A method of preparing a temperature-responsive hydrogel-based wound dressing material

Abstract

The application belongs to the field of functional materials and medical dressing materials, and relates to a preparation method of a temperature-responsive hydrogel-based wound dressing material. + ] Br ‑ ) is polymerized onto a double-network structure of polyacrylic acid (PAA) and polyacrylamide (PAM) by means of ultrasonic method, and carboxymethyl cellulose (CMC) is introduced; subsequently, the obtained hydrogel precursor liquid is poured into a mold for heating to synthesize a pre-gel, and the pre-gel is soaked in a phosphate buffer solution containing a drug, so that a temperature-responsive PVMAC hydrogel is obtained. Under optimal conditions, the conversion temperature can be controlled at 37 DEG C. In addition, the temperature-responsive PVMAC hydrogel has excellent mechanical properties and good antibacterial and biocompatible properties, which provides conditions for the temperature-responsive hydrogel-based wound dressing. The invention of the hydrogel-based dressing material has important significance for the rapid healing of a wound, the alleviation of pain of a patient and the real-time monitoring of wound treatment.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of functional materials and medical dressing materials, and relates to a preparation method of a temperature-responsive hydrogel-based wound dressing material. BACKGROUND

[0002] The information disclosed in this Background section is only for the purpose of increasing the understanding of the general background of the application and does not necessarily constitute an admission by the patent applicant or the patent owner that this information constitutes prior art.

[0003] Wound healing is one of the major challenges faced by global medical systems, with long treatment time and susceptibility to infection. Generally, the healing rate and recovery condition of a wound are affected by factors such as bacterial infection and chronic inflammation, and if not treated in time, serious consequences such as suppuration and even gangrene can occur. Therefore, precise and timely wound management is crucial to accelerate wound healing. In this regard, many wound dressing products have been developed by scholars, but most of them 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 can damage newly formed epithelial cells and collagen deposition, increasing the risk of secondary skin infection or injury. Therefore, the development of temperature-responsive hydrogel dressing that can realize real-time monitoring and on-demand treatment of wounds is imminent and also challenging.

[0004] In recent years, hydrogels have unique advantages such as excellent flexibility, mechanical properties, and biocompatibility, and have potential applications not only in biosensors, tissue engineering, friction nanogenerators, and supercapacitors, but also in drug delivery and wound dressing.

[0005] Poly (N-isopropylacrylamide) (PNIPAM) hydrogel with temperature-sensitive response ability has both hydrophilic amido groups and hydrophobic isopropyl groups on its macromolecular chain, making the cross-linked PNIPAM hydrogel exhibit temperature-sensitive characteristics (generally 32℃). Its use in drug-controlled wound dressing shows potential and has been widely studied. However, the temperature-sensitive characteristics of PNIPAM hydrogel are quite different from the temperature of the wound, making it difficult to achieve precise sensing and drug release requirements for the wound.

[0006] Therefore, there is an urgent need to develop hydrogel dressing with better temperature response performance to achieve precise sensing and drug release for the wound. SUMMARY

[0007] To solve the above problems, the present application provides a preparation method of a temperature-responsive hydrogel-based wound dressing material. The present application uses 1-vinyl-3-butylimidazole bromide ([VBIM+ ] Br - As a temperature sensitive material medium, it is mixed with polymer monomers such as acrylic acid (AA) and acrylamide (AM) to form a double network structure by means of ultrasonic assisted radical polymerization, and carboxymethyl cellulose (CMC) is introduced to enhance the mechanical properties and biocompatibility, and the prepared hydrogel dressing material can accurately sense the wound temperature, the material conversion temperature can be controlled at 37℃, not only can realize the on-demand drug delivery of the wound, but also has the characteristics of visual drug delivery. Therefore, the hydrogel-based wound dressing material of the application has important significance for the rapid healing of the wound, the relief of the patient's pain, and the real-time monitoring of the wound treatment.

[0008] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0009] The first aspect of the present application provides a preparation method of a temperature responsive hydrogel-based wound dressing material, comprising:

[0010] 1-vinyl-3-butyl imidazole bromide and acrylic acid, acrylamide and carboxymethyl cellulose are mixed uniformly in a solvent by ultrasonic treatment, then an initiator and a crosslinking agent are added and mixed uniformly to obtain a PVMAC hydrogel precursor solution; the PVMAC hydrogel precursor solution is injection molded to obtain a PVMAC hydrogel (i.e. temperature responsive hydrogel);

[0011] The PVMAC hydrogel is soaked in a phosphate buffer solution containing a drug, and the temperature responsive hydrogel-based wound dressing material is obtained.

[0012] The amount of each raw material has a great influence on the performance of the hydrogel, therefore, the amount of 1-vinyl-3-butyl imidazole bromide, acrylic acid, acrylamide and carboxymethyl cellulose is researched in the present application, preferably, the mass-volume ratio of 1-vinyl-3-butyl imidazole bromide, acrylic acid, acrylamide and carboxymethyl cellulose is 0.168 g-0.84 g:1.2 mL:0.75 g:0.02 g.

[0013] The type of the initiator is not specially limited in the present application, preferably, the initiator is ammonium persulfate (APS).

[0014] The type of the crosslinking agent is not specially limited in the present application, preferably, the crosslinking agent is N,N'-methylene bisacrylamide (MBA).

[0015] Temperature is a factor affecting the efficiency of polymerization reaction. Generally speaking, the increase of temperature can accelerate the polymerization reaction, thereby shortening the reaction time. However, too high temperature can also lead to the decline of product performance or produce side reactions. Therefore, preferably, the PVMAC hydrogel precursor solution is subjected to polymerization reaction at 60-65 DEG C in the injection molding process.

[0016] The length of polymerization reaction time can affect the structure and properties of the polymer, therefore, the time of polymerization reaction is studied in the present application, preferably, the time of polymerization reaction is 30-60 min.

[0017] With the increase of the concentration of the drug in the solution, the drug loading capacity of the hydrogel gradually increases, but when the concentration of the drug reaches a certain value, the increase of the concentration of the drug has little effect on the drug loading capacity of the hydrogel. Therefore, preferably, the concentration of the drug in the phosphate buffer containing the drug is 30-40 μg / mL.

[0018] The kind of drug is not particularly limited in the present application, 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).

[0019] The soaking treatment can remove the acrylic acid and acrylamide which do not participate in the reaction, and immerse the drug into the hydrogel, therefore, the time of soaking is studied in the present application, preferably, the soaking time is 6-12 hours.

[0020] Preferably, the conversion temperature of the temperature-responsive hydrogel-based wound dressing material is 37 DEG C.

[0021] Advantages of the present application

[0022] (1) The hydrogel-based wound dressing material of the present application has excellent temperature response performance, and under the optimal conditions, the conversion temperature can be controlled at 37 DEG C, that is, it is opaque below 37 DEG C, and it is transparent above 37 DEG C, and it is also accompanied by the change of the pore size of the hydrogel.

[0023] (2) The hydrogel-based wound dressing material prepared in the present application has excellent mechanical properties and good antibacterial and biocompatible properties, which provides conditions for its use as a temperature-responsive hydrogel dressing.

[0024] (3) The preparation method of the present application is simple, practical and easy to popularize, and has excellent effect on the healing of the wound, and has important practical significance for expanding its application in hydrogel-based dressing. BRIEF DESCRIPTION OF DRAWINGS

[0025] The accompanying drawings, which form a part of this specification, are included to provide a further understanding of the application and are incorporated herein for explanation.

[0026] Figure 1 are scanning electron microscope (SEM) images and pore size distribution of PVMAC hydrogel prepared in Example 3 at different temperatures, (a) below 37℃, (b) above 37℃.

[0027] Figure 2 is a real scene image of the change of transparency of PVMAC hydrogel prepared in Example 3.

[0028] Figure 3 are mechanical property tests of PVMAC hydrogel prepared in Example 3: (a) under artificial operation, PVMAC hydrogel can be stretched and twisted; (b) a real scene image of PVMAC hydrogel lifting a 300 g weight; (c) a real scene image of PVMAC hydrogel resisting a screwdriver.

[0029] Figure 4 The tensile force of the hydrogel is tested by a texture analyzer. (a) mechanical property test of PVMAC hydrogel of Examples 1-5; (b) comparison of toughness and modulus of PVMAC hydrogel of Examples 1-5; (c) cyclic loading-unloading test of PVMAC hydrogel of Example 3 at different strains; (d) loading-unloading test of PVMAC hydrogel of Example 3 at 100% strain for 10 times without rest interval. Wherein, 0 wt.% is a hydrogel without [VBIM + ] Br - ‌of 2%, 4%, 6%, 8%, 10% respectively correspond to PVMAC hydrogel prepared in Examples 1-5.

[0030] Figure 5 is a test image of drug diffusion release of NOR-loaded PVMAC hydrogel dressing prepared in Example 3 in a diffusion cell filled with phosphate buffer.

[0031] Figure 6 is a test image of wound healing promotion of PVMAC hydrogel dressing prepared in Example 3; (a) representative photos of wound surface treated with different samples on day 0, 4, 7, 10 and 14; (b) a simulation schematic diagram of wound surface healing; (c) statistical analysis of wound surface healing rate on day 4, 7, 10, 14; wherein, Control is 3M Tegaderm covering the wound, PVMAC is PVMAC hydrogel without drug loading covering the wound, PVMAC- EM is PVMAC hydrogel dressing loaded with EM covering the wound, PVMAC- NORThe PVMAC hydrogel dressing is applied to the wound.

[0032] Figure 7 is the design schematic of the present application. DETAILED DESCRIPTION

[0033] It should be noted that the following detailed description is exemplary in nature and is intended to provide further description of the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0034] The present application will be described in further detail below with specific examples. It should be noted that the specific examples are illustrative of the present application and are not limiting.

[0035] In the following examples, the PVMAC hydrogel dressing promotes wound healing test uses direct measurement method, the initial area of the wound is measured before treatment, and the area of the remaining wound is measured again after a period of treatment, and the wound healing rate is calculated by the following formula:

[0036] .

[0037] Example 1

[0038] A method for preparing a temperature-responsive hydrogel-based wound dressing material, comprising the following steps:

[0039] First, 0.168 g [VBIM + ] Br - is dissolved in 7.4 mL of deionized water, and after ultrasonic stirring for 10 min, a polyion solution is obtained; then 0.75 g of AM and 1.2 mL of AA are dissolved into the above polyion solution under ultrasonic stirring, and 20 mg of uniformly dispersed CMC is added to the above solution. Subsequently, 20 mg of initiator (APS) and 10 mg of crosslinking agent (MBA) are added to the above solution, and after ultrasonic stirring until completely dissolved, a PVMAC hydrogel precursor solution is obtained. The PVMAC hydrogel precursor solution is uniformly poured into a mold. After heating in an oven at 65°C for 30 min, the complete PVMAC hydrogel is manually peeled off from the mold. Finally, the PVMAC hydrogel is soaked in a phosphate buffer containing 30 μg / mL norfloxacin for 6 hours to remove unreacted acrylic acid and acrylamide, and the drug is immersed into the hydrogel, obtaining a PVMAC hydrogel dressing.

[0040] Example 2

[0041] A method for preparing a temperature-responsive hydrogel-based wound dressing material, comprising the following steps:

[0042] First, 0.336 g [VBIM + ] Br - was dissolved in 7.4 mL of deionized water, and after ultrasonic stirring for 10 min, a polyion solution was obtained; then 0.75 g of AM and 1.2 mL of AA were dissolved in the above polyion solution under ultrasonic stirring, and 20 mg of uniformly dispersed CMC was added to the above solution. Subsequently, 20 mg of initiator (APS) and 10 mg of crosslinking agent (MBA) were added to the above solution, and after ultrasonic stirring until complete dissolution, a PVMAC hydrogel precursor solution was obtained. The PVMAC hydrogel precursor solution was uniformly poured into a 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 unreacted acrylic acid and acrylamide, and the drug was immersed in the hydrogel, obtaining a PVMAC hydrogel dressing.

[0043] Example 3

[0044] A method for preparing a temperature-responsive hydrogel-based wound dressing material, comprising the following steps:

[0045] First, 0.504 g [VBIM + ] Br - was dissolved in 7.4 mL of deionized water, and after ultrasonic stirring for 10 min, a polyion solution was obtained; then 0.75 g of AM and 1.2 mL of AA were dissolved in the above polyion solution under ultrasonic stirring, and 20 mg of uniformly dispersed CMC was added to the above solution. Subsequently, 20 mg of initiator (APS) and 10 mg of crosslinking agent (MBA) were added to the above solution, and after ultrasonic stirring until complete dissolution, a PVMAC hydrogel precursor solution was obtained. The PVMAC hydrogel precursor solution was uniformly poured into a 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 or erythromycin for 8 hours, respectively, to remove unreacted acrylic acid and acrylamide, and the drug was immersed in the hydrogel, obtaining a NOR-loaded PVMAC hydrogel dressing and an EM-loaded PVMAC hydrogel dressing, respectively.

[0046] Example 4

[0047] A method for preparing a temperature-responsive hydrogel-based wound dressing material, comprising the following steps:

[0048] First, 0.672 g [VBIM + ] Br - was dissolved in 7.4 mL of deionized water, and after ultrasonic stirring for 10 min, a polyion solution was obtained; then 0.75 g of AM and 1.2 mL of AA were dissolved in the above polyion solution under ultrasonic stirring, and 20 mg of uniformly dispersed CMC was added to the above solution. Subsequently, 20 mg of initiator (APS) and 10 mg of crosslinking agent (MBA) were added to the above solution, and after ultrasonic stirring until complete dissolution, a PVMAC hydrogel precursor solution was obtained. The PVMAC hydrogel precursor solution was uniformly poured into a 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 9 hours to remove unreacted acrylic acid and acrylamide, and the drug was immersed in the hydrogel, obtaining a PVMAC hydrogel dressing.

[0049] Example 5

[0050] A method for preparing a temperature-responsive hydrogel-based wound dressing material, comprising the following steps:

[0051] First, 0.84 g [VBIM + ] Br - was dissolved in 7.4 mL of deionized water, and after ultrasonic stirring for 10 min, a polyion solution was obtained; then 0.75 g of AM and 1.2 mL of AA were dissolved in the above polyion solution under ultrasonic stirring, and 20 mg of uniformly dispersed CMC was added to the above solution. Subsequently, 20 mg of initiator (APS) and 10 mg of crosslinking agent (MBA) were added to the above solution, and after ultrasonic stirring until complete dissolution, a PVMAC hydrogel precursor solution was obtained. The PVMAC hydrogel precursor solution was uniformly poured into a 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 10 hours to remove unreacted acrylic acid and acrylamide, and the drug was immersed in the hydrogel, obtaining a PVMAC hydrogel dressing.

[0052] The temperature-responsive hydrogel-based wound dressing material described above was characterized and performance tested. The scanning electron micrograph and pore size distribution of the PVMAC hydrogel in Example 3 are shown in Figure 1 , and the real scene graph of the transparency change of the PVMAC hydrogel in Example 3 is shown in Figure 2 , and the mechanical property test results of the PVMAC hydrogel prepared in Example 3 are shown in Table 1.Figure 3 As shown, the tensile force of the hydrogel prepared in Example 1-5 was tested by using a texture analyzer, and the test results are shown in Table 1. Figure 4 As shown, Figure 5 is a test chart of drug diffusion release of the PVMAC hydrogel dressing loaded with 30 μg / mL norfloxacin prepared in Example 3 in a diffusion cell containing phosphate buffer. Figure 6 is a test chart of wound healing promotion of the PVMAC hydrogel dressing prepared in Example 3.

[0053] Therefore, it is known that the conversion temperature of the PVMAC hydrogel dressing prepared in the present application can be controlled at 37℃, i.e. it is in an opaque state below 37℃ and in a transparent state above 37℃, and the change of temperature is also accompanied by the change of the pore size of the hydrogel. In addition, it has excellent mechanical properties and good antibacterial and biocompatible properties, which all provide conditions for it as a temperature-responsive hydrogel dressing. The preparation of the temperature-responsive hydrogel in the present application has important practical significance for expanding its application in hydrogel-based dressings.

[0054] The above only describes the preferred embodiments of the present application and is not used to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method of making a temperature-responsive hydrogel-based wound dressing material, characterized by, The application relates to a temperature-responsive hydrogel-based wound dressing material, comprising the following steps: 1-vinyl-3-butyl imidazole bromide and acrylic acid, acrylamide and carboxymethyl cellulose are uniformly mixed in a solvent through ultrasonic treatment, an initiator and a crosslinking agent are added, and mixing is uniformly carried out, so as to obtain a PVMAC hydrogel precursor solution; The PVMAC hydrogel precursor solution is injection molded to obtain a PVMAC hydrogel; The PVMAC hydrogel is soaked in a phosphate buffer solution containing a drug to obtain the temperature-responsive hydrogel-based wound dressing material; The mass-volume ratio of 1-vinyl-3-butyl imidazole bromide, acrylic acid, acrylamide and carboxymethyl cellulose is 0.168 g-0.84 g:1.2 mL:0.75 g:0.02 g; The conversion temperature of the temperature-responsive hydrogel-based wound dressing material is 37 DEG C; In the injection molding process, the PVMAC hydrogel precursor solution is subjected to a polymerization reaction; The polymerization reaction time is 30 min-60 min; The soaking time is 6-12 hours.

2. The method of claim 1, wherein the temperature-responsive hydrogel-based wound dressing material is prepared by the steps of: The initiator is ammonium persulfate.

3. The method of claim 1, wherein the temperature-responsive hydrogel-based wound dressing material is prepared by the steps of: The crosslinking agent is N,N'-methylene bisacrylamide.

4. The method of claim 1, wherein the temperature-responsive hydrogel-based wound dressing material is prepared by the steps of: In the injection molding process, the PVMAC hydrogel precursor solution is subjected to a polymerization reaction at 60 DEG C-65 DEG C.

5. The method of claim 1, wherein the temperature-responsive hydrogel-based wound dressing material is prepared by the steps of: In the phosphate buffer solution containing the drug, the concentration of the drug is 30 mu g / mL-40 mu g / mL.

6. The method of claim 1, wherein the temperature-responsive hydrogel-based wound dressing material is prepared by the steps of: The drug is erythromycin or norfloxacin.

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