CN116082713B - PH/temperature dual-response intelligent hydrogel and preparation method thereof - Google Patents

PH/temperature dual-response intelligent hydrogel and preparation method thereof Download PDF

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CN116082713B
CN116082713B CN202211556182.1A CN202211556182A CN116082713B CN 116082713 B CN116082713 B CN 116082713B CN 202211556182 A CN202211556182 A CN 202211556182A CN 116082713 B CN116082713 B CN 116082713B
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张琦红
林欣雨
苏为科
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses a pH/temperature dual-response intelligent hydrogel and a preparation method thereof, wherein the method comprises the following steps: (1) Preparing temperature-sensitive hydrogel through chemical crosslinking of hyaluronic acid, hydroxypropyl methylcellulose and 1, 4-butanediol diglycidyl ether; (2) Preparing a pH responsive hydrogel by free radical in situ polymerization using silane coupling agent modified nanocellulose, potassium persulfate, and a polymer precursor; (3) And (3) chemically crosslinking the hydrogel in the step (1) and the hydrogel in the step (2) to obtain the intelligent hydrogel with dual pH/temperature response. The obtained hydrogel is sensitive to the change of environmental pH and temperature, can keep the drug stable in the pH environment of inflammatory wounds and release the drug in the pH environment of acute inflammatory wounds, and can remarkably improve the cytotoxicity and bioavailability of the drug.

Description

PH/temperature dual-response intelligent hydrogel and preparation method thereof
Technical Field
The invention belongs to the technical field of hydrogel preparation, and particularly relates to a pH/temperature dual-response intelligent hydrogel and a preparation method thereof.
Background
The hydrogel is a biological material with a three-dimensional cross-linked network structure and is composed of hydrophilic polymers, and is widely applied to the synthesis of bionic structures in tissue engineering and regenerative medicine. The stimulus-responsive intelligent hydrogel is an intelligent polymer material which deforms and changes phase of a gel network under the stimulus of the surrounding environment so as to generate swelling-shrinkage or gel-sol conversion. Compared with the traditional hydrogel, the stimulus-responsive hydrogel has spatial and temporal sensitivity, and the product made of the material has multiple, variable and controllable properties. The smart hydrogels can be classified into temperature responsiveness, light responsiveness, pressure responsiveness, pH responsiveness, magnetic responsiveness, etc. according to their stimulus signals. At present, the pH response and temperature response hydrogel has very wide application, especially application to wound dressing (Zuki, et al, IOP conf. Series: materials Science and Engineering, 2018, 334, 012046), and has a rich three-dimensional (3D) network structure, good wound exudate absorption performance, can be tightly combined with irregular wound surfaces, effectively prevents microbial penetration, can keep wound surfaces clean and is beneficial to the growth of fresh skin.
Cellulose Nanocrystals (CNC) are a kind of nanoscale cellulose extracted from natural fibers, and Shan et al propose that cellulose nanocrystals have not only nanoparticle characteristics, but also good biocompatibility, flexibility and water retention capacity, and remarkable permeability to gases and liquids, are cellulose derivatives commonly used for preparing composite hydrogels, and in addition, are widely used as reinforcing fillers to improve the mechanical properties of hydrogels due to their excellent tensile strength and rigidity (Yue Shan, et al RSC Advances, 2019, 9, 22966-22979). Hivechi et al studied hydrogels formed by crosslinking nanocellulose with Polycaprolactone (PCL), and the addition of CNC allowed relaxation of the lattice and polymer chains, and the combined drug released into the system with very good controlled release (Ahmad Hivechi et al, cellulose, 2020, 27, 5179-5196).
Currently, pH and temperature dual-response hydrogels still have certain drawbacks. Such as insufficient rigidity strength of the hydrogel in terms of mechanical properties, and insufficient stretching and compressive resistance of the hydrogel, resulting in relatively easy deformation. In addition, hydrogels have low drug loading capacity, limiting the application of functional hydrogels. Therefore, on the premise of ensuring the dual response stimulation of the hydrogel, the rigidity, stretching resistance and compression resistance of the hydrogel are improved, so that the application value and the application range of the hydrogel can be further expanded.
Disclosure of Invention
Aiming at the problem of hydrogel, the invention provides a preparation method of pH/temperature dual-response intelligent hydrogel containing a cellulose nanocrystalline framework and a preparation method thereof.
The preparation method of the pH/temperature dual-response intelligent hydrogel comprises the following steps:
1) Neutralizing hyaluronic acid and sodium hydroxide solution at 40-50deg.C for 15-30 min to obtain hyaluronate solution;
2) Dispersing hypromellose in 80-90deg.C hot water, hydrating for 30-50 min, and stirring in ice bath for dissolving for 10-20 min to obtain pale yellow hypromellose solution;
3) Uniformly mixing the hyaluronate solution in the step 1) and the hypromellose solution in the step 2), adding 1, 4-butanediol diglycidyl ether, and stirring for 1-3 hours to form chemical crosslinking to obtain hyaluronic acid-hypromellose hydrogel;
4) Uniformly dispersing the nanocellulose crystal in toluene solution, adding a silane coupling agent, stirring in an oil bath at 100-110 ℃ for reaction for 6-8 h, protecting with nitrogen, filtering under reduced pressure after the reaction is finished, washing with ethanol, and drying in an oven at 50-70 ℃ to obtain the nanocellulose crystal modified by the silane coupling agent;
5) Adding deionized water, a polymer precursor, silane coupling agent modified nanocellulose crystal and ammonium persulfate solution into a reaction kettle in the step 3), and carrying out polymerization reaction at a reaction temperature of 55-75 ℃ under the protection of nitrogen for 6-12 h to obtain hydrogel;
6) Soaking the hydrogel in the step 5) in deionized water for 48 hours, changing water every 4 hours, washing off unreacted organic reagent, and drying the hydrogel by freeze drying after the soaking is finished to obtain the product.
Further, the molar concentration of the sodium hydroxide solution in the step 1) is 0.5 mol/l to 1.5 mol/l, and the mass fraction of the hyaluronate solution is 2% -10%.
Further, the mass fraction of the hypromellose solution in the step 2) is 2.5% -15%.
Further, the mass ratio of the hyaluronate solution, the hypromellose solution and the 1, 4-butanediol diglycidyl ether in the step 3) is 1:1:0.6.
Further, in the step 4), the mass ratio of the nanocellulose crystal to the silane coupling agent is 1:5-10.
Further, the silane coupling agent in the step 4) isγMethacryloxypropyl trimethoxysilane or vinyltriethoxysilane.
Further, the polymer precursor in step 5) is acrylic acid or acrylamide.
Further, the volume ratio of deionized water to polymer precursor in step 5) is 5:0.5-1.
Further, the mass ratio of the silane coupling agent modified nanocellulose crystal to deionized water to the polymer precursor in the step 5) is 1:100-300.
Further, the mass fraction of the ammonium persulfate solution in the step 5) is 8-12%.
The pH/temperature dual-response intelligent hydrogel prepared by the method.
By adopting the technology, compared with the prior art, the invention has the following beneficial effects:
(1) The invention relates to a preparation method of pH/temperature dual response intelligent hydrogel, which is characterized in that innovation is carried out on selection and combination of materials, hyaluronic acid and hypromellose are selected for crosslinking to be used as a temperature-sensitive system, CNC grafted polymer is selected as a pH response system, the selected materials are common and easy to obtain, and the reaction cost is low; the modified cellulose nanocrystals replace common cross-linking agents such as N, N-methylene bisacrylamide, so that the toxicity of a reaction medium is reduced, and the method is suitable for industrial popularization and application;
(2) The mechanical property of the hydrogel adopting the nano cellulose crystal skeleton is greatly superior to that of common hydrogels, the tensile strength is improved by 2-3 times, and the hydrogel has wider application range;
(3) The pH/temperature dual-response intelligent hydrogel prepared by the invention contains the nanocellulose skeleton, so that the drug carrying capacity of the hydrogel can be enhanced, the slow release of the drug at a wound is facilitated, the bioavailability of the drug in vivo is improved, and the active substance can be promoted to play a role due to the activity of the drug, so that the wound healing is accelerated;
(4) The intelligent response hydrogel prepared by the invention can control the release of the medicine by sensing the change of the environment at the wound, improves the bioavailability of the medicine, and has better mechanical property to prevent the hydrogel from being deformed easily under the action of external force. Thus, the present invention represents a significant technical advance.
Drawings
FIG. 1 is an infrared comparison of silane coupling agent modified CNC and CNC in example 1.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1
(1) Neutralizing 0.4. 0.4 g hyaluronic acid (the number average molecular weight is 110 w) with 10 ml of 1 mol/l sodium hydroxide solution at a reaction temperature of 45 ℃ for 15 min to obtain a hyaluronate solution;
(2) Adding 1 g hypromellose (viscosity of 15 mPa.s) into 10 ml hot water, stirring and dispersing at 88 ℃ for 30 min, and stirring and dissolving in ice bath for 10 min to obtain pale yellow HPMC solution;
(3) Uniformly mixing the hyaluronate solution in the step (1) and the HPMC solution in the step (2), adding 6 ml of 1, 4-butanediol diglycidyl ether (BDDE) into the mixture, stirring the mixture for 2 h, and forming chemical crosslinking to obtain HA-HPMC hydrogel;
(4) Uniformly dispersing 0.5. 0.5 g nano cellulose crystal (CNC) in 50 ml toluene solution, adding 2.5. 2.5 mlγStirring and reacting methacryloxypropyl trimethoxy silane in an oil bath at 100 ℃ for 6 h, protecting with nitrogen, decompressing and filtering after the reaction is finished, washing with ethanol four times, and drying in a baking oven at 60 ℃ to obtain the silane coupling agent modified CNC;
(5) Adding 20 ml deionized water, 4 ml acrylic acid, 0.1 g silane coupling agent modified CNC and 1 ml ammonium persulfate solution with the mass fraction of 10% into a reaction kettle in the step (3), and carrying out polymerization reaction at the reaction temperature of 65 ℃ under the protection of nitrogen to obtain hydrogel;
(6) Soaking the hydrogel in deionized water for 48 and h, changing water every 4 and h, washing out unreacted organic reagent, and drying the hydrogel by freeze drying after the soaking is finished to obtain a product;
(7) The swelling degree of the hydrogel was measured as a function of pH and temperature, and the results showed that: the swelling degree of the hydrogel increases with increasing pH, and increases most rapidly at pH 4-6, and is nearly stable at pH greater than 6. As the temperature increases, the swelling degree decreases continuously, and the swelling degree decreases most rapidly around 34 ℃. Young's modulus was measured, and the tensile property of the hydrogel was measured, and the result showed that the Young's modulus of the hydrogel was 50.1MPa.
As shown in fig. 1, 3416.34 cm -1 Stretching vibration 2925.79 cm at-OH -1 at-CH 3 and-CH 2 Is 1726.79 cm -1 And 1637.48 cm -1 Tensile vibration peaks at c=o and c=c, 1273.88 cm, respectively -1 at-CH 3 Deformation vibration peak of 759.57 cm) -1 At the tensile vibration peak of Si-C, the typical absorption peak of Si-O-Si is 1000-1130 cm -1 In the range, but overlapping with the cellulose band due to the C-O bending mode, the success of the modification of cellulose nanocrystals was confirmed in summary.
Embodiment case 2:
(1) Neutralization reaction of 1 g hyaluronic acid (number average molecular weight 110 w) with 10 ml of 1.5 mol/l sodium hydroxide solution at a reaction temperature of 45 ℃ for 30 min to obtain hyaluronate solution;
(2) Adding 1.5 g hypromellose (viscosity of 15 mPa.s) into 10 ml hot water, stirring and dispersing at 88 ℃ for 30 min, and stirring and dissolving in ice bath for 20 min to obtain pale yellow HPMC solution;
(3) Uniformly mixing the hyaluronate solution in the step (1) and the HPMC solution in the step (2), adding 6 ml of 1, 4-butanediol diglycidyl ether (BDDE) into the mixture, and stirring the mixture for 3h to form a chemical crosslinking to obtain HA-HPMC hydrogel;
(4) Uniformly dispersing 0.5. 0.5 g nano cellulose crystal (CNC) in 50 ml toluene solution, adding 5 mlγStirring and reacting methacryloxypropyl trimethoxy silane in an oil bath at 100 ℃ for 8h, protecting with nitrogen, decompressing and filtering after the reaction is finished, washing with ethanol four times, and drying in a baking oven at 60 ℃ to obtain the silane coupling agent modified CNC;
(5) Adding 20 ml deionized water, 4 ml acrylamide, 0.24 g silane coupling agent modified CNC and 1 ml ammonium persulfate solution with the mass fraction of 12% into a reaction kettle in the step (3), and carrying out polymerization reaction 8h at the reaction temperature of 65 ℃ under the protection of nitrogen to obtain hydrogel;
(6) Soaking the hydrogel in deionized water for 48 and h, changing water every 4 and h, washing out unreacted organic reagent, and drying the hydrogel by freeze drying after the soaking is finished to obtain a product;
(7) The swelling degree of the hydrogel was measured as a function of pH and temperature, and the results showed that: the swelling degree of the hydrogel increases with increasing pH, and increases most rapidly at pH 4-6, and is nearly stable at pH greater than 6. With increasing temperature, the swelling degree decreases continuously, and the swelling degree decreases most rapidly around 35 ℃. Young's modulus was measured, and the tensile property of the hydrogel was measured, and the result showed that the Young's modulus of the hydrogel was 64.2 MPa.
Embodiment 3:
(1) Neutralizing 0.6. 0.6 g hyaluronic acid (the number average molecular weight is 110 w) with 10 ml of 0.8 mol/l sodium hydroxide solution at a reaction temperature of 40 ℃ for 30 min to obtain a hyaluronate solution;
(2) Adding 0.25 g hypromellose (viscosity of 15 mPa.s) into 10 ml hot water, stirring and dispersing at 90 ℃ for 30 min, and stirring and dissolving in ice bath for 20 min to obtain a pale yellow HPMC solution;
(3) Uniformly mixing the hyaluronate solution in the step (1) and the HPMC solution in the step (2), adding 6 ml of 1, 4-butanediol diglycidyl ether (BDDE) into the mixture, and stirring the mixture for 3h to form a chemical crosslinking to obtain HA-HPMC hydrogel;
(4) Uniformly dispersing 0.5. 0.5 g nano cellulose crystal (CNC) in 50 ml toluene solution, adding 5 mlγStirring and reacting methacryloxypropyl trimethoxy silane in an oil bath at 100 ℃ for 7 h, protecting with nitrogen, decompressing and filtering after the reaction is finished, washing with ethanol four times, and drying in a baking oven at 60 ℃ to obtain the silane coupling agent modified CNC;
(5) Adding 20 ml deionized water, 4 ml acrylamide, 0.24 g silane coupling agent modified CNC and 1 ml ammonium persulfate solution with the mass fraction of 12% into a reaction kettle in the step (3), and carrying out polymerization reaction 8h at the reaction temperature of 65 ℃ under the protection of nitrogen to obtain hydrogel;
(6) Soaking the hydrogel in deionized water for 48 and h, changing water every 4 and h, washing out unreacted organic reagent, and drying the hydrogel by freeze drying after the soaking is finished to obtain a product;
(7) The swelling degree of the hydrogel was measured as a function of pH and temperature, and the results showed that: the swelling degree of the hydrogel increases with increasing pH, and increases most rapidly at pH 4-6, and is nearly stable at pH greater than 6. With increasing temperature, the swelling degree decreases continuously, and the swelling degree decreases most rapidly around 32 ℃. Young's modulus was measured, and the tensile property of the hydrogel was measured, and the result showed that the Young's modulus of the hydrogel was 63.4 MPa.
Embodiment 4:
(1) Neutralizing 0.6. 0.6 g hyaluronic acid (the number average molecular weight is 110 w) with 10 ml of 0.8 mol/l sodium hydroxide solution at the reaction temperature of 50 ℃ for 15 min to obtain hyaluronate solution;
(2) Adding 1.5 g hydroxypropyl methylcellulose (viscosity of 15 mPa.s) into 10 ml hot water, stirring and dispersing at 90 ℃ for 50 min, and stirring and dissolving in ice bath for 10 min to obtain a pale yellow HPMC solution;
(3) Uniformly mixing the hyaluronate solution in the step (1) and the HPMC solution in the step (2), adding 6 ml of 1, 4-butanediol diglycidyl ether (BDDE) into the mixture, stirring the mixture for 2 h, and forming chemical crosslinking to obtain HA-HPMC hydrogel;
(4) Uniformly dispersing 0.5 g nano cellulose crystal (CNC) in 50 ml toluene solution, adding 5 ml vinyl triethoxysilane, stirring in 110 ℃ oil bath for reaction 8h, protecting with nitrogen, filtering under reduced pressure after the reaction is finished, washing four times with ethanol, and drying in a 60 ℃ oven to obtain silane coupling agent modified CNC;
(5) Adding 20 ml deionized water, 4 ml acrylamide, 0.24 g silane coupling agent modified CNC and 1 ml ammonium persulfate solution with the mass fraction of 8% into a reaction kettle in the step (3), and carrying out polymerization reaction at the reaction temperature of 75 ℃ under the protection of nitrogen to obtain hydrogel 8 h;
(6) Soaking the hydrogel in deionized water for 48 and h, changing water every 4 and h, washing out unreacted organic reagent, and drying the hydrogel by freeze drying after the soaking is finished to obtain a product;
(7) The swelling degree of the hydrogel was measured as a function of pH and temperature, and the results showed that: the swelling degree of the hydrogel increases with increasing pH, and increases most rapidly at pH 4-6, and is nearly stable at pH greater than 6. With increasing temperature, the swelling degree decreases continuously, and the swelling degree decreases most rapidly around 35 ℃. Young's modulus was measured, and the tensile property of the hydrogel was measured, and the result showed that the Young's modulus of the hydrogel was 62.1 MPa.
Embodiment case 5:
(1) Neutralizing 0.6. 0.6 g hyaluronic acid (the number average molecular weight is 110 w) with 10 ml of 1.2 mol/l sodium hydroxide solution at a reaction temperature of 50 ℃ for 15 min to obtain a hyaluronate solution;
(2) Adding 1 g hydroxypropyl methylcellulose (viscosity of 15 mPa.s) into 10 ml hot water, stirring and dispersing at 90 ℃ for 40 min, and stirring and dissolving in ice bath for 15 min to obtain a pale yellow HPMC solution;
(3) Uniformly mixing the hyaluronate solution in the step (1) and the HPMC solution in the step (2), adding 6 ml of 1, 4-butanediol diglycidyl ether (BDDE) into the mixture, stirring the mixture for 2 h, and forming chemical crosslinking to obtain HA-HPMC hydrogel;
(4) Uniformly dispersing 0.5 g nano cellulose crystal (CNC) in 50 ml toluene solution, adding 2.5 ml vinyl triethoxysilane, stirring in 110 ℃ oil bath to react for 8h, protecting with nitrogen, decompressing and filtering after the reaction is finished, washing four times with ethanol, and drying in a 70 ℃ oven to obtain silane coupling agent modified CNC;
(5) Adding 20 ml deionized water, 4 ml acrylamide, 0.24 g silane coupling agent modified CNC and 1 ml ammonium persulfate solution with the mass fraction of 8% into a reaction kettle in the step (3), and carrying out polymerization reaction at the reaction temperature of 75 ℃ under the protection of nitrogen to obtain hydrogel 8 h;
(6) Soaking the hydrogel in deionized water for 48 and h, changing water every 4 and h, washing out unreacted organic reagent, and drying the hydrogel by freeze drying after the soaking is finished to obtain a product;
(7) The swelling degree of the hydrogel was measured as a function of pH and temperature, and the results showed that: the swelling degree of the hydrogel increases with increasing pH, and increases most rapidly at pH 4-6, and is nearly stable at pH greater than 6. With increasing temperature, the swelling degree decreases continuously, and the swelling degree decreases most rapidly around 35 ℃. Young's modulus was measured, and the tensile property of the hydrogel was measured, and the result showed that the Young's modulus of the hydrogel was 57.8 MPa.
Embodiment 6:
(1) Neutralizing 0.8 g hyaluronic acid (the number average molecular weight is 110 w) with 10 ml of 1 mol/l sodium hydroxide solution at a reaction temperature of 50 ℃ for 15 min to obtain a hyaluronate solution;
(2) Adding 0.5 g hydroxypropyl methylcellulose (viscosity of 15 mPa.s) into 10 ml hot water, stirring and dispersing at 90 ℃ for 40 min, and stirring and dissolving in ice bath for 15 min to obtain a pale yellow HPMC solution;
(3) Uniformly mixing the hyaluronate solution in the step (1) and the HPMC solution in the step (2), adding 6 ml of 1, 4-butanediol diglycidyl ether (BDDE) into the mixture, and stirring the mixture for 3h to form a chemical crosslinking to obtain HA-HPMC hydrogel;
(4) Uniformly dispersing 0.5 g nano cellulose crystal (CNC) in 50 ml toluene solution, adding 2.5 ml vinyl triethoxysilane, stirring in 110 ℃ oil bath to react for 8h, protecting with nitrogen, decompressing and filtering after the reaction is finished, washing four times with ethanol, and drying in a 70 ℃ oven to obtain silane coupling agent modified CNC;
(5) Adding 20 ml deionized water, 4 ml acrylic acid, 0.24 g silane coupling agent modified CNC and 1 ml 8% ammonium persulfate into a reaction kettle in the step (3), and carrying out polymerization reaction at the reaction temperature of 75 ℃ under the protection of nitrogen to obtain hydrogel;
(6) Soaking the hydrogel in deionized water for 48 and h, changing water every 4 and h, washing out unreacted organic reagent, and drying the hydrogel by freeze drying after the soaking is finished to obtain a product;
(7) The swelling degree of the hydrogel was measured as a function of pH and temperature, and the results showed that: the swelling degree of the hydrogel increases with increasing pH, and increases most rapidly at pH 4-6, and is nearly stable at pH greater than 6. As the temperature increases, the swelling degree decreases continuously, and the swelling degree decreases most rapidly around 34 ℃. Young's modulus was measured, and the tensile property of the hydrogel was measured, and the result showed that the Young's modulus of the hydrogel was 55.6 MPa.
Embodiment 7:
(1) Neutralizing 0.8 g hyaluronic acid (the number average molecular weight is 110 w) with 10 ml of 0.5 mol/l sodium hydroxide solution at a reaction temperature of 50 ℃ for 15 min to obtain a hyaluronate solution;
(2) Adding 1.5 g hydroxypropyl methylcellulose (viscosity of 15 mPa.s) into 10 ml hot water, stirring and dispersing at 90 ℃ for 50 min, and stirring and dissolving in ice bath for 20 min to obtain a pale yellow HPMC solution;
(3) Uniformly mixing the hyaluronate solution in the step (1) and the HPMC solution in the step (2), adding 6 ml of 1, 4-butanediol diglycidyl ether (BDDE) into the mixture, and stirring the mixture for 3h to form a chemical crosslinking to obtain HA-HPMC hydrogel;
(4) Uniformly dispersing 0.5 g nano cellulose crystal (CNC) in 50 mL toluene solution, adding 2.5 ml vinyl triethoxysilane, stirring in 110 ℃ oil bath to react for 8h, protecting with nitrogen, decompressing and filtering after the reaction is finished, washing four times with ethanol, and drying in a 70 ℃ oven to obtain silane coupling agent modified CNC;
(5) Adding 20 ml deionized water, 4 ml acrylic acid, 0.24 g silane coupling agent modified CNC and 1 ml ammonium persulfate solution with the mass fraction of 10% into a reaction kettle in the step (3), and carrying out polymerization reaction at the reaction temperature of 70 ℃ under the protection of nitrogen to obtain hydrogel 12 h;
(6) Soaking the hydrogel in deionized water for 48 and h, changing water every 4 and h, washing out unreacted organic reagent, and drying the hydrogel by freeze drying after the soaking is finished to obtain a product;
(7) The swelling degree of the hydrogel was measured as a function of pH and temperature, and the results showed that: the swelling degree of the hydrogel increases with increasing pH, and increases most rapidly at pH 4-6, and is nearly stable at pH greater than 6. With increasing temperature, the swelling degree was continuously decreased, and the swelling degree was most rapidly decreased near 37 ℃. Young's modulus was measured, and the tensile property of the hydrogel was measured, and the result showed that the Young's modulus of the hydrogel was 65.3 MPa.
Experiment case 8:
(1) Neutralizing 0.8 g hyaluronic acid (the number average molecular weight is 110 w) with 10 ml of 1 mol/l sodium hydroxide solution at a reaction temperature of 50 ℃ for 15 min to obtain a hyaluronate solution;
(2) Adding 1 g hydroxypropyl methylcellulose (viscosity of 15 mPa.s) into 10 ml hot water, stirring and dispersing at 80deg.C, hydrating for 50 min, and stirring and dissolving in ice bath for 20 min to obtain pale yellow HPMC solution;
(3) Uniformly mixing the hyaluronate solution in the step (1) and the HPMC solution in the step (2), adding 6 ml of 1, 4-butanediol diglycidyl ether (BDDE) into the mixture, stirring the mixture for 1 h, and forming chemical crosslinking to obtain HA-HPMC hydrogel;
(4) Uniformly dispersing 0.25-g nano cellulose crystals (CNC) in 50-ml toluene solution, adding 2.5-ml vinyl triethoxysilane, stirring in an oil bath at 110 ℃ to react for 8-h, protecting with nitrogen, performing reduced pressure filtration after the reaction is finished, washing four times with ethanol, and drying in a baking oven at 70 ℃ to obtain silane coupling agent modified CNC;
(5) Adding 20 ml deionized water, 4 ml acrylic acid, 0.1 g silane coupling agent modified CNC and 1 ml ammonium persulfate solution with the mass fraction of 10% into a reaction kettle in the step (3), and carrying out polymerization reaction at the reaction temperature of 70 ℃ under the protection of nitrogen to obtain hydrogel 12 h;
(6) Soaking the hydrogel in deionized water for 48 and h, changing water every 4 and h, washing out unreacted organic reagent, and drying the hydrogel by freeze drying after the soaking is finished to obtain a product;
(7) The swelling degree of the hydrogel was measured as a function of pH and temperature, and the results showed that: the swelling degree of the hydrogel increases with increasing pH, and increases most rapidly at pH 4-6, and is nearly stable at pH greater than 6. With increasing temperature, the swelling degree decreases continuously, and the swelling degree decreases most rapidly around 36 ℃. Young's modulus was measured, and the tensile property of the hydrogel was measured, and the result showed that the Young's modulus of the hydrogel was 54.1 MPa.
Finally, it is to be noted that the above examples merely describe the technical solution of the invention, which is not limited thereto. Modifications and enhancements to the above description may be made by those of ordinary skill in the art, which modifications and enhancements are intended to be within the scope of the present invention as described in the claims.

Claims (9)

1. The preparation method of the pH/temperature dual-response intelligent hydrogel is characterized by comprising the following steps of:
1) Neutralizing hyaluronic acid and sodium hydroxide solution at 40-50deg.C for 15-30 min to obtain hyaluronate solution;
2) Dispersing hypromellose in 80-90deg.C hot water, hydrating for 30-50 min, and stirring in ice bath for dissolving for 10-20 min to obtain pale yellow hypromellose solution;
3) Uniformly mixing the hyaluronate solution in the step 1) and the hypromellose solution in the step 2), adding 1, 4-butanediol diglycidyl ether, and stirring for 1-3 hours to form chemical crosslinking to obtain hyaluronic acid-hypromellose hydrogel;
4) Uniformly dispersing the nanocellulose crystal in toluene solution, adding a silane coupling agent, stirring in an oil bath at 100-110 ℃ for reaction for 6-8 h, protecting with nitrogen, filtering under reduced pressure after the reaction is finished, washing with ethanol, and drying in an oven at 50-70 ℃ to obtain the nanocellulose crystal modified by the silane coupling agent;
5) Adding deionized water, a polymer precursor, silane coupling agent modified nanocellulose crystal and ammonium persulfate solution into a reaction kettle in the step 3), and carrying out polymerization reaction at a reaction temperature of 55-75 ℃ under the protection of nitrogen for 6-12 h to obtain hydrogel;
6) Soaking the hydrogel obtained in the step 5) in deionized water for 48 hours, changing water every 4 hours, washing out unreacted organic reagent, and drying the hydrogel by freeze drying after the soaking is finished to obtain a product;
the polymer precursor in the step 5) is acrylic acid or acrylamide, and the volume ratio of deionized water to the polymer precursor is 5:0.5-1.
2. The preparation method according to claim 1, wherein the molar concentration of the sodium hydroxide solution in the step 1) is 0.5 mol/l to 1.5 mol/l, and the mass fraction of the hyaluronate solution is 2% -10%.
3. The preparation method according to claim 1, wherein the mass fraction of the hypromellose solution in step 2) is 2.5% -15%.
4. The preparation method according to claim 1, wherein the mass ratio of the hyaluronate solution, the hypromellose solution, and the 1, 4-butanediol diglycidyl ether in the step 3) is 1:1:0.6.
5. The preparation method according to claim 1, wherein the mass ratio of the nanocellulose crystal to the silane coupling agent in the step 4) is 1:5-10.
6. The process according to claim 1 or 5, wherein the silane coupling agent in step 4) isγMethacryloxypropyl trimethoxysilane or vinyltriethoxysilane.
7. The preparation method according to claim 1, wherein the mass ratio of the silane coupling agent modified nanocellulose crystal to deionized water and polymer precursor in step 5) is 1:100-300.
8. The method according to claim 1, wherein the mass fraction of the ammonium persulfate solution in the step 5) is 8% -12%.
9. A pH/temperature dual-response smart hydrogel prepared according to the preparation method of claim 1.
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