CN109265709B - Preparation method and application of conductive hydrogel capable of slowly releasing drugs and factors - Google Patents

Preparation method and application of conductive hydrogel capable of slowly releasing drugs and factors Download PDF

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CN109265709B
CN109265709B CN201810939782.3A CN201810939782A CN109265709B CN 109265709 B CN109265709 B CN 109265709B CN 201810939782 A CN201810939782 A CN 201810939782A CN 109265709 B CN109265709 B CN 109265709B
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conductive
polydopamine
monomer
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CN109265709A (en
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鲁雄
黄自强
甘东林
闫力维
王笑
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Southwest Jiaotong University
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Abstract

The invention discloses a preparation method and application of conductive hydrogel capable of slowly releasing drugs and factors, which comprises the following steps: step 1: preparing a conductive high molecular monomer solution, adding an oxidant, and fully reacting to obtain a conductive high molecular polymer; step 2: preparing a dopamine aqueous solution with a concentration, adding the conductive high molecular polymer obtained in the step (1), and fully reacting to obtain a polydopamine/conductive high molecular polymer compound; and step 3: preparing a metal ion salt solution and an organic ligand solution; and 4, step 4: adding a polydopamine/conductive high-molecular polymer compound into a metal ion salt solution, uniformly mixing, and adding an organic ligand solution; fully reacting; and 5: adding a monomer or double-bonded biomacromolecule solution into the metal organic framework/polydopamine/conductive high-molecular polymer compound; adding additives and polymerizing to form the needed hydrogel; the invention has excellent conductivity and electrochemical activity, and can be used for preparing drug carriers and bioelectrode.

Description

Preparation method and application of conductive hydrogel capable of slowly releasing drugs and factors
Technical Field
The invention relates to the technical field of biological materials, in particular to a preparation method and application of a conductive hydrogel capable of slowly releasing drugs and factors.
Background
In recent years, the metal organic framework has the advantages of large surface area, adjustable pore diameter, moderate pore volume, high porosity and the like, and is widely applied to drug carriers; the high specific surface area can load biological macromolecules, the large pore size can encapsulate different types of medicines, and the drug loading capacity is large. However, the environment in the organism is relatively complex, and the medicine carried by the metal organic framework is easy to generate structural disintegration in the process of being transmitted to the lesion part, so that the medicine loss is caused, the medicine concentration of the lesion part is too low, and the due curative effect cannot be achieved; on the other hand, the metal organic framework material has a unique pore structure, can buffer the volume expansion of an electrode, increase the contact area of a substrate and a product with electrolyte and shorten the electron transfer process; the metal organic framework material has great potential in the field of biological electrodes; however, the metal organic framework material has poor conductivity, so that the application of the metal organic framework material is limited.
The existing metal organic framework material has the following problems: the drug-loaded metal-organic framework is easy to run off during the transportation in the organism, so that the drug concentration of the lesion part is too low; the poor conductivity and stability of the metal organic framework material limit the application of the metal organic framework material in the aspects of bioelectrode and the like.
Disclosure of Invention
The invention provides a preparation method and application of conductive hydrogel with excellent conductivity and electrochemical activity and capable of slowly releasing drugs and factors.
The technical scheme adopted by the invention is as follows: a preparation method of conductive hydrogel capable of slowly releasing drugs and factors comprises the following steps:
step 1: preparing a conductive high molecular monomer solution with the mass concentration of 0.04-2%, adding an oxidant, and fully reacting to obtain a conductive high molecular polymer;
step 2: preparing a dopamine aqueous solution with the concentration of 0.05-10 mg/mL, and adjusting the pH value to 8-13; adding the conductive high molecular polymer obtained in the step (1), and fully reacting to obtain a polydopamine/conductive high molecular polymer compound;
and step 3: preparing a metal ion salt solution with the mass concentration of 0.1-1% and an organic ligand solution with the mass concentration of 0.1-2%;
and 4, step 4: adding the polydopamine/conductive high-molecular polymer compound prepared in the step (2) into a metal ion salt solution, uniformly mixing, and adding an organic ligand solution; after full reaction, a metal organic framework/polydopamine/conductive high molecular polymer compound is obtained;
and 5: preparing an aqueous solution with the mass concentration of 0.1-1% of a metal organic framework/polydopamine/conductive high molecular polymer compound, and adding a monomer or double-bonded biomacromolecule solution with the mass concentration of 0.5-20%; the additives are added and polymerized to form the desired hydrogel.
Further, the mass ratio of the conductive polymer monomer to the oxidant in the step 1 is 1: 1-20; the oxidant is one of ferric trichloride, ferric nitrate, ferric sulfate and ferric ammonium sulfate.
Furthermore, the conductive polymer monomer is one of pyrrole monomer, aniline monomer, thiophene monomer and 5-carboxyl indole monomer.
Further, the metal ion salt in the step 3 is one of zinc nitrate, zinc acetate and zinc acetate; the organic ligand is one of benzimidazole, 2-methylimidazole and 4, 5-dichloroimidazole.
Further, in the step 3, the solvent in the metal ion salt solution and the organic ligand solution is one of methanol and N, N-dimethylformamide.
Further, the monomer in the step 5 is one of acrylamide, acrylic acid, methacrylic acid, dimethylaminoethyl methacrylate and methacrylamide; the double-bonded biomacromolecule is one or the combination of two or more than two of double-bonded hyaluronic acid, double-bonded gelatin, double-bonded chitosan, double-bonded sodium alginate and double-bonded chondroitin sulfate.
Further, the additive in the step 5 comprises one of an initiator or a photoinitiator, a cross-linking agent and an auxiliary agent; the mass concentration of the initiator or the photoinitiator is 0.05-20%, the mass concentration of the cross-linking agent is 0.01-0.1%, and the mass concentration of the auxiliary agent is 0.01-0.1%.
Further, the initiator is one of ammonium persulfate, potassium persulfate and sodium persulfate; the photoinitiator is one of Irgacure2959, Irgacure500, Irgacure127, TPO and ultraviolet photoinitiator 184/1173/907; the cross-linking agent is one of N, N-methylene diacrylamide and polyethylene glycol dimethacrylate; the assistant is N, N, N ', N' -tetramethyl diethylamine.
Use of a conductive hydrogel as a pharmaceutical carrier.
Use of a conductive hydrogel for the preparation of a bioelectrode.
The invention has the beneficial effects that:
(1) the unique pore structure of the metal organic framework in the hydrogel prepared by the invention can increase the flow rate of electrons, and the hydrogel has synergistic effect with a conductive high polymer so as to improve the conductivity and electrochemical activity of the hydrogel;
(2) the metal organic framework in the hydrogel prepared by the invention has good drug-loading capacity due to the unique macroporosity and large specific surface area structure, and the poly-dopamine grafted on the surface of the conductive high polymer can be combined with some groups on the drug and also has certain drug-loading capacity;
(3) the three-dimensional network structure in the hydrogel prepared by the invention can delay the disintegration rate of the metal organic framework structure, and the two have synergistic effect, and have the effects of stabilizing the metal organic framework structure and delaying the disintegration rate.
Drawings
FIG. 1 is an SEM image of a ZIF-8/polydopamine/poly-3, 4-ethylenedioxythiophene complex obtained in step B of example 1 of the present invention.
Fig. 2 is a graph comparing the electrical conductivity of the poly 3, 4-ethylenedioxythiophene hydrogel, the polydopamine/poly 3, 4-ethylenedioxythiophene hydrogel and the ZIF-8/polydopamine/poly 3, 4-ethylenedioxythiophene composite conductive hydrogel of the present invention.
Detailed Description
The present invention is further illustrated by the following specific examples.
The preparation method of the conductive hydrogel capable of slowly releasing the drugs and factors comprises the following steps:
step 1: preparing a conductive polymer monomer solution with the mass concentration of 0.04-2%, adding an oxidant, stirring and reacting for 4-10 days at the temperature of 0-5 ℃, and performing centrifugal cleaning for several times after full reaction to obtain a conductive polymer; the mass ratio of the conductive polymer monomer to the oxidant is 1: 1-20; the oxidant is one of ferric trichloride, ferric nitrate, ferric sulfate and ferric ammonium sulfate; the conductive polymer monomer is one of pyrrole monomer, aniline monomer, thiophene monomer and 5-carboxyl indole monomer.
Step 2: preparing 0.05-10 mg/mL dopamine aqueous solution, and adjusting the pH value to 8-13 by using ammonia water or a triaminomethane buffer solution; and (3) adding the conductive high molecular polymer obtained in the step (1), stirring for 6-48 hours at normal temperature, fully reacting, and cleaning for several times to obtain the polydopamine/conductive high molecular polymer compound.
And step 3: preparing a metal ion salt solution with the mass concentration of 0.1-1% and an organic ligand solution with the mass concentration of 0.1-2%; the metal ion salt is one of zinc nitrate, zinc acetate and zinc acetate; the organic ligand is one of benzimidazole, 2-methylimidazole and 4, 5-dichloroimidazole; the solvent in the metal ion salt solution and the organic ligand solution is one of methanol and N, N-dimethylformamide.
And 4, step 4: adding the polydopamine/conductive high-molecular polymer compound prepared in the step (2) into a metal ion salt solution, uniformly mixing, and adding an organic ligand solution; stirring and reacting for 6-24 hours at normal temperature, after full reaction, centrifugally cleaning the solution for a plurality of times to obtain the metal organic framework/polydopamine/conductive high polymer compound.
And 5: dispersing the metal organic framework/polydopamine/conductive high molecular polymer compound in deionized water to obtain an aqueous solution with the mass concentration of the metal organic framework/polydopamine/conductive high molecular polymer compound being 0.1-1%, and adding a monomer or double-bonded biomacromolecule solution with the mass concentration of 0.5-20%; adding initiator or photoinitiator, cross-linking agent and assistant, and static polymerizing at normal temperature or under illumination condition to form the required hydrogel.
The monomer is one of acrylamide, acrylic acid, methacrylic acid, dimethylaminoethyl methacrylate and methacrylamide; the double-bonded biomacromolecule is one or the combination of two or more of double-bonded hyaluronic acid, double-bonded gelatin, double-bonded chitosan, double-bonded sodium alginate and double-bonded chondroitin sulfate; the mass concentration of the initiator or the photoinitiator is 0.05-20%, the mass concentration of the cross-linking agent is 0.01-0.1%, and the mass concentration of the auxiliary agent is 0.01-0.1%; the initiator is one of ammonium persulfate, potassium persulfate and sodium persulfate; the photoinitiator is one of Irgacure2959, Irgacure500, Irgacure127, TPO and ultraviolet photoinitiator 184/1173/907; the cross-linking agent is one of N, N-methylene diacrylamide and polyethylene glycol dimethacrylate; the assistant is N, N, N ', N' -tetramethyl diethylamine.
The prepared conductive hydrogel can be used for preparing a drug carrier or a bioelectrode.
When the compound is used as a drug carrier, drugs with the concentration of 1 g/L-5 g/L, any one of penicillin, nifedipine, dexamethasone, dimethylbis (ARC) hydrochloride and isoniazid, are added into the organic ligand solution in the step 3.
When the hydrogel prepared by the invention is used as a carrier of the slow-release growth factor, after the hydrogel is obtained in the step 5, the hydrogel is washed by phosphate buffer solution, sodium chloride solution or water, and then dehydrated by ethanol solution with volume concentration of 40-99%; the operations of cleaning and dehydration are carried out for a plurality of times; and then transferring the hydrogel to a phosphate buffer solution, a sodium chloride solution or water with the concentration of the growth factor of 0.01-0.2 mu g/ml, and swelling to obtain the hydrogel.
The growth factor is one of the following growth factors, transforming growth factor: TGF-beta 1, TGF-beta 2, or TGF-beta 3; bone morphogenetic protein BMP-2 or BMP-7; insulin growth factors IGF-I or IGF-II.
Example 1
A preparation method of a conductive hydrogel comprises the following steps:
A. preparation of polydopamine/poly 3, 4-ethylenedioxythiophene complex
266 mu L of 3, 4-ethylenedioxythiophene monomer is dissolved in 30mL of absolute ethyl alcohol to obtain a solution with the mass concentration of 3, 4-ethylenedioxythiophene monomer being 1.5%; adding 7g of ferric trichloride into the solution, and stirring and reacting for 5 days at the temperature of 0-5 ℃; centrifugally cleaning the reacted solution for 3 times by using deionized water to obtain poly (3, 4-ethylenedioxythiophene) particles; dissolving dopamine in deionized water to obtain a solution with the dopamine concentration of 0.5mg/mL, and adjusting the pH of the solution to 8.5 by using ammonia water; then, adding the poly 3, 4-ethylenedioxythiophene particles into the solution, stirring for 12 hours at normal temperature, and cleaning for several times to obtain the polydopamine/poly 3, 4-ethylenedioxythiophene compound.
B. Preparation of ZIF-8/polydopamine/poly 3, 4-ethylenedioxythiophene compound
Dissolving 50mg of zinc nitrate in 5mL of methanol to obtain a solution with the mass concentration of the zinc nitrate being 1.26%; dissolving 80mg of 2-methylimidazole in 5mL of methanol to obtain a solution with the mass concentration of 2-methylimidazole, and adding isoniazide into a mixed solution formed by the 2-methylimidazole solution, wherein the concentration of isoniazide in the mixed solution is 3 g/L; adding the polydopamine/poly 3, 4-ethylenedioxythiophene compound into a zinc nitrate solution; after uniformly mixing, adding a mixed solution of 2-methylimidazole and isoniazid, stirring for reaction for 12 hours, and then washing the solution for 3 times by using deionized water to obtain a ZIF-8/polydopamine/poly 3, 4-ethylenedioxythiophene compound; and dispersing the compound in deionized water to obtain a solution with the mass concentration of 10 mg/mL.
C. Preparation of hydrogel:
taking 10 mLZIF-8/polydopamine/poly-3, 4-ethylenedioxythiophene compound water solution, adding 2.6g of acrylamide, then adding 0.26g of ammonium persulfate, 300 mu L of 0.001g/mL of N, N-methylene-bisacrylamide and 20 mu L of N, N, N ', N' -tetramethyl-diethylamine, and then carrying out static polymerization on the solution at normal temperature to form hydrogel.
FIG. 1 is an SEM image of the ZIF-8/polydopamine/poly-3, 4-ethylenedioxythiophene complex obtained in step B of the present invention, from which it can be seen that ZIF-8 is tightly bound to polydopamine/poly-3, 4-ethylenedioxythiophene.
FIG. 2 is a graph comparing the electrical conductivity of poly 3, 4-ethylenedioxythiophene hydrogel (PEDOT-PAM), polydopamine/poly 3, 4-ethylenedioxythiophene hydrogel (PEDOT-PDA-PAM), and ZIF-8/polydopamine/poly 3, 4-ethylenedioxythiophene composite conductive hydrogel (PEDOT-PDA-MOF-PAM); the poly 3, 4-ethylenedioxythiophene hydrogel is prepared by the poly 3, 4-ethylenedioxythiophene particles obtained in the step A through the step C; and D, preparing the polydopamine/poly 3, 4-ethylenedioxythiophene hydrogel from the polydopamine/poly 3, 4-ethylenedioxythiophene compound in the step A by the step C.
From FIG. 2 it can be seen that the conductivity of PEDOT-PDA-MOF-PAM is significantly higher than that of the other two hydrogels; the addition of ZIF-8 obviously improves the conductivity of the hydrogel.
Example 2
A. Preparation of polydopamine/polypyrrole complexes
Dissolving 190 mu L of pyrrole monomer in 40mL of absolute ethyl alcohol to obtain a solution with the mass concentration of the pyrrole monomer being 0.58%; adding 5g of ferric sulfate into the solution, and stirring and reacting for 3 days at the temperature of 0-5 ℃; centrifugally cleaning the reacted solution for 3 times by using deionized water to obtain polypyrrole granules; dissolving dopamine in deionized water to obtain a solution with the dopamine concentration of 0.4mg/mL, and adjusting the pH of the solution to 8.5 by using a triaminomethane buffer solution; then, polypyrrole granules are added into the solution, stirred for 12 hours at normal temperature, and washed for several times to obtain the polydopamine/polypyrrole compound.
B. Preparation of ZIF-7/polydopamine/polypyrrole complex
Dissolving zinc acetate in N, N-dimethylformamide to obtain a solution with the mass concentration of the zinc acetate being 2.15%; dissolving benzimidazole in methanol to obtain a solution with the mass concentration of benzimidazole being 3.21%; adding a polydopamine/polypyrrole complex to a solution of zinc acetate; after uniformly mixing, adding a benzimidazole solution, stirring for reacting for 24 hours, and then centrifugally cleaning the solution for 3 times by using deionized water to obtain a ZIF-7/polypyrrole/polydopamine compound; and dispersing the compound in deionized water to obtain a solution with the mass concentration of 5 mg/mL.
C. Preparation of hydrogel:
taking 10mL of ZIF-7/polydopamine/polypyrrole compound solution, and adding double-bonded gelatin as a monomer into the solution, wherein the concentration of the double-bonded gelatin is 0.2 g/mL; adding a photoinitiator 2959 accounting for 3.4 percent of the double-bonded gelatin by mass, stirring until the mixture is completely dissolved, and stirring the solution at the wavelength of 365nm and the power of 15mW/cm2Under ultraviolet lamp for 10 minutes to form hydrogel. Washing the hydrogel by using a phosphate buffer solution, and dehydrating the hydrogel by using an ethanol solution with the volume concentration of 75%; cleaning and dehydrating for 3 times; then transferring the hydrogel into a phosphate buffer solution with the concentration of transforming growth factor TGF-beta 3 being 0.02 mu g/ml, and swelling to obtain the hydrogel.
Example 3
A. Preparation of polydopamine/polyaniline compound
Dissolving 380 mu L of aniline monomer in 40mL of absolute ethyl alcohol to obtain a solution with the mass concentration of the aniline monomer being 0.58%; adding 10g of ferric nitrate into the solution, and stirring and reacting for 4 days at the temperature of 0-5 ℃; centrifugally cleaning the reacted solution for 3 times by using deionized water to obtain polyaniline particles; dissolving dopamine in deionized water to obtain a solution with the dopamine concentration of 0.5mg/mL, and adjusting the pH of the solution to 8.5 by using a triaminomethane buffer solution; then adding polyaniline particles into the solution, stirring for 12 hours at normal temperature, and cleaning for several times to obtain the polydopamine/polyaniline compound.
B. Preparation of ZIF-71/polydopamine/polyaniline compound
Dissolving 60mg of zinc nitrate in 10mL of methanol, and adding the polydopamine/polyaniline compound into a zinc nitrate solution; after uniformly mixing, adding 85mg of 4, 5-dichloroimidazole and dexamethasone with the concentration of 3g/L, stirring for 23 hours at normal temperature, and washing the solution for 3 times by using deionized water to obtain a ZIF-71/polydopamine/polyaniline compound; and dispersing the compound in deionized water to obtain a solution with the mass concentration of 5 mg/mL.
C. Preparation of hydrogel:
dissolving 10 mLZIF-71/polydopamine/polyaniline compound in water, and adding double-bonded sodium alginate into the solution, wherein the concentration of the double-bonded sodium alginate is 0.2 g/ml; adding a photoinitiator 2959 accounting for 1.5 percent of double-bonded sodium alginate by mass, stirring until the photoinitiator is completely dissolved, and stirring the solution at a wavelength of 365nm and a power of 5mW/cm2 Under an ultraviolet lamp for 5 minutes to form hydrogel.
Example 4
A. Preparation of polydopamine/poly 3, 4-ethylenedioxythiophene complex
760 mu L of 3, 4-ethylenedioxythiophene monomer is dissolved in 150mL of absolute ethyl alcohol to obtain a solution with the mass concentration of the 3, 4-ethylenedioxythiophene monomer being 0.86%; adding 20g of ammonium ferric sulfate into the solution, stirring and reacting for 7 days at 0-5 ℃, and centrifugally cleaning the reacted solution for 3 times by using deionized water to obtain poly (3, 4-ethylenedioxythiophene) particles; dissolving dopamine in deionized water to obtain a solution with the dopamine concentration of 0.5mg/mL, and adjusting the pH of the solution to 8.5 by using ammonia water; then, adding the poly 3, 4-ethylenedioxythiophene particles into the solution, stirring for 12 hours at normal temperature, and cleaning for several times to obtain the polydopamine/poly 3, 4-ethylenedioxythiophene compound.
B. Preparation of ZIF-7/polydopamine/poly 3, 4-ethylenedioxythiophene compound
Dissolving 110mg of zinc acetate in 5mL of methanol to obtain a solution with the mass concentration of the zinc acetate of 2.77%; 160mg of benzimidazole was dissolved in 5mL of methanol to obtain a solution with a benzimidazole mass concentration of 4.04%; adding the polydopamine/poly 3, 4-ethylenedioxythiophene compound into a solution of zinc acetate; after uniformly mixing, adding a benzimidazole solution, stirring for reacting for 16 hours, and then centrifugally cleaning the solution for 3 times by using deionized water to obtain a ZIF-7/polydopamine/poly 3, 4-ethylenedioxythiophene compound; and dispersing the compound in deionized water to obtain a solution with the mass concentration of 10 mg/mL.
C. Preparation of hydrogel:
taking 10mL of aqueous solution of a ZIF-7/polydopamine/poly 3, 4-ethylenedioxythiophene compound, and adding double-bonded sodium alginate into the aqueous solution; the concentration of the double-bonded sodium alginate is 0.2g/ml, a photoinitiator TPO accounting for 1.5 percent of the double-bonded sodium alginate by mass percent is added, the mixture is stirred to be completely dissolved, and the solution is stirred at the wavelength of 365nm and the power of 5mW/cm2Under ultraviolet light for 15 minutes to form hydrogel. Cleaning the hydrogel by using a sodium chloride solution, and dehydrating the hydrogel by using an ethanol solution with the volume concentration of 50%; cleaning and dehydrating for 3 times; then transferring the hydrogel into a sodium chloride solution with the concentration of bone morphogenetic protein BMP-7 being 0.1 mu g/ml, and swelling to obtain the bone morphogenetic protein.
Example 5
A. Preparation of polydopamine/poly 3, 4-ethylenedioxythiophene complex
266 mu L of 3, 4-ethylenedioxythiophene monomer is dissolved in 30mL of absolute ethyl alcohol to obtain a solution with the mass concentration of 3, 4-ethylenedioxythiophene monomer being 1.5%; adding 7g of ammonium ferric sulfate into the solution, and stirring and reacting for 6 days at the temperature of 0-5 ℃; centrifugally cleaning the reacted solution for 3 times by using deionized water to obtain poly (3, 4-ethylenedioxythiophene) particles; dissolving dopamine in deionized water to obtain a solution with the dopamine concentration of 0.2mg/mL, and adjusting the pH of the solution to 9 by using ammonia water; then, adding the poly 3, 4-ethylenedioxythiophene particles into the solution, stirring for 14 hours at normal temperature, and cleaning for several times to obtain the polydopamine/poly 3, 4-ethylenedioxythiophene compound.
B. Preparation of ZIF-8/polydopamine/poly 3, 4-ethylenedioxythiophene compound
Dissolving 55mg of zinc nitrate in 5mL of methanol to obtain a solution with the mass concentration of the zinc nitrate being 1.3%; dissolving 80mg of 2-methylimidazole in 5mL of methanol to obtain a solution with the mass concentration of 2-methylimidazole, and adding penicillin into the solution to form a mixed solution, wherein the concentration of the penicillin in the mixed solution is 5 g/L; adding the polydopamine/poly 3, 4-ethylenedioxythiophene compound into a zinc nitrate solution; after uniformly mixing, adding a mixed solution of 2-methylimidazole and penicillin, stirring for reacting for 16 hours, and then washing the solution for 3 times by using deionized water to obtain a ZIF-8/polydopamine/poly 3, 4-ethylenedioxythiophene compound; and dispersing the compound in deionized water to obtain a solution with the mass concentration of 7 mg/mL.
C. Preparation of hydrogel:
taking 10 mLZIF-8/polydopamine/poly-3, 4-ethylenedioxythiophene compound water solution, and adding 2.6g of methacrylamide; then, 0.26g of ammonium persulfate, 400. mu.L of 0.001g/mL of N, N-methylenebisacrylamide and 25. mu.L of N, N, N ', N' -tetramethyldiethylamine were added, and then the solution was allowed to stand at ordinary temperature to polymerize to form a hydrogel.
Example 6
A. Preparation of dopamine/polypyrrole complexes
Dissolving 210 mu L of pyrrole monomer in 40mL of absolute ethyl alcohol to obtain a solution with the mass concentration of the pyrrole monomer being 0.6%; adding 7g of ammonium ferric sulfate into the solution, and stirring and reacting for 3 days at the temperature of 0-5 ℃; centrifugally cleaning the reacted solution for 3 times by using deionized water to obtain polypyrrole granules; dissolving dopamine in deionized water to obtain a solution with the dopamine concentration of 0.6mg/mL, and adjusting the pH of the solution to 8 by using ammonia water; then, adding polypyrrole granules into the solution, stirring for 10 hours at normal temperature, and cleaning for several times to obtain the polydopamine/polypyrrole compound.
B. Preparation of ZIF-7/polydopamine/polypyrrole complex
Dissolving zinc acetate in N, N-dimethylformamide to obtain a solution with the mass concentration of the zinc acetate being 3%; dissolving benzimidazole in methanol to obtain a solution with the mass concentration of benzimidazole being 4.5%; adding the polydopamine/polypyrrole compound into a solution of zinc acetate; after uniformly mixing, adding a benzimidazole solution, stirring for reacting for 24 hours, and then centrifugally cleaning the solution for 3 times by using deionized water to obtain a ZIF-7/polypyrrole/polydopamine compound; and dispersing the compound in deionized water to obtain a solution with the mass concentration of 6 mg/mL.
C. Preparation of hydrogel:
taking 10mL of ZIF-7/polydopamine/polypyrrole compound solution, and adding double-bonded hyaluronic acid serving as a monomer into the solution; the concentration of the double-bonded hyaluronic acid is 0.2g/ml, and a photoinitiator 2959 accounting for 5% of the mass of the double-bonded hyaluronic acid is added; stirring to dissolve completely, and adding the solution at 365nm with power of 15mW/cm2Under ultraviolet light for 15 minutes to form hydrogel. Washing the hydrogel by using water, and dehydrating the hydrogel by using an ethanol solution with the volume concentration of 75%; cleaning and dehydrating for 3 times; then transferring the hydrogel into an aqueous solution of insulin growth factor IGF-II with the concentration of 0.02 mu g/ml, and swelling to obtain the hydrogel.
Example 7
A. Preparation of polydopamine/polyaniline compound
Dissolving 400 mu L of aniline monomer in 40mL of absolute ethyl alcohol to obtain a solution with the mass concentration of the aniline monomer being 0.6%; adding 7g of ferric sulfate into the solution, and stirring and reacting for 4 days at the temperature of 0-5 ℃; centrifugally cleaning the reacted solution for 3 times by using deionized water to obtain polyaniline particles; dissolving dopamine in deionized water to obtain a solution with the dopamine concentration of 0.7mg/mL, and adjusting the pH of the solution to 8.5 by using a triaminomethane buffer solution; then adding polyaniline particles into the solution, stirring for 12 hours at normal temperature, and cleaning for several times to obtain the polydopamine/polyaniline compound.
B. Preparation of ZIF-7/polydopamine/polyaniline compound
Dissolving 70mg of zinc nitrate in 15mL of methanol, and adding the polydopamine/polyaniline compound into a zinc nitrate solution; after uniformly mixing, adding 70mg of benzimidazole and nifedipine, wherein the concentration of the nifedipine in the mixed solution is 2g/L, stirring for 14 hours at normal temperature, and then washing the solution for 3 times by using deionized water to obtain a ZIF-7/polydopamine/polyaniline compound; and dispersing the compound in deionized water to obtain a solution with the mass concentration of 5 mg/mL.
C. Preparation of hydrogel:
dissolving 10 mLZIF-7/polydopamine/polyaniline compound in water, and adding double-bonded chondroitin sulfate into the solution; the concentration of the double-bonded chondroitin sulfate is 0.3g/ml, and a photoinitiator 2959 accounting for 2.5 percent of the mass of the double-bonded chondroitin sulfate is added; stirring to dissolve completely, and adding the solution at a wavelength of 365nm and a power of 10mW/cm2 Under ultraviolet lamp for 10 minutes to form hydrogel.
The invention grafts a layer of polydopamine on the surface of a conductive high molecular polymer, and the polydopamine induces a metal organic framework compound to grow on the surface of the conductive high molecular polymer to obtain a metal organic framework/polydopamine/conductive high molecular polymer compound; and mixing the compound with monomer or double-bonded biomacromolecule solution, and polymerizing to form hydrogel.
By grafting polydopamine on the surface of the conductive high-molecular polymer and utilizing chelation of the polydopamine and metal ion sites exposed on MOFs, the growth of a metal-organic framework on the surface of the conductive high-molecular polymer is further induced, so that a metal-organic framework/conductive high-molecular polymer compound is obtained, the unique pore structure of the metal-organic framework can increase the circulation rate of electrons, and the conductivity and the electrochemical activity of the hydrogel are synergistically improved together with the conductive high-molecular polymer in the hydrogel; the metal organic framework has good drug-loading capacity due to the unique macropore and large specific surface area structure; the poly-dopamine grafted on the surface of the conductive high molecular polymer can be combined with some groups on the medicine, and also has a certain medicine carrying capacity, and the poly-dopamine and the groups have synergistic effect, so that the medicine carrying efficiency and the immobilized bioactive growth factor of the hydrogel can be increased, and the cartilage repair capacity can be promoted; compounding polydopamine, conductive high molecular polymer and a metal organic framework; the metal organic framework has an unstable structure in a water environment and is easy to hydrolyze and collapse, and the combination of the former two and the metal organic framework increases the stability of the structure in the water phase; the compound is doped into the hydrogel, the three-dimensional network structure in the hydrogel can delay the disintegration rate of the metal-organic framework structure, and the two have synergistic effect and have the effects of stabilizing the metal-organic framework structure and delaying the disintegration rate of the metal-organic framework structure.

Claims (7)

1. A preparation method of conductive hydrogel capable of slowly releasing drugs and factors is characterized by comprising the following steps:
step 1: preparing a conductive high molecular monomer solution with the mass concentration of 0.04-2%, adding an oxidant, and fully reacting to obtain a conductive high molecular polymer;
the conductive polymer monomer is one of pyrrole monomer, aniline monomer, thiophene monomer and 5-carboxyl indole monomer;
step 2: preparing a dopamine aqueous solution with the concentration of 0.05-10 mg/mL, and adjusting the pH value to 8-13; adding the conductive high molecular polymer obtained in the step (1), and fully reacting to obtain a polydopamine/conductive high molecular polymer compound;
and step 3: preparing a metal ion salt solution with the mass concentration of 0.1-1% and an organic ligand solution with the mass concentration of 0.1-2%;
the metal ion salt is one of zinc nitrate and zinc acetate; the organic ligand is one of benzimidazole, 2-methylimidazole and 4, 5-dichloroimidazole;
and 4, step 4: adding the polydopamine/conductive high polymer compound prepared in the step (2) into a metal ion salt solution, uniformly mixing, and adding a mixed solution of a medicine and an organic ligand; after full reaction, a compound of a metal organic framework/polydopamine/conductive high molecular polymer carrying a medicament is obtained;
and 5: preparing an aqueous solution with the mass concentration of 0.1-1% of a metal organic framework/polydopamine/conductive high molecular polymer compound, and adding a monomer or double-bonded biomacromolecule solution with the mass concentration of 0.5-20%; adding additives and polymerizing to form the needed hydrogel;
the monomer is one of acrylamide, acrylic acid, methacrylic acid, dimethylaminoethyl methacrylate and methacrylamide; the double-bonded biomacromolecule is one or the combination of two or more than two of double-bonded hyaluronic acid, double-bonded gelatin, double-bonded chitosan, double-bonded sodium alginate and double-bonded chondroitin sulfate.
2. The preparation method of the conductive hydrogel capable of slowly releasing the drugs and factors according to claim 1, wherein the mass ratio of the conductive polymer monomer to the oxidant in the step 1 is 1: 1-20; the oxidant is one of ferric trichloride, ferric nitrate, ferric sulfate and ferric ammonium sulfate.
3. The method for preparing the conductive hydrogel capable of slowly releasing the drugs and factors according to claim 1, wherein the solvent in the metal ion salt solution and the organic ligand solution in the step 3 is one of methanol and N, N-dimethylformamide.
4. The method for preparing the conductive hydrogel capable of slowly releasing the drugs and the factors according to claim 1, wherein the additives in the step 5 comprise one of an initiator or a photoinitiator, a cross-linking agent and an auxiliary agent; the mass concentration of the initiator or the photoinitiator is 0.05-20%, the mass concentration of the cross-linking agent is 0.01-0.1%, and the mass concentration of the auxiliary agent is 0.01-0.1%; the initiator is one of ammonium persulfate, potassium persulfate and sodium persulfate.
5. The method for preparing the conductive hydrogel capable of slowly releasing the drugs and the factors according to claim 4, wherein the photoinitiator is one of Irgacure2959, Irgacure500, Irgacure127, TPO and an ultraviolet photoinitiator 184/1173/907; the cross-linking agent is one of N, N-methylene diacrylamide and polyethylene glycol dimethacrylate; the assistant is N, N, N ', N' -tetramethyl diethylamine.
6. The application of the conductive hydrogel prepared by the preparation method of the conductive hydrogel capable of slowly releasing the drugs and the factors according to any one of claims 1 to 5, wherein the conductive hydrogel is used for preparing a drug carrier.
7. The application of the conductive hydrogel prepared by the preparation method of the conductive hydrogel capable of slowly releasing the drugs and the factors according to any one of claims 1 to 5, wherein the conductive hydrogel is used for preparing a bioelectrode.
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