JP7839287B2 - Method for measuring particles in a solution and apparatus for carrying out the same. - Google Patents

Description

This invention relates to a method for measuring particles present in a solution.

Various particle counting techniques have been developed for determining the purity of solutions containing fine particles and for analyzing them at the cellular level.

For example, in the light scattering method, light passes directly through the sample and is reflected by the surface of particles within the sample. The number and size of particles are calculated based on the relationship between the amount of light detected and the size or refractive index of the particles being measured. However, if the particle surface has an irregular shape, the degree of light reflection may vary depending on the surface, leading to errors.

On the other hand, the method using electrical resistance involves passing a conductive sample through the gap between electrodes and counting the particles using the electrical pulses generated at this time.

Typically, impedance-based flow cytometers measure particle size and distribution using the principle of electrical resistance. When particles dispersed in an electrolyte solution pass through small pores in a microchannel, the resistance between two electrodes carrying a predetermined current increases, generating a potential difference. This difference is then converted into particle size and distribution.

However, flow cytometry requires well-controlled micro-environments and trained operators, and its complex equipment makes it difficult to use outside of a laboratory setting.

Therefore, for portable analysis and diagnosis purposes, a simpler structure needs to be devised.

This invention aims to propose a simpler method for measuring particles in a solution.

More specifically, the present invention aims to propose a method for measuring particles in a solution by processing the signals output by configuring a chip with microchannels and a bridge circuit separately.

More specifically, the present invention aims to propose a method for counting the passage of minute particles using electrical signals sensed via a Wheatstone bridge.

More specifically, the present invention aims to propose a method for measuring particle characteristics using the magnitude and time of electrical state changes caused by input and output signals.

The particle measuring apparatus according to the present invention, for solving the above technical problems, includes a power supply unit for applying voltage, a chip with a plurality of electrodes formed sequentially on a microchannel through which a fluid passes, a circuit unit on which at least a portion of a bridge circuit is printed so as to be in a predetermined electrical state with respect to the plurality of electrodes formed on the chip, and a measuring unit in which the power supply unit applies voltage to the circuit unit and measures the change in the output signal of the bridge circuit due to particles in the fluid passing through the microchannel.

The measurement unit detects the phase change of the electrical signal caused by the position of the particles between the arranged electrodes, and counts the particles in the fluid based on the number of phase changes.

The measurement unit preferably calculates the size of the particles in the fluid based on the amplitude of the phase-shifted electrical signal.

The system further includes a signal conversion unit that converts the electrical signal applied by the power supply unit into an AC signal, amplifies the converted AC signal, and adjusts it to a predetermined offset. Preferably, the measurement unit measures the change in the electrical state using the output signal measured by the bridge circuit after the offset-adjusted electrical signal has been applied.

Preferably, the measurement unit multiplies and amplifies the output signal using the offset-adjusted initial electrical signal, removes specific frequency signals from the amplified output signal to convert it to DC, and detects the electrical phase value signal due to the change in the electrical state.

Preferably, the frequency to be removed is set to a frequency similar to at least the frequency of the initial electrical signal.

The measurement unit preferably calculates the time it takes for the particles to pass through the channel using the generation period of the DC-converted output signal.

The particle measurement method according to the present invention, for solving the aforementioned technical problems, includes the steps of: applying a voltage to a bridge circuit that enters a predetermined electrical state with a plurality of electrodes arranged sequentially on a microchannel through which a fluid passes; and measuring the change in the output signal of the bridge circuit due to particles in the fluid passing through the microchannel.

The measurement step preferably involves detecting the phase change of the electrical signal caused by the position of the particles between the arranged electrodes, and counting the particles in the fluid based on the number of phase changes.

The measurement step preferably involves calculating the size of the particles in the fluid based on the magnitude of the phase-shifted electrical signal.

The step of applying the voltage includes the steps of converting the electrical signal to an AC signal, amplifying the converted AC signal, adjusting the amplified electrical signal to a predetermined offset, and applying the offset-adjusted electrical signal to the bridge circuit.

The measurement step includes calculating the difference between the output signals output from the bridge circuit and amplifying the difference; multiplying the amplified signal using the offset-adjusted initial electrical signal; and removing specific frequency signals within the amplified output signal to convert it to DC.

According to this invention, minute particles in a solution can be accurately measured using changes in electrical signals.

Furthermore, by using the magnitude and time of changes in electrical signals, the properties of fine particles can be measured more accurately.

Furthermore, this invention allows for efficient measurement of particle characteristics even at relatively low voltages, using a simple circuit configuration.

Furthermore, this invention can be directly applied to clinical diagnosis by quantifying the biological characteristics of particles measured using individual reference values.

Furthermore, this invention can be widely adopted as a portable measuring device due to its miniaturization.

This figure shows the structure of the apparatus for measuring particle values according to the present invention. This figure shows the structure of the power supply unit of the device for measuring particle values according to the present invention. This figure shows the processing process of the power supply unit for input electrical signals according to the present invention. This figure shows the processing process of the power supply unit for input electrical signals according to the present invention. This figure shows the processing process of the power supply unit for input electrical signals according to the present invention. This figure shows the structure of the measuring unit of the apparatus for measuring particle values according to the present invention. This figure shows the processing process of the output electrical signal measurement unit according to the present invention. This figure shows the processing process of the output electrical signal measurement unit according to the present invention. This figure shows the processing process of the output electrical signal measurement unit according to the present invention. This figure shows the processing process of the output electrical signal measurement unit according to the present invention. This figure shows the process of detecting electrical signals using particles according to the present invention. This figure shows the process of detecting electrical signals using particles according to the present invention. This figure shows the process of detecting electrical signals using particles according to the present invention. This figure shows the process of detecting electrical signals using particles according to the present invention. This figure shows the characteristics of the measured signal used to measure particle values according to the present invention. This figure shows the characteristics of the electrode structure for measuring particle values according to the present invention. This figure shows the flow chart of the method for measuring particle values according to the present invention.

The following content merely illustrates the principle of the invention. Therefore, those skilled in the art can invent various devices that realize the principle of the invention and fall within the concept and scope of the invention, even if not explicitly described or illustrated herein. Furthermore, all conditional terms and embodiments mentioned herein are, in principle, expressly intended solely for the purpose of enabling understanding of the concept of the invention, and should be understood as not being limited to such specifically mentioned embodiments and states.

The aforementioned objectives, features, and benefits will become clearer from the following detailed description relating to the attached drawings, thereby enabling a person with ordinary skill in the art to easily implement the technical idea of the invention.

Furthermore, when describing the invention, if it is determined that a specific explanation of prior art related to the invention may obscure the gist of the invention, such detailed explanation will be omitted. Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the attached drawings.

Figure 1 shows the structure of the apparatus 100 for measuring particle values according to the present invention.

Referring to Figure 1, the particle measuring device 100 according to the present invention includes a power supply unit 110 that provides power, a circuit unit 120 on which a circuit is printed, and a measuring unit 130 that detects and measures the electrical signal output from the circuit unit 120.

Furthermore, the particle measuring device 100 can be configured to include a microchannel formed on a substrate between an inlet and outlet that are open to the outside, and a measuring chip 140 in which multiple electrodes are arranged in contact with the channel.

The tip 140 can be formed with a structure that allows it to be attached to and detached from the particle measuring device 100, thereby enabling the user to measure particles in the solution they intend to measure by changing the tip during each measurement.

Furthermore, the electrodes on the inserted chip 140, together with the electrodes in the circuit section, form a bridge circuit, enabling the measurement unit 130 to detect even more minute changes in electrical characteristics.

In this embodiment, the measurement unit 130 measures the electrical signal output from the bridge circuit, assuming a basic state where the electrolyte solution passes through the microchannel but particles in the solution do not pass between the electrodes. The measurement unit 130 detects particles based on the measured signal, specifically by changes in the electrical signal caused by changes in electrical characteristics such as impedance due to particles in the solution passing between the electrodes in the channel.

Specifically, by detecting the phase change of an electrical signal caused by the position of particles in a solution between electrodes arranged in a grid, the number of particles in the fluid can be counted based on the number of occurrences of the phase-changed signal.

Here, the particle measuring device 100 according to this embodiment can be operated using a DC voltage power source from a portable power supply such as a dry cell battery. Therefore, a pre-treatment process to convert the power applied by the power supply unit to AC voltage can be performed before application.

Refer to Figure 2 for a more detailed explanation of the input signal preprocessing process.

Figure 2 is a block diagram showing the detailed configuration of the power supply unit according to this embodiment.

Referring to Figure 2, the power supply unit further includes a function generator 114 and a signal conversion unit 116, in addition to the power supply 112.

Generally, in the case of power sources for portable devices such as batteries, electrical signals are output in the form of a DC power source by maintaining predetermined pole positions at the terminals. Therefore, in this embodiment, the function generator 114 converts the DC signal into an AC signal from the potential difference provided by the power source 112 in order to clearly detect changes in components such as phase due to particles.

Specifically, the function generator 114 converts the applied voltage into a periodic signal having a continuous waveform with a predetermined function period. The function generator 114 can be implemented in various forms, such as a microcontroller unit or a function generator, as needed.

Next, the signal conversion unit 116 amplifies the AC signal having a continuous waveform and adjusts it to a predetermined offset. The amplified AC signal, after offset adjustment, is finally converted into a form where positive and negative voltage values repeat, resulting in a sinusoidal waveform. This AC signal, with its periodically repeating positive and negative voltage values, prevents electrolysis of the analytical solution by the power supply through the electrodes.

The signals converted during the above signal processing process will be explained in more detail with reference to Figure 3.

Referring to Figure 3a, as described above, the voltage output from batteries primarily used in portable devices has a predetermined signal in DC form. In the case of a DC signal without periodicity, it is difficult to detect an electrical signal with minute phase differences depending on the properties of the conductive material.

Therefore, the function generator 114 can convert the DC signal from the power supply 112 into a continuous waveform, and then into a periodic signal in the form shown in Figure 3b.

Next, the signal conversion unit 116 amplifies the input signal to increase the amount of change in the electrical signal from the output of the function generator 114, and at the same time adjusts the offset so that it has a sinusoidal shape, thereby generating the final input signal as shown in Figure 3c.

In other words, the power supply unit 110 according to the present invention solves the problem of extreme ion imbalance in the electrolyte due to the unidirectional electrical signal of batteries commonly used in portable devices, leading to electrolysis of the solution and increased resistance, by converting the AC signal. Furthermore, it enables detection of particle flow in the electrolyte solution using the periodic component of a sinusoidal periodic signal.

After the periodic signal generated through the above process is applied to the circuit unit 120, the measurement unit 130 detects, preferably, the change in voltage magnitude over time as an electrical signal output from the bridge circuit.

In this embodiment, the bridge circuit can be designed such that the impedances of the multiple resistors and electrodes are balanced relative to each other in a Wheatstone bridge. Therefore, detection can be more sensitive to electrical signals generated by state changes within the bridge circuit compared to detecting absolute signal values.

However, in the case of electrical signals detected from a bridge circuit, since they are also sensitive to noise, the measurement unit 130 in this embodiment needs to accurately distinguish the changes in the signal components caused by the specific particles to be detected.

Therefore, the measurement unit 130 according to the present invention includes a configuration for accurate detection.

Referring to Figure 4, the measurement unit 130 includes a buffer 132, an amplifier 134, a multiplier 136, and a filter 138.

Buffer 132 utilizes its characteristic of having a near-infinite input impedance to ensure that the output signal from the bridge circuit is not affected by other circuit components of the measurement unit 130, and that the signal is input to the amplifier 134 almost unchanged.

Amplifier 134 calculates the difference between the input signals and amplifies the difference value. The input signals may contain various noises from the solution; by amplifying the difference value, the noise is temporarily removed, and only the asymmetric signal values generated from the particles are extracted. The extracted signals are then fed into multiplier 136.

Next, the multiplier 136 multiplies and amplifies the output signal of the amplifier 134. Specifically, it can be amplified by multiplying the output signals together using the first electrical signal in the form of an offset-adjusted sinusoidal wave. The first signal is used because it has the same signal frequency as the output signal, and other signals with the same frequency as the first signal can be used as needed.

When particles in a solution are positioned between electrodes in a channel while passing through it, the impedance between the electrodes due to the particles can instantaneously increase, and furthermore, a potential difference can be generated due to the capacitor-like action of the particles. This can cause changes in the amplitude and phase of the voltage signal.

Therefore, the multiplier 136 amplifies the waveform signal by multiplying the initial electrical signal and the output signal to extract the signal with a phase difference, while simultaneously constantizing the phase value. The output of the multiplier 136 is calculated as the sum of an AC wave with frequency as a variable and a DC wave affected by the phase difference. Therefore, in order to finally extract only the phase difference generated by the particle, the filter 138 filters the AC wave with the output signal of the multiplier 136.

In other words, the processing steps for extracting the pure target signal generated by the particles from the output signal detected by the measurement unit 130 described above will be explained in more detail with reference to Figure 5.

Referring to Figure 5a, the electrical signal output from the first Wheatstone bridge can have a complex waveform that is uninterpretable due to the difference in electrical properties between the solution and the particles.

Therefore, buffer 132 compensates for the amount of signal bouncing in the output signal, converting it into an interpretable waveform signal. The converted signal has the form shown in Figure 5b, and the overall signal can have a form close to a sine wave.

Here, buffer 132 utilizes its characteristic of having a near-infinite input impedance to ensure no loss in the signal values measured while connecting different circuits. The signal values that have passed through the buffer are amplified via amplifier 134 to remove the signal difference and temporarily eliminate noise. Electrical component changes due to particles in the signal are amplified and extracted using multiplier 136. For signal amplification and extraction, in this embodiment, the input signal can be multiplied by the offset-adjusted sinusoidal input signal and output signal of the power supply unit 110. The amplified signal in the form shown in Figure 5c can be output from multiplier 136.

After compensation via a buffer, the amplified signal, upon passing through the multiplication circuit, becomes a mixture of frequency components and constant-form DC waveforms corresponding to the phase difference. Filter 138 detects the minute phase difference signals generated by the particle's influence by removing the frequency component signal.

In other words, after removing the frequency component signal, the remaining signal contains a signal with a phase difference, in the form shown in Figure 5d.

The output signal, from which the component corresponding to the input signal frequency has been removed, is converted to DC in a form similar to the signal initially applied by the power supply. Therefore, the measurement unit 130 can more clearly extract the particle-induced change component within the signal.

As described above, the signal output from filter 138 acquires a specific waveform because the particle momentarily positions itself on the electrode and then disappears. This allows for the determination of whether or not a particle has passed through.

In this embodiment, the process of generating a specific waveform signal with a phase shift detected by the passage of particles will be described in more detail below with reference to Figure 6.

Referring first to Figure 6a, before the particles pass through the electrodes, the voltage signals in the bridge circuit are in equilibrium and have the same phase as the input electrical signals. Therefore, the signal output from filter 138 retains its DC waveform.

Next, when the particle travels further and is located between the first and second electrodes, a voltage drop occurs due to the particle acting as a resistor or capacitor between the electrodes. Consequently, the phase θ1 of voltage V1 decreases compared to the phase θ2 of voltage V2. Therefore, the electrical signal due to the phase change can be detected as a partial waveform, as shown in Figure 6b, after the input signal and signals of the same frequency have been removed via filter 138. Alternatively, the waveform can be detected by removing the input signal and similar frequency signals within a predetermined range.

Next, when the particle passes the first electrode again and lies between the second and third electrodes, a voltage drop occurs between the second and third electrodes, creating a difference between the phase θ2 of voltage V2 and the phase θ1 of voltage V1. This again creates a phase difference, and the signal resulting from the phase of V1 becoming larger than the phase of V2 is detected in the form shown in Figure 6c.

Once the final particle has passed through all the electrodes, the system returns to its basic state, and a signal in the form shown in Figure 6d is detected.

Furthermore, if the particles are cells, due to their characteristics, they can act as capacitors when positioned between electrodes. Therefore, the size and characteristics of the particles may influence the capacitance, and these characteristics may be reflected in the signal.

Therefore, in this embodiment, it is also possible to count the number of particles by detecting the waveform of continuous particles, and to calculate the size of the particles using the magnitude of the waveform.

Referring to Figure 7, the wavelength of the signal can be calculated from the particle's transit time. Furthermore, the magnitude of the signal can also be calculated from the particle's size, as it is proportional to the voltage change caused by the particle acting as a capacitor, as described above.

Furthermore, since the above signals are generated from the start to the completion of particle passage through the electrode, it is possible to convert these signals into temporal characteristics or particle passage velocities to calculate further particle characteristics.

For example, if particles in a solution possess elasticity like cells, they can change their shape and size according to their inherent stiffness, and can pass through narrower passages by reducing the diameter of the particle itself. However, when cells in the human body bind with various substances or increase in physical stiffness due to aging, their elasticity decreases, and they become harder.

Cells with increased rigidity take longer to pass through a passage of the same width. The particle measuring device according to this embodiment utilizes the proportional relationship between the passage time (wavelength) and factors affecting rigidity to understand the characteristics of cells and enable biological judgments such as diagnosis.

For example, red blood cells in blood that have become more rigid due to glycated hemoglobin take longer to pass through a passage of the same width. The particle measuring device according to this embodiment can determine the degree of glycation of individual red blood cells using the proportional relationship between the passage time and the glycated hemoglobin level (HbA1c Level).

Furthermore, referring to Figures 7 and 8, the fluid is formed by a pattern of fine electrodes. Since the distance d between electrodes can be calculated in advance, it is also possible to calculate the electrode passage velocity based on the wavelength b of the waveform.

As described above, the measurement unit 130 according to this embodiment can count the number of particles using the characteristics of the DC signal output from the filter 138, and can also classify particles based on their unique characteristics using the magnitude and length of the signal.

The particle measurement method according to this embodiment will be described below with reference to Figure 9.

Referring to Figure 9, in order to apply a voltage to a bridge circuit that has multiple electrodes arranged sequentially in a microchannel through which the fluid passes and is in a predetermined electrical state, the electrical signal is first converted to an AC signal, and then the converted AC signal is amplified.

Next, the amplified electrical signal is adjusted to a predetermined offset (S200) to transform it into a sinusoidal wave-like form.

The pre-processed input signal is then applied to the bridge circuit (S300).

Next, the change in the electrical state of the bridge circuit due to particles in the fluid passing through the microchannel is measured from the output electrical signal (S400). Specifically, for measurement purposes, only the bouncing signals resulting from the difference in properties between the particles and the solution can be extracted and amplified from a portion of the output signal from the bridge circuit.

By removing specific frequency signals from the amplified output signal and converting it to DC, it is possible to detect minute signals generated by the position of particles between electrodes arranged in the flow path, and count the particles in the fluid by the number of times these signals are detected.

Furthermore, it is possible to calculate the size of the particles in the fluid based on the magnitude of the phase-shifted electrical signal, and to calculate the transit time based on the amplitude of the electrical signal.

In summary, according to the present invention, it is possible to accurately measure fine particles in a solution using changes in electrical signals.

Furthermore, by using the magnitude and time of changes in electrical signals, the properties of fine particles can be measured more accurately.

Furthermore, this invention enables efficient measurement of particle characteristics even at relatively low voltages, using a simple circuit configuration.

The degree of glycation can be easily measured by using the changes in the physical properties of particles caused by glycation.

Furthermore, by calculating the hardness of each individual particle based on the time it takes for them to pass through a fine channel, the degree of glycation can be measured stably, regardless of external and human factors, compared to measurement equipment using biochemical techniques.

Furthermore, this invention enables the detection of minute electrical changes caused by the passage of particles using a simple circuit configuration, thereby allowing for the measurement of the degree of glycation of the particles.

Furthermore, this invention can be directly applied to clinical diagnosis by correcting particle values measured using individual reference values.

Furthermore, the various embodiments described herein can be implemented, for example, using software, hardware, or a combination thereof, within a recording medium readable by a computer or similar device.

In terms of hardware implementation, the embodiments described herein can be implemented using at least one of the following: ASICs (application specific integrated circuits), DSPs (digital signal processors), DSPDs (digital signal processing devices), PLDs (programmable logic devices), FPGAs (field programmable gate arrays), processors, controllers, microcontrollers, microprocessors, and other electrical units for performing functions. In some cases, the embodiments described herein can be implemented as the control module itself.

In software implementation, embodiments such as the procedures and functions described herein can be implemented in separate software modules. Each of these software modules can perform one or more of the functions and operations described herein. Software code can be implemented in a software application written in a suitable programming language. This software code can be stored in a memory module and executed by a control module.

The above description is merely illustrative of the technical concept of the present invention, and any person with ordinary skill in the art to which the present invention pertains can make various modifications, alterations, and substitutions without departing from the essential characteristics of the present invention.

Therefore, the embodiments and accompanying drawings disclosed herein are for illustrative purposes only, and not to limit the technical idea of the present invention, and the scope of the technical idea of the present invention is not limited by such embodiments and accompanying drawings. The scope of protection of the present invention should be interpreted in accordance with the following claims, and all technical ideas within an equivalent scope should be interpreted as being included within the scope of the rights of the present invention.

Claims (12)

A power supply unit that applies voltage,
A chip in which multiple electrodes are formed in sequence on a microchannel through which a fluid passes,
Circuit elements connected to the multiple electrodes, such that a bridge circuit is formed with multiple electrodes formed at intervals on the chip,
A circuit section including a circuit section to which voltage is applied from the power supply section,
A measuring unit that measures changes in the output signal of the bridge circuit due to particles in the fluid passing through the microchannel ,
Includes ,
The measuring unit measures the characteristics of the particles by determining, based on the order in which the fluid passes through the plurality of electrodes arranged in sequence, the first change in the output signal when the particles are located between the first electrode and the second electrode , and the second change in the output signal when the particles are located between the second electrode and the third electrode.
A device for measuring particles in a solution, characterized by the following features. The measuring unit is characterized by detecting a phase change in the electrical signal caused by the position of the particles between the arranged electrodes, and counting the particles in the fluid based on the number of phase changes, as described in claim 1. The apparatus for measuring particles in a solution according to claim 2, characterized in that the measuring unit calculates the size of the particles in the fluid based on the amplitude of the phase-shifted electrical signal. The system further includes a signal conversion unit that converts the electrical signal applied by the power supply unit into an AC signal, then amplifies the converted AC signal and adjusts it to a predetermined offset,
The apparatus for measuring particles in a solution according to claim 1, characterized in that the measuring unit measures the change in electrical state using the output signal measured by the bridge circuit after the application of an electrical signal adjusted to an offset by the signal conversion unit. The measuring unit is characterized by amplifying the output signal using the initial electrical signal adjusted to an offset by the signal conversion unit, removing specific frequency signals within the amplified output signal to convert it to DC, and detecting the signal resulting from the change in the electrical state, as described in claim 4. The apparatus for measuring particles in a solution according to claim 5, characterized in that the frequency to be removed is set to the same or similar frequency as the frequency of the initial electrical signal. The apparatus for measuring particles in a solution according to claim 5, characterized in that the measuring unit calculates the passage time of the particles through the microchannel using the generation period of the DC-converted output signal. A circuit element connected to a plurality of electrodes is formed to form a bridge circuit with a plurality of electrodes formed at intervals in a microchannel through which a fluid on the chip passes.
The steps include applying a voltage to the circuit section,
The steps include measuring the change in the output signal of the bridge circuit due to particles in the fluid passing through the microchannel ,
Includes ,
The measurement step involves measuring the characteristics of the particles by determining, based on the order in which the fluid passes through the plurality of electrodes arranged in sequence, the first change in the output signal when the particles are located between the first electrode and the second electrode , and the second change in the output signal when the particles are located between the second electrode and the third electrode.
A method for measuring particles in a solution. The measurement step involves detecting a phase change in the electrical signal caused by the position of the particles between the arranged electrodes.
The method for measuring particles in a solution according to claim 8, characterized in that the number of phase changes is used to count the particles in the fluid. The method for measuring particles in a solution according to claim 9, characterized in that the measurement step involves calculating the size of the particles in the fluid, as well as their structural and electrical characteristics, based on the magnitude of the phase-shifted electrical signal. The step of applying the aforementioned voltage is:
The steps include: converting an electrical signal into an AC signal, and then amplifying the converted AC signal;
The steps include adjusting the amplified electrical signal to a predetermined offset,
The method for measuring particles in a solution according to claim 8, characterized in that the step of adjusting to the offset includes the step of applying the offset-adjusted electrical signal to the bridge circuit. The aforementioned measurement step is,
The steps include: calculating the difference between the output signals output from the aforementioned bridge circuit and amplifying the difference;
The step of adjusting to the offset involves multiplying and amplifying the signal amplified by the difference using the first electrical signal that has been adjusted to the offset,
The method for measuring particles in a solution according to claim 11, characterized by comprising the step of removing a specific frequency signal in the multiplied and amplified signal and converting it to DC.