CN108904875B - Antibacterial self-healing hydrogel auxiliary material for promoting chronic wound healing and preparation method and application thereof - Google Patents
Antibacterial self-healing hydrogel auxiliary material for promoting chronic wound healing and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an antibacterial self-healing hydrogel auxiliary material for promoting chronic wound healing, and a preparation method and application thereof. The preparation method is simple, no organic solvent is remained, and the used chemical synthesis method is environment-friendly, convenient to operate and low in raw material cost.
Description
Technical Field
The invention belongs to the technical field of degradable biomedical materials, and particularly relates to an antibacterial self-healing hydrogel auxiliary material for promoting healing of chronic wounds, and a preparation method and application thereof.
Background
The wound surface is the injury of human tissues or organs caused by external injury factors such as surgery, external force, heat, low temperature, current, chemical substances and internal factors of the organism such as local blood supply disorder, and the healing process comprises four stages of coagulation stage, inflammation stage, cell proliferation stage and new tissue remodeling stage. The healing speed is affected by various factors such as wound surface type, pathological condition, dressing type and the like, and along with continuous research of science and technology, the wound surface dressing has the functions of protecting wound surface, stopping bleeding, preventing infection and the like, and has the function of promoting wound surface healing.
The wound dressing used at present mainly comprises traditional auxiliary materials, natural synthetic dressing, artificial synthetic dressing and the like. At present, the most widely used traditional dressing in clinic comprises gauze, cotton pad, bandage and the like, which have the advantages of low cost and simple manufacturing process, but cannot keep the wound surface moist, granulation tissues are easy to grow into meshes of the gauze, and the dressing is easy to cause exogenous infection when penetrating, so that the application of the dressing is greatly limited; the natural synthetic dressing is obtained by processing, extracting and molding natural materials, mainly comprises animal skin dressing, collagen dressing and alginate dressing, although the dressing has a certain excellent effect, the animal skin dressing has poor rejection reaction, blood transport reconstruction and antibacterial performance, the collagen dressing has poor liquid seepage absorption capability, is not suitable for exudative and infectious wounds, the alginate dressing needs auxiliary fixation, is not suitable for dry or hard scab wounds, and the defects greatly limit the clinical application of the animal skin dressing. The artificial synthetic dressing mainly comprises a film dressing, a foam dressing, a hydrogel dressing and a hydrocolloid dressing, and compared with the natural material, the artificial synthetic dressing can better control the synthetic process of the material and improve the performance of the material, so that the artificial synthetic dressing is more beneficial to serving as a dressing for various wound surfaces and has the functions of resisting bacteria and the like.
Hydrogels have many unique advantages as wound dressings, for example, 1. They can be used as drug carriers, have the ability to slow release drugs, thereby promoting wound healing; 2. the moist environment of the wound surface is maintained; 3. the porous ceramic material contains a large amount of water, and the pore diameter is more beneficial to evaporation of exudates; 4. repeated hydration may occur upon contact with tissue, continuously absorbing exudates from the wound; 5. the hydrogel has low self temperature and mild cooling effect, and can remarkably reduce postoperative pain and inflammation; 6. has tissue compatibility, can excrete metabolites, and has no irritation; 7. the translucent state aids in observing the healing of the wound. Therefore, hydrogels have many desirable properties as an ideal wound dressing, both to maintain a mechanical wound and to promote healing of the wound by maintaining a suitable environment and achieving controlled delivery of bioactive molecules.
Disclosure of Invention
The invention aims to provide an antibacterial self-healing hydrogel auxiliary material for promoting chronic wound healing, and a preparation method and application thereof.
In order to achieve the purpose, the invention is realized by adopting the following technical scheme:
the preparation method of the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds comprises the following steps:
1) Mixing polysaccharide and strong oxidant, oxidizing reaction, stirring at room temperature for 4 hours under dark condition; adding ethylene glycol to terminate the reaction, stirring for 1 hour at room temperature, dialyzing and purifying the reaction product in deionized water for 2 days, and freeze-drying to obtain oxidized polysaccharide;
2) Dissolving polyether F127 and cationic polymer with antibacterial ability in PBS buffer solution, oscillating in ice bath to fully mix the solution, adding the prepared oxidized polysaccharide, oscillating to fully mix the solution, and incubating the solution in water bath to form hydrogel to obtain antibacterial self-healing hydrogel;
3) The exosomes and the prepared hydrogel are oscillated in ice bath to be fully and evenly mixed, and are incubated in water bath to form the hydrogel with exosomes, thus preparing the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
As a further improvement of the invention, the molar ratio of the polysaccharide and the strong oxidizer in the step 1) is 1 (0.5-2); the molar ratio of ethylene glycol to strong oxidizer is 2:1.
As a further improvement of the present invention, the strong oxidizing agent in step 1) is sodium periodate.
As a further development of the invention, the polysaccharide in step 1) is sodium hyaluronate, sodium alginate or pullulan.
As a further improvement of the invention, in step 2), the mass to volume ratio of polyether F127 in PBS buffer is 20% g/mL; the mass volume ratio of the cationic polymer in the PBS buffer solution is 5-15% g/mL; the mass to volume ratio of oxidized polysaccharide in PBS buffer was 5% g/mL.
As a further development of the invention, in step 2), the pH of the PBS buffer is 7.4.
As a further development of the invention, the cationic polymer in step 2) is epsilon-polylysine, polyethylenimine or chitosan quaternary ammonium salt.
As a further development of the invention, the antibacterial self-healing hydrogel in step 2) is a hydrogel with a double network structure formed by a network of oxidized polysaccharide and cationic polymer together with F127.
As a further improvement of the invention, the mass-to-volume ratio of the exosomes to the hydrogel in step 3) is 1:100 μg/μl.
The antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces, which is prepared by the method, is characterized in that the prepared antibacterial self-healing hydrogel auxiliary material loads exosomes on cationic polymers through electrostatic action and wraps the exosomes in the cationic polymers by utilizing hydrogel with a double-network structure.
The antibacterial self-healing hydrogel auxiliary material for promoting the healing of the chronic wound is applied to promoting the healing of the chronic wound and resisting bacteria.
Compared with the prior art, the invention has the following beneficial effects:
aiming at the defects that the existing wound dressing cannot ensure the wetting of the wound surface, is easy to infect and the like, the invention provides a preparation method of an antibacterial self-healing hydrogel auxiliary material for promoting the healing of the chronic wound surface. And then the exosomes are loaded on a cationic polymer through electrostatic action, and the exosomes are wrapped in the cationic polymer by utilizing hydrogel with a double-network structure, so that the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds is prepared. The preparation method is simple, no organic solvent is remained, and the used chemical synthesis method is environment-friendly, convenient to operate and low in raw material cost. Experimental results prove that: the antibacterial self-healing hydrogel auxiliary material for promoting the healing of the chronic wound surface, which is prepared by the method, has excellent mechanical properties such as temperature sensitivity, injectability, self-healing and the like, good antibacterial property and the capability of promoting the healing of the wound surface, and has good application prospect in promoting the healing and antibacterial of the chronic wound surface.
Furthermore, the sodium hyaluronate, sodium alginate and pullulan used in the invention are degradable polysaccharides, have a plurality of excellent characteristics, so that the sodium hyaluronate, sodium alginate and pullulan can be widely applied in the biomedical field, have good biocompatibility and are cheap and easy to obtain;
furthermore, the epsilon-polylysine, the polyethylene imine and the chitosan used by the invention are degradable high molecular polymers, have good antibacterial performance, and are cheap and easy to obtain.
In the invention, sodium periodate is used for oxidizing sodium hyaluronate, sodium alginate and pullulan to form polysaccharide with aldehyde groups, and the polysaccharide can effectively react with amino epsilon-polylysine, polyethylene imine, chitosan and other cationic polymers through Schiff base reaction to form the polymer.
Further, in the invention, the polysaccharide and the cationic polymer react to form a network structure I, and F127 is used as a network structure II, and the two networks are fully mixed to form the hydrogel with a three-dimensional double-network structure.
Further, prepared in the invention is a hydrogel auxiliary material which loads exosomes on a cationic polymer through electrostatic action and wraps the exosomes in the cationic polymer by utilizing hydrogel with a double-network structure.
Furthermore, the antibacterial self-healing hydrogel auxiliary material for promoting the healing of the chronic wound surface has excellent temperature-sensitive, injectable and self-healing mechanical properties, good antibacterial properties and the effect of promoting the healing of the chronic wound surface.
Drawings
FIG. 1 is a schematic diagram of the synthesis of the hydrogel formulation of the present invention.
FIG. 2 is a Fourier infrared spectrum of hydrogel, monomer and prepolymer thereof in the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Fig. 3 shows the temperature sensitivity of hydrogel (FXE) in the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Fig. 4 shows injectability and self-healing properties of hydrogel (FXE) in the antibacterial self-healing hydrogel adjuvant for promoting chronic wound healing prepared by the invention.
Figure 5 shows the antibacterial properties of hydrogel (FXE, FHY) in the antibacterial self-healing hydrogel adjuvant for promoting healing of chronic wound surfaces prepared according to the present invention.
Figure 6 shows the controlled release results of exosomes in the antibacterial self-healing hydrogel adjuvant (FHE) prepared according to the present invention to promote healing of chronic wounds.
Fig. 7 shows the result of the antibacterial self-healing hydrogel auxiliary material (FHE@exo) for promoting the healing of chronic wound surface prepared by the invention on the healing of skin wound surface.
Detailed Description
The invention is described in further detail below with reference to the attached drawing figures:
the invention aims to prepare an antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds, and can effectively promote the healing of the wounds and prevent bacterial infection. As shown in fig. 1, the basic preparation steps include:
1) Adding polysaccharide and sodium periodate with the molar ratio of (05-2) into a 100mL round-bottomed flask for oxidation reaction, and stirring for 4 hours at room temperature under the dark condition; adding ethylene glycol with the molar ratio of 2:1 with a strong oxidant to terminate the reaction, stirring for 1 hour at room temperature, dialyzing and purifying the reaction product in deionized water for 2 days, and freeze-drying for later use; the sugar is sodium hyaluronate, sodium alginate or pullulan; the structural formula is as follows:
2) Polyether F127 with the mass-volume ratio of 20% (g/mL) and cationic polymers with the antibacterial capacity with the mass-volume ratio of 5-15% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are vigorously shaken in an ice bath to be fully and uniformly mixed, oxidized polysaccharide with the mass-volume ratio of 5% (g/mL) is added, and is vigorously shaken to be fully and uniformly mixed, and the mixture is incubated in a water bath at 37 ℃ for 1 hour to form hydrogel, so that the antibacterial self-healing hydrogel (the hydrogel with a double-network structure, which is formed by a network formed by the oxidized polysaccharide and the cationic polymer and F127) is obtained. The cationic polymer is epsilon-polylysine, polyethylene imine or chitosan quaternary ammonium salt; the structural formula is as follows:
3) And (3) mixing exosomes (exosomes are vesicles secreted by adipose mesenchymal stem cells) with the mass-volume ratio (mug/mul) of 1:100 with the prepared hydrogel in an ice bath, vigorously oscillating to ensure that the exosomes are fully and uniformly mixed, and incubating the mixture in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, so as to obtain the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds. The hydrogel dressing is prepared by loading exosomes on a cationic polymer through electrostatic action and wrapping the exosomes in the hydrogel dressing by utilizing hydrogel with a double-network structure, so as to promote the healing of chronic wound surfaces.
Wherein, the pramipexole F127 (Pluronic F127) is a polyoxyethylene-polypropylene triblock polymer (PEO-PPO-PEO), the formed hydrogel has temperature sensitive property, when the temperature is increased, the PPO block of F127 starts to dehydrate and cross-link with PEO blocks with water at two ends to form micelles, and the micelles can form a porous three-dimensional network structure after cross-linking, thereby being converted into a semisolid gel state from a liquid state. The polysaccharide such as sodium hyaluronate, sodium alginate and pullulan has good biocompatibility and wide application prospect in the biomedical field; the epsilon-polylysine, polyethylene imine, chitosan and other cationic polymers have good antibacterial performance, and exosomes are vesicles secreted by mesenchymal stem cells, and the mRNA, miRNA and protein contained by the vesicles can be targeted to specific cells to regulate and control the communication among cells, so that the chronic wound healing is promoted, and the vesicles are well applied to antibacterial and wound healing. Therefore, in the invention, firstly, sodium hyaluronate, sodium alginate and pullulan are oxidized by sodium periodate to obtain polysaccharide with aldehyde groups, so that the polysaccharide can react with epsilon-polylysine, polyethylene imine, chitosan and other cationic polymers through Schiff base to form a polymer with a network, finally, the polymer is fully mixed with F127 to form hydrogel with a double-network structure, and then, exosomes are loaded on the cationic polymer through electrostatic action and are wrapped in the hydrogel with the double-network structure, so that the antibacterial self-healing hydrogel auxiliary material for promoting chronic wound healing is obtained.
For a better understanding of the present invention, the present invention will be described in detail with reference to the following examples, but the present invention is not limited to the following examples.
Example 1
1) Preparation of AHA Polymer: adding 2g of sodium hyaluronate into 100mL of deionized water, and stirring vigorously to dissolve the sodium hyaluronate sufficiently; after the sodium hyaluronate is completely dissolved, adding sodium periodate with the molar ratio of 1:1, stirring at room temperature in a dark place, and reacting for 4 hours. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (AHA) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FHE-5 hydrogel: polyether F127 with the mass-volume ratio of 20% (g/mL) and EPL with the mass-volume ratio of 5% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are vigorously shaken in an ice bath to be fully mixed, AHA with the mass-volume ratio of 5% (g/mL) is added, and is vigorously shaken to be fully mixed, and the mixture is incubated in a water bath at 37 ℃ for 1 hour to form hydrogel (FHE-5) with a double-network structure, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Example 2
1) Preparation of AHA Polymer: adding 2g of sodium hyaluronate into 100mL of deionized water, and stirring vigorously to dissolve the sodium hyaluronate sufficiently; after the sodium hyaluronate is completely dissolved, adding sodium periodate with the molar ratio of 1:1, stirring at room temperature in a dark place, and reacting for 4 hours. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (AHA) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FHE-10 hydrogel: polyether F127 with the mass-volume ratio of 20% (g/mL) and EPL with the mass-volume ratio of 10% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are vigorously shaken in an ice bath to be fully mixed, AHA with the mass-volume ratio of 5% (g/mL) is added, and is vigorously shaken to be fully mixed, and the mixture is incubated in a water bath at 37 ℃ for 1 hour to form hydrogel (FHE-10) with a double-network structure, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Example 3
1) Preparation of AHA Polymer: adding 2g of sodium hyaluronate into 100mL of deionized water, and stirring vigorously to dissolve the sodium hyaluronate sufficiently; after the sodium hyaluronate is completely dissolved, adding sodium periodate with the molar ratio of 1:0.5, and stirring and reacting for 4 hours at room temperature in a dark place. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (AHA) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FHE-15 hydrogel: polyether F127 with the mass-volume ratio of 20% (g/mL) and EPL with the mass-volume ratio of 15% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are vigorously shaken in an ice bath to be fully mixed, AHA with the mass-volume ratio of 5% (g/mL) is added, and is vigorously shaken to be fully mixed, and the mixture is incubated in a water bath at 37 ℃ for 1 hour to form hydrogel (FHE-15) with a double-network structure, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Example 4
1) Preparation of AHA Polymer: adding 2g of sodium hyaluronate into 100mL of deionized water, and stirring vigorously to dissolve the sodium hyaluronate sufficiently; after the sodium hyaluronate is completely dissolved, adding sodium periodate with the molar ratio of 1:1, stirring at room temperature in a dark place, and reacting for 4 hours. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (AHA) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FHI hydrogel: polyether F127 with the mass-volume ratio of 20% (g/mL) and PEI with the mass-volume ratio of 5% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are thoroughly mixed by vigorous shaking in an ice bath, AHA with the mass-volume ratio of 5% (g/mL) is added, and is thoroughly mixed by vigorous shaking, and after being incubated for 1 hour in a water bath with the temperature of 37 ℃, the hydrogel (FHI) with a double-network structure is formed, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Example 5
1) Preparation of AHA Polymer: adding 2g of sodium hyaluronate into 100mL of deionized water, and stirring vigorously to dissolve the sodium hyaluronate sufficiently; after the sodium hyaluronate is completely dissolved, adding sodium periodate with the molar ratio of 1:2, and stirring and reacting for 4 hours at room temperature in a dark place. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (AHA) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FHC hydrogel: polyether F127 with the mass-volume ratio of 20% (g/mL) and CTS with the mass-volume ratio of 10% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are thoroughly mixed by vigorous shaking in an ice bath, AHA with the mass-volume ratio of 5% (g/mL) is added, and is thoroughly mixed by vigorous shaking, and after being incubated for 1 hour in a water bath with the temperature of 37 ℃, hydrogel (FHC) with a double-network structure is formed, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Example 6
1) Preparation of APu Polymer: 2g of pullulan is added into 100mL of deionized water, and is stirred vigorously to be fully dissolved; after the pullulan is completely dissolved, adding sodium periodate with the molar ratio of 1:1, and stirring and reacting for 4 hours at room temperature in a dark place. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (APu) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FPE hydrogels: polyether F127 with the mass-volume ratio of 20% (g/mL) and EPL with the mass-volume ratio of 10% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are thoroughly mixed by vigorous shaking in an ice bath, APu with the mass-volume ratio of 5% (g/mL) is added, and is thoroughly mixed by vigorous shaking, and after being incubated for 1 hour in a water bath at 37 ℃, a hydrogel (FPE) with a double-network structure is formed, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Example 7
1) Preparation of APu Polymer: 2g of pullulan is added into 100mL of deionized water, and is stirred vigorously to be fully dissolved; after the pullulan is completely dissolved, adding sodium periodate with the molar ratio of 1:1, and stirring and reacting for 4 hours at room temperature in a dark place. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (APu) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FPI hydrogels: polyether F127 with the mass-volume ratio of 20% (g/mL) and PEI with the mass-volume ratio of 5% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are thoroughly mixed by vigorous shaking in an ice bath, APu with the mass-volume ratio of 5% (g/mL) is added, and are thoroughly mixed by vigorous shaking, and after being incubated for 1 hour in a water bath at 37 ℃, a hydrogel (FPI) with a double-network structure is formed, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Example 8
1) Preparation of APu Polymer: 2g of pullulan is added into 100mL of deionized water, and is stirred vigorously to be fully dissolved; after the pullulan is completely dissolved, adding sodium periodate with the molar ratio of 1:1, and stirring and reacting for 4 hours at room temperature in a dark place. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (APu) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FPC hydrogel: polyether F127 with the mass-volume ratio of 20% (g/mL) and CTS with the mass-volume ratio of 10% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are thoroughly mixed by intense shaking in an ice bath, APu with the mass-volume ratio of 5% (g/mL) is added, and are thoroughly mixed by intense shaking, and after incubation for 1 hour in a water bath at 37 ℃, a hydrogel (FPC) with a double-network structure is formed, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Example 9
1) Preparation of ASA polymer: adding 2g of sodium alginate into 50mL of absolute ethyl alcohol, and stirring vigorously to enable the sodium alginate to be fully dispersed to form a suspension; sodium periodate with the molar ratio of 1:1.5 is dissolved in 50mL of deionized water, and is slowly added into the suspension, and the reaction is stirred at room temperature for 4 hours in a dark place. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (ASA) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FSE hydrogels: polyether F127 with the mass-volume ratio of 20% (g/mL) and EPL with the mass-volume ratio of 10% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are vigorously shaken in an ice bath to be fully mixed, ASA with the mass-volume ratio of 5% (g/mL) is added, and is vigorously shaken to be fully mixed, and the mixture is incubated in a water bath at 37 ℃ for 1 hour to form hydrogel (FSE) with a double-network structure, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Example 10
1) Preparation of ASA polymer: adding 2g of sodium alginate into 50mL of absolute ethyl alcohol, and stirring vigorously to enable the sodium alginate to be fully dispersed to form a suspension; sodium periodate with the molar ratio of 1:1 is dissolved in 50mL of deionized water, and is slowly added into the suspension, and the reaction is stirred at room temperature for 4 hours in a dark place. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (ASA) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FSI hydrogels: polyether F127 with the mass-volume ratio of 20% (g/mL) and PEI with the mass-volume ratio of 5% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are vigorously shaken in an ice bath to be fully mixed, ASA with the mass-volume ratio of 5% (g/mL) is added, and is vigorously shaken to be fully mixed, and the mixture is incubated in a water bath at 37 ℃ for 1 hour to form hydrogel (FSI) with a double-network structure, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
Example 11
1) Preparation of ASA polymer: adding 2g of sodium alginate into 50mL of absolute ethyl alcohol, and stirring vigorously to enable the sodium alginate to be fully dispersed to form a suspension; sodium periodate with the molar ratio of 1:1 is dissolved in 50mL of deionized water, and is slowly added into the suspension, and the reaction is stirred at room temperature for 4 hours in a dark place. Then adding glycol with the molar ratio of 2:1 with sodium periodate to terminate the reaction, stirring for 1 hour, dialyzing and purifying the reaction product (ASA) in deionized water for 2 days, and freeze-drying for later use;
2) Preparation of FSC hydrogels: polyether F127 with the mass-volume ratio of 20% (g/mL) and CTS with the mass-volume ratio of 10% (g/mL) are dissolved in 10mM PBS buffer solution with the pH of 7.4, and are thoroughly mixed by vigorous shaking in an ice bath, ASA with the mass-volume ratio of 5% (g/mL) is added, and is thoroughly mixed by vigorous shaking, and after being incubated for 1 hour in a water bath at 37 ℃, a hydrogel (FSC) with a double-network structure is formed, so that the antibacterial self-healing hydrogel is obtained.
3) And (3) mixing the exosomes with the mass-volume ratio (mug/mug) of 1:100 with the prepared hydrogel in an ice bath in a vigorous shaking way, and incubating in a water bath at 37 ℃ for 1 hour to form the hydrogel with the exosomes, thus obtaining the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces.
The antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds, which is prepared by the invention, has excellent mechanical properties such as temperature sensitivity, injectability, self-healing and the like, good antibacterial property and the effect of promoting the healing of the wounds, and is analyzed in detail by combining experimental data.
Fig. 2 is a fourier infrared spectrum of an antibacterial self-healing hydrogel adjuvant (FHE) and its monomer and precursor prepared by the present invention for promoting chronic wound healing. As can be seen from the figure, 1735cm in AHA -1 The occurrence of the absorption peak indicates the formation of aldehyde (-CHO) groups in sodium hyaluronate, which provides the possibility for further chemical reactions; 1660cm -1 Absorption peaks at (a) are derived from carbonyl (-c=o) groups of EPL and HA; 1467cm -1 And 1342cm -1 The absorption peak at F127 is attributed to an ether linkage (-C-O-C-); furthermore, 1735cm in FHE hydrogels -1 The disappearance of the absorbance peak indicates the successful occurrence of the schiff base reaction between AHA and EPL.
Fig. 3 shows the temperature sensitivity of the antibacterial self-healing hydrogel auxiliary material (FXE) for promoting the healing of chronic wounds. X represents three polysaccharides AHA, APu and ASA, it can be seen from FIG. 4A that as the temperature gradually increases from 10deg.C to 38deg.C, the storage modulus (G ') and loss modulus (G ") of the hydrogel gradually increase and tend to stabilize, i.e., the hydrogel has a certain temperature-sensitive effect, and it can also be seen from FIG. 4B that the hydrogels exhibit good stability under different temperature conditions, G' and G".
Fig. 4 shows injectability and self-healing properties of the antibacterial self-healing hydrogel auxiliary material (FXE) for promoting chronic wound healing. As can be seen from fig. 5A, the FXE hydrogel can be successfully extruded from a medical plastic hose with an inner diameter of 0.8mm and a diameter of 10cm and is not blocked, which indicates that the hydrogel has good injectability; as can be seen in fig. 5B, after a period of time, the hydrogels separated from each other have healed completely into one hydrogel, indicating that it has a good self-healing ability.
Figure 5 shows the antibacterial properties of the antibacterial self-healing hydrogel auxiliary material (FXE, FHY) for promoting chronic wound healing. X represents three polysaccharides of AHA, APu and ASA, Y represents three cationic polymers of EPL, PEI and QCS; the surface antibacterial activity of the hydrogel is evaluated by adopting escherichia coli (figure 5A) and staphylococcus aureus (figure 5B), and the result shows that the two bacteria of the hydrogel group are killed by more than 99 percent due to the existence of the antibacterial cationic polymer, thus indicating that the hydrogel has good antibacterial capability.
FIG. 6 shows the controlled release results of exosomes in the antibacterial self-healing hydrogel adjuvant for promoting chronic wound healing prepared by the invention. From the results, it can be seen that the exosomes can be effectively encapsulated in the hydrogel and have a certain sustained release capacity with different pH values.
Fig. 7 shows the result of the skin wound repair and healing by the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound. From the results of the wound closure rate, it can be seen that the fhe@exo group healed faster than the other groups at day 14, with a closure rate of about 88.67% and the other groups reached a final cure rate of about 76.3% (exosomes), 64.3% (FHE) and 36.3% (control), respectively. In addition, with the addition of exosomes in the FHE hydrogel, the healing properties of fhe@exo are significantly improved compared to pure exosomes, indicating that the fhe@exo hydrogel is able to promote the healing process by sustained release of the exosomes.
The antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds, which is prepared by the invention, has simple preparation process, and the prepared hydrogel auxiliary material has excellent mechanical properties such as temperature sensitivity, injectability, self-healing and the like and good antibacterial property. Therefore, the hydrogel has good application prospect in promoting the healing of chronic wound and resisting bacteria.
The above is only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited by this, and any modification made on the basis of the technical scheme according to the technical idea of the present invention falls within the protection scope of the claims of the present invention.
Claims (7)
1. The preparation method of the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds is characterized by comprising the following steps of:
1) Mixing polysaccharide and strong oxidant, oxidizing reaction, stirring at room temperature for 4 hours under dark condition; adding ethylene glycol to terminate the reaction, stirring for 1 hour at room temperature, dialyzing and purifying the reaction product in deionized water for 2 days, and freeze-drying to obtain oxidized polysaccharide;
2) Dissolving polyether F127 and a cationic polymer with antibacterial capability in PBS buffer solution, oscillating in ice bath to fully mix the solution, adding the prepared oxidized polysaccharide, oscillating to fully mix the solution, and incubating the solution in water bath to form hydrogel with a double-network structure, thereby obtaining the antibacterial self-healing hydrogel;
3) The exosomes and the prepared hydrogel are oscillated in ice bath to fully and uniformly mix, the exosomes and the prepared hydrogel are incubated in water bath to form the hydrogel with the exosomes, the exosomes are loaded on a cationic polymer through electrostatic action, and the hydrogel with a double-network structure is used for wrapping the exosomes, so that the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wound surfaces is prepared;
in the step 2), the mass-volume ratio of polyether F127 in the PBS buffer solution is 20% g/mL; the mass volume ratio of the cationic polymer in the PBS buffer solution is 5-15% g/mL; the mass-volume ratio of oxidized polysaccharide in PBS buffer is 5% g/mL;
the cationic polymer in the step 2) is epsilon-polylysine, polyethyleneimine or chitosan quaternary ammonium salt;
the mass to volume ratio of exosomes to hydrogel in step 3) was 1:100 μg/μl.
2. The method for preparing the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds according to claim 1, wherein the molar ratio of the polysaccharide to the strong oxidizer in the step 1) is 1 (0.5-2); the molar ratio of ethylene glycol to strong oxidizer is 2:1.
3. The method for preparing the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds according to claim 1, wherein the strong oxidizer in the step 1) is sodium periodate.
4. The method for preparing the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds according to claim 1, wherein the polysaccharide in the step 1) is sodium hyaluronate, sodium alginate or pullulan.
5. The method for preparing the antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds according to claim 1, wherein in the step 2), the pH value of the PBS buffer solution is 7.4.
6. An antibacterial self-healing hydrogel auxiliary material for promoting the healing of chronic wounds, prepared by the method of any one of claims 1 to 5, wherein the prepared antibacterial self-healing hydrogel auxiliary material is prepared by loading exosomes on a cationic polymer through electrostatic action and wrapping the exosomes in hydrogel with a double-network structure.
7. The use of the antibacterial self-healing hydrogel auxiliary material for promoting chronic wound healing according to claim 6 in the preparation of materials for promoting chronic wound healing and antibacterial.
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