KR20190000761A - Apparatus for micro-dialysis of interstitial fluid using electroosmotic pump and operating method thereof - Google Patents

Abstract

Provided is an interstitial fluid microdialysis apparatus based on an electroosmotic pump. The apparatus comprises: an electroosmotic pump which includes a first electrode and a second electrode provided on both sides of a membrane and a fluid path unit, and alternately generates suction force and discharge power by alternately supplying polarities of a voltage to the first and second electrodes; a first transfer line and a second transfer line which have one end coupled to the fluid path unit of the electroosmotic pump and alternately transfers the suction force and the discharge power to a perfusion fluid; a reservoir which stores the perfusion fluid and discharges the perfusion fluid along a discharge path inserted and coupled to the other end of the first transfer line; a micro-dialysis (MD) probe which including an inlet path which has one end injected into an object to perform microdialysis of an interstitial fluid, and is inserted into the other end of the second transfer line to insert the perfusion fluid, and a discharge path which discharges the perfusion fluid after the microdialysis; and a sensor which has a discharge path of the MD probe inserted and coupled to one side surface to inject the perfusion fluid after microdialysis through the discharge path and measures biometric information from the perfusion fluid after the microdialysis.

Description

TECHNICAL FIELD [0001] The present invention relates to an intra-cellular microdialysis device for microdialysis of intracellular fluid using an electroosmotic pump, and an operation method thereof. [0002]

The present invention relates to an intracellular microdialysis device for micro-dialysis of an interstitial fluid (ISF) using an electroosmosis pump and an operation method thereof.

Electroosmotic pump is an electroosmotic pump that uses fluid to move due to electroosmotic phenomenon when a voltage is applied to both ends of capillary or porous membrane by electrode. Unlike general pump, there is no mechanical moving part and noiseless , The flow rate can be effectively controlled in proportion to the applied voltage.

In the conventional electroosmotic pump, chemically stable platinum is used as an electrode material. When an aqueous solution is used as a fluid, oxygen gas is continuously generated by the oxidation reaction of water at the (+) electrode and water Hydrogen gas generated by the reduction reaction continuously occurs.

The movement of electrons and ions due to such oxidation and reduction reactions is an essential phenomenon for the continuous movement of fluid in an electroosmotic pump. In the case where the electroosmotic pump is implemented using the platinum electrode as described above, it is difficult to realize a stable flow rate due to the phenomenon that the gas generated by the above reaction is trapped in the small pores of the porous membrane, It is difficult to implement a closed-loop system because of the safety problem.

An electroosmotic pump that operates stably and safely without generating a gas is possible if the electrode material is constructed using a gas-free reaction. For example, when the silver / silver oxide electrode reaction is utilized, the oxidation reaction of silver occurs at the (+) electrode and the reduction reaction of silver oxide occurs at the (-) electrode. In this case, the electrode becomes a material participating in the electrode reaction. However, when such a consumable electrode is applied to an electroosmosis pump, there is a problem that the amount of fluid that can be transferred using the electroosmotic pump is limited due to a limited amount of electrode material.

Therefore, it has been difficult to stably transfer a large amount of fluid for a long period of time safely and safely without using a conventional osmosis pump. That is, the electroosmotic pump employing the consumable electrode reaction is suitable for moving a small amount of fluid in a disposable manner due to the electrode reaction that can be performed in this amount because the amount of the electrode active material is limited. However, And thus it is not suitable for moving the light source to the light source.

Meanwhile, the interstitial fluid in the body plays a very important role in the body, supplying nutrients and oxygen between blood vessels and tissues, and transporting waste and carbon dioxide back into the vein. Therefore, the intracellular fluid is very similar in composition to plasma and has various important information to diagnose the condition of the body. Therefore, it is possible to diagnose, test and monitor various types of cells using intercellular fluid.

In this way, intercellular fluid is one of the most direct test objects for diagnosis, and various studies are being conducted to extract intercellular fluid or to apply it to diagnosis by dialysis. In one study (Life Science. 2002, p 2457), intercellular fluid was dialyzed through polyimide polymeric fibers (MWCO 20 kDa, CMA 60) with an outer diameter of 0.64 mm, The concentration was measured. However, in this study report, there was a limitation in that the suction pump could not be miniaturized, and large scale and complex equipment was used. Another study (A. Merinari Diagnosis) developed a continuous glucose device that measures glucose levels through micro-dialysis under the name "GlucoMen® Day". However, this study also has a problem that the compatibility is low such as the size of the apparatus is increased by using a peristaltic pump.

United States Patent No. 8246541 entitled " Real-time microdialysis system "

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made to solve the above-mentioned problems of the prior art, and it is an object of the present invention to provide a method for microdialysis of intracellular fluid based on a microdialysis probe and a microelectronic osmotic pump, And to provide a microdialysis apparatus and an operation method thereof. It should be understood, however, that the technical scope of the present invention is not limited to the above-described technical problems, and other technical problems may exist.

According to an aspect of the present invention, there is provided a plasma display apparatus including a first electrode and a second electrode provided on both sides of a membrane, and a fluid path portion, An electric osmotic pump alternately generating a suction force and a discharge power as the polarities are alternately supplied; A first conveyance line and a second conveyance line, one end of which is connected to the fluid path portion of the electroosmosis pump to alternately deliver the suction force and the fold output to the perfusion fluid; A reservoir for storing the perfusion liquid and discharging the perfusion liquid along the discharge path inserted and coupled to the other end of the first transfer line; An MD probe having micro-dialyzed intercellular fluid once injected into the subject and inserted into the other end of the second transfer line to introduce the perfusion fluid and a discharge passage for discharging the perfusion fluid after the microdialysis -dialysis probe); An electroosmotic pump-based intracellular microdialysis device comprising a sensor for inserting a discharge passage of an MD probe into the one side and introducing a perfusion fluid after fine dialysis through a discharge passage and measuring biometric information from the perfusion fluid after microdialysis Lt; / RTI >

According to a second aspect of the present invention, there is provided a power supply apparatus comprising: a power supply unit; An electric osmotic pump for alternately generating a suction force and a discharge power; A porous polymeric fiber, and a needle, and a microdialysis device for introducing the perfusion fluid according to the repeated generation of the suction force and the discharge power of the electro-osmotic pump to perform microdialysis of the intercellular fluid and discharging the perfusion fluid after the microdialysis, dialysis probe); And a sensor for measuring biometric information from the perfusion fluid after fine dialysis. The present invention also provides an electroosmotic pump-based intracellular microdialysis device comprising: At this time, the electroosmotic pump includes a membrane and a first electrode and a second electrode, which are disposed on both sides of the membrane and allow movement of the fluid, and are formed of a porous material to allow movement of the fluid, The polarity of the voltage is alternately supplied to each of the first electrode and the second electrode, thereby alternately generating the suction force and the discharge power of the electroosmotic pump.

According to a third aspect of the present invention, there is provided a method of manufacturing a semiconductor device, comprising the steps of: (a) adjusting a pulse voltage and a pulse time corresponding to a calibration mode; (b) alternately supplying voltages of different polarities to the first and second electrodes of the electroosmotic pump to move the perfusion liquid to the microdialysis probe; (c) performing microdialysis in the microdialysis probe, and then measuring biometric information from the perfusion solution after microdialysis; (d) performing calibrating based on the measured biometric information if the flow rate of the perfusion fluid after fine dialysis exceeds a threshold value; (e) adjusting a pulse voltage and a pulse time corresponding to the measurement mode. At this time, if the flow rate of the perfusion liquid after the microdialysis in step (d) does not exceed the threshold, the method repeats steps (b) and (c).

A fourth aspect of the present invention provides a computer-readable recording medium on which a program for implementing the method of the third aspect is recorded.

According to the above-described object of the present invention, there is no mechanical moving part and noiseless sound is obtained by using an electroosmotic pump composed of a material in which both electrodes disposed on both sides of the membrane through which the fluid passes cause a reversible electrochemical reaction, The flow rate can be effectively controlled in proportion to the applied voltage. The suction power / drain output of the electroosmotic pump is effective because the intercellular fluid can be continuously microdialed. In addition, the flow rate in the device can be changed to effect microdialysis and gum / calibration together.

FIG. 1 illustrates an electroosmotic pump-based intercellular microdialysis device according to an embodiment of the present invention.
2A is a cross-sectional view of region A of FIG. 1 according to one embodiment of the present invention.
2B is a perspective view of the conveyance path portion according to an embodiment of the present invention
2C is a rear view of the conveyance path portion according to an embodiment of the present invention.
FIG. 2D shows the construction of an electroosmotic pump according to an embodiment of the present invention.
2E and 2F are views for explaining the operation principle of the electroosmosis pump according to an embodiment of the present invention.
FIG. 3 illustrates an example in which the fluid flow is changed according to the reversible electrochemical reaction of the electroosmotic pump according to an embodiment of the present invention.
4A is a cross-sectional view of region B of FIG. 1 according to one embodiment of the present invention.
4B shows a configuration of an MD probe according to an embodiment of the present invention.
4C is an example in which the sensor according to an embodiment of the present invention measures glucose concentration.
5A is a top view of the lower case.
5B and 5C are side views of the lower case, respectively.
6 is a schematic diagram showing a flow of a perfusion liquid in an intercellular fluid microdialysis apparatus according to an embodiment of the present invention.
FIG. 7 is a schematic diagram showing a flow of a perfusion liquid in an intercellular fluid microdialysis apparatus according to another embodiment of the present invention. FIG.
8 shows the configuration of a reservoir & waist bag of the intercellular fluid microdialysis apparatus of Fig.
9 is an example of an experimental result of measuring sugar concentration using an intercellular microdialysis device according to an embodiment of the present invention.
10 is an example of an experimental result obtained by performing an automatic test and calibration using an intercellular fluid microdialysis apparatus according to an embodiment of the present invention.
FIGS. 11 and 12 are a block diagram and a flowchart for explaining an operation of the intercellular microdialysis device according to an embodiment of the present invention to perform both calibrating and microdialysis.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, which will be readily apparent to those skilled in the art. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In order to clearly illustrate the present invention, parts not related to the description are omitted, and similar parts are denoted by like reference characters throughout the specification.

In the entire specification of the present invention, when a part is referred to as being "connected" to another part, it is not necessarily the case that it is "directly connected", but also "electrically connected" .

In the entire specification of the present invention, when a member is located on another member, this includes not only a case where a member is in contact with another member but also a case where another member exists between the two members.

Throughout the specification of the present invention, when a part is referred to as " including " an element, it is understood that it may include other elements as well, without excluding other elements unless specifically stated otherwise. The terms " about ", " substantially ", etc. used to the extent that they are used throughout the present disclosure are used in their numerical value or in close proximity to their numerical values when the manufacturing and material tolerances inherent in the stated meanings are presented, Accurate or absolute numbers are used to prevent unauthorized exploitation by unauthorized intruders of the referenced disclosure. The word " step (or step) " or " step " used in the specification of the present invention does not mean " step for.

FIG. 1 illustrates an intracellular fluid microdialysis apparatus based on an electroosmosis pump according to an embodiment of the present invention.

1, an electroosmotic pump-based intercellular microdialysis apparatus 10 according to an embodiment of the present invention includes various modules for microdialysis of intracellular fluid from an object.

1, an electroosmotic pump-based intercellular microdialysis apparatus 10 includes a micro-dialysis probe (hereinafter referred to as "MD probe") 11 for microdialysis of intercellular fluid, a reservoir 12 for storing perfusion fluid, an electroosmotic pump 13 for alternately generating a suction force and a discharge power by the electroosmosis phenomenon, A transfer path 14 including first and second transfer lines 14a and 14b for transferring microdialysis, a sensor 16 for sensing biometric information from the perfusion solution after microdialysis, and a waist for finally storing the perfusion solution after microdialysis And a waste-bag (17).

(Not shown) for controlling the operation of the intercellular microdialysis apparatus 10, a power supply unit (not shown) for supplying power to the components, And an upper case (not shown).

Hereinafter, the intercellular microdialysis system 10 will be divided into the A region consisting of the components for moving the perfusion solution before microdialysis and the B region composed of the components for moving the perfusion solution after microdialysis. At this time, the area A is composed of the reservoir 12, the electroosmotic pump 13 and the conveyance path part 14, and the area B is composed of the MD probe 11, the sensor 16 and the waste bag 17 . However, the A region and the B region are categorized for the convenience of explanation. The intercellular microdialysis apparatus 10 can be realized by mixing A and B regions, and the components of the A region and the B region are organically It should be understood by those skilled in the art that the present invention should be combined and operated.

First, the components contained in the region A and the movement of the perfusion fluid in the region A will be described in detail.

2A is a cross-sectional view of region A of Fig.

Referring to FIG. 2A, the reservoir 12 is a storage container for storing a perfusion liquid as a material that can be shielded against external gases and ions, and has a discharge passage 12a through which a perfusion liquid is discharged. Here, the perfusion liquid may be deionized water, but is not limited thereto.

The end of the discharge passage 12a is inserted into one end of the first transfer line 14a of the transfer path portion 14. [ At this time, a fastening member 42a is provided at one end face of the first conveyance line 14a and is fastened to the end of the discharge passage 12b. Meanwhile, an O-ring 43a is coupled to the fastening member 42a to prevent a gap. At this time, the O-ring 43a is a circular ring and may be composed of natural rubber, synthetic rubber, synthetic resin, or the like.

The perfusion liquid is discharged along the discharge path 12a by the suction force of the electroosmotic pump 13, which is transferred through the first transfer line 14a, and is moved to the first transfer line 14a.

The conveying path portion 14 is connected to the electroosmotic pump 13 at the other end thereof so that the suction force and the discharge power of the electroosmotic pump 13 are alternately transmitted to the fluid to be conveyed Transfer lines 14a and 14b. The conveying path portion 14 includes a case 14c for receiving and supporting the first and second conveying lines 14a and 14b and the first and second conveying lines 14a and 14b and the case 14c May be provided integrally.

Fig. 2B is a perspective view of the conveying path portion 14, and Fig. 2C is a rear view of the conveying path portion 14. Fig. 2B, openings (21 and 22 in FIG. 2B) for exposing one end of the first and second transfer lines 14a and 14b to the outside of the case 14c are provided on one surface of the case 14c, And the other end of the first and second transfer lines 14a and 14b is exposed on the other surface so that the other end of the first and second transfer lines 14a and 14b can engage with the fluid path portion of the electroosmotic pump 13 An opening (23 in Fig. 2C) is provided. The conveying path portion 14 and the electroosmotic pump 13 can be housed in the lower case 18 in a state where they are fastened to each other and the one end portion of the electroosmotic pump 13 and the other end portion of the conveying path portion 14 The end portions may include fastening means that can be coupled with each other. At this time, the electroosmotic pump 13 and the conveyance path unit 14 may be integrally provided.

First and second open / close devices (not shown) are provided at one end or both ends of the first and second transfer lines 14a and 14b of the transfer path unit 14 to open or close the fluid flow direction to allow or restrict the fluid flow direction . Such an opening / closing device (not shown) is synchronized with the suction force and the discharge output of the electroosmotic pump 13, and is opened / closed in the opposite direction so that the perfusion liquid of the reservoir 15 moves in one direction, and is illustratively a valve, more specifically, The check valve may be a check valve that allows the flow of the fluid only to the outside.

Specifically, when the suction force is generated in the electroosmotic pump 13, the first opening and closing device provided on the first conveying line 14a is opened and the second opening and closing device provided on the second conveying line 14b is blocked, The perfusion liquid is drawn into the first transfer line 14a and transferred to the electroosmotic pump 13. On the contrary, when a discharge power is generated in the electroosmotic pump 13, the first opening and closing device is shut off and the second opening and closing device is opened, and the perfusion liquid flows in the opposite direction through the second conveyance line 14b. Since the inlet 11a of the MD probe 11 is inserted and coupled at one end of the second transfer line 14b, the perfusion liquid is transferred to the MD probe 11 through the inlet path 11a.

2d to 2f are views for explaining the operation principle of the electroosmotic pump 13. Fig.

Referring to FIG. 2D, the electroosmotic pump 13 includes a membrane 203, a first electrode 201 and a second electrode 202 provided on both sides of the membrane 203, and each electrode 201 202 for supplying power to the electrodes 201, 202, respectively. The strips 204 and 205 are provided with connecting members 204a and 205a to a power supply unit (not shown) to transmit power supplied from a power supply unit (not shown) to the electrodes 201 and 202.

The electroosmotic pump 13 generates a suction force and an abdomen output through fluid flow between the membrane 203 and the first and second electrodes 201, 202.

Specifically, the membrane 203 is installed in the fluid path portion 209 through which the fluid moves, and is formed of a porous material or structure to allow the fluid to move. Illustratively, membrane 203 may be fabricated using, but not limited to, silica, glass, or the like, in the form of particulate matter having a size of from about 0.1 microns to about 5 microns. Also, illustratively, the membrane 203 may be a disk membrane, a membrane electrode assembly (MEA), or may have various other porous materials or structures.

The first electrode 201 and the second electrode 202 are provided on both sides of the membrane 203 on the fluid path portion 209. The first electrode 201 and the second electrode 202 are formed by mixing an anionic polymer Based conductive polymer. In addition, the first electrode 201 and the second electrode 202 are kept constant in spacing by the membrane 203. Like the membrane 203, the first electrode 201 and the second electrode 202 are formed of a porous material or structure to allow movement of the fluid.

When a voltage is applied to each of the electrodes 201 and 202, a redox reaction is caused between the first electrode 201 and the second electrode 202 due to a voltage difference between the first electrode 201 and the second electrode 202 And the charge balance is broken. At this time, the positive ions are moved in the electrode to balance the charge. At this time, any one of the first electrode 201 and the second electrode 202 may generate positive ions through the electrochemical reaction, and the other may consume the positive ions. The cation generated during the electrochemical reaction may be a monovalent cation, but the present invention is not limited thereto. It may include various ions such as hydrogen ion (H +), sodium ion (Na +), potassium ion (K + have.

The fluid can be moved along the fluid path portion 209 when the ions are moved through the membrane 203 in accordance with the oxidation-reduction reaction. Membrane 203 may allow movement of ions as well as fluids. Accordingly, as shown in FIG. 2E, the fluid and ions can be moved from one side of the membrane 203 to the other, or from one side to the other, when the electrodes 201 and 202 are supplied with power.

The conductive polymer may be electrodeposited on the first electrode 201 and the second electrode 202. Since the electroosmotic pump 13 includes a large anion polymer, that is, an anionic polymer, the anion polymer can not be fixed and moved during the redox reaction of the electrodes 201 and 202, And balance the charge. That is, when the conductive polymer matrix is neutralized during the reduction reaction of the (-) electrode, the cation existing in the fluid is mixed in order to balance the charge of the fixed anion polymer. In other words, during the redox reaction of the electrodes 201 and 202, the anionic polymer does not move but the cations in the fluid move. These cations can cause a rapid oxidation / reduction reaction since the negatively charged membrane 203 can be easily attracted to the membrane 203 by the attraction force. This means that the electroosmotic pump 13 can move the fluid at a high speed.

At this time, the conductive polymer may be formed through the polymerization of monomers in a fluid containing an anionic polymer. For example, when a monomer is oxidized in a fluid in which an anionic polymer is present, the anionic polymer in the fluid is mixed and the polymerization reaction proceeds, so that a polymer complex composed of a cationic polymer-anionic polymer can be synthesized. Alternatively, the conductive polymer may be synthesized through electrochemical oxidation or chemical oxidation using an oxidizing agent. In addition, the conductive polymer may be a variety of polymers having electrical conductivity or negatively charged.

In addition, the electrodes 201 and 202 may further include a carbon nanostructure. The carbon nanostructure may include, but is not limited to, carbon nanotubes (CNTs), graphenes, carbon nanoparticles, fullerenes, graphite, and the like. In an electrode in which a complex of a conductive polymer containing carbon nanotubes among carbon nanostructures is electrodeposited, a redox reaction can be more stably and rapidly performed.

Meanwhile, the conductive polymer included in the first electrode 201 and the second electrode 202 may cause a reversible electrochemical reaction. That is, both the first electrode 201 and the second electrode 202 may have both a forward reaction and a reverse reaction. The reversible electrode reaction of the electroosmotic pump 13 can be achieved by alternately supplying a voltage polarity to each of the first electrode 201 and the second electrode 202 by a power supply unit (not shown).

FIG. 2F shows an example in which the flow of the fluid is changed in accordance with the reversible electrochemical reaction. The positive electrode is supplied to the first electrode 201 and the negative electrode is supplied to the second electrode 202 as shown in FIG. (-) electrode (that is, the second electrode 202) from the first electrode 201 to the negative electrode (second electrode 202) (I.e., the first electrode 201) from the positive electrode (that is, the second electrode 202) to the positive electrode (i.e., the first electrode 201) by supplying the positive electrode to the second electrode 202, .

In addition, the first electrode 201 and the second electrode 202 can change the fluid flow by utilizing an electrode material that performs a reversible electrode reaction. In addition, as the electrode reaction occurs in the opposite direction, The active material can be returned to its original state. Thus, the life of the electroosmotic pump 13 can be increased by repeating the consumption and the regeneration of the electrodes 201, 202.

The power supply unit (not shown) supplies a DC voltage to each of the first electrode 201 and the second electrode 202 in order to alternately supply the polarity of the voltage. (Not shown) for alternating the polarity of the DC voltage supplied to the switches 202 and 203 at predetermined time intervals. Accordingly, the voltage applied to each of the first electrode 201 and the second electrode 202 can be continuously changed to the opposite polarity every predetermined time. However, the present invention is not limited to the above-described example, and the power supply unit (not shown) may be implemented with an alternating current supplying device (not shown) supplying a stirring current at a constant cycle.

The suction force and the discharge power are alternately generated in the electroosmotic pump 13 by the movement of the fluid as described above and the generated suction force and the discharge power are transmitted to the conveyance path portion 14 fastened to the electroosmotic pump 13 Thereby moving the perfusion liquid. At this time, the electroosmotic pump 13 includes an insulator (206 in Fig. 2D) for separating the fluid and the perfusion liquid. Referring to FIG. 2D, the separator 206 separates a space containing the fluid and a space through which the perfusion liquid moves so that the fluid and the perfusion liquid are prevented from being mixed, and the suction force and the discharge power, Effectively. Such an isolation material may include diaphragms, polymer membranes, sliders, and the like, such as rubber or metal plate made of an oil for forming an oil gap or a thin film having elasticity, as a non-limiting example. An isolation material 207 and a cover 208 are also provided at the other end of the electroosmotic pump 13 to prevent the fluid in the fluid path portion 209 from flowing out to the outside.

FIG. 3 is a view for explaining the principle in which the perfusion liquid is moved in one direction through the suction force and the fold output of the electroosmosis pump 13 according to an embodiment of the present invention.

3, a negative (-) voltage is applied to the first electrode 201 located on the upper side of the electroosmosis pump 13 in FIG. 3 of the electroosmosis pump 13, a negative (+) voltage is applied to the second electrode 202 located on the lower side, A suction force is generated. By this suction force, the perfusion liquid is moved in the direction (1). At this time, the second opening and closing device of the second conveying line 14b is shut off and the suction force is not transmitted to the second conveying line 14b.

On the contrary, when a positive voltage is applied to the first electrode 201 located on the upper side of the electroosmosis pump 13 and a negative voltage is applied to the second electrode 202 located on the lower side, reversible electrochemical reactions A multiplication output in the opposite direction is generated. Therefore, the perfusion liquid drawn into the electroosmotic pump 13 is moved in the direction (2) through the second transfer line 14b. At this time, the first opening and closing device of the first conveying line 14a is cut off so that the folding output is not transmitted to the first conveying line 14a. Therefore, the perfusion liquid moved in the direction 2 is moved to the MD probe 11 along the inlet path 11a of the MD probe 11.

Hereinafter, the configuration and operation of the MD probe 11, the sensor 16, and the waste bag 17 arranged in the region B of Fig. 1 will be described in detail.

4A is a cross-sectional view of the region B in Fig.

First, the MD probe 11 is infiltrated into a subject once, and the intracellular fluid is microdialyzed. The MD probe 11 is supplied with an inlet 11a into which a perfusion liquid is introduced and a perfusion fluid after microdialysis (that is, And a discharge outlet 11b through which the gas is discharged. At this time, the inlet passage 11a is fastened to one end face of the second conveyance line 14b of the conveyance path portion 14. Referring to FIG. 2A again, the end of the inlet passage 11a is inserted into the end surface of the second transfer line 14b, and the one end surface of the second transfer line 14b is provided with a fastening member 42b, And is fastened to the end of the inlet passage 11a. In addition, an O-ring 43b is coupled to the fastening member 42b to prevent a gap.

The end of the discharge passage 11b is inserted into one side of the sensor 16 and inserted into the sensor 16. At this time, a fastening device may be provided at one end of the discharge passage 11b and at the sensor 16 side.

One end of the MD probe 11 is formed of a porous polymer fiber and / or a needle, and is exposed to the outside through the lower case 19 so as to be injected into a target body (see FIGS. 5B and 5C). Illustratively, MD probe 11 can be exposed over the dermal layer of the skin depth (e.g., 637 u than m) a predetermined length (e.g., 0.1 ~ 10cm) to be introduced into the outside of the lower case 18 .

In the corresponding part, intercellular fluid is microdialyzed. Fig. 4B shows the configuration of the MD probe 11. Fig. Referring to FIG. 4B, each of the inlet passage 11a and the discharge passage 11b of the MD probe 11 is fastened to the first tube 411 and the second tube 412.

One end of the first tube 411 is fastened to the inlet passage 11a and the other end is connected to one end of the second tube 412 at the end of the MD probe 11. Accordingly, the perfusion liquid drawn into the first tube 411 through the inlet passage 11a is moved to the second tube 412. [ At this time, the movement of the perfusion liquid is caused by the repetition of the suction force and the discharge power of the electroosmotic pump 13 alternately.

The second tube 412 is connected to the first tube 411 at the end of the MD probe 11 and the outer surface of the second tube 412 is formed of a semi-permeable membrane 403 And contacts the object. At this time, the semi-permeable membrane includes pores capable of moving fluids / ions and can be dialyzed to several to several ten kDa depending on the size of pores. In the second tube 32, the intercellular fluid in the subject is diffused into the second tube 412 and diluted in the perfusion liquid due to the difference in concentration between the inside and the outside of the semipermeable membrane.

Illustratively, the semi-permeable membrane is made of a cellulose series such as cellulose acetate, cellulose diacetate, Cuprophan, Hemophan, etc., polysulfone, polyacrylonitrile Polyacrylonitrile, PAN-methyl sulfonate, polymethyl methacrylate, sulphonated polysulphone, polyamide, polycarbonate, polyvinyl sulphide poly vinyl sulfide, polytetrafluoroethylene (PTFE), polyamine, poly ethylene oxide, polyethersulfone, poly styrene sulfonate, polyacrylic acid polyacrylic acid polyacrylic acid, polyvinyl sulfonate or poly (acrylamide-2-methyl-propanesulfonate) 2-methyl-propanesulfonate), but the present invention is not limited thereto.

On the other hand, the perfusion liquid after fine dialysis is moved through the discharge passage 11b and enters the sensor 16. Thereafter, the perfusion liquid after the microdialysis is finally stored in the waste bag 17 via the sensor 16.

The waste bag 17 is constituted of a storage container for storing the perfusion solution after microdialysis as a material which can be shielded against external gases and ions, and is received and supported by the waste bag case 17b. At this time, the waste bag case 17b is provided with a hollow in which the sensor 16 can be housed, so that the inflow path 17d of the waste bag 17 is stably inserted into the other side surface of the sensor 16 . On the other hand, the sensor 16 and the waste bag 17 may be integrally formed.

As described above, the sensor 16 has the discharge path 11b of the MD probe 11 inserted into one side and the insertion path 17d of the waste bag 17 inserted into the other side, And is accommodated and supported in the back case 17b. Meanwhile, the waste back case 17b may further contain a PCB (printed circuit board) 19 in which the control circuit 401 and the power supply unit 402 are housed.

The sensor 16 measures biometric information from the perfusion fluid. At this time, the measured biometric information may vary depending on the sensor 16, and may be, for example, sugar concentration, lactic acid concentration, and the like, but is not limited thereto.

4C is a diagram for explaining a case of measuring the sugar concentration as an example of the sensor 16.

4C, the sensor 16 includes a reaction chamber 16e through which the perfusion liquid flows after microdialysis, a reference electrode (for example, Ag / AgCl) 16a provided so as to contact the perfusion liquid in the reaction chamber 16e, And a counter electrode (e.g., Pt) 16c, and an insulating film 16b is disposed between the electrodes. At this time, one end face of each electrode is in contact with the conductive member 403 disposed on one side of the sensor 16, and the conductive member 403 is supplied with the voltage supplied through the power supply unit 402. The conductive member 403 may be a conductive rubber, but is not limited thereto.

When the voltage is swept, the reference electrode 16a serves as a reference for reading the potential change of the working electrode. The counter electrode 16c is a path through which electrons flow by adjusting the potential. Here, the potential of the open circuit is a constant potential difference formed by the intrinsic characteristics of the protein thin film and the intrinsic properties of the electrolyte, in the state where no voltage is applied, a kind of circuit is cut off and a system constituted naturally has a specific potential reaching equilibrium . Using this principle in reverse, applying the open-circuit potential to the system when the open-circuit potential of a particular system is known allows the system to artificially approach the equilibrium state. That is, when a specific reduction potential is applied to the protein thin film and the protein thin film is reduced by receiving electrons from the electrolyte, if the open circuit potential is applied thereto, the protein thin film returns to the original natural equilibrium state, . On the other hand, when the protein thin film is oxidized by emitting electrons, when the open-circuit potential is applied, the electrons flowing back are returned to the original potential state. The sensor 16 can measure the sugar concentration in the perfusion liquid by measuring the amount of current in accordance with the change in the potential state. The sugar concentration thus measured is transmitted to the control circuit 401.

On the other hand, the sensor 16 may further include a glucose sensing film 16d formed in the expression of the reference electrode 16a, but is not essential.

5A is a top view of the lower case 18, and Figs. 5B and 5C are side views of the lower case 18. Fig.

5A to 5C, the lower case 18 includes a plurality of openings for accommodating the MD probe 11, the electroosmotic pump 13, the conveyance path portion 14, and the reservoir 15, (That is, a discharge path 12b of the reservoir 12), an inlet path of the MD probe 11 (an outlet path of the reservoir 12, 11a and the discharge passage 11b). The lower case 18 also includes a hole 506 through which one end of the MD probe 11 (i.e., the porous polymer fibers and / or the needle) can be inserted. The waste bag 17 is fitted to the bottom surface of the lower case 18 and the lower case 18 includes a support 508 for supporting the waste bag 17.

Further, the lower case 18 includes a fastening portion 37 that can be fitted to an upper case (not shown).

The intercellular microdialysis apparatus 10 may further include a USB port capable of outputting information processed by the control circuit 401 to the outside, and the lower case 18 may include a USB port (Fig. 5C).

FIG. 6 is a schematic diagram showing the flow of perfusion liquid in the intercellular fluid microdialysis apparatus 10 described above with reference to FIGS. 1 to 5. FIG.

Referring to FIG. 6, the short dashed line shown in FIG. 6 represents the perfusion fluid movement before microdialysis, and the long dotted line represents the perfusion fluid movement after microdialysis. As the suction force and the discharge power of the electroosmotic pump 13 are alternately generated, the perfusion liquid of the reservoir 12 is transferred to the MD probe 11 through the electroosmotic pump 13, and in the MD probe 11, Lt; RTI ID = 0.0 > intercellular < / RTI > That is, the intercellular fluid of the subject diffuses into the MD probe 11 and is diluted with the perfusion liquid, and the perfusion fluid after the microdialysis moves to the waist bag 17 via the sensor 16.

FIG. 7 is a schematic diagram showing the flow of perfusion liquid in the intercellular fluid microdialysis apparatus 10a according to another embodiment of the present invention.

Referring to FIG. 7, the reservoir and the waste bag may be different spaces separated by the flexible film in one storage space. That is, the reservoir and the waste bag can be integrally implemented. Since a minute amount of intracellular fluid is mixed with the perfusion solution by microdialysis, the flow rate in the intercellular fluid microdialysis device 10a does not change greatly. Therefore, as shown in FIG. 7, it is possible to combine the reservoir and the waste bag in an integrated manner, thereby making it possible to further miniaturize the intracellular microdialysis apparatus 10a.

Illustratively, the reservoir & waist bag 70 has different storage spaces (the first storage space and the first storage space) defined by the flexible film 70a provided therein, as shown in FIG. 8 The perfusion fluid before fine dialysis is stored in the first storage space, and the perfusion fluid after fine dialysis is stored in the second storage space. In the initial stage of driving, the first storage space storing the perfusion solution before fine dialysis occupies most of the volume of the reservoir & waist bag 70, but as the driving progresses, the perfusion solution after fine dialysis gradually increases, The volume decreases and the volume of the second storage space increases. The flexible film 70a is flexibly deformed as the volume of each storage space changes.

On the other hand, the flow rate of the perfusion liquid can be adjusted by adjusting the cycle of repeating the suction and discharge of the electroosmotic pump 13. Illustratively, the control circuit 401 can adjust the suction and discharge cycles by changing the pulse voltage and pulse time applied to the electroosmotic pump 13. Accordingly, the intracellular microdialysis apparatus 10 can adjust the flow rate of the perfusate, adjust the dialysis amount (i.e., the amount of intercellular fluid diffusion), and further calibrate itself.

The microdialysis in the MD probe 11 is greatly influenced by the flow rate of the perfusion liquid. Therefore, when the flow velocity is increased, the degree of the concentration in the MD probe 11 reaching equilibrium becomes extremely low, and the perfusion liquid itself (that is, the perfusion liquid not diluted in the intracellular fluid) is moved to the discharge passage 11b. Since the perfusate thus moved is introduced into the sensor 16, the intercellular microdialysis device 10 can perform the calibrating based on the concentration of the perfusate itself measured. In addition, it is possible to determine the degree of flow rate suitable for dialysis.

Thereafter, the intracellular microdialysis unit 10 can slow down the flow rate and microdialysis the intercellular fluid. Thus, the intracellular fluid microdialysis apparatus 10 according to the embodiment of the present invention can perform the calibration and the microdialysis together by adjusting the flow velocity, thereby efficiently measuring the biometric information of the subject.

9 is an example of an experimental result of measuring biometric information (glucose concentration) using the intercellular fluid microdialysis apparatus 10 according to an embodiment of the present invention.

In FIG. 9, the electroosmotic pump for the experiment uses a carbon electrode oxidized as an electrode, and a membrane made by pressing silica nanoparticles as a porous membrane. A commercially available MD probe (CMA 11) having a length of 18 mm, an outer diameter of 0.24 mm and a cuprophane material which does not transmit molecules of 6 kDa or more was used as a dialysis part (one end of the MD probe) Artificial interstitial fluid made by dissolving glucose in physiological saline was used as a dialysis target. Deionized water was used as a perfusion solution.

As an implementation method, the MD probe was immersed in the artificial intracellular fluid, and then the electroosmotic pump was repeatedly applied with 2.5 V for 5 seconds once every 2 minutes to flow the infusion liquid through the inlet and outlet As a result, it was confirmed that glucose concentration of peritoneal fluid after microdialysis changes according to glucose concentration in interstitial fluid. Such an electroosmotic pump can be used for microdialysis.

10 is an example of an experimental result obtained by performing an automatic test and calibration using an intercellular fluid microdialysis apparatus according to an embodiment of the present invention.

In the experiment of FIG. 10, microdialysis was performed from the artificial intracellular fluid while controlling the flow rate of the perfusion liquid using the MD probe (i.e., CMA 11) as in the experiment of FIG. In this case, a syringe pump was used to adjust the flow rate.

In the experiment of Fig. 10, it can be confirmed that the concentration of the perfusion liquid shows a correlation with the sugar concentration of the artificial intracellular fluid as in Fig. The higher the flow rate, the lower the sugar concentration equilibrium, and it was confirmed that the sugar concentration reached equilibrium only at a very low level of 15% or less at a flow rate of about 6 μL / min or more.

In the case of the electroosmotic pump used in this experiment, a flow rate of about 6-10 μL / min can be achieved. Therefore, by adjusting the flow rate using an electroosmotic pump, it is possible to perform calibration by measuring the sugar concentration of the perfusate at a high flow rate while measuring the glucose concentration by microdialysis at a slow flow rate.

FIGS. 11 and 12 show a block diagram and a flowchart for explaining the operation in which the intercellular microdialysis device 10 according to an embodiment of the present invention performs the calibration and the microdialysis together.

First, the control circuit 401 adjusts the pulse voltage and the pulse time supplied to the power supply unit 402 in accordance with the calibration mode (S1200). At this time, the pulse voltage and the pulse time can be shortened by adjusting the pulse voltage so that the flow rate of the perfusion liquid in the intercellular microdialysis device 10 is increased (about 6-10 μL / min).

Subsequently, the control circuit 401 alternately supplies voltages of different polarities to the first electrode 201 and the second electrode 202 of the electroosmosis pump 13 based on the adjusted pulse voltage and pulse time , The perfusion liquid is moved (S1210).

Illustratively, the control circuit 401 controls the power supply 402 so that the negative voltage is applied to the first electrode 201 of the electroosmosis pump 13, the positive voltage (+) voltage is applied to the second electrode 202, . The positive ions are moved by the electrochemical reaction between the first electrode 201 and the second electrode 202 and the positive osmotic pump 13 is driven by the positive electrode (that is, the second electrode 202) -) electrode (i.e., the first electrode 201). Then, the control circuit 401 applies a (+) voltage to the first electrode 201 of the electroosmosis pump 13 and a negative (-) voltage to the second electrode 202. Thus, a reversible electrochemical reaction is induced in the first and second electrodes 201 and 202. Therefore, positive ions move in the electroosmotic pump 13 in the direction opposite to that in S1210, which generates a discharge power for moving the fluid from the first electrode 201 to the second electrode 202. [

As the suction force and the drainage output are generated, the perfusion liquid of the reservoir 12 is drawn into the inlet passage 11a of the MD probe 11 through the conveying path portion 14 and the electroosmotic pump 13. At this time, the first and second open / close devices provided on the first and second transfer lines 14a and 14b of the transfer path unit 14 act in opposite directions.

Thereafter, the perfusion liquid drawn into the MD probe 11 is moved to the lower end of the MD probe 11 injected into the subject and is microdialyzed.

The perfusion liquid after fine dialysis is transferred to the sensor 16 through the discharge path 11b of the MD probe 11. [ In the sensor 16, under the control of the control circuit 401, the biometric information (for example, glucose concentration) is measured based on the electrochemical detection method (S1230).

At this time, if the flow velocity of the perfusion liquid is high, the degree of concentration in the MD probe 11 reaching equilibrium becomes extremely low, and the perfusion liquid itself moves to the sensor 16 via the discharge passage 11b. Therefore, when the flow velocity of the perfusion liquid exceeds the threshold value (for example, 6 L / min) in step S1240, the control circuit 401 recognizes the calibration mode and performs calibration based on the biometric information measured by the sensor 16 (S1250).

Thereafter, the control circuit 401 adjusts the pulse voltage and the pulse time supplied to the power supply unit 402 in response to the measurement mode (S1260). That is, the control circuit 401 can adjust the pulse voltage and the pulse time so as to reduce the flow rate of the perfusion liquid in the intercellular fluid microdialysis device 10 to a degree that can be microdialyzed. To this end, the control circuit 401 down-adjusts the pulse voltage and extends the pulse time.

However, if the flow velocity of the perfusion liquid is less than the threshold value in step S1240, the control circuit 401 recognizes the measurement mode, stores the biometric information measured by the sensor 16 in a memory (not shown) or performs monitoring / analysis , Voltages of different polarities may be alternately supplied to the first electrode 201 and the second electrode 202 of the electroosmosis pump 13 repeatedly (S1210).

The intercellular fluidic microdialysis apparatus and its operation method according to an embodiment of the present invention described above may be implemented in the form of a recording medium including instructions executable by a computer such as a program module executed by a computer . Computer readable media can be any available media that can be accessed by a computer and includes both volatile and nonvolatile media, removable and non-removable media. The computer-readable medium may also include computer storage media. Computer storage media includes both volatile and nonvolatile, removable and non-removable media implemented in any method or technology for storage of information such as computer readable instructions, data structures, program modules or other data.

While the systems and methods of the present invention have been described with reference to particular embodiments, some or all of their components or operations may be implemented using a computer system having a general purpose hardware architecture.

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive. For example, each component described as a single entity may be distributed and implemented, and components described as being distributed may also be implemented in a combined form.

The scope of the present invention is defined by the appended claims rather than the detailed description and all changes or modifications derived from the meaning and scope of the claims and their equivalents are to be construed as being included within the scope of the present invention do.

10: Intracellular microdialysis device
11: MD-probe (micro-dialysis probe)
11a: MD probe inlet path 11b: MD probe outlet path
12: reservoir 12a: reservoir discharging path
13: Electrolytic pump 14: Feed path part
14a: first conveyance line 14b: second conveyance line
14c: Feed line case
16: sensor 17: waste-bag
17b: waist bag case 17d: waist bag inflow path
18: Lower case
19: printed circuit board (PCB)
43a, b: Oring,
201, 202: electrode 203: membrane,
70: Reservoir & waste-bag

Claims (29)

In an intercellular microdialysis device based on an electroosmotic pump,
A first electrode and a second electrode provided on both sides of a membrane, and a fluid path portion, wherein polarities of voltages are alternately supplied to the first and second electrodes, ;
A first transfer line and a second transfer line, one end of which is connected to the fluid path portion of the electroosmotic pump to alternately deliver the suction force and the discharge power to the perfusion fluid;
A reservoir for storing the perfusion liquid and discharging the perfusion liquid along an exit passage inserted and coupled to the other end of the first transfer line;
An MD probe which comprises an inlet for once injecting the additional substance into the subject to perform microdialysis of the intercellular fluid and inserted into the other end of the second transfer line to draw the perfusion fluid and a discharge passage for discharging the perfusion fluid after fine dialysis (micro-dialysis probe); And
And a sensor for inserting a discharge passage of the MD probe into the one side and introducing the perfusion liquid after the microdialysis through the discharge passage and measuring biometric information from the perfusion liquid after the microdialysis. The method according to claim 1,
The intercellular microdialysis device
Further comprising a waste bag which is inserted into the other side of the sensor so as to draw in and store the perfusion solution after the microdialysis. 3. The method of claim 2,
Wherein the sensor is housed in a hollow formed in a waste back case in which the waist bag is received and supported. 3. The method of claim 2,
Wherein the reservoir and the waste bag are different spaces separated by a flexible membrane in one storage space. The method according to claim 1,
The inlet and outlet passages of the MD probe are respectively connected to a first tube and a second tube,
Wherein the first tube and the second tube are interconnected at an end of the MD probe. 6. The method of claim 5,
Wherein the outer surface of the second tube contacting the subject is formed as a semi-permeable membrane. The method according to claim 1,
The sensor includes a reaction chamber through which the perfusion liquid flows after the microdialysis, a counter electrode, a reference electrode, and an insulator,
Wherein one end face of the counter electrode and the reference electrode contacts a conductive member and is supplied with a voltage through the conductive member. The method according to claim 1,
The first and second electrodes are formed of a porous material to allow movement of the fluid,
The electroosmotic pump
Further comprising an isolation material for separating the fluid and the perfusion liquid. The method according to claim 1,
The electroosmotic pump
Further comprising a strip for storing the first and second electrodes and delivering power to the first and second electrodes, respectively. The method according to claim 1,
Wherein the first transfer line and the second transfer line are respectively provided with a first opening / closing device and a second opening / closing device for allowing or blocking the flow of the fluid,
Wherein the opening and closing of the first opening and closing device and the opening and closing of the second opening and closing device are opposite to each other. The method according to claim 1,
Wherein the first transfer line and the second transfer line are check valves. In an intercellular microdialysis device based on an electroosmotic pump,
Power supply;
An electric osmotic pump for alternately generating a suction force and a discharge power;
A porous polymeric fiber, and a needle, wherein the permeation fluid is drawn in accordance with the repeated generation of the suction force and the discharge power of the electroosmotic pump to perform microdialysis of the intercellular fluid and discharging the perfusion fluid after the microdialysis -dialysis probe); And
And a sensor for measuring biometric information from the perfusion solution after the microdialysis,
The electroosmotic pump comprises:
A first electrode and a second electrode disposed on both sides of the membrane, the first electrode and the second electrode being made of a porous material to allow movement of the fluid,
The power supply unit,
Wherein a polarity of a voltage is alternately supplied to each of the first electrode and the second electrode so that a suction force and a discharge power of the electric osmotic pump are alternately generated. 13. The method of claim 12,
The intercellular microdialysis device
A reservoir for storing the perfusion fluid and discharging the perfusion fluid by a suction force of the electroosmotic pump; And
Further comprising a waste-bag connected to the sensor for finally storing the perfusion solution after the microdialysis moved from the sensor. 14. The method of claim 13,
The intercellular microdialysis device
A first transfer line connected to the fluid path portion of the electroosmotic pump and connected to the reservoir and the MD probe at the other end to alternately transfer the suction force and the discharge power of the electroosmosis pump to the perfusion liquid, A second transfer line,
Wherein the first transfer line and the second transfer line each include a first opening and closing device and a second opening and closing device that are opened or closed to permit or restrict fluid flow so that the perfusion liquid moves in one direction. Device. 15. The method of claim 14,
Wherein the opening and closing of the first opening and closing device and the opening and closing of the second opening and closing device are opposite to each other. 16. The method of claim 15,
Wherein when the suction force is generated in the electroosmotic pump, the first opening and closing device is opened and the second opening and closing device is closed so that the perfusion liquid is moved from the reservoir to the electroosmotic pump through the first transfer line Intracellular microdialysis device. 16. The method of claim 15,
The first opening and closing device is closed and the second opening and closing device is opened so that the perfusion liquid is moved from the electroosmotic pump to the MD probe through the second transfer line when the discharge output is generated in the electroosmotic pump An intracellular sodium microdialysis device. 13. The method of claim 12,
The intercellular microdialysis device
Further comprising a control circuit,
The control circuit
Wherein the pulse voltage and the pulse time applied to the electroosmotic pump are adjusted. 19. The method of claim 18,
The control circuit
Adjusting the pulse voltage applied to the electroosmotic pump upward, shortening the pulse time, increasing the flow rate of the perfusion liquid to perform calibrating,
Wherein the pulse voltage applied to the electroosmotic pump is adjusted downward and the pulse time is extended to reduce the flow rate of the perfusion liquid to micro-dialyze the intracellular fluid. 13. The method of claim 12,
The suction force and the discharge power
Wherein the second electrode is formed by reversible electrochemical reaction at the first electrode and the second electrode,
Wherein the reversible electrochemical reaction of the first electrode and the second electrode occurs by moving the cation in a direction in which charge balance is achieved. 21. The method of claim 20,
Wherein the first electrode and the second electrode are repeatedly consumed and regenerated by the reversible electrochemical reaction. 13. The method of claim 12,
Wherein the first electrode and the second electrode comprise a conductive polymer having an anionic polymer incorporated therein. 13. The method of claim 12,
Wherein the first electrode and the second electrode comprise carbon nanostructures. A method of operating an intercellular microdialysis device based on an electroosmotic pump,
(a) adjusting a pulse voltage and a pulse time corresponding to the calibration mode;
(b) alternately supplying voltages of different polarities to the first electrode and the second electrode of the electroosmotic pump to move the perfusion liquid to a micro-dialysis probe;
(c) performing microdialysis in the microdialysis probe, and then measuring biometric information from the perfusion solution after microdialysis;
(d) performing calibrating based on the measured biometric information if the flow rate of the perfusion liquid after the microdialysis exceeds a threshold value; And
(e) adjusting the pulse voltage and pulse time corresponding to the measurement mode,
In the step (d), if the flow rate of the perfusion solution after the microdialysis does not exceed the threshold value, the steps (b) and (c) are repeated. 25. The method of claim 24,
In the step (a)
Wherein the pulse voltage is adjusted upward and the pulse time is shortened. 25. The method of claim 24,
In the step (e)
Wherein the pulse voltage is adjusted downward and the pulse time is extended. 25. The method of claim 24,
Wherein a reversible electrochemical reaction occurs at the first electrode and the second electrode. 28. The method of claim 27,
Wherein the reversible electrochemical reaction causes each of the first electrode and the second electrode to be repeatedly consumed and regenerated. 28. A computer-readable recording medium on which a program for implementing the method of any one of claims 24 to 28 is recorded.

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