Hydrogel composition for human body ultrasonography simulation, preparation method therefor, and artificial organ comprising tissue formed therefrom

Abstract

The present invention relates to a hydrogel composition for an ultrasonography simulation, a preparation method therefor, and an artificial organ comprising tissue formed therefrom, and more specifically to a hydrogel composition for human body ultrasonography simulation, a preparation method therefor, and an artificial organ comprising tissue formed therefrom.

Description

Hydrogel composition for human ultrasound examination simulation, method for producing the hydrogel composition, and artificial organ comprising tissue formed from the hydrogel composition

[0001] This application claims the benefit of priority from Republic of Korea Patent Application No. 10-2023-0181430, dated December 14, 2023, and incorporates herein all the contents of the document disclosed in that Republic of Korea Patent Application.

[0002] The present invention relates to a hydrogel composition for ultrasound examination simulation, a method for producing the same, and an artificial organ comprising a tissue formed from the hydrogel composition, and more particularly, to a hydrogel composition for human ultrasound examination simulation, a method for producing the same, and an artificial organ comprising a tissue formed from the hydrogel composition.

[0003] Despite the steadily increasing number of patients requiring organ transplants, the supply of available organs is limited. To address this, the need for the development of artificial organs or tissues is emerging. Active research is underway on the manufacture of hydrogel-based artificial organs or tissues that reduce immune rejection and foreign body sensation when transplanted into the body.

[0004] Furthermore, ultrasound examination is a method of examining body tissue for abnormalities using ultrasound. More specifically, it involves transmitting ultrasound waves into the body part to be measured and then capturing the reflected image to determine the presence of abnormal tissue. Currently, ultrasound examinations are widely used for most medical examinations, not just for diagnosing lesions such as tumors and fetuses.

[0005] However, conventional artificial organs or tissues made of hydrogel materials suffer from the drawback that, when measured by ultrasound, they appear black without any color differentiation, limiting their usability. The development of hydrogel materials for human ultrasound examination simulation that can address this issue is needed.

[0006] [Prior Art Literature]

[0007] [Patent Document]

[0008] (Patent Document 1) Republic of Korea Patent Publication No. 10-1725311 (April 4, 2017)

[0009] The present invention is to solve the above problems of the prior art,

[0010] The purpose is to provide a hydrogel composition for ultrasound examination simulation that is useful for manufacturing artificial organs or artificial tissues for transplantation into the body.

[0011] In addition, the purpose is to provide a hydrogel composition for ultrasound examination simulation in which each tissue is implemented separately during ultrasound observation and observed like an actual human organ or tissue.

[0012] In addition, it is an object to provide an artificial organ including a tissue formed from the hydrogel composition for ultrasound examination simulation.

[0013] In addition, the purpose is to provide a method for efficiently manufacturing a hydrogel composition for the ultrasound examination simulation.

[0014] In order to achieve the above purpose, the present invention,

[0015] A hydrogel composition for ultrasound examination simulation is provided, comprising a hydrogel monomer and a water-dispersible fibrous material, wherein the content of the fibrous material is 0.001 wt% to 5.0 wt% based on the total weight of the composition.

[0016] In addition, the present invention provides a hydrogel monomer selected from the group consisting of acrylamide, agarose, methacrylamide, bis-acrylamide, NN-dimethylacrylamide, N,N-methylenebisacrylamide, polyaniline, acrylic acid, methacrylic acid, vinylsulfonic acid, styrenesulfonic acid, polyacrylic acid, allylamine, methyl methacrylate, poly(ethylene glycol) methacrylate, poly(ethylene glycol) diacrylate, sodium polyacrylate, N-vinylpyrrolidone, imide, amide, agarose, gelatin, gelatin methacrylate, collagen, fibrinogen, fibrin, methyl cellulose, chitosan, chitin, polyethylene glycol, polyvinyl alcohol carrageenan, 2-acrylamido-2-methylpropane-sulfonic acid, alginate. A hydrogel composition for ultrasound examination simulation is provided, wherein the composition comprises at least one selected from 2-hydroxyethyl methacrylate and mixtures thereof.

[0017] In addition, the present invention provides a hydrogel composition for ultrasound inspection simulation, wherein the fibrous material is at least one selected from cellulose, cellulose nanofibers, glass fibers, and silicon oxide (SiO2).

[0018] In addition, the present invention provides a hydrogel composition for ultrasound examination simulation, which comprises, based on the total weight of the composition, 10 to 25 wt% of acrylamide, 1 to 4 wt% of agarose, 0.001 to 5.0 wt% of cellulose, 0.005 to 0.03 wt% of N,N-methylenebisacrylamide (MBA), 0.05 to 0.10 wt% of ammonium persulfate (APS), and 70 to 90 wt% of water.

[0019] In addition, the present invention provides an artificial organ comprising a tissue formed from the hydrogel composition for ultrasound examination simulation.

[0020] The artificial organ may be an artificial kidney, an artificial liver, an artificial small intestine, an artificial large intestine, an artificial stomach, an artificial gallbladder, an artificial blood vessel, an artificial bladder, an artificial heart, an artificial lung, an artificial womb, artificial skin, or a lymph node.

[0021] In addition, the present invention provides a method for producing a hydrogel composition for ultrasound examination simulation, comprising the steps of: (a) dissolving 10 to 25 wt% of acrylamide and 1 to 4 wt% of agarose in 70 to 90 wt% of water based on the total weight of the composition; (b) adding 0.001 to 5.0 wt% of cellulose to the dissolved solution of step (a) and dispersing the same; and (c) adding 0.005 to 0.03 wt% of N,N-methylenebisacrylamide (MBA) and 0.05 to 0.10 wt% of ammonium persulfate (APS) to the dispersed solution of step (b) and dissolving the same.

[0022] The hydrogel composition for ultrasound examination simulation of the present invention can be usefully used in the manufacture of artificial tissues or artificial organs for transplantation into the body.

[0023] In addition, the artificial tissue formed with the hydrogel composition for ultrasound examination simulation of the present invention can be observed like actual human tissue or organs, with each tissue being implemented to be distinct when observed with ultrasound.

[0024] In addition, the present invention provides a method for manufacturing a hydrogel composition for ultrasound examination simulation that is observed like actual human tissue or organs during ultrasound observation.

[0025] Figure 1 is a drawing showing an ultrasonic photographic image of actual human skin according to a conventional technique.

[0026] FIG. 2 is a drawing showing an ultrasonic imaging image of a hydrogel according to one embodiment of the present invention.

[0027] FIG. 3 is a drawing showing an ultrasonic imaging image of a hydrogel according to one embodiment of the present invention.

[0028] Figure 1 is a drawing showing an ultrasound image of actual human skin according to a prior art technique. As shown in the image of Figure 1, actual human skin has different amounts of reflection for each tissue, and thus, the degree to which it appears white to the naked eye in the ultrasound image results can be seen to vary.

[0029] However, conventional artificial tissues or organs made of hydrogel materials had a problem in that they were observed as black without color differentiation when measured by ultrasound, which reduced the usability of the artificial tissues or organs.

[0030] Accordingly, the inventors of the present invention developed a hydrogel for ultrasound examination simulation in which each tissue is distinguished and appears like actual human tissue or organ when observed with ultrasound.

[0031] In particular, the present invention seeks to provide a hydrogel that allows each tissue to be distinguished when observing all artificial organs and artificial tissues, such as lymph nodes, lesions, artificial kidneys, and artificial skin, using ultrasound.

[0032]

[0033] Hereinafter, the present invention will be described in detail.

[0034] According to one embodiment of the present invention, a hydrogel composition for ultrasound examination simulation includes a hydrogel monomer and a water-dispersible fibrous material, and the content of the fibrous material may be 0.001 wt% to 5.0 wt% based on the total weight of the composition.

[0035] The above hydrogel monomer is one of the components constituting the hydrogel for ultrasound examination simulation, and is selected from the group consisting of acrylamide, agarose, methacrylamide, bis-acrylamide, NN-dimethylacrylamide, N,N-methylenebisacrylamide, polyaniline, acrylic acid, methacrylic acid, vinylsulfonic acid, styrenesulfonic acid, polyacrylic acid, allylamine, methyl methacrylate, poly(ethylene glycol) methacrylate, poly(ethylene glycol) diacrylate, sodium polyacrylate, N-vinylpyrrolidone, imide, amide, agarose, gelatin, gelatin methacrylate, collagen, fibrinogen, fibrin, methyl cellulose, chitosan, chitin, polyethylene glycol, polyvinyl alcohol carrageenan, 2-acrylamido-2-methylpropane-sulfonic acid, alginate. It may be at least one selected from 2-hydroxyethyl methacrylate and mixtures thereof.

[0036] The above fibrous material is a material that can be dispersed in water, and may be at least one selected from cellulose, cellulose nanofibers, glass fibers, and silicon oxide (SiO2).

[0037] The content of the fibrous material may be 0.001 wt% to 5.0 wt% based on the total weight of the composition. When the fibrous material is included in an amount of less than 0.001 wt% based on the total weight of the composition, the manufactured hydrogel may be observed as black without color distinction when observed by ultrasound, which reduces its usability as an artificial organ or tissue. In addition, when the fibrous material is included in an amount exceeding 5.0 wt% based on the total weight of the composition, the manufactured hydrogel may be observed as white like an actual tissue when observed by ultrasound, but it is difficult to distinguish colors, which reduces its usability as an artificial organ or tissue.

[0038] According to one embodiment of the present invention, a hydrogel composition for ultrasound examination simulation may include, based on the total weight of the composition, 10 to 25 wt% acrylamide, 1 to 4 wt% agarose, 0.01 to 5.0 wt% cellulose, 0.001 to 0.03 wt% N,N-methylenebisacrylamide (MBA), 0.05 to 0.10 wt% ammonium persulfate (APS), and 70 to 90 wt% water.

[0039] If the acrylamide content is less than 10 wt%, the hydrogel may not sufficiently harden. Furthermore, if the acrylamide content exceeds 25 wt%, the modulus may become excessively high, resulting in properties different from those of actual organs, making it difficult to use the hydrogel as an artificial organ or tissue.

[0040] Therefore, it is preferable that the acrylamide is included in an amount of 10 to 25 wt% based on the total weight of the composition, and more specifically, it may be 10 wt% or more, 11 wt% or more, 12 wt% or more, 13 wt% or more, 14 wt% or more, 15 wt% or more, 16 wt% or more, 17 wt% or more, or 25 wt% or less, 24 wt% or less, 23 wt% or less, 22 wt% or less, 21 wt% or less, or 20 wt% or less based on the total weight of the composition.

[0041] If the agarose is included in an amount of less than 1 wt%, the mechanical properties of the hydrogel become too weak, causing it to tear and break easily. Furthermore, if the agarose is included in an amount exceeding 4 wt%, the agarose does not dissolve well in water, making it difficult to manufacture the hydrogel.

[0042] Therefore, it is preferable that the agarose be included in an amount of 1 to 4 wt% based on the total weight of the composition, and more specifically, it may be 1 wt% or more, 1.2 wt% or more, 1.4 wt% or more, 1.6 wt% or more, or 4 wt% or less, 3.8 wt% or less, 3.6 wt% or less, 3.4 wt% or less, or 3.2 wt% or less based on the total weight of the composition.

[0043] When the cellulose is included in an amount of less than 0.001 wt%, when observing the manufactured hydrogel with ultrasound, the reflection and scattering effect of the particle ultrasound is minimal, so the hydrogel is observed as black without color distinction, which reduces its usability as an artificial organ or tissue. In addition, when the cellulose is included in an amount exceeding 5.0 wt%, when observing the manufactured hydrogel with ultrasound, the hydrogel may be observed as white like an actual tissue, but the signal becomes irregular due to the excessive reflection and scattering effect of the ultrasound due to the high content in the entire composition, and the color distinction is difficult, which reduces its usability as an artificial organ or tissue.

[0044] Therefore, it is preferable that the cellulose is included in an amount of 0.001 to 5.0 wt% based on the total weight of the composition, and more specifically, 0.001 wt% or more, 0.003 wt% or more, 0.005 wt% or more, 0.007 wt% or more, 0.009 wt% or more, 0.01 wt% or more, 0.02 wt% or more, 0.03 wt% or more, 0.04 wt% or more, 0.05 wt% or more, 0.06 wt% or more, 0.07 wt% or more, 0.08 wt% or more, 0.09 wt% or more, 0.10 wt% or more, 0.12 wt% or more, 0.14 wt% or more, 0.16 wt% or more, 0.18 wt% or more, 0.20 wt% or more, 0.22 wt% or more, 0.24 wt% based on the total weight of the composition. The above may be 0.26 wt% or more, 0.28 wt% or more, 0.30 wt% or more, or 5.0 wt% or less, 4.8 wt% or less, 4.6 wt% or less, 4.4 wt% or less, 4.2 wt% or less, 4.0 wt% or less, 3.8 wt% or less, 3.6 wt% or less, 3.4 wt% or less, 3.2 wt% or less, or 3.0 wt% or less.

[0045] When the above N,N-methylenebisacrylamide (MBA) is included in an amount of less than 0.005 wt%, crosslinking with acrylamide is not sufficient, making it difficult to manufacture a hydrogel. In addition, when the above N,N-methylenebisacrylamide (MBA) is included in an amount exceeding 0.03 wt%, the degree of chemical crosslinking increases, thereby reducing the toughness of the hydrogel, resulting in properties that are different from those of actual organs, making it difficult to use as an artificial tissue.

[0046] Therefore, it is preferable that the N,N-methylenebisacrylamide (MBA) is included in an amount of 0.005 to 0.03 wt% based on the total weight of the composition, and more specifically, it may be 0.005 wt% or more, 0.007 wt% or more, 0.009 wt% or more, 0.01 wt% or more, or 0.03 wt% or less, 0.028 wt% or less, 0.026 wt% or less, 0.024 wt% or less, 0.022 wt% or less, or 0.02 wt% or less based on the total weight of the composition.

[0047] If the above ammonium persulfate (APS) is included in an amount less than 0.05 wt%, there is a problem that the hydrogel curing time becomes longer. In addition, if the above ammonium persulfate is included in an amount exceeding 0.10 wt%, components not used for curing may remain, causing surface stickiness, which is undesirable.

[0048] Therefore, it is preferable that the ammonium persulfate (APS) is included in an amount of 0.05 to 0.10 wt% based on the total weight of the composition, and more specifically, it may be 0.05 wt% or more, 0.06 wt% or more, 0.07 wt% or more, or 0.1 wt% or less, 0.09 wt% or less, or 0.08 wt% or less based on the total weight of the composition.

[0049] If the water content is less than 70 wt%, cellulose and agarose do not dissolve well in water, making it difficult to manufacture a hydrogel. Furthermore, if the water content exceeds 90 wt%, the hydrogel may not sufficiently harden, or its mechanical properties, such as modulus and toughness, may be significantly reduced, resulting in properties different from those of actual organs, making it difficult to use it as an artificial organ or tissue.

[0050] Therefore, it is preferable that the water is included in an amount of 70 to 90 wt% based on the total weight of the composition, and more specifically, it may be 70 wt% or more, 71 wt% or more, 72 wt% or more, 73 wt% or more, 74 wt% or more, 75 wt% or more, 76 wt% or more, 77 wt% or more, 78 wt% or more, 79 wt% or more, 80 wt% or more, or 90 wt% or less, 89 wt% or less, 88 wt% or less, 87 wt% or less, 86 wt% or less, 85 wt% or less, 84 wt% or less, 83 wt% or less, 82 wt% or less, 81 wt% or less, 80 wt% or less based on the total weight of the composition.

[0051] According to one embodiment of the present invention, the hydrogel composition for ultrasound examination simulation can be used to construct tissues such as an artificial kidney, an artificial liver, an artificial small intestine, an artificial large intestine, an artificial stomach, an artificial gallbladder, an artificial blood vessel, an artificial bladder, an artificial heart, an artificial lung, an artificial uterus, artificial skin, a lymph node, a lesion, etc.

[0052] In particular, the hydrogel composition for ultrasound examination simulation can be preferably used to construct artificial kidneys, artificial skin, lymph nodes, and lesion tissues.

[0053] According to one embodiment of the present invention, an artificial organ may include tissue formed from the hydrogel composition for ultrasound examination simulation. The artificial organ may be observed with each tissue distinctly visible during ultrasound observation, allowing it to be observed like an actual human organ or tissue.

[0054] The above artificial organs may be, but are not limited to, an artificial kidney, an artificial liver, an artificial small intestine, an artificial large intestine, an artificial stomach, an artificial gallbladder, an artificial blood vessel, an artificial bladder, an artificial heart, an artificial lung, an artificial womb, artificial skin, or lymph nodes.

[0055] According to one embodiment of the present invention, a method for manufacturing a hydrogel composition for ultrasound examination simulation comprises:

[0056] (a) a step of dissolving 10 to 25 wt% of acrylamide and 1 to 4 wt% of agarose in 70 to 90 wt% of water based on the total weight of the composition;

[0057] (b) a step of adding and dispersing 0.001 to 5.0 wt% of cellulose into the dissolved solution of step (a); and

[0058] (c) a step of adding and dissolving 0.005 to 0.03 wt% of N,N-methylenebisacrylamide (MBA) and 0.05 to 0.10 wt% of ammonium persulfate (APS) into the dispersed solution of step (b);

[0059] The method for manufacturing the hydrogel composition for ultrasound examination simulation described above has a problem in that, when ammonium persulfate, a thermosetting agent, is mixed all at once into the high-temperature agarose solution, the reaction begins before other materials are mixed or the reaction occurs before all materials in the solution are uniformly mixed. Therefore, to solve this problem, the manufacturing method of the present invention is characterized in that the hydrogel composition for ultrasound examination simulation is manufactured by performing step (c) after steps (a) and (b).

[0060] Since the above manufacturing method can be applied in the same manner as the content described for the hydrogel composition for ultrasound examination simulation mentioned above, overlapping content is omitted.

[0061] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only illustrative of the present invention, and it is obvious to those skilled in the art that various changes and modifications are possible within the scope and technical idea of ​​the present invention, and it is also natural that such changes and modifications fall within the scope of the appended patent claims.

[0062] Example 1: Preparation of a hydrogel composition for ultrasound examination simulation

[0063] (1) Preparation of monomer solution

[0064] 4.8 g of acrylamide (AM) and 0.8 g of agarose were dissolved sufficiently in 20 ml of distilled water (DI) to prepare a monomer solution.

[0065] (2) Preparation of cellulose dispersion

[0066] A cellulose dispersion was prepared by adding 0.01 g of cellulose to the above monomer solution and uniformly dispersing it.

[0067] (3) Preparation of hydrogel composition

[0068] N,N-methylenebisacrylamide (MBA) and ammonium persulfate (APS) were added to the above cellulose dispersion and dissolved to prepare a hydrogel composition.

[0069] Examples 2 to 10: Preparation of hydrogel compositions for ultrasound examination simulation

[0070] A hydrogel composition for ultrasound examination simulation was prepared in the same manner as in Example 1, except that the contents of each component were included as shown in Table 1 below.

[0071]

[0072] DI (ml)AM (g)Agarose (g)MBA (g)APS (g)Cellulose (g)Example 1204.80.80.00460.02150.01Example 2204.80.80.00460.02150.05Example 3204.80.80.00460.02150.25Example 4204.80.80.00460.02151.0Example 5204.80.50.00380.02480.001Example 6204.80.50.00380.02480.01Example 7204.80.50.00380.02480.05Example 8204.80.50.00380.02480.1 Example 9204.80.50.00380.02480.5 Example 10204.80.50.00380.02481.0

[0073]

[0074] Comparative example

[0075] A hydrogel composition for ultrasound examination simulation was prepared in the same manner as in Example 1 except that cellulose was not included.

[0076]

[0077] Experimental Example: Ultrasound Images of Hydrogels for Ultrasound Testing Simulation

[0078] The hydrogel compositions for ultrasonic inspection simulation prepared in Examples 1 to 4 and Comparative Examples were poured into a mold and cured at 70°C for 20 minutes to produce a hydrogel for ultrasonic inspection simulation. An ultrasound image of the hydrogel is shown in Fig. 2.

[0079] Looking at Figure 2, it was confirmed that the hydrogels of Examples 1 to 4 containing cellulose were observed as whiter in the ultrasound image due to increased reflection compared to the hydrogels of the comparative examples that did not contain cellulose. In addition, it was found that as the cellulose content increased, the ultrasound image was observed as whiter.

[0080] In addition, the hydrogel compositions for ultrasonic inspection simulation manufactured in Examples 1, 5, and 8 were each poured into a mold and cured at 70°C for 20 minutes to produce a hydrogel for ultrasonic inspection simulation. The ultrasonic image of the hydrogel is shown in Fig. 2.

[0081] Looking at Figure 3, when the hydrogels manufactured in Examples 1, 5, and 8 with different cellulose contents were laminated and the ultrasound images were observed, it was found that as the cellulose content increased, the ultrasound images were observed to be whiter.

Claims

1. Contains a hydrogel monomer and a fibrous material capable of being dispersed in water, A hydrogel composition for ultrasound inspection simulation, wherein the content of the fibrous material is 0.001 wt% to 5.0 wt% based on the total weight of the composition.

2. In paragraph 1, The above hydrogel monomers are acrylamide, agarose, methacrylamide, bis-acrylamide, NN-dimethylacrylamide, N,N-methylenebisacrylamide, polyaniline, acrylic acid, methacrylic acid, vinylsulfonic acid, styrenesulfonic acid, polyacrylic acid, allylamine, methyl methacrylate, poly(ethylene glycol) methacrylate, poly(ethylene glycol) diacrylate, sodium polyacrylate, N-vinylpyrrolidone, imide, amide, agarose, gelatin, gelatin methacrylate, collagen, fibrinogen, fibrin, methyl cellulose, chitosan, chitin, polyethylene glycol, polyvinyl alcohol carrageenan, 2-acrylamido-2-methylpropane-sulfonic acid, alginate. A hydrogel composition for ultrasound examination simulation, comprising at least one selected from 2-hydroxyethyl methacrylate and mixtures thereof.

3. In paragraph 1, A hydrogel composition for ultrasound inspection simulation, wherein the fibrous material is at least one selected from cellulose, cellulose nanofibers, glass fibers, and silicon oxide (SiO2).

4. A hydrogel composition for ultrasound examination simulation, comprising 10 to 25 wt% of acrylamide, 1 to 4 wt% of agarose, 0.001 to 5.0 wt% of cellulose, 0.005 to 0.03 wt% of N,N-methylenebisacrylamide (MBA), 0.05 to 0.10 wt% of ammonium persulfate (APS), and 70 to 90 wt% of water, based on the total weight of the composition.

5. An artificial organ comprising a tissue formed from a hydrogel composition for ultrasound examination simulation according to any one of claims 1 to 4.

6. In paragraph 5, The artificial organ is an artificial kidney, an artificial liver, an artificial small intestine, an artificial large intestine, an artificial stomach, an artificial gallbladder, an artificial blood vessel, an artificial bladder, an artificial heart, an artificial lung, an artificial womb, artificial skin or a lymph node.

7. A method for manufacturing a hydrogel composition for ultrasound examination simulation, (a) a step of dissolving 10 to 25 wt% of acrylamide and 1 to 4 wt% of agarose in 70 to 90 wt% of water, based on the total weight of the composition; (b) a step of adding and dispersing 0.001 to 5.0 wt% of cellulose into the dissolved solution of step (a); and (c) a step of adding 0.005 to 0.03 wt% of N,N-methylenebisacrylamide (MBA) and 0.05 to 0.10 wt% of ammonium persulfate (APS) to the dispersed solution of step (b) and dissolving them; a method for producing a hydrogel composition for ultrasound examination simulation.

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