KR102098078B1 - Hydro gel and glucose sensor including the same - Google Patents

Abstract

As a hydrogel comprising a polymer matrix, the matrix includes a unit structure represented by Formula 1A below.
<Formula 1A>

Description

HYDRO GEL AND GLUCOSE SENSOR INCLUDING THE SAME

The present invention relates to a hydrogel and a glucose sensor comprising the hydrogel.

Diabetes mellitus is a type of metabolic disease, such as lack of insulin secretion or normal function, and the symptoms of diabetes are mainly related to high blood sugar levels, which increase the concentration of glucose in the blood. Chronic hyperglycemia due to diabetes not only causes damage and dysfunction of the organs of the body, but also causes microvascular complications such as coronary artery disease, peripheral artery disease, cerebrovascular disease, etc. Can lead to death.

In order to prevent complications caused by diabetes, select treatment methods, and improve prognosis, it is important to evaluate the appropriateness of treatment through continuous blood glucose measurement and apply the results quickly to the treatment process. From this perspective, the role of self-blood glucose measurement is gradually increasing.

However, most of the existing self blood glucose meters have limitations that cause pain and discomfort to the patient because blood glucose is measured by taking blood in an invasive manner. In addition, since the method of measuring the concentration of glucose in the sample blood by sampling the blood is a discontinuous measurement method, there is a possibility of overlooking the significant fluctuation in blood sugar level. Therefore, there is a need to develop a glucose sensor for autologous blood glucose measurement that can continuously monitor a patient's blood glucose concentration in a non-invasive manner.

The problem to be solved by the present invention is to provide a hydrogel capable of continuously detecting changes in the surrounding glucose concentration.

Another problem to be solved by the present invention is to provide a glucose sensor capable of continuously monitoring a patient's blood glucose concentration in a non-invasive manner.

The problems of the present invention are not limited to the technical problems mentioned above, and other technical problems that are not mentioned will be clearly understood by those skilled in the art from the following description.

The hydrogel according to an embodiment of the present invention for solving the above problems is a hydrogel comprising a polymer matrix, and the matrix includes a unit structure represented by the following formula 1A.

A glucose sensor according to an embodiment of the present invention for solving the above other problems is a hydrogel comprising a base and a polymer matrix disposed on the base, wherein the matrix is a hydrogel comprising a unit structure represented by the following formula 1A It includes.

Specific details of other embodiments are included in the detailed description and drawings.

1 is a perspective view of a glucose sensor according to an embodiment of the present invention.
FIG. 2 is a cross-sectional view taken along line II-II 'of FIG. 1.
3 and 4 are views for explaining the change in volume of the hydrogel of FIG. 1.
5 and 6 are views for explaining the reflection color of the hydrogel of FIG. 1.

Advantages and features of the present invention, and methods for achieving them will be clarified with reference to embodiments described below in detail together with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various different forms, and only the embodiments make the disclosure of the present invention complete, and have ordinary knowledge in the art to which the present invention pertains. It is provided to fully inform the person of the scope of the invention, and the invention is only defined by the scope of the claims.

An element or layer being referred to as the 'on' of another element or layer includes all cases in which another layer or other element is interposed immediately above or in between. On the other hand, when a device is referred to as 'directly on', it indicates that no other device or layer is interposed therebetween.

Also, 'and / or' includes each and every combination of one or more of the items mentioned. Numeric ranges indicated by using 'to' indicate numerical ranges that include the values described before and after them as the lower limit and the upper limit, respectively. 'About' or 'approximately' means a value or numerical range within 20% of the value or numerical range described thereafter.

Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings.

1 is a perspective view of a glucose sensor according to an embodiment of the present invention. FIG. 2 is a cross-sectional view taken along line II-II 'of FIG. 1.

1 and 2, the glucose sensor 1000 according to the present embodiment may include a base 200 and a hydrogel 100 disposed on the base 200. The base 200 may provide a space in which the hydrogel 100 is supported. The base 200 may be a transparent or opaque film or plate.

The hydrogel 100 includes a polymer matrix. In an exemplary embodiment, the hydrogel 100 may have a plurality of pores 100v formed therein. The pores 100v may form a low refractive region compared to the surrounding hydrogel 100. The pores 100v may be arranged substantially regularly. For example, the pores 100v may be regularly arranged along the X-axis direction, the Y-axis direction, and the Z-axis direction to form a grid.

For example, the hydrogel 100 may have an inverse-opal structure formed by a plurality of pores 100v. In general, a photonic crystal having an opal structure in which a spherical substance is filled in a polymer matrix of a hydrogel, light of different wavelengths is diffracted at different angles, and a color pattern may be generated over the entire wavelength range of visible light. In the present specification, the term 'reverse-opal structure' refers to a structure in which the opal structure is inverted, specifically, a structure in which approximately spherical pores or voids are formed in a polymer matrix to diffract at least a portion of transmitted light.

In the initial state, the pores 100v of the hydrogel 100 may be substantially spherical. In the present specification, 'initial state' means a state in which glucose is not present in the surroundings. Also, 'substantially spherical' means a substantially complete spherical shape, and a shape in which a difference between the maximum diameter and the minimum diameter in any cross section of the spherical shape is less than 10%. However, the present invention is not limited to this, and in the initial state, the pores 100v may have a crushed spherical shape.

The pores 100v of the hydrogel 100 may refract and / or diffract at least a portion of transmitted light or reflected light. The degree to which transmitted light or transmitted light is refracted and / or diffracted may vary depending on the size of the pores 100v and / or the separation distance between adjacent pores 100v. In an exemplary embodiment in which the pores 100v are substantially spherical, the diameter of the pores 100v may be about 200 nm to 330 nm, or about 270 nm to 310 nm. It is possible to control the reflection color in the initial state of the hydrogel 100 by making the diameter of the pores 100v within the above range. In an exemplary embodiment, the peak wavelength of the reflected color in the initial state of the hydrogel 100 may be in the range of about 450 nm to 465 nm.

The polymer matrix of the hydrogel 100 may have an internal network structure by crosslinking a plurality of polymer main chains with each other. The matrix of the hydrogel 100 is separate from the pores 100v, and may have a porous structure due to the network structure of the matrix itself. Through this, the matrix of the hydrogel 100 can reversibly absorb and release the liquid medium. In addition, since the absorption / release rate of the liquid medium of the matrix of the hydrogel 100 is fast, when the hydrogel 100 is applied to the glucose sensor 1000, the response speed of the sensor can be improved. The hydrogel 100 according to the present embodiment uses the reversible absorption and release of a liquid medium in the presence of glucose and thus the volume change of the hydrogel 100, and the size of the pores 100v and / or the separation between the pores 100v The distance d can be changed. Furthermore, the change in the size of the pores 100v and / or the separation distance d between the pores 100v can induce a change in the reflected color by the hydrogel 100. That is, the hydrogel 100 may implement a color change in the visible light region according to the surrounding glucose concentration. The reflection color may be changed by diffraction of light.

In an exemplary embodiment, the polymer matrix of the hydrogel 100 may include a unit structure represented by Formula 1A below.

<Formula 1A>

In Formula 1A, R ₁ is hydrogen or a methyl group, and n2 is an integer of 1 or 2.

'는 인접한 단위 구조 간의 결합 사이트 내지는 연결 사이트를 의미한다.In the formula of the present specification, square brackets mean repetition of the unit structure of the main chain of the polymer, and the symbol '

'Means a bonding site or a linking site between adjacent unit structures.

The boronic acid group (-B (OH) ₂ ) having a planar triangular structure may be covalently bonded to a diol group under basic conditions. For example, the boronic acid group introduced into the side chain of the polymer matrix of the hydrogel 100 is reversibly bound / dissociated from the vicinal diol group of glucose to form a dioxaborolane structure or dioxaborori Dioxaborinane can form. For example, when the boronic acid group introduced into the side chain is combined with the bisinaldiol group of glucose, the interaction force between the main chains can be increased to reduce the adjacent distance between the main chains, and as a result, the polymer matrix of the hydrogel 100 absorbs the liquid medium. And swelling behavior. On the other hand, when the boronic acid group dissociates from the bisinaldiol group of glucose, the interaction force between the main chains is reduced, and as a result, the liquid medium absorbed by the polymer matrix of the hydrogel 100 can be released and contracted again.

In addition, the fluorine group can facilitate bonding and dissociation between the boronic acid group and the bisinaldiol group. That is, the polymer matrix of the hydrogel 100 may include a fluorine group together with a boronic acid group to facilitate the shrinkage and swelling behavior of the hydrogel 100, and the hydrogel 100 during shrinkage and the volume of the hydrogel 100 during shrinkage ( 100) The difference in volume can be maximized. Through this, the sensitivity of the hydrogel 100 to glucose can be significantly improved. Furthermore, the peak wavelength shift of the reflection color of the hydrogel 100 may be configured in a monotone form.

In a non-limiting example, the unit structure represented by Chemical Formula 1A may be a unit structure represented by Chemical Formula 1B.

<Formula 1B>

In Formula 1B, R ₁ is the same as defined in Formula 1A, respectively.

The boronic acid group and the fluorine group may be disposed adjacent to facilitate bonding and dissociation between the boronic acid group and the bisinaldiol group. For example, boronic acid groups and fluorine groups can be introduced at the meta-position and para-position of the benzene ring, respectively.

In some embodiments, the polymer matrix of the hydrogel 100 may further include a unit structure represented by Chemical Formula 1C, Chemical Formula 1D, and / or Chemical Formula 1E.

<Formula 1C>

<Formula 1D>

<Formula 1E>

.

.

In Formula 1C, Formula 1D, and Formula 1E, R ₁ and n2 are the same as defined in Formula 1A, respectively.

The unit structure represented by Chemical Formula 1C, Chemical Formula 1D, and Chemical Formula 1E may be combined or connected to the unit structure represented by Chemical Formula 1A. The unit structures represented by Chemical Formula 1C, Chemical Formula 1D, and Chemical Formula 1E may refer to a unit structure in which at least a part of the unit structure represented by Chemical Formula 1A forms a chemical bond. In addition, in Chemical Formula 1C, Chemical Formula 1D and Chemical Formula 1E, a unit structure formed by chemically bonding the glucose to at least a portion of the unit structure represented by Chemical Formula 1A in which the hydrogel 100 is contained in the polymer matrix in the presence of glucose However, the present invention is not limited thereto.

In some embodiments, the polymer matrix of the hydrogel 100 may further include a hydroxyl group-containing side chain bound to the polymer main chain. For example, the polymer matrix of the hydrogel 100 may further include a unit structure represented by Formula 2 below. The unit structure represented by the following Chemical Formula 2 may be combined or connected to the above-described unit structures represented by Chemical Formulas 1A to 1E.

<Formula 2>

In Chemical Formula 2, R ₃ is hydrogen or a methyl group.

The hydrogel 100 matrix having a unit structure represented by Chemical Formula 2 has excellent absorption and release capacity for a liquid medium without affecting the binding / dissociation between the boronic acid group and the bisinaldiol group, as well as excellent biocompatibility. Can have

In an exemplary embodiment, the polymer matrix of the hydrogel 100 may not include a carboxyl group (-COOH) -containing side chain. When a carboxyl group is introduced into the polymer main chain of the hydrogel 100 polymer matrix, the shrinkage or swelling behavior of the hydrogel 100 according to glucose concentration may not exhibit a monotone form. That is, when a carboxyl group is introduced into the polymer main chain of the polymer matrix of the hydrogel 100, the peak wavelength shift of the reflection color of the hydrogel 100 according to the glucose concentration may not have a monotonic form. This will be described later together with the experimental example.

Hereinafter, the contraction / swelling behavior of the glucose sensor 1000 and the hydrogel 100 according to the present embodiment and changes in optical properties thereof will be described in more detail with reference to FIGS. 3 to 6.

3 is a view for explaining the volume of the hydrogel under low concentration of glucose conditions, and FIG. 4 is a view for explaining the volume of the hydrogel under high concentration of glucose conditions. 5 is a view for explaining the peak wavelength of the reflection color of the hydrogel under low concentration of glucose conditions, and FIG. 6 is a view for explaining the peak wavelength of the reflection color of the hydrogel under high concentration of glucose conditions.

First, referring to FIGS. 3 and 4, the hydrogel 100 according to the present embodiment may gradually swell as the surrounding glucose concentration increases. That is, the volume of the hydrogel 100 is increased by the surrounding glucose, and the separation distance d between the pores 100v of the hydrogel 100 may be increased.

The glucose solution can induce swelling of the matrix of the hydrogel 100. For example, the thickness (t ₁ , t ₂ ) of the hydrogel 100 in the presence of glucose at a pH of about 7.4 may be greater than the thickness t ₀ of the hydrogel 100 in an initial state where glucose is not present. In the presence of glucose, the thickness direction diameter and length diameter of the pores 100v in the hydrogel 100 are increased so that the pores 100v have a substantially spherical shape, or a crushed spherical shape, or a substantially elliptic spherical shape, or a crushed elliptical spherical shape It can be transformed. In addition, the separation distances d1 and d2 between the adjacent pores 100v in the thickness direction and the longitudinal direction in the presence of glucose are the separation distances d0 between the adjacent pores 100v in the thickness direction and the longitudinal direction in the initial state. It may increase.

In addition, a relatively high concentration of glucose solution at a pH of about 7.4 may induce swelling of the matrix of the hydrogel 100 compared to a relatively low concentration of glucose solution. For example, the thickness t ₂ of the hydrogel 100 in the presence of high concentration of glucose may be greater than the thickness t ₁ of the hydrogel 100 in the presence of low concentration of glucose. The separation distance d2 between adjacent pores 100v in the thickness direction and the longitudinal direction in the presence of high concentration of glucose is less than the separation distance d1 between adjacent pores 100v in the thickness direction and the longitudinal direction in the presence of low concentration of glucose. Can increase.

In some embodiments, the volume of the hydrogel 100 may increase monotonically as the surrounding glucose concentration increases. That is, the hydrogel 100 can always satisfy the following conditions (1) and (2) under the same pH conditions.

Condition (1): 0mM ≤ C1 <C2 ≤ 20mM

Condition (2): V _C1 <V _C2

In the conditions (1) and (2), C1 and C2 are the concentrations of glucose around the hydrogel 100, meaning a concentration section of 0 mM to 20 mM, and V _C means the volume of the hydrogel at the glucose concentration C. .

By always satisfying the conditions (1) and (2), the reliability of the glucose sensor can be secured when the hydrogel 100 is used as a glucose sensor.

The absorption / release characteristics of the liquid medium possessed by the hydrogel 100 according to this embodiment and the resulting swelling / shrinking behavior may be reversible and instantaneous. Therefore, the hydrogel 100 can continuously detect the surrounding glucose concentration. This is largely different from the irreversible method of measuring the blood glucose level by sampling the patient's local blood in that it is possible to detect the result reflecting the continuous fluctuation of the patient's blood sugar level.

Next, referring to FIGS. 5 and 6 further, the peak wavelength of the reflected color of the hydrogel 100 according to this embodiment may increase as the surrounding glucose concentration increases.

The volume change of the matrix of the hydrogel 100, the size / shape change of the pores 100v of the matrix of the hydrogel 100, and / or the change in the separation distance d between the pores 100v is the reflection color of the hydrogel 100 Can cause peak wavelength changes. For example, the peak wavelength of the reflected color of the hydrogel 100 in the presence of glucose at a pH of about 7.4 (λ _1, λ ₂ ) is the peak wavelength of the reflected color of the hydrogel 100 in the initial state where glucose is not present ( λ ₀ ).

In addition, the peak wavelength (λ ₂ ) of the reflected color of the hydrogel 100 in the presence of relatively high concentration of glucose at about pH 7.4 is the peak of the reflected color of the hydrogel 100 in the presence of relatively low concentration of glucose at about pH 7.4. It may be larger than the wavelength (λ ₁ ). That is, the hydrogel 100 according to the present embodiment increases the peak wavelength of the reflection color of the hydrogel 100 of the inverse opal structure as the glucose concentration increases, and may exhibit a red shift.

In some embodiments, the peak wavelength of the reflection color of the hydrogel 100 may increase monotonically as the surrounding glucose concentration increases. That is, the hydrogel 100 can always satisfy the following conditions (3) and (4) under the same pH conditions.

Condition (3): 0mM ≤ C1 <C2 ≤ 20mM

Condition (4): λ _C1 <λ _C2

In the conditions (3) and (4), C1 and C2 are the concentrations of glucose around the hydrogel 100, meaning a concentration section of 0 mM to 20 mM, and λ _C is the peak of the reflection color of the hydrogel at the glucose concentration C. It means wavelength.

The hydrogel 100 according to the present embodiment can improve the reaction rate of the glucose sensor 1000 and diversify its utilization by making the reflection color show a red transition, for example, a monotonous red transition as the glucose concentration increases. For example, the swelling behavior may be faster when the surrounding glucose concentration is increased, compared to the contraction behavior when the surrounding glucose concentration is decreased. That is, by making the hydrogel 100 exhibit a more rapid change in swelling behavior, it is possible to allow the patient to quickly recognize an increase in blood sugar level.

Here, the swelling behavior and red transition of the hydrogel 100 according to the above-described glucose concentration are boron (B) in which the hydroxyl group (-OH) contained in the unit structure represented by Formula 1C, Formula 1D and Formula 1E is combined. It may be caused by the negative charge.

Boronic acid can combine with glucose to form a boronic ester. Here, the boron (B) of the boronic ester group is combined with a hydroxyl group (-OH), the hydrogel 100 is able to absorb the counter charge (Counter charge) of water and negative charges in the aqueous solution of glucose dissolved by osmotic pressure phenomenon have. The hydrogel 100 that absorbs moisture exhibits swelling behavior, and a red transition may occur due to an increase in the separation distance d.

On the other hand, in the environment of pH 7.4, the reaction of glucose and boronic acid groups is dominant in the reverse reaction, that is, in the direction in which the boronic ester is decomposed. The glucose sensor using a conventional boronic acid group was driven under a basic condition of pH 9 or higher to form a boronic ester. Alternatively, a separate cationic monomer was added to counteract the negative charge of boron (B) in the glucose sensor.

On the other hand, in the case of the hydrogel 100 of the present invention, since the unit structure represented by Formula 1C, Formula 1D, and Formula 1E includes a fluorine group (F) in a benzene group combined with a boronic ester, it has a pH of 7.4. It is possible to stabilize boronic ester binding even in physiological environments. Since the fluorine group (F) is a strong electron withdrawing group having an electronegativity of 4.0, the formation reaction of the boronic ester is dominant even in an environment of pH 7.4. In addition, since the negative charge of boron (B) can be stabilized, a separate cationic monomer may not be added.

According to one embodiment, the unit structure represented by the formula 1A or 1B contained in the hydrogel 100 in the presence of glucose may form a covalent bond with the glucose to form the formula 1C, the formula 1D and the formula 1E have. The Chemical Formula 1C, the Chemical Formula 1D, and the Chemical Formula 1E formed by the reaction with the glucose may combine with a hydroxyl group to boron (B) to form a negative charge. Due to this, the polymer matrix of the hydrogel 100 increases the interaction force between the main chains and, at the same time, increases the hydrophilicity due to the negative charge, thereby rapidly absorbing the liquid medium in which the glucose is dissolved. At this time, as described above, the polymer matrix of the hydrogel 100 absorbing the liquid medium exhibits swelling behavior, and as a result, a red transition may occur. This is a change through the chemical bond between the polymer matrix of the glucose to be detected and the hydrogel 100, so the rate of change is fast. In addition, a small amount of glucose, for example, may cause the above change even at a concentration of 0mM to 20mM, in particular, in the presence of the fluorine group (F) contained in Formula 1A or 1B, the above-described change can be maximized. .

Therefore, since the hydrogel 100 according to the present embodiment can rapidly exhibit a red transition in the presence of glucose through the above-described mechanism, it is possible to secure sensitivity as a glucose detection sensor.

In addition, the glucose sensor 1000 including the hydration gel 100 according to the present embodiment can detect a sample in a sample. The method of detecting a sample can be achieved by a non-invasive method, for example, exposing the hydrogel 100 of the glucose sensor 1000 to a sample. The sample may be body fluids such as tears or sweat, and the sample may be glucose.

In this regard, the sensitivity of the glucose sensor 1000 is very important to detect a small amount of glucose contained in body fluids. In particular, for continuous blood glucose measurement in a diabetic patient, a glucose sensor having a level of sensitivity capable of qualitative and quantitative analysis of glucose in a concentration ranging from about 0 mM to less than 20 mM, particularly 1 mM to 10 mM, in the body fluid of the patient is required. . The change in optical properties caused by the interaction between the hydrogel 100 and the specimen according to the present embodiment, that is, the peak wavelength shift of the reflected color may be at least visible in the visible light region and may be a clear change that can be recognized by humans. This enables qualitative and quantitative analysis of the glucose concentration range of interest in body fluids and achieves continuous and accurate blood glucose measurements in diabetic patients. This will be described in detail in the experimental example to be described later.

On the other hand, the glucose sensor 1000 according to the present embodiment may be implemented in a form in which a user can easily come into contact with body fluids such as tears and sweats, for example, a contact lens, a patch for skin attachment, or a wearable device. The change in the reflected color of the hydrogel 100 of the glucose sensor 1000 can be confirmed by the user directly with the naked eye or by using an application capable of analyzing the transition of the peak wavelength.

Hereinafter, a method of manufacturing a hydrogel according to an embodiment of the present invention will be described.

In an exemplary embodiment, the method for preparing a hydrogel may include polymerizing a monomer composition including a first monomer represented by the following Chemical Formula 4A.

<Formula 4A>

In Formula 4A, R ₁ is hydrogen or a methyl group, and n2 is an integer of 1 or 2. The first monomer may form a unit structure represented by Formula 1A described above.

In some embodiments, the monomer composition may further include a second monomer represented by the following Formula 4B and / or a third monomer represented by the following Formula 4C.

<Formula 4B>

<Formula 4C>

The second monomer may form a unit structure represented by Formula 2 described above. In addition, the third monomer may be a crosslinking agent that bonds between adjacent polymer main chains.

In addition, the monomer composition may include 2 mole parts or more and 10 mole parts or less of the first monomer, based on 100 mole parts of the second monomer. In addition, the third monomer may include 0.5 mol part or more and 5 mol part or less.

According to the method of manufacturing a hydrogel according to the present embodiment, a first monomer (for example, a monomer forming a unit structure represented by Formula 1A) comprising a boronic acid group and a fluorine group capable of forming a chemical bond with glucose, liquid By preparing a hydrogel by polymerizing a monomer composition comprising a second monomer (for example, a monomer forming a unit structure represented by Chemical Formula 2) forming a matrix that enables smooth absorption / release of a medium, the molar ratio of each monomer And the ratio of side chains bound to the polymer main chain of the matrix of the hydrogel. In addition, the type of side chain bound to the polymer main chain of the matrix of the hydrogel can be clearly limited.

The ratio between side chains having boronic acid groups and fluorine groups, side chains having hydroxyl groups, and the type of side chains may affect the degree of transition of the peak wavelength of the reflection color of the hydrogel, and the transition speed. In addition, the ratio between the side chains and the type of side chains may affect the tendency of the shift of the peak wavelength of the reflection color of the hydrogel. That is, depending on the proportion and type of side chains, a blue transition may appear, a red transition may appear, or a blue transition and a red transition may appear together in a glucose concentration range of interest.

Particularly, when the blue transition and the red transition appear together in the glucose concentration range of interest, the user may not be able to detect an increase or decrease in blood sugar.

For example, after preparing a hydrogel containing a hydroxyl group, the hydroxyl group is converted to a carboxyl group through post-treatment, such as hydrolysis and carboxylation, through amidation reaction (amidation). When a hydrogel is prepared through a reaction such as conversion of a carboxyl group to an amide group, not only its reproducibility is extremely low, but it is difficult to completely control the ratio and type of carboxyl groups and / or side chains remaining in the hydrogel, thereby achieving desired wavelength transition. none.

On the other hand, the method of manufacturing the hydrogel according to the present embodiment controls the content of the above-mentioned monomers and polymerizes to prepare the hydrogel, so that the ratio and type of functional groups and / or side chains remaining in the hydrogel can be controlled. Therefore, in the method of manufacturing the hydrogel according to the present embodiment, the peak wavelength of the reflected color of the hydrogel can be clearly controlled according to the concentration of glucose, and a hydrogel excellent in sensitivity can be produced.

Hereinafter, the present invention will be described in more detail with further reference to experimental examples of the present invention.

<Production Example 1-1: 4-acrylamido-3-fluorofluorophenylboronic acid production>

4-acrylamido-3-fluorophenylboronic acid (hereinafter, compound (1)) was synthesized through the following reaction.

<Production Example 1-2: Preparation of hydrogel>

Compound (1) 0.07 g, acrylamide (arcylamide, AAm, hereinafter, compound (2)) 0.12 g, N, N'-methylenebisacrylamide (N, N'-Methylenebis (acrylamide), hereinafter, compound (3 )) 0.01g, 2,2-diethoxyacetophenone (2,2-Diethoxyacetophenone, hereinafter, compound (4)) having a reverse opal structure using a monomer composition containing 0.003g and DMSO (Dimethylsulfoxide) 0.5g A hydrogel was prepared.

<Comparative Example 1>

As a comparative example for Preparation Example 1-2, without using 4-acrylamido-3-floorophenylboronic acid, 3-acrylamido phenylboronic acid was used as a hydrogel. To manufacture. 3-acrylamidophenylboronic acid (hereinafter compound (5)) 0.084 g, 2-hydroxyethylene methacrylate (HEMA, compound (6)) 0.916 g, ethylene glycol dimethacryl Rate (Ethylene glycol dimethacrylate, hereinafter, compound (7)) 0.015 g, 2,2-dimethoxy-1,2-diphenylethan-1-one (2,2-Dimethoxy-1,2-diphenylethan-1- one, hereinafter, compound (8)) A hydrogel was prepared using a monomer composition comprising 0.019 g and 0.229 g of distilled water.

<Comparative Example 2>

In the same manner as in Comparative Example 1, 3-acrylamido phenylboronic acid was used to prepare a hydrogel. 3-acrylamidophenylboronic acid 0.076 g (Compound (5)), acrylamide (Compound (2)) 0.47 g, N, N'-methylenebisacrylamide (Compound (3)) 0.038 g, 2,2- A hydrogel was prepared using a monomer composition comprising 0.022 g of dimethoxy-1,2-diphenylethan-1-one (Compound (7)) and 0.47 g of distilled water.

<Comparative Example 3>

Unlike Preparation Example 1-2, after preparing a hydrogel containing acrylamide, 4-acrylamido-3-fluorofluorophenyl boron of Compound (1) is obtained through hydrolysis and amidation. A hydrogel comprising an acid is prepared.

Contains 0.1 g of acrylamide, 0.0025 g of N, N'-methylenebisacrylamide, 0.02 g of ethylene glycol, 7 μL of 2,2'-diethoxyacetophenone, and 3 g (14 wt%) of CCA having a particle size of 170 nm. The hydrogel is polymerized using the monomer composition described above. Here, the hydrogel is polymerized by photopolymerization for 90 minutes in ultraviolet light having a wavelength of 365 nm. Then, it is washed with an aqueous sodium chloride solution of 150 mM, and a hydrolysis and animation process is performed.

At this time, a total of three hydrogels were prepared as follows, by varying the conditions of the hydrolysis and the amination process.

First, the polymerized hydrogel was hydrolyzed for 16 hours using a mixed solution of 0.1 mmol / L sodium hydroxide (NaOH) and 100 mL tetramethylenediamine (TEMED), and 25 mmol / L 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide (EDC) and 25mmol / L aminotetrafluorobenzoic acid (AFBA) mixed solution for 3 hours for the formation To prepare a hydrogel. As described above, the hydrogel prepared by performing the amination process for 3 hours is hereinafter referred to as Comparative Example 3-1.

Then, in Comparative Example 3-1, a hydrolysis process was performed for 3 hours, and an amination process was performed for 20 hours using a mixed solution containing compound (1) to prepare a hydrogel, which was compared below. Referred to as Example 3-2.

Finally, in Comparative Example 3-2, a hydrolysis process was performed for 16 hours, and an amidation process was performed for 54 hours to prepare a hydrogel, which is hereinafter referred to as Comparative Example 3-3.

Unlike the preparation examples 1-2 as described above, after hydrogel polymerization, hydrolysis and amidation processes under various conditions were performed to prepare hydrogels (Comparative Examples 3-1, 3-2, and 3-3).

<Experimental Example 1>

The hydrogels prepared according to Preparation Examples 1-2, Comparative Examples 1 and 2 were exposed to a glucose solution having a pH of 7.4, and the peak wavelength change of the color indicated by the hydrogels was measured.

The hydrogel according to Preparation Example 1-2 was exposed to a 0 mM glucose concentration (i.e., an initial state), a 1.0 mM glucose concentration, a 4.0 mM glucose concentration, and a 10 mM glucose concentration. And the image is shown in Table 1 below.

In addition, the hydrogels according to Comparative Examples 1 and 2 were exposed to 0.1 mM glucose concentration, 1.0 mM glucose concentration, 10 mM glucose concentration, and 100 mM glucose concentration. And the image is shown in Table 2 below.

[Table 1]

[Table 2]

Referring to Table 1, it can be seen that the hydrogel prepared according to Preparation Example 1-2 had a change in reflection color at a level visually observable in a glucose concentration range of 0 mM to 10 mM. That is, it can be confirmed that the hydrogel prepared according to Preparation Example 1-2 clearly exhibited a red transition in the peak wavelength of the reflected color in the glucose concentration range.

In particular, it can be seen that the hydrogel prepared according to Preparation Example 1-2 exhibits a vivid color change even in the range of 0 mM to 10.0 mM glucose. Considering that the normal range of glucose concentration in the blood of the human body is 4 mM to 7 mM, it shows a color change such that it can be discerned with the naked eye even with a small change of 1 mM to 2 mM in the normal range. That is, a glucose sensor having high sensitivity in a physiological environment can be implemented using a hydrogel prepared according to Preparation Examples 1-2.

On the other hand, referring to Table 2, it can be seen that the hydrogels prepared according to Comparative Example 1 and Comparative Example 2 were invisible to the naked eye because of a slight shift in the peak wavelength of the reflected color in the glucose concentration range of 0.1 mM to 100 mM. Although the change range of glucose concentration has a large value as compared to Table 1, it shows a color change that is impossible to distinguish with the naked eye.

The degree and tendency of transition of the peak wavelength may be due to the presence or absence of a fluorine group introduced into a benzene ring having a boronic acid group.

<Experimental Example 2>

The hydrogel prepared according to Preparation Example 1-2 and Comparative Example 3 was exposed to a glucose solution having a pH of 7.4 and the peak wavelength change of the color indicated by the hydrogel was measured.

The hydrogel according to Preparation Example 1-2 was exposed to a 0mM glucose concentration (that is, an initial state), a 1.0mM glucose concentration, and a 10mM glucose concentration, and the peak wavelength of the reflected color at each glucose concentration was measured. In addition, the hydrogels according to Comparative Example 3 (a total of three hydrogels as described above, Comparative Examples 3-1, 3-2, and 3-3) were 0 mM glucose concentration (i.e., initial state), 1.0 mM glucose concentration, and 10 mM, respectively. Exposure to glucose concentration and measuring the peak wavelength of the reflected color at each glucose concentration. And the results are shown in Table 3.

[Table 3]

Referring to Table 3, it can be seen that the hydrogel prepared according to Preparation Example 1-2 clearly exhibited a red transition in the peak wavelength of the reflected color in the glucose concentration range of 0 nm to 10 nm. That is, it can be confirmed that the peak wavelength of the reflected color monotonically increases as the concentration of glucose increases.

On the other hand, the hydrogel prepared according to Comparative Example 3 can be confirmed that the peak wavelength of the reflected color in the initial state is not constant according to repeated experiments. In addition, it can be confirmed that the peak wavelength change of the reflected color according to the glucose concentration is also not constant according to the repeated experiment. As described above, the ratio and / or type of the side chains of the polymer of the hydrogel may affect the initial reflection color and change in the color of the hydrogel. It can be seen that the hydrogel prepared according to Comparative Example 3 has no reproducibility because the proportions and types of side chains cannot be constantly controlled.

In addition, it can be seen that the hydrogels prepared according to Comparative Examples 3-1, Comparative Examples 3-2, and 3-3 show a blue transition and a red transition together in a glucose concentration range of 0 mM to 10 mM. That is, it can be confirmed that the hydrogel prepared according to Comparative Example 3 could not constitute the peak wavelength shift of the reflected color in a monotonic form. This may be due to the carboxyl group remaining after the hydrolysis and amidation reaction.

The hydrogel according to an embodiment of the present invention can continuously / reversibly detect changes in surrounding glucose concentration. In addition, the glucose sensor according to an embodiment of the present invention can continuously monitor the blood glucose concentration in a relatively simple manner without giving pain and discomfort to the patient. In addition, while having excellent reproducibility, it is possible to configure the peak wavelength shift of the reflected color in a monotonic form, so that the reliability can be secured when the hydrogel is applied as a glucose sensor.

The embodiments of the present invention have been mainly described above, but this is merely an example and does not limit the present invention, and a person having ordinary knowledge in the field to which the present invention pertains does not depart from the essential characteristics of the embodiments of the present invention. It will be appreciated that various modifications and applications not illustrated above are possible. For example, each component specifically shown in the embodiments of the present invention can be implemented by modification. And differences related to these modifications and applications should be construed as being included in the scope of the invention defined in the appended claims.

Claims (8)

A hydrogel comprising a polymer matrix,
The matrix is a hydrogel comprising a unit structure represented by the following formula 1A.
<Formula 1A>

(In the formula 1A, R ₁ is hydrogen or a methyl group, n2 is an integer of 1 or 2) According to claim 1,
The unit structure represented by Chemical Formula 1A is a hydrogel, which is a unit structure represented by Chemical Formula 1B.
<Formula 1B>

(In Formula 1B, R ₁ is the same as defined in Formula 1A) According to claim 1,
In the presence of glucose,
The matrix is a hydrogel further comprising a unit structure represented by the following formula 1C, a unit structure represented by the following formula 1D, or a unit structure represented by the following formula 1E, combined with the unit structure represented by the formula 1A.
<Formula 1C>

<Formula 1D>

<Formula 1E>

(In Formula 1C, Formula 1D and Formula 1E, R ₁ and n2 are the same as defined in Formula 1A, respectively) According to claim 1,
The hydrogel,
A first monomer represented by the following formula 4A;
A second monomer represented by the following Chemical Formula 4B; And
A hydrogel prepared by polymerizing a monomer composition comprising a third monomer represented by the following Chemical Formula 4C.
<Formula 4A>

<Formula 4B>

<Formula 4C>

(In the above formula 4A, R ₁ are each hydrogen or methyl group) According to claim 4,
The matrix includes a main chain and a side chain bound to the main chain, wherein the side chain is a hydrogel that does not contain a carboxyl group (-COOH). According to claim 1,
In the glucose concentration section of 0mM to 20mM,
The hydrogel having a monotonically increasing volume of the hydrogel according to an increase in glucose concentration. According to claim 1,
In the glucose concentration section of 0mM to 20mM,
The peak wavelength of the reflection color of the hydrogel according to an increase in glucose concentration is monotonically increasing. Base; And
A glucose sensor comprising the hydrogel according to claim 1 disposed on the base

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