CN117085170A - Injectable antibacterial hydrogel for promoting healing of diabetic infected wound surface as well as preparation method and application thereof - Google Patents
Injectable antibacterial hydrogel for promoting healing of diabetic infected wound surface as well as preparation method and application thereof Download PDFInfo
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- CN117085170A CN117085170A CN202310864248.1A CN202310864248A CN117085170A CN 117085170 A CN117085170 A CN 117085170A CN 202310864248 A CN202310864248 A CN 202310864248A CN 117085170 A CN117085170 A CN 117085170A
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- diabetic
- antibacterial hydrogel
- wound surface
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Abstract
The application discloses a preparation method of injectable antibacterial hydrogel for promoting healing of diabetic infected wound, which comprises the following steps: dissolving copper-tannic acid nanosheets CuTA, borax and a photoinitiator in deionized water, and then adding methacrylic gelatin GelMA for dissolution to obtain a first solution; dispersing quaternary ammonium salt type guar gum CG in deionized water to obtain a second solution; and mixing the first solution with the second solution in a stirring state, and performing photocuring crosslinking after mixing to form the injectable antibacterial hydrogel. The application also discloses the injectable antibacterial hydrogel for promoting the healing of the diabetic infected wound surface, which is prepared by the preparation method, and the application of the injectable antibacterial hydrogel in preparing the diabetic infected wound surface dressing. The hydrogel provided by the application has good physical properties, and can meet the requirements of multifunctional composite hydrogel at various stages in the skin healing process.
Description
Technical Field
The application belongs to the field of medical dressing, and in particular relates to injectable antibacterial hydrogel for promoting healing of diabetic infected wound surfaces, and a preparation method and application thereof.
Background
Poor wound healing is one of the complications of diabetes, particularly diabetic feet, and can lead to infection, necrosis and even death. The hyperglycemic microenvironment of diabetics is easy to be infected by bacteria, and the wound surface is difficult to heal due to the characteristics of high oxidative stress, continuous inflammation, microcirculation damage and the like. Hydrogel dressings are becoming increasingly popular in the clinic. The three-dimensional network structure of the tissue repair agent has good exudate absorption capacity, water retention capacity and gas exchange capacity, and can be used as a delivery platform of antibacterial drugs, cytokines, nano-drugs and therapeutic stem cells, thereby providing a more suitable tissue repair microenvironment for the cells. Chinese patent publication No. CN108744025a discloses an antioxidative hydrogel for promoting wound healing, which includes a model drug, polydopamine nanoparticles, polyethylene glycol diacrylate, a photoinitiator, and water, and a preparation method and application thereof. And chinese patent publication No. CN115337446a discloses a method for preparing a bio-based adhesive hydrogel patch for promoting wound healing: (1) Mixing lipoic acid and cytidine to react to obtain lipoic acid cytosine; (2) Mixing gelatin and methacrylic anhydride and then reacting to obtain methacrylic acylated gelatin GelMA; (3) And (3) blending and heating the thioctic acid cytosine and GelMA, and polymerizing to obtain the bio-based adhesive hydrogel patch.
Wound healing has four phases: hemostasis, inflammation, proliferation, remodeling. Existing hydrogel dressings can support some of the stages described above, but few hydrogels provide assistance in various stages of wound healing. Meanwhile, due to infection of wounds, conventional methods incorporate antibiotics into hydrogels, but abuse of antibiotics may lead to the appearance of drug-resistant bacteria.
Therefore, it is necessary to design a multifunctional composite hydrogel which has good physical properties, can meet the functional requirements of various stages in the skin healing process, and does not generate antibiotic drug resistance reaction.
Disclosure of Invention
The application aims to provide an injectable antibacterial hydrogel for promoting healing of diabetic infected wound and a preparation method thereof.
In order to achieve the above purpose, the present application adopts the following technical scheme:
a method for preparing injectable antibacterial hydrogel for promoting healing of diabetic infected wound, comprising the following steps:
(1) Dissolving copper-tannic acid nanosheets CuTA, borax and a photoinitiator in deionized water, and then adding methacrylic gelatin GelMA for dissolution to obtain a first solution;
(2) Dispersing quaternary ammonium salt type guar gum CG in deionized water to obtain a second solution;
(3) And mixing the first solution with the second solution in a stirring state, and performing photocuring crosslinking after mixing to form the injectable antibacterial hydrogel.
The technical conception of the application is as follows: mixing copper-tannic acid nano-sheets with solutions of methacrylic gelatin, quaternary ammonium salt guar gum and borax, and forming composite hydrogel through photoinitiated free radical crosslinking; by using quaternary ammonium guar gum with antibacterial property and methacrylic acid gelatin with good biocompatibility as a cross-linked network, borate ester bonds are introduced after borax and copper-tannic acid nano-sheets are doped, the hydrogel is endowed with the property of responsively releasing nano-drugs under the conditions of low pH value and high oxidative stress, and meanwhile, the copper-tannic acid nano-sheets have good antibacterial property and oxidation resistance to promote the healing of diabetic wounds.
In the step (1), the preparation method of the methacrylic gelatin GelMA comprises the following steps:
10% w/v pigskin gelatin was added to PBS and the mixture was magnetically stirred at 45-55℃for 1 hour. Then 8-10mL of Methacrylic Anhydride (MA) was added dropwise to the gelatin solution and kept stirring at 50 ℃ for 3 hours. The reaction was terminated by adding an equal amount of PBS preheated to 50 ℃. The reaction solution was dialyzed in deionized water for 7-10 days with a dialysis bag (molecular cut-off 8-14 KD) to remove MA, and the solution was filtered and lyophilized to obtain the methacrylated gelatin.
Since the reaction of gelatin and MA is a two-phase reaction, a proper amount of MA needs to be added dropwise to the gelatin solution. The amount and rate of MA added will affect the degree of substitution of the methylpropenyl group in the product. Wherein the dialysis time is more than 7 days, and the dialysis solution is changed at least twice a day to obtain the best effect, so as to sufficiently remove MA and methacrylic acid byproducts with potential toxicity, etc.
In the step (1), the preparation method of the copper-tannic acid nanosheet CuTA comprises the following steps: dissolving tannic acid and copper sulfate pentahydrate in deionized water, regulating the pH of the mixture to 7-8 with sodium hydroxide solution, and heating in oil bath to obtain copper-tannic acid nanosheet CuTA.
Specifically, the solution was heated to 50 ℃ in an oil bath and magnetically stirred for 4 hours. The product was then collected by centrifugation and washed with deionized water. And (3) vacuum drying the product in a baking oven at 55-65 ℃ for 12-24 hours to obtain the copper-tannic acid nano-sheet. Wherein the concentration of tannic acid is 0.54g/L, and the concentration of anhydrous copper sulfate is 17.5g/L.
Reaction pH and Cu 2+ Concentration is two key factors in the evolution of the CuTA morphology. Higher reaction pH promotes deprotonation of catechol groups, higher concentration of Cu 2+ The formation of a CuTA coordination framework is ensured. Further preferably, the pH is adjusted to 7.4, cu 2+ The concentration is 7.0X10 -3 M。
In the step (1), the concentration of CuTA in the first solution is 0.1-0.5% w/v, the concentration of borax is 0.25-0.5% w/v, and the concentration of GelMA is 5-10% w/v.
In the step (1), the photoinitiator is one of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone or 2,4, 6-trimethyl benzoyl lithium phosphite, and the concentration of the initiator in the first solution is 0.1-1% w/v. Too low an initiator concentration may result in incomplete crosslinking of the hydrogel and too high a concentration may cause potential biotoxicity.
In step (2), the concentration of CG in the second solution is 8-10% w/v.
The injectability, self-healing property, biocompatibility, antibacterial property and antioxidation of the hydrogel are regulated and controlled by regulating and controlling the concentration of CuTA, borax and GelMA in the first solution and the concentration of CG in the second solution.
In step (3), the conditions of the photo-curing crosslinking are: the wavelength of ultraviolet light is 300-400nm, and the curing time is 1-3 minutes.
Preferably, in step (3), the ratio of the first solution to the second solution is 1:1, stirring conditions are 500-800rpm.
The application also provides the injectable antibacterial hydrogel for promoting the healing of the diabetic infected wound surface, which is prepared by the preparation method.
The application also provides application of the injectable antibacterial hydrogel in preparing wound dressing for treating diabetes.
Compared with the prior art, the application has the beneficial effects that:
1. the composite hydrogel prepared by the application has good injectability, self-healing property and adhesiveness, so that the hydrogel can adapt to irregular wounds, adhere to the surfaces of the wounds to prevent the hydrogel from falling off, and the self-healing property can enable the hydrogel dressing to recover to the original state when broken.
2. The borate ester bond with response performance is introduced into the hydrogel by adding borax, on one hand, the borate ester bond is formed between quaternary ammonium salt guar gum networks, and the characteristic of responsive decomposition of the hydrogel is endowed; on the other hand, the formation of the borate bond between the CuTA and guar gum imparts drug-responsive release characteristics to the hydrogel.
3. The copper-tannic acid nano-sheets are doped in the hydrogel, so that the antibacterial performance of the hydrogel is enhanced, and meanwhile, the drug resistance is not generated. The copper-tannic acid nano-sheet also has good oxidation resistance and can remove excessive active oxygen in the wound surface. The nanometer tablet disintegrates to release copper ions and tannic acid in acid environment, and has the functions of promoting angiogenesis and resisting inflammation.
In conclusion, the injectable antibacterial hydrogel prepared by the application has self-healing performance, weak acid and oxidation environment responsive drug release performance, excellent antibacterial and oxidation resistance, excellent biocompatibility and the like, and can be used for preparing a wound dressing for treating diabetes (three-dimensional dressing for promoting healing of wound infected by diabetes).
Drawings
A-I of FIG. 1 are respectively a transmission electron microscope image (A), an element distribution image (B), a particle size distribution image (C), a Fourier infrared spectrum (D), X-ray photoelectron spectra (E and F), disintegration images under acidic conditions (G and H), and an ABST oxidation resistance curve (I) of the copper-tannic acid nanoplatelets prepared in example 1. Scale in the figure: a is 100nm, B is 200nm, and G is 50nm.
A-H of FIG. 2 are a scanning electron microscope (A), an element distribution diagram (B), a rheological property diagram (C-F), an injectability general diagram (G) and a self-healing general diagram (H), respectively, of the GGB-CT composite hydrogel prepared in example 2. Scale in the figure: a is 300 μm and B is 500 μm.
FIGS. 3A-I show the hydroxyl radical scavenging properties (A and B), superoxide radical scavenging properties (C and D), catalase activities (E and F) and intracellular active oxygen radical scavenging properties (H and I), respectively, of the hydrogels prepared in example 2 and comparative example. Scale in the figure: i is 50 μm.
A-M of FIG. 4 are the activity tests (A and B), live/dead staining (C), hemocytocompatibility (D), clotting properties (E and F), rat liver hemostasis properties (G-I), rat tail hemostasis properties (J-L) of the hydrogels prepared in example 2 and comparative example, respectively, on the L929X cell line and on the HUVEC cell line CCK-8. Scale in the figure: c is 100 μm.
Fig. 5 a-C are the antimicrobial properties of hydrogels prepared in example 2 and comparative example, respectively: agarose plate culture (A), bacterial live/dead staining (B), bacterial scanning electron microscopy (C). Scale in the figure: b is 500 μm and C is 500nm.
Fig. 6 a-F show the therapeutic effects of hydrogels prepared in example 2 and comparative example, respectively, in a rat diabetic infection model: wound healing effect (a and B), antibacterial effect (C and D), H & E staining and Masson staining (E and F).
Detailed Description
The following description of the embodiments of the present application will be made apparent and fully in view of the accompanying drawings, in which some, but not all embodiments of the application are shown. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
Example 1
27mg of tannic acid and 875mg of copper sulfate pentahydrate were dissolved in 50mL of deionized water, and the pH of the mixture was adjusted to 7 with sodium hydroxide solution. The solution was then heated to 50 ℃ in an oil bath and magnetically stirred for 4 hours. The product was then collected by centrifugation and washed with deionized water. And (5) drying the product in a 60 ℃ oven for 12 hours in vacuum to obtain the copper-tannic acid nano-sheet.
The preparation of CuTA nanoplatelets is characterized as shown in fig. 1. A and B in fig. 1 show the morphology under transmission electron microscopy and elemental separation; c in FIG. 1 is a particle size distribution diagram, and the particle size is about 190 nm; d in fig. 1 is a fourier infrared spectrum, illustrating the successful synthesis of CuTA; e and F in FIG. 1 are XPS spectra of copper, illustrating that copper elements in the nanoplatelets exist predominantly in the divalent copper state; g and H in FIG. 1 are transmission electron microscope images and concentration curves of CuTA disintegrated in weak acid environment, and illustrate the characteristic of the response decomposition of CuTA in weak acid; i in FIG. 1 illustrates the concentration dependence of the ABST antioxidant capacity of CuTA.
Example 2
(1) Preparing GelMA: 10g of pigskin gelatin was added to 100mL of PBS and the mixture was magnetically stirred at 50℃for 1 hour. Then 8mL of Methacrylic Anhydride (MA) was added dropwise to the gelatin solution and kept stirring at 50 ℃ for 3 hours. The reaction was terminated by adding an equal amount of PBS preheated to 50 ℃. The reaction solution was dialyzed in deionized water with a dialysis bag (molecular cut-off 8-14 KD) for 7-10 days to remove unreacted MA, and the solution was filtered and lyophilized to obtain methacrylic gelatin GelMA.
(2) CuTA nanoplatelets were synthesized according to example 1.
(3) 5mg of CuTA, 5mg of borax and 2mg of LAP are dissolved in 5mL of deionized water, and 0.5g of GelMA is dissolved in the solution to obtain GelMA hydrogel solution.
(4) Dispersing 0.8g of quaternary ammonium salt guar gum in 5mL of deionized water, stirring for 10min, and adding the GelMA hydrogel solution in the step (3) under stirring. After mixing the two, the hydrogel GGB-CT (0.5%) was formed by irradiation with ultraviolet light at 365nm for 2 minutes.
Comparative example 1
(1) CuTA nanoplatelets were synthesized according to example 1.
(2) GelMA was synthesized according to example 2.
(3) 2mg of LAP was dissolved in 5mL of deionized water, and 0.5g of the prepared GelMA was dissolved in the above solution to obtain a GelMA hydrogel solution.
(4) Dispersing 0.8g of quaternary ammonium salt guar gum in 5mL of deionized water, stirring for 10min, and adding the GelMA hydrogel solution in the step (3) in the stirring process. After the two are mixed uniformly, the hydrogel GG is formed by irradiation with ultraviolet light with the wavelength of 365nm for 2 minutes.
Comparative example 2
(1) CuTA nanoplatelets were synthesized according to example 1.
(2) GelMA was synthesized according to example 2.
(3) 5mg of borax and 2mg of LAP are dissolved in 5mL of deionized water, and 0.5g of prepared GelMA is dissolved in the solution to obtain GelMA hydrogel solution.
(4) Dispersing 0.8g of quaternary ammonium salt guar gum in 5mL of deionized water, stirring for 10min, and adding the GelMA hydrogel solution in the step (3) under stirring. After the both were mixed uniformly, the mixture was irradiated with ultraviolet light having a wavelength of 365nm for 2 minutes to form hydrogel GGB.
Comparative example 3
(1) CuTA nanoplatelets were synthesized according to example 1.
(2) GelMA was synthesized according to example 2.
(3) 5mg of CuTA and 2mg of LAP were dissolved in 5mL of deionized water, and 0.5g of the prepared GelMA was dissolved in the above solution to obtain a GelMA hydrogel solution.
(4) Dispersing 0.8g of quaternary ammonium salt guar gum in 5mL of deionized water, stirring for 10min, and adding the GelMA hydrogel solution in the step (3) under stirring. After mixing the two, the hydrogel GG-CT (0.2%) was formed by irradiation with ultraviolet light having a wavelength of 365nm for 2 minutes.
Comparative example 4
(1) CuTA nanoplatelets were synthesized according to example 1.
(2) GelMA was synthesized according to example 2.
(3) 2mg of CuTA, 5mg of borax and 2mg of LAP are taken and dissolved in 5mL of deionized water, and 0.5g of prepared GelMA is taken and dissolved in the solution to obtain GelMA hydrogel solution.
(4) Dispersing 0.8g of quaternary ammonium salt guar gum in 5mL of deionized water, stirring for 10min, and adding the GelMA hydrogel solution in the step (3) under stirring. After mixing the two, the hydrogel GGB-CT (0.2%) was formed by irradiation with ultraviolet light of 365nm wavelength for 2 minutes.
A in fig. 2 is a scanning electron microscope image of example 2, comparative example 1 and comparative example 2, and the hydrogel is seen to have a porous structure; b in fig. 2 is a distribution diagram of copper, oxygen, and boron elements in example 2; c and G in FIG. 2 are the injectability performance analyses of example 2, demonstrating that GGB-CT has good shear thinning properties (G); d and H in FIG. 2 are self-healing performance analyses of example 2, and GGB-CT can still be restored to the original state (D in FIG. 2) under cycles of large and small strain; e in FIG. 2 is that the modulus change GG in the strain sweep mode of example 2, comparative example 1 and comparative example 2 has an elastic modulus of 1100Pa which is superior to those of GGB and GGB-CT (800 Pa), but a compliance which is inferior to those of GGB and GGB-CT; f in fig. 2 shows the stability of example 2, comparative example 1 and comparative example 2 in the frequent-note mode.
Application example 1
Test of antioxidant ability of composite hydrogels:
using methylene blueThe hydrogels were tested for their anti-hydroxyl radical ability, and it can be seen from FIGS. 3A and B that the GGB-CT hydrogels have better anti-hydroxyl radical ability than the GG-CT hydrogels due to their ROS-responsive drug release properties. GGB, GGB-CT (0.2%), GGB-CT (0.5%) were tested for superoxide anion scavenging ability and catalase activity using a superoxide anion kit and a catalase activity kit. As can be seen from C-F in FIG. 3, GGB has no oxidation resistance, and the oxidation resistance of GGB-CT and the amount of CuTA added are positively correlated. Mouse fibroblasts (L929) were combined with three hydrogel groups containing 200. Mu. M H 2 O 2 After 24 hours of co-culture in the medium of (C) and detection of intracellular ROS content using DCFH fluorescent probe, as seen in FIGS. 3, H and I, GGB-CT reduced the production of H 2 O 2 Resulting in intracellular ROS accumulation.
Application example 2
And (3) testing biocompatibility and coagulation hemostasis performance of the composite hydrogel:
three groups of composite hydrogels were co-cultured with L929 cells and Human Umbilical Vein Endothelial Cells (HUVEC) for 1, 3 and 5 days, and then tested for cell activity by using a CCK-8 kit, and A and B in FIG. 4 can be seen to have no obvious difference in cell activity compared with a control group, and meanwhile, the L929 cells were tested for cell activity by using a live/dead staining kit (C in FIG. 4), and the results were the same as the CCK-8 results, indicating that the hydrogels have good biocompatibility. To verify the hemocompatibility of the hydrogels, the composite hydrogels were incubated with rat red blood cell suspensions for 4 hours, and the results showed that the hemolysis rate of the hydrogel groups was less than 5% (D in fig. 4). The procoagulant power of hydrogels was evaluated with the coagulation index, and briefly, 50uL of calcified blood droplets were incubated on the hydrogel surface for 2 minutes and then red blood cells were resuspended with deionized water. E and F in FIG. 4 illustrate that the clotting effect of GGB-CT is evident from the other two sets of hydrogels due to the presence of CuTA. In vivo, the change in bleeding amount after 100uL of hydrogel was added dropwise to the wound was evaluated by using a liver bleeding model and a rat tail bleeding model, and it was found that GGB-CT had the best hemostatic effect (H-M in FIG. 4).
Application example 3
Antibacterial property test of composite hydrogel:
after the composite hydrogel was co-cultured with staphylococcus aureus for 24 hours, the culture broth was uniformly spread on an agarose plate medium, and the colony formation number was recorded (a in fig. 5). Meanwhile, bacteria after co-culture were stained with a live/dead staining kit (B in fig. 5). The result shows that GG and GGB have a certain antibacterial effect due to the antibacterial capability of the quaternary ammonium salt guar gum, and the nano-drug added in GGB-CT further kills bacteria to play a synergistic antibacterial role. After the bacteria treated by the hydrogel are fixed by glutaraldehyde, the morphology of the bacteria is observed under a scanning electron microscope, and the bacteria cells can be seen to absorb the surface of the hydrogel and shrink and break.
Application example 4
Effect of the composite hydrogel on wound surface model of diabetes mellitus infection of rats:
a diabetic rat model is constructed by adopting a streptozotocin intraperitoneal injection method, a circular skin full-layer infection wound surface model with the diameter of 8mm is constructed on the back skin of the rat, the composite hydrogel is adopted for treatment for 2 weeks, and wound images are acquired at a specific time point during the treatment. The A and B in FIG. 6 show that the healing effect of the GGB-CT group is better than that of the GG and GGB groups. The exudates from the wound were collected on day 2 for bacterial culture (C and D in fig. 6), and the results showed that the hydrogel still exerted excellent antibacterial effect in vivo. Rat skin specimens were collected on day 7 and day 14 for H & E and Masson staining, and as shown by E and F in fig. 6, GGB-CT hydrogel was seen to better promote re-epithelialization of the skin and collagen deposition.
Further, it is to be understood that various changes and modifications of the present application may be made by those skilled in the art after reading the above description of the application, and that such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (8)
1. A method for preparing injectable antibacterial hydrogel for promoting healing of diabetic infected wound, which is characterized by comprising the following steps:
(1) Dissolving copper-tannic acid nanosheets CuTA, borax and a photoinitiator in deionized water, and then adding methacrylic gelatin GelMA for dissolution to obtain a first solution;
(2) Dispersing quaternary ammonium salt type guar gum CG in deionized water to obtain a second solution;
(3) And mixing the first solution with the second solution in a stirring state, and performing photocuring crosslinking after mixing to form the injectable antibacterial hydrogel.
2. The method for preparing injectable antibacterial hydrogel for promoting healing of wound surface of diabetic infection according to claim 1, wherein in step (1), the method for preparing copper-tannic acid nanoplatelets CuTA comprises the following steps: dissolving tannic acid and copper sulfate pentahydrate in deionized water, regulating the pH of the mixture to 7-8 with sodium hydroxide solution, and heating in oil bath to obtain copper-tannic acid nanosheet CuTA.
3. The method for preparing injectable antibacterial hydrogel for promoting healing of wound surface of diabetic infection according to claim 1, wherein in step (1), the concentration of CuTA in the first solution is 0.1-0.5% w/v, the concentration of borax is 0.25-0.5% w/v, and the concentration of GelMA is 5-10% w/v.
4. The method for preparing injectable antibacterial hydrogel for promoting healing of wound surface of diabetic infection according to claim 3, wherein in the step (1), the photoinitiator is one of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone or 2,4, 6-trimethylbenzoyl lithium phosphite, and the concentration of the initiator in the first solution is 0.1-1% w/v.
5. The method of preparing an injectable antibacterial hydrogel for promoting healing of wound surface of diabetic infection according to claim 1, wherein the concentration of CG in the second solution in step (2) is 8-10% w/v.
6. The method for preparing an injectable antibacterial hydrogel for promoting healing of wound surface of diabetic infection according to claim 1, wherein in step (3), the conditions of photocuring crosslinking are: the wavelength of ultraviolet light is 300-400nm, and the curing time is 1-3 minutes.
7. An injectable antibacterial hydrogel for promoting healing of diabetic infected wound surface obtained by the preparation method of any one of claims 1 to 6.
8. Use of the injectable antibacterial hydrogel of claim 7 in the preparation of a wound dressing for diabetic infection.
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