WO2019054727A1 - Dispositif de microdialyse de liquide intercellulaire pour la microdialyse de liquide intercellulaire à l'aide d'une pompe électro-osmotique, et son procédé de fonctionnement - Google Patents

Dispositif de microdialyse de liquide intercellulaire pour la microdialyse de liquide intercellulaire à l'aide d'une pompe électro-osmotique, et son procédé de fonctionnement Download PDF

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WO2019054727A1
WO2019054727A1 PCT/KR2018/010634 KR2018010634W WO2019054727A1 WO 2019054727 A1 WO2019054727 A1 WO 2019054727A1 KR 2018010634 W KR2018010634 W KR 2018010634W WO 2019054727 A1 WO2019054727 A1 WO 2019054727A1
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electrode
microdialysis
fluid
electroosmotic pump
perfusion
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PCT/KR2018/010634
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English (en)
Korean (ko)
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신운섭
김석준
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서강대학교산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14525—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using microdialysis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue

Definitions

  • 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.
  • ISF interstitial fluid
  • 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.
  • 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.
  • 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.
  • the electrode material is constructed using a gas-free reaction.
  • the oxidation reaction of silver occurs at the (+) electrode and the reduction reaction of silver oxide occurs at the (-) electrode.
  • the electrode becomes a material participating in the electrode reaction.
  • the amount of fluid that can be transferred using the electroosmotic pump is limited due to a limited amount of electrode material.
  • 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.
  • the electrode reaction that can be performed in this amount because the amount of the electrode active material is limited.
  • it is not suitable for moving the light source to the light source.
  • 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.
  • 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.
  • 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.
  • MWCO 20 kDa, CMA 60 polyimide polymeric fibers
  • CMA 60 polyimide polymeric fibers
  • the concentration was measured.
  • 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".
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • FIG. 1 illustrates an electroosmotic pump-based intercellular microdialysis device according to an embodiment of the present invention.
  • FIG. 2A is a cross-sectional view of region A of FIG. 1 according to one embodiment of the present invention.
  • FIG. 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.
  • FIG. 4A is a cross-sectional view of region B of FIG. 1 according to one embodiment of the present invention.
  • FIG. 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.
  • FIG. 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.
  • FIG. 1 illustrates an intracellular fluid microdialysis apparatus based on an electroosmosis pump according to an embodiment of the present invention.
  • an electroosmotic pump-based intercellular microdialysis apparatus 10 includes various modules for microdialysis of intracellular fluid from an object.
  • 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).
  • MD probe micro-dialysis probe
  • 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.
  • 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 .
  • 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.
  • FIG. 2A is a cross-sectional view of region A of Fig.
  • 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.
  • 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.
  • 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.
  • an O-ring 43a is coupled to the fastening member 42a to prevent a gap.
  • 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.
  • the electroosmotic pump 13 and the conveyance path unit 14 may be integrally provided.
  • First and second open / close devices 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.
  • 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.
  • 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.
  • FIG. 2d to 2f are views for explaining the operation principle of the electroosmotic pump 13. Fig.
  • 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.
  • 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.
  • 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.
  • 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.
  • the first electrode 201 and the second electrode 202 are kept constant in spacing by 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.
  • the electrodes 201 and 202 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.
  • the conductive polymer may be formed through the polymerization of monomers in a fluid containing an anionic polymer.
  • 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.
  • the conductive polymer may be synthesized through electrochemical oxidation or chemical oxidation using an oxidizing agent.
  • the conductive polymer may be a variety of polymers having electrical conductivity or negatively charged.
  • 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.
  • CNTs carbon nanotubes
  • a redox reaction can be more stably and rapidly performed.
  • 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, .
  • first electrode 201 and the second electrode 202 can change the fluid flow by utilizing an electrode material that performs a reversible electrode reaction.
  • the active material can be returned to its original state.
  • 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.
  • 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 electroosmotic pump 13 includes an insulator (206 in Fig. 2D) for separating the fluid and the perfusion liquid.
  • 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.
  • FIG. 4A is a cross-sectional view of the region B in Fig.
  • 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.
  • the inlet passage 11a is fastened to one end face of the second conveyance line 14b of the conveyance path portion 14.
  • 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.
  • 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.
  • 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).
  • 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 .
  • FIG. 4B shows the configuration of the MD probe 11.
  • 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.
  • 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.
  • 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.
  • 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.
  • a cellulose series such as cellulose acetate, cellulose diacetate, Cuprophan, Hemophan, etc.
  • polysulfone polyacrylonit
  • 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.
  • 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 .
  • the sensor 16 and the waste bag 17 may be integrally formed.
  • the senor 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.
  • 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.
  • 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.
  • the senor 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.
  • a reaction chamber 16e through which the perfusion liquid flows after microdialysis
  • a reference electrode for example, Ag / AgCl
  • a counter electrode e.g., Pt
  • an insulating film 16b is disposed between the electrodes.
  • 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.
  • 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.
  • 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.
  • the protein thin film 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, .
  • 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.
  • the senor 16 may further include a glucose sensing film 16d formed in the expression of the reference electrode 16a, but is not essential.
  • FIG. 5A is a top view of the lower case 18, and Figs. 5B and 5C are side views of the lower case 18. Fig.
  • 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.
  • 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. 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.
  • the short dashed line shown in FIG. 6 represents the perfusion fluid movement before microdialysis
  • the long dotted line represents the perfusion fluid movement after microdialysis.
  • 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.
  • 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.
  • 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
  • the perfusion fluid after fine dialysis is stored in the second storage space.
  • 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.
  • 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.
  • 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.
  • 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.
  • the intracellular microdialysis unit 10 can slow down the flow rate and microdialysis the intercellular fluid.
  • 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.
  • 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.
  • 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.
  • 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.
  • a syringe pump was used to adjust the flow rate.
  • the concentration of the perfusion liquid shows a correlation with the sugar concentration of the artificial intracellular fluid as in Fig.
  • 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.
  • 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 ⁇ L / min).
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the biometric information for example, glucose concentration
  • S1230 the electrochemical detection method
  • the control circuit 401 recognizes the calibration mode and performs calibration based on the biometric information measured by the sensor 16 (S1250).
  • 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.
  • 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.

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Abstract

L'invention concerne un dispositif de microdialyse de liquide intercellulaire basé sur une pompe électro-osmotique, comprenant : une pompe électro-osmotique qui comprend des première et seconde électrodes, disposées sur les deux côtés d'une membrane, et une partie de passage de fluide, et génère en alternance une force d'aspiration et une force d'expulsion en fonction de l'alimentation d'une tension de polarité alternée aux première et seconde électrodes; une première ligne de transfert et une seconde ligne de transfert dont l'une des extrémités est fixée à la partie de passage de fluide de la pompe électro-osmotique, transférant ainsi en alternance la force d'aspiration et la force d'expulsion à un fluide de perfusion; un réservoir pour stocker le fluide de perfusion, et le décharger à travers un trajet de décharge inséré dans l'autre extrémité de la première ligne de transfert; une sonde de microdialyse (une sonde MD) qui microdialyse un liquide intercellulaire en ayant une extrémité de celle-ci injectée dans un objet cible, et comprend un trajet d'introduction, inséré dans l'autre extrémité de la seconde ligne de transfert, pour l'introduction du fluide de perfusion, et un trajet de décharge pour la décharge du fluide de perfusion après la microdialyse; et un capteur qui reçoit le fluide de perfusion après la microdialyse à travers le trajet de décharge, de la sonde MD, inséré dans un côté du capteur et mesure des informations biométriques à partir du fluide de perfusion après la microdialyse.
PCT/KR2018/010634 2017-06-23 2018-09-11 Dispositif de microdialyse de liquide intercellulaire pour la microdialyse de liquide intercellulaire à l'aide d'une pompe électro-osmotique, et son procédé de fonctionnement WO2019054727A1 (fr)

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KR20240010960A (ko) * 2022-07-18 2024-01-25 이오플로우(주) 전기 삼투 펌프 시스템 및 투석 시스템
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KR102667642B1 (ko) * 2021-03-16 2024-05-22 주식회사 케어메디 유연 전극을 포함하는 전기삼투펌프 및 유연 전극의 제조방법

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