Sterile medical wound repair hydrogel dressing and application thereof

Abstract

The invention belongs to the technical field of medical biological material preparation, and particularly relates to a sterile medical wound repair hydrogel dressing which takes dual-modified hyaluronic acid, polyvinyl alcohol, nano zinc, a humectant and a lubricant as main raw materials. The preparation method comprises the following steps: firstly, utilizing dual-modified hyaluronic acid as a core skeleton of a hydrogel system, and jointly constructing a double-layer network structure through free radical polymerization and crosslinking of boric acid ester bonds and carbon-carbon double bonds formed between phenylboronic acid groups and polyvinyl alcohol; meanwhile, polyvinyl alcohol and zinc ions form coordinate bonds which are interpenetrated in a network, so that the hydrogel dressing with a triple network structure is formed. The unique network structure can simulate an extracellular matrix microenvironment and is beneficial to promoting cell proliferation. In the using process, the hydrogel dressing can play a role in integrating multiple functions. Firstly, the hydrogel dressing can be attached to the surface of the skin to form a breathable physical barrier, meanwhile, invasion of bacteria is effectively isolated, secondly, moisture of the skin can be supplemented through the moisturizing performance of the hydrogel dressing, and due to the flexibility and elasticity of the hydrogel dressing, the use comfort of the hydrogel dressing is further improved, and painless dressing change is achieved. More importantly, long-acting release of the zinc ions can inhibit bacterial infection at the wound, promote wound repair and accelerate wound healing.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of medical biomaterials, and specifically refers to a sterile medical wound repair hydrogel dressing that isolates bacterial invasion, reduces wound load, promotes cell proliferation, and accelerates wound healing, and its application. Background Art

[0002] Wound care after surgical suture is an important issue that cannot be ignored in medical practice. Once the postoperative wound becomes infected, it will not only seriously hinder the patient's recovery process and increase the economic burden, but may also endanger the patient's life safety in severe cases. The manifestations of postoperative wound infection are diverse, and common conditions include suture dehiscence, wound swelling, pus exudation, bacterial infection, and wound ulceration, etc. At present, for postoperative wound care, the main measures taken include wound cleaning, isolation from external environmental stimuli, regular dressing change, prevention of infection, and so on. In this process, traditional dressings such as gauze and bandage have been widely used in clinical practice for a long time due to their simple production and basic protection functions. However, these traditional dressings have obvious limitations. For example, it is difficult to effectively isolate bacterial invasion, the air permeability is poor, which easily leads to local hypoxia of the wound, and it is easy to adhere to the skin, making the dressing change process cause tearing of the wound, thus being unfavorable for wound healing.

[0003] With the continuous progress of technology, the research and development of new dressings emerge in an endless stream, bringing new solutions to the field of wound repair. Among them, film dressings are convenient to use during wound care and have excellent sealing properties, which can effectively block the interference of the external environment. However, their insufficient ability to absorb exudate limits their application in some cases. In contrast, hydrogel dressings have become a hot spot in the field of skin repair in recent years due to their excellent biocompatibility, moisturizing property, and biodegradability. Hydrogel dressings can not only reduce the pressure on the wound, are painless and residue-free during dressing change, but their unique network structure can also promote the exchange of nutrients, simulate the extracellular matrix microenvironment, and provide an ideal growth environment for cell growth. However, the existing hydrogel dressings still need to improve their antibacterial performance. Therefore, it is particularly important to optimize the design according to the characteristics of their components and develop hydrogel dressings suitable for postoperative wound repair.

[0004] Therefore, the present invention designs a hydrogel dressing with the ability to absorb exudate, reduce wound load, ensure painless and residue-free dressing change, long-term antibacterial, supplement nutrition, and promote cell proliferation, so as to effectively improve the postoperative wound care situation, accelerate the wound healing process, and significantly enhance the wound repair effect and the patient's quality of life. Summary of the Invention

[0005] The present invention provides a sterile medical wound repair hydrogel dressing and a preparation method thereof in view of the above-mentioned needs for wound repair after surgery. In the present invention, a phenylboronic acid group and a carbon-carbon double bond are successively introduced onto a hyaluronic acid molecule, and crosslinked with polyvinyl alcohol to form a first network structure. Then, a second network is formed through a coordination bond between polyvinyl alcohol and nano-zinc, wherein the addition of zinc significantly enhances the antibacterial performance of the hydrogel dressing. In order to further improve the moisturizing performance and flexibility of the dressing, a moisturizer and a lubricant are also specifically added. Finally, under ultraviolet light irradiation, through the action of a photo-crosslinking agent, a hydrogel dressing with a triple network structure is formed. While maintaining excellent performance, the hydrogel dressing provides more comprehensive and efficient care for wound repair.

[0006] The mass concentration of the hydrogel dressing composition is as follows: double-modified hyaluronic acid 5 mg / mL to 30 mg / mL, polyvinyl alcohol 10 mg / mL to 50 mg / mL, nano-zinc 5 mg / mL to 20 mg / mL, moisturizer 10 mg / mL to 50 mg / mL, lubricant 10 mg / mL to 50 mg / mL, photo-crosslinking agent 0.1 mg / mL to 0.5 mg / mL.

[0007] Preferably, the moisturizer is glycerol or butanediol.

[0008] Preferably, the lubricant is polydimethylsiloxane.

[0009] Preferably, the photo-crosslinking agent is I2959.

[0010] Preferably, the mass concentration in the hydrogel dressing is double-modified hyaluronic acid 10 mg / mL, polyvinyl alcohol 30 mg / mL, nano-zinc 5 mg / mL, glycerol 20 mg / mL, butanediol 20 mg / mL, polydimethylsiloxane 20 mg / mL, I2959 0.2 mg / mL.

[0011] A preparation method of the sterile medical wound repair hydrogel dressing as described above specifically includes the following steps:

[0012] Step 1: First, add hyaluronic acid to 2-(N-morpholino)ethanesulfonic acid buffer solution and stir until completely dissolved under the action of a magnetic stirrer. Subsequently, under light-shielded conditions, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, and 3-aminophenylboronic acid in sequence. After thorough mixing, react for 24 hours. After the reaction is completed, use a dialysis bag to dialyze the reaction mixture to remove unreacted components. After dialysis is completed, freeze-dry the solution to obtain phenylboronic acid-modified hyaluronic acid. Then, add phenylboronic acid-modified hyaluronic acid to phosphate buffer solution and stir with a magnetic stirrer until completely dissolved. Under ice bath conditions, slowly drop methacrylic anhydride into the above solution while continuously stirring until thoroughly mixed. Then, use 5 mol / L sodium hydroxide solution to adjust the pH value of the reaction mixture to 8.5 and react for 24 hours in a light-shielded environment. After the reaction is completed, perform dialysis and freeze-drying treatments to finally obtain double-modified hyaluronic acid modified with phenylboronic acid groups and carbon-carbon double bonds.

[0013] Step 2: Dissolve the double-modified hyaluronic acid in purified water, then add glycerol, butanediol, and nano-zinc, stir thoroughly and load into syringe A. Heat and dissolve polyvinyl alcohol, polydimethylsiloxane, and I2959 and load into syringe B. Finally, inject them into a customized mold for preliminary shaping. After the mixed solution is allowed to stand for 5 minutes, crosslink it under ultraviolet light irradiation to finally form a hydrogel dressing.

[0014] Preferably, the diameter size range of the hydrogel dressing is 1 cm - 10 cm, and hydrogel dressings with different diameters can be selected and applied accordingly according to the size of the wound.

[0015] The composition of the present invention is described as follows:

[0016] The double-modified hyaluronic acid refers to introducing phenylboronic acid groups and carbon-carbon double bonds onto the hyaluronic acid molecule through a chemical reaction. On the basis of retaining the excellent biocompatibility, biodegradability, and moisturizing property of hyaluronic acid, diverse functional characteristics are achieved through different chemical modifications. During the formation of the hydrogel network, the grafting of carbon-carbon double bonds can form a stable network structure through photo-crosslinking. At the same time, by controlling the grafting degree, the structure and properties of the hydrogel can be adjusted. The introduction of phenylboronic acid groups not only enhances the interaction between the hydrogel and cells but also endows the hydrogel with a unique dynamic bond crosslinking ability, enabling it to respond to external stimuli.

[0017] Polyvinyl alcohol is a water-soluble polymer with excellent biocompatibility, bioadhesion, and thermal stability. Polyvinyl alcohol is rich in a large number of hydroxyl groups, and these hydroxyl groups can form a network structure through hydrogen bonding interactions. In addition, polyvinyl alcohol can also form a more stable and durable network structure with other materials through chemical crosslinking, further enhancing its application performance.

[0018] Nano zinc is a nano-scale metal ion with high activity and low toxicity. Compared with ordinary zinc ions, nano zinc has a larger specific surface area and better dispersibility. This characteristic greatly improves the bioavailability of zinc and promotes its effective absorption and uniform distribution in the body. In addition, nano zinc can be safely degraded and removed step by step in the body, effectively reducing the potential risks caused by long-term accumulation. More importantly, nano zinc also has excellent antibacterial properties and can promote cell proliferation and migration, which helps wound healing.

[0019] Glycerol is a mild and non-toxic polyol compound. With its unique polyhydroxyl structure, it can form hydrogen bonds with water molecules, thus effectively locking in moisture. During the preparation of hydrogels, adding glycerol can significantly improve its moisture retention and softness. The presence of glycerol can not only increase the skin's water reserve but also effectively prevent skin dryness.

[0020] Butanediol is an organic compound with both moisture retention and permeability. Adding butanediol to the hydrogel can not only effectively adjust the viscosity of the hydrogel, enhance its adhesion and lubricity, but also its excellent solubility can promote the dissolution of different substances, helping to maintain the homogeneity and stability of the hydrogel system.

[0021] Polydimethylsiloxane is a silicone-based polymer with unique physical and chemical properties. The presence of polydimethylsiloxane can improve the plasticity of the hydrogel, making it easier to mold and maintain its shape. At the same time, it can also enhance the flexibility and ductility of the hydrogel to meet different application requirements.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] The present invention provides a preparation method and application of a triple-network hydrogel dressing for postoperative wound repair. The hydrogel dressing is double-modified by grafting phenylboronic acid groups and carbon-carbon double bonds onto hyaluronic acid molecules. This double-modified hyaluronic acid can not only form a stable network structure but also enhance the interaction with cells. As the core framework of the hydrogel system, the double-modified hyaluronic acid forms a bilayer network structure through borate ester bonds between phenylboronic acid groups and hydroxyl groups of polyvinyl alcohol and free radical polymerization cross-linking of carbon-carbon double bonds. Then, the coordination bonds between polyvinyl alcohol and zinc ions interpenetrate in the network to further form a triple-network structure. This unique triple-network structure effectively promotes the exchange of nutrients, simulates the microenvironment of the extracellular matrix, and provides ideal conditions for cell growth. In addition, nano-zinc exhibits excellent antibacterial properties and the ability to promote cell proliferation. The presence of glycerol and butanediol improves the moisture retention of the hydrogel dressing, while polydimethylsiloxane can also improve the flexibility of the hydrogel. During use, the hydrogel dressing can adhere to the skin surface, effectively isolate external pollution, inhibit the growth of bacteria, and promote wound healing. Generally speaking, the hydrogel dressing described in the present invention has excellent biocompatibility, moisture retention, flexibility, and antibacterial properties, can absorb exudate, reduce wound load, achieve painless dressing change, promote cell proliferation, and accelerate the wound healing process. Description of the Drawings

[0024] Figure 1 The antibacterial results of the hydrogels of Example 1, Example 3 and Comparative Example 3 after co-incubation with Escherichia coli for 24 hours.

[0025] Figure 2 The antibacterial results of the hydrogels of Example 1, Example 3 and Comparative Example 3 after co-incubation with Staphylococcus aureus for 24 hours.

[0026] Figure 3 The plate coating results of the hydrogels of Example 1, Example 3 and Comparative Example 3 after co-incubation with bacteria for 5 hours.

[0027] Figure 4 The effects of the hydrogels of Example 1, Example 3 and Comparative Example 3 on cell proliferation ability.

[0028] Figure 5 The live / dead cell staining results of the hydrogels of Example 1, Example 3 and Comparative Example 3. Detailed Embodiments

[0029] The present invention will be further described in conjunction with specific embodiments. It should be clear that the embodiments of the present invention are not limited thereto.

[0030] Example 1

[0031] Weigh 100 mg of double-modified hyaluronic acid and dissolve it in 10 mL of purified water. Then add 200 mg of glycerol, 200 mg of butanediol, and 50 mg of nano-zinc, mix well, and load it into syringe A. Weigh 300 mg of polyvinyl alcohol, 200 mg of polydimethylsiloxane, and 2 mg of I2959, heat and dissolve them, and load them into syringe B. Finally, inject them into a customized mold respectively for preliminary shaping. After the mixed solution stands for 5 minutes, crosslinking is carried out under ultraviolet light to form a hydrogel dressing.

[0032] Example 2

[0033] Weigh 300 mg of double-modified hyaluronic acid and dissolve it in 10 mL of purified water. Then add 200 mg of glycerol, 200 mg of butanediol, and 50 mg of nano-zinc, mix well, and load it into syringe A. Weigh 300 mg of polyvinyl alcohol, 200 mg of polydimethylsiloxane, and 2 mg of I2959, heat and dissolve them, and load them into syringe B. Finally, inject them into a customized mold respectively for preliminary shaping. After the mixed solution stands for 5 minutes, crosslinking is carried out under ultraviolet light to form a hydrogel dressing. The difference from Example 1 is that the dosage of double-modified hyaluronic acid is changed to 300 mg.

[0034] Example 3

[0035] Weigh 100 mg of double-modified hyaluronic acid and dissolve it in 10 mL of purified water. Then add 200 mg of glycerol, 200 mg of butanediol, and 100 mg of nano-zinc, mix well, and load it into syringe A. Weigh 300 mg of polyvinyl alcohol, 200 mg of polydimethylsiloxane, and 2 mg of I2959, heat and dissolve them, and load them into syringe B. Finally, inject them into a customized mold respectively for preliminary shaping. After the mixed solution stands for 5 minutes, crosslinking is carried out under ultraviolet light to form a hydrogel dressing. The difference from Example 1 is that the dosage of nano-zinc is changed to 100 mg.

[0036] Comparative Example 1

[0037] Weigh 100 mg of carbon-carbon double bond-modified hyaluronic acid and dissolve it in 10 mL of purified water. Then add 200 mg of glycerol, 200 mg of butanediol, and 50 mg of nano-zinc, mix well, and load it into syringe A. Weigh 300 mg of polyvinyl alcohol, 200 mg of polydimethylsiloxane, and 2 mg of I2959, heat and dissolve them, and load them into syringe B. Finally, inject them into a customized mold respectively for preliminary shaping. After the mixed solution stands for 5 minutes, crosslinking is carried out under ultraviolet light to form a hydrogel dressing. The difference from Example 1 is that double-modified hyaluronic acid is changed to carbon-carbon double bond-modified hyaluronic acid.

[0038] Comparative Example 2

[0039] Weigh 100 mg of hyaluronic acid modified with phenylboronic acid groups and dissolve it in 10 mL of purified water. Then add 200 mg of glycerol, 200 mg of butanediol, and 50 mg of nano-zinc, mix well, and load it into syringe A. Weigh 300 mg of polyvinyl alcohol and 200 mg of polydimethylsiloxane, heat and dissolve them, and load them into syringe B. Finally, inject them into a customized mold respectively to crosslink and form a hydrogel dressing. The difference from Example 1 is that the double-modified hyaluronic acid is changed to hyaluronic acid modified with phenylboronic acid groups, and there is no need to crosslink and form under ultraviolet light.

[0040] Comparative Example 3

[0041] Weigh 100 mg of double-modified hyaluronic acid and dissolve it in 10 mL of purified water. Then add 200 mg of glycerol and 200 mg of butanediol, mix well, and load it into syringe A. Weigh 300 mg of polyvinyl alcohol, 200 mg of polydimethylsiloxane, and 2 mg of I2959, heat and dissolve them, and load them into syringe B. Finally, inject them into a customized mold respectively for preliminary forming. After the mixed solution stands for 5 minutes, crosslink it under ultraviolet light to form a hydrogel dressing. The difference from Example 1 is that nano-zinc is not added.

[0042] For the performance evaluation of the hydrogel dressing of the present invention, taking the hydrogel dressing described in the examples as the research object, the specific experimental conditions are as follows: 1. Swelling performance test

[0043] The hydrogel dressings with a diameter of 1 cm prepared in Examples 1-3 and Comparative Examples 1-3 were respectively immersed in phosphate buffer solution, and the swelling performance test was carried out at 37 °C. After 12 hours, take out the hydrogel dressings of each group for weighing, and calculate the swelling rate of the hydrogel dressings.

[0044] Experimental results: The test results are shown in Table 1. The swelling rate of the hydrogel in the examples is between 20.2% and 25.7%, while the swelling rates of Comparative Examples 1 and 2 are significantly higher than those of the examples. The reason for this phenomenon is that the hydrogel dressing described in the examples has a dense triple network structure that can reduce swelling, that is, the hydrogel dressing can absorb wound exudate while avoiding excessive absorption of exudate causing wound compression. The network structure of the single-modified hyaluronic acid in Comparative Examples 1 and 2 has larger pores and a looser structure, so its water absorption ability is significant and the swelling rate is higher. In contrast, in Comparative Example 3, due to the presence of borate bonds and carbon-carbon double bonds, a more stable and denser network structure is formed, and its swelling rate also becomes lower.

[0045] Table 1 Swelling rates of hydrogel dressings in each group

[0046] Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Swelling ratio (%) 25.7％±2.60 20.2％±1.65 25.1％±2.04 50.5％±2.30 63.7％±1.56 28.3％±2.07

[0047] 2. Use feeling test

[0048] In this experiment, 5 subjects were selected, and the inner skin of both forearms was chosen for testing. After cleaning both arms, 3 test points were selected on each of the left and right hands, and a commercially available plaster, a commercially available film dressing, and the hydrogel dressing described in Example 1 were used in sequence. The subjects sat still and observed the changes in the skin. After 2 hours of applying the dressing, it was removed and replaced, and the usage experience was recorded simultaneously.

[0049] Experimental results: As can be seen from Table 2, all three dressings showed good safety during application and did not cause skin redness or allergic reactions. The commercially available plaster and film dressing fit tightly to the skin, but at the same time brought a certain degree of tight discomfort. This may be because the backing material of the plaster is relatively hard and the material of the film dressing has insufficient elasticity, resulting in the dressing being difficult to move after being fixed, which may cause tearing of the skin when the dressing is replaced later. The hydrogel dressing described in the present invention can fit on the skin surface, and the added glycerol, butylene glycol, and polydimethylsiloxane components enhance the softness and ductility of the hydrogel dressing. This enables the hydrogel dressing to stretch with skin movement without breaking, and at the same time can be easily lifted when replacing the dressing, without causing harm to the skin or leaving residues.

[0050] Table 2 Usage feelings of different dressings

[0051]

[0052]

[0053] 3. Antibacterial performance test

[0054] First, Staphylococcus aureus and Escherichia coli were cultured to the exponential growth phase, and then Example 1, Example 3, and Comparative Example 3 were added respectively. After moderate oscillation to ensure full contact between the bacterial suspension and the hydrogel, it was incubated in a constant temperature incubator at 37°C. The absorbance value was detected using an enzyme-linked immunosorbent assay (ELISA) at different time points within 24 hours to measure the concentration of bacteria, and the antibacterial efficiency of each group was calculated accordingly. At the same time, after co-incubation for 5 hours, an appropriate amount of the bacterial suspension was taken for dilution and plating, and the morphology and number of bacterial colonies were observed.

[0055] Experimental results: As Figures 1-3 shown, Example 1 and Example 3 can achieve antibacterial efficacy by releasing nanozinc, and as the content of nanozinc increases, its antibacterial efficacy also shows an increasing trend. In sharp contrast, the antibacterial effect of Control Group 3 is significantly inferior to that of the hydrogel dressing containing zinc ions, indicating that the release of nanozinc plays a significant role in enhancing antibacterial efficacy.

[0056] 4. Cell proliferation ability test

[0057] L929 cells were seeded in 96-well plates at a density of 3000 cells / well, and co-cultured with the extracts of the hydrogel dressings of Examples 1-3 for 24 and 48 hours. The cell proliferation ability of each group was measured by a CCK8 kit. The absorbance value of the supernatant was measured using a microplate reader, and the cell viability of each group was calculated accordingly.

[0058] Experimental results: As Figures 4-5 shown, compared with the control group, the hydrogel of the example had no toxic effect on cells and significantly promoted cell proliferation. This indicates that the hydrogel dressing of the present invention has good biocompatibility and can promote wound healing.

[0059] In summary, the sterile medical wound repair hydrogel dressing of the present invention exhibits more excellent wound repair effects compared with traditional hydrogel dressings. During use, this hydrogel dressing effectively improves the nursing quality of postoperative wounds and accelerates the wound repair and healing process by absorbing exudate, reducing wound load, achieving painless dressing change, exerting long-term antibacterial effects, supplementing nutrition, and promoting cell proliferation.

Claims

1. A sterile medical wound repair hydrogel dressing, characterized in that, By forming a borate ester bond between the phenylboronic acid group of the double-modified hyaluronic acid and polyvinyl alcohol, and at the same time achieving cross-linking through the free radical polymerization reaction of carbon-carbon double bonds, a stable double-network structure is jointly formed. Further, the coordination bond formed between polyvinyl alcohol and zinc ions interpenetrates in the network structure, and finally a hydrogel dressing with a triple-network structure is formed. The mass concentrations of each composition are as follows: Double-modified hyaluronic acid 5 mg / mL - 30 mg / mL; Polyvinyl alcohol 10 mg / mL - 50 mg / mL; Nano zinc 5 mg / mL - 20 mg / mL; Humectant 10 mg / mL - 50 mg / mL; Lubricant 10 mg / mL - 50 mg / mL; Photo-crosslinking agent 0.1 mg / mL - 0.5 mg / mL.

2. The sterile medical wound repair hydrogel dressing according to claim 1, characterized in that, The double-modified hyaluronic acid has successfully introduced two functional functional groups, namely phenylboronic acid group and carbon-carbon double bond.

3. The sterile medical wound repair hydrogel dressing according to claim 1, wherein The humectant is glycerol or butanediol.

4. The sterile medical wound repair hydrogel dressing according to claim 1, wherein The lubricant is polydimethylsiloxane.

5. The sterile medical wound repair hydrogel dressing according to claim 1, wherein The photo-crosslinking agent is I2959.

6. The preparation method of the sterile medical wound repair hydrogel dressing according to claim 1, comprising the following steps: Dissolve the double-modified hyaluronic acid, glycerol, butanediol and nano zinc in purified water, fully mix them and load them into syringe A. Heat and dissolve polyvinyl alcohol, polydimethylsiloxane and I2959 in purified water and load them into syringe B. Finally, synchronously inject the solutions in syringes A and B into a customized mold for preliminary shaping. After standing for 5 minutes, carry out curing treatment under ultraviolet light irradiation to obtain the hydrogel dressing.

7. The application of the sterile medical wound repair hydrogel dressing according to any one of claims 1 or 6 in the wound care after surgical suture.

8. The application according to claim 7, wherein The sterile medical wound repair hydrogel dressing can effectively improve the postoperative wound care effect by absorbing exudate, reducing wound load, painless dressing change, long-term antibacterial, supplementing nutrition and promoting cell proliferation. This dressing can effectively promote the wound healing process, accelerate wound repair, and provide a more comfortable and efficient wound repair experience for patients.

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