Preparation method and application of soft tissue-like elastic hydrogel and hydrogel tissue organ model

Abstract

The present invention provides a preparation method and application of a soft tissue-like elastic hydrogel and its tissue and organ model, belonging to the technical field of hydrogel-based tissue and organ model manufacturing. The present invention utilizes acrylamide and an unsaturated double-bond monomer containing a negative electron group to perform photocuring to form a covalent cross-linking network, and then coordinates the negative electron group with zirconium ions to form an ion cross-linking network, thereby constructing a double-network elastic hydrogel with mechanical properties close to those of soft tissue and adjustable. With the advantage of light-curing rapid prototyping technology to construct fine structures, various personalized tissue and organ models that match natural soft tissues can be printed and prepared, solving the contradiction between the mechanical properties and processing properties of soft materials. The preparation method of the elastic hydrogel provided by the present invention is simple and easy, has adjustable mechanical properties, can better match soft tissues, can simulate the mechanical behavior of human soft tissues, and is expected to be applied to medical preoperative simulation, organ transplantation, and surgical resection medical fields.

Description

Technical Field

[0001] The present invention relates to the technical field of hydrogel-based tissue and organ model manufacturing, and in particular to a soft tissue-like elastic hydrogel and a preparation method and application of a tissue and organ model thereof. Background Art

[0002] Human tissue and organ models are an important means for doctors to use for preoperative simulation and medical teaching. For example, in clinical diagnosis, when doctors perform interventional surgery (cardiovascular and tumor interventional treatment), they need to know in advance the size of blood vessels and tissue organs, the location of diseased tissues and their spatial relationships, so as to make adequate surgical plans and contingency plans, assess the possible risks of the surgery and take measures to deal with potential risks. In addition, artificial tissue and organ models are also needed to carry out simulation tests during robotic surgery training. Compared with traditional living tissues and organs, artificial human tissue and organ models have significant advantages in low cost, ethics, portability and other aspects.

[0003] At present, the base materials for constructing artificial human tissue and organ models are mainly hard materials such as photosensitive resin and polylactic acid, and soft materials such as elastic silicone and polyurethane elastomer. These materials have high strength and high rigidity and are not suitable for the construction of soft tissue organs. In addition, the mechanical feedback of surgical instruments made of these materials is inconsistent with that of natural soft tissue organs, which limits their application in surgical operation simulation. In addition, the vast majority of tissue and organ models are currently prepared mainly through template casting. However, tissue and organ models manufactured by mold technology cannot construct tissue and organ models with complex vascular channels and heterogeneous structures, which greatly limits the function and application of human tissue and organ models.

[0004] As one of the typical representatives of soft materials, hydrogels have a structure similar to biological soft tissues and the advantages of a high water content, and have broad application prospects in biomedicine and other fields. However, due to the single component, difficulty in manufacturing and lack of post-processing, traditional hydrogels have poor mechanical properties and cannot simulate the mechanical behavior of human soft tissues. Elastic hydrogels have greater potential in the manufacture of soft tissue and organ models due to their unique viscoelasticity and can better meet their requirements for material mechanical properties. In addition, the softness of elastic hydrogels is closer to that of living organs, giving them a touch close to organs and excellent durability. However, to date, there is still a lack of effective methods to regulate the mechanical properties of elastic hydrogels to match various natural soft tissues. In addition, the poor mechanical properties of elastic hydrogels make it difficult to directly construct tissue and organ models with vascular channels and heterogeneous structures, which is the biggest challenge in the current field of artificial hydrogel tissue and organ model construction. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a preparation method and application of a soft tissue-like elastic hydrogel and its tissue organ model. The soft tissue-like elastic hydrogel provided by the present invention has good elasticity, strength and toughness, and can simulate the mechanical behavior of human soft tissue.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing a soft tissue-like elastic hydrogel, comprising the following steps:

[0008] Mixing acrylamide monomer, an unsaturated double bond monomer containing a negative electron group, a water-soluble photoinitiator, a crosslinking agent, a light absorber and water to obtain a hydrogel light-curable ink solution;

[0009] performing photocuring on the hydrogel photocurable ink solution to obtain a photocurable hydrogel precursor;

[0010] Immersing the photocurable hydrogel precursor in a zirconium salt solution to perform a metal coordination reaction to obtain a photocurable hydrogel precursor with enhanced metal coordination;

[0011] The metal coordination enhanced light-curable hydrogel precursor is immersed in water to carry out ion balance to obtain a soft tissue-like elastic hydrogel.

[0012] Preferably, the unsaturated double bond monomer containing a negative electron group is one or more of 2-acrylamide-2-methylpropanesulfonic acid, sodium 2-acrylamide-2-methylpropanesulfonate, methacrylic acid, acrylic acid and vinylsulfonic acid or sodium sulfonate;

[0013] The water-soluble photoinitiator is one or more of phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, azobisisobutyramidine hydrochloride, α-ketoglutaric acid, 2-hydroxy-2-methylpropiophenone and 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone;

[0014] The cross-linking agent is one of methylene bisacrylamide and / or polyethylene glycol dimethacrylate;

[0015] The light absorber is lemon yellow.

[0016] Preferably, the molar ratio of the acrylamide monomer to the unsaturated double bond monomer containing an electron-negative group is 1:0.05 to 0.25;

[0017] The amount of the water-soluble photoinitiator added is 3 to 5‰ of the total mass of the acrylamide monomer and the unsaturated double bond monomer containing a negative electron group;

[0018] The added amount of the cross-linking agent is 0.05 to 0.25% of the total molar amount of the acrylamide monomer and the unsaturated double bond monomer containing a negative electron group;

[0019] The concentration of the light absorber is 0.10-0.30 g / L.

[0020] Preferably, the wavelength of the light source used for the photocuring is 365-405 nm, the intensity is 500-1000 mW; the photocuring time is 3-7 min;

[0021] The concentration of the zirconium salt aqueous solution is 0.05 to 0.25 mol / L; the time for the metal coordination reaction is 3 to 7 days; and the time for the ion balance is 3 to 7 days.

[0022] The present invention provides a soft tissue-like elastic hydrogel prepared by the above preparation method, wherein the soft tissue-like elastic hydrogel comprises a covalent cross-linked network formed by an acrylamide monomer and an unsaturated double bond monomer containing a negative electron group, and an ionic cross-linked network formed by the coordination of the negative electron group and the zirconium ion.

[0023] The present invention provides the use of the soft tissue-like elastic hydrogel in preparing a hydrogel tissue organ model.

[0024] Preferably, the tissue organ is one or more of blood vessels, heart, kidney, liver, lung, brain, ear, nose and valve.

[0025] The present invention provides a method for preparing a hydrogel tissue organ model, comprising the following steps:

[0026] Acquire image data of tissues and organs through medical imaging, and obtain 3D printing slice data based on the image data;

[0027] Mixing acrylamide monomer, an unsaturated double bond monomer containing a negative electron group, a water-soluble photoinitiator, a crosslinking agent, a light absorber and water to obtain a hydrogel light-curable ink solution;

[0028] Performing photocuring 3D printing on the hydrogel photocurable ink solution according to the 3D printing slice data to obtain a hydrogel tissue organ model precursor;

[0029] Immersing the hydrogel tissue organ model precursor in a zirconium salt solution to perform a metal coordination reaction to obtain a hydrogel tissue organ model precursor with enhanced metal coordination;

[0030] The metal coordination enhanced hydrogel tissue organ model precursor is immersed in water to perform ion balance to obtain a hydrogel tissue organ model.

[0031] Preferably, the parameters of the light-curing 3D printing include:

[0032] The wavelength of the light source is 365-405nm;

[0033] The exposure time for a single layer is 10 to 20 seconds;

[0034] The thickness of single-layer slices is 0.05-0.1 mm;

[0035] The light intensity of the light source is 500-1000mW.

[0036] Preferably, the concentration of the zirconium salt solution is 0.05 to 0.25 mol / L;

[0037] When the hydrogel tissue organ model is a heart, liver, kidney, brain or lung, the metal coordination reaction time is 5 to 10 days;

[0038] When the hydrogel tissue organ model is a blood vessel, an ear, a nose or a valve, the metal coordination reaction time is 5 to 7 days.

[0039] The present invention provides a method for preparing a soft tissue-like elastic hydrogel. The method utilizes acrylamide monomers and unsaturated double-bond monomers containing negative electron groups for photocuring to form a covalent crosslinked network. The resulting photocured hydrogel contains negative electron groups that can react with zirconium ions to form an ionic crosslinked network. Therefore, the resulting soft tissue-like elastic hydrogel has a double network structure and good strength. Furthermore, the method uses zirconium ions as a coordination metal, which prevents the formation of a gradient structure or skin layer with high surface strength and weak internal strength during the coordination process. The resulting hydrogel has good elasticity and toughness. Compared with hydrogels formed by metal coordination such as iron ions and aluminum ions, it can better match the performance of soft tissue and simulate the mechanical behavior of human soft tissue.

[0040] The present invention provides a method for preparing a hydrogel tissue and organ model. The method obtains image data of the tissue and organ through medical imaging, obtains 3D printing slice data based on the image data, and performs photocuring 3D printing using a hydrogel precursor solution as ink according to the 3D printing slice data to obtain a hydrogel tissue and organ model precursor. The hydrogel tissue and organ model precursor is then immersed in a zirconium salt aqueous solution and then in water to obtain the hydrogel tissue and organ model. The present invention enables the customizable preparation of elastic hydrogels and can construct various tissue and organ models with mechanical properties matching those of natural soft tissue, including the heart, internal organs, lungs, kidneys, brain, and valves. The hydrogel tissue and organ models prepared by the present invention have the mechanical feedback, tactile feel, softness, and durability of surgical instruments similar to those of internal human organs, and are suitable for surgical rehearsals and teaching demonstrations, especially for manual skill practice and cutting operations that require surgical resection instruments during surgery; the present invention adopts light-curing 3D printing to construct fine structures, and the resulting models can truly reflect the internal pipeline structure of human organs and simulate the circulation of various fluids in human organs, intuitively showing the real condition of the organs, thereby effectively improving the predictability of the surgical process. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 The figure is a flow chart for the preparation of soft tissue-like elastic hydrogel;

[0042] Figure 2 Flow chart for the preparation of hydrogel tissue organ models;

[0043] Figure 3 This is a scanning electron micrograph of the soft tissue-like elastic hydrogel obtained in Example 1;

[0044] Figure 4 The results of fatigue resistance test on the soft tissue elastic hydrogel obtained in Example 1 are as follows;

[0045] Figure 5 This is an optical photograph of the hydrogel tissue organ model obtained in Example 2;

[0046] Figure 6 The mechanical properties test results of the hydrogel tissue organ model obtained in Example 2;

[0047] Figure 7 This is an optical photograph of the hydrogel tissue organ model obtained in Example 3;

[0048] Figure 8 The mechanical properties test results of the hydrogel tissue organ model obtained in Example 3;

[0049] Figure 9 This is an optical photograph of the hydrogel tissue organ model obtained in Example 4;

[0050] Figure 10 The mechanical properties test results of the hydrogel tissue organ model obtained in Example 4;

[0051] Figure 11 This is an optical photograph of the hydrogel tissue organ model obtained in Example 5;

[0052] Figure 12 The mechanical properties test results of the hydrogel tissue organ model obtained in Example 5;

[0053] Figure 13 This is an optical photograph of the hydrogel tissue organ model obtained in Example 6;

[0054] Figure 14 The mechanical properties test results of the hydrogel tissue organ model obtained in Example 6;

[0055] Figure 15 This is an optical photograph of the hydrogel tissue organ model obtained in Example 7;

[0056] Figure 16 The mechanical properties test results of the hydrogel tissue organ model obtained in Example 7;

[0057] Figure 17 This is an optical photograph of the hydrogel tissue organ model obtained in Example 8;

[0058] Figure 18 The mechanical properties test results of the hydrogel tissue organ model obtained in Example 8;

[0059] Figure 19 This is an optical photograph of the hydrogel tissue organ model obtained in Example 9;

[0060] Figure 20 These are the mechanical property test results of the hydrogel tissue organ model obtained in Example 9. DETAILED DESCRIPTION

[0061] The present invention provides a method for preparing a soft tissue-like elastic hydrogel, comprising the following steps:

[0062] Mixing acrylamide monomer, an unsaturated double bond monomer containing a negative electron group, a water-soluble photoinitiator, a crosslinking agent, a light absorber and water to obtain a hydrogel light-curable ink solution;

[0063] performing photocuring on the hydrogel photocurable ink solution to obtain a photocurable hydrogel precursor;

[0064] Immersing the photocurable hydrogel precursor in a zirconium salt solution to perform a metal coordination reaction to obtain a photocurable hydrogel precursor with enhanced metal coordination;

[0065] The metal coordination enhanced light-curable hydrogel precursor is immersed in water to carry out ion balance to obtain a soft tissue-like elastic hydrogel.

[0066] The present invention mixes an acrylamide monomer, an unsaturated double-bond monomer containing an electron-negative group, a water-soluble photoinitiator, a crosslinker, a light absorber, and water to produce a hydrogel photocurable ink solution. In the present invention, the electron-negative group in the unsaturated double-bond monomer containing an electron-negative group is one or more of a carboxylic acid group, a sulfonic acid group, and a sulfate ester group. In the present invention, the electron-negative unsaturated double-bond monomer containing an electron-negative group is preferably one or more of 2-acrylamido-2-methylpropanesulfonic acid, sodium 2-acrylamido-2-methylpropanesulfonate, methacrylic acid, acrylic acid, vinylsulfonic acid, and sodium sulfonate.

[0067] In the present invention, the water-soluble photoinitiator is preferably one or more of phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, azobisisobutyramidine hydrochloride, α-ketoglutaric acid, 2-hydroxy-2-methylpropiophenone and 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone.

[0068] In the present invention, the cross-linking agent is preferably methylene bisacrylamide and / or polyethylene glycol dimethacrylate.

[0069] In the present invention, the light absorber is preferably tartrazine.

[0070] In the present invention, the total molar concentration of monomers in the hydrogel photocurable ink solution is preferably 2 to 4 mol / L, more preferably 3 mol / L.

[0071] In the present invention, the molar ratio of the acrylamide monomer to the unsaturated double bond monomer containing an electron-negative group is preferably 1:0.05-0.25, more preferably 1:0.1-0.2.

[0072] In the present invention, the added amount of the water-soluble photoinitiator is preferably 3 to 5‰ of the total mass of the acrylamide monomer and the unsaturated double bond monomer containing a negative electron group, and more preferably 4‰; the added amount of the cross-linking agent is preferably 0.05 to 0.25% of the total molar amount of the acrylamide monomer and the unsaturated double bond monomer containing a negative electron group, and more preferably 0.1 to 0.2%.

[0073] In the present invention, the concentration of the light absorber in the hydrogel photocurable ink solution is preferably 0.1 to 0.3 g / L, more preferably 0.2 g / L.

[0074] The present invention has no special requirements for the mixing method, and a mixing method well known to those skilled in the art can be used, such as stirring. In the present invention, after the mixing, the present invention preferably deoxygenates the obtained mixed solution, and the deoxygenation method is preferably nitrogen deoxygenation.

[0075] After obtaining the hydrogel photocurable ink solution, the present invention photocures the hydrogel photocurable ink solution to obtain a photocurable hydrogel precursor. In the present invention, the photocuring is preferably ultraviolet light curing. In the present invention, the wavelength of the light source used for the photocuring is preferably 365 to 405 nm, more preferably 380 to 400 nm; the intensity is preferably 500 to 1000 mW, more preferably 600 to 800 mW; the photocuring time is preferably 3 to 7 minutes, more preferably 4 to 6 minutes. The present invention forms a covalent cross-linked network of monomers through the photocuring.

[0076] After obtaining the photocurable hydrogel precursor, the present invention immerses the photocurable hydrogel precursor in a zirconium salt solution to perform a metal coordination reaction to obtain a metal-coordinated photocurable hydrogel precursor. In the present invention, the zirconium salt is preferably zirconium tetrachloride and / or zirconium oxychloride. In the present invention, the concentration of the zirconium salt aqueous solution is preferably 0.05 to 0.25 mol / L, more preferably 0.1 to 0.2 mol / L. The present invention has no special requirements for the volume of the zirconium salt solution, as long as it can immerse the photocurable hydrogel precursor.

[0077] In the present invention, the metal coordination reaction is preferably carried out at room temperature for 3 to 7 days, more preferably 4 to 6 days. Through the metal coordination reaction, the zirconium ions can be ionically coordinated with the electron-negative groups, forming an ionically crosslinked network in the hydrogel and imparting good strength, elasticity, and toughness to the hydrogel.

[0078] After obtaining the metal coordination-enhanced photocurable hydrogel precursor, the present invention immerses the metal coordination-enhanced photocurable hydrogel precursor in water for ion equilibration to obtain a soft tissue-like elastic hydrogel. In the present invention, the water is preferably deionized water. In the present invention, the ion equilibration time is preferably 3 to 7 days, more preferably 4 to 6 days. The present invention has no particular requirements for the volume of the water; it only needs to be sufficient to submerge the metal coordination-enhanced photocurable hydrogel precursor.

[0079] In the present invention, the preparation flow chart of the soft tissue-like elastic hydrogel is as follows: Figure 1 shown.

[0080] The present invention provides a soft tissue-like elastic hydrogel prepared by the above-mentioned preparation method, wherein the soft tissue-like elastic hydrogel includes a covalent cross-linked network formed by an acrylamide monomer and an unsaturated double bond monomer containing a negative electron group, and an ionic cross-linked network formed by the coordination of the negative electron group and the zirconium ion. Specifically, the present invention utilizes the covalent cross-linked network formed by the cross-linking of two monomers and the double network hydrogel formed by the metal coordination post-treatment process as an elastic hydrogel, and regulates its mechanical properties through parameters such as the molar ratio of the monomers, the monomer concentration, the metal ion concentration, and the cross-linking agent content, so that the obtained elastic hydrogel has mechanical properties that match those of soft tissue organs, and with the advantage of the light-curing rapid prototyping technology that can construct fine structures, it can provide a soft tissue organ model with mechanical properties that match those of various natural soft tissues and can be personalized and customized, which is conducive to its wide application in medical preoperative simulation, organ transplantation, and surgical resection.

[0081] The present invention provides the use of the soft tissue-like elastic hydrogel in preparing tissue and organ models. In the present invention, the tissue and organ are preferably one or more of blood vessels, heart, kidney, liver, lung, brain, ear, nose, and valve.

[0082] The present invention provides a method for preparing a hydrogel tissue organ model, comprising the following steps:

[0083] Acquire image data of tissues and organs through medical imaging, and obtain 3D printing slice data based on the image data;

[0084] Mixing acrylamide monomer, an unsaturated double bond monomer containing a negative electron group, a water-soluble photoinitiator, a crosslinking agent, a light absorber and water to obtain a hydrogel light-curable ink solution;

[0085] Performing photocuring 3D printing on the hydrogel photocurable ink solution according to the 3D printing slice data to obtain a hydrogel tissue organ model precursor;

[0086] Immersing the hydrogel tissue organ model precursor in a zirconium salt solution to perform a metal coordination reaction to obtain a hydrogel tissue organ model precursor with enhanced metal coordination;

[0087] The metal coordination enhanced hydrogel tissue organ model precursor is immersed in water to perform ion balance to obtain a hydrogel tissue organ model.

[0088] The present invention obtains image data of tissues and organs through medical imaging, and obtains 3D printing slice data based on the image data. In the present invention, the method for obtaining the image data of the tissue and organ model is preferably electronic computed tomography (CT) and / or magnetic resonance imaging (MRI).

[0089] In the present invention, the method of obtaining 3D printing slice data according to the image data is preferably: electronic computed tomography (CT).

[0090] A three-dimensional digital model of the tissue and organ model was established using the software Materialise Magics 24.0 according to the image data of the tissue and organ model. The three-dimensional digital model was converted into a 3D-printable STL file using the software Materialise Magics 24.0. The STL file was sliced ​​to obtain 3D printing slice data.

[0091] The present invention prepares a hydrogel precursor solution according to the above preparation method, and performs photocuring 3D printing on the hydrogel precursor solution according to the 3D printing slice data to obtain a hydrogel tissue organ model precursor. In the present invention, the parameters of the photocuring 3D printing include:

[0092] The wavelength of the light source is preferably 365 to 405 nm, more preferably 380 to 400 nm;

[0093] The exposure time of a single layer is preferably 10 to 20 seconds, more preferably 15 seconds;

[0094] The thickness of a single slice is preferably 0.05 to 0.1 mm, more preferably 0.06 to 0.08 mm;

[0095] The light intensity of the light source is preferably 500 to 1000 mW, more preferably 600 to 800 mW.

[0096] After obtaining the hydrogel tissue organ model precursor, the present invention sequentially immerses the hydrogel tissue organ model precursor in a zirconium salt aqueous solution and water to obtain a hydrogel tissue organ model. In the present invention, the zirconium salt is preferably zirconium tetrachloride and / or zirconium oxychloride. In the present invention, the concentration of the zirconium salt aqueous solution is preferably 0.05 to 0.25 mol / L, more preferably 0.1 to 0.2 mol / L. The present invention has no special requirements for the volume of the zirconium salt solution, as long as it can immerse the hydrogel tissue organ model precursor.

[0097] In the present invention, the hydrogel tissue organ model precursor is preferably immersed in the zirconium salt aqueous solution for 5 to 10 days, more preferably 6 to 8 days; the immersion is preferably carried out at room temperature.

[0098] In the present invention, the time for which the hydrogel tissue organ model precursor is immersed in water is preferably determined according to the type of tissue organ model. Specifically, when the tissue organ model is a heart, liver, kidney, brain or lung, the immersion time in water is preferably 7 to 10 days; when the tissue organ model is an ear, nose or valve, the immersion time in water is preferably 5 to 7 days.

[0099] In the present invention, the preparation process of the hydrogel tissue organ model is as follows Figure 2 shown.

[0100] The preparation method and application of the soft tissue-like elastic hydrogel and the hydrogel tissue and organ model provided by the present invention are described in detail below with reference to the examples. However, these examples should not be construed as limiting the scope of protection of the present invention.

[0101] Example 1

[0102] 25.6 g acrylamide, 8.3 g 2-acrylamide-2-methylpropanesulfonic acid, 0.17 g phenyl (2,4,6-trimethylbenzoyl) lithium phosphate, 0.09 g methylene bisacrylamide, and 0.01 g tartrazine were fully dissolved in 100 mL of deionized water, and the mixture was deoxygenated by passing nitrogen gas to obtain a hydrogel precursor solution. The hydrogel precursor solution was photocured at a light intensity of 500 mW for 3 minutes to obtain a photocured hydrogel. The photocured hydrogel was immersed in a 0.1 mol / L zirconium oxychloride salt solution for 5 days to carry out a metal coordination reaction to obtain a metal coordination-enhanced photocured hydrogel. Finally, the metal coordination-enhanced photocured hydrogel was immersed in water for ion balance for 5 days to obtain a soft tissue-like elastic hydrogel.

[0103] The scanning electron microscopy image of the obtained soft tissue elastic hydrogel is as follows: Figure 3 As shown. Figure 3 It can be seen that the soft tissue-like elastic hydrogel has a good three-dimensional network structure.

[0104] The fatigue resistance test of the obtained soft tissue elastic hydrogel was carried out, and the results were as follows: Figure 4 As shown. Figure 4 It can be seen that the soft tissue-like elastic hydrogel has good fatigue resistance.

[0105] Example 2

[0106] 25.6 g of acrylamide, 8.3 g of 2-acrylamide-2-methylpropanesulfonic acid, 0.17 g of phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, 0.09 g of methylenebisacrylamide, and 0.01 g of lemon yellow were fully dissolved in 100 mL of deionized water, and after deoxygenation by nitrogen gas, a photocurable hydrogel ink was obtained.

[0107] The prepared photocurable printable hydrogel ink was transferred to the photocurable 3D printer material box, and the STL file of the ear tissue and organ model was created using 3D modeling software. The file was then imported into the 3D printer software for slicing to obtain slicing data. Under the conditions of a light source of 405nm, a single-layer slice thickness of 0.1mm, a single-layer exposure time of 15s, a light source intensity of 500mW, and a printing environment temperature of room temperature, the photocurable 3D printer was driven to manufacture the ear tissue model.

[0108] The photocured tissue and organ model was immersed in a 0.10 mol / L zirconium oxychloride solution for metal coordination treatment for 5 days; the metal coordination-enhanced photocured hydrogel was balanced in deionized water for 5 days to obtain a soft tissue-like elastic hydrogel organ model. The optical photograph of the obtained hydrogel tissue and organ model is shown in Figure 2. Figure 5 shown.

[0109] Mechanical properties test results are as follows Figure 6 As shown, the soft tissue elastic hydrogel of the present invention has a tensile strength of 0.57±0.10MPa, an elastic modulus of 73.8±2.3kPa, and a toughness of 1.07±0.24MJ / m when the strain is 596±50%. 3 .

[0110] Example 3

[0111] The difference from Example 2 is that 19.2 g acrylamide, 6.2 g 2-acrylamide-2-methylpropanesulfonic acid, 0.13 g phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, and 0.04 g methylene bisacrylamide were added.

[0112] The light-curing 3D printing steps and parameters and tissue model post-processing are the same as in Example 2.

[0113] The printed soft tissue organ model is a nose. The optical photograph of the obtained hydrogel tissue organ model is as follows Figure 7 shown.

[0114] Mechanical properties test results are as follows Figure 8 As shown in Figure 2, the soft tissue elastic hydrogel of the present invention has a tensile strength of 0.75±0.08MPa, an elastic modulus of 87.7±4.8kPa, and a toughness of 1.63±0.16MJ / m when the strain is 706±22%. 3 .

[0115] Example 4

[0116] The difference from Example 3 is that the light-cured tissue and organ model is immersed in a 0.25 mol / L zirconium oxychloride solution.

[0117] The light-curing 3D printing steps and parameters are the same as those in Example 2.

[0118] The printed soft tissue organ model is the liver. The optical photograph of the hydrogel tissue organ model is as follows: Figure 9 shown.

[0119] Mechanical properties test results are as follows Figure 10 As shown in Figure 2, the soft tissue elastic hydrogel of the present invention has a tensile strength of 2.04±0.16MPa, an elastic modulus of 184.7±14.5kPa, and a toughness of 4.16±1.03MJ / m when the strain is 541±47%. 3 .

[0120] Example 5

[0121] The difference from Example 2 is that 16.0 g acrylamide, 15.5 g 2-acrylamide-2-methylpropanesulfonic acid, 0.16 g phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, and 0.04 g methylene bisacrylamide were added.

[0122] The light-curing 3D printing steps and parameters and tissue model post-processing are the same as in Example 2.

[0123] The printed soft tissue organ model is a kidney. The optical photograph of the hydrogel tissue organ model is as follows: Figure 11 shown.

[0124] Mechanical properties test results are as follows Figure 12 As shown, the soft tissue elastic hydrogel of the present invention has a tensile strength of 2.0±0.3MPa, an elastic modulus of 192±24kPa, and a toughness of 6.2±0.3MJ / m when the strain is 848±50%. 3 .

[0125] Example 6

[0126] The difference from Example 2 is that 19.2 g of acrylamide, 6.2 g of 2-acrylamide-2-methylpropanesulfonic acid, 0.13 g of phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, and 0.12 g of methylenebisacrylamide were added.

[0127] The light-curing 3D printing steps and parameters and tissue model post-processing are the same as in Example 2.

[0128] The printed soft tissue organ model is lung. The optical photograph of the hydrogel tissue organ model is as follows: Figure 13 shown.

[0129] Mechanical properties test results are as follows Figure 14As shown in Figure 2, the soft tissue elastic hydrogel of the present invention has a tensile strength of 0.31±0.03MPa, an elastic modulus of 90.6±8.5kPa, and a toughness of 0.42±0.01MJ / m when the strain is 362±25%. 3 .

[0130] Example 7

[0131] The difference from Example 2 is that 19.2 g acrylamide, 6.2 g 2-acrylamide-2-methylpropanesulfonic acid, 0.13 g phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, and 0.07 g methylene bisacrylamide were added.

[0132] The light-curing 3D printing steps and parameters and tissue model post-processing are the same as in Example 2.

[0133] The printed soft tissue organ model is a valve. The optical photograph of the hydrogel tissue organ model is as follows: Figure 15 shown.

[0134] Mechanical properties test results are as follows Figure 16 As shown in Figure 2, the soft tissue elastic hydrogel of the present invention has a tensile strength of 0.53±0.12MPa, an elastic modulus of 69.3±2.5kPa, and a toughness of 0.82±0.07MJ / m when the strain is 521±27%. 3 .

[0135] Example 8

[0136] The difference from Example 2 is that 18.1 g acrylamide, 9.3 g 2-acrylamide-2-methylpropanesulfonic acid, 0.14 g phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, and 0.04 g methylene bisacrylamide were added.

[0137] The light-curing 3D printing steps and parameters and tissue model post-processing are the same as in Example 2.

[0138] The printed soft tissue organ model is the brain. The optical photograph of the obtained hydrogel tissue organ model is as follows Figure 17 shown.

[0139] Mechanical properties test results are as follows Figure 18 As shown in Figure 2, the soft tissue elastic hydrogel of the present invention has a tensile strength of 1.27±0.05MPa, an elastic modulus of 103.6±6.8kPa, and a toughness of 2.94±0.16MJ / m when the strain is 718±25%. 3 .

[0140] Example 9

[0141] The difference from Example 2 is that 25.6 g acrylamide, 4.2 g 2-acrylamide-2-methylpropanesulfonic acid, 1.5 g acrylic acid, 0.16 g phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, and 0.09 g methylene bisacrylamide were added.

[0142] The light-curing 3D printing steps and parameters and tissue model post-processing are the same as in Example 2.

[0143] The printed soft tissue organ model is a heart. The optical photograph of the hydrogel tissue organ model is as follows: Figure 19 shown.

[0144] Mechanical properties test results are as follows Figure 20 As shown in Figure 2, the soft tissue elastic hydrogel of the present invention has a tensile strength of 3.15±0.27MPa, an elastic modulus of 177.7±33.5kPa, and a toughness of 9.37±0.71MJ / m when the strain is 926±28%. 3 .

[0145] Comparative Example 1

[0146] The difference from Example 2 is that the step of soaking in the zirconium oxychloride solution is omitted. The remaining operations are the same as in Example 2.

[0147] The printed soft tissue organ model is a nose. The mechanical properties test results of the hydrogel tissue organ model show that when the strain is 317±17%, the tensile strength reaches 0.02±0.002MPa, the elastic modulus is 12.5±0.8kPa, and the toughness is 0.03±0.002MJ / m 3 .

[0148] Comparative Example 2

[0149] The difference from Example 2 is that the zirconium oxychloride solution is replaced by a ferric chloride solution with the same molar concentration. The remaining operations are the same as in Example 2.

[0150] The printed soft tissue organ model is a nose. The mechanical properties test results of the hydrogel tissue organ model show that when the strain is 326±18%, the tensile strength reaches 4.35±0.37MPa, the elastic modulus is 1077.7±93.5kPa, and the toughness is 13.37±0.79MJ / m 3 .

[0151] Comparative Example 3

[0152] The difference from Example 2 is that the zirconium oxychloride solution is replaced by an aluminum chloride solution with the same molar concentration. The remaining operations are the same as in Example 2.

[0153] The printed soft tissue organ model is a nose. The mechanical properties test results of the hydrogel tissue organ model show that when the strain is 286±22%, the tensile strength reaches 2.35±0.25MPa, the elastic modulus is 1377.7±113.5kPa, and the toughness is 10.37±0.39MJ / m 3 .

[0154] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a soft tissue-like elastic hydrogel, comprising the following steps: Mixing acrylamide monomer, an unsaturated double bond monomer containing a negative electron group, a water-soluble photoinitiator, a crosslinking agent, a light absorber and water to obtain a hydrogel light-curable ink solution; performing photocuring on the hydrogel photocurable ink solution to obtain a photocurable hydrogel precursor; Immersing the photocurable hydrogel precursor in a zirconium salt aqueous solution to perform a metal coordination reaction to obtain a metal coordination-enhanced photocurable hydrogel precursor; Soaking the metal coordination enhanced light-curable hydrogel precursor in water to perform ion balance to obtain a soft tissue-like elastic hydrogel; The unsaturated double bond monomer containing a negative electron group is 2-acrylamide-2-methylpropanesulfonic acid, or 2-acrylamide-2-methylpropanesulfonic acid and acrylic acid; The molar ratio of the acrylamide monomer to the unsaturated double bond monomer containing a negative electron group is 1:0.05-0.25; The amount of the water-soluble photoinitiator added is 3-5‰ of the total mass of the acrylamide monomer and the unsaturated double bond monomer containing a negative electron group; The added amount of the cross-linking agent is 0.05-0.25% of the total molar amount of the acrylamide monomer and the unsaturated double bond monomer containing a negative electron group; The concentration of the light absorber is 0.10-0.30 g / L; The concentration of the zirconium salt aqueous solution is 0.05-0.25 mol / L; the time of the metal coordination reaction is 3-7 days; and the time of the ion equilibrium is 3-7 days.

2. The preparation method according to claim 1, characterized in that The water-soluble photoinitiator is one or more of phenyl (2, 4, 6-trimethylbenzoyl) phosphate lithium salt, azobisisobutyramidine hydrochloride, α-ketoglutaric acid, 2-hydroxy-2-methylpropiophenone and 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone; The cross-linking agent is one of methylene bisacrylamide and / or polyethylene glycol dimethacrylate; The light absorber is lemon yellow.

3. The preparation method according to claim 1, characterized in that The wavelength of the light source used for the photocuring is 365-405 nm, and the intensity is 500-1000 mW; the photocuring time is 3-7 min.

4. The soft tissue-like elastic hydrogel prepared by the preparation method according to any one of claims 1 to 3, wherein the soft tissue-like elastic hydrogel comprises a covalent cross-linked network formed by acrylamide monomers and unsaturated double bond monomers containing negative electron groups, and an ionic cross-linked network formed by the coordination of negative electron groups and zirconium ions.

5. Use of the soft tissue-like elastic hydrogel according to claim 4 in preparing a hydrogel tissue and organ model.

6. The use according to claim 5, characterized in that The tissue organ is one or more of blood vessels, heart, kidney, liver, lung, brain, ear, nose and valve.

7. A method for preparing a hydrogel tissue organ model, comprising the following steps: Acquire image data of tissues and organs through medical imaging, and obtain 3D printing slice data based on the image data; Mixing acrylamide monomer, an unsaturated double bond monomer containing a negative electron group, a water-soluble photoinitiator, a crosslinking agent, a light absorber and water to obtain a hydrogel light-curable ink solution; Performing photocuring 3D printing on the hydrogel photocurable ink solution according to the 3D printing slice data to obtain a hydrogel tissue organ model precursor; soaking the hydrogel tissue organ model precursor in a zirconium salt aqueous solution to perform a metal coordination reaction to obtain a hydrogel tissue organ model precursor with enhanced metal coordination; Soaking the metal coordination enhanced hydrogel tissue organ model precursor in water to perform ion balance to obtain a hydrogel tissue organ model; The unsaturated double bond monomer containing a negative electron group is 2-acrylamide-2-methylpropanesulfonic acid, or 2-acrylamide-2-methylpropanesulfonic acid and acrylic acid; The molar ratio of the acrylamide monomer to the unsaturated double bond monomer containing a negative electron group is 1:0.05-0.25; The amount of the water-soluble photoinitiator added is 3-5‰ of the total mass of the acrylamide monomer and the unsaturated double bond monomer containing a negative electron group; The added amount of the cross-linking agent is 0.05-0.25% of the total molar amount of the acrylamide monomer and the unsaturated double bond monomer containing a negative electron group; The concentration of the light absorber is 0.10-0.30 g / L; The concentration of the zirconium salt aqueous solution is 0.05-0.25 mol / L.

8. The preparation method according to claim 7, characterized in that The parameters of the light-curing 3D printing include: The wavelength of the light source is 365~405 nm; The exposure time for a single layer is 10–20 s; The thickness of single-layer sections was 0.05–0.1 mm; The light intensity of the light source is 500~1000 mW.

9. The preparation method according to claim 7, characterized in that When the hydrogel tissue organ model is a heart, liver, kidney, brain or lung, the metal coordination reaction time is 5 to 10 days; When the hydrogel tissue organ model is a blood vessel, an ear, a nose or a valve, the metal coordination reaction time is 5 to 7 days.

Images