CN116785228A - Multi-functional injectable hydrogel with microenvironment response as well as preparation method and application thereof - Google Patents
Multi-functional injectable hydrogel with microenvironment response as well as preparation method and application thereof Download PDFInfo
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- CN116785228A CN116785228A CN202310164899.XA CN202310164899A CN116785228A CN 116785228 A CN116785228 A CN 116785228A CN 202310164899 A CN202310164899 A CN 202310164899A CN 116785228 A CN116785228 A CN 116785228A
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Abstract
The application discloses a micro-environment-responsive multifunctional injectable hydrogel, a preparation method and application thereof, wherein the micro-environment-responsive multifunctional injectable hydrogel is formed by interaction of a functional polymer containing phenylboronic acid and aldehyde groups and a polymer containing hydroxyl groups, the multifunctional injectable hydrogel responds to an acidic condition and/or an active oxygen condition, and the multifunctional injectable hydrogel is loaded with a therapeutic substance, wherein the therapeutic substance is at least one of a hydrophilic drug, a hydrophobic drug, a bioactive substance and nanoparticles. The injectable hydrogels allow for better and faster repair of chronic wounds.
Description
The application discloses a multifunctional injectable hydrogel with a micro-environment response, a preparation method and application thereof, and a divisional application of the multifunctional injectable hydrogel with the micro-environment response, wherein the application date of the original application is 2021, 10 and 28, and the application number of the original application is 202111265582.2.
Technical Field
The application relates to the technical field of biomedical materials, in particular to a multifunctional injectable hydrogel with microenvironment response, a preparation method and application thereof.
Background
Currently, with the increasing problem of global population aging and the increasing incidence of diabetes and obesity, the number of patients with diabetes chronic wounds caused by the problem is rapidly increasing, and the global medical system is brought with a heavy economic burden. It is counted that 1-2% of the population in developed countries is currently suffering from chronic wounds. Diabetic chronic wounds have affected over 650 ten thousand patients in the united states, with about 18% of diabetics over 65 years suffering from incurable foot ulcers, with economic losses of over 250 million dollars per year. In China, the incidence rate of diabetic patients over 50 years old is as high as 8.1%, the annual death rate is as high as 11%, and the death rate of amputees is as high as 22%, so that the diabetic patients become one of the main causes of disability and death of the diabetic patients, and the medical cost is huge. Rapid healing and functional integrity recovery of diabetic chronic wounds remains a significant challenge in the clinic today.
The rapid healing and functional integrity recovery of the chronic wounds of diabetes are seriously affected due to the characteristics of high risk of bacterial infection, unbalanced inflammatory reaction, easy formation of drug-resistant bacterial biomembrane, poor blood vessel regeneration, and loss of the response capability of dermal cells and epidermal cells to repair stimulation. Antibiotics are currently widely used in chronic wound therapy, but in recent years, research indicates that bacterial resistance problems due to antibiotic abuse are forming a serious threat to human health. If bacterial resistance problems are not effectively controlled, by 2050, the cumulative loss of world economy may reach $100 trillion. Hydrogels have received great attention in the biomedical field due to their natural similarity in structure to human tissue, and have been used to treat chronic wounds over the past decades. However, the traditional hydrogel is limited by single function, and the drug release amount can not be adjusted according to the change of the microenvironment of the wound, so that the requirements of different wound healing stages can not be met, the cure rate of the chronic wound is less than 30%, and the recurrence rate is higher.
In recent years, the development of multifunctional intelligent carrier hydrogel and the application of the multifunctional intelligent carrier hydrogel in chronic wound repair are hot spot problems in the fields of tissue engineering and regenerative medicine research, and have great application potential. The intelligent medicine-carrying hydrogel can realize the relevant change of the shape or the characteristic of the hydrogel material according to the single/multiple changes of in-vitro environment (ultraviolet rays, near infrared light radiation, magnetic fields, ultrasound) or wound part microenvironment (pH value, enzyme, reactive Oxygen Species (ROS), temperature, glucose) and the like, through a plurality of different mechanisms such as charge formation, charge conversion, hydrophilic-hydrophobic interaction, combination/dissociation of hydrogen bonds and host guest/host molecules and the like, thereby realizing the response controllable release of medicines. Compared with the traditional medicine-carrying gel, the intelligent response medicine-carrying gel can improve the treatment effect of chronic wound diseases, reduce the administration frequency and reduce the side effect of medicines, and has great clinical transformation prospect. Along with the proposal of the precise medical treatment and precise drug delivery concepts, the multifunctional hydrogel with micro-environment response is designed and constructed in a personalized way aiming at the micro-environment characteristics of chronic wound diseases so as to realize the precise treatment of chronic wounds. It is expected that the advent and maturation of accurate medical technology will significantly improve the patient's experience and effect of diagnosis and treatment, which will also greatly promote the development and clinical transformation of microenvironment responsive multifunctional hydrogels.
On the other hand, the complex microenvironment of chronic wound sites results in four successive and interdigitated healing stages of hemostasis, inflammation, proliferation and remodeling, resulting in different demands for biotherapeutic substances at different healing stages. Therefore, the ideal chronic wound treatment method also needs to adjust the release rates of different treatment substances in time according to the change of the chronic wound healing stage, thereby meeting the requirements of different stages of wound healing on antibiosis, anti-inflammation, cell proliferation promotion, migration, angiogenesis promotion and the like, and finally realizing quick and good healing of the chronic wound.
In summary, aiming at the micro-environmental characteristics and the multi-stage property of the chronic wound site of the diabetes, the multifunctional hydrogel which can rapidly respond to the wound site and can release the therapeutic substances in a procedural way as required is developed, and has important significance for promoting rapid repair of the chronic wound of the diabetes, relieving pains of patients and shortening the course of the diseases.
Disclosure of Invention
Aiming at the recovery problem of chronic wounds, the application provides the multifunctional injectable hydrogel with microenvironment response and the preparation method thereof, which realize better and faster recovery of chronic wounds.
A microenvironmentally responsive multifunctional injectable hydrogel formed by interaction of a functional polymer comprising phenylboronic acid and an aldehyde group with a polymer comprising a hydroxyl group, the multifunctional injectable hydrogel being responsive to acidic conditions and/or reactive oxygen conditions, the multifunctional injectable hydrogel being loaded with a therapeutic substance, the therapeutic substance being at least one of a hydrophilic drug, a hydrophobic drug, a bioactive substance, a nanoparticle.
The functional polymer and the polymer containing hydroxyl form hydrogel through reversible covalent bonds between phenylboronic acid and hydroxyl, and the hydrogel disintegrates after being subjected to reversible covalent bond decomposition in response to acidic conditions and/or active oxygen conditions.
The hydrogel has good self-repairing and injectability, and realizes the controllable release of the drug program through a pH and ROS double-response mediated mechanism.
The therapeutic substances loaded in the hydrogel can be combined with a plurality of ways of resisting bacteria, resisting inflammation, promoting cell proliferation, migration, angiogenesis and the like to accelerate the healing of chronic wounds, and have great application potential in the aspect of bacterial infection chronic wound diseases.
The following provides several alternatives, but not as additional limitations to the above-described overall scheme, and only further additions or preferences, each of which may be individually combined for the above-described overall scheme, or may be combined among multiple alternatives, without technical or logical contradictions.
The hydrogel acts on chronic wounds to gradually release the therapeutic substances loaded in the hydrogel, so that the wounds are repaired better.
The substance loaded in the injectable hydrogel is selectively selected from one to a plurality of substances loaded in the hydrogel according to the needs of the actual therapeutic purpose.
Optionally, the therapeutic substance is at least two of hydrophilic drugs, hydrophobic drugs, bioactive substances and nanoparticles.
The chronic wound part of diabetes has complicated microenvironment, and the healing process presents the characteristics of multistage, load two kinds of therapeutic substances simultaneously on the hydrogel, release corresponding therapeutic substance according to the change of microenvironment, realize the procedural release of different therapeutic substances to satisfy the required therapeutic substance of different stages of wound healing, reach and collect multiple functions in an organic whole and realize diabetes chronic infection wound faster, better demand of restoration in coordination.
Optionally, the therapeutic substance is at least one of a hydrophilic drug, a hydrophobic drug, a nanoparticle, and a bioactive substance.
Optionally, the therapeutic substance is a bioactive substance and a nanoparticle.
Alternatively, the therapeutic substance is recombinant humanized collagen and nanoparticles.
Optionally, the therapeutic substance is recombinant type III humanized collagen and dopamine silver-loaded nanoparticles.
The dopamine silver-loaded nanoparticle is used for resisting bacteria and diminishing inflammation at a skin injury part, the recombinant human type III collagen promotes proliferation and migration of fibroblasts and endothelial cells, the dopamine silver-loaded nanoparticle is released first, and the recombinant human type III collagen interact with each other, so that repair of damaged skin tissues can be effectively promoted.
Optionally, the therapeutic substance is a bioactive substance, a nanoparticle, or a hydrophilic drug.
Optionally, the therapeutic substance is a bioactive substance, a nanoparticle, or a hydrophobic drug.
Optionally, the therapeutic substance is a bioactive substance, a nanoparticle, a hydrophilic drug, and a hydrophobic drug.
Optionally, the functional polymer is at least one of sodium alginate containing phenylboronic acid and aldehyde groups, chitosan, gelatin, hyaluronic acid, carboxymethyl cellulose, dextran, methylcellulose, starch, cyclodextrin, gum dragon, konjac gum, gum arabic, lignin, bletilla striata polysaccharide and modified products thereof.
Under neutral or weak alkaline conditions, the phenylboronic acid and the hydroxyl group form a boron ester bond to form a hydrogel, and under acidic conditions and/or active oxygen conditions, the boron ester bond breaks, the hydrogel disintegrates, and the therapeutic substances in the hydrogel are released.
In the present application, natural polymers are understood to include modified products thereof, i.e., hyaluronic acid includes unmodified hyaluronic acid as well as modified products of hyaluronic acid, and similarly, chitosan, gelatin, sodium alginate, hyaluronic acid, heparin, carboxymethyl cellulose, dextran, methyl cellulose, starch, cyclodextrin, gum tragacanth, konjac, gum arabic, lignin, and bletilla striata polysaccharide also include their corresponding modified products, and the modified products themselves do not adversely affect the formation and disintegration of hydrogels.
Optionally, the hydroxyl-containing polymer is at least one of polyvinyl alcohol, sodium alginate, hyaluronic acid, starch, cellulose (such as carboxymethyl cellulose, methyl cellulose), gum tragacanth, konjac gum, gum arabic, lignin, dextran, cyclodextrin, and rhizoma Bletillae polysaccharide.
Optionally, the bioactive substance is at least one of recombinant humanized collagen, animal collagen, amino acid polypeptide, non-collagen, elastin, proteoglycan, and aminoglycan.
Optionally, the bioactive substance is recombinant humanized collagen.
Optionally, the bioactive substance is at least one of recombinant type I humanized collagen, recombinant type III humanized collagen, and recombinant type XVII humanized collagen.
Optionally, the bioactive substance is recombinant type III humanized collagen.
Alternatively, the nanoparticles may take various forms, such as gels, micelles, metallic nanomaterials, and the like.
Optionally, the nanoparticle is a dopamine silver-loaded nanoparticle.
Optionally, the hydrophobic drug is at least one of ibuprofen, acetaminophen, curcumin and indomethacin.
Optionally, the hydrophobic drug is assembled into drug-loaded nano-micelle loaded in the hydrogel by taking the amphiphilic polymer as a carrier.
Use of a multifunctional injectable hydrogel responsive to said microenvironment in the repair of skin lesions.
A preparation method of a microenvironment-responsive multifunctional injectable hydrogel comprises the following steps:
preparing a functional polymer containing phenylboronic acid and aldehyde groups;
and mixing a therapeutic substance, a functional polymer and a polymer containing hydroxyl groups to obtain the hydrogel, wherein the therapeutic substance is at least one of hydrophilic drugs, hydrophobic drugs, bioactive substances and nanoparticles.
The polymer containing hydroxyl groups contains a plurality of hydroxyl groups, and the functional polymer and the polymer containing hydroxyl groups can form gel after being mixed.
The following provides several alternatives, but not as additional limitations to the above-described overall scheme, and only further additions or preferences, each of which may be individually combined for the above-described overall scheme, or may be combined among multiple alternatives, without technical or logical contradictions.
Optionally, the preparation of the functional polymer adopts one of the following methods:
The first preparation method comprises the following steps:
step a1, oxidizing a polymer containing amino and hydroxyl to obtain a polymer containing amino and aldehyde groups;
step a2, reacting a polymer containing amino and aldehyde groups with phenylboronic acid containing carboxyl and/or amino to obtain the functional polymer;
the second preparation method comprises the following steps:
step b1, oxidizing a polymer containing carboxyl and hydroxyl to obtain a polymer containing carboxyl and aldehyde groups;
and b2, reacting the polymer containing carboxyl and aldehyde groups with phenylboronic acid containing hydroxyl and/or amino groups to obtain the functional polymer.
Both preparation methods can introduce phenylboronic acid groups into the functional polymer, and can be carried out through amidation reaction of amino groups and carboxyl groups, esterification reaction of hydroxyl groups and carboxyl groups, and Schiff base reaction of aldehyde groups and amino groups, so that the polymer contains amino groups, aldehyde groups or hydroxyl groups, and phenylboronic acid contains amino groups or carboxyl groups, and phenylboronic acid groups can be introduced into the polymer.
The functional polymer has a plurality of groups, e.g., amino, aldehyde, hydroxyl, carboxyl groups, present therein, and the hydrogel is formed based on at least one of the following interactions between the groups:
a. phenylboronic acid and hydroxy;
b. Aldehyde groups and amino groups.
Alternatively, the steps a1 and b1 are performed at 30 to 40 ℃, and the steps a2 and b2 are performed at 30 to 40 ℃.
Optionally, the preparation of the functional polymer adopts one of the following methods:
the first preparation method comprises the following steps:
step a1, after the polymer containing amino and hydroxyl is dissolved, reacting for 2-9 hours at 30-40 ℃ under the action of an oxidant to prepare the polymer containing amino and hydroxyl;
step a2, after the polymer containing amino and aldehyde groups is dissolved, reacting the polymer with phenylboronic acid containing carboxyl and/or amino at the temperature of 30-40 ℃ for 12-36h to obtain the functional polymer;
the second preparation method comprises the following steps:
step b1, after the polymer containing carboxyl and hydroxyl is dissolved, reacting for 2-9 hours at the temperature of 30-40 ℃ under the action of an oxidant to prepare the polymer containing carboxyl and hydroxyl;
and b2, after the polymer containing carboxyl and aldehyde groups is dissolved, reacting the polymer with phenylboronic acid containing hydroxyl and/or amino groups for 12-36 hours at the temperature of 30-40 ℃ to obtain the functional polymer.
After the reaction of the two preparation methods is finished, proper post-treatment is needed, including dialysis in deionized water, freeze drying and the like, and the obtained functional polymer contains phenylboronic acid and aldehyde groups.
The amount of phenylboronic acid groups in the polymer will affect the formation and dissociation of the hydrogel, and the amount of phenylboronic acid groups introduced is required to be appropriate.
Optionally, in step a1, the mass ratio of the polymer containing amino groups and hydroxyl groups to the oxidizing agent is 10: 3-10: 9, a step of performing the process;
in the step b1, the mass ratio of the polymer containing carboxyl groups and hydroxyl groups to the oxidant is 10: 3-10: 9.
optionally, the oxidant is one of sodium periodate, pyridinium chlorochromate (PCC), potassium permanganate and hydrogen peroxide.
Optionally, in the step a2, the polymer containing amino and aldehyde groups reacts with the phenylboronic acid containing carboxyl under the action of a condensing agent and a catalyst, wherein the mass ratio of the polymer containing amino and aldehyde groups to the phenylboronic acid containing carboxyl, the condensing agent and the catalyst is 7 (4-5): 2-3): 1;
the mass ratio of the polymer containing amino groups and aldehyde groups to the phenylboronic acid containing amino groups is 10 (2-4);
in the step b2, the polymer containing carboxyl and aldehyde groups reacts with phenylboronic acid containing hydroxyl and/or hydroxyl under the action of condensing agent and catalyst, and the mass ratio of the polymer containing carboxyl and aldehyde groups, phenylboronic acid containing hydroxyl and/or hydroxyl, condensing agent and catalyst is 7 (4-5): 2-3): 1;
the mass ratio of the polymer containing carboxyl and aldehyde groups to the phenylboronic acid containing amino is 10 (2-4).
Optionally, the condensing agent is at least one of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, O-benzotriazol-tetramethylurea hexafluorophosphate, benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate and dicyclohexylcarbodiimide.
Optionally, the catalyst is at least one of 4-dimethylaminopyridine, N-hydroxysuccinimide and 1-hydroxybenzotriazole.
Optionally, the preparation method of the functional polymer comprises the following steps:
dissolving the raw materials, reacting for 4 hours at 37 ℃, dialyzing in deionized water for 3 days, and then freeze-drying to prepare a polymer with aldehyde groups; wherein:
the mass ratio of the polymer containing amino and hydroxyl to the oxidant is 10:8, 8;
the mass ratio of the polymer containing carboxyl and hydroxyl to the oxidant is 10:8.
the mass ratio of the polymer containing amino and aldehyde groups to the phenylboronic acid containing carboxyl to the condensing agent to the catalyst is 7:4.5:2.5:1;
the mass ratio of the polymer containing amino groups and aldehyde groups to the phenylboronic acid containing amino groups is 10:3;
the mass ratio of the polymer containing carboxyl and aldehyde groups, the phenylboronic acid containing hydroxyl and/or hydroxyl, the condensing agent and the catalyst is 7:4.5:2.5:1;
the mass ratio of the polymer containing carboxyl groups and aldehyde groups to the phenylboronic acid containing amino groups is 10:3.
Optionally, the nanoparticle is a dopamine silver-loaded nanoparticle, and the preparation method of the dopamine silver-loaded nanoparticle includes:
step 1, preparing dopamine nano particles;
and step 2, mixing the dopamine nano particles with silver nitrate at 0-10 ℃ to obtain the dopamine silver-loaded nano particles.
Optionally, the preparation of the dopamine nanoparticle comprises the following steps:
and slowly adding dopamine hydrochloride into the mixed aqueous solution of ammonia water and ethanol, and reacting for 18-36 h to obtain the dopamine nano particles.
The mass fraction of the ammonia water is 25-28%, the ammonia water, the ethanol and the water are stirred for 0.5-2 h at the temperature of 30-40 ℃ to obtain a mixed aqueous solution of the ammonia water and the ethanol, and then the dopamine hydrochloride is slowly added into the mixed aqueous solution.
After the reaction is finished, the mixture is centrifuged for 8 to 15 minutes at 5000 to 8000 rpm, and the mixture is washed for 3 to 6 times by deionized water, so that the dopamine nanometer particles are obtained.
Optionally, in the mixed aqueous solution of ammonia water and ethanol, the volume ratio of ammonia water, ethanol and water is as follows: 1: 15-30: 35 to 55.
Optionally, the volume ratio of ammonia water, ethanol and water is 2:40:90.
Optionally, the dopamine hydrochloride is added into a mixed aqueous solution of ammonia water and ethanol in the form of an aqueous solution, and the concentration of the dopamine hydrochloride in the aqueous solution of the dopamine hydrochloride is 25-100 mg/mL.
Optionally, in the step 2, the dopamine nano particles and 2-12 mg/mL silver nitrate are mixed for 0.5-2h at the temperature of 0-10 ℃ to obtain the dopamine silver-carrying nano particles.
After the dopamine nano particles and the silver nitrate are mixed, the core is separated for 8-15min at 5000-8000 rpm, and the dopamine silver-loaded nano particles are obtained after the dopamine nano particles are washed for 3-6 times by deionized water.
Optionally, the preparation method of the dopamine silver-loaded nanoparticle comprises the following steps:
step 1, ammonia water, ethanol and deionized water are slightly stirred for 0.5-2h at the temperature of 30-40 ℃, a dopamine hydrochloride aqueous solution is slowly dripped into the mixed solution, the color of the solution immediately turns to light yellow and then gradually turns to dark brown, the reaction is carried out for 18-36 h, centrifugation is carried out for 8-15min at 5000-8000 rpm, and after 3-6 times of deionized water washing, dopamine nano particles are collected and stored for standby.
Step 2, mixing dopamine nano particles with 2-12 mg/mL AgNO 3 Mixing in ice water bath for 0.5-2 hrThe silver-loaded dopamine nano particles are then separated from the heart for 8-15min at 5000-8000 rpm, washed with deionized water for 3-6 times, and then collected and stored for later use.
The substances with better water solubility such as hydrophilic drugs, bioactive substances, nano particles and the like can be directly mixed with the functional polymer and the polymer containing hydroxyl groups to obtain the injectable hydrogel, and the injectable hydrogel is mixed with the functional polymer and the polymer containing hydroxyl groups after the hydrophobic drugs are subjected to special treatment.
Optionally, the hydrophobic drug is prepared into drug-loaded nano-micelle by taking amphiphilic polymer as a carrier, and the drug-loaded nano-micelle is mixed with functional polymer and polymer containing hydroxyl to prepare the injectable hydrogel containing the hydrophobic drug.
The drug-loaded nano micelle is prepared between the amphiphilic polymer and the hydrophobic drug in a self-assembly mode, the amphiphilic polymer is a drug carrier, and the hydrophobic drug is a wrapped drug.
The amphiphilic polymer consists of a hydrophilic chain segment and a hydrophobic chain segment, wherein the hydrophilic chain segment is at least one of polyethylene glycol, polyvinyl ether, polyvinyl alcohol, polyethylenimine, polyvinylpyrrolidone and polyacrylamide, and the hydrophobic chain segment is at least one of polypropylene oxide, polystyrene, polysiloxane, polybutadiene, polymethyl methacrylate, polymethyl acrylate and polybutyl acrylate.
Optionally, the preparation method of the drug-loaded nano micelle comprises the following steps:
dissolving amphiphilic polymer and hydrophobic drug in benign solvent with proper volume, slowly dripping into water under continuous stirring, and dialyzing to obtain drug-loaded nano micelle solution with concentration of 1-2 mg/mL.
The benign solvent is at least one of DMSO, DMF, methanol and acetone. Further preferably, the benign solvent is DMSO and/or acetone.
Specifically, amphiphilic polymer and hydrophobic drug are dissolved in benign solvent, slowly added into deionized water in a dropwise manner under the condition of continuous stirring, stirred for 2-6 hours, dialyzed in deionized water, and then drug-loaded nano-micelle with the concentration of 1-2mg/mL is prepared.
Alternatively, the mass ratio of amphiphilic polymer to hydrophobic drug is (3-7): 1.
Specifically, amphiphilic polymer and hydrophobic drug are dissolved in benign solvent, slowly added into deionized water in a dropwise manner under the condition of continuous stirring, stirred for 4 hours, dialyzed in deionized water, and then drug-loaded nano-micelle is prepared, wherein the mass ratio of the amphiphilic polymer to the hydrophobic drug is 5:1.
Optionally, mixing an aqueous solution of a functional polymer with an aqueous solution of a polymer containing hydroxyl groups to obtain the injectable hydrogel, wherein the aqueous solution of the functional polymer contains at least one of hydrophilic drugs, hydrophobic drugs, bioactive substances and nano particles, and the mass concentration of the functional polymer in the aqueous solution of the functional polymer is 0.5-30% w/v.
Optionally, mixing an aqueous solution of a functional polymer with an aqueous solution of a polymer containing hydroxyl groups to obtain the injectable hydrogel, wherein the aqueous solution of the functional polymer contains at least one of hydrophilic drugs, hydrophobic drugs, bioactive substances and nano particles, and the mass concentration of the functional polymer in the aqueous solution of the functional polymer is 1-10% w/v.
Optionally, mixing an aqueous solution of a functional polymer with an aqueous solution of a polymer containing hydroxyl groups to obtain the injectable hydrogel, wherein the aqueous solution of the functional polymer contains at least one of hydrophilic drugs, hydrophobic drugs, bioactive substances and nano particles, and the mass concentration of the functional polymer in the aqueous solution of the functional polymer is 10-25% w/v.
Optionally, the mass concentration of the hydrophilic drug in the functional polymer aqueous solution is 0.1-500 mug/mL.
Optionally, the mass concentration of the hydrophilic drug in the functional polymer aqueous solution is 0.2-300 mug/mL.
Optionally, the mass concentration of the bioactive substances in the functional polymer aqueous solution is 1-6 mg/mL.
Optionally, the mass concentration of the bioactive substances in the functional polymer aqueous solution is 1-3 mg/mL.
Optionally, the mass concentration of the nano particles in the functional polymer aqueous solution is 10-400 mug/mL.
Optionally, the mass concentration of the nano particles in the functional polymer aqueous solution is 50-250 mug/mL.
Alternatively, the mass concentration of the hydroxyl group-containing polymer in the aqueous solution of the hydroxyl group-containing polymer is 1 to 20% w/v.
Alternatively, the mass concentration of the hydroxyl group-containing polymer in the aqueous solution of the hydroxyl group-containing polymer is 1 to 15% w/v.
Alternatively, the mass concentration of the hydroxyl group-containing polymer in the aqueous solution of the hydroxyl group-containing polymer is 2 to 10% w/v.
Alternatively, the volume ratio of the aqueous functional polymer solution to the aqueous hydroxyl-containing polymer solution is 1:0.5-1.5.
Alternatively, the volume ratio of the aqueous functional polymer solution to the aqueous hydroxyl-containing polymer solution is 1:0.8-1.2. +
Alternatively, the volume ratio of the aqueous functional polymer solution to the aqueous hydroxyl-containing polymer solution is 1:1.
Optionally, mixing an aqueous solution of a functional polymer with an aqueous solution of polyvinyl alcohol to obtain the injectable hydrogel, wherein the aqueous solution of the functional polymer contains at least one of hydrophilic drugs, hydrophobic drugs, bioactive substances and nanoparticles, the mass concentration of the functional polymer in the aqueous solution of the functional polymer is 20% w/v, the mass concentration of the polyvinyl alcohol in the aqueous solution of the polyvinyl alcohol is 10% w/v, and the aqueous solution of the functional polymer is mixed with the aqueous solution of the polyvinyl alcohol in equal volume to obtain the hydrogel.
Optionally, the polymer containing amino and hydroxyl groups is at least one of gelatin, gelatin derivatives, chitosan and chitosan derivatives.
Optionally, the polymer containing carboxyl and hydroxyl is at least one of sodium alginate, hyaluronic acid, heparin and carboxymethyl cellulose.
Optionally, the polymer containing hydroxyl is at least one of polyvinyl alcohol, sodium alginate, hyaluronic acid, starch, cellulose, dragon gum, konjac gum, gum arabic, lignin, dextran, cyclodextrin, and rhizoma Bletillae polysaccharide
Optionally, the phenylboronic acid containing carboxyl is at least one of 4-carboxyphenylboronic acid, 2-carboxyphenylboronic acid, 3-carboxyphenylboronic acid, 4-carboxyl-3-fluorobenzeneboronic acid, 3-carboxyl-4-fluorobenzeneboronic acid, 5-carboxyl-2-chlorobenzeneboronic acid and 4-carboxyl-2-chlorobenzeneboronic acid;
the phenylboronic acid containing amino is at least one of 4-aminophenylboronic acid, 2-aminophenylboronic acid, 3-carbamoylphenylboronic acid, 3-amino-4-fluorophenylboronic acid and 3-amino-4-methylphenylboronic acid;
the hydroxyl-containing phenylboronic acid is at least one of 4-hydroxyphenylboronic acid, 3-fluoro-4-hydroxyphenylboronic acid, 2-fluoro-3-hydroxyphenylboronic acid, 2-fluoro-5-hydroxyphenylboronic acid, 3-hydroxy-4-chlorophenylboronic acid and 3-fluoro-4-hydroxyphenylboronic acid.
Optionally, the bioactive substance is at least one of recombinant humanized collagen, animal collagen, amino acid polypeptide, non-collagen, elastin, proteoglycan, and aminoglycan.
Optionally, the bioactive substance is recombinant humanized collagen.
Optionally, the hydrophobic drug is at least one of ibuprofen, acetaminophen, curcumin and indomethacin.
The multifunctional injectable hydrogel with microenvironment response is prepared by adopting the preparation method.
The application provides a microenvironment-responsive multifunctional injectable hydrogel and a preparation method thereof, wherein the hydrogel has good injectability, and can be coated on the surface of a wound to realize better and faster repair of a chronic wound.
Drawings
FIG. 1 is a gel-forming diagram of a hydrogel in example 1 of the present application;
FIG. 2 is a graph showing bacterial plate colonies of Staphylococcus aureus and Escherichia coli at 12 hours after treatment with different hydrogels according to example 1 of the present application;
fig. 3 is a photograph of wound healing at various time points according to the present application.
Detailed Description
The following describes the embodiments of the present application in detail with reference to the drawings.
In the examples below, the chemicals other than the substrate are chemically pure unless specifically stated.
Example 1
A preparation method of injectable hydrogel with antibacterial, antiinflammatory and angiogenesis promoting effects is provided, and the preparation steps are shown below.
1. Synthesis of oxidized hyaluronic acid (HA-CHO)
10.0g of hyaluronic acid and 8.0g of sodium periodate were dissolved in Deionized Water (DW) and stirred for 4h at 37 ℃. Then, 1.2mL of ethylene glycol was added to the above solution and stirred for 2 hours to terminate the oxidation reaction. Finally, dialyzing for 48 hours by using deionized water, and obtaining the HA-CHO after freeze drying.
2. Synthesis of oxidized hyaluronic acid (HA-CHO-BA) grafted with phenylboronic acid
5.00g of HA-CHO-hyaluronate was precisely weighed out and dissolved in 200mL of water, and 1.5g of 3-aminophenylboronic acid (BA) was added thereto. Then, stirring at 37℃for 12 hours, finally dialyzing in deionized water (pH 7.4) for 3 days, and freeze-drying the obtained product by a freeze dryer to obtain purified HA-CHO-BA.
3. Preparation of polydopamine nanoparticles
2mL of ammonia NH 4 OH (concentration 25-28 wt%) was gently stirred with 40mL of ethanol and 90mL of deionized water at 30℃for 30min, 500mg of dopamine hydrochloride was dissolved in 10mL of deionized water, and slowly dropped into the above mixture. The color of the solution immediately turned pale yellow and then gradually turned dark brown. After 24h of reaction, the heart was separated at 6000 rpm for 12min, and after 3 washes with deionized water, the polydopamine nanoparticle PDANPs were collected and stored for future use.
4. Preparation of polydopamine silver nano-particles
Ag + Adsorbing on the surface of PDANPs, and then in-situ reducing to AgNPs by using PDA, which comprises the following steps:
Combining polydopamine nanoparticle PDANPs with AgNO 3 (4 mg/mL) was mixed in an ice-water bath for 1 hour to give PDA@AgNPs. PDA@AgNPs are then placed in6000 rpm/separating core for 12min, washing with deionized water three times, dispersing into deionized water with mass concentration of 5%, and placing in dark environment for further use.
5. Particle size and TEM of polydopamine nanoparticles and polydopamine silver nanoparticles
The particle size of the nanoparticles (100. Mu.g/mL) was measured by a Markov dynamic light scattering particle sizer DLS. All measurements were repeated 3 times. For TEM detection, the solution was dropped on a copper mesh and the structure was observed with a transmission electron microscope.
6. Preparation of hydrogels
The multifunctional hydrogel can be formed rapidly by mixing 4mL of 10% by mass polyvinyl alcohol (PVA), 2mL of HA-CHO-BA containing collagen III (the mass fraction of HA-CHO-BA is 20%) and 2mL of a solution containing PDA@AgNPs with each other. The final concentration of PDA@Ag was 200. Mu.g/mL, and the final concentration of collagen III (hCOLI) was 2mg/mL.
The control hydrogel was prepared as follows: the aqueous PVA solution with a mass fraction of 10% of 4mL and the HA-CHO-BA solution with a mass fraction of 10% of 4mL were mixed with each other to prepare the mixture immediately. Four hydrogels, namely hydrogel 1, blank hydrogel; hydrogel 2, hydrogel encapsulates PDA@Ag; hydrogel 3 hydrogel encapsulated hcolliii; hydrogel 4 hydrogel encapsulates pda@ag and hcolliii the hydrogel is in a sterile operating environment during the preparation process and the solvents used are sterile.
Example 2
A preparation method of injectable hydrogel with antibacterial, antiinflammatory and angiogenesis promoting effects is provided, and the preparation steps are shown below.
1. Synthesis of oxidized sodium alginate (ALG-CHO)
10.0g sodium alginate and 8.0g sodium periodate were dissolved in Deionized Water (DW) and stirred for 4h at 37 ℃. Then, 1.2mL of ethylene glycol was added to the above solution and stirred for 2 hours to terminate the oxidation reaction. Finally, dialyzing with deionized water for 48 hours, and obtaining the ALG-CHO after freeze drying.
2. Synthesis of oxidized sodium alginate (ALG-CHO-BA) grafted with phenylboronic acid
5.00g of oxidized sodium alginate was weighed precisely and dissolved in 200mL of water, to which was added 1.5g of 3-aminophenylboric acid (BA). Then, stirring was carried out at 37℃for 12 hours, and finally, dialysis was carried out in deionized water (pH 7.4) for 3 days, followed by freeze-drying with a freeze dryer to obtain purified ALG-CHO-BA.
3. Preparation of polydopamine nanoparticles
2mL of ammonia NH 4 OH (concentration 25-28 wt%) was gently stirred with 40mL of ethanol and 90mL of deionized water at 30℃for 30min, 500mg of dopamine hydrochloride was dissolved in 10mL of deionized water, and the mixture was slowly dropped. The color of the solution immediately turned pale yellow and then gradually turned dark brown. After 24h of reaction, the cores were separated at 6000 rpm for 12min, washed 3 times with deionized water, and the PDANPs were collected and stored for later use.
4. Preparation of polydopamine silver nano-particles
Ag + Adsorbing on the surface of PDANPs, and then in-situ reducing to AgNPs by using PDA, which comprises the following steps:
polydopamine nanoparticles and AgNO 3 (4 mg/mL) was mixed in an ice-water bath for 1 hour to give PDA@AgNPs. The PDA@AgNPs were then spun at 6000 rpm for 12min, rinsed three times with deionized water, dispersed into deionized water at a mass concentration of 5% and placed in a dark environment for further use.
5. Particle size and TEM of polydopamine nanoparticles and polydopamine silver nanoparticles
The particle size of the nanoparticles (100. Mu.g/mL) was measured by a Markov dynamic light scattering particle sizer DLS. All measurements were repeated 3 times. For TEM detection, the solution was dropped on a copper mesh and the structure was observed with a transmission electron microscope.
6. Preparation of hydrogels
The multifunctional hydrogel can be formed rapidly by mixing 4mL of 10% by mass polyvinyl alcohol (PVA), 2mL of ALG-CHO-BA containing collagen III (20% by mass of ALG-CHO-BA) and 2mL of a solution containing PDA@Ag with each other. The final concentration of PDA@Ag was 200. Mu.g/mL, and the final concentration of type III collagen was 2mg/mL. The control hydrogel was prepared as follows: the mixture of 4mL of PVA with a mass fraction of 10% and 4mL of ALG-CHO-BA solution with a mass fraction of 10% was immediately prepared. The hydrogel is in a sterile operating environment during the preparation process, and the solvents used are all sterile.
Example 3
A preparation method of injectable hydrogel with antibacterial, antiinflammatory and angiogenesis promoting effects is provided, and the preparation steps are shown below.
1. Synthesis of sodium carboxymethylcellulose oxide (CMC-CHO)
10.0g of sodium carboxymethylcellulose and 8.0g of sodium periodate were dissolved in Deionized Water (DW) and stirred for 4h at 37 ℃. Then, 1.2mL of ethylene glycol was added to the above solution and stirred for 2 hours to terminate the oxidation reaction. Finally, dialyzing with deionized water for 48 hours, and obtaining CMC-CHO after freeze drying.
2. Synthesis of sodium carboxymethylcellulose oxide grafted with phenylboronic acid (CMC-CHO-BA)
5.00g of sodium carboxymethylcellulose oxide was precisely weighed out and dissolved in 200mL of water, and 1.5g of 3-aminophenylboric acid (BA) was added thereto. Then, stirring at 37℃for 12 hours, finally dialyzing in deionized water (pH 7.4) for 3 days, and freeze-drying the obtained product by a freeze dryer to obtain purified CMC-CHO-BA.
3. Preparation of drug-loaded nanoparticle (PLGA@Nap)
Polylactic acid-glycolic acid copolymer (PLGA, 60 mg) and naproxen (Nap, 12 mg) were completely dissolved in DMSO (5 mL) at 37℃and then added dropwise to 15mL of deionized water with stirring, followed by continuous stirring for 4h at 37 ℃; then dialyzing the mixture in water for 3 days to obtain PLGA@Nap solution, freeze-drying and storing the solution at the temperature of 4 ℃ in a dark place;
4. Preparation of hydrogels
A control hydrogel was prepared by mixing 4mL of 10% by mass polyvinyl alcohol (PVA, 2mL of CMC-CHO-BA containing collagen III (CMC-CHO-BA: 20% by mass) and 2mL of a solution containing PLGA@Nap and amikacin with each other, and the multifunctional hydrogel was rapidly formed, and the final concentration of PLGA@Nap and amikacin was 200. Mu.g/mL, and the final concentration of collagen III was 2mg/mL. A control hydrogel was prepared by mixing 4mL of 10% by mass PVA and 4mL of 10% by mass of ALG-CHO-BA with each other.
Example 4
A preparation method of injectable hydrogel with antibacterial, antiinflammatory and angiogenesis promoting effects is provided, and the preparation steps are shown below.
1. Synthesis of oxidized starch
10.0g of starch and 8.0g of sodium periodate are dissolved in Deionized Water (DW) and stirred for 4h at 37 ℃. Then, 1.2mL of ethylene glycol was added to the above solution and stirred for 2 hours to terminate the oxidation reaction. Finally, dialyzing with deionized water for 48 hours, and freeze-drying to obtain the product.
2. Synthesis of oxidized starch grafted with phenylboronic acid
5.00g of oxidized starch was precisely weighed and dissolved in 200mL of water, to which 1.5g of 3-aminophenylboronic acid (BA) was added. Then, stirring at 37℃for 12 hours, finally dialyzing in deionized water (pH 7.4) for 3 days, and freeze-drying the obtained product by a freeze dryer to obtain a purified product.
3. Preparation of antibacterial material silver nano particles
Freshly prepared sodium borohydride (NaBH 4 2.00 mM) was mixed with an aqueous solution of trisodium citrate (TSC, 4.28 mM) and heated to 60℃with vigorous stirring in a dark environment. After 30min, 2mL AgNO was added dropwise 3 (1.00 mM) and then the temperature was raised to 90℃again, and the pH of the solution was adjusted to 10.5. After stirring for 25 minutes, the mixture solution was slowly cooled at room temperature. Finally, the mixture was centrifuged at 12000rpm/min for 15 minutes, and the precipitate was silver nanoparticles (AgNPs) and redispersed in deionized water for future use.
4. Preparation of hydrogels
4mL of 10% by mass polyvinyl alcohol (PVA), 2mL of oxidized starch containing grafted phenylboronic acid of type III collagen (the mass fraction of the oxidized starch of grafted phenylboronic acid is 20%) and 2mL of solution containing silver nanoparticles are mixed with each other, and the multifunctional hydrogel can be rapidly formed. The final concentration of silver nanoparticles was 200 μg/mL and the final concentration of type III collagen was 2mg/mL.
The control hydrogel was prepared as follows: the preparation is immediately carried out by mixing 4mL of PVA with a mass fraction of 10% and 4mL of oxidized starch solution of grafted phenylboronic acid with each other with a mass fraction of 10%. The hydrogel is in a sterile operating environment during the preparation process, and the solvents used are all sterile.
Example 5
A preparation method of injectable hydrogel with antibacterial, antiinflammatory and angiogenesis promoting effects is provided, and the preparation steps are shown below.
1. Synthesis of oxidized carboxymethyl chitosan
10.0g of carboxymethyl chitosan and 8.0g of sodium periodate were dissolved in Deionized Water (DW) and stirred for 4h at 37 ℃. Then, 1.2mL of ethylene glycol was added to the above solution and stirred for 2 hours to terminate the oxidation reaction. Finally, dialyzing with deionized water for 48 hours, and freeze-drying to obtain the product.
2. Phenylboronic acid grafted oxidized carboxymethyl chitosan
Carboxymethyl chitosan oxide (10.00 g) and 3-carboxyphenylboronic acid (6.50 g) were precisely weighed into 500mL MES buffer (0.1 mol, pH 5.0), and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,4.00 g) and N-hydroxysuccinimide (NHS, 1.5 g) were added thereto. Then, stirring was carried out at 37℃for 48 hours, and finally, dialysis was carried out in deionized water (pH 7.4) for 3 days, and after 3 days, freeze-drying was carried out by a freeze dryer to obtain a purified functional polymer.
3. Preparation of antibacterial material mesoporous zinc oxide
50mM Zn (NO) 3 ) 2 ·6H 2 O (zinc nitrate hexahydrate) and 25mM HMT (hexamethylenetetramine) were dissolved in 100mL of deionized water, and stirred under sealed conditions for 10 minutes. After heating in a water bath at 65℃for 15 minutes, 0.14g of Na was added 3 C 6 H 5 O 7 (sodium citrate), 0.1g HPMC (hydroxypropyl methylcellulose) and 0.025g carbon were added to the above solution and kept under water bath conditions of 85℃for 10 hours. The mixture was then washed twice with absolute ethanol and twice with water, subjected to microwave irradiation for 15 minutes (850 watts), frozen at-80 ℃ and freeze-dried for 12 hours, finally obtaining zinc oxide (ZnO) powder.
4. Preparation of hydrogels
4mL of 10% by mass of polyvinyl alcohol (PVA), 2mL of carboxymethyl chitosan (20% of carboxymethyl chitosan grafted with phenylboronic acid) grafted with type III collagen and 2mL of solution containing zinc oxide nano particles are mixed with each other, and the multifunctional hydrogel can be rapidly formed. The final concentration of the zinc oxide nanoparticles was 200. Mu.g/mL, and the final concentration of type III collagen was 2mg/mL.
The control hydrogel was prepared as follows: the preparation can be immediately carried out by mixing 4mL of PVA with a mass fraction of 10% and 4mL of a carboxymethyl chitosan solution grafted with phenylboronic acid with each other with a mass fraction of 10%. The hydrogel is in a sterile operating environment during the preparation process, and the solvents used are all sterile.
Example 6
A preparation method of injectable hydrogel with antibacterial, antiinflammatory and angiogenesis promoting effects is provided, and the preparation steps are shown below.
1. Synthesis of oxidized sodium alginate
10.0g sodium alginate and 8.0g sodium periodate were dissolved in Deionized Water (DW) and stirred for 4h at 37 ℃. Then, 1.2mL of ethylene glycol was added to the above solution and stirred for 2 hours to terminate the oxidation reaction. Finally, dialyzing with deionized water for 48 hours, and freeze-drying to obtain the product.
2. Phenylboronic acid grafted oxidized sodium alginate
Oxidized sodium alginate (10.00 g) and 3-aminophenylboronic acid (6.50 g) were precisely weighed into 500mL of MES buffer (0.1 mol, pH 5.0), to which were added 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,4.00 g) and N-hydroxysuccinimide (NHS, 1.5 g). Then, stirring was carried out at 37℃for 48 hours, and finally, dialysis was carried out in deionized water (pH 7.4) for 3 days, and after 3 days, freeze-drying was carried out by a freeze dryer to obtain a purified functional polymer.
3. Preparation of antibacterial material silver nanocluster
Freshly prepared glutathione (GSH, 300. Mu.L, 50 mM) and AgNO 3 The aqueous solution (250. Mu.L, 20 mM) was mixed with vigorous stirring in 4.45mL of deionized water. White precipitate formation was immediately observed, indicating GSH-Ag (I) complexA certain amount of NaOH solution (180 μl, 0.1M) was then added, the pH of the solution was adjusted to 6.1, and the white precipitate dissolved in a few seconds, and the reaction solution was cleared. The reaction solution was heated to 175 ℃ for about 5 hours, and then incubated overnight at 4 ℃ to prepare silver nanoclusters.
4. Preparation of hydrogels
4mL of 10% by mass of polyvinyl alcohol (PVA), 2mL of oxidized sodium alginate containing III-type collagen grafted phenylboronic acid (the mass fraction of the oxidized sodium alginate grafted phenylboronic acid is 20%) and 2mL of solution containing silver nanoclusters are mixed with each other, and the multifunctional hydrogel can be rapidly formed. The final concentration of silver nanoclusters is 200 μg/mL and the final concentration of type III collagen is 2mg/mL.
The control hydrogel was prepared as follows: the preparation can be immediately carried out by mixing 4mL of PVA with a mass fraction of 10% and 4mL of oxidized sodium alginate solution with a mass fraction of 10% of grafted phenylboronic acid with each other. The hydrogel is in a sterile operating environment during the preparation process, and the solvents used are all sterile.
Test example 1
Taking the substance prepared in example 1 as an example, detection was carried out, and the specific operation procedure and results were as follows:
the following experimental legend, unless otherwise specified, sets 1-4 of hydrogels represent the following combinations: hydrogel group 1 (Hydrogel 1): blank hydrogel; hydrogel group 2 (Hydrogel 4): the hydrogel loaded with dopamine silver-loaded nano particles and recombinant human type III collagen.
1. And (3) detecting the gel forming property and the injection property of the hydrogel prepared in the step (6).
FIG. 1 is a gel forming diagram of a hydrogel, demonstrating the success of hydrogel preparation.
2. Antibacterial property detection of hydrogels
Staphylococcus aureus and escherichia coli were selected to evaluate the antimicrobial effect of the hydrogels. The experiments were divided into 3 groups: 1. bacteria group (blank) 2, bacteria+blank hydrogel group (hydrogel 1 group) 3, bacteria+hydrogel @ Ag & hcolliii (hydrogel 2 group). After each group of hydrogel samples and bacteria are co-cultured for 12 hours at 37 ℃, the treated bacterial liquid is uniformly coated on the surface of LB solid culture medium by a bacteria coating rod, and the bacteria are placed in a bacteria incubator at 37 ℃ for inverted culture. Photographing was performed after 12 hours. As shown in FIG. 2, the colony count experiment results of the agar plates show that the number of the colonies on the agar plates of the hydrogel 2 group is the least, which indicates that the sterilization capability is the strongest.
3. Detection of in-vivo skin repair promoting effect of hydrogel
All animal experiments were performed according to the university of Sichuan laboratory animal management and instructions. The model of type 2 diabetes rats was established by tail vein injection of streptozotocin at a dose of 60 μg/g once daily until the fasting blood glucose level of the rats exceeded 16.7mM. Rats were anesthetized with 10% chloral hydrate (0.3 mL/100 g), and 4 full-thickness wounds (1 cm in diameter) were made on the back of each rat using a medical jig, and divided into different groups of 8 rats each. mu.L of E.coli (1X 10) was added dropwise to the wound site of each rat 8 CFUmL -1 ) After infection is initiated, different hydrogel samples are respectively coated on infected wounds for treatment after one day, and the wound surface of a control group is not treated. After the hydrogel is coated, a Tegaderm transparent film is coated on each wound to prevent the wound from being polluted. The hydrogel was administered once every two days for a total of three administrations. The wound sites of rats were photographed at designated time points (0, 2, 4, 7 and 14 days) and wound boundaries were tracked on a transparent drawing sheet, and wound sizes were monitored.
The results are shown in fig. 3, with hydrogel 2 (hydrogel @ ag & hColIII) treated group wounds healed most rapidly compared to the other groups, whereas on day 14, hydrogel 2 (hydrogel @ ag & hColIII) treated group wounds had almost healed, while none of the other groups had healed. These results indicate that hydrogel group 2 (hydrogel@ag & hcolliii) has a significant effect of accelerating healing of infected wounds.
The foregoing is merely illustrative and explanatory of the application as it is claimed, as modifications and additions may be made to, or similar to, the particular embodiments described, without the benefit of the inventors' inventive effort, and as alternatives to those of skill in the art, which remain within the scope of this patent.
Claims (10)
1. A microenvironmentally responsive multifunctional injectable hydrogel formed by interaction of a functional polymer comprising phenylboronic acid and an aldehyde group with a polymer comprising a hydroxyl group, the multifunctional injectable hydrogel being responsive to acidic conditions and/or reactive oxygen conditions, the multifunctional injectable hydrogel being loaded with a therapeutic substance, the therapeutic substance being recombinant humanized collagen and dopamine silver-loaded nanoparticles;
The functional polymer is at least one of sodium alginate, chitosan, gelatin, hyaluronic acid, carboxymethyl cellulose, dextran, methyl cellulose, starch, cyclodextrin, dragon gum, konjac gum, gum arabic, lignin and bletilla striata polysaccharide containing phenylboronic acid and aldehyde groups;
the polymer containing hydroxyl is at least one of polyvinyl alcohol, sodium alginate, hyaluronic acid, starch, cellulose, gum Dragon, konjac gum, gum arabic, lignin, dextran, cyclodextrin, and rhizoma Bletillae polysaccharide.
2. Use of the microenvironmentally-responsive multifunctional injectable hydrogel of claim 1 in the repair of skin lesions.
3. The method for preparing the microenvironmentally-responsive multifunctional injectable hydrogel according to claim 1, comprising the steps of:
preparing a functional polymer containing phenylboronic acid and aldehyde groups;
and mixing a therapeutic substance, a functional polymer and a polymer containing hydroxyl groups to obtain the hydrogel, wherein the therapeutic substance is at least one of hydrophilic drugs, hydrophobic drugs, bioactive substances and nanoparticles.
4. A method of preparing a microenvironmentally responsive multifunctional injectable hydrogel in accordance with claim 3, wherein the functional polymer is prepared by one of the following methods:
The first preparation method comprises the following steps:
step a1, oxidizing a polymer containing amino and hydroxyl to obtain a polymer containing amino and aldehyde groups;
step a2, reacting a polymer containing amino and aldehyde groups with phenylboronic acid containing carboxyl and/or amino to obtain the functional polymer;
the second preparation method comprises the following steps:
step b1, oxidizing a polymer containing carboxyl and hydroxyl to obtain a polymer containing carboxyl and aldehyde groups;
and b2, reacting the polymer containing carboxyl and aldehyde groups with phenylboronic acid containing hydroxyl and/or amino groups to obtain the functional polymer.
5. The method for preparing a microenvironmentally-responsive multifunctional injectable hydrogel according to claim 4,
in the step a1, the mass ratio of the polymer containing amino groups and hydroxyl groups to the oxidant is 10: 3-10: 9, a step of performing the process;
in the step b1, the mass ratio of the polymer containing carboxyl groups and hydroxyl groups to the oxidant is 10: 3-10: 9.
6. the method for preparing the microenvironment-responsive multifunctional injectable hydrogel according to claim 3, wherein the nanoparticles are dopamine silver-loaded nanoparticles, and the method for preparing the dopamine silver-loaded nanoparticles comprises the following steps:
step 1, preparing dopamine nano particles;
And step 2, mixing the dopamine nano particles with silver nitrate at 0-10 ℃ to obtain the dopamine silver-loaded nano particles.
7. The method of preparing a microenvironmentally-responsive multifunctional injectable hydrogel according to claim 6, wherein preparing the dopamine nanoparticle comprises the steps of:
and slowly adding dopamine hydrochloride into the mixed aqueous solution of ammonia water and ethanol, and reacting for 18-36 h to obtain the dopamine nano particles.
8. The method for preparing a microenvironment-responsive multifunctional injectable hydrogel according to claim 3, wherein the injectable hydrogel is obtained by mixing an aqueous solution of a functional polymer with an aqueous solution of a hydroxyl group-containing polymer, wherein the aqueous solution of the functional polymer contains at least one of a hydrophilic drug, a hydrophobic drug, a bioactive substance and nanoparticles, and wherein the mass concentration of the functional polymer in the aqueous solution of the functional polymer is 10-25% w/v.
9. The method for preparing the microenvironment-responsive multifunctional injectable hydrogel according to claim 4, wherein the polymer containing amino groups and hydroxyl groups is at least one of gelatin, gelatin derivatives, chitosan and chitosan derivatives;
the polymer containing carboxyl and hydroxyl is at least one of sodium alginate, hyaluronic acid, heparin and carboxymethyl cellulose.
10. A microenvironmentally responsive multifunctional injectable hydrogel prepared by the method of any one of claims 3 to 9.
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