WO2025127861A1 - Hydrogel composition for human body ultrasonography simulation, preparation method therefor, and artificial organ comprising tissue formed therefrom - Google Patents

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 simulating human ultrasound examination, method for producing said hydrogel composition, and artificial organ comprising tissue formed from said hydrogel composition

This application claims the benefit of priority from Republic of Korea Patent Application No. 10-2023-0181430, dated December 14, 2023, which is incorporated herein by reference in its entirety.

The present invention relates to a hydrogel composition for ultrasound examination simulation, a method for producing the same, and an artificial organ including 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 including a tissue formed from the hydrogel composition.

Compared to the steadily increasing number of patients in need of organ transplantation, the supply of organs available for transplantation is limited. To solve this problem, the need for developing artificial organs or artificial tissues has been raised, and active research is being conducted on the production of artificial organs or tissues made of hydrogel materials that have less immune rejection and foreign body sensation when transplanted into the body.

Also, ultrasound examination is a method of examining abnormalities in body tissues using ultrasound. More specifically, it is an examination method that transmits ultrasound to the body part to be measured, and then acquires the reflected image as an image to determine the presence of abnormal tissues. Currently, ultrasound examination is being used not only for diagnosing lesions such as tumors or fetuses, but also for most medical examinations.

However, conventional artificial organs or tissues made of hydrogel materials have a problem in that they are observed as black without color differentiation when measured by ultrasound, which reduces the usability of artificial organs or tissues. There is a need for the development of hydrogel materials for human ultrasound examination simulation that can improve this problem.

[Prior art literature]

[Patent Document]

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

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

The purpose is to provide a hydrogel composition for ultrasound examination simulation, which is useful for the production of artificial organs or artificial tissues for transplantation into the body.

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.

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

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

In order to achieve the above purpose, the present invention,

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.

In addition, the present invention relates to a hydrogel monomer selected from the group consisting of acrylamide, agarose, methacrylamide, bis-acrylamide, N-N-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 hydrogel composition comprises at least one selected from 2-hydroxyethyl methacrylate and mixtures thereof.

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 (SiO ₂ ).

In addition, the present invention provides 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.

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

The above 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.

In addition, the present invention provides a method for producing a hydrogel composition for ultrasound examination simulation, comprising: (a) a step of dissolving 10 to 25 wt% of acrylamide and 1 to 4 wt% of agarose, based on the total weight of the composition, in 70 to 90 wt% of water; (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 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).

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.

In addition, an artificial tissue formed using the hydrogel composition for ultrasound examination simulation of the present invention can be observed like an actual human tissue or organ, since each tissue is implemented to be distinct when observed using ultrasound.

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

Figure 1 is a drawing showing an ultrasonic photographic image of actual human skin according to conventional technology.

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

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

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, as a result of ultrasound imaging, it can be seen that the degree to which it appears white to the naked eye varies.

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.

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 organs when observed with ultrasound.

In particular, the present invention seeks to provide a hydrogel that enables 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.

Hereinafter, the present invention will be described in detail.

According to one embodiment of the present invention, a hydrogel composition for ultrasound examination simulation includes a hydrogel monomer and a fibrous material capable of being dispersed in water, and the content of the fibrous material may be 0.001 wt% to 5.0 wt% based on the total weight of the composition.

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, N-N-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.

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 (SiO ₂ ).

The content of the fibrous material may be from 0.001 wt% to 5.0 wt% based on the total weight of the composition. If the fibrous material is included in an amount of less than 0.001 wt% based on the total weight of the composition, there is a problem that the manufactured hydrogel is observed as black without color distinction when observed by ultrasonic waves, thereby reducing its usability as an artificial organ or tissue. In addition, if 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 ultrasonic waves, but it is difficult to distinguish colors, thereby reducing its usability as an artificial organ or tissue.

According to one embodiment of the present invention, a hydrogel composition for ultrasound examination simulation may include 10 to 25 wt% of acrylamide, 1 to 4 wt% of agarose, 0.01 to 5.0 wt% of cellulose, 0.001 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.

If the acrylamide is included in an amount less than 10 wt%, there is a problem that the hydrogel is not sufficiently hardened. In addition, if the acrylamide is included in an amount exceeding 25 wt%, there is a problem that the modulus becomes too large and has properties different from those of actual organs, making it difficult to use as an artificial organ or artificial tissue.

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.

When the agarose is included in an amount of less than 1 wt%, there is a problem that the mechanical properties of the hydrogel become too weak and are easily torn and destroyed. In addition, when 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.

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.

When the cellulose is included in an amount of less than 0.001 wt%, when the manufactured hydrogel is observed using ultrasonic waves, the reflection and scattering effect of the ultrasonic waves is minimal, so that 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 the manufactured hydrogel is observed using ultrasonic waves, it may be observed as white like an actual tissue, but the signal becomes irregular due to the excessive reflection and scattering effect of the ultrasonic waves due to the high content in the entire composition, and it is difficult to distinguish colors, which reduces its usability as an artificial organ or tissue.

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% or more based on the total weight of the composition. Above, 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, 3.0 wt% or less.

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

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.

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 that are not used for curing may remain, causing surface stickiness, which is not preferable.

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.

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. In addition, if the water content exceeds 90 wt%, the hydrogel may not be sufficiently hardened, or 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 the hydrogel as an artificial organ or artificial tissue.

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, or 80 wt% or less based on the total weight of the composition.

According to one embodiment of the present invention, the hydrogel composition for ultrasound examination simulation can be used to form 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, lymph nodes, and lesions.

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

According to one embodiment of the present invention, the artificial organ may include a tissue formed from the hydrogel composition for ultrasound examination simulation. The artificial organ may be observed like an actual human organ or tissue, with each tissue implemented to be distinct when observed by ultrasound.

The above artificial organs may be, but are not limited to, examples of 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.

According to one embodiment of the present invention, a method for producing a hydrogel composition for ultrasound examination simulation comprises:

(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 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).

The method for manufacturing the hydrogel composition for ultrasound examination simulation above has a problem in that, when ammonium persulfate, a thermosetting agent, is mixed all at once into the agarose solution at a high temperature, the reaction starts before other materials are mixed or the reaction occurs before all materials in the solution are uniformly mixed. Therefore, in order 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).

Since the above manufacturing method can be applied identically to the content described for the hydrogel composition for ultrasound examination simulation mentioned above, redundant content is omitted.

Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only illustrative of the present invention, and it will be apparent 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.

Example 1: Preparation of hydrogel composition for ultrasound examination simulation

(1) Preparation of monomer solution

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

(2) Preparation of cellulose dispersion

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

(3) Preparation of hydrogel composition

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

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

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.

DI (ml) AM (g) Agarose (g) MBA (g) APS (g) Cellulose (g) Example 1 20 4.8 0.8 0.0046 0.0215 0.01 Example 2 20 4.8 0.8 0.0046 0.0215 0.05 Example 3 20 4.8 0.8 0.0046 0.0215 0.25 Example 4 20 4.8 0.8 0.0046 0.0215 1.0 Example 5 20 4.8 0.5 0.0038 0.0248 0.001 Example 6 20 4.8 0.5 0.0038 0.0248 0.01 Example 7 20 4.8 0.5 0.0038 0.0248 0.05 Example 8 20 4.8 0.5 0.0038 0.0248 0.1 Example 9 20 4.8 0.5 0.0038 0.0248 0.5 Example 10 20 4.8 0.5 0.0038 0.0248 1.0

Comparative example

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

Experimental example: Ultrasonic image of hydrogel for ultrasound inspection simulation

The hydrogel compositions for ultrasonic inspection simulation manufactured in Examples 1 to 4 and Comparative Examples were poured into a mold and cured at 70° C. for 20 minutes to manufacture a hydrogel for ultrasonic inspection simulation. The ultrasonic image of the hydrogel is shown in Fig. 2.

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

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 manufacture a hydrogel for ultrasonic inspection simulation. The ultrasonic image of the hydrogel is shown in Fig. 2.

Looking at Figure 3, the hydrogels manufactured in Examples 1, 5, and 8 with different cellulose contents were laminated and the ultrasound images were observed. As the cellulose content increased, it was observed to be whiter in the ultrasound images.

Claims (7)

Containing 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. In the first paragraph, The above hydrogel monomers are acrylamide, agarose, methacrylamide, bis-acrylamide, N-N-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. In the first paragraph, 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 (SiO ₂ ). 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. An artificial organ comprising a tissue formed from a hydrogel composition for ultrasound examination simulation according to any one of claims 1 to 4. 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. 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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