Semi-IPN type and Full-IPN type temperature / pH dual-response intelligent hydrogel as well as preparation method and application thereof

Abstract

The invention provides a Semi-IPN type and Full-IPN type temperature / pH dual response intelligent hydrogel as well as a preparation method and application thereof, and belongs to the field of response materials. The preparation method comprises the following steps: dissolving N-isopropylacrylamide, N-hydroxymethyl acrylamide and N, N '-methylene bisacrylamide in distilled water together, and stirring in a cold bath in a nitrogen atmosphere to obtain a mixed solution A; adding carboxymethyl chitosan into the mixed solution A, uniformly mixing, adding an initiator ammonium persulfate, uniformly stirring, adding a tetramethylethylenediamine solution, uniformly stirring, transferring into a container, and reacting to obtain the Semi-IPN temperature / pH dual-response intelligent hydrogel; dialyzing, soaking in a genipin aqueous solution, and dialyzing, so as to obtain the Full-IPN temperature / pH dual-response intelligent hydrogel. The obtained IPN type temperature / pH dual response intelligent hydrogel is good in biocompatibility, has temperature and pH dual response, and has potential application prospects in the fields of wound dressing, drug delivery, tissue engineering and the like.

Description

Technical Field

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

[0002] Smart hydrogel, also known as sensitive hydrogel, refers to a type of polymer hydrogel that can sense small changes or stimuli in the external environment (such as temperature, pH value, light and biomolecules, etc.) and produce corresponding changes in physical structure and chemical properties. Due to the intelligence of sensitive hydrogel, it is possible to be applied in many fields, especially in the sustained release of drugs, separation and purification of proteins, embedding of active enzymes and artificial muscles. Therefore, its research has attracted extensive attention from scholars at home and abroad.

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

[0004] However, due to the complex environment around human tissues, single-response hydrogel drug carriers are gradually unable 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 the temperature-responsive material is copolymerized with the pH-responsive monomer, the LCST of the original hydrogel will often be changed, or even its temperature-responsive performance will be reduced. 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 preparation methods and applications thereof, 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 finds that the structures of monomers N-hydroxymethyl acrylamide (NHMA) and N-isopropyl acrylamide (NIPAM) are very similar, and the P(NIPAM-co-NHMA) hydrogel formed by copolymerization of the two is non-sensitizing, non-acute systemic toxicity and non-genotoxic, and has good biocompatibility. By adopting the above technical solution, the newly added hydrophilic group hydroxymethyl changes the hydrophobic / hydrophilic balance of the isopropyl group and the amide group in the original PNIPAM hydrogel, increases its LCST, and can intelligently respond 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 for reaction 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, which 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-cross-linked chain to form a semi-interpenetrating polymer network (Semi-IPN). The present invention can overcome 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-mentioned technical scheme.

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

[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 S02 is 8.82-1.28 g: 0.01-0.1 g: 0.01-0.05 g: 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 prepare the tetramethylethylenediamine solution to a concentration of 3% to 6% (v / v).

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

[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 Semi-IPN temperature / pH dual-responsive smart hydrogel obtained above was dialyzed with distilled water for 2 to 4 days and then freeze-dried. It was then immersed in a genipin aqueous solution for 18 to 30 hours and then continued to be dialyzed with distilled water for 2 to 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 scheme, the product cross-linked with Genipin (GP) is more stable, and on the basis of forming the first layer of synthetic polymer P (NIPAM-co-NHMA) rigid network, the introduction of the second layer of natural polymer CMCS-GP flexible network not only gives the entire gel high strength and high flexibility, but also improves the poor mechanical properties of CMCS, thereby 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 dressings and drug delivery.

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

[0027] The IPN temperature / pH dual-responsive smart hydrogel developed by the present invention has excellent performance, and is copolymerized by using a monomer NIPAM with temperature responsive characteristics and a hydrophilic monomer NHMA. The Semi-IPN type temperature / pH dual-responsive smart hydrogel has good temperature responsiveness, and increases the LCST of the IPN hydrogel to about 37°C, the physiological temperature of the human body. When the temperature of the hydrogel is greater than 37°C, the color will quickly turn white and the volume will shrink. Increasing the concentration of NHMA can further increase the LCST of the smart hydrogel, and has potential application prospects in visual high-temperature detectors or temperature-controlled alarm switches.

[0028] The Full-IPN temperature / pH dual-responsive smart hydrogel introduces the natural polymer CMCS-GP flexible network, which not only gives the entire gel high strength and high flexibility, but also forms a deeper and more penetrating mesh channel. It is expected to load different water-soluble drugs in the field of drug delivery, protect drug stability, and improve drug bioavailability. It can be used for oral, rectal, transdermal, vaginal administration and other routes to achieve intelligent response release of drugs to different temperature / pH environments, providing new ideas for 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 2;

[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 2;

[0032] Figure 4 Temperature-saturated swelling degree diagram of the Semi-IPN and Full-IPN temperature / pH dual-responsive smart hydrogels prepared in Example 1 and Example 2;

[0033] Figure 5pH-saturated swelling degree diagram of Semi-IPN and Full-IPN temperature / pH dual-responsive smart hydrogels prepared for Example 1 and Example 2;

[0034] Figure 6 The 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 The swelling curves of the Full-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 2 at different pH values ​​at 25°C;

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

[0037] Fig. 9 The deswelling curves of the Full-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 2 at 55°C and different pH values;

[0038] Fig.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] Fig.11 The repeated swelling curves of the Full-IPN temperature / pH dual-responsive smart hydrogel prepared in Example 2 at different pH and temperature alternating between 55°C and 25°C.

[0040] Fig.12 The kinetic curves of the Semi-IPN of Example 1 and the Full-IPN of Example 2 under different pH conditions.

[0041] Fig.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 through the accompanying drawings and embodiments.

[0043] Unless otherwise defined, technical or scientific terms used in the present invention shall have the common meanings understood by one having ordinary skills in the field to which the present invention belongs.

[0044] It is obvious to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the main idea or essential features of the present invention. Therefore, from all points of view, the embodiments should be regarded as exemplary and non-restrictive, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims are included in the present invention, and any reference numerals in the claims should not be regarded as limiting the claims involved.

[0045] In addition, it should be understood that although this specification is described according to the implementation modes, not every implementation mode includes only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation modes that can be understood by those skilled in the art. These other implementation modes are also covered within the protection scope of the present invention.

[0046] It should also be understood that the specific embodiments described above are only used to explain the present invention, and the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, can make equivalent replacements or changes based on the technical solutions and inventive concepts of the present invention, which should be covered by the protection scope of the present invention / invention.

[0047] N-isopropylacrylamide (98%), N-hydroxymethylacrylamide (98%), N,N'-methylenebisacrylamide (AR), ammonium persulfate (AR, 98.5%), and carboxymethyl chitosan (BR) used in the following examples were purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; tetramethylethylenediamine (AR) was purchased from Tianjin Bohai Chemical Co., Ltd.; and genipin (>98%) was purchased from Linchuan Zhixin Biotechnology Co., Ltd.

[0048] Example 1

[0049] This embodiment provides a method for preparing a Semi-IPN temperature / pH dual-responsive smart hydrogel, and the preparation steps of the method are as follows:

[0050] 1) Preparation of tetramethylethylenediamine solution: adjust the pH to 7.0 with glacial acetic acid, and then add an appropriate amount of distilled water to prepare the tetramethylethylenediamine solution concentration to 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'-methylenebisacrylamide and dissolve them in 10 mL of distilled water, introduce nitrogen gas to maintain the entire reaction environment as a nitrogen atmosphere, and stir for 10 min in a cold water bath at 4°C to obtain a mixed solution A;

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

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

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

[0055] like Figure 1 The FT-IR image of Semi-IPN hydrogel shows that compared with the FT-IR image of P(NIPAM-co-NHMA), the Semi-IPN hydrogel has a 1572 cm -1 The peak is attributed to -NH on CMCS 2 The characteristic absorption peak of -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 The 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, thus providing diffusion channels for water molecules and drugs. In the 50μm and 20μm Semi-IPN images, chain-like substances can be seen running through them, and the mesh distribution is very uniform, and the pore size is also consistent;

[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 Semi-IPN hydrogel gradually decreases with the increase of pH, showing obvious pH response performance. This may be because the free amino groups on CMCS exist in ionic form at low pH, at which time the electrostatic and hydrophilic effects increase, and the repulsion of the same charges makes the gel mesh larger, and the gel absorbs water; on the contrary, when the pH increases, the water absorption of the gel weakens and the saturated swelling degree decreases.

[0058] like Figure 6As shown, in a 25°C environment, 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, and the swelling performance increases with decreasing pH.

[0059] like Figure 8 As shown, 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 Fig.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 have the same trend under different pH values. During the several shrinkage and swelling processes, the swelling degree of the hydrogel at the same temperature did not change much, whether it was acidic, neutral or alkaline conditions, and 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 of the hydrogel at high pH, ​​which further verifies 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, and 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, and then add an appropriate amount of distilled water to prepare the tetramethylethylenediamine solution concentration to 3% (v / v);

[0064] 2) Weigh 0.8 g of N-isopropyl acrylamide, 0.01 g of N-hydroxymethyl acrylamide and 0.01 g of N,N'-methylenebisacrylamide and dissolve them in 8 mL of distilled water, introduce nitrogen gas to maintain the entire reaction environment as a nitrogen atmosphere, and stir for 10 min in a cold water bath at 4°C to obtain a mixed solution A;

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

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

[0067] 5) The Semi-IPN temperature / pH dual-responsive smart hydrogel was taken out, cut into 0.5 cm thick cylinders, 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, and 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, and then add an appropriate amount of distilled water to prepare the tetramethylethylenediamine solution concentration to 6% (v / v);

[0071] 2) Weigh 1.2 g of N-isopropyl acrylamide, 0.03 g of N-hydroxymethyl acrylamide and 0.05 g of N,N'-methylenebisacrylamide and dissolve them in 12 mL of distilled water, introduce nitrogen gas to maintain the entire reaction environment as a nitrogen atmosphere, and stir for 12 min in a 2°C cold water bath to obtain a mixed solution A;

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

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

[0074] 5) The Semi-IPN temperature / pH dual-responsive smart hydrogel was taken out, cut into 0.5 cm thick cylinders, 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, and then add an appropriate amount of distilled water to prepare the tetramethylethylenediamine solution concentration to 5% (v / v);

[0078] 2) Weigh 1 g of N-isopropyl acrylamide, 0.025 g of N-hydroxymethyl acrylamide and 0.02 g of N,N'-methylenebisacrylamide and dissolve them in 10 mL of distilled water, introduce nitrogen gas to maintain the entire reaction environment as a nitrogen atmosphere, and stir for 10 min in a cold water bath at 4°C to obtain a mixed solution A;

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

[0080] 4) Finally, add 300 μL of 5% tetramethylethylenediamine solution, stir until the solution is uniform, put into a 10 mL EP tube, seal and react at 4°C for 24 hours. Take out the hydrogel, cut it into 0.5 cm thick cylinders, and dialyze with distilled water for 3 days.

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

[0082] like Figure 1 The FT-IR results of Full-IPN hydrogel show that the -1 and 1592cm -1 The characteristic peaks at are the C=O stretching vibration peak of CMCS and -NH 2 Characteristic absorption peak, 1105cm -1 The stretching vibration peak of CN is 1066cm -1 The peak is the CO stretching vibration peak. -1 With 3237cm -1 The characteristic peak at 1682 cm is the intermolecular hydrogen bond of GP. -1 The stretching vibration peak of C=O is at 1300cm -1 With 1204cm -1 The peaks at 3399 cm-1 are the CO stretching vibration peaks on the ester group and the ether ring respectively. -1 With 3237cm -1 The strong absorption peak at 1648cm -1 (C=O) and 1546cm -1 The ratio of the absorption peak at 1300 cm -1 With 1204cm -1 The strong peaks of CO on the ester group and ether ring disappeared, 1130cm -1 With 1066cm -1 The absorption peak ratio at 100 nm increased, indicating that the new amide bond produced in the reaction consumed the original CO bond and generated more CN bonds. The FT-IR results also further verified the cross-linking reaction mechanism of CMCS and GP.

[0083] like Figure 3SEM results show that the mesh of Full-IPN hydrogel is much larger than that of Semi-IPN hydrogel, the pore size is not uniform, and is distributed in layers, and a second layer of network structure appears in some large holes. Further zooming in and observing the second layer of network structure, 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 microscopic morphology.

[0084] like Figure 4 As shown, the saturated swelling degree of the Full-IPN temperature / pH dual-responsive smart hydrogel gradually decreases with increasing temperature until reaching equilibrium, showing obvious temperature responsive performance.

[0085] like Figure 5 As shown in the figure, the saturated swelling degree of Full-IPN hydrogel gradually decreases with the increase of pH, showing obvious pH responsiveness.

[0086] like Figure 7 As shown, in a 25°C environment, when the pH is low, the Full-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, and the swelling performance increases with decreasing pH.

[0087] like Fig. 9 As shown in the figure, in a 55°C environment, when the pH is low, the Full-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.

[0088] like Fig.11 As shown in the figure, the repeated swelling kinetic curves of the Full-IPN temperature / pH dual-responsive smart hydrogel at 55°C and 25°C have the same trend under different pH. During the several shrinkage and swelling processes, the swelling degree of the hydrogel at the same temperature did not change much, whether it was acidic, neutral or alkaline conditions, and 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 of the hydrogel at high pH, ​​which further verifies the temperature and pH response characteristics of the Full-IPN temperature / pH dual-responsive smart hydrogel.

[0089] like Fig.12 As 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, and then add an appropriate amount of distilled water to prepare the tetramethylethylenediamine solution concentration to 5% (v / v);

[0097] 2) Weigh 1 g of N-isopropyl acrylamide, 0.025 g of N-hydroxymethyl acrylamide and 0.02 g of N,N'-methylenebisacrylamide and dissolve them in 10 mL of distilled water, introduce nitrogen gas to maintain the entire reaction environment as a nitrogen atmosphere, and stir for 10 min in a cold water bath at 4°C to obtain a mixed solution A;

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

[0099] 4) Finally, add 300 μL of 5% tetramethylethylenediamine solution, stir until the solution is uniform, put it into a 10 mL EP tube, seal it and react at 4°C for 24 hours to obtain P(NIPAM-co-NHMA) temperature-responsive hydrogel;

[0100] 5) The P(NIPAM-co-NHMA) hydrogel was taken out and cut into 0.5 cm thick cylinders, dialyzed with distilled water for 3 days, and then freeze-dried for storage.

[0101] from Figure 1 The FT-IR of P(NIPAM-co-NHMA) can be seen at 2974 cm -1 With 2939cm -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 1460cm -1 The peak at 1387cm is the asymmetric deformation vibration peak of the CH of the methylene group on the isopropyl group; -1With 1368cm -1 The double peak of CH symmetric deformation vibration between methyl groups on isopropyl is 1173cm -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 Fig.13 As shown in the figure, it can be seen that the transmittance curves of P(NIPAM-co-NHMA), Semi-IPN and Full-IPN hydrogels have the same trend. The transmittance gradually decreases with the increase of temperature until it approaches 0, and the temperature points when the transmittance of the three hydrogels drops sharply to zero are exactly the same, that is, the LCST of the 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 only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing a Semi-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 under a nitrogen atmosphere and stirred in a cold water bath to obtain a mixed solution A; 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 for reaction to obtain Semi-IPN temperature / pH dual-responsive smart hydrogel.

2. The preparation method according to claim 1, characterized in that: The mass ratio of N-isopropyl acrylamide, N-hydroxymethyl acrylamide, N,N'-methylenebisacrylamide and distilled water in S01 is 0.8-1.2g: 0.01-0.03g: 0.01-0.05g: 8-12g.

3. 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.

4. The preparation method according to claim 1, characterized in that: The mass volume ratio of the mixed solution A, carboxymethyl chitosan, ammonium persulfate and tetramethylethylenediamine solution in the S02 is 8.82-1.28 g: 0.01-0.1 g: 0.01-0.05 g: 100-500 μL.

5. The preparation method according to claim 4, characterized in that: The concentration of the tetramethylethylenediamine solution is 3-6 v / v%.

6. The preparation method according to claim 5, characterized in that: The preparation method of the tetramethylethylenediamine solution is: using glacial acetic acid to adjust the pH to 7.0, and then adding a proper amount of distilled water to prepare the tetramethylethylenediamine solution concentration to 3-6 v / v%.

7. The preparation method according to claim 1, characterized in that: The reaction temperature in the S02 is 2-6°C and the reaction time is 18-30h.

8. A method for preparing a Full-IPN temperature / pH dual-responsive smart hydrogel, characterized in that: The following steps are involved: The Semi-IPN temperature / pH dual-responsive smart hydrogel obtained in claim 1 is dialyzed with distilled water for 2 to 4 days and then freeze-dried, then immersed in a genipin aqueous solution for 18 to 30 hours, and then dialyzed with distilled water for 2 to 4 days to obtain a Full-IPN temperature / pH dual-responsive smart hydrogel, which is freeze-dried and stored.

9. The preparation method according to claim 8, characterized in that: The mass concentration of the genipin aqueous solution is 0.3-7%.

10. Application of the Semi-IPN type temperature / pH dual-responsive smart hydrogel obtained by the preparation method of any one of claims 1 to 7 or the Full-IPN type temperature / pH dual-responsive smart hydrogel obtained by the preparation method of any one of claims 8 to 9 in the fields of wound dressing and drug delivery.

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