CN111905152A

CN111905152A - Silicon-based bioactive glass composite hydrogel with self-healing characteristic, preparation method thereof and application thereof in myocardial repair

Info

Publication number: CN111905152A
Application number: CN202010641451.9A
Authority: CN
Inventors: 常江; 高龙; 周艳玲
Original assignee: Shanghai Institute of Ceramics of CAS
Current assignee: Shanghai Institute of Ceramics of CAS
Priority date: 2020-07-06
Filing date: 2020-07-06
Publication date: 2020-11-10
Anticipated expiration: 2040-07-06
Also published as: CN111905152B

Abstract

The invention provides a silicon-based bioactive glass composite hydrogel with a self-healing characteristic, a preparation method thereof and application thereof in myocardial repair. The silicon-based bioactive glass composite hydrogel is provided with a cross-linked gel network formed by an imine bond formed by a macromolecular material containing aldehyde groups and a macromolecular material containing amino groups through Schiff base reaction of the aldehyde groups and the amino groups, and a composite gel structure in which silicon-based bioactive glass is uniformly dispersed in the gel network; in the silicon-based bioactive glass composite hydrogel, the mass percentages of the aldehyde-containing high polymer material, the amino-containing high polymer material and the silicon-based bioactive glass are respectively 1-10%, 1-10% and 0.1-1.0%.

Description

Silicon-based bioactive glass composite hydrogel with self-healing characteristic, preparation method thereof and application thereof in myocardial repair

Technical Field

The invention relates to the fields of biomedicine, material technology, myocardial repair and medical equipment, in particular to a silicon-based bioactive glass composite hydrogel for treating myocardial injury and a preparation method and application thereof.

Background

Cardiovascular disease is currently one of the leading diseases of human death worldwide. The World Health Organization (WHO) reports that 1750 thousands of people die of cardiovascular diseases in 2012 all over the world, accounting for 31 percent of the death population, far exceeding the death population of other single disease species and even exceeding the death population of various cancers, although medical technology and medical quality have been obviously improved in recent years. According to the report 2014 of the cardiovascular system diseases in China issued by the national center for research on the cardiovascular system diseases, the total hospitalization cost of the patients suffering from acute myocardial infarction in 2013 is as high as 114.7 billion yuan. Cardiovascular system diseases consume huge medical resources and increasingly burden the society, and become a great public health problem. Therefore, the search for new and effective methods to repair damaged cardiovascular and myocardial tissue and to reestablish cardiac function has become an urgent problem to be solved.

Stem cell therapy is considered to be an effective method of treating myocardial infarction. Stem cell repair of cardiomyocytes following myocardial infarction proceeds primarily through two mechanisms: one mechanism suggests that stem cells can differentiate directly into cardiomyocytes; another mechanism is thought to be that stem cells repair cardiac myocytes by secreting molecules useful for treating myocardial infarction through paracrine action. The improvement of the myocardial phenotype of the stem cells can improve the curative effect of stem cell therapy on myocardial infarction. In addition, stem cells secrete a variety of beneficial paracrine factors to enhance the repair of damaged hearts. Many researches show that the paracrine effect of the stem cells is improved, and the curative effect of stem cell therapy on myocardial infarction can be obviously improved. However, the weak interaction between stem cells and cardiomyocytes and the lack of sufficient intercellular communication lead to insufficient development of the cardiomyocyte phenotype and paracrine effect of stem cells, which limits the effectiveness of stem cell therapy.

To increase the efficiency of stem cell therapy in treating myocardial infarction, a variety of biomaterials are used to deliver stem cells to the site of the myocardial infarction. The hydrogel, as a high molecular material with high water content, has wide application in myocardial stem cell therapy, and can protect stem cells after being injected into target tissues. Considering that the heart is a continuously beating organ, the hydrogel having the self-healing function can have a longer service life in an environment where the heart frequently vibrates.

The silicon-based bioactive glass has good bioactivity, can inhibit inflammation and promote angiogenesis differentiation in vivo, and the released ions can stimulate cells to secrete growth factors such as Vascular Endothelial Growth Factor (VEGF) and basic fibroblast growth factor (bFGF) to stimulate the proliferation and differentiation of cells such as endothelial cells, so that the regeneration of blood vessels is promoted, the proliferation and migration of stem cells in vitro can be remarkably promoted, the activity of myocardial cells in ischemic myocardial tissues and the mutual communication among the cells are improved, and the silicon-based bioactive glass has a good effect on improving the condition of myocardial infarction parts.

Chinese patent CN107115562A discloses an injectable hydrogel for repairing cardiac muscle, which comprises bioactive glass, sodium alginate and gluconolactone as main ingredients. The hydrogel is formed by complexing calcium ions released by bioactive glass and carboxyl in alginic acid based on gluconolactone, and has no self-healing property due to physical electrostatic combination. In addition, the patent only verifies that the composite hydrogel can be used for filling the damaged part of the myocardium to play a supporting role and promoting the vascularization of the damaged myocardium, and the effect of the composite hydrogel in the stem cell therapy is not verified in the damaged part of the myocardium.

Chinese invention patent CN106267364A discloses an alginic acid/PEDOT conductive porous scaffold, which can promote differentiation of brown adipose-derived stem cells towards cardiac muscle cells by electrical stimulation, but the method needs additional electrical stimulation, is complex to operate and is not beneficial to practical clinical operation.

Chinese patent CN109503863A discloses that a chitosan-based temperature-sensitive hydrogel loaded Umbilical Cord Mesenchymal Stem Cells (UCMSCs) is applied to cardiac injury repair of myocardial infarction, but the hydrogel has temperature-sensitive characteristics, needs to be mixed in ice bath, forms gel at body temperature, is complex to operate, has relatively short gel forming time (about 3 minutes), and is not favorable for clinical use of injectable hydrogel for myocardial repair.

Disclosure of Invention

In view of the above-mentioned defects of the prior art, the technical problem to be solved by the present invention is to provide an injectable hydrogel for myocardial repair, which can increase the activity of cells, improve the interaction between the loaded stem cells and myocardial cells, and thus promote myocardial repair at myocardial infarction sites.

In order to achieve the aim, the invention provides a silicon-based bioactive glass composite hydrogel. The silicon-based bioactive glass composite hydrogel is provided with a cross-linked gel network formed by an imine bond formed by a macromolecular material containing aldehyde groups and a macromolecular material containing amino groups through Schiff base reaction of the aldehyde groups and the amino groups, and a composite gel structure formed by uniformly dispersing silicon-based bioactive glass in the gel network.

The silicon-based bioactive glass plays multiple roles in the composite hydrogel with the structure.

Firstly, the silicon-based bioactive glass can regulate the injectability and gelling time of the composite hydrogel. The silicon-based bioactive glass undergoes rapid ion exchange with water (e.g., water in a buffer solution) and creates an alkaline microenvironment. The bioactive glass is rendered alkaline by the following reaction: na in bioactive glass⁺First dissolved from the glass surface and rapidly reacts with H in the body fluid⁺Or H₃O⁺The exchange takes place, whereby the OH concentration in the solution increases, resulting in an increase in the alkalinity. In addition, due to Na⁺Releasing from the silicon-oxygen tetrahedral network structure to cause the destruction of the silicon-oxygen network structure and form silicon hydroxyl (Si-OH) on the surface; followed by Si-O-Si and H of the surface layer₂The O action is broken and further increases the OH concentration in the solution. The alkaline microenvironment generated by the silicon-based bioactive glass can regulate and control Schiff base reaction based on aldehyde group and amino group, so as to regulate and control gelling time. The Schiff base reaction of aldehyde group and amino group has pH sensitivity, and the chemical reaction rate is accelerated along with the increase of pH in a certain basic range (8-11). Therefore, the invention can control the pH change by changing the content of the added bioactive glass so as to achieve the purpose of regulating and controlling the gelling time.

And secondly, the silicon-based bioactive glass can regulate and control the self-healing property of the composite hydrogel. The Schiff base structure is formed by condensation reaction of aldehyde group and amino group, and chemical bonds formed by the Schiff base are in dynamic reversible balance through dehydration and hydrolysis processes, so that a foundation is provided for the self-healing performance of the hydrogel. The hydrogel without adding bioactive glass has certain self-healing property, but the self-healing efficiency is low; after the bioactive glass is added, the self-healing efficiency of the hydrogel is greatly improved because the bioactive glass can be continuously degraded and maintain the alkaline microenvironment of the whole system.

It is noteworthy that if only basic buffer solutions are used to create a basic microenvironment, the pH of the whole solution system shows a tendency to decrease due to the acidity of the degradation products of the hydrogel (e.g., degradation products of aldehyde polyglutamic acid and 2-hydroxypropionic acid modified chitosan), which is not conducive to enhancing the self-healing properties of the imine bond-based hydrogel. If a strong alkaline buffer solution is added, the whole system is always in an alkaline state, the gelling is too fast, the controllable gelling time range is narrow, and the self-healing property of the hydrogel is influenced. After the bioactive glass is added, the effect is far better than that of only adopting an alkaline buffer solution because the bioactive glass can be continuously degraded to maintain the alkaline environment of the whole system.

In addition, bioactive ions released by the silicon-based bioactive glass composite hydrogel can regulate and control the interaction between the myocardial cells and the stem cells, and the capacity of the stem cells for inhibiting the apoptosis of the myocardial cells under the anoxic condition is improved.

In the silicon-based bioactive glass composite hydrogel, the mass ratio of the aldehyde-containing high polymer material to the amino-containing high polymer material to the silicon-based bioactive glass is 1-10%, 1-10% and 0.1-1.0%, respectively. The sum of the mass percentages of all the raw materials of the composite hydrogel is 100%, and the balance is buffer solution. If the mass percent of the silicon-based bioactive glass exceeds 1.0 percent, the alkalinity of the system is too strong, and partial raw materials such as modified chitosan are separated out.

Preferably, the silicon-based bioactive glass contains CaO and SiO₂、Na₂O and P₂O₅The inorganic silicon-based bioactive glass. The silica-based bioactive glass generates alkalinity in water environment, and can promote Schiff base reaction. Other bioglasses, such as phosphate glass, are not capable of providing an alkaline environment and are therefore not suitable for use in the present invention. Moreover, silicon-based bioactive glass releases silicon ions with angiogenesis promoting activity and maintains stem cell activity during degradation, while other bioactive glass does not have the activity.

Preferably, the content of CaO in the silicon-based bioactive glass is 10-60% by mass, and P is₂O₅Is 3-20% of SiO₂The content of (A) is 40-80%, and Na₂The content of O is 10-60%.

Preferably, the aldehyde group-containing polymer material comprises periodate-oxidized sodium alginate, periodate-oxidized dextran, periodate-oxidized hyaluronic acid and aldehyde-modified polyglutamic acid.

Preferably, the amino-containing polymer material comprises 2-hydroxypropionic acid modified chitosan and polylysine. Since unmodified chitosan can only be dissolved in an acidic solution, and schiff base reaction needs to occur under an alkaline condition, the unmodified chitosan cannot achieve the effect of the present invention.

Preferably, the silicon-based bioactive glass is doped with at least one of potassium, lithium, magnesium, boron, zinc, copper and strontium, and the doping amount is 1-20 wt%.

Preferably, the particle size of the silicon-based bioactive glass is less than 100 μm, and preferably 1-10 μm.

Preferably, the molar ratio of the aldehyde group to the amino group is 1: 3-3: 1. controlling the molar ratio of aldehyde groups to amino groups at the above ratio is advantageous for Schiff base reactions to occur and for sufficient crosslinking sites to form a stable hydrogel network, and beyond this range, formation of a hydrogel is not favored.

The schiff base reaction is a chemical reaction between an amino group and an aldehyde group to generate an imine bond, which may respond to pH, and the schiff base reaction may move toward the formation of the imine bond in a high pH environment. Based on the characteristic, the Schiff base reaction is selected as the crosslinking site of the hydrogel network, and the silicon-based bioactive glass can generate rapid ion release in a water environment and cause the pH microenvironment to rise, so that the pH change can be controlled by changing the content of the added bioactive glass, and the aim of regulating and controlling the gelling time is fulfilled. Preferably, the gelling time of the silicon-based bioactive glass composite hydrogel is more than 4min, preferably 4-20 min, and more preferably 8-20 min. The gel product of the invention has obviously prolonged gelling time, thus avoiding too fast gelling time, causing the situation that the cells are not covered in time and being not beneficial to the preparation operation before the operation. In addition, the invention can also avoid hydrogel collapse and adverse stem cell retention caused by that the hydrogel is injected into a body too slowly to be gelatinized in time.

In a second aspect, the present invention further provides a preparation method of any one of the above silicon-based bioactive glass composite hydrogels, comprising the following steps:

(1) dissolving a macromolecular material containing aldehyde groups in a buffer solution with the pH value of 5.0-8.0 to obtain a solution A with the mass volume fraction (g/mL) of the macromolecular material containing aldehyde groups being 1-10%;

(2) dissolving a macromolecular material containing amino in a buffer solution with the pH value of 5.0-8.0 to obtain a solution B with the mass volume fraction (g/mL) of the macromolecular material containing amino being 1-10%;

(3) mixing the solution A and the solution B in a volume ratio of 1: 3-3: 1, mixing, and then adding silicon-based bioactive glass powder to form the silicon-based bioactive glass composite hydrogel.

Such buffer solutions include, but are not limited to, phosphoric acid (phosphate), citric acid, carbonic acid, acetic acid, barbituric acid, Tris (Tris) solution within a certain pH range. The invention can be realized as long as the buffer solution meets the pH range of 5.0-8.0. In a specific embodiment, a phosphate buffer solution (PBS buffer solution) is used.

In a third aspect, the invention further provides an application of the silicon-based bioactive glass composite hydrogel with the self-healing characteristic in myocardial repair, especially an application of the silicon-based bioactive glass composite hydrogel loaded with stem cells in repairing damaged myocardial cells after myocardial infarction.

Drawings

FIG. 1 is gel formation time of composite hydrogel with different mass fractions of silicon-based bioactive glass;

FIG. 2 is a schematic diagram showing the self-healing performance of a composite hydrogel;

FIG. 3 is an echocardiogram of the heart of a mouse after treatment by different methods; wherein Sham means that the heart is not treated by myocardial infarction only by opening the chest, AMI means that the heart is opened and the myocardial infarction is not treated, MSC means that the heart is opened and the myocardial infarction is only injected for treatment, Gel + MSC means that the heart is opened and the myocardial infarction is produced, and the MSC is wrapped by the composite hydrogel for treatment;

FIG. 4 is a BG/γ -PGA/CS hydrogel encapsulating MSCs to improve cardiac function; (a) is the left ventricular end diastolic diameter, (b) is the left ventricular end systolic diameter, (c) is the left ventricular short axis shortening index, (d) is the left ventricular ejection fraction;

figure 5 is the healing efficiency of composite hydrogels of different silicon-based bioactive glass mass fractions.

Detailed Description

The present invention is further illustrated by the following examples, which are to be understood as merely illustrative and not restrictive.

The following is an exemplary illustration of the method for preparing the silicon-based bioactive glass composite hydrogel of the present invention.

Dissolving the aldehyde group-containing high polymer material in a phosphate buffer solution with the pH value of 5.0-8.0 to obtain a solution A with the aldehyde group-containing high polymer material mass volume fraction of 1-10%. The aldehyde group-containing polymer material comprises sodium alginate oxidized by periodic acid, dextran oxidized by periodic acid, hyaluronic acid oxidized by periodic acid and aldehyde group-modified polyglutamic acid. Preferred is aldehyde-modified polyglutamic acid. The reason is that: the cell adhesion of polysaccharide substances including glucan, chitosan and the like is usually poor, and after the polysaccharide substances are compounded with polyglutamic acid, the composite material has higher hydrophilicity, and is favorable for adsorbing protein, so that the cell adhesion is favorable.

Dissolving the macromolecular material containing the amino into a phosphate buffer solution with the pH value of 5.0-8.0 to obtain a solution B with the mass volume fraction of the macromolecular material containing the amino being 1-10%. The amino-containing high polymer material comprises 2-hydroxypropionic acid modified chitosan and polylysine. 2-hydroxypropionic acid modified chitosan is preferred. Other modified chitosan products (such as carboxymethyl chitosan and hydroxypropyl chitosan), although having amino groups in their molecular structure, cannot form hydrogels with high molecular materials containing aldehyde groups due to the low site reactivity of the amino groups.

The solution A and the solution B are mixed in equal proportion (volume proportion). Then adding silicon-based bioactive glass powder to mix into glue. In the silicon-based bioactive glass, the content of CaO is 10 to 60 percent by mass, and P is₂O₅Is 3-20% of SiO₂The content of (A) is 40-80%, and Na₂The content of O is 10-60%.

The hydrogel is based on Schiff base reaction as a crosslinking site of a hydrogel network, silicon-based bioactive glass can generate rapid ion release in a water environment and cause the pH microenvironment to rise, and the pH change can be controlled by changing the content of the added bioactive glass, so that the purpose of regulating and controlling the gelling time is achieved. Specifically, in the embodiment, the gel forming time of the composite hydrogel is regulated and controlled by controlling the mass percentage of the silicon-based bioactive glass in the composite hydrogel. Preferably, when the mass percent of the silicon-based bioactive glass is 0.125-0.375%, the gelling time of the composite hydrogel is 8.2-19 min.

In the composite hydrogel, the particle size of the silicon-based bioactive glass is less than 100 microns, and preferably 1-10 microns. The bioglass has a particle size within the above range, and can be easily and uniformly mixed with the polymer solution. Meanwhile, the silicon-based bioactive glass with small particle size is not easy to block a needle (for example, a 23-gauge needle is used in a specific embodiment) and is convenient to inject.

The hydrogel system is based on amino and aldehyde groups as crosslinking sites of the hydrogel network, and the silicon-based bioactive glass can generate rapid ion release in a water environment and cause the pH value of the microenvironment of the system to rise, so that the amino and aldehyde groups move towards the direction of formation of imine bonds, and the crosslinking network is further formed. Therefore, the three components have a synergistic relationship with the formation of the hydrogel. In the silicon-based bioactive glass composite hydrogel provided by the invention, the mass ratio of the aldehyde-containing high polymer material to the amino-containing high polymer material to the silicon-based bioactive glass is (1-10%): (1-10%): (0.1-1.0%). Wherein the silicon-based bioactive glass is uniformly dispersed in the cross-linked network in a granular shape.

The silicon-based bioactive glass composite hydrogel is injectable hydrogel which is liquid at room temperature and can be directly injected into a human body through a needle. The hydrogel of the invention has no temperature sensitive characteristic, namely, the hydrogel can be gelled at room temperature. And the gelling time can be adjusted according to the content of the added bioactive glass.

The PBS solution used in the following examples is not limited in its source, and may be commercially available or self-made. For example, the PBS buffer solution is prepared by: firstly, 0.2M sodium dihydrogen phosphate aqueous solution (solution A) is prepared, then 0.2M disodium hydrogen phosphate aqueous solution (solution B) is prepared, 39 ml of solution A and 61 ml of solution B are taken to make the volume to 200 ml, and then 0.1M PBS solution is obtained.

Example 1

1. Aldehyde modification of gamma-PGA (polyglutamic acid): 0.30g of γ -PGA powder was dissolved in 60mL of deionized water, and stirred to be completely dissolved. Then, 0.42g of aminopropanediol and 0.31g N-hydroxysuccinimide were added. After sufficient dissolution, the pH was adjusted to 4.0 with 0.1M NaOH solution or 0.1M HCl solution. Then, 0.89g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added thereto and reacted at room temperature for 24 hours. And (4) pouring the mixture into a dialysis bag (with molecular weight cutoff of 30000Da) for dialysis for 3 days to obtain the aminopropanediol modified gamma-PGA solution. Then, 0.02g of sodium periodate was added under protection from light, and the reaction was carried out for 5min, and terminated by adding an excess of ethylene glycol. And finally, pouring the obtained aldehyde modified gamma-PGA solution into a dialysis bag (with molecular weight cutoff of 30000Da) for dialysis for 3 days, changing water for 2 times every day, freeze-drying to obtain aldehyde modified gamma-PGA, and preparing the aldehyde modified gamma-PGA into a solution with the mass fraction of 5% by using a PBS solution.

2. Modification for improving water solubility of chitosan: 0.3g of powdery chitosan and 1.0g of 2-hydroxypropionic acid were added to 100mL of deionized water and sufficiently dissolved. Then, 0.42g N-hydroxysuccinimide was added and dissolved by stirring. The pH was adjusted to 5.0-5.5 with 0.1M NaOH solution and 0.60g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added for a reaction time of 12 h. After sufficient dissolution, the pH was adjusted to 4.0 with 0.1M NaOH solution or 0.1M HCl solution. Then, 1.41g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added and reacted at room temperature for 24 hours. Finally, the product is added into a dialysis bag (molecular weight cutoff 30000Da) for dialysis for 3 days, water is changed for 2 times every day, 2-hydroxypropionic acid modified chitosan is obtained after freeze drying, and the chitosan is prepared into solution with mass fraction of 5% by using PBS solution.

3. Preparation of composite hydrogel: mixing a 5% aldehyde modified gamma-PGA solution and a 5% 2-hydroxypropionic acid modified chitosan solution in an equal volume ratio, adding silicon-based bioactive glass, and stimulating the aldehyde modified gamma-PGA and the 2-hydroxypropionic acid modified chitosan to perform Schiff base reaction by utilizing the alkalinity created by the bioactive glass to form the bioactive glass composite hydrogel gel. As can be seen from fig. 1, when the mass fractions of the bioactive glass are 0.125%, 0.250%, 0.375%, 0.500% and 0.625%, the gelling time is 19min, 13min, 8.2min, 5.4min and 4.6min, respectively, and the gelling time decreases with the increase of the content of the bioactive glass.

Example 2

Mixing a 5% aldehyde modified gamma-PGA solution and a 5% 2-hydroxypropionic acid modified chitosan solution in an equal volume ratio, and adding 1.00% of bioactive glass by mass to prepare the bioglass composite hydrogel. The gelling time of the composite hydrogel is 3 min. Two portions of composite hydrogel were prepared in parallel, one portion being dyed green with a dye. Then, the two hydrogels were cut in half and, after interchanging, re-spliced together. After 5min, the hydrogel can be stably spliced together, and the spliced interface cannot be broken by pulling forcefully. This is because: the Schiff base structure is formed by condensation reaction of aldehyde group and amino group, and chemical bonds formed by the Schiff base are in dynamic reversible equilibrium through dehydration and hydrolysis processes, so that a foundation is provided for the self-healing performance of the hydrogel. After the silicon-based bioactive glass is added, the silicon-based bioactive glass can continuously degrade by slowly releasing alkaline ions through the bioglass particles to maintain the alkaline microenvironment of the whole system, so that the self-healing efficiency of the composite hydrogel is greatly improved.

Example 3

Mixing a 5% aldehyde modified gamma-PGA solution and a 5% 2-hydroxypropionic acid modified chitosan solution in an equal volume ratio, and adding bioactive glass with the mass fraction of 0.500% to prepare the bioglass composite hydrogel.

The stem cells are human mesenchymal stem cells (hBMSCs, Cyagen Biosciences), and the culture medium used for culturing is a Cyagen adult mesenchymal stem cell complete culture medium matched with manufacturers. The culture condition is a constant temperature incubator at 37 ℃ and the atmosphere environment is 5% CO₂The frequency of medium change was 3 days/time. When the cell density reached 80.0%, the medium was removed and washed with PBS, then digested, centrifuged, and subcultured. Passage 3 to 8 MSCs were used for experimental studies.

Left anterior descending ligated mice were randomly divided into 3 groups, i.e.: myocardial infarction group (AMI group), MSC treatment group (MSC group), and hydrogel encapsulated MSC treatment group (Gel + MSC group). Each timeThere were 5 mice in each group, and there were no significant differences in cardiac function prior to treatment. For MSC group, 1X 10 contained injections were injected into the perimyocardial region of the heart by using a syringe ⁶30 μ l of PBS solution of individual MSC cells. For the Gel + MSC group, 1X 10 doses were injected in the same manner around the perimyocardial infarction region ⁶30 μ l of composite hydrogel of individual MSC cells. Sham refers to the heart without infarct treatment with the heart open chest only as a control.

To examine the effect of BG/γ -PGA/CS hydrogel and its encapsulated MSCs on cardiac function after myocardial onset, we first evaluated cardiac function in mice by cardiac ultrasound. As shown in fig. 3, there was a very significant change in the ultrasound of the heart in mice after undergoing anterior left-descending ligation and treatment with different methods.

By analyzing the cardiac ultrasound data, it can be seen from fig. 4 that after 28 days from myocardial infarction, the cardiac ejection fraction of the mice in the control myocardial infarction group is significantly reduced to below 20% compared with that in the Sham group. This indicates that after ligation of the left anterior descending branch, severe impairment of mouse cardiac function occurred. Meanwhile, after myocardial infarction, the heart ejection fraction of mice treated by single MSCs injection is improved to a certain extent compared with AMI group. This indicates that MSCs alone can improve cardiac function to some extent. After myocardial infarction, when the mice are treated by injecting BG/gamma-PGA/CS hydrogel-encapsulated MSCs, the ejection fraction of the hearts of the mice is improved to more than 40 percent, and although the ejection fraction is different compared with the Sham group, the ejection fraction is obviously improved compared with the AMI group and the MSC group. This demonstrates that BG/γ -PGA/CS hydrogels are effective in increasing the efficiency of MSCs in improving cardiac function.

The result shows that the silicon-based bioactive glass composite hydrogel prepared by the invention can effectively improve the efficiency of treating the damaged myocardium by stem cells.

Comparative example 1

Essentially the same as example 1, except that: the composite hydrogel is not added with silicon-based bioactive glass.

The healing efficiency was calculated as shown in figure 5 for strain cycling measurements with no bioactive glass added, 0.25% bioactive glass added, and 0.50% bioactive glass added. The healing efficiency was calculated as follows: performing strain cycle measurement on the composite hydrogel under the condition of an angular frequency of 10rad/s, and measuring a stable storage modulus under the condition of small strain (the experimental condition that the storage modulus is larger than the loss modulus due to the small strain and the storage modulus and the loss modulus are kept stable) (G1); then applying a large strain to make the loss modulus larger than the storage modulus, and breaking the gel structure; when the large strain is removed, a stable storage modulus is again determined under small strain conditions (experimental conditions such that the storage modulus is greater than the loss modulus and both the storage modulus and the loss modulus remain stable) (G2); the calculation formula of the healing efficiency is as follows: the healing efficiency is G2/G1 × 100%. It can be seen that the healing efficiency of the composite hydrogel is greatly improved after the bioglass is added, which shows that the bioactive glass plays an important role in the self-healing performance of the hydrogel.

Claims

1. The silicon-based bioactive glass composite hydrogel with the self-healing characteristic is characterized by comprising a cross-linked gel network and a composite gel structure, wherein the cross-linked gel network is formed by performing Schiff base reaction on aldehyde-group-containing high polymer materials and amino-group-containing high polymer materials through aldehyde groups and amino groups to form imine bonds, and the composite gel structure is formed by uniformly dispersing silicon-based bioactive glass in the gel network; in the silicon-based bioactive glass composite hydrogel, the mass percentages of the aldehyde-containing high polymer material, the amino-containing high polymer material and the silicon-based bioactive glass are respectively 1-10%, 1-10% and 0.1-1.0%.

2. The silicon-based bioactive glass composite hydrogel according to claim 1, wherein the silicon-based bioactive glass contains CaO and SiO₂、Na₂O and P₂O₅The inorganic silicon-based bioactive glass comprises 10-60% of CaO and P₂O₅Is 3-20% of SiO₂The content of (A) is 40-80%, and Na₂The content of O is 10-60%.

3. The silicon-based bioactive glass composite hydrogel according to claim 1 or 2, wherein the aldehyde-group-containing polymer material comprises periodate-oxidized sodium alginate, periodate-oxidized dextran, periodate-oxidized hyaluronic acid, aldehyde-modified polyglutamic acid.

4. The silicon-based bioactive glass composite hydrogel according to any one of claims 1 to 3, wherein the amino-containing polymeric material comprises 2-hydroxypropionic acid-modified chitosan and polylysine.

5. The silicon-based bioactive glass composite hydrogel according to any one of claims 1 to 4, wherein the silicon-based bioactive glass is doped with at least one of potassium, lithium, magnesium, boron, zinc, copper and strontium in an amount of 1-20 wt%.

6. The silicon-based bioactive glass composite hydrogel according to any one of claims 1 to 5, wherein the particle size of the silicon-based bioactive glass is less than 100 μm, preferably 1-10 μm.

7. The silicon-based bioactive glass composite hydrogel according to any one of claims 1 to 6, wherein the molar ratio of the aldehyde groups to the amino groups is 1: 3 to 3: 1.

8. the silicon-based bioactive glass composite hydrogel according to any one of claims 1 to 7, wherein the gel forming time can be controlled by controlling the content of the silicon-based bioactive glass; preferably, the gelling time of the silicon-based bioactive glass composite hydrogel is more than 4 min.

9. The method for preparing the silicon-based bioactive glass composite hydrogel according to any one of claims 1 to 8, comprising the following steps:

(2) dissolving a high polymer material containing amino in a buffer solution with pH of 5.0-8.0 to obtain a solution B with the mass volume fraction (g/mL) of the high polymer material containing amino being 1% -10%;

(3) mixing the solution A and the solution B in a volume ratio of 1: 3-3: 1, mixing, then adding silicon-based bioactive glass powder, and fully and uniformly mixing to form the silicon-based bioactive glass composite hydrogel.

10. Use of a silicon-based bioactive glass composite hydrogel having self-healing properties according to any one of claims 1 to 8 in myocardial repair, in particular in the use of a silicon-based bioactive glass composite hydrogel loaded with stem cells for repairing damaged cardiomyocytes after myocardial infarction.