Preparation method of hydrogel-based wound dressing material with temperature responsiveness

Abstract

The invention belongs to the field of functional materials and medical dressing materials, and relates to a preparation method of a hydrogel-based wound dressing material with temperature responsiveness. The preparation method comprises the following steps: firstly, polymerizing 1-vinyl-3-butylimidazolium bromide ([VBIM < + >] Br <->) onto a double-network structure of polyacrylic acid (PAA) and polyacrylamide (PAM) through an ultrasonic method, and introducing carboxymethyl cellulose (CMC) at the same time; and pouring the obtained hydrogel precursor liquid into a mold, heating to synthesize a pregel, and soaking the pregel in a phosphate buffer solution containing drugs to obtain the PVMAC hydrogel with temperature responsiveness. Under the optimal condition, the conversion temperature can be controlled at 37 DEG C. In addition, the hydrogel has excellent mechanical properties and good antibacterial and biocompatibility, which provides conditions for the hydrogel as a temperature-responsive hydrogel-based wound dressing. The hydrogel-based dressing material disclosed by the invention has important meanings on rapid healing of wounds, relieving of pains of patients and real-time monitoring of wound treatment.

Description

Technical Field

[0001] The invention belongs to the field of functional materials and medical dressing materials, and relates to a method for preparing a temperature-responsive hydrogel-based wound dressing material. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Wound healing is one of the major challenges facing the global medical system, with problems such as long treatment time and easy infection. Generally, the healing rate and recovery status of wounds are affected by factors such as bacterial infection and chronic inflammation. If the treatment is not timely, it will also cause serious consequences such as suppuration or even decay. Therefore, accurate and timely wound management is crucial to accelerate wound healing. In this regard, many wound dressing products have been developed and prepared by scholars. However, most wound dressing products only have the function of protecting wounds from bacterial infection, and do not have the ability to promote wound healing and monitor wound status; at the same time, frequent dressing changes may also destroy new epithelial cells and collagen deposition, increasing the risk of secondary skin infection or injury. Therefore, the development of temperature-responsive hydrogel dressings that can achieve real-time monitoring and on-demand treatment of wounds is imminent and challenging.

[0004] In recent years, hydrogels have been widely studied not only in biosensors, tissue engineering, triboelectric nanogenerators, and supercapacitors due to their unique advantages such as superior flexibility, mechanical properties, and biocompatibility, but also in the fields of drug delivery and wound dressings.

[0005] Poly(N-isopropylacrylamide) (PNIPAM) hydrogels with temperature-sensitive response capabilities have both hydrophilic amide groups and hydrophobic isopropyl groups on their macromolecular chains, making cross-linked PNIPAM hydrogels temperature-sensitive (generally 32°C), showing potential for use in wound dressings for controlled drug release and have been widely studied. However, the temperature-sensitive characteristics of PNIPAM hydrogels differ greatly from the temperature of the wound, making it difficult to achieve the requirements of accurate sensing and drug release of the wound.

[0006] Therefore, there is an urgent need to develop hydrogel dressings with better temperature responsiveness to achieve precise sensing and drug delivery to wounds. Summary of the invention

[0007] In order to solve the above problems, the present invention provides a method for preparing a temperature-responsive hydrogel-based wound dressing material. The present invention comprises 1-vinyl-3-butyl imidazolium bromide ([VBIM+ ] Br - ‌‌) is used as a temperature-sensitive material medium, and is combined with polymer monomers such as acrylic acid (AA) and acrylamide (AM) to form a double network structure through ultrasound-assisted free radical polymerization. At the same time, carboxymethyl cellulose (CMC) is introduced to enhance its mechanical properties and biocompatibility. The prepared hydrogel dressing material can accurately sense the temperature of the wound. The conversion temperature of the material can be controlled at 37°C, which can not only achieve on-demand drug administration of the wound, but also has the characteristics of visual drug administration. Therefore, the hydrogel-based wound dressing material of the present invention is of great significance for the rapid healing of wounds, the relief of patient pain, and the real-time monitoring of wound treatment.

[0008] In order to achieve the above object, the present invention adopts the following technical solution: The first aspect of the present invention provides a method for preparing a temperature-responsive hydrogel-based wound dressing material, comprising: 1-vinyl-3-butyl imidazole bromide is mixed with acrylic acid, acrylamide and carboxymethyl cellulose in a solvent by ultrasonic treatment, and then an initiator and a cross-linking agent are added and mixed to obtain a PVMAC hydrogel precursor solution; the PVMAC hydrogel precursor solution is injection molded to obtain a PVMAC hydrogel (i.e., a temperature-responsive hydrogel); The PVMAC hydrogel is immersed in a phosphate buffer solution containing drugs to obtain the hydrogel.

[0009] The amount of each raw material has a great influence on the performance of the hydrogel. Therefore, the present invention studies the amount of 1-vinyl-3-butylimidazolium bromide, acrylic acid, acrylamide, and carboxymethyl cellulose. Preferably, the mass volume ratio of 1-vinyl-3-butylimidazolium bromide to acrylic acid, acrylamide, and carboxymethyl cellulose is 0.168 g-0.84 g: 1.2 mL: 0.75 g: 0.02 g.

[0010] The present invention does not impose any particular limitation on the type of initiator. Preferably, the initiator is ammonium persulfate (APS).

[0011] The present invention does not specifically limit the type of the cross-linking agent. Preferably, the cross-linking agent is ‌N,N'-methylenebisacrylamide (MBA).

[0012] Temperature is a factor that affects the efficiency of the polymerization reaction. Generally speaking, an increase in temperature will accelerate the polymerization reaction, thereby shortening the reaction time. However, too high a temperature may also lead to a decrease in product performance or produce side reactions. Therefore, preferably, during the injection molding process, the PVMAC hydrogel precursor solution is polymerized at 60°C-65°C.

[0013] The length of the polymerization reaction time will affect the structure and properties of the polymer. Therefore, the present invention studies the polymerization reaction time. Preferably, the polymerization reaction time is 30 min-60 min.

[0014] As the drug concentration in the solution increases, the drug loading capacity of the hydrogel gradually increases, but after the drug concentration reaches a certain value, continuing to increase the drug concentration has little effect on the drug loading capacity of the hydrogel. Therefore, preferably, the drug concentration in the drug-containing phosphate buffer is 30 μg / mL-40 μg / mL.

[0015] The present invention does not impose any particular limitation on the type of drug, as long as it can be loaded by the hydrogel and promote the healing of the wound. Therefore, preferably, the drug is erythromycin (EM) or norfloxacin (NOR).

[0016] The immersion treatment can remove acrylic acid and acrylamide that have not participated in the reaction, and immerse the drug into the hydrogel. Therefore, the present invention studies the immersion time. Preferably, the immersion time is 6-12 hours.

[0017] Preferably, the conversion temperature of the temperature-responsive hydrogel-based wound dressing material is 37°C.

[0018] Beneficial effects of the present invention (1) The hydrogel-based wound dressing material of the present invention has excellent temperature response performance. Under optimal conditions, its conversion temperature can be controlled at 37°C, that is, it is opaque when it is below 37°C and transparent when it is above 37°C, and it is also accompanied by changes in the pore size of the hydrogel.

[0019] (2) The hydrogel-based wound dressing material prepared by the present invention has excellent mechanical properties and good antibacterial and biocompatibility properties, which provide conditions for it to be used as a temperature-responsive hydrogel dressing.

[0020] (3) The preparation method of the present invention is simple, practical, and easy to promote. It has an excellent effect on wound healing and has important practical significance for expanding its application in hydrogel-based dressings. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention, and the exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute improper limitations on the present invention.

[0022] Figure 1 These are scanning electron microscope (SEM) images and pore size distribution diagrams of the PVMAC hydrogel in Example 3 of the present invention at different temperatures, (a) below 37°C, and (b) above 37°C.

[0023] Figure 2 This is a real picture of the change in transparency of the PVMAC hydrogel in Example 3 of the present invention.

[0024] Figure 3 The mechanical properties test of the PVMAC hydrogel prepared in Example 3 of the present invention: (a) Under manual operation, the PVMAC hydrogel can be stretched and twisted; (b) A real picture of the PVMAC hydrogel lifting a 300 g weight; (c) A real picture of the PVMAC hydrogel resisting a screwdriver piercing.

[0025] Figure 4 The tensile force of the hydrogel was tested using a texture analyzer. (a) Mechanical property test of the PVMAC hydrogels of Examples 1-5. (b) Comparison of toughness and modulus of the PVMAC hydrogels of Examples 1-5. (c) Cyclic loading-unloading test of the PVMAC hydrogel of Example 3 at different strains. (d) 10 consecutive loading-unloading tests without rest intervals at 100% strain on the PVMAC hydrogel of Example 3. Among them, 0 wt.% is free of [VBIM + ] Br - ‌‌ hydrogels, 2%, 4%, 6%, 8%, and 10% correspond to the PVMAC hydrogels prepared in Examples 1-5, respectively.

[0026] Figure 5 This is a test chart of drug diffusion release of the NOR-loaded PVMAC hydrogel dressing prepared in Example 3 of the present invention in a diffusion cell filled with phosphate buffer.

[0027] Figure 6 : The PVMAC hydrogel dressing prepared in Example 3 of the present invention promotes wound healing test diagram; (a) Representative photos of wounds treated with different samples on days 0, 4, 7, 10 and 14; (b) Schematic diagram of wound healing simulation; (c) Statistical analysis of wound healing rates on days 4, 7, 10 and 14; wherein, Control is a wound covered with ‌3M Tegaderm, PVMAC is a wound covered with a PVMAC hydrogel without drug loading, and PVMAC- EM Cover the wound with EM-loaded PVMAC hydrogel dressing, PVMAC- NOR The wound was covered with NOR-loaded PVMAC hydrogel dressing.

[0028] Figure 7 It is a design principle diagram of the present invention. DETAILED DESCRIPTION

[0029] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0030] The present invention will be further described in detail below in conjunction with specific embodiments. It should be noted that the specific embodiments are intended to explain the present invention rather than to limit it.

[0031] In the following examples, the direct measurement method was used to test the effect of PVMAC hydrogel dressing on wound healing. The initial area of ​​the wound was measured before treatment. After a period of treatment, the area of ​​the remaining wound was measured again. The wound healing rate was calculated by the following formula: .

[0032] Example 1 A method for preparing a temperature-responsive hydrogel-based wound dressing material comprises the following steps: First, 0.168 g [VBIM + ] Br - Dissolved in 7.4 mL of deionized water, ultrasonically stirred for 10 min to obtain a polyion solution; then 0.75 g AM and 1.2 mL AA were dissolved in the polyion solution under ultrasonic stirring, and 20 mg CMC was evenly dispersed into the solution. Subsequently, 20 mg initiator (APS) and 10 mg cross-linker (MBA) were added to the solution, ultrasonically stirred until completely dissolved, and a PVMAC hydrogel precursor solution was obtained. The PVMAC hydrogel precursor solution was uniformly poured into the mold. After heating in an oven at 65 °C for 30 min, the complete PVMAC hydrogel was manually peeled off from the mold. Finally, the PVMAC hydrogel was soaked in a phosphate buffer containing 30 μg / mL norfloxacin for 6 hours to remove the acrylic acid and acrylamide that did not participate in the reaction, and the drug was immersed in the hydrogel to obtain a PVMAC hydrogel dressing.

[0033] Example 2 A method for preparing a temperature-responsive hydrogel-based wound dressing material comprises the following steps: First, 0.336 g [VBIM + ] Br -Dissolved in 7.4 mL of deionized water, ultrasonically stirred for 10 min to obtain a polyion solution; then 0.75 g AM and 1.2 mL AA were dissolved in the polyion solution under ultrasonic stirring, and 20 mg CMC was evenly dispersed into the solution. Subsequently, 20 mg initiator (APS) and 10 mg cross-linker (MBA) were added to the solution, ultrasonically stirred until completely dissolved, and a PVMAC hydrogel precursor solution was obtained. The PVMAC hydrogel precursor solution was uniformly poured into the mold. After heating in an oven at 60 ° C for 60 min, the complete PVMAC hydrogel was manually peeled off from the mold. Finally, the PVMAC hydrogel was soaked in a phosphate buffer containing 40 μg / mL norfloxacin for 12 hours to remove the acrylic acid and acrylamide that did not participate in the reaction, and the drug was immersed in the hydrogel to obtain a PVMAC hydrogel dressing.

[0034] Example 3 A method for preparing a temperature-responsive hydrogel-based wound dressing material comprises the following steps: First, 0.504 g [VBIM + ] Br - Dissolved in 7.4 mL of deionized water, ultrasonically stirred for 10 min to obtain a polyion solution; then 0.75 g AM and 1.2 mL AA were dissolved in the above polyion solution under ultrasonic stirring, and 20 mg CMC was evenly dispersed into the above solution. Subsequently, 20 mg initiator (APS) and 10 mg cross-linker (MBA) were added to the above solution, ultrasonically stirred until completely dissolved, and PVMAC hydrogel precursor solution was obtained. The PVMAC hydrogel precursor solution was uniformly poured into the mold. After heating in an oven at 65°C for 30 min, the complete PVMAC hydrogel was manually peeled off from the mold. Finally, the PVMAC hydrogel was immersed in phosphate buffer containing 30 μg / mL norfloxacin or erythromycin for 8 hours to remove acrylic acid and acrylamide that did not participate in the reaction, and the drug was immersed in the hydrogel to obtain NOR-loaded PVMAC hydrogel dressings and EM-loaded PVMAC hydrogel dressings, respectively.

[0035] Example 4 A method for preparing a temperature-responsive hydrogel-based wound dressing material comprises the following steps: First, 0.672 g [VBIM + ] Br -Dissolved in 7.4 mL of deionized water, ultrasonically stirred for 10 min to obtain a polyion solution; then 0.75 g AM and 1.2 mL AA were dissolved in the polyion solution under ultrasonic stirring, and 20 mg CMC was evenly dispersed into the solution. Subsequently, 20 mg initiator (APS) and 10 mg cross-linker (MBA) were added to the solution, ultrasonically stirred until completely dissolved, and PVMAC hydrogel precursor solution was obtained. The PVMAC hydrogel precursor solution was uniformly poured into the mold. After heating in an oven at 65 ° C for 30 min, the complete PVMAC hydrogel was manually peeled off from the mold. Finally, the PVMAC hydrogel was soaked in phosphate buffer containing 30 μg / mL norfloxacin for 9 hours to remove acrylic acid and acrylamide that did not participate in the reaction, and the drug was immersed in the hydrogel to obtain a PVMAC hydrogel dressing.

[0036] Example 5 A method for preparing a temperature-responsive hydrogel-based wound dressing material comprises the following steps: First, 0.84 g [VBIM + ] Br - Dissolved in 7.4 mL of deionized water, ultrasonically stirred for 10 min to obtain a polyion solution; then 0.75 g AM and 1.2 mL AA were dissolved in the above polyion solution under ultrasonic stirring, and 20 mg CMC was evenly dispersed into the above solution. Subsequently, 20 mg initiator (APS) and 10 mg cross-linker (MBA) were added to the above solution, ultrasonically stirred until completely dissolved, and PVMAC hydrogel precursor solution was obtained. The PVMAC hydrogel precursor solution was uniformly poured into the mold. After heating in an oven at 65 ° C for 30 min, the complete PVMAC hydrogel was manually peeled off from the mold. Finally, the PVMAC hydrogel was soaked in phosphate buffer containing 30 μg / mL norfloxacin for 10 hours to remove acrylic acid and acrylamide that did not participate in the reaction, and the drug was immersed in the hydrogel to obtain a PVMAC hydrogel dressing.

[0037] The above-mentioned temperature-responsive hydrogel-based wound dressing material was characterized and its performance was tested. The scanning electron microscope image and pore size distribution diagram of the PVMAC hydrogel in Example 3 are shown in FIG. Figure 1 As shown, the actual picture of the change in transparency of PVMAC hydrogel in Example 3 is as follows Figure 2 The mechanical properties test results of the PVMAC hydrogel prepared in Example 3 are shown in Figure 3 As shown, the tensile strength of the hydrogels prepared in Examples 1-5 was tested using a texture analyzer, and the test results are shown in Figure 4 As shown, Figure 5This is a test chart of drug diffusion release of the PVMAC hydrogel dressing loaded with 30 μg / mL norfloxacin prepared in Example 3 of the present invention in a diffusion cell filled with phosphate buffer. Figure 6 This is a test diagram of the PVMAC hydrogel dressing prepared in Example 3 of the present invention promoting wound healing.

[0038] It can be seen that under the optimal conditions, the conversion temperature of the PVMAC hydrogel dressing prepared by the present invention can be controlled at 37°C, that is, it is opaque when it is below 37°C and transparent when it is above 37°C, and the change in temperature is also accompanied by the change in the pore size of the hydrogel. In addition, it has excellent mechanical properties and good antibacterial and biocompatible properties, which provide conditions for it to be used as a temperature-responsive hydrogel dressing. The preparation of the temperature-responsive hydrogel by the present invention has important practical significance for expanding its application in hydrogel-based dressings.

[0039] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a temperature-responsive hydrogel-based wound dressing material, characterized in that: include: 1-vinyl-3-butyl imidazole bromide, acrylic acid, acrylamide and carboxymethyl cellulose are mixed uniformly in a solvent by ultrasonic treatment, and then an initiator and a cross-linking agent are added and mixed uniformly to obtain a PVMAC hydrogel precursor solution; injection molding the PVMAC hydrogel precursor solution to obtain a PVMAC hydrogel; The PVMAC hydrogel is immersed in a phosphate buffer solution containing drugs to obtain a hydrogel-based wound dressing material with temperature responsiveness.

2. The method for preparing a temperature-responsive hydrogel-based wound dressing material according to claim 1, wherein: The mass volume ratio of the 1-vinyl-3-butyl imidazole bromide to acrylic acid, acrylamide and carboxymethyl cellulose is 0.168 g-0.84 g: 1.2 mL: 0.75 g: 0.02 g.

3. The method for preparing a temperature-responsive hydrogel-based wound dressing material according to claim 1, wherein: The initiator is ammonium persulfate.

4. The method for preparing a temperature-responsive hydrogel-based wound dressing material according to claim 1, characterized in that: The cross-linking agent is ‌N,N'-methylenebisacrylamide.

5. The method for preparing a temperature-responsive hydrogel-based wound dressing material according to claim 1, wherein: During the injection molding process, the PVMAC hydrogel precursor solution is polymerized at 60°C-65°C.

6. The method for preparing a temperature-responsive hydrogel-based wound dressing material according to claim 5, characterized in that: The polymerization reaction time is 30 min-60 min.

7. The method for preparing a temperature-responsive hydrogel-based wound dressing material according to claim 1, characterized in that: In the drug-containing phosphate buffer, the concentration of the drug is 30 μg / mL-40 μg / mL.

8. The method for preparing a temperature-responsive hydrogel-based wound dressing material according to claim 1, wherein: The drug is erythromycin or norfloxacin.

9. The method for preparing a temperature-responsive hydrogel-based wound dressing material according to claim 1, wherein: The soaking time is 6-12 hours.

10. The method for preparing a temperature-responsive hydrogel-based wound dressing material according to claim 1, characterized in that: The temperature-responsive hydrogel-based wound dressing material has a conversion temperature of 37°C.

Images