation of self-healing hydrogels based on metal ion-ligand coordination is an effective and viable strategy.
At present, in the related research of preparing self-healing hydrogel based on metal ion-ligand coordination crosslinking, the field successfully prepares macromolecule hydrogel based on metal-catechol, metal-histidine coordination and the like, and the macromolecule hydrogel has the advantages of high mechanical strength, excellent self-repairing property and good adhesive property, and has been widely applied to the fields of coating, adhesive and the like.
However, the existing metal ion-ligand coordination crosslinked hydrogel is still few in variety, and the binding force of part of metal ion-ligand coordination is weak, more metal ions are needed for coordination crosslinking, so that the biocompatibility of the metal ion-ligand coordination crosslinked hydrogel is poor, the application range of the cation-ligand coordination crosslinked hydrogel is limited, and more cation-ligand coordination crosslinked hydrogels are urgently needed to be developed to promote the development of biomedical materials.
Disclosure of Invention
The application aims to provide a cationic crosslinked thiourea grafted polymer hydrogel, and a preparation method and application thereof, and aims to solve the technical problems of few types and poor biocompatibility of the conventional cationic-ligand coordination crosslinked hydrogel.
In order to achieve the above object, the technical scheme of the present application is as follows:
the first aspect of the application provides a preparation method of cationic crosslinked thiourea grafted polymer hydrogel. The preparation method of the cationic crosslinked thiourea grafted polymer hydrogel comprises the following steps:
mixing the thiourea grafted polymer aqueous solution with the cationic aqueous solution to obtain cationic crosslinked thiourea grafted polymer hydrogel;
Wherein the volume ratio of the thiourea grafted polymer aqueous solution to the cationic aqueous solution is 1-9:1.
In a preferred implementation of the first aspect, the cation of the aqueous cation solution is formulated to include any one of Ag +、Cu2+、Fe3+、Zn2+、Se6+、Mg2+、Ca2+.
In a preferred implementation manner of the first aspect, the concentration of the thiourea grafted polymer aqueous solution is 1-15 w/v%;
The concentration of the Ag + aqueous solution is 0.1-2w/v%; the concentration of the Cu 2+ aqueous solution is 0.1-2w/v%;
The concentration of the Fe 3+ aqueous solution is 0.1-2w/v%; the concentration of Zn 2+ water solution is 5-30w/v%;
The concentration of Se 6+ water solution is 5-30w/v%; the concentration of the Mg 2+ aqueous solution is 5-30w/v%;
The concentration of the Ca 2+ aqueous solution is 5-30w/v%.
In a preferred implementation manner of the first aspect, the thiourea graft polymer for preparing the thiourea graft polymer aqueous solution includes any one of thiourea graft hyaluronic acid and thiourea graft chitosan.
In a preferred implementation manner of the first aspect, the preparation method of the thiourea grafted hyaluronic acid includes:
Sodium hyaluronate reacts with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and adipic acid dihydrazide, and after the reaction is finished, the reaction product is dialyzed and dried in vacuum to obtain hydrazinized hyaluronic acid;
and (3) reacting the hydrazinized hyaluronic acid with methyl isothiocyanate, and after the reaction is finished, dialyzing and vacuum drying the reaction product to obtain the thiourea grafted hyaluronic acid.
In a preferred implementation of the first aspect, the sodium hyaluronate is reacted with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, adipic acid dihydrazide in a molar ratio of 1:6:6:8 to the sodium hyaluronate, the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the 1-hydroxybenzotriazole and the adipic acid dihydrazide.
In a preferred implementation of the first aspect, when the hydrazinized hyaluronic acid is reacted with methyl isothiocyanate, the mass ratio of the hydrazinized hyaluronic acid to the methyl isothiocyanate is 1:2.
In a preferred implementation manner of the first aspect, the preparation method of the thiourea grafted chitosan includes:
Reacting acetic acid solution of chitosan with glycidyl trimethyl ammonium chloride, dialyzing and vacuum drying reaction products after the reaction is finished to obtain quaternized chitosan;
And (3) reacting the quaternized chitosan with methyl isothiocyanate, and dialyzing and vacuum drying a reaction product after the reaction is finished to obtain thiourea grafted chitosan.
In a preferred implementation of the first aspect, the molar ratio of the chitosan to the glycidyl trimethylammonium chloride is 1:2 when the acetic acid solution of the chitosan is reacted with the glycidyl trimethylammonium chloride.
In a preferred implementation of the first aspect, the quaternized chitosan is reacted with methyl isothiocyanate in a molar ratio of the quaternized chitosan to the methyl isothiocyanate of 1:2.
The second aspect of the application also provides the cationic crosslinked thiourea grafted polymer hydrogel prepared by the preparation method of the first aspect.
The third aspect of the application also provides application of the cationic crosslinked thiourea grafted polymer hydrogel in preparing skin dressing.
Compared with the prior art, the application has the advantages or beneficial effects that at least comprises:
According to the preparation method provided by the application, the cationic crosslinked thiourea grafted polymer hydrogel coordinated by the cations and the thiourea can be formed by carrying out the mixing reaction of the thiourea grafted polymer aqueous solution and the cationic aqueous solution at the volume ratio of 1-9:1, so that the preparation method has the advantages of simplicity, mild reaction, easiness in operation, environmental friendliness and convenience in industrial production, and the formed cationic crosslinked thiourea grafted polymer hydrogel has excellent swelling property, adhesion property, rheological property and good biocompatibility, is wide in application range, meets the environmental protection requirement, and has excellent biomedical application value; meanwhile, the adhesive can be used as a skin dressing to be fixed on the surface of the skin without an adhesive medium, and the moist environment of the surface of the skin can be maintained.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are required to be used in the description of the embodiments will be briefly described below. It is obvious that the drawings in the following description are only some embodiments of the present application, and that other drawings may be obtained from these drawings without inventive effort for a person of ordinary skill in the art.
FIG. 1 is a diagram showing the appearance of various cationic crosslinked thiourea grafted hyaluronic acid hydrogels provided in the examples of the present application;
fig. 2 is an appearance characterization diagram of a silver ion crosslinked hydrazidated hyaluronic acid hydrogel provided in an embodiment of the application;
Fig. 3 is an SEM image of a silver ion crosslinked thiourea grafted hyaluronic acid hydrogel provided in the embodiment of the application;
fig. 4 is a TEM image of a silver ion crosslinked thiourea grafted hyaluronic acid hydrogel provided in the embodiment of the application;
FIG. 5 is a graph showing the swelling ratio of the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel with different concentrations according to the embodiment of the application;
FIG. 6 is a graph showing the change of the weight loss rate of the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel with different concentrations over time according to the embodiment of the application;
fig. 7 is a strain scan of a silver ion crosslinked thiourea grafted hyaluronic acid hydrogel provided in an embodiment of the application;
FIG. 8 is a frequency scan of a silver ion crosslinked thiourea grafted hyaluronic acid hydrogel provided by an embodiment of the application;
FIG. 9 is a high-low shear alternating strain scan of a silver ion crosslinked thiourea grafted hyaluronic acid hydrogel provided by an embodiment of the application;
FIG. 10 is a photograph showing the process of "injection-molding" a silver ion crosslinked thiourea grafted hyaluronic acid hydrogel according to an embodiment of the present application;
FIG. 11 is a graph showing the adhesive properties of various concentrations of silver ion crosslinked thiourea grafted hyaluronic acid hydrogel provided in the example of the present application;
Fig. 12 is a diagram showing the appearance of various cationic crosslinked thiourea grafted chitosan hydrogels provided in the example of the present application.
Detailed Description
The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present application. It will be apparent that the described embodiments are some, but not all, embodiments of the application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
In the following description of the present embodiment, the term "and/or" is used to describe an association relationship of association objects, which means that three relationships may exist, for example, a and/or B may mean: a alone, B alone and both a and B. Wherein A, B may be singular or plural. The character "/" generally indicates that the context-dependent object is an "or" relationship.
In the following description of the present embodiments, the term "at least one" means one or more, and "a plurality" means two or more. "at least one of" or the like means any combination of these items, including any combination of single item(s) or plural items(s). For example, "at least one (individual) of a, b, or c," or "at least one (individual) of a, b, and c" may each represent: a, b, c, a-b (i.e., a and b), a-c, b-c, or a-b-c, wherein a, b, c may be single or multiple, respectively.
It should be understood by those skilled in the art that, in the following description of the present embodiment, the sequence number does not mean that the execution sequence is sequential, and some or all of the steps may be executed in parallel or sequentially, and the execution sequence of each process should be determined by its functions and inherent logic, and should not constitute any limitation on the implementation process of the embodiment of the present application.
The terminology used in the embodiments of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
In a first aspect, the embodiment of the application provides a preparation method of cationic crosslinked thiourea grafted polymer hydrogel, which comprises the following steps:
mixing the thiourea grafted polymer aqueous solution and the cationic aqueous solution for reaction to obtain the cationic crosslinked thiourea grafted polymer hydrogel, wherein the volume ratio of the thiourea grafted polymer aqueous solution to the cationic aqueous solution is 1-9:1.
According to the preparation method provided by the embodiment of the application, the cationic crosslinked thiourea grafted polymer hydrogel coordinated by the cation-thiourea can be prepared by carrying out a mixing reaction between the thiourea grafted polymer aqueous solution and the cation aqueous solution at the volume ratio of 1-9:1, so that the preparation method has the advantages of simplicity, mild reaction, easiness in operation, environmental friendliness and convenience in industrial production, and the formed cationic crosslinked thiourea grafted polymer hydrogel has excellent water absorption performance, adhesion performance, rheological property, good mechanical property and good biocompatibility, is wide in application range, meets the environmental protection requirement, and has excellent biomedical application value. Meanwhile, the cation-thiourea coordination bond is a covalent bond with dynamic reversibility and strong binding force, so that the synthesized hydrogel is reversibly crosslinked and has excellent stability, and based on the characteristic of strong binding force of the cation-thiourea coordination bond, the cation crosslinked thiourea grafted polymer hydrogel can be synthesized by only carrying out mixed reaction on a thiourea grafted polymer aqueous solution and a small amount of cation crosslinking agent, so that the toxicity of excessive cations to cells can be effectively avoided, and the safety performance is good. In addition, the injectable hydrogel formed by the cation-thiourea coordination bond has certain universality and can be widely applied.
In an embodiment of the present application, the cation of the aqueous cation solution is selected from any one of Ag +、Cu2+、Fe3+、Zn2+、Se6+、Mg2 +、Ca2+.
In the embodiment of the application, in order to ensure that stable hydrogel is formed, the concentration of the thiourea grafted polymer aqueous solution is 1-15 w/v%;
The concentration of the Ag + aqueous solution is 0.1-2w/v%; the concentration of the Cu 2+ aqueous solution is 0.1-2w/v%;
The concentration of the Fe 3+ aqueous solution is 0.1-2w/v%; the concentration of Zn 2+ water solution is 5-30w/v%;
The concentration of Se 6+ water solution is 5-30w/v%; the concentration of the Mg 2+ aqueous solution is 5-30w/v%;
The concentration of the Ca 2+ aqueous solution is 5-30w/v%.
In the embodiment of the application, the thiourea graft polymer for preparing the thiourea graft polymer aqueous solution comprises any one of thiourea graft hyaluronic acid and thiourea graft chitosan. Wherein, the thiourea grafted hyaluronic acid can be selected from thiourea grafted sodium hyaluronate.
In the embodiment of the application, the preparation method of the thiourea grafted sodium hyaluronate preferably comprises the following steps:
Step one: sodium hyaluronate is reacted with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and adipic acid dihydrazide, and after the reaction is completed, the reaction product is dialyzed and dried in vacuum to obtain the hydrazinized hyaluronic acid. Wherein, the mol ratio of the sodium hyaluronate to the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the 1-hydroxybenzotriazole to the adipic dihydrazide is 1:6:6:8.
Step two: and (3) reacting the hydrazinized hyaluronic acid with methyl isothiocyanate, and dialyzing and vacuum drying the reaction product after the reaction is finished to obtain the thiourea grafted hyaluronic acid. Wherein the mass ratio of the hydrazinized hyaluronic acid to the methyl isothiocyanate is 1:2.
In the embodiment of the application, the preparation method of the thiourea grafted chitosan preferably comprises the following steps:
Step one: and (3) reacting acetic acid solution of chitosan with glycidyl trimethyl ammonium chloride, and dialyzing and vacuum drying reaction products after the reaction is finished to obtain quaternized chitosan. Wherein the molar ratio of chitosan to glycidyl trimethyl ammonium chloride is 1:2.
Step two: and (3) reacting the quaternized chitosan with methyl isothiocyanate, and dialyzing and vacuum drying the reaction product after the reaction is finished to obtain thiourea grafted chitosan. Wherein the molar ratio of the quaternized chitosan to the methyl isothiocyanate is 1:2.
In a second aspect, the embodiment of the application also provides the cationic crosslinked thiourea grafted polymer hydrogel prepared by the preparation method of the first aspect. The preparation method based on the first aspect can form the hydrogel crosslinked based on the cation-thiourea coordination bond, and the cation-thiourea coordination bond is a covalent bond which is dynamic reversible and has strong binding force, so that the prepared and formed cation-crosslinked thiourea grafted polymer hydrogel has excellent swelling performance, adhesion performance, rheological property and good biocompatibility, has wide application range, meets the environmental protection requirement, and has excellent biomedical application value.
In a third aspect, the embodiment of the application also provides an application of the cationic crosslinked thiourea grafted polymer hydrogel in the second aspect in preparing skin dressing. In particular, the cationic crosslinked thiourea grafted polymer hydrogel based on the second aspect has excellent water absorption performance, adhesion performance, rheological performance and good biocompatibility. Therefore, when the cationic crosslinked thiourea grafted polymer hydrogel is used for preparing skin dressing, the cationic crosslinked thiourea grafted polymer hydrogel can be fixed on the skin surface without an adhesive medium, and the moist environment of the skin surface can be effectively maintained.
The technical scheme of the invention will be further described in connection with specific embodiments.
Example 1
The example 1 provides a preparation method of cationic crosslinked thiourea grafted hyaluronic acid hydrogel, which comprises the following specific steps:
Step one: dissolving sodium hyaluronate with molecular weight of 2×10 6 dalton in morpholinoethanesulfonic acid solution with pH=6.5, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, stirring at room temperature for 2h, adding adipic acid dihydrazide, stirring for 24h, dialyzing in deionized water for 3 days, and freeze-drying under vacuum to obtain hydrazinized hyaluronic acid. Wherein, the mol ratio of the sodium hyaluronate to the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the 1-hydroxybenzotriazole to the adipic dihydrazide is 1:6:6:8.
Step two: and dissolving the hydrazinized hyaluronic acid in pure water to form a hydrazinized hyaluronic acid aqueous solution, mixing the hydrazinized hyaluronic acid aqueous solution with a dimethyl sulfoxide solution of methyl isothiocyanate, stirring for 3 days under the protection of N 2, sequentially dialyzing the reaction product in deionized water and NaCl solution, and finally freeze-drying under vacuum to obtain the thiourea grafted hyaluronic acid. Wherein the mass ratio of the hydrazide grafted hyaluronic acid to the methyl isothiocyanate is 1:2.
Step three: dissolving thiourea grafted hyaluronic acid in pure water to form a thiourea grafted hyaluronic acid aqueous solution with the concentration of 5w/v%, and then carrying out a mixing reaction on the thiourea grafted hyaluronic acid aqueous solution with the concentration of 5w/v% and a cationic aqueous solution according to the volume ratio of 9:1 to obtain the cationic crosslinked thiourea grafted hyaluronic acid hydrogel. Wherein, cations of the prepared cation water solution comprise Ag +、Cu2+、Fe3+、Zn2+、Se6+、Mg2+ and Ca 2+, and the method specifically comprises the following steps:
0.2w/v% Ag + in water; 0.2w/v% Cu 2+ aqueous solution;
0.2w/v% Fe 3+ in water; 10w/v% Zn 2+ in water;
10w/v% aqueous Se 6+; 10w/v% Mg 2+ in water;
and 10w/v% Ca 2+ aqueous solution.
Wherein, the volume ratio of the thiourea grafted hyaluronic acid aqueous solution to the cationic aqueous solution for mixing and crosslinking can be 1:1, 5:1, 8:1 and the like; the concentration of the thiourea grafted hyaluronic acid aqueous solution can be 1w/v%, 10w/v%, 15w/v% and the like; the concentration of the Ag + aqueous solution can be 1.2w/v%, 1.5w/v%, 1.7w/v%, etc.; the concentration of the Cu 2+ water solution can be 1.2w/v%, 1.5w/v%, 1.7w/v%, etc.; the concentration of the Fe 3+ aqueous solution can be 1.2w/v%, 1.5w/v%, 1.7w/v%, etc.; the concentration of Zn 2+ water solution can be 5w/v%, 15w/v%, 25w/v%, etc.; the concentration of Se 6+ aqueous solution can be 5w/v%, 15w/v%, 25w/v%, etc.; the concentration of the Mg 2+ aqueous solution can be 5w/v%, 15w/v%, 25w/v%, etc.; the concentration of the Ca 2+ aqueous solution may also be 5w/v%, 15w/v%, 25w/v%, etc. The cross-linking agent can be crosslinked with thiourea grafted hyaluronic acid to form gel, and the cross-linked cationic cross-linked thiourea grafted high molecular hydrogel has the optional concentration which is comparable with the physical and chemical properties, and the embodiment is not listed one by one.
The cationic crosslinked thiourea grafted hyaluronic acid hydrogel prepared in the present example 1 was subjected to appearance and performance characterization, and specifically as follows:
1. Appearance characterization
The appearance of the different cationic crosslinked thiourea grafted hyaluronic acid hydrogels prepared in example 1 is characterized in the application, and the results are shown in figure 1. Wherein, figure 1 shows the appearance characterization diagram of different cationic cross-linked thiourea grafted hyaluronic acid hydrogels.
As can be seen from fig. 1: the thiourea grafted hyaluronic acid aqueous solution and the aqueous solution of different cations (Ag +、Cu2+、Fe3+、Zn2+、Se6+、Mg2+、Ca2+) are mixed and crosslinked according to the volume ratio of 9:1 to form stable hydrogel, which shows that the gel forming performance of the thiourea grafted hyaluronic acid aqueous solution and the aqueous solution of the cations are mixed and crosslinked according to the volume ratio of 9:1 is good.
Meanwhile, the silver ion cross-linked hydrazinized hyaluronic acid hydrogel formed by mixing and cross-linking a hydrazinized hyaluronic acid aqueous solution with the concentration of 5w/v% and an Ag + aqueous solution with the concentration of 3w/v% in a volume ratio of 9:1 is subjected to appearance characterization. The results are shown in FIG. 2. Among them, fig. 2 shows an appearance characterization diagram of a silver ion crosslinked hydrazidated hyaluronic acid hydrogel.
As can be seen from fig. 1 to 2: the aqueous solution of the hydrazinized hyaluronic acid with the concentration of 5w/v% needs to be mixed and crosslinked with the aqueous solution of the Ag + with the concentration of 3w/v% according to the volume ratio of 9:1 to form the silver ion cross-linked hydrazinized hyaluronic acid hydrogel, but the aqueous solution of the hydrazinized hyaluronic acid with the concentration of 5w/v% and the aqueous solution of the Ag + with the concentration of 1.2w/v% are mixed and crosslinked according to the volume ratio of 9:1 to form the silver ion cross-linked thiourea grafted hyaluronic acid hydrogel, which shows that the hydrazinized hyaluronic acid and the cationic cross-linked hydrogel have certain defects, probably because the coordination bond binding force of the hydrazinized hyaluronic acid group and the cation is lower than that of the coordination bond of the thiourea group and the cation, more cations are needed to be crosslinked with the hydrazinized hyaluronic acid, and excessive cations can generate toxicity to cells. Therefore, when the thiourea grafted polymer is used for constructing the cation-ligand coordination bond hydrogel, the use amount of the cation serving as the cross-linking agent is less, and the hydrogel is safer.
Sem characterization
According to the application, SEM characterization is carried out on silver ion cross-linked thiourea grafted hyaluronic acid hydrogel formed by mixing and cross-linking thiourea grafted hyaluronic acid aqueous solution with the concentration of 5w/v% and Ag + aqueous solution with the concentration of 1.7w/v% in a volume ratio of 9:1, and the result is shown in figure 3. Among them, fig. 3 shows SEM images of silver ion crosslinked thiourea grafted hyaluronic acid hydrogel.
As can be seen from fig. 3: the silver ion cross-linked thiourea grafted hyaluronic acid hydrogel formed by mixing and cross-linking the thiourea grafted hyaluronic acid aqueous solution with the concentration of 5w/v% and the Ag + aqueous solution with the concentration of 1.7w/v% in the volume ratio of 9:1 has a three-dimensional pore size structure.
TEM characterization
According to the application, TEM characterization is carried out on silver ion cross-linked thiourea grafted hyaluronic acid hydrogel formed by mixing and cross-linking thiourea grafted hyaluronic acid aqueous solution with the concentration of 5w/v% and Ag + aqueous solution with the concentration of 1.7w/v% according to the volume ratio of 9:1, and the result is shown in fig. 4. Among them, fig. 4 shows a TEM image of a silver ion crosslinked thiourea grafted hyaluronic acid hydrogel.
As can be seen from fig. 4: the S, N, C, O, ag of the silver ion cross-linked thiourea grafted hyaluronic acid hydrogel formed by mixing and cross-linking the thiourea grafted hyaluronic acid aqueous solution with the concentration of 5w/v% and the Ag + aqueous solution with the concentration of 1.7w/v% in the volume ratio of 9:1 is uniformly distributed.
4. Physical and chemical characterization
4.1 Swelling Properties
The swelling performance of the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel with different concentrations is explored, and the result is shown in fig. 5. Among them, fig. 5 shows the swelling ratios of silver ion crosslinked thiourea grafted hyaluronic acid hydrogels of different concentrations.
As can be seen from fig. 5: when the concentration of silver ions is 1.2-1.7w/v%, the silver ion cross-linked thiourea grafted hyaluronic acid hydrogel can absorb water with the dry weight of more than 2000%, has high water absorption performance, is beneficial to the application of the hydrogel, and can maintain the moist environment of skin when used as skin dressing.
Meanwhile, the degradation performance of the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel with different concentrations is also studied, and the result is shown in fig. 6. Wherein, fig. 6 shows the change curves of the weight loss rate of the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel with different concentrations over time.
As can be seen from fig. 6: the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel with different concentrations prepared in the embodiment can still be maintained to be more than 50% of the original weight after 14 days, which shows that the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel has excellent stability.
4.2 Rheological Properties
The rheological properties of thiourea grafted hyaluronic acid hydrogels crosslinked with silver ions at different concentrations were investigated in this example, and the results are shown in fig. 7 to 10. Wherein, fig. 7 shows a strain scan of a silver ion crosslinked thiourea grafted hyaluronic acid hydrogel; FIG. 8 shows a frequency scan of a silver-ion crosslinked thiourea grafted hyaluronic acid hydrogel; FIG. 9 shows a high-low shear alternating strain scan of a silver ion crosslinked thiourea grafted hyaluronic acid hydrogel; fig. 10 shows a photograph of a process of "injection-molding" a silver-ion crosslinked thiourea grafted hyaluronic acid hydrogel.
As can be seen from fig. 7: when the strain is smaller, G' is always larger than G ", which indicates that the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel has an undamaged structure, and indicates that the structure of the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel is complete under the strain of 1%. However, when the strain was large, the G' values of various silver-ion crosslinked hydrogels were significantly reduced, indicating that the silver-ion crosslinked thiourea grafted hyaluronic acid hydrogel structure collapsed. Thus, 1% and 150% of silver-ion crosslinked thiourea grafted hyaluronic acid hydrogel were selected to evaluate rheological recovery behavior.
As can be seen from fig. 8: the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel has good viscoelasticity.
As can be seen from fig. 9: at high shear strain, the storage modulus (G') of the hydrogel drops sharply to a level below the loss modulus (G ") revealing that shear thinning occurs due to temporary fracture of thiourea-cation crosslinks. When switching to low shear strain, the hydrogel network recovered almost immediately, as evidenced by G' exceeding G ", indicating that the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel was thiourea-cationic coordination crosslinked and was a reversible crosslink.
As can be seen from fig. 10: after the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel is injected by the injector, a whole hydrogel can be formed after a period of time, and further proves that the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel is reversible dynamic crosslinked hydrogel.
4.3 Adhesion Properties
The adhesive properties of thiourea grafted hyaluronic acid hydrogels crosslinked by silver ions with different concentrations are explored, and the results are shown in fig. 11. Among them, fig. 11 shows the adhesive property characterization graph of the silver ion crosslinked thiourea grafted hyaluronic acid hydrogel of different concentrations.
As can be seen from fig. 11: the silver ion cross-linked thiourea grafted hyaluronic acid hydrogel prepared by the embodiment has excellent adhesion performance, can be adhered on pigskin, metal and glass, and can be identified and combined with part of protein by thiourea groups. Thus, the silver-ion crosslinked thiourea grafted hyaluronic acid hydrogel prepared in this example was conducive to adhesion to skin tissue, the adhesion properties enabling the silver-ion crosslinked thiourea grafted hyaluronic acid hydrogel to be used as a skin dressing and no adhesive medium was required for fixation to the skin surface.
Example 2
The embodiment 2 provides a preparation method of cationic crosslinked thiourea grafted chitosan hydrogel, which comprises the following specific steps:
Step one: after dissolving chitosan with molecular weight of 1×10 5-3×105 dalton in acetic acid solution (0.5 v/v%) at concentration of 2.78w/v%, adding glycidyl trimethyl ammonium chloride, stirring at 55deg.C for 18h, dialyzing in deionized water for three days, and freeze drying under vacuum to obtain quaternized chitosan. Wherein the molar ratio of chitosan to glycidyl trimethyl ammonium chloride is 1:2.
Step two: dissolving quaternized chitosan in pure water to form quaternized chitosan aqueous solution, mixing the quaternized chitosan aqueous solution with dimethyl sulfoxide solution of methyl isothiocyanate, stirring for 3 days under the protection of N 2, dialyzing the reaction product in deionized water and NaCl solution in sequence, and finally freeze-drying under vacuum to obtain thiourea grafted chitosan. Wherein the mass ratio of the quaternized chitosan to the methyl isothiocyanate is 1:2.
Step three: dissolving thiourea grafted chitosan in pure water to form thiourea grafted chitosan aqueous solution, and then mixing the thiourea grafted chitosan aqueous solution and the cationic aqueous solution for reaction according to the volume ratio of 9:1 to obtain the cationic crosslinked thiourea grafted chitosan hydrogel. Wherein the cations of the cationic aqueous solution comprise Ag + aqueous solution with the concentration of 1.7 w/v%; an aqueous Cu 2+ solution having a concentration of 1.7 w/v%; an aqueous solution of Fe 3+ having a concentration of 1.7 w/v%; a 10w/v% aqueous Zn 2+ solution; an aqueous solution of Se 6+ having a concentration of 10 w/v%; an aqueous solution of Mg 2+ at a concentration of 10w/v% and an aqueous solution of Ca 2+ at a concentration of 10 w/v%; the volume ratio of the thiourea grafted chitosan aqueous solution to the cationic aqueous solution for mixing and crosslinking can be 1:1, 5:1, 8:1 and the like; the concentration of the aqueous solution of thiourea grafted hyaluronic acid may be 1w/v%, 10w/v%, 15w/v%, etc. Of course, the cross-linking with thiourea grafted hyaluronic acid to form gel is all possible, and the cross-linking forms cationic cross-linked thiourea grafted polymer hydrogel with comparable appearance and physical and chemical properties, and the examples are not listed.
The appearance of the cationic crosslinked thiourea grafted chitosan hydrogel prepared in this example 2 was characterized, and the result is shown in fig. 12. Wherein, figure 12 shows the appearance characterization diagram of different cationic crosslinked thiourea grafted chitosan hydrogels.
As can be seen from fig. 12: the thiourea grafted chitosan aqueous solution and the different cation (Ag +、Cu2+、Fe3+、Zn2+、Se6 +、Mg2+、Ca2+) aqueous solutions are mixed and crosslinked at the volume ratio of 9:1 to form stable hydrogel, so that the gel forming performance of the thiourea grafted chitosan aqueous solution and the cation aqueous solution mixed and crosslinked at the volume ratio of 9:1 is good.
Various embodiments in this specification are described in an incremental manner, and identical or similar parts of the various embodiments are referred to each other, with each embodiment focusing on differences from the other embodiments.
The above embodiments are only for illustrating the technical solution of the present application, and not for limiting the present application; although the application has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced with equivalents; such modifications and substitutions do not depart from the spirit of the application.
Claims (7)
1. The preparation method of the cationic crosslinked thiourea grafted polymer hydrogel is characterized by comprising the following steps of:
mixing the thiourea grafted polymer aqueous solution with the cationic aqueous solution to obtain cationic crosslinked thiourea grafted polymer hydrogel;
Wherein the volume ratio of the thiourea grafted polymer aqueous solution to the cationic aqueous solution is 1-9:1;
the thiourea grafted polymer is thiourea grafted hyaluronic acid, and the preparation method of the thiourea grafted hyaluronic acid comprises the following steps:
sodium hyaluronate reacts with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and adipic dihydrazide, and after the reaction is finished, the reaction product is dialyzed and dried in vacuum to obtain hydrazinized hyaluronic acid;
and (3) reacting the hydrazinized hyaluronic acid with methyl isothiocyanate, and after the reaction is finished, dialyzing and vacuum drying the reaction product to obtain the thiourea grafted hyaluronic acid.
2. The method of claim 1, wherein the cation of the aqueous cation solution comprises any one of Ag +、Cu2+、Fe3+、Zn2+、Se6+、Mg2+、Ca2+.
3. The method according to claim 2, wherein the concentration of the thiourea grafted polymer aqueous solution is 1 to 15 w/v%;
The concentration of the Ag + aqueous solution is 0.1-2w/v%; the concentration of the Cu 2+ aqueous solution is 0.1-2w/v%;
the concentration of the Fe 3+ aqueous solution is 0.1-2w/v%; the concentration of Zn 2+ water solution is 5-30w/v%;
The concentration of Se 6+ water solution is 5-30w/v%; the concentration of the Mg 2+ aqueous solution is 5-30w/v%;
The concentration of the Ca 2+ aqueous solution is 5-30w/v%.
4. The method according to claim 1, wherein the molar ratio of the sodium hyaluronate, the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the 1-hydroxybenzotriazole and the adipic acid dihydrazide is 1:6:6:8.
5. The method of claim 1, wherein the mass ratio of sodium hyaluronate hydrazide to methyl isothiocyanate is 1:2.
6. The cationic crosslinked thiourea grafted polymer hydrogel prepared by the preparation method according to any one of claims 1-5.
7. The use of the cationic crosslinked thiourea grafted polymer hydrogel according to claim 6 for preparing a skin dressing.
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