Multi-response antibacterial multilayer wound dressing

Abstract

The invention discloses a multi-response antibacterial multi-layer wound dressing, and belongs to the technical field of medical instruments. The dressing is composed of a pH-responsive antibacterial hydrogel layer, a fluorescence-responsive polyvinyl alcohol (PVA) foam layer, a substrate fixing layer with a visible window and release paper. The visible window is reserved in the substrate fixing layer and used for directly observing the color change of the dressing, and whether a wound is infected or not can be visually judged; the wound dressing prepared by the invention has pH response and fluorescence response, and meanwhile, along with obvious macroscopic color change, the wound infection condition can be monitored on site / in real time; pH-responsive itaconic acid and guanidyl cation-containing antibacterial substances are loaded in the hydrogel layer in a chemical bonding manner and can actively respond to the pH of the wound and promote healing of the wound, and methylene blue (MB) is loaded in the PVA foam layer, so that whether the wound is infected or not can be detected and treated at the same time.

Description

Technical Field

[0001] The invention relates to the field of medical devices, and in particular to a multi-response antibacterial multi-layer wound dressing. Background Art

[0002] Wound dressings are a type of material widely used in the medical field to protect and promote wound healing. With the development of nanotechnology, various types of biological scaffolds including hydrogels and electrospun nanofibers have emerged in the field of tissue engineering as a new generation of wound dressings, and have achieved good healing effects. Hydrogels are generally composed of hydrophilic three-dimensional networks, which can effectively absorb tissue exudates, provide a breathable and moist microenvironment for wounds, and accelerate wound healing. They are considered to be the most promising modern dressings. pH-sensitive hydrogels are a type of smart material containing acidic and alkaline groups that respond to pH changes. Wound exudate increases the pH value of the wound from the normal slightly acidic range of 4.80~5.70 to above 7.4. Due to the alkaline byproducts produced by microorganisms, the pH value of infected chronic wounds is generally between 7.50~8.70. Therefore, using pH-responsive dressings to monitor changes in wound pH can understand the wound healing stage and bacterial infection, which is conducive to guiding rational medication.

[0003] The sustained release of drugs is an important function of wound dressings, but traditional hydrogel dressings often cannot achieve sustained and controlled release of drugs. When hydrogels directly encapsulate drugs, the drugs are mainly distributed in the pore walls inside the hydrogels and are quickly released during the liquid exchange between the hydrogels and the wound extract, resulting in a decrease in the efficacy of the drugs. Therefore, the development of antibacterial dressings with good antibacterial properties and intelligent responsive sustainable release has become a research hotspot in the biomedical field today. Polyhexamethylene guanidine hydrochloride (PHMG) is a cationic antibacterial agent containing guanidine groups. The positively charged guanidine groups in its structure are easy to adsorb negatively charged bacteria and viruses, inhibit cell division and reproduction, have good antibacterial activity, and are not easy to develop drug resistance. It has been widely used. Among the series of wound dressings developed in recent decades, PVA is considered to be the first choice for negative pressure wound therapy due to its biocompatibility, breathability, ideal mechanical properties and low cost. In addition, due to its open-pore structure with rich hydroxyl surface functional groups, the water absorption rate can reach 6-9 times its own mass. MB is an organic antimicrobial cationic dye with a strong affinity for dead cells. When in contact with bacteria, its blue color fades due to local hypoxia. The unique color change visible to the naked eye is a good feature that can be used for on-site and real-time monitoring of wound infection.

[0004] At present, traditional dressings such as gauze are used clinically, and it is difficult for doctors to quickly diagnose patients' wound infections. When detecting infection, the bandage needs to be removed to monitor and observe the degree of wound healing. This process is painful for patients, and bacteria may enter the wound when the dressing is removed, causing secondary infection to the wound. Some limitations of microbial analysis are long analysis time, invasive technology when performing microbial analysis on biopsy tissue, and the inability to identify bacteria that invade deep tissues during swab culture. Therefore, in personal care and daily use, there is a great demand for constructing intelligent non-invasive sensor materials that are easily identified by the naked eye. Therefore, in order to meet the requirements of being able to easily observe the true condition of the wound with the naked eye, but avoiding errors caused by blood or tissue fluid contamination of the dressing, we need to further design a dual-color monitoring system with pH-dependent visible and fluorescence intensity changes to improve the sensitivity and accuracy of the detection system. Antimicrobial drugs act on wounds through physical mixing, which will cause the drugs to burst and release. Not only is the antibacterial effect short-lived, but the toxic side effects caused by high doses may also affect the normal tissues at the wound site. Therefore, the development of antibacterial dressings with good antibacterial properties and intelligent responsive sustainable release has become a research hotspot in the biomedical field today. Therefore, achieving dye fixation is also a major challenge in the construction of monitoring dressings.

[0005] In summary, there is an urgent need to further develop new wound dressings with integrated pH-responsive diagnosis and treatment using fluorescent dyes. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a multi-response antibacterial multilayer wound dressing. The hydrogel layer in the present invention uses acrylamide (AM) as the hydrogel matrix, and the main chain connects pH-sensitive itaconic acid (IA) and positively charged quaternary ammonium salt allyltrimethylammonium chloride (TAAC) as the side chain to synthesize pH-sensitive antibacterial hydrogel, and at the same time, PHMG and -COOH in the hydrogel matrix are loaded into the hydrogel through electrostatic adsorption. The second layer is a PVA layer loaded with MB. The unique color change characteristics of MB can better detect bacterial infection of the wound in real time. The above two structures can not only effectively treat the wound, but also monitor the infection of the wound in real time.

[0007] The present invention prepares a multi-response antibacterial multi-layer wound dressing, and its specific technical scheme is: a multi-response antibacterial multi-layer wound dressing, comprising a base fixing layer, a PVA foam layer, a hydrogel layer and a release paper, the base fixing layer comprises a transparent care film, an adhesive tape, a composite dressing treatment area in which the PVA foam layer and the hydrogel layer are superimposed, the composite dressing treatment area is superimposed by the hydrogel layer and the PVA foam layer, and the composite dressing treatment area and the adhesive tape are respectively fixed to the treatment area and the adhesive tape area by spraying glue; the preparation method of the composite dressing treatment area in which the PVA foam layer and the hydrogel layer are superimposed is as follows: Preparation method of PVA sponge layer: S1, adding PVA to deionized water and stirring to obtain a uniform PVA solution, cooling the solution to room temperature, and then adding sulfuric acid and formaldehyde solution to obtain a prepolymer solution; S2, heating the prepolymer solution of MB to obtain a foam product; Preparation method of hydrogel layer: S1, dissolving itaconic acid in a 17wt% sodium hydroxide solution and pre-treating in an ice bath to make the neutralization degree of the raw material 75%; S2, adding acrylamide, quaternary ammonium salt allyltrimethylammonium chloride, N,N-methylenebisacrylamide, ammonium persulfate, tetramethylethylenediamine and antimicrobial agent to the IA pretreatment solution; S3, ultrasonic oscillation, obtain a uniformly dispersed reaction solution, transfer the solution to a polytetrafluoroethylene mold, put it into a 60°C drying oven for reaction for 3 hours, and obtain a colorless and transparent hydrogel; Preferably, the antibacterial drug in step S2 of the hydrogel layer is a cationic antibacterial agent containing a guanidine group; Preferably, the antibacterial drug in step S2 of the hydrogel layer is polyhexamethylene guanidine hydrochloride; Preparation of the treatment area for overlay composite dressing: The PVA layer and the hydrogel layer are cut into film layers of equal size and different thicknesses, and the hydrogel layer is attached to the bottom surface of the PVA foam having multiple side holes to form a superimposed composite dressing treatment area.

[0008] As described above, the hydrogel in the hydrogel layer of the present invention uses acrylamide (AM) as the hydrogel matrix, and the main chain is connected to pH-sensitive itaconic acid (IA) and positively charged quaternary ammonium salt allyltrimethylammonium chloride (TAAC) as the side chain to synthesize a pH-sensitive antibacterial hydrogel. PHMG and -COOH in the hydrogel matrix are loaded into the hydrogel through electrostatic adsorption, and the antibacterial drug is loaded into the pH-responsive hydrogel, thereby realizing the properties of a controlled release wound dressing; MB is loaded in the PVA foam layer for detecting wound infection. When in contact with bacteria, its blue color will fade due to local hypoxia. The above two structures enable the wound dressing with two functions to achieve visual diagnosis and controllable treatment of wounds.

[0009] The hydrogel layer in the present invention is a pH-sensitive hydrogel, and the principle of its pH response is that a large amount of hydrogen ions contained in the acidic buffer system reversibly bind to free carboxylate ions, which enhances the hydrogen bonding between the aqueous solution and the polymer network, resulting in a tighter hydrogel network, thereby limiting the release of the drug. Loading MB in the PVA foam layer can be used to intuitively detect wound infection. The principle is that MB itself is blue, and when bacteria are present, oxygen is consumed, and the oxidized MB product is colorless. The color change is visible to the naked eye, and visual detection can be achieved.

[0010] Compared with the prior art, the present invention has the following technical effects: the wound dressing prepared by the present invention has dual responsiveness of pH and fluorescence. The present invention fixes MB in the PVA foam layer, which can provide a clear and visible color change from blue to colorless. At the same time, acrylamide (AM) is used as the hydrogel matrix in the hydrogel layer, and the main chain is connected with pH-sensitive itaconic acid (IA) and positively charged quaternary ammonium salt allyltrimethylammonium chloride (TAAC) as the side chain to synthesize pH-sensitive antibacterial hydrogel. PHMG and -COOH in the hydrogel matrix are loaded into the hydrogel through electrostatic adsorption, and the antibacterial drug is loaded into the pH-responsive structure. When the wound is infected and the pH rises, the antibacterial drug is released, thereby achieving the property of on-demand drug release, thereby realizing visualization and controllable treatment of chronic wounds; BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 : A plan view of a multi-responsive antimicrobial multilayer wound dressing Figure 2 : Hierarchical structure diagram of the present invention Figure 3 :Bacterial detection mechanism of methylene blue in PVA foam layer Reference numerals: 1-transparent care film, 2-adhesive tape, 3-PVA foam layer, 4-hydrogel layer, 5-release paper; DETAILED DESCRIPTION

[0012] The present invention will be further described below with reference to Examples and Comparative Examples.

[0013] Example 1 A multi-response antibacterial multi-layer wound dressing, the antibacterial multi-layer wound dressing is composed of a base fixing layer, a PVA foam layer, a hydrogel layer and a release paper, the base fixing layer comprises a composite dressing treatment area on which a transparent care film 1, an adhesive tape 2, a PVA foam layer 3 and a hydrogel layer 4 are superimposed, the composite dressing treatment area is located in the central area of ​​the transparent care film 1 and is rectangular in shape, the adhesive tape area is located in other areas of the transparent care film 1 except the composite dressing treatment area, the size of the transparent care film is a 15 cm square, the treatment area is 10 cm, the fixed adhesive strip 4 is rectangular in shape, 1.5 cm in width and 15 cm in length, and the release paper 5 is exactly the same size as the care film; The method of preparing the superimposed composite dressing treatment area is as follows: 2 g of PVA was added to deionized water and stirred to obtain a uniform PVA solution. After the solution was cooled to room temperature, 1 ml of H 2 SO 4 and 5 ml of formaldehyde solution to obtain a prepolymer solution; 0.2 g / L of MB was loaded into the prepolymer solution, and the mixture was heated at 80° C. for 2 h to obtain a PVA foam layer; 1.14 g of itaconic acid was dissolved in 30 ml of 17 wt % sodium hydroxide solution and pretreated in an ice bath to make the neutralization degree of the raw material 75%; 3.6 g of acrylamide, 1.88 g of quaternary ammonium salt allyltrimethylammonium chloride, 0.04 g of N,N-methylenebisacrylamide, 0.06 g of ammonium persulfate, 0.30 g of tetramethylethylenediamine and 0.2 g of polyhexamethyleneguanidine hydrochloride were added to the itaconic acid pretreatment solution; ultrasonic oscillation was performed for 5 min to obtain a uniformly dispersed reaction solution, and the solution was transferred to a polytetrafluoroethylene mold and placed in a 60°C drying oven for reaction for 3 h to obtain a colorless and transparent hydrogel layer; The PVA layer and the hydrogel layer are cut into the same length, the thickness ratio of the PVA foam layer to the hydrogel layer is 2:1, and the hydrogel layer is attached to the bottom layer of the PVA foam layer to form an overlapping composite dressing treatment area.

[0014] Example 2 The process is the same as in Example 1, except that the thickness ratio of the PVA foam layer to the hydrogel layer is 1.5:1.

[0015] Example 3 The process is the same as in Example 1, except that the thickness ratio of the PVA foam layer to the hydrogel layer is 1:1.

[0016] Example 4 The process is the same as that of Example 1, except that the transparent care film is 10 cm square, the treatment area is 7.5 cm, and the fixing strip 4 is rectangular, 1.5 cm wide and 15 cm long.

[0017] Example 5 The process is the same as that of Example 1, except that the transparent care film is 5 cm square, the treatment area is 3 cm, and the fixing strip 4 is rectangular, 1.5 cm wide and 15 cm long.

[0018] Comparative Example 1 The difference between this example and Example 1 is that methylene blue is not added in this comparative example.

[0019] Comparative Example 2 The sterile film, which is composed of a transparent adhesive-coated care film and release paper, is used to protect wounds and prevent microorganisms from invading the wound surface.

[0020] Comparative Example 3 The difference between this example and Example 1 is that no quaternary ammonium salt allyltrimethylammonium chloride is added in this comparative example.

[0021] Comparative Example 4 The difference between this example and Example 1 is that this comparative example does not contain polyhexamethylene guanidine hydrochloride.

[0022] The specific detection plan is as follows: 1. Antibacterial rate test: Escherichia coli, which represents Gram-negative bacteria, is used as the test strain to test the antibacterial activity of the dressing; the antibacterial performance of the dressing is characterized by the inhibition zone method; 2. Air permeability test: Connect the matching flow meter to the exhaust pipe of the oxygen cylinder (internal pressure is twice the indoor air pressure), turn on the switch to exhaust for 1 minute, and record the air flow value. Then take a 25*200 mm tape and stick it on the exhaust hole, exhaust for 1 minute, and record the air flow value; 3. Color change test: drop a bacterial suspension of Escherichia coli with an OD value of 2.2 onto the dressing and observe the corresponding color change.

[0023] Antibacterial rate Breathability Color Change Example 1 99.92% 100% From blue to colorless Example 2 98.76% 100% From blue to colorless Example 3 96.54% 100% From blue to colorless Example 4 99.56% 100% From blue to colorless Example 5 99.23% 100% From blue to colorless Comparative Example 1 97.42% 100% none Comparative Example 2 11.17% 60% none Comparative Example 3 78.86% 100% From blue to colorless Comparative Example 4 96.34% 100% From blue to colorless

Claims

1. A multi-response antibacterial multi-layer wound dressing, characterized in that The antibacterial multilayer wound dressing is composed of a base fixing layer, a PVA foam layer (3), a hydrogel layer (4) and a release paper (5); the base fixing layer comprises a transparent care film (1), an adhesive tape (2), a composite dressing treatment area on which the PVA foam layer (3) and the hydrogel layer (4) are superimposed, the PVA foam layer (3) being a methylene blue fluorescence detection layer; the hydrogel layer (4) being a hydrogel layer loaded with pH response and antibacterial drugs; the preparation method of the composite dressing treatment area on which the PVA foam layer (3) and the hydrogel layer (4) are superimposed is as follows: Preparation method of PVA sponge layer: S1, adding PVA to deionized water and stirring to obtain a uniform PVA solution, cooling the solution to room temperature, and then adding sulfuric acid and formaldehyde solution to obtain a prepolymer solution; S2, adding MB to the prepolymer solution and heating to obtain a foam product; Preparation method of hydrogel layer: S1, dissolving itaconic acid in a 17wt% sodium hydroxide solution and pre-treating in an ice bath to make the neutralization degree of the raw material 75%; S2, adding acrylamide, quaternary ammonium salt allyltrimethylammonium chloride, N,N-methylenebisacrylamide, ammonium persulfate, tetramethylethylenediamine and antimicrobial agent to the IA pretreatment solution; S3, ultrasonic oscillation, obtain a uniformly dispersed reaction solution, transfer the solution to a polytetrafluoroethylene mold, put it into a 60°C drying oven for reaction for 3 hours, and obtain a colorless and transparent hydrogel; Preparation of the treatment area for overlay composite dressing: The PVA layer and the hydrogel layer are cut into film layers of equal size but different thicknesses, and the hydrogel layer is attached to the bottom surface of the PVA foam having multiple side holes to form a superimposed composite dressing treatment area.

2. The multi-responsive antibacterial multi-layer wound dressing according to claim 1, characterized in that: The base fixing layer is composed of a transparent care film (1), a composite dressing treatment area and an adhesive tape (2); the composite dressing treatment area and the adhesive tape (2) are fixed to the treatment area and the adhesive tape area respectively by spraying glue; the composite dressing treatment area is located in the central area of ​​the transparent care film (1) and is rectangular in shape; the adhesive tape (2) area is located in other areas of the transparent care film (1) except the composite dressing treatment area; the transparent care film (1) is a rectangle with a size of 5-15 cm; the composite dressing treatment area is a rectangle with a side length of 3-10 cm; the size of the release paper (5) is consistent with that of the transparent care film (1).

3. The multi-responsive antibacterial multi-layer wound dressing according to claim 1, characterized in that: There are four adhesive tapes (2) in total, which are rectangular in shape, 15 mm in width, and whose length depends on the size of the transparent care film (1). The adhesive tapes (2) are evenly distributed on the transparent care film (1), respectively on the left side, right side, top side, and bottom side of the transparent care film (1).

4. The multi-responsive antibacterial multi-layer wound dressing according to claim 1, characterized in that The antibacterial drug in the pH-responsive hydrogel layer (4) is a cationic antibacterial agent containing a guanidine group, which includes polyhexamethylene guanidine hydrochloride (PHMG), polyhexamethylene biguanide, and polydimethylguanidine.

5. The multi-responsive antibacterial multi-layer wound dressing according to claim 1, characterized in that The guanidine-containing cationic antibacterial agent in the pH-responsive hydrogel layer (4) is chemically bonded to the hydrogel layer.

6. The multi-responsive antibacterial multi-layer wound dressing according to claim 1, characterized in that: When the methylene blue of the PVA foam layer (3) comes into contact with bacteria, its blue color will fade due to local hypoxia, and can be used for on-site / real-time detection of wound dressings.

7. The multi-responsive antibacterial multi-layer wound dressing according to claim 1, characterized in that: The thickness ratio of the PVA foam layer (3) to the hydrogel layer (4) is 1:1-2:1.

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