A self-healing injectable hydrogel dressing and a method of preparing the same

Abstract

The application discloses a self-repairing injectable hydrogel dressing and a preparation method thereof. The hydrogel dressing comprises a biodegradable polymer, a polyphenol compound and an active drug. The biodegradable polymer and the polyphenol compound are dynamically combined through an imine bond, a disulfide bond, a borate ester bond or an acylhydrazone bond. The active drug comprises at least one of a nano material with a photothermal effect, an antioxidant drug, an anti-inflammatory drug and a pro-angiogenic drug. The dynamic bond is introduced into the hydrogel dressing, so that the hydrogel dressing has self-repairing and injectable properties, can be suitable for wounds with different shapes and areas, has strong mechanical properties, can maintain the integrity of the structure of the hydrogel dressing during use, and prolongs the service life.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of hydrogel dressings, and particularly relates to a self-repairing injectable hydrogel dressing and a preparation method thereof. BACKGROUND

[0002] Wounds can be divided into acute wounds and chronic wounds according to healing time. Acute wounds can heal quickly in a short time, while chronic wounds usually refer to refractory wounds that have no healing tendency and cannot heal for more than one month, such as diabetic foot ulcers, venous ulcers and pressure sores. Although chronic wounds have different causes, they all have the common characteristics of persistent wound infection, high levels of pro-inflammatory factors, proteases and ROS, and cell dysfunction. Chronic wounds often require frequent dressing changes and multiple hospitalizations, which adversely affect the health and quality of life of patients and cause huge economic burden. The treatment of chronic wounds is a long-term combined treatment process, and the standard treatment method includes regular wound debridement, pressure reduction treatment, blood vessel perfusion recovery, infection control, and local use of dressings to provide a moist environment. Traditional dressings, as a means of local treatment for chronic wounds, are usually used for clean and dry wounds and mainly serve to cover the wound and maintain gas exchange.

[0003] However, the problem with traditional dressings is that it is difficult to keep the wound moist, and when replaced, the absorption of wound exudate can cause adhesion to the wound, causing pain to the patient and further damaging the wound. Compared with traditional dressings, modern dressings with advanced functions have better biocompatibility, degradability and moisturizing properties, which can reduce pain and improve the hypoxic or anoxic environment. The characteristics of modern dressings are semi-permeability and the presence of a high absorption layer, which play an active role in the wound healing process.

[0004] Hydrogel dressings, as one of the most common modern dressings in clinical practice, have a three-dimensional network cross-linked structure, high water content and porous structure that can promote adequate gas exchange and provide a moist environment for the wound. However, ordinary hydrogel dressings only serve as a simple physical barrier and create a moist environment, and do not have therapeutic effects. In addition, the fit with irregularly shaped wounds is poor, and the mechanical force generated by daily movement can damage the integrity of the hydrogel dressing network structure, thereby reducing the therapeutic effect of the hydrogel dressing and significantly reducing its service life. Therefore, there is great interest in developing hydrogel dressings with multiple biological functions that adapt to the wound microenvironment. SUMMARY

[0005] In view of the above problems in the prior art, the self-repairing injectable hydrogel dressing and a preparation method thereof are provided, the dynamic bond is introduced into the hydrogel dressing, so that the hydrogel dressing has self-repairing and injectable properties, can be suitable for wounds of different shapes and areas, and has strong mechanical properties, so that the integrity of the structure of the hydrogel dressing can be maintained during use, and the service life is prolonged.

[0006] To achieve the above object, the technical scheme adopted by the present application to solve its technical problems is:

[0007] A self-repairing injectable hydrogel dressing, comprising a biodegradable polymer, a polyphenol compound and an active drug, the biodegradable polymer and the polyphenol compound are dynamically combined through an imine bond, a disulfide bond, a borate ester bond or an acylhydrazone bond, and the active drug comprises at least one of a nano material with photothermal effect, an antioxidant drug, an anti-inflammatory drug and a pro-angiogenic drug.

[0008] Further, the biodegradable polymer comprises at least one of starch and its derivatives, chitosan and its derivatives, cellulose and its derivatives, gelatin and its derivatives, alginic acid and its derivatives, hyaluronic acid and its derivatives, liver sugar and its derivatives, and inulin and its derivatives.

[0009] Further, the polyphenol compound comprises at least one of caffeic acid, dopamine, rutin, veratryl alcohol, phloretin, phlorizin and tannic acid.

[0010] Further, the nano material with photothermal effect comprises at least one of gold nanorods, copper-sulfur nanoparticles, copper-selenium nanoparticles, Nb2C MXene nanosheets, Ti3C2 MXene nanosheets, W 18 O 49 nanorods and Prussian blue nanoparticles.

[0011] Further, the particle size of the nano material with photothermal effect is 1-200nm.

[0012] Further, the mass percentage of the biodegradable polymer in the hydrogel dressing is 0.5-99.5%, the mass percentage of the polyphenol compound is 0.5-99.5%, and the mass percentage of the active drug is 0.5-99.5%.

[0013] The preparation method of the above self-repairing injectable hydrogel dressing, when the biodegradable polymer and the polyphenol compound are crosslinked through a borate ester bond, comprises the following steps:

[0014] (1) biodegradable polymer and glacial acetic acid are dissolved in water to prepare a biodegradable polymer solution, then 2,3-epoxypropyl trimethylammonium chloride aqueous solution is added dropwise to the biodegradable polymer solution under heating, then centrifugation is performed, and the supernatant is taken to perform purification and freeze-drying, so as to prepare a quaternary ammonium biodegradable polymer;

[0015] (2) a quaternary ammonium biodegradable polymer solution is prepared; 4-carboxyl-3-aminobenzoic acid, NHS and EDC are dissolved in DMSO to prepare a carboxyl activation solution, the quaternary ammonium biodegradable polymer solution and the carboxyl activation solution are mixed, the pH value of the mixed solution is adjusted to weak acidity, then activation reaction is performed, and then dialysis and freeze-drying are performed, so as to prepare a 4-carboxyl-3-aminobenzoic acid quaternary ammonium biodegradable polymer;

[0016] (3) biodegradable polymer is dissolved in a PBS solution to prepare a biodegradable polymer solution, then NHS and EDC are added to the biodegradable polymer solution to activate carboxyl, then 3-aminobenzoic acid is added to the biodegradable polymer solution to perform grafting reaction, and then dialysis and freeze-drying are performed, so as to prepare a 3-aminobenzoic acid biodegradable polymer;

[0017] (4) 4-carboxyl-3-aminobenzoic acid biodegradable polymer, 3-aminobenzoic acid biodegradable polymer and active drugs are dissolved to prepare a mixture solution, the mixture solution is mixed with a polyphenol compound solution, and stirring is performed, so as to prepare a hydrogel dressing.

[0018] Further, in step (1), the reaction temperature is 50-60 DEG C, the reaction time is 22-24 h, the centrifugal speed is 6000-7000 rpm, and the centrifugal time is 6-10 min.

[0019] Further, in step (2), the pH value of the mixed solution is 5-6, the activation reaction temperature is 20-30 DEG C, and the activation reaction time is 3-5 h.

[0020] Further, in step (3), the pH value of the PBS solution is 5-6, the carboxyl activation reaction time is 3-5 h, and the grafting reaction time is 44-50 h.

[0021] The application has the following beneficial effects:

[0022] 1. In the application, biodegradable polymer and polyphenol compound are dynamically crosslinked through a dynamic bond to form a hydrogel dressing structure, the hydrogel dressing has good self-healing performance, can prolong mechanical durability and service life, and avoid causing secondary damage to a wound; the hydrogel dressing can be used in the form of injection, and can be coated according to the shape of a wound of a patient, so that the covering effect on the wound is improved.

[0023] 2、The hydrogel dressing also introduces a polyphenol compound, which has good antioxidant, antibacterial and anti-inflammatory properties, can improve the treatment effect of the hydrogel dressing on the wound, and the polyphenol compound is grafted in the hydrogel dressing matrix, which can improve its stability, gradually release with the increase of use time, and provide sustained-release treatment effect.

[0024] 3、The hydrogel dressing also introduces an active drug, when the active drug is a nano material with photothermal effect, the photothermal conversion performance can be used to increase the temperature of the hydrogel dressing, so that the wound is in a micro-thermal environment, promoting the formation of new blood vessels, thereby promoting the healing of chronic wounds. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The preparation process and treatment process of the hydrogel dressing of the application are shown in the figure;

[0026] Figure 2 The self-repairing performance result of the hydrogel dressing of the application is shown in the figure;

[0027] Figure 3 The injection performance effect of the hydrogel dressing of the application is shown in the figure;

[0028] Figure 4 The H2O2 removal capacity of the hydrogel dressing of the application is shown in the figure;

[0029] Figure 5 The ·OH removal capacity of the hydrogel dressing of the application is shown in the figure;

[0030] Figure 6 The ·O 2- removal capacity of the hydrogel dressing of the application is shown in the figure;

[0031] Figure 7 The DPPH removal capacity of the hydrogel dressing of the application is shown in the figure;

[0032] Figure 8 The ABTS +· removal capacity of the hydrogel dressing of the application is shown in the figure;

[0033] Figure 9 The photothermal performance result of the hydrogel dressing of the application is shown in the figure;

[0034] Figure 10 The anti-inflammatory performance result of the hydrogel dressing of the application is shown in the figure;

[0035] Figure 11 The effect of the hydrogel dressing of the application on promoting wound healing is shown in the figure. DETAILED DESCRIPTION

[0036] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only intended to explain the present application and not to limit the present application, i.e., the described embodiments are only a part of the embodiments of the present application, but not all the embodiments.

[0037] Therefore, the detailed description of the embodiments of the present application provided below is not intended to limit the scope of the claimed present application, but only represents selected embodiments of the present application. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of the present application.

[0038] It should be noted that the relational terms such as "first" and "second" and the like are merely used to distinguish one entity or operation from another, and do not necessarily require or imply that there is any such actual relationship or order between these entities or operations. Moreover, the terms "include", "contain" or any other variants thereof are intended to cover non-exclusive inclusion, so that the process, method, article or device including a series of elements not only includes those elements, but also includes other elements not explicitly listed or inherent to such process, method, article or device. Without more limitations, the element defined by the statement "including a" does not exclude the presence of another identical element in the process, method, article or device including the element.

[0039] The features and performances of the present application will be further described in detail below with reference to the embodiments and the accompanying drawings.

[0040] Embodiment 1

[0041] A self-repairing injectable hydrogel dressing, the preparation method thereof comprises the following steps:

[0042] (1) 5 g of chitosan (CS) and 0.9 g of glacial acetic acid are added into 180 mL of water in turn, and the CS is dissolved under magnetic stirring, then 6.7 g of 2,3-epoxypropyltrimethylammonium chloride (GTMAC) is dissolved in 11.2 mL of water to prepare a GTMAC solution, which is then added dropwise into the CS solution, and reacted at 55°C for 23 h, after the reaction is completed, centrifugation is performed at 6500 rpm for 8 min, the supernatant is purified with pre-cooled acetone for three times, and finally the reaction product quaternary ammonium chitosan (QCS) is obtained by dialysis and freeze-drying;

[0043] (2) 0.5 g of hyaluronic acid (HA) was dissolved in PBS with pH 5.5 to prepare a HA solution, then 0.7 g of EDC and 0.4 g of NHS were added to the HA solution to activate the carboxyl group for 4 h, then 0.2 g of 3-aminophenylboronic acid was added to the solution and reacted at 25°C for 48 h, after the reaction was completed, the product was dialyzed and freeze-dried to obtain the product 3-aminophenylboronic acid hyaluronic acid (HA-PBA);

[0044] (3) 0.3 g of QCS was dissolved in 150 mL of PBS to prepare a QCS solution, then 0.6 g of 4-carboxy-3-fluorophenylboronic acid, 1.2 g of NHS and 2 g of EDC were dissolved in 90 mL of DMSO and activated at 25°C for 4 h, the two solutions were mixed and the pH was adjusted to 5.5, and the reaction was carried out at 25°C for 48 h, after the reaction was completed, the product was dialyzed and freeze-dried to obtain the product 4-carboxy-3-fluorophenylboronic acid quaternary ammonium chitosan (QCSF);

[0045] (4) 1.1 g of polyvinyl phenol (PVP) was ultrasonically dispersed in 20 mL of water, then 27.03 mg of FeCl3·6H2O was added and ultrasonically dispersed for 30 min, the solution was transferred to a 60°C water bath and stirred for 30 min to prepare a FeCl3·6H2O solution; 42.2 mg of K4[Fe(CN)6]·3H2O was ultrasonically dispersed in 20 mL of water for 5 min, and the solution was transferred to a 20 mL syringe, the K4[Fe(CN)6]·3H2O solution was added to the FeCl3·6H2O solution at a speed of 40 mL / h, then the reaction was continued in a 60°C water bath for 1 h, after the reaction was completed, centrifugation was carried out at 12000 rpm for 10 min, and the product was repeatedly purified with acetone and ethanol for five times, and then vacuum dried to obtain Prussian blue nanoparticles (PBNPs);

[0046] (5) 3% w / v QCSF, 2% w / v HA-PBA, 0.1% w / v PBNPs were dissolved in water, then the solution was mixed with a 5% w / v tannic acid solution to ensure that the concentration of the polymer was 4.5 w / v%, and stirring was carried out until a solid gel was formed to obtain a QHT@PBNPs hydrogel dressing crosslinked by borate ester bonds.

[0047] Example 2

[0048] A self-repairing injectable hydrogel dressing, the preparation method thereof comprises the following steps:

[0049] (1) 5 g of chitosan (CS) and 0.9 g of glacial acetic acid were added into 180 mL of water in turn, and the CS was dissolved under magnetic stirring, then 6.7 g of 2,3-epoxypropyltrimethylammonium chloride (GTMAC) was dissolved in 11.2 mL of water to prepare a GTMAC solution, which was then added dropwise into the CS solution, and reacted at 55°C for 23 h. After the reaction was completed, the supernatant was obtained by centrifugation at 6500 rpm for 8 min, and then purified with pre-cooled acetone for three times. Finally, the reaction product, quaternary ammonium chitosan (QCS), was obtained by dialysis and freeze-drying;

[0050] (2) 0.5 g of hyaluronic acid (HA) was dissolved in PBS with pH of 5.5 to prepare an HA solution, then 0.7 g of EDC and 0.4 g of NHS were added into the HA solution to activate the carboxyl group for 4 h, then 0.2 g of 3-aminophenylboronic acid was added into the solution and reacted at 25°C for 48 h. After the reaction was completed, the product was dialyzed and freeze-dried to obtain the product, 3-aminophenylboronic acid hyaluronic acid (HA-PBA);

[0051] (3) 0.3 g of QCS was dissolved in 150 mL of PBS to prepare a QCS solution, then 0.6 g of 4-carboxy-3-fluorophenylboronic acid, 1.2 g of NHS and 2 g of EDC were dissolved in 90 mL of DMSO, and the carboxyl group was activated at 25°C for 4 h. The two solutions were mixed, and the pH was adjusted to 5.5. The reaction was carried out at 25°C for 48 h. After the reaction was completed, the product was dialyzed and freeze-dried to obtain the product, 4-carboxy-3-fluorophenylboronic acid quaternary ammonium chitosan (QCSF);

[0052] (4) 1.1 g of polyvinyl phenol (PVP) was ultrasonically dispersed in 20 mL of water, then 27.03 mg of FeCl3·6H2O was added and ultrasonically dispersed for 30 min. The solution was transferred into a 60°C water bath and stirred for 30 min to prepare a FeCl3·6H2O solution. 42.2 mg of K4[Fe(CN)6]·3H2O was added into 20 mL of water and ultrasonically dispersed for 5 min, and the solution was transferred into a 20 mL syringe. The K4[Fe(CN)6]·3H2O solution was added into the FeCl3·6H2O solution at a speed of 40 mL / h, and then the reaction was continued in a 60°C water bath for 1 h. After the reaction was completed, the product was centrifuged at 12000 rpm for 10 min, and then purified with acetone and ethanol for five times. The product was vacuum dried to obtain Prussian blue nanoparticles (PBNPs);

[0053] (5) Dissolve 3% w / v QCSF, 2% w / v HA-PBA, 0.15% w / v PBNPs in water, then mix the solution with 5% w / v tannic acid solution, ensure the concentration of polymer is 4.5 w / v%, stir until a solid gel is formed, and obtain QHT@PBNPs hydrogel dressing crosslinked by borate ester bond.

[0054] Example 3

[0055] A self-repairing injectable hydrogel dressing, the preparation method thereof comprises the following steps:

[0056] (1) 5 g of chitosan (CS) and 0.9 g of glacial acetic acid are added into 180 mL of water in turn, and the CS is dissolved under magnetic stirring, then 6.7 g of 2,3-epoxypropyltrimethylammonium chloride (GTMAC) is dissolved in 11.2 mL of water to prepare a GTMAC solution, which is then added dropwise into the CS solution, and reacted at 55°C for 23 h, after the reaction is completed, centrifugation is performed at 6500 rpm for 8 min, the supernatant is purified with pre-cooled acetone for three times, and finally the reaction product quaternary ammonium chitosan (QCS) is obtained by dialysis and freeze-drying;

[0057] (2) 0.5 g of hyaluronic acid (HA) is dissolved in PBS with pH of 5.5 to prepare an HA solution, then 0.7 g of EDC and 0.4 g of NHS are added into the HA solution to activate the carboxyl group for 4 h, then 0.2 g of 3-aminophenylboronic acid is added into the solution and reacted at 25°C for 48 h, after the reaction is completed, the product is dialyzed and freeze-dried to obtain the product 3-aminophenylboronic acid hyaluronic acid (HA-PBA);

[0058] (3) 0.3 g of QCS is dissolved in 150 mL of PBS to prepare a QCS solution, then 0.6 g of 4-carboxy-3-fluorophenylboronic acid, 1.2 g of NHS and 2 g of EDC are dissolved in 90 mL of DMSO, and the carboxyl group is activated at 25°C for 4 h, the two solutions are mixed, and the pH is adjusted to 5.5, and the reaction is carried out at 25°C for 48 h, after the reaction is completed, the product is dialyzed and freeze-dried to obtain the product 4-carboxy-3-fluorophenylboronic acid quaternary ammonium chitosan (QCSF);

[0059] (4) 1.1 g of polyvinylphenol (PVP) was ultrasonically dispersed in 20 mL of water, and then 27.03 mg of FeCl3·6H2O was added and ultrasonicated for 30 min. The solution was transferred to a 60°C water bath and heated with stirring for 30 min to prepare a FeCl3·6H2O solution. 42.2 mg of K4[Fe(CN)6]·3H2O was added to 20 mL of water and ultrasonically dispersed for 5 min. The solution was transferred to a 20 mL syringe, and the K4[Fe(CN)6]·3H2O solution was added to the FeCl3·6H2O solution at a rate of 40 mL / h. The reaction was continued in a 60°C water bath for 1 h. After the reaction was completed, the solution was centrifuged at 12,000 rpm for 10 min, purified repeatedly with acetone and ethanol five times, and the product was vacuum dried to obtain Prussian blue nanoparticles (PBNPs).

[0060] (5) 3% w / v QCSF, 2% w / v HA-PBA, and 0.3% w / v PBNPs were dissolved in water, and the solution was then mixed with 5% w / v tannic acid solution to ensure that the polymer concentration was 4.5 w / v%. The mixture was stirred until a solid gel was formed to obtain a QHT@PBNPs hydrogel dressing cross-linked by borate bonds.

[0061] Example 4

[0062] A self-repairing injectable hydrogel dressing, the preparation method of which comprises the following steps:

[0063] (1) 5 g of chitosan (CS) and 0.9 g of glacial acetic acid were added to 180 mL of water, and CS was dissolved under magnetic stirring. Subsequently, 6.7 g of 2,3-epoxypropyltrimethylammonium chloride (GTMAC) was dissolved in 11.2 mL of water to prepare a GTMAC solution, which was then added dropwise to the CS solution and reacted at 55 °C for 23 h. After the reaction was completed, the solution was centrifuged at 6500 rpm for 8 min. The supernatant was purified three times with pre-cooled acetone, and finally dialyzed and freeze-dried to obtain the reaction product, quaternized chitosan (QCS).

[0064] (2) 0.5 g of hyaluronic acid (HA) was dissolved in PBS with a pH of 5.5 to prepare a HA solution, and then 1.08 g of sodium periodate was added to the HA solution to react for 12 h. After the reaction was completed, ethylene glycol was added to terminate the reaction. The product was dialyzed and freeze-dried to obtain the product oxidized hyaluronic acid (OHA);

[0065] (3) 1.1 g of polyvinyl phenol (PVP) was ultrasonically dispersed in 20 mL of water, then 27.03 mg of FeCl3·6H2O was added and ultrasonically dispersed for 30 min, the solution was transferred to a 60°C water bath and stirred for 30 min to prepare a FeCl3·6H2O solution; 42.2 mg of K4[Fe(CN)6]·3H2O was ultrasonically dispersed in 20 mL of water for 5 min, and the solution was transferred to a 20 mL syringe, the K4[Fe(CN)6]·3H2O solution was added to the FeCl3·6H2O solution at a speed of 40 mL / h, then the reaction was continued in a 60°C water bath for 1 h, after the reaction was completed, centrifugation was performed at 12000 rpm for 10 min, and the product was repeatedly purified with acetone and ethanol for five times, and then vacuum dried to obtain Prussian blue nanoparticles (PBNPs);

[0066] (4) 3% w / v QCS, 6% w / v OHA, and 0.3% w / v PBNPs were dissolved in water, and then the solution was mixed with a 5% w / v dopamine solution to form a solid gel by stirring, thereby obtaining a QHT@PBNPs hydrogel dressing crosslinked by Schiff base bonds.

[0067] Example 5

[0068] A self-repairing injectable hydrogel dressing, the preparation method thereof comprising the following steps:

[0069] (1) 5 g of chitosan (CS) and 0.9 g of glacial acetic acid were added to 180 mL of water in sequence, and the CS was dissolved under magnetic stirring, then 6.7 g of 2,3-epoxypropyltrimethylammonium chloride (GTMAC) was dissolved in 11.2 mL of water to prepare a GTMAC solution, which was then added dropwise to the CS solution and reacted at 55°C for 23 h, after the reaction was completed, centrifugation was performed at 6500 rpm for 8 min, the supernatant was purified with pre-cooled acetone three times, and finally the reaction product quaternary ammonium chitosan (QCS) was obtained by dialysis and freeze-drying; (2) 0.5 g of hyaluronic acid (HA) was dissolved in PBS with a pH of 5.5 to prepare an HA solution, then 0.7 g of EDC and 0.4 g of NHS were added to the HA solution to activate the carboxyl group for 4 h, then 0.2 g of selenocystamine was added to the solution and reacted at 25°C for 48 h, after the reaction was completed, the product was dialyzed and freeze-dried to obtain the product selenocystamine hyaluronic acid (HA-SeC);

[0070] (3) 1.1 g of polyvinyl phenol (PVP) was ultrasonically dispersed in 20 mL of water, then 27.03 mg of FeCl3·6H2O was added and ultrasonically dispersed for 30 min, the solution was transferred to a 60°C water bath and stirred for 30 min to prepare a FeCl3·6H2O solution; 42.2 mg of K4[Fe(CN)6]·3H2O was added to 20 mL of water and ultrasonically dispersed for 5 min, and the solution was transferred to a 20 mL syringe, the K4[Fe(CN)6]·3H2O solution was added to the FeCl3·6H2O solution at a speed of 40 mL / h, then the reaction was continued in a 60°C water bath for 1 h, after the reaction was completed, centrifugation was performed at 12000 rpm for 10 min, and the product was repeatedly purified with acetone and ethanol for five times, and then vacuum dried to obtain Prussian blue nanoparticles (PBNPs);

[0071] (4) 3% w / v QCS, 6% w / v HA-SeC, 0.3% w / v PBNPs were dissolved in water, then the solution was mixed with a 5% w / v dopamine solution, and stirred until a solid gel was formed to obtain a QHT@PBNPs hydrogel dressing crosslinked by Schiff base bonds and diselenide bonds.

[0072] Test Example

[0073] Figure 1 Schematic diagram of the preparation process and treatment process of the hydrogel dressing of the application;

[0074] Taking the hydrogel dressing in Example 1 as an example, the hydrogel dressing prepared in step (5) of Example 1 without adding PBNPs is a QHT hydrogel dressing, and the hydrogel dressing prepared by adding PBNPs is a QHT@PBNPs hydrogel dressing, the injectability and self-repairing performance of the hydrogel dressing are determined, and the rheological properties of the hydrogel dressing are determined, which are specifically shown in Figure 2 , Figure 2 The rheological property diagram of the hydrogel dressing without adding PBNPs is shown in a graph in FIG. 1, it can be seen that when the strain γ is 1%, the storage modulus (G’) of the hydrogel dressing is greater than the loss modulus (G”), and the hydrogel dressing is in a gel state; when the strain is 1300%, G’ decreases, and G” is greater than G’, indicating that the hydrogel dressing has been damaged; when the applied strain returns to 1%, G’ and G” return to the original values, indicating that the network structure of the hydrogel dressing is reconstructed. After 3 repeated experiments, the hydrogel dressing can always return to the gel state at a strain γ of 1%, indicating that the hydrogel dressing has good self-repairing performance, and the rheological property diagram of the hydrogel dressing with PBNPs added is shown in b graph in FIG. 1, it can be seen that the addition of PBNPs does not affect the self-repairing performance of the QHT hydrogel dressing;

[0075] Two hydrogel dressings of different colors were placed close to each other to make them contact, and after 10 min, the hydrogel dressing was picked up with tweezers. The hydrogel dressing had no obvious cracks, as shown in FIG. c of Figure 2 , indicating that the hydrogel dressing had self-repairing performance.

[0076] Shearing experiments were performed on the QHT hydrogel dressing and the QHT@PBNPs hydrogel dressing to determine the viscosity of the hydrogel dressing. The hydrogel dressing was added to a syringe, and then the letter "SWJTU" was injected out, as shown in Figure 3 . As can be seen from FIG. a, the viscosity of the hydrogel dressing gradually decreased as the shearing proceeded. As can be seen from FIG. b, the hydrogel dressing had injectability.

[0077] The RONS scavenging function of the hydrogel dressing was determined, and the specific operation was as follows:

[0078] (1) The color reaction of Ti(SO4)2 and H2O2 was used to evaluate the H2O2 scavenging ability of the hydrogel dressing and the PBNPs. First, a 0.1M H2SO4 solution was prepared, Ti(SO4)2 was added to the H2SO4 to obtain a 0.03M titanium sulfate solution, and 4mL of 1mM H2O2 solution was incubated with 200μL of QHT hydrogel dressing, 200μL of QHT@PBNPs hydrogel dressing, and 200μL of PBNPs with a concentration of 0.15mg / mL and 0.3mg / mL, respectively. At different time intervals, 100μL of supernatant was taken to a 96-well plate, and 30μL of Ti(SO4)2 solution was added. The reaction was color-developed for 30min, after which the ultraviolet absorption spectrum of the solution and the absorbance at 405nm were measured to evaluate the H2O2 scavenging performance of the sample.

[0079] (2) The SA method was used to experiment on the scavenging of ·OH. First, 200μL of QHT hydrogel dressing, PBNPs with a concentration of 0.15mg / mL and 0.3mg / mL, and 200μL of QHT@PBNPs hydrogel dressing were added to 1mL of FeSO4 (concentration of 2mM), followed by the addition of 1mL of H2O2 (concentration of 5mM) and standing for 10min. Then, 1mL of SA (concentration of 1.5mM) was added, and the solution was incubated at 37℃ for 30min in the dark. Subsequently, the ultraviolet absorption spectrum of the mixed solution and the absorbance at 510nm were measured, and the ·OH scavenging rate was calculated according to the following formula: ·OH scavenging rate (%) = (Ac-As) / Ac x 100%. Ac is the absorbance at 510nm of the blank control group containing only FeSO4, SA and H2O2, and As is the absorbance at 510nm of the experimental group.

[0080] (3) The scavenging ability of hydrogel dressing and PBNPs on ·O2- was evaluated by testing the inhibition rate of photoreduction of NBT. First, 200 μL QHT hydrogel dressing, PBNPs with concentrations of 0.15 mg / mL and 0.3 mg / mL, 200 μL QHT@PBNPs were added into 1 mL Met (concentration of 12.5 mM) respectively, then 1 mL NBT (concentration of 75 μM) and 1 mL riboflavin (concentration of 20 μM) were added into the solution, then the mixed solution was irradiated with ultraviolet light for 15 min, after irradiation, the ultraviolet absorption spectrum of the solution and the absorbance at 560 nm were measured, and the scavenging rate of ·O2- was calculated by the following formula: 2- Scavenging rate of ·O2- (%) = (A0-An) / (Ap-An) x 100%

[0081]

[0082] A0 is the absorbance of the experimental group, An is the absorbance at 560 nm of the negative control group (containing riboflavin, Met, NBT but in the dark environment), and Ap is the absorbance at 560 nm of the positive control group (containing riboflavin, Met, NBT after ultraviolet irradiation).

[0083] (4) The steps of DPPH scavenging experiment are as follows: first, prepare 0.1 mM DPPH ethanol solution. 200 μL QHT hydrogel, PBNPs with concentrations of 0.15 mg / mL and 0.3 mg / mL, 200 μL QHT@PBNPs were added into 3 mL DPPH ethanol solution respectively and incubated in the dark for 30 min. After incubation, the ultraviolet absorption spectrum of the mixed solution and the absorbance at 517 nm were measured. The scavenging rate of DPPH was calculated by the following formula: DPPH scavenging rate (%) = (Ac-As) / Ac x 100%

[0084] Ac is the absorbance at 517 nm of the blank control group containing only DPPH ethanol solution, and As is the absorbance at 517 nm of the experimental group.

[0085] (5) The steps of ABTS +· scavenging experiment are as follows: first, 2 mL ABTS (concentration of 7 mM) and 2 mL K2S2O8 (concentration of 4.95 mM) were oxidized at room temperature for 12 h in the dark, then the solution was diluted with PBS to 5% of the original concentration, 200 μL QHT hydrogel dressing, PBNPs with concentrations of 0.15 mg / mL and 0.3 mg / mL, 200 μL QHT@PBNPs were added into 3 mL ABTS +· solution respectively and incubated in the dark for 30 min, and the ultraviolet absorption spectrum of the mixed solution and the absorbance at 734 nm were measured.

[0086] ​The clearance rate of ABTS was calculated by the following formula: ABTS ·+ +· Clearance rate (%) = (Ac-As) / Ac x 100% Ac is the absorbance of blank control group containing only ABTS +· solution at 734 nm, and As is the absorbance of experimental group at 734 nm.

[0087] The specific test results are shown in Figures 4-8 , wherein the concentration of PBNPs-1 is 0.75 mg / mL, the concentration of PBNPs-2 is 1.5 mg / mL, QHT@PBNPs-1 is QHT hydrogel dressing added with PBNPs at a concentration of 0.75 mg / mL, and QHT@PBNPs-2 is QHT hydrogel dressing added with PBNPs at a concentration of 1.5 mg / mL, as shown in Figure 4 , at 24 h, the residual amount of H2O2 in the blank control group is 92.5%, the residual amount of H2O2 is 29.5% when the concentration of PBNPs is 0.15 mg / mL, and the residual amount of H2O2 is 11.6% when the concentration of PBNPs is 0.3 mg / mL, indicating that PBNPs has good H2O2 clearance capacity, and the clearance of H2O2 is related to the concentration of PBNPs.

[0088] As shown in Figure 5 , the clearance rate of PBNPs on ·OH is weak, and the clearance rate of PBNPs on ·OH is only 14.2% and 17.0% when the concentration of PBNPs is 0.15 mg / mL and 0.3 mg / mL. It may be because the clearance capacity of PBNPs on ·OH is affected by pH, and the clearance capacity of PBNPs on ·OH is weak in PBS solution at pH 7.4. In contrast, the clearance rate of QHT hydrogel dressing on ·OH reaches 56.4%, and the clearance of QHT hydrogel dressing on ·OH is realized by electron transfer of tannic acid TA in the hydrogel dressing. The clearance rate of QHT@PBNPs-2 hydrogel dressing on ·OH reaches 69.4%, and the experimental results show that QHT@PBNPs can effectively clear ·OH.

[0089] As shown in Figure 6 , PBNPs and QHT hydrogel dressing both show ·O2- clearance capacity. The clearance rate of PBNPs on ·O2- reaches 64.1% and 74.6% when the concentration of PBNPs is 0.15 mg / mL and 0.3 mg / mL, indicating that the clearance of PBNPs on ·O2- is dependent on the concentration of PBNPs; the clearance rate of QHT hydrogel dressing on ·O 2- ​The clearance rate of ·O2- reached 83.8%, and the clearance of ·O2- was achieved by tannic acid in the QHT hydrogel dressing; the clearance rate of ·O2- reached 95.7% in the QHT@PBNPs-2 hydrogel dressing, indicating that the combination of PBNPs and QHT hydrogel dressing can effectively remove ·O2-.

[0090] As shown in Figure 7 , the clearance rate of DPPH reached 51.3% and 60.7% when the concentration of PBNPs was 0.15 mg / mL and 0.3 mg / mL, indicating that the clearance of DPPH by PBNPs was dependent on the concentration of PBNPs. In contrast, the clearance rate of DPPH by QHT hydrogel dressing was 89.1%, and the clearance rate of DPPH by QHT@PBNPs hydrogel dressing was 92%, indicating that QHT@PBNPs hydrogel dressing can effectively remove DPPH.

[0091] As shown in Figure 8 , PBNPs had poor ABTS+· clearance ability, and the clearance rate of ABTS+· was only 12.9% and 22.9% when the concentration of PBNPs was 0.15 mg / mL and 0.3 mg / mL. In contrast, the clearance rate of ABTS+· by QHT hydrogel dressing reached 100%, indicating that QHT hydrogel dressing had good ABTS+· clearance ability, and similarly, the clearance rate of ABTS+· by QHT@PBNPs hydrogel dressing also reached 100%.

[0092] The thermal conversion performance of the hydrogel dressing was determined as follows: PBNPs and QHT@PBNPs hydrogel dressing were irradiated with an 808 nm laser at different PBNPs concentrations and different power densities, and the temperature rise process and temperature rise image were recorded with a thermal imager. In addition, the photothermal stability of QHT@PBNPs hydrogel dressing was investigated by 3 on-off cycles of the laser.

[0093] The specific test results are shown in Figure 9 , Figure 9 Figure a in the figure is a temperature change graph of QHT hydrogel dressing and QHT@PBNPs hydrogel dressing containing different concentrations of PBNPs, as shown in figure a, under the condition of power density of 0.5 W / cm 2 , after 10 min of light irradiation, the temperature reached 36.2, 42.7, and 51.1°C, respectively.

[0094] b. Figure b is a statistical diagram of the temperature change of QHT@PBNPs 0.1 hydrogel dressing under different power density conditions. As shown in Figure b, the temperature of QHT@PBNPs 0.1 hydrogel dressing reached 33.3, 37.5, 47.8℃ under the power density conditions of 0.25, 0.5, 0.75 W / cm 2 ;

[0095] c. Figure c is a statistical diagram of the temperature change of QHT@PBNPs 0.1 hydrogel dressing in the process of 3 laser on-off cycles under the condition of 0.5 W / cm 2 ;

[0096] d. Figure d is a thermal imaging diagram of QHT hydrogel dressing and QHT@PBNPs hydrogel dressing containing different concentrations of PBNPs.

[0097] e. Figure e is a thermal imaging diagram of QHT@PBNPs 0.1 hydrogel dressing, which shows that the temperature rise of QHT@PBNPs 0.1 hydrogel dressing is related to the concentration of PBNPs, the light power density and the light irradiation time.

[0098] The anti-inflammatory performance of the hydrogel dressing was determined, and the experiment was divided into 5 groups: LPS group, Control group, quaternized chitosan / tannic acid hydrogel dressing grafted with phenylboronic acid (QT) group, quaternized chitosan / hyaluronic acid / tannic acid hydrogel dressing grafted with phenylboronic acid (QHT) group and QHT@PBNPs group. The specific test process is as follows: first, blow down the Raw 264.7 cells to 1 × 10 5The density of cells was inoculated into 12-well plates, and incubated with DMEM medium (containing 10% FBS) for 24 h. Then, the medium was replaced with DMEM medium (containing 10% FBS) containing 1 μg / mL of LPS for continued incubation for 12 h, and the blank control group was not added with LPS. After 12 h, the LPS-containing medium was discarded, washed with sterile PBS, and then added with 5 mg / mL of QT, QHT, and QHT@PBNPs hydrogel dressing DMEM medium for continued incubation for 24 h. Subsequently, CD16 / 32 antibody was added for blocking of non-specific proteins for 15 min, and then discarded and washed with sterile PBS. The cells were fixed with 4% paraformaldehyde for 15 min, and then the paraformaldehyde was aspirated and washed with sterile PBS, and then a membrane breaker was added for incubation for 30 min. After 30 min, the membrane breaker was aspirated and washed with sterile PBS, and then CD206-PE was added for incubation for 30 min, and finally DAPI was added for incubation for 15 min. The fluorescence staining of Raw 264.7 cells was observed using a fluorescence microscope. In addition, the levels of inflammatory-related factors IL-10, IL-6, TNF-α, and TGF-β1 representing macrophage polarization were detected by ELISA. The cell culture steps were the same as above, and after the hydrogel dressing solution was co-incubated with Raw 264.7 cells for 24 h, the cell culture medium was collected for detection of inflammatory factors. According to the steps of the ELISA kit, the concentrations of IL-10, IL-6, TNF-α, and TGF-β1 were detected.

[0099] The specific test results are shown in Figure 10 , Figure 10 Fig. a is a statistical diagram of IL-10 content, Fig. b is a statistical diagram of TGF-β1 content, Fig. c is a statistical diagram of TNF-α content, and Fig. d is a statistical diagram of IL-6 content. It can be seen that, compared with the LPS group, the TNF-α and IL-6 levels of the QHT@PBNPs group were significantly decreased, and the IL-10 and TGF-β1 levels were increased, indicating that the hydrogel dressing can inhibit the expression of pro-inflammatory factors and promote the expression of anti-inflammatory factors, and the QHT@PBNPs hydrogel dressing group has the best anti-inflammatory effect.

[0100] The hydrogel dressing was used to promote the wound healing of diabetic rats, and the experiment was divided into 5 groups: a Control group, a quaternized chitosan / tannic acid hydrogel dressing grafted with phenylboronic acid (QT) group, a quaternized chitosan / hyaluronic acid / tannic acid hydrogel dressing grafted with phenylboronic acid (QHT) group, a QHT@PBNPs group, and a QHT@PBNPs hydrogel dressing photothermal (QHT@PBNPs+L) group. The QHT@PBNPs+L group was irradiated with an 808 nm near-infrared laser (0.5 W / cm2) for 5 min, and the other groups were not irradiated. The wound healing of the diabetic rats was observed and recorded every day. 2) irradiation for 10 min, the temperature was kept at 40℃, and the light was given once a day for the first 5 days, and then once every two days. Before the operation, the hydrogel dressings of each group were sterilized, and during the operation, the Control group was not treated, and the other groups were covered with 400 μL of hydrogel dressing. Then 3M transparent dressing was covered on the wound of each rat, and sterile gauze was used for fixation. After the operation, the rats were caged and fed. The hydrogel dressing was replaced every 2-3 days, and the wound healing was recorded by taking pictures on the 0th, 3rd, 7th, 10th, and 14th days after the operation.

[0101] Specifically see Figure 11 , by Figure 11 It can be seen that the hydrogel dressing group can promote the healing of diabetic wounds, and the combination of QHT@PBNPs hydrogel dressing and mild heat stimulation can further accelerate the healing of diabetic wounds.

Claims

1. A self-repairing injectable hydrogel dressing, characterized in that, The biodegradable polymer, the polyphenol compound and the active drug are dynamically combined through borate ester bond, the active drug is a nano material with photothermal effect; the biodegradable polymer is 4-carboxyl-3-fluorine quaternary ammonium chitosan and 3-amino boronic acid hyaluronic acid; the nano material with photothermal effect includes gold nanorods, copper-sulfur nanoparticles, copper-selenium nanoparticles, Nb2C MXene nanosheets, Ti3C2 MXene nanosheets, W 18 O 49 at least one of nanorods and prussian blue nanoparticles.

2. The self-repairing injectable hydrogel dressing according to claim 1, wherein, The polyphenol compound includes at least one of caffeic acid, dopamine, rutin, veratryl alcohol, phloretin, phlorizin and tannic acid.

3. The self-repairing injectable hydrogel dressing of claim 1, wherein, The particle size of the photothermal effect nano material is 1-200 nm.

4. Process for the preparation of a self-repairing injectable hydrogel dressing according to any one of claims 1 to 3, characterized in that, When the biodegradable polymer and the polyphenol compound are crosslinked through a borate ester bond, the preparation method comprises the following steps: (1) chitosan and glacial acetic acid are dissolved in water to prepare a chitosan solution, then 2,3-epoxypropyltrimethylammonium chloride aqueous solution is added dropwise, and the reaction is carried out under heating, then centrifugation is carried out, and the supernatant is taken for purification and freeze-drying to prepare quaternary ammonium chitosan; (2) quaternary ammonium chitosan solution is prepared; 4-carboxyl-3-fluorophenyl boronic acid, NHS and EDC are dissolved in DMSO to prepare a carboxyl activation solution, the quaternary ammonium chitosan solution and the carboxyl activation solution are mixed, the pH value of the mixed solution is adjusted to weak acidity, and then the activation reaction is carried out, then dialysis and freeze-drying are carried out to prepare 4-carboxyl-3-fluorophenyl boronic acid quaternary ammonium chitosan; (3) hyaluronic acid is dissolved in PBS solution to prepare a hyaluronic acid solution, NHS and EDC are added to activate the carboxyl group, then 3-aminophenyl boronic acid is added for grafting reaction, then dialysis and freeze-drying are carried out to prepare 3-aminophenyl boronic acid hyaluronic acid; (4) 4-carboxyl-3-fluorophenyl boronic acid quaternary ammonium chitosan, 3-aminophenyl boronic acid hyaluronic acid and active drugs are dissolved to prepare a mixture solution, the mixture solution is mixed with a polyphenol compound solution, and stirring is carried out to prepare a hydrogel dressing.

5. The method of producing a self-repairing injectable hydrogel dressing as claimed in claim 4, characterized in that, In step (1), the reaction temperature is 50-60℃, the reaction time is 6-48h, the centrifugal speed is 6000-7000rpm, and the centrifugal time is 6-30min.

6. The method of producing a self-repairing injectable hydrogel dressing as claimed in claim 4, characterized in that, In step (2), the pH value of the mixed solution is 5-7, the activation reaction temperature is 20-40℃, and the activation reaction time is 1-8h.

7. The method of producing a self-repairing injectable hydrogel dressing as claimed in claim 4, characterized in that, In step (3), the pH value of the PBS solution is 5-7, the carboxyl group activation reaction time is 1-8h, and the grafting reaction time is 12-96h.

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