KR101916841B1 - Bio chip with underwater ultrasonic intergrated module and the observation system thereof - Google Patents

Abstract

A biochip equipped with a water-immersion ultrasonic generator is disclosed. The biochip of the present invention comprises a cell culture chamber on which a cell or a biological sample is mounted, a sample injection port connected to the cell culture chamber by a microchannel and injecting a sample, a water immersion type ultrasonic wave generator for generating ultrasonic waves in the cell culture chamber, And a water tank filled with deaeration water so as to surround the cell culture chamber, wherein the ultrasonic wave generating device is configured to generate ultrasonic waves in the deaeration water, thereby making it possible to provide an ultrasonic wave-based sample transfer efficiency improving stimulation device and a low- The effectiveness, safety and reliability of the device can be easily tested at the pre-clinical stage.

Description

TECHNICAL FIELD [0001] The present invention relates to a biochip equipped with a water-immersion ultrasonic generator, and an observation system using the biochip and an observation system using the same. ≪ Desc / Clms Page number 1 >

The present invention relates to a biochip, and more particularly, to a biochip using a biochip using a water-immersion type ultrasonic wave generating module, and a biochip capable of observing the biochip to ensure effectiveness and safety through ultrasonic stimulation. A biochip equipped with an ultrasonic generator, and an observation system using the biochip.

Recently, attention has been focused on various therapeutic effects of ultrasound in the medical field. In addition, a number of clinical experimental results have been published on the therapeutic effect, and therapeutic apparatuses have been developed accordingly. However, the effect of ultrasound on cells has not been studied precisely. Accordingly, studies have been made to clarify the exact mechanism of the effect of ultrasound on the body. Various ultrasound stimulators capable of giving ultrasound stimulation to cells have been developed.

In particular, ultrasound-based medical devices such as improving the delivery efficiency of a sample using ultrasound or directly treating diseases of cells and organs using low-intensity ultrasound have been actively studied.

Ultrasonic cell stimulators currently in use can be roughly divided into three types.

First, there is a device that stimulates a cell by attaching it to a system where a cell is being cultured using a commercialized ultrasonic stimulator ("Therapeutic Ultrasound Stimulation of Tendon Cell Migration ", Liang-Wei Chieh, 5): 367-73).

Secondly, there is a device made by attaching an ultrasonic stimulator to the bottom surface of a cell culture chamber, such as a cell stimulator described in U.S. Patent Publication No. US20070299539A1 "Ultrasound accelerated tissue engineering process ".

Such a cell stimulator is advantageous in that the uniform delivery of ultrasonic waves is easier than that of the first cell stimulator, and the size of the transmitted ultrasonic waves can be controlled. However, since the ultrasonic stimulator is attached to the bottom surface of the cell culture chamber, there is a problem that it is not easy to observe with a microscope, which is indispensable in cell experiments.

Further, since a device for maintaining the temperature of the cell culture solution and the CO ₂ concentration is provided inside the device, it is difficult to observe cells using a microscope because of this.

Third, there is a cell stimulator that inserts a needle-shaped ultrasonic generator into a cell culture chamber to stimulate cells.

According to such a cell stimulator, it becomes possible to observe a change of a cell with a microscope. However, in this case, since a point source is used, there is a problem that it is difficult to precisely control the size of the cell stimulus or to continuously apply the cell stimulation to a certain size.

One of the methods for verifying the ultrasound medical device at the preclinical stage is one of the measures to secure the efficacy and safety through ultrasound stimulation at the cell / biological sample stage.

On the other hand, ultrasonic waves can effectively treat cell disruption, particle dispersion, particle grinding, homogenization, heterogeneous liquid emulsification, DNA fragmentation, effective substance extraction, and chemical reaction catalysis. , And growth effects, and thus, attempts have been actively made to utilize ultrasound medically.

When the cell response to the ultrasound is tested or the ultrasound treatment is performed on the cells, the ultrasound intensity, the cell growth rate, the number of cells, and the number of cells are determined according to the exposure conditions such as the frequency, pressure, The occurrence of abnormal cells, and the like.

Therefore, in order to test the reaction of the cells to the ultrasound or to perform the ultrasound treatment on the cells, the power / pressure / intensity of the ultrasound actually irradiated to the cells and the secondary acoustical phenomenon of the ultrasound are non-invasively monitored in real time Should be able to.

The size of a cell can change with respect to a physical stimulus such as an ultrasonic wave, which can be interpreted as the sensitivity of the cell to stimulation and the growth effect of the cell.

However, it is very difficult to observe changes in cell volume (cell layer thickness) or morphological response while simultaneously irradiating ultrasound.

When continuous wave ultrasound is irradiated, the sound field in the culture dish has a standing wave characteristic, and such standing waves are sensitive to the height of the culture liquid. When ultrasonic irradiation is applied to the culture dish, the height of the culture liquid is important information for accurately grasping the characteristics of the ultrasonic waves applied to the cells. However, it is not easy to measure the height of the culture liquid non-invasively at the same time while irradiating the ultrasound.

When the ultrasound is irradiated to the cells in the culture dish, the temperature rises due to the thermal effect of the ultrasonic waves. The temperature of the culture medium

Is a biologically important environmental factor and affects cavitation, an important mechanism for the biological effects of ultrasound.

When the cell's dynamic response to ultrasound is examined or ultrasound treatment is applied to the cells, the change in temperature should be monitored non-invasively in real time.

In conclusion, in order to test the reaction of cells using ultrasound, or to efficiently perform ultrasound treatment on cells, a culture dish made of a material having good ultrasonic transmission characteristics is required. In addition, when ultrasound is irradiated, ultrasound exposure There is a need for a monitoring device capable of observing characteristics (frequency, pressure, intensity, power, etc.), scattering / attenuation characteristics of ultrasound waves on cells, temperature changes of cells, and a system for controlling the output of ultrasonic waves based on the monitoring device.

In particular, there is a problem in that a single element must be physically moved to adjust the focus of the ultrasonic wave, and it is difficult to focus on the ultrasonic wave.

That is, there is not a method that can intuitively confirm that ultrasound is transmitted to a specific cell.

Therefore, a device acting as a guide for indicating the center line of the ultrasonic wave generated from the ultrasonic generator is needed.

Korean Registered Patent No. 10-537343 (December 12, 2005)

In order to solve these problems, it is an object of the present invention to provide a biochip equipped with an ultrasonic stimulation device for verifying the effectiveness and safety of ultrasonic stimulation in a cell / biological sample stage.

In addition, the present invention is characterized in that a water-immersion type ultrasonic generator equipped with a guide laser capable of forming a low-output guide laser beam coinciding with a focussing point of ultrasonic waves emitted from an ultrasonic wave generator using a ultrasonic wave generator module equipped with a guide laser is mounted The present invention also provides a biochip for a biochip.

It is still another object of the present invention to provide a biochip equipped with a water-immersion type ultrasonic wave generating device having an ultrasonic wave integrated module having a guide laser constituting a laser diode on the central axis of the ultrasonic wave generating device.

It is another object of the present invention to provide an observation system using a biochip equipped with a water-immersion ultrasonic generator for verifying the effectiveness and safety of ultrasound stimulation in a cell / biological sample stage using a microscope.

To achieve these and other advantages and in accordance with the purpose of the present invention, as embodied and broadly described herein, a biochip includes a cell culture chamber on which a cell or a biological sample is mounted, a sample injection port connected to the cell culture chamber through a micro channel, An ultrasonic generator for generating ultrasonic waves in the degassed water by inclining at a predetermined angle with respect to a plane on which the cell culture chamber is placed, and a water tank filled with deaeration water to surround the cell culture chamber.

The ultrasonic wave generator includes a ring-shaped piezoelectric element for generating ultrasonic waves, and a laser pointer connected to the center axis of the piezoelectric element to set a focus direction of the ultrasonic wave. The piezoelectric element is coupled to a front surface of the hollow case And is coupled to the inside of the case so that the laser pointer is positioned at the center of the piezoelectric element.

And a control panel electrically connected to the case to control the operation of the piezoelectric element and the laser pointer on and off, the laser pointer having a laser module electrically connected to the control panel and projecting a laser beam, A polarizing plate for polarizing the laser beam projected from the laser module; and a focus lens for adjusting the laser beam polarized in the polarizing plate to a focal distance coinciding with an ultrasonic focusing length, And one end of the laser module may be coupled to the rear portion of the case.

A temperature control device connected to the cell culture chamber through the degassing water to regulate the temperature of the culture solution; and a control device connected to the cell culture chamber through the degassing water to control the CO ₂ concentration in the cell culture chamber CO ₂ generator.

Further, two or more cell culture chambers can be constituted, and the chamber can be distinguished into a chamber in which the ultrasonic generator is mounted and a chamber in which the ultrasonic generator is not mounted.

Meanwhile, a biochip observation system equipped with a water-immersion ultrasonic generator according to another embodiment of the present invention includes a cell culture chamber on which a cell or a biological sample is mounted, a sample which is connected to the cell culture chamber by a micro channel, An ultrasonic generator for generating ultrasonic waves in the deaeration water, and a water tank filled with deaeration water for surrounding the cell culture chamber, and a microscope equipped with a water-immersion type ultrasonic generator, And observing it by observing it on the objective lens of the microscope.

Therefore, according to the biochip equipped with the water-immersion ultrasonic stimulating apparatus of the present invention, it is possible to easily test the effectiveness, safety and reliability of the ultrasonic-based sample transfer efficiency improving stimulation apparatus and the low-intensity or high- .

In addition, it is possible to reduce the cost and time loss that may occur in the failure of the clinical stage of medical device authentication evaluation, and also to provide a complementary point and improvement point for the ultrasound-based medical device at a low cost.

In addition, according to the biochip equipped with the water-immersion ultrasonic stimulating apparatus of the present invention, since the irradiation position of the ultrasonic wave emission can be directly detected by the eye and the stimulation can be observed, it is possible to provide a high user convenience and safety to the user It is effective.

According to the observation system of the biochip equipped with the water-immersion ultrasonic generator of the present invention, observation with a microscope can improve safety and reliability in the use of ultrasonic waves for medical treatment, such as improvement of sample transfer efficiency, ultrasonic skin treatment, There is an effect.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic view of a biochip equipped with a water-immersion ultrasonic generator according to an embodiment of the present invention;
2 is a top view of the cell culture chamber,
3 is a top view of another cell culture chamber,
FIG. 4 is a diagram illustrating a configuration in which a biochip equipped with a water-immersion ultrasonic generator of the present invention is used to observe with a microscope,
FIG. 5 is a flow chart for explaining a method of driving a biochip equipped with a water-immersion ultrasonic generator according to the present invention;
FIG. 6 is a schematic configuration diagram of an ultrasonic wave integrated module having a guide laser according to an embodiment of the present invention;
7 is a cross-sectional view of the ultrasonic integrated module,
8 is a cross-sectional view of an ultrasonic integrated module according to another embodiment,
9 is a main configuration diagram of the control panel,
And,
10 is a flowchart illustrating an operation of an ultrasonic wave integrated module including a guide laser according to an embodiment of the present invention.

It is to be understood that the words or words used in the present specification and claims are not to be construed in a conventional or dictionary sense and that the inventor can properly define the concept of a term in order to describe its invention in the best possible way And should be construed in light of the meanings and concepts consistent with the technical idea of the present invention.

Throughout the specification, when an element is referred to as "comprising ", it means that it can include other elements as well, without excluding other elements unless specifically stated otherwise. It should be noted that the terms such as " part, "" module, " .

It is to be understood that when an element is referred to as being "connected" to another element throughout the specification, it may be directly connected to the other element, but other elements may be present in between. Also, other expressions describing the relationship between the components, such as "between" and "between" or "neighboring to" and "directly adjacent to" should be interpreted as well.

Identification codes (e.g., a, b, c, ...) in each step throughout the specification are used for convenience of description, and the identification codes do not limit the order of each step, Unless the context clearly states a particular order, it may take place differently from the stated order. That is, each step may occur in the same order as described, may be performed substantially concurrently, or may be performed in reverse order.

Hereinafter, a biochip equipped with an ultrasonic generator according to an embodiment of the present invention will be described with reference to the drawings.

FIG. 1 is a block diagram of a biochip equipped with a water erosion type ultrasonic generator according to an embodiment of the present invention. The biochip 100 of the present invention includes a cell culture chamber 210 and a cell culture chamber 210 for generating ultrasound waves, and a water tank 200 filled with deaeration water.

The biochip 100 of the present invention includes a CO ₂ generator 120 for supplying CO ₂ to the cell culture chamber 210, a sample injection module 150 for injecting a sample into the cell culture chamber 210, And a thermoelectric element 140 serving as a temperature regulating element for keeping the temperature of the deaerated water in the water tank at a constant level.

In order to enable the biochip 100 to observe the effectiveness and safety of the ultrasonic stimulation with a microscope, the ultrasonic generator 300 is inclined at a predetermined angle? With respect to the plane in which the cell culture chamber 210 is located, Thereby preventing the ultrasonic wave generator 300 from interfering with the ultrasonic wave generator 300 during observation with a microscope.

1, the ultrasonic generator 300 is inclined at a predetermined angle? With respect to the vertical line of the plane on which the cell culture chamber 210 is located, and is provided in the support table 260 of the water tank 200.

With such a configuration, when the biochip of the present invention is mounted on a microscope, when the ultrasonic generator is disposed above and below the cell culture chamber as in the prior art, it is difficult to observe the cell because it is obscured by the ultrasonic generator 300 It can be solved.

In addition, when the biochip 100 of the present invention is mounted on a microscope, the sample injection module 150, the circulation unit 130, the thermoelectric element 140, and the CO ₂ generator 120 interfere with observation of cells All of which are mounted on the outer wall or the inner wall of the water tub 200. [

The cell culture chamber 210 is operated so that a cell or a biological sample is mounted, a culture liquid is contained therein, and the sample is injected through the micro channel 220 and the sample is discharged.

The supply of the sample to the cell culture chamber 210 through the micro channel 220 is supplied to the sample injection port 151 through the injection tube 151a by the sample injection module 150, .

The sample injection port 151 supplies the sample to the cell culture chamber 210 through the first micro flow path 221 and the used sample is discharged from the cell culture chamber 210 through the second micro flow path 222 And is discharged to the port 152.

These samples may include drugs, fluorescent substances, genes, and the like.

In addition, the sample discharged to the sample discharge port 152 is discharged to the outside through the discharge pipe 152a.

Preferably, the injection pipe 151a is mounted through one side of the water tub 200, and the discharge pipe 152a is mounted through the other side of the water tub 200. [

At this time, it is preferable that the sample injection port 151 and the sample discharge port 152 are disposed on the bottom of the water tank 200 so as to be located in the water-deaeration water 230.

The circulation unit 130 is installed on the outer wall of the water tub 200 and is configured by a circulation pump or the like so as to circulate the water in the water bath 200 to prevent the water from being contaminated. A degassing water inflow portion 131 is provided to penetrate and a degassing water outflow portion 132 is provided to the other side to circulate and refine.

CO ₂ generator 120 is the CO ₂ concentration of the predetermined (not shown), the concentration of the CO ₂ supply tank for storing the CO ₂ gas to the flow meter (Flow meter) (not shown), the cell culture chamber (210) including Keep it constant.

In addition, the CO ₂ generator 120 may be continuously supplied with a suitable humidity through an unshown humidity controller, so that the concentration of CO ₂ in the cell culture chamber 210 can be maintained constant.

The CO ₂ generator 120 is installed on the outer wall of the water tub 200 so that a CO ₂ inlet pipe 121 such as a tube is installed through one side of the water tub 200 and CO ₂ outlet pipe (122).

However, if the CO ₂ generator 120 is attached to the circulation unit 130, a separate tube may be omitted.

It is of course also possible to provide a carbon dioxide concentration sensor for keeping the carbon dioxide concentration constant.

This invention may, inlet 131 and outlet 132 and CO ₂ CO ₂ inlet pipe of the generator 120, 121 of the corrosion cell so oriented the culture chamber, the above-described rotation unit 130 and the CO ₂ It is preferable that the outflow pipe 122 is installed at a position that is contained in the deaeration water 230 in the water tank 200, that is,

The thermoelectric element 140 is a part directly contacting the degassing water 230 in order to control the temperature of the cell culture chamber 210 to be maintained properly by keeping the temperature of the degassing water in the water tank constant, , And is mounted on one side of the water tub (200).

Accordingly, it is needless to say that the thermoelectric element 140 may be a thermostat heater or a semiconductor thermoelectric thermistor for temperature control, and a temperature sensor may be included for temperature feedback.

Since the temperature of the cell culture chamber 210 is appropriately maintained by the control of the thermoelectric element 140, the cells can survive well during the experiment on the cells.

In the present invention, a thermoelectric element capable of controlling the temperature by simple control is taken as an example. However, the present invention is not limited to this, and it is not excluded to use a device capable of maintaining the temperature through the control, such as a constant temperature heater.

Inside the cell culture chamber 210, a control space in which ultrasonic stimulation is controlled is formed.

The cell culture chamber 210 has a cell or biological sample loaded therein and a sample is injected through the micro channel 220. The cell or the biological sample is stimulated by the ultrasonic wave generated in the ultrasonic generator 300, .

Referring to the plan view of the cell culture chamber of FIG. 2, the sample injected from the sample injection port 151 is supplied to the cell culture chamber 210 along the first micro flow path 221, And is discharged to the sample discharge port 152 along the discharge port 222.

In order to more effectively observe the effectiveness and safety of the ultrasonic stimulation, the present invention can be configured to include two or more cell culture chambers and to distinguish the chamber equipped with the ultrasonic generator from the chamber without the ultrasonic generator.

That is, the biochip of the present invention may include a single cell culture chamber or a biological sample test unit, and an ultrasonic generator may be installed in each test unit, and an ultrasonic generator may be installed in some test units And can be used as an indicator for comparing and analyzing the results.

3, a cell culture chamber 210 and a second cell culture chamber 240 are formed, and each of the cell culture chambers 210 and 240 includes a plurality of different sample injection ports 151 and 153 The sample is supplied through the sample discharge ports 152 and 154 and then one of the cell culture chambers is controlled by the ultrasonic generator and the other cell culture chambers are cultured without the ultrasonic generator and then compared with each other.

At this time, the sample injection ports 151 and 153 are also injected into the cell culture chambers 210 and 240 through different micro channels 221 and 241, respectively, and are discharged to the sample discharge ports 152 and 154 through the different micro channels 222 and 242, respectively.

The water tank 200 is connected to the control unit 110, the ultrasonic generator 300, the circulation unit 130, the thermoelectric element 140, and the CO ₂ generator 120 in the above- Al) and a metal material such as plastic, stainless steel, etc., and a waterproof film and a coating treatment may be performed to prevent water from leaking if necessary.

The above-described structures may be constructed by mounting a platform on the inner and outer walls of the water tub 200. [

The control panel 110 controls the ultrasound generator 300, the circulation unit 130, the thermoelectric element 140 and the CO ₂ generator 120 to maintain the surrounding environment under optimal conditions, So that the mounted sample can more effectively observe the effectiveness and safety of the ultrasonic stimulation.

The control panel 110 includes a touch screen and includes an ultrasonic generator 113 for driving the ultrasonic generator 300, a laser driver 115 for controlling the laser pointer 320, for controlling the circulation unit driving part 117, a thermal element 140, the heater driving unit (119), CO ₂ generator CO ₂ generator for controlling (120) driving unit 118 and the sample injection module 150 to control the And a sample injection module driver 116 for the sample injection module.

In this embodiment, a key or the like for driving the ultrasonic integrated module having a guide laser is displayed on the display unit 111 by a touch pad, and the key input unit 112 is connected to the power on / off switch of the control panel 110 Will be described.

9, the ultrasonic wave generator 113 includes an electric signal generator 113c for generating an electric signal having a continuous RF frequency, and an electric signal generator 113c for generating electric signals having a continuous RF frequency, And a linear amplifier 113a connected to the waveform modulator 113b and amplifying the modulated pulse waveform, the waveform modulator 113b modulating the electric signal output from the wave modulator into a square wave or sine wave pulse waveform, .

The ultrasonic wave generator 113 according to the present invention generates an ultrasonic waveform, and the electric signal generator 113c generates an electric signal having a continuous RF frequency. The electric signal used here uses a square wave or a sine wave depending on the characteristics of the piezoelectric material.

The waveform modulator 113b according to the present invention includes a waveform modulator 113b provided at one side of the electric signal generator 113c and configured to generate a waveform wave of an electric signal having a continuous RF frequency output from the electric signal generator 113c, Or a sinusoidal waveform. This is to pulse the above-mentioned RF frequency through waveform modulation.

The electric signal generating unit 113c, the waveform modulator 113b and the linear amplifier 113a constituting the ultrasonic generator 113 according to the present invention are commonly used in the art and their detailed description is omitted.

The control unit 114 controls the power of the control panel on and off according to the key input of the key input unit 112 and drives the laser driving unit 115 to turn on and off the power of the laser pointer 320, (113) to control the ultrasonic waves to be applied to the piezoelectric element (330).

At this time, the display unit 111 displays a screen necessary for driving the ultrasonic wave integrated module having the guide laser of the present invention.

Further, the ultrasonic wave generator 113 is configured to have a focal distance of ultrasonic waves at a depth of 1 mm to 20 cm into the skin of the subject.

In order to enable the laser pointer to confirm the focusing point of the ultrasonic waves, a laser beam of a focal point coinciding with the ultrasonic focusing length of the ultrasonic wave collecting module includes a ring- To be projected from the center.

Referring to the schematic configuration of the ultrasonic integrated module having guide laser and the sectional view of the ultrasonic integrated module shown in FIG. 7 according to an embodiment of the present invention shown in FIG. 6, a hollow case 310 having a cylindrical shape The piezoelectric element 330 for generating ultrasonic waves and the laser pointer 320 are mounted in the hollow case 310. The hollow case 310 has a center hole 331 formed at the front side of the case, And a laser module mounting hole 316 having a center hole 331 formed on the front surface and a laser module mounting groove 313 formed on the rear surface of the piezoelectric module 120, (150) is mounted.

A cable connection port 315 is provided at one side of the case 310 so that a driving power cable for electrically connecting the ultrasonic generation piezoelectric element 330 and the ultrasonic generation signal output from the control panel 110 is connected .

The piezoelectric element 330 is operated to generate ultrasonic waves by the voltage applied from the control panel 110, specifically, the voltage applied from the ultrasonic generator 113.

At this time, a better ultrasonic wave can be generated by applying an AC voltage having a frequency corresponding to a natural frequency of the applied voltage.

The front face of the laser point 320 is inserted and fixed in the center hole 331 of the piezoelectric element 330 so that the laser is positioned at the ultrasonic focusing point.

Referring to FIG. 7, it can be seen that the front surface of the laser point 320 is inserted and fixed in the center hole 331 of the piezoelectric element 330.

As described above, according to the present invention, the piezoelectric element and the laser point are integrally formed and the laser pointer is located at the ultrasound focusing point, so that the ultrasound focusing point is guided by the laser so that the subject can be treated more easily .

For this purpose, it is preferable that the piezoelectric element 330 is formed in a hemispherical shape having a radius of curvature that is not a planar shape in order to facilitate the shape of the converging point of the ultrasonic waves.

Referring to a cross-sectional view of the ultrasonic integrated module according to another embodiment of FIG. 8, the piezoelectric element 330a is formed in a hemispherical shape, and a central hole is provided therein, so that the ultrasonic focusing point can be more easily formed.

Further, by configuring the radius of curvature of the hemispherical piezoelectric element to be different, the ultrasonic focusing point can be configured differently, so that the radius of curvature can be used differently if necessary.

The laser pointer 320 is connected to the center axis of the piezoelectric element 330 so that the focal point of the ultrasonic wave can be determined by the laser pointer so that the focal point of the ultrasonic wave can be determined. So that the focus direction can be set.

A polarizing plate 322 for polarizing the laser beam projected from the laser module 323 and a polarizing plate 322 for polarizing the polarized light in the polarizing plate 322 And a focusing lens 321 that adjusts the laser beam to a focal distance that matches the length of the ultrasound focusing lens. The focusing lens 321 is assembled so as to protrude from the center hole 331, And to be coupled to the rear portion.

Through this configuration, the laser pointer can aim the laser beam at the corresponding focus according to the distance of the ultrasonic generating surface so that the focus can be visually confirmed.

Since the laser beam is not for treatment, it is preferable that the power is less than 5 mWatt and the diameter is less than 1 cm so that the operator can easily identify the focus.

And a laser module 323 such as a focusing lens 321 and a polarizing plate 322 and is mounted in the mounting hole 314. [

Since these optical elements focus the laser light by the optical element, it is needless to say that additional optical elements including the light scattering plate can be used for securing the stability.

7, the focusing lens 321, the polarizing plate 322 and the laser module 323 are sequentially mounted on the mounting hole 314 so that the front surface of the focusing lens 321 protrudes partially from the center hole 331 And the rear surface of the laser module 323 is mounted in the laser module mounting groove 313. [

In the present invention, the case 310 is filled with a backing material 317 so as to enclose the mounting hole 314, so that the piezoelectric element 311 is inserted into the case 310, So that the element 330 and the laser pointer 320 are stably fixed in the case 310. [

When the focus lens 321 is formed of a lens having a focal distance coinciding with the length of the ultrasound focusing beam and the ultrasonic integrated module having the guide laser of the present invention is used as a water immersion ultrasonic wave irradiation device using water as a medium, Use a lens.

A water-immersion lens means a lens in which the refraction of laser light is corrected in water when the medium is water.

One end of the laser module 323 is electrically connected to the control panel 140 so that the laser driving power source is connected.

Hereinafter, a control method of the ultrasonic wave integrated module including the guide laser having the above-described configuration will be described with reference to the drawings.

10 is a flow chart for explaining the operation of the ultrasonic wave integrated module with guide laser according to the embodiment of the present invention. As shown in the figure, the ultrasonic wave integrated module having the guide laser of the present invention firstly includes a control panel 110 The voltage is applied to the laser module 323 (S210).

When power is applied to the control panel 110, a switch for applying a voltage to the laser module 323 is displayed on the display unit 111 with a touch panel.

A button for applying power to the laser module 323 may be touched.

In this case, the control unit 114 drives the laser driving unit 115 to apply power to the cable connected to the control panel 110 and the laser module 320 to operate the laser module 320.

When power is applied to the laser module 323 in step S210, the experimenter adjusts the support table 260 so as to confirm the position of the focus of the cell or sample in the cell culture chamber 210 with the projected laser (S220).

When the position to scan the ultrasonic waves is confirmed in step S220, the laser power is turned off (S230), and power is applied to the ultrasonic generator 300 so that the ultrasonic waves are irradiated to the cells (S240 to S250).

When the irradiation of the ultrasonic waves is completed for the set time in step S240, the power of the ultrasonic wave generator is turned off and the process is terminated (S260).

On the other hand, in the laser focus confirmation process in step S220, the ultrasound power application and signal generation step in step S240, and the ultrasound irradiation step in step S250, a UI (User Interface) displayed on the display unit 111 of the control panel 110, To perform the detection-related monitoring and, if necessary, operate the safety device so that the desired procedure can be performed.

That is, the ultrasonic generator 300 of the present invention is designed to project a laser beam of a focal point coinciding with the ultrasonic focusing length so that the focal point of the ultrasonic wave can be confirmed by the laser pointer.

The present invention is to be fabricated in such a size that the biochip having the above-described structure can be observed directly by a microscope.

That is, in order to mount the ultrasonic wave generator 300, the circulation unit 130, the thermoelectric element 140, and the CO ₂ generator 120 mounted on the inner and outer walls of the water tank, And the ultrasonic wave generating device is configured to irradiate the ultrasonic wave by tilting the ultrasonic wave generating device at a predetermined angle? With respect to the vertical line of the plane where the cell culture chamber 210 is located so as not to interfere with microscopic observation .

4, the biochip 100 of the present invention is mounted on the objective lens 450 of the microscope 400, and the ultrasound generated by the ultrasound generating device It can be seen that the device 300 is configured to irradiate the cell culture chamber 210 at an angle so as not to interfere with the observation of the microscope.

Reference numeral 420 denotes a light source. Reference numeral 421 denotes an optical element for emitting incident light for fluorescence excitation. Reference numerals 430 and 440 denote optical distribution filters. Reference numeral 410 denotes a high sensitivity camera.

In addition, a modularized microscope may be mounted in engagement with the ultrasonic generator, and the microscope and the ultrasonic generator may be sequentially operated by an electronic circuit such as a trigger box.

Biocompatible materials such as glass and polydimethylsiloxane (PDMS) can be used as the material of the biochip of the present invention, and the case can be formed of polycarbonate, acrylic, or the like.

Hereinafter, a method of observing with a microscope using the biochip of the present invention will be described with reference to the drawings.

FIG. 5 is a flowchart for explaining a method of driving a biochip equipped with a water-immersion ultrasonic generator according to the present invention. Referring to FIG. 5, it is first determined whether various devices are provided in the water tank 200, (S110) whether the cell culture chamber 300 is attached to the support table 260 of the water tank at a predetermined angle? With respect to the vertical line of the plane where the cell culture chamber 210 is located.

If it is determined in step S110 that attachment of various devices is confirmed, a cell or a biological sample to be observed is injected into the cell culture chamber 210 in step S120 (S120).

Thereafter, the cells are incubated or stabilized according to the type of cells or samples injected into the cell culture chamber 210 (S130).

When the cell or sample is stabilized in step S130, the biochip 100 of the present invention is mounted on a microscope to confirm that preparation of the biological sample is completed. The control unit 110 controls the sample injection module driving unit 116 to move the sample injection module 150 So that the sample to be tested is injected into the sample injection port 151 through the injection tube 151a and the sample injection port 151 is connected to the sample introduction port 151 through the first micro flow path 221, So that the sample is injected into the chamber 210 (S140).

When the sample is injected into the cell culture chamber 210, the control unit 110 transmits an ultrasonic generation signal to be tested to the ultrasonic generator 113 so that ultrasonic waves are generated in the cell culture chamber 210 Or the sample is injected (S150).

At this time, the control panel 110 controls the circulation part driving part 117, the heater driving part 119 and the CO ₂ generator driving part 118 so that the cell culture chamber 210 maintains the constant temperature and the CO ₂ concentration, If necessary, the number of degassing steps 230 can be controlled to be circulated.

The control of the circulation part driving part 117, the heater driving part 119 and the CO ₂ generator driving part 118 of the control panel 110 can be performed not only at this stage but also before the test for quick testing Of course.

If ultrasound is injected into the cell culture chamber 210 in step S150, a cell or a sample in the cell culture chamber 210 is observed through a microscope to check the sample transfer efficiency or the like (S160).

As described above, the biochip 100 is attached to a microscope to observe a change in a cell / biological sample with a fluorescence microscope, and to adjust CO ₂ , temperature, humidity, etc. for observation of long-term cell / biological sample changes.

In step S160, the delivery efficiency and the like of the sample to be tested may be checked, and the validity and stability of the sample may be analyzed on the basis of the confirmed result (S170).

On the other hand, when a plurality of cell culture chambers are constituted, it is possible to comparatively analyze the difference between the presence or absence of the ultrasonic stimulation or the sample injection at a time.

As described above, by observing the biochip of the present invention through a microscope, it is possible to improve the delivery efficiency according to the ultrasound stimulation of a specific sample to specific cells or to analyze the therapeutic effect of a diseased biological sample according to ultrasonic stimulation.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art.

100: Biochip 120: CO ₂ generator
130: circulation part 140: thermoelectric element
150: sample injection module 151: sample injection port
152: sample discharge port 200: water tank
210: cell culture chamber 220: microchannel
221: First micro flow path 222: Second micro flow path
230: number of degassing 260: support
300: Ultrasonic generator 400: Microscope

Claims (9)

A cell culture chamber on which a cell or a biological sample is mounted;
A sample injection port connected to the cell culture chamber by a micro channel and injecting a sample;
An ultrasonic wave generating device for generating ultrasonic waves in the degassing water;
A control panel for controlling the ultrasonic wave generator;
A water tank filled with the deaeration water to surround the cell culture chamber;
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The ultrasonic generator
A ring-shaped piezoelectric element for generating ultrasonic waves;
A laser pointer connected to the center axis of the piezoelectric element to set a focus direction of the ultrasonic wave;
A case to which the piezoelectric element and the laser pointer are coupled;
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The laser pointer
A laser module electrically connected to the control panel to project a laser beam;
A polarizer for polarizing the laser beam projected from the laser module;
A focusing lens for adjusting the polarized laser beam in the polarizing plate to a focal distance coinciding with an ultrasonic focusing length;
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The control panel
The piezoelectric element and the laser pointer being electrically connected to the case to control on / off operation of the laser pointer,
A center hole is formed in the piezoelectric element,
The piezoelectric element is mounted in close contact with the front surface of the case,
A front surface of the laser pointer is inserted and fixed in the center hole of the piezoelectric element so that the laser pointer is positioned on a central axis of the piezoelectric element, a rear surface of the laser pointer is mounted in a mounting groove formed in a rear surface of the case, The laser pointer is mounted along a mounting hole formed in the case,
Wherein one end of the laser module is coupled to the mounting groove formed on a rear surface of the case,
Wherein a filling material is filled in the case so as to surround the mounting hole. ≪ RTI ID = 0.0 > 11. < / RTI >
The method according to claim 1,
The ultrasonic generator
Wherein the cell culture chamber is inclined at a predetermined angle with respect to a plane on which the cell culture chamber is located to irradiate ultrasonic waves.
delete delete The method according to claim 1,
A biochip equipped with a water-immersion ultrasonic generator in which a temperature controlling element for controlling the temperature of a culture liquid is installed in the water tank.
The method according to claim 1,
And a CO ₂ generator connected to the cell culture chamber through the deaeration water to adjust CO ₂ concentration in the cell culture chamber.
The method according to claim 1,
The cell culture chamber
A biochip having two or more ultrasonic generating apparatuses and a water erosion type ultrasonic wave generating apparatus distinguished into a chamber equipped with an ultrasonic wave generator and a chamber not mounted with the ultrasonic wave generator.
A cell culture chamber in which a cell or a biological sample is mounted, a sample injection port connected to the cell culture chamber through a microchannel to inject a sample, an ultrasonic generator for generating ultrasonic waves in the degasser, a control panel for controlling the ultrasonic generator And a water tank filled with the degassing water so as to surround the cell culture chamber, wherein the ultrasonic generator includes a ring-shaped piezoelectric element for generating ultrasonic waves, a piezoelectric element connected on the center axis of the piezoelectric element to set a focus direction of the ultrasonic waves And a case coupled to the piezoelectric element and the laser pointer, wherein the laser pointer is electrically connected to the control panel to project a laser beam, and a laser module for polarizing the laser beam projected from the laser module The polarizing plate and the polarized laser beam from the polarizing plate are focused on the ultrasound focusing length Wherein the control panel is electrically connected to the case to turn on and off the operation of the piezoelectric element and the laser pointer, a center hole is formed in the piezoelectric element, The front face of the laser pointer is inserted and fixed in the center hole of the piezoelectric element so that the piezoelectric element is closely attached to the front face of the case and the laser pointer is positioned on the central axis of the piezoelectric element, Wherein the rear surface of the laser pointer is mounted in a mounting groove formed in the case, the laser pointer is mounted along a mounting hole formed in the case, the focus lens is assembled to protrude into the center hole of the piezoelectric element, One end of the laser module is coupled to the mounting groove formed in the case, A bio-chip mounting can erode ultrasonic generator, characterized in that filled so as to surround the mounting hole; and
microscope;
Wherein the bio-chip is mounted on an objective lens of the microscope, wherein the bio-chip is mounted on an objective lens of the microscope.
The method of claim 8,
The ultrasonic generator
Wherein the cell culture chamber is inclined at a predetermined angle with respect to a plane on which the cell culture chamber is located, and generates ultrasonic waves in the degassed water.

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