JP7417992B2 - Free water measurement method and free water measurement device - Google Patents

Description

The present invention relates to a free water measuring method and a free water measuring device.

Water contained in living tissues such as skin, cells, crystals, aqueous solutions, etc. is classified into free water (bulk water) and hydration water (bound water). Free water can freely move inside living tissues and the like. On the other hand, hydration water binds to structures such as proteins and plays a very important role in life activities. In any field, the amount of free water and hydrated water can be one of the important parameters for understanding the state of a substance containing water in detail. It is believed that assessing the amount of free water and hydration water will become even more important.

For example, Patent Document 1 discloses a method of determining the proportion of free water by heating a sample and measuring the mass of the sample before and after heating. For example, Patent Documents 2 to 5 and Non-Patent Document 1 disclose that a change in dielectric constant caused by a sample near an electrode is detected as a change in oscillation frequency due to a change in parasitic capacitance of the electrode. A method for evaluating the moisture contained in

Japanese Patent Application Publication No. 2009-85699 Japanese Patent Application Publication No. 2017-187463 International Publication No. 2017/130962 JP 2018-158 Publication Japanese Patent Application Publication No. 2017-131230

Ken Mitsunaka and 6 others, “CMOS biosensor IC that evaluates dielectric relaxation of water using 120 GHz and 60 GHz oscillator arrays,” Institute of Image Information and Television Engineers Technical Report, ITE Technical Report, March 11, 2016, Vol. 40. , No. 12, p. 41-44

However, the method disclosed in Patent Document 1 requires heating the sample. Therefore, the measurement target is limited, and it is difficult to improve the accuracy of the measurement result of the amount of free water. Furthermore, with the methods disclosed in Patent Documents 2 to 5 and Non-Patent Document 1, it is difficult to measure only free water or hydration water with high precision.

In this way, with conventional technology, only free water or hydrated water can be extracted with high precision from among the water contained in biological tissues such as skin, cells, crystals, or aqueous solutions without any state changes resulting from heating. It is difficult to evaluate the

The present invention was made in view of the above circumstances, and its purpose is to remove free water or hydrated water from the water contained in biological tissues such as skin, cells, crystals, or aqueous solutions. Our goal is to provide new technology for highly accurate evaluation of just water.

A first aspect of some embodiments includes a first detection step of detecting a first oscillation frequency that varies depending on air in the vicinity of the first oscillator; a second detection step of detecting a second oscillation frequency that changes according to the physical properties of the object to be inspected; and a step of detecting a free water amount of the object to be inspected based on a frequency shift amount of the second oscillation frequency with respect to the first oscillation frequency. A method for measuring free water, including a specific step of specifying.

A second aspect of some embodiments, in the first aspect, includes a calculation step of calculating the amount of hydration water in the object to be inspected by subtracting the amount of free water specified in the specifying step from the total amount of water.

In a third aspect of some embodiments, in the first aspect or the second aspect, the identifying step includes determining the amount of free water with respect to the change in the dielectric constant of the object to be inspected on the distribution of the amount of frequency shift in the complex permittivity space. The amount of free water is specified based on the change characteristics of.

A fourth aspect of some embodiments includes a first detection step of detecting a first oscillation frequency that varies depending on physical properties of a medium in the vicinity of the first oscillator; a second detection step of detecting a second oscillation frequency that changes depending on the physical properties of the object to be inspected; and a determination step of identifying the state of free water in the object to be inspected based on the first oscillation frequency and the second oscillation frequency. A method for measuring free water, comprising the steps of:

In a fifth aspect of some embodiments, in the fourth aspect, the identifying step identifies the state of the free water based on the difference between the second oscillation frequency and the first oscillation frequency.

In a sixth aspect of some embodiments, in any of the first to fifth aspects, the first oscillator and the second oscillator are arranged adjacent to each other.

A seventh aspect of some embodiments includes an oscillator, a first oscillation frequency that changes depending on the air near the oscillator, and a second oscillation frequency that changes depending on the physical properties of the object to be inspected near the oscillator. The present invention is directed to a free water measuring device, comprising: a detecting section that detects the second oscillation frequency; and a specifying section that specifies the amount of free water in the object based on the frequency shift amount of the second oscillation frequency with respect to the first oscillation frequency.

An eighth aspect of some embodiments, in the seventh aspect, includes a calculating section that calculates the amount of hydration water in the object to be inspected by subtracting the amount of free water specified by the specifying section from the total amount of water.

In a ninth aspect of some embodiments, in the seventh aspect or the eighth aspect, the specifying unit determines the amount of free water with respect to the change in the dielectric constant of the test object on the distribution of the frequency shift amount in the complex dielectric constant space. The amount of free water is specified based on the change characteristics of.

In a tenth aspect of some embodiments, in any of the seventh to ninth aspects, the detection unit includes a first oscillator, and the first oscillator changes depending on the air near the first oscillator. a first detection section that detects an oscillation frequency; and a second detection section that includes a second oscillator and detects the second oscillation frequency that changes depending on the physical properties of the object to be inspected near the second oscillator. include.

An eleventh aspect of some embodiments includes a first detection unit that includes a first oscillator and detects a first oscillation frequency that changes depending on physical properties of a medium near the first oscillator, and a second oscillator. , a second detection unit that detects a second oscillation frequency that changes depending on the physical properties of the object to be inspected dispersed in a medium near the second oscillator; and a specifying section that specifies the state of free water in the object to be inspected.

In a twelfth aspect of some embodiments, in the eleventh aspect, the identification unit identifies the state of the free water based on a difference between the second oscillation frequency and the first oscillation frequency.

In a thirteenth aspect of some embodiments, in any of the tenth to twelfth aspects, the first oscillator and the second oscillator are arranged adjacent to each other.

Note that it is possible to arbitrarily combine the configurations according to the plurality of aspects described above.

According to the present invention, a new technique is provided for highly accurately evaluating only free water or hydration water among the water contained in a test object such as a biological tissue such as skin, cells, crystals, or an aqueous solution. It becomes possible to do so.

FIG. 1 is a schematic diagram showing an example of the configuration of a free water measuring device according to an embodiment. FIG. 1 is a schematic diagram showing an example of the configuration of an oscillator according to an embodiment. FIG. 3 is an explanatory diagram for explaining the operation of the free water measuring device according to the embodiment. FIG. 3 is an explanatory diagram for explaining the operation of the free water measuring device according to the embodiment. FIG. 1 is a schematic diagram showing an example of the configuration of a processing device according to an embodiment. FIG. 3 is an explanatory diagram for explaining the operation of the free water measuring device according to the embodiment. FIG. 3 is an explanatory diagram for explaining the operation of the free water measuring device according to the embodiment. It is a flow diagram showing an example of operation of the free water measuring device concerning an embodiment. FIG. 3 is an explanatory diagram for explaining the operation of the free water measuring device according to the embodiment. FIG. 3 is an explanatory diagram for explaining the operation of the free water measuring device according to the embodiment. FIG. 3 is an explanatory diagram for explaining the operation of the free water measuring device according to the embodiment. FIG. 3 is an explanatory diagram for explaining the operation of the free water measuring device according to the embodiment. It is a flow diagram showing an example of operation of the free water measuring device concerning an embodiment. FIG. 3 is an explanatory diagram for explaining the operation of the free water measuring device according to the embodiment. FIG. 3 is an explanatory diagram for explaining the operation of the free water measuring device according to the embodiment. It is a flow diagram showing an example of operation of the free water measuring device concerning an embodiment.

Embodiments of the free water measuring method and free water measuring device according to the present invention will be described in detail with reference to the drawings. Note that the contents of the documents cited in this specification and any known technology can be incorporated into the following embodiments.

The free water measuring device according to the embodiment detects a change in at least one oscillation parameter of an oscillator that occurs according to the physical properties of an object to be inspected near the oscillator as a change in oscillation frequency, and Measure the physical properties of the corresponding test object. The oscillation parameters include a resistance component, a capacitance component, an inductive component, etc. of the oscillator. The free water measuring method according to the embodiment is realized by the free water measuring device according to the embodiment. Hereinafter, a case in which the oscillation frequency changes depending on the complex dielectric constant, which is one of the physical properties of the object to be inspected, will be mainly described.

FIG. 1 shows a block diagram of a configuration example of a free water measuring device according to an embodiment.

The free water measuring device 1 according to the embodiment includes a sensor device 100, a controller 200, and a processing device 300. The sensor device 100 detects an oscillation frequency that changes depending on the physical properties of the object to be inspected. The controller 200 receives control from the processing device 300 and controls the sensor device 100 . The processing device 300 controls the sensor device 100 via the controller 200, analyzes the detection results obtained by the sensor device 100, and obtains the measurement results of the physical properties of the object to be inspected. In some embodiments, controller 200 is integrally formed with processing device 300. In some embodiments, sensor device 100 is integrally formed with controller 200.

Sensor device 100 includes an oscillator array 10 and an oscillation frequency detection section 30. Oscillator array 10 includes a plurality of oscillators 20 two-dimensionally arranged on a semiconductor integrated circuit board. Each of the plurality of oscillators 20 has the same configuration. The configuration according to the embodiment is not limited to the arrangement of the plurality of oscillators 20. For example, the plurality of oscillators 20 are arranged one-dimensionally or three-dimensionally on a semiconductor integrated circuit board. For example, the plurality of oscillators 20 are arranged in a matrix or staggered pattern on a semiconductor integrated circuit board.

Each of the plurality of oscillators 20 functions as a sensor element. The oscillator 20 changes the oscillation frequency by changing the oscillation parameter depending on the physical properties of the object to be inspected (or the air) placed nearby. This change in oscillation frequency is detected as a change corresponding to the physical properties (eg, complex permittivity) of the object to be inspected.

In FIG. 1, for convenience of explanation, a first oscillator ₂₀₁ and a second oscillator ₂₀₂ among the plurality of oscillators 20 are illustrated. The environmental change operational characteristics of the first oscillator ₂₀₁ are substantially similar to the environmental change operational characteristics of the second oscillator ₂₀₂ (or the difference in characteristics is within a predetermined tolerance range). The environmental change characteristics are characteristics that represent changes in operating characteristics (temperature operating characteristics, humidity operating characteristics) in response to changes in the measurement environment (temperature changes, humidity changes). In some embodiments, the second oscillator ₂₀₂ is located within a predetermined distance with respect to the first oscillator ₂₀₁ such that the environmental change operating characteristics of both are substantially similar. In some embodiments, the second oscillator ₂₀₂ is located adjacent to the first oscillator ₂₀₁ .

The oscillation frequency detection section 30 detects the oscillation frequency of the oscillator 20. The function of the oscillation frequency detection section 30 is realized by a known frequency detection circuit. In some embodiments, the oscillation frequency detection section 30 is provided corresponding to each of the plurality of oscillators 20. In some embodiments, the oscillation frequency detection section 30 is provided for each of two or more oscillators of the plurality of oscillators 20.

FIG. 2 shows a configuration example of the oscillator 20 according to the embodiment. In FIG. 2, the oscillation frequency detection section 30 is also illustrated for convenience of explanation.

Oscillator 20 includes a resonant circuit 21 and a differential circuit 22.

Resonant circuit 21 includes an inductor L0 and capacitors C0, C1, and C2. Capacitor C0 is electrically connected in parallel with inductor L0. One end of the capacitor C1 is electrically connected to one of a pair of electrodes that constitute the sensor section 25. The other end of the capacitor C1 is electrically connected to one end of the inductor L0 and one end of the capacitor C0. One end of the capacitor C2 is electrically connected to the other of the pair of electrodes that constitute the sensor section 25. The other end of the capacitor C2 is electrically connected to the other end of the inductor L0 and the other end of the capacitor C0.

The differential circuit 22 is a known differential circuit including a differential transistor pair. The differential circuit 22 drives the resonant circuit 21.

An object to be inspected can be placed near the sensor section 25 . By arranging the object to be inspected near the sensor section 25, capacitor C1 and capacitor C2 are electrically connected via the object to be inspected. In some embodiments, the capacitor C1 and the capacitor C2 are electrically connected via the test object by a pair of electrodes forming the sensor section 25 coming into contact with the test object. In some embodiments, the state of the parasitic element between the capacitor C1 and the capacitor C2 ( at least one of a resistance component, a capacitance component, and an inductive component) changes. For example, as described in Patent Document 4, an object to be inspected is configured to be electromagnetically connected to an electrode via a coating film.

For example, as shown in FIG. 2, the equivalent circuit of the object to be inspected is represented by a capacitance component and a resistance component connected in parallel. In this case, by arranging the object to be inspected near the sensor section 25, the capacitance component and resistance component connected in parallel with the inductor L0 and the capacitor C0 change. This change in the oscillation parameters causes the oscillation frequency to change. The capacitance component is proportional to the dielectric constant (complex dielectric constant). That is, the oscillation frequency changes depending on the dielectric constant of the object to be inspected. Therefore, by detecting the oscillation frequency, it is possible to estimate the physical properties of the object to be inspected corresponding to the detected oscillation frequency.

As an example of the oscillator 20 according to the embodiment, there is an oscillator disclosed in Patent Document 2, for example. Here, the capacitance detected when the test object is air is _Cair , the combined capacitance value of capacitors C1 and C2 is _C1 , the inductive component of inductor L0 is _L0 , and the complex permittivity of the test object is Let the real part of ε be ε' (polarization component), and the imaginary part of the complex permittivity ε be ε'' (absorption component). At this time, the oscillation frequency f is expressed as equation (1).Equation In (1), the effective inductive component of the resonant circuit is L _eff , and the effective capacitance component is C _eff .

The controller 200 selectively controls the plurality of oscillators 20 of the oscillator array 10 and performs measurement control of changes in the oscillation frequency of a desired oscillator 20. The controller 200 can selectively control two or more oscillators among the plurality of oscillators 20 and execute the above measurement control in parallel or sequentially. The controller 200 can control one or more oscillators of the plurality of oscillators 20 at mutually different control timings, and perform measurement control to detect changes in the oscillation frequency of each oscillator within a predetermined time.

3A and 3B show the imaginary part (dielectric loss spectrum, representing the magnitude of absorption) of the complex permittivity of water. FIG. 3A represents an example of absorption spectra of water and biomolecules (eg, proteins). In FIG. 3A, the vertical axis represents the imaginary part of the complex dielectric constant, and the horizontal axis represents frequency. FIG. 3B represents an example of the absorption spectra of room temperature water and hot water. In FIG. 3B, the vertical axis represents the imaginary part of the complex dielectric constant, and the horizontal axis represents frequency.

As shown in FIG. 3A, when the absorption spectrum P1 of water and the absorption spectrum P2 of biomolecules are compared, the frequency bands with high absorption are different from each other. For example, from 20 GHz to 100 GHz, water absorption is high, but biomolecule absorption is low. Further, as shown in FIG. 3B, when the absorption spectrum P3 of water at room temperature and the absorption spectrum P4 of hot water are compared, the change in absorbance differs at a boundary of 20 GHz. Considering the sensitivity of water to changes in its state, using an oscillation frequency in the 60 GHz band is effective for selectively observing the physical properties of water.

Therefore, the free water measuring device 1 according to the embodiment uses the 60 GHz band oscillator 20.

In the 60 GHz band, free water orientation relaxation becomes dominant, and the effects of ion polarization (<MHz), polymer orientation relaxation (~10 MHz), and hydrated water orientation relaxation (~several GHz) are negligible. This is the band that becomes smaller. In frequency bands lower than 10 GHz, it is difficult to selectively observe free water because it is affected by the above components. On the other hand, in a frequency band higher than 100 GHz, the influence of intermolecular vibrations and intramolecular vibrations of water molecules and biomolecules becomes large, making it difficult to focus only on free water.

Furthermore, the complex permittivity of water in the 60 GHz band has greater temperature dependence than in the high frequency region of 1000 GHz or higher. This means that it becomes sensitive to changes in the state of water molecules (specifically, changes in the hydrogen bonding environment).

Furthermore, electromagnetic waves in the 60 GHz band are non-invasive to living organisms. The energy of photons is about 10,000 times smaller than that of visible light.

Moreover, according to the sensor device 100 according to the embodiment, spatial resolution independent of wavelength can be obtained. In general, the spatial resolution of propagating light is determined by the diffraction limit, so it is difficult to recognize substances smaller than several mm in a far field with a frequency of 60 GHz (ie, a wavelength of 5 mm). However, in the sensor device 100, the electromagnetic waves are localized near the resonator and the waves do not propagate far, so the "near field" is sensitive only to the permittivity near (for example, directly above) the resonator. ” functions as a sensor. Therefore, the size of a material that can be observed is determined by the array density of resonators (oscillators), without depending on the diffraction limit. For example, by arranging oscillators at intervals of 50 μm, it becomes possible to clearly detect substances that are two orders of magnitude smaller than the wavelength.

Further, the sensor device 100 according to the embodiment can generate electromagnetic waves with very weak power. In this case, the output of localized electromagnetic waves is very small, and almost no temperature rise due to forced movement of water molecules is observed. On the other hand, when the sensor device 100 according to the embodiment operates, the circuit board slightly generates heat. There are also temperature fluctuations due to environmental fluctuations. The temperature change due to these factors is, for example, about 0.4° C. during 60 hours of continuous operation. Since the temperature rise is about 0.4° C. even after continuous measurement for 60 hours, the measurement does not cause a heat shock response in the cells, and the measurement does not cause cell death in living cells.

As described above, by detecting changes in the oscillation frequency in the 60 GHz band, it becomes possible to measure the physical properties of biomolecule water non-invasively and without staining. The free water measurement device 1 can measure the physical properties of water in test objects such as biological tissues such as skin, cells, crystals, or aqueous solutions, as well as biological molecules, without causing state changes due to heating. It is possible.

The processing device 300 performs analysis processing on the oscillation frequency obtained by the sensor device 100.

FIG. 4 shows a block diagram of a configuration example of the processing device 300 in FIG. 1.

Processing device 300 includes a specifying section 310 and a calculating section 320.

The identification unit 310 obtains information regarding moisture contained in the object to be inspected based on the first oscillation frequency of the first oscillator ₂₀₁ and the second oscillation frequency of the second oscillator ₂₀₂ detected by the oscillation frequency detection unit 30. Identify. Information regarding water content includes free water content, hydration water content, and the like. The identification unit 310 identifies information regarding moisture contained in the object to be inspected based on a second oscillation frequency based on the first oscillation frequency. Specifically, the identification unit 310 identifies information regarding moisture contained in the object to be inspected based on the frequency shift amount obtained by subtracting the first oscillation frequency from the second oscillation frequency.

For example, the specifying unit 310 determines the first oscillation frequency detected when the sensor section of the first oscillator ₂₀₁ is air, and the first oscillation frequency detected when the sensor section of the second oscillator ₂₀₂ is placed near the sensor section of the second oscillator 202. and the detected second oscillation frequency. The specifying unit 310 obtains the frequency shift amount by subtracting the first oscillation frequency from the second oscillation frequency. The identification unit 310 identifies the amount of free water based on the amount of frequency shift, as described later. Note that the oscillator that detects the first oscillation frequency may be the same oscillator as the oscillator that detects the second oscillation frequency. That is, when specifying the amount of free water, the same oscillator is used to determine the first oscillation frequency when the sensor section is air and the second oscillation frequency when the object to be inspected is placed near the sensor section. It may be configured to detect.

Furthermore, the identification unit 310 identifies the first oscillation frequency detected when a culture medium (medium in a broad sense) is placed near the sensor unit of the first oscillator ₂₀₁ and the sensor unit of the second oscillator ₂₀₂ . A second oscillation frequency detected when the object to be inspected dispersed in the culture medium is placed nearby is acquired. The identifying unit 310 can cancel the measurement environment change by using the difference obtained by subtracting the first oscillation frequency from the second oscillation frequency. Note that the oscillator for detecting the oscillation frequency of the air may be different from the oscillator for detecting the oscillation frequency of the culture medium.

The calculation unit 320 calculates the amount of hydration water using the amount of free water specified by the identification unit 310. Specifically, when the amount of water is known in advance, the calculation unit 320 calculates the amount of hydration water by subtracting the amount of free water from the amount of water.

Such functions of the processing device 300 are realized by a processor. The processor is, for example, a CPU (Central Processing Unit), a GPU (Graphics Processing Unit), an ASIC (Application Specific Integrated Circuit), a programmable logic device (for example, an SPLD (S complex programmable logic device), CPLD (complex programmable logic device), FPGA (Field Programmable Gate Array)). The processor realizes the functions according to the embodiment by, for example, reading and executing a program stored in a memory circuit or a memory device. A memory circuit or device may be included in the processor. Further, a memory circuit or a memory device may be provided outside the processor. Similarly, the functions of controller 200 may be implemented by a processor.

The first oscillator 20 ₁ , the second oscillator 20 ₂ and the oscillation frequency detection section 30 are examples of the "detection section" according to the embodiment. The first oscillator ₂₀₁ and the oscillation frequency detection section 30 are an example of a "first detection section" according to the embodiment. The second oscillator ₂₀₂ and the oscillation frequency detection section 30 are an example of a "second detection section" according to the embodiment.

(Quantitative evaluation of free water amount)
Next, the quantitative evaluation of the amount of free water mentioned above will be explained.

FIG. 5 shows an example of the measurement results of the complex permittivity of an aqueous protein solution. Figure 5 shows the real part (polarization spectrum) of the complex permittivity and the imaginary part of the complex permittivity of a 10 wt% aqueous solution (25°C) of human serum albumin (HSA) (an example of protein) as a test object (measurement sample). (absorption spectrum) measurement results. FIG. 5 is a plot of complex susceptibility components at each oscillation frequency for solute Q1, hydration water Q2, and free water, bulk water Q3. In the band of 0.01 to 0.5 GHz, the frequency measurement results of an impedance analyzer are used. In the band from 0.5 to 50 GHz, frequency measurement results from a network analyzer are used. In the band of 50 to 1000 GHz, frequency measurement results from terahertz time domain spectroscopy are used.

FIG. 5 shows an absorption spectrum Q4 obtained by performing peak fitting analysis on the measurement results according to the following equation using the Debye function.

In equation (2), ω (=2πf) represents the angular frequency, σ represents the electrical conductivity [S/m], and ε ₀ represents the permittivity of vacuum (8.85×10 ⁻¹² ) [F/m ], Δε represents the relaxation strength, τ represents the relaxation time [s], and ε _∞ represents the high frequency limit of the dielectric constant. The first term on the right side corresponds to solute Q1, the second and third terms on the right side correspond to hydration water Q2, and the fourth and fifth terms on the right side correspond to free water Q3. The second term on the right side corresponds to the peak h1 (not shown), and the third term on the right side corresponds to the peak h2 (not shown). Similarly, the fourth term on the right side corresponds to peak b1 (not shown), and the fifth term on the right side corresponds to peak b2 (not shown).

As described above, according to the free water measuring device 1, it is possible to detect a change in oscillation frequency corresponding to a change in dielectric constant. Here, the oscillation frequency of the first oscillator 20 ₁ detected when there is no measurement sample (that is, the measurement sample is air) is defined as f _{LC (BKG)} , and the oscillation frequency of the second oscillator 20 ₂ detected when there is a measurement sample Let the oscillation frequency of f _{LC (SAM) be f LC (SAM)} . At this time, as the real part and imaginary part of the complex permittivity increase, the frequency shift amount Δf (=f _{LC (BKG)} - f _{LC (SAM)} ) also increases. Therefore, if the relationship between the complex dielectric constant and the frequency shift amount is known for a plurality of cases in which the amount of free water differs, it becomes possible to directly specify the amount of free water from the amount of frequency shift obtained by measurement.

FIG. 6 shows an example of the relationship between the complex dielectric constant and the amount of frequency shift according to the embodiment. FIG. 6 shows a two-dimensional plot (contour map, distribution of the frequency shift amount of the oscillation frequency in the complex permittivity space) representing the relationship between the complex permittivity and the frequency shift amount of the oscillation frequency detected by the sensor device 100. This is a superimposition of the change characteristics of the amount of free water with respect to the change in dielectric constant of the protein aqueous solution in No. 5. In FIG. 6, the vertical axis represents the imaginary part of the complex permittivity, and the horizontal axis represents the real part of the complex permittivity. Changes in dielectric constant are plotted when the amount of free water is 100%, 80%, 60%, 40%, and 20%. This dielectric constant can be determined from the graph of FIG. 5, for example.

That is, the specifying unit 310 determines the first oscillation frequency detected when the sensor section of the first oscillator ₂₀₁ is air, and the first oscillation frequency detected when the sensor section of the second oscillator ₂₀₂ is placed near the sensor section of the second oscillator 202. and the detected second oscillation frequency. The specifying unit 310 obtains the frequency shift amount Δf by subtracting the first oscillation frequency from the second oscillation frequency. The identification unit 310 can uniquely identify a position on the characteristic line representing the change in free water amount shown in FIG. 6 from the obtained frequency shift amount Δf, and quantitatively identify the free water amount from the identified position. It is.

In some embodiments, the identification unit 310 identifies the amount of free water at a desired position by interpolating (for example, linear interpolation) the measurement results at two points on the characteristic line. For example, when the frequency shift amount is 0.6 GHz, the specifying unit 310 interpolates the position where the free water amount is 60% and the position where the free water amount is 40%. The amount of free water (%) can be determined.

FIG. 7 shows a flow diagram of a first operation example of the free water measuring device 1 according to the embodiment. A storage unit (not shown) of the processing device 300 stores a computer program for implementing the processing shown in FIG. The processing device 300 can execute the processing shown in FIG. 7 by operating according to this computer program.

(S1: Detect the oscillation frequency of air)
First, the processing device 300 controls the sensor device 100 via the controller 200 to cause the sensor device 100 to detect the oscillation frequency of the air.

Thereby, the oscillation frequency detection unit 30 detects the oscillation frequency f _{LC (BKG)} of the oscillator (predetermined oscillator (first oscillator 20 ₁ )) for which there is no measurement sample among the plurality of oscillators in the oscillator array 10. . The controller 200 acquires the detected oscillation frequency f _{LC (BKG)} and sends the acquired oscillation frequency f _{LC (BKG)} to the processing device 300 .

(S2: Detect the oscillation frequency of the measurement sample)
Subsequently, the processing device 300 controls the sensor device 100 via the controller 200 to cause the sensor device 100 to detect the oscillation frequency of the measurement sample.

As a result, the oscillation frequency detection unit ₃₀ detects the oscillation frequency f _{LC (SAM )} is detected. The controller 200 acquires the detected oscillation frequency f _{LC (SAM)} and sends the acquired oscillation frequency f _{LC (SAM)} to the processing device 300 .

(S3: Calculate frequency shift amount)
Next, the processing device 300 causes the specifying unit 310 to calculate the frequency shift amount Δf.

The specifying unit 310 obtains the frequency shift amount Δf by subtracting the oscillation frequency f LC ( _{SAM) obtained in step S2 from the oscillation frequency f LC (BKG)} obtained in step S1.

(S4: Identify free water amount)
Next, the processing device 300 causes the identification unit 310 to identify the amount of free water.

The specifying unit 310 uniquely specifies a position on the characteristic line representing the change in free water amount shown in FIG. 6 from the frequency shift amount Δf calculated in step S3, and specifies the free water amount from the specified position.

(S5: Identify the amount of hydration water)
Subsequently, the processing device 300 causes the calculation unit 320 to calculate the amount of hydration water.

As described above, the calculation unit 320 calculates the amount of hydration water by subtracting the amount of free water identified in step S4 from the known amount of water.

This is the end of the operation of the free water measuring device 1 (end).

<Example of change in hydration state due to thermal denaturation of albumin>
Next, a case will be described in which the configuration according to the embodiment is applied to quantitative evaluation of abnormal changes in hydration state due to thermal denaturation of albumin.

When a 10 wt% HSA aqueous solution is thermally denatured, the higher-order structure of albumin changes and the hydration state changes. According to the free water measuring device 1 according to the embodiment, it is possible to observe changes in the hydration state with higher accuracy than conventional spectroscopic measurements.

FIG. 8 shows an example of a time change in the amount of frequency shift before and after thermal denaturation of a 10 wt % HSA aqueous solution. The small graph on the left side of FIG. 8 represents the time change of the difference between the frequency shift amount (R2) of water and the frequency shift amount (R1) of the HSA aqueous solution. The graph on the right side of FIG. 8 is an enlarged version of the baseline portion (portion at steady state) of the graph on the left side.

Specifically, FIG. 8 shows that the HSA aqueous solution was left at 25°C for 2 hours (procedure 1), the HSA aqueous solution was heated at 70°C for 15 minutes (procedure 2), and the HSA aqueous solution was heated until 7 hours had elapsed. It shows the change in frequency shift amount over time when left at 25°C (procedure 3).

The amount of frequency shift of the HSA aqueous solution heated at 70°C is greater than the amount of frequency shift of the HSA aqueous solution when it is left at 25°C. This is because the dielectric constant of water and HSA aqueous solution in the 60 GHz band increases as the temperature increases.

At 25°C, water (R2) remains constant before and after heating (before and after denaturation). On the other hand, the amount of frequency shift in the HSA aqueous solution changes before and after heating even if the temperature is the same. This corresponds to the change in free water amount accompanying thermal denaturation. Therefore, using the method described above in the embodiment, the amount of free water that has changed before and after thermal denaturation can be determined from the change amount Δf1 in the frequency shift amount. That is, the amount of free water before heat denaturation and the amount of free water after heat denaturation can be determined with high precision, and the amount of hydration water before heat denaturation and the amount of hydration water after heat denaturation can also be determined with high precision. Therefore, as shown in FIG. 9, the amount of hydration per molecule of albumin before and after heat denaturation (hydration number) can be determined with high accuracy.

(Stability of long-term measurement)
When observing the state of water in biological tissues or biomolecules, long-term measurements may be necessary. However, when a physical device such as the sensor device 100 is operated for a long time, its operating characteristics change due to environmental fluctuations and heat generation of the element itself.

FIG. 10 shows an example of a change in oscillation frequency over time. FIG. 10 shows the results of measuring the oscillation frequency of water using the sensor device 100 over a long period of time in a constant temperature bath whose interior was kept at 37°C. In FIG. 10, the vertical axis represents oscillation frequency, and the horizontal axis represents time.

As shown in FIG. 10, although ideally a constant oscillation frequency should be detected over time, the oscillation frequency increases as time passes. For example, the standard deviation is 9.5×10 ⁻³ GHz, and a measurement error occurs in the long-term measurement results using the sensor device 100.

Therefore, in the embodiment, the identifying section 310 uses the first oscillation frequency detected when the culture medium is placed near the sensor section of the first oscillator ₂₀₁ and the culture medium near the sensor section of the second oscillator ₂₀₂ . and a second oscillation frequency detected when the object to be inspected dispersed within is placed. The identification unit 310 calculates the difference obtained by subtracting the first oscillation frequency from the second oscillation frequency, and uses the calculated difference to evaluate the state of the water (for example, calculate the amount of free water). Obtain measurement results with the environmental changes canceled. Specifically, the identification unit 310 obtains the first oscillation frequency and the second oscillation frequency as described above, and calculates the difference in the oscillation frequencies by subtracting the first oscillation frequency from the second oscillation frequency. By replacing the second oscillation frequency with this difference and evaluating the state of water, it becomes possible to measure the state of water in the test object in the culture medium with high precision.

As mentioned above, it is desirable that the first oscillator 20 ₁ and the second oscillator 20 ₂ are arranged adjacent to each other.

FIG. 11 shows an example of a temporal change in the difference in oscillation frequency. FIG. 11 shows an example of the time course of the difference Δf obtained by subtracting the first oscillation frequency from the second oscillation frequency. In FIG. 11, the vertical axis represents the difference in oscillation frequency, and the horizontal axis represents time.

As shown in FIG. 11, the difference in oscillation frequency becomes almost zero. For example, the standard deviation is 3.1×10 ⁻⁴ GHz, and the influence of measurement errors on the long-term measurement results using the sensor device 100 is almost eliminated.

FIG. 12 shows a flow diagram of a second operation example of the free water measuring device 1 according to the embodiment. A storage unit (not shown) of the processing device 300 stores a computer program for implementing the processing shown in FIG. 12. The processing device 300 can execute the processing shown in FIG. 12 by operating according to this computer program.

(S11: Detect the oscillation frequency of the culture medium)
First, the processing device 300 controls the sensor device 100 via the controller 200 to cause the sensor device 100 to detect the oscillation frequency of the culture medium.

Thereby, the oscillation frequency detection section 30 detects the oscillation frequency f medium of the oscillator (predetermined oscillator (first oscillator 20 ₁ )) in which the medium is arranged near the sensor section among the plurality of oscillators of the oscillator array _10. Detect. The controller 200 obtains the detected oscillation frequency f _medium and sends the obtained oscillation frequency f _medium to the processing device 300 .

(S12: Detect the oscillation frequency of the measurement sample)
Subsequently, the processing device 300 controls the sensor device 100 via the controller 200 to cause the sensor device 100 to detect the oscillation frequency of the measurement sample dispersed in the culture medium.

Thereby, the oscillation frequency detection unit 30 detects the oscillator (predetermined oscillator (second oscillator ₂₀ )) to detect the oscillation frequency f _SAM . The controller 200 acquires the detected oscillation frequency f _SAM and sends the acquired oscillation frequency f _SAM to the processing device 300 .

(S13: Calculate the difference in oscillation frequency)
Next, the processing device 300 causes the specifying unit 310 to calculate the difference in oscillation frequencies.

The specifying unit 310 obtains the difference in oscillation frequencies by subtracting the oscillation frequency f _SAM obtained in step S12 from the oscillation frequency f _medium obtained in step S11.

(S14: Evaluate the difference)
Next, the processing device 300 evaluates the difference in the oscillation frequencies obtained in step S13.

For example, the processing device 300 executes the process of quantitatively determining the free water amount shown in FIG. 7 using the difference in the oscillation frequencies determined in step S13. In this case, in step S1, the oscillation frequency of the air is determined as the first difference as described above, in step S2, the oscillation frequency of the measurement sample is determined as the second difference as described above, and in step S3, the oscillation frequency of the air is determined as the first difference as described above. The frequency shift amount is calculated from the two differences.

This is the end of the operation of the free water measuring device 1 (end).

In some embodiments, before starting the measurement, the processing device 300 detects the oscillation frequency of each of the plurality of oscillators of the oscillator array 10 with the culture medium placed near the sensor section, and Calibration information for canceling variations in multiple oscillation frequencies is calculated. After starting the measurement, the processing device 300 may use the calibration information to correct the detected oscillation frequency, and evaluate the state of the water with respect to the corrected oscillation frequency as described above.

<Example of long-term measurement of SG1 cells>
Next, a case will be described in which the configuration according to the embodiment is applied to long-term measurement of SG1 cells.

The outermost layer of the skin is the stratum corneum, which is a layer of dead cells. On the deep side of the stratum corneum is the granular layer. The cells of the granular layer are called SG1 cells, SG2 cells, and SG3 cells in order from the outside. In the granular layer, SG1 cells undergo programmed cell death and transform into corneocytes.

FIG. 13 shows an example of a temporal change in the difference in oscillation frequency using SG1 cells, SG2 cells, and a medium as measurement samples. In FIG. 13, the vertical axis represents the difference in oscillation frequency, and the horizontal axis represents the time since SG1 cell death was induced. Note that in FIG. 13, SG2 cells are cells that have undergone cell death immediately after collection.

As shown in FIG. 13, the time change T1 of the difference in oscillation frequency using a culture medium as a measurement sample changes within a range of ±3.1×10 ⁻⁴ GHz. Further, the time change T2 of the difference in oscillation frequency using SG2 cells as a measurement sample changes within the range of ±4.6×10 ⁻⁴ GHz. That is, the time changes T1 and T2 are approximately constant over 24 hours.

On the other hand, the time change T3 of the difference in oscillation frequency using SG1 cells as a measurement sample changes within the range of 35 × 10 ^-4 GHz, and in particular, the difference in oscillation frequency changes immediately after the start of measurement. . This change is a change in water that accompanies cell death.

FIG. 14 shows an enlarged view of the time change T3 immediately after the start of the measurement.

Conventionally, cell death is defined by observing changes in membrane permeability using a fluorescent probe or the like. In this example, by observing the SG1 cells in Figure 14 with a fluorescent probe, the time required for the change in membrane permeability to reach 50% is defined as the time for cell death to occur, t _50% = 1.27 ± 0.04 h. was observed. On the other hand, according to the embodiment, the time required for the change in the difference in oscillation frequency to reach 50% is t _50% =0.43±0.07h, which is the time required for cell death to occur. In other words, by detecting changes in intracellular water with high precision, it becomes possible to determine cell death at an earlier stage than the conventional point of time when cell death is determined (time to transition to true cell death). ).

In this way, according to the embodiment, the state of transition to cell death can be identified with high accuracy. Thereby, by providing a predetermined threshold value for determining that cell death has occurred, it becomes possible to instantly determine whether or not cell death has occurred.

(Other operation examples)
The free water measuring device 1 according to the embodiment can also operate as follows.

FIG. 15 shows a flow diagram of a third operation example of the free water measuring device 1 according to the embodiment. A storage unit (not shown) of the processing device 300 stores a computer program for implementing the processing shown in FIG. 15. The processing device 300 can execute the processing shown in FIG. 15 by operating according to this computer program.

(S21: Detect the oscillation frequency of air and culture medium)
First, the processing device 300 controls the sensor device 100 via the controller 200 to cause the sensor device 100 to detect the oscillation frequencies of the air and the culture medium.

As a result, the oscillation frequency detection section 30 detects the oscillation frequency f _air of the oscillator among the plurality of oscillators of the oscillator array 10, which does not have a measurement sample such as a culture medium near the sensor section. Furthermore, the oscillation frequency detection unit 30 detects an oscillation frequency f _medium1 by an oscillator in which a medium is placed near the sensor unit among the plurality of oscillators in the oscillator array 10. The controller 200 acquires the detected oscillation frequencies f _air and f _medium1 and sends the acquired oscillation frequencies f _air and f _medium1 to the processing device 300 .

(S22: Calculate frequency shift amount Δf _medium )
Next, the processing device 300 causes the specifying unit 310 to calculate the frequency shift amount Δf _medium .

The specifying unit 310 obtains the frequency shift amount Δf _medium by subtracting the oscillation frequency f _medium1 from the oscillation frequency f _air obtained in step S21. For example, when the oscillation frequency f _air is 65.0 GHz and the oscillation frequency f _medium1 is 63.2 GHz, the frequency shift amount Δf _medium is 1.8 (=65.0-63.2) GHz.

(S23: Measure the oscillation frequency of the measurement sample for a long time)
Subsequently, the processing device 300 controls the sensor device 100 via the controller 200 to perform long-term measurement of the oscillation frequency using the cells suspended in the medium as a measurement sample. The processing device 300 repeatedly calculates the difference δf between the oscillation frequencies of adjacent oscillators at predetermined timing.

For example, at the 0th hour, δf = 0.1 GHz, at the 1st hour, δf = 0.1 GHz, ..., at the 24th hour, δf = 0.2 GHz.

(S24: Calculate frequency shift amount Δf _cell )
Next, the processing device 300 causes the specifying unit 310 to calculate the frequency shift amount Δf _cell . Specifically, the processing device 300 causes the specifying unit 310 to calculate the frequency shift amount Δf _cell of the cell at each predetermined timing.

The specifying unit 310 uses the frequency shift amount Δf _medium and the difference δf to calculate the frequency shift amount Δf _cell of the cell at each predetermined timing. For example, at the 0th hour, Δf _cell = Δf _medium - δf = 1.8 GHz - 0.1 GHz = 1.7 GHz, at the 1st hour, Δf _cell = Δf _medium - δf = 1.7 GHz, ..., at the 24th hour. Δf _cell = Δf _medium - δf = 1.8 GHz - 0.2 GHz = 1.6 GHz.

(S25: Calculate free water amount)
Next, the processing device 300 causes the identification unit 310 to identify the amount of free water.

The specifying unit 310 uniquely specifies a position on the characteristic line representing the change in free water amount shown in FIG. 6 from the frequency shift amount Δf _cell calculated in step S24, and specifies the free water amount from the specified position.

In some embodiments, the processing device 300 causes the calculation unit 320 to calculate the amount of hydration water. As described above, the calculation unit 320 calculates the amount of hydration water by subtracting the amount of free water identified in step S25 from the known amount of water.

This is the end of the operation of the free water measuring device 1 (end).

As described above, in the embodiment, an oscillation frequency that changes depending on the dielectric constant of the object to be inspected near an oscillator that oscillates at a frequency in the 60 GHz band is detected. Then, the frequency shift amount is determined from the first oscillation frequency detected when the object to be inspected in the sensor section is air and the second oscillation frequency detected when the object to be inspected is placed in the sensor section. . By using a characteristic line representing a change in free water amount obtained in advance, it is possible to quantitatively identify the free water amount from the obtained frequency shift amount. Furthermore, since changes in the measurement environment are canceled using the oscillation frequency of the oscillator adjacent to which the culture medium is placed in the sensor section, it is possible to obtain more accurate measurement results.

Therefore, according to the embodiment, only free water or hydration water is extracted non-destructively, non-staining, and with high precision out of the water contained in a test object such as a biological tissue such as skin, cells, crystals, or an aqueous solution. can be measured. In particular, even at the single cell level, the average intracellular state of water can be measured with high precision and high reproducibility.

[effect]
A free water measuring method and a free water measuring device according to an embodiment will be described.

A free water measurement method according to some embodiments includes a first detection step of detecting a first oscillation frequency that changes depending on the air near the first oscillator (20 ₁ ), and a first oscillator or a first oscillator. a second detection step of detecting a second oscillation frequency that changes according to the physical properties of the object to be inspected in the vicinity of the different second oscillators (20 ₂ ); and a second detection step of detecting a second oscillation frequency that changes depending on the physical properties of the object to be inspected in the vicinity of the different second oscillators (20 2 ), and a second detection step that is based on a frequency shift amount of the second oscillation frequency with respect to the first oscillation frequency. and a step of identifying the amount of free water in the test object.

According to such a method, based on the relationship between the real part and imaginary part of the complex permittivity of the object to be inspected and the frequency shift amount, the real part and imaginary part of the complex permittivity corresponding to the obtained frequency shift amount are determined. can be identified. Thereby, it becomes possible to specify the amount of free water in the object to be inspected based on the relationship between the real part and imaginary part of the complex permittivity and the amount of free water. Therefore, of the water contained in a living tissue such as skin, cells, crystals, or an object to be examined such as an aqueous solution, only free water can be measured non-destructively and with high precision without staining.

Some embodiments include a calculation step of calculating the amount of hydration water in the test object by subtracting the amount of free water specified in the specific step from the total amount of water.

According to such a method, only hydration water contained in a test object such as a biological tissue such as skin, cells, crystals, or an aqueous solution can be measured non-destructively and with high precision without staining. Can be done.

In some embodiments, the identifying step identifies the amount of free water based on a change characteristic of the amount of free water with respect to a change in the dielectric constant of the test object on the distribution of the amount of frequency shift in the complex permittivity space.

According to such a method, by measuring in advance the change characteristics of the amount of free water with respect to changes in the dielectric constant of the object to be inspected, it becomes possible to specify the amount of free water in the object to be inspected from the amount of frequency shift.

The free water measurement method according to some embodiments includes a first detection step of detecting a first oscillation frequency that changes depending on the physical properties of a medium near the first oscillator (20 ₁ ), and a second oscillator (20 _{2 )} . ), a second detection step of detecting a second oscillation frequency that changes according to the physical properties of the object to be inspected dispersed in a medium near the object; a step of identifying the state of the water.

According to such a method, a first oscillation frequency that changes depending on the physical properties of the medium and a second oscillation frequency that changes depending on the physical properties of the object to be inspected dispersed in the medium are detected, and the first oscillation frequency changes depending on the physical properties of the object to be inspected dispersed in the medium. Since the state of free water in the test object is specified based on the frequency and the second oscillation frequency, the state of free water can be measured with high accuracy regardless of changes in the measurement environment or temperature characteristics of the element. It becomes possible.

In some embodiments, the identifying step identifies the free water condition based on a difference in the second oscillation frequency with respect to the first oscillation frequency.

According to such a method, it is possible to measure the state of free water with high precision by simple processing, regardless of changes in the measurement environment or temperature characteristics of the element.

In some embodiments, the first oscillator and the second oscillator are located adjacent to each other.

According to such a method, the state of free water can be measured with even higher accuracy regardless of changes in the measurement environment or temperature characteristics of the element.

The free water measuring device (1) according to some embodiments includes an oscillator (first oscillator 20 ₁ or second oscillator 20 ₂ ), and has a first oscillation frequency that changes depending on the air near the oscillator and a frequency of the oscillator. a detection unit that detects a second oscillation frequency that changes according to the physical properties of a nearby object to be inspected; and a detection unit that identifies the amount of free water in the object to be inspected based on a frequency shift amount of the second oscillation frequency with respect to the first oscillation frequency. (310).

According to such a configuration, based on the relationship between the real part and imaginary part of the complex permittivity of the object to be inspected and the frequency shift amount, the real part and imaginary part of the complex permittivity corresponding to the obtained frequency shift amount are determined. can be identified. Thereby, it becomes possible to specify the amount of free water in the object to be inspected based on the relationship between the real part and imaginary part of the complex permittivity and the amount of free water. Therefore, of the water contained in a living tissue such as skin, cells, crystals, or an object to be examined such as an aqueous solution, only free water can be measured non-destructively and with high precision without staining.

Some embodiments include a calculation unit (320) that calculates the amount of hydration water in the test object by subtracting the amount of free water specified by the identification unit from the total amount of water.

According to such a configuration, only hydration water among the water contained in a test object such as a living tissue such as skin, cells, crystals, or an aqueous solution can be measured with high accuracy in a non-destructive and non-staining manner. Can be done.

In some embodiments, the identifying unit identifies the amount of free water based on the change characteristics of the amount of free water with respect to the change in the dielectric constant of the test object on the distribution of the amount of frequency shift in the complex permittivity space.

According to such a configuration, by measuring in advance the change characteristics of the amount of free water with respect to changes in the dielectric constant of the object to be inspected, it becomes possible to specify the amount of free water in the object to be inspected from the amount of frequency shift.

In some embodiments, the detection unit includes a first oscillator (20 ₁ ), and detects a first oscillation frequency that changes depending on the air near the first oscillator (first oscillator 20 1 ). ₁ and oscillation frequency detection unit 30), and a second oscillator (20 ₂ ), the second detection unit (second oscillator ₂₀₂ and oscillation frequency detection section 30).

With this configuration, the first oscillator can be used to detect the first oscillation frequency, and the second oscillator can be used to detect the second oscillation frequency, which simplifies measurement control and reduces measurement time. It becomes possible to shorten it.

A free water measuring device (1) according to some embodiments includes a first oscillator (20 ₁ ), and a first detection device that detects a first oscillation frequency that changes depending on the physical properties of a medium near the first oscillator. (the first oscillator 20 ₁ and the oscillation frequency detection unit 30) and the second oscillator (20 ₂ ), the second oscillator changes depending on the physical properties of the object to be inspected dispersed in the medium near the second oscillator. A second detection section (second oscillator ₂₀₂ and oscillation frequency detection section 30) that detects the oscillation frequency, and a specification section (second detection section) that specifies the state of free water in the object to be inspected based on the first oscillation frequency and the second oscillation frequency. 310).

According to such a configuration, the first oscillation frequency that changes depending on the physical properties of the medium and the second oscillation frequency that changes depending on the physical properties of the object to be inspected dispersed in the medium are detected, and the first oscillation frequency changes depending on the physical properties of the object to be inspected dispersed in the medium. Since the state of free water in the test object is specified based on the frequency and the second oscillation frequency, the state of free water can be measured with high accuracy regardless of changes in the measurement environment or temperature characteristics of the element. It becomes possible.

In some embodiments, the identification unit identifies the state of free water based on the difference between the second oscillation frequency and the first oscillation frequency.

According to such a configuration, it becomes possible to measure the state of free water with high precision by simple processing, regardless of changes in the measurement environment or temperature characteristics of the element.

In some embodiments, the first oscillator and the second oscillator are located adjacent to each other.

According to such a configuration, it becomes possible to measure the state of free water with even higher precision regardless of changes in the measurement environment or temperature characteristics of the element.

<Others>
The embodiment shown above is only an example for implementing this invention. Those who wish to implement this invention can make arbitrary modifications, omissions, additions, etc. within the scope of the gist of this invention.

For example, the free water measuring device 1 includes a channel through which a culture medium containing a test object flows, and a sensor device 100 (oscillator 20) provided in the middle of the channel measures the oscillation frequency of the test object flowing through the channel. It may be configured to detect.

1 Free water measurement device 10 Oscillator array 20 Oscillator 20 ₁ First oscillator 20 ₂ Second oscillator 30 Oscillation frequency detection section 100 Sensor device 200 Controller 300 Processing device 310 Specification section 320 Calculation section

Claims (9)

a first detection step of detecting a first oscillation frequency that changes depending on the physical properties of the air or the physical properties of the medium near the first oscillator;
a second detection step of detecting a second oscillation frequency that changes depending on physical properties of the object to be inspected near the first oscillator or a second oscillator different from the first oscillator;
A specifying step of specifying the amount of free water in the object to be inspected based on the frequency shift amount of the second oscillation frequency with respect to the first oscillation frequency;
including;
The free water measuring method is characterized in that the specifying step specifies the free water amount based on a change characteristic of the free water amount with respect to a change in the dielectric constant of the object to be inspected on a distribution of the frequency shift amount in a complex permittivity space . a first detection step of detecting a first oscillation frequency that changes depending on the physical properties of the air or the physical properties of the medium near the first oscillator;
a second detection step of detecting a second oscillation frequency that changes depending on physical properties of the object to be inspected near the first oscillator or a second oscillator different from the first oscillator;
A frequency shift amount of the second oscillation frequency with respect to the first oscillation frequency is obtained, and based on a known relationship between the complex permittivity of the object to be inspected and the frequency shift amount, the frequency shift amount is determined based on the obtained frequency shift amount. determining the amount of free water in the object;
Free water measurement methods, including: Free water measurement according to claim 1 or claim 2, further comprising a calculation step of calculating the amount of hydration water of the test object by subtracting the amount of free water specified in the specifying step from the total amount of water. Method. The free water measuring method according to any one of claims 1 to 3 , wherein the first oscillator and the second oscillator are arranged adjacent to each other. Detection that includes an oscillator and detects a first oscillation frequency that changes depending on the physical properties of the air or the physical properties of the medium near the oscillator, and a second oscillation frequency that changes depending on the physical properties of the object to be inspected near the oscillator. Department and
a specifying unit that specifies the amount of free water in the object to be inspected based on a frequency shift amount of the second oscillation frequency with respect to the first oscillation frequency;
including;
The identifying unit identifies the free water amount based on a change characteristic of the free water amount with respect to a change in the dielectric constant of the object to be inspected on a distribution of the frequency shift amount in a complex permittivity space. Detection that includes an oscillator and detects a first oscillation frequency that changes depending on the physical properties of the air or the physical properties of the medium near the oscillator, and a second oscillation frequency that changes depending on the physical properties of the object to be inspected near the oscillator. Department and
A frequency shift amount of the second oscillation frequency with respect to the first oscillation frequency is obtained, and based on a known relationship between the complex permittivity of the object to be inspected and the frequency shift amount, the frequency shift amount is determined based on the obtained frequency shift amount. a specific part that specifies the amount of free water in the object;
Free water measuring device, including: Free water measurement according to claim 5 or claim 6, further comprising a calculating section that calculates the amount of hydration water of the test object by subtracting the amount of free water specified by the specifying section from the total amount of water. Device. The detection unit includes:
a first detection unit that includes a first oscillator and detects the first oscillation frequency that changes depending on the physical properties of the air or the physical properties of the medium near the first oscillator;
a second detection unit that includes a second oscillator and detects the second oscillation frequency that changes depending on the physical properties of the object to be inspected near the second oscillator;
The free water measuring device according to any one of claims 5 to 7 , comprising: The free water measuring device according to claim 8 , wherein the first oscillator and the second oscillator are arranged adjacent to each other.

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