CN111333871B - Intrinsic self-repairing zwitterionic hydrogel and preparation method thereof - Google Patents

Intrinsic self-repairing zwitterionic hydrogel and preparation method thereof Download PDF

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CN111333871B
CN111333871B CN202010262160.9A CN202010262160A CN111333871B CN 111333871 B CN111333871 B CN 111333871B CN 202010262160 A CN202010262160 A CN 202010262160A CN 111333871 B CN111333871 B CN 111333871B
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刘云鸿
彭新艳
刘云晖
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Qingdao Zhongteng Biotechnology Co ltd
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Abstract

The invention discloses an intrinsic self-repairing zwitterionic hydrogel and a preparation method thereof. The invention adopts polysuccinimide as a material main body, and pyrimidine compounds, amine compounds and the like are selected to carry out ring-opening reaction and crosslinking reaction on the polysuccinimide to prepare the intrinsic self-repairing zwitterionic hydrogel material. The zwitterionic hydrogel has a self-repairing function, biodegradability and good biocompatibility; the preparation method has simple process and low cost.

Description

Intrinsic self-repairing zwitterionic hydrogel and preparation method thereof
Technical Field
The invention relates to the field of hydrogel and preparation thereof, in particular to intrinsic self-repairing zwitterionic hydrogel and a preparation method thereof.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
The hydrogel material has important potential application value in the field of flexible electronics, wearable equipment, wound healing and cartilage repair. For example, the molecular chain segments of the zwitterionic hydrogel material have positive and negative charges, so that the zwitterionic hydrogel material can be combined with water molecules through ion solvation, a large number of water molecules can be bound, the water molecules are retained in the material structure, and a good wet environment can be maintained; meanwhile, a hydration layer formed on the surface of the zwitterionic polymer material has strong nonspecific protein adsorption resistance and biocompatibility, so that protein adhesion can be effectively resisted, foreign body rejection and bacterial attachment can be resisted, and better biocompatibility is shown.
However, the current hydrogel still has some problems, such as easy breaking in deformation, unrecoverable damage and short service life; on the other hand, most of the hydrogels adopt non-biodegradable main chain segments, and cannot be applied to special application fields needing biodegradation, so that the application of the hydrogels is greatly limited. Development of hydrogels having self-healing and biodegradation functionalities is a new direction of research. However, the hydrogel having self-repairing property and degradability has some problems that are difficult to ignore, such as poor self-repairing property, not simple preparation method, relatively high preparation cost, and the like. For example, the existing hydrogel molecular structure usually adopts an introduced quadruple hydrogen bond unit based on the ureido pyrimidone unit UPy, and the introduction mode and the preparation process are complex and tedious and have high cost.
The polyaspartic acid polymer material has the advantages of biodegradability, good biocompatibility, low toxicity, convenient synthesis, easy bonding with drugs and the like, and is considered to be a biomedical polymer with considerable application prospect. Many studies on such materials have been conducted by scholars at home and abroad. Compared with other degradable high molecular materials, Polysuccinimide (PSI) is prepared by thermal polycondensation of L-aspartic acid, and a series of derivatives of polyaspartic acid modified by side chain functional groups can be prepared by selecting different nucleophiles to carry out ring-opening reaction on PSI. The main chain of the polymer is polyamino acid, which fundamentally ensures good biodegradability and biocompatibility of the material. And secondly, the L-aspartic acid is easy to obtain and has good reproducibility. And the structure and the property of the polymer can be regulated and designed by changing the type and the proportion of the PSI ring-opening reagent so as to realize different purposes.
Disclosure of Invention
The invention aims to: provides an intrinsic self-repairing zwitterionic hydrogel which has a self-repairing function and biodegradability.
The second object of the present invention is to: the preparation method of the intrinsic self-repairing zwitterionic hydrogel is simple in preparation process and low in cost, and the self-repairing function of the zwitterionic hydrogel is effectively achieved.
The object of the invention is achieved by:
the intrinsic self-repairing zwitterionic hydrogel is prepared by using Rn-NH as the polyamino acid derivative with intrinsic self-repairing property2Compound, Rm-NH2Compound, containing R1、R2、R3The amino compound of the group performs a ring opening reaction on polysuccinimide, and further performs a quaternization reaction and utilization of NH2—RX—NH2The compound is obtained through crosslinking reaction;
the chemical structural formula of the intrinsic self-repairing zwitterionic hydrogel is as follows:
Figure 440975DEST_PATH_IMAGE001
wherein n is an integer of 10 to 1500, x is an integer of 1 to 1400, y is an integer of 1 to 1400, z is an integer of 1 to 1400, and g is an integer of 1 to 1400; r1An alkylene group having 1 to 6 carbon atoms; r2、R3Is H, methyl or ethyl; r4Alkylene of 0 to 6 carbon atoms; y is-Is COO-Or SO3 -；
Further, the Rn-NH2The compound is a pyrimidine compound; the pyrimidine compound is 5-methylcytosine, cytosine, 6-methylisocytosine, 2-amino-4-hydroxy-6-methylpyrimidine, 5-azacytosine, 5-aminopyrimidine, 2-amino-4-methylpyrimidine, 2-mercaptocytosine, 4, 6-diaminopyrimidine, at least one of 5-aminouracil, 2, 4-diamino-6-hydroxypyrimidine, 4-amino-5-cyanopyrimidine, 6-aminouracil, 2, 4-diaminopyrimidine, 4, 5-diamino-2-thiouracil, 2-amino-4-methoxy-6-methylpyrimidine, isocytosine, 4-amino-6-hydroxy-2-mercaptopyrimidine;
further, said Rm-NH2The compound is at least one of amino acid, ethanolamine, diethanolamine, isopropylamine, taurine and methyl phenylalanine; the amino acid is at least one of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, asparagine, glutamic acid, histidine, lysine, glutamine, methionine, serine, threonine, cysteine, proline and arginine;
further, said NH2—RX—NH2The compound is at least one of ethylenediamine, propylenediamine, butylenediamine, hexylenediamine, decyldiamine, diethylenetriamine, triethylenetetramine and tetraethylenepentamine, polyethylene polyamine and amino-terminated polyethylene glycol;
a preparation method of intrinsic self-repairing zwitterionic hydrogel comprises the following steps:
(1) preparation of zwitterionic functionalized polyasparagine derivatives
Dissolving Polysuccinimide (PSI) in a solvent A; adding Rn-NH2Compound, Rm-NH2Compound, composition containing R1、R2、R3Carrying out ring opening reaction on the amino compound of the group; then adding sultone or alkyl lactone to carry out quaternization reaction on the pendant tertiary amine group grafted to the polyasparagine derivative; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing the zwitterion functionalized polyasparagine derivative with water, and stirring to dissolve uniformly; addition of NH2—RX—NH2And (3) carrying out crosslinking reaction on the compound, and purifying to prepare the intrinsic self-repairing zwitterionic hydrogel.
In the step (1), the solvent A is at least one of DMSO, DMF and ethyl acetate; the reaction condition of the ring-opening reaction is that the reaction is carried out for 1-24 h at 30-80 ℃; the reaction condition of the quaternization reaction is that the reaction is carried out for 1-48 h at the temperature of 20-50 ℃; the Rn-NH2Compound Rm-NH2Compound, containing R1、R2、R3The molar ratio of amino compounds of the groups is 1: (0.1-10): (0.1 to 10); the molar ratio of the amino compound containing R1, R2 and R3 groups to sultone or alkyl lactone is 1: (1-1.2); the mass ratio of the polysuccinimide PSI to the solvent A is 1: (0.2 to 100).
In the step (2), the zwitterion functionalized polyasparagine derivative, water and NH2—RX—NH2The mass ratio of the compounds is 100: (30-20000): (0.01 to 100); the crosslinking reaction condition is that the reaction is carried out for 1-24 h at 40-99 ℃.
The invention adopts polysuccinimide as a material main body, and pyrimidine compounds, amine compounds and the like are selected to carry out ring-opening reaction and crosslinking reaction on the polysuccinimide to prepare the intrinsic self-repairing zwitterionic hydrogel material. On one hand, the main body of the material is polyamino acid, which fundamentally ensures good biodegradability and biocompatibility of the material; on the other hand, molecular structures such as a pyrimidine compound and a zwitterionic group are compounded on the material, and the material can be endowed with a better self-repairing function by utilizing the mutual hydrogen bond action of chemical structures such as an amide structure on a main chain after ring opening of polysuccinimide, a hydrogen bond donor and an acceptor of the pyrimidine compound and the like and the electrostatic action presented between the zwitterionic group structures.
Taking ring-opening grafting of 5-methylcytosine and zwitterion on polysuccinimide as an example, the grafting principle is shown in figure 2;
5-methylcytosine and zwitterions are grafted on polysuccinimide through ring opening, and hydrogen bond action and electrostatic action among different molecular structures exist in the obtained zwitterion hydrogel material, as shown in the following, so that the material is endowed with a better self-repairing function, and as shown in the attached figure 3.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. according to the invention, the pyrimidine compound and the zwitterionic group are grafted through the ring-opening reaction of polysuccinimide, so that the novel zwitterionic hydrogel material has a good self-repairing function;
2. the zwitterionic hydrogel has a self-repairing function, biodegradability and good biocompatibility;
3. the preparation method has simple process and low cost.
Drawings
FIG. 1 is a photograph of a self-healing process of a zwitterionic hydrogel in example 1 of the present invention; FIG. 2 is a schematic diagram of the grafting principle of ring-opening grafting of 5-methylcytosine and zwitterion on polysuccinimide; FIG. 3 is a schematic diagram of hydrogen bonding and electrostatic interaction between different molecular structures existing in the interior of a zwitterionic hydrogel material obtained by ring-opening grafting of 5-methylcytosine and zwitterion on polysuccinimide.
Detailed Description
The following describes in detail embodiments of the present invention with reference to the drawings and examples, but the embodiments of the present invention are not limited thereto.
Example 1
(1) Preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI (average molecular weight of about 7000 g/mol) were dissolved in 200g of DMF; adding 30g of 5-methylcytosine, 20g of ethanolamine and 20g of N, N-dimethyl-1, 3-propane diamine, and reacting at 60 ℃ for 24 hours to carry out ring-opening reaction; then, 24g of 1, 3-propane sultone is added to react for 8h at 38 ℃, and the tertiary amine group with the side group grafted to the polyasparagine derivative is subjected to quaternization reaction; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative and 5000g of water, and stirring to dissolve uniformly; adding 5g of butanediamine, reacting at 66 ℃ for 12h for crosslinking reaction, and purifying to obtain the intrinsic self-repairing zwitterionic hydrogel.
As shown in the attached figure 1, the obtained intrinsic self-repairing zwitterionic hydrogel material is cut open and contacted again, and the hydrogel material can heal and repair within 1 second and can be stretched. Therefore, after the contact at room temperature in a short time, efficient healing and repair can be realized.
Through detection, the intrinsic self-repairing zwitterionic hydrogel disclosed by the invention can be finally degraded after being placed in an outdoor environment for 3 months.
The biocompatibility of the intrinsic self-repairing zwitterionic hydrogel prepared by the embodiment is evaluated through protein adsorption, cytotoxicity, antibacterial adhesion and the like. The protein adsorption resistance of the prepared intrinsic self-repairing zwitterionic hydrogel material is evaluated by adopting a static protein adsorption experiment, bovine serum albumin (BSA, 5mg/ml) is selected, the adsorption capacity per unit area and the protein adsorption resistance of a sample are calculated, and the result shows that the protein adsorption capacity of the hydrogel is 0.01 mu g/mm2Significantly lower than the adsorption capacity of the glass control (1.2. mu.g/mm)2). According to the requirements of ISO 10993-52009 on cytotoxicity, the invention adopts CCK-8 method to carry out in-vitro cytotoxicity on hydrogelThe properties were evaluated. As a result, the hydrogel of this example was found to have a toxicity rating of 1 and no cytotoxicity. And (3) evaluating the antibacterial adhesion capability of the prepared intrinsic self-repairing zwitterionic hydrogel material by adopting in vitro bacterial adhesion. When the hydrogel material was cultured in a bacterial suspension for 4 hours using Escherichia coli and Staphylococcus aureus as test bacteria, it was found that the amount of adhered bacteria on the surface of the hydrogel of this example was extremely small and the number of bacteria was reduced to 0.4% of the number of bacteria on the surface of the blank glass control sample, as compared with the blank glass sample. It can be seen that the hydrogel material of this example exhibits a better anti-bacterial adhesion function.
Example 2
(1) Preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI (average molecular weight approximately 10000 g/mol) were dissolved in 400g of DMSO; adding 40g of 5-methylcytosine, 10g of isopropylamine and 15g of N, N-dimethyl-1, 3-propanediamine, and reacting at 40 ℃ for 9h to perform a ring-opening reaction; then, 18g of 1, 3-propane sultone is added to react for 18h at 30 ℃, and the tertiary amine group with the side group grafted to the polyasparagine derivative is subjected to quaternization reaction; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative and 500g of water, and stirring to dissolve uniformly; adding 6g of hexamethylene diamine, reacting at 70 ℃ for 20h for crosslinking reaction, and purifying to obtain the intrinsic self-repairing zwitterionic hydrogel.
The biocompatibility of the intrinsic self-repairing zwitterionic hydrogel prepared by the embodiment is evaluated through protein adsorption, cytotoxicity, antibacterial adhesion and the like. The protein adsorption resistance of the prepared intrinsic self-repairing zwitterionic hydrogel material is evaluated by adopting a static protein adsorption experiment, bovine serum albumin (BSA, 5mg/ml) is selected, the adsorption capacity per unit area and the protein adsorption resistance of a sample are calculated, and the result shows that the protein adsorption capacity of the hydrogel is 0.04 mu g/mm2Significantly lower than the adsorption capacity of the glass control (1.2. mu.g/mm)2). The hydrogel was evaluated for cytotoxicity in vitro according to ISO 10993-52009 using CCK-8. As a result, the hydrogel of this example was found to have a toxicity rating of 1 and no cytotoxicity. And (3) evaluating the antibacterial adhesion capability of the prepared intrinsic self-repairing zwitterionic hydrogel material by adopting in vitro bacterial adhesion. When the hydrogel material was cultured in a bacterial suspension for 4 hours using Escherichia coli and Staphylococcus aureus as test bacteria, the adhesion of bacteria on the surface of the hydrogel of this example was very small compared to the blank glass sample, and the number of bacteria was reduced to 0.1% of the number of bacteria on the surface of the blank glass sample. It can be seen that the hydrogel material of this example exhibits a better anti-bacterial adhesion function.
Through detection, the intrinsic self-repairing zwitterionic hydrogel disclosed by the invention can be finally degraded after being placed in an outdoor environment for 3 months.
Example 3
(1) Preparation of zwitterionic functionalized polyasparagine derivatives
100g of polysuccinimide PSI (average molecular weight about 140000 g/mol) was dissolved in 100g of DMF; adding 10g of 2-amino-4-hydroxy-6-methylpyrimidine, 10g of arginine and 10g of N, N-dimethyl-1, 3-propane diamine, and reacting at 60 ℃ for 24h to carry out ring-opening reaction; then, 12g of 1, 3-propane sultone is added to react for 18h at 40 ℃, and the tertiary amine group with the side group grafted to the polyasparagine derivative is subjected to quaternization reaction; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative and 1000g of water, and stirring to dissolve uniformly; adding 8g of triethylene tetramine, reacting at 60 ℃ for 12h for crosslinking reaction, and purifying to obtain the intrinsic self-repairing zwitterionic hydrogel.
The biocompatibility of the intrinsic self-repairing zwitterionic hydrogel prepared by the embodiment is evaluated through protein adsorption, cytotoxicity, antibacterial adhesion and the like. Intrinsic self-repairing zwitterionic hydrogel prepared by evaluation of static protein adsorption experimentThe protein adsorption resistance of the material is determined by selecting bovine serum albumin (BSA, 5mg/ml) and calculating the adsorption quantity per unit area and the protein adsorption resistance of a sample, and the result shows that the protein adsorption quantity of the hydrogel is 0.05 mu g/mm2Significantly lower than the adsorption capacity of the glass control sample (1.2 mug/mm)2). The hydrogel was evaluated for cytotoxicity in vitro according to ISO 10993-52009 using CCK-8. As a result, the hydrogel of this example was found to have a toxicity rating of 1 and no cytotoxicity. And (3) evaluating the antibacterial adhesion capability of the prepared intrinsic self-repairing zwitterionic hydrogel material by adopting in vitro bacterial adhesion. When the hydrogel material was cultured in a bacterial suspension for 4 hours using Escherichia coli and Staphylococcus aureus as test bacteria, it was found that the amount of adhered bacteria on the surface of the hydrogel of this example was extremely small and the number of bacteria was reduced to 0.1% of the number of bacteria on the surface of the blank glass control sample, as compared with the blank glass sample. It can be seen that the hydrogel material of this example exhibits a better anti-bacterial adhesion function.
Through detection, the intrinsic self-repairing zwitterionic hydrogel disclosed by the invention can be finally degraded after being placed in an outdoor environment for 3 months.
Example 4
(1) Preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI (average molecular weight about 20000 g/mol) were dissolved in 200g of DMF; adding 23g of 6-aminouracil, 22g of phenylalanine and 8g of N, N-dimethyl-1, 3-propane diamine, and reacting at 60 ℃ for 4 hours to carry out ring-opening reaction; then, 9.7g of 1, 3-propane sultone is added to react for 8 hours at 25 ℃, and the tertiary amine group of the side group grafted to the polyasparagine derivative is subjected to quaternization reaction; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative and 30g of water, and stirring to dissolve uniformly; adding 10g of amino-terminated polyethylene glycol (the molecular weight is about 2000 g/mol), reacting at 70 ℃ for 6h for crosslinking reaction, and purifying to obtain the intrinsic self-repairing zwitterionic hydrogel.
The biocompatibility of the intrinsic self-repairing zwitterionic hydrogel prepared by the embodiment is evaluated through protein adsorption, cytotoxicity, antibacterial adhesion and the like. The protein adsorption resistance of the prepared intrinsic self-repairing zwitterionic hydrogel material is evaluated by adopting a static protein adsorption experiment, bovine serum albumin (BSA, 5mg/ml) is selected, the adsorption capacity per unit area and the protein adsorption resistance of a sample are calculated, and the result shows that the protein adsorption capacity of the hydrogel is 0.04 mu g/mm2Significantly lower than the adsorption capacity of the glass control (1.2. mu.g/mm)2). The hydrogel was evaluated for cytotoxicity in vitro according to ISO 10993-52009 using CCK-8. As a result, the hydrogel of this example was found to have a toxicity rating of 1 and no cytotoxicity. And (3) evaluating the antibacterial adhesion capability of the prepared intrinsic self-repairing zwitterionic hydrogel material by adopting in vitro bacterial adhesion. When the hydrogel material was cultured in a bacterial suspension for 4 hours using Escherichia coli and Staphylococcus aureus as test bacteria, the adhesion of bacteria on the surface of the hydrogel of this example was very small compared to the blank glass sample, and the number of bacteria was reduced to 0.2% of the number of bacteria on the surface of the blank glass sample. It can be seen that the hydrogel material of this example exhibits a superior anti-bacterial adhesion function.
Through detection, the intrinsic self-repairing zwitterionic hydrogel disclosed by the invention can be finally degraded after being placed in an outdoor environment for 3 months.
Example 5
(1) Preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI (average molecular weight of about 7000 g/mol) were dissolved in 99g of ethyl acetate; adding 50g of 5-methylcytosine, 15g of ethanolamine and 20g of N, N-dimethyl-1, 3-propane diamine, and reacting at 60 ℃ for 5 hours to carry out ring-opening reaction; then, 27g of 1, 4-butanesultone was added, and the reaction was carried out at 20 ℃ for 48 hours to carry out quaternization of the pendant tertiary amine group grafted to the polyasparagine derivative; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative with 1000g of water, and stirring and dissolving uniformly; adding 50g of diethylenetriamine, reacting at 40 ℃ for 24h for crosslinking reaction, and purifying to obtain the intrinsic self-repairing zwitterionic hydrogel.
The biocompatibility of the intrinsic self-repairing zwitterionic hydrogel prepared by the embodiment is evaluated through protein adsorption, cytotoxicity, antibacterial adhesion and the like. The protein adsorption resistance of the prepared intrinsic self-repairing zwitterionic hydrogel material is evaluated by adopting a static protein adsorption experiment, bovine serum albumin (BSA, 5mg/ml) is selected, the adsorption capacity per unit area and the protein adsorption resistance of a sample are calculated, and the result shows that the protein adsorption capacity of the hydrogel is 0.06 mu g/mm2Significantly lower than the adsorption capacity of the glass control (1.2. mu.g/mm)2). The hydrogel was evaluated for cytotoxicity in vitro according to ISO 10993-52009 using CCK-8. As a result, the hydrogel of this example was found to have a toxicity rating of 1 and no cytotoxicity. And (3) evaluating the antibacterial adhesion capability of the prepared intrinsic self-repairing zwitterionic hydrogel material by adopting in vitro bacterial adhesion. When the hydrogel material was cultured in a bacterial suspension for 4 hours using Escherichia coli and Staphylococcus aureus as test bacteria, it was found that the amount of adhered bacteria on the surface of the hydrogel of this example was extremely small and the number of bacteria was reduced to 0.2% of the number of bacteria on the surface of the blank glass control sample, as compared with the blank glass sample. It can be seen that the hydrogel material of this example exhibits a better anti-bacterial adhesion function.
Through detection, the intrinsic self-repairing zwitterionic hydrogel disclosed by the invention can be finally degraded after being placed in an outdoor environment for 3 months.
Example 6
(1) Preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI (average molecular weight approximately 10000 g/mol) were dissolved in 19.4g of DMF; adding 111g of cytosine, 1250g of taurine and 10.2g of N, N-dimethyl-1, 3-propane diamine, and reacting at 80 ℃ for 1 hour to carry out ring-opening reaction; then 8.64g of beta-propiolactone is added to react for 1h at 50 ℃, and the tertiary amine group with the side group grafted to the polyasparagine derivative is subjected to quaternization reaction; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative and 20000g of water, and stirring to dissolve uniformly; 0.01g of decamethylene diamine is added to react for 1 hour at the temperature of 99 ℃ to carry out cross-linking reaction and purification, thus obtaining the intrinsic self-repairing zwitterionic hydrogel.
The biocompatibility of the intrinsic self-repairing zwitterionic hydrogel prepared by the embodiment is evaluated through protein adsorption, cytotoxicity, antibacterial adhesion and the like. The protein adsorption resistance of the prepared intrinsic self-repairing zwitterionic hydrogel material is evaluated by adopting a static protein adsorption experiment, bovine serum albumin (BSA, 5mg/ml) is selected, the adsorption capacity per unit area and the protein adsorption resistance of a sample are calculated, and the result shows that the protein adsorption capacity of the hydrogel is 0.02 mu g/mm2Significantly lower than the adsorption capacity of the glass control sample (1.2 mug/mm)2). The hydrogel was evaluated for cytotoxicity in vitro according to ISO 10993-52009 using CCK-8. As a result, the hydrogel of this example was found to have a toxicity rating of 1 and no cytotoxicity. And (3) evaluating the antibacterial adhesion capability of the prepared intrinsic self-repairing zwitterionic hydrogel material by adopting in vitro bacterial adhesion. When the hydrogel material was cultured in a bacterial suspension for 4 hours using Escherichia coli and Staphylococcus aureus as test bacteria, it was found that the amount of adhered bacteria on the surface of the hydrogel of this example was extremely small and the number of bacteria was reduced to 0.3% of the number of bacteria on the surface of the blank glass control sample, as compared with the blank glass sample. It can be seen that the hydrogel material of this example exhibits a better anti-bacterial adhesion function.
Through detection, the intrinsic self-repairing zwitterionic hydrogel disclosed by the invention can be finally degraded after being placed in an outdoor environment for 3 months.
Example 7
(1) Preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI (average molecular weight approximately 100000 g/mol) were dissolved in 9700g of DMSO; adding 125g of 5-methylcytosine, 6.1g of ethanolamine and 1020g of N, N-dimethyl-1, 3-propane diamine, and reacting at 30 ℃ for 24 hours to carry out ring-opening reaction; then 1360g of 1, 4-butanesultone was added and reacted at 50 ℃ for 1 hour to quaternize the pendant tertiary amine group grafted to the polyasparagine derivative; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative and 500g of water, and stirring to dissolve uniformly; adding 100g of tetraethylenepentamine, reacting at 60 ℃ for 24h for crosslinking reaction, and purifying to prepare the intrinsic self-repairing zwitterionic hydrogel.
The biocompatibility of the intrinsic self-repairing zwitterionic hydrogel prepared by the embodiment is evaluated through protein adsorption, cytotoxicity, antibacterial adhesion and the like. The protein adsorption resistance of the prepared intrinsic self-repairing zwitterionic hydrogel material is evaluated by adopting a static protein adsorption experiment, bovine serum albumin (BSA, 5mg/ml) is selected, the adsorption capacity per unit area and the protein adsorption resistance of a sample are calculated, and the result shows that the protein adsorption capacity of the hydrogel is 0.01 mu g/mm2Significantly lower than the adsorption capacity of the glass control sample (1.2 mug/mm)2). The hydrogel was evaluated for cytotoxicity in vitro according to ISO 10993-52009 using CCK-8. As a result, the hydrogel of this example was found to have a toxicity rating of 1 and no cytotoxicity. And (3) evaluating the antibacterial adhesion capability of the prepared intrinsic self-repairing zwitterionic hydrogel material by adopting in vitro bacterial adhesion. When the hydrogel material was cultured in a bacterial suspension for 4 hours using Escherichia coli and Staphylococcus aureus as test bacteria, it was found that the amount of adhered bacteria on the surface of the hydrogel of this example was extremely small and the number of bacteria was reduced to 0.4% of the number of bacteria on the surface of the blank glass control sample, as compared with the blank glass sample. It can be seen that the hydrogel material of this example exhibits a better anti-bacterial adhesion function.
Through detection, the intrinsic self-repairing zwitterionic hydrogel disclosed by the invention can be finally degraded after being placed in an outdoor environment for 3 months.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (4)

1. A preparation method of intrinsic self-repairing zwitterionic hydrogel is characterized by comprising the following steps:
(1) preparation of zwitterionic functionalized polyasparagine derivatives
Dissolving Polysuccinimide (PSI) in a solvent A; adding Rn-NH2Compound, Rm-NH2Compound, containing R1、R2、R3Carrying out ring opening reaction on the amino compound of the group; then adding sultone or alkyl lactone to carry out quaternization reaction on the pendant tertiary amine group grafted to the polyasparagine derivative; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing the zwitterion functionalized polyasparagine derivative with water, and stirring to dissolve uniformly; addition of NH2—RX—NH2And (3) carrying out crosslinking reaction on the compound, and purifying to prepare the intrinsic self-repairing zwitterionic hydrogel.
2. The preparation method of the intrinsic self-repairing zwitterionic hydrogel as claimed in claim 1, characterized in that:
in the step (1), the first step of the method,
the solvent A is at least one of DMSO, DMF and ethyl acetate;
the reaction condition of the ring-opening reaction is that the reaction is carried out for 1-24 h at 30-80 ℃;
the reaction condition of the quaternization reaction is that the reaction is carried out for 1-48 h at the temperature of 20-50 ℃;
the Rn-NH2Compound, Rm-NH2Compound, containing R1、R2、R3The molar ratio of amino compounds of the groups is 1: (0.1-10): (0.1 to 10);
said group containing R1、R2、R3The molar ratio of amino compound of the group to sultone or alkyl lactone is 1: (1-1.2);
the mass ratio of the polysuccinimide PSI to the solvent A is 1: (0.2 to 100).
3. The preparation method of the intrinsic self-repairing zwitterionic hydrogel as claimed in claim 1, characterized in that:
in the step (2), the zwitterion functionalized polyasparagine derivative, water and NH2—RX—NH2The mass ratio of the compounds is 100: (30-20000): (0.01 to 100);
the crosslinking reaction condition is that the reaction is carried out for 1-24 h at 40-99 ℃.
4. An intrinsic self-repairing zwitterionic hydrogel is characterized by being prepared by one of the following methods:
the method comprises the following steps:
(1) preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI, having an average molecular weight of about 7000g/mol, are dissolved in 200g of DMF; adding 30g of 5-methylcytosine, 20g of ethanolamine and 20g of N, N-dimethyl-1, 3-propane diamine, and reacting at 60 ℃ for 24 hours to carry out ring-opening reaction; then, 24g of 1, 3-propane sultone is added to react for 8h at 38 ℃, and the tertiary amine group with the side group grafted to the polyasparagine derivative is subjected to quaternization reaction; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative and 5000g of water, and stirring to dissolve uniformly; adding 5g of butanediamine, reacting at 66 ℃ for 12h for a crosslinking reaction, and purifying to obtain the intrinsic self-repairing zwitterionic hydrogel;
the second method comprises the following steps:
(1) preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI, having an average molecular weight of approximately 10000g/mol, are dissolved in 400g of DMSO; adding 40g of 5-methylcytosine, 10g of isopropylamine and 15g of N, N-dimethyl-1, 3-propanediamine, and reacting at 40 ℃ for 9h to perform a ring-opening reaction; then, 18g of 1, 3-propane sultone is added to react for 18h at 30 ℃, and the tertiary amine group with the side group grafted to the polyasparagine derivative is subjected to quaternization reaction; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative and 500g of water, and stirring to dissolve uniformly; adding 6g of hexamethylene diamine, reacting at 70 ℃ for 20h for crosslinking reaction, and purifying to prepare the intrinsic self-repairing zwitterionic hydrogel;
the third method comprises the following steps:
(1) preparation of zwitterionic functionalized polyasparagine derivative
100g of polysuccinimide PSI, having an average molecular weight of about 140000g/mol, are dissolved in 100g of DMF; adding 10g of 2-amino-4-hydroxy-6-methylpyrimidine, 10g of arginine and 10g of N, N-dimethyl-1, 3-propane diamine, and reacting at 60 ℃ for 24h to carry out ring-opening reaction; then, 12g of 1, 3-propane sultone is added to react for 18h at 40 ℃, and the tertiary amine group with the side group grafted to the polyasparagine derivative is subjected to quaternization reaction; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative with 1000g of water, and stirring and dissolving uniformly; adding 8g of triethylene tetramine, reacting at 60 ℃ for 12h to perform a crosslinking reaction, and purifying to prepare the intrinsic self-repairing zwitterionic hydrogel;
the method four comprises the following steps:
(1) preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI, having an average molecular weight of approximately 20000g/mol, are dissolved in 200g of DMF; adding 23g of 6-aminouracil, 22g of phenylalanine and 8g of N, N-dimethyl-1, 3-propane diamine, and reacting at 60 ℃ for 4 hours to carry out ring-opening reaction; then, 9.7g of 1, 3-propane sultone is added to react for 8 hours at 25 ℃, and the tertiary amine group of the side group grafted to the polyasparagine derivative is subjected to quaternization reaction; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative and 30g of water, and stirring to dissolve uniformly; adding 10g of amino-terminated polyethylene glycol with the molecular weight of about 2000g/mol, reacting at 70 ℃ for 6h for crosslinking reaction, and purifying to prepare the intrinsic self-repairing zwitterionic hydrogel;
the method five comprises the following steps:
(1) preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI, having an average molecular weight of about 7000g/mol, are dissolved in 99g of ethyl acetate; adding 50g of 5-methylcytosine, 15g of ethanolamine and 20g of N, N-dimethyl-1, 3-propane diamine, and reacting at 60 ℃ for 5 hours to carry out ring-opening reaction; then, 27g of 1, 4-butanesultone was added, and the reaction was carried out at 20 ℃ for 48 hours to carry out quaternization of the pendant tertiary amine group grafted to the polyasparagine derivative; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparagine derivative and 1000g of water, and stirring to dissolve uniformly; adding 50g of diethylenetriamine, reacting at 40 ℃ for 24h for crosslinking reaction, and purifying to prepare the intrinsic self-repairing zwitterionic hydrogel;
the method six comprises the following steps:
(1) preparation of zwitterionic functionalized polyasparagine derivatives
97g of polysuccinimide PSI, having an average molecular weight of approximately 10000g/mol, are dissolved in 19.4g of DMF; adding 111g of cytosine, 1250g of taurine and 10.2g of N, N-dimethyl-1, 3-propane diamine, and reacting at 80 ℃ for 1 hour to carry out ring-opening reaction; then 8.64g of beta-propiolactone is added and reacted at 50 ℃ for 1h, and the tertiary amine group of the side group grafted to the polyasparagine derivative is subjected to quaternization reaction; purifying and drying to obtain the zwitterion functionalized polyasparagine derivative;
(2) preparation of intrinsic self-repairing zwitterionic hydrogel
Mixing 100g of zwitterion functionalized polyasparamide derivative and 20000g of water, and stirring to dissolve uniformly; adding 0.01g of decamethylene diamine, reacting at 99 ℃ for 1h for crosslinking reaction, and purifying to obtain the intrinsic self-repairing zwitterionic hydrogel.
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