CN110194877B

CN110194877B - A kind of nanocomposite hydrogel and its preparation method and use

Info

Publication number: CN110194877B
Application number: CN201910212220.3A
Authority: CN
Inventors: 高勇; 黄伟伟
Original assignee: Xiangtan University
Current assignee: Xiangtan University
Priority date: 2019-03-20
Filing date: 2019-03-20
Publication date: 2021-07-20
Anticipated expiration: 2039-03-20
Also published as: CN110194877A

Abstract

The invention designs a novel multifunctional nano composite hydrogel which has injectability, self-healing property, good mechanical strength, irritation reaction and adhesiveness. The multifunctional nano composite hydrogel is prepared by using a polymer containing diol (PGMA) and a polymer containing phenylboronic acid (PAPBA-stat-PDMA) as precursors and adding a certain amount of polydopamine coated modified nano particles (rGO @ PDA). In an alkaline environment, the hydrogel network can be readily achieved by phenylboronic acid-containing polymer/diol-containing polymer interactions. Compared with pure polymer hydrogel without polydopamine coated modified nano particles (rGO @ PDA), the storage modulus (G') of the obtained nano composite hydrogel is obviously improved, and the nano composite hydrogel has adhesiveness.

Description

Nano composite hydrogel and preparation method and application thereof

Technical Field

The invention relates to hydrogel, in particular to injectable nano-composite hydrogel with pH response and self-repairing property and self-adhesiveness and a preparation method and application thereof, belonging to the field of preparation of biomedical materials.

Background

Hydrogels are three-dimensional network structures composed of hydrophilic polymer chains. It has wide application prospect in the aspects of physical, chemical, biological and highly biocompatible drug release. Despite the many advantages of hydrogels, there are some drawbacks. Such as low mechanical strength, poor mechanical properties, single properties, poor stability, etc. These drawbacks limit the applications of hydrogels in various fields. For these reasons, researchers have designed and developed new hydrogels to overcome the hydrogel deficiencies while imparting some unique properties to the hydrogel. With the improvement of mechanical properties of hydrogels, many strategies for preparing hydrogels have been proposed, including double-network structures, nanocomposites and supramolecular networks. Among them, nanocomposite hydrogels having non-covalently or covalently immobilized nanoparticles are receiving increasing attention due to their simple and effective properties. Nanocomposite hydrogels are prepared by combining nanoparticles with polymer networks like nanoparticles such as carbon-based nanoparticles (carbon nanotubes, graphene, C)₆₀) Polymeric nanoparticles (polymeric nanoparticles, hyperbranched nanoparticles), inorganic/ceramic nanoparticles (silicates, calcium phosphate), metal/metal oxide nanoparticles (gold, silver, ferroferric oxide).

Although the physical properties of the polymer network are improved due to the addition of functionalized nanoparticles, the nanoparticles act as physical fillers in the polymer network and are not covalently incorporated into the resulting material in most studies. We increase mechanical strength and toughness by transferring mechanical forces within the crosslinked network through covalent crosslinks between the polymer and the nanoparticles. Graphene is a two-dimensional (2D) monolayer of sp2 hybridized carbon atoms with excellent electrical, mechanical and thermal properties. Geom and his colleagues discovered graphene in 2004 and won the nobel prize for physics. Since the discovery of graphene, research into graphene has gradually increased from the diverse properties and applications of photoconductive materials in electronics, photovoltaic devices and solar cells, drug delivery and tissue engineering. However, pristine graphene is hydrophobic in nature and has a water contact angle of 95-100 °. To enhance the dispersion effect of graphene, graphene sheets may be treated with a strong oxidant to obtain Graphite Oxide (GO). GO can interact with hydrophilic polymers to form physically or covalently crosslinked networks.

Dopamine belongs to a class of catecholamines with good biocompatibility. It spontaneously polymerizes to Polydopamine (PDA), forming adhesive coatings on a variety of substrates, inspired by the viscous protein nature of marine mussels. The use of dopamine reducing agents enables us to prepare functionalized graphene hydrogels under mild conditions, which is more flexible than previously reported time-consuming hydrothermal methods. PDA-coated chemically reduced graphene oxide (rGO @ PDA) was successfully prepared in this work by a one-step process, taking into account the reductive, self-polymerizing and strong adhesive properties of dopamine.

Disclosure of Invention

Aiming at the problems of low mechanical strength, insufficient toughness and the like of the composite hydrogel in the prior art, the mechanical strength and toughness are increased by transferring mechanical force in a crosslinking network through covalent crosslinking between polymers and nanoparticles. The invention designs a novel multifunctional nano composite hydrogel which has injectability, self-healing property, good mechanical strength, irritation reaction and adhesiveness. The multifunctional nano composite hydrogel is prepared by using a polymer containing diol (PGMA) and a polymer containing phenylboronic acid (PAPBA-stat-PDMA) as precursors and adding a certain amount of polydopamine coated modified nano particles (rGO @ PDA). In a basic environment, the hydrogel network can be easily achieved by the interaction of the PBA/diol complex. Compared with the pure polymer hydrogel without the poly-dopamine coated modified nano particles (rGO @ PDA), the storage modulus (G') of the obtained nano composite hydrogel is obviously improved, and the nano composite hydrogel has adhesiveness.

The invention aims to provide a nano composite hydrogel, which is prepared by synthesizing two polymers: phenylboronic acid-containing polymers, glycol-containing polymers, plus nanoparticles: coating the modified nanoparticles with polydopamine; the polymer containing phenylboronic acid, the polymer containing glycol and the polydopamine-coated modified nanoparticles are respectively dissolved in an alkaline aqueous solution, and the two polymers and the nanoparticles are blended to obtain gel, so that the nanocomposite hydrogel with pH response, self-repairing property, self-adhesiveness and injectability is provided for the field of biomedical materials. The nano composite hydrogel can be applied to the fields of controllable release of medicines, tissue engineering and the like.

According to a first embodiment provided herein, a nanocomposite hydrogel is provided.

A nanocomposite hydrogel that reacts by: the boric acid group and the diol group are crosslinked through a boric acid ester dynamic covalent bond, and the poly-dopamine-coated nano particle is used as a reinforcing agent to prepare the poly-dopamine-coated nano particle.

In the invention, the nano composite hydrogel is prepared by blending two polymers and nano particles; wherein: the two polymers are a polymer containing phenylboronic acid and a polymer containing glycol, and the nanoparticles are polydopamine-coated modified nanoparticles.

Preferably, the polymer containing phenylboronic acid is a polymer containing hydrophilic units.

Preferably, the hydrophilic unit is one or more of N, N-dimethylacrylamide, N-vinylpyrrolidone, acrylic acid, acrylamide and N-isopropylacrylamide.

Preferably, the diol-containing polymer is a 1, 2-diol-or 1, 3-diol-containing polymer. Preferably one or more of polyethylene glycol, polyvinyl alcohol and poly (glycerol methacrylate).

Preferably, the nano particles are one or more of carbon nano tubes, graphene, nano silicon dioxide and nano clay.

According to a second embodiment provided by the present invention, a method of preparing a nanocomposite hydrogel is provided.

A method of preparing a nanocomposite hydrogel or a method of preparing a nanocomposite hydrogel according to the first embodiment, the method comprising the steps of:

(1) synthesis of polymer containing phenylboronic acid: dissolving a substance containing phenylboronic acid in a solvent, adding a chain transfer agent and an initiator, and reacting to obtain a polymer containing phenylboronic acid;

(2) synthesis of diol-containing polymers: dissolving a substance containing 1, 2-diol or 1, 3-diol in a solvent, adding a chain transfer agent and an initiator, and reacting to obtain a polymer containing diol;

(3) synthesis of poly-dopamine coated modified nanoparticles: dispersing the nano particles in a buffer solution, adding dopamine, stirring and reacting for a period of time, and separating out solids to obtain polydopamine-coated modified nano particles;

(4) preparing the nano composite hydrogel: dissolving the polydopamine-coated modified nanoparticles obtained in the step (3) in a dispersion liquid, adjusting the pH value to be alkaline, and then adding the polymer containing glycol obtained in the step (2) and marking as a mixture I; dissolving the polymer containing the phenylboronic acid obtained in the step (1) in an alkaline solution, and marking as a mixture II; and mixing the mixture I and the mixture II, and stirring for reaction to obtain the nano composite hydrogel.

Preferably, the step (1) is specifically: in the reactor, a substance containing phenylboronic acid (the substance containing phenylboronic acid is a substance containing hydrophilic units, wherein the hydrophilic units are one or more of N, N-dimethylacrylamide, N-vinyl pyrrolidone, acrylic acid, acrylamide and N-isopropylacrylamide) is dissolved in a solvent (the solvent is preferably DMF and H)₂A mixed solvent of O, more preferably DMF and H₂In a mixed solvent of O, DMF and H₂O is 1-100:1), adding a chain transfer agent (preferably EMP) and an initiator (preferably AIBN), discharging oxygen in the reactor (preferably blowing nitrogen into the reactor and then sealing the reactor), reacting at constant temperature (preferably using an oil bath at constant temperature, the reaction temperature is 40-100 ℃, the reaction time is 0.5-6h), stopping the reaction (preferably using liquid nitrogen quenching to stop the reaction), diluting (preferably using DMF), and settling (preferably using diethyl ether to settle) to obtain the polymer containing the phenylboronic acid.

Preferably, the degree of polymerization of the phenylboronic acid-containing polymer is 20 to 1000, preferably 40 to 600, more preferably 50 to 500; the mass ratio of the substance containing the phenylboronic acid to the solvent is 1:1-50, preferably 1:2-30, more preferably 1: 3-20; the molar ratio of chain transfer agent to initiator is 1-50:1, preferably 2-30:1, more preferably 3-20: 1.

Preferably, the step (2) is specifically: dissolving a 1, 2-diol or 1, 3-diol-containing substance (the 1, 2-diol or 1, 3-diol-containing substance is preferably one or more of ethylene glycol, vinyl alcohol and glycerol methacrylate), a chain transfer agent (preferably EMP) and an initiator (preferably AIBN) in a solvent (preferably DMF) in a reactor, discharging oxygen in the reactor (preferably blowing nitrogen into the reactor and then sealing the reactor), reacting at constant temperature (preferably using an oil bath, keeping the temperature of the reaction at 40-100 ℃, and the reaction time at 1-24h), stopping the reaction (preferably using liquid nitrogen quenching), diluting (preferably using DMF), settling (preferably using diethyl ether), and drying (preferably using vacuum drying) to obtain a diol-containing polymer.

Preferably, the degree of polymerization of the diol-containing polymer is from 20 to 1000, preferably from 40 to 600, more preferably from 50 to 500; the mass ratio of the 1, 2-diol or 1, 3-diol-containing substance to the solvent is 1:1-50, preferably 1:2-30, more preferably 1: 3-20; the molar ratio of chain transfer agent to initiator is 1-50:1, preferably 2-30:1, more preferably 3-20: 1.

Preferably, the step (3) is specifically: dispersing nano particles (the nano particles are one or more of carbon nano tubes, graphene, nano silicon dioxide and nano clay) in an alkaline solution (the alkaline solution is preferably Tris-HCl solution, more preferably Tris-HCl solution with the pore size of 0.001-0.1M, pH of 8-10), then adding dopamine solution (preferably dopamine hydrochloride), stirring for reaction (preferably stirring at room temperature for 1-48h, preferably 2-24h), separating out solids (preferably performing suction filtration separation by using an organic membrane, more preferably performing suction filtration by using an organic membrane with the pore size of 100-500 nm), washing (preferably washing by using ethanol), performing suction filtration (preferably performing suction filtration by using an organic membrane, more preferably performing suction filtration by using an organic membrane with the pore size of 100-500 nm), drying (preferably performing vacuum drying), obtaining the polydopamine-coated modified nano-particles.

Preferably, the nanoparticles are dispersed in the alkaline solution, and the concentration of the nanoparticles is 0.1-5mg/mL, preferably 0.3-3 mg/mL; after the dopamine solution is added, the concentration of the dopamine solution in the alkaline solution is 0.1-5mg/mL, preferably 0.5-3 mg/mL.

Preferably, the step (4) is specifically: dissolving the polydopamine-coated modified nanoparticles obtained in the step (3) in a dispersion liquid (preferably an aqueous solution of sodium hydroxide), adjusting the pH value to be alkaline, adding the polymer containing glycol obtained in the step (2), and marking the polymer as a mixture I; dissolving the polymer containing the phenylboronic acid obtained in the step (1) in an alkaline solution (preferably an aqueous solution of sodium hydroxide), and marking the solution as a mixture II; and mixing the mixture I and the mixture II, and stirring for reaction to obtain the nano composite hydrogel.

Preferably, in the mixture I, the content of the polydopamine-coated modified nanoparticles is 0.1-5%, and the content of the polymer containing glycol is 1-20%; mixture II, containing polymer of phenylboronic acid 1-20%; the mixing volume ratio of the mixture I to the mixture II is 0.1 to 10:1, preferably 0.5 to 5:1, more preferably 1 to 2: 1.

Preferably, the phenylboronic acid-containing substance in step (1) is a mixture of acrylamidophenylboronic acid and N-isopropylamidophenylboronic acid, and the molar ratio of acrylamidophenylboronic acid to N-isopropylamidophenylboronic acid is 1:0.1 to 20, preferably 1:0.2 to 10. The polymer containing the phenylboronic acid is an acrylamide phenylboronic acid-N-isopropylacrylamide phenylboronic acid copolymer.

Preferably, the 1, 2-diol or 1, 3-diol-containing substance in step (2) is glycidyl acrylate. The polymer containing glycol is polyglycidyl acrylate.

Preferably, the nanoparticles in step (3) are graphene oxide.

According to a third embodiment provided by the present invention, there is provided a use of a nanocomposite hydrogel.

Use of the nanocomposite hydrogel according to the first embodiment or the nanocomposite hydrogel prepared according to the method of the second embodiment for biomedical materials, tissue engineering materials.

In the invention, firstly, a substance containing phenylboronic acid is subjected to polymerization reaction to synthesize a polymer containing phenylboronic acid; synthesizing a diol-containing polymer by polymerizing a diol-containing substance (preferably, a 1, 2-diol-or 1, 3-diol-containing substance); coating and modifying the nanoparticles with dopamine, and carrying out self-polymerization reaction on the dopamine on the nanoparticles to form polydopamine-coated nanoparticles; then polymerizing the polymer containing phenylboronic acid, the substance containing diol and the polydopamine-coated modified nanoparticles in an alkaline environment; in an alkaline environment, hydroxide ions in the alkaline environment are combined with the polymer containing the phenylboronic acid, so that the polymer containing the phenylboronic acid is negatively charged, and the polymer containing the phenylboronic acid reacts with a substance containing glycol to form a borate dynamic covalent bond; thereby forming a gel; meanwhile, catechol groups on the surfaces of the polydopamine-coated modified nanoparticles can also be combined with boric acid to form borate dynamic covalent bonds, so that the polydopamine-coated modified nanoparticles are also combined on gel, and finally the nano composite hydrogel is obtained.

In the invention, the polymer containing phenylboronic acid, the polymer containing glycol and the dopamine-coated nanoparticle containing glycol are combined through borate dynamic covalent bonds, so that the two polymers and the nanoparticle form an integral structure, namely the nanocomposite hydrogel.

In the invention, the hydrogel formed by the borate dynamic covalent crosslinking network formed by the boric acid group of the phenylboronic acid and the hydroxyl group of the glycol has pH responsiveness, self-repairability and injectability due to the inherent characteristic of the borate dynamic covalent bond. Meanwhile, the nano particles coated and modified by the polydopamine have catechol groups, so that the hydrogel has self-adhesion. Therefore, the nano-composite hydrogel is completely built on the basis of borate dynamic covalent bonds to form the nano-composite hydrogel.

In the invention, the crosslinking density and the mechanical property of the hydrogel can be adjusted by changing the molar ratio of phenylboronic acid to diol groups, namely the blending ratio of the PAPBA-stat-PDMA solution to the PGMA solution, and meanwhile, the content of the added rGO @ PDA can be changed to adjust the mechanical property of the nano composite hydrogel.

In the invention, boric acid groups on the structure of the polymer containing phenylboronic acid are combined with the polymer containing glycol and the polydopamine-coated nano-particles containing catechol groups through borate ester bonds to form the nano-composite hydrogel. In the structure of the nano-composite hydrogel, a polymer containing phenylboronic acid and a polymer containing glycol form a cross-linked network structure skeleton, and the poly-dopamine-coated nano-particles are inlaid in the middle, so that the whole structure of the nano-composite hydrogel comprises a boric acid ester dynamic covalent bond and a catechol group of dopamine, and the nano-composite hydrogel prepared by the method has pH responsiveness, self-repairability, injectability and self-adhesiveness.

According to the nano-composite hydrogel obtained by the invention, a cross-linked network framework is formed through borate dynamic covalent bonds, and meanwhile, the nano-particles coated and modified by polydopamine are combined into the cross-linked network framework, so that the mechanical strength of the nano-composite hydrogel is obviously improved, and the storage modulus (G') of the obtained nano-composite hydrogel is obviously improved.

Compared with the prior art, the technical scheme of the invention has the following beneficial technical effects:

1. the nano-composite hydrogel provided by the invention is crosslinked by phenylboronic acid-diol dynamic covalent bonds, so that the prepared nano-composite hydrogel has pH responsiveness, self-repairability and injectability;

2. according to the invention, the catechol group of dopamine is combined to the hydrogel through the interaction of the nanoparticles and the polymer by the polydopamine-coated modified nanoparticles, so that the prepared nano composite hydrogel has self-adhesiveness;

3. the invention can adjust the crosslinking density and mechanical property of the prepared nano composite hydrogel by adjusting the molar ratio of the polymer containing phenylboronic acid to the polymer containing glycol;

4. the invention can adjust the mechanical property of the prepared nano composite hydrogel by adjusting the content of the added rGO @ PDA.

Drawings

FIG. 1 is a schematic diagram of the formation of a nanocomposite hydrogel according to the invention.

FIG. 2 is a reaction scheme of the present invention for preparing a polymer containing phenylboronic acid.

FIG. 3 is a reaction scheme of the present invention for preparing a polymer containing a diol.

FIG. 4 is a nuclear magnetic characterization of PGMA and PAPBA-stat-PDMA of the present invention;

wherein: FIG. A is a nuclear magnetic representation of PGMA, FIG. B is a nuclear magnetic representation of PAPBA-stat-PDMA, and FIG. c is a terminal group-CH in PGMA₂Partial enlargement of the nuclear magnetic map, map f is the terminal group-CH in PAPBA-stat-PDMA₃Local enlargement of the nuclear magnetic map.

FIG. 5 shows GPC characterization of PGMA (A) and PAPBA-stat-PDMA of the present invention.

FIG. 6 is AEM, TEM, Raman spectra and thermogravimetric characterization of GO and rGO @ PDA of the present invention;

wherein: FIG. A is an AFM characterization of GO; FIG. B is an AFM characterization of rGO @ PDA; FIG. C is TEM characterization of GO; FIG. D is a TEM representation of rGO @ PDA; FIG. E is a Raman spectral characterization of GO and rGO @ PDA; panel F is a thermogravimetric characterization of GO and rGO @ PDA.

FIG. 7 is a schematic representation of the rheological characterization of the nanocomposite hydrogels of the invention.

FIG. 8 is an SEM image of the polymer content and after freeze-drying of the nanocomposite hydrogel of the invention;

FIG. A is an SEM image of sample S1 after freeze-drying; FIG. B is an SEM image of sample S2 after freeze-drying; FIG. C is an SEM image of sample S3 after freeze-drying; FIG. D is an SEM image of sample S4 after freeze-drying; fig. E is an SEM image of sample S5 after freeze-drying. Comparing samples S1 and S2, it is shown that under the condition of certain total polymer content, the modulus (G) and the cross-linking density pore size of the polymer can be changed by changing the proportion of PGMA and PAPBA-stat-PDMA, S3, S4 and S5 are that rGO @ PDA with different contents is added on the basis of S1, the mechanical property (G) of the nano-composite hydrogel is increased along with the increase of the content of rGO @ PDA, but the increase of the content of rGO @ PDA can block the cross-linking of polymer chains, so that the cross-linking pore size is enlarged, which can be proved from SEM images of freeze-dried samples.

FIG. 9 is a graph showing the self-repairing effect of the nanocomposite hydrogel of the present invention.

FIG. 10 is a graph of injectability of nanocomposite hydrogels of the present invention;

wherein: panel B is a stress-strain scan of sample S4; plot C is an oscillation frequency scan of sample S4; plot D is the viscosity versus shear rate for sample S4; fig. E is a schematic injectable sample S4.

FIG. 11 is a pH responsiveness graph of a nanocomposite hydrogel of the present invention;

the specific detection process is that a certain amount of hydrochloric acid is added into the nano composite hydrogel, then the gel disappears, a certain amount of sodium hydroxide is added, then the gel is formed again, and the gel-sol conversion is realized by adding acid and alkali.

FIG. 12 is a graph showing the effect of adhesion of the nanocomposite hydrogel of the present invention;

wherein: a is bonding two aluminum sheets by using nano composite hydrogel; FIG. B is a drawing in which a nano-composite hydrogel is used to bond an aluminum sheet and a glass sheet; panel C two glass sheets were bonded with nanocomposite hydrogel.

Detailed Description

The technical solution of the present invention is illustrated below, and the claimed scope of the present invention includes, but is not limited to, the following examples. (all the raw materials are commercial raw materials, and the purity is analytical grade without special indication)

In accordance with embodiments provided herein, a nanocomposite hydrogel is provided.

A nanocomposite hydrogel that reacts by: boric acid groups and hydroxyl groups are crosslinked through boric acid ester dynamic covalent bonds, and poly-dopamine-coated nanoparticles are used as reinforcing agents to prepare the poly-dopamine-coated nanoparticles.

Example 1

Example 2

A method for preparing a nanocomposite hydrogel having pH response, self-replenishing property, self-adhesive property and injectability, comprising the steps of:

(1) synthesis of polymer containing phenylboronic acid: APBA and GMA monomers, DMF and H₂Adding a mixed solvent of O, a chain transfer agent EMP and an initiator AIBN into a round-bottom flask, sealing the round-bottom flask after blowing nitrogen and discharging oxygen, reacting in an oil bath kettle at constant temperature, stopping reaction after liquid nitrogen quenching after a period of time, diluting with a solvent DMF, and then settling with diethyl ether to obtain a product, and drying the product in vacuum at room temperature;

(2) synthesis of diol-containing polymers: adding a GMA monomer, a chain transfer agent EMP, an initiator AIBN and a solvent DMF into a round-bottom flask, sealing the round-bottom flask after blowing nitrogen and discharging oxygen, reacting in an oil bath kettle at constant temperature, stopping reaction after liquid nitrogen quenching after a period of time, diluting with the solvent DMF, settling with diethyl ether, and drying the obtained product in vacuum at room temperature;

(3) synthesis of poly-dopamine coated modified nanoparticles: ultrasonically dispersing GO into a Tris-HCl buffer solution (with the pH value of 8.5 and the pH value of 0.01M), adding Dopamine (DA) into the Tris-HCl buffer solution, stirring the mixture at room temperature, stopping reaction after a period of time, performing suction filtration, collecting solid obtained by filtration, and performing freeze drying to obtain black blocky solid rGO @ PDA;

(4) preparing the nano composite hydrogel: dissolving PAPBA-stat-PDMA in alkaline water, dissolving PGMA in alkaline rGO @ PDA dispersion liquid, blending the two solutions according to the proportion of 1:1, and slightly stirring to obtain the nano composite hydrogel.

Example 3

(1) PAPBA-stat-PDMA Synthesis: 90mg of EMP (0.4mmol of RAFT group), DMA (3.172g, 32mmol), APBA (1.528g, 8mmol), AIBN (6.56mg, 0.04mmol), 19mL of fresh DMF and 1mLH₂Adding O into a dry round-bottom flask; blowing nitrogen, discharging oxygen in the reactor, sealing the flask,then immerging the mixture into oil bath at 70 ℃; after 2 hours, the polymerization was terminated by liquid nitrogen; after cooling to room temperature, the polymer was diluted with DMF; precipitating the polymer in anhydrous ether to obtain a polymer containing phenylboronic acid;

(2) PGMA Synthesis: 45.0mg of EMP (0.2mmol of RAFT group), GMA (3.2g, 20mmol), AIBN (3.28mg, 0.02mmol), 16mL of fresh DMF was charged to a dry round bottom flask; blowing nitrogen, discharging oxygen in the reactor, sealing the flask, and then immersing in an oil bath at 70 ℃; after 3 hours, the polymerization was terminated by liquid nitrogen. After cooling to room temperature, the polymer was diluted with DMF; precipitating the polymer in anhydrous ether; the obtained product is dried in vacuum at room temperature; obtaining a polymer containing diol;

(3) preparation of rGO @ PDA: GO was prepared by oxidation of natural graphite powder according to the modified Hummers method; performing ultrasonic treatment on GO in Tris-HCl buffer (pH 8.5 and 0.01mol/L) for 1 hour; dopamine (2mg/ml) was then added to the suspension and stirred at room temperature for 4 hours; the suspension is then filtered; washing the filter cake several times with water to remove unreacted dopamine; finally, washing the black solid with ethanol and performing suction filtration by adopting an organic membrane; drying the obtained product under freeze drying; obtaining poly-dopamine coated and modified nano particles;

(4) preparing the nano composite hydrogel: adding the PAPBA-stat-PDMA prepared in step (1) to an aqueous NaOH solution (pH 12.5) and accelerating dissolution to form an aqueous PAPBA-stat-PDMA solution under the action of ultrasonic waves (final pH of solution equals 10); the resulting aqueous PAPBA-stat-PDMA solution is referred to as mixture I; dispersing PGMA prepared in step (2) and rGO @ PDA prepared in step (3) in aqueous NaOH (pH 10), which solution is referred to as mixture II; and mixing the mixture I and the mixture II according to the volume ratio of 1.5:1 at room temperature, and rapidly forming gel under mild stirring to obtain the nano composite hydrogel.

Example 4

(1) PAPBA-stat-PDMA Synthesis:120mg of EMP (0.4mmol of RAFT group), DMA (4.758g, 48mmol), APBA (3.056g, 16mmol), AIBN (9.84mg, 0.06mmol), 320mL of fresh DMF and 20mL of H₂Adding O into a dry round-bottom flask; blowing nitrogen, discharging oxygen in the reactor, sealing the flask, and then immersing in an oil bath at 60 ℃; after 4 hours, the polymerization was terminated by liquid nitrogen; after cooling to room temperature, the polymer was diluted with DMF; precipitating the polymer in anhydrous ether to obtain a polymer containing phenylboronic acid; the polymer containing phenylboronic acid was tested to have a degree of polymerization of 68 and a phenylboronic acid content of about 18%. The structure is PAPBA₁₂-stat-PDMA₅₆The molecular weight is 7800 and the PDI is 1.09.

(2) PGMA Synthesis: 67.5mg of EMP (0.3mmol of RAFT group), GMA (6.4g, 40mmol), AIBN (4.92mg, 0.03mmol), 300mL of fresh DMF was charged to a dry round bottom flask; blowing nitrogen, discharging oxygen in the reactor, sealing the flask, and then immersing in an oil bath at 60 ℃; after 12 hours, the polymerization was terminated by liquid nitrogen. After cooling to room temperature, the polymer was diluted with DMF; precipitating the polymer in anhydrous ether; the obtained product is dried in vacuum at room temperature; obtaining a polymer containing diol; the polymer containing the diol was examined to have a polymerization degree of 170, a molecular weight of 27000g/mol, and PDI of 1.30.

(3) Preparation of rGO @ PDA: GO was prepared by oxidation of natural graphite powder according to the modified Hummers method; performing ultrasonic treatment on GO in a Tris-HCl buffer (the pH value is 9 and the concentration of the GO is 0.05mol/L) for 3 hours, wherein the concentration of the GO in the Tris-HCl buffer is 3 mg/mL; dopamine (3.5 mg/ml dopamine in Tris-HCl buffer) was then added to the suspension and stirred at room temperature for 4 hours; then, adopting an organic membrane with the aperture of 300nm for suction filtration; washing the filter cake several times with water to remove unreacted dopamine; finally, washing the black solid with ethanol and performing suction filtration by adopting an organic membrane; drying the obtained product under freeze drying; obtaining poly-dopamine coated and modified nano particles;

(4) preparing the nano composite hydrogel: adding the PAPBA-stat-PDMA prepared in step (1) to an aqueous NaOH solution (pH 12) and accelerating dissolution to form an aqueous PAPBA-stat-PDMA solution under the action of ultrasonic waves (final pH of the solution is equal to 10); the resulting aqueous PAPBA-stat-PDMA solution is referred to as mixture I; dispersing PGMA prepared in step (2) and rGO @ PDA prepared in step (3) in aqueous NaOH (pH 10), which solution is referred to as mixture II; and mixing the mixture I and the mixture II according to the volume ratio of 2:1 at room temperature, and rapidly forming gel under mild stirring to obtain the nano composite hydrogel.

Example 5

Example 4 was repeated except that in step (1), APBA was replaced with methacrylamidophenylboronic acid, in step (2), polyglyceryl methacrylate was replaced with polyethylene glycol, and in step (3), graphene oxide was replaced with nano-silica.

Example 6

Example 4 was repeated except that APBA was added in an amount of 4.584g, 24 mmol; the amount of DMA added was 6.8g, 42.5 mmol; the polymer containing phenylboronic acid was found to have a degree of polymerization of 86 and a phenylboronic acid content of about 29%. The structure is PAPBA25-stat-PDMA61, the molecular weight is 14500, and the PDI is 1.07.

Example 7

Example 4 was repeated except that GMA was added in an amount of 9.6g, 60 mmol; the polymer containing the diol was found to have a degree of polymerization of 251, a molecular weight of 40000g/mol, and a PDI of 1.37.

Example 8

Example 4 was repeated except that in step (4) mixture I and mixture II were mixed in a volume ratio of 3: 1.

The crosslink density can be judged by pore size in SEM images of the lyophilized aqueous nanocomposite hydrogel. In the SEM, the larger the pore size in the gel network, the smaller the crosslink density, and the smaller the pore size, the higher the crosslink density. Since the crosslinking is the formation of borate bonds, the more densely the two polymer chains are crosslinked, and the smaller and denser the voids (pore diameters) without crosslinking in between are, of course. From the SEM images of the present invention, it can be seen how the nanocomposite gel prepared by the present invention has a better crosslinking density.

The nanocomposite gel prepared by the invention is subjected to rheological characterization test:

the mechanical property in the rheological test is most directly known by the storage modulus (G '), and the storage modulus (G') is indicated in general literature. In the figure, G "represents the loss modulus.

The mechanical properties of hydrogels are generally expressed in terms of modulus in rheological tests. The results are shown in FIG. 7, and it can be seen from the test results that the addition of 0.25% rGO @ PDA to sample S1 increased the storage modulus (G ') from 5.5KPa to 39.8KPa by about 6.3 times, and the addition of 0.50% rGO @ PDA increased the storage modulus (G') from 5.5KPa to 60.3KPa by about 10 times, indicating that the mechanical properties of the hydrogel can be greatly improved by the nanocomposite hydrogel with the addition of a certain amount of rGO @ PDA. Of course, when the rGO @ PDA content increased from 0.5% to 0.75%, the storage modulus (G') did not increase, which may be that excessive rGO @ PDA may be difficult to disperse, hindering the crosslinking of the polymer, resulting in too low a crosslinking density of the hydrogel, resulting in a reduction in the mechanical properties of the hydrogel. The nano-composite hydrogel prepared by the invention has larger storage modulus (G') and excellent mechanical property.

Claims

1. a nano-composite hydrogel is characterized in that: this nano-composite hydrogel is by following reaction: boronic acid group and diol group are cross-linked by boric acid ester dynamic covalent bond, with the nanometer of polydopamine coating. The particle is a reinforcing agent, which is prepared;

Specifically: the nanocomposite hydrogel is prepared by blending two polymers and nanoparticles; wherein: the two polymers are a polymer containing phenylboronic acid and a polymer containing diol, and the nanoparticles are Nanoparticles modified by polydopamine coating; the polymer containing phenylboronic acid is a polymer containing a hydrophilic unit; the polymer containing diol is a polymer containing 1,2-diol or 1,3-diol Polymer; the nanoparticles are one or more of carbon nanotubes, graphene, nano-silica, and nanoclay.

2. The nanocomposite hydrogel according to claim 1, wherein the hydrophilic unit is N,N-dimethylacrylamide, N-vinylpyrrolidone, acrylic acid, acrylamide, N-isopropyl one or more of acrylamides; and/or

The diol-containing polymer is one or more of polyethylene glycol, polyvinyl alcohol, and polyglycerol methacrylate.

3. the method for preparing the described nanocomposite hydrogel of claim 1 or 2, the method comprises the following steps:

(1) Synthesis of a polymer containing phenylboronic acid: Dissolving a substance containing phenylboronic acid in a solvent, adding a chain transfer agent and an initiator, and reacting to obtain a polymer containing phenylboronic acid;

(2) Synthesis of diol-containing polymers: Dissolve a substance containing 1,2-diol or 1,3-diol in a solvent, add a chain transfer agent and an initiator, and carry out the reaction to obtain a diol-containing polymer. polymer;

(3) Synthesis of polydopamine-coated nanoparticles: disperse the nanoparticles in a buffer solution, add dopamine, stir and react for a period of time, separate the solid, and obtain polydopamine-coated nanoparticles;

(4) Preparation of nanocomposite hydrogel: the polydopamine-coated nanoparticles obtained in step (3) are dissolved in the dispersion, the pH value is adjusted to be alkaline, and then the diol-containing diol obtained in step (2) is added. The polymer obtained in step (1) is marked as mixture I; the polymer containing phenylboronic acid obtained in step (1) is dissolved in an alkaline solution and marked as mixture II; mixture I and mixture II are mixed and stirred to react to obtain the nanocomposite hydrogel glue.

4 . The method according to claim 3 , wherein step (1) is specifically as follows: in the reactor, the substance containing phenylboronic acid is dissolved in a mixed solvent of DMF and H ₂ O, and a chain transfer agent and The initiator, the oxygen in the reactor is discharged, and the reaction is held at a constant temperature. The reaction temperature is 40-100 ° C, and the reaction time is 0.5-6 h. The reaction is stopped, diluted and settled to obtain a polymer containing phenylboronic acid.

5. The method according to claim 4, wherein: the substance containing phenylboronic acid is a substance containing a hydrophilic unit; wherein: the hydrophilic unit is N,N-dimethylacrylamide, N- One or more of vinylpyrrolidone, acrylic acid, acrylamide, N-isopropylacrylamide; in the mixed solvent of DMF and _H2O , the volume ratio of DMF and _H2O is 1-100:1, The chain transfer agent is EMP, and the initiator is AIBN; the oxygen in the discharge reactor is to blow nitrogen into the reactor and then seal the reactor; the constant temperature reaction is to use an oil bath constant temperature; the stop reaction In order to stop the reaction by quenching with liquid nitrogen, the dilution was dilution with DMF, and the sedimentation was sedimentation with diethyl ether.

6. method according to claim 5 is characterized in that: the degree of polymerization of the polymer containing phenylboronic acid is 20-1000; the mass ratio of the substance containing phenylboronic acid and solvent is 1:1-50; chain transfer agent and The molar ratio of initiator is 1-50:1.

7. method according to claim 6 is characterized in that: the degree of polymerization of the polymer containing phenylboronic acid is 40-600; the mass ratio of the substance containing phenylboronic acid and solvent is 1:2-30; chain transfer agent and The molar ratio of initiators is 2-30:1.

8. method according to claim 7 is characterized in that: the degree of polymerization of the polymer containing phenylboronic acid is 50-500; the mass ratio of the substance containing phenylboronic acid and solvent is 1:3-20; chain transfer agent and The molar ratio of initiator is 3-20:1.

9. The method according to any one of claims 3-8, wherein step (2) is specifically: in the reactor, the substance containing 1,2-diol or 1,3-diol is , the chain transfer agent and the initiator are dissolved in the solvent, the oxygen in the reactor is discharged, and the reaction is carried out at a constant temperature. The reaction temperature is 40-100 ° C, and the reaction time is 1-24 h. Alcohol polymers.

10 . The method according to claim 9 , wherein the substance containing 1,2-diol or 1,3-diol is one of ethylene glycol, vinyl alcohol, and glycerol methacrylate. 11 . or more; the chain transfer agent is EMP, the initiator is AIBN; the solvent is DMF; the oxygen in the exhaust reactor is to blow nitrogen into the reactor and then seal the reactor; the constant temperature reaction In order to use an oil bath constant temperature; the stop reaction is to use liquid nitrogen quenching to stop the reaction, the dilution is to use DMF dilution, the sedimentation is to use ether sedimentation, and the drying is vacuum drying.

11. The method according to claim 10, characterized in that: the degree of polymerization of the diol-containing polymer is 20-1000; the mass ratio of the substance containing 1,2-diol or 1,3-diol to the solvent is 1:1-50; the molar ratio of chain transfer agent and initiator is 1-50:1.

12. The method according to claim 11, characterized in that: the degree of polymerization of the diol-containing polymer is 40-600; the mass ratio of the substance containing 1,2-diol or 1,3-diol to the solvent is 1:2-30; the molar ratio of chain transfer agent and initiator is 2-30:1.

13. The method according to claim 12, characterized in that: the degree of polymerization of the diol-containing polymer is 50-500; the mass ratio of the substance containing 1,2-diol or 1,3-diol to the solvent is 1:3-20; the molar ratio of chain transfer agent and initiator is 3-20:1.

14. The method according to any one of claims 3-8 and 10-13, wherein step (3) is specifically as follows: dispersing nanoparticles in Tris-HCl solution, then adding dopamine solution, stirring at room temperature , the stirring time is 1-48h, and the solid is separated by suction filtration, and the suction filtration adopts organic membrane suction filtration, washed with ethanol, adopts organic membrane suction filtration, and dried to obtain polydopamine-coated modified nanoparticles.

15. The method according to claim 14, wherein: the nanoparticles are one or more of carbon nanotubes, graphene, nano-silica, and nanoclay; the Tris-HCl solution is 0.001 -0.1M Tris-HCl solution with a pH of 8-10; the dopamine solution is dopamine hydrochloride, the stirring time at room temperature is 2-24h, and the organic membrane suction filtration adopts an organic membrane with a pore size of 100-500 nm Suction filtration, and the drying is vacuum drying.

16. The method according to claim 15, wherein the nanoparticles are dispersed in the alkaline solution, and the concentration of the nanoparticles is 0.1-5 mg/mL; after adding the dopamine solution, the concentration of the dopamine solution in the alkaline solution 0.1-5 mg/mL.

17. The method according to claim 16, wherein the concentration of the nanoparticles is 0.3-3 mg/mL; the concentration of the dopamine solution in the alkaline solution is 0.5-3 mg/mL.

18. The method according to any one of claims 3-8, 10-13, and 15-17, wherein step (4) is specifically: coating the polydopamine obtained in step (3) on the modified nanometer The particles are dissolved in the dispersion, the pH value is adjusted to be alkaline, and then the diol-containing polymer obtained in step (2) is added, which is marked as mixture I; the phenylboronic acid-containing polymer obtained in step (1) is dissolved in alkali Mixture II is marked as mixture II; mixture I and mixture II are mixed, and the reaction is stirred to obtain a nanocomposite hydrogel.

19. The method according to claim 18, characterized in that: the dispersion liquid is an aqueous solution of sodium hydroxide; and the alkaline solution is an aqueous solution of sodium hydroxide.

20. The method according to claim 19, wherein: in the mixture I, the content of the nanoparticles modified by polydopamine coating is 0.1-5%, and the content of the diol-containing polymer is 1-20%; the mixture II, the content of the polymer containing phenylboronic acid is 1-20%; the mixing volume ratio of mixture I and mixture II is 0.1-10:1.

21. The method according to claim 20, wherein the mixing volume ratio of mixture I and mixture II is 0.5-5:1.

22. The method according to claim 21, wherein the mixing volume ratio of mixture I and mixture II is 1-2:1.

23. The purposes of the nanocomposite hydrogel according to claim 1 or 2 or the nanocomposite hydrogel prepared according to any one of the methods in claims 3-22, characterized in that: the nanocomposite hydrogel for biomedical materials.

24. The purposes of the nanocomposite hydrogel according to claim 1 or 2 or the nanocomposite hydrogel prepared according to any one of claims 3-22, characterized in that: the nanocomposite hydrogel Materials for tissue engineering.