CN112426981B - Metal ion crosslinked hydrogel and preparation method and application thereof - Google Patents
Metal ion crosslinked hydrogel and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a metal ion crosslinked hydrogel and a preparation method and application thereof. The hydrogel takes metal ions as a cross-linking agent, has the advantages of controllable gelation time, adjustable mechanical property, self-healing property and the like, and has the advantages of simple preparation method, mild process conditions and wide applicable metal ion types. The hydrogel disclosed by the invention has wide application prospects in the fields of three-dimensional tumor model construction, tumor local treatment, biomedical diagnosis and treatment agents, wound antibacterial dressings, drug delivery, removal of heavy metal ions in sewage and the like.
Description
Technical Field
The invention belongs to the technical field of hydrogel, and particularly relates to metal ion crosslinked hydrogel and a preparation method and application thereof.
Background
The hydrogel is a high molecular system with a water content of more than 95 percent and a three-dimensional network structure. The hydrogel has the advantages of good biocompatibility, high water absorption rate, adjustable mechanical properties, flexible preparation method and the like, and has important application value in the fields of biomedicine, medical and aesthetic products, water treatment, 3D printing, drug delivery and the like.
The preparation methods of the hydrogel are various and mainly divided into two main categories, namely chemical crosslinking hydrogel and physical crosslinking hydrogel. The chemical crosslinking hydrogel is a three-dimensional network structure system formed mainly by chemical crosslinking polymerization reaction or covalent bond connection formed among macromolecular chains, has the advantages of stable structure, high strength and the like, but often has the characteristics of no self-healing property, no stimulation responsiveness and the like. The physical crosslinking hydrogel is formed through intermolecular electrostatic interaction, hydrogen bonding, eutectic, host-guest interaction or coordination, has a non-permanent characteristic, and is generally sensitive to external stimuli such as light, heat, pH value and the like. The preparation of physically cross-linked hydrogels is relatively simple and such hydrogels are receiving increasing attention. In particular, the preparation of hydrogel by using metal ions as a cross-linking agent draws attention, and the hydrogel not only can show the functionality of the metal ions, but also has the advantages of responsiveness to pH value and ionic strength, self-healing property, mild preparation conditions and the like. However, the metal ion crosslinked hydrogel is only suitable for single or a few metal ions or organic ligands, and the application range is limited.
Disclosure of Invention
The invention aims to provide a metal ion crosslinked hydrogel, a preparation method and application thereof, and solves the problems that the existing hydrogel preparation method is complex, the release of metal ions cannot be controlled, and the application range of a metal ion crosslinked system is narrow.
A preparation method of metal ion crosslinked hydrogel comprises the following steps:
(1) grafting organic micromolecules containing hydrazide groups on water-soluble macromolecules containing carboxyl by using a carbodiimide method, and obtaining hydrazide macromolecules with the modification degree of 5-80% by a dialysis-freeze drying process or a non-solvent precipitation process;
(2) and uniformly mixing the hydrazide macromolecule aqueous solution with the metal ion solution to obtain the metal ion crosslinked hydrogel.
The invention further improves the following steps: the specific process of the step (1) is as follows: adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide into a water-soluble macromolecule aqueous solution containing carboxyl, adjusting the pH value to 4.0-7.0, adding organic micromolecules containing hydrazide groups, reacting at room temperature for 12-36 hours, and obtaining the hydrazide macromolecule with the modification degree of 5-80% through a dialysis-freeze drying process or a non-solvent precipitation process.
The invention further improves the following steps: in the step (1), the dosage of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 1-1.2 times of the hydrazide degree, the dosage of the N-hydroxysuccinimide is 1-1.5 times of the hydrazide degree, and the mass concentration of the water-soluble polymer aqueous solution containing carboxyl is 0.2-10%.
The invention further improves the following steps: the organic micromolecules containing the hydrazide groups are organic micromolecules containing at least two hydrazide groups, and the number of the hydrazide groups is 5-40 times of that of the carboxyl to be modified;
the water-soluble polymer containing carboxyl is carboxyl polysaccharide, carboxyl polypeptide or carboxyl polyacrylate.
The invention further improves the following steps: the organic small molecule containing at least two hydrazide groups is 3,3' -dithiodipropylhydrazide, 2' -dithiodiethanohydrazide, 4' -dithiodibutylhydrazine, oxalic dihydrazide, adipic dihydrazide, malonic dihydrazide, succinic dihydrazide, sebacic dihydrazide, isophthalic dihydrazide, terephthalic dihydrazide, citric acid trihydrazide or 1,3, 5-benzenetrimethylhydrazide;
the carboxyl-containing polysaccharide is sodium hyaluronate, sodium alginate, sodium carboxymethylcellulose or carboxymethyl chitosan, the carboxyl-containing polypeptide is polyglutamic acid or polyaspartic acid, and the carboxyl-containing polyacrylate is polyacrylic acid, polymethacrylic acid, polymaleic acid or polymaleic acid copolymer.
The invention further improves the following steps: the molecular weight of the water-soluble polymer containing carboxyl in the step (1) is 5000 Da-3000 kDa;
the dialysis conditions in the step (1) are as follows: the molecular weight cut-off of the dialysis bag is 1000Da, the dialysis time is 8 hours to 4 days, and the freeze-drying conditions are as follows: drying at-20 deg.c for 12-72 hr.
The invention further improves the following steps: the solvent used in the non-solvent precipitation process in the step (1) is acetone, ethanol, methanol or sodium chloride aqueous solution with the mass concentration of 5-25%, and the dosage of the solvent is 3-8 times of the volume of the reaction solution obtained after the reaction is carried out for 12-36 hours.
The invention further improves the following steps: the mass concentration of the hydrazide macromolecule aqueous solution in the step (2) is 0.2-30%, and the mass content of metal ions in the metal ion solution is 0.01-5%; the metal ion solution is an aqueous solution of nitrate, chloride or sulfate of metal ions.
The invention further improves the following steps: the metal ion solution is an aqueous solution of calcium chloride, copper chloride, silver nitrate, copper nitrate, zinc chloride, chromium nitrate, gadolinium chloride, cisplatin, chloroauric acid or copper sulfate.
A metal ion crosslinked hydrogel prepared according to the above method.
Application of the metal ion crosslinked hydrogel in biomedicine, drug delivery and removal of heavy metal ions in water is provided.
Compared with the prior art, the invention has the following beneficial effects: (1) the metal ion crosslinked hydrogel realizes the crosslinking effect through the coordination effect between metal ions and hydrazide groups, and the coordination reaction has no specific selectivity on the metal ions and is suitable for various metal ions; (2) the metal ion crosslinked hydrogel is based on coordination bonds, has the characteristic of dynamic change, and has the advantages of self-healing property, adjustable mechanical property, controllable metal ion release rate and the like; (3) the metal ion hydrogel can be obtained by mixing hydrazide macromolecules and metal ions in a room-temperature water phase, and has the advantages of mild preparation conditions, simple process, controllable gelation time and good large-scale production prospect.
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FIG. 1 shows Ca prepared in examples 1 to 62+、Ag+、Zn2+、Cu2+、Pt2+And Cr3+Photograph of crosslinked hyaluronic acid hydrogel. Wherein (a) is example 1, (b) is example 2, (c) is example 3, (d) is example 4, (e) is example 5, and (f) is example 6.
FIG. 2 shows Zn prepared in example 32+Photograph of antibacterial property of crosslinked hyaluronic acid hydrogel.
Detailed Description
The present invention will be further illustrated by reference to specific examples, which are intended to illustrate the invention and not to limit the scope thereof, and it will be apparent that the examples are given by way of illustration only and are not intended to limit the scope thereof.
The preparation method of the metal ion crosslinked hydrogel comprises the following steps:
(1) grafting organic micromolecules containing hydrazide groups on water-soluble macromolecules containing carboxyl by using a carbodiimide method, reacting for 12-36 hours at room temperature, and then performing dialysis-freeze drying process or non-solvent precipitation process to obtain hydrazide macromolecules with the modification degree of 5-80%;
(2) and uniformly mixing the hydrazide macromolecule aqueous solution and the metal ion solution to obtain the metal ion crosslinked hydrogel.
The reagents used in the carbodiimide method in the step (1) are 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, the dosage of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 1-1.2 times of the mole number of the carboxyl to be modified in the water-soluble polymer containing the carboxyl, the dosage of the N-hydroxysuccinimide is 1-1.5 times of the mole number of the carboxyl to be modified in the water-soluble polymer containing the carboxyl, and the mass percentage concentration of the water-soluble polymer is 0.2-10%.
The organic small molecule containing hydrazide groups in the step (1) is an organic small molecule containing at least two hydrazide groups, and includes, but is not limited to, 3' -dithiodipropionazide, 2' -dithiodiethanehydrazide, 4' -dithiodibutylhydrazide, oxalic dihydrazide, adipic dihydrazide, malonic dihydrazide, succinic dihydrazide, sebacic dihydrazide, isophthalic dihydrazide, terephthalic dihydrazide, citric acid trihydrazide, 1,3, 5-benzenetrihydrazide, and the like, wherein the number of hydrazide groups is 5-40 times that of carboxyl groups to be modified.
The water-soluble polymer in the step (1) is carboxyl-containing polysaccharide such as sodium hyaluronate, sodium alginate, sodium carboxymethylcellulose, carboxymethyl chitosan and the like, carboxyl-containing polypeptide such as polyglutamic acid, polyaspartic acid and the like, or carboxyl-containing polyacrylate such as polyacrylic acid, polymethacrylic acid, polymaleic acid and copolymers thereof and the like.
The molecular weight of the water-soluble polymer in the step (1) is 5000 Da-3000 kDa.
The dialysis condition of the step (1) is that the molecular weight cut-off is 1000Da, the dialysis time is 8 hours to 4 days, and the freeze drying condition is 20 ℃ below zero and 12 hours to 72 hours.
The solvent used in the non-solvent precipitation process in the step (1) is acetone, ethanol, methanol or 5-25% sodium chloride aqueous solution, and the dosage of the solvent is 3-8 times of the volume of the reaction solution.
The concentration of the hydrazide high molecular water solution in the step (2) is 0.2-30%.
The metal ion solution in the step (2) is nitrate, chloride or sulfate of metal ions, such as calcium chloride, copper chloride, silver nitrate, copper nitrate, zinc chloride, chromium nitrate, gadolinium chloride, cisplatin, chloroauric acid, copper sulfate and the like; wherein the mass percentage content of the metal ions is 0.01-5%.
The metal ion crosslinked hydrogel prepared by the invention can be used in the fields of biomedicine, drug delivery, removal of heavy metal ions in water and the like.
The following are specific examples.
Example 1
Preparing sodium hyaluronate with the molecular weight of 200kDa into a solution with the mass percentage concentration of 1%; then, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1.1 times of N-hydroxysuccinimide of which the degree of modification is to be 1 times are added, followed by addition of 3,3' -dithiodipropylhydrazide of which the number of hydrazide groups is 10 times the degree of modification; reacting at room temperature for 24 hours under the condition that the pH value is 5.0, dialyzing water for 10 hours by using a dialysis bag with the molecular weight cutoff of 1000Da, and freeze-drying at minus 20 ℃ for 24 hours to obtain hydrazide hyaluronic acid with the modification degree of 20%; and finally, preparing the hydrazide hyaluronic acid into an aqueous solution with the mass concentration of 3%, and uniformly mixing the aqueous solution with a calcium chloride solution to obtain the calcium ion crosslinked hyaluronic acid hydrogel, wherein the mass percentage concentration of calcium ions is 0.1%.
The photo of the hydrogel prepared in this example is shown in fig. 1 (a), and it can be seen from the figure that the calcium ion solution and the hydrazide hyaluronic acid solution are uniformly mixed, and then gradually change into a gel state, and the gel cannot be deformed when being inverted.
Example 2
Preparing sodium hyaluronate with the molecular weight of 200kDa into a solution with the mass percentage concentration of 1%; then, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1.1 times of N-hydroxysuccinimide of which the degree of modification is to be 1 times are added, followed by addition of 3,3' -dithiodipropylhydrazide of which the number of hydrazide groups is 10 times the degree of modification; reacting at room temperature for 24 hours under the condition that the pH value is 5.0, dialyzing water for 10 hours by using a dialysis bag with the molecular weight cutoff of 1000Da, and freeze-drying at minus 20 ℃ for 24 hours to obtain hydrazide hyaluronic acid with the modification degree of 20%; and finally, preparing the hydrazide hyaluronic acid into an aqueous solution with the mass concentration of 3%, and uniformly mixing the aqueous solution with a silver nitrate solution to obtain the silver ion crosslinked hyaluronic acid hydrogel, wherein the mass percentage concentration of silver ions is 0.2%.
The photograph of the hydrogel prepared in this example is shown in fig. 1 (b), and the phenomenon is similar to that in example 1.
Example 3
Preparing sodium hyaluronate with the molecular weight of 200kDa into a solution with the mass percentage concentration of 1%; then, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1.3 times of N-hydroxysuccinimide of which the degree of pseudo-modification is 1.1 times were added, followed by addition of 3,3' -dithiodipropylhydrazide of which the number of hydrazide groups is 10 times the degree of pseudo-modification; reacting at room temperature for 24 hours under the condition that the pH value is 5.0, dialyzing water for 10 hours by using a dialysis bag with the molecular weight cutoff of 1000Da, and freeze-drying for 24 hours at minus 20 ℃ to obtain hydrazide hyaluronic acid with the modification degree of 40%; and finally, preparing the hydrazide hyaluronic acid into an aqueous solution with the mass concentration of 3%, and mixing the aqueous solution with a zinc ion solution uniformly, wherein the using amount of zinc ions is 15% of the mass of the hydrazide hyaluronic acid, so as to obtain the zinc ion crosslinked hyaluronic acid hydrogel.
The photograph of the hydrogel prepared in this example is shown in fig. 1 (c), and the phenomenon is similar to that in example 1. The zinc ion crosslinked hyaluronic acid hydrogel prepared by the embodiment has excellent antibacterial property, the antibacterial rate of staphylococcus aureus and escherichia coli reaches 100%, and the specific result is shown in fig. 2.
Example 4
Preparing sodium hyaluronate with the molecular weight of 200kDa into a solution with the mass percentage concentration of 1%; then, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1.1 times of N-hydroxysuccinimide of which the degree of modification is to be 1 times are added, followed by addition of 3,3' -dithiodipropylhydrazide of which the number of hydrazide groups is 10 times the degree of modification; reacting at room temperature for 24 hours under the condition that the pH value is 5.0, dialyzing water for 10 hours by using a dialysis bag with the molecular weight cutoff of 1000Da, and freeze-drying at minus 20 ℃ for 24 hours to obtain hydrazide hyaluronic acid with the modification degree of 20%; and finally, preparing the hydrazide hyaluronic acid into an aqueous solution with the mass concentration of 3%, and uniformly mixing the aqueous solution with a copper ion solution to obtain the copper ion crosslinked hyaluronic acid hydrogel, wherein the mass of the copper ions is 5% of that of the hydrazide hyaluronic acid.
The photograph of the hydrogel prepared in this example is shown in (d) of FIG. 1, and the phenomenon is similar to that of example 1.
Example 5
Preparing sodium hyaluronate with the molecular weight of 200kDa into a solution with the mass percentage concentration of 1%; then, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1.1 times of N-hydroxysuccinimide of which the degree of modification is to be 1 times are added, followed by addition of 3,3' -dithiodipropylhydrazide of which the number of hydrazide groups is 10 times the degree of modification; reacting at room temperature for 24 hours under the condition that the pH value is 5.0, dialyzing water for 10 hours by using a dialysis bag with the molecular weight cutoff of 1000Da, and freeze-drying at minus 20 ℃ for 24 hours to obtain hydrazide hyaluronic acid with the modification degree of 20%; and finally, preparing the hydrazide hyaluronic acid into an aqueous solution with the mass concentration of 3%, and uniformly mixing the aqueous solution with a cisplatin solution to obtain the platinum ion crosslinked hyaluronic acid hydrogel, wherein the mass of the cisplatin is 4% of that of the hydrazide hyaluronic acid.
The photograph of the hydrogel prepared is shown in fig. 1 (e), and the phenomenon is similar to that in example 1.
Example 6
Preparing sodium hyaluronate with the molecular weight of 200kDa into a solution with the mass percentage concentration of 1%; then, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1.1 times of N-hydroxysuccinimide of which the degree of modification is to be 1 times are added, followed by addition of 3,3' -dithiodipropylhydrazide of which the number of hydrazide groups is 10 times the degree of modification; reacting at room temperature for 24 hours under the condition that the pH value is 5.0, dialyzing water for 10 hours by using a dialysis bag with the molecular weight cutoff of 1000Da, and freeze-drying at minus 20 ℃ for 24 hours to obtain hydrazide hyaluronic acid with the modification degree of 20%; and finally, preparing the hydrazide hyaluronic acid into an aqueous solution with the mass concentration of 3%, and uniformly mixing the aqueous solution with the chromium ion solution to obtain the chromium ion crosslinked hyaluronic acid hydrogel, wherein the mass percentage concentration of the chromium ions is 1%.
The photograph of the hydrogel prepared is shown in fig. 1 (f), and the phenomenon is similar to that in example 1.
Example 7
Adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide into a water-soluble macromolecular aqueous solution containing carboxyl, adjusting the pH value to 4.0, adding an organic micromolecule containing a hydrazide group, reacting at room temperature for 12 hours, and dialyzing and freeze-drying the reaction solution to obtain the hydrazide macromolecule with the modification degree of 5%. And uniformly mixing the hydrazide macromolecule aqueous solution with the metal ion solution to obtain the metal ion crosslinked hydrogel.
Wherein the dosage of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 1 time of the hydrazide degree, the dosage of the N-hydroxysuccinimide is 1 time of the hydrazide degree, and the mass concentration of the water-soluble polymer aqueous solution containing carboxyl is 0.2%.
The number of hydrazide groups is 5 times of the number of carboxyl groups to be modified in the carboxyl-containing water-soluble polymer.
The organic small molecule containing at least two hydrazide groups is oxalic dihydrazide.
The water-soluble polymer containing carboxyl is sodium alginate.
The molecular weight of the water-soluble polymer containing carboxyl is 1000 kDa.
The dialysis-freeze drying process comprises the steps of intercepting molecular weight of 1000Da, dialyzing for 2 days, and drying for 12 hours at minus 20 ℃.
The mass concentration of the hydrazide macromolecule aqueous solution is 0.2 percent, and the mass concentration of metal ions in the metal ion solution is 1 percent;
the metal ion solution is an aqueous solution of calcium chloride.
Example 8
Adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide into a water-soluble macromolecular aqueous solution containing carboxyl, adjusting the pH value to 5.0, adding an organic micromolecule containing a hydrazide group, reacting at room temperature for 36 hours, and dialyzing and freeze-drying the reaction solution to obtain the hydrazide macromolecule with the modification degree of 80%. And uniformly mixing the hydrazide macromolecule aqueous solution with the metal ion solution to obtain the metal ion crosslinked hydrogel.
Wherein the dosage of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 1.2 times of the hydrazide degree, the dosage of the N-hydroxysuccinimide is 1.2 times of the hydrazide degree, and the mass concentration of the water-soluble polymer aqueous solution containing the carboxyl is 10 percent.
The number of hydrazide groups is 10 times of the number of carboxyl groups to be modified in the carboxyl-containing water-soluble polymer;
the organic micromolecule containing at least two hydrazide groups is isophthalic dihydrazide;
the water-soluble polymer containing carboxyl is sodium carboxymethyl cellulose.
The molecular weight of the water-soluble polymer containing carboxyl is 2000 kDa.
The dialysis-freeze drying process comprises the steps of intercepting molecular weight of 1000Da, dialyzing for 1 day, and drying for 72 hours at minus 20 ℃.
The mass concentration of the hydrazide macromolecule aqueous solution is 30 percent, and the mass concentration of metal ions in the metal ion solution is 0.01 percent;
the metal ion solution is an aqueous solution of copper nitrate.
Example 9
Adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide into a water-soluble macromolecular aqueous solution containing carboxyl, adjusting the pH value to 6.0, adding an organic micromolecule containing a hydrazide group, reacting at room temperature for 20 hours, and carrying out a non-solvent precipitation process on the reaction solution to obtain a hydrazide macromolecular with the modification degree of 30%. And uniformly mixing the hydrazide macromolecule aqueous solution with the metal ion solution to obtain the metal ion crosslinked hydrogel.
Wherein the dosage of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 1.2 times of the hydrazide degree, the dosage of the N-hydroxysuccinimide is 1.5 times of the hydrazide degree, and the mass concentration of the water-soluble polymer aqueous solution containing the carboxyl is 3%.
The number of hydrazide groups is 20 times of the number of carboxyl groups to be modified in the carboxyl-containing water-soluble polymer;
the organic micromolecule containing at least two hydrazide groups is citric acid trihydrazide;
the water-soluble polymer containing carboxyl is polyglutamic acid.
The molecular weight of the water-soluble polymer containing carboxyl is 200 kDa.
The solvent used in the non-solvent precipitation process was acetone, and the amount of solvent was 3 times the volume of the reaction solution.
The mass concentration of the hydrazide macromolecule aqueous solution is 10 percent, and the mass concentration of metal ions in the metal ion solution is 5 percent;
the metal ion solution is an aqueous solution of chloroauric acid.
Example 10
Adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide into a water-soluble macromolecular aqueous solution containing carboxyl, adjusting the pH value to 7.0, adding an organic micromolecule containing a hydrazide group, reacting at room temperature for 24 hours to obtain a reaction solution, and carrying out a non-solvent precipitation process on the reaction solution to obtain a hydrazide macromolecular with a modification degree of 60%. And uniformly mixing the hydrazide macromolecule aqueous solution with the metal ion solution to obtain the metal ion crosslinked hydrogel.
Wherein the dosage of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 1.1 times of the hydrazide degree, the dosage of the N-hydroxysuccinimide is 1.3 times of the hydrazide degree, and the mass concentration of the water-soluble polymer aqueous solution containing the carboxyl is 7 percent.
The number of hydrazide groups is 40 times of the number of carboxyl groups to be modified in the carboxyl-containing water-soluble polymer;
the organic small molecule containing at least two hydrazide groups is 1,3, 5-benzenetricarboxylic acid hydrazide;
the water-soluble polymer containing carboxyl is polymaleic acid copolymer.
The molecular weight of the water-soluble polymer containing carboxyl is 150 kDa.
The solvent used in the non-solvent precipitation process was methanol, the amount of solvent used was 8 times the volume of the reaction solution.
The mass concentration of the hydrazide macromolecule aqueous solution is 20 percent, and the mass concentration of metal ions in the metal ion solution is 3 percent;
the metal ion solution is an aqueous solution of copper sulfate.
The metal ion crosslinked hydrogel prepared by the invention can be applied to biomedicine, drug delivery and removal of heavy metal ions in water.
The invention utilizes a carbodiimide method to prepare hydrazide group modified water-soluble polymer, and then mixes the hydrazide polymer aqueous solution and the metal ion solution uniformly to obtain the metal ion crosslinked hydrogel. The hydrogel takes metal ions as a cross-linking agent, has the advantages of controllable gelation time, adjustable mechanical property, self-healing property and the like, and has the advantages of simple preparation method, mild process conditions and wide applicable metal ion types. The hydrogel disclosed by the invention has wide application prospects in the fields of three-dimensional tumor model construction, tumor local treatment, biomedical diagnosis and treatment agents, wound antibacterial dressings, drug delivery, removal of heavy metal ions in sewage and the like.
Claims (8)
1. A preparation method of metal ion crosslinked hydrogel is characterized by comprising the following steps:
(1) grafting an organic micromolecule containing a hydrazide group on a water-soluble macromolecule containing carboxyl by using a carbodiimide method, and obtaining a hydrazide macromolecule with the modification degree of 5-80% through a dialysis-freeze drying process or a non-solvent precipitation process;
the specific process is as follows: adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide into a water-soluble macromolecule aqueous solution containing carboxyl, adjusting the pH value to 4.0-7.0, adding organic micromolecules containing hydrazide groups, reacting at room temperature for 12-36 hours, and obtaining hydrazide macromolecules with the modification degree of 5-80% through a dialysis-freeze drying process or a non-solvent precipitation process;
(2) uniformly mixing the hydrazide macromolecule aqueous solution with the metal ion solution to obtain metal ion crosslinked hydrogel; wherein the metal ion solution is an aqueous solution of nitrate, chloride or sulfate of metal ions;
the organic micromolecules containing the hydrazide groups are organic micromolecules containing at least two hydrazide groups;
the water-soluble polymer containing carboxyl is carboxyl-containing polysaccharide, carboxyl-containing polypeptide or carboxyl-containing polyacrylate;
the organic small molecule containing at least two hydrazide groups is 3,3' -dithiodipropylhydrazide, 2' -dithiodiethanohydrazide, 4' -dithiodibutylhydrazine, oxalic dihydrazide, adipic dihydrazide, malonic dihydrazide, succinic dihydrazide, sebacic dihydrazide, isophthalic dihydrazide, terephthalic dihydrazide, citric acid trihydrazide or 1,3, 5-benzenetrimethylhydrazide;
the carboxyl-containing polysaccharide is sodium hyaluronate, sodium alginate, sodium carboxymethylcellulose or carboxymethyl chitosan, the carboxyl-containing polypeptide is polyglutamic acid or polyaspartic acid, and the carboxyl-containing polyacrylate is polyacrylic acid, polymethacrylic acid, polymaleic acid or polymaleic acid copolymer;
the mass concentration of the hydrazide macromolecule aqueous solution is 0.2-30%, and the mass content of metal ions in the metal ion solution is 0.01-5%.
2. The method for preparing a metal ion crosslinked hydrogel according to claim 1, wherein: in the step (1), the dosage of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 1-1.2 times of the mole number of the carboxyl to be modified, the dosage of the N-hydroxysuccinimide is 1-1.5 times of the mole number of the carboxyl to be modified, and the mass concentration of the water-soluble polymer aqueous solution containing the carboxyl is 0.2% -10%.
3. The method for preparing a metal ion crosslinked hydrogel according to claim 1, wherein: the number of hydrazide groups is 5 to 40 times the number of carboxyl groups to be modified.
4. The method for preparing a metal ion crosslinked hydrogel according to claim 1, wherein: the molecular weight of the water-soluble polymer containing carboxyl in the step (1) is 5000 Da-3000 kDa;
the dialysis conditions in the step (1) are as follows: the molecular weight cut-off of the dialysis bag is 1000Da, and the dialysis time is 8 hours to 4 days; the freeze-drying conditions are as follows: drying at-20 ℃ for 12-72 hours.
5. The method for preparing a metal ion crosslinked hydrogel according to claim 1, wherein: the solvent used in the non-solvent precipitation process in the step (1) is acetone, ethanol, methanol or a sodium chloride aqueous solution with the mass concentration of 5-25%, and the using amount of the solvent is 3-8 times of the volume of a reaction solution obtained after the reaction is carried out for 12-36 hours.
6. The method for preparing a metal ion crosslinked hydrogel according to claim 5, wherein: the metal ion solution is an aqueous solution of calcium chloride, copper chloride, silver nitrate, copper nitrate, zinc chloride, chromium nitrate, gadolinium chloride, cisplatin, chloroauric acid or copper sulfate.
7. A metal ion crosslinked hydrogel prepared according to the method of any one of claims 1 to 6.
8. Use of the metal ion crosslinked hydrogel of claim 7 in biomedicine, drug delivery and removal of heavy metal ions from a body of water.
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| CN113648982A (en) * | 2021-08-20 | 2021-11-16 | 湖南瑞福尼新材料科技有限公司 | Preparation method of biomass-based hydrogel material capable of adsorbing heavy metal ions |
| CN113827501B (en) * | 2021-10-09 | 2022-07-22 | 长沙麓羽生物科技有限责任公司 | Hyaluronic acid hydrogel mask with skin repair function and preparation method thereof |
| CN113861311B (en) * | 2021-10-09 | 2022-11-22 | 长沙麓羽生物科技有限责任公司 | Hyaluronic acid double-crosslinked polymer and preparation method and application thereof |
| CN114350035B (en) * | 2021-12-31 | 2023-04-25 | 常州百瑞吉生物医药有限公司 | Hyaluronic acid crosslinking active material and application thereof |
| CN114933717A (en) * | 2022-06-07 | 2022-08-23 | 山东圳谷新材料科技有限公司 | Preparation method and application of erasable hydrogel material |
| CN114984875A (en) * | 2022-07-13 | 2022-09-02 | 西安交通大学 | Metal-hydrazide coordination self-assembly nanosphere and preparation method and application thereof |
| CN115850734B (en) * | 2022-12-07 | 2024-05-03 | 重庆大学 | Cationic crosslinked thiourea grafted polymer hydrogel and preparation method and application thereof |
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| US5616568A (en) * | 1993-11-30 | 1997-04-01 | The Research Foundation Of State University Of New York | Functionalized derivatives of hyaluronic acid |
| US6432449B1 (en) * | 1998-05-18 | 2002-08-13 | Amgen Inc. | Biodegradable sustained-release alginate gels |
| CN102617867B (en) * | 2012-03-31 | 2013-07-10 | 南开大学 | Preparation method of injectable aquagel based on polyaspartic acid derivative |
| CN102871951B (en) * | 2012-09-11 | 2013-11-06 | 长春理工大学 | Hyaluronic acid nano microgel loaded with anti-cancer medicine and preparation method for hyaluronic acid nano microgel |
| DE102013008769A1 (en) * | 2013-05-23 | 2014-11-27 | Tougas Oilfield Solutions Gmbh | Temperature-stable, electrolyte-containing hydrogel and method for stimulating oil and gas deposits |
| CN109880125B (en) * | 2019-02-21 | 2021-07-13 | 武汉纺织大学 | Preparation method of hyaluronic acid gel filled under skin |
| CN111518289B (en) * | 2020-05-21 | 2021-11-19 | 山东大学 | Injectable self-healing hydrogel with adjustable mechanical properties and preparation method and application thereof |
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