CN112876694B - Preparation method and application of acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel - Google Patents
Preparation method and application of acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel Download PDFInfo
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- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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Abstract
The invention discloses an acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, a preparation method and application thereof. According to the invention, through the free radical polymerization generated by carbon-carbon double bond on acrylic acid through illumination and the electrostatic complexation between nitrogen heterocycle and phenolic hydroxyl of pyrrolidone, epsilon-polylysine is crosslinked with acrylic acid to form the hydrogel with a three-dimensional network structure, and the hydrogel has the advantages of controllable performance, good biocompatibility, illumination molding, spectrum antibacterial property, adjustable adhesion strength and the like, is mild and controllable in implementation condition, and can be applied to the biomedical material fields such as tissue adhesives, medical dressings, tissue engineering materials and the like.
Description
Technical Field
The invention belongs to the field of biomedical high polymer materials, and particularly relates to a photo-crosslinked acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, and a preparation method and application thereof.
Background
For the treatment of wound sites, the traditional method mainly adopts surgical suturing, however, the method has higher technical literacy requirement for clinical operators, needs higher expertise and technical means, can generate side effects such as inflammatory reaction, secondary infection, scar formation, bacterial breeding, wound edema and the like, and can increase economic cost due to the requirement of drug anesthesia in the wound suturing process. Therefore, it is critical to develop tissue adhesives to aid in the suturing and repair of wounds to address the above drawbacks. The ideal tissue adhesive needs to have high tissue adhesiveness, broad-spectrum antibacterial property, no immunological rejection reaction, biological innocuity, higher biocompatibility to human tissues, no irritation to human tissues, certain self-adaptive property and the like.
The existing biological adhesives mainly comprise fibrin glue and cyanoacrylate, but the biological adhesives have the problems of poor tissue adhesion strength, easy falling, poor antibacterial performance, certain skin irritation and the like.
The hydrogel is a multifunctional three-dimensional porous scaffold material with high water content and similar structure to natural soft tissues, can be reasonably modified by using a chemically modifiable group of a high polymer material, can construct an adhesive hydrogel scaffold, and has important application potential in the field of biomedical high polymer materials. Adhesive hydrogels are an important biomaterial that can be used in surgical sealants and wound dressings.
Disclosure of Invention
Aiming at the problems of the prior art, the invention provides a photocrosslinked high-adhesion acrylic acid/epsilon-polylysine antibacterial hydrogel as well as a preparation method and application thereof.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a preparation method of acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel comprises the following steps:
(1) Adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) to ethanol-water solution containing Gallic Acid (GA) for activation; then adding epsilon-polylysine (epsilon-PL) to react to obtain a gallic acid modified epsilon-polylysine polymer, which is marked as epsilon-PL-GA;
(2) Adding epsilon-PL-GA, epsilon-polylysine, acrylic acid and polyvinylpyrrolidone (PVP) into a water solution containing a photoinitiator to obtain a stock solution; and irradiating the stock solution under ultraviolet light to obtain the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel.
Preferably, the reaction time in the step (1) is 12-48 hours.
Preferably, the volume ratio of ethanol to water in the ethanol-water solution in the step (1) is 5:1-1:2.
Preferably, the epsilon-polylysine added in the step (1) is an epsilon-polylysine aqueous solution with the concentration of 5-10 g/L.
Preferably, the epsilon-polylysine of step (1) has a molecular weight of 1000 to 4000 daltons.
Preferably, the molar ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the N-hydroxysuccinimide in the step (1) is 3:1-1:3; the molar ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the carboxyl in the gallic acid is 1:1-1:5; the molar ratio of the amino groups in the gallic acid and the epsilon-polylysine is 5:1-1:3.
Preferably, the pH of the solution after adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide to the ethanol-water solution containing gallic acid in step (1) is 4.5 to 5.5.
Preferably, the activation time in the step (1) is 15-90 min.
Preferably, the activation temperature in step (1) is 0-30 ℃.
Preferably, step (1) further comprises a step of reaction to dialysis, freeze drying.
Preferably, the dialysis in step (1) takes 1 to 7 days.
Preferably, the lyophilization time in step (1) is 2 days.
Preferably, the photoinitiator in the step (2) is alpha-ketoglutaric acid.
Preferably, the mass concentration of the photoinitiator in the stock solution in the step (2) is 0.2%.
Preferably, the mass concentration of the acrylic acid in the stock solution in the step (2) is 30%.
Preferably, the mass concentration of polyvinylpyrrolidone in the stock solution in the step (2) is 0.2-4%.
Preferably, the mass concentration of epsilon-PL-GA in the stock solution in the step (2) is 0.1-1%.
Preferably, the mass concentration of epsilon-polylysine in the stock solution in the step (2) is 1-10%.
Preferably, the irradiation time under the ultraviolet light in the step (2) is 2-10 min. The raw solutions are mixed under the condition of ultraviolet irradiation to prepare the stock solution, and the stock solution can be quickly gelled within a minimum of 2 minutes.
The invention also provides the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel prepared by the method.
The invention also provides application of the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel prepared by the method in the field of biomedical materials.
The application comprises: preparing medical dressing, tissue engineering material or tissue adhesive.
The invention has the beneficial effects that:
the ultraviolet light irradiation initiates the free radical polymerization, so that harmful toxic byproducts are hardly generated, the operation is simple, the condition controllability is high, the gel forming mode is simple and convenient, and the method is regarded as an ideal hydrogel curing means; secondly, the electrostatic complexation between the nitrogen heterocycle of pyrrolidone and phenolic hydroxyl can be utilized to enhance the mechanical property of the hydrogel, then the synergistic effect of the N-hydroxysuccinimide modified acrylic ester and the gallic acid modified epsilon-polylysine polymer can be utilized to promote the adhesion of tissue parts, and finally the combined effect of gallic acid and epsilon-polylysine is utilized to achieve the aim of tissue adhesive antibacterial.
The invention takes safe and nontoxic biodegradable material epsilon-polylysine as a natural antibacterial material, modifies gallic acid on the high molecular side chain, utilizes the synergistic effect of amino cations, phenolic hydroxyl groups and aromatic heterocycle to achieve the aim of broad-spectrum antibacterial, and has excellent biocompatibility. The simple controllable ultraviolet light-initiated free radical polymerization reaction and the simple electrostatic complexation can provide certain mechanical properties for the hydrogel, the special properties of the gallic acid and the N-hydroxysuccinimide modified acrylic ester can better solve the problem of weak adhesion strength of the hydrogel material, and the hydrogel material has wide clinical application prospect in the fields of medical dressings and tissue adhesives.
The method adopts a one-step gel forming technology, and has the characteristics of single curing means, excellent biocompatibility and broad-spectrum antibacterial property and good adhesion strength.
Drawings
FIG. 1 is a graph showing the adhesion performance of the hydrogel according to the present invention in example 9.
FIG. 2 is a drawing of a tensile test of a hydrogel according to the invention.
FIG. 3 is a graph comparing cell viability of hydrogels of the present invention to cell culture media.
Detailed Description
The invention will be better understood from the following examples. However, it will be readily appreciated by those skilled in the art that the description of the embodiments is provided for illustration only and should not limit the invention as detailed in the claims.
Example 1
(1) Gallic Acid (GA) was dissolved in an ethanol-water system at a volume ratio of 1:2, and after stirring thoroughly and dissolving uniformly, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were added, ph=4.5 was adjusted, and the mixture was stirred and activated at 30 ℃ for 30 minutes. Adding epsilon-polylysine (epsilon-PL, molecular weight is 1500 daltons), wherein the mass concentration of epsilon-PL is 5g/L, and stirring and reacting for 24 hours at 30 ℃; the molar ratios of the substances are as follows, EDC: GA=1:1, EDC: NHS=2:1, GA: ε -PL=1:1. Transferring the system obtained by the reaction into a dialysis bag, and dialyzing in deionized water for 2 days; and freeze-drying the dialyzed solution for 2 days to obtain a polymer of the gallic acid modified epsilon-polylysine (epsilon-PL-GA), wherein the grafting rate of the epsilon-PL-GA is 10 percent.
(2) Adding gallic acid modified epsilon-polylysine polymer (epsilon-PL-GA), polylysine (epsilon-PL), polyvinylpyrrolidone (PVP) and acrylic acid (Aa) into an aqueous solution containing alpha-ketoglutaric acid, and fully stirring and uniformly mixing to obtain a stock solution; the raw solution is irradiated for 5min under ultraviolet light to obtain the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, wherein the mass concentration of epsilon-PL-GA in the raw solution is 0.2%, the mass concentration of PVP is 2%, the mass concentration of epsilon-PL is 4%, the mass concentration of Aa is 30%, and the mass concentration of alpha-ketoglutaric acid is 0.2%.
Example 2
(1) Gallic Acid (GA) was dissolved in an ethanol-water system at a volume ratio of 1:2, and after stirring thoroughly and dissolving uniformly, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were added, ph=4.8 was adjusted, and the mixture was stirred and activated at 4 ℃ for 90 minutes. Adding epsilon-polylysine (epsilon-PL, molecular weight is 3000 daltons), wherein the mass concentration of epsilon-PL is 5g/L, and stirring and reacting for 24 hours at 30 ℃; the molar ratios of the substances are as follows, EDC: GA=1:5, EDC: NHS=1:1, GA: ε -PL=5:1. Transferring the system obtained by the reaction into a dialysis bag, and dialyzing in deionized water for 3 days; and freeze-drying the dialyzed solution to obtain a polymer of the gallic acid modified epsilon-polylysine (epsilon-PL-GA), wherein the grafting rate of the epsilon-PL-GA is 12 percent.
(2) Adding gallic acid modified epsilon-polylysine polymer (epsilon-PL-GA), polylysine (epsilon-PL), polyvinylpyrrolidone (PVP) and acrylic acid (Aa) into an aqueous solution containing alpha-ketoglutaric acid, and fully stirring and uniformly mixing to obtain a stock solution; the raw solution is irradiated for 2min under ultraviolet light to obtain the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, wherein the mass concentration of epsilon-PL-GA in the raw solution is 0.3%, the mass concentration of PVP is 4%, the mass concentration of epsilon-PL is 2%, the mass concentration of Aa is 30%, and the mass concentration of alpha-ketoglutaric acid is 0.2%.
Example 3
(1) Gallic Acid (GA) was dissolved in an ethanol-water system at a volume ratio of 5:1, and after being stirred well and dissolved uniformly, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were added, ph=5 was adjusted, and the mixture was stirred and activated at 0 ℃ for 30 minutes. Adding epsilon-polylysine (epsilon-PL, molecular weight is 1000 daltons), wherein the mass concentration of epsilon-PL is 5g/L, and stirring and reacting for 24 hours at 30 ℃; the molar ratios of the various materials are as follows, EDC: ga=1:1, EDC: nhs=3:1, GA: epsilon-pl=1:1. Transferring the system obtained by the reaction into a dialysis bag, and dialyzing in deionized water for 1 day; and freeze-drying the dialyzed solution to obtain a polymer of the gallic acid modified epsilon-polylysine (epsilon-PL-GA), wherein the grafting rate of the epsilon-PL-GA is 10%.
(2) Adding gallic acid modified epsilon-polylysine polymer (epsilon-PL-GA), polylysine (epsilon-PL), polyvinylpyrrolidone (PVP) and acrylic acid (Aa) into an aqueous solution containing alpha-ketoglutaric acid, and fully stirring and uniformly mixing to obtain a stock solution; the raw solution is irradiated for 3min under ultraviolet light to obtain the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, wherein the mass concentration of epsilon-PL-GA in the raw solution is 0.1%, the mass concentration of PVP is 2%, the mass concentration of epsilon-PL is 4%, the mass concentration of Aa is 30%, and the mass concentration of alpha-ketoglutaric acid is 0.2%.
Example 4
(1) Gallic Acid (GA) was dissolved in an ethanol-water system at a volume ratio of 1:2, and after stirring thoroughly and dissolving uniformly, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were added, ph=4.5 was adjusted, and the mixture was stirred and activated at 30 ℃ for 15 minutes. Adding epsilon-polylysine (epsilon-PL, molecular weight is 1500 daltons), wherein the mass concentration of epsilon-PL is 5g/L, and stirring and reacting for 12 hours at 30 ℃; the molar ratios of the substances are as follows, EDC: GA=1:1, EDC: NHS=2:1, GA: ε -PL=1:3. Transferring the system obtained by the reaction into a dialysis bag, and dialyzing in deionized water for 2 days; and freeze-drying the dialyzed solution to obtain a polymer of the gallic acid modified epsilon-polylysine (epsilon-PL-GA), wherein the grafting rate of the epsilon-PL-GA is 10%.
(2) Adding gallic acid modified epsilon-polylysine polymer (epsilon-PL-GA), polylysine (epsilon-PL), polyvinylpyrrolidone (PVP) and acrylic acid (Aa) into an aqueous solution containing alpha-ketoglutaric acid, and fully stirring and uniformly mixing to obtain a stock solution; the raw solution is irradiated for 10min under ultraviolet light to obtain the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, wherein the raw solution comprises 0.5% of epsilon-PL-GA, 0.2% of PVP, 1% of epsilon-PL, 30% of Aa and 0.2% of alpha-ketoglutaric acid.
Example 5
(1) Gallic Acid (GA) was dissolved in an ethanol-water system at a volume ratio of 2:1, and after being stirred well and dissolved uniformly, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were added, ph=4.5 was adjusted, and the mixture was stirred and activated at 15 ℃ for 30 minutes. Adding epsilon-polylysine (epsilon-PL, molecular weight is 1500 daltons), wherein the mass concentration of epsilon-PL is 7g/L, and stirring and reacting for 24 hours at 30 ℃; the molar ratios of the substances are as follows, EDC: GA=1:1, EDC: NHS=1:3, GA: ε -PL=1:1. Transferring the system obtained by the reaction into a dialysis bag, and dialyzing in deionized water for 5 days; and freeze-drying the dialyzed solution to obtain a polymer of the gallic acid modified epsilon-polylysine (epsilon-PL-GA), wherein the grafting rate of the epsilon-PL-GA is 10%.
(2) Adding gallic acid modified epsilon-polylysine polymer (epsilon-PL-GA), polylysine (epsilon-PL), polyvinylpyrrolidone (PVP) and acrylic acid (Aa) into an aqueous solution containing alpha-ketoglutaric acid, and fully stirring and uniformly mixing to obtain a stock solution; the raw solution is irradiated for 3min under ultraviolet light to obtain the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, wherein the mass concentration of epsilon-PL-GA in the raw solution is 0.3%, the mass concentration of PVP is 4%, the mass concentration of epsilon-PL is 4%, the mass concentration of Aa is 30%, and the mass concentration of alpha-ketoglutaric acid is 0.2%.
Example 6
(1) Gallic Acid (GA) was dissolved in an ethanol-water system at a volume ratio of 1:2, and after stirring thoroughly and dissolving uniformly, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were added, ph=5.5 was adjusted, and the mixture was stirred and activated at 30 ℃ for 30 minutes. Adding epsilon-polylysine (epsilon-PL, molecular weight is 4000 daltons), wherein the mass concentration of epsilon-PL is 5g/L, and stirring and reacting for 48 hours at 30 ℃; the molar ratios of the various materials are as follows, EDC: ga=1:1, EDC: nhs=2:1, GA: epsilon-pl=3:1. Transferring the system obtained by the reaction into a dialysis bag, and dialyzing in deionized water for 2 days; and freeze-drying the dialyzed solution to obtain a polymer of the gallic acid modified epsilon-polylysine (epsilon-PL-GA), wherein the grafting rate of the epsilon-PL-GA is 10%.
(2) Adding gallic acid modified epsilon-polylysine polymer (epsilon-PL-GA), polylysine (epsilon-PL), polyvinylpyrrolidone (PVP) and acrylic acid (Aa) into an aqueous solution containing alpha-ketoglutaric acid, and fully stirring and uniformly mixing to obtain a stock solution; the raw solution is irradiated for 8min under ultraviolet light to obtain the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, wherein the mass concentration of epsilon-PL-GA in the raw solution is 0.5%, the mass concentration of PVP is 1%, the mass concentration of epsilon-PL is 8%, the mass concentration of Aa is 30%, and the mass concentration of alpha-ketoglutaric acid is 0.2%.
Example 7
(1) Gallic Acid (GA) was dissolved in an ethanol-water system at a volume ratio of 4:1, and after being stirred well and dissolved uniformly, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were added, ph=4.8 was adjusted, and the mixture was stirred and activated at 4 ℃ for 60 minutes. Adding epsilon-polylysine (epsilon-PL, molecular weight is 1500 daltons), wherein the mass concentration of epsilon-PL is 10g/L, and stirring and reacting at 30 ℃ for 36 hours; the molar ratios of the substances are as follows, EDC: ga=1:3, EDC: nhs=1.2:1, GA: epsilon-pl=5:1. Transferring the system obtained by the reaction into a dialysis bag, and dialyzing in deionized water for 7 days; and freeze-drying the dialyzed solution to obtain a polymer of the gallic acid modified epsilon-polylysine (epsilon-PL-GA), wherein the grafting rate of the epsilon-PL-GA is 14%.
(2) Adding gallic acid modified epsilon-polylysine polymer (epsilon-PL-GA), polylysine (epsilon-PL), polyvinylpyrrolidone (PVP) and acrylic acid (Aa) into an aqueous solution containing alpha-ketoglutaric acid, and fully stirring and uniformly mixing to obtain a stock solution; the raw solution is irradiated for 4min under ultraviolet light to obtain the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, wherein the mass concentration of epsilon-PL-GA in the raw solution is 0.3%, the mass concentration of PVP is 4%, the mass concentration of epsilon-PL is 3%, the mass concentration of Aa is 30%, and the mass concentration of alpha-ketoglutaric acid is 0.2%.
Example 8
(1) Gallic Acid (GA) was dissolved in an ethanol-water system at a volume ratio of 4:1, and after being stirred well and dissolved uniformly, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were added, ph=4.8 was adjusted, and the mixture was stirred and activated at 4 ℃ for 60 minutes. Adding epsilon-polylysine (epsilon-PL, molecular weight is 1500 daltons), wherein the mass concentration of epsilon-PL is 10g/L, and stirring and reacting at 30 ℃ for 36 hours; the molar ratios of the substances are as follows, EDC: ga=1:3, EDC: nhs=1.2:1, GA: epsilon-pl=5:1. Transferring the system obtained by the reaction into a dialysis bag, and dialyzing in deionized water for 3 days; and freeze-drying the dialyzed solution to obtain a polymer of the gallic acid modified epsilon-polylysine (epsilon-PL-GA), wherein the grafting rate of the epsilon-PL-GA is 14%.
(2) Adding gallic acid modified epsilon-polylysine polymer (epsilon-PL-GA), polylysine (epsilon-PL), polyvinylpyrrolidone (PVP) and acrylic acid (Aa) into an aqueous solution containing alpha-ketoglutaric acid, and fully stirring and uniformly mixing to obtain a stock solution; the raw liquid is irradiated for 3min under ultraviolet light to obtain the adhesive acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, wherein the raw liquid contains 1% of epsilon-PL-GA, 0.5% of PVP, 10% of epsilon-PL, 30% of Aa and 0.2% of alpha-ketoglutaric acid.
Example 9: adhesion Performance evaluation experiment
The adhesive performance of the adhesive acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel was evaluated by a CMT2103 universal tester (Meter MTS Co., USA), i.e., the mechanical energy was characterized by the compression performance. The specific experimental steps are as follows: the gel was applied to fresh pigskin at a stretching speed of 10mm/min and the results are shown in Table 1. Compared with commercial tissue adhesive fibrin glue, the hydrogel prepared by the invention has good tissue adhesion; in addition, in order to more vividly show the adhesive property of the hydrogel, the pigskin adhesive test of the hydrogel is shown in fig. 1, and the adhesive property of the hydrogel is shown in fig. 2 (fig. 2 shows that the hydrogel can show high adhesive property by stretching after being pressed by hand).
TABLE 1 evaluation of hydrogel adhesion Properties of different monomer ratios
| Sample (wt%) | Adhesive strength (kPa) |
| Fibrin glue | 4.8±0.6 |
| 30％Aa/2％PVP/4％PL/0.1％PL-GA | 6±1.4 |
| 30％Aa/2％PVP/4％PL/0.2％PL-GA | 8±2.4 |
| 30％Aa/4％PVP/4％PL/0.3％PL-GA | 15±1.2 |
| 30％Aa/4％PVP/3％PL/0.3％PL-GA | 13±1.5 |
| 30％Aa/4％PVP/2％PL/0.3％PL-GA | 12±2.6 |
Example 10: cytotoxicity evaluation experiment
The cell compatibility of the acrylic acid/epsilon-polylysine antibacterial adhesive hydrogel was evaluated by dead-living staining, and the experimental object was mouse fibroblasts (L929). The specific experimental operation steps are as follows: (1) L929 cells were cultured in high sugar DMEM medium containing 10% fetal bovine serum and 1% diabody, and placed at 37℃in 5% CO 2 Culturing in incubator until cell confluence rate reaches above 85%, digesting with trypsin, centrifuging, and regulating cell density to 5×10 with culture medium 5 cell suspension of cell/mL; (2) Then inoculating L929 cells into a 24-well plate, placing 200 mu L of each well into a cell culture box, and culturing overnight until the cells are completely adhered; sucking out the original culture solution, and respectively adding 1mL of the leaching solution of the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel, a blank control solution (namely fresh complete culture medium) and the leaching solution of the GelMA hydrogel with the same concentration, wherein each group has 3 parallel samples; (4) The AO/EB dye solution staining working solution was added at a ratio of 40. Mu.L per ml to each well at three time points of 24h,48h and 72h, respectively, and after 5 minutes of placing in a constant temperature incubator at 37 ℃, the fluorescence-stained cells were observed under a fluorescence inversion microscope. Observing the cell morphology of the stained cells under a fluorescence microscope, wherein the living cells show a green normal structure; dead cells exhibit a orange-red, shrunken or beaded structure. FIG. 3 shows that the present invention exhibits higher cell viability compared to Gel-MA Gel and cell culture medium DMEM.
Note that: preparing a dyeing working solution: the Acridine Orange (AO) solution and Ethidium Bromide (EB) solution are mixed into working solution according to the volume ratio of 1:1, and the working solution is prepared at present. The concentrations of the AO and EB solutions in the experiment are 100 mug/ml respectively, and the contained stabilizer does not influence the experimental effect.
Example 11: evaluation of antibacterial Properties
The invention adopts a nutrient broth dilution method to examine the antibacterial performance of the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel. Firstly, placing hydrogel samples of different monomers in an alcohol solution with the volume fraction of 75% for soaking for 4 hours to ensure thorough disinfection, then using a sterile PBS solution to wash alcohol in gel, placing the hydrogel samples in a 48-well plate, finally dripping activated bacterial suspension (such as escherichia coli and 200 mu L of bacterial suspension) on the surface of the hydrogel samples, performing gel bacteria co-cultivation for 24 hours, adding the bacterial samples into a 300 mu L nutrient broth solution, using an ultraviolet spectrophotometer to test absorbance (OD) at a wavelength of 600nm, using an untreated bacterial solution as a control group, and using a calculation formula (OD-experimental group OD)/OD multiplied by 100% of the control group to calculate the result, wherein each group of experiments is performed 3 times, and the experimental results are shown in table 2.
TABLE 2 evaluation of antibacterial Properties of hydrogels with different monomer ratios
| Sample (wt%) | Coli (%) | Staphylococcus aureus (%) |
| 30％Aa | 3.12±0.11 | 2.12±0.23 |
| 30％Aa/2％PVP/4％PL/0.1％PL-GA | 75.63±6.17 | 64.65±1.26 |
| 30％Aa/2％PVP/4％PL/0.2％PL-GA | 83.32±2.65 | 75.14±3.11 |
| 30％Aa/4％PVP/4％PL/0.3％PL-GA | 87.14±3.64 | 86.24±2.01 |
| 30％Aa/4％PVP/3％PL/0.3％PL-GA | 85.25±2.13 | 82.33±1.21 |
| 30％Aa/4％PVP/2％PL/0.3％PL-GA | 79.29±4.17 | 79.22±3.41 |
In summary, we provide a method for preparing tissue adhesives by utilizing acrylic acid/epsilon-polylysine through photoinitiated free radical polymerization and electrostatic complexation, which not only has better tissue adhesion performance, but also has excellent tissue compatibility, has stronger broad-spectrum antibacterial performance, and is expected to be used for clinical application and development of tissue engineering scaffolds such as skin auxiliary materials, tissue adhesives, hemostatic materials and the like in the later period.
Claims (8)
1. The preparation method of the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel is characterized by comprising the following steps of:
(1) Adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide to ethanol-water solution containing gallic acid, and activating; then adding epsilon-polylysine for reaction to obtain a gallic acid modified epsilon-polylysine polymer, which is marked as epsilon-PL-GA; the molar ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the N-hydroxysuccinimide is 3:1-1:3; the molar ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the carboxyl in the gallic acid is 1:1-1:5; the molar ratio of the amino groups in the gallic acid and the epsilon-polylysine is 5:1-1:3;
(2) Adding epsilon-PL-GA, epsilon-polylysine, acrylic acid and polyvinylpyrrolidone into a water solution containing a photoinitiator to obtain a stock solution; the mass concentration of the acrylic acid in the stock solution is 30%; the mass concentration of polyvinylpyrrolidone in the stock solution is 0.2-4%; the mass concentration of epsilon-PL-GA in the stock solution is 0.1-1%; the mass concentration of epsilon-polylysine in the stock solution is 1-10%;
and irradiating the stock solution under ultraviolet light to obtain the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel.
2. The method according to claim 1, wherein the epsilon-polylysine in step (1) has a molecular weight of 1000-4000 daltons.
3. The method according to claim 1, wherein in the step (1), after 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide are added to the ethanol-water solution containing gallic acid, the pH of the solution is 4.5 to 5.5.
4. The method of claim 1, wherein the photoinitiator in step (2) is α -ketoglutaric acid.
5. The method according to claim 1, wherein the mass concentration of the photoinitiator in the stock solution in the step (2) is 0.2%.
6. The preparation method of claim 1, wherein the irradiation time under ultraviolet light in the step (2) is 2 min-10 min.
7. An acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel prepared by the preparation method of any one of claims 1 to 6.
8. Use of the acrylic acid/epsilon-polylysine adhesive antibacterial hydrogel prepared by the preparation method of any one of claims 1-6 in preparation of biomedical materials.
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