WO2016121351A1

WO2016121351A1 - Determination of a state of biological tissue using terahertz waves

Info

Publication number: WO2016121351A1
Application number: PCT/JP2016/000309
Authority: WO
Inventors: Sayuri Yamaguchi; Oichi Kubota
Original assignee: Canon Inc
Current assignee: Canon Inc
Priority date: 2015-01-30
Filing date: 2016-01-21
Publication date: 2016-08-04
Anticipated expiration: 2017-07-30

Abstract

An information acquisition apparatus (100) which acquires information regarding a subject by using terahertz waves includes an irradiating unit (104) which irradiates terahertz waves to the subject, a detecting unit (107) which detects terahertz waves from the subject, a spectrum acquiring unit (123) which acquires a spectrum of an optical characteristic by using a detection result from the detecting unit, and a determining unit (125) which determines a state of a biological tissue based on a result of a comparison between a first spectrum and a second spectrum acquired by the spectrum acquiring unit by using detection results when the biological tissue is used as the subject and when pure water is used as the subject, respectively, and a criterion. The criterion is acquired by using a result of a comparison between a plurality of spectra acquired by measuring a plurality of biological tissues and at least one spectrum acquired by measuring pure water.

Description

[Title established by the ISA under Rule 37.2] DETERMINATION OF A STATE OF BIOLOGICAL TISSUE USING TERAHERTZ WAVES

The present invention relates to an information acquisition apparatus and an information acquisition method for acquiring information regarding a subject by using terahertz waves.

A terahertz wave is an electromagnetic wave having a component in an arbitrary frequency band within a range from 30 GHz or higher to 30 THz or lower. In recent years, non-invasive sensing technologies using terahertz waves have been developed. With electromagnetic waves in such a frequency band, spectroscopy technologies have been developed for examining a physical property such as molecular bonding state, which is expected to be applied to identification of a component of a solid, a solution and a gas containing a plurality of components and identification of a biological tissue containing a mixture of different tissue states.

PTL 1 discloses a method and an apparatus for determining the presence/absence and rate of crystalline particles, for example, within an aqueous solution in order to determine the state of the aqueous solution. According to PTL 1, an absorption spectrum in a terahertz region is used for the determination, and an absorption spectrum of water is defined as a reference. Then absorption coefficients in an arbitrary frequency of the absorption spectrum of water and a measured spectrum are compared.

However, when a biological tissue is a subject of the identification, the difference in spectrum may sometimes be small even though frequency spectra of biological tissues in a terahertz region have different states. For example, a normal tissue region and an abnormal tissue region of a biological tissue not only have a small difference in spectrum but also tend to have an individual difference in shape of spectra or in value of optical characteristic. A biological tissue is an ununiform substance in which the cell distribution and construction vary in accordance with the region, unlike a uniform subject solution in PTL 1. For that reason, the determination of a state of a biological tissue may not be performed with sufficiently high accuracy even when a change from the reference spectrum is acquired as in PTL 1.

U.S. Patent No. 9,128,041

P.U. Jepsen et al., Optics Letters, (2007), 15, 14717

An information acquisition apparatus according to an aspect of the present invention which acquires information regarding a subject by using terahertz waves includes an irradiating unit configured to irradiate terahertz waves to the subject, a detecting unit configured to detect terahertz waves from the subject, a spectrum acquiring unit configured to acquire a spectrum of an optical characteristic by using a detection result from the detecting unit, and a determining unit configured to determine a state of a biological tissue based on a comparison result of a comparison between a first spectrum acquired by the spectrum acquiring unit by using a detection result from the detecting unit in a case where the biological tissue is used as the subject and a second spectrum acquired by the spectrum acquiring unit by using a detection result from the detecting unit in a case where pure water is used as the subject and a criterion. In this case, the criterion is acquired by using a result of a comparison between a plurality of spectra acquired by measuring a plurality of biological tissues and at least one spectrum acquired by measuring pure water.

Further aspects of the present invention will become apparent from the following description of exemplary embodiments with reference to the attached drawings.

Fig. 1 is a schematic diagram illustrating a configuration of an information acquisition apparatus according to a first exemplary embodiment. Fig. 2A is a schematic diagram illustrating a configuration of a sample unit in the apparatus of a reflective type according to the first exemplary embodiment. Fig. 2B is a schematic diagram illustrating a configuration of a sample unit in the apparatus of a transmission type according to the first exemplary embodiment. Fig. 3 is a flowchart describing an information acquisition method according to the first exemplary embodiment. Fig. 4A illustrates refractive index spectra of pure water and biological tissue contained in a subject according to the first exemplary embodiment. Fig. 4B illustrates a comparison value and a reference value based on the ratio of refractive index spectra according to the first exemplary embodiment. Fig. 5A illustrates a relationship between a refractive index spectrum and an absorption coefficient spectrum of pure water and biological tissue contained in a subject according to the first exemplary embodiment. Fig. 5B illustrates a comparison value and a reference value based on the relationship between the ratio of spectra according to the first exemplary embodiment. Fig. 6A is a plot diagram of scores acquired by analyzing principal components of refractive index spectra of pure water and biological tissue contained in a subject according to the first exemplary embodiment. Fig. 6B illustrates comparison values and a reference value based on the principal component analysis according to the first exemplary embodiment. Fig. 7 illustrates a configuration around a sample unit in an information acquisition apparatus according to a second exemplary embodiment. Fig. 8 illustrates a configuration of a sample unit according to the second exemplary embodiment. Fig. 9 illustrates a configuration of an information acquisition apparatus according to a third exemplary embodiment. Fig. 10A illustrates refractive index spectra of normal tissue of the brains of three rats according to a first example. Fig. 10B illustrates refractive index spectra of tumor tissues of three rats according to the first example. Fig. 10C illustrates a refractive index spectrum of pure water to be compared with the refractive index spectra of three rats according to the first example. Fig. 11 illustrates comparison values from which the ratio of refractive index spectra of pure water and a biological tissue according to the first example. Fig. 12A is a plot diagram of scores when no comparison value is used according to second example. Fig. 12B is a plot diagram of scores when a spectrum difference is used as a comparison value according to the second example. Fig. 12C is a plot diagram of scores when a spectrum ratio is used as the comparison value according to the second example. Fig. 13 is a flowchart illustrating an information acquisition method using a time waveform according to the first exemplary embodiment.

According to the following exemplary embodiments, a configuration for improving the accuracy of determination of a state of a biological tissue in an information acquisition apparatus therefor will be described below. More specifically, whether a biological tissue at a position irradiated with terahertz waves has a first state or a second state is determined. The following exemplary embodiments will be described with reference to a case where a normal tissue region without an abnormality in a biological tissue and an abnormal tissue region with an abnormality such as a cancer in a cell is are a first state and a second state, respectively, though the first state and the second state are not limited. For such a determination, a comparison result such as a ratio of a spectrum (reference spectrum) of pure water and a spectrum (measurement spectrum) of a biological tissue acquired by a measurement, for example, is used.

The reason why the ratio of the reference spectrum and a measurement spectrum is suitable for the determination of the state of a biological tissue may be that a large amount of water is contained in a living body. Furthermore, it is because a normal tissue region and an abnormal tissue region which have different states have different amounts of water. An abnormal tissue region tends to have a more amount of water than that of a normal tissue region because extensive angiogenesis occur for supplementing oxygen deficiency or undernutrition in the abnormal tissue region. Terahertz waves are suitable for detection of a difference in amount of water because Terahertz waves are sensitive to an amount of water. Furthermore, pure water is suitable for use as a reference because pure water is easily available in general and has a stable physical property under a constant environment such as a temperature and a humidity.

It should be noted that the term "pure water" herein refers to high purity water with less impurity and may include distilled water, ion exchanged water, reverse osmosis (RO) water, RO-EDI (electrode ionization) water, for example. There is not a general standard for the definition of Pure water, but water preferably having a specific resistance of 0.1 MΩ cm or higher is called pure water herein. The state of pure water to be used for acquiring a reference spectrum in the following exemplary embodiments is desirably matched with the state of a subject to be used for acquiring a measurement spectrum. For example, when water contained in a subject is a liquid state, the spectrum of pure water in a liquid state is used as the reference state.

First Exemplary Embodiment

An information acquisition apparatus 100 (hereinafter, called an "apparatus 100") according to the first exemplary embodiment will be described with reference to Fig. 1. According to this exemplary embodiment, the apparatus 100 is a THz Time-Domain Spectroscopy (THz-TDS) apparatus using terahertz wave pulses (hereinafter called a "pulsed wave").

First, a configuration of the apparatus 100 will be described with reference to Fig. 1. Fig. 1 illustrates a configuration of the apparatus 100. The apparatus 100 includes a light source 101, a branch unit 102, a

lens

103, 112, a mirror pair 108, an adjusting unit 130, a mirror 111, an irradiating unit 104, a sample unit 105, a parabolic mirror 106, a detecting unit 107, an amplifier 113, and a lock-in amplifier 114. The apparatus 100 further includes a control unit 121, a time waveform acquiring unit 122 (hereinafter, called a "waveform acquiring unit 122"), a spectrum acquiring unit 123, a selecting unit 124, a determining unit 125, an image forming unit 126 and a storage unit 127. The irradiating unit 104 has a power supply 141, a generating unit 142, and a parabolic mirror 143.

The light source 101 is a part which outputs ultrashort pulsed light. The ultrashort pulsed light refers to pulsed light having a pulse width of the femto-second order. The light source 101 of this exemplary embodiment outputs femto-second pulse laser (hereinafter, called a "laser") having a pulse width in a range equal to or higher than 10 femto-seconds and equal to or lower than 100 femto-seconds as ultrashort pulsed light. The laser from the light source 101 branches off at a half mirror serving as the branch unit 102, and one is converged by the lens 103 and is irradiated to the generating unit 142.

The generating unit 142 is a part which generates pulsed wave when laser enters thereto. According to this exemplary embodiment, the generating unit 142 is a photoconductive device having an antenna made of a conductor on a semiconductor film. Without limiting thereto, the generating unit 142 may be a generating element which irradiates laser to a semiconductor substrate or a surface of organic crystal or which guides laser to non-linear crystal. The generating unit 142 may generate pulsed waves in response to input of laser, and known technologies achieving the purpose are applicable thereto. A bias voltage of the generating unit 142 is modulated by the power supply 141, and modulated pulsed waves are irradiated by the parabolic mirror 143 to a subject 230 in the sample unit 105.

The sample unit 105 is a part in which a sample such as a

cells

202 and 220 including the subject 230 is placed. Through the combination including a parabolic mirror, not illustrated, pulsed waves are irradiated from the generating unit 142 to the subject 230. The pulsed waves transmitted through the subject 230 or reflected by the subject 230 enter to the detecting unit 107 through the parabolic mirror 106. A sample including the subject 230 is placed on a movable stage on which the irradiation position for pulsed waves can be selected. A sample is placed on the movable stage so that the irradiation area (measurement point) for pulsed waves on the subject (or on the subject 230) can be changed as required.

According to this exemplary embodiment, a sample including the subject 230 prepared externally to the apparatus is placed in the sample unit 105. Fig. 2A is a schematic diagram illustrating a cross section of the sample unit 105 in a case where the apparatus 100 is a reflective measurement apparatus which detects pulsed waves reflected by the subject 230. Fig. 2B is a schematic diagram illustrating a cross section of the sample unit 105 in a case where the apparatus 100 is a transmission measurement apparatus which detects pulsed waves having transmitted through the subject 230.

When the apparatus 100 is a reflective measurement apparatus, the sample unit 105 has holding

units

201 and 205 provided on the movable stage, and a cell 202 is provided on the holding

units

201 and 205. The cell 202 has a space 204 in which the subject 230 is placed. The cell 202 is tightly closed by a lid 203 to prevent drying of a biological tissue placed in the space 204 and transpiration and outflow of pure water. The cell 202 may be made of any known material through which terahertz waves can transmit well and which has a stable physical property. More specifically, a quartz substrate or a single crystal silicon plate may be used, for example.

Referring to Fig. 2A, terahertz waves are irradiated from a lower side of the cell 202 and are reflected by a surface 206 of a window member of the cell 202 and an interface(sample surface) 207 between the cell 202 and the subject 230. The window member is a surface to which pulsed waves reach earlier than the subject 230 in the sample, and the pulsed waves are irradiated to the subject 230 through the window member.

An information acquisition method of this exemplary embodiment performs a measurement on a biological tissue after a pure water measurement. After a pure water measurement, a biological tissue prepared in a different cell 202 is placed on the holding

units

201 and 205 to perform a measurement on the biological tissue. Alternatively, the cell 202 in which pure water is provided and the cell 202 in which a biological tissue is provided may be mounted at different positions on the holding

units

201 and 205 in advance, and a measurement is performed on the biological tissue after performing a pure water measurement by using the movable stage. Alternatively, after performing a pure water measurement, the cell 202 having the pure water is cleaned, and a biological tissue may be placed in the same cell 202 to perform a measurement on the biological tissue. Use of the same cell 202 is desirable for suppression of an influence of a difference in construction such as the thickness of the cell 202 in a process for spectrum acquisition.

When the apparatus 100 is a transmission measurement apparatus, the cell 220 has

plates

210 and 211,

spacers

212 and 213, and screws 215 and 216. The subject 230 is placed in a space 214 enclosed by the

plates

210 and 211 and

spacers

212 and 213, and the subject 230 is sandwiched between the

plates

210 and 211. The thickness of the subject 230 may be adjusted with the

spacers

212 and 213, and the subject 230 is fixed with the

screws

215 and 216. They may be mounted in a sample holding unit, not illustrated, for example, so as to move in synchronization with the movable stage. Like the reflective apparatus, the

plates

210 and 211 may be made of any known material through which terahertz waves can transmit well and which has a stable physical property.

The pulsed waves may be irradiated from one of the right and left sides of the cell 220 in Fig. 2B. According to this exemplary embodiment, the plate 210 serves as the window member, and pulsed waves are irradiated from the left side of the cell 220 in Fig. 2B. In this case, the interface 217 between the plate 210 and the subject 230 is defined as a sample surface.

Also in the transmission measurement apparatus, when the subject 230 is changed, the

same plates

210 and 211 are desirably used to reduce the influence of the difference in construction such as the thicknesses of the

plates

210 and 211 on the spectrum. The thickness of the subject 230 to be adjusted with the

spacers

212 and 213 is also important in order to acquire information regarding the subject 230 highly accurately. For that, it is desirable to apply a method in which the thickness of the subject 230 is estimated by using multipath reflected waves within a biological tissue or a pure water layer or provide a configuration which estimates the thickness of the subject 230 by using light having another frequency. When the apparatus 100 is a transmission measurement apparatus and when

different plates

210 and 211 are used for a pure water measurement and a biological tissue measurement, all of them may be prepared in advance in the sample holding unit, not illustrated, and they may be replaced after a pure water measurement and before a biological tissue measurement by moving the movable stage.

The apparatus 100 may be configured to be adjustable such that the position and gradient in a depth direction of the subject 230 of the sample surfaces 207 and 217 can be constant about the focal depth of pulsed waves between a pure water measurement and a biological tissue measurement. This is because a difference or differences in position and/or gradient in the depth direction of the sample surfaces 207 and 217 has or have an influence depending on the frequency on the resulting spectra when the detecting unit 107 is a photoconductive device. When a measurement spectrum acquired by measuring a biological tissue and a reference spectrum acquired by measuring pure water are used as in this exemplary embodiment, it is important to adjust the position and gradient in the depth direction of the subject 230 to the extent that the target tissue determination is not influenced.

It should be noted that the focal depth of a pulsed wave refers to a wave optical focal depth and corresponds to a parallel propagation area of pulsed waves from the irradiating unit 104. The parallel propagation area is an area in which it can be regarded that pulsed waves of pulsed waves from the irradiating unit 104 propagate substantially in parallel. The "focal depth" is defined as a range in which the beam diameter of a pulsed wave from the irradiating unit 104 is equal to or smaller than w × √2 where w is the smallest beam diameter in a case where the irradiating unit 104 reduces the beam diameter of pulsed waves.

The position and gradient of a sample surface about a parallel propagation area of terahertz waves for a pure water measurement may be stored and may be referred for adjusting the position and gradient for a biological tissue measurement by moving the movable stage such that the positions and gradients can agree in a micrometer order between the pure water measurement and the biological tissue measurement. The position and gradient of a sample including the subject 230 may be adjusted automatically or may be adjusted manually by a user. It may be configured such that both of the automatic adjustment and the manual adjustment may be supported.

When the apparatus 100 is a reflective measurement apparatus, the position and gradient of the sample surface 207 can be acquired from a peak position of a plurality of time waveforms measured by irradiating pulsed waves to a plurality of measurement points on the sample surface 207. For example, when two time waveforms in the horizontal direction and two time waveforms in the vertical direction are acquired at an equal distance from the center of the sample surface 207, the gradient can be acquired from a difference in height which can be calculated from a peak position of reflected waves from the sample surface 207. The position and gradient may be adjusted before a biological tissue measurement such that the peak positions at each measurement point can agree between a pure water measurement and the biological tissue measurement.

When the apparatus 100 is a transmission measurement apparatus, the gradient of the sample surface 217 can be acquired from multipath reflected waves within the

plates

210 and 211. For example, when the thicknesses and physical properties of the

plates

210 and 211 are known, the difference in time between peaks of time waveforms between transmitted waves passing through the

plates

210 and 211 and the subject 230 and multipath reflected waves within the

plates

210 and 211 can be predicted. When the cell 220 has a gradient against the parallel propagation area of pulsed waves, the distance of propagation of a pulsed wave in the plate 210 or plate 211 as the gradient increases. The difference in time between observed peaks is larger than the predicted difference in time between the peaks. Therefore, the position and gradient of a sample may be adjusted before a biological tissue measurement such that the difference in time between peaks in a pure water measurement and the difference in time between peaks in a biological tissue measurement can agree.

The other one of the branched lasers at the branch unit 102 is irradiated to the detecting unit 107 through the mirror pair 108, the adjusting unit 130, the mirror 111, and the lens 112, which are positionally fixed. The adjusting unit 130 has a mirror pair 110 which reflects and folds laser light and a movable stage 109 on which the mirror pair 110 is mounted. The adjusting unit 130 adjusts the timing when pulsed waves are detected by the detecting unit 107. More specifically, the optical path length of laser light is changed by moving the movable stage 109. As a result, the relative optical path lengths of the laser light input to the detecting unit 107 and the laser light input to the generating unit 142 are changed.

According to this exemplary embodiment, the adjusting unit 130 is provided between the light source 101 and the detecting unit 107, and the optical path length of laser light reaching from the light source 101 to the detecting unit 107 is adjusted. Without limiting to this method, the adjusting unit 130 may be provided on a propagation path of laser light input to the generating unit 142 so that the optical path length of laser light input to the generating unit 142 can be changed. For adjustment of the optical path length, the optical path length may be changed by changing the refractive index in the propagation path, for example.

The detecting unit 107 detects pulsed waves in response to incident pulsed waves and laser light. More specifically, the detecting unit 107 detects the instantaneous value of the electric field intensity of a pulsed wave reaching when laser light enters thereto. According to this exemplary embodiment, the detecting unit 107 is a photoconductive device. The detecting unit 107 may only be required to detect pulsed waves from incident laser light. A known technology which can achieve this goal is applicable to the detecting unit 107.

A component having the same phase as the modulation of the power supply 141 of a signal based on pulsed waves detected by the detecting unit 107 is extracted through the amplifier 113 which amplifies the signal intensity and the lock-in amplifier 114 which improves the signal accuracy by reducing noise therein. The extracted component is converted to information such as image information through the waveform acquiring unit 122, the spectrum acquiring unit 123, the selecting unit 124, the determining unit 125, and the image forming unit 126.

It should be noted that the apparatus 100 has a computer (not illustrated) having a CPU, a memory, a store device and so on, and the computer has functions corresponding to the control unit 121, waveform acquiring unit 122, spectrum acquiring unit 123, selecting unit 124, determining unit 125, and image forming unit 126, for example. The computer, not illustrated, has the storage unit 127 which may store a detection result from the detecting unit 107 and a time waveform of terahertz waves. The storage unit 127 stores a program corresponding to steps on the flowchart in Fig. 3, and the CPU reads and executes the program to implement the corresponding processing. The steps on the flowchart in Fig. 3 will be described below.

The control unit 121 controls the components of the apparatus 100. The control unit 121 mainly controls the driving of the movable stage 109 and sample unit 105.

The waveform acquiring unit 122 acquires a time waveform of a terahertz wave. More specifically, the waveform acquiring unit 122 acquires a time waveform by using the amount of adjustment of the optical path length performed by the adjusting unit 130 including the movable stage 109 and the mirror pair 110 and a detection result from the detecting unit 107.

The spectrum acquiring unit 123 acquires an optical characteristic of the subject 230 by using the time waveform acquired by the waveform acquiring unit 122 and acquires a spectrum of the optical characteristic by defining frequency in the horizontal axis. The spectrum acquiring unit 123 calculates a standard deviation σ from a plurality of measurement results acquired by performing the measurement at a plurality of different positions of the subject 230 or from a plurality of measurement results acquired by performing the measurement a plurality of number of times at one position of the subject 230. According to this exemplary embodiment, the spectrum of the optical characteristic may be a refractive index spectrum or an absorption coefficient spectrum by defining frequency in the horizontal axis. The optical characteristic herein may be defined as including a complex amplitude reflectivity, a complex refractive index, a complex dielectric constant, a reflectivity, a refractive index, an absorption coefficient, a dielectric constant, an electrical conductivity and so on of the subject 230. A method for acquiring such a spectrum in the spectrum acquiring unit 123 will be described below. The time waveform acquired by the waveform acquiring unit 122 includes at least a peak of a terahertz wave (first reflected wave) reflected by a front side of window members of the

cells

202 and 220 and a peak of a terahertz wave (second reflected wave) reflected by the sample surfaces 207 and 217. First, the spectrum acquiring unit 123 extracts a first area containing the first reflected wave only and a second area containing the second reflected wave only from the time waveform. For the extraction from the time waveform, it is desirable that other peaks are not included as much as possible and that the width of the time defined as the horizontal axis is long. The spectrum acquiring unit 123 may perform a Fourier transformation on the extracted first area and second area to acquire the amplitude spectrum with frequency as the horizontal axis. The amplitude spectrum acquired from a first time waveform is used as a reference spectrum (reference). In other words, the ratio of the amplitude spectrum acquired from the first time waveform and the amplitude spectrum acquired from the second time waveform is acquired to acquire an amplitude spectrum of the sample surface. The acquired spectrum may be used to acquire the spectrum of the optical characteristic of the subject. Details of the method for acquiring the spectrum of an optical characteristic are disclosed in NPL 1.

The spectrum acquired by the spectrum acquiring unit 123 is transmitted to the selecting unit 124 and is used for selecting the frequency range suitable for determination. The frequency range to be extracted may be determined by using the standard deviation σ acquired as described above. Details will be described below. The frequency range selected by the selecting unit 124 is transmitted to the determining unit 125.

The determining unit 125 analyzes the time waveform and the refractive index spectrum or absorption coefficient spectrum, for example, to determine the state of the biological tissue being the subject 230. More specifically, the determining unit 125 uses the result of the comparison between the measurement spectrum and the reference spectrum to determine the state of the subject 230 at each measurement point. For example, a normal tissue region without an abnormality in the biological tissue and an abnormal tissue region with an abnormality such as a malignant transformation in a cell are determined (identified). In this case, the comparison result in the frequency range selected by the selecting unit 124 is desirably used to determine the state of the biological tissue. The details of the information acquisition method (determination method) will be described below.

The image forming unit 126 generates an image by using information regarding an irradiation position of pulsed waves changed by scanning of the stage of the sample unit 105 and the value of the optical characteristic acquired by the spectrum acquiring unit 123 or the determination result from the determining unit 125. The time waveform and spectrum of the pulsed waves, information regarding the subject 230 and images acquired in the aforementioned configuration may be displayed as required by a display unit, not illustrated, connected to the computer.

The configuration of the apparatus 100 according to this exemplary embodiment has been described above. The information acquisition method for determining the state of a biological tissue by using the apparatus 100 will be described below with reference to Fig. 3. Fig. 3 is a flowchart of the information acquisition method for determining the state of the subject 230 by using the apparatus 100. The following description assumes that the apparatus 100 is a reflective measurement apparatus.

First, the apparatus 100 measures pulsed waves reflected by pure water being the subject 230 (S301). The pure water is one extracted from a pure water production apparatus immediately before the measurement and is poured into the cell 202 by using a syringe, for example, so as to prevent mixing of air bubbles which may cause scattering, for example, into the pure water. Next, the apparatus 100 measures pulsed waves reflected by the biological tissue prepared by using the same cell 202 cleaned after the pure water measurement and used again or a different cell 202 (S302). The biological tissue is adhered to the cell 202 to prevent mixing of air bubbles.

Desirably the coordinates of each measurement point in the pure water measurement performed in step S301 are identical to the coordinates of each measurement point in the biological tissue measurement performed in step S302. When there is a plurality of measurement points for determining the state of a biological tissue, the signal acquisition and measurement may be performed on pure water at identical coordinates to those of the measurement points for a biological tissue. This is because a terahertz signal is sensitive to the position and gradient about a condensing point of terahertz waves and therefore measurement at under an identical condition performed on a biological tissue to be determined and pure water being a comparison target for improved accuracy of the determination can improve the accuracy of the measurements. In order to capture an image by performing a two-dimensional measurement on a whole biological tissue, a two-dimensional measurement may be performed on pure water.

Use of an identical cell 202 for both of a pure water measurement and a biological tissue measurement is desirable in terms of accuracy of measurement, but the cell 202 must be washed therefor. In consideration of the measurement time and labors, different cells 202 may be used between the pure water measurement and the biological tissue measurement. When different cells 202 are used, a difference in thickness distribution between the window members of the cells 202 may possibly affect the resulting spectra even though the measurement coordinates are identical between the pure water measurement and the biological tissue measurement. In order to prevent the effect, the thickness distributions of the window members of all cells to be used may be mechanically or optically acquired in advance and may be stored in the storage unit 127 and may be referred when spectra are acquired.

Next, the waveform acquiring unit 122 and the spectrum acquiring unit 123 acquire a spectrum of an optical characteristic by using a detection result acquired by detecting resulting pulsed waves from the pure water and the biological tissue by the detecting unit 107. More specifically, the waveform acquiring unit 122 first acquires a time waveform by using the detection result provided by the detecting unit 107. Then, the spectrum acquiring unit 123 performs a Fourier transformation and analyzes the time waveform to acquire the spectrum of the optical characteristic in the frequency area (S303). The time waveform of reflected pulsed waves acquired by irradiating pulsed waves from the surface 206 side of the cell 202 has pulsed waves reflected by the surface 206 and sample surface 207 of the cell 202. Performing a Fourier transformation and analyzing them separately results in spectrum information regarding an optical characteristic such as a complex refractive index of the pure water or the biological tissue.

Next, the determining unit 125 compares the reference spectrum and the measurement spectrum (S304). As a comparison unit, a statistical analysis scheme may be used which acquires a difference, a ratio or the like for a plurality of frequencies, for example, between the reference spectrum and the measurement spectrum.

Performing the comparison such as acquiring a difference or a ratio for frequencies between spectra is effective from viewpoints that the effect of a measurement error or an apparatus difference can be reduced by the comparison with stable pure water and the comparison with water causing a difference in optical characteristic between tissue states. However, for some types of biological tissue being the subject 230, there is a small difference between spectra of tissues having different states and a data dispersion due to the individual difference easily occurs. Therefore, the application of such a statistical analysis may sometimes be effective for determination with high accuracy. For example, a multivariate analysis may be used to statistically extract a minute difference between spectra. A proper comparison unit may be selected in accordance with the determination target.

A spectrum of an abnormal tissue region and a spectrum of a normal tissue region will be described below. Fig. 4A is a schematic view illustrating refractive index spectra acquired in pure water, an abnormal tissue region and a normal tissue region. As described above, an abnormal tissue region tends to contain a larger amount of water than that in a normal tissue region. Thus, a spectrum in an abnormal tissue region is closer to a spectrum of pure water than a spectrum of a normal tissue region. More specifically, the refractive index is greater in the order of pure water, an abnormal tissue region, and a normal tissue region.

Therefore, when a difference between a spectrum of pure water and a spectrum of a biological tissue is acquired, the abnormal tissue region exhibits a value closer to 0 than the value exhibited by the normal tissue region. When a ratio of a spectrum of the pure water and a spectrum of the biological tissue is acquired, the abnormal tissue region exhibits a value closer to 1 than the value exhibited by the normal tissue region as illustrated in Fig. 4B. Alternatively, spectra of a plurality of different optical characteristics may be used for the comparison. As an example, Fig. 5A illustrates a relationship diagram with the horizontal axis denoting the average value of the refractive indices at a certain frequency or in a certain frequency band and the vertical axis denoting the average value of the absorption coefficients. Because both of the refractive index and the absorption coefficient are greater in the order of a pure water, an abnormal tissue region, and normal tissue region, the relationship among them is as illustrated in Fig. 5A. Performing the comparison by acquiring a difference or a ratio between a measurement spectrum and the reference spectrum results in a tendency as illustrated in Fig. 5B.

As described above, various statistical analysis schemes may be used for the comparison between a measurement spectrum and the reference spectrum performed in step S304. An example of the statistical analysis schemes may be a principal component analysis. The principal component analysis contracts quantative data having many variables like a spectrum to a smaller number of uncorrelated synthetic variables. A measurement spectrum of a biological tissue in a terahertz area appears to have monotonous changes only. With focus on a principal one of synthetic variables (hereinafter, called a first principal component, a second principal component and so on having a larger dispersion in the order) acquired by performing a principal component analysis, it may be used as an index for separating a different state.

For example, plotting spectrum information of an abnormal tissue region, a normal tissue region and pure water with the axes denoting the principal components acquired by the principal component analysis on a so-called score plot, plot groups of the tissues can roughly be separated. Fig. 6A is a score plot diagram acquired by performing a principal component analysis on refractive index spectra of pure water and a biological tissue. In this case, the plot positions of scores of the abnormal tissue region are closer to the plot positions of the score of the pure water than the plot positions of the score of the normal tissue region (Fig. 6A). Thus, the proximity between the plot positions of the scores regarding a measurement spectrum on the score plot and the plot positions of the scores regarding the reference spectrum may be converted into numbers so that the data regarding the pure water and the data regarding the biological tissue can be compared.

Fig. 6B illustrates comparison values and a reference value when the principal component analysis is applied. After a difference or ratio between a measurement spectrum of a biological tissue and a spectrum of pure water is acquired, the principal component analysis is performed on the measurement spectra so that a relationship diagram as illustrated in Fig. 6B can be acquired (Fig. 6B). As described above, in step S304, the ratio or difference between a measurement spectrum and a pure water spectrum, a relationship diagram of the spectra, or a statistical analysis result of the principal component analysis, for example, may be used for comparing the pure water spectrum (reference spectrum) and the measurement spectrum of the biological tissue.

Next, the selecting unit 124 determines a frequency range effective for the determination (S305), and the determining unit 125 extracts a comparison result in the frequency range (S306). The frequency range effective for the determination corresponds to a range where the standard deviation σ acquired by the spectrum acquiring unit 123 is equal to or lower than 1/2 times or desirably equal to or lower than 1/6 times of the difference (difference between average values of spectra acquired for each of a plurality of different states) Δ of spectra necessary for the identification of a different state.

For example, when 0.03 is needed as the difference Δ in a refractive index spectrum, the frequency range where the standard deviation σ is 0.015 or more desirably 0.005 is effective for the determination. As already known, in a spectrum of a biological tissue in a terahertz area, there is a small difference Δ between spectra of a normal tissue region and an abnormal tissue region. The difference Δ in refractive index, for example, is approximately equal to 0.02 at a minimum. In order to distinguish two spectra having a difference of 0.02, the standard deviation σ for the measurement of the spectra may be equal to or lower than at least the half, that is, equal to or lower than 0.01.

When a holding member such as the

cells

202 and 220 is used for the measurement, pulsed waves detected by the detecting unit 107 are pulsed waves through the subject 230 such as pure water or a biological tissue and the holding member. This results in pulsed waves having attenuated terahertz waves entering to the detecting unit 107 even when the holding member is made of a material which is highly transmissive to terahertz waves. In consideration of this, the signal to noise (SN) ratio of a signal acquired by the apparatus 100 must be high to some extent. The frequency range satisfying it may easily vary in accordance with the configuration of the apparatus 100 and the measurement conditions such as the adjustment state and the measurement environment. For example, when the cumulative number is 10 in order to acquire one signal in several tens seconds or shorter as a realistic acquisition time, the SN ratio of an amplitude spectrum must be appropriately 100. For that, in order to observe a minute difference between different states with high accuracy, a comparison result within the frequency range satisfying the requirement must be used.

A frequency range may be extracted in accordance with an area to be observed. In the apparatus 100, generated pulsed waves are terahertz waves in a wide band containing a plurality of different frequency components. When such pulsed waves are condensed to be irradiated to the subject 230, the diffraction limit varies in accordance with the frequency. Therefore, the beam diameter may differ in accordance with the frequency. In other words, the pulsed waves are terahertz wave s containing a plurality of frequency components having different beam diameters. Therefore, the frequency range can be set in accordance with the size of the area to be observed or the measurement pitch for an imaging measurement. Because a biological tissue is an ununiform system which varies in cell distribution and structure, for example, in accordance with the area, frequency setting in consideration of them may sometimes be important.

As described above, the determining unit 125 extracts a comparison result or comparison results in one or a plurality of frequencies in an effective frequency range from comparison results between an acquired measurement spectrum and the reference spectrum. The comparison result extracted by the determining unit 125 will be called a comparison value, hereinafter.

The information acquisition method of this exemplary embodiment is not limited to the method illustrated in the flowchart in Fig. 3, but changes may be made thereto as required. For example, in the flowchart in Fig. 3, after the determining unit 125 performs the comparison (S304), the selecting unit 124 selects a frequency range. However, before step S304, the selecting unit 124 may determine the frequency range. After that, the determining unit 125 may performs the comparison processing in step S304 within the frequency range. When the frequency range effective for the determination is known in advance, step S305 may be omitted.

In step S307, the determining unit 125 acquires a criterion with reference to a database acquired in advance and compares the acquired criterion and the comparison value acquired in step S306.

The database stores data regarding a plurality of spectra or time waveforms, for example, acquired in the same procedure as that in step S301 to step S303 or step S304 in the flowchart in Fig. 3 by using the apparatus 100 or a different information acquisition apparatus. More specifically, data regarding various biological tissues whose states are known are acquired for various organs which are acquired from different solids and can be determination targets, and results of comparisons with data regarding pure water measured under the measurement conditions which are also used for measuring the biological tissues are classified in accordance with the organs and states of the biological tissues.

The measurement conditions may include a measurement apparatus and set conditions for the measurement apparatus based on a measurement environment and for a measurement. A spectrum as data regarding pure water can be measured under measurement conditions which are used for measuring each of biological tissues. The measurement conditions may not necessarily completely equal, but use of a same measurement apparatus and substantially equal measurement environment and set conditions for the measurement apparatus, and substantially equal sample mounting state are preferable. As a measurement environment, the difference in temperature for measurements is equal to or smaller than ± 1°C, and the difference in humidity in a propagation path of pulsed waves within the apparatus is equal to or smaller than ± 0.1%. As a set condition for the measurement apparatus, it is important to equally set the sweep rate and sweep step width of the adjusting unit 130 and equally set the lock-in amplifier, for example. A sample may be mounted such that the position and gradient of a sample surface about a parallel propagation area of pulsed waves can substantially agree in a micrometer order between the pure water measurement and the biological tissue measurement and the measurements may be performed with respect to identical measurement coordinates.

As described above, biological tissues tend to have individual differences in shape of spectra and values of optical characteristics. For that, unlike samples made of uniform substance, in order to create a highly reliable database, data regarding an identical organ and identical state must be acquired from a plurality of different individuals, and their average values, for example, must be stored therein. When data regarding a plurality of different individuals are to be acquired, the apparatus to be used for a measurement and the measurement conditions such as the measurement environment may differ between individuals, and the acquired data regarding the individuals may include measurement errors and apparatus differences. Because the spectrum difference between a normal tissue region and an abnormal tissue region of a biological tissue in a terahertz area tends to be small, the inclusion of measurement errors and apparatus differences in data regarding individuals may possibly prevent accurate observation of a spectrum difference between those tissues.

According to this exemplary embodiment, data regarding pure water which is a uniform and stable substance and data regarding a biological tissue of each individual are acquired under equal measurement conditions, and the data regarding the pure water and the data regarding the biological tissue are then compared. Because the measurement errors and apparatus differences due to different measurement conditions can be reduced in the database regarding biological tissues created by using results of comparisons with pure water, the precision of the database can be higher than a case without comparisons with pure water. As a result, the accuracy of determination of a state of a biological tissue using the database can be improved.

The criterion may be a reference value or reference line which is acquired with reference to the database, and a criterion necessary in accordance with the comparison scheme in step S304 may be used. The determining unit 125 uses the range between a result of a comparison between a spectrum of a biological tissue having a known first state and a spectrum of pure water and a result of a comparison between a spectrum of the biological tissue having a known second state and the spectrum of the pure water as the criterion.

When the comparison values are a difference or ratio between the spectra in a frequency area, the determining unit 125 first acquires the average values of the differences or ratios of spectra having states of the biological tissue and a standard deviation σ from the database. Then, the difference between the highest average value of the average values for different states to be determined and the standard deviation σ and the sum of the lowest average value and the standard deviation σ are calculated, and the intermediate value between these values is defined as a reference value. As illustrated in Fig. 4B, when the determination is performed based on the ratio with the spectrum of pure water, the intermediate value between the difference between the average value for an abnormal tissue region and the standard deviation σ and the sum of the average value for a normal tissue region and the standard deviation σ is defined as a reference value. The determining unit 125 determines as abnormal tissue region if the comparison value is higher than the reference value and determines as a normal tissue region if the value is lower than it (S308, S309).

When the comparison value for the determination is a relationship diagram with the vertical axis and horizontal axis denoting different optical characteristics as illustrated in Fig. 5A, the average value of differences or ratios of spectra in states of the biological tissue is acquired from the database with respect to the frequency range for acquiring the comparison value. After that, as illustrated in Fig. 5B, a reference line for the determination is drawn on the relationship diagram. The determining unit 125 determines as an abnormal tissue region if the comparison value is in an abnormal tissue region side on the relationship diagram and determines as a normal tissue region if it is in a normal tissue side (S308, S309).

When the comparison value for the determination is a score acquired by performing a principal component analysis, one score plot is first created from all data regarding different states to be determined in the database, and a reference line for the determination is drawn on the score plot as illustrated in Fig. 6B. The determining unit 125 determines as an abnormal tissue region if the comparison value is in an abnormal tissue region on the score plot and determined as a normal tissue region if it is in a normal tissue side (S308, S309).

This determination scheme uses a reference value acquired with reference to the database with improved accuracy having a reduced effect due to measurement errors and apparatus differences through comparisons with pure water. Because pure water causes a difference between a spectrum of a normal tissue region and a spectrum in an abnormal tissue region, a clear difference is provided through the comparison with pure water. Therefore, the determination accuracy of this determination method improves more than the determination without comparison with pure water.

When an imaging measurement is performed on a whole biological tissue, the determining unit 125 performs a determination following the flowchart in Fig. 3 with respect to all measurement points. Based on the result, the image forming unit 126 displays all of the measurement points in colors corresponding to states. Thus, an image illustrating a biological tissue having states colored differently.

The method for acquiring information regarding a state of a biological tissue has been described above with reference to Fig. 3. However, without limiting the information acquisition method using spectra, time waveforms acquired by the apparatus 100 may be used for the determination. Fig. 13 illustrates a flowchart for an information acquisition method using time waveforms.

First, the detecting unit 107 detects pulsed waves from pure water and a biological tissue (S1301, S1302), and the waveform acquiring unit 122 acquires time waveforms (S1303). Hereinafter, the time waveform acquired by using a detection result from the detecting unit 107 when the subject 230 is pure water will be called a "reference waveform", and the time waveform acquired by using a detection result from the detecting unit 107 when the subject 230 is a biological tissue will be called a "measurement waveform". Next, in order to keep high measurement accuracy by reducing the effect of intensity changes in a pulsed wave signal during a measurement, the intensity of pulsed waves from the sample surface 207 is normalized with the intensity of pulsed waves from a surface of the cell 202 (S1304).

Next, reflected waves from the sample surface 207 are extracted from a plurality of pulsed waves present on the time waveform (S1305). Next, the measurement waveform and the reference waveform are compared (S1306), and, a comparison result such as a difference is acquired (S1307). After that, a criterion is acquired with reference to the database, and the comparison result acquired in step S1307 and the criterion are compared (S1308). When a difference is acquired by the comparison processing, a reference value for states of organs may be expressed by an average value of time waveform differences and the standard deviation σ. If the comparison value acquired in step S1307 is in the range of the average value of a normal tissue ± standard deviation σ, a normal tissue is determined. If it is in the range of the average value of an abnormal tissue ± standard deviation σ, an abnormal tissue is determined (S1309, S1310).

The apparatus 100 determines a criterion by using a result of a comparison between spectra or time waveforms acquired by measuring a plurality of different biological tissues, which are stored in the database, and a spectrum or time waveform acquired by performing the measurement on pure water under the same measurement conditions for the biological tissues. The state of a biological tissue is determined by using the result of the comparison between a measurement spectrum or measurement waveform acquired by performing the measurement on the biological tissue and a reference spectrum or a reference waveform acquired by performing the measurement on pure water and the aforementioned criterion.

According to the apparatus 100, the accuracy of the determination of the state of a biological tissue can be improved, compared with a case where a comparison between the reference spectrum or reference waveform acquired by performing the measurement on pure water.

Second Exemplary Embodiment

According to the first exemplary embodiment, a sample provided in the sample unit 105 is replaced or changed its position by a movable stage between a pure water measurement and a biological tissue measurement. In a case where a sample is replaced, even when an identical cell 202 is used, the position and/or gradient of the sample surface 207 about the pulsed waves may possibly be changed in accordance with how the sample is placed. As a result, the measurement condition may differ between a pure water measurement and a biological tissue measurement, and a correct comparison value may not be acquired. In a case where the position of the sample is changed by the movable stage, different cells 202 are used for a pure water measurement and a biological tissue measurement. As a result, there is a possibility that an analysis error due to a difference in thickness of the window members of the cells 202 during the spectrum acquisition process and a correct comparison value may not be acquired. This is also true for transmission measurement apparatuses using the cells 220.

This exemplary embodiment has a configuration which may overcome the problems and by which a pure water measurement and a biological tissue measurement can be performed by using one cell without replacing or changing the cell. More specifically, an information acquisition apparatus according to this exemplary embodiment has a sample unit 701 instead of the sample unit 105 in the apparatus 100 and a pure water supply unit 702. Fig. 7 illustrates a configuration of the sample unit 701 according to this exemplary embodiment and its surroundings. The same information acquisition method as that of the first exemplary embodiment is applied.

Fig. 8 illustrates an example of a reflective cell 802 in the sample unit 701 according to this exemplary embodiment. Like the first exemplary embodiment, the cell 802 has a space 804 in which a subject 230 such as a biological tissue or pure water is mounted, and the cell 802 is placed and is fixed on holding

units

801 and 805 which move in synchronization with a movable stage. The cell 802 is tightly closed by a lid 803 to prevent drying of a biological tissue and transpiration and outflow of pure water. The cell 802 may be made of any known material through which terahertz waves can transmit well and which has a stable physical property. More specifically, a quartz substrate or a single crystal silicon plate may be used, for example. Pulsed waves are irradiated from a lower side of the cell 802 in Fig. 8 and are reflected by a surface of the cell 802 and an interface between the cell 802 and the subject 230.

The cell 802 is connected with the pure water supply unit 702 via a supply line 703 and a collecting line 704 for pure water circulation. The pure water supply unit 702 is a container such as a tank configured to store pure water. Because of this structure, pure water is poured from the supply line 703 into the space 804 for performing a pure water measurement, and the collecting line 704 is used after the pure water measurement to collect pure water without replacing or changing the cell 802.

Before a biological tissue is mounted, the lid 803 may be opened and be left, or drying air may be fed from the supply line 703 and the collecting line 704 so that the space 804 may be dried to prevent pure water from remaining. In a case where drying air, for example, is fed, both or one of the supply line 703 and the collecting line 704 in Fig. 7 may be connected to a supply line connecting to a drying air generator, for example, and the wiring may be changed between a case where pure water is being circulated and a case where drying air, for example, is being supplied. After drying is confirmed, a biological tissue may be placed in tight contact with the cell 802 within the space 804, and the lid 803 is tightly closed. In this way, a biological tissue measurement is performed on a biological tissue placed in the cell 802, and the determination may be performed by following the flowchart illustrated in Fig. 3.

Though the cell 802 is fixed to the holding

units

801 and 805, it may be removed from the holding units because it requires cleaning after the biological tissue measurement. A cleaning mechanism may be incorporated around the holding

units

801 and 805, such as a dense ultraviolet ray lamp capable of photo chemical cleaning which decomposes an organic compound. By incorporating such a cleaning mechanism, a biological tissue to be measured may be changed by keeping the cell 802 fixed, and the influence of the replacement of the cell 802 on the measurement accuracy can be reduced.

Also in the information acquisition apparatus of this exemplary embodiment, the accuracy of the determination of the state of a biological tissue can be improved compared with a case where the comparison with a reference spectrum or reference waveform acquired by performing the pure water measurement.

This exemplary embodiment is configured to have a pure water circulation mechanism by providing the pure water supply unit 702 so that a pure water measurement and a biological tissue measurement can be performed by using the same cell 802 without replacing it. Thus, a condition having a large influence on a measurement result, such as the position and gradient of a sample surface about pulsed waves, can be fixed. Therefore, the accuracy of the comparison value to be acquired in step S306 for the determination can be improved. The information acquisition apparatus of this embodiment may also be used for measurement of data to be included in the database so that the accuracy of the determination can be improved.

Though a reflective type has been described as an example, this embodiment is also applicable to a transmission type. Also with a transmission type, an identical cell can be used for both of a pure water measurement and a biological tissue measurement, and a condition such as the position and gradient of a sample surface against pulsed waves can be fixed. Thus, the accuracy of the comparison value can be improved, and the accuracy of the determination can be improved.

Third Exemplary Embodiment

An information acquisition apparatus 900 (hereinafter, called an "apparatus 900") according to a third exemplary embodiment will be described with reference to Fig. 9. While the apparatus 100 according to the first and second exemplary embodiments acquires a time waveform of terahertz waves by using pulsed waves, the apparatus 900 performs measurements by using continuous waves of terahertz waves. The apparatus 900 does not acquire a time waveform because continuous waves in a plurality of different frequencies are irradiated for performing measurements. It is therefore different from the first exemplary embodiment in the method for acquiring a spectrum in step S303 in the flowchart of the information acquisition method. The same as the first exemplary embodiment is true for other configurations. The description on the same configuration as that of the first exemplary embodiment will be omitted. The apparatus 900 also has a storage unit 127 storing a program corresponding to the steps in the flowchart in Fig. 3, and a CPU reads and executes the program to perform the corresponding processing.

Fig. 9 illustrates a configuration of an irradiating unit and a detecting unit in the information acquisition apparatus according to this exemplary embodiment. Continuous waves of terahertz waves radiated from a light source (continuous wave light source) 901 configured to output continuous waves are irradiated to a sample including the subject 230 mounted in a sample unit 902. After that, terahertz waves transmitted through the sample or reflected by the sample are detected by a detecting unit (detector) 903. The sample unit 902 may be replaced or changed as in the first exemplary embodiment or may include a pure water circulation mechanism as in the second exemplary embodiment.

The light source 901 configured to generate continuous waves of terahertz waves may be a resonant tunneling diode oscillator or a quantum cascade laser. The detector 903 may be of a CMOS type or a Schottky type.

Also in this exemplary embodiment, the determination with respect to a biological tissue is performed by following the flowchart illustrated in Fig. 3, like the first and second exemplary embodiments. The measurements are performed by changing the frequency of terahertz waves to be output from the light source 901 or by using a plurality of light sources 901 which generates terahertz waves in different frequencies. Because the terahertz signals acquired by the pure water measurement in step S301 and the biological tissue measurement in step S302 are continuous waves in a certain frequency, the spectra may be acquired in step S303 without using time waveforms. The frequency of the terahertz waves to be used for the measurements is set so as to satisfy the condition for a frequency range determined in step S305.

When the light source generates continuous waves, a pulse waveform in a time domain cannot be acquired. Therefore, information regarding pure water or a biological tissue only, which is mounted within a sample cell or enclosed by plates, cannot be separated in a time waveform. In order to separate information regarding pure water or a biological tissue only, which is acquired from the acquired spectrum information, a measurement result of a measurement of the sample cell or plates must be subtracted as a reference.

According to the first and second exemplary embodiments, terahertz waves used for measurements are terahertz waves in a wide band containing a plurality of different frequency components. Therefore, a fixed measurement condition may be required to detect occurring terahertz waves in a wide band as many as possible. Particularly, detection of a frequency component on a higher frequency side having a smaller focal depth and beam diameter may be influenced largely by the position and gradient of a sample surface about terahertz waves irradiated to the sample surface. In order to detect terahertz waves in a broad band by one operation, the measurement condition may be required to be adjusted to the higher frequency side with more strict conditions. However, the light source generating continuous waves may eliminate the necessity for detection of all frequency bands by one operation. Thus, the measurement conditions may only be required to be optimum for measurements in corresponding frequencies. Limiting the frequency range for extraction in step S305 to a lower frequency side can reduce the load of the adjustment in preparation for measurements, compared with a THz-TDS apparatus.

As described above, according to the apparatus 900 and the information acquisition method using the same according to this exemplary embodiment, the accuracy of the determination of the state of a biological tissue can be improved compared with a case where the comparison with a reference spectrum or a reference waveform acquired by performing a pure water measurement.

First Example

As a first example, the apparatus 100 according to the first exemplary embodiment will be described more specifically. According to this example, the pure water to be measured has a specific resistance of 18.2 MΩcm collected from an ultra-pure water generating apparatus. The biological tissue to be used is a brain tissue of a Sprague-Dawley rat (hereinafter, simply called a "rat"). The sample cell is made of z-cut quartz. An example will be described in which a comparison value between pure water and a biological tissue is acquired by acquiring a ratio in refractive index spectrum. The frequency range for the extraction is 0.8 THz to 1.2 THz, and a refractive index difference of 0.02 or larger can be identified in this range.

Fig. 10A illustrates refractive index spectra of normal tissue areas of the brain of three different rat individuals A, B, and C measured by the apparatus configuration according to the first exemplary embodiment. Fig. 10B illustrates refractive index spectra of tumor tissue areas of the brain of the rats A, B and C. Each of the spectra exhibits an average value of results of measurements at five different positional points in each of the areas. The five points for the measurements include one point at the center of the area and points at 250 μm above, below, right and left from the center point. Fig. 10C illustrates refractive index spectra of pure water acquired before biological tissue measurements performed on the three rat individuals A, B, and C. There are large variations between the individuals in the normal tissue, but the tumor area has a higher refractive index than that of the normal area. This means that the tumor area has a closer spectrum to that of pure water.

Differences in accuracy of the determination based on the presence/absence of the comparison with pure water will be examined. First, a percentage of correct answers of the determination is calculated in a case where the comparison with pure water is not executed. The percentage of correct answers refers to a probability of determination of a normal tissue as a normal tissue and an abnormal tissue as an abnormal tissue. A database with respect to a normal tissue area and a tumor tissue area of the brains of the rats was created based on the refractive index spectra illustrated in Figs. 10A and 10B. If the spectrum for the normal tissue of each of the individuals is in the range of the average value of the normal tissues of the three individuals ± standard deviation σ, it is determined that the normal tissue determination has succeeded. If not, it is determined that the determination has failed. The determination was performed at five frequency points (0.8 THz, 0.9 THz, 1.0 THz, 1.1 THz, and 1.2 THz), if the success is determined in all frequency points, it is determined that the determinations have been performed correctly. As a result, the percentage of correct answers with respect to normal tissues of the three individuals was equal to 33%. The percentage of correct answers with respect to tumor tissues of the three individuals calculated by performing the same steps was also 33%.

Next, the percentage of correct answers of the determination is calculated in a case where the comparison with pure water is performed. Fig. 11 illustrates ratios of refractive index spectra of the normal tissues and tumor tissues of the three individuals against the refractive index spectrum of pure water, that is, comparison values with respect to five frequency points (0.8 THz, 0.9 THz, 1.0 THz, 1.1 THz, 1.2 THz). At each of the frequency points, the three left bar graphs represent the ratios to the tumor tissues, and the three right bar graphs represent the ratios to the normal tissues. Each of broken lines drawn on the bar graphs at the frequency points represents an intermediate value between a value acquired by subtracting the standard deviation σ from the average value for the tumor tissues and a value acquired by adding the standard deviation σ to the average value for the normal tissues. According to this example, the reference values of the determinations are 0.9886@0.8 THz, 0.9840@0.9 THz, 0.9876@1.0 THz, 0.9808@1.1 THz, and 0.9889@1.2 THz. If the comparison value is higher than the reference value, it is determined as a tumor tissue. If the comparison value is lower than the reference value, it is determined as a normal tissue. As illustrated in Fig. 11, the tumor tissues could be determined as tumor tissues and the normal tissues could be determined as normal tissues at all of the frequency points. As a result, all of the percentages of correct answers for the determinations were 100%. It can be understood from the result that the accuracy of the determination was improved compared with the case where the comparison with pure water was not performed.

One reason why the accuracy of determination is improved by the comparison with pure water is the use of the database having spectra or time waveforms acquired by measuring a plurality of different biological tissues and a spectrum or time waveform acquired by measuring pure water under the same measurement conditions as those for the biological tissues. The state of a biological tissue may be determined by using a criterion acquired by using the data contained in the database as described above and a result of a comparison between a measurement spectrum or time waveform acquired by measuring the biological tissue and a spectrum or time waveform acquired by measuring pure water. This configuration can reduce the influences of measurement errors and apparatus differences caused by differences in measurement conditions.

Another reason why the accuracy of the determination is improved by the comparison with pure water is that the amount of water is associated with a difference in component between a tumor tissue being a subject of the determination and a normal tissue. As already described above, a tumor tissue tends to have a higher amount of water than that of a normal tissue. Applying of the comparison value using one factor causing a difference in a subject of the determination can contribute the improvement of the accuracy of determination.

With the apparatus 100 and the information acquisition method using the same according to this exemplary embodiment, the accuracy of determination of the state of a biological tissue can be improved compared with a case where the comparison with a reference spectrum or time waveform acquired by measuring pure water.

Second Example

An example of the apparatus 100 according to the first exemplary embodiment will be described more specifically as a second example. In this example, the pure water and biological tissue being the subject 230 and the data to be used are the same as those of the first example, but a principal component analysis which is one of statistical analysis schemes is used for the comparison with pure water. The extracted frequency range is from 0.8 THz to 1.5 THz, and a difference in refractive index of 0.02 or higher can be identified in this range.

A difference in score plot acquired by a principal component analysis caused by a difference between the presence and absence of the comparison with pure water will be described below. Fig. 12A illustrates a score plot acquired by performing a principal component analysis on results of measurements performed on normal tissues and tumor tissues of the brains of three rat individuals A, B, and C and results of a measurement performed on pure water immediately before the measurements performed on the individuals. The spectrum data to be used for the principal component analysis is refractive index spectra and extinction coefficient spectra, and the results are plotted with a first principal component (PC1) axis and a second principal component(PC2) axis. Because the measurements were performed at five points in each area of each of the individuals, a total of 33 points including results of measurements on pure water at three points are plotted.

Fig. 12B illustrates a score plot acquired by performing a principal component analysis by using a difference between a spectrum of pure water and a spectrum (measurement spectrum) of a biological tissue as the comparison value by following the flowchart illustrated in Fig. 3. Fig. 12C illustrates a score plot acquired by performing a principal component analysis by using the ratio between a spectrum of pure water and a measurement spectrum as the comparison value by following the flowchart illustrated in Fig. 3.

Because performing a principal component analysis includes normalization processing first, the degrees of dispersion of all score plots can be compared. From the score plots, it is understood that use of either difference or ratio of spectra can suppress the dispersion of plots compared with a case where the comparison with pure water is not performed. This may be considered as an effect produced by the comparison with pure water reducing an influence due to measurement errors caused by difference in states of the apparatus and measurement environments.

In order to acquire a comparison value by performing a principal component analysis, a reference line is acquired as a reference value for determining a normal tissue or a tumor tissue by performing a linear determination analysis, for example. Because of the suppression of dispersions of plots by using a comparison value with pure water, the boundary between states of a biological tissue is clarified, and the position of the reference line can thus be accurately determined. Therefore, it is expected that the determination based on the reference line acquired from the comparison value with pure water can increase the percentage of correct answers, that is, the accuracy of the determination, compared with the determination in a case where the comparison with pure water is not performed.

Having described that the score plots described according to this example have a lower number of individuals to be used for forming the database and results acquired at measurement points where tissue states are clearly different, the dispersion of data may increase as the number of individuals used for forming the database increases. Because data regarding an area where a difference in tissue state is ambiguous such as a boundary between a normal tissue and an abnormal tissue are plotted near the reference line, there is a possibility that an influence of a measurement error may cause an improper determination and thus lower the percentage of correct answers. In consideration of this, it can be expected that performing the comparison with pure water also in the determination based on a principal component analysis can improve the accuracy of determination of the state of a biological tissue.

Also according to this example, as described above, the accuracy of determination of the state of a biological tissue can be improved, compared with a case where the comparison with a reference spectrum or reference waveform acquired by measuring pure water.

Other Embodiments

Embodiment(s) of the present invention can also be realized by a computer of a system or apparatus that reads out and executes computer executable instructions (e.g., one or more programs) recorded on a storage medium (which may also be referred to more fully as a 'non-transitory computer-readable storage medium') to perform the functions of one or more of the above-described embodiment(s) and/or that includes one or more circuits (e.g., application specific integrated circuit (ASIC)) for performing the functions of one or more of the above-described embodiment(s), and by a method performed by the computer of the system or apparatus by, for example, reading out and executing the computer executable instructions from the storage medium to perform the functions of one or more of the above-described embodiment(s) and/or controlling the one or more circuits to perform the functions of one or more of the above-described embodiment(s). The computer may comprise one or more processors (e.g., central processing unit (CPU), micro processing unit (MPU)) and may include a network of separate computers or separate processors to read out and execute the computer executable instructions. The computer executable instructions may be provided to the computer, for example, from a network or the storage medium. The storage medium may include, for example, one or more of a hard disk, a random-access memory (RAM), a read only memory (ROM), a storage of distributed computing systems, an optical disk (such as a compact disc (CD), digital versatile disc (DVD), or Blu-ray Disc (BD)^TM), a flash memory device, a memory card, and the like.

Having described the preferred embodiments of the present invention, the present invention is not limited to those exemplary embodiments. Various modifications and changes may be made without departing from the scope and spirit.

For example, according to one of the aforementioned exemplary embodiments, a refractive index spectrum is mainly used as a spectrum. However, the present invention is not limited thereto and any spectrum of an optical characteristic of the subject 230 can be used for determination of the state of the subject 230. For example, absorption coefficient spectra may be acquired to calculate a comparison value and a reference value of the spectra in the same manner as in the aforementioned method so that the state of the subject 230 can be determined by following the flowchart in Fig. 3. The type of spectrum to be used may be selectable based on the type or state of the subject 230 and the performance of the apparatus, for example.

Having described examples of rat brain tissues in the examples, the aforementioned exemplary embodiments may also be applicable to various human organs (brain, colon, stomach, etc.). A rat and a human are different in animal species, but they are common in that their tissue is an assembly of cells and that an abnormal tissue region tends to have a higher amount of water than a normal tissue region. Thus, the improvement of the accuracy of determination based on comparison with pure water can also be expected for human tissues.

Both of the first example and the second example apply the apparatus 100 according to the first exemplary embodiment. However, use of the configuration according to the second exemplary embodiment may suppress the influence of the position and gradient of a sample surface about pulsed waves. Thus, further improvement of accuracy of determination can be expected. In a case where limited frequencies are usable for the determination, the apparatus 900 according to the third exemplary embodiment may be used to reduce loads including adjustment of a sample surface.

Having described that a principal component analysis is applied as a statistical analysis for comparison between a reference spectrum and a measurement spectrum according to the aforementioned exemplary embodiments and examples, the present invention is not limited thereto. A multivariate analysis which handles multivariate data statistically is applicable such as an independent component analysis and a cluster analysis. In this case, the comparison can be implemented by using feature values acquired by performing a multivariate analysis.

Having described that the interface between the window member of the

cells

202 and 220 and the subject 230 is handled as the sample surface according to the aforementioned exemplary embodiments, the present invention is not limited thereto. A state of an internal interface of the subject 230 or a back surface of the subject 230 facing a surface in contact with the window member may be used for the determination.

While the present invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. The scope of the following claims is to be accorded the broadest interpretation so as to encompass all such modifications and equivalent structures and functions.

This application claims the benefit of Japanese Patent Application No. 2015-017715, filed January 30, 2015 and No. 2015-254741 filed December 25, 2015, which are hereby incorporated by reference herein in their entirety.

Claims

An information acquisition apparatus which acquires information regarding a subject by using terahertz waves, the apparatus comprising:
an irradiating unit configured to irradiate terahertz waves to the subject;
a detecting unit configured to detect terahertz waves from the subject;
a spectrum acquiring unit configured to acquire a spectrum of an optical characteristic by using a detection result from the detecting unit; and
a determining unit configured to determine a state of a biological tissue based on a comparison result of a comparison between a first spectrum acquired by the spectrum acquiring unit by using a detection result from the detecting unit in a case where the biological tissue is used as the subject and a second spectrum acquired by the spectrum acquiring unit by using a detection result from the detecting unit in a case where pure water is used as the subject and a criterion,
wherein the criterion is acquired by using a result of a comparison between a plurality of spectra acquired by measuring a plurality of biological tissues and at least one spectrum acquired by measuring pure water.
The information acquisition apparatus according to claim 1, further comprising a selecting unit configured to select a frequency range effective for the determination of a state of the subject,
wherein the determining unit determines a state of the biological tissue based on the comparison result at one or a plurality of frequencies within the frequency range and the criterion.
The information acquisition apparatus according to claim 2, wherein the frequency range is a frequency range where a standard deviation acquired by using the first spectrum is 1/2 times of difference between a spectrum of a first state of the biological tissue and a spectrum of a second state of the biological tissue.
The information acquisition apparatus according to claim 2 or 3, wherein the frequency range is a frequency range where a standard deviation acquired by using the first spectrum is 1/6 times of the difference between the spectrum of the first state of the biological tissue and the spectrum of the second state of the biological tissue at each of frequencies.
The information acquisition apparatus according to any one of claims 1 to 4, wherein the at least one spectrum is acquired by measuring pure water under a measurement condition used for measuring each of the plurality of biological tissues.
The information acquisition apparatus according to any one of claims 1 to 5, wherein each of the first spectrum, the second spectrum, the plurality of spectra and the pure water spectrum is a refractive index spectrum or an absorption coefficient spectrum.
The information acquisition apparatus according to any one of claims 1 to 6, wherein the determining unit defines the criterion between a result of a comparison between a spectrum of the biological tissue having a known first state and a spectrum of the pure water and a result of a comparison between a spectrum of the biological tissue having a known second state and the spectrum of the pure water.
The information acquisition apparatus according to any one of claims 1 to 7, wherein the determining unit handles as the comparison result a result of a multivariate analysis performed on a ratio or difference between the first spectrum and the second spectrum or a difference or ratio between a feature value acquired by performing a multivariate analysis on the first spectrum and a feature value acquired by performing a multivariate analysis on the second spectrum.
The information acquisition apparatus according to claim 8, wherein the determining unit acquires the criterion by using a result of a multivariate analysis performed on a ratio or difference between the plurality of spectra and the at least one spectrum.
The information acquisition apparatus according to claim 8 or 9, wherein the multivariate analysis includes a principal component analysis, an independent component analysis, or a cluster analysis.
The information acquisition apparatus according to any one of claims 1 to 7, wherein the determining unit handles a ratio or difference between the first spectrum and the second spectrum as the comparison result.
The information acquisition apparatus according to claim 11, wherein the determining unit acquires a standard deviation and an average value for each of a plurality of different states by using a ratio or difference between the plurality of spectra and the at least one spectrum and defines as the criterion an intermediate value between a difference between the highest average value and the standard deviation and a sum of the lowest average value and the standard deviation among the average values for each of the plurality of different states.
The information acquisition apparatus according to any one of claims 1 to 7, wherein the determining unit acquires a ratio or difference between the first spectrum and the second spectrum with respect to a first optical characteristic, acquires a ratio or difference between the first spectrum and the second spectrum with respect to a second optical characteristic, and handles as the comparison result a relationship diagram with a horizontal axis denoting the first optical characteristic and a vertical axis denoting the second optical characteristic.
The information acquisition apparatus according to claim 13, wherein the determining unit acquires the criterion by using the relationship diagram created by using a ratio or difference between the plurality of spectra and the at least one spectrum.
The information acquisition apparatus according to any one of claims 1 to 14, wherein a database is provided which includes data regarding the plurality of spectra and the at least one spectrum.
An information acquisition apparatus which acquires information regarding a subject by using terahertz waves, the apparatus comprising:
an irradiating unit configured to irradiate terahertz waves to the subject;
a detecting unit configured to detect terahertz waves from the subject;
a waveform acquiring unit configured to acquire a time waveform of an optical characteristic by using a detection result from the detecting unit; and
a determining unit configured to determine a state of a biological tissue based on a comparison result of a comparison between a first time waveform acquired by the waveform acquiring unit by using a detection result from the detecting unit in a case where the biological tissue is used as the subject and a second time waveform acquired by the waveform acquiring unit by using a detection result from the detecting unit in a case where pure water is used as the subject and a criterion,
wherein the criterion is acquired by using a result of a comparison between a plurality of time waveforms acquired by measuring a plurality of biological tissues and at least one time waveform acquired by measuring the pure water.
The information acquisition apparatus according to any one of claims 1 to 16, wherein the determining unit determines whether the biological tissue is a normal tissue region or an abnormal tissue region in an area where terahertz waves are irradiated from the irradiating unit of the biological tissue.
An information acquisition method for acquiring information regarding a subject by using terahertz waves, the method comprising:
irradiating terahertz waves to the subject;
detecting terahertz waves from the subject;
acquiring a spectrum of an optical characteristic by using a detection result from the detecting unit; and
determining a state of a biological tissue based on a comparison result of a comparison between a first spectrum acquired by using a detection result from the detecting in a case where the biological tissue is used as the subject and a second spectrum acquired by using a detection result from the detecting in a case where pure water is used as the subject and a criterion,
wherein the criterion is acquired by using a result of a comparison between a plurality of spectra acquired by measuring a plurality of biological tissues and at least one spectrum acquired by measuring the pure water.
An information acquisition method for acquiring information regarding a subject by using terahertz waves, the method comprising:
irradiating terahertz waves to the subject;
detecting terahertz waves from the subject;
acquiring a time waveform of an optical characteristic by using a detection result from the detecting; and
determining a state of a biological tissue based on a comparison result of a comparison between a first time waveform acquired by using a detection result from the detecting in a case where the biological tissue is used as the subject and a second time waveform acquired by using a detection result from the detecting in a case where pure water is used as the subject and a criterion,
wherein the criterion is acquired by using a result of a comparison between a plurality of time waveforms acquired by measuring a plurality of biological tissues and at least one time waveform acquired by measuring the pure water.
A program usable for an information acquisition apparatus which acquires information regarding a subject by using terahertz waves, the program comprising:
determining a state of a biological tissue based on a comparison result of a comparison between a first time waveform or first spectrum acquired in a case where the biological tissue is used as the subject and a second time waveform or second spectrum acquired in a case where pure water is used as the subject and a criterion,
wherein the criterion is a reference value acquired by using a result of a comparison between a plurality of time waveform or a plurality of spectra acquired by measuring a plurality of biological tissues and at least one time waveform or at least one spectrum acquired by measuring pure water.