KR102483862B1 - Eco-friendly biocompatible conductive hydrogel for medical device electrode and manufacturing method thereof - Google Patents

Abstract

The present invention relates to conductive hydrogel and a preparation method thereof and, more specifically, to eco-friendly biocompatible conductive hydrogel and a preparation method thereof, which has little toxicity because the eco-friendly natural polymer is used and does not give stimulation to a body when used for a long time, so that the hydrogel can be utilized as an electrode of a medical device. The eco-friendly biocompatible conductive hydrogel of the present invention comprises: an anionic natural polymer; cationic cellulose nanofiber obtained by modifying the surface of anionic cellulose fiber and converting the width of the fiber into a nano size to introduce a cationic group; an electrolyte salt; and an adhesive, wherein the anionic natural polymer is cross-linked by the cationic cellulose nanofiber to form a natural polymer matrix.

Description

Biocompatible eco-friendly conductive hydrogel for electrodes in medical devices and its manufacturing method

The present invention relates to a conductive hydrogel and a method for manufacturing the same, and more particularly, to a biocompatible, eco-friendly conductive hydrogel that can be used as an electrode for medical devices because it uses eco-friendly natural polymers, has little toxicity, and does not stimulate the body when used for a long time. It relates to a gel and a manufacturing method thereof.

Conductive hydrogel has adhesive properties and high water content, and has the ability to improve conductivity by being treated with ion-conductive materials, allowing it to be attached to the skin as electrodes. In particular, it is used as a material that enhances the electrical signal transmission power of the living body.

For example, conductive hydrogels can be used for electrocardiogram (ECG) electrodes, electroencephalography (EEG) electrodes, electromyogram (EMG) electrodes, transcutaneous electrical nerve stimulation (TENS) electrodes, and electrosurgical devices. unit, ESU) can be used for medical device electrodes such as ground electrodes.

Conductive hydrogels are generally prepared by polymerizing monomers of a conductive polymer, known as a material that allows current to flow, through chemical cross-linking with a cross-linking agent in a three-dimensional network structure of a gel composed of a non-conductive polymer.

However, the polymer forming the network structure of the conductive hydrogel and the crosslinking agent for crosslinking the polymer are artificially synthesized synthetic polymers. In addition, biocompatibility cannot be obtained unless it is thoroughly managed due to the toxicity of synthetic polymers.

Polyacetylene, polyaniline, polypyrrole, polythiophene, or poly(3,4-ethylenedioxythiophene) are typical examples of conductive polymers that impart conductivity to hydrogels, but they do not dissolve well in aqueous solvents. Since the conductive polymer is also toxic and causes skin trouble when attached to the human body as an electrode for a long time, the use of the conductive hydrogel containing the conductive polymer is limited.

In 'Electrical Conductive Microgel and Manufacturing Method (Registration No.: 10-0357902)', 3 to 30% by weight of a monomer that induces a conductive polymer such as polyaniline, polypyrrole or polythiophene and 1 to 20% by weight of a dopant are polymer microgels. After adding 15 to 80% by weight of an organic solution containing 5 to 60% by weight of gel, 2 to 40% by weight of an aqueous solution containing 1 to 40% by weight of an oxidizing agent polymerization catalyst is added and reacted at a temperature of 0 to 80 ° C. Disclosed is a microgel prepared and having excellent electrical conductivity.

However, since the use of synthetic polymers has not been ruled out, it still does not satisfy the demand for a biocompatibility, eco-friendly, and conductive hydrogel used in electrodes of medical devices, which has recently been increasing, and can be commercialized immediately. The composition and blending ratio of is not provided.

KR 10-0357902 B1

The present invention was invented to solve the above problems, and provides a conductive hydrogel that can be used as an electrode for medical devices because it has little toxicity using eco-friendly natural polymers and does not stimulate the body when used for a long time and a manufacturing method thereof Doing so is a technical solution.

In order to solve the above technical problem, the present invention, an anionic natural polymer; Cationic cellulose nanofibers, into which cationic functional groups are introduced by surface modification of anionic cellulose fibers and nanoization of fiber width; electrolyte salts; and an adhesive, wherein the anionic natural polymer is crosslinked by the cationic cellulose nanofibers to form a natural polymer matrix, providing a biocompatible, eco-friendly conductive hydrogel for electrodes in medical devices.

In the present invention, the conductive hydrogel comprises 0.1 to 5 parts by weight of the anionic natural polymer, 0.1 to 5 parts by weight of the cationic cellulose nanofibers, and 0.1 to 10 parts by weight of the electrolyte salt in the presence of 75 to 120 parts by weight of an aqueous solvent. It is characterized in that it is formed by mixing parts by weight and 20 to 50 parts by weight of the pressure-sensitive adhesive, followed by coating and heat treatment.

In the present invention, the electrolyte salt is at least one chloride selected from the group consisting of calcium chloride (CaCl ₂ ), lithium chloride (LiCl), sodium chloride (NaCl), potassium chloride (KCl) and cesium chloride (CsCl). to be

In order to solve the above other technical problems, the present invention, in the presence of an aqueous solvent, surface modification of anionic natural polymers and anionic cellulose fibers and nanoization of fiber width to cationic cellulose nanofibers and electrolyte salts into which cationic functional groups are introduced and preparing a hydrogel solution by mixing an adhesive; coating the hydrogel solution in a sheet form; and heat-treating the hydrogel solution coated in the form of a sheet; wherein, in the heat-treating the hydrogel solution, the anionic natural polymer is crosslinked by the cationic cellulose nanofibers to form a natural polymer matrix Characterized in that, it provides a method for producing a biocompatible eco-friendly conductive hydrogel for electrodes of medical devices.

In the present invention, the hydrogel solution, in the presence of 75 to 120 parts by weight of the aqueous solvent, 0.1 to 5 parts by weight of the anionic natural polymer, 0.1 to 5 parts by weight of the cationic cellulose nanofibers, 0.1 to 5 parts by weight of the electrolyte salt It is characterized in that it is prepared by mixing 10 parts by weight and 20 to 50 parts by weight of the pressure-sensitive adhesive.

According to the biocompatible eco-friendly conductive hydrogel for electrodes of medical devices of the present invention by means of solving the above problems, it is not only biocompatible and eco-friendly with little toxicity by excluding the use of synthetic polymers, but also does not cause stimulation despite long-term use. Since it does not cause skin trouble, there is an effect that can replace the electrode of a diagnostic measuring device such as a wearable electrocardiogram measuring device. That is, the biocompatible, eco-friendly conductive hydrogel of the present invention can be used as an electrode for medical devices.

In particular, since anionic natural polymers can be crosslinked in a matrix form of a three-dimensional network structure by cationic cellulose nanofibers into which cationic functional groups are introduced through surface modification and nanoization, even without adding a crosslinking agent made of a separate synthetic polymer. has the effect of

1 is a manufacturing process of a biocompatible eco-friendly conductive hydrogel for electrodes for medical devices according to the present invention.

Since the present invention can have various changes and various forms, specific embodiments will be described in detail in the text. However, this is not intended to limit the present invention to a specific form disclosed, and should be understood to include all modifications, equivalents, and substitutes included in the spirit and scope of the present invention.

Terms used in this application are only used to describe specific embodiments, and are not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this application, terms such as "comprise" or "having" are intended to designate that a combination of features, numbers, steps, elements, etc. described in the specification exist, but one or more other features, numbers, steps, etc. It should be understood that it does not preclude the possibility of existence or addition of combinations of components and the like.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and unless explicitly defined in this application, it should not be interpreted in an ideal or excessively formal meaning. don't

Here, repetitive descriptions, well-known functions that may unnecessarily obscure the subject matter of the present invention, and detailed descriptions of configurations are omitted. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

The present invention relates to a biocompatible, eco-friendly conductive hydrogel with a water-soluble network structure, which uses anionic natural polymer and cationic cellulose nanofibers, but crosslinks the anionic natural polymer by cationic cellulose nanofibers without adding a separate crosslinking agent. It is characterized in that it is used as a medical device electrode by forming a natural polymer matrix of a three-dimensional network structure.

The biocompatible eco-friendly conductive hydrogel of the present invention having these characteristics is an anionic natural polymer, an anionic cellulose fiber, a cationic cellulose nanofiber into which a cationic functional group is introduced by modifying the surface of the anionic cellulose fiber and making the fiber width nano, an electrolyte salt, It may contain an adhesive.

In particular, unlike conventional metal ions used as a cross-linking agent, cationic cellulose nanofibers function as a cross-linking agent so that an anionic natural polymer is cross-linked to form a natural polymer matrix with a three-dimensional network structure.

Accordingly, the electrical resistance value of the conductive hydrogel may be 0.7 to 4.8 kΩ·cm, and it is effective to be used as an electrode for medical devices when the range is above. If the resistance value of the conductive hydrogel exceeds 4.8 kΩ cm, the electrical conductivity is too low to be used as an electrode for medical devices, and if it is less than 0.7 kΩ cm, the electrical conductivity is too high, making it difficult to use it as an electrode attached to the living body. .

The anionic natural polymer is an eco-friendly superabsorbent polymer having biocompatibility, which is crosslinked by cationic cellulose nanofibers to form a three-dimensional network structured natural polymer matrix on a conductive hydrogel.

As the anionic natural polymer, at least one selected from the group consisting of alginate, xanthan gum, carrageenan, and sodium carboxymethyl cellulose (CMC) may be used. However, it is not limited to the above types as an anionic natural polymer, and any natural polymer that reacts with an aqueous solvent and exhibits anionic properties can be used in various ways.

Among them, sodium carboxymethyl cellulose has a hydroxyl group (-OH), is highly water-absorbent and hydrophilic polymer, dissolves well in water, and has excellent biocompatibility and is harmless to the human body.

The content of the anionic natural polymer may be included in 0.1 to 5 parts by weight. Since the anionic natural polymer must constitute the matrix of the conductive hydrogel, it is preferable to contain at least 0.1 parts by weight or more. When the anionic natural polymer is contained in an amount exceeding 5 parts by weight, anions that cannot be combined with the cationic functional groups of the cationic cellulose nanofibers remain, and the crosslinking performance is lowered, so that gelation is not generated and mechanical properties are lowered.

Cationic cellulose nanofibers have a configuration in which cationic functional groups are introduced by modifying the surface of anionic cellulose fibers and nanonizing the fiber width.

Prior to explaining the cationic cellulose nanofibers, cellulose is a natural polymer that accounts for 40 to 50% of most plant constituents as an environmentally friendly material. Cellulose differentiated at the nano level is called nanocellulose. Among them, cellulose nanofiber (CNF) itself has a large aspect ratio and specific surface area, high strength and thermal stability, and is manufactured from cellulose with a negative charge. Because of its anionic nature, it has low reactivity with eco-friendly anionic natural polymers and cannot be combined. To this end, cellulose nanofibers in which cationic functional groups are introduced through surface modification and nanoization of anionic cellulose fibers are used to improve reactivity with anionic natural polymers to achieve crosslinking.

In other words, when cellulose fibers exhibiting anionic nature are surface modified and nanosized, they become cellulose nanofibers in which the charge is completely reversed to cationic nature, and an electrostatic attraction occurs between the anions of anionic natural polymers and cations of cationic cellulose nanofibers, resulting in ionization. Since cross-linking is performed while being combined, a separate cross-linking agent is not required to cross-link the anionic natural polymer through the cationic cellulose nanofibers.

Accordingly, the anion of the natural polymer and the cation of the surface-modified cellulose nanofiber are ionic bonded by electrostatic attraction, and the anionic natural polymer is cross-linked by the cationic cellulose nanofiber and entangled with each other to form a three-dimensional network structure matrix to be able to configure.

The mechanism by which cationic cellulose nanofibers are synthesized is as follows. Cationic cellulose nanofibers can be prepared by introducing a cationic functional group on the surface of the anionic cellulose fibers through an amination reaction in which a cationizing agent is reacted with anionic cellulose fibers and then nano-nizing the fiber width.

The cationizing agent is glycidyltrimethylammonium chloride, (2-3-epoxypropyl) trimethylammonium chloride ((2-3-epoxypropyl) trimethylammonium chloride), (2-chloroethyl) trimethylammonium chloride ((2 -chloroethyl) trimethylammonium chloride), (3-chloro-2-hydroxypropyl) trimethylammonium chloride ((3-chloro-2-hydroxypropyl) trimethylammoniumchloride) and (2-hydrazinyl-2-oxoethyl) trimethylammonium chloride ( (2-hydrazinyl-2-oxoethyl) trimethylammonium chloride), and for example, the amination reaction may proceed through (1) and (2) of Scheme 1 below.

[Scheme 1]

In the case of the cationic cellulose nanofiber synthesized by the above method, when it is included in less than 0.1 parts by weight, there is a disadvantage in that the cationic functional group is insufficient and the anionic natural polymer is not completely crosslinked. If the cationic cellulose nanofiber exceeds 5 parts by weight, the cationic functional groups that are not combined with the anionic natural polymer remain, and when the hydrogel is made in the form of a sheet, surface defects may occur, and in particular, it may cause a decrease in conductivity. It is preferable to add in parts by weight or less. Therefore, cationic cellulose nanofibers are preferably included in the range of 0.1 to 5 parts by weight.

The electrolyte salt is a component that reduces electrical resistance and improves conductivity while being ionized by reacting with an aqueous solvent.

Conventionally, conductive polymers such as polyacetylene, polyaniline, polypyrrole, polythiophene, or poly(3,4-ethylenedioxythiophene), silver nanowires, carbon nanotubes, etc. have been used to impart conductivity to hydrogels. , which causes skin trouble when attached to the body for a long time, and is not desirable to add to the hydrogel used as a medical electrode.

Therefore, by using an electrolyte salt that stably imparts conductivity to the hydrogel and has little biotoxicity, it is possible to replace the conventional artificially synthesized and biotoxic conductive polymer.

In the case of an electrolyte salt, it may be included in 0.1 to 10 parts by weight. If the amount of electrolyte salt is less than 0.1 part by weight, it is not sufficient to impart conductivity to the hydrogel, so the electrical signal transmission ability of the body cannot be increased. If it exceeds 10 parts by weight, it may be good to improve conductivity, but due to the nature of chloride, Re-precipitation may occur, which is undesirable.

The adhesive is a component that imparts adhesiveness and moisturizing power to the conductive hydrogel.

The adhesive is a skin adhesive that provides adhesion to the skin of the hydrogel, and glycerol may be used. Glycerol has the advantage of being relatively inexpensive, so it may not have a significant effect on the increase in content, but if it exceeds 50 parts by weight, it is undesirable because it can lead to the precipitation of electrolyte salts from the hydrogel. It has a disadvantage in that it is insignificant to impart adhesiveness to the gel and easily falls off after being attached to the skin with electrodes, and it can cause skin itching because it cannot provide a certain amount of moisture. Therefore, it is preferable to appropriately adjust the amount of the pressure-sensitive adhesive within the range of 20 to 50 parts by weight.

On the other hand, the biocompatible eco-friendly conductive hydrogel for the electrode of the medical device, as shown in FIG. 1 simulating the manufacturing method of the conductive hydrogel according to the present invention, the step of preparing a hydrogel solution (S10), the hydrogel It can be prepared through the step of coating the solution in the form of a sheet (S20) and the step of heat-treating the hydrogel solution coated in the form of a sheet (S30).

According to the above-described manufacturing method, first, in the presence of an aqueous solvent, anionic natural polymer and anionic cellulose fibers are surface-modified and the fiber width is nanonized, and cationic cellulose nanofibers into which cationic functional groups are introduced, electrolyte salts, and an adhesive are mixed. A hydrogel solution is prepared (S10).

The aqueous solvent used is a water (H ₂ O)-based solvent, and distilled water, ultrapure water, or deionized water may be used. The aqueous solvent is preferably added to the container in an amount of 75 to 120 parts by weight in consideration of processability such as defoaming later.

The aqueous solvent may be used in less than 75 parts by weight, but if it is less than 75 parts by weight, there is a disadvantage in that the agitation between the anionic natural polymer, the cationic cellulose nanofiber, the electrolyte salt and the adhesive is not smooth and aggregation occurs. On the other hand, if the aqueous solvent exceeds 120 parts by weight, the hydrogel solution is coated in the form of a sheet, and the phenomenon of flowing down occurs, and there is a disadvantage in that a lot of time is consumed in the drying process in which the aqueous solvent must be evaporated later.

75 to 120 parts by weight of an aqueous solvent was added to a container, 0.1 to 5 parts by weight of an anionic natural polymer, 0.1 to 5 parts by weight of cationic cellulose nanofibers, 0.1 to 10 parts by weight of an electrolyte salt, and 20 to 50 parts by weight of an adhesive were added. In the stirring means to prepare a hydrogel solution.

A homogenizer may be used as the stirring means, and stirring conditions may be performed at a speed of 7,000 to 8,000 RPM for 1 to 20 minutes. If the RPM is less than 7,000 RPM, it takes more than 20 minutes to homogeneously stir the anionic natural polymer, cationic cellulose nanofiber, electrolyte salt, and adhesive in an aqueous solvent, resulting in no process efficiency, and if it exceeds 8,000 RPM, the anionic natural polymer It is undesirable because crosslinking performance may be impaired. At least 1 minute is required for stirring, but if it is less than 1 minute, homogeneous mixing is difficult, and if it exceeds 20 minutes, fairness is not good.

Next, the hydrogel solution is coated in a sheet form (S20).

A known wet coating method may be applied as a method of coating the hydrogel solution in which the components are homogeneously mixed in the form of a sheet on a flat plate. For example, it can be performed by a doctor blade coating, slit die coating, or bar coating method, and it is preferable to apply a bar coating method among them.

In the case of bar coating, the hydrogel solution may be formed in the form of a sheet by setting a moving speed of a bar coater on a flat plate in the range of 1 to 10 mm/sec. When the bar coater coats the hydrogel solution at a moving speed of less than 1 mm/sec, the hydrogel loses orientation, and when the bar coater moves on a flat plate at a speed exceeding 10 mm/sec, excessive heat is generated between the hydrogel solution and the bar coater. This is undesirable because it may cause deterioration of physical properties.

Finally, the hydrogel solution coated in the form of a sheet is heat treated (S30).

Although the crosslinking action of the anionic natural polymer may be partially performed in the previous step of preparing the hydrogel solution through an agitation means, the anionic natural polymer is crosslinked by the cationic cellulose nanofibers as the main reaction through the heat treatment in this step. It forms a natural polymer matrix.

A dry oven may be used for heat treatment of the hydrogel solution. The heat treatment consists of a first heat treatment in which the anionic natural polymer is crosslinked and a second heat treatment for stabilization of physical properties. Stabilize through secondary heat treatment for 3 to 3 hours.

When the first heat treatment is performed at less than 120 ° C. or less than 1 minute, the crosslinking action is slowed down, and it is difficult to evaporate the liquid contained in the hydrogel solution, so that the gelation into the hydrogel is not stably achieved. On the other hand, if the first heat treatment exceeds 180 ℃ or exceeds 10 minutes, compared to the case of the first heat treatment at a temperature or time lower than that, no better effect is obtained. It is preferable to perform the primary heat treatment for the following time.

In the case of the secondary heat treatment, it may be performed at a temperature and time range that are relatively lower than the primary heat treatment conditions in order to stabilize the physical properties of the conductive hydrogel in which the liquid including the aqueous solvent is evaporated and crosslinked. The secondary heat treatment at less than 50 ° C. or less than 1 hour is insufficient to stabilize the conductive hydrogel in a gel state, and when the temperature exceeds 100 ° C. or exceeds 3 hours, this is also undesirable in terms of stabilization.

The conductive hydrogel prepared by the above method is not only biocompatible and eco-friendly with little toxicity by excluding the use of synthetic polymers, but also does not cause irritation and skin trouble even when used for a long time. It has the advantage of being able to replace conventional medical electrodes used in the same diagnostic instrument.

Hereinafter, an embodiment of the present invention will be described in more detail. However, the following examples are merely illustrative to aid understanding of the present invention, and the scope of the present invention is not limited thereby.

<Example 1>

In a container containing 100 parts by weight of De-Ionized Water, 2 parts by weight of sodium carboxymethyl cellulose (CMC), 0.5 parts by weight of 2% high concentration cationic cellulose nanofibers, 30 parts by weight of glycerol, and 3 parts by weight of an electrolyte salt were added. and stirred for 10 minutes at 7,500 RPM using a homogenizer.

The prepared hydrogel solution was provided on a flat plate and bar-coated at a rate of 5 mm/sec using a bar coater having a diameter of 2.5 mm to form a sheet.

Thereafter, the hydrogel solution coated in the form of a sheet was stabilized by first heat treatment at 150 ° C. for 5 minutes in a dry oven and then second heat treatment at 80 ° C. for 2 hours and 30 minutes.

<Example 2>

In a container containing 100 parts by weight of De-Ionized Water, 2 parts by weight of sodium carboxymethyl cellulose (CMC), 1.0 parts by weight of 2% high-concentration cationic cellulose nanofibers, 30 parts by weight of glycerol, and 3 parts by weight of electrolyte salt were added. and stirred for 10 minutes at 7,500 RPM using a homogenizer.

The prepared hydrogel solution was provided on a flat plate and bar-coated at a rate of 5 mm/sec using a bar coater having a diameter of 2.5 mm to form a sheet.

Thereafter, the hydrogel solution coated in the form of a sheet was stabilized by performing a first heat treatment in a dry oven at 150 ° C. for 5 minutes and then additionally performing a second heat treatment at 80 ° C. for 2 hours and 30 minutes.

<Example 3>

In a container containing 100 parts by weight of De-Ionized Water, 2 parts by weight of sodium carboxymethyl cellulose (CMC), 0.5 parts by weight of 2% high concentration cationic cellulose nanofibers, 30 parts by weight of glycerol, and 1.5 parts by weight of an electrolyte salt were added. and stirred for 10 minutes at 7,500 RPM using a homogenizer.

The prepared hydrogel solution was provided on a flat plate and bar-coated at a rate of 5 mm/sec using a bar coater having a diameter of 2.5 mm to form a sheet.

Thereafter, the hydrogel solution coated in the form of a sheet was stabilized by performing a first heat treatment in a dry oven at 150 ° C. for 5 minutes and then additionally performing a second heat treatment at 80 ° C. for 2 hours and 30 minutes.

<Example 4>

In a container containing 100 parts by weight of De-Ionized Water, 2 parts by weight of sodium carboxymethyl cellulose (CMC), 0.5 parts by weight of low-concentration cationic cellulose nanofibers with a concentration of 1.2%, 30 parts by weight of glycerol, and 3 parts by weight of electrolyte salt were added. and stirred for 10 minutes at 7,500 RPM using a homogenizer.

The prepared hydrogel solution was provided on a flat plate and bar-coated at a rate of 5 mm/sec using a bar coater having a diameter of 2.5 mm to form a sheet.

Thereafter, the hydrogel solution coated in the form of a sheet was stabilized by performing a first heat treatment in a dry oven at 150 ° C. for 5 minutes and then additionally performing a second heat treatment at 80 ° C. for 2 hours and 30 minutes.

<Comparative Example 1>

In a container containing 100 parts by weight of De-Ionized Water, 2 parts by weight of sodium carboxymethyl cellulose (CMC), 0.06 parts by weight of metal ion as a cross-linking agent, 30 parts by weight of glycerol, and 3 parts by weight of an electrolyte salt are added and a homogenizer is used. and stirred for 10 minutes at 7,500 RPM.

The prepared hydrogel solution was provided on a flat plate and bar-coated at a rate of 5 mm/sec using a bar coater having a diameter of 2.5 mm to form a sheet.

Thereafter, the hydrogel solution coated in the form of a sheet was stabilized by performing a first heat treatment in a dry oven at 150 ° C. for 5 minutes and then additionally performing a second heat treatment at 80 ° C. for 2 hours and 30 minutes.

As described above, in Examples 1 and 2, conductive hydrogels were prepared by varying the content of the high-concentration cationic cellulose nanofibers, and in Example 3, the content of the high-concentration cationic cellulose nanofibers was the same as in Example 1, but the electrolyte A conductive hydrogel was prepared by reducing the salt content. In the case of Example 4, low-concentration cationic cellulose nanofibers were used instead of the high-concentration cationic cellulose nanofibers of Examples 1 to 3, and the contents of CMC, glycerol, electrolyte salt and De-Ionized Water in Example 1 were the same conditions. . In Comparative Example 1, metal ions were used as a crosslinking agent without using cationic cellulose nanofibers. Specific formulations are shown in Table 1 below, and units are parts by weight.

Example
One Example
2 Example
3 Example
4 comparative example
One Anionic natural polymer 2 2 2 2 2 High-concentration cationic cellulose nanofibers
(concentration 2%) 0.5 1.0 0.5 - - Low Concentration Cationic Cellulose Nanofibers
(Concentration 1.2%) - - - 0.5 - metal ion - - - - 0.06 skin adhesive 30 30 30 30 30 electrolyte salt 3 3 1.5 3 3 DI Water 100 100 100 100 100 Resistance (kΩ cm) 0.7 4.8 1.1 0.8 0.6

Referring to Table 1, the components mixed in the preparation of the conductive hydrogel using the high or low concentration cationic cellulose nanofibers as a crosslinking agent in Examples 1 to 4 and the preparation of the conductive hydrogel using the conventional metal ion as a crosslinking agent in Comparative Example 1 Mixed ingredients are identified.

In addition, electrical conductivity means the degree to which the conductive hydrogel can carry current, and at this time, the electrical resistance value has a reciprocal relationship with the electrical conductivity and has a range of 0.7 to 4.8 kΩ cm. It can be seen through Table 1. When the electrical resistance value is in the range of 0.7 to 4.8 kΩ·cm, it can be said to be effective for electrical signal transmission in the living body, and this was demonstrated in Examples 1 to 4, and Example 1 was particularly effective. Through this, compared to Comparative Example 1 using metal ions, the resistance value can be minimized, and the use of synthetic polymers is excluded, so there is little toxicity and it does not stimulate the body when used for a long time, so it can be actively used as an electrode for medical devices. was able to confirm

<Test Example 1>

In this test example, a cytotoxicity test was performed to confirm the degree of cytotoxicity reaction between the conductive hydrogel of Example 1 and the conventional conductive hydrogel (company A sample).

ISO 10993-5 (2009) Biological Evaluation of Medical Devices, Part 5: Tests for in In accordance with the in vitro cytotoxicity test method and the common standard for biological safety of medical devices provided by the Ministry of Food and Drug Safety, the extract test method was applied among the cytotoxicity test methods.

In order to apply the test material to the cells, the supernatant eluted using MEM medium supplemented with 10% FBS was used. After the test material was sufficiently absorbed in the elution solvent, the elution solvent was added according to the area ratio and eluted. In addition, it was decided to observe the effect of each test material on cells with the naked eye under a microscope and measure the growth and reaction of the cells.

Preparation of test materials

The test material is the test material of Example 1 (model name: HGX-004, storage conditions: room temperature storage), negative control group (model name: High density polyethylene film (HDPE), manufacturer: Hatano Research Institute, storage conditions: room temperature storage), positive Control group (model name: polyethylene film containing 0.1% ZDEC, manufacturer: Hatano Research Institute, storage conditions: room temperature), medium (model name: MEM (Minimum essential medium) + 10% FBS, manufacturer: WELGENE, storage conditions: refrigeration) ), serum (model name: Fetal Bovine Serum (FBS), manufacturer: WELGENE, storage condition: frozen storage).

test substance manufacturing

MEM medium supplemented with 10% FBS was eluted at 6 cm ² /mL at 37 ± 2 °C for 24 ± 2 hours. At this time, after sufficiently absorbing the elution solvent into the test substance, elution was performed by adding the elution solvent according to the area ratio. The negative control group and the positive control group were used after elution in 1X MEM medium at a rate of 3 cm ² /mL based on a thickness of 10 mm at 37 ± 2 ° C for 24 ± 2 hours. For the blank test solution, an elution solvent containing no test substance was used under the same conditions and methods as for extracting the test substance.

culture conditions

Using MEM medium containing 10% FBS, 20 mM L-glutamine and 10 ml/L antibiotics, incubation was performed under conditions of 37 ± 2 °C, 5% CO ₂ , and 99% humidity. Cells were cultured prior to testing to stabilize the cells.

Test Methods

The cells were dispensed at a concentration of 1 × 10 ⁵ cells/well to a culture plate having a diameter of 1 cm and cultured for 24 hours to confirm monolayer culture, and the medium was removed after marking each test group and control group. Afterwards, the test substance elution solution and the negative/positive control group were diluted to 100%, 50%, and 25%. Each diluted test group and negative/positive control group were repeatedly treated with cells three times and incubated at 37 ± 2 ℃, 5% CO ₂ , 99% humidity conditions. After 48 hours of treatment of each test group, cell morphological changes and lysis of the test group and negative/positive control group were observed under a microscope and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide ) Cell growth was measured by the assay method. The test results were confirmed using an absorber at a wavelength of 570 nm.

Qualitative assessment of cytotoxicity

Changes in cell morphology, vacuole formation, separation, cell lysis, and cell membrane state were examined under a microscope, and the degree of change in general cell morphology was described descriptively based on Table 2 below. At this time, if the reactivity is greater than 2 grades according to Table 2 (> 2), it is considered to have cytotoxicity.

solubility index reaction Point 0 doesn't exist
(None) Separation of intracytoplasmic granules, no cell lysis
No inhibition of cell growth One very weak
(Slight) Cells are round in shape, loosely attached, have lost intracytoplasmic granules, or do not exceed 20% of cells with changes in morphology.
Occasionally lysed cells present and slight growth inhibition observed 2 weak
(Mild) Cells become round in shape, no more than 50% of cells have lost intracytoplasmic granules, and no extensive cell lysis is seen.
Growth inhibition of cells does not exceed 50% 3 severity
(Moderate) Cells are round in shape or less than 70% of the cells are lysed
Although the cell layer was not completely destroyed, growth was inhibited by more than 50%. 4 severe
(Severe) Cell layer is almost or completely destroyed

Quantitative evaluation of cytotoxicity

MTT assay was performed to objectively quantify cell viability. If the cell viability is reduced to less than 70% (< 70%) of the blank, it is considered potentially cytotoxic.

result

As a result of qualitative analysis of cell morphological changes or degree of lysis under the above conditions through a microscope, separation of intracytoplasmic granules, no cell lysis, and inhibition of cell growth were not observed in the cells treated with the test substance. did not In addition, as a result of quantitative analysis, the eluate of the test material showed a cell viability of 96%.

As a result of qualitative analysis of the negative/positive control group, no inhibition of cell proliferation was observed in the negative control group, and severe toxicity was observed in the positive control group, in which the cell layer was almost destroyed. In the results of quantitative analysis, the negative control group showed no toxicity to cells, and the positive control group showed cytotoxicity.

The dissolution index results of the qualitative evaluation are shown in Table 3 below, and the quantitative evaluation results are shown in Table 4 below.

eluate
(%) 100 50 25 reps One 2 3 One 2 3 One 2 3 Test substance treatment group 0 0 0 0 0 0 0 0 0 positive control 4 4 4 4 4 4 4 4 4 negative control group 0 0 0 0 0 0 0 0 0 blank test solution 0 0 0 0 0 0 0 0 0

Test substance treatment group positive control negative control group blank test solution eluate
(%) 100 50 25 100 50 25 100 50 25 100 survival rate
(%) 96 98 103 0 0 24 104 99 100 100

From the above results, as a result of qualitative analysis of the morphological change or degree of lysis of cells in Example 1 as a test material through a microscope, a uniform monolayer was maintained after culture in the cells treated with the test material and no inhibition of proliferation was observed. did not According to the results of quantitative analysis, the cell viability was 96% in the group where 100% of the elution solution of the test substance was applied. Therefore, in accordance with the cytotoxicity standards for medical devices, which are considered to be cytotoxic if the cell lysis index is greater than Grade 2 or if the cell viability is reduced to less than 70% (< 70%) of the blank test solution, Example 1 is non-cytotoxic. It is judged to be In addition, the test results of the negative control group and the positive control group are as expected, proving the reliability of the test results.

On the other hand, the information of the conventional conductive hydrogel (company A sample) is shown in Table 5 below, and the method was performed as described above. The reactivity grade results of cytotoxicity are shown in Table 6 below.

name article amount volume of vehicle test article 64 cm2 10.6ml untreated control N.A. 10ml negative control 0.79g 7.9ml positive control 0.86g 8.6ml

exposure time test article extract control untreated negative positive A B C A B C A B C A B C (48±2)hrs 4 4 4 0 0 0 0 0 0 4 4 4

Referring to Table 6, it was confirmed that the conventional conductive hydrogel (company A sample) had a cell viability of grade 4 below the target value, which means that the untreated control group, the negative control group, and the positive control group meet the standard requirements and are effective. . In addition, it was confirmed under a microscope that the cultured cells applied to the test solution were completely destroyed. Accordingly, it can be seen that the conventional conductive hydrogel (company A sample) is not suitable for living body use and cannot be used as a medical electrode.

In summary, the present invention provides an eco-friendly conductive hydrogel used in electrodes of medical devices, including anionic natural polymers, cationic cellulose nanofibers, electrolyte salts, and adhesives, excluding the use of synthetic polymers.

In particular, cationic cellulose nanofibers introduce a cationic functional group through surface modification and nanoization of anionic cellulose fibers, so that anionic natural polymers form a three-dimensional network while being ionically bonded with anions of anionic natural polymers by electrostatic attraction. Since the crosslinking is performed in the form of a natural polymer matrix, there is no need for a crosslinking agent composed of a separate synthetic polymer to crosslink the anionic natural polymer.

In addition, since it was confirmed that the conductive hydrogel of the present invention has stability from the results of the above test examples, it is biocompatible with little toxicity and does not cause trouble even when attached to the skin for a long time, so it is a medical electrode that has been previously used in diagnostic instrumentation. is expected to be able to replace

The above description is merely an example of the technical idea of the present invention, and various modifications and variations can be made to those skilled in the art without departing from the essential characteristics of the present invention. Therefore, the embodiments disclosed in the present invention are not intended to limit the technical idea of the present invention, but are intended to explain, and the scope of the technical idea of the present invention is not limited by these embodiments. The protection scope of the present invention should be construed according to the claims, and all technical ideas within the scope equivalent thereto should be construed as being included in the scope of the present invention.

Claims (5)

anionic natural polymers;
Cationic cellulose nanofibers, into which cationic functional groups are introduced by surface-modifying anionic cellulose fibers and nanonizing fiber width;
electrolyte salts; and
Including; adhesive,
The anionic natural polymer is crosslinked by the cationic cellulose nanofibers to form a natural polymer matrix,
The conductive hydrogel is
In the presence of 75 to 120 parts by weight of an aqueous solvent, 0.1 to 5 parts by weight of the anionic natural polymer, 0.1 to 5 parts by weight of the cationic cellulose nanofibers, 0.1 to 10 parts by weight of the electrolyte salt, and 20 to 50 parts by weight of the adhesive are mixed Characterized in that it is formed by coating and heat treatment after coating, biocompatible eco-friendly conductive hydrogel for electrodes of medical devices. delete According to claim 1,
The electrolyte salt,
It is characterized in that it is one or more chlorides selected from the group consisting of calcium chloride (CaCl ₂ ), lithium chloride (LiCl), sodium chloride (NaCl), potassium chloride (KCl) and cesium chloride (CsCl), biocompatible and eco-friendly for electrodes of medical devices. conductive hydrogel. In the presence of an aqueous solvent, preparing a hydrogel solution by surface-modifying anionic natural polymer and anionic cellulose fiber and nanonizing the fiber width to mix cationic functional group-introduced cationic cellulose nanofiber, an electrolyte salt, and an adhesive;
coating the hydrogel solution in a sheet form; and
Including; heat-treating the hydrogel solution coated in the form of a sheet,
The step of heat-treating the hydrogel solution,
Characterized in that the anionic natural polymer is crosslinked by the cationic cellulose nanofibers to form a natural polymer matrix, a method for producing a biocompatible eco-friendly conductive hydrogel for electrodes in medical devices. According to claim 4,
The hydrogel solution,
In the presence of 75 to 120 parts by weight of the aqueous solvent, 0.1 to 5 parts by weight of the anionic natural polymer, 0.1 to 5 parts by weight of the cationic cellulose nanofibers, 0.1 to 10 parts by weight of the electrolyte salt, and 20 to 50 parts by weight of the adhesive Characterized in that it is prepared by mixing, a method for producing a biocompatible eco-friendly conductive hydrogel for electrodes of medical devices.

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