CN117338697A - 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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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
The application discloses an intelligent hydrogel with heart injury repair function and a preparation method and application thereof, belonging to the technical field of medical materials, wherein the preparation method of the hydrogel is as follows: the polymer containing aldehyde groups and the molecules containing amino groups are reacted through Schiff base to prepare the intelligent hydrogel material with good biocompatibility, and meanwhile, the bioactive material is loaded to achieve the purposes of repairing heart injury and relieving heart failure.
Description
The application is a divisional application with the name of 'intelligent hydrogel with heart injury repair function, a preparation method and application', the application date of the original application is 2022, 05 and 19, and the application number of the original application is 202210555813.1.
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 death in humans, and myocardial infarction and associated heart failure are the leading causes of death, with heart failure occurring in about 50% of patients, although direct percutaneous coronary intervention improves early myocardial survival. Currently, effective methods for treating heart failure are left ventricular assist devices and heart transplantation, however, the former method is limited due to its reliance on long-term use of external devices, the latter method is limited due to a severe lack of donor organs, and both methods have extremely high risks, so new clinical methods for repairing hearts after myocardial infarction are urgently needed.
Existing treatment methods include direct injection of growth factors, small molecule drugs, stem cells and nucleic acids to treat myocardial infarction, but suffer from a series of problems such as low bioavailability, non-specific molecular delivery, limited cell proliferation, inability to form new functional heart tissue, poor gene retention, etc. The injectable hydrogel can be used for minimally invasive injection of bioactive substances or cells with therapeutic effects to an infarct site, realizes targeted release, and greatly solves the problems.
Stimulus-responsive hydrogels have attracted considerable attention for their ability to change shape in response to environmental changes, such as Reactive Oxygen Species (ROS), pH, temperature, enzymes, light, ultrasound, and the like. In drug delivery, the stimulus-responsive hydrogel can achieve intelligent local on-demand release of drug at the disease site, as compared to conventional hydrogels. Aiming at the microenvironment of the myocardial infarction part, the intelligent hydrogel capable of realizing accurate and rapid response to multiple stimulation of the microenvironment is designed, and the intelligent hydrogel has important effects in the aspects of repairing heart injury, promoting regeneration of heart blood vessels and improving heart functions.
Disclosure of Invention
The invention aims to solve the technical problems that the prior hydrogel formula is improved, the injectability and the controllable release capacity of active substances are improved, the hydrogel is used for loading recombinant I-type humanized collagen bioactive materials, and the intelligent hydrogel which can be used for heart failure auxiliary treatment and promoting the pH response of damaged heart repair is provided, so that the hydrogel has good biocompatibility and can promote the proliferation and the regeneration of cells of damaged heart parts under physiological conditions, can respond to acidic inflammation microenvironments of myocardial infarction parts to release active substances, and realize the functions of damaged heart remodeling and the like.
In order to achieve the above purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of intelligent hydrogel with heart injury repair function comprises the following steps under aseptic conditions:
step 1, respectively preparing an aldehyde group-containing polymer solution and an amino group-containing polymer solution by taking PBS as a solvent;
step 2, dissolving bioactive substances in the polymer solution containing aldehyde groups;
the bioactive substance is recombinant I-type humanized collagen;
and 3, mixing the polymer solution containing the aldehyde groups of the bioactive substances with the polymer solution containing the amino groups 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 heart 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 needed, the room temperature is usually between-10 ℃ and 40 ℃, and the dissolution and the mixing are all needed to be fully completed.
The hydrogel is prepared by cross-linking an aldehyde group-containing polymer and an amino group-containing polymer through Schiff base reaction.
The recombinant type I humanized collagen refers to: the full-length or partial amino acid sequence segment coded by the specific type-I collagen gene prepared by the DNA recombination technology, or the combination containing the functional segment of the human collagen.
The sequence of the recombinant type I humanized collagen is as follows:
GEKGSPGADGPAGAPGTPGPQGIAGQRGVVGLPGQRGERGFPGLPGPSG EPGKQGPSGAS
the recombinant humanized collagen is a collagen material which is obtained by systematically researching the full-length sequence of human type I collagen, screening out a high cell adhesion active gene sequence with concentrated positive and negative charges, predicting, verifying and screening through a computer-aided protein structure, and biosynthesizing through genetic engineering and fermentation engineering and has the same sequence as 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, and compared with animal collagen, the immunogenicity of animal-derived tissues is greatly reduced, and heart injury after myocardial infarction can be effectively treated.
The hydrogel for repairing heart injury provided by the application is prepared by uniformly mixing an aldehyde group-containing polymer solution loaded with a bioactive substance and an amino group-containing polymer solution into a gel in a sterile environment to generate hydrogel with higher water content, and then filling the hydrogel into a syringe or a transmission system, and directly injecting the hydrogel into a ventricular wall for treatment.
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, in the polymer solution containing aldehyde groups, the mass concentration of the polymer containing aldehyde groups is as follows: 0.5-12% w/w.
Optionally, in the polymer solution containing aldehyde groups, the mass concentration of the polymer containing aldehyde groups is as follows: 0.5-10% w/w.
Optionally, in the polymer solution containing aldehyde groups, the mass concentration of the polymer containing aldehyde groups is as follows: 2.5-10% w/w.
Optionally, in the amino group-containing polymer solution, the mass concentration of the amino group-containing polymer is: 0.5-15% w/w.
Optionally, in the amino group-containing polymer solution, the mass concentration of the amino group-containing polymer is: 0.5-10% w/w.
Optionally, in the amino group-containing polymer solution, the mass concentration of the amino group-containing polymer is: 5-10% w/w.
Optionally, the aldehyde group-containing polymer is at least one of the following:
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 forming the hydrogel, the aldehyde group-containing polymer used is at least soluble in PBS solvent to form a solution of uniform nature, and therefore, at least the aldehyde group-containing polymer has good solubility in PBS in terms of molecular weight selection. Typically, the weight average molecular weight of the aldehyde group PEG aldehyde group, the four-arm PEG aldehyde group, the six-arm PEG aldehyde group, and the eight-arm PEG aldehyde group is not more than 10000.
The aldehyde group-containing polymer described in step (1) is an oxidized ortho-hydroxyl group-containing polymer comprising: dextran, sodium alginate, hyaluronic acid, methylcellulose or modified products thereof, and the oxidant is sodium periodate.
Optionally, the amino group-containing polymer is at least one of the following:
water-soluble chitosan derivatives, polylysine, polyethylenimine, gelatin, amino-PEG amino, four-arm PEG amino, six-arm PEG amino, eight-arm PEG amino.
In order to form the hydrogel, the amino group-containing polymer employed is at least soluble in the PBS solvent to form a solution of uniform nature, and therefore, at least the amino group-containing polymer is selected to have good solubility in PBS. Typically, the amino-PEG amino group, the four-arm PEG amino group, the six-arm PEG amino group, and the eight-arm PEG amino group have a weight average molecular weight of no more than 10000.
The water-soluble chitosan derivative includes: carboxymethyl chitosan and hydroxypropyl chitosan.
Optionally, the aldehyde group-containing polymer is at least one of the following:
aldehyde PEG aldehyde group, four-arm PEG aldehyde group, six-arm PEG aldehyde group and eight-arm PEG aldehyde group;
the polymer containing amino is carboxymethyl chitosan or hydroxypropyl chitosan.
Optionally, the aldehyde group-containing polymer is a four-arm PEG aldehyde group;
the amino group-containing polymer is at least one of the following substances:
polylysine, polyethylenimine, gelatin, amino PEG amino groups, four-arm PEG amino groups, six-arm PEG amino groups, eight-arm PEG amino groups.
Optionally, the aldehyde group-containing polymer is at least one of the following:
oxidized dextran polymer, oxidized sodium alginate polymer, oxidized hyaluronic acid polymer, oxidized methylcellulose polymer;
the polymer containing amino is carboxymethyl chitosan or hydroxypropyl chitosan.
Alternatively, the concentration of the biologically active substance in the aldehyde group-containing polymer solution is 1 to 8g/L.
Alternatively, the concentration of the biologically active substance in the aldehyde group-containing polymer solution is 1 to 5g/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: 1:1-1:6.
The application also provides hydrogel for repairing heart 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 a sterile environment to generate hydrogel with high water content, filling the hydrogel into a syringe or a transmission system, and directly injecting the hydrogel into ventricular wall for treatment.
The application also provides a hydrogel for repairing heart injury, wherein the hydrogel is the intelligent hydrogel acting on heart lesion sites.
The application also provides the application of the intelligent hydrogel in treating cardiac injury.
The beneficial effects produced by the application include at least one of the following:
1. the intelligent hydrogel loaded with the active substances is crosslinked by utilizing Schiff base reaction between aldehyde groups and amino groups, so that the gel is formed rapidly;
2. the hydrogel has the advantages of simple preparation process, excellent rheological property and injectability, and 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 from the acidic inflammation microenvironment of the myocardial infarction part.
3. The hydrogel has the function of mechanical support, has an obvious cell growth promoting function, and can effectively promote the generation and repair of blood vessels at the damaged heart.
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 the injectability results of the hydrogel of 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 an experimental plot of alternating step-strain scans of hydrogels of example 1 and example 2 of the present application;
FIG. 5 shows the results of live-dead staining of H9C2 cells in examples 1 and 2 of the present application;
FIG. 6 shows the cytotoxicity results of hydrogels of examples 1 and 2 of the present application on H9C2 cells;
fig. 7 is a graph of cardiac ultrasound results for hydrogels 14d, 28d of examples 1 and 2 of the present application.
Detailed Description
The following detailed description of specific embodiments of the present application refers to the accompanying drawings.
In the examples below, the chemicals other than the substrate are chemically pure unless specifically stated.
In the following examples, the recombinant type I humanized collagen sequences used were as follows:
GEKGSPGADGPAGAPGTPGPQGIAGQRGVVGLPGQRGERGFPGLPGPSG EPGKQGPSGAS
example 1
A preparation method of intelligent hydrogel with heart injury repair function comprises the following preparation steps:
(1) Preparation of aldehyde group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(2) Preparation of amino group-containing Polymer solutions
Under the aseptic condition, precisely weighing 50mg of carboxymethyl chitosan, dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(3) Aldehyde group-containing polymer solutions loaded with active substances
Under the aseptic condition, 4mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution, and the solution is fully dissolved at room temperature;
(4) Preparation of gels
1mL of the four-arm PEG aldehyde group solution loaded with the active substance is slowly added into 1mL of the carboxymethyl chitosan solution at room temperature, and the mixture is immediately crosslinked to form the hydrogel.
Example 2
A preparation method of intelligent hydrogel with heart injury repair function comprises the following preparation steps:
(1) Preparation of aldehyde group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(2) Preparation of amino group-containing Polymer solutions
Under the aseptic condition, precisely weighing 50mg of carboxymethyl chitosan, dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(3) Aldehyde group-containing polymer solutions loaded with active substances
Under the aseptic condition, 1mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution, and the solution is fully dissolved at room temperature;
(4) Preparation of gels
1mL of the four-arm PEG aldehyde group solution loaded with the active substance is slowly added into 1mL of the carboxymethyl chitosan solution at room temperature, and the mixture is immediately crosslinked to form the hydrogel.
Example 3
A preparation method of intelligent hydrogel with heart injury repair function comprises the following preparation steps:
(1) Preparation of aldehyde group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of aldehyde PEG aldehyde group (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(2) Preparation of amino group-containing Polymer solutions
Under the aseptic condition, precisely weighing 50mg of carboxymethyl chitosan, dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(3) Aldehyde group-containing polymer solutions loaded with active substances
Under the aseptic condition, 4mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of aldehyde group PEG aldehyde group solution, and the solution is fully dissolved at room temperature;
(4) Preparation of gels
At room temperature, 1mL of active material-loaded aldehyde PEG aldehyde solution was slowly added to the stirred 1mL carboxymethyl chitosan solution, and immediately crosslinked to form a hydrogel.
Example 4
A preparation method of intelligent hydrogel with heart injury repair function comprises the following preparation steps:
(1) Preparation of aldehyde group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of six-arm PEG aldehyde group (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(2) Preparation of amino group-containing Polymer solutions
Under the aseptic condition, precisely weighing 50mg of carboxymethyl chitosan, dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(3) Aldehyde group-containing polymer solutions loaded with active substances
Under the aseptic condition, 4mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of six-arm PEG aldehyde group solution, and the solution is fully dissolved at room temperature;
(4) Preparation of gels
1mL of the six-arm PEG aldehyde group solution loaded with the active substance is slowly added into 1mL of the carboxymethyl chitosan solution at room temperature, and immediately crosslinked to form the hydrogel.
Example 5
A preparation method of intelligent hydrogel with heart injury repair function comprises the following preparation steps:
(1) Preparation of aldehyde group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(2) Preparation of amino group-containing Polymer solutions
Under the aseptic condition, precisely weighing 50mg of hydroxypropyl chitosan to dissolve in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(3) Aldehyde group-containing polymer solutions loaded with active substances
Under the aseptic condition, 4mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution, and the solution is fully dissolved at room temperature;
(4) Preparation of gels
1mL of the four-arm PEG aldehyde group solution loaded with the active substance is slowly added into 1mL of the hydroxypropyl chitosan solution at room temperature, and is immediately crosslinked to form the hydrogel.
Example 6
A preparation method of intelligent hydrogel with heart injury repair function comprises the following preparation steps:
(1) Preparation of aldehyde group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(2) Preparation of amino group-containing Polymer solutions
Under aseptic condition, precisely weighing 50mg gelatin, dissolving in 1mL aseptic PBS, and stirring overnight at room temperature to make it fully dissolved;
(3) Aldehyde group-containing polymer solutions loaded with active substances
Under the aseptic condition, 4mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution, and the solution is fully dissolved at room temperature;
(4) Preparation of gels
1mL of the active-loaded four-arm PEG aldehyde solution was slowly added to the stirred 1mL gelatin solution at room temperature, and immediately crosslinked to form a hydrogel.
Example 7
A preparation method of intelligent hydrogel with heart injury repair function comprises the following preparation steps:
(1) Preparation of aldehyde group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(2) Preparation of amino group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of amino PEG amino (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(3) Aldehyde group-containing polymer solutions loaded with active substances
Under the aseptic condition, 4mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution, and the solution is fully dissolved at room temperature;
(4) Preparation of gels
1mL of the four-arm PEG aldehyde group solution loaded with the active substance is slowly added into 1mL of the amino PEG amino solution at room temperature, and immediately crosslinked to form the hydrogel.
Example 8
A preparation method of intelligent hydrogel with heart injury repair function comprises the following preparation steps:
(1) Preparation of aldehyde group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(2) Preparation of amino group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of four-arm PEG amino (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(3) Aldehyde group-containing polymer solutions loaded with active substances
Under the aseptic condition, 4mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution, and the solution is fully dissolved at room temperature;
(4) Preparation of gels
1mL of the four-arm PEG aldehyde group solution loaded with the active substance is slowly added into 1mL of the four-arm PEG amino group solution at room temperature, and the four-arm PEG aldehyde group solution is immediately crosslinked to form hydrogel.
Example 9
A preparation method of intelligent hydrogel with heart injury repair function comprises the following preparation steps:
(1) Preparation of aldehyde group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(2) Preparation of amino group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of six-arm PEG amino (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(3) Aldehyde group-containing polymer solutions loaded with active substances
Under the aseptic condition, 4mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution, and the solution is fully dissolved at room temperature;
(4) Preparation of gels
1mL of the four-arm PEG aldehyde group solution loaded with the active substance is slowly added into 1mL of the six-arm PEG amino solution at room temperature, and the mixture is immediately crosslinked to form the hydrogel.
Example 10
A preparation method of intelligent hydrogel with heart injury repair function comprises the following preparation steps:
(1) Preparation of aldehyde group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of four-arm PEG aldehyde group (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(2) Preparation of amino group-containing Polymer solutions
Under aseptic conditions, precisely weighing 50mg of eight-arm PEG amino (weight average molecular weight 2000) and dissolving in 1mL of aseptic PBS, and stirring overnight at room temperature to fully dissolve;
(3) Aldehyde group-containing polymer solutions loaded with active substances
Under the aseptic condition, 4mg of bioactive substance recombinant type I humanized collagen is dissolved in 1mL of four-arm PEG aldehyde group solution, and the solution is fully dissolved at room temperature;
(4) Preparation of gels
1mL of the four-arm PEG aldehyde group solution loaded with the active substance is slowly added into 1mL of the eight-arm PEG amino group solution at room temperature, and the four-arm PEG aldehyde group solution is immediately crosslinked to form hydrogel.
Test examples
Taking the substances prepared in example 1 and example 2 as examples, detection was carried out, and the specific operation procedure and results were as follows:
hydrogel, unless specified: blank hydrogel; 4mg/ml I: 4mg/ml of hydrogel of recombinant type I humanized collagen is loaded; 1mg/ml I: hydrogel loaded with 1mg/ml recombinant type I humanized collagen.
1. And (3) detecting the hydrogel prepared in the step (4), and testing the rheological property of the hydrogel by using an MCR302 rheometer. A double concentric cylinder geometry with a gap of 4mm was used for steady state shear flow at 37 ℃. The frequency sweep uses a 1% strain and an oscillation frequency from 0.1 to 100 rad/s. The oscillation frequency of strain sweep is 1Hz, and the strain is 0.01-1000%. In the self-healing experiment, an alternating step-strain sweep experiment (large strain: 1000%,60s and small strain: 1%,60 s) was 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 microscope image 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 an injectability diagram of a 4mg/ml I hydrogel capable of being injected from a 27G needle, demonstrating that the hydrogel is injectable; FIG. 4a is a frequency scan of hydrogels, showing that the storage modulus of all three hydrogels is between 550 and 580Pa, and the storage modulus is greater than the loss modulus, with a stable hydrogel structure. FIG. 4b is a graph of alternate step-strain scan results of hydrogels, showing that after the hydrogel structure is destroyed 3 times, the storage modulus of three groups of hydrogels is recovered by more than 85%, which proves that the hydrogels have stronger self-repairing performance.
2. Biocompatibility of hydrogels and function to protect cardiomyocytes from oxidative stress injury
The hydrogel is used for protecting the myocardial cells from oxidative stress injury and reducing myocardial cell apoptosis by adopting a rat myocardial cell (H9C 2) culture method. The sterilized hydrogel was leached in cell culture medium (0.1 g/mL) for 48h to prepare a material leaching 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 used 2 O 2 The H9C2 was subjected to oxidative stress injury pretreatment for 1H, followed by addition of hydrogel leach liquor to the well plate instead of the different hydrogel samples. 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), then 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 hydrogel relative survival rate results are shown in fig. 6, and the results show that all hydrogel groups have better biocompatibility on cells at 24h and 72h, and in addition, after the hydrogel is loaded with bioactive substances and recombinant type I humanized collagen, the cell survival rate is higher than that of a blank hydrogel group, so that the recombinant type I humanized collagen protects myocardial cells from oxidative stress injury.
3. Detection of in vivo cardiac repair effect of hydrogels
In order to study the influence of hydrogel on in vivo heart repair effect, a rat myocardial infarction disease model is established. M-type echocardiography detection is carried out on the myocardial infarction rats successfully modeled on the 14 th day and the 28 th day, and the result is shown in figure 7, the ventricular wall contraction and diastole movements of the hydrogel group loaded with the bioactive substance recombinant type I humanized collagen are obviously better, which indicates that the hydrogel loaded with the bioactive substance recombinant type I humanized collagen has a certain promoting effect on cardiac function repair after myocardial infarction.
The above examples merely represent a few embodiments of the present application, which are described in more detail and are not to be construed as limiting the scope of the invention. It should be noted that it would be apparent to those skilled in the art that various modifications and improvements could be made without departing from the spirit of the present application, which would be within the scope of the present application. Accordingly, the scope of protection of the present application is to be determined by the claims appended hereto.
Claims (9)
1. The intelligent hydrogel with the heart injury repair function is characterized by being prepared by sequentially mixing an aldehyde group-containing polymer solution with a bioactive substance and an amino group-containing polymer solution;
the polymer containing aldehyde groups is at least one of the following substances:
aldehyde PEG aldehyde group, four-arm PEG aldehyde group and six-arm PEG aldehyde group;
the amino group-containing polymer is at least one of the following substances:
water-soluble chitosan derivatives, gelatin, amino-PEG amino groups, four-arm PEG amino groups, six-arm PEG amino groups, eight-arm PEG amino groups;
the bioactive substance is recombinant type I humanized collagen, and the sequence of the recombinant type I humanized collagen is as follows:
GEKGSPGADGPAGAPGTPGPQGIAGQRGVVGLPGQRGERGFPGLPGPSG EPGKQGPSGAS。
2. the intelligent hydrogel with heart damage repair function of claim 1,
the polymer solution containing aldehyde groups is mixed with the bioactive substances to obtain the polymer solution containing aldehyde groups and the concentration of the bioactive substances in the polymer solution containing aldehyde groups and containing the bioactive substances is 1-8 g/L.
3. The intelligent hydrogel with heart damage repair function according to claim 1, wherein the preparation method of the intelligent hydrogel comprises the following steps performed under aseptic conditions:
step 1, respectively preparing an aldehyde group-containing polymer solution and an amino group-containing polymer solution by taking PBS as a solvent;
step 2, dissolving bioactive substances in the polymer solution containing aldehyde groups;
and 3, mixing the polymer solution containing the aldehyde groups of the bioactive substances with the polymer solution containing the amino groups to obtain the intelligent hydrogel.
4. The intelligent hydrogel with heart damage repair function of claim 3,
in the polymer solution containing aldehyde groups, the mass concentration of the polymer containing aldehyde groups is as follows: 0.5-12% w/w.
5. The intelligent hydrogel with heart damage repair function of claim 3,
in the polymer solution containing amino, the mass concentration of the polymer containing amino is as follows: 0.5-15% w/w.
6. The intelligent hydrogel with heart damage repair function of claim 3,
in the step 3, the volume ratio of the polymer solution containing aldehyde groups to the polymer solution containing amino groups is as follows: 6:1-1:6.
7. A hydrogel for repairing cardiac injury, characterized in that a smart hydrogel according to any one of claims 1-6 is used.
8. A hydrogel for repairing cardiac injury, wherein the hydrogel is a smart hydrogel for repairing cardiac injury according to claim 7 applied to the site of cardiac injury.
9. Use of the hydrogel for repairing cardiac injury according to claim 7 in the treatment of cardiac injury.
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| WO2020047394A1 (en) * | 2018-08-31 | 2020-03-05 | The Trustees Of The University Of Pennsylvania | Injectable hydrogels for local delivery to the heart |
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