KR20200007626A - Open microfluidic channel integrated biosensor and manufacturing method the same - Google Patents

Abstract

An open microfluidic channel integrated biosensor and a method of manufacturing the same are disclosed. The biosensor according to one embodiment includes a substrate; and a membrane layer formed on the substrate and having an oxide layer comprising a cavity and a microfluidic channel including a plurality of nanopillars formed on the oxide layer.

Description

Open microfluidic channel integrated biosensor and its manufacturing method {OPEN MICROFLUIDIC CHANNEL INTEGRATED BIOSENSOR AND MANUFACTURING METHOD THE SAME}

The examples below relate to an open microfluidic channel integrated biosensor and a method of manufacturing the same.

Real time biosensors have brought a paradigm shift from traditional therapeutic medicine to disease-oriented medicine. With the development of biosensor technology, there is a growing interest in the management of chronic diseases and continuous monitoring system technology for diagnosis of acute diseases.

Real-time biosensors have increased the potential for biosensors to identify disease mechanisms. By using real-time biosensors, it is possible to identify disease mechanisms beyond simple prevention and diagnosis, and to measure real-time interactions between biomaterials.

Currently, biosensors are expanding the market in various fields such as environmental monitoring, pharmaceutical, and military as well as point of care (POC). Recently, with increasing interest in healthcare, the biosensor market is expanding rapidly.

Currently commercially available real-time biosensors use closed microfluidic channels for real-time detection when the target material is to be detected. Biosensors using closed microfluidic channels have low detection sensitivity, require complex manufacturing processes, and large detection devices.

Embodiments form a wicking phenomenon of the microfluidic channel by integrally forming a membrane layer including an open microfluidic channel having nano pillars formed on an oxide layer including a cavity. The large inspection surface area allows for the provision of very small and sensitive biosensor technology.

According to an embodiment, a biosensor includes a substrate and a membrane layer formed on the substrate and on which a microfluidic channel including a plurality of nano pillars is formed.

The biosensor may further include an insulation layer formed between the substrate and the membrane layer and including a cavity.

The cavity may be filled with a gas medium.

The microfluidic channel may be formed open on top of the membrane layer.

The biosensor may have the microfluidic channel integrally formed in the membrane layer.

The plurality of nano pillars may be uniformly formed between the plurality of nano pillars.

The plurality of nano pillars may be formed by changing at least one of a height of a pillar, a width between the pillars, and physical properties of the pillar.

An upper portion of the membrane layer may include a first coating layer that is hydrophilically coated on top of the plurality of nano pillars, and a second coating layer that is hydrophobicly coated on a region other than the top of the plurality of nano pillars on the membrane layer. It may include.

The first coating layer and the second coating layer may be coated on the membrane layer by an iCVD (initiated chemical vapor deposition) method.

A biosensor manufacturing method according to an embodiment includes forming a substrate, and forming a membrane layer on which a microfluidic channel including a plurality of nano pillars is formed on the substrate. It includes.

The method includes forming an insulator comprising a cavity between the substrate and the membrane layer;

The cavity may be filled with a gas medium.

The forming of the membrane layer may include forming a silicon film on the insulating layer, and etching the silicon film to form the microfluidic channel.

The forming of the microfluidic channel may include forming the microfluidic channel by etching the silicon film in a predetermined shape and a predetermined pattern using coating particles, a photoresist layer, and a mask layer sequentially formed on the silicon film. It may include a step.

The forming of the microfluidic channel may include forming coating particles on the silicon film in a predetermined shape, coating a photoresist layer on the silicon film including the silver nanoparticles, and Stacking a mask layer in a predetermined pattern on the layer, etching the photosensitive liquid layer in the predetermined pattern, removing the mask layer, and etching the silicon film in the predetermined form to form the microfluid Forming a channel, and removing the photoresist layer and the coating particles.

Etching the photoresist layer may include etching the photoresist layer in the predetermined pattern by a light exposure process.

The etching of the silicon film in the predetermined shape to form the microfluidic channel may include etching the silicon film in the predetermined shape by a reactive ion etching (RIE) process.

Forming the coating particles in a predetermined shape may include forming the coating particles in a predetermined shape by annealing the coating particles at a predetermined temperature.

The biosensor manufacturing method may include coating a hydrophilic first coating layer on the plurality of nano pillars, and applying a hydrophobic second coating layer on the remaining portion of the membrane layer except for the top of the plurality of nano pillars. The method may further include coating.

Coating the first coating layer includes coating a first coating layer on the membrane layer by an initiated chemical vapor deposition (iCVD) method, and coating the second coating layer comprises: And coating the first coating layer thereon by an initiated chemical vapor deposition (iCVD) method.

1 is a view showing the structure of a CMUT sensor.
2 is a view showing the operating principle of the closed microfluidic channel CMUT sensor.
3 is a diagram illustrating a biosensor according to an exemplary embodiment.
4 and 5 are diagrams for explaining implementation examples of the open microfluidic channel.
6 to 8 are diagrams for describing a method of manufacturing a biosensor according to an embodiment.
9 illustrates a surface of a silicon film coated with silver nanoparticles during a manufacturing process of a biosensor according to an embodiment.
10 illustrates a membrane layer in which open microfluidic channels are formed during a biosensor manufacturing process, according to one embodiment.
11 is a diagram illustrating a principle of detecting a target substance of a biosensor according to an exemplary embodiment.
12 is a view illustrating a pillar structure of a microfluidic channel of a biosensor detecting a target material according to an embodiment.
13 is a view for comparing the target substance detection principle of the conventional closed CMUT with the target substance detection principle of the biosensor according to an embodiment.

Hereinafter, exemplary embodiments will be described in detail with reference to the accompanying drawings. However, various changes may be made to the embodiments so that the scope of the patent application is not limited or limited by these embodiments. It is to be understood that all changes, equivalents, and substitutes for the embodiments are included in the scope of rights.

The terminology used herein is for the purpose of description and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this specification, terms such as "comprise" or "have" are intended to indicate that there is a feature, number, step, operation, component, part, or combination thereof described on the specification, and one or more other features. It is to be understood that the present invention does not exclude the possibility of the presence or the addition of numbers, steps, operations, components, components, or a combination thereof.

Terms such as first or second may be used to describe various components, but the components should not be limited by the terms. The terms are intended only to distinguish one component from another, for example, without departing from the scope of rights according to the concepts of the embodiment, the first component may be named a second component, and similarly The second component may also be referred to as a first component.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art. Terms such as those defined in the commonly used dictionaries should be construed as having meanings consistent with the meanings in the context of the related art, and shall not be construed in ideal or excessively formal meanings unless expressly defined in this application. Do not.

In addition, in the description with reference to the accompanying drawings, the same components will be given the same reference numerals regardless of the reference numerals and duplicate description thereof will be omitted. In the following description of the embodiment, if it is determined that the detailed description of the related known technology may unnecessarily obscure the gist of the embodiment, the detailed description thereof will be omitted.

1 is a view showing the structure of the CMUT sensor, Figure 2 is a view showing the operating principle of the closed microfluidic channel CMUT sensor.

Referring to FIG. 1, a capacitive micromachined ultrasonic transducer (CMUT) sensor may detect a target material by a change in resonance frequency generated due to a change in mass of the membrane m when the target material is coupled to the membrane m.

Referring to FIG. 2, when the CMUT sensor and the closed microfluidic channel are integrated, a damping phenomenon occurs in the closed microfluidic channel due to pressure of the fluid in the channel into which the fluid is introduced and energy loss due to the fluid. This can happen. Damping in the closed microfluidic channel can reduce the Q-factor (Quality factor) of the CMUT sensor. Therefore, integrating the CMUT sensor with the closed microfluidic channel and using it as a biosensor platform for real-time detection may not be possible because real-time detection of the target material may be impossible due to damping. When a CMUT sensor is applied to a closed microfluidic channel, it is difficult to detect very small amounts of target material because of its low sensitivity. In addition, when the CMUT sensor and the closed microfluidic channel are integrated, there may be a limitation in miniaturization and integration due to the large size detection device.

To address the limitations of applying closed microfluidic channels, embodiments can provide biosensors in which open microfluidic channels are integrated. Through this, the sensitivity of the sensor can also be improved.

Hereinafter, the embodiments will be described with reference to FIGS. 3 to 13.

3 is a diagram illustrating a biosensor according to an exemplary embodiment.

Referring to FIG. 3, the biosensor 10 includes a substrate 100, and an insulating layer 200 and a membrane layer 300. In addition, the biosensor 10 may further include an insulator 200 formed between the substrate 100 and the membrane layer 300.

The biosensor 10 detects the target material through the nano pillars 310 based on spontaneous fluid flow due to wicking, thereby improving the sensitivity of the sensor and miniaturizing the size of the sensor. The biosensor 10 may be embodied by forming nano pillars 310 of a desired shape according to the purpose of the sensor.

The biosensor 10 forms a microfluidic channel having an open pillar structure in the silicon membrane layer of the CMUT sensor by using a MEMS nano process technology, thereby providing a microfluidic channel having an open pillar structure with the CMUT sensor. It may be a sensor implemented integrally.

The biosensor 10 combines the biomaterials (antibodies and receptors, etc.) reacting with the target materials to be detected on the nanopillars 310 to detect the target materials by binding the target materials to the nanopillars 310. Can be.

The substrate 100 may serve to transmit a change in resonance frequency generated due to a change in mass of the membrane layer 300 as an electrical signal when the target material is coupled to the membrane layer 300.

The insulating layer 200 may be formed on the substrate 100. The insulating layer 200 may be formed of oxide, nitride, or the like. In this case, the insulating layer 200 may include a cavity 210. For example, cavity 210 may be filled with a gas medium. In addition, the cavity 210 may be a vacuum.

The membrane layer 300 is formed on the insulating layer 200 and may include a microfluidic channel including a plurality of nano pillars 310. The microfluidic channel including the plurality of nano pillars 310 may be formed on the membrane layer 300 to be open. The open microfluidic channel refers to a repetitive structure of the nano pillars 310 without the external pressure of the fluid, rather than the fluid flowing under pressure in a channel formed as a closed passage like the channel of a conventional closed CMUT sensor. Due to the wicking through it may mean a channel of the structure that can flow between the nano pillars (310).

For example, the microfluidic channel including the membrane layer 300 and the nano pillars 310 may be integrally formed. The membrane layer 300, the substrate 100, and the insulating layer 200 may be integrally formed. The membrane layer 300, the insulating layer 200, and the process of forming the substrate are formed on the same wafer and formed integrally, such as a bonding process using PDMS or glass of the closed microfluidic channel. Additional process steps can be omitted. In addition, since the biosensor 10 is integrally formed, the biosensor 10 may increase process yield and reduce manufacturing cost.

4 and 5 are diagrams for explaining implementation examples of the open microfluidic channel.

4 and 5, the biosensor 10 may include an asymmetric channel having different widths and heights of the microfluidic channel including the nano pillars 310, 310a, 310b, and 310c. The nano pillars 310 may act as one channel to generate a wicking effect.

The biosensor 10 may be formed between the nano pillars 310 through a width change 310b between the nano pillars, a height change 310c of the nano pillars, a change in the physical properties of the microfluidic channel 311 and 312, and the like. You can adjust the speed of the fluid flowing, the amount of fluid and the like.

4 shows the form with the width change between pillars, respectively. As shown in FIG. 4A, the nano pillars 310 included in the membrane layer 300 may have a constant spacing 310a between the nano pillars. On the other hand, as shown in Figure 4 (b), the nano pillars 310 included in the membrane layer 300 may be generated 310b by changing the width between the nano pillars.

Figure 5 shows the form with the change in the height of the column and the form of the physical properties of the column, respectively. As illustrated in FIG. 5C, the nano pillars 310 included in the membrane layer 300 may be generated 310 c by changing the height of the nano pillars.

In addition, as shown in FIG. 5D, the upper portion of the membrane layer 300 may be coated with a hydrophilic first coating layer 311 and / or a hydrophobic second coating layer 312. The first coating layer 311 may be hydrophilically coated on the nano pillars 310. The second coating layer 312 may be hydrophobicly coated on the remaining area except the upper portion of the nano pillars 310 coated with the first coating layer 311 on the membrane layer 300. The first coating layer 311 and the second coating layer 312 may be coated by an iCVD (initiated chemical vapor deposition) method. By coating the first and second coating layers 311 and 312 on the membrane layer 300, the flow of fluid flowing between the nano pillars 310 may be more smoothly maintained.

As such, the biosensor 10 may be used in a wide range of fields related to environmental monitoring, healthcare, pharmaceutical, military, etc., in which various materials should be detected in real time by changing widths, heights, and physical properties of the nano pillars 310. In addition, the biosensor 10 may be applied to sensors in various fields such as electrochemical sensors, pressure sensors, gas sensors, and the like.

6 to 8 are views for explaining a method of manufacturing a biosensor according to an embodiment.

The biosensor 10 may be manufactured in the order of (a), (b), (c) and (d) of FIG. 6, and (e), (f) and (g) of FIG. 8. 6 (a), (b), 7 (c), (d), and 8 (e), (f), and (g) in order to explain the manufacturing method of the biosensor 10. do.

In FIG. 6A, the insulating layer 200 may be formed on the substrate 100. The insulating layer 200 may include a cavity 210. The silicon film 300a may be formed on the insulating layer 200. The coating particles 500 may be formed by spin coating on the silicon film 300a. The coated particles 500 may be annealed to a predetermined temperature to form a predetermined shape. For example, the coating particles 500 may be nanoparticles such as silver nanoparticles and gold nanoparticles. The coated particle 500 is not limited to the nanoparticles, and may be various particles for forming the microfluidic channel.

As shown in FIG. 6B, the photoresist layer 600 may be coated on the silicon film 300a including the coated particles 500.

In FIG. 7C, the mask layer 700 may be stacked on the photoresist layer 600 in a predetermined pattern. The photoresist layer 600 may be etched in a predetermined pattern through a light exposure process (UV & Wash).

Subsequently, in FIG. 7D, the mask layer 700 may be removed. The silicon film 300a may be etched in a predetermined form through a reactive ion etching (RIE) process.

In FIG. 8E, the membrane layer 300 may be formed through an RIE process. Next, in FIG. 8F, the photoresist layer 600a may be removed. The coated particles 500 may be removed by an etching process.

Next, in FIG. 8F, the photoresist layer 600a may be removed. The coated particles 500 may be removed by an etching process.

In FIG. 8G, the silicon layer 300a is etched in a predetermined form through the biosensor 10 manufacturing method to form the membrane layer 300 including the nano pillars 310.

The length of the pillars of the nano pillars 310 and the width between the nano pillars 310 may be changed by adjusting the power and time of the etching process. The flow of fluid may be controlled by changing the length of the nano pillars 310 and the width between the nano pillars.

When the open microfluidic channel using the nano pillars 310 is formed together with the CMUT sensor, the target material detection surface area of the channel may be wider than that of the closed CMUT sensor, and thus high sensitivity may be detected.

Since the manufacturing method of the biosensor 10 may be manufactured at the wafer level through the MEMS process, it may be advantageous for mass production and commercialization of the biosensor 10.

FIG. 9 illustrates a surface of a silicon film coated with silver nanoparticles during a biosensor manufacturing process, and FIG. 10 illustrates a membrane layer on which open microfluidic channels are formed during a biosensor manufacturing process according to an embodiment.

9, after hundreds of nano-sized coated particles 500 are coated on the silicon film 300 in the biosensor 10 manufacturing process, silver nanoparticles 500 (Ag nanoparticles) are determined by controlling annealing temperature. You can see the figure formed in the form of. When the silicon substrate is etched by the etching process, the coating particles 500 having a predetermined shape serve as a metal mask, and the etching height may be adjusted by controlling the inflow of the etching power and the gas.

Referring to FIG. 10, when the photoresist is removed and the coating particles are also removed through a metal etching process, nano pillars 310 having a pillar structure may be formed.

11 is a diagram illustrating a principle of detecting a target substance of a biosensor according to an embodiment, and FIG. 12 is a view illustrating a pillar structure of a microfluidic channel of a biosensor according to an embodiment of detecting a target substance. 13 is a view for comparing the target substance detection principle of the conventional closed CMUT with the target substance detection principle of the biosensor according to an embodiment.

Referring to FIG. 11, it can be seen that the fluid flows through the wicking phenomenon to the membrane layer 300 of the nano-pillar structure. The fluid may flow in the flow direction due to the wicking phenomenon. The target material included in the fluid may be detected in a sensing part in which the cavity 210 of the insulating layer 200 exists.

Referring to FIG. 12, the biosensor 10 targets a target material through binding of a biomaterial (eg, an antibody and a receptor) and a target material that react with the target material included in the nano pillars 310. ) Can be detected.

Referring to FIG. 13, the target material detection surface area (b) of the nano pillars 310 of the biosensor 10 according to the exemplary embodiment is smaller than the target material detection surface area (a) of the closed microfluidic channel. It can be seen that due to the nano-pillar structure, it is formed more widely. The biosensor 10 may increase the detection surface area through the nano pillars 310 to bind more antibodies and / or receptors to the same area, thereby improving the sensitivity of the sensor. The biosensor 10 may detect a difference in the concentration of the target material by improving the sensitivity of the sensor.

As described above, by forming a membrane layer including an open microfluidic channel in which nano pillars are formed, a microscopic high sensitivity biosensor technology is provided through the wicking phenomenon of the microfluidic channel and a large inspection surface area. can do.

In addition, embodiments can minimize the damping phenomenon by using a micro electro mechanical systems (MEMS) nano process technology for biosensor manufacturing and by integrating an open microfluidic channel with a CMUT sensor, and the manufacturing process is simple. It is possible to manufacture ultra-high sensitivity biosensor.

Although the embodiments have been described with reference to the accompanying drawings, those skilled in the art may apply various technical modifications and variations based on the above. For example, the described techniques may be performed in a different order than the described method, and / or components of the described systems, structures, devices, circuits, etc. may be combined or combined in a different form than the described method, or other components. Or, even if replaced or substituted by equivalents, an appropriate result can be achieved.

Therefore, other implementations, other embodiments, and equivalents to the claims are within the scope of the following claims.

Claims (20)

Substrate; And
A membrane layer is formed on the substrate and is formed with a microfluidic channel including a plurality of nano pillars.
Biosensor comprising a.
The method of claim 1,
An insulator formed between the substrate and the membrane layer, the insulator comprising a cavity
Biosensor further comprising a.
The method of claim 2,
The cavity is filled with a gas medium
Biosensor.
The method of claim 1,
The microfluidic channel is formed open on top of the membrane layer.
Biosensor.
The method of claim 4, wherein
The microfluidic channel is integrally formed in the membrane layer
Biosensor.
The method of claim 1,
The plurality of nano pillars,
The spacing between the plurality of nano pillars is formed uniformly
Biosensor.
The method of claim 1,
The plurality of nano pillars,
Formed by varying at least one of the height of the column, the width between the columns, and the properties of the column.
Biosensor.
The method of claim 1,
The top of the membrane layer is
A first coating layer hydrophilically coated on the plurality of nano pillars; And
A second coating layer hydrophobicly coated on a region other than the top of the plurality of nano pillars on the membrane layer
Biosensor comprising a.
The method of claim 7, wherein
The first coating layer and the second coating layer,
Coated on top of the membrane layer by iCVD (Initiated Chemical Vapor Deposition)
Biosensor.
Forming a substrate; And
Forming a membrane layer on which the microfluidic channel including a plurality of nano pillars is formed;
Biosensor manufacturing method comprising a.
The method of claim 10,
Forming an insulator comprising a cavity between the substrate and the membrane layer
Biosensor manufacturing method further comprising.
The method of claim 11,
The cavity is filled with a gas medium
Biosensor manufacturing method.
The method of claim 11,
Forming the membrane layer,
Forming a silicon film on the insulating layer; And
Etching the silicon film to form the microfluidic channel
Biosensor manufacturing method comprising a.
The method of claim 13,
Forming the microfluidic channel,
Etching the silicon film in a predetermined shape and a predetermined pattern using coating particles, a photoresist layer, and a mask layer sequentially formed on the silicon film to form the microfluidic channel
Biosensor manufacturing method comprising a.
The method of claim 11,
Forming the microfluidic channel,
Forming coating particles on the silicon film in a predetermined shape;
Coating a photoresist layer on the silicon film including the coating particles;
Stacking a mask layer on the photoresist layer in a predetermined pattern;
Etching the photoresist layer in the predetermined pattern;
Removing the mask layer;
Etching the silicon film in the predetermined form to form the microfluidic channel; And
Removing the photoresist layer and the coating particles
Biosensor manufacturing method comprising a.
The method of claim 15,
Etching the photoresist layer,
Etching the photoresist layer into the predetermined pattern by a light exposure process
Biosensor manufacturing method comprising a.
The method of claim 16,
Etching the silicon film in the predetermined form to form the microfluidic channel,
Etching the silicon film into the predetermined shape by a reactive ion etching (RIE) process
Biosensor manufacturing method comprising a.
The method of claim 15,
Forming the coating particles in a predetermined form,
Annealing the coated particles to a predetermined temperature to form a predetermined shape
Biosensor manufacturing method comprising a.
The method of claim 15,
Coating a hydrophilic first coating layer on top of the plurality of nano pillars; And
Coating a hydrophobic second coating layer on a region other than the top of the plurality of nano pillars on the membrane layer
Biosensor manufacturing method further comprising.
The method of claim 19,
Coating the first coating layer,
Coating a first coating layer on top of the membrane layer by an initiated chemical vapor deposition (iCVD) method;
Coating the second coating layer,
Coating a first coating layer on top of the membrane layer by an initiated chemical vapor deposition (iCVD) method;
Biosensor manufacturing method.

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