WO2020175780A1 - 입자 분리 농축 장치 및 그 동작 방법 - Google Patents

입자 분리 농축 장치 및 그 동작 방법 Download PDF

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Publication number
WO2020175780A1
WO2020175780A1 PCT/KR2019/018272 KR2019018272W WO2020175780A1 WO 2020175780 A1 WO2020175780 A1 WO 2020175780A1 KR 2019018272 W KR2019018272 W KR 2019018272W WO 2020175780 A1 WO2020175780 A1 WO 2020175780A1
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WIPO (PCT)
Prior art keywords
particles
separation
chamber
electric field
channel
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PCT/KR2019/018272
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English (en)
French (fr)
Inventor
홍종욱
신규순
김주영
Original Assignee
한양대학교 에리카산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority claimed from KR1020190169781A external-priority patent/KR102297288B1/ko
Application filed by 한양대학교 에리카산학협력단 filed Critical 한양대학교 에리카산학협력단
Publication of WO2020175780A1 publication Critical patent/WO2020175780A1/ko

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C5/00—Separating dispersed particles from liquids by electrostatic effect
    • B03C5/02—Separators
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples

Definitions

  • the present invention relates to a particle separation and concentration device and its operation method, specifically, a particle separation and concentration device that separates and concentrates particles at different locations according to their size by using the ion concentration polarization phenomenon and its operation method. .
  • the molecules that affect us from the discovery of low-concentration environmental substances distributed in the air to the discovery of low-concentration environmental substances in the air, vary in size and concentration.
  • the target substance In order to measure and analyze them efficiently, the target substance must be separated from other substances. This is because a stable analysis of the target material can be achieved only through the pretreatment of separating and thickening the material to the desired level.
  • various technologies have been proposed to effectively separate and concentrate the target material.
  • Antibody-based separation method is a high level of antigen and antibody to form a complex.
  • the present invention is to solve the above problem, and the ion concentration polarization phenomenon is
  • Its purpose is to provide a particle separation and concentration device and a method of operation that separate and concentrate particles at different locations according to their size.
  • a particle separation and concentration apparatus is provided according to an embodiment of the present invention.
  • the apparatus includes: a chamber in which a fluid including first particles and second particles is provided; an ion-permeable membrane layer disposed on one side of the chamber; An electric field part separating the first particles and the second particles by particle size by applying an electric field to the ion-permeable membrane layer to form an ion depletion zone due to ion concentration polarization in the chamber side.
  • the electric field unit may change the strength of the electric field so that the first particles and the second particles are sequentially located in the separation region.
  • the electric field unit applies a first electric field such that the first particles are located in the separation region and the second particles are located in the chamber, and after the first particles are discharged through the discharge channel,
  • the electric field unit may apply a second electric field such that the second particles are located in the separation region.
  • the first particle may be larger than the second particle, and the first electric field may be smaller than the second electric field.
  • a gate valve that communicates or blocks the separation region from the chamber may be formed between the chamber and the separation region.
  • an inlet channel is formed and an inlet channel extending to the one side of the chamber
  • An outlet is formed and further includes a sample channel including an outlet channel extending to the other side of the separation region and an outlet valve for opening and closing the outlet channel, and when the fluid flows into the sample channel, the chamber by the gate valve
  • the fluid in the chamber is isolated by being cut off from the virtual machine separation area, the outlet valve is opened, and the fluid in the separation area and the outlet channel is discharged through the outlet, and the outlet valve contains particles located in the separation area.
  • the discharge channel can be sealed.
  • a pump unit that moves particles located in the separation area through a pressure change of the pump, including a pump channel in which one end communicates with the separation region and the other end communicates with the pump and a pump valve that opens and closes the pump channel It can contain more.
  • the gate valve transfers particles in the separation area from the chamber.
  • the pump unit When blocked, the pump unit may move particles in the separation area to the discharge channel.
  • the discharge channel may include a plurality of separate discharge channels forming different paths and a plurality of separate discharge valves for opening and closing each of the plurality of separate discharge channels.
  • a method of operating a particle separation and concentration device includes: supplying a fluid including first particles and second particles into a chamber; The ion-permeable membrane layer disposed on one side of the chamber forms an ion depletion zone due to ion concentration polarization as the chamber, so that the first particles and the second particles are separated by particle size. Applying a first electric field to the permeable membrane layer; Discharging the first particles located in a separation area formed on the other side of the chamber; A second electric field so that the second particles located in the chamber move to the separation area. Applying; And it may include the step of discharging the second particles located in the separation region.
  • the first particle may be larger than the second particle, and the first electric field may be smaller than the second electric field.
  • the step of blocking the separation area from the chamber through a gate valve positioned between the chamber and the separation area may be further included.
  • step of discharging the first particles and the step of discharging the second particles may be performed by moving the particles located in the separation region to the discharge channel after the blocking step.
  • microparticles especially nanoparticles, can be quickly
  • the isolated particles are pumped through a valve and
  • Figures 1 to 3 are in the particle separation and concentration device according to the embodiment of the present invention.
  • the ion concentration polarization phenomenon is shown.
  • FIG 9 shows the operation of the particle separation and concentration apparatus according to the embodiment of the present invention.
  • FIG 10 shows the operation of the particle separation and concentration apparatus according to the embodiment of the present invention.
  • FIG 11 shows the operation of the particle separation and concentration apparatus according to the embodiment of the present invention.
  • a particle separation and concentration device is provided.
  • the particle separation and concentration device is for separating fine particles from a mixture, and in particular, various types of fine particles using ion concentration polarization (ICP).
  • ICP ion concentration polarization
  • Particles separated by the particle size can be separated by particle size.
  • the particles separated by the particle separation and concentration device are nano-unit particles, and may be biological nanoparticles, including, for example, exosomes, but is not limited thereto. .
  • Figures 1 to 3 are in the particle separation and enrichment apparatus according to an embodiment of the present invention
  • FIG. 1 is a schematic diagram of a particle separation and concentration device in which the ion concentration polarization phenomenon occurs
  • FIG. 2 is a cross-sectional view A-A' of FIG. 1
  • FIG. 3 is B-B of FIG. 'It is a cross-sectional view.
  • an ion concentration polarization phenomenon occurs in the ion-permeable membrane.
  • the concentration polarization phenomenon is one of the electrochemical transfer phenomena observed around structures having a nano film. It can be understood as an ion-transmitting film layer. Assuming that the thickness of the electric double layer is similar to the size of the nano film, the electric double layer overlaps inside the nano film to show single ion permeability. Due to the diffusion and drifting force, only ions having an opposite charge to that of the wall phone pass through the nano-film, and the deficiency and excess of ions appear at the nano-film boundary.
  • Charged particles, cells, and droplets are affected by the electrical repulsion of ions and are pushed to the surroundings.
  • the electrical repulsion can also increase, i.e., since the electrophoretic force acting on a particle is proportional to the strength of the electric field, changing the electric field can also change the equilibrium position of the particles. Specifically, by increasing the strength of the electric field, the particles are brought together. It is possible to move the particles further to the ion-deficient region or to reduce the strength of the electric field so that the particles are closer to the ion-deficient region. In this way, the separation and concentration position of the particles can be changed through the change of the electric field strength.
  • FIG. 4 shows a particle separation and concentration apparatus according to an embodiment of the present invention.
  • the particle separation and concentration apparatus 1000 may include a sample channel 100, an ion-permeable membrane layer 200, an electric field unit 300, a discharge channel 400, and a buffer channel 500.
  • the sample channel 100 provides a space for inflowing, filling, or discharging a fluid to be separated, and may include a chamber 110, a separation region 120, and a gate valve 130.
  • the chamber (no) can provide a space through which the fluid to be separated is introduced and filled.
  • the fluid may be, for example, a mixture containing a first particle and a second particle as an electrolyte solution, wherein the first particle and the second particle are each nano-unit particle, and the first particle is smaller than the second particle.
  • the first particle and the second particle are included in the fluid, but this is illustrative and less or more types of particles are included in the fluid.
  • Can be A separation region 120 may be formed on one side of the chamber 110.
  • the separation region 120 is a space in which at least a part of the particles in the chamber 110 moves due to the ion concentration polarization of the ion-permeable membrane layer 200.
  • the first particles and the second particles may be sequentially located.
  • the particles located in the separation region 120 may be separated and recovered through the discharge channel 400.
  • a gate valve 130 may be formed on one side of the separation region 120 (that is, the chamber 110 side).
  • the gate valve 130 spatially blocks particles separated and concentrated at different positions. As for the purpose, specifically, it is located between the chamber 110 and the separation area 120 to communicate or block the separation area 120 and the chamber 110 with each other. For example, when the first particle is located in the separation region 120 and the second particle is located in the chamber no, the gate valve 130 is closed, so that the first particle and the second particle are spatially Can be separated
  • An ion-permeable membrane layer 200 may be disposed on the other side of the chamber no.
  • the ion-permeable membrane layer 200 is formed by ion concentration polarization in an electric field environment.
  • An ion-deficient region can be formed.
  • the ion-depleted region is formed from the ion-permeable film layer 200 toward the chamber H0, thereby causing separation and concentration of particles in the chamber H0.
  • the ion-permeable film layer 200 Can connect the chamber (no) and the buffer channel 500 to each other, and the electrolyte in the fluid can move to the buffer channel 500 through the ion-permeable membrane layer 200.
  • the ion-permeable membrane layer 200 may include at least one polymer electrolyte membrane.
  • the polymer electrolyte membrane may include a number of nanochannels through which either cationic or anionic ions pass.
  • the polymer electrolyte membrane is a DuPont
  • TM TM's brand name NAFION® may be used.
  • the electric field part 300 applies an electric field to the ion-transmitting film layer 200
  • the ion concentration polarization phenomenon may occur in the ion-permeable membrane layer 200.
  • the ion concentration polarization phenomenon of the ion permeable membrane 200 can separate and concentrate particles by forming an ion depletion zone toward the chamber 110.
  • the electric field unit 300 may include a pair of electrodes 310 and 320. Of the pair of electrodes 310 and 320, the positive electrode 310 is formed on one side of the chamber 110, and the buffer channel 500 ), the cathode 320 is formed, so that an electric field can be directed toward the chamber (no) and the ion-transmitting film layer 200. Accordingly, the ion-transmitting film layer 200 can form an ion-deficient region in the direction of the chamber 110.
  • the cathode 320 may be a ground electrode, and may be formed in one of the buffer channels 500, but, A power supply (not shown) may be electrically connected to the electrode 3 320 of the electric field 300.
  • the power supply is any electricity that can be used to provide the desired voltage or current. It can be a source, for example, the electricity source is a piezoelectrical source, 2020/175780 1»(:1 ⁇ 1 ⁇ 2019/018272 It may be a device powered by a battery or a household/industrial current.
  • This electric field part 300 can change the strength of the applied electric field.
  • the electric field part 300 can sequentially apply the first electric field and the second electric field, and at this time, the second electric field This sequential change in the strength of the electric field can cause a change in the location of separation and concentration of particles in the chamber (0).
  • the electric field part 300 separates the first particles by applying the first electric field.
  • the power of the electric field unit 300 is the electrodes 310 and 320 to generate a first electric field that moves the first particles to the separation region 120 and a second electric field that moves the second particles to the separation region 120.
  • the discharge channel 400 may include a separate discharge channel through which the particles move and a separate discharge valve for opening and closing the separated discharge channel.
  • the discharge channel 400 in the separation region 120 Particles may be discharged through the separated discharge channel.
  • the discharge channel 400 may include a plurality of separated discharge channels and a plurality of separated discharge valves corresponding thereto.
  • a buffer channel 500 Adjacent to the chamber (0), a buffer channel 500 may be formed.
  • the buffer channel 500 may be filled with a buffer solution, and may include an inlet and an outlet connected to circulate the buffer solution.
  • the buffer solution is As the electrolyte solution, the same electrolyte as the fluid in the chamber 0 may be included.
  • the electrolyte concentration may be the same as or different from the electrolyte concentration of the fluid.
  • the buffer channel 500 is the ion-permeable membrane layer 200. To provide a path through which the electrolyte is discharged
  • a region of the ion-permeable membrane layer 200 may be connected to the buffer channel 500.
  • the buffer channel 500 may be grounded so that a current flows through the ion-permeable membrane layer 200.
  • the cathode 320 of the electric field unit 300 serves as a ground electrode in one region of the buffer channel 500. Can be formed
  • the electric field unit 300 may be excluded from the particle separation and concentration device 1000. At this time, by the electric field existing outside the particle separation and concentration device (1000)
  • An electric field may be applied to the ion-permeable membrane layer 200.
  • FIG. 5 shows a particle separation and concentration apparatus according to an embodiment of the present invention.
  • the apparatus 1000' may further include a sample channel 100', an exhaust channel 400', and a pump unit 600.
  • sample channel (100') is compared to the sample channel (100), the inlet channel 140, the outlet channel 150 and 2020/175780 1»(:1 ⁇ 1 ⁇ 2019/018272 Can include outlet valve 160.
  • This inlet channel 140 extends to the other side of the chamber 110 (that is, the ion-permeable membrane layer 200 side)
  • the fluid can flow in through the inlet and move toward the chamber (:B0).
  • the fluid filled in the chamber 110 can then be separated by particle size and recovered through the discharge channel 400'.
  • Outflow channel 150 is one side of the separation region 120 (that is, away from the chamber 110
  • the fluid that has passed through the chamber 0 and the separation region 120 can move to the outside through the outlet.
  • an outlet valve 160 is formed in one region of the outlet channel 150, The opening and closing of the outlet channel 150 can be adjusted.
  • the fluid (or particles) moving through the channel 150 may move to a discharge channel 400' directly or indirectly connected to the separation region 120, or may be discharged to the outside through an outlet. In the latter case, it is used for fluid filling in the chamber (0) and for the drainage or recovery of the remaining fluid.
  • the gate valve 130 and the outlet valve 160 may be open.
  • the gate is By closing the valve 130, the chamber 110 and the separation region 120 can be spatially separated, that is, the fluid in the chamber 0 is isolated by the gate valve 130, and the separation region 120 and The fluid in the outlet channel 150 can be discharged through the outlet.
  • the outlet valve 160 can be opened for discharge. After that, when the particles separated by particle size are discharged, the outlet valve 160 is turned into the outlet channel ( 150), so that the flow of particles can be directed to the discharge channel 400'.
  • the discharge channel (400') is for separating and recovering particles separated by particle size, and a plurality of separate discharge channels (company 0, 420) and a plurality of separate discharge channels (410, 420) forming different paths It may include a plurality of separate discharge valves (430, 440) to open and close each.
  • the separate discharge channels (410, 420) are a first separate discharge channel for recovering the first particles (four 0), a first separate discharge valve 430 for opening and closing the first separated discharge channel 410, The second separate discharge channel 420 and the second separate discharge for recovering the second particles
  • It may include a second separate discharge valve 440 to open and close the channel 420.
  • valves 430 and 440 are shown, this is exemplary, and one or more separate discharge channels and corresponding separate discharge valves may be applied according to the embodiment. 7]
  • the pump unit 600 can move fluid or particles in the device 1000'.
  • the pump unit 600 may include a pump channel 610 that is once communicated with the separation region 120 and a pump valve 620 that opens and closes the pump channel 0.
  • the pump may include a pump channel 610 that is once communicated with the separation region 120 and a pump valve 620 that opens and closes the pump channel 0.
  • Channel 610 is connected so that the other end communicates with the pump
  • the pump unit 600 may include a pump in the pump channel 610.
  • the pump part 600 drives the pump and is connected through the pump channel 610 to separate
  • a pressure change may occur in the region 120, which may cause a fluid or particle flow to the separation region 120 and the outlet channel 150, outlet channel 400', etc. in communication therewith.
  • the valve 620 opens the pump channel 610 when the pump is driven and closes the pump channel 0 when the pump is not driven, so that the flow of fluid or particles is not affected by the pump channel 610. have.
  • the fluid in the region 120 and the outlet channel 150 can be moved toward the outlet.
  • the pump unit 600 discharges the particles in the separation region 120.
  • Channel 400' i.e., the first separate discharge channel (scene 0) or the second separate discharge channel 420).
  • FIG. 6 shows a coupling structure of a particle separation and concentration device according to an embodiment of the present invention.
  • the particle separation and concentrating device (1000') may include an upper substrate (10003 ⁇ 4 and a lower substrate (10003 ⁇ 4).
  • the upper substrate (10003 ⁇ 4 and the lower substrate (10003 ⁇ 4) are used to control the flow pipe through which fluids, etc. And provide a space in which a valve or the like is formed or is formed as part of the device 1000 ′. Also, a communication hole communicating with a configuration outside the device 1000 ′ may be formed.
  • a valve may be formed on the upper substrate (1000 3 ⁇ 4).
  • the valve includes at least one of the outlet valve 160, the gate valve 130, the pump valve 620 and the separate discharge valves 430 and 440.
  • the valve may have a structure capable of blocking a channel located on the lower substrate (1000 3 ⁇ 4) by selectively applying pressure, for example.
  • a sample channel (100'), a buffer channel (500), a pump channel (610), a separate discharge channel (new 0, 420) can be formed of various channels.
  • the electrodes 310 and 320 of the electric field unit 300 for applying an electric field can be respectively located in the outflow channel 150 and the buffer channel 500, and the ion-permeable layer 200 is the sample channel 100' )
  • Over-buffering 2020/175780 1»(:1 ⁇ 1 ⁇ 2019/018272 Can be formed to connect channels 500.
  • communication holes such as inlets can be formed for the movement of fluids and/or particles.
  • the upper substrate (1000 3 ⁇ 4 and the lower substrate (1000 3 ⁇ 4) may be bonded to each other by plasma bonding.
  • plasma bonding it is not limited thereto, and various substrate bonding techniques may be applied.
  • the upper substrate (10003 ⁇ 4 and the lower substrate (10003 ⁇ 4) may be made of silicon, polymer, etc.
  • the polymer is 0]; 8(]301) ⁇ 111 11)4 10 116) Can be used.
  • step 8710 the fluid containing the first particles and the second particles into the chamber 110
  • step 8710 may include introducing a fluid into the sample channel 100' and discharging a portion of the fluid (fluid in the separation region 120 and the outlet channel 150).
  • the fluid when the fluid flows into the sample channel 100', the fluid can flow through the inflow channel 140, the chamber 0, the separation area 120 and the outflow channel 150 in order.
  • the gate valve 130 and the outlet valve 160 may be in an open state, and the pump valve 620 and the separate discharge valves 430 and 440 may be in a closed state.
  • the valve 130 can be changed to a closed state, that is, the fluid in the chamber 110 and the fluid in the separation region 120 and the outlet channel 150 can be spatially separated by the gate valve 130.
  • the pump valve 620 can be changed to an open state, and the pump can change the pressure to discharge the fluid in the separation region 120 and the outlet channel 150 through the outlet.
  • the method 700 may further include the step of filling the buffer channel 500 with a buffer solution.
  • the step may be performed at the same time as step 8710, or before and after.
  • the electric field unit 300 may apply a first electric field to the ion-permeable membrane layer 200.
  • the ion-depleted region of the ion-permeable membrane layer 200 due to the ion concentration polarization phenomenon in the chamber ( 110) to form the first particle and the second particle by particle size 2020/175780 1»(:1 ⁇ 1 ⁇ 2019/018272 Particles can be separated.
  • the first particle can be located in the separation zone 120, and the second particle can be located in the chamber 0.
  • the gate valve 130 and the discharge valve 160 may be open, and the pump valve 620 and the separation discharge valves 430 and 440 may be closed.
  • step 3730 the separation region 120 formed on the other side of the chamber 110
  • the located first particle can be discharged. It is for recovering the first particle separately from the second particle.
  • the gate valve 130 can be changed to a closed state. That is, the gate valve ( By 130), the second particles in the chamber 110 and the first particles in the separation region 120 can be spatially separated.
  • the pump valve 620 and the first separation and discharge valve 430 are changed to an open state.
  • the discharge valve 160 can be changed to a closed state. Through this, a separate discharge path from the pump channel 0 through the separation region 120 to the first separation discharge channel (S0) can communicate.
  • the pump can change the pressure to move the first particles in the separation region 120 to the first separation discharge channel (new 0).
  • the electric field unit 300 may apply a second electric field.
  • the second particles in the chamber 110 may move to the separation region 120 through step 8740.
  • the gate valve 130 and the outlet valve 160 are opened for movement of the second particles. It may be in a state, and the pump valve 620 and the separate discharge valve 430,
  • the second particles in the separation region 120 can be discharged. This is for recovering the second particles.
  • the gate valve 130 can be changed to a closed state. That is, the second particles in the separation region 120 can be spatially separated from the chamber 110 by the gate valve 130.
  • the pump valve 620 and the second separation and discharge valve 440 are opened.
  • the discharge valve 160 can be changed to a closed state. Through this, a separate discharge path from the pump channel 0 through the separation region 120 to the second separation discharge channel 420 can communicate. , The pump may change the pressure to move the second particles in the separation region 120 to the second separation discharge channel 420.
  • Method 700 discloses a process for separating the first particles and the second particles, but this is illustrative, and the method can be applied to the separation of less or more particles.
  • Method 700 discloses a process for separating the first particles and the second particles, but this is illustrative, and the method can be applied to the separation of less or more particles.
  • two separate discharge channels 410 and 420 and separate discharge valves 430 and 440 corresponding thereto are shown, but these are illustrative, and one or three or more separate discharge channels and corresponding thereto are illustrated.
  • a separate discharge valve may be applied.
  • FIG 9 shows the operation of the particle separation and concentration apparatus according to an embodiment of the present invention.
  • ion concentration polarization may occur in the ion-transmitting film layer (for example, Nafion).
  • Electric field can be generated by applying voltage of 10 or 20 V. Electric field
  • an ion-deficient region is formed in the channel, and particles (eg, 100 nm liposomes) in the chamber are pushed around the ion-deficient region, that is, to the separation region.
  • the size of the ion-deficient region is controlled by controlling the strength of the electric field, and particles are separated accordingly. The location of concentration can be adjusted.
  • FIG 10 shows the operation of the particle separation and concentration apparatus according to an embodiment of the present invention.
  • the ion-permeable membrane layer 200 can form an ion-deficient region toward the chamber 110. Accordingly, the particles in the chamber no can move to a position where the drag force caused by electroosmosis and the electrophoretic force are balanced.
  • FIG. W shows a state of separation and concentration of particles having a size of WO nm under a first electric field
  • ratio of FIG. W shows a state of separated and concentrated state of particles having a size of 500 nm under a first electric field.
  • FIG. And (d) of FIG. W shows a state of separation and concentration of particles having a size of 500 nm under an increased electric field. As shown, when the strength of the electric field increases, each particle moves away from the ion-permeable layer 200 It can be seen that it moves further in the direction.
  • FIG 11 shows the operation of the particle separation and concentration apparatus according to an embodiment of the present invention.
  • WOnm, 300nm liposomes have an equilibrium between the drag and electrophoretic forces due to electroosmosis.
  • WOnm liposomes are concentrated around the ion-permeable membrane layer (e.g., Nafion), and 300nm liposomes are pushed further away and concentrated. That is, liposomes are separated and concentrated by particle size. Able to know.
  • ion-permeable membrane layer e.g., Nafion
  • a resolution of 1 or more means complete separation without overlapping chips on the Gaussian distribution.
  • exosomes are concentrated around the ion-permeable membrane layer (e.g., Nafion), and 30011111 liposomes are pushed further away and concentrated. That is, it can be seen that it is separated and concentrated by particle size

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Abstract

본 발명의 실시예에 따라 입자 분리 농축 장치가 제공된다. 상기 장치는, 제 1 입자 및 제 2 입자를 포함하는 유체가 제공되는 챔버; 상기 챔버의 일 측에 배치되는 이온투과막층; 상기 이온투과막층에 전기장을 인가함으로써 상기 이온투과막층이 이온농도분극 현상에 의한 이온결핍영역(ion depletion zone)을 상기 챔버 측으로 형성하게 하여 입도 별로 상기 제 1 입자 및 상기 제 2 입자를 분리하는 전계부; 상기 챔버의 타 측에 형성되고, 상기 전계부에 의해 분리되는 상기 제 1 입자 및 상기 제 2 입자 중 하나의 입자가 위치하는 분리 영역; 및 상기 분리 영역에 위치한 입자가 배출되는 배출 채널을 포함하고, 상기 전계부는 상기 전기장의 세기를 변화하여 상기 제 1 입자 및 상기 제 2 입자가 순차적으로 상기 분리 영역에 위치하게 할 수 있다.

Description

2020/175780 1»（：1/10公019/018272 명세서
발명의명칭:입자분리농축장치및그동작방법 기술분야
[1] 본발명은입자분리농축장치및그동작방법에관한것으로서 ,구체적으로, 이온농도분극현상을이용해입자들을크기에따라다른위치에서분리 농축되게하는입자분리농축장치및그동작방법에관한것이다.
배경기술
[2] 생명유체내에서의생체정보를획득할수있는다양한분자를측정하는
것에서부터,공기중에분포하는저농도의환경물질을발견하는것까지 우리에게영향을끼치는분자들은그크기와농도가다양하다.이를효율적으로 측정하고분석하기위해서대상물질이다른물질들과분리되어야한다.대상 물질을원하는수준으로분리및농죽하는전처리과정을통해야대상물질에 대한안정적인분석이이루어질수있기때문이다.이와관련하여대상물질을 효과적으로분리및농축하기위한다양한기술이제안되고있다.
[3] 우선,초원심분리법에따르면,혼합물을초원심분리기의로터에넣고축을 중심으로회전시켜원심력을가하면,혼합물안의물질의질량에따라서로다른 원심력을받게되어분리될수있다.나노미터수준의입자는작은크기와낮은 밀도로인해효과적으로분리하기쉽지않지만,초원심분리법은낮은밀도의 입자분리에도적용될수있다.그러나엑소좀과같은생체나노입자를 원심분리를이용해분리하기위해서는 150,000 (3이상의고속회전이
요구되는데,생체입자를분리할경우,입자들이분리과정에서치명적인손상을 받게되어순도와수득율이떨어진다는한계를가진다.또한,시료를처리하는 과정이복잡하고시간도오래걸린다는단점이있다.
[4] 항체기반의분리방법은항원과항체가복합체를형성하기위하여높은
친화력으로결합하는항원·항체반응을이용하여입자를분리하는기술이다. 항원과항체의특이적결합은항체의특정한화학적구조에의해결정되며, 분리하고자하는입자의표면항원과특이적으로결합하는항체를선택하여 분리에사용한다.따라서높은선택성에의해비교적높은순도의입자의분리가 가능하다.특히 엑소좀의표면마커 (0063, 009, 0081, 1«모70등)에대한여러 종류의항체가개발되어 있으며마이크로칩또는자성입자와함께사용하는등 많은응용이되고있다.그러나항체기반의분리방법은특정마커를발현하고 있는입자만을분리할수있다는특징적인한계를가진다.따라서특정마커를 포함하지않는입자의경우는분리가불가능하다.또한,항체자체비용때문에 분리비용이크며수득율이낮다는문제가있다.
[5] 이외에엑소좀을분리하기위해침전제기반의분리키트들이 있다.키트의 용액안에는 3011111에서 20011111크기의입자들을포집하여침전하는고분자 물질들로채워져있다.키트를사용하기전,샘늘의세포들을제거하고,고분자 용액을샘플에첨가하여,소정의시간냉장보관한후원심분리를이용해펠렛을 만들어입자들을분리할수있다.침전제기반의분리방법은분리과정이 간단하다는장점을가지지만,통상하루이상의인큐베이션 (Incubation)시간이 필요하고,고분자가포함되는과정에서나노입자의순도가낮아지게된다는 단점이 있다.
[6] 이와같이,마이크로크기에서나노크기에이르는다양한크기의입자를
하나의장치에서분리할수있는통합적분리장치의개발은여전히미흡한 상황이며 ,따라서이러한문제점을해결하기위한기술이요구된다.
발명의상세한설명
기술적과제
[7] 본발명은상기문제점을해결하기위한것으로서 ,이온농도분극현상을
이용해입자들을크기에따라다른위치에서분리농축되게하는입자분리농축 장치및그동작방법을제공하는것을그목적으로한다.
[8] 본발명의기술적과제들은이상에서언급한기술적과제들로제한되지
않으며,언급되지않은또다른기술적과제들은아래의기재들로부터 당업자에게명확하게이해될수있을것이다.
과제해결수단
[9] 본발명의실시예에따라입자분리농축장치가제공된다.상기장치는,제 1 입자및제 2입자를포함하는유체가제공되는챔버;상기챔버의일측에 배치되는이온투과막층;상기이온투과막층에전기장을인가함으로써상기 이온투과막증이이온농도분극현상에의한이온결핍영역 (ion depletion zone)을 상기챔버측으로형성하게하여입도별로상기제 1입자및상기제 2입자를 분리하는전계부;상기챔버의타측에형성되고,상기전계부에의해분리되는 상기제 1입자및상기제 2입자중하나의입자가위치하는분리영역;및상기 분리영역에위치한입자가배출되는배출채널을포함하고,상기전계부는상기 전기장의세기를변화하여상기제 1입자및상기제 2입자가순차적으로상기 분리영역에위치하게할수있다.
[1이 또한,상기전계부는,상기제 1입자가상기분리영역에위치하고상기제 2 입자가상기챔버내에위치하도록제 1전기장을인가하고,상기제 1입자가 상기배출채널을통해배출된후에,상기전계부는상기제 2입자가상기분리 영역에위치하도록제 2전기장을인가할수있다.
[11] 또한,상기제 1입자는상기제 2입자보다크고,상기제 1전기장은상기제 2 전기장보다작을수있다.
[12] 또한,상기분리영역을상기챔버로부터연통하거나차단하는게이트밸브가 상기챔버와상기분리영역사이에형성될수있다.
[13] 또한,유입구가형성되고상기챔버의상기일측으로연장되는유입채널, 유출구가형성되고상기분리영역의타측으로연장되는유출채널및상기 유출채널을개폐하는유출밸브를포함하는샘플채널을더포함하고,상기 샘플채널로상기유체가유입되면,상기게이트밸브에의해상기챔버가상기 분리영역으로부터차단되어상기챔버내의유체가고립되고,상기유출밸브가 개방되어상기분리영역및상기유출채널내의유체가상기유출구를통해 배출되며 ,상기유출밸브는상기분리영역에위치한입자가상기배출채널을 통해배출될때상기유출채널을밀폐할수있다.
[14] 또한,일단이상기분리영역과연통하고타단이펌프와연통하는펌프채널 및상기펌프채널을개폐하는펌프밸브를포함하여상기펌프의압력변화를 통해상기분리영역에위치한입자를이동시키는펌프부를더포함할수있다.
[15] 또한,상기게이트밸브가상기분리영역내의입자를상기챔버로부터
차단하면,상기펌프부는상기분리영역내의입자를상기배출채널로 이동시킬수있다.
[16] 또한,상기배출채널은,서로상이한경로를형성하는복수의분리배출채널 및상기복수의분리배출채널각각을개폐하는복수의분리배출밸브를 포함할수있다.
[17] 또한,제 1분리배출밸브가제 1분리배출채널을밀폐한상태에서제 2분리 배출밸브가제 2분리배출채널을개방하면,상기분리영역에위치한입자가 상기제 2분리배출채널로배출되고,상기제 2분리배출밸브가상기제 2분리 배출채널을밀폐한상태에서상기제 1분리배출밸브가상기제 1분리배출 채널을개방하면,상기분리영역에위치한입자가상기제 1분리배출채널로 배줄될수있다.
[18] 본발명의실시예에따라,입자분리농축장치의동작방법이제공된다.상기 방법은,챔버내로제 1입자및제 2입자를포함하는유체를공급하는단계; 상기챔버의일측에배치되는이온투과막층이이온농도분극현상에의한 이온결핍영역 (ion depletion zone)을상기챔버즉으로형성하게하여입도별로 상기제 1입자및상기제 2입자가분리되도록상기이온투과막층에제 1 전기장을인가하는단계;상기챔버의타측에형성되는분리영역에위치한 상기제 1입자를배출하는단계 ;상기챔버내에위치하는상기제 2입자가상기 분리영역으로이동하도록제 2전기장을인가하는단계;및상기분리영역내에 위치하는상기제 2입자를배출하는단계를포함할수있다.
[19] 또한,상기제 1입자는상기제 2입자보다크고,상기제 1전기장은상기제 2 전기장보다작을수있다.
[2이 또한,상기챔버와상기분리영역사이에위치하는게이트밸브를통해상기 분리영역을상기챔버로부터차단하는단계를더포함할수있다.
[21] 또한,상기제 1입자를배출하는단계및상기제 2입자를배출하는단계는, 상기차단하는단계이후에,상기분리영역에위치한입자를배출채널로 이동시킴으로써수행될수있다. 2020/175780 1»（：1^1{2019/018272 발명의효과
[22] 본발명에 따르면,미세 입자,특히 나노입자를손상없이크기별로빠르게
분리하고고농도로농축할수있어,생화학,환경,의약학등다양한분야에걸쳐 기반기술로활용될수있다.
[23] 또한,본발명에 따르면,전기장의 변화를통해 입자의 평형위치를변화시키고, 이를통해 입자를분리회수하도록함으로써,장치의 전반적인구조복잡성을 낮추고,제조및사용효율성을개선할수있다.
[24] 또한,본발명에 따르면,밸브를통해고립된입자를펌프및 이와연통되는
배출채널을통해회수함으로써,다양한입자들의분리 및농축을가능하게할 수있다.
도면의간단한설명
[25] 본발명의상세한설명에서 인용되는도면을보다충분히 이해하기위하여 각 도면의 간단한설명이 제공된다.
[26] 도 1내지도 3은본발명의실시예에 따른입자분리농축장치에서의
이온농도분극현상을도시한다.
[27] 예에따른입자분리농축장치를도시한다.
[28] 예에따른입자분리농축장치를도시한다.
[29] 예에따른입자분리농축장치의 결합구조를도시한다.
[3이 예에따른입자분리농축장치의동작방법을도시한다.
[31]
Figure imgf000006_0001
발명의실시예에 따른입자분리농축장치의동작을
도시한다.
[32] 도 9는본발명의실시예에따른입자분리농축장치의동작을도시한다.
[33] 도 10은본발명의실시예에따른입자분리농축장치의동작을도시한다.
[34] 도 11은본발명의실시예에따른입자분리농축장치의동작을도시한다.
[35] 도 12는본발명의실시예에따른입자분리농축장치의동작을도시한다. 발명의실시를위한형태
[36] 이하,첨부된도면들에 기재된내용들을참조하여본발명에따른예시적
실시예를상세하게설명한다.또한,첨부된도면들에기재된내용들을참조하여 본발명의실시예에 따른전자장치를구성하고사용하는방법을상세히 설명한다.각도면에서제시된동일한참조번호또는부호는실질적으로동일한 기능을수행하는부품또는구성요소를나타낸다.이하에서기재되는편의상 상하좌우의 방향은도면을기준으로한것이며,해당방향으로본발명의 권리범위가반드시 한정되는것은아니다.
[37] 제 1,제 2등과같이서수를포함하는용어는다양한구성요소들을설명하는데 사용될수있지만,구성요소들은용어들에 의해한정되지는않는다.용어들은 하나의구성요소를다른구성요소로부터구별하는목적으로만사용된다.예를 들어 ,본발명의권리 범위를벗어나지 않으면서제 1구성요소는제 2구성요소로 명명될수있고,유사하게제 2구성요소도제 1구성요소로명명될수있다. "및/또는”이라는용어는복수의관련된항목들의조합또는복수의관련된 항목들중의어느하나의항목을포함한다.
[38] 본명세서에서사용한용어는실시예를설명하기위해사용된것으로,본
발명을제한및/또는한정하려는의도가아니다.단수의표현은문맥상명백하게 다르게뜻하지않는한,복수의표현을포함한다.본명세서에서,포함하다또는 가지다등의용어는명세서상에기재된특징,숫자,단계,동작,구성요소,부품 또는이들을조합한것이존재함을지정하려는것이지 ,하나또는그이상의 다른특징들이나숫자,단계,동작,구성요소,부품또는이들을조합한것들의 존재또는부가가능성을미리배제하지않는것으로이해되어야한다.
[39] 명세서전체에서,어떤부분이다른부분과연결되어 있다고할때,이는
직접적으로연결되어있는경우뿐만아니라,그중간에다른소자를사이에두고 전기적으로연결되어있는경우도포함한다.또한어떤부분이어떤구성요소를 포함한다고할때,이는특별히반대되는기재가없는한다른구성요소를 제외하는것이아니라다른구성요소를더포함할수있는것을의미한다.
[4이 또한,명세서에기재된” 부”,”모듈”등의용어는적어도하나의기능이나 동작을처리하는단위를의미하며 ,이는하드웨어또는소프트웨어로
구현되거나하드웨어와소프트웨어의결합으로구현될수있다.
[41] 본발명의기술적사상에바탕을둔다른변형예들이실시가능하다는것은본 발명의속하는기술분야에서통상의지식을가진자에게자명한것이다.또한 각각의실시예는필요에따라서로조합되어운용할수있다.예컨대,본발명의 실시예와다른실시예의일부분들이서로조합되어장치의동작이운용될수 있다.
[42]
[43] 실시예에서 ,입자분리농축장치가제공된다.입자분리농축장치는,미세 입자를혼합물로부터분리하기위한것으로서,특히이온농도분극현상 (Ion concentration polarization, ICP)을이용하여다양한종류의미세입자들을입도 별로분리할수있다.여기서입자분리농축장치에의해분리되는입자는나노 단위의입자 (nanoparticles)로서,예를들어,엑소좀등을비롯한생체나노입자일 수있다.다만,이에한정되는것은아니다.
[44] 도 1내지도 3은본발명의실시예에따른입자분리농축장치에서의
이온농도분극현상을도시한다.구체적으로,도 1은이온농도분극현상이 발생하는입자분리농축장치의개략도이고,도 2는도 1의 A-A’단면도이며,도 3은도 1의 B-B'단면도이다.
[45] 도 1내지도 3을참조하면,이온투과막층 (예를들어,나피온등)의양단에 전기장이인가되면,이온투과막증에는이온농도분극 (ion concentration polarization)현상이발생하는데,이온농도분극현상은나노막을갖는구조 주변에서관찰되는전기화학전달현상중의하나이다.나노막은 이온투과막층으로이해될수있다.전기이중층의두께가상기나노막의크기와 비슷하다고가정할때,나노막내부에서전기이중층이겹침으로써단일이온 투과성을보인다.나노막의벽면전하와같은전하를갖는이온들은확산과 표류력에의해나노막을통과하지못하고벽면전화와반대전하를갖는 이온들만이통과하게되면서,나노막경계면에서는이온들의결핍과과다 현상이나타난다.
[46] 이온들의결핍에의한이온결핍영역 (ion depletion zone)에서는,나노막을
통과하지못한이온들사이에서는강한전기적인반발력이작용하여양이온과 음이온모두영향을받게되고,이에따라이온농도구배현상이나타난다.
전하를띠고있는입자나세포,액적등이이온들의전기적반발력에영향을 받아주변으로밀려나게된다.
[47] 이때,전기삼투에의한유체의흐름에의해입자가받는항력 (drag force)과
입자가이온결핍영역으로부터받는전기적인반발력인
전기영동력 (electrophoretic force)에의한힘이서로반대방향으로작용하게되며, 입자들은이들힘들이평형을이루는위치로이동할수있다.입자의크기와 전하량에따라그힘이평형을이루는지점은모두다르며,평형을이루는 영역에서는모든입자는농축될수있다.
[48] 한편,전기장의세기가증가하면,이온결핍영역이확대되면서 ,입자가받는
전기적인반발력또한증가할수있다.즉,입자에작용하는전기영동력이 전기장의세기에비례하기때문에,전기장을변화시키면입자들의평형위치 또한달라질수있다.구체적으로,전기장의세기를증가하여,입자들을보다 이온결핍영역으로멀어지도록하거나,전기장의세기를감소시켜 ,입자들을 이온결핍영역으로가까워지도록할수있다.이와같이전기장의세기변화를 통해입자들의분리농축위치를변화시킬수있다.
[49]
[5이 도 4는본발명의실시예에따른입자분리농축장치를도시한다.
[51] 입자분리농축장치 (1000)는,샘플채널 (100),이온투과막층 (200),전계부 (300), 배출채널 (400)및완충채널 (500)을포함할수있다.
[52] 샘플채널 (100)은분리대상인유체가유입,충전되거나배출되기위한공간을 제공하는것으로서,챔버 (110),분리영역 (120)및게이트밸브 (130)를포함할수 있다.
[53] 챔버 (no)는,분리대상인유체가유입및충전되는공간을제공할수있다. 상기유체는,예를들어,전해질용액으로서제 1입자및제 2입자를포함하는 혼합물일수있다.여기서제 1입자및제 2입자는각각나노단위의입자이며, 제 1입자는제 2입자보다작을수있으나,이에한정되는것은아니다.또한, 설명의간이함을위해유체내에제 1입자및제 2입자가포함되는것으로 기재되나,이는예시적인것으로서 ,그보다적은또는그보다많은종류의 입자가유체내에포함될수있다. [54] 챔버 (110)의일측에는분리영역 (120)이형성될수있다.분리영역 (120)은 이온투과막층 (200)의이온농도분극현상에의해챔버 (110)내의입자중적어도 일부가이동하는공간으로서 ,예를들어 ,제 1입자및제 2입자가순차적으로 위치할수있다.분리영역 (120)에위치하는입자는배출채널 (400)을통해분리 회수될수있다.
[55] 분리영역 (120)의일측 (즉,챔버 (110)측)에는게이트밸브 (130)가형성될수 있다.게이트밸브 (130)는,서로다른위치에서분리및농축되는입자들을 공간적으로차단하기위한것으로서,구체적으로,챔버 (110)와분리영역 (120) 사이에위치하여분리영역 (120)과챔버 (110)를서로연통하거나차단할수있다. 예를들어,분리영역 (120)내에제 1입자가위치하고챔버 (no)내에제 2입자가 위치하는경우,게이트밸브 (130)가닫힘 (closed)으로써 ,제 1입자와제 2입자가 공간적으로분리될수있다.
[56] 챔버 (no)의타측에는이온투과막층 (200)이배치될수있다.
이온투과막층 (200)은전기장환경에서이온농도분극현상에의한
이온결핍영역을형성할수있다.이온결핍영역은이온투과막층 (200)에서 챔버 (H0)를향하여형성됨으로써 ,챔버 (H0)내의입자들의분리농죽을야기할 수있다.또한,이온투과막층 (200)은챔버 (no)와완충채널 (500)을서로연결할 수있으며,이온투과막층 (200)을통해유체내의전해질이완충채널 (500)로 이동할수있다.
[57] 이온투과막층 (200)은적어도하나의고분자전해질막을포함할수있다.
여기서,고분자전해질막은양이온또는음이온중어느하나가통과하는다수의 나노채널을포함할수있다.예를들어,고분자전해질막은듀퐁 (DuPont
TM)사의상품명나피온 (NAFION®)이사용될수있다.나피온은
폴리테트라플루오르에틸렌의골격에술폰산기를도입한폴리머로,선택적으로 양이온은통과하되,음이온은통과하지못하는나노채널을포함할수있다.
[58] 전계부 (300)는,이온투과막층 (200)에전기장을인가함으로써
이온투과막층 (200)에이온농도분극현상을발생시킬수있다.
이온투과막증 (200)의이온농도분극현상은이온결핍영역 (ion depletion zone)을 챔버 (110)측으로형성하게하여입자들을분리농축할수있다.
[59] 전계부 (300)는,한쌍의전극 (310, 320)을포함할수있다.한쌍의전극 (310, 320) 중양극 (310)이챔버 (110)의일측으로형성되고,완충채널 (500)에음극 (320)이 형성되어,전기장이챔버 (no)및이온투과막층 (200)을향하도록할수있다. 이에의해이온투과막층 (200)은챔버 (110)방향으로이온결핍영역을형성하도록 할수있다.이때,음극 (320)은접지전극일수있으며,완충채널 (500)중일 영역에형성될수있으며,다만,이에한정하는것은아니다.전계부 (300)의 전극 (3 320)에는전원 (power supply,도시되지않음)이전기적으로연결될수 있다.전원은목적하는전압또는전류을제공하기위해사용될수있는임의의 전기공급원일수있다.예를들어,전기공급원은압전 (pizoelectrical)공급원, 2020/175780 1»（：1^1{2019/018272 배터리,또는가정용/산업용전류등을동력으로하는장치일수있다.
[6이 전계부 (300)는,인가되는전기장의세기를변화시킬수있다.전계부 (300)는 순차적으로제 1전기장및제 2전기장을인가할수있으며,이때,제 2전기장은 제 1전기장보다클수있다.이와같은순차적인전기장의세기변화는챔버 ( 0) 내의입자의분리및농축위치에변화를야기할수있다.
[61] 구체적으로전계부 (300)는,제 1전기장을인가하여제 1입자가분리
영역 (120)에위치하고제 2입자가챔버 (110)내에위치하도록할수있으며 , 이후에 (특히 ,제 1입자가배출된이후에)제 2전기장을인가하여챔버 ( 0) 내에위치하던제 2입자가분리영역 (120)으로이동하도록할수있다.
[62] 전계부 (300)의전원은,제 1입자를분리영역 (120)으로이동시키는제 1전기장 및제 2입자를분리영역 (120)으로이동시키는제 2전기장을발생시키도록 전극 (310, 320)에전압을인가할수있으며,이때,전압은분리및농축의대상이 되는입자의크기나종래,유체내의전해질농도등에따라달라질수있다.
[63] 분리영역 (120)내의입자,특히,전기장에의해분리영역 (120)으로이동한후 게이트밸브 (130)에의해챔버 (110)로부터분리된입자는,배출채널 (400)을통해 외부로회수될수있다.배출채널 (400)은입자가이동하는분리배출채널및 분리배출채널을개폐하는분리배출밸브를포함할수있다.분리배출밸브에 의해분리배출채널이개방되면,분리영역 (120)내의입자가분리배출채널 (을 통해배출될수있다.실시예에따라배출채널 (400)은복수의분리배출채널및 이에대응하는복수의분리배출밸브를포함할수있다.
[64] 챔버 ( 0)에인접하여완충채널 (500)이형성될수있다.완충채널 (500)에는 완충용액이채워질수있으며,완충용액이순환되도록연결되는유입부와 유출부를포함할수있다.여기서완충용액은전해질용액으로서，챔버 ( 0) 내의유체와동일한전해질이포함될수있다.실시예에따라,전해질농도는 상기유체의전해질농도와동일하거나상이할수있다.완충채널 (500)은 이온투과막층 (200)의전해질이배출되는경로를제공하기위해
이온투과막층 (200)의일영역이완충채널 (500)과연결되도록할수있다.
이온투과막층 (200)을통해전류가흐를수있도록완충채널 (500)은접지될수 있다.예를들어,전계부 (300)의음극 (320)이접지전극으로서완충채널 (500)중 일영역에형성될수있다.
[65] 실시예에따라,입자분리농축장치 (1000)에서전계부 (300)는제외될수있다. 이때,입자분리농축장치 (1000)의외부에존재하는전계부에의해
이온투과막층 (200)에전기장이인가될수있다.
[66]
[67] 도 5는본발명의실시예에따른입자분리농축장치를도시한다.
[68] 도 5를참조하면,장치 (1000’)는샘플채널 (100’),배출채널 (400’),펌프부 (600)를 더포함할수있다.
[69] 샘플채널 (100’)은샘플채널 (100)에비하여유입채널 (140),유출채널 (150)및 2020/175780 1»（：1^1{2019/018272 유출밸브 (160)를포함할수있다.
이 유입채널 (140)은챔버 (110)의타측 (즉,이온투과막층 (200)측)으로연장
형성되는것으로서,유입구를통해유체가유입되어챔버 (:나0)를향하여 이동하도록할수있다.챔버 (110)에충전된유체는이후입도별로분리되어배출 채널 (400’)을통해회수될수있다.
1] 유출채널 (150)은분리영역 (120)의일측 (즉,챔버 (110)로부터멀어지는
측)으로연장형성되는것으로서,챔버 ( 0)및분리영역 (120)을통과한유체가 유출구를통해외부로이동할수있다.이때유출채널 (150)의일영역에는유출 밸브 (160)가형성되어,유출채널 (150)의개폐를조절할수있다.유출
채널 (150)을이동하는유체 (또는입자)는분리영역 (120)에직,간접적으로 연결된배출채널 (400’)로이동하거나,유출구를통해외부로배출될수있다. 후자의경우,챔버 ( 0)의유체충전에이용되고남은유체의배출또는회수를 위한것이다.
[72] 구체적으로,샘플채널 (100’)로유체가유입되면,유체는유입채널 (140),
챔버 ( 0),분리영역 (120)및유출채널 (150)을흐를수있다.이때게이트 밸브 (130)및유출밸브 (160)는열린상태일수있다.챔버 ( 0)내에유체가 충전되면,게이트밸브 (130)가닫힘으로써,챔버 (110)와분리영역 (120)이 공간적으로분리될수있다.즉,게이트밸브 (130)에의해챔버 ( 0)내의유체가 고립되고,분리영역 (120)및유출채널 (150)내의유체는유출구를통해배출될 수있다.이때,배출을위해유출밸브 (160)가개방될수있다.이후입도별로 분리된입자가배출될때에는유출밸브 (160)가유출채널 (150)을밀폐하여, 입자의흐름이배출채널 (400’)로향하도록할수있다.
3] 배출채널 (400’)은,입도별로분리된입자들을분리회수하기위한것으로서, 서로상이한경로를형성하는복수의분리배출채널 (사 0, 420)및복수의분리 배출채널 (410, 420)각각을개폐하는복수의분리배출밸브 (430, 440)를포함할 수있다.
4] 구체적으로,분리배출채널 (410, 420)은제 1입자를회수하기위한제 1분리 배출채널 (사 0),제 1분리배출채널 (410)을개폐하는제 1분리배출밸브 (430), 제 2입자를회수하기위한제 2분리배출채널 (420)및제 2분리배출
채널 (420)을개폐하는제 2분리배출밸브 (440)를포함할수있다.
5] 즉,제 2분리배출밸브 (440)가제 2분리배출채널 (420)을밀폐한상태에서제 1분리배출밸브 (430)가제 1분리배출채널 (410)을개방하면분리영역 (120)에 위치한입자가제 1분리배출채널 (사 0)로배출될수있으며,제 1분리배출 밸브 (430)가제 1분리배출채널 (사 0)을밀폐한상태에서제 2분리배출 밸브 (440)가제 2분리배출채널 (420)을개방하면분리영역 (120)에위치한 입자가제 2분리배출채널 (420)로배출될수있다.또한,배출채널 (400’)로 입자가배출되지않을때에는 (예를들어 ,유체가샘플채널 ( 100’)로유입되거나 이로부터유출될때)제 1분리배출밸브 (430)및제 2분리배출밸브 (440)가제 1 2020/175780 1»（：1^1{2019/018272 분리배출채널 (신 0)및제 2분리배출채널 (420)을밀폐하여,유체의흐름이 배출채널 (400’)로향하는것을방지할수있다.
6] 도 5에서는두개의분리배출채널 (410, 420)및이에대응하는분리배출
밸브 (430, 440)가도시되나,이는예시적인것으로서,실시예에따라하나또는셋 이상의분리배출채널및이에대응하는분리배출밸브가적용될수도있다. 7] 펌프부 (600)는,장치 (1000’)내의유체또는입자를이동시킬수있다.
펌프부 (600)는일단이분리영역 (120)과연통하는펌프채널 (610)및펌프 채널 ( 0)을개폐하는펌프밸브 (620)를포함할수있다.여기서펌프
채널 (610)은타단이펌프와연통하도록연결되어펌프의동작시펌프
채널 ( 0)을경유하여압력변화를야기할수있다.다만,실시예에따라, 펌프부 (600)는펌프채널 (610)내에펌프를포함할수도있다.
8] 펌프부 (600)는펌프를구동하여,펌프채널 (610)을통해연결된분리
영역 (120)으로압력변화를발생시킬수있다.이는분리영역 (120)및이와 연통된유출채널 (150),배출채널 (400’)등으로의유체또는입자흐름을야기할 수있다.이때펌프밸브 (620)는펌프의구동시펌프채널 (610)을개방하고, 펌프의미구동시에는펌프채널 ( 0)을밀폐하여,유체또는입자의흐름이펌프 채널 (610)에의해영향을받지않도록할수있다.
9] 구체적으로,펌프부 (600)는,챔버 (110)내로유체충전이완료되면,분리
영역 (120)및유출채널 (150)내의유체가유출구를향해이동시킬수있다.또한, 펌프부 (600)는전계부 (300)에의해입자의분리가완료되면,분리영역 (120)내의 입자를배출채널 (400’) (즉,제 1분리배출채널 (신 0)또는제 2분리배출 채널 (420))로이동시킬수있다.
[8이
[81] 도 6은본발명의실시예에따른입자분리농축장치의결합구조를도시한다.
[82] 도시되는바와같이，입자분리농축장치 (1000’)는상부기판 (1000¾및하부 기판 (1000¾)을포함할수있다.상부기판 (1000¾및하부기판 (1000¾)은유체 등이이동하는유관을형성하고,장치 (1000’)의일부로서밸브등이형성되거나 형성되는공간을제공할수있다.또한장치 (1000’)외부의구성과연통하는연통 홀이형성될수있다.
[83] 구체적으로,상부기판 (1000¾에는밸브가형성될수있다.상기밸브는유출 밸브 (160),게이트밸브 (130),펌프밸브 (620)및분리배출밸브 (430, 440)중 적어도하나를포함할수있다.또한,상기밸브는예를들어,선택적으로압력을 가하여하부기판 (1000¾)에위치한채널을막을수있는구조로이루어질수 있다.
[84] 또한,하부기판 (1000¾)에는,샘플채널 (100’),완충채널 (500),펌프채널 (610), 분리배출채널 (신 0, 420)등의각종채널의유관이형성될수있다.또한, 전기장을인가하기위한전계부 (300)의전극 (310, 320)이유출채널 (150)및완충 채널 (500)에각각위치할수있으며,이온투과막층 (200)이샘플채널 (100’)과완충 2020/175780 1»（：1^1{2019/018272 채널 (500)을연결하도록형성될수있다.또한,유체및/또는입자의 이동을위해 유입구등의 연통홀이 형성될수있다.
[85] 실시예에서 ,상부기판 (1000¾및하부기판 (1000¾)은플라즈마접합에 의해 서로결합할수있다.다만,이에 한정되는것은아니며,다양한기판결합기술이 적용될수있다.
[86] 실시예에서 ,상부기판 (1000¾및하부기판 (1000¾)중적어도일부는실리콘, 중합체등으로제조될수있다.상기중합체는 0] ；8(]301)^111 11)4 10 116)를 사용할수있다.
[87] 다만,도 6에서는상부기판 (1000¾및하부기판 (1000¾)이장치 (1000’)를
구성하는것으로도시되나,이는예시적인것으로서,실시예에 따라더 많은 또는더 적은기판이 적용될수있다.또한,상기 기재되는상하좌우의 방향은 편의상도면을기준으로한것이며,해당방향으로본발명의권리범위가 한정되는것은아니다.
[88]
[89] 을도시하고,
Figure imgf000013_0001
동작을 도시한다.
[9이 8710단계에서 ,챔버 (110)내로제 1입자및제 2입자를포함하는유체를
공급할수있다.구체적으로, 8710단계는샘플채널 (100’)로유체를유입하는 단계 및유체중일부 (분리 영역 (120)및유출채널 (150)내의유체)를배출하는 단계를포함할수있다.
[91] 도 8&를참조하면,샘플채널 (100’)로유체가유입되면,유체는순서대로유입 채널 (140),챔버 ( 0),분리 영역 (120)및유출채널 (150)을흐를수있다.이러한 흐름을위해게이트밸브 (130)및유출밸브 (160)는열린상태일수있으며,펌프 밸브 (620)및분리 배출밸브 (430, 440)는닫힌상태일수있다.
[92] 계속해서,도 ¾를참조하면,챔버 (110)내에유체가충전되면,게이트
밸브 (130)가닫힌상태로변화할수있다.즉,게이트밸브 (130)에의해 챔버 (110) 내의유체와분리 영역 (120)및유출채널 (150)내의유체가공간적으로분리될 수있다.이때펌프밸브 (620)가열린상태로변화할수있으며,펌프는압력을 변화시켜,분리 영역 (120)및유출채널 (150)내의유체를유출구를통해배출할 수있다.
[93] 실시예에서,방법 (700)은완충채널 (500)을완충용액으로충전하는단계를더 포함할수있다.상기 단계는 8710단계와동시에,또는그전후로수행될수 있다.
[94] 8710단계에 의해챔버 (110)내에유체가충전되면, 8720단계에서 ,
전계부 (300)는이온투과막층 (200)에 제 1전기장을인가할수있다.도 를 참조하면, 3720단계에의해 이온투과막층 (200)이 이온농도분극현상에의한 이온결핍영역을챔버 (110)측으로형성하게하여 입도별로제 1입자및제 2 2020/175780 1»（：1^1{2019/018272 입자가분리될수있다.특히제 1입자는분리 영역 (120)에위치할수있으며,제 2입자는챔버 ( 0)내에 위치할수있다.제 1입자및제 2입자의분리 이동을 위해 게이트밸브 (130)및유출밸브 (160)는열린상태일수있으며,펌프 밸브 (620)및분리 배출밸브 (430, 440)는닫힌상태일수있다.
[95] 계속해서, 3730단계에서,챔버 (110)의 타측에 형성되는분리 영역 (120)에
위치한제 1입자를배출할수있다.제 1입자를제 2입자와는분리하여 회수하기 위한것이다.도 8(1를참조하면,게이트밸브 (130)가닫힌상태로 변화할수있다.즉,게이트밸브 (130)에 의해챔버 (110)내의제 2입자와분리 영역 (120)내의 제 1입자가공간적으로분리될수있다.또한,펌프밸브 (620)및 제 1분리 배출밸브 (430)가열린상태로변화하고,유출밸브 (160)는닫힌상태로 변화할수있다.이를통해펌프채널 ( 0)로부터분리 영역 (120)을거쳐제 1 분리 배출채널 (사 0)까지의분리 배출경로가연통할수있다.이때,펌프는 압력을변화시켜,분리 영역 (120)내의 제 1입자를제 1분리 배출채널 (신 0)로 이동시킬수있다.
[96] 계속해서, 3740단계에서,전계부 (300)는,제 2전기장을인가할수있다.도
8 를참조하면, 8740단계를통해챔버 (110)내에 제 2입자가분리 영역 (120)으로 이동할수있다.이때,제 2입자의 이동을위해 게이트밸브 (130)및유출 밸브 (160)는열린상태일수있으며,펌프밸브 (620)및분리 배출밸브 (430,
440)는닫힌상태일수있다.
[97] 계속해서 , 8750단계에서 ,분리 영역 (120)내의 제 2입자를배출할수있다.제 2 입자를회수하기위한것이다.도 8를참조하면,게이트밸브 (130)가닫힌 상태로변화할수있다.즉,게이트밸브 (130)에의해분리 영역 (120)내의제 2 입자가챔버 (110)와공간적으로분리될수있다.또한,펌프밸브 (620)및제 2 분리 배출밸브 (440)가열린상태로변화하고,유출밸브 (160)는닫힌상태로 변화할수있다.이를통해펌프채널 ( 0)로부터분리 영역 (120)을거쳐제 2 분리 배출채널 (420)까지의분리 배출경로가연통할수있다.이때,펌프는 압력을변화시켜,분리 영역 (120)내의 제 2입자를제 2분리 배출채널 (420)로 이동시킬수있다.
[98] 방법 (700)은제 1입자및제 2입자의분리과정에 대해 개시하고있으나,이는 예시적인것으로서 ,그보다적은또는그보다많은입자의분리에도상기 방법이 적용될수있다.또한,상기 방법과관련하여
Figure imgf000014_0001
내지도 8에서는두개의분리 배출채널 (410, 420)및이에 대응하는분리 배출밸브 (430, 440)이도시되나,이는 예시적인것으로서,실시예에따라하나또는셋이상의분리 배출채널및 이에 대응하는분리 배출밸브가적용될수도있다.
[99]
[100] 도 9는본발명의실시예에따른입자분리농축장치의동작을도시한다.
[101] 도 9를참조하면,전계부가전기장을형성하였을때,이온투과막층 (예를들어, 나피온)에서 이온농도분극현상이 발생할수있다.구체적으로,전극에각각 0, 10, 20 V의전압을인가하여전기장을발생시킬수있다.전기장이
이온투과막층에인가되면,채널내에는이온결핍영역이형성되어,챔버내의 입자 (예를들어, lOOnm리포좀)가이온결핍영역주변으로,즉분리영역으로 밀려나게된다.
[102] 특히,전극에인가되는전압이증가할수록이온결핍영역이커지고,이에따라 입자가밀려나는거리또한증가하게된다.따라서전기장의세기를조절하여 이온결핍영역의크기를조절하고,이에따라입자가분리농축되는위치를 조절할수있다.
[103]
[104] 도 10은본발명의실시예에따른입자분리농축장치의동작을도시한다.
[105] 전계부가이온투과막층 (200)을향하여전기장을인가하면,
이온투과막층 (200)은챔버 (110)를향하여이온결핍영역을형성할수있다.이에 따라챔버 (no)내의입자들은전기삼투에의한항력과전기영동력이평형을 이루는위치로이동할수있다.
[106] 구체적으로,도 W의 (a)는제 1전기장하에서크기가 WOnm인입자의분리 농축상태를도시하고,도 W의 (비는제 1전기장하에서크기가 500nm인입자의 분리농축상태를도시한다.
[107] 도시되는바와같이,동일한전기장이인가되더라도,입자는그크기에따라 상이한 (평형)위치로이동하여분리농축되게된다.특히,크기가큰입자일수록 이온투과막층 (200)으로멀어짐을알수있다.
[108] 이때,이온투과막층 (200)에인가되는전기장의세기를증가시키면,입자들의 평형위치가변화될수있다.구체적으로,도 W의 ( 는증가된전기장하에서 크기가 WOnm인입자의분리농축상태를도시하고,도 W의 (d)는증가된전기장 하에서크기가 500nm인입자의분리농축상태를도시한다.도시되는바와같이 , 전기장의세기가증가하면,각입자는이온투과막층 (200)으로부터멀어지는 방향으로추가적으로이동함을알수있다.
[109]
[110] 도 11은본발명의실시예에따른입자분리농축장치의동작을도시한다.
[111] 챔버내에 lOOnm, 300nm리포좀을충전하고,전계부에 0.7 ^iA전기장을
인가하였다.
[112] WOnm, 300nm리포좀은전기삼투에의한항력과전기영동력이평형을
이루는위치로이동할수있다.구체적으로, WOnm리포좀은이온투과막층 (예를 들어,나피온)주변에서농축되고, 300nm리포좀은보다멀리밀려나서농축되게 된다.즉,리포좀이입도별로분리농축되는것을알수있다.
[113] 전기장을인가하고 2분이경과한시점에두리포좀의분리능 (separation
resolution, Rs)은계산하였다.여기서분리능은 (peak to peak distance)/( average width of bands)에의해계산될수있으며 , lOOnm와 300nm리포좀의경우에 , 분리능이계산되었다. 2020/175780 1»（：1^1{2019/018272
[114] 분리능이 1이상이라는것은가우시안분포상겹칩이없는완전한분리를
의미하며 ,따라서 011111, 30011111리포좀입자가완벽하게분리되었음을알수 있다.
[115]
[116] 도 12는본발명의실시예에따른입자분리농축장치의동작을도시한다.
[117] 챔버내에 엑소좀과 30011111리포좀을충전하고,전계부에 0.7 ^전기장을
인가하였다.
[118] 엑소좀과 30011111리포좀은전기삼투에의한항력과전기영동력이평형을
이루는위치로이동할수있다.구체적으로,엑소좀은이온투과막층 (예를들어, 나피온)주변에서농축되고, 30011111리포좀은보다멀리밀려나서농축되게된다. 즉,입도별로분리농축되는것을알수있다
[119] 또한,전기장을인가하고 4분이경과한시점에두입자의분리능은 3.38 (=
(494.44 ^((77.78 ^ + 137.22나111)/2)))로서 ,두입자가완벽하게분리되었음을 확인할수있다.
[12이
[121] 이상과같이실시예들이비록한정된실시예와도면에의해설명되었으나, 해당기술분야에서통상의지식을가진자라면상기의기재로부터다양한수정 및변형이가능하다.예를들어,설명된기술들이설명된방법과다른순서로 수행되거나,및/또는설명된시스템,구조,장치,회로등의구성요소들이설명된 방법과다른형태로결합또는조합되거나,다른구성요소또는균등물에의하여 대치되거나치환되더라도적절한결과가달성될수있다.그러므로,다른 구현들,다른실시예들및특허청구범위와균등한것들도후술하는
특허청구범위의범위에속한다.

Claims

2020/175780 1»（：1/10公019/018272 청구범위
[청구항 1] 입자분리농축장치로서 ,
제 1입자및제 2입자를포함하는유체가제공되는챔버; 상기챔버의일측에배치되는이온투과막층;
상기이온투과막층에전기장을인가함으로써상기이온투과막층이 이온농도분극현상에의한이온결핍영역 (ion depletion zone)을상기챔버 측으로형성하게하여입도별로상기제 1입자및상기제 2입자를 분리하는전계부;
상기챔버의타측에형성되고,상기전계부에의해분리되는상기제 1 입자및상기제 2입자중하나의입자가위치하는분리영역 ;및 상기분리영역에위치한입자가배출되는배출채널을포함하고, 상기전계부는상기전기장의세기를변화하여상기제 1입자및상기제 2입자가순차적으로상기분리영역에위치하게하는,장치 .
[청구항 2] 제 1항에 있어서,
상기전계부는,상기제 1입자가상기분리영역에위치하고상기제 2 입자가상기챔버내에위치하도록제 1전기장을인가하고,상기제 1 입자가상기배출채널을통해배출된후에,상기전계부는상기제 2 입자가상기분리영역에위치하도록제 2전기장을인가하는,장치 .
[청구항 3] 제 2항에 있어서,
상기제 1입자는상기제 2입자보다크고,상기제 1전기장은상기제 2 전기장보다작은,장치 .
[청구항 4] 제 1항에 있어서,
상기분리영역을상기챔버로부터연통하거나차단하는게이트밸브가 상기챔버와상기분리영역사이에형성되는,장치.
[청구항 5] 제 4항에 있어서,
유입구가형성되고상기챔버의상기일측으로연장되는유입채널, 유출구가형성되고상기분리영역의타측으로연장되는유출채널및 상기유출채널을개폐하는유출밸브를포함하는샘플채널을더 포함하고,
상기샘플채널로상기유체가유입되면,상기게이트밸브에의해상기 챔버가상기분리영역으로부터차단되어상기챔버내의유체가 고립되고,상기유출밸브가개방되어상기분리영역및상기유출채널 내의유체가상기유출구를통해배출되며 ,
상기유출밸브는상기분리영역에위치한입자가상기배출채널을통해 배출될때상기유출채널을밀폐하는,장치.
[청구항 6] 제 4항에 있어서,
일단이상기분리영역과연통하고타단이펌프와연통하는펌프채널 및상기펌프채널을개폐하는펌프밸브를포함하여상기펌프의압력 변화를통해상기분리영역에위치한입자를이동시키는펌프부를더 포함하는,장치 .
［청구항 7］ 제 6항에 있어서,
상기게이트밸브가상기분리영역내의입자를상기챔버로부터 차단하면,상기펌프부는상기분리영역내의입자를상기배출채널로 이동시키는,장치 .
［청구항 8］ 제 1항에 있어서,
상기배출채널은,서로상이한경로를형성하는복수의분리배출채널 및상기복수의분리배출채널각각을개폐하는복수의분리배출밸브를 포함하는,장치 .
［청구항 9］ 제 8항에 있어서,
제 1분리배출밸브가제 1분리배출채널을밀폐한상태에서제 2분리 배출밸브가제 2분리배출채널을개방하면,상기분리영역에위치한 입자가상기제 2분리배출채널로배출되고,
상기제 2분리배출밸브가상기제 2분리배출채널을밀폐한상태에서 상기제 1분리배출밸브가상기제 1분리배출채널을개방하면,상기 분리영역에위치한입자가상기제 1분리배출채널로배출되는,장치 .
［청구항 ］ 입자분리농축장치의동작방법으로서,
챔버내로제 1입자및제 2입자를포함하는유체를공급하는단계; 상기챔버의일측에배치되는이온투과막층이이온농도분극현상에 의한이온결핍영역 (ion depletion zone)을상기챔버즉으로형성하게하여 입도별로상기제 1입자및상기제 2입자가분리되도록상기
이온투과막층에제 1전기장을인가하는단계;
상기챔버의타측에형성되는분리영역에위치한상기제 1입자를 배출하는단계 ;
상기챔버내에위치하는상기제 2입자가상기분리영역으로 이동하도록제 2전기장을인가하는단계;및
상기분리영역내에위치하는상기제 2입자를배출하는단계를 포함하는,방법 .
［청구항 11］ 제 W항에 있어서,
상기제 1입자는상기제 2입자보다크고,상기제 1전기장은상기제 2 전기장보다작은,방법 .
［청구항 12］ 제 W항에 있어서,
상기챔버와상기분리영역사이에위치하는게이트밸브를통해상기 분리영역을상기챔버로부터차단하는단계를더포함하는,방법.
［청구항 제 12항에 있어서,
상기제 1입자를배출하는단계및상기제 2입자를배출하는단계는, 2020/175780 1»（：1/10公019/018272 상기차단하는단계이후에,상기분리영역에위치한입자를배출채널로 이동시킴으로써수행되는,방법 .
PCT/KR2019/018272 2019-02-25 2019-12-23 입자 분리 농축 장치 및 그 동작 방법 WO2020175780A1 (ko)

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