Patent Description:
A flow path filled with a liquid sample containing particles is irradiated with an ultrasonic wave to form a node of a standing wave in the flow path, and particles focused on the node of the standing wave are recovered.

For example, Japanese Patent Application Laid-Open (<CIT> discloses a technique of a fine particle processing device that applies an ultrasonic wave to a flow path through which a solution containing a solvent component and a fine particle component flows to generate a node of a sound pressure of a standing wave at a predetermined position of the flow path, and thus to separate and recover the fine particle component.

In the clinical examination field, for example, a urine sediment test is performed in which the amount and type of tangible components such as red blood cells and white blood cells contained in a liquid sample such as urine are analyzed to examine a health condition of a person who has excreted urine. Since the amount of the tangible component contained in the urine is very small, it is desirable to obtain a concentrated solution in which the concentration of the tangible component in the urine is increased by recovering the tangible component contained in the urine in a small amount of solvent, and to analyze the tangible component contained in the concentrated solution.

An object of the present disclosure is to recover particles contained in a liquid sample well.

In a liquid sample such as urine, an excretion amount of urine and a component excreted from a body into urine vary depending on situations, such as water intake, sweating, and dietary restriction, and a health condition of a person who excretes urine, and therefore, the density and components of a liquid portion of urine vary. The discloser has found that a frequency of an ultrasonic wave at which a tangible component is recovered well is different depending on the density of the liquid portion of the liquid sample when the ultrasonic wave of a single frequency is applied in a flow path of a cell filled with the liquid sample such as urine to generate a standing wave having a node in the flow path, the tangible component focused on the node is recovered into a small amount of liquid to obtain a concentrated solution of the tangible component, and a recovery rate of the tangible component recovered in the concentrated solution is measured.

<CIT> discusses systems and methods of concentrating particulate matter in a fluid stream by using acoustic waves. Once concentrated, the particulate matter can be separated from the fluid stream. <CIT> discusses a cell detection device and a method of using such a cell detection device. <CIT> discusses a method and system to separate a subgroup of cells and/or particles from a mixture of cells and/or particles present in a suspension.

The present invention relates to a particle recovery device as defined by claim <NUM> and to a corresponding particle recovery method as defined in claim <NUM>. Preferred features of the invention are set out in the dependent claims.

According to the present disclosure, particles contained in a liquid sample having various densities and the like can be recovered well.

Exemplary embodiments will be described in detail based on the following figures, wherein:.

First, a configuration of a particle recovery device <NUM> according to a first exemplary embodiment of the present disclosure will be described.

As shown in <FIG> and <FIG>, the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure includes a flow cell <NUM>, a supporting member <NUM> that supports the flow cell <NUM>, a piezoelectric element <NUM> provided on a wall surface of the flow cell, an oscillator <NUM> that oscillates the piezoelectric element, a spitz tube <NUM> that stores a sample solution <NUM> (an example of a "particle-containing liquid sample" according to an exemplary embodiment of the present disclosure), an introduction path <NUM> that causes the sample solution <NUM> to flow from the spitz tube <NUM> into the flow cell <NUM>, a first pump <NUM> and a second pump <NUM> that suck the sample solution <NUM>, a control unit <NUM>, and a density measurement unit <NUM> as a density acquisition unit that measures density of the sample solution <NUM>.

As an example, the sample solution <NUM> is a body fluid, in particular, such as human urine containing particles such as epithelial cells, and the body fluid is recovered from a living body. The sample solution <NUM> flows into the flow cell <NUM> from a state of being stored in the spitz tube <NUM> through the introduction path <NUM>.

As an example, the flow cell <NUM> is a substantially rectangular parallelepiped member supported by the supporting member <NUM>, and as shown in <FIG>, a circular hole-shaped flow path <NUM> communicating from an upstream side to a downstream side in a longitudinal direction is formed. The piezoelectric element <NUM> is disposed on the wall surface of the flow cell.

The density measurement unit <NUM> is a device that measures the density of the sample solution <NUM> flowing through the introduction path <NUM> and flowing into the flow cell <NUM> or a physical property value correlated with the density (hereinafter, the density or the physical property value correlated with the density is simply referred to as "density"). Examples of the physical property value correlated with the density include the specific gravity, osmotic pressure, electric resistance value, and a refractive index of the sample solution. When the sample solution is urine, a creatinine concentration contained in the urine can be mentioned. As the density measurement unit <NUM>, for example, a densimeter, an osmotic pressure meter, an electric resistance meter, a refractive index meter, or the like can be used.

The density measurement unit <NUM> is, for example, a refractive index meter provided in the introduction path <NUM>. The refractive index meter measures a refractive index of the sample solution <NUM> flowing through the introduction path <NUM>. The sample solution <NUM> whose refractive index has been measured flows through the flow cell provided downstream of the density measurement unit <NUM>. The refractive index meter which is the density measurement unit <NUM> is connected to the control unit <NUM> described later, and a measurement value of the refractive index of the sample solution <NUM> measured by the refractive index meter is transmitted to the control unit <NUM>.

As an example, the flow cell <NUM> is formed of a hard material such as glass, and is formed by cutting a central portion of a quadrangular prism block into a circular hole shape.

The upstream side of the flow path <NUM> is a suction port <NUM> into which the sample solution <NUM> flows from the introduction path <NUM> as described above, and the downstream side of the flow path <NUM> is a discharge port <NUM> that discharges the sample solution <NUM>. In the present exemplary embodiment, a direction communicating from the suction port <NUM> to the discharge port <NUM> of the flow path <NUM> (direction in which the sample solution flows) is defined as a "flow direction".

As shown in <FIG>, a double tube having an outer tube <NUM> and an inner tube <NUM> disposed at a center of the outer tube <NUM> is connected to the discharge port <NUM>. The inner tube <NUM> extends from an opening of the outer tube <NUM> to the outside of the outer tube <NUM>. As an example, the double tube is connected to the discharge port <NUM> of the flow path <NUM> such that the inner tube <NUM> is disposed along a central axis of an inner diameter of the flow path <NUM>.

As shown in <FIG>, the inner tube <NUM> is located on the downstream side (downstream side with respect to a portion where a standing wave SW to be described later is generated) of a portion of the flow path <NUM> with which the piezoelectric element <NUM> is in contact, on the central axis of the flow path <NUM>, and is opened toward the upstream side.

Here, the outer tube <NUM> is bent in an L shape and is connected to the first pump <NUM>. The inner tube <NUM> is connected to the second pump <NUM>. Thus, by driving the first pump <NUM> and the second pump <NUM>, the sample solution <NUM> stored in the spitz tube <NUM> can be sucked to the flow cell <NUM> and caused to flow into the flow cell <NUM>, and the sample solution <NUM> in the flow path <NUM> can be separately discharged to the outside through the outer tube <NUM> and the inner tube <NUM>.

The particles in the sample solution <NUM> are discharged to the outside through the inner tube <NUM> and then recovered. That is, the first pump <NUM>, the second pump <NUM>, the outer tube <NUM>, and the inner tube <NUM> constitute "recovery means" according to an exemplary embodiment of the present disclosure.

It is desirable that the first pump <NUM> and the second pump <NUM> can be driven independently, and the sample solution <NUM> can be sucked from the spitz tube <NUM> to the flow cell <NUM> by driving only the first pump <NUM>.

As shown in <FIG>, an inner diameter of the outer tube <NUM> is substantially the same as an inner diameter of the flow path <NUM>, and an inner diameter of the inner tube <NUM> is equal to or less than about half of the inner diameter of the flow path <NUM>. That is, a cross-sectional area of an inside of the inner tube <NUM> is equal to or less than about <NUM>/<NUM> of a cross-sectional area of an inside of the outer tube <NUM>. A diameter of the inner tube <NUM> is smaller than a wavelength of an ultrasonic wave generated by the piezoelectric element <NUM>.

The piezoelectric element <NUM> is a member that expands and contracts in a predetermined direction when an alternating-current voltage is supplied, and is provided in a state of being in contact with one side surface of the flow cell <NUM> along the flow direction of the flow cell <NUM>.

The oscillator <NUM> supplies the alternating-current voltage to the piezoelectric element <NUM> of the flow cell <NUM> described above, thereby expanding and contracting the piezoelectric element <NUM> in a thickness direction (direction toward an inner wall surface of the flow cell <NUM>). As a result, the ultrasonic wave, which is a compressional wave directed toward the inside of the flow cell <NUM> from the side surface of the flow cell <NUM> to which the piezoelectric element <NUM> is attached, is transmitted to the inner wall surface of the flow cell <NUM>, that is, the inside of the flow path <NUM>. When the generated ultrasonic wave is transmitted to the flow path <NUM>, the sample solution <NUM> stored in the flow path <NUM> is irradiated with the ultrasonic wave.

Here, as shown in <FIG>, in an inner wall surface of the flow path <NUM>, the wall surface on a side on which the piezoelectric element <NUM> is provided is defined as an inner wall surface A, and the wall surface on an opposite side of the inner wall surface A across the central axis is defined as an inner wall surface B.

As described above, since the ultrasonic wave emitted from the piezoelectric element <NUM> is transmitted to the flow path <NUM> through the wall surface of the flow cell <NUM>, the sample solution <NUM> is irradiated with the ultrasonic wave (ultrasonic wave A) from the inner wall surface A side in the flow path <NUM>. The piezoelectric element <NUM>, the inner wall surface A, and the oscillator <NUM> correspond to a first ultrasonic irradiation unit that irradiates the sample solution <NUM> with the ultrasonic wave.

Then, the ultrasonic wave (ultrasonic wave A) transmitted to the sample solution <NUM> reaches the inner wall surface B side on an opposite side across an axial center of the flow path <NUM>.

At this time, a part of the ultrasonic wave (ultrasonic wave A) having reached the inner wall surface B is not transmitted through the inner wall surface B but reflected by the inner wall surface B. That is, a part of the ultrasonic wave having reached the inner wall surface B travels through the sample solution <NUM> again toward the inner wall surface A side. That is, the piezoelectric element <NUM>, the inner wall surface B, and the oscillator <NUM> correspond to a second ultrasonic irradiation unit that irradiates the ultrasonic wave B having the same frequency and amplitude as those of the ultrasonic wave A but having the opposite traveling direction and overlapping with the ultrasonic wave A. The second ultrasonic irradiation unit faces the first ultrasonic irradiation unit.

A part of the ultrasonic wave B having reached the inner wall surface A again is additionally not transmitted through the inner wall surface A and is reflected by the inner wall surface A. That is, a part of the ultrasonic wave having reached the inner wall surface A travels through the sample solution <NUM> toward the inner wall surface B side again.

Since the piezoelectric element <NUM> continuously generates the ultrasonic wave (ultrasonic wave A), the inside of the above-described flow path <NUM> is continuously irradiated with the ultrasonic wave.

At this time, when the wavelengths of the ultrasonic wave A and the ultrasonic wave B satisfy the condition described in the following expression (<NUM>), the ultrasonic waves reflected on the inner wall surface A side and the inner wall surface B side overlap and are amplified, so that the standing wave SW is generated in a direction orthogonal to the flow direction inside the flow path <NUM>. L is an inner diameter [m] of the flow path <NUM>, λ is a wavelength [m] of the ultrasonic wave, and n is an arbitrary integer of <NUM> or more. <NUM>] <MAT>.

That is, the oscillator <NUM>, the piezoelectric element <NUM>, the inner wall surface A, and the inner wall surface B are an example of a "standing wave forming means" according to an exemplary embodiment of the present disclosure.

The frequency of the alternating-current voltage supplied from the oscillator <NUM> is equal to the frequency of the ultrasonic wave emitted from the piezoelectric element <NUM> to the sample solution <NUM> in the flow path <NUM>. That is, the frequency of the ultrasonic wave emitted from the piezoelectric element <NUM> can be changed by changing the frequency of the alternating-current voltage supplied from the oscillator <NUM> to the piezoelectric element <NUM>.

In addition, a voltage value (amplitude) of the alternating-current voltage supplied from the oscillator <NUM> and the amplitude of the ultrasonic wave emitted from the piezoelectric element <NUM> have a correspondence relationship, and it is possible to modulate the amplitude of the ultrasonic wave emitted from the piezoelectric element <NUM> by modulating the voltage value (amplitude) of the alternating-current voltage supplied from the oscillator <NUM> to the piezoelectric element <NUM>.

Here, in the oscillator <NUM>, the frequency and amplitude of the alternating-current voltage supplied to the piezoelectric element <NUM> are controlled by a waveform controller <NUM> included in the control unit <NUM> to be described later.

The control unit <NUM> includes, for example, a storage unit <NUM>, a waveform controller <NUM>, a reception unit <NUM> that receives a density value from the density measurement unit <NUM>, and a waveform derivation unit <NUM>. The reception unit <NUM> receives the density value of the sample solution <NUM> from the density measurement unit <NUM>. That is, the control unit <NUM> and the density measurement unit <NUM> are an example of a density acquisition unit that acquires the density of the sample solution <NUM>. The waveform derivation unit <NUM> determines the frequency and amplitude of the alternating-current voltage supplied to the piezoelectric element <NUM> by the oscillator <NUM> based on the density value of the sample solution <NUM> received by the reception unit <NUM> and a correspondence relationship between the density of the sample solution <NUM> and the frequency stored in the storage unit <NUM>. Then, the waveform controller <NUM> controls the oscillator <NUM> so that the frequency and amplitude of the alternating-current voltage determined by the waveform derivation unit <NUM> are supplied to the piezoelectric element <NUM>.

The configuration of the reception unit <NUM> is not particularly limited, and the receiving unit may be connected to the density measurement unit <NUM> in a wired manner to receive the density value of the sample solution <NUM> from the density measurement unit <NUM>, or may be connected to the density measurement unit <NUM> in a wireless manner to receive the density value of the sample solution <NUM> from the density measurement unit <NUM>. The control unit <NUM> may instruct the density measurement unit <NUM> to transmit the density value to the reception unit <NUM>, and the density measurement unit <NUM> may transmit the density value to the reception unit <NUM> according to the instruction from the control unit <NUM>.

The density measurement unit <NUM> may actively transmit the density value to the reception unit <NUM>. Similarly, examples of the waveform controller <NUM> and the waveform derivation unit <NUM> include an arithmetic device and a control device such as a microcontroller and a microprocessor.

As shown in <FIG>, in a state before the flow path <NUM> is filled with the sample solution <NUM> and irradiated with the ultrasonic wave, the particles contained in the sample solution <NUM> are uniformly dispersed in the sample solution <NUM>.

When the alternating-current voltage is supplied to the piezoelectric element <NUM> in this state and the ultrasonic wave is emitted from the piezoelectric element <NUM>, the ultrasonic wave is applied into the sample solution <NUM> in the flow path <NUM> along the wall surface of the flow cell <NUM>.

Here, when a wavelength λ of the ultrasonic wave propagating through the sample solution <NUM> has a length of about <NUM>/<NUM> with respect to the diameter of the flow path <NUM>, that is, when n = <NUM> in the expression (<NUM>) described above, the standing wave SW is generated in the sample solution <NUM> in a radial direction of the flow path <NUM> as shown in <FIG>. The inner wall surface A and the inner wall surface B are free ends of the standing wave.

In this case, as shown in <FIG>, a node N of the standing wave SW is generated on the central axis of the flow path <NUM>, and an antinode AN of the standing wave SW is generated on the inner wall surface of the flow path <NUM>, that is, the inner wall surface A and the inner wall surface B. Then, the particles dispersed between the antinode AN and the node N of the standing wave SW move toward a position of the node N of the standing wave SW. As a result, the particles in the sample solution <NUM> are focused at the position of the node N of the standing wave SW, and at a portion other than the node N of the standing wave SW, the particles in the sample solution <NUM> are reduced, that is, the concentration is reduced; therefore, a portion (concentrated solution) <NUM> where the particles are focused and a portion (low-concentration liquid) <NUM> where the particles are hardly contained are generated in the sample solution <NUM>. In other words, the density of the particles in the sample solution <NUM> is biased depending on the position in the flow path <NUM>, the concentration (density) of the particles is high at a position where the node N of the standing wave SW is present, and the concentration (density) of the particles is low at a position other than the position where the node N is present.

Here, even when vibration of the piezoelectric element <NUM> is stopped from the state shown in <FIG>, the particles are not immediately dispersed in the entire sample solution <NUM> and remain at the position where the node N of the standing wave SW has been present for a while. Thus, a state in which the sample solution <NUM> is divided into the concentrated solution <NUM> and the low-concentration liquid <NUM> is maintained inside the flow cell <NUM>. That is, the concentration (density) of the particles is high at the position where the node N of the standing wave SW has been present, and the concentration (density) of the particles is low at the position other than the position where the node N has been present.

Then, as shown in <FIG>, when the first pump <NUM> and the second pump <NUM> are each driven in a state where the concentration (density) of the particles of the sample solution <NUM> at the position where the node N of the standing wave SW is present is high, the particles focused at the position of the node N are discharged to the inner tube <NUM> provided downstream as the concentrated solution <NUM>, and the low-concentration liquid <NUM> is discharged to the outer tube <NUM>.

As described above, the piezoelectric element <NUM> is vibrated so as to generate the standing wave SW in the radial direction of the flow path <NUM> with respect to the sample solution <NUM>, and the liquid in which the particles are focused is recovered from the inner tube <NUM>, so that the particles can be concentrated.

As shown in <FIG>, when the particles are discharged by the first pump <NUM> and the second pump <NUM> after the particles in the sample solution <NUM> are focused, it is preferable to discharge the particles in a state where the flow of the sample solution <NUM> is a laminar flow inside the flow path <NUM> in order to prevent the particles from being discharged from the outer tube <NUM> due to disturbance of the liquid flow. The sample solution <NUM> may be recovered in a state of being irradiated with the ultrasonic wave.

A discharge amount of the first pump <NUM> connected to the outer tube <NUM> is larger than a discharge amount of the second pump <NUM> connected to the inner tube <NUM>. A ratio of the discharge amounts in the first pump <NUM> and the second pump <NUM> according to an exemplary embodiment of the present disclosure is desirably equal to a ratio of a cross-sectional areas of the diameters of the outer tube <NUM> and the inner tube <NUM>.

In the particle recovery device according to the present exemplary embodiment, an example of a procedure for determining an optimal frequency which is the frequency of the ultrasonic wave capable of recovering the particles in the sample solution <NUM> well will be described as a procedure for measuring the sample solutions <NUM> of Samples <NUM> to <NUM>. For each sample, the same human urine was used as a matrix as a standard component.

As the sample solution <NUM> of Sample <NUM>, human epithelial cells which were tangible components in urine were added as particles to urine prepared by mixing a plurality of urine of healthy persons for averaging. The density of the sample solution <NUM> of Sample <NUM> was <NUM>/cm<NUM>.

As the sample solution <NUM> of Sample <NUM>, glucose was added to Sample <NUM> to adjust the density to <NUM>/cm<NUM>.

As the sample solution <NUM> of Sample <NUM>, urea was added to Sample <NUM> to adjust the density to <NUM>/cm<NUM>.

As the sample solution <NUM> of Sample <NUM>, albumin was added to Sample <NUM> to adjust the density to <NUM>/cm<NUM>.

Table <NUM> below summarizes the description of Samples <NUM> to <NUM> above.

For the sample solutions <NUM> of Samples <NUM> to <NUM>, the concentration of the tangible component contained in the concentrated solution <NUM> after undergoing the following concentration treatment procedure was compared with the concentration of the tangible component of the sample solution <NUM> before performing the concentration treatment procedure, and a concentration ratio was calculated. In addition, the concentration ratio was multiplied by a ratio between the flow rate of the concentrated solution <NUM> and the flow rate of the sample solution <NUM> to obtain a recovery rate. The recovery rate indicates a ratio (B/A) of the number (B) of the tangible components contained in the concentrated solution <NUM> to the number (A) of the tangible components contained in the sample solution <NUM> before performing the concentration treatment procedure. In the present exemplary embodiment, since the flow rate of the concentrated solution <NUM> is <NUM>% of the flow rate of the sample solution <NUM>, it can be said that the concentration is performed when the recovery rate exceeds <NUM>%. When the recovery rate exceeds <NUM>%, it can be said that the standing wave SW having a node formed at the center of the flow path <NUM> is generated.

<FIG> is a flowchart of an operation procedure of the particle recovery device for measuring the frequency of the ultrasonic wave where the standing wave SW is generated.

First, as a first step S11, only the first pump <NUM> is driven in a state where the second pump <NUM> is stopped, whereby the sample solution <NUM> stored in the spitz tube <NUM> is caused to flow into the flow path <NUM> in the flow cell <NUM>.

Next, in a second step S12, after the sample solution <NUM> is caused to flow into the flow path <NUM>, the first pump <NUM> is stopped, and waiting is performed for a predetermined time T1 until the flow of the sample solution <NUM> in the flow path <NUM> does not flow.

Next, as a third step S13, the piezoelectric element <NUM> is vibrated by supplying the alternating-current voltage of <NUM> V constant voltage from the oscillator <NUM> to the piezoelectric element <NUM>, and the sample solution <NUM> in the flow path <NUM> is irradiated with an ultrasonic wave of a constant frequency for a predetermined time T2, so that the node N is generated on the central axis with respect to the flow cell <NUM>.

Next, as a fourth step S14, the supply of the alternating-current voltage from the oscillator <NUM> to the piezoelectric element <NUM> is stopped, and the vibration of the piezoelectric element <NUM> is stopped.

Next, as a fifth step S15, the first pump <NUM> and the second pump <NUM> are driven to cause the concentrated solution <NUM> to flow out to the inner tube <NUM> and the low-concentration liquid <NUM> to flow out to the outer tube <NUM> as shown in <FIG>, thereby discharging the sample solution <NUM> from the flow path <NUM>.

Here, in the third step S13, Sample <NUM> was irradiated with ultrasonic waves having frequencies of <NUM>, <NUM>, and <NUM>, Samples <NUM> to <NUM> were irradiated with ultrasonic waves having frequencies of <NUM>, <NUM>, and <NUM>, Samples <NUM> and <NUM> were irradiated with ultrasonic waves having frequencies of <NUM>, <NUM>, and <NUM>, and Sample <NUM> was irradiated with ultrasonic waves having frequencies of332. <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>.

<FIG> show the results of measuring the recovery rate by performing the concentration treatment described above on the sample solutions <NUM> of Samples <NUM> to <NUM> and measuring and comparing the concentration of the tangible component before and after the concentration treatment.

As shown in <FIG>, in the sample solution <NUM> of Sample <NUM> having a density of <NUM>/cm<NUM>, the recovery rate exceeded <NUM>% at frequencies of <NUM>, <NUM>, and <NUM>, and therefore it can be said that the standing wave SW was generated. The recovery rate was most improved when the frequency of the ultrasonic wave to be applied was set to <NUM>. It was estimated that the recovery rate was low when the ultrasonic wave having a frequency of <NUM> or more was applied. As described above, by irradiating the sample solution <NUM> of Sample <NUM> with the ultrasonic wave having a frequency of <NUM>, the particles in the sample solution <NUM> were efficiently recovered.

Similarly, as shown in <FIG>, in the sample solutions <NUM> of Samples <NUM>, <NUM>, and <NUM> having a density of <NUM>/cm<NUM>, the recovery rate exceeded <NUM>% at frequencies of <NUM>, <NUM>, and <NUM>, and therefore it can be said that the standing wave SW was generated. The recovery rate was most improved when the frequency of the ultrasonic wave to be applied was set to <NUM>. As described above, by irradiating the sample solutions <NUM> of Samples <NUM>, <NUM>, and <NUM> with the ultrasonic wave having a frequency of <NUM> higher than <NUM> at which the highest recovery rate was obtained in Sample <NUM>, the particles in the sample solution <NUM> can be efficiently recovered.

Similarly, as shown in <FIG>, in the sample solutions <NUM> of Samples <NUM> and <NUM> having a density of <NUM>/cm<NUM>, the recovery rate exceeded <NUM>% at frequencies of <NUM>, <NUM>, and <NUM>, and therefore it can be said that the standing wave SW was generated. In the sample solution <NUM> of Sample <NUM> having a density of <NUM>/cm<NUM>, the recovery rate exceeded <NUM>% at frequencies of <NUM> or more and <NUM> or less, and therefore it can be said that the standing wave SW was generated. The recovery rate was most improved when the frequency of the ultrasonic wave to be applied was set to <NUM> in Sample <NUM>, <NUM> in Sample <NUM>, and <NUM> in Sample <NUM>. As described above, by irradiating the sample solutions of Samples <NUM>, <NUM>, and <NUM> with the ultrasonic waves respectively having frequencies of <NUM>, <NUM>, and <NUM> higher than <NUM> at which the highest recovery rate was obtained in Samples <NUM> to <NUM>, the particles in the sample solution <NUM> were efficiently recovered.

From this, it can be seen that it is possible to generate the standing wave SW and set the frequency of the ultrasonic wave at which the recovery rate is improved for any of the sample solutions <NUM> of Samples <NUM> to <NUM> by the concentration treatment described above. In Samples <NUM> to <NUM>, since the density is different for each sample, it is found that the frequency of the ultrasonic wave at which the particles in the sample solution <NUM> can be efficiently recovered is different. The frequency at which particles of a sample having a high density are recovered well tended to be higher than the frequency at which particles of a sample having a low density are recovered well. From this, it is found that the density of the sample and the frequency at which the particles of the sample are recovered well have a correlation, and the particles contained in the sample are recovered well by irradiating the sample with the ultrasonic wave having a frequency corresponding to the density of the sample.

Therefore, as in Samples <NUM> to <NUM>, when the sample solutions <NUM> having different densities are irradiated with the ultrasonic waves at frequencies corresponding to the respective densities, the standing wave SW can be generated even when the densities of the sample solutions <NUM> are different.

Thus, a first frequency at which the tangible component contained in the sample representing the sample solution <NUM> of each density is recovered well is obtained. The first frequency is the frequency of the ultrasonic wave at which the standing wave SW is generated on the central axis of the flow path <NUM> containing the sample solution <NUM> and the particles in the sample solution <NUM> are efficiently recovered. Then, a "density versus frequency relationship" described later, which is a correspondence relationship between the density and the first frequency, is obtained, and the "density versus frequency relationship" is stored in the storage unit <NUM>.

Then, a second frequency is derived from the density measurement value obtained by measuring the density of the sample solution <NUM> and the density versus frequency relationship. It is presumed that the second frequency is the frequency at which the particles contained in the sample solution <NUM> are recovered well. Then, the frequency of the ultrasonic wave with which the sample solution in the flow path according to the first exemplary embodiment is irradiated is determined.

As the first frequency, for example, a plurality of the sample solutions <NUM> having the same density are provided, the frequencies at which the tangible components contained in the sample solution <NUM> are recovered at a high recovery rate are obtained, and a median or an average value of the obtained frequencies can be taken as the first frequency. Moreover, the plurality of sample solutions <NUM> are mixed to prepare an averaged sample solution, and the frequency at which the tangible components contained in the averaged sample solution are recovered well can be taken as the first frequency.

When the frequency of the ultrasonic wave is f[Hz], f can be obtained by the following expression (<NUM>). v is a sound velocity [m/s] traveling in the sample solution <NUM>. <NUM>] <MAT>.

Then, by substituting the expression (<NUM>) into the expression (<NUM>) and deforming the expression, the following expression (<NUM>) is obtained. <NUM>] <MAT>.

Here, in the expression (<NUM>) described above, n can take an arbitrary integer value (n = <NUM>, <NUM>, <NUM>,. ) as a so-called vibration mode. That is, if the frequency f of the ultrasonic wave is set to a frequency at which n is an integer value, the standing wave SW can be generated in the flow path <NUM>.

A number of the nodes N in the standing wave SW is an integer value having the same value as n. For example, when the frequency f of the ultrasonic wave is set such that n is <NUM>, the number of the nodes N of the generated standing wave SW is <NUM>.

As the position where the node N is generated, the node N is generated at a position obtained by equally dividing a distance from the inner wall surface A to the inner wall surface B (radial length of the flow path <NUM>) by n + <NUM>. For example, when n = <NUM>, the node N is generated at a position of <NUM>/<NUM> with respect to the length from the inner wall surface A to the inner wall surface B. When n = <NUM>, the node N is generated at positions of <NUM>/<NUM> and <NUM>/<NUM> with respect to the length from the inner wall surface A to the inner wall surface B.

In this way, when n = <NUM>, the position of the node N of the standing wave SW in the particle recovery device <NUM> according to the present exemplary embodiment is only on the central axis of the flow path <NUM> as in the state shown in <FIG>.

Subsequently, a particle concentration method according to the first exemplary embodiment of the present disclosure will be described with appropriate reference to <FIG>.

<FIG> is a flowchart of a particle concentration procedure according to the first exemplary embodiment of the present disclosure, and a procedure of particle concentration treatment will be described with reference to <FIG>.

First, as a first step S21, only the first pump <NUM> is driven in the state where the second pump <NUM> is stopped, whereby the sample solution <NUM> stored in the spitz tube <NUM> is caused to flow into the density measurement unit <NUM>. Then, the density measurement unit <NUM> measures the density of the sample solution <NUM> and transmits the density measurement value of the sample solution <NUM> to the control unit <NUM>.

Next, as a second step S22, the control unit <NUM> derives the second frequency for the sample solution <NUM> based on the density value of the sample solution <NUM> received from the density measurement unit <NUM> and the density versus frequency relationship stored in the storage unit <NUM>.

Next, as a third step S23, only the first pump <NUM> is further driven, whereby the sample solution <NUM> is caused to flow into the flow path <NUM> in the flow cell <NUM>.

Next, in a fourth step S24, after the sample solution <NUM> is caused to flow into the flow path <NUM>, the first pump <NUM> is stopped, and waiting is performed only for the predetermined time T1 until the flow of the sample solution <NUM> in the flow path <NUM> does not flow.

Next, as a fifth step S25, the piezoelectric element <NUM> is vibrated by supplying the alternating-current voltage from the oscillator <NUM> to the piezoelectric element <NUM>, and the sample solution <NUM> in the flow path <NUM> is irradiated with vibration (ultrasonic wave) of the second frequency derived in S22 for the predetermined time T2. The node N is generated on the central axis of the flow path <NUM>, and the particles in the flow path <NUM> move to the position of the node N.

Next, a sixth step S26 is performed. Since S26 is the same as S14, the description thereof will be omitted.

Next, a seventh step S27 is performed. Since S27 is the same as S15, the description thereof will be omitted.

Next, as an eighth step S28, an amount of the concentrated solution discharged to the inner tube <NUM> is measured, and it is confirmed whether the amount of the concentrated solution suitable for the intended use has been obtained. At this time point, when a sufficient amount of the concentrated solution has not been obtained, the process returns to the third step S23, and when a sufficient amount of the concentrated solution has been obtained, the concentration procedure is terminated.

By performing the particle concentration treatment by the above-described procedure, the following operations and effects are obtained.

First, in the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure, the frequency (second frequency) of the ultrasonic wave with which the flow path <NUM> is irradiated by the control unit <NUM> is derived from the density value of the sample solution <NUM> measured by the density measurement unit <NUM> and the density versus frequency relationship. The second frequency derived from the density value of the sample solution <NUM> and the density versus frequency relationship is presumed to be a frequency showing a high recovery rate. Then, the sample solution <NUM> in the flow path <NUM> is irradiated with the ultrasonic wave of the second frequency derived by the control unit <NUM> from the ultrasonic irradiation unit.

As a result, the particles dispersed in the sample solution <NUM> are focused at the position of the node N of the standing wave SW.

Here, when the plurality of sample solutions <NUM> are provided and the density of the sample solution <NUM> is different among the plurality of sample solutions <NUM>, the frequency of the ultrasonic wave at which the particles in the sample solution <NUM> are efficiently recovered is different for each of the sample solutions <NUM>.

However, in the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure, the density of the sample solution <NUM> is measured by the density measurement unit <NUM>. Thus, the density is measured for each of the sample solutions <NUM>, and the frequency of the ultrasonic wave at which the particles contained in the sample solution <NUM> are recovered well are obtained from the obtained density value of the sample solution <NUM> and the density versus frequency relationship stored in the storage unit <NUM>.

As described above, in the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure, for the plurality of sample solutions <NUM>, even when the density is different for each of the sample solutions <NUM> and the frequency at which the particles in the sample solution <NUM> are efficiently recovered is different, by determining the frequency of the ultrasonic wave with which the flow path is irradiated for each of the sample solutions <NUM>, it is possible to apply the ultrasonic wave having the frequency at which the particles in the sample solution <NUM> can be efficiently recovered.

Therefore, even when the particles of the plurality of sample solutions <NUM> are measured by a series of operations, the particles can be concentrated, operation efficiency can be improved, and the recovery rate of the tangible component can be stabilized.

As described above, since the number of the nodes N of the standing wave SW at the optimal frequency is <NUM>, the particles are concentrated at the radial center of the flow path <NUM>, which is the position of the node N.

Here, a double tube including the outer tube <NUM> and the inner tube <NUM> disposed inside the outer tube <NUM> along the central axis of the outer tube <NUM> is connected to the discharge port <NUM> of the particle recovery device <NUM> according to an exemplary embodiment of the present disclosure, the outer tube <NUM> is disposed coaxially with the flow path <NUM>, and the inner tube <NUM> is disposed on the central axis of the flow path <NUM>.

Therefore, in the sample solution <NUM> filled in the flow path <NUM>, the concentrated solution <NUM> easily flows to the inner tube <NUM>, the low-concentration liquid <NUM> easily flows to the outer tube <NUM>, and the concentration efficiency of the particles can be improved.

As described above, in the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure, the flow of the sample solution <NUM> stops in the flow path <NUM> after the sample solution <NUM> flows into the flow path <NUM>, and vibration is applied to the sample solution <NUM> in a stored state, so that the sample solution <NUM> can be suppressed from flowing inside the flow path <NUM>.

Therefore, when the sample solution <NUM> is discharged from the flow path <NUM>, the flow of the sample solution <NUM> can be brought into a laminar flow state so that the concentrated solution <NUM> easily flows to the inner tube <NUM> and the low-concentration liquid <NUM> easily flows to the outer tube <NUM>. As a result, the concentration efficiency of the particles can be improved.

In the above description, the density measurement unit <NUM> and the storage unit <NUM> are the configurations of the particle recovery device <NUM>; however, the configuration of the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure is not limited thereto.

For example, as shown in <FIG>, the density measurement device <NUM> and the storage device <NUM> may be provided separately from a housing <NUM> that stores the supporting member <NUM>, the oscillator <NUM>, the first pump <NUM>, the second pump <NUM>, and the control unit <NUM>. The density measurement device <NUM> and the storage device <NUM> are connected to the control unit <NUM>. Also in this case, the introduction path <NUM> is connected to the spitz tube <NUM>, and the sample solution <NUM> stored in the spitz tube <NUM> flows through the introduction path <NUM> and is introduced into the flow cell <NUM>.

Then, the density measurement device <NUM> provided in the middle of the introduction path <NUM> transmits the density value of the sample solution <NUM> to the control unit <NUM> of the particle recovery device <NUM>. The control unit <NUM> determines the frequency of the ultrasonic wave by receiving the density value of the sample solution <NUM> received from the density measurement device <NUM> and the density versus frequency relationship from the storage device <NUM>.

Also in this case, the same effects as those of the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure can be obtained.

For example, not only the frequency may be determined according to the density of the sample solution <NUM> as described above, but also the amplitude of the ultrasonic wave to be applied in S25 and the irradiation time T2 of the ultrasonic wave may be determined according to the density of the sample solution <NUM>.

Even when the sample solution <NUM> is irradiated with the ultrasonic wave of the second frequency, the recovery rate of the tangible component contained in the sample solution <NUM> having a high density is lower than the recovery rate of the tangible component contained in the sample solution <NUM> having a low density. Thus, the sample solution <NUM> having a high density is irradiated with the ultrasonic wave having an amplitude larger than the amplitude of the ultrasonic wave with which the sample solution <NUM> having a low density is irradiated, or the sample solution <NUM> having a high density is irradiated with the ultrasonic wave for a time longer than the time for irradiating the sample solution <NUM> having a low density with the ultrasonic wave. As a result, the particles of the sample solution <NUM> having different densities can be recovered at a stable recovery rate.

As described above, since the flow cell <NUM> is formed of glass as an example, the tangible component contained in the sample solution <NUM> flowing in the flow path <NUM> are observed through the flow cell <NUM>. From this, as shown in <FIG>, the particle recovery device <NUM> according to the present disclosure may further include an image detector <NUM> that observes the inside of the flow path <NUM> at a position where the flow cell <NUM> is viewed from the side.

In this case, the image detector <NUM> acquires a state in which the particles are focused in the flow path <NUM> and transmits the state to the control unit <NUM>. As a result, the control unit <NUM> can correct the frequency of the ultrasonic wave, the amplitude of the ultrasonic wave, or the predetermined time T2 in S25 of the concentration treatment procedure based on the state in which the particles are focused.

When the control unit <NUM> has an input unit to which the density of the sample solution <NUM> measured in advance is input, and the frequency is determined based on the input density value of the sample solution <NUM>, the particle recovery device <NUM> may be a configuration that does not have the density measurement unit <NUM>. The input unit corresponds to the density acquisition unit.

The input unit is, for example, a button, a terminal, or the like for an operator of the particle recovery device <NUM> to input the density to the control unit. For example, when the sample solution <NUM> is urine, a part of the urine of a subject collected in a urine collection cup is dispensed into the spitz tube <NUM>, and a part of the urine is left in the urine collection cup. A creatinine concentration in the urine correlated with the density of urine is measured by immersing a creatinine test paper in the urine remaining in the urine collection cup. By inputting the measurement value of the creatinine concentration to the input unit, the density can be input to the control unit <NUM>.

When the operator who operates the particle recovery device <NUM> directly determines the frequency corresponding to the density of the sample solution <NUM>, the particle recovery device <NUM> may be a configuration that does not have the storage unit <NUM>.

In the above description, the density measurement unit <NUM> measures the density of the sample solution <NUM> from the volume and weight of the sample solution <NUM>; however, the present invention is not limited thereto, and a value having a known correlation with the density may be used. For example, the osmotic pressure, refractive index, electrical resistivity, the creatinine concentration, or the like of the sample solution <NUM> may be measured, and the obtained value may be used instead of the density in the above description.

By further providing pressurizing means, such as a liquid feeding pump, in the middle of the introduction path <NUM>, the sample solution <NUM> in the flow path <NUM> may be pressurized in a state where the inflow of the sample solution <NUM> into the flow path <NUM> is completed.

In this case, since the sample solution <NUM> in the flow path <NUM> is pressurized by the pressurizing means during S25, it is possible to prevent cavitation from occurring in the sample solution <NUM> filled in the flow path <NUM>. As a result, the concentration efficiency of the particles can be improved, and breakage of the particles can be prevented.

In the present exemplary embodiment, the piezoelectric element <NUM> is provided only on one side with respect to the flow direction of the flow cell <NUM>; however, the present invention is not limited thereto. For example, the second piezoelectric element may be provided on the side opposite to the piezoelectric element <NUM> with respect to the flow direction of the flow cell <NUM>. In this case, the ultrasonic wave generated from the second piezoelectric element and applied into the flow path <NUM> is an ultrasonic wave having a frequency and amplitude equal to those of the ultrasonic wave generated from the piezoelectric element <NUM> and applied into the flow path <NUM>, and having a phase equal to that of the ultrasonic wave on the central axis of the flow path <NUM>.

In the particle recovery device <NUM> described above, the diameter of the inner tube <NUM> is about half of that of the outer tube <NUM>; however, an exemplary embodiment of the present disclosure is not limited thereto. For example, the recovery rate of the particles in the sample solution <NUM> may be appropriately set by variously preparing the ratio between the diameter of the inner tube <NUM> and the diameter of the outer tube <NUM>.

Although the ratio of the discharge amount of the sample solution <NUM> according to the first pump <NUM> and the second pump <NUM> is equivalent to the ratio of the cross-sectional area of the inner tube <NUM> and the cross-sectional area of the outer tube <NUM>, the ratio of the discharge amount of the sample solution <NUM> according to the first pump <NUM> and the second pump <NUM> in the particle recovery device <NUM> according to an exemplary embodiment of the present disclosure is not limited thereto. For example, the recovery rate of the particles in the sample solution <NUM> may be appropriately set by variously changing the ratio of the discharge amount of the sample solution <NUM> according to the first pump <NUM> and the second pump <NUM>.

In the particle recovery device <NUM> described above, the predetermined number (the number of the nodes N obtained by the standing wave SW) is <NUM>; however, the standing wave SW that can be taken by the particle recovery device <NUM> according to an exemplary embodiment of the present disclosure is not limited thereto. For example, as shown in the above-described expression (<NUM>), the frequency of the ultrasonic wave may be set such that n is an integer of <NUM> or more, and the number of the nodes N obtained by the standing wave SW is <NUM> or more (so-called high-order mode) to generate the standing wave SW. In this case, since the node N is also generated at a position deviated from the radial center of the flow path <NUM>, the diameter of the inner tube <NUM> may be changed so as to correspond to the position of the node N. Instead of the double tube, the discharge port <NUM> may be a multiple tube in which a larger number of tubes are connected coaxially, and the inner tube <NUM> may be disposed at each position corresponding to the position where the node is generated.

Although the particle recovery device <NUM> according to an exemplary embodiment of the present disclosure can concentrate the particles in the sample solution <NUM>, depending on the density, physical properties, and the like of the sample solution <NUM> and the particles, the particles may be concentrated not at the position of the node N but at the position of the antinode in the standing wave generated by the vibration of the piezoelectric element <NUM>. In this case, the relationship among the first pump <NUM>, the second pump <NUM>, the outer tube <NUM>, and the inner tube <NUM> described above may be reversed. That is, the particles can be concentrated when the inner tube <NUM> side is the low-concentration liquid <NUM> and the outer tube <NUM> side is the concentrated solution <NUM>.

In the above description, the flow cell <NUM> has a substantially rectangular parallelepiped shape as an example; however, an exemplary embodiment of the present disclosure is not limited thereto. For example, the flow cell <NUM> may have a cylindrical shape or a regular polygonal columnar shape.

In the above description, the flow path <NUM> has a circular hole shape; however, an exemplary embodiment of the present disclosure is not limited thereto. For example, the flow path <NUM> may have a polygonal hole shape.

Subsequently, a particle recovery device <NUM> according to a second exemplary embodiment of the present disclosure will be described. The same configuration and the same principle as those of the first exemplary embodiment will not be described.

<FIG> is a view showing a configuration of particle recovery according to the second exemplary embodiment of the present disclosure. As shown in <FIG>, the particle recovery device <NUM> according to the second exemplary embodiment of the present disclosure is different from the particle recovery device <NUM> according to the first exemplary embodiment in the following points. That is, the particle recovery device <NUM> according to the second exemplary embodiment includes a component information acquisition unit <NUM> in the middle of an introduction path <NUM>.

As an example, the component information acquisition unit <NUM> is provided in the middle of the introduction path <NUM>, and measures the concentrations of a plurality of components contained in the sample solution <NUM> flowing through the introduction path <NUM> and flowing into the flow cell <NUM>. Then, the component information acquisition unit <NUM> transmits a measurement value of the concentrations of the plurality of components of the sample solution <NUM> to a control unit <NUM>. That is, the control unit <NUM> according to the second exemplary embodiment receives the density value of the sample solution <NUM> from a density measurement unit <NUM>, and receives the measurement value of the concentrations of the plurality of components contained in the sample solution <NUM> from the component information acquisition unit <NUM>.

The component measured by the component information acquisition unit <NUM> is a component having a significantly different concentration and contained in the sample solution <NUM> depending on an individual of the sample solution <NUM>, and is a component that affects the density of the sample solution <NUM>. The component measured by the component information acquisition unit <NUM> can be appropriately set according to the type of the sample solution <NUM>. When the sample solution <NUM> is urine, the components measured by the component information acquisition unit <NUM> are, for example, glucose, urea, and albumin. As the component information acquisition unit <NUM>, for example, a biosensor such as a glucose sensor can be used.

Then, the frequency of the alternating-current voltage supplied to the piezoelectric element by the oscillator <NUM> is determined based on the received density value of the sample solution <NUM>, the received value of the concentrations of the plurality of components contained in the sample solution <NUM>, and the correspondence relationship between the density and the frequency for each component measured by the component information acquisition unit and stored in the storage unit <NUM>.

Other configurations are the same as those of the particle recovery device <NUM> according to the first exemplary embodiment.

Also in the particle recovery device <NUM> according to the second exemplary embodiment, similarly to the particle recovery device <NUM> according to the first exemplary embodiment, the first frequency is obtained by the procedure shown in <FIG>.

First, the density of the sample solution <NUM> and the concentrations of the plurality of components contained in the sample solution <NUM> are measured, and the correspondence relationship between the density of the sample solution <NUM> and the first frequency obtained as shown in <FIG> to be described later by the procedure for determining the first frequency according to the first exemplary embodiment is stored in the storage unit <NUM> as a "density versus frequency relationship" according to the second exemplary embodiment of the present disclosure.

In addition, in the procedure for measuring the frequency of the ultrasonic wave with which the sample solution <NUM> is irradiated according to the second exemplary embodiment, the measurement of the first frequency similarly showing the high recovery rate is performed on the plurality of sample solutions <NUM> containing the respective components measured by the component information acquisition unit <NUM> at the highest concentration.

Then, the correspondence relationship between the density of the sample solution <NUM> and the first frequency is stored in the storage unit <NUM> for each type of component contained in the sample solution <NUM> at the highest concentration.

Then, the optimal frequency according to the second exemplary embodiment is determined by deriving a second frequency from the density versus frequency relationship created using the sample containing the component contained at the highest concentration in the sample solution <NUM>, the measurement value of the density of the sample solution <NUM>, and the measurement values of the concentrations of the plurality of components.

Subsequently, a particle concentration method according to the second exemplary embodiment of the present disclosure will be described with appropriate reference to <FIG>.

<FIG> is a flowchart of a particle concentration procedure according to the second exemplary embodiment of the present disclosure, and a procedure of particle concentration treatment will be described with reference to <FIG>.

First, as a first step S31, only a first pump <NUM> is driven in the state where a second pump <NUM> is stopped, whereby the sample solution <NUM> stored in a spitz tube <NUM> is caused to flow into the density measurement unit <NUM> and the component information acquisition unit <NUM>. Then, the density measurement unit <NUM> transmits the density value of the sample solution <NUM> to the control unit <NUM>, and the component information acquisition unit <NUM> transmits the concentrations of the plurality of components contained in the sample solution <NUM> to the control unit <NUM>.

Next, as a second step S32, the control unit <NUM> derives the second frequency for the sample solution <NUM> based on the density value of the sample solution <NUM> received from the density measurement unit <NUM> and the density versus frequency relationship stored in the storage unit <NUM>.

The component contained in the sample solution <NUM> at the highest concentration is selected from among the components contained in the sample solution <NUM> based on the concentrations received from the component information acquisition unit <NUM>, and the density versus frequency relationship stored in the storage unit <NUM>, which is created using the sample solution <NUM> containing the same component as the selected component, is selected based on the selected component. Then, the second frequency is obtained based on the selected density versus frequency relationship and the value of the density of the sample solution <NUM>, and the frequency (second frequency) of the ultrasonic wave with which the sample solution <NUM> is irradiated is determined.

Alternatively, the second frequency for each component is obtained from the "density versus frequency relationship" for each component stored in the storage unit <NUM> and the density value of the sample solution <NUM>. The second frequency weighted by the concentration of each component can be obtained by multiplying the obtained second frequency for each component by a ratio of the measured concentration of each component, and the frequency of the ultrasonic wave with which the sample solution <NUM> is irradiated can be determined.

In the particle concentration procedure according to the second exemplary embodiment, S33 to S38 are the same as S23 to S28 in the particle concentration procedure according to the first exemplary embodiment.

First, when the plurality of sample solutions <NUM> are provided and liquid properties such as the density and viscosity of the sample solution <NUM> are different among the plurality of sample solutions <NUM>, the frequency of the ultrasonic wave at which the particles in the sample solution <NUM> can be efficiently recovered is different for each of the sample solutions <NUM>. Specifically, the frequency at which particles of a sample having a high density can be recovered well tends to be higher than the frequency at which particles of a sample having a low density can be recovered well. However, when the concentration of each component contained in the sample solution <NUM> is different even in the sample solution <NUM> having the same density, the frequency of the ultrasonic wave at which the particles in the sample solution <NUM> can be efficiently recovered also slightly changes.

Here, since the particle recovery device <NUM> according to the second exemplary embodiment of the present disclosure further includes the component information acquisition unit <NUM> as compared with the particle recovery device <NUM> according to the first exemplary embodiment, the concentrations of the plurality of components of the sample solution <NUM> can be acquired.

Therefore, in the particle recovery device <NUM> according to the second exemplary embodiment of the present disclosure, the concentrations of the plurality of components contained in the sample solution <NUM> is measured, the second frequency is derived from the density versus frequency relationship created using the sample containing the measured component, the measurement value of the density of the sample solution <NUM>, and the measured concentrations of the plurality of components, and the sample solution <NUM> is irradiated with the ultrasonic wave of the second frequency. Thus, the frequency of the ultrasonic wave with which the sample solution <NUM> is irradiated can be determined.

As a result, in the particle recovery device <NUM> according to the second exemplary embodiment of the present disclosure, it is possible to derive the optimal frequency that generates a stationary wave more accurately than the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure, and to recover the particles contained in the sample solution <NUM>.

Other operation and advantageous effects are the same as those of the particle recovery device <NUM> according to the first exemplary embodiment.

In the above description, the particle recovery device <NUM> according to the second exemplary embodiment may further perform the following control.

In the particle recovery device <NUM> according to the second exemplary embodiment, the amplitude of the ultrasonic wave with which the sample solution <NUM> is irradiated may be adjusted according to the concentrations of the plurality of components measured by the component information acquisition unit <NUM>. For example, when the amplitude of the ultrasonic wave with which the sample solution <NUM> is irradiated is reduced, it is possible to suppress the occurrence of the cavitation in the flow path and prevent the breakage of the particles. When the amplitude of the ultrasonic wave with which the sample solution <NUM> is irradiated is increased, the pressure due to the stationary wave generated in the flow path increases, so that the focusing of the particles can be accelerated.

For example, a predetermined time T2 for irradiating the sample solution <NUM> with the ultrasonic wave may be adjusted according to the type of the component measured at the highest concentration among the components measured by the component information acquisition unit <NUM>. When the predetermined time T2 for irradiating the sample solution <NUM> with the ultrasonic wave is increased, the time during which the particles in the sample solution <NUM> are focused increases, so that the recovery rate can be improved. When the predetermined time T2 for irradiating the sample solution <NUM> with the ultrasonic wave is reduced, a time related to particle recovery operation is reduced, so that efficiency of particle recovery processing can be improved.

The control unit <NUM> has an input unit to which the concentrations of the plurality of components of the sample solution <NUM> measured in advance is input, and the control unit <NUM> can determine the frequency based on the input value of the concentrations of the plurality of components of the sample solution <NUM>. In this case, the particle recovery device <NUM> may be a configuration that does not include the component information acquisition unit <NUM>. The concentrations of the plurality of components contained in the sample solution <NUM> can be measured using, for example, a urine test paper.

When the operator who operates the particle recovery device <NUM> based on the concentrations of the plurality of components of the sample solution <NUM> directly determines the frequency of the ultrasonic wave with which the sample solution <NUM> is irradiated, the particle recovery device <NUM> may be a configuration that does not have the storage unit <NUM>.

The modification of the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure can also be applied to the particle recovery device <NUM> according to the second exemplary embodiment of the present disclosure.

Next, the effects of the first exemplary embodiment of the present disclosure were verified from the following various experimental results. In the flow cell <NUM> used in the experiment, the longitudinal direction was <NUM>, a long side in the lateral direction (radial direction) was <NUM>, a short side in the lateral direction was <NUM>, and the diameter of the flow path <NUM> was <NUM>. The piezoelectric element <NUM> was disposed on one surface along the longitudinal direction on the short side in the lateral direction of the flow cell <NUM>.

As the sample solution <NUM> of Sample <NUM>, human epithelial cells which were tangible components were added as particles to urine prepared by mixing a plurality of urine of healthy persons. The density of the sample solution <NUM> of Sample <NUM> was <NUM>/cm<NUM>. As Samples <NUM>, <NUM>, and <NUM>, those described above were used. The contents of the description of Sample <NUM> are summarized in Table <NUM>.

As Experiment <NUM>, the first frequency of each sample was measured at intervals of <NUM> using the sample solutions <NUM> of Samples <NUM> to <NUM>, and the effect of the particle recovery method according to the first exemplary embodiment of the present disclosure was confirmed.

<FIG> is a view showing the results of measuring the first frequency at intervals of <NUM> in each of the sample solutions <NUM> of Samples <NUM> to <NUM> by the procedure shown in <FIG>, and using the median of the first frequency for each density (<NUM>/cm<NUM>, <NUM>/cm<NUM>, and <NUM>/cm<NUM>) from the obtained results.

More specifically, as shown in <FIG>, Sample <NUM> having a density of <NUM>/cm<NUM> was irradiated with the ultrasonic waves of <NUM>, <NUM>, and <NUM> to measure the recovery rate of the tangible components contained in Sample <NUM>. As a result, the highest recovery rate was shown at <NUM>. Thus, the first frequency of the sample solution <NUM> having a density of <NUM>/cm<NUM> was set to <NUM>, and plotted in <FIG>.

Samples <NUM> to <NUM> having a density of <NUM>/cm<NUM> were irradiated with the ultrasonic waves of <NUM>, <NUM>, and <NUM>, and the recovery rate of the tangible components contained in Samples <NUM> to <NUM> was measured. The highest recovery rate was shown at <NUM> in any of the sample solutions <NUM> of Samples <NUM> to <NUM>. Thus, the first frequency of the sample solution <NUM> having a density of <NUM>/cm<NUM> was set to <NUM>, and plotted in <FIG>.

Samples <NUM> and <NUM> having a density of <NUM>/cm<NUM> were irradiated with the ultrasonic waves of <NUM>, <NUM>, and <NUM> to measure the recovery rate of the tangible components contained in Samples <NUM> and <NUM>.

For Sample <NUM> having a density of <NUM>/cm<NUM>, the recovery rate of the tangible component was measured when the ultrasonic waves of <NUM> and <NUM> were further applied. The highest recovery rate was shown at <NUM> for Sample <NUM>, <NUM> for Sample <NUM>, and <NUM> for Sample <NUM>. <NUM> which was the median of the frequency showing the highest recovery rate in Samples <NUM>, <NUM>, and <NUM> was plotted as the first frequency of the sample solution <NUM> having a density of <NUM>/cm<NUM> in <FIG>.

In this experiment, the median obtained by measuring the first frequency of each of the plurality of sample solutions <NUM> having a density of <NUM>/cm<NUM> and having different components contained in the sample solution <NUM> is <NUM>/cm<NUM> and is used as the first frequency of the sample solution <NUM>; however, an averaged sample solution obtained by mixing the plurality of sample solutions <NUM> having a density of <NUM>/cm<NUM> is prepared, and the first frequency of the averaged sample solution can be used as the first frequency of the sample solution <NUM> having a density of <NUM>/cm<NUM>. The first frequency of the sample solution <NUM> having a density of <NUM>/cm<NUM> can also be determined in the same manner.

From <FIG>, it can be seen that the optimal frequency increases as the density increases at each plot point. That is, from <FIG>, it can be seen that the optimal frequency changes depending on the difference in density of the sample solution <NUM>.

As shown in <FIG>, the correspondence relationship between the density and the optimal frequency, that is, the density versus frequency relationship could be obtained in a linear function manner by interpolating between the plot points. In the example shown in <FIG>, when the density was ρ (g/cm<NUM>) and the frequency was f (kHz), f = <NUM>ρ + <NUM> was obtained as indicated by a dotted line in <FIG>.

By storing the density versus frequency relationship thus obtained in the storage unit <NUM> of the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure, it can be said that the control unit <NUM> can determine the second frequency based on the density versus frequency relationship stored in the storage unit <NUM> even when the particles contained in the unknown sample solution <NUM> are focused and recovered. In this experiment, a correlation equation between the density and the first frequency is used as the density versus frequency relationship; however, a lookup table in which the density and the first frequency are compared may be used.

<FIG> show the relationship between the density of the sample solution <NUM> and the first frequency for each of the added various components (glucose, urea, and albumin) in the sample solutions of Samples <NUM> to <NUM>. That is, <FIG> shows the relationship between the density of the sample solutions <NUM> of Samples <NUM> and <NUM> in which the component contained in the sample solution at the highest concentration among the components contained in the sample solution is glucose and the first frequency. <FIG> shows the relationship between the density of the sample solutions <NUM> of Samples <NUM> and <NUM> in which the component contained in the sample solution at the highest concentration among the components contained in the sample solution is urea and the first frequency. <FIG> shows the relationship between the density of the sample solutions <NUM> of Samples <NUM> and <NUM> in which the component contained in the sample solution at the highest concentration among the components contained in the sample solution is albumin and the first frequency.

From <FIG>, it can be seen that, as in <FIG>, at each plot point, the density increases, and the first frequency also increases; however, a slope of the plot point, that is, the density versus frequency relationship is different for each of the various components. Therefore, from <FIG>, it can be seen that the first frequency changes due to the difference in contained components even when the density of the sample solution <NUM> is about the same. In the examples shown in <FIG>, when the frequency of the sample solution <NUM> to which glucose was added was fG (kHz), the frequency of the sample solution <NUM> to which urea was added was fB (kHz), and the frequency of the sample solution <NUM> to which albumin was added was fA (kHz), fG = <NUM>ρ + <NUM> was obtained as indicated by a dotted line in <FIG>, fB = <NUM>ρ + <NUM> was obtained as indicated by a dotted line in <FIG>, and fA = <NUM>ρ + <NUM> was obtained as indicated by a dotted line in <FIG>.

As described above, the correspondence relationship between the density of the sample solution <NUM> and the first frequency is stored in advance in the storage unit <NUM> of the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure for each component contained in the sample solution <NUM> (for each component measured by the component information acquisition unit <NUM>). Then, the correspondence relationship between the density and the first frequency for the component having the highest measured value among concentration measured values of the components detected by the component information acquisition unit <NUM> is read from the storage unit. The second frequency is derived using the read correspondence relationship and the density acquired by the density acquisition unit. As a result, even when the particles of the unknown sample solution <NUM> are focused and recovered, it can be said that the control unit <NUM> can determine the optimal frequency based on the density versus frequency relationship stored for each component in the storage unit <NUM>.

As shown in <FIG>, the inclination is different for each of the various components. Therefore, the control unit <NUM> may correct the frequency by weighting the concentrations of the plurality of components contained in the unknown sample solution <NUM> based on the density versus frequency relationship for each of the various components described above. As a result, the frequency of the ultrasonic wave that generates the standing wave SW with respect to the unknown sample solution <NUM> can be determined with higher accuracy.

As Experiment <NUM>, the recovery rate was measured using the sample solutions <NUM> of Samples <NUM> to <NUM>, and the effect in the particle recovery method according to the first exemplary embodiment of the present disclosure was confirmed.

<FIG> is a view showing the results of measuring the recovery rate by irradiating each of the sample solutions <NUM> of Samples <NUM> to <NUM> with the first frequency obtained in Experiment <NUM> described above in the procedure shown in <FIG> and using the median of the recovery rate for each density (<NUM>/cm<NUM>, <NUM>/cm<NUM>, and <NUM>/cm<NUM>) from the obtained result. More specifically, the plot point of <NUM>/cm<NUM> is the recovery rate of the sample solution <NUM> of Sample <NUM>, the plot point of <NUM>/cm<NUM> is the recovery rate of the sample solution <NUM> of Sample <NUM>, and the plot point of <NUM>/cm<NUM> is the recovery rate of the sample solution <NUM> of Sample <NUM>.

From <FIG>, it can be seen that the recovery rate decreases as the density increases at each plot point. That is, from <FIG>, it can be seen that the recovery rate changes depending on the difference in density of the sample solution <NUM>.

As shown in <FIG>, the correspondence relationship between the density and the recovery rate could be obtained in a linear function manner by interpolating between the plot points. In the example shown in <FIG>, when the density was ρ (g/cm<NUM>) and the recovery rate was C (%), C = -<NUM>ρ + <NUM> was obtained as indicated by a dotted line in <FIG>.

By storing the correspondence relationship between the density of the sample solution <NUM> and the recovery rate thus obtained in the storage unit <NUM> of the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure, it can be said that the control unit <NUM> can determine the recovery rate based on the correspondence relationship stored in the storage unit <NUM> even when the particles contained in the unknown sample solution <NUM> are focused and recovered.

In the case of recovering the sample solution <NUM> in which the recovery rate decreases, that is, the particles of the sample solution <NUM> having a high density, measures such as increasing an amount of the sample solution <NUM> introduced and increasing the predetermined time T2 for applying the ultrasonic wave may be taken in order to compensate for the decreased recovery rate.

<FIG> show the relationship between the density of the sample solution <NUM> and the recovery rate for each of the added various components (glucose, urea, and albumin) in the sample solutions of Samples <NUM> to <NUM>. That is, <FIG> shows the results of Samples <NUM> and <NUM> with respect to the sample solution <NUM>, <FIG> shows the results of Samples <NUM> and <NUM> with respect to the sample solution <NUM>, and <FIG> shows the results of Samples <NUM> and <NUM> with respect to the sample solution <NUM>.

From <FIG>, it can be seen that, as in <FIG>, at each plot point, the density increases, and the recovery rate decreases; however, the slope of the plot point, that is, the correspondence relationship between the density and the recovery rate is different for each of the various components. Therefore, from <FIG>, it can be seen that the recovery rate changes due to the difference in components contained in the sample solution <NUM>. In the examples shown in <FIG>, when the recovery rate of the sample solution <NUM> to which glucose was added was CG (%), the recovery rate of the sample solution <NUM> to which urea was added was CB (%), and the recovery rate of the sample solution <NUM> to which albumin was added was CA (%), CG = -<NUM>ρ + <NUM> was obtained as indicated by a dotted line in <FIG>, CB = -<NUM>ρ + <NUM> was obtained as indicated by a dotted line in <FIG>, and Ca = -<NUM>ρ + <NUM> was obtained as indicated by a dotted line in <FIG>.

By storing the correspondence relationship between the density of the sample solution <NUM> and the recovery rate thus obtained in the storage unit <NUM> of the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure, it can be said that the control unit <NUM> can determine the recovery rate based on the correspondence relationship stored in the storage unit <NUM> even when the particles in the unknown sample solution <NUM> are focused and recovered.

As shown in <FIG>, the slope is different for each of the various components. Therefore, the control unit <NUM> may estimate the recovery rate based on the concentrations of the plurality of components acquired by the component information acquisition unit <NUM>, a density measured value of the sample solution <NUM> acquired by the density acquisition unit, and the above-described correspondence relationship between the density and the recovery rate. As a result, the above measures can be more reliably applied to the unknown sample solution <NUM>, and the particles in the sample solution <NUM> can be recovered.

As Experiment <NUM>, an influence of the amplitude in the ultrasonic wave to be applied was measured using the sample solutions <NUM> of Samples <NUM> and <NUM>, and the effect in the particle recovery method according to the first exemplary embodiment of the present disclosure was confirmed.

In Experiment <NUM>, with respect to the sample solutions <NUM> of Samples <NUM> and <NUM>, in the procedure shown in <FIG>, the frequency of the ultrasonic wave to be applied was used as the optimal frequency obtained in Experiment <NUM> described above, and a change in focusing efficiency was confirmed by changing the amplitude of the ultrasonic wave. More specifically, the amplitude of the ultrasonic wave was controlled by changing the alternating-current voltage supplied from the oscillator <NUM> to the piezoelectric element <NUM> between <NUM> V and <NUM> V, and the focusing efficiency at each voltage value was measured.

Here, the focusing efficiency is derived by using the reciprocal of the time (focusing time) taken from the start of irradiating the flow cell <NUM> with the ultrasonic wave until the tangible components contained in the sample solutions <NUM> of Samples <NUM> and <NUM> filled in the flow path <NUM> are focused at the center inside the flow path <NUM>. That is, it can be said that as the reciprocal of the focusing time is larger, concentration is performed in a shorter time, and therefore efficiency is higher.

<FIG> are views showing the result of the reciprocal of the obtained focusing time. <FIG> shows the result of Sample <NUM> with respect to the sample solution <NUM>, and <FIG> shows the result of Sample <NUM> with respect to the sample solution <NUM>.

From <FIG>, at each plot point, the value of the reciprocal of the focusing time increases as the voltage supplied from the oscillator <NUM> to the piezoelectric element <NUM>, that is, the amplitude of the ultrasonic wave increases; however, the reciprocal of the focusing time decreases when the density increases. Therefore, it can be seen that the focusing efficiency decreases when the density increases.

As shown in <FIG>, the correspondence relationship between the voltage and the reciprocal of the focusing time could be obtained in a linear function manner by interpolating between the plot points. In the examples shown in <FIG>, when the reciprocal of the focusing time of Sample <NUM> was R<NUM> (<NUM>/s), the reciprocal of the focusing time of Sample <NUM> was R<NUM> (<NUM>/s), and the voltage supplied to the piezoelectric element <NUM> was E (V), R<NUM> = <NUM> E - <NUM> was obtained as indicated by a dotted line in <FIG> and R<NUM> = <NUM> E - <NUM> was obtained as indicated by the dotted line in <FIG>, respectively.

By storing the correspondence relationship between the amplitude of the ultrasonic wave (the voltage value of the alternating-current voltage supplied to the piezoelectric element <NUM>) and the focusing time with respect to the density of the sample solution <NUM> thus obtained in the storage unit <NUM> of the particle recovery device <NUM> according to the first exemplary embodiment of the present disclosure, the control unit <NUM> can adjust the focusing time based on the correspondence relationship stored in the storage unit <NUM> even when the particles contained in the unknown sample solution <NUM> are focused and recovered.

As can be seen from <FIG>, when the particles of the sample solution <NUM> having a low density are recovered, in other words, when the particles of the sample solution <NUM> having high focusing efficiency are efficiently recovered, a measure for reducing the predetermined time T2 for applying the ultrasonic wave for focusing may be taken.

As a result, when the particles contained in the sample solution <NUM> having a low density are recovered, it can be said that the time for applying the ultrasonic wave can be shortened, and the efficiency of the operation of recovering the particles can be improved.

As can be seen from <FIG>, when the particles of the sample solution <NUM> having a low density are recovered, in other words, when the particles of the sample solution <NUM> having high focusing efficiency are efficiently recovered, a measure for reducing the amplitude of the alternating-current voltage supplied from the oscillator <NUM> to the piezoelectric element <NUM>, that is, the amplitude of the ultrasonic wave applied to the sample solution <NUM> may be taken.

As a result, when the particles contained in the sample solution <NUM> having a small density are recovered, it can be said that the generation of cavitation in the flow path <NUM> can be suppressed and the breakage of the particles can be prevented by reducing the amplitude of the ultrasonic wave to be applied.

Hereinabove, although the exemplary embodiments of the present disclosure have been described above with reference to the accompanying drawings, it is obvious that a person having ordinary knowledge in the technical field to which the present disclosure belongs can conceive of various modifications or applications within the scope of the present invention as defined in the appended claims.

Claim 1:
A particle recovery device (<NUM>) for recovering particles contained in a liquid sample (<NUM>), the particle recovery device comprising:
a flow cell (<NUM>) having a flow path (<NUM>) through which the liquid sample (<NUM>) flows;
a density acquisition unit that acquires a density of the liquid sample (<NUM>);
standing wave forming means (<NUM>,<NUM>) that applies an ultrasonic wave into the flow path (<NUM>) to generate a standing wave;
recovery means (<NUM>,<NUM>,<NUM>,<NUM>) that recovers particles focused at a predetermined location in the flow path (<NUM>) by the standing wave; and
a control unit (<NUM>) that determines a frequency of the ultrasonic wave that generates the standing wave in the flow path (<NUM>) based on the density acquired by the density acquisition unit and causes the standing wave forming means (<NUM>,<NUM>) to apply the ultrasonic wave of the determined frequency,
wherein the frequency is determined so that a node of the standing wave is formed at the predetermined location in the flow path (<NUM>), and the recovery means recovers the particles gathered by the standing wave.