Composition for forming adipose tissue-like structure and method for producing adipose tissue-like structure

Abstract

The present invention relates to a composition for forming an adipose tissue-like structure and a method for producing an adipose tissue-like structure, using same, the composition comprising a biocompatible polymer in a form dispersed in the composition, a biocompatible hydrogel included together in the form of a plurality of spherical particles, an acrylamide-based monomer, an initiator, a cross-linking agent, and a solvent.

Description

Composition for forming adipose tissue-like structure and method for producing adipose tissue-like structure

[0001] This application claims the benefit of priority from Republic of Korea Patent Application No. 10-2024-0018658, dated February 7, 2024, and all contents of that Republic of Korea patent application are incorporated herein by reference.

[0002] The present invention relates to a composition for forming an adipose tissue-like structure and a method for producing an adipose tissue-like structure.

[0003] Adipose tissue, composed of fat cells, is an endocrine organ that closely interacts with other organs and plays a crucial role in metabolic regulation. In modern medicine and regenerative medicine, damage and deficiency of this adipose tissue cause numerous health and aesthetic problems. Obesity, metabolic syndrome, and age-related adipose tissue loss stemming from excessive subcutaneous or visceral fat are serious medical problems in our society, increasing the risk of diseases such as cardiovascular disease, diabetes, and arthritis and diminishing the quality of life of patients.

[0004] To address this, in recent years, research on adipose tissue regeneration and formation of similar structures has been actively conducted in the fields of tissue engineering and stem cell technology, and innovative approaches to adipose tissue are being studied in various fields such as cell regeneration, biomaterial engineering, and stem cell transplantation technology.

[0005] However, current treatment and regeneration technologies are difficult to effectively address damage and deficiency of adipose tissue, and fat grafting, fat injection, or cosmetic surgery are only temporary solutions, with limitations in long-term maintenance and stability.

[0006] In response, constructs with properties similar to human adipose tissue have recently emerged as a solution. Adipose tissue-like constructs have potential applications in a variety of fields. These constructs could contribute to innovative solutions in obesity management, cosmetic surgery, fat transplantation, new drug development and testing, and body restoration.

[0007] However, although these adipose tissue-like structures can exhibit similar appearance and function to actual human tissue, they are not completely identical to actual human tissue because human tissue is composed of various tissue layers each with different physical properties. Therefore, there is a limitation that each tissue layer must be implemented individually for realistic surgical simulations targeting human surgery.

[0008] In particular, adipose tissue is often sutured by pulling on the relatively hard skin layer (e.g., the dermis or muscle layer) during human surgery, and adipose tissue is often cut or removed in the process of finding the target organ during surgery. Therefore, it is more urgent than ever to present a solution that can be implemented so that it can exhibit properties similar to those of actual human adipose tissue.

[0009] [Prior Art Literature]

[0010] (Patent Document 1) Republic of Korea Publication No. 10-2019-0080830

[0011] The purpose of the present invention is to provide a composition for forming an adipose tissue-like structure that can be simulated similarly to an actual human surgical procedure.

[0012] Another object of the present invention is to provide a method for producing an adipose tissue-like structure.

[0013] One embodiment of the present invention provides a composition for forming an adipose tissue-like structure, comprising a biocompatible polymer dispersed in the composition, a biocompatible hydrogel in the form of a plurality of spherical particles, an acrylamide-based monomer, an initiator, a crosslinking agent, and a solvent.

[0014] The biocompatible polymers and biocompatible hydrogels are gelatin, gelatin methacrylate, collagen, alginate, fibrinogen, fibrin, hyaluronic acid, methyl cellulose, chitosan, chitin, and Extracel, respectively. TM ), pectin, polylactic acid (PLA), polyacrylic acid (PAA), polyphosphoric acid, and synthetic peptides.

[0015] The above acrylamide monomers are acrylamide, N-isopropyl acrylamide (NIPAM: N-isopropylacrylamide), N-tert-butyl acrylamide, N,N-diethylacrylamide, N-ethylacrylamide, Nn-propylacrylamide, N,N-ethylmethylacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide, N-(isobutoxymethyl)acrylamide, N-tert-butyl methacrylamide, It may contain at least one of N,N-diethylmethacrlamide and N-ethylmethacrylamide.

[0016] The biocompatible hydrogel in the form of a plurality of spherical particles may include ionic functional groups.

[0017] The above ionic functional group may be at least one selected from the group consisting of a carboxyl group, a hydroxyl group, a thiol group, an amine group, a sulfonate group, an ammonium group, a urea group, a thiourea group, an imidazole group, a phosphate group, a sulfonic acid group, and a phosphonic acid group.

[0018] The composition may contain 0.2 to 1 part by weight of a biocompatible polymer dispersed in the composition based on 100 parts by weight of the entire composition.

[0019] The biocompatible hydrogel in the form of multiple spherical particles may be included in an amount of 40 to 60 parts by weight based on 100 parts by weight of the entire composition.

[0020] The acrylamide-based monomer may be included in an amount of 3 to 16 parts by weight based on 100 parts by weight of the entire composition.

[0021] The above plurality of spherical particles may be in the form of granules.

[0022] In the biocompatible hydrogel in the form of a plurality of spherical particles, the average particle diameter of each individual particle may be 0.1 to 3 mm.

[0023] The composition may be a biocompatible hydrogel comprising a plurality of spherical particles, which is immersed in a solution containing a biocompatible polymer, an acrylamide-based monomer, an initiator, and a crosslinking agent dispersed in the composition in a solvent.

[0024] Another embodiment of the present invention provides a method for producing an adipose tissue-like structure, comprising: (1) a step of preparing a biocompatible hydrogel in the form of a plurality of spherical particles by dropping a biocompatible hydrogel into a solution containing a multivalent metal ion compound, (2) a step of preparing a mixed solution by adding the biocompatible hydrogel in the form of a plurality of spherical particles prepared in step (1) into a network solution containing an acrylamide-based monomer, an initiator, a crosslinking agent, a biocompatible polymer, and a solvent, and (3) a step of curing the mixed solution of step (2).

[0025] The mixing ratio of the biocompatible hydrogel in the form of multiple spherical particles of step (1) and the network solution of step (2) may be a weight ratio of 1:0.7 to 1:1.3.

[0026] After the above step (1), a step of immersing the plurality of spherical particle-shaped biocompatible hydrogels in a network precursor solution containing an acrylamide-based monomer, an initiator, and a crosslinking agent may be further included.

[0027] The above multivalent metal ion compound may include at least one of sodium chloride, zirconium chloride, iron chloride, calcium chloride, magnesium chloride, aluminum chloride, aluminum sulfate, potash alum, iron alum chloride, ammonium alum, ferric sulfate, aluminum hydroxide, aluminum silicate, aluminum phosphate, iron citrate, magnesium oxide, calcium phosphate, calcium carbonate, calcium oxide, zinc oxide, and zinc sulfate.

[0028] According to the present invention, a composition capable of forming an adipose tissue-like structure comprises a biocompatible polymer dispersed in the composition, a biocompatible hydrogel in the form of a plurality of spherical particles, an acrylamide-based monomer, an initiator, and a cross-linking agent, so that the adipose tissue-like structure formed by curing the composition not only exhibits a shape similar to that of fat cells in actual human organs due to the biocompatible hydrogel included in the form of a plurality of spherical particles having a granular shape, but also has the advantage of being soft in physical properties and having a non-sticky surface, and securing physical and mechanical properties sufficient to enable actual suturing during surgical simulation.

[0029] Figure 1 is a schematic diagram showing a process for manufacturing an adipose tissue-like structure using a composition for forming an adipose tissue-like structure according to one embodiment of the present invention.

[0030] Figures 2 to 5 illustrate images of adipose tissue-like structures formed through a composition for forming adipose tissue-like structures according to one embodiment and a comparative example of the present invention.

[0031] Hereinafter, embodiments of the present invention will be described in detail. Prior to this, terms and words used in this specification and claims should not be interpreted as limited to their conventional or dictionary meanings. Rather, they should be interpreted with meanings and concepts that conform to the technical spirit of the present invention, based on the principle that the inventor can appropriately define the concept of a term to best explain his or her invention. Accordingly, the configurations described in the embodiments described in this specification are merely the most preferred embodiments of the present invention and do not represent all of the technical spirit of the present invention. Therefore, it should be understood that various equivalents and modified examples may exist as of the time of this application.

[0032] Throughout this specification, whenever a part is said to 'include' a component, this does not mean that it excludes other components, but rather that it may include other components, unless otherwise specifically stated.

[0033] Additionally, the description that concretizes or adds components can be applied to all inventions unless there are special limitations, and is not limited to a specific invention.

[0034] Additionally, throughout the description and claims of the invention herein, the singular includes the plural unless otherwise stated.

[0035] Additionally, throughout the description and claims of the present invention, the term "or" includes "and" unless otherwise stated. Therefore, "comprising A or B" means all three cases of including A, including B, or including A and B.

[0036] Additionally, all numerical ranges include the extreme values ​​and all intermediate values ​​between them, unless explicitly stated otherwise.

[0037] Throughout this specification, the average particle diameter of the particles may be, for example, the median diameter (D50) measured using a laser particle size distribution meter.

[0038]

[0039] Composition for forming adipose tissue-like structures

[0040] The present invention relates to a composition for forming an adipose tissue-like structure, which comprises a biocompatible polymer, a biocompatible hydrogel, an acrylamide monomer, an initiator, a crosslinking agent, and a solvent, and in which the biocompatible hydrogel in the adipose tissue-like structure formed by hardening has a granular form including a plurality of particles, thereby exhibiting a form similar to the form of adipose cells in an actual human organ in which spherical particles of adipose cells are embedded in loose connective tissue, and has soft physical properties, a non-sticky surface, and can secure physical and mechanical properties sufficient to enable actual suturing during surgical simulation.

[0041] Hereinafter, each component of the composition for forming an adipose tissue-like structure according to one embodiment of the present invention will be described.

[0042] (1) Biocompatible hydrogels and biocompatible polymers

[0043] The above biocompatible hydrogel is a material that can exhibit a shape similar to that of fat cells in human organs, and can be included in the form of a plurality of spherical particles in a composition for forming an adipose tissue-like structure according to one embodiment of the present invention.

[0044] The biocompatible hydrogels include, for example, gelatin, gelatin methacrylate, collagen, alginate, fibrinogen, fibrin, hyaluronic acid, methyl cellulose, chitosan, chitin, Extracel TM), pectin, polylactic acid (PLA), polyacrylic acid (PAA), polyphosphoric acid, synthetic peptides, etc., may refer to a network structure formed by physical and chemical bonding of biocompatible polymers to form a three-dimensional cross-link, thereby containing an aqueous solvent such as water inside, and may be formed into a spherical particle shape, and in the case of the hydrogel according to the present invention, as long as it is a material that exhibits biocompatibility, the type thereof may not be limited, but preferably, a hydrogel containing alginate can be used.

[0045] In the case of the biocompatible hydrogel in the form of a plurality of spherical particles, the average particle diameter of individual particles of the hydrogel in the form of a plurality of spherical particles may be 0.1 to 3 mm, for example, 0.5 to 2 mm or 0.5 to 1 mm.

[0046] When the average particle diameter of the individual particles of the hydrogel in the form of multiple spherical particles is within the above range, fat cells contained in the human fat layer can be more realistically implemented.

[0047] In one embodiment of the present invention, the biocompatible hydrogel in the form of a plurality of spherical particles may be immersed in the composition, and the entire composition may be immersed in a solution containing a biocompatible polymer, an acrylamide-based monomer, an initiator, and a crosslinking agent in a solvent, in which the biocompatible hydrogel implemented in the form of spherical particles is dispersed in the composition.

[0048] In particular, the biocompatible hydrogel included in the form of the plurality of spherical particles may be in the form of granules in which the plurality of spherical particles are aggregated, and according to this structural characteristic, in the adipose tissue-like structure formed through the composition for forming an adipose tissue-like structure according to one embodiment of the present invention, the biocompatible hydrogel in the form of granules may exhibit properties similar in shape and physicality to actual human fat cells.

[0049] Additionally, in one embodiment of the present invention, the biocompatible hydrogel included in the form of a plurality of spherical particles may include an ionic functional group.

[0050] When the biocompatible hydrogel included in the above composition in the form of a plurality of spherical particles includes an ionic functional group, and the biocompatible hydrogel including the ionic functional group is dropped into a solution including a polyvalent metal ion compound according to the method for producing an adipose tissue-like structure described later, the ionic functional group included in the biocompatible hydrogel is crosslinked by the polyvalent metal ions generated from the polyvalent metal compound in the solution, thereby forming the biocompatible hydrogel in the form of spherical particles.

[0051] The ionic functional group included in the biocompatible hydrogel as described above may be of any type as long as it can form a biocompatible hydrogel in the form of a spherical particle by crosslinking the biocompatible hydrogel through crosslinking with a multivalent metal ion, and for example, it may include at least one selected from the group consisting of a carboxyl group, a hydroxyl group, a thiol group, an amine group, a sulfonate group, an ammonium group, a urea group, a thiourea group, an imidazole group, a phosphate group, a sulfonic acid group, and a phosphonic acid group.

[0052] In one embodiment of the present invention, the biocompatible hydrogel in the form of a plurality of spherical particles may be included in an amount of 40 to 60 parts by weight based on 100 parts by weight of the entire composition, for example, 40 parts by weight or more, 41 parts by weight or more, 42 parts by weight or more, 43 parts by weight or more, 44 parts by weight or more, 45 parts by weight or more, 46 parts by weight or more, 47 parts by weight or more, 48 parts by weight or more, 49 parts by weight or more, or 50 parts by weight or more, and 60 parts by weight or less, 59 parts by weight or less, 58 parts by weight or less, 57 parts by weight or less, 56 parts by weight or less, 55 parts by weight or less, 54 parts by weight or less, 53 parts by weight or less, 52 parts by weight or less, or 51 parts by weight or less.

[0053] When the content of the biocompatible hydrogel in the form of a plurality of spherical particles is within the above range, the adipose tissue-like structure formed through the composition according to the present invention may exhibit properties similar to those of fat cells in human fat layers. If the content of the biocompatible hydrogel in the form of a plurality of spherical particles exceeds 60 parts by weight based on 100 parts by weight of the total composition, the hardening process for forming the adipose tissue-like structure may not proceed well, and therefore, the content is appropriately adjusted within the above range.

[0054] In one embodiment of the present invention, the type of biocompatible polymer dispersed in the composition includes, for example, gelatin, gelatin methacrylate, collagen, alginate, fibrinogen, fibrin, hyaluronic acid, methyl cellulose, chitosan, chitin, and Extracel included in the biocompatible hydrogel. TM ), pectin, polylactic acid (PLA), polyacrylic acid (PAA), polyphosphoric acid, synthetic peptides, etc.

[0055] In one embodiment of the present invention, the biocompatible polymer dispersed in the composition may be included in an amount of 0.2 to 1 part by weight based on 100 parts by weight of the entire composition, for example, 0.3 to 0.9 parts by weight, 0.4 to 0.8 parts by weight, and preferably 0.35 to 0.75 parts by weight.

[0056] When the content of the biocompatible polymer dispersed in the composition is less than 0.2 parts by weight, the mechanical properties of the fat tissue-like structure formed through the composition are lower than those of the actual fat layer of the human body, and thus the structure may be easily damaged when external pressure is applied, and may not be suitable for a process simulating a human surgical procedure through the structure, such as not being easily cut with a scalpel or being easily torn.

[0057] If the content of the biocompatible hydrogel dispersed in the above composition exceeds 1 part by weight, it may exhibit properties that are harder than the actual human fat layer, resulting in a feeling of incongruity. Therefore, it is appropriately adjusted within the above range.

[0058]

[0059] (2) Acrylamide monomer

[0060] The composition for forming an adipose tissue-like structure according to the present invention further comprises an acrylamide-based monomer along with the biocompatible polymer and biocompatible hydrogel. The acrylamide-based monomer is a type of material capable of forming a hydrogel, and changes into polyacrylamid after the composition according to the present invention is cured. The acrylamide-based monomer forms a hydrogel network as the composition according to the present invention is cured, thereby playing a role in simulating connective tissue in an actual human fat layer.

[0061] In one embodiment of the present invention, the acrylamide monomer is acrylamide, N-isopropyl acrylamide (NIPAM: N-isopropylacrylamide), N-tert-butyl acrylamide, N,N-diethylacrylamide, N-ethylacrylamide, Nn-propylacrylamide, N,N-ethylmethylacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide, N-(isobutoxymethyl)acrylamide, N-tert-butyl methacrylamide, It may be at least one selected from the group consisting of N,N-diethylmethacrlamide and N-ethylmethacrylamide, and for example, acrylamide may be used.

[0062] In one embodiment of the present invention, the acrylamide-based monomer may be included in an amount of 3 to 16 parts by weight based on 100 parts by weight of the entire composition, for example, 3.5 to 14 parts by weight, preferably 4 to 12 parts by weight.

[0063] If the content of the acrylamide-based monomer is less than 3 parts by weight based on 100 parts by weight of the entire composition, the biocompatible hydrogel included in the form of the plurality of particles included in the composition may be weaker than the physical properties of actual human fat cells, and thus, when external pressure is applied, the adipose tissue-like structure may be easily torn, or the curing speed may be slowed down during the curing process of the composition. If it exceeds 16 parts by weight, the adipose tissue-like structure formed through the composition may exhibit physical properties that are harder than an actual human fat layer, which may result in a feeling of incongruity. Therefore, the content is appropriately adjusted within the above range so that the adipose tissue-like structure can exhibit physical properties similar to those of a human fat layer.

[0064] (3) Other ingredients

[0065] The composition for forming an adipose tissue-like structure of the present invention may further include a crosslinking agent and an initiator in addition to the above-described components for controlling physical properties.

[0066] The above cross-linking agent is a material that acts as a cross-linker between the network formed through the biocompatible polymer, biocompatible hydrogel, and acrylamide-based monomer in the composition, and specifically, by cross-linking between polyacrylamide chains formed by curing the acrylamide-based monomer, it can further enhance the mechanical strength and chemical stability of the adipose tissue-like structure.

[0067] Therefore, as long as it is a substance capable of crosslinking the network formed through the biocompatible polymer, biocompatible hydrogel and acrylamide monomer of the present invention, the type thereof may not be limited, and for example, N,N'-methylenebisacrylamide (MBA), trimethylolpropane tri(meth)acrylate, ethylene glycol di(meth)acrylate, polyethylene glycol (meth)acrylate, polyethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, polypropylene glycol (meth)acrylate, butanediol di(meth)acrylate, butylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, hexanediol di(meth)acrylate, triethylene glycol di(meth)acrylate, tripropylene glycol di(meth)acrylate, tetraethylene glycol di(meth)acrylate, dipentaerythritol At least one selected from the group consisting of pentaacrylate, glycerin tri(meth)acrylate, pentaerythritol tetraacrylate, triarylamine, ethylene glycol diglycidyl ether, propylene glycol, glycerin, and ethylene carbonate may be used.

[0068] In the case of the cross-linking agent, it may be included in an amount of 0.001 to 0.05 parts by weight based on 100 parts by weight of the entire composition according to the present invention, for example, 0.003 to 0.04 parts by weight, preferably 0.005 to 0.03 parts by weight. If the content of the cross-linking agent is less than the above range, sufficient cross-linking may not be achieved to provide mechanical strength and chemical stability to the adipose tissue-like structure, and the adipose tissue-like structure formed through the composition may be weaker than the physical properties of actual human fat cells, so that the adipose tissue-like structure may be easily torn when external pressure is applied. If it exceeds the above range, excessive cross-linking may be achieved, so that the adipose tissue-like structure may exhibit physical properties that are harder than the actual human fat layer, which may cause a problem of a foreign feeling.

[0069] The above initiator is a substance used to initiate a chain reaction for curing the composition, and specifically refers to a substance that easily generates radicals using a light source such as UV or heat.

[0070] The above initiator may be any substance that can initiate a curing reaction by a light source or by heat, and may be, for example, riboflavin (vitamin B2), lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), benzyl dimethyl ketal, acetophenone, benzoin methylether, diethoxyacetophenone, benzoyl phosphine oxide, 1-hydroxycyclohexyl phenyl ketone, tris(bipyridine)ruthenium(II) chloride (Ru(bpy3) 2+), APS (ammonium persulfate), HRP (horse radish peroxide) and H2O2 (hydrogen peroxide), potassium persulfate, ammonium persulfate, etc.; azo compounds such as 4,4-azobis(4-cyanovaleric acid), dimethyl-2,2'-azobis(2-methylpropionate), 2,2-azobis(2-amidinopropane) dihydrochloride, 2,2-azobis(2-methylpropionitrile), 2,2-azobis-2-methyl-N-1,1-bis(hydroxymethyl)-2-hydroxyethylpropionamide, 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobisisobutyronitrile, 1,1'-azobis(1-cyclohexanecarbonitrile); It may include at least one of peroxides such as methyl ethyl peroxide, di-t-butyl peroxide, acetyl peroxide, dicumyl peroxide, lauroyl peroxide, benzoyl peroxide, t-butyl peroxy-2-ethylhexanoate, di-isopropyl peroxydicarbonate, and di-t-butyl peroxyisophthalate, and preferably, APS (ammonium persulfate) may be used.

[0071] In the case of the above initiator, it may be included in an amount of 0.008 to 0.08 parts by weight based on 100 parts by weight of the entire composition according to the present invention. If the content of the initiator is less than the above range, the curing process of the composition according to the present invention may not proceed smoothly, or the curing time may be excessively delayed, or the adipose tissue-like structure formed through the composition may be weaker than the physical properties of actual human fat cells, so that the adipose tissue-like structure may be easily torn when external pressure is applied, and if it exceeds the above range, a rapid radical reaction may proceed, causing a side reaction, or unintended effects may be exerted on other components of the composition according to the present invention, and after curing, excessive residual components may remain, so that the surface of the adipose tissue-like structure may be sticky, and the adipose tissue-like structure may exhibit physical properties that are harder than the actual human fat layer, which may cause a foreign feeling.

[0072] The composition for forming an adipose tissue-like structure according to the present invention may further include, in addition to the crosslinking agent and initiator, additives such as a surfactant, a plasticizer, a (thermal) polymerization inhibitor, a stabilizer, an anti-foaming agent, a diluent, and a viscosity modifier. The additives may be included in the minimum amount that can cause the above-described action from an economical perspective, and preferably, may be included in an amount of 0.01 to 5 parts by weight based on 100 parts by weight of the entire composition.

[0073] (4) Solvent

[0074] In one embodiment of the present invention, the solvent in the composition is not limited to any type as long as it can dissolve each component, such as a biocompatible polymer, a biocompatible hydrogel, an acrylamide-based monomer, an initiator, a crosslinking agent, etc., well, but for example, an aqueous solvent such as water can be used.

[0075] The content of the above solvent may be included in an amount such that each component in the composition can be included within a desirable range depending on the purpose of the present invention.

[0076]

[0077] Method for manufacturing adipose tissue-like structures

[0078] Another embodiment of the present invention provides a method for producing an adipose tissue-like structure using the composition for forming the adipose tissue-like structure.

[0079] Figure 1 illustrates a method for manufacturing an adipose tissue-like structure according to one embodiment of the present invention.

[0080] Referring to FIG. 1, the method for manufacturing the adipose tissue-like structure includes: (1) a step of adding a biocompatible hydrogel solution dropwise to a solution containing a multivalent metal ion compound to manufacture a biocompatible hydrogel in the form of a plurality of spherical particles; (2) a step of adding the biocompatible hydrogel in the form of a plurality of spherical particles manufactured in step (1) to a network solution containing an acrylamide-based monomer, an initiator, a crosslinking agent, a biocompatible polymer, and a solvent to manufacture a mixed solution; and (3) a step of curing the mixed solution of step (2).

[0081] Hereinafter, the method for manufacturing the above-mentioned adipose tissue-like structure is specifically described step by step.

[0082] First, (1) a biocompatible hydrogel solution is added dropwise to a solution containing a multivalent metal ion compound to produce a biocompatible hydrogel in the form of multiple spherical particles.

[0083] As for the above biocompatible hydrogel, it is the same as that described in the composition for forming the above adipose tissue-like structure, and thus a detailed description thereof is omitted.

[0084] The biocompatible hydrogel solution may be prepared by dissolving gelatin, gelatin methacrylate, collagen, alginate, fibrinogen, fibrin, hyaluronic acid, methyl cellulose, chitosan, chitin, or Extracel in an aqueous solvent such as water. TM ), pectin, polylactic acid (PLA), polyacrylic acid (PAA), polyphosphoric acid, and synthetic peptides can be dissolved and formed into biocompatible polymers capable of forming hydrogels.

[0085] The biocompatible hydrogel solution of step (1) above may contain, for example, 0.5 to 3 parts by weight of the biocompatible polymer relative to 100 parts by weight of the solvent, and preferably 0.7 to 2 parts by weight.

[0086] In the biocompatible hydrogel solution of step (1) above, if the content of the biocompatible polymer is less than 0.5 parts by weight based on 100 parts by weight of the solvent, the biocompatible hydrogel in the form of multiple spherical particles formed by dropping the solution containing the polyvalent metal ion compound described later may have lower mechanical properties than the fat layer of an actual human body, and may be easily damaged when external pressure is applied, and may not be suitable for a process that simulates a human surgical procedure using the structure, such as not being able to be cut well with a scalpel or being easily torn.

[0087] In the biocompatible hydrogel solution of step (1) above, if the content of the biocompatible polymer exceeds 3 parts by weight per 100 parts by weight of the solvent, the biocompatible hydrogel in the form of multiple spherical particles may exhibit properties that are harder than the actual human fat layer, which may result in a feeling of incongruity. Therefore, it is appropriately adjusted within the above range.

[0088] Next, the biocompatible hydrogel solution is added dropwise to a solution containing a multivalent metal ion compound.

[0089] When the above biocompatible hydrogel solution is dropped into a solution containing a multivalent metal ion compound, the multivalent metal ions promote coagulation of the biocompatible hydrogel, thereby producing a biocompatible hydrogel in the form of multiple spherical particles.

[0090] The solution containing the above multivalent metal ion compound can be formed by dissolving the multivalent metal ion compound in an aqueous solvent such as water.

[0091] The solution containing the above multivalent metal ion compound may contain, for example, 1 to 3 parts by weight of the multivalent metal ion compound relative to 100 parts by weight of the solvent, and preferably 1.8 to 2.5 parts by weight.

[0092] In the solution containing the above polyvalent metal ion compound, if the content of the polyvalent metal ion compound is less than 1 part by weight relative to 100 parts by weight of the solvent, when the biocompatible hydrogel solution of step (1) is dropped into the solution containing the polyvalent metal ion compound, a biocompatible hydrogel in the form of multiple spherical particles may not be effectively formed, and if it is contained in excess of 3 parts by weight, the biocompatible hydrogel in the form of multiple spherical particles ultimately formed may exhibit properties that are harder than actual human fat cells, resulting in a feeling of incongruity. Therefore, the content is appropriately adjusted within the above range.

[0093] The above multivalent metal ion compound may be any type of compound that includes a multivalent metal ion so as to promote coagulation of the biocompatible hydrogel, and may include, for example, one or more of sodium chloride, zirconium chloride, iron chloride, calcium chloride, magnesium chloride, aluminum chloride, aluminum sulfate, potassium alum, iron alum, ammonium alum, ferric sulfate, aluminum hydroxide, aluminum silicate, aluminum phosphate, iron citrate, magnesium oxide, calcium phosphate, calcium carbonate, calcium oxide, zinc oxide, and zinc sulfate, and specifically, calcium chloride (CaCl2) may be used.

[0094] The hydrogel in the form of multiple spherical particles manufactured through the above step (1) can exhibit a granule form in which multiple individual particles clump together.

[0095] After the above step (1), a step of washing the biocompatible hydrogel in the form of multiple spherical particles manufactured using ultrapure water, etc. may be further performed.

[0096] In one embodiment of the present invention, after step (1), a step of immersing the plurality of spherical particle-shaped biocompatible hydrogels in a network precursor solution containing an acrylamide-based monomer, an initiator, and a crosslinking agent may be further included.

[0097] If the step of immersing the biocompatible hydrogel in the form of a plurality of spherical particles in a network precursor solution is not performed, the biocompatible hydrogel in the form of a plurality of spherical particles absorbs the acrylamide-based monomer, initiator, and crosslinking agent contained in the network solution described below, thereby reducing the overall content of the acrylamide-based monomer, initiator, and crosslinking agent in the network solution.

[0098] The above network precursor solution can be formed by dissolving the acrylamide monomer, initiator, and crosslinking agent in an aqueous solvent such as water, for example.

[0099] In the above network precursor solution, the content of the acrylamide-based monomer may be included in an amount of 20 to 35 parts by weight, and preferably 25 to 30 parts by weight, based on 100 parts by weight of the solvent in the network precursor solution.

[0100] If the content of the acrylamide-based monomer contained in the network precursor solution is less than 20 parts by weight based on 100 parts by weight of the solvent contained in the network precursor solution, the curing speed of the network solution is greatly reduced, and the physical properties of the adipose tissue-like structure formed through the subsequent curing process may be weak, unlike the connective tissue of an actual human fat layer. If the content of the acrylamide-based monomer contained in the network precursor solution exceeds 35 parts by weight based on 100 parts by weight of the solvent contained in the network precursor solution, the adipose tissue-like structure may exhibit physical properties that are harder than an actual human fat layer, resulting in a feeling of incongruity.

[0101] In the above network precursor solution, the content of the crosslinking agent may be included in an amount of 0.01 to 0.06 parts by weight, and preferably 0.02 to 0.05 parts by weight, based on 100 parts by weight of the acrylamide monomer content in the network precursor solution.

[0102] If the content of the cross-linking agent included in the network precursor solution is below the above range, sufficient cross-linking may not be achieved to provide mechanical strength and chemical stability to the adipose tissue-like structure, and the adipose tissue-like structure may be weaker than the physical properties of actual human fat cells, so that the adipose tissue-like structure may be easily torn when external pressure is applied. If the content exceeds the above range, excessive cross-linking may be achieved, so that the adipose tissue-like structure may exhibit physical properties that are harder than the actual human fat layer, which may cause a foreign feeling.

[0103] In the above network precursor solution, the content of the initiator may be included in an amount of 0.04 to 0.12 parts by weight, and preferably 0.06 to 0.11 parts by weight, based on 100 parts by weight of the acrylamide monomer content in the network precursor solution.

[0104] If the content of the initiator included in the above network precursor solution is less than the above range, the curing process may not proceed smoothly, the curing time may be excessively delayed, or the adipose tissue-like structure may become weaker than the physical properties of actual human fat cells, so that the adipose tissue-like structure may be easily torn when external pressure is applied. If the content exceeds the above range, a rapid radical reaction may occur, causing a side reaction or unintended effects on other components in the network precursor solution. In addition, after curing, an excessive amount of residual components may remain, making the surface of the adipose tissue-like structure sticky, and the adipose tissue-like structure may exhibit physical properties that are harder than actual human fat layers, which may cause a foreign feeling.

[0105] Next, (2) a mixed solution is prepared by adding a plurality of spherical particle-shaped biocompatible hydrogels prepared in step (1) to a network solution containing an acrylamide monomer, an initiator, a crosslinking agent, a biocompatible polymer, and a solvent.

[0106] In the above step (2), the acrylamide monomer, initiator, and biocompatible polymer are the same as those described in the composition for forming the adipose tissue-like structure, so a detailed description thereof is omitted.

[0107] The above network solution can be implemented as a part corresponding to the 'connective tissue' of the fat layer of an actual human body in an adipose tissue-like structure formed through a hardening process described later, and can be formed by dissolving the acrylamide-based monomer, initiator, crosslinking agent, and biocompatible polymer in a solvent, for example, an aqueous solvent such as water, and at this time, the biocompatible polymer included in the network solution may be included in a dispersed form in the solution.

[0108] In one embodiment of the present invention, the acrylamide-based monomer included in the network solution may be included in an amount of 8 to 32 parts by weight, and preferably 10 to 29 parts by weight, based on 100 parts by weight of the solvent included in the network solution.

[0109] If the content of the acrylamide-based monomer contained in the network solution is less than 8 parts by weight based on 100 parts by weight of the solvent contained in the network solution, the curing speed of the network solution is greatly reduced, and the physical properties of the adipose tissue-like structure formed through the subsequent curing process may be weak, unlike the connective tissue of the actual human fat layer. If the content of the acrylamide-based monomer contained in the network solution exceeds 32 parts by weight based on 100 parts by weight of the solvent contained in the network solution, the adipose tissue-like structure may exhibit physical properties that are harder than the actual human fat layer, resulting in a feeling of incongruity.

[0110] In addition, in one embodiment of the present invention, the biocompatible polymer (in a form dispersed in the network solution) included in the network solution may be included in an amount of 0.6 to 2.5 parts by weight, and preferably 0.8 to 2.0 parts by weight, based on 100 parts by weight of the solvent included in the network solution.

[0111] If the content of the biocompatible polymer contained in the above network solution is less than 0.6 parts by weight based on 100 parts by weight of the solvent contained in the network solution, the physical properties of the adipose tissue-like structure formed through the hardening process may be weak, unlike the connective tissue of the actual human fat layer. If the content of the biocompatible polymer contained in the above network solution exceeds 2.5 parts by weight based on 100 parts by weight of the solvent contained in the network solution, the adipose tissue-like structure may exhibit physical properties that are harder than the actual human fat layer, resulting in a feeling of incongruity.

[0112] In the case of the cross-linking agent, it may be included in an amount of 0.006 to 0.05 parts by weight based on 100 parts by weight of the solvent included in the network solution, for example, 0.008 to 0.04 parts by weight, preferably 0.01 to 0.04 parts by weight. If the content of the cross-linking agent is less than the above range, sufficient cross-linking may not be achieved to provide mechanical strength and chemical stability to the adipose tissue-like structure, and the adipose tissue-like structure may be weaker than the physical properties of actual human fat cells, so that the adipose tissue-like structure may be easily torn when external pressure is applied. If it exceeds the above range, excessive cross-linking may be achieved, so that the adipose tissue-like structure may exhibit physical properties that are harder than the actual human fat layer, which may cause a problem of a foreign feeling.

[0113] In the case of the above initiator, it may be included in an amount of 0.01 to 0.15 parts by weight based on 100 parts by weight of the solvent included in the network solution, for example, 0.01 to 0.1 parts by weight, preferably 0.03 to 0.1 parts by weight. If the content of the initiator is less than the above range, the curing process may not proceed smoothly, the curing time may be excessively delayed, or the adipose tissue-like structure may be weaker than the physical properties of actual human fat cells, so that the adipose tissue-like structure may be easily torn when external pressure is applied. If it exceeds the above range, a rapid radical reaction may proceed, causing a side reaction or unintended effects on other components in the network solution. After curing, excessive residual components may remain, so that the surface of the adipose tissue-like structure may be sticky, and the adipose tissue-like structure may exhibit physical properties that are harder than the actual human fat layer, which may cause a foreign feeling.

[0114] The above network solution may be used together with a tetramethylethylenediamine (TEMED) accelerator in addition to an acrylamide-based monomer, an initiator, and a biocompatible polymer, and specifically, may be included in an amount of 0.008 to 0.02 parts by weight based on 100 parts by weight of the solvent included in the network solution.

[0115] In one embodiment of the present invention, the mixing ratio of the biocompatible hydrogel in the form of a plurality of spherical particles of step (1) and the network solution of step (2) may be a weight ratio of 1:0.5 to 1:1.5, specifically a weight ratio of 1:0.6 to 1:1.4, and more specifically a weight ratio of 1:0.7 to 1:1.3.

[0116] If the content of the biocompatible hydrogel in the form of multiple spherical particles in step (1) is greater than 1:1.5, the network solution may not be effectively cured, and thus the adipose tissue-like structure may not be formed well. In addition, if the content of the biocompatible hydrogel is less than 1:0.5, it may be difficult to implement the structure so as to have properties and texture similar to those of fat cells in an actual human fat layer.

[0117] Next, (3) the mixed solution of step (2), specifically, the mixed solution of the biocompatible hydrogel in the form of multiple spherical particles of step (1) and the network solution of step (2), is cured to manufacture an adipose tissue-like structure.

[0118] The above curing process can be carried out, for example, by applying heat to the mixed solution in an oven at a temperature of 60 to 80°C for 10 to 180 minutes, at which time the heat curing agent included in the network solution can cause a radical reaction to carry out the curing process of the mixed solution.

[0119] Below, specific embodiments of the present invention are presented. However, the embodiments described below are intended solely to specifically illustrate or explain the present invention and are not intended to limit the scope of the invention. Furthermore, any details not described herein are technically feasible to those skilled in the art and thus are omitted.

[0120]

[0121] Example 1: Preparation of adipose tissue-like structures

[0122] (1) (Manufacturing of multiple spherical particle-shaped alginate) 0.75 g of alginate containing a carboxyl group is dissolved in 100 g of deionized water (DI) as a solvent to prepare an alginate aqueous solution as a biocompatible hydrogel solution. 1.11 g of calcium chloride (CaCl2) is dissolved in 100 g of deionized water as a solvent to prepare a calcium chloride aqueous solution as a solution containing a polyvalent metal ion compound. The alginate aqueous solution is added dropwise to the calcium chloride aqueous solution to prepare alginate in the form of spherical particles. The average particle diameter (D) of the individual particles of the manufactured multiple spherical particles of alginate 50 ) is 1.0 mm, and multiple particles of alginate are gathered to form granules. The granular alginate is washed using deionized water.

[0123] (2) (Network precursor solution soaking) 28.2 g of acrylamide, 0.034 g of N,N'-methylenebisacrylamide (MBA) as a crosslinking agent, and 0.095 g of ammonium persulfate (APS) as a heat curing agent are added to 100 g of deionized water as a solvent, and dissolved to prepare a network precursor solution. The granular alginate prepared in (1) is added thereto and soaked for 180 minutes.

[0124] (3) (Network solution mixing and curing) 100 g of deionized water as a solvent, 28.2 g of acrylamide, 0.034 g of N,N'-methylenebisacrylamide (MBA) as a crosslinking agent, 0.095 g of ammonium persulfate (APS) as a heat curing agent, 1.28 g of alginate as a biocompatible polymer, and 18.6 μl of tetramethylethylenediamine (TEMED) were added and dissolved to prepare a network solution. Here, 130 g of the granular particulate alginate immersed in (2) was taken out and added to the network solution, followed by heating in an oven at 60°C for 60 minutes and curing to prepare an adipose tissue-like structure. The results are shown in Fig. 2.

[0125]

[0126] Examples 2 to 7: Preparation of adipose tissue-like structures

[0127] In the above Example 1, except that the alginate and calcium chloride contents of step (1), the acrylamide, crosslinking agent, and photocuring agent contents of step (2), and the acrylamide, alginate, crosslinking agent, and photocuring agent contents of step (3) were as shown in Table 1 below, an adipose tissue-like structure was manufactured in the same manner as in Example 1. The results are shown in FIGS. 3 and 4, respectively.

[0128] (Unit: g) Particulate alginate manufacturing network precursor solution immersion network solution Alginate aqueous solution Calcium chloride aqueous solution DIALG DICACl2 DIAMMBAAPS DIAMMBAAPS ALG Example 2 1000.75 1001.1110028.20.034 0.095 10028.20.034 0.095 1.92 Example 3 1001.5 1001.1110028.20.034 0.095 10028.20.034 0.095 1.92 Example 4 1001.5 1002.22 10028.20.034 0.095 10028.20.034 0.095 1.92 Example 51001.51002.2210028.20.0340.095100120.0150.0411.12Example 61001.51002.2210028.20.0340.095100180.0220.0611.18Example 71001.51002.2210028.20.0340.095100220.0270.0751.22

[0129] * ALG: Alginate

[0130] ** AM: Acrylamide

[0131]

[0132] Comparative Examples 1 to 3: Preparation of adipose tissue-like structures

[0133] In the above Examples 5 to 7, except that the network precursor solution immersion step of step (2) was performed, an adipose tissue-like structure was manufactured in the same manner as in the above Examples 5 to 7, and the results are shown in Fig. 5.

[0134]

[0135] Experimental Example 1: Evaluation of Adipose Tissue-Like Structures

[0136] For the adipose tissue-like structures according to Examples 1 to 7 and Comparative Examples 1 to 3, the appearance, suture performance, elasticity, touch, and surface stickiness were measured, respectively.

[0137] In the case of the adipose tissue-like structures according to Examples 1 to 7, it was confirmed that the shape of the multiple spherical particle-shaped alginate contained in the network solution was completely maintained, and the structure exhibited a texture (soft) and elasticity similar to actual human adipose tissue. In addition, when the adipose tissue-like structures of the examples were sutured using a suture, it was confirmed that the structures maintained their structure well without being torn or crushed, and the outer surface of the structures was also confirmed to be non-sticky.

[0138] In the case of the adipose tissue-like structure according to Comparative Example 1, it can be seen that the network solution was not cured at all, and in the case of Comparative Example 2, the network solution was not completely cured, so that when external pressure was applied to the structure, multiple spherical particles of alginate were detached, and uncured network solution was found to be present on the surface of the structure, resulting in a sticky phenomenon. In the case of the adipose tissue-like structure according to Comparative Example 3, it can be seen that curing did not progress completely, resulting in a somewhat sticky phenomenon on the surface.

[0139]

[0140] Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concept of the present invention defined in the following claims also fall within the scope of the present invention.

Claims

1. A biocompatible polymer dispersed in a composition; A biocompatible hydrogel in the form of multiple spherical particles; Acrylamide monomer; initiator; crosslinking agent; and containing a solvent; A composition for forming a fat tissue-like structure.

2. In paragraph 1, The biocompatible polymers and biocompatible hydrogels are gelatin, gelatin methacrylate, collagen, alginate, fibrinogen, fibrin, hyaluronic acid, methyl cellulose, chitosan, chitin, and Extracel, respectively. TM ), pectin, polylactic acid (PLA), polyacrylic acid (PAA), polyphosphoric acid, and synthetic peptides, A composition for forming a fat tissue-like structure.

3. In paragraph 1, The above acrylamide monomers are acrylamide, N-isopropyl acrylamide (NIPAM: N-isopropylacrylamide), N-tert-butyl acrylamide, N,N-diethylacrylamide, N-ethylacrylamide, Nn-propylacrylamide, N,N-ethylmethylacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide, N-(isobutoxymethyl)acrylamide, N-tert-butyl methacrylamide, Containing at least one of N,N-diethylmethacrlamide and N-ethylmethacrylamide, A composition for forming a fat tissue-like structure.

4. In paragraph 1, The biocompatible hydrogel in the form of a plurality of spherical particles contains ionic functional groups. A composition for forming a fat tissue-like structure.

5. In paragraph 4, The above ionic functional group is at least one selected from the group consisting of a carboxyl group, a hydroxyl group, a thiol group, an amine group, a sulfonate group, an ammonium group, a urea group, a thiourea group, an imidazole group, a phosphate group, a sulfonic acid group, and a phosphonic acid group. A composition for forming a fat tissue-like structure.

6. In paragraph 1, The composition comprises 0.2 to 1 part by weight of a biocompatible polymer dispersed in the composition based on 100 parts by weight of the entire composition. A composition for forming a fat tissue-like structure.

7. In paragraph 1, The composition comprises 40 to 60 parts by weight of the biocompatible hydrogel in the form of multiple spherical particles based on 100 parts by weight of the entire composition. A composition for forming a fat tissue-like structure.

8. In paragraph 1, The composition contains 3 to 16 parts by weight of the acrylamide monomer based on 100 parts by weight of the entire composition. A composition for forming a fat tissue-like structure.

9. In paragraph 1, The above plurality of spherical particles are in the form of granules, A composition for forming a fat tissue-like structure.

10. In paragraph 1, In the biocompatible hydrogel in the form of a plurality of spherical particles, The average particle diameter of each individual particle is 0.1 to 3 mm, A composition for forming a fat tissue-like structure.

11. In paragraph 1, The above composition is a biocompatible hydrogel in the form of a plurality of spherical particles, which is immersed in a solution containing a biocompatible polymer, an acrylamide-based monomer, an initiator, and a crosslinking agent dispersed in the composition in a solvent. A composition for forming a fat tissue-like structure. 12.(1) A step of producing a biocompatible hydrogel in the form of a plurality of spherical particles by dropping a biocompatible hydrogel solution into a solution containing a multivalent metal ion compound; (2) a step of preparing a mixed solution by adding a plurality of spherical particle-shaped biocompatible hydrogels prepared in step (1) to a network solution containing an acrylamide monomer, an initiator, a crosslinking agent, a biocompatible polymer, and a solvent; and (3) a step of curing the mixed solution of step (2); including; Method for manufacturing adipose tissue-like structure.

13. In paragraph 12, The mixing ratio of the biocompatible hydrogel in the form of multiple spherical particles of the step (1) and the network solution of the step (2) is a weight ratio of 1:0.7 to 1:1.

3. Method for manufacturing adipose tissue-like structure.

14. In paragraph 12, After the above step (1), a step of immersing the plurality of spherical particle-shaped biocompatible hydrogels in a network precursor solution containing an acrylamide-based monomer, an initiator, and a crosslinking agent is further included. Method for manufacturing adipose tissue-like structure.

15. In paragraph 12, The above multivalent metal ion compound comprises at least one of sodium chloride, zirconium chloride, iron chloride, calcium chloride, magnesium chloride, aluminum chloride, aluminum sulfate, potassium alum, iron alum chloride, ammonium alum, ferric sulfate, aluminum hydroxide, aluminum silicate, aluminum phosphate, iron citrate, magnesium oxide, calcium phosphate, calcium carbonate, calcium oxide, zinc oxide, and zinc sulfate. Method for manufacturing adipose tissue-like structure.

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