A self-healing hydrogel dressing and its preparation method and application

Abstract

The application discloses a self-healing hydrogel dressing. The self-healing hydrogel dressing is prepared by a freeze-thaw cycle method from polyvinyl alcohol, maltodextrin, allantoin and glycerol; the mass percentage concentration of the polyvinyl alcohol is 6-15%; the mass ratio of the maltodextrin to the polyvinyl alcohol is (0.5-2):1; and the mass ratio of the allantoin, the glycerol and hot water is 1-3:1-2:1-2. In order to obtain a mixed solution of the allantoin, the glycerol and the hot water, the glycerol is first mixed with the hot water, and then the allantoin is mixed with the glycerol and the hot water. The hydrogel dressing has a porous three-dimensional network structure, good water absorption, can absorb exudates, can provide a moist microenvironment, can reduce wound temperature and pain, and can prevent microorganisms from planting on a wound surface; in addition, the hydrogel dressing also has good self-healing performance and antibacterial effect, has a good treatment and repair effect on incised wounds, and is suitable for skin wound healing.

Description

TECHNICAL FIELD

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

[0002] Skin, as the largest organ of the human body, is the first barrier to protect the body from physical, chemical damage and microbial infection, can resist the invasion of bacteria from the outside world and maintain the stability of the internal environment of the body, when the skin is wounded, the body will undergo a series of physiological and pathological changes. Skin wound healing is divided into four stages, including hemostasis, inflammation, cell proliferation and tissue remodeling four stages. The treatment based on microenvironment reconstruction can indirectly affect the internal microenvironment of the wound by directly changing the external microenvironment of the wound, and find a more effective new solution for wound healing.

[0003] At present, a variety of wound dressings have been developed for wound care, including traditional wound dressings such as gauze, cotton and bandage, but they cannot provide a moist environment at the wound interface, and these traditional dressings are easy to adhere to the wound when dressing, which damages the regenerative tissue. The existing hydrogel dressing has poor skin fitting performance and cannot be well fitted to the moving wound, which limits the application of hydrogel dressing in wound repair.

[0004] Hydrogels with high water content and porous structure are similar to the extracellular matrix (ECM) of living organisms, and have also been widely used in wound repair, which usually provides the best structural and functional microenvironment for tissue reconstruction. Allantoin is a major metabolic intermediate found in animals and comfrey, which has the effects of keratolytic, hydration, analgesic, anti-irritation, promoting epithelial growth, anti-inflammatory, antibacterial, etc. It shows significant resistance to ulcers, acne, seborrhea and hemorrhoids. Maltodextrin is a polymer of D-glucose, mainly connected by alpha-1, 4 glycosidic bond, and a small amount of alpha-1, 6 glycosidic bond at the branch point. This polysaccharide has a high specific surface area and a porous structure. In addition, maltodextrin has a chemotactic effect on polymorphonuclear leukocytes in vitro, showing great potential to promote wound healing. Polyvinyl alcohol is a biodegradable, non-toxic, biocompatible and inexpensive hydrophilic polymer with good physical properties such as good transparency, low interfacial tension and high swelling rate. However, maltodextrin has high solubility in water, and this polysaccharide cannot form hydrogel alone, which limits its use as a wound dressing alone. During the preparation of polyvinyl alcohol, most of them will add initiators, crosslinking agents, stabilizers and unreacted monomers, etc. If they penetrate into biological tissues, they may poison host cells, which will limit the application of hydrogel in wound dressings.

[0005] Therefore, it is a technical problem to be solved to develop a multifunctional dressing with simple preparation method, non-toxic and low cost, which has good adhesion, self-healing, antibacterial performance, and can effectively regulate the biological activity in the wound microenvironment to prevent bacterial infection. SUMMARY

[0006] In view of the above technical problems, the primary purpose of the present application is a self-healing hydrogel dressing, which does not contain toxic chemical crosslinking agents, initiators and other components, and has good biocompatibility. In addition, the self-healing hydrogel dressing has a porous three-dimensional network structure, good water absorption, excellent self-healing performance, good antibacterial performance and wound repair ability.

[0007] The second purpose of the present application is to provide a preparation method of the self-healing hydrogel dressing.

[0008] The third purpose of the present application is to provide the application of the self-healing hydrogel dressing in wound repair.

[0009] In order to achieve the above purposes, the present application is realized by the following technical solutions:

[0010] The self-healing hydrogel dressing is prepared by a freeze-thaw cycle method from polyvinyl alcohol, maltodextrin, allantoin and glycerol; the mass percentage concentration of the polyvinyl alcohol is 6-15%, the mass ratio of the maltodextrin to the polyvinyl alcohol is (0.5-2):1; and the mass ratio of the allantoin, glycerol and hot water is 1-3:1-2:1-2.

[0011] The self-healing hydrogel dressing mainly comprises polyvinyl alcohol, maltodextrin and allantoin, and the inventor has found through experiments that when the mass percentage concentration of the polyvinyl alcohol is within the above range, a self-healing hydrogel dressing with good mechanical properties can be prepared, and it is difficult to form a hydrogel using polyvinyl alcohol with a concentration lower than the above range. In addition, the inventor has further found that in the hydrogel dressing system of the present application, the maltodextrin serves as a flexible chain and the polyvinyl alcohol serves as a rigid chain, and when the mass ratio of the maltodextrin to the polyvinyl alcohol is too low, the tensile strength and flexibility of the prepared hydrogel will decrease; and when the mass ratio of the maltodextrin to the polyvinyl alcohol is too high, it is difficult to form a hydrogel. Further, the inventor has found that the maltodextrin has freeze-thaw cycle stability, and using the freeze-thaw cycle method can enhance the stability of functional substances, promote the proliferation of fibroblasts, and has little damage to the matrix structure of the hydrogel dressing and therapeutic compounds. Through the above process control, the inventor has successfully prepared a self-healing hydrogel dressing which has a porous three-dimensional network structure, good water absorption, excellent self-healing performance, good antibacterial performance and wound repair capacity.

[0012] Preferably, the mass percentage concentration of the polyvinyl alcohol is 10-15%.

[0013] Preferably, the viscosity of the polyvinyl alcohol is 20-30 mPa.s, and the alcoholysis degree of the polyvinyl alcohol is 98-99 mol%.

[0014] Preferably, the DE value of the maltodextrin is 15-20.

[0015] Preferably, the mass percentage concentration of the maltodextrin is 5-15%.

[0016] Preferably, the mass ratio of the allantoin to the polyvinyl alcohol is (0.1-25):1.

[0017] Further, the present application also claims a preparation method of the self-healing hydrogel dressing, comprising the following steps:

[0018] S1. mixing a maltodextrin aqueous solution and a polyvinyl alcohol aqueous solution, stirring to obtain a mixed solution A;

[0019] S2. Mixing allantoin, glycerol and hot water, adding to the mixed solution A, stirring, defoaming treatment and freeze-thaw cycle to prepare the self-healing hydrogel dressing.

[0020] Preferably, the temperature during stirring in the step S1 and the step S2 is 85-95℃.

[0021] Preferably, the stirring time of the aqueous maltodextrin solution and the aqueous polyvinyl alcohol solution in the step S1 is 1-3h.

[0022] Preferably, the preparation method of the aqueous maltodextrin solution is mixing maltodextrin and ultrapure water, stirring at room temperature for 5-20min to make it completely dissolved, and the aqueous maltodextrin solution is obtained.

[0023] Preferably, the preparation method of the aqueous polyvinyl alcohol solution is mixing polyvinyl alcohol and ultrapure water, stirring for 1-3h to make it completely dissolved, and then placing at room temperature, and then defoaming treatment by ultrasonic, and the aqueous polyvinyl alcohol solution is obtained.

[0024] Preferably, in order to better obtain the mixed solution of allantoin, glycerol and hot water, glycerol and hot water can be mixed first, and then mixed with allantoin.

[0025] Preferably, in the step S2, ultrasonic is used for defoaming treatment, and the defoaming treatment time is 5-30min.

[0026] More specifically, the freeze-thaw cycle treatment is freezing the solution after defoaming treatment in the step S2, thawing, and repeating the freezing-thawing cycle for multiple times.

[0027] Preferably, in the freeze-thaw cycle, the freezing temperature is-20--80℃, and the freezing time is 16-20h.

[0028] Preferably, in the freeze-thaw cycle, thawing is carried out at room temperature, and the thawing time is 4-8h.

[0029] Preferably, in the freeze-thaw cycle, the freezing-thawing cycle is repeated for 3-5 times.

[0030] Compared with the prior art, the present application has the following beneficial effects:

[0031] (1) The self-healing hydrogel dressing for simulating extracellular matrix is provided, which uses allantoin as an antibacterial and anti-inflammatory functional component and is compatible with maltodextrin having a fibroblast proliferation effect, has a porous three-dimensional network structure, has good water absorption, can absorb exudate, can provide a moist microenvironment, reduces wound temperature and pain, and can prevent microorganisms from colonizing on the wound surface; in addition, the hydrogel dressing has good self-healing performance and antibacterial effect, has good treatment and repair effect on incised wounds, and is suitable for skin wound healing.

[0032] (2) The hydrogel dressing is prepared by using freeze-thaw cycle technology, the method is simple, the damage to the matrix structure and therapeutic compounds is small, and the problems of complexity of chemical cross-linking method and potential toxicity of additives such as cross-linking agents can be effectively solved. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 SEM image of the self-healing hydrogel dressing prepared in Example 4.

[0034] Figure 2 Infrared spectrum of the self-healing hydrogel dressing prepared in Examples 1-4, and polyvinyl alcohol powder, maltodextrin powder, and allantoin powder.

[0035] Figure 3 Self-healing performance display of the self-healing hydrogel dressing prepared in Example 4.

[0036] Figure 4 Display of the skin adhesion of the self-healing hydrogel dressing prepared in Example 4.

[0037] Figure 5 Bacteriostatic test result graph of the hydrogel dressing prepared in Example 8.

[0038] Figure 6 Wound healing of each treatment group at 0d, 3d, and 7d.

[0039] Figure 7 Wound healing rate diagram of the blank group and the AL-MP hydrogel treatment group at 3d and 7d. DETAILED DESCRIPTION

[0040] The present application will be further described below in conjunction with the drawings and specific examples, but the examples do not limit the present application in any form. Unless otherwise specified, the reagents, methods, and devices used in the present application are conventional reagents, methods, and devices in the technical field.

[0041] Example 1 Preparation of self-healing hydrogel dressing

[0042] (1) 5 g maltodextrin was dissolved in ultrapure water, stirred for 10 min, and 5 wt% maltodextrin solution (DE value of maltodextrin was 15-20) was prepared;

[0043] (2) 10 g polyvinyl alcohol was dissolved in ultrapure water, stirred for 1.5 h, and after standing at room temperature, ultrasonic defoaming treatment was performed for 15 min, and 10 wt% polyvinyl alcohol solution (alcoholysis degree of polyvinyl alcohol was 98-99 mol%, and viscosity of polyvinyl alcohol was 20-30 mPa.s) was prepared;

[0044] (3) After the maltodextrin solution and the polyvinyl alcohol solution were mixed according to a mass ratio of 1:1, stirring was performed for 1.5 h, and a mixed solution A was obtained;

[0045] (4) Glycerol was mixed with hot water at a mass ratio of 1:1 to obtain a glycerol solution; allantoin was mixed with the glycerol solution at a mass ratio of 1:1, stirred for 0.5 h, and an allantoin solution was obtained;

[0046] (5) The allantoin solution was mixed with the mixed solution A at a mass ratio of 1:2, stirred uniformly at 90°C, and a mixed solution B was obtained, followed by defoaming treatment;

[0047] (6) The mixed solution B was poured into a mold, placed in a refrigerator, and frozen at -20°C for 18 h; then the sample was taken out, thawed at room temperature for 6 h, and the freezing-thawing cycle was repeated for 3 times to obtain a self-healing hydrogel dressing.

[0048] Preparation of a self-healing hydrogel dressing in Example 2

[0049] The difference between this example and Example 1 is that in step (1), 10 wt% maltodextrin solution was prepared.

[0050] Preparation of a self-healing hydrogel dressing in Example 3

[0051] The difference between this example and Example 1 is that in step (1), 15 wt% maltodextrin solution was prepared.

[0052] Preparation of a self-healing hydrogel dressing in Example 4

[0053] The difference between this example and Example 1 is that in step (1), 15 wt% maltodextrin solution was prepared; 15 wt% polyvinyl alcohol solution was prepared; and in step (5), the allantoin solution was mixed with the mixed solution A at a mass ratio of 1:3.

[0054] Preparation of a self-healing hydrogel dressing in Example 5

[0055] The difference between this example and Example 1 is that in step (1), a 15wt% maltodextrin solution is prepared; a 15wt% polyvinyl alcohol solution is prepared; in step (4), the allantoin solution is mixed with the glycerol solution at a mass ratio of 1:2; in step (5), the allantoin solution is mixed with mixed solution A at a mass ratio of 1:5.

[0056] Preparation of a self-healing hydrogel dressing

[0057] The difference between this example and Example 1 is that in step (1), a 15wt% maltodextrin solution is prepared; a 15wt% polyvinyl alcohol solution is prepared; in step (4), the allantoin solution is mixed with the glycerol solution at a mass ratio of 1:2; in step (5), the allantoin solution is mixed with mixed solution A at a mass ratio of 1:5.

[0058] Preparation of a self-healing hydrogel dressing

[0059] The difference between this example and Example 1 is that in step (1), a 12wt% maltodextrin solution is prepared; a 6wt% polyvinyl alcohol solution is prepared.

[0060] Preparation of a self-healing hydrogel dressing

[0061] The difference between this example and Example 1 is that in step (5), the allantoin solution is mixed with mixed solution A at a mass ratio of 1:7.5.

[0062] Comparative Example 1

[0063] The difference between this example and Example 1 is that in step (1), a 15wt% polyvinyl alcohol solution is prepared; in step (5), the allantoin solution is mixed with mixed solution A at a mass ratio of 1:3.

[0064] Comparative Example 2

[0065] The difference between this example and Example 1 is that in step (1), a 10wt% maltodextrin solution is prepared; a 5wt% polyvinyl alcohol solution is prepared; in step (5), the allantoin solution is mixed with mixed solution A at a mass ratio of 1:3.

[0066] Characterization of a self-healing hydrogel dressing

[0067] The self-healing hydrogel dressing prepared in Example 4 was subjected to scanning electron microscopy testing, Figure 1 The SEM image of the self-healing hydrogel dressing prepared in Example 4 is shown in Figure 1. Figure 1 As can be seen, the self-healing hydrogel dressing prepared in Example 4 exhibits a porous three-dimensional network structure, which can effectively absorb wound exudate.

[0068] The self-healing hydrogel dressings prepared in Examples 1-4 were freeze-dried for 48 hours and then subjected to infrared spectroscopy tests using polyvinyl alcohol powder, maltodextrin powder, and allantoin powder. Figure 2 Infrared spectra of the self-healing hydrogel dressings prepared in Examples 1-4, and of polyvinyl alcohol, maltodextrin, and allantoin (Figures 1-4 represent the infrared spectra of the hydrogel dressings prepared in Examples 1, 2, 3, and 4, respectively; PVA is polyvinyl alcohol, MD is maltodextrin, and AL is allantoin). Figure 2 Infrared analysis revealed that in the allantoin infrared spectrum, 1780 cm⁻¹ -1 and 1650cm -1 The absorption peak at 1420 cm⁻¹ is attributed to the characteristic peaks of the carbonyl group (-C=O) on the ring and in the amide; in the infrared spectrum of polyvinyl alcohol, the peak at 1420 cm⁻¹ is... -1 The absorption peak at 3290 cm⁻¹ is attributed to the characteristic peak of the CH₂ special bending vibration mode of polyvinyl alcohol; -1 The absorption peak at 1002 cm⁻¹ is attributed to the -OH stretching vibration mode of polyvinyl alcohol; in the infrared spectrum of maltodextrin, the peak at 1002 cm⁻¹ is... -1 The absorption peak at that location is attributed to the characteristic peak of CO stretching vibration in maltodextrin. As can be seen from the infrared spectra of Examples 1, 2, 3, and 4, no characteristic peaks of new groups appeared, indicating that the hydrogel was formed through physical cross-linking.

[0069] Test Example 2: Self-healing test of self-healing hydrogel dressing

[0070] The self-healing hydrogel dressing prepared in Example 4 was cut into two pieces, 1 and 2, and then spliced ​​together. It was stored in a sealed container at room temperature, and the healing was observed with the naked eye after a period of time.

[0071] Figure 3 This image illustrates the self-healing properties of the self-healing hydrogel dressing prepared in Example 4. Figure 3 It can be seen that after 24 hours of splicing, the two separate pieces of hydrogel prepared in Example 4 healed together, the crack was almost completely healed, and it did not break when stretched, indicating that the hydrogel has a certain strength and has good self-healing properties after the split-bond process. The inventors speculate that the reason is that there are a large number of reversible hydrogen bonds inside the hydrogel. The hydrogen bonds at the cut and spliced ​​points re-bond, the cross-linked network is restored, and the damage is finally repaired.

[0072] Test Example 3: Adhesion Performance Test of Self-Healing Hydrogel Dressing

[0073] The bending experiment was used to investigate whether the hydrogel dressing could conform to the contour and morphology of the skin surface under dynamic conditions. The specific steps were as follows: the self-healing hydrogel dressing prepared in Example 4 was attached to the knuckle of the index finger, and the bending of the finger was repeated for 10 times. The conformability between the hydrogel dressing and the finger was photographed during the bending process.

[0074] Figure 4 The display diagram of the skin conformability of the self-healing hydrogel dressing prepared in Example 4 is shown in FIG. 4. Figure 4 It can be seen that the prepared hydrogel dressing can adapt to the moving wound. During the bending process of the finger, the hydrogel dressing still conforms well to the skin.

[0075] Example 4: Antibacterial test of the self-healing hydrogel dressing

[0076] Preparation of bacterial solution: 100 μL of bacteria suspension in a resting state was inoculated into 10 mL of LB medium for recovery, and cultured at 37°C in a constant temperature shaker for 12 hours. After 1% transfer, it was also cultured under the same conditions for 12 hours. In order to ensure the consistency of the bacterial concentration, the OD value of the bacteria was measured by using an enzyme marker. A certain amount of Staphylococcus aureus (ATCC 25923) was taken in a sterile test tube, a certain amount of PBS was added, 3-5 appropriate dilutions were selected, 10-fold gradient dilution was performed, 100 μL of bacteria from each centrifugal tube after dilution was taken into a 96-well plate, 3 parallel samples were taken for each sample, and the OD value was measured at 595 nm by using an enzyme marker. Two kinds of bacterial solution with a concentration of 10 8 CFU·mL -1 were diluted with PBS to a concentration of 10 6 CFU·mL -1 (OD value is 0.1, which represents a bacterial concentration of 10 8 CFU·mL -1 ).

[0077] Bacteriostatic circle experiment: 100 μL of bacterial suspension (10 6 CFU·ml -1 ) was added to the LB agar plate and evenly dispersed. Then the water gel dressing sample disc prepared in Example 8 (sterilized under ultraviolet for 30 min) was placed in the LB agar plate, and then the plate was sealed with a sealing film, and cultured in a biochemical incubator at 37°C for 12-24 h. Finally, the sample bacteriostatic circle diameter was observed and recorded, and a circular filter paper was used as a control.

[0078] Figure 5 The bacteriostatic test result diagram of the hydrogel dressing prepared in Example 8 is shown in FIG. 6. Figure 5It can be seen that the red circle is a circular filter paper without obvious inhibition zone, the red circle is its own size (8.58 mm), and the diameter of the inhibition zone formed by the AL-MPA hydrogel is represented by the blue circle, which is 9.46 mm, wherein the red circle is the size of the hydrogel itself, and it can be seen that the hydrogel dressing provided by the application has good antibacterial effect.

[0079] Test Example 5: Test of wound repair performance of self-healing hydrogel dressing

[0080] The male SD rats were weighed one by one, and after being anesthetized by intraperitoneal injection of 10% chloral hydrate solution (3 mL / kg), the rats were placed on the operation board in a prone position, the hair on the back of the rats was shaved, the skin was disinfected with 75% alcohol disinfectant, and a full-thickness skin defect wound was made on the back, the skin that was not completely cut was cut to a depth of subcutaneous tissue using surgical scissors without damaging the fascia and adipose tissue (to ensure that the skin in the wound area is in a natural relaxed state). After modeling, the wound was washed with normal saline, and the SD rats were randomly divided into 3 groups (normal saline treatment group, AL-MP hydrogel treatment group (using the hydrogel dressing prepared in Example 4)), and single-cage feeding was performed after treatment. The hydrogel dressing was replaced once a day, and the wound healing was recorded by taking pictures at the predetermined time points (0d, 3d, 7d).

[0081] Figure 6 The wound healing of each treatment group at 0d, 3d, 7d. Figure 7 The wound healing rate of the blank group and the AL-MP hydrogel treatment group at 3d, 7d is shown in the schematic diagram. Figure 6 and Figure 7 It can be clearly observed that in the 7 days after the operation, the healing rate of the AL-MP hydrogel treatment group is obviously faster than that of the normal saline group. At the seventh day, the wound healing effect of the AL-MP hydrogel treatment group is better, and the wound healing rate reaches 80.9%, while the control group is only 44.8%.

[0082] The foregoing examples are merely illustrative, for explaining some features of the method described in the application. The appended claims aim to require as wide a range as possible, and the examples presented herein are demonstrated by the real test results of the applicant. Therefore, the intention of the applicant is that the appended claims are not limited by the selection of examples illustrating the features of the application. Some numerical ranges used in the claims also include sub-ranges within them, and the variations in these ranges should also be interpreted as covered by the appended claims, if possible.

Claims

1. A self-healing hydrogel dressing, characterized in that, The self-healing hydrogel dressing is prepared by a freeze-thaw cycle method from polyvinyl alcohol, maltodextrin, allantoin and glycerol; the mass percentage concentration of the polyvinyl alcohol is 15%; The preparation method of the self-healing hydrogel dressing comprises the following steps: S1. mixing a maltodextrin aqueous solution and a polyvinyl alcohol aqueous solution according to a mass ratio of 1:1, stirring to obtain a mixed solution A; S2. mixing glycerol and hot water according to a mass ratio of 1:1, then mixing with allantoin according to a mass ratio of 1:1, then adding into the mixed solution A according to a mass ratio of 1:3, stirring, defoaming treatment and freeze-thaw cycle to prepare the self-healing hydrogel dressing; The viscosity of the polyvinyl alcohol is 20-30 mPa.s, the alcoholysis degree of the polyvinyl alcohol is 98-99 mol%, the DE value of the maltodextrin is 15-20, and the mass percentage concentration of the maltodextrin is 15%.

2. The self-healing hydrogel dressing according to claim 1, wherein, In the freeze-thaw cycle, the freezing temperature is -20 to -80℃, and the freezing time is 16-20 h.

3. The self-healing hydrogel dressing according to claim 1, wherein, In the freeze-thaw cycle, the freezing-thawing cycle number is 3-5 times.

4. Use of the self-healing hydrogel dressing according to any one of claims 1-3 in the preparation of a hydrogel dressing with wound repair effect.

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