阅读说明：本技术 一种可喷雾成膜的自愈合海藻酸钠/明胶基水凝胶材料 (Self-healing sodium alginate/gelatin-based hydrogel material capable of spraying to form film ) 是由 李鸿 杜艳 李林 杨爱萍 吕国玉 彭海涛 郑衡 于 2019-10-28 设计创作，主要内容包括：本发明公开了一种可喷雾成膜的自愈合海藻酸钠/明胶基凝胶材料,它是以单醛改性的海藻酸钠溶液和酰肼改性的明胶溶液为原料,发生希夫碱反应后而得；所述单醛改性的海藻酸钠为重复结构单元中含1个醛基的海藻酸钠衍生物。实验证明,本发明的可喷雾成膜的自愈合海藻酸钠/明胶基凝胶材料具有良好的生物相容性,能够在10s内快速成胶,并且同时具有优异的喷雾成膜性和自愈合性,在制备可喷雾成膜的自愈合生物材料中,特别是伤口敷料中,具有非常好的应用前景。(The invention discloses a self-healing sodium alginate/gelatin-based gel material capable of spraying to form a film, which is prepared by taking a mono-aldehyde modified sodium alginate solution and a hydrazide modified gelatin solution as raw materials and performing Schiff base reaction; the single-aldehyde modified sodium alginate is a sodium alginate derivative with a repeating structural unit containing 1 aldehyde group. Experiments prove that the self-healing sodium alginate/gelatin-based gel material capable of spraying to form a film has good biocompatibility, can be quickly formed into a gel within 10s, has excellent spraying film forming property and self-healing property, and has a very good application prospect in preparation of a self-healing biomaterial capable of spraying to form a film, particularly a wound dressing.)

1. A self-healing sodium alginate/gelatin-based hydrogel material capable of spraying to form a film is characterized in that: the sodium alginate solution is obtained by taking a mono-aldehyde modified sodium alginate solution and a hydrazide modified gelatin solution as raw materials and performing Schiff base reaction; the single-aldehyde modified sodium alginate is a sodium alginate derivative with a repeating structural unit containing 1 aldehyde group.

2. A self-healing sodium alginate/gelatin-based hydrogel that can be sprayed to form a film according to claim 1, wherein: the repetitive structural unit of the single aldehyde modified sodium alginate is

3. A self-healing sodium alginate/gelatin-based hydrogel that can be sprayed to form a film according to claim 2, wherein: the preparation method of the monoaldehyde modified sodium alginate solution comprises the following steps:

(1) stirring sodium alginate and 3-amino-1, 2-propylene glycol in deionized water, and mixing;

(2) adding a carbodiimide catalyst into the liquid obtained in the step (1), stirring for reaction, and purifying to obtain dialdehyde-modified sodium alginate;

(3) and (3) dissolving the dialdehyde-modified sodium alginate obtained in the step (2) in deionized water, adding an oxidant, carrying out oxidation reaction, and purifying to obtain the monoaldehyde-modified sodium alginate.

4. A self-healing sodium alginate/gelatin-based hydrogel that can be sprayed to form a film according to claim 3, wherein: in the step (1), the molar ratio of the sodium alginate to the 3-amino-1, 2-propylene glycol is 1: (0.8 to 1.2), preferably 1: 1; the viscosity of the sodium alginate is 350-550 mPa.s;

and/or, in the step (2), the catalyst is 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride; the reaction is carried out under the condition of pH 5.0-6.0, the reaction temperature is room temperature, the reaction time is 20-30 hours, and preferably 24 hours; the molar ratio of the sodium alginate to the catalyst is 1: (0.8 to 1.2), preferably 1: 1;

in the step (2), the purification method comprises the following steps: putting the liquid obtained after the reaction into a dialysis bag, alternately dialyzing the liquid in ethanol and deionized water, and then freeze-drying the dialyzed liquid to obtain the product; the molecular interception of the dialysis bag is 14000 Da;

and/or, in the step (3), the oxidation reaction is carried out under the condition of keeping out light, and the oxidizing agent is sodium periodate; the temperature of the oxidation reaction is room temperature, and the time of the oxidation reaction is 1-3 hours, preferably 2 hours; the mass ratio of the dialdehyde-modified sodium alginate to the oxidant is (5-10): 1, preferably 8: 1;

in the step (3), the purification method comprises the following steps: putting the liquid obtained after the oxidation reaction into a dialysis bag, dialyzing the liquid in deionized water, and then freezing and drying the dialyzed liquid; the molecular cut-off of the dialysis bag was 14000 Da.

5. A self-healing sodium alginate/gelatin-based hydrogel that can be sprayed to form a film according to any one of claims 1 to 4, wherein: the hydrazide-modified gelatin is prepared by the following method:

dissolving gelatin and adipic acid dihydrazide in deionized water under stirring, performing amidation reaction, and purifying to obtain hydrazide-modified gelatin.

6. A self-healing sodium alginate/gelatin-based hydrogel that can be sprayed to form a film according to claim 5, wherein: the mass ratio of the gelatin to the adipic acid dihydrazine is 3.0: (1.5 to 2.5), preferably 3.0: 2.1, the average molecular weight of the gelatin is 50000 Da;

the amidation reaction is carried out in the presence of 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole; the mass ratio of the 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride to the 1-hydroxybenzotriazole is 1: 1;

the amidation reaction is carried out under the condition of pH 5.5, the reaction temperature is room temperature, and the reaction time is 24 hours;

the purification method comprises the following steps: putting the liquid obtained after the amidation reaction into a dialysis bag, dialyzing the liquid in deionized water, and then freeze-drying the dialyzed liquid to obtain the liquid; the molecular cut-off of the dialysis bag was 14000 Da.

7. A self-healing sodium alginate/gelatin-based hydrogel that can be sprayed to form a film according to claim 1, wherein: the volume ratio of the mono-aldehyde modified sodium alginate solution to the hydrazide modified gelatin solution is 1 (1-3), preferably 1: 2;

and/or the concentration of the monoaldehyde modified sodium alginate solution is 0.02g/ml, and the concentration of the hydrazide modified gelatin solution is 0.1 g/ml.

8. A single aldehyde modified sodium alginate is characterized in that: the repetitive structural unit of the single aldehyde modified sodium alginate is

9. The monoaldehyde-modified sodium alginate according to claim 8, wherein: the preparation method of the monoaldehyde modified sodium alginate comprises the following steps:

(1) stirring sodium alginate and 3-amino-1, 2-propylene glycol in deionized water, and mixing;

(2) adding a carbodiimide catalyst into the liquid obtained in the step (1), stirring for reaction, and purifying to obtain dialdehyde-modified sodium alginate;

(3) and (3) dissolving the dialdehyde-modified sodium alginate obtained in the step (2) in deionized water, adding an oxidant, carrying out oxidation reaction, and purifying to obtain the monoaldehyde-modified sodium alginate.

10. The monoaldehyde-modified sodium alginate as set forth in claim 9, characterized in that: in the step (1), the molar ratio of the sodium alginate to the 3-amino-1, 2-propylene glycol is 1: (0.8 to 1.2), preferably 1: 1; the viscosity of the sodium alginate is 350-550 mPa.s;

and/or, in the step (2), the catalyst is 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride; the reaction is carried out under the condition of pH 5.0-6.0, the reaction temperature is room temperature, the reaction time is 20-30 hours, and preferably 24 hours; the molar ratio of the sodium alginate to the catalyst is 1: (0.8 to 1.2), preferably 1: 1;

in the step (2), the purification method comprises the following steps: putting the liquid obtained after the reaction into a dialysis bag, alternately dialyzing the liquid in ethanol and deionized water, and then freeze-drying the dialyzed liquid to obtain the product; the molecular interception of the dialysis bag is 14000 Da;

and/or, in the step (3), the oxidation reaction is carried out under the condition of keeping out light, and the oxidizing agent is sodium periodate; the temperature of the oxidation reaction is room temperature, and the time of the oxidation reaction is 1-3 hours, preferably 2 hours; the mass ratio of the dialdehyde-modified sodium alginate to the oxidant is (5-10): 1, preferably 8: 1;

in the step (3), the purification method comprises the following steps: putting the liquid obtained after the oxidation reaction into a dialysis bag, dialyzing the liquid in deionized water, and then freezing and drying the dialyzed liquid; the molecular cut-off of the dialysis bag was 14000 Da.

Technical Field

The invention belongs to the field of hydrogel materials, and particularly relates to a self-healing sodium alginate/gelatin-based hydrogel material capable of spraying to form a film.

Background

Hydrogels are a "soft and wet" class of materials with unique physical properties (soft, aqueous and tunable porous structures) and a 3D network structure of good biocompatibility. Therefore, they are widely used in tissue engineering and regenerative medicine, diagnosis, drug delivery, wound dressings, and medical devices. The self-healing hydrogel material can be fitted with the characteristics of organisms when the material has microcracks, defects and is damaged, and the self body can generate the defect repairing function under certain conditions without the need of additional material supply. The self-healing hydrogel can restore the original structure and performance after being damaged due to the unique self-healing capacity, prolongs the service life of the material, and has very good application potential in the field of biomedicine.

Trauma is one of the main disease spectrum of emergency department, and can be caused by various reasons such as disasters, war, traffic accidents, frame injury and the like, and has the characteristics of urgent disease condition, complex and various disease conditions and the like. The traditional method for treating the traumatic wound is to wrap a wound dressing at the wound, but the pain and fear of a patient are caused by pulling vulnerable fresh granulation tissue when dressing or dressing change; in addition, to avoid further wound contamination, rapid administration of the drug is often required, and conventional wound dressings are complicated in dressing procedures, increasing the probability of wound contamination. Therefore, wound dressings that can be sprayed to form films have attracted attention. The wound dressing capable of spraying to form a film can be sprayed to form a film on a wound of a patient, the medicine application procedure is simple, pain caused by easy damage due to traction in the binding process is avoided, and the wound pollution probability in the medicine application process is reduced.

However, no hydrogel has the self-healing property and the spraying film-forming property at present, so that the application of the hydrogel in the aspect of wound dressing is limited to a great extent. Hydrogels such as PAM/alginate, PEG/chitosan, and agarose/PEG, while exhibiting many advantages as wound dressings, including self-healing ability, pH response, tissue adhesion, and cell compatibility, cannot be used for the treatment of large-scale pre-hospital trauma (caused in disasters, wars, and traffic accidents) because they cannot immediately form protective membranes.

Therefore, the research of the hydrogel which can be rapidly gelled and has excellent spray film forming property and self-healing property has very important significance.

Disclosure of Invention

The invention aims to provide the sodium alginate/gelatin-based hydrogel which can be rapidly gelled and has excellent spray film forming property and self-healing property.

The invention provides a self-healing sodium alginate/gelatin-based hydrogel material capable of spraying to form a film, which is prepared by taking a mono-aldehyde modified sodium alginate solution and a hydrazide modified gelatin solution as raw materials and performing Schiff base reaction; the single-aldehyde modified sodium alginate is a sodium alginate derivative with a repeating structural unit containing 1 aldehyde group.

Further, the repetitive structural unit of the mono-aldehyde modified sodium alginate is

Further, the preparation method of the monoaldehyde modified sodium alginate solution comprises the following steps:

(1) stirring sodium alginate and 3-amino-1, 2-propylene glycol in deionized water, and mixing;

(2) adding a carbodiimide catalyst into the liquid obtained in the step (1), stirring for reaction, and purifying to obtain dialdehyde-modified sodium alginate;

(3) and (3) dissolving the dialdehyde-modified sodium alginate obtained in the step (2) in deionized water, adding an oxidant, carrying out oxidation reaction, and purifying to obtain the monoaldehyde-modified sodium alginate.

Further, in the step (1), the molar ratio of the sodium alginate to the 3-amino-1, 2-propylene glycol is 1: (0.8 to 1.2), preferably 1: 1; the viscosity of the sodium alginate is 350-550 mPa.s;

and/or, in the step (2), the catalyst is 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride; the reaction is carried out under the condition of pH 5.0-6.0, the reaction temperature is room temperature, the reaction time is 20-30 hours, and preferably 24 hours; the molar ratio of the sodium alginate to the catalyst is 1: (0.8 to 1.2), preferably 1: 1;

in the step (2), the purification method comprises the following steps: putting the liquid obtained after the reaction into a dialysis bag, alternately dialyzing the liquid in ethanol and deionized water, and then freeze-drying the dialyzed liquid to obtain the product; the molecular interception of the dialysis bag is 14000 Da;

and/or, in the step (3), the oxidation reaction is carried out under the condition of keeping out light, and the oxidizing agent is sodium periodate; the temperature of the oxidation reaction is room temperature, and the time of the oxidation reaction is 1-3 hours, preferably 2 hours; the mass ratio of the dialdehyde-modified sodium alginate to the oxidant is (5-10): 1, preferably 8: 1;

in the step (3), the purification method comprises the following steps: putting the liquid obtained after the oxidation reaction into a dialysis bag, dialyzing the liquid in deionized water, and then freezing and drying the dialyzed liquid; the molecular cut-off of the dialysis bag was 14000 Da.

Further, the hydrazide-modified gelatin is prepared by the following method:

dissolving gelatin and adipic acid dihydrazide in deionized water under stirring, performing amidation reaction, and purifying to obtain hydrazide-modified gelatin.

Further, the mass ratio of the gelatin to the adipic acid dihydrazine is 3.0: (1.5 to 2.5), preferably 3.0: 2.1, the average molecular weight of the gelatin is 50000 Da;

the amidation reaction is carried out in the presence of 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole; the mass ratio of the 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride to the 1-hydroxybenzotriazole is 1: 1;

the amidation reaction is carried out under the condition of pH 5.5, the reaction temperature is room temperature, and the reaction time is 24 hours;

the purification method comprises the following steps: putting the liquid obtained after the amidation reaction into a dialysis bag, dialyzing the liquid in deionized water, and then freeze-drying the dialyzed liquid to obtain the liquid; the molecular cut-off of the dialysis bag was 14000 Da.

Further, the volume ratio of the mono-aldehyde modified sodium alginate solution to the hydrazide modified gelatin solution is 1 (1-3), preferably 1: 2;

and/or the concentration of the monoaldehyde modified sodium alginate solution is 0.02g/ml, and the concentration of the hydrazide modified gelatin solution is 0.1 g/ml.

The invention also provides the single-aldehyde modified sodium alginate, and the repeating structural unit of the single-aldehyde modified sodium alginate is

Further, the preparation method of the mono-aldehyde modified sodium alginate comprises the following steps:

(1) stirring sodium alginate and 3-amino-1, 2-propylene glycol in deionized water, and mixing;

(2) adding a carbodiimide catalyst into the liquid obtained in the step (1), stirring for reaction, and purifying to obtain dialdehyde-modified sodium alginate;

(3) and (3) dissolving the dialdehyde-modified sodium alginate obtained in the step (2) in deionized water, adding an oxidant, carrying out oxidation reaction, and purifying to obtain the monoaldehyde-modified sodium alginate.

Further, in the step (1), the molar ratio of the sodium alginate to the 3-amino-1, 2-propylene glycol is 1: (0.8 to 1.2), preferably 1: 1; the viscosity of the sodium alginate is 350-550 mPa.s;

and/or, in the step (2), the catalyst is 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride; the reaction is carried out under the condition of pH 5.0-6.0, the reaction temperature is room temperature, the reaction time is 20-30 hours, and preferably 24 hours; the molar ratio of the sodium alginate to the catalyst is 1: (0.8 to 1.2), preferably 1: 1;

in the step (2), the purification method comprises the following steps: putting the liquid obtained after the reaction into a dialysis bag, alternately dialyzing the liquid in ethanol and deionized water, and then freeze-drying the dialyzed liquid to obtain the product; the molecular interception of the dialysis bag is 14000 Da;

and/or, in the step (3), the oxidation reaction is carried out under the condition of keeping out light, and the oxidizing agent is sodium periodate; the temperature of the oxidation reaction is room temperature, and the time of the oxidation reaction is 1-3 hours, preferably 2 hours; the mass ratio of the dialdehyde-modified sodium alginate to the oxidant is (5-10): 1, preferably 8: 1;

in the step (3), the purification method comprises the following steps: putting the liquid obtained after the oxidation reaction into a dialysis bag, dialyzing the liquid in deionized water, and then freezing and drying the dialyzed liquid; the molecular cut-off of the dialysis bag was 14000 Da.

Experimental results show that the self-healing sodium alginate/gelatin-based hydrogel material capable of spraying to form a film is prepared by taking a monoaldehyde modified sodium alginate solution and a hydrazide modified gelatin solution as raw materials and performing Schiff base reaction. The problem that the ring-opening oxidation forms unstable hydrogel is avoided by the mono-aldehyde modified sodium alginate, the obtained hydrogel material has good biocompatibility, can be quickly formed into gel within 10s, has excellent spraying film forming property and self-healing property, and has a good application prospect in preparation of self-healing biomaterials capable of being sprayed into films, particularly wound dressings.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Drawings

FIG. 1 is a schematic diagram of the preparation of monoaldehyde sodium alginate.

FIG. 2 is a schematic diagram of the preparation of hydrazide gelatin.

FIG. 3 is a schematic diagram of the preparation of hydrogel.

FIG. 4 is a self-healing diagram of a hydrogel; wherein, the figure I is an original hydrogel sample, the figure II is a sectioned hydrogel sample, the figure III is a sample in which hydrogel sections with different colors are alternately connected after being sectioned, and the figure IV is a stretched self-healing sample.

FIG. 5 is a diagram of spray filming of hydrogels.

Detailed Description

The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.

Wherein the viscosity of the sodium alginate is 350-550mPa.s), and the structure is as follows:

the average molecular weight of gelatin was 50000Da and was purchased from Sigma-Aldrich.