KR100860075B1 - Micro filtration device for the separation of blood plasma and method for fabricating the same - Google Patents

Abstract

The present invention relates to a micro-filter element and a method for manufacturing the same for separating blood plasma from whole blood, which can find biological information of the human body, and for the present invention, a whole blood inlet for introducing whole blood; A plasma outlet through which plasma separated from the introduced whole blood is released to the outside; A microchannel connecting the whole blood inlet and the plasma outlet; A micropump formed under the whole blood inlet and the microchannel formed in the microchannel to separate the plasma from the whole blood to move the whole blood introduced into the plasma outlet through the microchannel by the air pressure generated by itself without external driving. It provides a micro filter element comprising a microstructure.

Whole blood, plasma, microheater, microstructure, polymer, biochip

Description

Micro filter element for plasma separation and its manufacturing method {MICRO FILTRATION DEVICE FOR THE SEPARATION OF BLOOD PLASMA AND METHOD FOR FABRICATING THE SAME}

The present invention relates to a micro filter element and a method for manufacturing the same, and more particularly, to a micro filter element and a method for manufacturing the same that can separate plasma from the whole blood itself without external driving.

The present invention is derived from the research conducted as part of the IT new growth engine core technology development project of the Ministry of Information and Communication and the Ministry of Information and Communication Research and Development. [Task Management No .: 2006-S-007-01, Title: Ubiquitous Health Management Module] /system]

In general, whole blood, human blood, is the best indicator for diagnosing health because it collects and contains a lot of information while constantly circulating inside all human tissues.

In particular, a protein chip, which is a kind of biochip, can diagnose specific cancer by quantitatively detecting or concentrating specific proteins dissolved in plasma from whole blood samples. At this time, the whole blood of a person used includes blood cell components such as red blood cells, white blood cells and platelets, and plasma components such as water, proteins, fats, sugars and other mineral ions. Therefore, it is very important to manufacture a biochip that can be detected with high sensitivity by effectively removing blood cells and other unnecessary components in human blood to isolate or concentrate only a specific protein.

Accordingly, various methods have been proposed for separating plasma from whole blood. For example, by placing microstructures smaller than blood cells in the flow path and pumping blood with a syringe pump installed outside, blood cells are filtered by the microstructures so that only plasma is extracted. A low-level diaphragm that prevents the release of plasma components only through the diaphragm by capillary forces; a porous medium or membrane is placed on the side or front of the blood flow to separate blood cells; By using the sedimentation effect of the blood cells caused by the formation of the blood cells and plasma layered method to extract only the plasma, the method of deflecting the flow of blood cells by applying an electrical signal has been proposed.

Hereinafter, looking at the conventional technical field proposed to separate plasma from whole blood.

Korean Patent No. 10-0577367, registered on April 28, 2006, entitled "Powerless Micro Blood Separator", suggests an apparatus for separating plasma by forceless capillary force. It is characterized in that the blood cell is installed by the blood extraction unit so as not to pass through only the plasma passes through the capillary force.

International Publication No. WO 04/027391, published on April 1, 2004 under the name of "blood analyzer and method of separating plasma," is provided with blood collection means, plasma separation means, and analysis means sequentially, An automatic analyzer for separating plasma in a flow path has been proposed, and the size of some flow paths is manipulated so that blood cell components can be stored and plasma components proceed smoothly.

United States Patent No. US 2005/0069459 A1, registered March 31, 2005, entitled “On chip sample preparation for whole blood analysis,” forms a channel on a biochip to separate biological particles and a large and short section at the inlet. We propose a technique and a device for separating by changing the particle transfer force by applying a pressure pulse of. It can be separated without a filter structure in the microchannel.

International Publication No. WO99 / 058172, published May 13, 1999 under the name of "filter device and method for processing blood," is wound in a state in which a blood processing filter layer and a space on a sheet in which blood flows more easily are stacked. It is related with the blood process filter apparatus which exposed the edge part of the sheet-shaped space layer to the outer peripheral surface or outer peripheral surface of a filter material. The laminated structure is spirally wound, and the filter material is characterized by using a nonwoven fabric, a woven fabric, a porous sheet, or the like.

However, in the related art, blood cells are stacked on a microstructure, a diaphragm, a membrane, a porous medium formed to separate plasma from whole blood, and the separation efficiency of plasma is reduced while closing the flow path, or it takes a long time to separate plasma. There is this. In addition, when an external device, such as a syringe pump, is used to move the sample, there is a problem in that it is difficult to separate or concentrate plasma continuously and efficiently due to a complicated driving method.

The present invention has been proposed to solve the above problems, and an object of the present invention is to provide a micro filter device and a method for manufacturing the same, which can separate plasma from whole blood by itself without the help of an external device such as a syringe pump.

Another object of the present invention is to provide a micro-filter element and a method for manufacturing the same, which use a microstructure to separate plasma from whole blood, and prevent the phenomenon of plasma separation efficiency being reduced by stacking blood cells on the microstructure. have.

Another object of the present invention is to provide a micro filter device and a method of manufacturing the same, which can separate or concentrate a specific biomaterial from separated plasma.

Another object of the present invention is to provide a micro filter device and a method of manufacturing the same, which can be manufactured at a low price so that it can be used as a disposable biochip.

Micro-filter element of the present invention according to an aspect for achieving the above object is a whole blood inlet for introducing whole blood; A plasma outlet through which plasma separated from the introduced whole blood is released to the outside; A microchannel connecting the whole blood inlet and the plasma outlet; Separating the plasma from the whole blood formed in the micro-channel and the micro-pump formed under the whole blood inlet to move the whole blood introduced into the plasma discharge direction through the micro channel by the air pressure generated by itself without external drive It may include a microstructure for.

The micropump includes a closed cavity; It may include a micro-heater for generating heat to expand or contract the air in the sealed cavity and a membrane formed in the cavity and driven according to the air pressure in the cavity.

The microstructures may include a first microstructure for separating blood cells from whole blood and a second microstructure in which complementary capture probe ligands are formed to separate or concentrate desired biomaterials.

The whole blood inlet and the plasma outlet may be formed in an upper substrate, the microchannel and the micropump may be formed in a lower substrate, and the upper substrate and the lower substrate may be aligned and sealed with each other. In this case, the upper substrate and the lower substrate may be formed of a plastic polymer, respectively.

In addition, the micro-filter device of the present invention further comprises a whole blood tank formed between the whole blood inlet and the micropump to store the introduced whole blood and a plasma tank formed below the plasma discharge port to store plasma separated from the whole blood. It may include.

According to another aspect of the present invention, there is provided a method of manufacturing a micro filter device, the method including: forming whole blood inlets for introducing whole blood into one side of an upper substrate; Forming a plasma room outlet through which plasma separated from whole blood flowing into the other side of the upper substrate is discharged to the outside; Forming a micropump on the lower substrate corresponding to the whole blood inlet to move whole blood by air pressure generated by itself without external driving; Forming a microchannel connecting the whole blood inlet and the plasma outlet on the lower substrate, forming a microstructure for separating plasma from whole blood in the microchannel, and adhering the upper substrate and the lower substrate to each other; Sealing may be included.

The forming of the micro pump may include forming a micro heater on the lower substrate; And forming a cavity at the same time as forming the support layer to surround the microheater, and forming a membrane on the support layer to seal the cavity.

The forming of the microchannel and the microstructure may include bonding a dry film resist on the lower substrate and exposing the dry film resist using a mask on which a microchannel and a microstructure pattern are formed. Developing may be included.

The upper substrate and the lower substrate may be sealed through a laminating process, and the upper substrate and the lower substrate may be each formed of a plastic polymer.

In addition, the method for manufacturing a micro filter device of the present invention may further include forming a complementary capture probe ligand for separating a desired biomaterial into the microstructure.

In addition, the method of manufacturing a micro filter device of the present invention may further include forming a whole blood tank for storing whole blood introduced into the lower substrate and a plasma tank for storing plasma separated from whole blood in the lower substrate. have.

 The present invention has the effect of simplifying the driving method as compared to the micro-filter element that separates the plasma through the external drive by forming a micropump operated by the air pressure generated by itself without the external drive inside the micro-filter element. In addition, there is an effect that can separate the plasma continuously and efficiently. In addition, the plasma can be separated from the whole blood in a short time, thereby accumulating blood cells in the microstructure, thereby preventing the phenomenon of decreasing plasma separation efficiency.

In addition, the micro-filter device of the present invention has an effect of separating or concentrating a desired specific biomaterial from the separated plasma by forming a microstructure to which the complementary capture probe ligand is attached.

In addition, by manufacturing the micro-filter element of the present invention made of a plastic polymer at a low cost, there is an effect that can be applied to a disposable biochip for detecting a specific disease using blood.

DETAILED DESCRIPTION Hereinafter, the most preferred embodiments of the present invention will be described with reference to the accompanying drawings so that those skilled in the art can easily implement the technical idea of the present invention. . Also in the figures, the thicknesses of layers and regions are exaggerated for clarity, and where it is said that a layer is on another layer or substrate it may be formed directly on another layer or substrate, Alternatively, a third layer may be interposed therebetween. Also, like reference numerals denote like elements throughout the specification.

1A is a perspective view illustrating a structure of a micro filter device according to an exemplary embodiment of the present invention, and FIG. 1B is a cross-sectional view taken along the line Y-Y ′ of FIG. 1A.

As shown in Figure 1a and Figure 1b, the micro-filter element of the present invention is a whole blood inlet 110, the whole blood flows inlet plasma, the plasma discharge port 120 is separated from the introduced whole blood is discharged to the outside, whole blood inlet ( 110, the microchannel 290 connecting the plasma outlet 120, to move the whole blood flows toward the plasma outlet 120 through the microchannel 290 by the air pressure generated by itself without external drive It is formed in the micro-pump (P) and the micro-channel 290 formed below the whole blood inlet 110 and includes a microstructure 270 for separating plasma from whole blood. In this case, the whole blood inlet 110 and the plasma outlet 120 may be formed on the upper substrate 100, and the microchannel 290, the microstructure 270, and the micropump P may be disposed on the lower substrate 200. The upper substrate 100 and the lower substrate 200 may be formed to be aligned and sealed to each other.

Here, the micropump (P) is formed inside the cavity 220, the micro-heater 210 and the cavity 220 for generating heat to expand or contract the air in the sealed cavity 220, the sealed cavity 220 It may include a membrane 230 for driving in accordance with the air pressure inside the 220. The support layer 260 may be further included to surround the microheater 210 to support the membrane 230.

Here, the micro heater 210 may be formed of a conductor, for example, gold (Au), to which a pulse bias is applied from the outside, and the support layer 260 may be formed of an insulating film, for example, silicon oxide (SiO ₂ ). can do.

The microstructure 270 is formed of a first microstructure 271 for separating plasma from the introduced whole blood and a second microstructure having a complementary capture probe ligand 300 capable of separating or concentrating a desired biomaterial from the separated plasma. It can include a structure 272. At this time, the first microstructure 271 for separating plasma from whole blood is preferably formed to have a space of about 5um. This is because the size of blood cell components such as red blood cells, white blood cells and platelets is generally 7 μm to 8 μm.

In addition, the microstructure 270 may be formed in a cylindrical, square, rectangular, and polyhedral form, and may be formed in the microchannel 290 singly or in combination thereof. In addition, the microstructures 270 may be arranged regularly or irregularly in the microchannel 290.

In addition, the micro filter device of the present invention may further include a whole blood tank 240 formed between the whole blood inlet 110 and the micropump P to store whole blood introduced through the whole blood inlet 110. In addition, in order to store the separated plasma may further include a plasma tank 250 formed below the plasma discharge port 120. In this case, the whole blood tank 240 and the plasma tank 250 may be formed to be connected to each other through the microchannel 290.

The upper substrate 100 and the lower substrate 200 may be formed of any one of a plastic polymer, silicon, glass, or rubber, and preferably, the upper substrate 100 and the lower substrate 200 may be formed of a plastic polymer having a low cost so as to be utilized in a disposable biochip. Plastic polymers include, for example, cycloolefin copolymers (COC), polydimethyl siloxane (PDMS), polymethylmethacrylate (PMMA), polycarbonate (PC), poly Amide (polyamide, PA), polyethylene (PE), polypropylene (PP), polyphenylene ether (PPE), polystyrene (PS), polyoxymethylene (POM), poly Polyetheretherketone (PEEK), polytetrafluoroethylene (PTFE), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (polybutyleneterephthalate, PBT) ), Fluorinated ethylenepropylene (FEP) and perfluoroalkoxyalkane (PFA) One can feel used.

Next, the operation principle of the micro filter device of the present invention will be described.

First, once the whole blood sample is introduced into the micro filter element through the whole blood inlet 110, it is stored in the whole blood tank 240. At this time, assuming that the whole blood sample injected through the whole blood inlet 110 is full in the whole blood tank 240, since the pressure difference does not change in such a situation, the whole blood sample will be stopped in the whole blood tank 240. In this state, when a pulse bias, for example, a voltage is periodically applied or shielded to the microheater 210 formed under the whole blood tank 240 to move the stopped whole blood sample, heat is generated or cooled by the microheater 210. Air expands or contracts in the sealed cavity 220. Accordingly, while the pressure in the sealed cavity 220 increases or decreases, the membrane 230 moves up and down. At this time, it is preferable to keep the temperature of the whole blood sample in the whole blood tank 240 lower than body temperature, that is, 36.5 ° C. so that the biomaterial existing in the whole blood sample introduced by the heat provided by the micro heater 210 is not destroyed. .

Subsequently, the whole blood sample stopped in the whole blood tank 240 is transferred to the microchannel 290 due to the up / down movement of the membrane 230, and is formed by the first microstructure 271 formed in the microchannel 290. Blood cell components, such as leukocytes, red blood cells, and platelets, can no longer progress and are filtered out, and plasma components, such as water, proteins, fats, sugars, and mineral ions, can pass through the first microstructure 271. And FIG. 4)

Subsequently, the desired biotide is formed by the second microstructure 272 having the complementary capture probe ligand 300 formed to capture specific biomaterials having desired biological information in the plasma components passed through the first microstructure 271. The material may be separated or concentrated. The separated plasma is first stored in the plasma tank 250 and is discharged to the outside of the chip through the plasma discharge port 120.

As described above, the micro-filter element of the present invention forms a micropump that operates by air pressure generated by itself without external driving, thereby enabling simple, continuous and efficient plasma separation. In addition, plasma can be separated from whole blood in a short time, and thus, a phenomenon in which blood cells accumulate in the microstructure and plasma separation efficiency is reduced can be prevented.

In addition, the micro-filter element of the present invention can form a microstructure with a complementary capture probe ligand attached thereto, thereby separating or concentrating a specific biomaterial from the separated plasma.

In addition, by fabricating the micro-filter element of the present invention with a low-cost plastic polymer, it can be applied to disposable biochips that detect specific diseases using blood.

2A to 2H are cross-sectional views illustrating a method of manufacturing a microfilter device according to an exemplary embodiment of the present invention, taken along the line X-X ′ of FIG. 1A. 2A to 2E are methods for manufacturing the lower substrate, 2F to 2G are methods for manufacturing the upper substrate, and FIG. 2H is for bonding and sealing the upper and lower substrates.

As shown in FIG. 2A, the micro heater 210 is formed in a predetermined region on the lower substrate 200. The micro heater 210 may form a conductor, for example, gold (Au) to a thickness of about 1000 kW by using E-beam evaporation.

Here, the micro heater 210 may be formed using various known semiconductor manufacturing techniques. For example, after forming a conductive film for a micro heater on the lower substrate 200, it may be formed through a photo etching process. In addition, after the photosensitive film pattern is formed on the lower substrate 200, a conductive film for a micro heater is formed on the entire surface including the photosensitive film pattern, and then a lift-off method of removing the photosensitive film may be performed. It may be.

The lower substrate 200 may be formed of any one of a plastic polymer, silicon, glass, or rubber, and preferably, the lower substrate 200 may be formed of an inexpensive plastic polymer so that the lower substrate 200 may be utilized in a low-cost disposable biochip. Plastic polymers include, for example, cycloolefin copolymers (COC), polydimethyl siloxane (PDMS), polymethylmethacrylate (PMMA), polycarbonate (PC), poly Amide (polyamide, PA), polyethylene (PE), polypropylene (PP), polyphenylene ether (PPE), polystyrene (PS), polyoxymethylene (POM), poly Polyetheretherketone (PEEK), polytetrafluoroethylene (PTFE), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (polybutyleneterephthalate, PBT) ), Fluorinated ethylenepropylene (FEP) and perfluoroalkoxyalkane (PFA) One can feel used.

As shown in FIG. 2B, the support layer 260 is formed on the lower substrate 200 to surround the micro heater 210. At this time, an area surrounded by the support layer 260 on the micro heater 210 becomes the cavity 220. The support film 260 may be formed of an insulating film, for example, a silicon oxide film.

Subsequently, the adhesion of the micro-heater 210. After placing the membrane 230 to the upper, the membrane 230 to the support film 260 by an oxygen plasma treatment (O ₂ plasma treatment). At this time, the cavity 220 is sealed while the support membrane 260 and the membrane 230 are bonded to each other.

In this case, the oxygen plasma treatment may be performed for 20 minutes by applying a bias of 100 W while injecting oxygen gas into the reaction chamber.

Meanwhile, in order to increase the adhesion between the support membrane 260 and the membrane 230, the lower substrate 200 is placed in a convection oven and left at 70 ° C. for 30 minutes to remove moisture from the surface. You can also proceed with the pretreatment process.

Through such a process, the micropump P including the micro heater 210, the sealed cavity 220, and the membrane 230 may be formed.

As shown in FIG. 2C, a first dry film register (DFR) is attached to an upper portion of the lower substrate 200 on which the micropump P is formed. A method of bonding the first DFR 280 is, first, an interface promoter on the lower substrate 200 on which the micropump P is formed, for example, spin coating of the AP3000. In this case, spin coating may be performed for 20 seconds at 2000 rpm. Next, tens or hundreds of micrometer-thick first DFR 280 may be laminated and bonded at a temperature of 120 ° C. and a pressure of 5 kg / cm ² .

As shown in FIG. 2D, the whole blood in the first DFR 280 is exposed and developed using a mask in which the whole blood tank 240, the plasma tank 250, the microchannel 290, and the microstructure 270 pattern are formed. The tank 240, the plasma tank 250, the microchannel 290 and the microstructure 270 are formed. In this case, the whole blood tank 240 and the plasma tank 250 are formed to be connected to each other by the microchannel 290, and the microstructure 270 is formed to be located in the microchannel 290.

Here, the exposure and development steps using a mask can be performed a plurality of times. That is, the whole blood tank 240, the plasma tank 250, the microchannel 290 and the microstructure 270 are all formed at one time by using a patterned mask or a plurality of masks each having a different pattern are formed. It may be formed by.

The exposure and development process using a mask in which the whole blood tank 240, the plasma tank 250, the microchannel 290, and the microstructure 270 patterns are formed is equipped with a mask on a contact aligner and the first DFR (280). ) Is formed by exposing a mask pattern to the first DFR by scanning 20 mW of UV light for 20 seconds on the entire lower substrate 200 and then developing the mask pattern.

Here, the microstructure 270 may be formed of a first microstructure 271 for separating plasma from whole blood and a second microstructure 272 on which a complementary capture probe ligand is formed to separate or concentrate a desired biomaterial. Can be.

At this time, the first microstructure 271 for filtering blood cells from whole blood is preferably formed to have an interval of about 5um. This is because the size of blood cell components such as red blood cells, white blood cells and platelets is generally 7 μm to 8 μm.

In addition, the microstructure 270 may be formed in the form of cylinders, squares, rectangles, and polyhedrons alone or in combination of a plurality thereof. In addition, the arrangement of the microstructures 270 may be arranged regularly or irregularly.

As shown in FIG. 2E, the complementary capture probe ligand 300 is immobilized on the surface of the second microstructure 272 to isolate or concentrate the specific biomaterial. At this time, the method of fixing the ligand 300 to the second microstructure 272, by selecting a linker molecule (linker molecule) in accordance with the ligand to be fixed first fixed to the second microstructure 272, and then on the ligand The method of fixing the 300 is used a lot, the methods and types are various and many documents are already disclosed, so detailed description thereof will be omitted.

Through such a process, the lower substrate 200 including the micropump P, the whole blood tank 240, the plasma tank 250, the microchannel 290, and the microstructure 270 may be formed.

As shown in FIG. 2F, the whole blood inlet 110 and the plasma outlet 120 are formed on the upper substrate 100 by drilling. In this case, the upper substrate 100 may be formed of any one of a plastic polymer, silicon, glass, or rubber, and preferably, the upper substrate 100 may be formed of an inexpensive plastic polymer so that the upper substrate 100 may be utilized in a low-cost disposable biochip.

As shown in FIG. 2G, the second DFR 130 is attached to the entire surface of the upper substrate 100 on which the whole blood inlet 110 and the plasma outlet 120 are formed. In this case, since the DFR is not adhered to a non-hydrophilic surface, the DFR may be adhered when the upper substrate 100 is a substrate having a non-hydrophilic surface such as a plastic polymer, for example, cycloolefin copolymer (hereinafter, COC). none. Therefore, in the case of using a material having a non-hydrophilic surface as the upper substrate 100, the surface must be changed to hydrophilic through a pretreatment process such as oxygen plasma treatment. For example, when COC is used as the upper substrate 100, oxygen plasma treatment at 100 W for 20 minutes may make the COC surface hydrophilic.

Subsequently, after spin coating the interfacial adhesive on the upper substrate 100, the second DFR 130 having a thickness of several tens of micrometers is attached onto the upper substrate 100. In this case, the second DFR may be laminated on the upper substrate 100 by laminating at a temperature of 120 ° C. and a pressure of 5 kg / cm ² .

Here, the whole blood inlet 110 and the plasma outlet 120 are blocked in the process of forming the second DFR 130 on the upper substrate 100 on which the whole blood inlet 110 and the plasma outlet 120 are formed. Since the thickness of the 2DFR 130 is very thin, several tens of micrometers, it is drilled when connecting a teflon hose to the inlet and outlet of the sample to the whole blood inlet 110 and the plasma outlet 120.

Through such a process, an upper substrate including the whole blood inlet 110 and the plasma outlet 120 may be formed.

As shown in FIG. 2h, the upper substrate 100 and the micropump P, the whole blood tank 240, the plasma tank 250, and the microchannel 290 on which the whole blood inlet 110 and the plasma outlet 120 are formed. And the lower substrate 200 including the microstructure 270 to be bonded and sealed. At this time, the method for sealing the upper substrate 100 and the lower substrate 200 is spin-coated the interface adhesive on the lower substrate 200, and then aligned and positioned the upper substrate 100 on the lower substrate 200. . In this case, the first DFR 280 and the second DFR 130 face each other. It can then be laminated and sealed at a temperature of 120 ° C. and a pressure of 5 kg / cm ² .

3 is an image showing the progress of the plasma separation experiment using the micro-filter device of the present invention, Figure 4 is an enlarged image of the microstructure region of FIG. At this time, the micro filter element used in the experiment is the same as the micro filter element shown in Figs. 1A and 1B, except that only the microstructure for separating plasma from whole blood is formed.

3 and 4, once whole blood is introduced into the micro filter element through the whole blood inlet, the whole blood is stored in the whole blood tank 240. The stored whole blood is moved along the microchannel 290 itself without external driving due to the micropump formed under the whole blood tank 240. In this case, the blood cells are filtered by the microstructure 270 formed in the microchannel 290, and the separated plasma may be moved to the plasma tank 250.

As described above, the present invention provides a simple driving method as compared with the micro filter device that separates plasma through external driving by forming a micro pump inside the micro filter device. Through this, plasma can be separated continuously and efficiently, and plasma can be separated from whole blood in a short time. In addition, the accumulation of blood cells in the microstructure can prevent the phenomenon that the plasma separation efficiency is reduced.

Although the technical spirit of the present invention has been described in detail according to the above preferred embodiment, it should be noted that the above embodiment is for the purpose of description and not of limitation. In addition, those skilled in the art will appreciate that various embodiments within the scope of the technical idea of the present invention are possible.

1A is a schematic diagram schematically showing the structure of a micro filter element of the present invention.

FIG. 1B is a cross-sectional view taken along the line Y-Y 'of FIG. 1A; FIG.

2A to 2H are cross-sectional views illustrating a method of manufacturing the microfilter device according to the exemplary embodiment of the present invention, taken along the line X-X ′ of FIG. 1A.

Figure 3 is an image showing the progress of the plasma separation experiment of the micro-filter device manufactured according to an embodiment of the present invention.

4 is an enlarged view of a portion of the microstructure of FIG. 3.

*** Explanation of symbols on the main parts of the drawing ***

100: upper substrate 110: whole blood inlet

120: plasma outlet 200: lower substrate

210: micro heater 220: cavity

230: membrane 240: whole blood tank

250: plasma tank 260: support membrane

270: microstructure 290: microchannel

271: first fine structure 272: second fine structure

300: ligand

Claims (22)

In a micro filter element for separating plasma from whole blood, Whole blood inlet for whole blood flow; A plasma outlet through which plasma separated from the introduced whole blood is released to the outside; A microchannel connecting the whole blood inlet and the plasma outlet; A micropump formed under the whole blood inlet to move the whole blood flowing in the direction of the plasma outlet through the microchannel by air pressure generated by itself without external driving; And Microstructures formed in the microchannels to separate plasma from whole blood Micro filter element comprising a. The method of claim 1, The micro pump, Closed cavities; A microheater for generating heat to expand or contract air in the sealed cavity; And Membrane formed in the cavity and driven according to the air pressure in the cavity Micro filter element comprising a. The method according to claim 1 or 2, The microstructures include a first microstructure for separating blood cells from whole blood; And A microfilter element comprising a second microstructure formed with complementary capture probe ligands to separate or concentrate a desired biomaterial. The method according to claim 1 or 2, And a whole blood tank formed between the whole blood inlet and the micropump to store the introduced whole blood. The method of claim 4, wherein The temperature of the whole blood tank is maintained below the body temperature so as not to damage the biomaterials in the whole blood sample by the heat generated in the micropump. The method according to claim 1 or 2, And a plasma tank formed below the plasma discharge port to store plasma separated from the whole blood. The method of claim 1, And the whole blood inlet and the plasma outlet are formed on an upper substrate, the microchannel and the micropump are formed on a lower substrate, and the upper substrate and the lower substrate are aligned and sealed to each other. The method of claim 7, wherein And the upper substrate and the lower substrate are plastic polymers, respectively. The method of claim 8, The plastic polymer may be cycloolefin copolymer (COC), polydimethyl siloxane (PDMS), polymethylmethacrylate (PMMA), polycarbonate (PC), polyamide (polyamide, PA), polyethylene, PE, polypropylene, PP, polyphenylene ether (PPE), polystyrene (PS), polyoxymethylene (POM), polyether Polyetheretherketone (PEEK), polytetrafluoroethylene (PTFE), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT) , Selected from the group consisting of fluorinated ethylenepropylene (FEP) and perfluoroalkoxyalkane (PFA) Micro-filter element consisting of Me. The method of claim 2, The micro heater is a micro filter element composed of a conductor to which a pulse bias is applied from the outside. Forming a whole blood inlet for introducing whole blood into one side of the upper substrate; Forming a plasma discharge port through which plasma separated from whole blood introduced to the other side of the upper substrate is discharged to the outside; Forming a micropump on the lower substrate corresponding to the whole blood inlet to move whole blood by air pressure generated by itself without external driving; Forming a microchannel connecting the whole blood inlet and the plasma outlet on the lower substrate, and forming a microstructure in the microchannel for separating plasma from whole blood in the microchannel; And Adhering and sealing the upper substrate and the lower substrate Micro filter device manufacturing method comprising a. The method of claim 11, Forming the micro pump, Forming a micro heater on the lower substrate; Forming a cavity at the same time as forming a support layer to surround the micro heater; And Forming a membrane on the support membrane to seal the cavity; Micro filter device manufacturing method comprising a. The method of claim 12, The micro heater is a micro filter element manufacturing method of forming a conductor that is subjected to a pulse bias from the outside. The method of claim 12, The support film is a micro filter element manufacturing method, characterized in that formed of a silicon oxide film. The method of claim 12, The membrane process for producing a micro filter element for adhering to the support film through the oxygen plasma treatment (O ₂ plasma treatment). The method of claim 12, Pretreatment in a convection oven to improve adhesion between the membrane and the support membrane prior to forming the membrane. The method of claim 11, Forming the microchannels and microstructures, Adhering a dry film resist to the lower substrate; And Exposing and developing the dry film resist using a mask on which microchannels and microstructure patterns are formed; Micro filter device manufacturing method comprising a. The method according to claim 11 or 17, Forming a complementary capture probe ligand to separate the desired biomaterial into the microstructure. The method of claim 11, Whole blood tank for storing the whole blood flowed into the lower substrate; And A plasma tank for storing plasma separated from whole blood on the lower substrate Micro-filter element manufacturing method further comprising the step of forming. The method of claim 11, The upper substrate and the lower substrate is characterized in that the sealing by laminating Micro filter element manufacturing method. The method of claim 11, And the upper substrate and the lower substrate are each formed of a plastic polymer. The method of claim 21, The plastic polymer may be cycloolefin copolymer (COC), polydimethyl siloxane (PDMS), polymethylmethacrylate (PMMA), polycarbonate (PC), polyamide ( polyamide, PA), polyethylene (PE), polypropylene (PP), polyphenylene ether (PPE), polystyrene (PS), polyoxymethylene (POM), polyether ether Ketone (polyetheretherketone (PEEK), polytetrafluoroethylene (PTFE), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), Any selected from the group consisting of fluorinated ethylenepropylene (FEP) and perfluoralkoxyalkane (PFA) The method of forming the micro filter element Me.

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