WO2010082790A2

WO2010082790A2 - Electroresponsive device for extending the life of biosensors, and a biosensor employing the same

Info

Publication number: WO2010082790A2
Application number: PCT/KR2010/000279
Authority: WO
Inventors: 김선정; 김선일; 윤장현
Original assignee: 한양대학교 산학협력단
Priority date: 2009-01-15
Filing date: 2010-01-15
Publication date: 2010-07-22
Also published as: WO2010082790A3

Abstract

The present invention relates to a biosensor to which an electroresponsive polymer layer is attached, and more specifically to a biosensor which comprises an electroresponsive polymer layer attached to the surface of a bioreceptor, and electrodes connected to the electroresponsive polymer layer, and which allows reversible deformation of the electroresponsive polymer layer when an electrical stimulus is supplied to an electrode, and can thereby analyse the concentration of an analyte when the surface of the bioreceptor is exposed to the analyte. When used as an implantable biosensor, the biosensor of the present invention is advantageous in that the time period for which and the frequency with which the bioreceptor is exposed to the analyte can be adjusted, and thus the lifespan of the biosensor is considerably extended.

Description

Electric sensor for extending the life of biosensor and biosensor using the same

The present invention relates to a biosensor with an electrically sensitive polymer layer, and more particularly, to a biosensor comprising an electrically sensitive polymer layer attached to a surface of a bioreceptor and an electrode connected to the electrically sensitive polymer layer. Providing an electrical stimulation relates to a biosensor that can cause a reversible deformation of an electrically sensitive polymer layer, thereby exposing the surface of the bioreceptor to an analyte and allowing analysis of the analyte concentration.

Analyte biosensors, which measure analytes such as glucose, which indicate the condition of a diabetic, have been receiving attention and research for the last several decades and have now developed a universal disposable sensor. With the development of this sensor technology, many researches are underway to develop implantable biosensors that accurately measure the level of analyte in vivo and allow continuous measurement (Jung et. Al. , Macromolecules 33, 3332-3336, 2000, Han et al., Biomacromolecules 3, 1271-1275, 2002, Wickramasinghe et al., Journal of Fluorescenece 14, 513-520, 2004, and Koschwanez et al. ., Biomaterials 28, 3687-3703, 2007).

Implantable biosensors developed to date, in addition to the most basic type of biosensor using a method for measuring the enzyme's electrochemical reaction according to the concentration of the analyte, it is determined by the change in pH or pressure by the enzyme inside the hydrogel. Development of biosensor (see patent documents PCT / US2000 / 23194 and PCT / US2001 / 12934) and skin penetrating biosensor (Korea Patent No. 10-0541267) using reverse ion osmosis method It became.

However, all of the biosensors described above have a common technical limitation regardless of their operation principle, which is that the lifespan of the biosensors in the body is remarkably short. In other words, all of the implantable biosensors presented to date are always exposed to blood or body fluids to come into contact with analyte, so that proteins or other body blockers present in the blood or body fluids adhere to the sensor surface or form a barrier film. . As a result, there is a significant problem that the performance of the biosensor is drastically deteriorated with time, or the performance is reduced such that it can no longer function as a biosensor.

Under this technical background, the present inventors attach an electrically sensitive polymer that causes reversible volume change by working with chemical free energy in the polymer by electrical stimulation to the surface of the biosensor and selectively impart electric stimulation to the conventional implantable biosensor. It was confirmed that the problem can be solved and came to complete the present invention.

After all, the main object of the present invention is to provide a biosensor capable of selective analysis of analyte concentration in accordance with the provision of electrical stimulation is attached to the electrosensitive polymer on the surface of the bioreceptor.

Another object of the present invention is to provide a concentration analysis device of analyte using an implantable biosensor in the body capable of selective concentration analysis.

Another object of the present invention is to provide a method of using an implantable biosensor in the body capable of selective concentration analysis.

Another object of the present invention is to provide a method for selectively controlling the operation of the implantable biosensor in the body by applying electrical stimulation.

In order to achieve the above object, the present invention provides a bio-receptor (detector) capable of detecting the analyte to be analyzed; A signal converter for converting the concentration information of the analyte detected from the bioreceptor into a signal that can be analyzed; An electroactive polymer layer attached to the surface of the bioreceptor; And it provides a biosensor comprising an electrode connected to the electrosensitive polymer layer.

According to one embodiment of the present invention, the electrically sensitive polymer may be one that exhibits a contraction-relaxation behavior, and more specifically, may be an artificial muscle material that exhibits a contraction-relaxation behavior.

According to one embodiment of the invention, the electrosensitive polymer may be an electrosensitive hydrogel.

According to an embodiment of the present invention, the biosensor may be an implantable body.

According to one embodiment of the invention, the analyte may be glucose.

In another aspect of the present invention, a biosensor implanted into a patient's body, a bio-receptor capable of detecting analyte to be analyzed, and converts concentration information of the analyte detected from the bioreceptor into a signal capable of analysis A signal converter; A biosensor comprising an electroactive polymer layer attached to a surface of the bioreceptor and an electrode connected to the electrosensitive polymer layer; Means for delivering an electrical stimulus to an electrode connected to the electrosensitive polymer of the biosensor; Means for conveying concentration analysis information generated from the biosensor; And a concentration analysis device for analyte using an implantable biosensor, which may include computer means for receiving and outputting concentration analysis information from the information transmission means.

According to an embodiment of the present invention, a biosensor in the analyte concentration analyzer may be provided with a plurality of sensors according to the number of channels in which the analyte to be analyzed exists.

In another aspect of the present invention, a bio-receptor capable of detecting analyte to be analyzed, a signal converter for converting concentration information of the analyte detected from the bioreceptor into a signal capable of analysis; Providing a biosensor comprising an electroactive polymer layer attached to a surface of the bioreceptor and an electrode connected to the electrosensitive polymer layer; Providing computer means coupled to the biosensor to output a concentration value of analyte as a data signal; Implanting the biosensor into the patient's body and providing electrical stimulation to an electrode connected to the biosensory polymer layer of the biosensor; And when the bioreceptor is exposed to the analyte by causing a reversible deformation of the electrically sensitive polymer layer by the provided electrical stimulation, the concentration information of the analyte detected by the bioreceptor is received through the computer means, and the received concentration information is received. Method of using a biosensor implanted in the body of a patient comprising the step of reading the concentration value may be provided.

According to another aspect of the present invention, a bio-receptor capable of detecting analyte to be analyzed, a signal converter for converting the concentration information of the analyte detected from the bioreceptor into a signal capable of analysis; Providing a biosensor comprising an electroactive polymer layer attached to a surface of the bioreceptor and an electrode connected to the electrosensitive polymer layer; Implanting the provided biosensor into the body of a patient; Imparting selective electrical stimulation to an electrode connected to the electrosensitive polymer layer of the biosensor implanted into the body of the patient; And receiving concentration information of the analyte detected by the bioreceptor when the bioreceptor is exposed to the analyte by causing the electrosensitive polymer layer to be reversibly modified by the selective electric stimulation, and reading a concentration value. Methods may be provided for selectively controlling the operation of a biosensor implanted in a patient's body.

According to one embodiment of the present invention, the electrically sensitive polymer layer may be made of a material exhibiting shrinkage relaxation behavior by electrical stimulation.

The biosensor according to the present invention can selectively control the contact frequency and time with the analyte using an electrosensitive polymer, thereby greatly extending the durability and lifespan of the biosensor. In particular, it is possible to control the contact between the surface of the biosensor and the analyte by using the reversible deformation behavior by the electrical stimulation of the electrosensitive polymer, which is a fundamental problem in the conventional implantable biosensors. It can be expected to solve the sensor life reduction problem.

1 is a cross-sectional view of a biosensor according to an embodiment of the present invention and its operating mechanism.

2 illustrates an embodiment in which a biosensor according to the present invention can be installed in a multi-channel environment and an operating mechanism thereof.

Figure 3 is a schematic diagram showing the device of the biosensor with the electrosensitive polymer according to the present invention.

* Names of symbols for main parts of drawings *

A: electrosensitive polymer

S: sensor

C: channel (fluid / vascular)

C_1: channel 1

C_2: channel 2

PS: power supply

CC: control unit

Hereinafter, the present invention will be described in more detail.

In the present invention, the term "analyte" refers to a chemical component that is to be analyzed as an object of analysis. In the present invention, as an analyte of the biosensor, biomaterials such as glucose, DNA, enzymes, proteins, cells, and hormones are described as an example, but general chemicals are not excluded from the analyte range of the present invention.

In the present invention, an electrosensitive polymer is used to attach to the bioreceptor, which is a material capable of causing reversible deformation by external stimulation such as pH, solvent composition, temperature, concentration of ions, electric field, and the like. Such a system in which chemical free energy is changed into mechanical work by stimulation of the surrounding environment is called 'Chemomechanical System', and mechanical free energy such as contraction relaxation or lateral movement is performed by chemical free energy in the polymer by electric stimulation. The polymer material that can be used is called Electroactive Polymers (EAP) and is a kind of polymer hydrogel.

The types of electrosensitive polymers are classified into those operated by electric fields and those operated by ions. The electric fields can be divided into piezoelectric, electrostrictive, and ferroelectric materials. The ionization causes the drift of ions inside the polymer when an electric field is applied. The deformation occurs due to the polymer gel and the ion thin film. In addition, various kinds of electrosensitive polymers such as carbon nanotubes, paper, cloth, and fluids have been studied.

The electrosensitive polymer has the advantage of being able to be deformed (move left and right and contract / reduce) by external stimulus, and have high elasticity, light weight and miniaturization. Therefore, artificial muscle similar to living muscle, small and noiseless driving device or living body It is possible to research and develop biosensors and actuators that can detect various signals generated, which will bring new technological innovations to many industries such as robot, biological, aviation, space, military, and micro electro mechanical system (MEMS) in the future. It is expected.

The electrosensitive polymer that can be used in the present invention can be a material that causes reversible volume change by electric stimulation, and in particular, mechanical work such as shrinkage relaxation behavior can be performed by changing chemical free energy in the polymer by electric stimulation. It is preferable if it is a material. Typically, a material capable of shrinkage relaxation behavior may be used as a material that can be used as artificial muscle.

Artificial muscle materials belonging to the EAP may include dielectric actuators (DEAs), relaxor ferroelectric polymers, and liquid crystal rubbers. Next, as artificial muscle material, there is an artificial muscle material which requires ions when driving and requires movement of such ions. These materials are called ionic EAPs, and the use of electrolytes is essential because the ions must move, and wet EAPs when the electrolyte is liquid. The use of a solid material as an electrolyte has not yet been classified. The use of conductive polymers, carbon nanotubes (CNTs), and ionic polymer metal composites (IMPC) In this case, the name of the substance is used as the artificial muscle material.

In the present invention, an IPN (interpenetrating polymer network) hydrogel may be used as the electrosensitive polymer. The IPN is at least partially cross-linked at a molecular scale but is not a covalent bond and has two or more network structures that do not separate until the chemical bond is broken. It refers to a polymer. The types of IPNs are divided according to the polymerization method and form, and these IPNs form a wide range of attenuating materials or reinforced elastomers to replace thermosetting resins, and some types of IPNs are continuous physical materials that are difficult for other polymers to exhibit. , Mechanical properties. Hydrogels are typically oxygen-permeable and biocompatible because they are hydrophilic crosslinked polymers with low crosslinking density and are hydrated crosslinked polymeric systems containing 20-90% water at equilibrium. IPN systems are fast and sensitive to electrical reactions and exhibit good mechanical properties (Kim et al, J. Appl. Polym. Sci, 73, 1675-1683, 1999). Can be used as a substance.

The operating mechanism of the biosensor according to the present invention will be described in more detail with reference to the drawings.

In the biosensor according to the present invention, the sensor S is selectively in contact with the channel C. The channel C may be a single channel C or may be composed of a plurality of channels (channel 1 (C_1), channel 2 (C_2) ...) (FIG. 2).

In the present invention, the electrosensitive polymer (A) is attached to the sensor (S) of the implantable biosensor device, and the electrodes are attached to both ends of the electrosensitive polymer (A) to supply electrical stimulation to the electrosensitive polymer (A). . As the electrode, a biocompatible electrode that is harmless to a human body is used, and a needle, plate, or circular electrode may be used. In addition, the electrode may be composed of a single electrode, or may be composed of an electrode in the form of an array so that a plurality of electrodes can be attached or fixed to the electrosensitive polymer to give an electrical stimulus.

1 is a cross-sectional view of a biosensor according to an embodiment of the present invention and its operating mechanism. When the electrosensitive polymer is attached to the biosensor, more specifically, the bioreceptor of the biosensor, and the electrical stimulation is applied to the electrode connected to the electrosensitive polymer, the electrosensitive polymer (A) exhibits a reversible shrinkage behavior. The surface of (S) is exposed to the channel (C), which makes it possible to contact the analyte.

In FIG. 1, the state of the upper OFF drawing is a state in which no electric stimulus is applied, and the state of the lower ON drawing is an electrical stimulus in which the electrosensitive polymer A exhibits shrinkage behavior and is covered by a biosensor S hidden underneath. Is exposed. In other words, the biosensitive polymer (A) located on the surface of the biosensor is subjected to electrical stimulation and exhibits shrinkage behavior. As a result, the biosensitive polymer (A) is hidden under the electrosensitive polymer (A), and thus is not in contact with the analyte (usually body fluid or blood). By exposing the sensor S, contact with the analyte is enabled, and the concentration of the analyte can be measured.

2 illustrates an embodiment in which a biosensor according to the present invention can be installed in a multi-channel environment and an operating mechanism thereof. As shown in FIG. 2, the first and second sensors from above may be exposed to the channel C_1 upon contraction of the electrosensitive polymer A, and the third sensor may be exposed to the contraction of the electrosensitive polymer A. Therefore, the channel C_2 may be exposed.

Figure 3 is a schematic diagram showing the device of the biosensor with the electrosensitive polymer according to the present invention. The power supply unit PS is a portion for supplying power to the electrosensitive polymer A through an electrode, and the control unit CC generates a power control signal and supplies it to the power supply unit PS when analyzing an analyte. It is an apparatus for doing this. The electrosensitive polymer A is set to a position where the sensor is not exposed to the channel C to protect the biosensor S when the power is turned off.

For example, when performing analyte analysis using the implantable biosensor (S), the control unit (CC) generates a signal for controlling the electrosensitive polymer (A) and transmits it to the power supply unit (PS) The power supply unit PS supplies power for controlling the electrosensitive polymer A. By the power supply by the control signal, the electrosensitive polymer A undergoes a reversible deformation (shrinkage), whereby the biosensor S can be in selective contact with the analyte of the channel C.

In the implantable biosensor, the control signal may be automatically sent to the control unit (CC) of the biosensor. According to the control signal, the control unit CC transmits an operation signal to the power supply unit PS, which can control the power supply of the power supply unit PS to control the measurement of analyte concentration of the biosensor. do. Through such a control operation, the biosensor may be brought into contact with blood or body fluid for a predetermined time or for a minimum time required for operating the biosensor when the user wants to measure.

Biosensor according to an embodiment of the present invention as described above means for transmitting the electrical stimulation to the electrode connected to the electrosensitive polymer of the biosensor, means for delivering the concentration analysis information generated from the biosensor and the information delivery means It may be provided as an apparatus for analyzing the concentration of analyte together with computer means for receiving and outputting the concentration analysis information from the same.

When a biosensor with an electrosensitive polymer layer is applied as an implantable biosensor, the method of using a biosensor implanted in a patient's body is as follows.

Provided is a biosensor equipped with an electrically sensitive polymer layer exhibiting reversible deformation (especially shrinkage) by electrical stimulation, and connected to the biosensor to provide a computer means for outputting a concentration value of analyte as a data signal. The provided biosensor is implanted into the body of the patient and imparts electrical stimulation to an electrode connected to the electrosensitive polymer layer of the biosensor. The bioreceptor is exposed to analyte when the electrosensitive polymer layer causes a reversible deformation by the imparted electrical stimulation, and receives concentration information of the analyte from the exposed bioreceptor through the computer means. The received concentration information can be read as a concentration value, and through this process, the biosensor according to the present invention can be used as an implant.

In addition, the biosensor according to an embodiment of the present invention can be selectively controlled by applying an electrical stimulus, the specific control method is as follows.

Provided is a biosensor with an electrically sensitive polymer layer that exhibits reversible deformation (especially contractile action) by electrical stimulation, and the biosensor provided is implanted into the body of a patient. The electrical stimulation is selectively given to the electrode connected to the electrosensitive polymer layer of the biosensor implanted in the patient's body. The selective electrostimulation causes the electrosensitive polymer layer to undergo reversible deformation, thereby receiving concentration information of the analyte from the bioreceptor exposed to the analyte. The received concentration information can be read as a concentration value, and through this process it is possible to selectively control the operation of the biosensor according to an embodiment of the present invention implanted in the body of the patient.

Through such a mechanism, the analysis of the concentration of the analyte of the biosensor may be selectively performed by the task of imparting electrical stimulation. This principle can reduce the exposure time and frequency of the bioreceptor, which causes protein adsorption on the surface of the sensor even after long-term use when the biosensor is implanted in the body, thereby preventing the biosensor from functioning and increasing its lifespan significantly. have.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these Examples are only for illustrating the present invention, and the scope of the present invention will not be construed as being limited by these Examples.

In particular, the following examples illustrate glucose as an analyte, but it will be apparent to those skilled in the art that the scope of the present invention is not limited thereto.

Example 1: Control of Biosensor with Electrosensitive Polymer in Single Channel Environment

First, we tested the control of biosensors with implantable electrosensitive polymers in a single channel environment.

In order to analyze glucose using the implantable biosensor (S) in a single channel (C), the control unit (CC) generates a signal for controlling the electrosensitive polymer (A) and transmits it to the power supply unit (PS). . As a result, a power source for controlling the electrosensitive polymer A could be supplied from the power supply unit PS (see FIGS. 1 and 3). At this time, the electric sensitive polymer (A) is contracted by the power supply by the control signal, it was confirmed that the biosensor (S) in contact with the glucose of the channel (see Fig. 1).

Example 2 Control of Biosensor with Electrosensitive Polymer in a Multichannel Environment

Next, the control of the biosensor with the implantable electrosensitive polymer in the environment in which two or more channels are present was tested.

In order to analyze glucose using the implantable biosensor S in the multi-channels C_1 and C_2, a control unit CC generates a signal for controlling the electrosensitive polymer A, and then transmits the signal to the power supply unit PS. Sent. As a result, a power supply for controlling the electrosensitive polymer A could be supplied from the power supply unit PS (see FIGS. 2 and 3). At this time, by generating the respective control signal for the channel 1 (C_1) and channel 2 (C_2), it was possible to selectively shrink and relax the electrosensitive polymer (A) by the individual power supply by each control signal, Thus, the sensor S could selectively contact the glucose of channel 1 (C_1) or channel 2 (C_2).

According to the present invention, by selectively exposing the biosensor surface to the body by using the contraction relaxation reaction of the electrosensitive polymer, it is possible to minimize the damage of the conventionally presented sensor surface to maximize the life of the implanted biosensor. For example, if the measurement of analyte is required every hour, exposing the biosensor for only one minute every hour can reduce the surface damage or malfunction of the sensor to 1/60 of the time compared to the case where the sensor surface is always exposed to blood or body fluids. As a result, the sensor's lifespan is 60 times longer than conventional implanted sensors. That is, according to the present invention, it is expected to provide a technology that can accelerate the commercialization of many existing implanted biosensors because the lifespan of the sensors can be significantly increased regardless of the operating principle of the biosensors.

The specific parts of the present invention have been described in detail above, and it is apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. something to do. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims

In the biosensor for the analysis of the concentration of analyte,

A bio-receptor capable of detecting the analyte to be analyzed;

A signal converter for converting the concentration information of the analyte detected from the bioreceptor into a signal that can be analyzed;

An electroactive polymer layer attached to the surface of the bioreceptor; And

An electrode connected to the electrosensitive polymer layer

Biosensor comprising a.
The biosensor of claim 1, wherein the electrosensitive polymer exhibits shrinkage relaxation behavior.
The biosensor of claim 2, wherein the electrically sensitive polymer is an artificial muscle material exhibiting shrinkage relaxation behavior.
The biosensor of claim 1, wherein the electrosensitive polymer is an electrosensitive hydrogel.
The biosensor of claim 1, wherein the biosensor is an implantable body.
The biosensor of claim 1, wherein the analyte is glucose.
A biosensor implanted into a patient's body, the biosensor capable of detecting analyte to be analyzed, a signal converter for converting concentration information of the analyte detected from the bioreceptor into a signal capable of analysis; A biosensor comprising an electroactive polymer layer attached to a surface of the bioreceptor and an electrode connected to the electrosensitive polymer layer;

Means for delivering an electrical stimulus to an electrode connected to the electrosensitive polymer of the biosensor;

Means for conveying concentration analysis information generated from the biosensor; And

Computer means for receiving and outputting concentration analysis information from the information transmitting means;

Analytical concentration analysis device using the implantable biosensor containing a body.
The apparatus of claim 7, wherein the biosensor is provided with a plurality of sensors according to the number of channels in which the analyte to be analyzed is present.
In the method using a biosensor implanted in the patient's body,

A bio-receptor capable of detecting analyte to be analyzed, a signal converter converting concentration information of the analyte detected from the bioreceptor into a signal capable of analysis; Providing a biosensor comprising an electroactive polymer layer attached to a surface of the bioreceptor and an electrode connected to the electrosensitive polymer layer;

Providing computer means coupled to the biosensor to output a concentration value of analyte as a data signal;

Implanting the biosensor into the patient's body and providing electrical stimulation to an electrode connected to the biosensory polymer layer of the biosensor; And

When the bioreceptor is exposed to the analyte by causing a reversible deformation of the electrosensitive polymer layer by the provided electrical stimulation, the concentration information of the analyte detected by the bioreceptor is received through the computer means, and the received concentration information is received. A method of using a biosensor implanted in the body of a patient comprising the step of reading the concentration value.
A bio-receptor capable of detecting analyte to be analyzed, a signal converter converting concentration information of the analyte detected from the bioreceptor into a signal capable of analysis; Providing a biosensor comprising an electroactive polymer layer attached to a surface of the bioreceptor and an electrode connected to the electrosensitive polymer layer;

Implanting the provided biosensor into the body of a patient;

Imparting selective electrical stimulation to an electrode connected to the electrosensitive polymer layer of the biosensor implanted into the body of the patient; And

A patient comprising the step of receiving concentration information of the analyte detected by the bioreceptor and reading the concentration value when the bioreceptor is exposed to the analyte by causing the electrosensitive polymer layer to be reversibly modified by the selective electric stimulation To selectively control the operation of a biosensor implanted in the body.
The method of claim 9 or 10, wherein the electrically sensitive polymer layer is characterized by using a material exhibiting shrinkage relaxation behavior by electrical stimulation.