CN114767625A - Intelligent hydrogel with heart injury repair function and preparation method and application thereof - Google Patents
Intelligent hydrogel with heart injury repair function and preparation method and application thereof Download PDFInfo
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Abstract
The application discloses an intelligent hydrogel with a heart injury repair function, a preparation method and an application thereof, belonging to the technical field of medical materials, wherein the preparation method of the hydrogel comprises the following steps: the aldehyde group-containing polymer and amino-containing molecules are reacted through Schiff base to prepare an intelligent hydrogel material with good biocompatibility, and meanwhile, a bioactive material is loaded to achieve the purposes of repairing heart damage and relieving heart failure.
Description
Technical Field
The application relates to the technical field of medical materials, in particular to an intelligent hydrogel with a heart injury repair function, and a preparation method and application thereof.
Background
Cardiovascular disease is currently the leading cause of human death, myocardial infarction and related heart failure are the leading causes of death, and despite the improved survival rates of early myocardial infarction resulting from direct percutaneous coronary intervention, heart failure occurs in about 50% of patients. Currently effective methods for treating heart failure are left ventricular assist devices and heart transplantation, however, the former method is limited by its dependence on long-term use of external devices, the latter method is limited by severe shortage of donor organs, and both methods have extremely high risk, and thus, there is an urgent need for new clinical methods for repairing the heart after myocardial infarction.
The existing treatment methods comprise direct injection of growth factors, small molecule drugs, stem cells and nucleic acids to treat myocardial infarction, but face a series of problems of low bioavailability, nonspecific molecule transmission, limited cell proliferation, failure to form new functional heart tissues, poor gene retention and the like. The injectable hydrogel can be used for minimally invasive injection of bioactive substances or cells with therapeutic effects to infarction parts, so that targeting release is realized, and the problems are greatly solved.
Stimuli-responsive hydrogels have attracted considerable attention because they can change shape according to environmental changes, such as Reactive Oxygen Species (ROS), pH, temperature, enzymes, light, and ultrasound. In drug delivery, stimulus-responsive hydrogels can achieve intelligent local on-demand release of drugs at the disease site, as compared to traditional hydrogels. Aiming at the microenvironment of the myocardial infarction part, the intelligent hydrogel capable of realizing accurate and quick response to microenvironment multiple stimulation is designed, and has important effects on repairing cardiac injury, promoting cardiac revascularization and improving cardiac function.
Disclosure of Invention
The technical problem to be solved by the invention is to improve the existing hydrogel formula, improve the injectable performance and the controllable release capacity of active substances, load a recombinant I-type humanized collagen bioactive material, provide an intelligent hydrogel which can be used for heart failure adjuvant therapy and promote the pH response of damaged heart repair, ensure that the hydrogel has good biocompatibility and can promote the cell proliferation and the blood vessel regeneration of damaged heart parts under physiological conditions, respond to the acidic inflammation microenvironment of heart infarction parts to release the active substances, and realize the functions of damaged heart remodeling and the like.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of intelligent hydrogel with a heart injury repair function comprises the following steps of under an aseptic condition:
step 2, dissolving a bioactive substance in the aldehyde group-containing polymer solution;
the bioactive substance is recombinant I-type humanized collagen;
and 3, mixing the aldehyde-group-containing polymer solution containing the bioactive substances with the amino-group-containing polymer solution to obtain the intelligent hydrogel.
In the step 1, the aldehyde group-containing polymer, the amino group-containing polymer solute and the PBS solvent all need to meet the requirements of sterility and no pyrogen so as to meet the application scene of repairing cardiac injury.
In the steps 1 to 3, the operation is carried out at room temperature, namely, the operation such as heating or cooling is not required to be additionally carried out, the room temperature is usually-10 ℃ to 40 ℃, and the dissolution and the mixing are required to be complete.
The hydrogel provided by the application is prepared by crosslinking an aldehyde group-containing polymer and an amino group-containing polymer through Schiff base reaction.
The recombinant type I humanized collagen refers to: the human type I collagen specific gene prepared by DNA recombination technology encodes full-length or partial amino acid sequence fragments, or contains the combination of human collagen functional fragments.
The recombinant type I humanized collagen protein has the following sequence:
GEKGSPGADGPAGAPGTPGPQGIAGQRGVVGLPGQRGERGFPGLPGPSGEPGKQGPSGAS
the recombinant humanized collagen is a collagen material which is obtained by systematically researching a human type I collagen full-length sequence, screening out a high cell adhesion activity gene sequence with concentrated positive and negative charges, and biosynthesizing through genetic engineering and fermentation engineering after computer-aided protein structure prediction and verification screening, has the same sequence with the human type I collagen, has higher water solubility and good biocompatibility, can promote cell adhesion and proliferation, and has no obvious cytotoxicity and immunogenicity.
The recombinant I-type humanized collagen used in the application has the effect of promoting cell proliferation, greatly reduces the immunogenicity of animal-derived tissues compared with animal collagen, and can effectively treat heart injury after myocardial infarction.
The hydrogel for repairing cardiac injury provided by the application is prepared by uniformly mixing aldehyde-containing polymer solution and amino-containing polymer solution loaded with bioactive substances into gel in a sterile environment to generate hydrogel with higher water content, and then filling the hydrogel into an injector or a transmission system to be directly injected into the ventricular wall for treatment.
Several alternatives are provided below, but not as an additional limitation to the above general solution, but merely as a further addition or preference, each alternative being combinable individually for the above general solution or among several alternatives without technical or logical contradictions.
Optionally, in the aldehyde group-containing polymer solution, the mass concentration of the aldehyde group-containing polymer is as follows: 0.5-12% w/w.
Optionally, in the aldehyde group-containing polymer solution, the mass concentration of the aldehyde group-containing polymer is as follows: 0.5-10% w/w.
Optionally, in the aldehyde group-containing polymer solution, the mass concentration of the aldehyde group-containing polymer is as follows: 2.5-10% w/w.
Optionally, in the amino-containing polymer solution, the mass concentration of the amino-containing polymer is as follows: 0.5 to 15% w/w.
Optionally, in the amino-containing polymer solution, the mass concentration of the amino-containing polymer is as follows: 0.5 to 10% w/w.
Optionally, in the amino-containing polymer solution, the mass concentration of the amino-containing polymer is as follows: 5 to 10% w/w.
Optionally, the aldehyde group-containing polymer is at least one of the following substances:
aldehyde group PEG aldehyde group, four-arm PEG aldehyde group, six-arm PEG aldehyde group, eight-arm PEG aldehyde group, oxidized dextran polymer, oxidized sodium alginate polymer, oxidized hyaluronic acid polymer and oxidized methyl cellulose polymer.
For the formation of hydrogels, the aldehyde-containing polymers used are at least soluble in the PBS solvent to form a solution that is homogeneous in nature, and therefore, the molecular weight is selected at least such that the aldehyde-containing polymers have good solubility in PBS. Generally, the weight average molecular weight of aldehyde group PEG aldehyde group, four-arm PEG aldehyde group, six-arm PEG aldehyde group and eight-arm PEG aldehyde group is not more than 10000.
The aldehyde group-containing polymer in the step (1) is an oxidized polymer containing ortho-hydroxyl groups, and the polymer containing ortho-hydroxyl groups comprises: dextran, sodium alginate, hyaluronic acid, methylcellulose or modified product thereof, and sodium periodate as oxidant.
Optionally, the amino-containing polymer is at least one of the following:
water-soluble chitosan derivative, polylysine, polyethyleneimine, gelatin, amino PEG amino, four-arm PEG amino, six-arm PEG amino and eight-arm PEG amino.
To form the hydrogel, the amino group-containing polymer employed is at least soluble in the PBS solvent to form a solution that is homogeneous in nature, and therefore, the molecular weight is selected to be at least sufficient for the amino group-containing polymer to have good solubility in PBS. In general, the weight average molecular weight of the amino-PEG amino group, the four-arm PEG amino group, the six-arm PEG amino group and the eight-arm PEG amino group is not more than 10000.
The water-soluble chitosan derivative includes: carboxymethyl chitosan, hydroxypropyl chitosan.
Optionally, the aldehyde group-containing polymer is at least one of the following substances:
aldehyde group PEG aldehyde group, four-arm PEG aldehyde group, six-arm PEG aldehyde group and eight-arm PEG aldehyde group;
the amino-containing polymer is carboxymethyl chitosan or hydroxypropyl chitosan.
Optionally, the aldehyde group-containing polymer is a four-arm PEG aldehyde group;
the amino-containing polymer is at least one of the following substances:
polylysine, polyethyleneimine, gelatin, amino PEG amino, four-arm PEG amino, six-arm PEG amino and eight-arm PEG amino.
Optionally, the aldehyde group-containing polymer is at least one of the following substances:
oxidized dextran polymers, oxidized sodium alginate polymers, oxidized hyaluronic acid polymers, oxidized methyl cellulose polymers;
the amino-containing polymer is carboxymethyl chitosan or hydroxypropyl chitosan.
Optionally, the concentration of the bioactive substances in the aldehyde group-containing polymer solution containing the bioactive substances is 1-8 g/L.
Optionally, the concentration of the bioactive substances in the aldehyde group-containing polymer solution containing the bioactive substances is 1-5 g/L.
Optionally, in step 3, the volume ratio of the aldehyde group-containing polymer solution to the amino group-containing polymer solution is: 6: 1-1: 6.
Optionally, in step 3, the volume ratio of the aldehyde group-containing polymer solution to the amino group-containing polymer solution is: 6: 1-1: 1.
Optionally, in step 3, the volume ratio of the aldehyde group-containing polymer solution to the amino group-containing polymer solution is: 1:1 to 1: 6.
The application also provides a hydrogel for repairing cardiac injury, which is prepared by the preparation method.
The pH-responsive intelligent hydrogel for repairing cardiac injury is prepared by uniformly mixing aldehyde-containing polymer solution loaded with bioactive substances and amino-containing polymer solution into gel in an aseptic environment to generate hydrogel with higher water content, filling the hydrogel into an injector or a transmission system, and directly injecting the hydrogel into a ventricular wall for treatment.
The application also provides a hydrogel for repairing heart injury, which is the intelligent hydrogel acting on the heart lesion part.
The application also provides application of the intelligent hydrogel in treating heart injury.
The beneficial effects produced by the application comprise at least one of the following:
1. the intelligent hydrogel loaded with active substances is crosslinked by virtue of Schiff base reaction between aldehyde groups and amino groups, so that gelling is rapid;
2. the hydrogel is simple in preparation process, has excellent rheological property and injectability, and has multiple dynamic functions of self-healing, injectability and the like;
3. the hydrogel has a pH response mechanism, and can rapidly respond to and release active substances in an acidic inflammation microenvironment at a myocardial infarction part.
3. The hydrogel plays a role in mechanical support, has an obvious function of promoting cell growth, and can effectively promote the generation and repair of blood vessels at damaged heart parts.
Drawings
FIG. 1 is an image of a hydrogel in example 1 of the present application;
FIG. 2a is a scanning electron microscope image of a blank hydrogel;
FIG. 2b is a scanning electron microscope image of the hydrogel prepared in example 2;
FIG. 2c is a scanning electron microscope image of the hydrogel prepared in example 1;
FIG. 3 is a graph showing injectability results of the hydrogel in example 1 of the present application;
FIG. 4a is a frequency scan of hydrogels of examples 1 and 2 of the present application;
FIG. 4b is a graph of an alternate step strain sweep experiment for hydrogels of examples 1 and 2 herein;
FIG. 5 shows the result of the live-dead staining of H9C2 cells in examples 1 and 2 of the present application;
FIG. 6 shows the results of the cytotoxicity of the hydrogels of examples 1 and 2 of the present application against H9C2 cells;
figure 7 shows the results of cardiac ultrasound with hydrogels 14d, 28d in examples 1 and 2 of the present application.
Detailed Description
The following detailed description of embodiments of the present application refers to the accompanying drawings.
In the following examples, the chemical agents other than the matrix are chemically pure unless otherwise stated.
In the following examples, the sequence of the recombinant type I humanized collagen used is as follows:
GEKGSPGADGPAGAPGTPGPQGIAGQRGVVGLPGQRGERGFPGLPGPSGEPGKQGPSGAS
example 1
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of carboxymethyl chitosan is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution and fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded four-arm PEG aldehyde-based solution was slowly added to the stirred 1mL of carboxymethyl chitosan solution at room temperature and immediately crosslinked to form a hydrogel.
Example 2
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of carboxymethyl chitosan is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 1mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution and is fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded four-arm PEG aldehyde-based solution was slowly added to the stirred 1mL of carboxymethyl chitosan solution at room temperature and immediately crosslinked to form a hydrogel.
Example 3
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of aldehyde group PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, precisely weighing 50mg of carboxymethyl chitosan, dissolving the carboxymethyl chitosan in 1mL of sterile PBS, and stirring overnight at room temperature to fully dissolve the carboxymethyl chitosan;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of aldehyde group PEG aldehyde group solution and is fully dissolved at room temperature;
(4) preparation of the gel
At room temperature, 1mL of aldehyde PEG aldehyde-based solution loaded with active substance was slowly added to the stirred 1mL of carboxymethyl chitosan solution, and immediately crosslinked to form hydrogel.
Example 4
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of six-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, precisely weighing 50mg of carboxymethyl chitosan, dissolving the carboxymethyl chitosan in 1mL of sterile PBS, and stirring overnight at room temperature to fully dissolve the carboxymethyl chitosan;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of six-arm PEG aldehyde group solution and is fully dissolved at room temperature;
(4) preparation of the gel
1mL of the six-arm PEG aldehyde-based solution loaded with the active substance was slowly added to the stirred 1mL of carboxymethyl chitosan solution at room temperature and immediately crosslinked to form a hydrogel.
Example 5
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of eight-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, precisely weighing 50mg of carboxymethyl chitosan, dissolving the carboxymethyl chitosan in 1mL of sterile PBS, and stirring overnight at room temperature to fully dissolve the carboxymethyl chitosan;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of eight-arm PEG aldehyde group solution and is fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded eight-arm PEG aldehyde-based solution was slowly added to the stirred 1mL of carboxymethyl chitosan solution at room temperature and immediately crosslinked to form a hydrogel.
Example 6
A preparation method of intelligent hydrogel with a heart injury repair function comprises the following preparation steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of hydroxypropyl chitosan is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution and fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded four-arm PEG aldehyde-based solution was slowly added to a stirred 1mL hydroxypropyl chitosan solution at room temperature and immediately crosslinked to form a hydrogel.
Example 7
A preparation method of intelligent hydrogel with a heart injury repair function comprises the following preparation steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of polylysine is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution and fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded four-arm PEG aldehyde-based solution was slowly added to a stirred 1mL polylysine solution at room temperature and immediately crosslinked to form a hydrogel.
Example 8
A preparation method of intelligent hydrogel with a heart injury repair function comprises the following preparation steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of polyethyleneimine is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution and is fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded four-arm PEG aldehyde-based solution was slowly added to a stirred 1mL polyethyleneimine solution at room temperature and immediately crosslinked to form a hydrogel.
Example 9
A preparation method of intelligent hydrogel with a heart injury repair function comprises the following preparation steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of gelatin is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution and fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded four-arm PEG aldehyde-based solution was slowly added to the stirred 1mL gelatin solution at room temperature and immediately crosslinked to form a hydrogel.
Example 10
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of amino PEG amino (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution and fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded four-arm PEG aldehyde solution was slowly added to 1mL of the amino PEG amino solution at room temperature and immediately crosslinked to form a hydrogel.
Example 11
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under aseptic conditions, 50mg of four-arm PEG amino (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution and fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded four-arm PEG aldehyde solution was slowly added to a stirred 1mL of four-arm PEG amino solution at room temperature and immediately crosslinked to form a hydrogel.
Example 12
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of six-arm PEG amino (with the weight-average molecular weight of 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution and fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded four-arm PEG aldehyde solution was slowly added to a stirred 1mL of six-arm PEG amino solution at room temperature and immediately crosslinked to form a hydrogel.
Example 13
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(2) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of eight-arm PEG amino (with the weight average molecular weight of 2000) is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution and fully dissolved at room temperature;
(4) preparation of the gel
1mL of the active-loaded four-arm PEG aldehyde solution was slowly added to a stirred 1mL of eight-arm PEG amino solution at room temperature and immediately crosslinked to form a hydrogel.
Example 14
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) synthesis of oxidized dextran Polymer (OD)
10.00g of dextran was precisely weighed and dissolved in 200mL of deionized water, and 8.00g of sodium periodate was added thereto. Then, the mixture was stirred at 37 ℃ for 6 hours, and 3mL of ethylene glycol was added thereto and stirred for 2 hours to terminate the reaction. Finally dialyzing in deionized water (pH 7.4) for 3 days, and freeze-drying in a freeze dryer after 3 days to obtain purified OD;
(2) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of OD is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) preparation of amino group-containing Polymer solutions
Under the aseptic condition, precisely weighing 50mg of carboxymethyl chitosan, dissolving the carboxymethyl chitosan in 1mL of sterile PBS, and stirring overnight at room temperature to fully dissolve the carboxymethyl chitosan;
(4) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of OD solution and is fully dissolved at room temperature;
(5) preparation of the gel
1mL of the active-loaded OD solution was slowly added to the stirred 1mL of carboxymethyl chitosan solution at room temperature and immediately crosslinked to form a hydrogel.
Example 15
A preparation method of intelligent hydrogel with heart injury repair function comprises the following steps:
(1) synthesis of oxidized sodium alginate polymer (OSA)
10.00g of sodium alginate was precisely weighed and dissolved in 200mL of deionized water, and 8.00g of sodium periodate was added thereto. Then, the mixture was stirred at 37 ℃ for 6 hours, and 3mL of ethylene glycol was added thereto and stirred for 2 hours to terminate the reaction. Finally dialyzing in deionized water (pH 7.4) for 3 days, and freeze-drying in a freeze dryer after 3 days to obtain purified OSA;
(2) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of OSA is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of carboxymethyl chitosan is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(4) aldehyde group-containing polymer solution loaded with active substance
Under aseptic conditions, 4mg of the bioactive substance, namely the recombinant type I humanized collagen, is dissolved in 1mL of OSA solution and is fully dissolved at room temperature;
(5) preparation of the gel
1mL of the active-loaded OSA solution was slowly added to the stirred 1mL carboxymethyl chitosan solution at room temperature and immediately crosslinked to form a hydrogel.
Example 16
A preparation method of intelligent hydrogel with a heart injury repair function comprises the following preparation steps:
(1) synthesis of oxidized hyaluronic acid Polymer (OHA)
10.00g of hyaluronic acid was precisely weighed and dissolved in 200mL of deionized water, and 8.00g of sodium periodate was added thereto. Then, the reaction mixture was stirred at 37 ℃ for 6 hours, and 3mL of ethylene glycol was added thereto and stirred for 2 hours to terminate the reaction. Finally dialyzing in deionized water (pH 7.4) for 3 days, and freeze-drying in a freeze dryer after 3 days to obtain purified OHA;
(2) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of OHA is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of carboxymethyl chitosan is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(4) aldehyde group-containing polymer solution loaded with active substance
Under aseptic conditions, 4mg of the bioactive substance, namely the recombinant type I humanized collagen, is dissolved in 1mL of OHA solution and is fully dissolved at room temperature;
(5) preparation of the gel
1mL of the active-loaded OHA solution was slowly added to the stirred 1mL of carboxymethyl chitosan solution at room temperature and immediately crosslinked to form a hydrogel.
Example 17
A preparation method of intelligent hydrogel with a heart injury repair function comprises the following preparation steps:
(1) synthesis of oxidized methyl cellulose polymers (OMC)
10.00g of methylcellulose was weighed out and dissolved in 200mL of deionized water, and 8.00g of sodium periodate was added thereto. Then, the mixture was stirred at 37 ℃ for 6 hours, and 3mL of ethylene glycol was added thereto and stirred for 2 hours to terminate the reaction. Finally dialyzing in deionized water (pH 7.4) for 3 days, and freeze-drying in a freeze dryer after 3 days to obtain purified OMC;
(2) preparation of aldehyde group-containing Polymer solution
Under the aseptic condition, 50mg of OMC is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(3) preparation of amino group-containing Polymer solutions
Under the aseptic condition, 50mg of carboxymethyl chitosan is precisely weighed and dissolved in 1mL of sterile PBS, and the mixture is stirred overnight at room temperature to be fully dissolved;
(4) aldehyde group-containing polymer solution loaded with active substance
Under the aseptic condition, 4mg of bioactive substance recombinant I-type humanized collagen is dissolved in 1mL of OMC solution and fully dissolved at room temperature;
(5) preparation of the gel
1mL of the active-loaded OMC solution was slowly added to the stirred 1mL of carboxymethyl chitosan solution at room temperature and immediately crosslinked to form a hydrogel.
Test examples
Taking the substances prepared in example 1 and example 2 as examples, the detection is carried out, and the specific operation processes and results are as follows:
unless otherwise stated, Hydrogel: blank hydrogel; 4mg/ml I: loading 4mg/ml of hydrogel of recombinant type I humanized collagen; 1mg/ml I: hydrogel loaded with 1mg/ml recombinant type I humanized collagen.
Firstly, detecting the hydrogel prepared in the step (4), and testing the rheological property of the hydrogel by using an MCR302 type rheometer. Steady state shear flow was carried out at 37 ℃ using a dual concentric cylinder geometry with a gap of 4 mm. The frequency sweep was with 1% strain and an oscillation frequency from 0.1 to 100 rad/s. The oscillation frequency of the strain sweep is 1Hz, and the strain is 0.01-1000%. In the self-healing experiments, alternating step strain sweep experiments (large strain: 1000%, 60s and small strain: 1%, 60s) were used. See in particular the figure.
FIG. 1 is an image of a 4mg/ml I hydrogel; FIG. 2a is a scanning electron microscope image of a blank hydrogel; FIG. 2b is a scanning electron micrograph of the hydrogel prepared in example 2; FIG. 2c is a scanning electron microscope image of the hydrogel prepared in example 1; all hydrogels were of uniform porous structure; FIG. 3 is a graph of injectability of a 4mg/ml I hydrogel, which was capable of being injected from a 27G needle, demonstrating the injectability of the hydrogel; FIG. 4a is a frequency scanning graph of hydrogel, and the result shows that the storage modulus of all three hydrogels is between 550-580Pa, and the storage modulus is larger than the loss modulus, and the hydrogels have stable hydrogel structures. Fig. 4b is a graph of the results of the alternative step strain scanning of the hydrogel, and the results show that after the hydrogel structure is destroyed for 3 times, the storage modulus of the three groups of hydrogels recovers by more than 85%, which proves that the hydrogels have strong self-repairing performance.
Secondly, the biocompatibility of the hydrogel and the function of protecting myocardial cells from oxidative stress damage
The hydrogel is used for evaluating the protection of the myocardial cells from oxidative stress damage and the reduction of myocardial cell apoptosis by adopting a rat myocardial cell (H9C2) culture method. Will be provided withThe sterilized hydrogel was leached in cell culture medium (0.1g/mL) for 48h to prepare a material leach solution. H9C2 was seeded into 96-well plates at a density of 8000 per well. After 24h, the cell culture broth was removed and 200. mu. L H was used2O2The H9C2 was pretreated for 1H for oxidative stress damage, followed by addition of hydrogel leach liquor instead of different hydrogel samples to the well plates. The proliferation rate and morphology of H9C2 cells cultured for 24H and 72H were detected by CCK-8 and FDA/PI staining, respectively. H9C2 cells were stained with FDA (30. mu.g/mL) and PI (10. mu.g/mL), allowed to stand for 5min, and then observed with a fluorescence microscope, see FIG. 5. After 24h, 72h incubation, fresh medium (90. mu.L) and diluted CCK-8 solution (10. mu.L) were added to each well. After 2h, the cell proliferation rate was calculated by measuring the absorbance at 450nm with a microplate reader.
The results of the hydrogel on the survival rate are shown in fig. 6, and the results show that all hydrogel groups have good biocompatibility on cells in 24h and 72h, and in addition, after the hydrogel is loaded with bioactive substances, namely the type I humanized collagen, the cell survival rate is higher than that of the blank hydrogel group, and the result shows that the recombinant type I humanized collagen protects the myocardial cells from oxidative stress damage.
Thirdly, detecting the in vivo heart repairing effect of the hydrogel
In order to research the influence of the hydrogel on the in-vivo heart repair effect, a rat myocardial infarction disease model is established. M-type echocardiography detection is carried out on myocardial infarction rats successfully modeled on the 14 th day and the 28 th day, and the results are shown in figure 7, the wall contraction and relaxation motions of the hydrogel group loaded with the bioactive substance recombinant I-type humanized collagen are obviously better, which shows that the hydrogel loaded with the bioactive substance recombinant I-type humanized collagen has a certain promotion effect on the cardiac function repair after myocardial infarction.
The above-mentioned embodiments only express several embodiments of the present application, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the concept of the present application, and these are all within the scope of protection of the present application. Therefore, the protection scope of the present patent shall be subject to the appended claims.
SEQUENCE LISTING
<110> Sichuan university
<120> intelligent hydrogel with heart injury repair function, and preparation method and application thereof
<130>
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 60
<212> PRT
<213> Artificial sequence
<220>
<223> Artificial sequence
<400> 1
Gly Glu Lys Gly Ser Pro Gly Ala Asp Gly Pro Ala Gly Ala Pro Gly
1 5 10 15
Thr Pro Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly Val Val Gly Leu
20 25 30
Pro Gly Gln Arg Gly Glu Arg Gly Phe Pro Gly Leu Pro Gly Pro Ser
35 40 45
Gly Glu Pro Gly Lys Gln Gly Pro Ser Gly Ala Ser
50 55 60
Claims (10)
1. A preparation method of intelligent hydrogel with heart injury repair function is characterized by comprising the following steps of:
step 1, respectively preparing an aldehyde group-containing polymer solution and an amino group-containing polymer solution by using PBS as a solvent;
step 2, dissolving a bioactive substance in the aldehyde group-containing polymer solution;
the bioactive substance is recombinant I-type humanized collagen;
and 3, mixing the polymer solution containing the aldehyde group and the amino group, wherein the polymer solution contains the bioactive substances, so as to obtain the intelligent hydrogel.
2. The method for preparing an intelligent hydrogel having a cardiac injury repair function according to claim 1, wherein the mass concentration of the polymer containing aldehyde groups in the aldehyde group-containing polymer solution is as follows: 0.5 to 12% w/w.
3. The method for preparing an intelligent hydrogel having a cardiac injury repair function according to claim 2, wherein the mass concentration of the amino-containing polymer in the amino-containing polymer solution is as follows: 0.5 to 15% w/w.
4. The method for preparing an intelligent hydrogel having a cardiac injury repair function according to any one of claims 1 to 3, wherein the aldehyde group-containing polymer is at least one of the following substances:
aldehyde group PEG aldehyde group, four-arm PEG aldehyde group, six-arm PEG aldehyde group, eight-arm PEG aldehyde group, oxidized dextran polymer, oxidized sodium alginate polymer, oxidized hyaluronic acid polymer and oxidized methyl cellulose polymer.
5. The method for preparing the intelligent hydrogel having the cardiac injury repair function according to any one of claims 1 to 3, wherein the amino group-containing polymer is at least one of the following substances:
water-soluble chitosan derivative, polylysine, polyethyleneimine, gelatin, amino PEG amino, four-arm PEG amino, six-arm PEG amino and eight-arm PEG amino.
6. The method for preparing an intelligent hydrogel having a cardiac injury repair function according to claim 3, wherein the concentration of the bioactive substance in the aldehyde group-containing polymer solution containing the bioactive substance is 1 to 8 g/L.
7. The method for preparing an intelligent hydrogel having a cardiac injury repair function according to claim 3, wherein in the step 3, the volume ratio of the aldehyde group-containing polymer solution to the amino group-containing polymer solution is: 6: 1-1: 6.
8. A hydrogel for repairing cardiac injury, which is prepared by the preparation method of any one of claims 1 to 7.
9. A hydrogel for repairing cardiac injury, wherein the hydrogel is the intelligent hydrogel for repairing cardiac injury according to claim 8, which acts on the cardiac injury site.
10. Use of a hydrogel for repairing a cardiac injury according to claim 8 in the treatment of a cardiac injury.
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| CN202311441142.7A CN117338697A (en) | 2022-05-19 | 2022-05-19 | Intelligent hydrogel with heart injury repair function and preparation method and application thereof |
| CN202210555813.1A CN114767625A (en) | 2022-05-19 | 2022-05-19 | Intelligent hydrogel with heart injury repair function and preparation method and application thereof |
| PCT/CN2022/094699 WO2023221152A1 (en) | 2022-05-19 | 2022-05-24 | Intelligent hydrogel with cardiac injury repair function, method for preparing same, and use thereof |
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