A hydrogel and its preparation method and application

Abstract

The present invention relates to a medical hydrogel, and in particular to a hydrogel and a preparation method and application thereof, which comprises the following steps: completely dissolving polyvinyl alcohol in deionized water to obtain component A in a clear state; dissolving acrylamide in deionized water, then adding N,N-methylenebisacrylamide and ammonium persulfate, and mixing evenly to obtain component B; mixing component A and component B in a volume ratio of 1:1 and stirring until completely clear and transparent, then adding Ag-ZnO nanoparticles, and finally dripping tetramethylethylenediamine solution to obtain a hydrogel prepolymer liquid, and obtaining a hydrogel after solidification. The hydrogel obtained by the present invention can be applied to an organ model for surgical training, so that the prepared organ model can more accurately simulate the properties of biological soft tissue, making surgical training more realistic, and has good performance in antibacterial, anti-fatigue, conductive, tensile, compression and other properties, and can also perform electrocoagulation hemostasis, endoscopy, suture cutting and other operations.

Description

Technical Field

[0001] The invention relates to a medical hydrogel, in particular to a hydrogel and a preparation method and application thereof. Background Art

[0002] The increase in the difficulty and complexity of operations has led to the widespread occurrence of medical errors in clinical practice in recent years. Among them, diseases related to the stomach and intestines have brought medical challenges and generated huge economic costs. There is an urgent need for empirical and high-fidelity gastrointestinal surgery training tools to provide surgical training for surgeons.

[0003] Most current studies use silicone as the raw material, but due to the limitations of its intrinsic physical and chemical properties, silicone cannot solve the common difficulties in the research of surgical training models: First, although silicone can realize routine operations such as surgical cutting and suturing, it cannot correct mechanical properties (such as elastic modulus) and provide a realistic feeling of soft biological tissue; second, silicone cannot simulate the surgical reactions produced by electrosurgical instruments that are currently commonly used in surgical simulations, such as ultrasonic scalpels, ligasure, and even electrocoagulation effects. For example, electrocoagulation can cause the material to char and coagulate to stop bleeding, ultrasonic scalpels to cut solid organs, and coagulate blood vessels. etc.; Third, conventional 3D printing models use various software such as mimics to obtain the required stl data by removing the tissues around organs or lesions. However, in real surgery, these surrounding tissues and vascular branches are the parts that need to be surgically treated in the process of exposing the lesions, which cannot be achieved with silicone; Fourth, surgical operations are all performed along the tissue level, which requires materials with more subtle physical properties, which is difficult to achieve with current models. This is the difficulty faced by the current 3D printing bionic gradient structured soft models for surgical training, and it is also the key to the use of 3D printing technology in surgery.

[0004] Hydrogel is a type of hydrophilic polymer material with a three-dimensional (3D) network structure. It is a slippery soft material with a large amount of bound water, interfacial water and free water medium in its three-dimensional polymer network. Hydrogel has physiological properties similar to those of biological tissues and organs and is widely used in biomedical research. However, there are not many anatomical models of hydrogel material surgical simulations used at home and abroad.

[0005] In recent years, with the development of printing technology and the urgent need for higher-quality surgical training models, hydrogels have gradually been used in surgical training models in more fields, especially in the field of surgery. However, the performance of existing hydrogel models in many aspects still needs to be further improved, such as poor time stability, susceptibility to microbial invasion, breeding of bacteria and fungi, and difficulty in achieving realistic surgical response to electrosurgical instruments. Summary of the invention

[0006] The present invention aims at the problems existing in the hydrogel model in the prior art and provides a hydrogel and a preparation method and application thereof.

[0007] In order to solve the above technical problems, the present invention is solved by the following technical solutions:

[0008] A method for preparing a hydrogel, characterized in that it comprises the following steps:

[0009] Step (1), preparing component A: completely dissolving polyvinyl alcohol in deionized water to obtain component A in a clear state;

[0010] Step (2), preparing component B: dissolving acrylamide in deionized water, then adding N,N-methylenebisacrylamide and ammonium persulfate, and mixing well to obtain component B;

[0011] Step (3), mixing component A and component B at a volume ratio of 1:1 and stirring until completely clear and transparent, then adding Ag-ZnO nanoparticles, and finally dropping tetramethylethylenediamine solution to obtain a hydrogel prepolymer solution;

[0012] In step (4), the hydrogel prepolymer solution is solidified to obtain a hydrogel.

[0013] Preferably, step (1) comprises dissolving polyvinyl alcohol in deionized water, stirring at 90° C. for 1-2 hours until the polyvinyl alcohol is completely dissolved and becomes clear, and then cooling to room temperature to obtain component A, wherein the mass ratio of polyvinyl alcohol to deionized water is 1:9.

[0014] Preferably, in step (3), the Ag-ZnO nanoparticles are synthesized by chemical precipitation method, specifically, Zn(Ac)2 and NaOH are dissolved in deionized water respectively, then mixed and stirred to obtain a mixed solution, and then AgNO3 is added to the mixed solution, and finally the Ag-ZnO nanoparticles are obtained by centrifugation, water washing, alcohol washing and drying.

[0015] Preferably, step (3) specifically includes:

[0016] Step (31), first dissolving Zn(Ac)2 and NaOH in deionized water to obtain a Zn(Ac)2 solution and a NaOH solution, respectively, and then mixing the Zn(Ac)2 solution and the NaOH solution at 65°C and stirring for 2-4 hours to obtain a mixed solution;

[0017] Step (32), then adding AgNO3 to the mixed solution of step (31) and stirring at 90°C for 2-4 hours;

[0018] Step (33), finally, centrifugation, water washing, alcohol washing and drying are performed in sequence to obtain Ag-ZnO nanoparticles.

[0019] A hydrogel is obtained by using the above-mentioned method for preparing a hydrogel.

[0020] An application of a hydrogel, applying the aforementioned hydrogel to an organ model for surgical training.

[0021] Preferably, the hydrogel is applied to the gastrointestinal model, specifically: the hydrogel prepolymer is injected into the 3D printed gastrointestinal organ mold prepared in advance through the pouring port until it is full, and after component B is gelled, it is placed in a -20°C freezer for low-temperature freezing for 4-8 hours and then taken out of the freezer. After being taken out, it is waited to return to room temperature and then removed from the mold to prepare a hydrogel gastrointestinal model.

[0022] Preferably, the hydrogel is applied to a vascular model, specifically:

[0023] The hollow 3D printing model was obtained through open source software (MIMICS) and computer-aided design (CAD) data;

[0024] Then, the hydrogel prepolymer solution is evenly coated on the surface of the 3D printed model, and after the coating is completed, it is frozen for 4-8 hours and then taken out to obtain a 3D blood vessel model with the hydrogel coated on the outer surface;

[0025] Finally, the 3D blood vessel model with the hydrogel coated on the outer surface was immersed in acetone as a whole to dissolve the 3D printed model inside the hydrogel to obtain the hydrogel blood vessel model.

[0026] The present invention has significant technical effects due to the adoption of the above technical solution:

[0027] The PVA / PAM double network hydrogel obtained by the present invention can be applied to organ models for surgical training, so that the prepared organ model can more accurately simulate the properties of biological soft tissue, making surgical training more realistic, and has good performance in antibacterial, anti-fatigue, electrical conductivity, stretching, compression and other properties. At the same time, it can also perform electrocoagulation hemostasis, endoscopic examination, suturing and cutting and other operations. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is a schematic diagram of the antibacterial performance of the hydrogel prepared by the present invention.

[0029] Figure 2 It is a schematic diagram of the solid-like elastic properties of the hydrogel prepared by the present invention.

[0030] Figure 3 It is a schematic diagram of the microstructure of the hydrogel prepared by the present invention.

[0031] Figure 4 It is a schematic diagram of the biosafety of the hydrogel prepared by the present invention.

[0032] Figure 5 It is a schematic diagram of the fatigue resistance of the hydrogel prepared by the present invention.

[0033] Figure 6 It is a schematic diagram of the water content and water retention rate of the hydrogel prepared by the present invention.

[0034] Figure 7 It is a schematic diagram of the Young's modulus of the hydrogel prepared by the present invention.

[0035] Figure 8 Schematic diagram of the hydrogel prepared by the present invention simulating real intestinal tissue.

[0036] Fig. 9 It is a schematic diagram of using the hydrogel prepared by the present invention for gastrointestinal anastomosis.

[0037] Fig.10 It is a schematic diagram of using the hydrogel prepared by the present invention for gastrointestinal endoscopy.

[0038] Fig.11 The schematic diagram is that the hydrogel prepared by the present invention is used for vascular permeability and electrocoagulation eschar hemostasis. DETAILED DESCRIPTION

[0039] The present invention is further described in detail below in conjunction with the accompanying drawings and embodiments.

[0040] Example 1

[0041] A method for preparing a hydrogel comprises the following steps:

[0042] Step (1), preparing component A: completely dissolving polyvinyl alcohol in deionized water to obtain component A in a clear state, wherein the mass ratio of polyvinyl alcohol to deionized water is 1:9;

[0043] Step (2), preparing component B: dissolving acrylamide in deionized water, then adding N,N-methylenebisacrylamide and ammonium persulfate, and mixing well to obtain component B;

[0044] Step (3), mixing component A and component B at a volume ratio of 1:1 and stirring until completely clear and transparent, then adding Ag-ZnO nanoparticles, and finally dropping tetramethylethylenediamine solution to obtain a hydrogel prepolymer solution;

[0045] In step (4), the hydrogel prepolymer solution is solidified to obtain a hydrogel.

[0046] In this embodiment, step (1) is specifically to dissolve 10 g of polyvinyl alcohol in 90 mL of deionized water, and stir at 90° C. for 1-2 hours until the polyvinyl alcohol is completely dissolved and in a clear state, and then cool to room temperature to obtain component A with a mass fraction of 10%.

[0047] In step (2), 40 g of acrylamide is dissolved in 100 mL of deionized water at room temperature, 0.3 mol % of N,N-methylenebisacrylamide (180 mg in total) and 2 mg / mL of ammonium persulfate (200 mg in total) are added, and the mixture is mixed uniformly to obtain component B.

[0048] In step (3), component A and component B are mixed at a volume ratio of 1:1 and stirred until completely clear and transparent, 0.125% by mass of Ag-ZnO nanoparticles are added and mixed, and finally 1 μL / mL of a total of 200 μL of tetramethylethylenediamine solution is added dropwise and mixed to obtain a hydrogel prepolymer solution;

[0049] In step (4), the hydrogel prepolymer solution is solidified to obtain a hydrogel.

[0050] In addition, in step (3) of this embodiment, the Ag-ZnO nanoparticles are synthesized by chemical precipitation method, specifically, Zn(Ac)2 and NaOH are dissolved in deionized water respectively, and then mixed and stirred to obtain a mixed solution, and then AgNO3 is added to the mixed solution, and finally, the Ag-ZnO nanoparticles are obtained by centrifugation, water washing, alcohol washing and drying in sequence, which specifically includes:

[0051] Step (31), first dissolving Zn(Ac)2 and NaOH in deionized water to obtain a Zn(Ac)2 solution and a NaOH solution, respectively, and then mixing the Zn(Ac)2 solution and the NaOH solution at 65°C and stirring for 2-4 hours to obtain a mixed solution;

[0052] Step (32), then adding AgNO3 to the mixed solution of step (31) and stirring at 90°C for 2-4 hours;

[0053] Step (33), finally, centrifugation, water washing, alcohol washing and drying are performed in sequence to obtain Ag-ZnO nanoparticles.

[0054] Example 2

[0055] A hydrogel is obtained by using the preparation method of a hydrogel in Example 1.

[0056] Example 3

[0057] An application of the hydrogel, applying the hydrogel in Example 2 to an organ model for surgical training.

[0058] The specific applications in this embodiment include the following two:

[0059] (1) The hydrogel is applied to the gastrointestinal model, specifically: the hydrogel prepolymer solution is injected into the 3D printed gastrointestinal organ mold prepared in advance through the pouring port until it is full, and after component B is first gelled due to free radical polymerization, it is placed in a -20°C freezer for low-temperature freezing for 4-8 hours and then taken out of the freezer. After being taken out, it is allowed to return to room temperature before being removed from the mold to prepare a hydrogel gastrointestinal model.

[0060] (2) applying the hydrogel to a vascular model, specifically:

[0061] A hollow 3D printing model is obtained through open source software (MIMICS) and computer-aided design (CAD) data; specifically, vascular medical imaging data (extracted by MIMICS) is first obtained through computed tomography (CT) angiography or magnetic resonance imaging (MRI) scanning, and then the data is converted into a three-dimensional model through computer-aided design (CAD), and the vascular part in the model is extracted and converted into 3D printable STL data, and then the STL data is made into a hollow 3D printing model through a 3D printer using soluble 3D printing materials; wherein the vascular medical imaging data obtained by computed tomography (CT) angiography or magnetic resonance imaging (MRI) scanning can be modified into a desired vascular shape, and the diameter of the 3D printing model is determined according to the required diameter of the blood vessel.

[0062] Then, the hydrogel prepolymer solution is evenly coated on the surface of the 3D printed model, and after the coating is completed, it is frozen for 4-8 hours and then taken out to obtain a 3D blood vessel model with the hydrogel coated on the outer surface;

[0063] Finally, the 3D blood vessel model with the hydrogel coated on the outer surface was immersed in acetone as a whole to dissolve the 3D printed model inside the hydrogel to obtain the hydrogel blood vessel model.

[0064] like Fig. 9 , Fig.10 As shown in the present embodiment, the hydrogel gastrointestinal model is specifically applied to gastrointestinal anastomosis and gastrointestinal endoscopy training, such as Fig.11 As shown, the hydrogel vascular model was used for vascular permeability and electrocoagulation eschar hemostasis training.

[0065] In this example, various performance tests were performed on the prepared hydrogel (PVA-AM@Ag-ZnO), specifically including:

[0066] (1) Figure 1As shown, the inhibition zone after Escherichia coli was co-cultured with the prepared hydrogel for 12 hours. The PVA-AM hydrogel with added 0.125% (upper left) and 0.075% (upper right) Ag-ZnO nanoparticles had obvious zones, indicating good antibacterial properties. The PVA-AM hydrogel with added 0% (lower left) and 0.025% (lower right) Ag-ZnO nanoparticles had no clear inhibition zone and poor antibacterial effect. In summary, we screened out 0.125% mass fraction of Ag-ZnO nanoparticles as the final content.

[0067] (2) Figure 2 As shown, in the entire frequency range, the storage modulus (G') of the two groups of hydrogels is always higher than the loss modulus (G"), which means that the hydrogel has higher elastic properties, proving the solid-like elastic properties of the hydrogel. The indicator tanδ (G" / G') in viscoelastic calculations is a commonly used parameter to describe viscoelastic properties. By calculating tanδ, the viscoelastic characteristics of simulated tissue hydrogels can be evaluated, further revealing their applicability in tissue-like simulations. The viscoelasticity of the simulated hydrogel gastrointestinal tissue in the PVA-AM@Ag-ZnO system is between 0.01207-0.17586, which is between 0.1-0.45 of the natural gastrointestinal tissue / organ, indicating that the hydrogel has flow properties close to those of living gastrointestinal tissue. The viscoelasticity of the simulated hydrogel gastrointestinal tissue in the pure PVA-AM system is below 0.01633, and the viscoelasticity is different from that of biological soft tissue.

[0068] (3) Figure 3 As shown in the figure, biological soft tissue has excellent flexibility and mechanical properties, which is attributed to its special loose porous structure. This structure enables biological soft tissue to maintain its shape and function under various stresses. As shown in the SEM electron microscope image, the PVA / PAM hydrogel gastrointestinal tract has a loose porous structure that is surprisingly similar to that of real human gastrointestinal tissue. The two have similar microstructures, which makes their mechanical properties similar.

[0069] (4) Figure 4As shown, in order to evaluate the biological safety of tissue elastic hydrogels during surgical training, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was used to evaluate the in vitro cell compatibility of four types of hydrogels. We used different concentrations of hydrogel extracts for 7 days to co-culture with L929 mouse fibroblasts to observe the viability of the cells. As shown in the figure, the survival rate of L929 is related to the addition of 0.125% mass fraction of Ag-ZnO nanoparticles, and the survival rate of cells in the group without adding nanoparticles is slightly decreased. Among them, the cell viability of L929 incubated with 100 mg / mL gastric simulated hydrogel with 0.125% mass fraction of Ag-ZnO nanoparticles for 7 days is 87.4±2.13%, and the cell viability of L929 incubated with 100 mg / mL intestinal simulated hydrogel with 0.125% mass fraction of Ag-ZnO nanoparticles for 7 days is 89.54±2.26%. The cell viability of L929 in the remaining groups reached more than 90%, indicating that various tissue elastic hydrogels have low cytotoxicity. According to ISO 10993-5-2016, cell viability exceeding 80% can be regarded as non-cytotoxic.

[0070] (5) Figure 5 As shown in the figure, in order to evaluate the fatigue resistance of DN hydrogel, the DN hydrogel of pure PVA-AM strategy and the DN hydrogel of PVA-AM@Ag-ZnO strategy were subjected to 50 consecutive compression-relaxation cycles to simulate the repeated stress of human tissue under 50% compressive strain. From the results, it can be observed that after the first few cycles, the maximum load decreased slightly, then stabilized and remained almost unchanged in the subsequent cycles. This shows that DN hydrogel exhibits long-lasting stability and reliable mechanical properties under simulated stress environments, and the addition of Ag-ZnO nanoparticles does not affect its fatigue resistance and can even increase its maximum load.

[0071] (6) Figure 6 As shown in the figure, the water content and water retention rate of DN hydrogel after drying at room temperature for different times were tested. As can be seen from the figure, after drying at room temperature for 12 hours, the water content and water retention rate of pure PVA-AM hydrogel were higher than 65% and 60%, respectively. Similarly, the water content and water retention rate of PVA-AM@Ag-ZnO hydrogel were still higher than 65% and 60%, respectively, which shows that our designed PVA-AM@Ag-ZnO hydrogel has good water retention performance.

[0072] (7) Figure 7As shown in the figure, when the addition amount of Ag-ZnO nanoparticles is 0.125%, the Young's modulus of PVA / PAM hydrogel is greatly improved, which is close to the Young's modulus of real human stomach. It may be that the addition of excessive nanoparticles can fill the gaps and defects in the PVA / PAM hydrogel, increase the density and strength of the gel, thereby increasing the Young's modulus and making it close to the real human stomach tissue.

[0073] (8) Figure 8 As shown, in order to further simulate real intestinal tissue, we used a secondary freeze-thaw method to enhance the mechanical properties of PVA / PAM hydrogel, with the aim of approaching the elongation at break and Young's modulus of the real human intestine.

[0074] (9) In practical applications, hydrogel organ models used for surgical training need to withstand repeated friction from surgical instruments. Therefore, the durability and stability of the model are the guarantee of success. It can be observed from the figure that DN hydrogel has excellent flexibility and high deformation ability, for example, it can resist strong deformation such as knotting and twisting. In addition, when the compressive force is removed, the hydrogel quickly returns to its original shape, showing excellent shape memory performance. As shown in the figure, after 500 bends, the DN hydrogel still maintains the same shape as the initial shape, and no obvious deformation and cracks occur. These results fully demonstrate the long-term stability and excellent bending resistance of DN hydrogel.

[0075] In summary, the PVA / PAM double-network hydrogel obtained in this embodiment can be applied to organ models for surgical training, so that the prepared organ model can more accurately simulate the properties of biological soft tissue, making surgical training more realistic, and has good performance in antibacterial, anti-fatigue, electrical conductivity, stretching, compression and other properties. At the same time, it can also perform electrocoagulation hemostasis, endoscopic examination, suturing and cutting and other operations.

[0076] It is easy to understand that those skilled in the art can combine, split, reorganize, etc. the embodiments of the present application to obtain other embodiments based on one or several embodiments provided in the present application, and these embodiments do not exceed the protection scope of the present application.

[0077] In conclusion, the above is only a preferred embodiment of the present invention, and all equivalent changes and modifications made according to the scope of the patent application of the present invention should fall within the scope of the patent of the present invention.

Claims

1. An application of a hydrogel, characterized in that: The hydrogel is applied to an organ model for surgical training, and the hydrogel is prepared by the following steps: Step (1), preparing component A: completely dissolving polyvinyl alcohol in deionized water to obtain component A in a clear state; Step (2), preparing component B: dissolving acrylamide in deionized water, then adding N,N-methylenebisacrylamide and ammonium persulfate, and mixing evenly to obtain component B; Step (3), mixing component A and component B at a volume ratio of 1:1 and stirring until completely clear and transparent, then adding Ag-ZnO nanoparticles, and finally dropping tetramethylethylenediamine solution to obtain a hydrogel prepolymer solution; In step (4), the hydrogel prepolymer solution is solidified to obtain a hydrogel.

2. The use of a hydrogel according to claim 1, wherein step (1) is to dissolve polyvinyl alcohol in deionized water, and stir at 90° C. for 1-2 hours until the polyvinyl alcohol is completely dissolved and becomes clear, and then cool to room temperature to obtain component A, wherein the mass ratio of polyvinyl alcohol to deionized water is 1:

9.

3. The use of a hydrogel according to claim 1, wherein in step (3), the Ag-ZnO nanoparticles are synthesized by a chemical precipitation method, namely, Zn(Ac)2 and NaOH are dissolved in deionized water respectively, and then mixed and stirred to obtain a mixed solution, and then AgNO3 is added to the mixed solution, and finally the Ag-ZnO nanoparticles are obtained by centrifugation, water washing, alcohol washing and drying in sequence.

4. The use of a hydrogel according to claim 3, wherein step (3) comprises: Step (31), first dissolving Zn(Ac)2 and NaOH in deionized water to obtain a Zn(Ac)2 solution and a NaOH solution, respectively, and then mixing the Zn(Ac)2 solution and the NaOH solution at 65° C. and stirring for 2-4 hours to obtain a mixed solution; Step (32), then adding AgNO3 to the mixed solution of step (31) and stirring at 90°C for 2-4 hours; Step (33), and finally, centrifugation, water washing, alcohol washing and drying are performed in sequence to obtain Ag-ZnO nanoparticles.

5. The use of a hydrogel according to claim 1, wherein the hydrogel is applied to a gastrointestinal model: the hydrogel prepolymer is injected into a 3D printed gastrointestinal organ mold prepared in advance through a pouring port until it is full, and after component B is gelled, it is placed in a -20°C freezer for low-temperature freezing for 4-8 hours and then taken out of the freezer. After being taken out, it is waited to return to room temperature before being removed from the mold to prepare a hydrogel gastrointestinal model.

6. The use of the hydrogel according to claim 1, wherein the hydrogel is applied to a vascular model: The hollow 3D printing model was obtained through open source software (MIMICS) and computer-aided design (CAD) data; Then, the hydrogel prepolymer solution is evenly coated on the surface of the 3D printed model, and after the coating is completed, it is frozen for 4-8 hours and then taken out to obtain a 3D blood vessel model with the hydrogel coated on the outer surface; Finally, the 3D blood vessel model with the hydrogel coated on the outer surface was immersed in acetone as a whole to dissolve the 3D printed model inside the hydrogel to obtain the hydrogel blood vessel model.

Images