Semi-ipn type, full-ipn type temperature / pH dual response intelligent hydrogel and preparation method and application thereof

Abstract

The application provides a Semi-IPN type, Full-IPN type temperature / pH dual-response intelligent hydrogel and a preparation method and application thereof, and belongs to the field of response materials. The preparation method is as follows: N-isopropyl acrylamide, N-hydroxymethyl acrylamide and N,N'-methylene bisacrylamide are dissolved in distilled water under a nitrogen atmosphere, and a mixed solution A is obtained by stirring in a cold water bath; carboxymethyl chitosan is added into the mixed solution A and uniformly mixed, then an initiator ammonium persulfate is added and uniformly stirred, then tetramethyl ethylenediamine solution is added and uniformly stirred, and the Semi-IPN temperature / pH dual-response intelligent hydrogel is obtained by transferring into a container and reacting; then the hydrogel is dialyzed, soaked in a ninhydrin aqueous solution and dialyzed again to obtain the Full-IPN temperature / pH dual-response intelligent hydrogel; the obtained IPN type temperature / pH dual-response intelligent hydrogel has good biocompatibility, simultaneously has temperature and pH dual-response, and has a potential application prospect in the fields of wound dressings, drug delivery and tissue engineering.

Description

Technical Field

[0001] The present invention belongs to the field of responsive materials, and specifically relates to Semi-IPN type and Full-IPN type temperature / pH dual-responsive smart hydrogels, as well as preparation methods and applications thereof. Background Art

[0002] Smart hydrogels, also known as sensitive hydrogels, are a class of polymer hydrogels that can sense subtle changes or stimuli in the external environment (such as temperature, pH, light, and biomolecules) and produce corresponding changes in physical structure and chemical properties. This intelligence makes sensitive hydrogels potentially applicable in a wide range of fields, particularly in the sustained release of drugs, protein separation and purification, encapsulation of active enzymes, and artificial muscles. Consequently, their research has garnered widespread attention from scholars both domestically and internationally.

[0003] As a typical temperature-responsive hydrogel carrier material, poly(N-isopropylacrylamide, PNIPAM) hydrogels typically undergo a volume phase transition near their lower critical solution temperature (LCST) of 33°C. Both hydrogels formed by the self-polymerization of N-isopropylacrylamide (NIPAM) and those copolymerized with other monomers exhibit excellent temperature-responsive properties.

[0004] However, due to the complex environment surrounding human tissue, single-responsive hydrogel drug carriers are gradually failing to meet people's needs. As two very important indicators in physiology, the combination of temperature and pH response is of great significance for protecting drugs from degradation, avoiding unnecessary effects when drugs pass through different organs and tissues, and delivering drugs to specific tissues.

[0005] However, if temperature-responsive materials are copolymerized with pH-responsive monomers, the LCST of the original hydrogel will often change, or even reduce its temperature-responsive performance. In addition, the uneven network structure of the single-layer gel will also reduce the mechanical strength of the hydrogel.

[0006] Therefore, there is an urgent need for a hydrogel material that is non-toxic, biocompatible, has good mechanical properties, and has dual temperature / pH responses. Summary of the Invention

[0007] In view of this, the purpose of the present invention is to provide Semi-IPN type and Full-IPN type temperature / pH dual-responsive smart hydrogels and their preparation methods and applications, which have functions such as temperature / pH dual response and good biocompatibility.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] In a first aspect, the present invention provides a method for preparing a Semi-IPN type temperature / pH dual-responsive smart hydrogel, comprising the following steps:

[0010] S01 N-isopropyl acrylamide, N-hydroxymethyl acrylamide and N, N'-methylenebisacrylamide were dissolved in distilled water under a nitrogen atmosphere and stirred in a cold water bath to obtain a mixed solution A;

[0011] The present invention discovered that the monomers N-hydroxymethyl acrylamide (NHMA) and N-isopropyl acrylamide (NIPAM) have very similar structures. The copolymerization of the two to form the P(NIPAM-co-NHMA) hydrogel exhibits no sensitization, acute systemic toxicity, or genotoxicity, and exhibits excellent biocompatibility. By employing the above-mentioned technical solution, the newly added hydrophilic hydroxymethyl group alters the hydrophobic / hydrophilic balance between the isopropyl and amide groups in the original PNIPAM hydrogel, increasing its LCST and enabling intelligent response to human body temperature.

[0012] S02. Add carboxymethyl chitosan to the mixed solution A and mix evenly. Then add the initiator ammonium persulfate and stir evenly. Then add tetramethylethylenediamine solution and stir evenly. Transfer to a container and react to obtain Semi-IPN temperature / pH dual-responsive smart hydrogel.

[0013] At the same time, carboxymethyl chitosan (CMCS) retains the good antibacterial properties, biocompatibility and biodegradability of chitosan, and makes up for the poor water solubility of chitosan. The amino and carboxyl groups in the CMCS structure give it pH responsive properties.

[0014] Interpenetrating polymer network (IPN) is composed of two or more polymers that penetrate each other through the network. There is no chemical bonding between the polymers in IPN. They are both independent and interdependent. They do not interfere with each other's temperature and pH response performance, and retain the properties of each polymer, with high stability, mechanical properties and biocompatibility. One of the polymers is cross-linked to form a network, and the other polymer is interspersed in the first network in a non-crosslinked chain to form a semi-interpenetrating polymer network (Semi-IPN). The present invention overcomes these shortcomings by forming an interpenetrating polymer network (IPN) with P (NIPAM-co-NHMA) and a highly safe ionizable hydrophilic polymer CMCS through the above technical solution.

[0015] Preferably, the mass ratio of N-isopropylacrylamide, N-hydroxymethylacrylamide, N,N'-methylenebisacrylamide and distilled water in S01 is 0.8-1.2 g: 0.01-0.03 g: 0.01-0.05 g: 8-12 g.

[0016] Preferably, the stirring temperature of the cold water bath in S01 is 2-6° C. and the stirring time is 8-12 min.

[0017] Preferably, the mass volume ratio of the mixed solution A, carboxymethyl chitosan, ammonium persulfate and tetramethylethylenediamine solution in the S02 is 8.82~1.28g:0.01~0.1g:0.01~0.05g:100~500 μL.

[0018] Preferably, the mass concentration of the tetramethylethylenediamine solution is 3% to 6% (v / v).

[0019] Preferably, the tetramethylethylenediamine solution is prepared by adjusting the pH to 7.0 using glacial acetic acid, and then adding an appropriate amount of distilled water to adjust the concentration of the tetramethylethylenediamine solution to 3% to 6% (v / v).

[0020] Preferably, the reaction temperature in the S02 is 2-6°C and the reaction time is 18-30 h.

[0021] In a second aspect, the present invention provides a method for preparing a Full-IPN type temperature / pH dual-responsive smart hydrogel, comprising the following steps:

[0022] The obtained Semi-IPN temperature / pH dual-responsive smart hydrogel was dialyzed with distilled water for 2-4 days and then freeze-dried. It was then immersed in a genipin aqueous solution for 18-30 hours and then dialyzed with distilled water for 2-4 days to obtain the Full-IPN temperature / pH dual-responsive smart hydrogel, which was then freeze-dried and stored.

[0023] By adopting the above technical solution, the product cross-linked with Genipin (GP) is more stable. On the basis of forming the first layer of synthetic polymer P (NIPAM-co-NHMA) rigid network, the second layer of natural polymer CMCS-GP flexible network is introduced. This not only gives the entire gel high strength and high flexibility, but also improves the poor mechanical properties of CMCS, realizing the blending of synthetic polymers and natural polymers.

[0024] Preferably, the mass concentration of the genipin aqueous solution is 0.3% to 7%.

[0025] In a third aspect, the present invention provides the use of the Semi-IPN type temperature / pH dual-responsive smart hydrogel or the Full-IPN type temperature / pH dual-responsive smart hydrogel obtained by the above preparation method in wound dressing and drug delivery.

[0026] Contains at least the following beneficial technical effects:

[0027] The IPN temperature / pH dual-responsive smart hydrogel developed by this invention exhibits excellent performance. It is copolymerized with the temperature-responsive monomer NIPAM and the hydrophilic monomer NHMA. The semi-IPN temperature / pH dual-responsive smart hydrogel exhibits excellent temperature responsiveness and increases the liquid crystal structure (LCST) of the IPN hydrogel to approximately 37°C, the physiological temperature of the human body. When the temperature exceeds 37°C, the hydrogel rapidly turns white and shrinks in volume. Increasing the NHMA concentration further increases the LCST of the smart hydrogel, suggesting potential applications in visual high-temperature detectors or temperature-controlled alarm switches.

[0028] The Full-IPN temperature / pH dual-responsive smart hydrogel incorporates a flexible network of natural polymer CMCS-GP, which not only imparts high strength and flexibility to the entire gel but also forms deeper, more perforated mesh channels. This approach is expected to be used in the field of drug delivery to load various water-soluble drugs, protect drug stability, and improve drug bioavailability. This approach can be used for oral, rectal, transdermal, and vaginal administration to achieve intelligent drug release in response to varying temperature / pH environments, offering new insights into the clinical treatment of diseases such as enteritis and cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Fourier transform infrared spectroscopy results of CMCS, GP, P(NIPAM-co-NHMA) temperature-responsive hydrogels, Semi-IPN prepared in Example 1, and Full-IPN temperature / pH dual-responsive smart hydrogels prepared in Example 4;

[0030] Figure 2 The scanning electron microscopy results of the Semi-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 1;

[0031] Figure 3 The scanning electron microscopy results of the Full-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 4;

[0032] Figure 4 Temperature-saturation swelling degree diagram of Semi-IPN and Full-IPN temperature / pH dual-responsive smart hydrogels prepared in Example 1 and Example 4;

[0033] Figure 5pH-saturation swelling degree diagrams of Semi-IPN and Full-IPN temperature / pH dual-responsive smart hydrogels prepared in Example 1 and Example 4;

[0034] Figure 6 Swelling curves of the Semi-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 1 at different pH values ​​at 25°C;

[0035] Figure 7 Swelling curves of the Full-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 4 at different pH values ​​at 25°C;

[0036] Figure 8 Deswelling curves of the Semi-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 1 at 55°C and different pH values;

[0037] Figure 9 Deswelling curves of the Full-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 4 at 55°C and different pH values;

[0038] Figure 10 The repeated swelling curves of the Semi-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 1 at different pH and temperature alternating between 55°C and 25°C;

[0039] Figure 11 The repeated swelling curves of the Full-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 4 at different pH and temperature alternating between 55°C and 25°C.

[0040] Figure 12 The kinetic curves of the Semi-IPN hydrogel of Example 1 and the Full-IPN hydrogel of Example 4 under different pH conditions are shown.

[0041] Figure 13 This is a transmittance curve of the hydrogel prepared in comparative example. DETAILED DESCRIPTION

[0042] The technical solution of the present invention is further described below with reference to the accompanying drawings and embodiments.

[0043] Unless otherwise defined, technical or scientific terms used in the present invention shall have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.

[0044] It will be obvious to a person skilled in the art that the application is not limited to the details of the foregoing exemplary embodiments and can be implemented in other concrete forms without departing from the spirit or essential characteristics of the application. Therefore, the embodiments should be considered in all respects as illustrative and not restrictive, the scope of the application being defined by the appended claims rather than by the foregoing description, and it is therefore intended that all changes and modifications that fall within the meaning and range of equivalency of the claims be embraced therein, and no picture reference in the claims should be considered limiting as to the claims concerned.

[0045] Furthermore, it should be understood that although the present specification describes particular embodiments, each of which contains only a single independent technical solution, the specification is written in such a way as to be clear for the purpose of clarity, and a person skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by a person skilled in the art. These other embodiments are also covered within the protection scope of the present application.

[0046] It should also be understood that the specific embodiments described above are only used to explain the present application, and the protection scope of the present application is not limited thereto, and any person skilled in the art can make equivalent replacements or changes to the technical solutions and inventive concepts of the present application within the technical scope disclosed by the present application, which should be covered within the protection scope of the present application / invention.

[0047] The following examples use N-isopropyl acrylamide (98%), N-hydroxymethyl acrylamide (98%), N,N'-methylene bisacrylamide (AR), ammonium persulfate (AR, 98.5%), carboxymethyl chitosan (BR) purchased from Shanghai Maikelin Biochemical Technology Co., Ltd.; tetramethyl ethylenediamine (AR) purchased from Tianjin Bohua Chemical Co., Ltd.; genipin (>98%) purchased from Linchuan Zhixin Biological Technology Co., Ltd.

[0048] Example 1

[0049] The present embodiment provides a preparation method of a Semi-IPN temperature / pH dual-responsive intelligent hydrogel, and the preparation steps of the method are as follows:

[0050] 1) Preparation of tetramethyl ethylenediamine solution: adjust the pH to 7.0 with glacial acetic acid, then add an appropriate amount of distilled water to prepare a tetramethyl ethylenediamine solution with a concentration of 5% (v / v);

[0051] 2) Weigh 1 g of N-isopropyl acrylamide, 0.025 g of N-hydroxymethyl acrylamide and 0.02 g of N,N'-methylene bisacrylamide, dissolve them in 10 mL of distilled water, introduce nitrogen, maintain the entire reaction environment in a nitrogen atmosphere, and stir under a 4℃ cold water bath condition for 10 min to obtain a mixed solution A;

[0052] 3) Add 0.01 g of carboxymethyl chitosan to the mixed solution A. After the above monomers are evenly dispersed and completely dissolved, add 0.03 g of initiator ammonium persulfate and continue stirring for 30 minutes.

[0053] 4) Finally, add 300 μL of 5% tetramethylethylenediamine solution, stir until the solution is homogeneous, place in a 10 mL EP tube, seal, and react at 4°C for 24 h to obtain the Semi-IPN temperature / pH dual-responsive smart hydrogel.

[0054] 5) The Semi-IPN temperature / pH dual-responsive smart hydrogel was removed and cut into 0.5 cm thick cylinders. The cylinders were dialyzed with distilled water for 3 days and then freeze-dried for storage.

[0055] like Figure 1 As shown in the FT-IR spectrum of Semi-IPN hydrogel, compared with the FT-IR spectrum of P(NIPAM-co-NHMA), the semi-IPN hydrogel showed a 1572 cm -1 The peak is attributed to the characteristic absorption peak of -NH2 on CMCS, 929 cm -1 The characteristic absorption peak is attributed to the NH out-of-plane deformation vibration peak of the primary amine on CMCS. It can be inferred that CMCS exists inside the Semi-IPN hydrogel;

[0056] like Figure 2 SEM results show that the Semi-IPN hydrogel has deeper, more obvious, and more penetrating mesh channels than the single-layer network temperature-responsive hydrogel, providing diffusion channels for water molecules and drugs. In the 50 μm and 20 μm Semi-IPN images, chain-like substances can be seen running through them, and the mesh distribution is very uniform, with consistent pore size.

[0057] like Figure 4 As shown in Figure 2, the saturated swelling degree of the Semi-IPN temperature / pH dual-responsive smart hydrogel gradually decreases with increasing temperature until it reaches equilibrium, showing obvious temperature-responsive performance; Figure 5 As shown in the figure, the saturated swelling degree of the Semi-IPN hydrogel gradually decreases with increasing pH, showing a significant pH-responsive property. This may be because the free amino groups on the CMCS exist in ionic form at lower pH, at which point electrostatic and hydrophilic interactions increase, and like-charge repulsion enlarges the gel pores, allowing the gel to absorb water. Conversely, as the pH increases, the gel's water absorption weakens, and the saturated swelling degree decreases.

[0058] like Figure 6As shown in the figure, in an environment of 25°C, when the pH is low, the Semi-IPN temperature / pH dual-responsive smart hydrogel has better water absorption performance and a greater swelling degree. At this time, the time required to reach saturated swelling is also longer, showing obvious pH response characteristics. The swelling performance increases with decreasing pH.

[0059] like Figure 8 As shown in the figure, in a 55°C environment, when the pH is low, the Semi-IPN temperature / pH dual-responsive smart hydrogel has a higher degree of deswelling and a faster deswelling speed, showing obvious pH response characteristics, and the water loss performance increases with decreasing pH.

[0060] like Figure 10 As shown in the figure, the repeated swelling kinetic curves of the Semi-IPN temperature / pH dual-responsive smart hydrogel at 55°C and 25°C show the same trend under different pH conditions. During the multiple shrinkage and swelling processes, the swelling degree of the hydrogel at the same temperature did not change much, whether under acidic, neutral or alkaline conditions. Different temperatures and pH values ​​did not destroy the overall network structure of the hydrogel. In addition, the swelling degree of the hydrogel at low pH in the curve is always greater than that at high pH, ​​further verifying the temperature and pH response characteristics of the Semi-IPN temperature / pH dual-responsive smart hydrogel.

[0061] Example 2

[0062] This embodiment provides a method for preparing a Semi-IPN temperature / pH dual-responsive smart hydrogel. The preparation steps of the method are as follows:

[0063] 1) Preparation of tetramethylethylenediamine solution: Adjust the pH to 7.0 with glacial acetic acid, then add appropriate amount of distilled water to prepare the tetramethylethylenediamine solution concentration to 3% (v / v);

[0064] 2) Weigh 0.8 g of N-isopropylacrylamide, 0.01 g of N-hydroxymethylacrylamide, and 0.01 g of N,N'-methylenebisacrylamide and dissolve them in 8 mL of distilled water. Pour nitrogen into the reaction mixture to maintain a nitrogen atmosphere. Stir in a 4°C cold water bath for 10 min to obtain a mixed solution A.

[0065] 3) Add 0.05 g of carboxymethyl chitosan to the mixed solution A. After the above monomers are evenly dispersed and completely dissolved, add 0.01 g of initiator ammonium persulfate and continue stirring for 30 minutes.

[0066] 4) Finally, add 100 μL of 3% tetramethylethylenediamine solution, stir until the solution is homogeneous, place in a 10 mL EP tube, seal, and react at 2°C for 30 h to obtain the Semi-IPN temperature / pH dual-responsive smart hydrogel.

[0067] 5) The Semi-IPN temperature / pH dual-responsive smart hydrogel was removed and cut into 0.5 cm thick cylinders. The cylinders were dialyzed with distilled water for 2 days and then freeze-dried for storage.

[0068] Example 3

[0069] This embodiment provides a method for preparing a Semi-IPN temperature / pH dual-responsive smart hydrogel. The preparation steps of the method are as follows:

[0070] 1) Preparation of tetramethylethylenediamine solution: Adjust the pH to 7.0 with glacial acetic acid, then add appropriate amount of distilled water to prepare the tetramethylethylenediamine solution concentration to 6% (v / v);

[0071] 2) Weigh 1.2 g of N-isopropylacrylamide, 0.03 g of N-hydroxymethylacrylamide, and 0.05 g of N,N'-methylenebisacrylamide and dissolve them in 12 mL of distilled water. Pour nitrogen into the reaction mixture to maintain a nitrogen atmosphere. Stir in a 2°C cold water bath for 12 min to obtain a mixed solution A.

[0072] 3) Add 0.1 g of carboxymethyl chitosan to the mixed solution A. After the above monomers are evenly dispersed and completely dissolved, add 0.05 g of initiator ammonium persulfate and continue stirring for 30 minutes.

[0073] 4) Finally, add 500 μL of 3% tetramethylethylenediamine solution, stir until the solution is homogeneous, place in a 10 mL EP tube, seal, and react at 2°C for 30 h to obtain the Semi-IPN temperature / pH dual-responsive smart hydrogel.

[0074] 5) The Semi-IPN temperature / pH dual-responsive smart hydrogel was removed and cut into 0.5 cm thick cylinders. The cylinders were dialyzed with distilled water for 4 days and then freeze-dried for storage.

[0075] Example 4

[0076] A method for preparing a Full-IPN temperature / pH dual-responsive smart hydrogel, the preparation steps of the method are as follows:

[0077] 1) Preparation of tetramethylethylenediamine solution: Adjust the pH to 7.0 with glacial acetic acid, then add appropriate amount of distilled water to prepare the tetramethylethylenediamine solution concentration to 5% (v / v);

[0078] 2) Weigh 1 g of N-isopropylacrylamide, 0.025 g of N-hydroxymethylacrylamide, and 0.02 g of N,N'-methylenebisacrylamide and dissolve them in 10 mL of distilled water. Pour nitrogen into the reaction mixture to maintain a nitrogen atmosphere. Stir in a 4°C cold water bath for 10 min to obtain a mixed solution A.

[0079] 3) Add 0.01 g of carboxymethyl chitosan to the mixed solution A. After the above monomers are evenly dispersed and completely dissolved, add 0.03 g of initiator ammonium persulfate and continue stirring for 30 minutes.

[0080] 4) Finally, add 300 μL of 5% tetramethylethylenediamine solution, stir until the solution is homogeneous, transfer to a 10 mL EP tube, seal, and incubate at 4°C for 24 h. Remove the hydrogel, cut it into 0.5 cm thick cylinders, and dialyze against distilled water for 3 days.

[0081] 5) The dialyzed gel was removed and placed in 150 mL of a 0.5% GP aqueous solution for 24 h. The dialyzed gel was then dialyzed with distilled water for 3 days to form a Full-IPN temperature / pH dual-responsive smart hydrogel, which was then freeze-dried for storage.

[0082] like Figure 1 The FT-IR results of Full-IPN hydrogel showed that the -1 and 1592 cm -1 The characteristic peaks at 1105 cm are the C=O stretching vibration peak of CMCS and the -NH2 characteristic absorption peak. -1 The stretching vibration peak of CN is at 1066 cm -1 The peak at 3399 cm is the CO stretching vibration peak. -1 and 3237 cm -1 The characteristic peak at 1682 cm is the intermolecular hydrogen bond of GP. -1 The stretching vibration peak of C=O is at 1300 cm -1 and 1204 cm -1 The peaks at 3399 cm-1 of Full-IPN hydrogel are the CO stretching vibration peaks on the ester group and ether ring respectively. -1 and 3237 cm -1 The strong absorption peak at 1648 cm -1 (C=O) and 1546 cm -1 The ratio of the absorption peak at 1300 cm -1 and 1204 cm -1 The strong peaks of CO on the ester group and ether ring disappeared, and the peak at 1130 cm -1 and 1066 cm -1 The absorption peak ratio at increases, indicating that the new amide bond produced in the reaction consumes the original CO bond and generates more CN bonds. FT-IR results also further verify the cross-linking reaction mechanism of CMCS and GP.

[0083] like Figure 3 SEM results show that the Full-IPN hydrogel has much larger mesh than the Semi-IPN hydrogel, and the pore size is not uniform, and the second layer network structure appears in some large holes. Further magnification of the second layer network structure shows that it has a shallow and huge network. Compared with the single-layer network temperature-responsive hydrogel, the double-layer network temperature / pH-responsive hydrogel has a more complex micro-morphology.

[0084] As shown in Figure 4 , the saturation swelling degree of the Full-IPN temperature / pH dual-responsive intelligent hydrogel gradually decreases with the increase of temperature until equilibrium, showing obvious temperature response performance.

[0085] As shown in Figure 5 , the saturation swelling degree of the Full-IPN hydrogel gradually decreases with the increase of pH, showing obvious pH response performance.

[0086] As shown in Figure 7 , in a 25℃ environment, when the pH is low, the Full-IPN temperature / pH dual-responsive intelligent hydrogel has better water absorption performance, and its swelling degree is larger, and the time required to reach saturation swelling is also longer, showing obvious pH response characteristics, and the swelling performance increases with the decrease of pH.

[0087] As shown in Figure 9 , in a 55℃ environment, when the pH is low, the Full-IPN temperature / pH dual-responsive intelligent hydrogel has a higher degree of deswelling and a faster deswelling speed, showing obvious pH response characteristics, and the water loss performance increases with the decrease of pH.

[0088] As shown in Figure 11 , the trends of the Full-IPN temperature / pH dual-responsive intelligent hydrogel under different pH values at 55℃ and 25℃ are the same. In several shrinkage and swelling processes, whether in acidic, neutral or alkaline conditions, the swelling degree of the hydrogel at the same temperature does not change much, and different temperatures and pH values do not destroy the overall network structure of the hydrogel. In addition, the swelling degree of the hydrogel at low pH is always larger than that at high pH, further verifying the temperature and pH response characteristics of the Full-IPN temperature / pH dual-responsive intelligent hydrogel.

[0089] As shown in Figure 12As shown in the figure, the swelling (a, b, c red) - deswelling (a, b, c black) - repeated swelling kinetics (d, e, f) curves of Semi-IPN and Full-IPN hydrogels under different pH conditions. It can be seen from the figure that Full-IPN hydrogel exhibits better swelling, repeated swelling and faster deswelling rate than Semi-IPN hydrogel.

[0090] Example 5

[0091] The preparation method of this embodiment is the same as that of embodiment 4, except that the mass concentration of the genipin aqueous solution in step 5) is 0.3%.

[0092] Example 6

[0093] The preparation method of this embodiment is the same as that of embodiment 4, except that the mass concentration of the genipin aqueous solution in step 5) is 0.7%.

[0094] Comparative Example 1

[0095] A method for preparing a P(NIPAM-co-NHMA) temperature-responsive hydrogel, the preparation steps of the method are as follows:

[0096] 1) Preparation of tetramethylethylenediamine solution: Adjust the pH to 7.0 with glacial acetic acid, then add appropriate amount of distilled water to prepare the tetramethylethylenediamine solution concentration to 5% (v / v);

[0097] 2) Weigh 1 g of N-isopropylacrylamide, 0.025 g of N-hydroxymethylacrylamide, and 0.02 g of N,N'-methylenebisacrylamide and dissolve them in 10 mL of distilled water. Pour nitrogen into the reaction mixture to maintain a nitrogen atmosphere. Stir in a 4°C cold water bath for 10 min to obtain a mixed solution A.

[0098] 3) After the above monomers are evenly dispersed and completely dissolved, add 0.03 g of initiator APS and continue stirring for 30 minutes;

[0099] 4) Finally, add 300 μL of 5% tetramethylethylenediamine solution, stir until the solution is homogeneous, place in a 10 mL EP tube, seal, and react at 4°C for 24 h to obtain the P(NIPAM-co-NHMA) temperature-responsive hydrogel.

[0100] 5) Remove the P(NIPAM-co-NHMA) hydrogel, cut it into 0.5 cm thick cylinders, dialyze it with distilled water for 3 days, and then freeze-dry it for storage.

[0101] from Figure 1 The FT-IR spectrum of P(NIPAM-co-NHMA) can be seen at 2974 cm -1and 2939 cm -1 The characteristic absorption peak is the CH stretching vibration between the methyl and methylene groups on the isopropyl group; 1655 cm -1 The C=O stretching vibration peak of amide is at 1460 cm -1 The peak at 1387 cm is the CH asymmetric deformation vibration peak of the methylene group on the isopropyl group; -1 and 1368 cm -1 The peak at 1173 cm is the doublet of CH symmetric deformation vibration between the methyl groups on the isopropyl group; -1 The peak at 1040 cm is the skeleton vibration peak of CC on the isopropyl group. -1 A strong peak appeared at 1620 cm-1, which is the CO stretching vibration peak of the primary alcohol on the hydroxymethyl group in P(NIPAM-co-NHMA). -1 There is no obvious absorption peak at the bottom, indicating that P(NIPAM-co-NHMA) was successfully prepared and there is no C=C olefin monomer remaining in the dialyzed gel.

[0102] like Figure 13 As shown in the figure, the transmittance curves of P(NIPAM-co-NHMA), Semi-IPN, and Full-IPN hydrogels have exactly the same trend. The transmittance gradually decreases with increasing temperature until it approaches 0. Moreover, the temperature point at which the transmittance of these three hydrogels drops sharply to near zero is exactly the same, that is, the LCST of all three hydrogels is 37°C. This indirectly confirms that both the CMCS chain (Semi-IPN) and the CMCS-GP network (Full-IPN) are independent of the P(NIPAM-co-NHMA) network, and the introduction of CMCS has no effect on the temperature response of P(NIPAM-co-NHMA).

[0103] The above description is merely a preferred embodiment of the present application and is not intended to limit the present application. Various modifications and variations are possible for those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present application shall be included within the scope of protection of the present application.

Claims

1. Preparation method of Full-IPN type temperature / pH dual-responsive smart hydrogel, characterized in that: The following steps are involved: S01 N-isopropyl acrylamide, N-hydroxymethyl acrylamide and N, N'-methylenebisacrylamide were dissolved in distilled water and stirred in a cold water bath under a nitrogen atmosphere to obtain a mixed solution A; S02. Carboxymethyl chitosan was added to the mixed solution A and mixed evenly. Then, the initiator ammonium persulfate was added and stirred evenly. Then, tetramethylethylenediamine solution was added and stirred evenly. The mixture was transferred to a container for reaction to obtain a Semi-IPN temperature / pH dual-responsive smart hydrogel. The mass ratio of N-isopropylacrylamide, N-hydroxymethylacrylamide, N,N'-methylenebisacrylamide and distilled water in S01 is 0.8-1.2 g: 0.01-0.03 g: 0.01-0.05 g: 8-12 g; The mass volume ratio of carboxymethyl chitosan, ammonium persulfate and tetramethylethylenediamine solution in the SO2 is 0.01-0.1 g: 0.01-0.05 g: 100-500 μL; The concentration of the tetramethylethylenediamine solution is 3-6 v / v; S03. The obtained Semi-IPN temperature / pH dual-responsive smart hydrogel was dialyzed with distilled water for 2-4 days and then freeze-dried. The hydrogel was then immersed in a genipin aqueous solution for 18-30 hours and then dialyzed with distilled water for another 2-4 days to obtain the Full-IPN temperature / pH dual-responsive smart hydrogel, which was then freeze-dried and stored. The mass concentration of the genipin aqueous solution is 0.3-7%.

2. The preparation method according to claim 1, characterized in that The stirring temperature of the cold water bath in S01 is 2-6°C and the stirring time is 8-12 minutes.

3. The preparation method according to claim 1, characterized in that The tetramethylethylenediamine solution is prepared by adjusting the pH to 7.0 using glacial acetic acid, and then adding an appropriate amount of distilled water to adjust the concentration of the tetramethylethylenediamine solution to 3-6 v / v%.

4. The preparation method according to claim 1, characterized in that The reaction temperature in the SO2 is 2-6°C and the reaction time is 18-30 h.

5. Application of the Full-IPN temperature / pH dual-responsive smart hydrogel obtained by the preparation method according to any one of claims 1 to 4 in the fields of wound dressing and drug delivery.

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