CN116549721A - Preparation method and application of antibacterial/wound repair type hydrogel - Google Patents
Preparation method and application of antibacterial/wound repair type hydrogel Download PDFInfo
- Publication number
- CN116549721A CN116549721A CN202310583807.1A CN202310583807A CN116549721A CN 116549721 A CN116549721 A CN 116549721A CN 202310583807 A CN202310583807 A CN 202310583807A CN 116549721 A CN116549721 A CN 116549721A
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- antibacterial
- hydrogel
- solution
- wound
- mussel
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Abstract
The invention belongs to the field of biomedical wound antibacterial and repairing materials, and particularly relates to preparation of antibacterial/wound repairing hydrogel and a biomedical method thereof. The object of the present invention is to overcome the drawbacks of the prior art described above. To this end, a first aspect of the invention provides a method for preparing mussel heuristic polysaccharide/oxidized cellulose composite hydrogels by Schiff base cross-linking, which can form hydrogels in situ at a wound site by mixing and adding a hydrogel precursor solution. After the gel is formed, oxidized cellulose can be double locked in the gel through two methods of Schiff base crosslinking and gel pore blocking, so that side effects are prevented. The hydrogel is particularly applied to a mouse skin injury repair model and an in-vitro bacteriostasis experiment. The hydrogel has the advantages of wet adhesion, antibacterial property and wound repair property, and has good biomedical application prospect.
Description
Technical Field
The invention belongs to the fields of biocatalysis, biomedical antibacterial materials and biomedical wound repair materials, and particularly relates to a preparation method of mussel heuristic polysaccharide/oxidized cellulose composite hydrogel and application thereof in the fields of antibacterial and wound repair.
Background
Infection is a major obstacle to wound healing and has become a leading cause of increased death in severely ill patients. Furthermore, the treatment of infections places a heavy burden on medical systems and even the whole society. At present, many types of modern wound dressings have been developed, including semipermeable membranes, semipermeable powders, and hydrogels with sustained drug release properties, which not only prevent infection of defective wounds, but also facilitate the wound repair process. However, many materials have a further reduced adhesion due to their low adhesion, especially in wet environments, and it is difficult to effectively act on the wound over a long period of time in these dressings. Mussel-like hydrogels can reduce the risk of wound infection by absorbing wound exudates and maintaining a moist environment, these properties provide good potential for improving repair of damaged tissue, and where catechol or pyrogallol groups can effectively promote wet adhesion of the material. Excessive Reactive Oxygen Species (ROS) during wound repair often alter or degrade extracellular matrix (ECM) proteins, disrupting dermal fibroblasts and reducing keratinocyte function, thereby affecting repair. Thus, controlling ROS levels has proven to be an effective method of promoting wound healing. The structure of catechol or pyrogallol has been shown to be widely present in a variety of natural antioxidants and plays an important role in scavenging ROS. They damage the physical bonding and chemical cross-linking between tissues and further accelerate wound repair. The oxidized cellulose has excellent new hemostatic and antibacterial properties, and is a medical material widely applied. However, oxidized cellulose also causes side effects such as neurotoxicity when it enters the blood system in large amounts through wounds. How to fully exert the advantages of wound management of oxidized cellulose and minimize the side effects of the oxidized cellulose is always a problem that such materials need to be optimized.
Disclosure of Invention
The object of the present invention is to overcome the drawbacks of the prior art described above. To this end, a first aspect of the invention provides a method for preparing mussel heuristic polysaccharide/oxidized cellulose composite hydrogels by Schiff base cross-linking, which can form hydrogels in situ at a wound site by mixing and adding a hydrogel precursor solution. After the gel is formed, oxidized cellulose can be double locked in the gel through two methods of Schiff base crosslinking and gel pore blocking, so that side effects are prevented.
The second aspect of the invention provides specific application of the hydrogel in a mouse skin injury repair model and an in-vitro bacteriostasis experiment.
According to a first aspect of the present invention, a method is presented for forming a hydrogel by cross-linking carboxyl groups in oxidized cellulose (ORC) with amino groups in mussel-like heuristic polysaccharides via schiff bases.
In some embodiments of the invention, ORC is dispersed in phosphate buffered saline (PBS, ph=7.4) at a concentration of 1.5% -5% by mass. Mussel-like polymer material is dispersed into PBS solution at a concentration of 1-3.5% by mass. ORC solution was set as A solution, mussel heuristic polysaccharide solution was set as B solution. And (3) mixing A, B solution to prepare the mussel heuristic polysaccharide/oxidized cellulose composite hydrogel.
Further, the mussel heuristic modified polysaccharide comprises all mussel heuristic compounds containing catechol and pyrogallol and rich in amino groups, wherein the mussel heuristic compounds can be grafted on a polymer.
In some embodiments of the invention, the material is preheated to a temperature in the range of 37 ℃.
In some embodiments of the invention, the mussel-like polymer material is dispersed in the PBS solution at a concentration of 1% -3.5% by mass.
In some embodiments of the invention, the gel time is 3s to 90s.
According to a third aspect of the invention, there is provided the use of a mussel-like hemostatic hydrogel in wound hemostasis. In an animal bleeding model, A, B solution is applied to bleeding wounds in sequence, so that the aim of stopping bleeding can be quickly and effectively achieved.
The beneficial effects of the invention are as follows:
1. the hydrogel of the invention has strong adhesiveness and good biocompatibility.
2. The hydrogel prepared by the invention has simple preparation process, controllable preparation process and amplified production.
3. The hydrogel disclosed by the invention has excellent antibacterial property and wound repair property, can be effectively crosslinked in situ at a skin defect site to rapidly close a wound, and can inhibit bacterial growth to prevent and treat infection.
Drawings
Figure 1 shows the bacteriostatic effect of hydrogels. A. Staphylococcus aureus shows antibacterial effect through a plate counting method; B. survival rate of staphylococcus aureus after hydrogel treatment; C. coliform bacteria show antibacterial effect by a plate counting method; D. survival rate of E.coli after hydrogel treatment
FIG. 2 is a graph with scale bars showing the cell compatibility test of example 1: 100 μm
FIG. 3 shows the proliferation of cells after 1, 3, 5 and 7 days of GES-1 contact with example 1. Uppercase letters indicate the difference in significance between two groups at the same time (p < 0.05), lowercase letters indicate the difference in significance between groups at different times (p < 0.05)
FIG. 4 shows the proliferation of cells after 1, 3, 5 and 7 days of Caco-2 exposure to example 1. Lower case letters indicate significant differences (p < 0.05) within groups at different times
FIG. 5 is a schematic view of the healing area of skin lesions
FIG. 6 is a line graph of the area of healing of skin lesions
Fig. 7 is a section of H & E stained skin, viscera of mice, scale bar: 100 μm
Table 1 shows the adhesive properties of hydrogels
Detailed Description
The present invention will be described in further detail with reference to examples.
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that some embodiments of the present invention are known to those of ordinary skill in the art based on the embodiments of the present invention, and other embodiments obtained without inventive effort from the precursors are within the scope of the present invention.
Unless otherwise indicated, all starting materials in the examples of this application were purchased commercially.
In this application, an ORC, oxidized microcrystalline cellulose (OMCC), is prepared as follows. TEMPO (0.40 g,2.5 mmol), naIO4 (2.70 g,12.50 mmol) and NaBr (4.00 g,40 mmol) were dissolved in 600.00mL distilled water with vigorous stirring. OMCC (5.00 g) was then suspended in the reaction mixture. The reaction vessel was covered with aluminum foil to prevent light-induced decomposition of periodate. A9% NaClO solution (2.97 g,40 mmol) was added to the cellulose suspension with continuous stirring and the resulting suspension was stirred for a certain period of time. Stirred separately for 4h at room temperature. The pH of the suspension was carefully maintained at about 10.50 by adding a 2mol/LNaOH solution. After the indicated time, 5.00mL of ethanol was added to stop the oxidation reaction. The oxidized cellulose was filtered and washed several times with deionized water and 0.5mol/L HCl solution. The resulting water insoluble fraction was lyophilized and dried, then dried in vacuo at 40 ℃ for 48 hours, and weighed to determine mass recovery. The water-soluble fraction was precipitated with ethanol and the precipitate formed was collected by centrifugation. After centrifugation, the solid fraction was redissolved in water, desalted and the oligomers removed by dialysis bags (MWCO: 10000 Da).
In the application, the preparation method of the mussel heuristic modified polysaccharide and the chitosan grafted caffeic acid (CHI-C) is as follows. CS (3.00 g,19.48 mmol) was dissolved in HCl solution (pH=5.00; 100.00 mL). HCA (2.37 g,15.58 mmol) and EDC (2.02 g,10.54 mmol) were dissolved in ultrapure water (50.00 mL) at low temperature. Both HCA and EDC solutions were slowly added to the chitosan solution. The pH of the solution was maintained at 5.00 to prevent oxidation of catechol groups. Ethanol (50.00 mL) was added as a co-solvent to the EDC/HCA mixture solution (50.00 mL) to avoid possible precipitation during the EDC coupling reaction (100.00 mL total). After 12h, the product was purified by dialysis against a dialysis bag (MWCO: 14000 Da) in NaCl solution at pH 4.00 for 48h, then dialyzed against ultra pure water for 4h, and then freeze-dried.
In the application, a preparation method of mussel heuristic modified polysaccharide and chitosan grafted gallic acid (CSG) is as follows. . CS (0.30 g,1.85 mmol) was stirred in deionized water (30.00 mL) and HOBt (0.28 g,1.85 mmol) overnight until a clear solution was obtained. GA (0.31 g,1.85 mmol) was introduced into the CS solution, followed by dropwise addition of an alcoholic solution of EDC (0.35 g,1.85mmol,2.00 mL). The reaction was carried out at ambient temperature with nitrogen (N) 2 ) The process was carried out in an atmosphere for 24 hours. The product was purified by dialysis in a dialysis bag (MWCO: 3500 Da) in NaCl solution at pH 4.00 for 48 hours, then in ultra pure water for 4 hours, and then freeze-dried.
Example 1
The lyophilized CHI-C, CSG and OMCC were added to Phosphate (PBS) buffer solution (ph=7.40) respectively to prepare respective solutions of different concentrations (1.50 mass% (wt%), 3.00 wt%). The OMCC solution was prepared by heating at 40 ℃ and sonicating for 4 hours. The OMCC solution was set as solution a and the CHI-C/CSG solution was set as solution b. And uniformly mixing the solution a and the solution b to prepare the hydrogel. Gelation occurs rapidly after mixing.
Comparative example 1
The lyophilized CHI-C and OMCC were added to PBS solutions (ph=7.40) respectively, and respective solutions of different concentrations (1.50 mass% (wt%), 3.00 wt%) were prepared. The OMCC solution was prepared by heating at 40 ℃ and sonicating for 4 hours. OMCC solution was set as solution a and CHI-C solution was set as solution b. And uniformly mixing the solution a and the solution b to prepare the hydrogel. Gelation occurs rapidly after mixing.
Comparative example 2
The lyophilized CSG and OMCC were added to PBS solution (ph=7.40) respectively to prepare respective solutions of different concentrations (1.50 mass% (wt%), 3.00 wt%). The OMCC solution was prepared by heating at 40 ℃ and sonicating for 4 hours. The OMCC solution was set as solution a and the CSG solution as solution b. And uniformly mixing the solution a and the solution b to prepare the hydrogel. Gelation occurs rapidly after mixing.
Comparative example 3
The lyophilized OMCC was added to PBS solution (ph=7.40) to prepare respective solutions of different concentrations (1.50 mass percent (wt%), 3.00 wt%). The OMCC solution was prepared by heating at 40 ℃ and sonicating for 4 hours.
Performance testing of the resulting samples
1. Adhesion performance and mechanical property test: experiments with binding weights were performed on hydrogels of example 1, comparative example 1 and comparative example 2: * The hydrogel in the three examples has better cohesiveness to human skin tissue, glass, plastic, hard paper, rubber and metal. The results are shown in Table 1 (mechanical properties of both hydrogels).
2. Antibacterial performance test: bacteria (Staphylococcus aureus or Escherichia coli) were cultured overnight at 37℃in Luria-Bertani (LB) medium. After this time, the bacteria were isolated and washed three times with PBS before use. The bacterial density was determined by testing the absorbance (OD 600) of the bacterial solution at 600nm wavelength and redispersing it in PBS solution for further antimicrobial application. The antibacterial properties of the hydrogels were measured using plate counting. Pure methacrylic acid acylated gelatin (Acylated gelatin methacrylate, gelMA) hydrogels served as control. Gram positive and negative bacteria (s.aureus and e.coli) were used for antibacterial activity assays. First, 100.00. Mu.L of the bacterial suspension (2X 10 6 CFU·mL -1 ) Contact with different hydrogel samples (GelMA, example 1, comparative example 2 and comparative example 3) for 4h (n=5, n represents the number of replicates). The bacterial suspension was then rinsed with PBS and transferred to a culture plate. Incubate with gentle shaking at 37℃for 12h. The incubated bacterial suspension was diluted 20-fold with PBS solution and 50.00. Mu.L of the diluted bacterial suspension was spread evenly on LB medium. After 24h incubation at 37 ℃, the plates were photographed and colonies on the plates were quantified by Image J software to calculate survival.
In general, each treatment group has a certain antibacterial effect, and the antibacterial rate of each group is increased along with the increase of the concentration. For gram-positive bacteria, comparative example 3 showed the best inhibitory effect, comparative example 1 showed slightly better inhibitory effect than comparative example 2, and example 1 showed the combined effect of several single components. For gram positive bacteria, both comparative example 1 and comparative example 2 showed excellent therapeutic effects, whereas comparative example 3 showed poor effects, and example 3 showed a combination of several single components. From this, it can be seen that the synergistic antibacterial properties of example 3 are able to cope well with both gram positive and gram negative species at a concentration of 3.00 wt%.
3. Cell compatibility test: cytotoxicity of the hydrogels was measured by employing direct contact between the hydrogels and human gastric mucosal cells (Ges-1), human colorectal adenocarcinoma cells (Caco-2), respectively. The precursor solution of example 1 was poured into a sterile petri dish to form a hydrogel disc (thickness=2.00 mm, diameter=6.00 mm). RPMI-1640 medium (Roswell Park Memorial Institute, RPMI-1640) and DMEM medium (Dulbecco's Modified Eagle Medium, DMEM) were supplemented with 10.00% fetal bovine serum (Fetal bovine serum, FBS), 1.0X105 U.L -1 Penicillin and 100.00 mg.L -1 Streptomycin was used as the complete growth medium. Ges-1 and Caco-2 were inoculated into 24-well plates at a density of 5.00X 104cell well-1 in 1.00mL of growth medium. After culturing Ges-1 for 24 hours, hydrogel discs were added to the wells. After 24h, cell viability was determined by Calcein acetoxymethyl ester/propidium iodide (Calcein-AM/PI) live/dead cell double staining kit. The hydrogel disks and spent media were removed from the wells and rinsed 2 times with 1 x Assay Buffer for 2min each to remove residual hydrogel and media. 200.00. Mu.L of Calcein-AM reagent was then added to each well, and the well plate was then placed in a chamber containing 5.00% CO 2 Incubate in humidified incubator at 37.0℃for 25min protected from light. The Calcein-AM dye solution was discarded, 200 μl of Propidium Iodide (PI) dye solution was added, and the wells were stained at room temperature in the dark for 5min, and then washed twice with PBS to remove residual dye. Cell viability was observed under an inverted fluorescence microscope. Ges-1, caco-2 (without hydrogel) were used alone as blank. The test was repeated three times, three wells each. Cell proliferation in the medium containing the hydrogel of example 1 was assessed by cell counting kit-8 (CCK-8) using the same Ges-1 and Caco-2 models. Ges-1 and Caco-2 were sealed at 1000.00cell well-1The degrees were transferred to 96-well plates in 100.00. Mu.L of complete growth medium and grown for 24h. Cells were cultured in complete growth medium with or without hydrogel for 1, 3, 5 and 7 days. At each time point, the hydrogel disks and spent media were discarded, and then 100.00. Mu.L of fresh alkaline media containing 10.00. Mu.L of CCK-8 reagent was added to each well. The plates were then exposed to 37.00℃and 5.0% CO 2 Incubate in humidified incubator for 2h. Finally, absorbance was measured at 450nm using a microplate reader. Each set was tested in duplicate.
Compared to the blank (cells cultured in wells without hydrogel), both GES-1 and Caco-2 grew well in hydrogels, indicating that hydrogels were relatively non-cytotoxic to GES-1 and Caco-2. The cell viability of GES-1 and Caco-2 was determined using CCK-8 and the results were expressed as Optical Density (OD) values. Higher OD values represent more cells were produced by proliferation. The OD of the GES-1 hydrogel group increased from 0.13 to 0.31 after 1 week of culture, and the OD of the Caco-2 hydrogel group increased from 0.16 to 1.32 after 1 week of culture, indicating that the number of cells increased with prolonged culture time. Example 1 shows a significant difference in cell proliferation (p < 0.05) and no significant difference in cell proliferation in the blank group, confirming that the hydrogel is non-cytotoxic and has a certain effect of promoting cell proliferation.
4. Skin wound healing test: the study was performed using a mouse hemorrhagic liver model and a tail-biting model.
BALB/c mice (females, body weight ≡ 20.00g-30.00 g) were randomized into 3 groups including the blank, example 1, and the mixed group of comparative example 1, comparative example 2 (n=5). Mice were anesthetized with 4.00% w/v chloral hydrate (0.01 mL/g). Then, we shave off the back and make 1.00cm on each side of the spine 2 Circular skin defect model. The defect was covered by either the mixed group of comparative example 2 or the group of example 1, and the control group was untreated. Mice were observed for wound healing at days 0, 3, 6, and 9, respectively. Viscera and defective wound tissue were collected after mice were sacrificed and immersed in 4.00% paraformaldehyde for hematoxylin and eosin (H&E) Dyeing. The defective area was photographed with an inverted microscope and measured by Image J. During the measurement and analysis, a thin ruler is placed to calibrate the woundMagnification of the mouth region photograph. The wound area is determined by calculating the surface area. The healing rate was faster for the example 1 group than for the other groups. We have also found that the wound defects of the example 1 and comparative example 1, comparative example 2 mixed groups scab faster than the blank group. H in three experimental groups&In E staining, visceral tissues had no apparent inflammation.
In summary, the blood-responsive hemostatic hydrogel of the present invention 1) has both good antibacterial performance and wound repair performance; 2) Has good blood compatibility and cell compatibility; 3) Has good adhesive property and mechanical property.
The last explanation is: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; the invention is described in detail with reference to the foregoing embodiments, but it should be understood by those skilled in the art that the present invention is not limited to the details of the embodiments described above: the technical scheme described in the foregoing embodiments can be modified or some of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
TABLE 1
Claims (7)
1. A method for preparing an antibacterial/wound repair hydrogel, comprising the steps of:
step 1: mussel heuristic compounds are grafted on a natural polysaccharide molecular chain by a 1-ethyl-3-dimethylaminopropyl carbodiimide chemical method, so that the water solubility, the adhesiveness, the antibacterial property and the wound repairing property of the mussel heuristic compounds are improved;
step 2: oxidizing cellulose to oxidized cellulose by a sodium periodate/2, 6-tetramethylpiperidine oxide oxidation method, and testing biocompatibility thereof;
step 3: and (3) mixing the prepared solutions in the step (1) and the step (2) to prepare the antibacterial/wound repair hydrogel.
2. The method for preparing an antibacterial/wound-repairing hydrogel according to claim 1, wherein the step 1 is dissolved by adding hydrochloric acid/acetic acid or 1-hydroxybenzotriazole and then the next reaction is performed.
3. The method of preparing an antimicrobial/wound-repair hydrogel according to claim 1, wherein the synthetic product is preheated to a temperature in the range of 37 ℃ prior to gel testing.
4. The method for preparing an antibacterial/wound-repairing hydrogel according to claim 1, wherein oxidized cellulose is dispersed in a phosphate buffer solution at a concentration of 1.5 to 5 mass%; mussel heuristic polymer materials are dispersed into phosphate buffer solution at the concentration of 1 to 3.5 percent by mass percent; setting an oxidized cellulose solution as a solution A, and setting a mussel heuristic polysaccharide solution as a solution B; and (3) mixing A, B solution to prepare the mussel heuristic polysaccharide/oxidized cellulose composite hydrogel.
5. The method of preparing an antibacterial/wound repair hydrogel according to claim 1, wherein the gel time ranges from 3s to 90s in all gel protocols.
6. The method of preparing an antibacterial/wound repair hydrogel according to claim 1, wherein the hydrogel is suitable for use in all mammalian wound repair and antibacterial applications.
7. The method for adding hydrochloric acid/acetic acid or 1-hydroxybenzotriazole to dissolve according to claim 2, wherein it is dispersed in PBS solution at a concentration of 1% -3.5% by mass.
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