CN115044037B - Photodegradable hydrogel and preparation method and application thereof - Google Patents

Abstract

The invention provides a photodegradable hydrogel and a preparation method and application thereof, and solves the defects that the existing hydrogel dressing has photodegradable performance only in the presence of an initiator, and is high in cost and complicated in steps during use. The hydrogel is prepared by a one-step thermal polymerization method by taking micromolecular olefin containing one double bond as a monomer and taking 1- (2-nitro) phenylethyl-acrylate modified polyethyleneimine with excellent water solubility as a cross-linking agent. Due to the introduction of the 1- (2-nitro) phenyl ethyl-acrylate crosslinking group, the hydrogel is endowed with rapid degradation behavior in response to ultraviolet light, so that rapid degradation of the hydrogel in the secondary dressing change process is realized when the hydrogel is used as a wound dressing without adding any photoinitiator or photodegradant.

Description

Photodegradable hydrogel and preparation method and application thereof

Technical Field

The invention belongs to the technical field of biomedical materials, and particularly relates to a photodegradable hydrogel and a preparation method and application thereof.

Background

Chronic wounds (e.g., burns, scalds, ulcers, etc.) do not heal easily and require periodic changes of wound dressings multiple times to accelerate healing. However, the current common medical dressing can adhere to the wound surface, and huge pain can be caused by tearing during dressing change, and the new granulation tissue can be damaged. Therefore, the design and development of a novel dressing that avoids the pain of changing the dressing is an effective way to solve the problem.

Chinese patent CN109529101A proposes a low-power ultra-violet light responsive ultra-fast degradable tough hydrogel, which can effectively avoid dressing change pain and injury. However, the dressing needs to have photodegradation performance in the presence of a phenyl-2, 4, 6-trimethylbenzoyl phosphinate photoinitiator, and the cost of the photoinitiator is high, so that when the hydrogel is used as a wound dressing, the cost is high, the steps are tedious and time-consuming during replacement, and the operation is inconvenient.

In view of this, it is necessary to design and develop a novel hydrogel to meet clinical demands.

Disclosure of Invention

The invention aims to solve the defects that the existing hydrogel dressing has photodegradation performance only in the presence of an initiator, is high in cost and complicated in steps during use, and provides a photodegradation hydrogel and a preparation method and application thereof.

The conception of the invention:

considering that the existing hydrogel dressing can be photodegraded only with the aid of an initiator, the research team of the invention aims to design ultraviolet-responsive chemical groups in the hydrogel structure, designs a hydrogel which can realize ultraviolet-responsive degradation without the aid of any additive, and realizes the technical upgrading of the photodegradation performance of the hydrogel.

In order to achieve the above purpose, the technical solution provided by the present invention is:

a cross-linking agent, which is characterized in that: the chemical name is 1- (2-nitro) phenyl ethyl-acrylic ester modified polyethyleneimine, and the chemical structure is as follows:

wherein n=1 to 20000.

The preparation method of the cross-linking agent is characterized by comprising the following steps:

1) Dissolving a photodegradable olefin monomer of a raw material 1, a coupling agent of benzotriazole-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole and triethylamine in N-methylpyrrolidone, and stirring until the components are dissolved to obtain a solution;

2) Adding raw material 2 polyethyleneimine into the solution obtained in the step 1), stirring for reaction, dialyzing the reaction mixture in deionized water after the reaction is completed, and then freeze-drying to obtain the 1- (2-nitro) phenylethyl-acrylate modified polyethyleneimine, namely the target product.

The synthesis process of the cross-linking agent is as follows:

further, the volume ratio (g/ml) of the mass of the photodegradable olefin monomer to the N-methylpyrrolidone is 2 to 20%;

the volume ratio (g/ml) of the benzotriazol-tetramethylurea hexafluorophosphate to the N-methylpyrrolidone is 2.1-25%;

the volume ratio (g/ml) of the mass of the 1-hydroxybenzotriazole to the N-methylpyrrolidone is 0.5-12%;

the volume ratio (ml/ml) of the triethylamine to the N-methylpyrrolidone is 0.5-15%;

the volume ratio (g/ml) of the mass of the polyethylenimine to the N-methyl pyrrolidone is 0.2-3%;

the temperature of the stirring reaction is 10-50 ℃ and the time is 24-72 h.

The invention also provides a photodegradable hydrogel, which is characterized in that the crosslinking agent is adopted, namely the crosslinking agent is used in the preparation of the photodegradable hydrogel.

Further, the wavelength range of the hydrogel in response to ultraviolet light is 190-400 nm.

The preparation method of the photodegradable hydrogel is characterized in that,

the preparation method comprises the steps of taking small molecular olefins containing one double bond as monomers (namely olefin monomers), and preparing the small molecular olefins in deionized water by a one-step thermal polymerization method under the assistance of a crosslinking agent, a thermal initiator and an accelerator, wherein the crosslinking agent is the crosslinking agent.

Further, the volume ratio (g/ml) of the monomer to the deionized water is 5-50%;

the volume ratio (g/ml) of the cross-linking agent to the deionized water is 0.01-10%;

the volume ratio (g/ml) of the thermal initiator to the deionized water is 0.01-5%;

the volume ratio (g/ml) of the accelerator to the deionized water is 0.01-5%;

and, in addition, the processing unit,

the molar ratio of the cross-linking agent to the monomer is 1:10-10000;

the molar ratio of the thermal initiator to the monomer is 1:50-10000;

the mol ratio of the accelerator to the monomer is 1:1100-10000;

the specific proportion can be properly adjusted according to the requirements (elasticity, viscosity and the like) on the performance of the hydrogel.

Further, the monomers include, but are not limited to, one or more of acrylamide, N-dimethylacrylamide, acrylic acid, sulfobetaine methacrylate, and allylamine;

the thermal initiator is 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl propiophenone, potassium persulfate, sodium persulfate or ammonium persulfate;

the accelerator is N, N, N, N-tetramethyl ethylenediamine.

Meanwhile, the invention provides application of the photodegradable hydrogel in preparing clinical medical materials.

Further, the clinical medical material is a wound dressing.

The photodegradable hydrogel can be applied to skin injury repair and painless dressing change as wound dressing, and can be decomposed (decomposed and hydrated by the viscous hydrogel) by only irradiating ultraviolet light with the wavelength range of 190-400 nm for 0.5-5 min when changing dressing, so that huge pain caused by tearing during dressing change is avoided, new granulation tissues are damaged, and pain of patients is relieved.

The principle of the invention is as follows:

the hydrogel prepared by the cross-linking agent disclosed by the invention is subjected to structural rearrangement (shown in figure 1) of 2-nitrophenylethyl-acrylate at the tail end of the cross-linking agent through free radical reaction under the irradiation of ultraviolet light, so that a three-dimensional network of the hydrogel wound dressing is rapidly collapsed, the hydrogel is further endowed with rapid degradation behavior responding to the ultraviolet light, and the problem of dressing change pain of a chronic wound patient during multiple dressing changes can be effectively avoided when the hydrogel is used as the wound dressing.

The invention has the advantages that:

1. the invention designs a novel macromolecular cross-linking agent with excellent water solubility, a 1- (2-nitro) phenyl ethyl-acrylic ester cross-linking group with a response function to ultraviolet light is introduced into the structure of the cross-linking agent, and the cross-linking agent has the advantages of simple preparation method and mild reaction condition, and the used raw materials can be obtained through the purchase of the market.

2. The crosslinking agent is a multi-arm crosslinking agent containing a plurality of double bonds, can effectively solve the problem that the existing linear crosslinking agent containing double-end double bonds has insufficient mechanical properties of hydrogel due to entanglement of molecular chain segments when the molecular weight is large, and can meet the requirements of a human body on the mechanical properties of hydrogel dressing by utilizing the mechanical properties of the hydrogel obtained by the crosslinking agent, especially the quick care of wound surfaces of movement parts such as joints.

3. The hydrogel is prepared by taking small-molecule olefin containing one double bond as a monomer, taking the 1- (2-nitro) phenyl ethyl-acrylate modified polyethyleneimine as a cross-linking agent and adopting a one-step thermal polymerization method. Due to the introduction of the 1- (2-nitro) phenyl ethyl-acrylic ester crosslinking group, the hydrogel is endowed with rapid degradation behavior in response to ultraviolet light, so that rapid degradation in the secondary dressing change process is realized when the hydrogel is used as a wound dressing without adding any photoinitiator or photodegradation agent, and the degradation time can be shortened to 0.5-5 min; meanwhile, the hydrogel wound dressing can also carry water-soluble drugs, bioactive factors, slow release carriers and the like according to the requirements, so that the hydrogel wound dressing has the functions of resisting bacteria, resisting inflammation, promoting healing and the like. The hydrogel wound dressing is prepared by a one-step thermal polymerization method, the process is simple, the reaction condition is mild, and the preparation efficiency is high; the hydrogel has good biocompatibility and shows great advantages in the aspect of skin injury repair.

4. The hydrogel disclosed by the invention is lower in cost when used as a wound dressing, is simple and convenient to operate, is high in replacement efficiency, and can better meet clinical requirements.

Drawings

FIG. 1 is a schematic diagram of the degradation of hydrogels of the present invention;

FIG. 2 is a graph of rheological data for example 4 of the present invention.

Detailed Description

The invention is described in further detail below with reference to the attached drawings and specific examples:

a cross-linking agent is 1- (2-nitro) phenylethyl-acrylate modified polyethyleneimine, and has the chemical structure:

wherein n=1 to 20000.

The synthesis process of the cross-linking agent comprises the following steps:

1) Dissolving a raw material 1, benzotriazole-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole and triethylamine in N-methylpyrrolidone, and stirring until the raw material 1, the benzotriazole-tetramethylurea hexafluorophosphate, the 1-hydroxybenzotriazole and the triethylamine are dissolved to obtain a solution;

2) And 2) adding the raw material 2 into the solution obtained in the step 1), stirring for reaction, dialyzing the reaction mixture in deionized water after the reaction is completed, and then freeze-drying to obtain the 1- (2-nitro) phenylethyl-acrylate modified polyethyleneimine, namely the target product.

Specific examples are shown in table 1:

TABLE 1

According to the amount of each material and the reaction conditions in the table 1, the target product, 1- (2-nitro) phenylethyl-acrylate modified polyethyleneimine, can be prepared according to the above process synthetic route.

In order to verify the performance of the cross-linking agent, the invention also carries out further experiments, and the cross-linking agent is used for preparing the photodegradable hydrogel.

In the embodiment, the photodegradable hydrogel is prepared by taking small-molecule olefin containing one double bond as a monomer, taking a macromolecular crosslinking agent containing a 1- (2-nitro) phenylethyl-acrylate crosslinking group as a 1- (2-nitro) phenylethyl-acrylate modified polyethyleneimine as a crosslinking agent and adopting a one-step thermal polymerization method. The wavelength range of the hydrogel in response to ultraviolet light is 190-400 nm.

When the hydrogel wound dressing is applied as a wound dressing, the specific preparation method of the hydrogel wound dressing comprises the following steps: dissolving 5-50% wt/v olefin monomer, 0.01-10% wt/v cross-linking agent, 0.01-5% wt/v thermal initiator and 0.01-5% wt/v accelerator in deionized water, mixing uniformly, placing in a mould, and heating at 50-80 ℃ to form the tough hydrogel wound dressing. Wherein the molar ratio of the cross-linking agent to the monomer is 1:10-10000; the molar ratio of the thermal initiator to the monomer is 1:50-10000; the mol ratio of the accelerator to the monomer is 1:1100-10000. Specific examples are as follows:

example 4:

1.2g of acrylamide, 0.2g of N, N-dimethylacrylamide, 0.005g of 1- (2-nitro) phenylethyl-acrylate modified polyethylenimine (n=50), 0.03g of ammonium persulfate and 20ul of N, N-tetramethyl ethylenediamine were dispersed in 10ml of water, and then heated at 60℃for 1 hour to form a gel, which was taken out from the mold to obtain a hydrogel dressing. Meanwhile, the photodegradation capability of the hydrogel dressing is further verified in the embodiment, the rheological test is shown in fig. 2, and in the rheological test result of fig. 2, G' is storage modulus and represents elasticity of hydrogel; g' is the loss modulus, representing the viscosity of the hydrogel; of which G' is most representative. The G 'of a normal hydrogel is about 270Pa, and under ultraviolet irradiation, the hydrogel collapses in chemical structure due to the breaking of the crosslinking bond, and the three-dimensional crosslinking network becomes a water-soluble polymer segment, so that the G' drops sharply to about 20 Pa. The ultraviolet irradiation start time was about 26s and the hydrogel complete melting time was about 126s, indicating that the hydrogel melting time was about 100s, which in turn represents the photodegradation time of the hydrogel was about 100s. Therefore, the hydrogel has photodegradation capability and high degradation speed.

Example 5:

0.1g of acrylamide, 0.2g of N, N-dimethylacrylamide, 0.2g of acrylic acid, 0.036g of 1- (2-nitro) phenylethyl-acrylate modified polyethylenimine (n=20000), 0.001g of ammonium persulfate and 8ul of N, N-tetramethyl ethylenediamine were dispersed in 10ml of water, and then heated at 80℃for 0.5 hours to form a gel, which was taken out of the mold to obtain a hydrogel dressing.

Example 6:

2.8g of acrylamide, 1.5g of N, N-dimethylacrylamide, 0.5g of acrylic acid, 0.1g of allylamine, 0.01g of 1- (2-nitro) phenylethyl-acrylate modified polyethylenimine (n=1000), 0.005g of ammonium persulfate and 5ul of N, N-tetramethyl ethylenediamine were dispersed in 10ml of water, and then heated at 70℃for 2.5 hours to form a gel, which was taken out of the mold to obtain a hydrogel dressing.

Example 7:

2g of acrylamide, 0.12g of N, N-dimethylacrylamide, 0.95g of allylamine, 3.1g of sulfobetaine methacrylate, 0.006g of 1- (2-nitro) phenylethyl-acrylate modified polyethylenimine (n=78), 0.005g of sodium persulfate and 2ul of N, N-tetramethyl ethylenediamine were dispersed in 10ml of water, and then heated at 55℃for 8 hours to form a gel, which was taken out of the mold to obtain a hydrogel dressing.

Example 8:

0.1g of acrylamide, 0.6g of N, N-dimethylacrylamide, 0.8g of acrylic acid, 1.1g of sulfobetaine methacrylate, 0.2g of 1- (2-nitro) phenylethyl-acrylate modified polyethylenimine (n=6), 0.005g of sodium persulfate and 10ul of N, N-tetramethyl ethylenediamine were dispersed in 10ml of water, and then heated at 67℃for 1.2 hours to form a gel, which was taken out of the mold to obtain a hydrogel dressing.

The hydrogel dressing prepared in the embodiments 5-8 is also illuminated by ultraviolet light, and the results show that the hydrogel dressing can be decomposed from gel into sol within 5 minutes and has considerable photodegradation capacity, so that the crosslinking agent provided by the invention can endow the hydrogel with rapid degradation behavior in response to ultraviolet light, and has better application prospect in clinical medical materials, and particularly can be used as wound dressing.

The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above examples, and all technical solutions belonging to the concept of the present invention belong to the protection scope of the present invention. It should be noted that modifications and adaptations to the present invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be within the scope of the present invention.

Claims (10)

1. A method for preparing a cross-linking agent, comprising the steps of:

1) Dissolving a photodegradable olefin monomer of a raw material 1, a coupling agent of benzotriazole-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole and triethylamine in N-methylpyrrolidone, and stirring until the components are dissolved to obtain a solution;

2) Adding raw material 2 polyethyleneimine into the solution obtained in the step 1), stirring for reaction, dialyzing the reaction mixture in deionized water after the reaction is completed, and then freeze-drying to obtain 1- (2-nitro) phenylethyl-acrylate modified polyethyleneimine, wherein the chemical structure is as follows:

wherein n=1 to 20000.

2. The method for producing a crosslinking agent according to claim 1, wherein:

the volume ratio of the mass of the photodegradable olefin monomer to the N-methyl pyrrolidone is 2-20%;

the volume ratio of the mass of the benzotriazol-tetramethylurea hexafluorophosphate to the N-methylpyrrolidone is 2.1-25%;

the volume ratio of the mass of the 1-hydroxybenzotriazole to the N-methylpyrrolidone is 0.5-12%;

the volume ratio of the triethylamine to the N-methyl pyrrolidone is 0.5-15%;

the volume ratio of the mass of the polyethylenimine to the N-methyl pyrrolidone is 0.2-3%;

the temperature of the stirring reaction is 10-50 ℃ and the time is 24-72 h.

3. A crosslinking agent characterized by: prepared by the method of claim 1.

4. A photodegradable hydrogel, characterized in that: a cross-linking agent prepared by the method of claim 1.

5. The photodegradable hydrogel of claim 4, wherein: the wavelength range of the ultraviolet light response is 190-400 nm.

6. A preparation method of photodegradable hydrogel is characterized in that,

taking micromolecular olefin containing a double bond as a monomer, and preparing the micromolecular olefin in deionized water by a one-step thermal polymerization method under the assistance of a cross-linking agent, a thermal initiator and an accelerator;

the crosslinking agent prepared by the method of claim 1.

7. The method for preparing the photodegradable hydrogel according to claim 6, wherein:

the volume ratio of the mass of the monomer to the deionized water is 5-50%;

the volume ratio of the cross-linking agent to the deionized water is 0.01-10%;

the volume ratio of the thermal initiator to the deionized water is 0.01-5%;

the volume ratio of the accelerator to the deionized water is 0.01-5%;

and, in addition, the processing unit,

the molar ratio of the cross-linking agent to the monomer is 1:10-10000;

the molar ratio of the thermal initiator to the monomer is 1:50-10000;

the mol ratio of the accelerator to the monomer is 1:1100-10000.

8. The method for preparing a photodegradable hydrogel according to claim 7, wherein:

the monomer is one or more of acrylamide, N-dimethylacrylamide, acrylic acid, sulfobetaine methacrylate and allylamine;

the thermal initiator is 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl propiophenone, potassium persulfate, sodium persulfate or ammonium persulfate;

the accelerator is N, N, N, N-tetramethyl ethylenediamine.

9. The use of the photodegradable hydrogel of claim 4 in the preparation of clinical medical materials.

10. Use of the photodegradable hydrogel of claim 4 as a wound dressing.

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