A robust polysaccharide hydrogel with excellent biocompatibility and biodegradability.

Abstract

To provide a polysaccharide hydrogel that is biocompatible, biodegradable, and possesses high toughness. [Solution] A hydrogel containing a crosslinked polymer obtained by crosslinking carrageenan with a crosslinking agent, potassium ions, tetravalent or higher metal cations, and water.

Description

[Technical Field]

[0001] This disclosure relates to polysaccharide hydrogels. [Background technology]

[0002] Hydrogels are materials in which water is trapped within a polymer network. Due to their high water content, they are biocompatible soft materials and are expected to be applied to biomedical materials such as artificial muscles, cartilage, and blood vessels. Hydrogels are generally mechanically fragile, and their low mechanical strength has limited the range of applications for hydrogels.

[0003] Polysaccharides are also used as polymer raw materials that constitute the polymer network of hydrogels. Carrageenan, a natural polysaccharide polymer derived from seaweed, is used as a thickener in food due to its high biocompatibility. When a salt such as KCl is added to an aqueous carrageenan solution, some of the carrageenan chains aggregate, and gelation occurs when these molecular chain aggregates link the carrageenan chains together. In such physically crosslinked carrageenan gels, the molecular chain aggregates, which are the crosslinking points, are easily destroyed by deformation, thus limiting their mechanical strength. Non-patent document 1 reports that when chemical crosslinking by covalent bonding is introduced to physically crosslinked carrageenan gels using epichlorohydrin as a crosslinking agent, the mechanical strength is improved.

[0004] Non-patent document 2 describes the development of a tough hydrogel by interpenetrating a carrageenan physical network with a polyacrylamide network, a synthetic polymer. ZrOCl2 is used as the salt. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Liu, Q. Zhang et al., Carbohydrate Polymers, 313, 120869 (2023) [Non-Patent Document 2] Yu, HC et al., Macromolecules, 52, 629-638 (2019). [Overview of the project] [Problems that the invention aims to solve]

[0006] Non-patent document 1 describes a low carrageenan concentration of 3%, and the only salt used for carrageenan aggregation being KCl, resulting in insufficient toughness of the hydrogel.

[0007] Non-patent document 2 combines carrageenan with polyacrylamide, and the carrageenan network is not chemically crosslinked. Using polyacrylamide may improve the toughness of the hydrogel, but it may impair the biocompatibility and biodegradability of carrageenan.

[0008] The problem to be solved in this disclosure is to provide a polysaccharide hydrogel that is biocompatible and biodegradable, as well as having high toughness. [Means for solving the problem]

[0009] This disclosure includes, for example, the following subjects:

[0010] Section 1. A hydrogel containing a crosslinked polymer obtained by crosslinking carrageenan with a crosslinking agent, potassium ions, tetravalent or higher metal cations, and water. Section 2. The hydrogel described in item 1, wherein the concentration of carrageenan in the hydrogel is 0.1 to 20% by mass or more. Section 3. The hydrogel according to item 1, comprising a metal cation with a valence of 4 or higher, wherein the cation is a zirconium ion. Section 4. The hydrogel according to item 1, comprising divinyl sulfone as the crosslinking agent. Section 5. The hydrogel according to any one of Items 1 to 4, having a tensile strength (maximum stress) of 1.0 MPa or more and a breaking strain of 100% or more. Item 6. The hydrogel according to Item 1 or 2, wherein the metal cation having a valence of 4 or more contains zirconium ions, the crosslinking agent contains divinyl sulfone, the tensile strength (maximum stress) is 1.5 MPa or more, and the breaking strain is 100% or more. Item 7. A composition containing carrageenan, a crosslinking agent, and water, a potassium salt, a metal salt having a valence of 4 or more, and a kit for producing a hydrogel. Item 8. A step of crosslinking carrageenan with a crosslinking agent to generate a crosslinked polymer, and a step of bringing the crosslinked polymer into contact with potassium ions and metal cations having a valence of 4 or more and a method for producing a hydrogel.

Advantages of the Invention

[0011] According to the present disclosure, it is possible to provide a polysaccharide hydrogel having biocompatibility and biodegradability and high toughness.

Brief Description of the Drawings

[0012] [Figure 1] Production of carrageenan gel via two types of crosslinking [Figure 2] Stress-strain curve of carrageenan gel using monovalent ions. [Figure 3] Stress-strain curve of carrageenan gel using ions of different valences. [Figure 4] Stress-strain curve of carrageenan gel using a mixture of KCl and ZrOCl2. [Figure 5] Schematic diagram showing physical aggregation of carrageenan.

Modes for Carrying Out the Invention

[0013] In this specification, "contains" is a concept that also includes "substantially consists only of" and "consists only of."

[0014] In the numerical ranges described stepwise in this specification, the upper or lower limit of a numerical range in one step can be arbitrarily combined with the upper or lower limit of a numerical range in another step. Furthermore, in the numerical ranges described in this specification, the upper or lower limit of a numerical range may be replaced with values ​​shown in the examples or values ​​that can be uniquely derived from the examples. Moreover, in this specification, numbers connected by "~" mean a numerical range that includes the numbers before and after "~" as the lower and upper limits.

[0015] The embodiments included in this disclosure will be described further below. The embodiments described below are examples of typical embodiments of this disclosure and do not limit the scope of the invention.

[0016] In this study, the inventors introduced both physical crosslinking to carrageenan through molecular chain aggregation in the presence of metal ions and chemical crosslinking through covalent bonds formed using a crosslinking agent. By appropriately adjusting the metal ion concentration and the structure of the carrageenan-containing crosslinked polymer, they succeeded in developing a polysaccharide hydrogel that is biocompatible, biodegradable, and highly tough.

[0017] This disclosure provides a hydrogel containing a crosslinked polymer obtained by crosslinking carrageenan with a crosslinking agent, potassium ions, tetravalent or higher metal cations, and water.

[0018] By having such a structure, the hydrogel can possess biocompatibility and biodegradability, as well as high toughness.

[0019] Carrageenan has a basic structure in which galactose alternates between α-1,3-linked and β-1,4-linked structures, and is classified into three types, κ, ι, and λ, based on differences in chemical structure. κ-carrageenan has one sulfate group per unit structure, while ι-carrageenan has two sulfate groups per unit structure, both having a unit structure of galactose and 3,6-anhydrogalactose. λ-carrageenan consists solely of galactose monosaccharide and has three sulfate groups per unit structure. Carrageenan is usually produced by alkaline extraction from red algae such as Gigartina, Chondrus, and Iridaea, and commercially available products are available.

[0020] The concentration of carrageenan in the hydrogel is not particularly limited, for example, 0.1 to 20% by mass, preferably 0.5 to 20% by mass, and more preferably 1 to 10% by mass. In order to obtain a polysaccharide hydrogel with high toughness, it is preferable that the concentration of carrageenan in the hydrogel be 5% by mass or more. The upper limit of the concentration of carrageenan in the hydrogel is not particularly limited, but for example, it is 30% by mass or less. Carrageenan is difficult to dissolve in water at high concentrations and has high viscosity even at about 1% by mass, but a higher concentration aqueous solution of carrageenan can be obtained by first preparing an aqueous solution of low concentration carrageenan, and then dehydrating and concentrating it by dialysis (for example, electrodialysis using a osmotic membrane).

[0021] In this specification, the proportion of each component in the hydrogel is calculated based on the mass of each component before mixing the hydrogel components. In other words, the proportion of a component in the hydrogel refers to the mass of that component relative to the total mass of the hydrogel components. The concentration of carrageenan in the hydrogel is calculated from the ratio of the mass of carrageenan before mixing with other components relative to the total mass of the hydrogel components.

[0022] The crosslinking agent is not particularly limited as long as it is capable of crosslinking the sugar chains of carrageenan. In particular, a crosslinking agent capable of crosslinking the hydroxyl groups of the constituent sugars of carrageenan is preferred, and examples include, but are not limited to, divinyl sulfone or epoxy compounds having two or more epoxy groups (etherification of hydroxyl groups), polyvalent carbodiimide (N-acylureation of hydroxyl groups), polyvalent aldehyde (acetalization of hydroxyl groups), and photopolymerizable compounds such as acrylic acid, methacrylic acid, and maleic acid (gelation by photopolymerization).

[0023] Divinyl sulfone is a suitable crosslinking agent because it can crosslink with the hydroxyl groups of carrageenan at relatively low concentrations, but it is not limited to this.

[0024] The crosslinking agent is preferably not a polymer. In one preferred embodiment, the crosslinking agent is not a polymer, and the only polymer component of the crosslinked polymer, which is formed by crosslinking carrageenan with the crosslinking agent, is carrageenan. With this configuration, the crosslinked structure can be optimized by chemically crosslinking the carrageenan network, and a tough hydrogel can be produced.

[0025] The concentration of the crosslinking agent in the hydrogel is not particularly limited, but it is preferably 0.01 to 0.5% by mass.

[0026] Potassium ions are used to promote the aggregation of carrageenan molecules by blocking the charge of the sulfate ions in carrageenan.

[0027] Potassium ions originate from potassium salts such as potassium chloride, potassium sulfate, potassium carbonate, potassium acetate, and potassium citrate. By incorporating these potassium salts as components of the hydrogel, potassium ions are generated in the resulting hydrogel.

[0028] The concentration of potassium salt in the hydrogel, that is, the concentration of potassium salt in the components of the hydrogel, is not particularly limited, but is preferably 10 to 500 mmol / L.

[0029] When potassium ions are not contained in the hydrogel, the toughness of the hydrogel decreases.

[0030] Metal cations with a valence of 4 or higher are used to promote the aggregation of carrageenans by blocking the charges of the sulfate ions of carrageenan. Since metal cations with a valence of 4 or higher have a higher valence than potassium ions, they are considered to have a stronger effect of aggregating carrageenans in the crosslinked polymer and aggregating the crosslinked polymer.

[0031] Examples of metal cations with a valence of 4 or higher include tetravalent metal cations, pentavalent metal cations, and hexavalent cations.

[0032] Examples of tetravalent metal cations include zirconium ions (Zr 4+ ), titanium ions (Ti 4+ ), germanium ions (Ge 4+ ), hafnium ions (Hf 4++ ), and ruthenium ions (Ru 4+ ).

[0033] Examples of pentavalent metal cations include niobium ions (Nb 5+ ), tantalum ions (Ta 5+ ), and antimony ions (Sb 5+ ).

[0034] Examples of hexavalent metal cations include molybdenum ions (Mo 6+ ), tungsten ions (W 6+ ), and chromium ions (Cr 6+ ).

[0035] These metal cations are derived from metal salts such as the hydrochlorides, sulfates, carbonates, acetates, and citrates of the ions.

[0036] For example, zirconium ions (Zr 4+) may be derived from any of the following: zirconium tetrachloride (ZrCl4), zirconium oxychloride (ZrOCl2), zirconium oxychloride octahydrate (ZrOCl2·8H2O), zirconium dioxide (ZrO2), zirconium tetrahydrate (Zr(OH)4), or a mixture thereof.

[0037] In order to obtain a polysaccharide hydrogel that is biocompatible and biodegradable, as well as highly tough, the metal cation with a valency of 4 or higher is preferably a tetravalent metal cation, and zirconium ion (Zr 4+ It is more preferable that it be )

[0038] The concentration of tetravalent or higher metal salts in the hydrogel, that is, the concentration of tetravalent or higher metal salts in the components of the hydrogel, is not particularly limited, but is preferably 10 to 500 mmol / L. In terms of the strength of the hydrogel, it is preferably 10 mmol / L or more, more preferably 100 mmol / L, and in terms of the ductility of the hydrogel, it is preferably 500 mmol / L or less.

[0039] Unexpectedly, the inventors discovered that hydrogels need to contain both potassium ions and metal cations with a valency of 4 or higher in order to increase both their strength and ductility. If a hydrogel contains only potassium ions and no metal cations with a valency of 4 or higher, its strength is insufficient. If a hydrogel contains only metal cations with a valency of 4 or higher and no potassium ions, its ductility decreases. Note that ductility is sometimes referred to as stretchability.

[0040] The mass ratio of potassium salts derived from potassium ions to metal salts with a valency of 4 or higher derived from metal cations with a valency of 4 or higher is, for example, 1:99 to 99:1, or 10:90 to 90:10. In a preferred embodiment, the mass of potassium salts derived from potassium ions incorporated into the hydrogel is greater than the mass of metal salts with a valency of 4 or higher derived from metal cations with a valency of 4 or higher.

[0041] The amount of water in the hydrogel is not particularly limited, but is, for example, 60-95% by mass.

[0042] The hydrogel may further contain electrolytes other than potassium salts derived from potassium ions and metal salts with a valency of 4 or higher derived from metal cations with a valency of 4 or higher.

[0043] The hydrogel may further contain sodium hydroxide (NaOH) and urea to improve the water solubility of carrageenan. For example, the concentration of sodium hydroxide is 0.1 to 0.3 M, and the concentration of urea is 5 to 15% by mass.

[0044] The hydrogel may optionally contain one or more additives, such as rust inhibitors, fungicides, antioxidants, defoamers, stabilizers, surfactants, colorants, and pH adjusters.

[0045] In a preferred embodiment, the hydrogel has a tensile strength (maximum stress) of 1.0 MPa or higher and a fracture strain of 100% or higher. Such a hydrogel achieves both high tensile strength and low fracture strain. In a preferred embodiment, the hydrogel has a tensile strength (maximum stress) of 1.5 MPa or more and a fracture strain of 100% or more. Such a hydrogel achieves both high tensile strength and low fracture strain. In a preferred embodiment, the hydrogel has a tensile strength (maximum stress) of 1.0 MPa or higher and a fracture strain of 150% or higher. Such a hydrogel achieves both high tensile strength and low fracture strain. In a preferred embodiment, the hydrogel has a tensile strength (maximum stress) of 1.5 MPa or more and a fracture strain of 150% or more. Such a hydrogel achieves both high tensile strength and low fracture strain. In a preferred embodiment, the hydrogel contains a zirconium ion as a tetravalent or higher metal cation, the crosslinking agent contains divinyl sulfone, and has a tensile strength (maximum stress) of 1.0 MPa or higher and a fracture strain of 100% or higher. Such a hydrogel achieves both high tensile strength and low fracture strain. In a preferred embodiment, the hydrogel contains a zirconium ion as a tetravalent or higher metal cation, the crosslinking agent contains divinyl sulfone, and has a tensile strength (maximum stress) of 1.5 MPa or more and a fracture strain of 100% or more. Such a hydrogel achieves both high tensile strength and low fracture strain. In a preferred embodiment, the hydrogel contains a zirconium ion as a tetravalent or higher metal cation, the crosslinking agent contains divinyl sulfone, and has a tensile strength (maximum stress) of 1.0 MPa or higher and a fracture strain of 150% or higher. Such a hydrogel achieves both high tensile strength and low fracture strain. In a preferred embodiment, the hydrogel contains a zirconium ion as a tetravalent or higher metal cation, the crosslinking agent contains divinyl sulfone, and has a tensile strength (maximum stress) of 1.5 MPa or more and a fracture strain of 150% or more. Such a hydrogel achieves both high tensile strength and low fracture strain.

[0046] The hydrogel of this disclosure allows for control of the molecular chain aggregation structure formed by the carrageenan chains by adjusting the concentration of carrageenan, the type and / or concentration of potassium salts and / or tetravalent or higher metal salts, and significantly improves the mechanical properties of the chemically and physically cross-linked gel. The carrageenan hydrogel of this disclosure, being tough, biocompatible, and biodegradable, can be used in a wide range of applications, including biomedical materials, biotechnology, and food.

[0047] This disclosure also provides a kit for hydrogel production comprising a composition containing carrageenan, a crosslinking agent, and water, a potassium salt, and a tetravalent or higher metal salt.

[0048] When potassium salts are dissolved in a composition containing carrageenan, a crosslinking agent, and water, potassium ions are produced.

[0049] When a metal salt with a valency of 4 or higher is dissolved in a composition containing carrageenan, a crosslinking agent, and water, it generates a metal cation with a valency of 4 or higher.

[0050] Carrageenan, crosslinking agents, potassium ions, potassium salts derived from potassium ions, tetravalent or higher metal cations, tetravalent or higher metal salts derived from tetravalent or higher metal cations, preferred examples of each component, and preferred amounts of each component are as described in the respective embodiments of the hydrogel described above.

[0051] A crosslinked polymer is formed by crosslinking carrageenan in a composition containing carrageenan, a crosslinking agent, and water with the crosslinking agent. Potassium ions and tetravalent or higher metal cations in the aqueous solution promote the aggregation of the crosslinked polymer.

[0052] Using a kit with this configuration, it is possible to manufacture a hydrogel that is biocompatible, biodegradable, and possesses high toughness.

[0053] The disclosure also provides a method for producing a hydrogel, comprising the steps of crosslinking carrageenan with a crosslinking agent to produce a crosslinked polymer, and contacting the crosslinked polymer with potassium ions and tetravalent or higher metal cations. To obtain a hydrogel that is biocompatible, biodegradable, and highly tough, chemical crosslinking is performed on carrageenan, followed by the introduction of physical crosslinking.

[0054] Carrageenan, crosslinking agents, potassium ions, potassium salts derived from potassium ions, tetravalent or higher metal cations, tetravalent or higher metal salts derived from tetravalent or higher metal cations, preferred examples of each component, and preferred amounts of each component are as described in the respective embodiments of the hydrogel described above.

[0055] Chemical crosslinking of carrageenan is performed by crosslinking it with a crosslinking agent. The crosslinking time in the process of crosslinking carrageenan with the crosslinking agent is not particularly limited, but is for example 30 minutes to 72 hours or 1 to 48 hours. The crosslinking time in the process of crosslinking carrageenan with the crosslinking agent is not particularly limited, but is for example 15 to 40°C or room temperature. Optionally, after the crosslinking process, the resulting crosslinked gel may be left to stand in a salt solution. The standing time is not particularly limited, but is for example 30 minutes to 72 hours or 1 to 48 hours. The temperature of the salt solution is preferably the same as or lower than the crosslinking temperature, for example 4 to 40°C or 4 to 15°C.

[0056] The step of contacting a crosslinked polymer with potassium ions and tetravalent or higher metal cations includes, for example, adding a potassium salt derived from potassium ions and a tetravalent or higher metal salt derived from tetravalent or higher metal cations to a composition containing the crosslinked polymer, usually an aqueous solution, after the crosslinked polymer has been produced, thereby contacting the crosslinked polymer with potassium ions and tetravalent or higher metal cations. The timing of adding the potassium salt and the tetravalent or higher metal salt may be simultaneous or separate.

[0057] In a composition containing a crosslinked polymer, when the crosslinked polymer is brought into contact with potassium ions and metal cations with a tetravalent or higher charge, the crosslinked polymer electrostatically bonds with the potassium ions and metal cations with a tetravalent or higher charge, promoting physical crosslinking between the crosslinked polymers and causing the hydrogel to aggregate. The time for contacting the crosslinked polymer with potassium ions and tetravalent or higher metal cations is not particularly limited, but is for example 30 minutes to 72 hours or 1 to 48 hours. The temperature of the reaction solution in the contact step is not particularly limited, but is for example 15 to 40°C or room temperature. After the contact step, a crosslinked gel is obtained. Optionally, after the contact step, the obtained crosslinked gel may be left to stand in a solution containing potassium chloride. The standing time is not particularly limited, but is for example 30 minutes to 72 hours or 1 to 48 hours. The temperature of the solution containing potassium chloride is preferably the same as or lower than the temperature of the reaction solution in the contact step, for example 4 to 40°C or 4 to 15°C.

[0058] Figure 1 is a schematic diagram of an example of a hydrogel manufacturing method.

[0059] When a crosslinking agent such as divinyl sulfone is added to an aqueous solution containing carrageenan and incubated at room temperature, the hydroxyl groups of the monosaccharide units of adjacent carrageenan chains react with the crosslinking agent, resulting in chemical crosslinking and the formation of a crosslinked polymer. Next, when potassium ions and tetravalent or higher metal cations are added to the aqueous solution of the crosslinked polymer and incubated at, for example, 5°C, the crosslinked polymer aggregates. In other words, physical crosslinking occurs.

[0060] All patent applications and disclosures cited herein are incorporated herein by reference in their entirety.

[0061] The following examples are for illustrative purposes only and are not intended to limit the technical scope of the present invention in any way. Unless otherwise specified, reagents are obtained or prepared from commercially available sources or according to methods commonly used in the art or procedures described in prior art. [Examples]

[0062] Example 1 Materials and methods Carrageenan powder was dissolved in an aqueous solution containing NaOH and urea using a high-speed mixer (AR-100, Thinky, USA) at room temperature for 20 minutes, and then degassed for 10 minutes. The carrageenan concentration in this solution was 6% by mass, the NaOH concentration was 0.2 mol / L, and the urea concentration was 10% by mass. This solution was allowed to cool to room temperature, and then divinyl sulfone was added. The divinyl sulfone concentration was 0.15% by mass. This solution was mixed at room temperature for 10 seconds, followed by degassing for 10 seconds, then poured into a mold and allowed to stand at room temperature for 24 hours to complete the chemical crosslinking reaction. Furthermore, this gel was immersed in an aqueous NaCl solution (NaCl concentration: 0.5 mol / L) and allowed to stand at 5°C for 48 hours to obtain a chemically crosslinked gel. To prepare the chemically and physically cross-linked gel, the gel after the chemical cross-linking reaction was immersed in an aqueous KCl solution (KCl concentration: 0.3 mol / L) and allowed to stand at 5°C for 48 hours to introduce physical cross-linking. Specifically, to prepare the physically cross-linked carrageenan, carrageenan powder was first dissolved in pure deionized water at 60°C for 30 minutes, and then at 90°C for 30 minutes. The carrageenan concentration in this solution was 6% by mass. Furthermore, an aqueous KCl solution was added to the solution to adjust the KCl concentration to 30 mM. The sample was then poured into a mold and allowed to gel at room temperature for 24 hours. Finally, this gel was immersed in an aqueous KCl solution (KCl concentration: 0.3 mol / L) and allowed to stand at 5°C for 48 hours to obtain a physically cross-linked gel. Uniaxial tensile testing was performed on dumbbell-shaped specimens using an RSA G2 (TA Instrument, USA). Uniaxial stretching was performed at a strain rate of 0.125 s⁻¹. -1 The method used was as follows: The fracture energy was calculated from the area under the stress-strain curve. Young's modulus was calculated by fitting a straight line to the small strain region of the stress-strain curve.

[0063] result Figure 2 shows the stress-elongation ratio curves for physically cross-linked carrageenan gel (solid line), chemically cross-linked carrageenan gel (dash-dotted line), and chemically and physically cross-linked carrageenan gel (dotted line). Chemically and physically cross-linked carrageenan gel showed larger fracture elongation and stress compared to physically and chemically cross-linked gels. Estimating the fracture energy from the area under the stress-strain curve, the fracture energy of chemically and physically cross-linked carrageenan gel is 1.9 J / m². 3 In previous studies, the fracture energy estimated similarly for chemically and physically cross-linked carrageenan gel with added KCl was 1.5 MJ / m³. 3 Our developed chemically and physically cross-linked gel exhibited superior toughness (Q. Liu, et al., Carbohydr. Polym., 313, 120869 (2023)). While previously reported chemically and physically cross-linked gels had a carrageenan concentration of 3%, we lowered the viscosity of the pre-gel solution by pre-dialysis of carrageenan with an aqueous NaCl solution, thereby increasing the carrageenan concentration to 6%. By introducing chemical and physical cross-linking and increasing the carrageenan concentration, we succeeded in achieving superior mechanical strength.

[0064] Example 2 Materials and methods Chemically crosslinked carrageenan gels were prepared in the same manner as in Example 1. Subsequently, the gels were immersed in aqueous solutions containing various types of salts and allowed to stand at 5°C for 48 hours to produce chemically and physically crosslinked gels. The types and concentrations of salts used were: (1) KCl 0.05 mol / L + ZrOCl 20.05 mol / L, (2) KCl 0.075 mol / L + ZrOCl 20.025 mol / L, (3) KCl 0.1 mol / L, (4) CaCl 20.1 mol / L, (5) AlCl 30.1 mol / L, and (6) FeCl 30.1 mol / L. The tensile test was performed in the same manner as in Example 1.

[0065] result Figure 3 shows the stress-strain curves of chemically and physically cross-linked gels containing various salts. (Divalent (Ca) 2+) and trivalent (Fe 3+ and Al 3+ The ions of (Ca) did not improve the toughness of the chemically and physically cross-linked gel. Compared to gels with K+, the Young's modulus was lower, suggesting that divalent (Ca) ions did not improve the toughness of the gel. 2+ ) and trivalent (Fe 3+ and Al 3+ In gels containing potassium ions and tetravalent ions (Zr), aggregation of carrageenan chains was suggested to be inhibited. On the other hand, potassium ions and tetravalent ions (Zr) 4+ Gels containing ) exhibited higher Young's modulus and fracture stress compared to gels containing potassium ions alone.

[0066] Example 3 Materials and methods Chemically crosslinked carrageenan gels were prepared in the same manner as in Example 1. Then, the gels were immersed in aqueous solutions containing various types of salts and allowed to stand at 4°C for 48 hours to produce chemically and physically crosslinked gels. The types and concentrations of salts were: (1) KCl 0.1 mol / L, (2) KCl 0.075 mol / L + ZrOCl 20.025 mol / L, (3) KCl 0.05 mol / L + ZrOCl 20.05 mol / L. (4) The ZrOCl concentration was 20.1 mol / L. The tensile test was performed in the same manner as in Example 1.

[0067] result The stress-strain curves of chemically and physically cross-linked carrageenan gels with different ratios of KCl and ZrOCl2 are shown. 4+ Samples containing only KCl fractured brittlely at low strain (Figure 4). This is thought to be due to excessive aggregation of carrageenan chains. Chemical and physical cross-linked gels containing both KCl and ZrOCl2 showed greater fracture elongation and fracture stress. Estimating the fracture energy from the area of ​​the stress-strain curve, the fracture energy for KCl 0.075 mol / L + ZrOCl2 0.025 mol / L is 2.64 MJ / m². 3This was greater than the fracture energy of the gel containing only KCl. 4+ K interacts with multiple sulfate groups in the carrageenan chain, + Compared to when Zr is added, it forms larger carrageenan aggregates. This has also been confirmed by structural analysis using small-angle X-ray scattering. 4+ and K + If they are allowed to coexist, some K + By shielding the sulfate group of the carrageenan chain, Zr 4+ This is thought to prevent excessive aggregation of carrageenan (Figure 5).

Claims

1. A hydrogel containing a crosslinked polymer obtained by crosslinking carrageenan with a crosslinking agent, potassium ions, tetravalent or higher metal cations, and water.

2. The hydrogel according to claim 1, wherein the concentration of carrageenan in the hydrogel is 0.1 to 20% by mass or more.

3. The hydrogel according to claim 1, wherein the aforementioned metal cation with a tetravalent or higher charge contains a zirconium ion.

4. The hydrogel according to claim 1, comprising divinyl sulfone as the crosslinking agent.

5. A hydrogel according to any one of claims 1 to 4, wherein the tensile strength (maximum stress) is 1.0 MPa or more and the fracture strain is 100% or more.

6. The hydrogel according to claim 1 or 2, wherein the tetravalent or higher metal cation contains a zirconium ion, the crosslinking agent contains divinyl sulfone, the tensile strength (maximum stress) is 1.5 MPa or more, and the fracture strain is 100% or more.

7. A composition containing carrageenan, a crosslinking agent, and water, Potassium salts, Metal salts with a tetravalent or higher valency, A kit for hydrogel production, including the following:

8. A process of crosslinking carrageenan with a crosslinking agent to produce a crosslinked polymer, and The process of contacting the crosslinked polymer with potassium ions and metal cations with a valency of 4 or higher. A method for producing hydrogels, including [the specified element].

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