CN110746615B - Preparation method and application of pH response type high-strength conductive hydrogel - Google Patents
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Abstract
The invention relates to a preparation method and application of pH response type high-strength conductive hydrogel in the technical field of biology, wherein the preparation method comprises the steps of preparing 5-20wt% of gamma-polyglutamic acid aqueous solution to obtain a first reaction solution; then adding gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane, and fully and uniformly stirring to obtain a second reaction solution; and adding hydrolyzed tetraethoxysilane into the second reaction liquid to adjust the crosslinking degree of the hydrogel, thereby obtaining the pH response type high-strength conductive hydrogel. The hydrogel prepared by the invention has high water absorption, adjustable mechanical property, good drug loading capacity, drug release behavior of pH regulation and control, good conductivity and biocompatibility. The hydrogel has short preparation time, simple method and low energy consumption, and can be widely applied to the aspects of drug carriers, wound dressings, biosensing and the like.
Description
Technical Field
The invention relates to a high molecular biomedical material, in particular to a preparation method and application of conductive hydrogel.
Background
Polyglutamic acid (γ -PGA), which is a water-soluble, biodegradable, non-toxic biopolymer produced using a microbial fermentation process. The gamma-PGA hydrogel material with three-dimensional network crosslinking can be formed by a chemical crosslinking agent, a radiation irradiation and other crosslinking modes. The gamma-PGA hydrogel material has good biocompatibility, water retention and conductivity, and can be used as a medicine carrier, a wound dressing, cosmetics, biosensing and the like.
The chinese invention patent CN101891954A discloses a preparation method of polyglutamic acid hydrogel, which is disclosed by the following days: 20101124, the method uses polyglutamic acid as main raw material, ethylene glycol diglycidyl ether as cross-linking agent, and adjusts the pH value of the system at regular intervals in the reaction process to prepare hydrogel, which comprises dissolving 15-30% polyglutamic acid in distilled water, adding corresponding amount of ethylene glycol diglycidyl ether according to 20-50% of the molar amount of polyglutamic acid monomer, stirring uniformly, adjusting the pH environment of the system to 3-5, reacting at 40-80 ℃, adjusting the pH value of the system to the initial value every 1-2 hours, and reacting for 4-10 hours; and fully swelling and dialyzing the prepared hydrogel, and drying. The reaction is carried out in aqueous solution, which is beneficial to environmental protection; the preparation time is short, and the obtained hydrogel has high water absorption, high swelling rate and biodegradability. The hydrogel prepared by the method can be used for drug carriers, medical and sanitary products, water-retaining agents for agriculture, forestry and gardening, thickening agents for cosmetics and foods, anti-dewing agents, flocculating agents, water treatment agents and the like. The disadvantages are that: the quantity of the cross-linking agent is large, waste is caused, the ethylene glycol diglycidyl ether has certain toxicity to human bodies, the reaction time is long, the change condition of the pH value of the reaction needs to be noticed at intervals in the reaction process, the hydrogel obtained by the reaction also needs to be subjected to swelling dialysis and freeze drying, the process is complicated, and the method has obvious defects when being used for large-scale preparation of materials.
Disclosure of Invention
The invention aims to provide a preparation method of a pH response type high-strength conductive hydrogel, which has the advantages of low cost, easy preparation, high strength of the hydrogel and safe use as a carrier of a medicament.
Therefore, the preparation method of the pH-responsive high-strength conductive hydrogel provided by the invention comprises the following steps:
(1) dissolving gamma-polyglutamic acid (gamma-PGA) into a beaker filled with an aqueous solution, placing the beaker on a magnetic stirrer, and uniformly stirring the beaker until the gamma-polyglutamic acid is completely dissolved to obtain a gamma-polyglutamic acid aqueous solution serving as a first reaction solution;
(2) then slowly adding gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane (GPTMS) into the first reaction liquid, and uniformly stirring to obtain a second reaction liquid; GPTMS as cross-linking agent;
(3) mixing Tetraethoxysilane (TEOS) with water to react to obtain hydrolyzed tetraethoxysilane water solution;
(4) and slowly adding the tetraethoxysilane aqueous solution into the second reaction solution while stirring, stirring for 15-25min, stopping stirring, taking out the solution, and putting the solution into an oven for 6-8h to obtain the gamma polyglutamic acid hydrogel, namely the pH response type high-strength conductive hydrogel.
Preferably, the molecular weight of the selected gamma-polyglutamic acid is 20-200 ten thousand units, and the gamma-polyglutamic acid with the molecular weight is easily obtained, so that the mass production of the hydrogel is facilitated.
Preferably, the mass concentration of the gamma-polyglutamic acid in the first reaction liquid is 5-20wt%, and the gamma-polyglutamic acid at the concentration can be dissolved quickly.
The further improvement of the invention is that the mass ratio of the gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane to the first reaction liquid in the step (2) is 1: (9-11), the gamma-polyglutamic acid can be more crosslinked together at the dosage, and the hydrogel structure is more stable.
The invention is further improved in that when the tetraethoxysilane is hydrolyzed in the step (3), the mass ratio of the tetraethoxysilane to the water is 1: (0.9-1.1). Acetic acid with the mass of 0.1-0.2% of the mixed solution can be added when the tetraethoxysilane is hydrolyzed so as to accelerate the hydrolysis process. The hydrolyzed tetraethyl orthosilicate (TEOS) is used to adjust the silicon content of the hydrogel, thereby further adjusting the mechanical and biological properties of the hydrogel.
The invention is further improved in that the volume usage ratio of the ethyl orthosilicate aqueous solution to the second reaction liquid is 1: 2-6. Can have better gel forming strength.
The pH response type high-strength conductive hydrogel can be used as a carrier of various water-soluble medicines. For example, the prepared hydrogel can be soaked in a mixed aqueous solution of doxorubicin hydrochloride (DOX) and tetracycline (TET) or a single aqueous solution for 36-60h to obtain a drug-loaded hydrogel; the concentration of the doxorubicin hydrochloride in the doxorubicin hydrochloride aqueous solution is 2g/L-4g/L and the concentration of the tetracycline in the tetracycline aqueous solution is 5g/L-10 g/L. Further, by immersing the drug-loaded hydrogel in PBS buffer of pH =1.2, 7.4, a graph of the drug release amount of the hydrogel was obtained by measuring the time-drug content, as a reference for drug administration.
The preparation method provided by the invention is a low-cost preparation method, provides a strength modification method of silicon hybrid gamma-PGA hydrogel, and solves the problem that the existing gamma-PGA hydrogel has insufficient strength. The method adopts polyglutamic acid as a reaction monomer, gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane (GPTMS) as a cross-linking agent and adopts the property of Tetraethoxysilane (TEOS) modified hydrogel to prepare the silicon hybrid hydrogel with higher strength.
Compared with the prior art, the invention has the following advantages:
(1) the silicon hybrid gamma-PGA hydrogel with higher strength and adhesiveness is prepared by using polyglutamic acid which is nontoxic and harmless to human bodies as a crosslinking monomer and using inorganic silane gamma- (2.3 glycidoxy) propyl trimethoxy silane (GPTMS) which is beneficial to osteogenesis and Tetraethoxysilane (TEOS) as a crosslinking agent for reaction.
(2) The silicon hybrid gamma-PGA hydrogel prepared by the method has simple preparation process and high gelling speed, and can form stable and uniform polymers in a short time.
(3) The reaction is carried out in the solution, which is beneficial to environmental protection; has high swelling rate and biodegradability.
The hydrogel prepared by the method can effectively promote osteoblast proliferation, and has good mechanical strength and electrical conductivity. The cost is low, the preparation is easy, and the strength of the hydrogel is high. The hydrogel prepared by the invention has high water absorption, adjustable mechanical property, good biological property, good drug loading capacity, good conductivity, drug release behavior of pH regulation and biodegradation performance, short preparation time, simple method and low energy consumption, and can be widely applied to drug carriers, wound dressings, biosensing and other aspects.
Drawings
Figure 1 is a compressed picture of a hydrogel prepared by adding 4ml TEOS hydrolysate (example 1).
FIG. 2 is a compressed picture of a hydrogel prepared by adding 2ml of TEOS hydrolysate (example 2).
FIG. 3 is a compressed picture of a hydrogel prepared without addition of hydrolysate (comparative example 1).
Fig. 4 is a graph of DOX drug release in pH1.2 buffer for drug-loaded hydrogels of examples 1, 2 and comparative example 1.
Figure 5 is a graph of the release of TET drug from the drug loaded hydrogels of examples 1, 2 and comparative example 1 in pH1.2 buffer.
Fig. 6 is a graph of DOX drug release in pH7.4 buffer for drug-loaded hydrogels of examples 1, 2 and comparative example 1.
Figure 7 is a graph of the release of TET drug from the drug loaded hydrogels of examples 1, 2 and comparative example 1 in pH7.4 buffer.
Detailed Description
Example 1
Weighing 1g of gamma-PGA powder, dissolving the gamma-PGA powder in 10mL of ultrapure water, enabling the gamma-PGA powder to have the molecular weight of 20-200 ten thousand units, uniformly dissolving the gamma-PGA powder by magnetic stirring for 2-3h, adding 1mL of GPTMS serving as a reaction cross-linking agent, stirring for 3-4h by magnetic stirring to obtain a clear semitransparent liquid, adding 4mL of hydrolyzed ethyl orthosilicate (TEOS) clear transparent solution with the mass content of 50%, and putting the reaction liquid into a 37 ℃ oven for 2-4h to obtain the hydrogel. FIG. 1 is a compressed picture of a hydrogel prepared by adding 4ml of TEOS hydrolysate. Therefore, the hydrogel is not subjected to plastic deformation after being compressed, and the strength of the hydrogel is better. The prepared hydrogel is respectively put into PBS (PBS, 8mL, pH7.4) DOX 50 μ M and TET 200 μ M solutions for 48h, the soaked hydrogel is washed 3 times by the PBS, the hydrogel is soaked in the prepared buffer solution with pH =1.2 and 7.48 mL, the hydrogel is put into an oven at 37 ℃ for drug release, and the buffer solution is taken out to measure the drug concentration to calculate the drug release amount.
Example 2
Weighing 1g of gamma-PGA powder, dissolving the gamma-PGA powder in 10mL of ultrapure water, stirring the solution for 2 to 3 hours by using magnetic force to enable the gamma-PGA powder to be uniformly dissolved, adding 1mL of LGPTMS serving as a reaction cross-linking agent, stirring the solution for 3 to 4 hours by using magnetic force to obtain a clear translucent liquid, adding 2mL of hydrolyzed ethyl orthosilicate (TEOS) clear transparent solution with the mass content of 50 percent, and putting the reaction liquid in a 37 ℃ oven for 4 to 6 hours to obtain the hydrogel. Figure 2 is a compressed picture of a hydrogel prepared by adding 2ml of the hydrolysate of eos. It can be seen that the hydrogel morphology did not plastically deform after compression of the hydrogel. The compressive stress of the hydrogel was not as good as that of the hydrogel in example 1. The hydrogel prepared in example 2 was used to repeat the drug release experiment in example 1.
Example 3
A preparation method of pH response type high-strength conductive hydrogel comprises the following steps:
(1) dissolving gamma-polyglutamic acid into a beaker filled with aqueous solution according to the mass concentration of 5wt%, and placing the beaker on a magnetic stirrer to be uniformly stirred until the gamma-polyglutamic acid is completely dissolved to obtain gamma-polyglutamic acid aqueous solution serving as first reaction liquid; the molecular weight of the gamma-polyglutamic acid is 20-200 ten thousand units.
(2) Then, slowly adding gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane into the first reaction liquid while stirring, and uniformly stirring to obtain a second reaction liquid; the mass ratio of the gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane to the first reaction liquid is 1: 11;
(3) mixing tetraethoxysilane with water to react to obtain hydrolyzed tetraethoxysilane water solution; during hydrolysis, the mass ratio of the ethyl orthosilicate to the water is 1: 1, simultaneously adding acetic acid with the mass of 0.1 percent of the mixed solution to accelerate the hydrolysis process;
(4) and slowly adding the ethyl orthosilicate aqueous solution into the second reaction liquid while stirring, wherein the volume usage ratio of the ethyl silicate aqueous solution to the second reaction liquid is 1: and 2, stirring for 25min, stopping stirring, taking out the solution, and putting the solution into an oven for 6h to obtain the gamma polyglutamic acid hydrogel, namely the pH response type high-strength conductive hydrogel.
Example 4
A preparation method of pH response type high-strength conductive hydrogel comprises the following steps:
(1) dissolving gamma-polyglutamic acid into a beaker filled with an aqueous solution according to the mass concentration of 20wt%, and uniformly stirring the beaker on a magnetic stirrer until the gamma-polyglutamic acid is completely dissolved to obtain a gamma-polyglutamic acid aqueous solution serving as a first reaction solution; the molecular weight of the gamma-polyglutamic acid is 20-200 ten thousand units.
(2) Then, slowly adding gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane into the first reaction liquid while stirring, and uniformly stirring to obtain a second reaction liquid; the mass ratio of the gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane to the first reaction liquid is 1: 9;
(3) mixing tetraethoxysilane with water to react to obtain hydrolyzed tetraethoxysilane water solution; during hydrolysis, the mass ratio of the tetraethoxysilane to the water is 1: 0.9, adding acetic acid with the mass of 0.2 percent of the mixed solution to accelerate the hydrolysis process;
(4) and slowly adding the ethyl orthosilicate aqueous solution into the second reaction liquid while stirring, wherein the volume usage ratio of the ethyl silicate aqueous solution to the second reaction liquid is 1: and 6, stirring for 15min, stopping stirring, taking out the solution, and putting the solution into an oven for 8h to obtain the gamma polyglutamic acid hydrogel, namely the pH response type high-strength conductive hydrogel.
Example 5
A preparation method of pH response type high-strength conductive hydrogel comprises the following steps:
(1) placing the beaker filled with the gamma-polyglutamic acid aqueous solution on a magnetic stirrer, and uniformly stirring until the gamma-polyglutamic acid aqueous solution is completely dissolved to obtain a gamma-polyglutamic acid aqueous solution serving as a first reaction solution; the molecular weight of the gamma-polyglutamic acid is 20-200 ten thousand units; the mass concentration of the gamma-polyglutamic acid in the first reaction liquid is 10 wt%.
(2) Then, slowly adding gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane into the first reaction liquid while stirring, and uniformly stirring to obtain a second reaction liquid; the mass ratio of the gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane to the first reaction liquid is 1: 10;
(3) mixing tetraethoxysilane with water to react to obtain hydrolyzed tetraethoxysilane water solution; during hydrolysis, the mass ratio of the ethyl orthosilicate to the water is 1: 1.1, simultaneously adding acetic acid with the mass of 0.15 percent of the mixed solution to accelerate the hydrolysis process;
(4) and slowly adding the ethyl orthosilicate aqueous solution into the second reaction liquid while stirring, wherein the volume usage ratio of the ethyl silicate aqueous solution to the second reaction liquid is 1: and 5, stirring for 20min, stopping stirring, taking out the solution, and putting the solution into an oven for 7h to obtain the gamma polyglutamic acid hydrogel, namely the pH response type high-strength conductive hydrogel.
Example 6
The pH-responsive high-strength electrically conductive hydrogels obtained in examples 1 to 5 can be used as carriers of water-soluble drugs. In order to obtain the drug release index, the prepared hydrogel is soaked in a mixed aqueous solution of doxorubicin hydrochloride and tetracycline for 60 hours to obtain a drug-loaded hydrogel; the concentration of the doxorubicin hydrochloride in the doxorubicin hydrochloride aqueous solution is 2g/L, the concentration of the tetracycline in the tetracycline aqueous solution is 10g/L, and the volume ratio of the doxorubicin hydrochloride aqueous solution to the tetracycline aqueous solution is 2: 1 are miscible.
Example 7
Different from the embodiment 6, the hydrogel is soaked in a mixed aqueous solution of doxorubicin hydrochloride and tetracycline for 36 hours to obtain a drug-loaded hydrogel; the concentration of the doxorubicin hydrochloride in the doxorubicin hydrochloride aqueous solution is 4g/L, the concentration of the tetracycline in the tetracycline aqueous solution is 5g/L, and the volume ratio of the doxorubicin hydrochloride aqueous solution to the tetracycline aqueous solution is 1: 4 are miscible.
Comparative example 1
Weighing 1g of gamma-PGA powder, dissolving the gamma-PGA powder in 10mL of deionized water, uniformly dissolving the gamma-PGA powder by magnetic stirring for 2-3h, adding 1mLGPTMS serving as a cross-linking agent, performing magnetic stirring for 4-5h to enable a gamma-PGA monomer and GPTMS to perform cross-linking reaction, pouring a liquid polymer solution into a mold, putting the mold into a 37 ℃ oven for 8-12h, and taking out the gel. Figure 3 is a compressed picture of a hydrogel prepared without added hydrolysate. It can be seen from the figure that the strength of the hydrogel is poor, the compressive stress of the hydrogel is not as good as that of the hydrogels in examples 1 and 2, the hydrogel is cracked when the compressive strain of the hydrogel reaches about 45%, and the strength of the hydrogel is greatly different from that of the hydrogels in examples 1 and 2. The drug release experiment in example 1 was repeated using the hydrogel prepared in example 3.
FIG. 4 is a graph showing the DOX drug release amount of the hydrogels of examples 1 and 2 and comparative example 1 under the environment of pH1.2. pH1.2 is the human gastric acid environment, in the figure, the boxes represent the hydrogel product of comparative example 1, the circles represent the product of example 2, and the triangles represent the product of example 1 (same below).
FIG. 5 is a graph showing TET drug release amount of the hydrogels of examples 1 and 2 and comparative example 1 under the environment of pH 1.2.
FIG. 6 is a graph showing the DOX drug release amount of the hydrogels of examples 1 and 2 and comparative example 1 under the pH7.4 environment. pH7.4 is the environment of human body fluid.
FIG. 7 is a graph showing TET drug release amounts of the hydrogels of examples 1 and 2 and comparative example 1 under a pH7.4 environment.
As can be seen from fig. 4 to 7, the release amount of the drug under the environment of different pH values has a tendency to change, so that the dose amount can be adjusted according to the tendency.
Comparative example 2
1g of gamma-PGA powder is weighed and dissolved in 10mL of deionized water, the solution is uniformly dissolved by magnetic stirring for 2-3h, and the solution is placed in an oven at 37 ℃ and is not gelled.
The present invention is not limited to the above-mentioned embodiments, and based on the technical solutions disclosed in the present invention, those skilled in the art can make some substitutions and modifications to some technical features without creative efforts according to the disclosed technical contents, and these substitutions and modifications are all within the protection scope of the present invention.
Claims (4)
1. A preparation method of pH response type high-strength conductive hydrogel is characterized by comprising the following steps:
(1) stirring the gamma-polyglutamic acid aqueous solution by magnetic force until the gamma-polyglutamic acid aqueous solution is completely dissolved to obtain a gamma-polyglutamic acid aqueous solution serving as a first reaction solution;
(2) then slowly adding gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane into the first reaction liquid, and uniformly stirring to obtain a second reaction liquid;
(3) mixing tetraethoxysilane with water, and stirring for a certain time to obtain a hydrolyzed tetraethoxysilane water solution;
(4) slowly adding the tetraethoxysilane aqueous solution into the second reaction liquid, stirring for 15-25min, stopping stirring, taking out the solution, putting the solution into a drying oven at 37 ℃ for 6-8h, and obtaining gamma-polyglutamic acid hydrogel, namely the pH response type high-strength conductive hydrogel;
the molecular weight of the selected gamma-polyglutamic acid is 20-200 ten thousand units;
the mass concentration of the gamma-polyglutamic acid in the first reaction liquid is 5-20 wt%;
adding gamma- (2, 3-epoxypropoxy) propyl trimethoxy silane into the step (2) according to the mass ratio of 1: 0.9-1.1;
when the tetraethoxysilane is hydrolyzed in the step (3), the mass ratio of the tetraethoxysilane to the water is 1: 0.9-1.1;
the volume usage ratio of the ethyl orthosilicate aqueous solution to the second reaction liquid is 1: 2-6.
2. The method for preparing pH-responsive high-strength conductive hydrogel according to claim 1, wherein acetic acid with a mass of 0.1-0.2% of the mixed solution is added during hydrolysis of tetraethoxysilane to accelerate the hydrolysis process.
3. Use of the pH-responsive high-strength electrically conductive hydrogel according to claim 1 or 2 as a carrier of water-soluble drugs.
4. The use of the pH-responsive high-strength conductive hydrogel according to claim 3, wherein the hydrogel is soaked in an aqueous solution of doxorubicin hydrochloride or tetracycline for 36-60h to obtain a drug-loaded hydrogel; the concentration of the doxorubicin hydrochloride in the doxorubicin hydrochloride aqueous solution is 2g/L-4 g/L; the concentration of the tetracycline in the tetracycline aqueous solution is 5g/L-10 g/L.
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| CN105664245A (en) * | 2016-02-18 | 2016-06-15 | 深圳市第二人民医院 | Injected supermolecule hydrogel and preparing method thereof |
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