JP7163019B2 - Synthetic light generating method, optical property changing unit, light source unit, measuring device, optical detection method, imaging method - Google Patents

Description

Embodiments of the present invention relate to detection methods that use light to obtain a signal from (or detect predetermined optical properties of) an object to be detected or imaging methods involving an object to be detected.

Furthermore, it may be applied to application fields using the optical detection or imaging described above. This range of applications also includes (production of) materials whose internal structures and internal activity states can be detected using light, as well as methods of controlling and manufacturing predetermined states using light.

Further, it is not limited to the above, and may include a calculation method for predicting the optical characteristics of the object to be detected.

Since the optical detection method and the optical imaging method are noncontact and noninvasive methods, the load on the object to be detected during detection is greatly reduced. As a result, the above-described detection method and imaging method using light are suitable for observing the natural state of an object to be detected, measuring minute changes, and the like. Therefore, the method is frequently used in a very wide range of fields.

Correspondingly, the fields of application (utilization) of these optical detection techniques and optical imaging techniques are also expanding. Part of this field of application also includes (production of) substances whose internal structures and internal activity states can be detected using light, and the field of management and manufacturing of predetermined states using light.

As these techniques are widely applied in this way, higher accuracy or higher reliability has been required for detection results and measurement results using light. Also, as a means of confirming the reliability and credibility of detection/measurement results using light, it is also necessary to confirm collation with a theoretical basis with high accuracy.

JP-A-6-167640 JP-A-2-240545 JP 2013-122443 A Japanese Patent Application Laid-Open No. 2003-500255 Japanese Patent No. 5098028

As one of the means to improve the detection accuracy and reliability of optical detection technology and imaging technology, the optical noise (noise component generated by optical causes) mixed in the detection signal and optical image is reduced. Reduction is raised.

As a specific example of such means, Japanese Patent Application Laid-Open No. 2002-100003 discloses a method of reducing the coherence of light and reducing the amount of optical noise in the detection/measurement system to improve the detection accuracy. However, there is a limit to speckle noise reduction within the scope disclosed in Patent Document 1, and there is a demand for ensuring even higher precision or reliability.

For the above reasons, we need to provide optical detection methods and optical imaging methods that can achieve higher reliability or higher accuracy, or provide application (utilization) development technology that utilizes these methods (using light to detect internal structures and There is a demand for (including the production of) substances capable of detecting/measuring/evaluating internal activity states, or the provision of manufacturing methods and predetermined state management methods that enable improvements in manufacturing efficiency and control accuracy. Furthermore, there is also a demand for provision of a measuring device and a light source section for embodying the above method.

As another story related to the above, there is a computer simulation method using various quantum chemical calculation software as means for supporting the reliability and credibility of the optical detection and imaging results. However, with existing quantum chemistry calculation software, it takes a huge amount of time to calculate the n-th overtone vibration of a polymer. Therefore, there is a demand for a calculation method that can easily and quickly determine the characteristics of the n-th overtone and combination of specific functional groups (atomic groups) in the polymer.

Light obtained by combining (or mixing) light with different optical path lengths is used for optical detection or optical imaging. Also, the optical path length difference (Difference Value of Optical Length) may be longer than the coherence length (Cohetence Length). Furthermore, in the light obtained by the above synthesis (or mixing), the direction of travel or the direction of electric field vibration may be the same or similar.

The above means may also be applied to application development techniques using optical detection methods or optical imaging methods. That is, the state management using light may be performed as described above. Furthermore, a chemical state or its change or a physico-chemical (or physical) state or its change or a structure or its change, a morphology or its change that can be detected, measured or controlled using light (during the manufacturing process) It may be applied to the production of a given substance produced and the evaluation of the product. Moreover, it is not limited to this, and may be applied to the functional substance itself produced or evaluated by the above method.

The means described below may be executed separately from the means described above, or the means described below may be used in combination with the means described above. The following means are
1) measuring a predetermined property of an object to be optically detected or optically imaged;
2) Based on the measurement results, feed back the properties of the light used for optical detection or optical imaging.
Here, the predetermined characteristic relates to the wavefront characteristic of light used for optical detection or optical imaging, or the influence of a part of the light on the direction of travel. Further, the above-mentioned "characteristics of light" means wavefront characteristics or characteristics that change the traveling direction of part of the light.

On the other hand, the following calculation method may be performed in order to theoretically predict the phenomenon signified by the optical characteristics of the object obtained as a result of optical detection or as a result of optical imaging.
[alpha]] Calculate potential characteristics related to group vibration in a predetermined region included in the object.
β] The results are used to predict the absorption wavelength or absorption wavenumber (frequency) of light.

FIG. 2 is an explanatory diagram of the basic configuration of the measuring apparatus showing the present embodiment (diverging light irradiation). FIG. 2 is an explanatory diagram of the basic configuration of the measuring device showing the present embodiment (parallel light irradiation). FIG. 2 is an explanatory diagram of the basic configuration of the measuring device showing the present embodiment (convergent light irradiation). FIG. 4 is an explanatory diagram of the uncertainty relationship between the frequency of light emitted from a light source and time; FIG. 4 is an illustration of partial coherence of light with a limited detection wavelength range. Effect of partially coherent light on imaging. Explanatory diagram of optical noise generated in scattered light from minute light scattering bodies. FIG. 4 is an explanatory diagram of the effect of partially coherent light on spectroscopic measurement. FIG. 4 is an explanatory diagram of the influence of unevenness in the thickness of a tungsten/halogen lamp tube; An explanatory view of an example of the structure of a near-infrared microscope device incorporating an optical noise reduction element. FIG. 2A is a diagram for explaining the basic principle of an optical noise reduction method according to the present embodiment; FIG. 2B is a diagram (B) for explaining the basic principle of the optical noise reduction method according to the present embodiment; FIG. 4 is an explanatory diagram of a case-by-case list of the photosynthesis/light mixing method according to the present embodiment. FIG. 4 is an explanatory diagram using another explanation method regarding the optical noise reduction method according to the present embodiment. FIG. 4 is an illustration of an example of a method of combining/mixing between lights emitted in different directions; FIG. 2 is an explanatory diagram of an embodiment relating to an optical path length changing method using wavefront split light; FIG. 4 is an explanatory diagram of an example of an optical characteristic changing member using wavefront split light; FIG. 4 is a detailed explanatory view of an example of an optical characteristic changing member using wavefront split light; FIG. 11 is an explanatory view of another embodiment of an optical characteristic changing member using wavefront split light; FIG. 4 is an explanatory diagram of an application example of an optical characteristic changing member using wavefront split light; FIG. 11 is an explanatory view of another application example of the optical characteristic changing member using wavefront split light; FIG. 4 is an explanatory diagram of an application example of the light source section structure using the optical noise reduction method of the present embodiment; FIG. 4 is an explanatory diagram of another synthesis/mixing method between wavefront split lights. Explanatory drawing of the application example regarding the synthesis|combination/mixing method between wavefront split lights. FIG. 4 is an explanatory diagram of a method of synthesizing/mixing wavefront-split light beams using imaging characteristics; A method for synthesizing/mixing wavefront split beams using optical processing of imaging/focusing positions. FIG. 4 is an explanatory diagram of points to consider regarding a method of changing the optical path length between wavefront-split beams; FIG. 4 is an explanatory view of a corresponding embodiment in a method of changing the optical path length between wavefront-split beams; FIG. 10 is an explanatory view of another corresponding embodiment in the method of changing the optical path length between wavefront-split beams; FIG. 2 is an explanatory diagram of conventionally known technology contents for comparative examination. FIG. 4 is an explanatory diagram of an optical noise reduction method using the optical guide fiber length; Schematic diagram (A) of a basic method for combining/mixing light emitted from different light-emitting regions. Schematic diagram (B) of a basic method for combining/mixing light emitted from different light emitting regions. FIG. 4 is an explanatory diagram of a synthesis/mixing method for light emitted from different light emitting regions in a specific region within the target body. An example (A) of a method of synthesizing/mixing light generated from different light emitting regions with a phase conversion element. An example of a method (B) of synthesizing/mixing light generated from different light emitting regions with a phase conversion element. An example (C) of a method of synthesizing/mixing light generated from different light emitting regions with a phase conversion element. Explanatory drawing of the optical system used for the experiment of the effect of a phase conversion element on light synthesis/mixing. Explanatory drawing (A) which shows the effect of photosynthesis/mixing by a phase conversion element. Explanatory drawing (B) which shows the effect of photosynthesis/mixing by a phase conversion element. An example of a method (A) of synthesizing/mixing light emitted from different light-emitting regions with a waveguide element. An example of a method (B) of synthesizing/mixing light emitted from different light emitting regions with a waveguide element. An example of a method (C) of synthesizing/mixing light emitted from different light emitting regions with a waveguide element. FIG. 2 is an explanatory diagram of the inside of a measurement apparatus using both coherent light and partially incoherent light. FIG. 4 is an explanatory diagram of the influence of multiple scattered light inside the target object; An image diagram of a light scatterer inside an object. FIG. 2 is a diagram for explaining the principle of how wavefront aberration occurs inside an object (transparent parallel plate). FIG. 4 is an explanatory diagram of the internal structure of the wavefront aberration coarse motion correction unit; Structural explanatory drawing inside a wavefront aberration fine movement correction|amendment part. Explanatory drawing of a reference light generation principle. Explanatory diagram of the principle of removing unnecessary scattered light generated inside the subject (partially modified for explanation). FIG. 3 is an optical principle explanatory diagram of a wavefront aberration characteristic detection method using partially incoherent light. FIG. 4 is an explanatory diagram of an electrical processing method for wavefront aberration characteristic detection using partially incoherent light; FIG. 4 is an explanatory diagram of a wavefront aberration characteristic detection method using coherent light; FIG. 4 is an explanatory diagram of the relationship between the direction of an external electric field and the direction of movement of charged particles moving therein. Explanatory drawing showing the position vector of the hydrogen nuclei constituting the specific functional group. Explanatory drawing of calculation method of group vibration in a specific functional group on quantum chemical calculation software. FIG. 2 is an explanatory diagram of classification according to the method of exhibiting the function of the functional biomaterial in the present embodiment. Schematic explanatory drawing of the molecular structure in fibroin. Explanatory drawing (A) of an embodiment of a functional biomaterial with improved fibroin. Explanatory drawing (B) of an embodiment of a functional biomaterial with improved fibroin. FIG. 2 is an illustration of an embodiment of a functional biomaterial having a conductive region inside. Explanatory drawing of an example of a functional biomaterial having a power amplification function or a switching function. Explanatory drawing of an example of the intraluminophore structure of a fluorescent protein having a fluorescence wavelength in the near-infrared wavelength region. FIG. 4 is an explanatory diagram of an example of a coping method for an affected part (defective part) related to a DNA failure; FIG. 2 is an explanatory view of an embodiment of a carrier for intranuclear transport having a double packaging structure; Explanatory drawing of the specific structure example of the selective joining part to the cell nuclear membrane surface, and its function example. FIG. 1 is an explanatory diagram of an embodiment relating to a method for mass production of functional biomaterials and a method for process control. Explanatory diagram of an example of the production process of a functional biomaterial using hair matrix-related cells. FIG. 4 is an explanatory diagram of an application form relating to a method for mass production of functional biomaterials and a method for process control. Explanatory diagram of an example of a method for producing a functional biomaterial using regional distribution. FIG. 4 is an explanatory view of an example of forming a structure in which improved β-sheet crystal parts are combined; Explanatory diagram of an example of a procedure for generating a crystal part assembly (multimer) block. FIG. 50 is an explanatory diagram of this embodiment showing the procedure for molding the structure of FIG. 49; FIG. 50 is an explanatory diagram of this application example showing the procedure of forming the structure of FIG. 49 ; FIG. 4 is a comparative illustration of optical path length differences between imaging optical systems with respect to a light source; Other Example explanatory drawing of a photosynthesis (mixing) part. Another application example explanatory drawing using a light guide (light pipe). Principle explanatory diagram of photosynthesis (mixing) within a light guide (light pipe). FIG. 4 is an explanatory diagram of a method for generating electromagnetic waves with high directivity and low partial coherence. Structure explanatory drawing in the water source / metal ore deposit exploration apparatus in this embodiment. Explanatory diagram of an example of a water source/metal deposit search method in an extraterrestrial region. Explanatory diagram of an example of a water source/metal deposit search procedure in an extraterrestrial area. FIG. 4 is an explanatory diagram for simply explaining the difference in partial coherence of light in this embodiment. FIG. 4 is an explanatory diagram for simply explaining a method for controlling partial coherence of light according to the present embodiment; Comparative example of measurement results of silk sheet transmitted light characteristics depending on differences in partial coherence of measurement light. An example of measurement results of the absorbance characteristics of a silk sheet. Comparative example of polyethylene sheet absorbance due to differences in partial coherence of measurement light. Explanatory drawing of an example of examination of the relationship between the baseline characteristics in the absorbance curve and the molecular structure to be measured. FIG. 2 is an explanatory diagram of a method for identifying a functional biosubstance using incoherent near-infrared light according to the present embodiment; FIG. 2 is an explanatory diagram of the relationship between the secondary structure in the functional biomaterial and the constituent amino acids in the present embodiment. FIG. 4 is another manufacturing procedure explanatory diagram for the functional biomaterial in the present embodiment. FIG. 4 is an explanatory diagram of the generation and molding steps in the functional biomaterial manufacturing procedure in this embodiment. FIG. 4 is an explanatory diagram of a purification step in the production of functional biosubstance material in this embodiment.

The light source unit, measuring device, near-infrared microscope device, optical detection method, imaging method, calculation method, state management method, and manufacturing method in this embodiment will be described below with reference to the drawings. First, a table of contents relating to the contents of the present embodiment is shown so as to facilitate understanding of the entire description.
Chapter 1 Basic configuration of the measurement apparatus showing this embodiment Chapter 2 Effect of partial coherence on optical noise Section 2.1 Outline of explanation procedure of this embodiment for optical noise reduction Section 2.2 White 2.3 Effect of partially coherent light on optical imaging Section 2.4 Partially coherent light for measurement of spectral properties Effect Section 2.5 Mathematical Expression of Example of Effect of Partially Coherent Light on Spectral Characteristics Section 2.6 Effect on Detection/Imaging Using Near Infrared Light and its Wavelength Range Chapter 3 Partial Interference Section 3.1 Basic principle for optical noise reduction Section 3.2 Utilization of emitted light in different directions Section 3.3 Optical property changing member 3 having wavefront splitting function Section 4 Synthesis (mixing) between split wavefronts
Section 3.5 Mathematical expression of light intensity when using partially incoherent light (optical noise reduction effect)
Section 3.6 Structural Ingenuity of Optical Property Changing Member Section 3.7 Comparison with Conventional Technology Using Wavefront Splitting Section 3.8 Optical Property Changing Member Having Optical Waveguide Function Section 3.9 Emission Light from Different Regions synthetic (mixed)
Section 3.10 Application example for synthesis (mixing) of emitted light from different regions Section 3.11 Partial coherence reduction method and application example for electromagnetic waves with longer wavelengths than infrared light Section 3.12 Partial light Brief explanation of coherence control method Chapter 4 Mixing/separation method of coherent light and partially incoherent light Section 4.1 In measurement equipment using both coherent light and partially incoherent light Section 4.2 Method of mixing and separating coherent light and partially incoherent light Chapter 5 Interaction with light inside the measurement object Effects of absorption and multiple scattering Section 5.2 Relationship between factors of scattering/absorption and scattering cross sections Section 5.3 Characteristics of scattering cross sections and light scattering Section 5.4 Detection characteristics using backscattered light (reflected light) Section 5.5 Formulation of interactions with electromagnetic waves inside the object to be measured Section 5.6 Effect on measurement results due to differences in partial coherence of irradiated light and its consideration Chapter 6 Occurs in the middle of the optical path Feedback method of wavefront aberration Section 6.1 Principle of generation of wavefront aberration inside target object (transparent parallel plate) Section 6.2 Correction method of wavefront aberration Section 6.3 Common part of wavefront aberration characteristic detection method Section 6.4 Wavefront aberration characteristic detection method using partially incoherent light Section 6.5 Wavefront aberration characteristic detection method using coherent light Section 1 Optical noise reduction method and absorption band wavelength prediction attributed to group vibration in specific functional groups Section 7.2 Mathematical expression for group vibration in functional groups Section 7.4 Simulation method of absorption band wavelength attributed to group vibration Chapter 8 Functional biomaterials Section 8.1 Functional biomaterials Section 8.3 Examples of functional biomaterials exhibiting functions in amino acid sequences and three-dimensional structures Section 8.4 Examples of functional biomaterials exhibiting functions as structures and enzymes in the active region Section 8.5 For production processing Examples of functional biomaterials exhibiting functions in related parts Chapter 9 Genome editing processing using functional biomaterials Section 9.1 Examples of dealing with affected areas related to DNA disorders and current problems 9.2 Section Structure and principle of operation of carrier for intranuclear delivery Section 9.3 Manufacturing method of carrier for intranuclear delivery (suitable for mass production)
Chapter 10 Manufacturing methods and process control of functional biomaterials Section 10.1 Basic procedures for manufacturing methods and process control Section 10.2 Regionally distributed mass production process Section 10.3 Estimation of functional biomaterials Section 10.4 Optical properties of functional biomaterials in this embodiment Section 10.5 Production method of functional biomaterials produced in extracellular environment Chapter 1 Basics of the measuring device showing this embodiment Configuration The basic configuration of the measuring apparatus using the optical detection method and the imaging method in this embodiment will be described with reference to FIGS. 1A to 1C. The basic configuration of this measurement apparatus is composed of a light source section 2 and detection sections 4 and 6 . The light source unit 2 emits irradiation light 12 corresponding to the first light, and irradiates the irradiation light 12 onto an object 10 to be measured or detected (object to be detected).

Here, the subject 10 is not limited to living organisms such as animals, plants, and microorganisms (including bacteria and viruses), but also includes nucleotides (Nucleotides), amino acids/proteins, lipids (including phospholipids), A biological constituent alone such as a carbohydrate may also be used. Alternatively, an organic material such as plastic, or an inorganic material that transmits at least part of the light may be used. Further, the form of the object to be detected 10 is not limited to a solid state, and may be in a liquid or gaseous state. The size of the object to be detected 10 alone can be arbitrarily selected from the maximum size of a meter (human or elephant size) to the minimum size of an atom or molecule.

The second light obtained from the object 10 (that is, the light after the irradiation light 12 has been reflected/transmitted/absorbed/scattered inside or on the surface of the object 10) is projected onto the detection units 4 and 6 as detection light 16. be done. As a result, the optical properties of the object 10 (detection object) are detected or measured.

The optical characteristics of the target object 10 obtained here include the light quantity characteristics after reflection/transmission/absorption/scattering of the target object 10 and their temporal changes, optical phase characteristics, spectral characteristics (wavelength spectrum), imaging (extracted video/image), image analysis results (spatial frequency characteristic analysis results, etc.), and all optical characteristics may be included in detection targets.

Further, based on the results obtained by the detection units 4 and 6, the light emission characteristics of the irradiation light 12 from the light source unit 2 may be controlled via the feedback unit 8. FIG. As a specific example, the control is not limited to constant light emission amount control or temporal change control of the light emission amount of the irradiation light 12, but the phase distribution and light amount distribution of the irradiation light 12 immediately before the target object 10 is irradiated may be controlled. Any other control may be performed.

1A, 1B, and 1C show the characteristics of the measurement apparatus when the irradiation light (first light) 12 applied to the object 10 diverges, is parallel, and converges, respectively. 1A, 1B, and 1C, (a) is for transmitted light detection (including forward scattered light detection), (b) is for reflected light/scattered light detection, and (c) is for light source unit 2. It shows the structure when the detection unit 6 is housed in the measuring device 30 as an integral unit.

In FIGS. 1A(c), 1B(c), and 1C(c), the beam splitter 20 is used to partially cut the optical path between the irradiation light (first light) 12 and the detection light (second light) 16. are common. Thereby, an effect of facilitating miniaturization of the measuring device 30 is produced.

On the other hand, in the structure without the beam splitter 20 of FIGS. 1A(b), 1B(b), and 1C(b), the relative position between the light source unit 2 and the detection unit 6 in the measuring device 30 can be arbitrarily set. becomes. As a result, there is an effect of increasing the flexibility of the measurement environment.

A light source 70 (a specific example will be described later with reference to FIG. 10A) that emits the irradiation light 12 in the light source unit 2 often emits divergent light. 1B and 1C for irradiating the object 10 with parallel light or converged light, it is necessary to mount the collimating lens 26 and the condensing lens 98 in the light source unit 2. FIG. In contrast, the structure in which the diverging light is directly used as shown in FIG. 1A does not require the above-mentioned mounting, and thus has the effect of reducing the price and miniaturizing the entire measuring device 30 .

When the parallel irradiation light 12 is used as shown in FIG. 1B, the degree of freedom of the installation position of the object 10 with respect to the traveling direction of the irradiation light 12 is increased. Therefore, it is suitable for optical characteristic measurement when the object 10 is in a gaseous state or dispersed in a solvent in a liquid state. Therefore, in this embodiment for the manufacturing method and the condition control method, parallel irradiation light 12 may be used as shown in FIG. 1B.

In this case, the object 10 dispersed in a gaseous or liquid medium is enclosed in the measurement sample column 34 in the transparent glass container 36 . Here, the measurement sample column 34 is provided with an injection port 42 with a lid 46 and an extraction port 44 with a lid 46 so that the object 10 can be easily exchanged.

Furthermore, inside the transparent glass container 36, a reference sample column 32 partitioned by the wall 9 is also installed. The inlet 42 and the outlet 44 of the reference sample column 32 are similarly provided with lids 46 so that the inside of the reference sample column 32 can be evacuated. Alternatively, the inside of the reference sample column 32 may be filled with the liquid solvent alone before the object 10 is dispersed.

The transparent glass container 36 is movable with respect to the measuring device 30 . In particular, the moving direction 38 of the glass container is in a non-parallel relationship (or may be orthogonal) to the traveling direction of the irradiation light 12 . Therefore, the optical characteristics in the reference sample column 32 may be measured first, then the optical characteristics in the measurement sample column 34 may be measured, and the results of both may be compared. By comparing the two in this way, there is an effect that the detection accuracy of the optical characteristics obtained as a result of measurement/detection is increased. As a method of comparing both, a difference between measurement data after arithmetic processing (which may include normalization) may be obtained, or division processing (difference processing on a logarithm) between the two may be performed. The measuring device 30 has its own optical transfer characteristics (functions), and the optical transfer characteristics described above are included in the optical characteristics obtained from the measurement sample column 34 . On the other hand, when the optical characteristics of the measurement sample column 34 and the reference sample column 32 are divided (difference processing on a logarithm), the optical transmission characteristics in the measurement device 30 are removed, and the object 10 alone has the effect of obtaining the optical characteristics of

The illuminating light (first light) 12 is scattered/absorbed by the target substance 10 in a vaporized (or dispersed in a liquid medium) molecular state. In FIG. 1B(b), the side scattered light at this time is detected as detection light (second light) 16 . On the other hand, in FIG. 1B(a), the transmitted light amount loss due to all-round scattering and absorption is detected. Also, when a mirror surface 48 is formed on the bottom surface of the transparent glass container 36 as shown in FIG. 1B(c), the transmitted light amount loss is detected in the same manner as in FIG. 1B(a). On the other hand, if the mirror surface 48 is not formed, the backward scattered light is detected as the detection light (second light) 16 . By using the parallel irradiation light 12 in this manner, it is possible to detect various types of forward/backward/sideward scattered light, which has the effect of improving the detection accuracy.

As shown in FIG. 1C, when the object 10 is irradiated with the converged irradiation light 12, the light is condensed at points α, β, and γ inside the object 10 (the method of convergence will be described later in Chapter 7). As a result, there is an effect that optical characteristics can be measured/detected limited to a specific location inside the object 10 . Forward scattered light can be measured/detected in FIG. 1C(a), side scattered light in FIG. 1C(b) and backscattered light in FIG. 1C(c).

Chapter 2: Partial Coherence affecting Optical Noise
It will be explained in Section 2 below that even white light has the property of partial coherence and can generate optical noise.

Section 2.1 Description of this embodiment for optical noise reduction Outline of procedure By reducing the optical noise mixed in the measurement device 30 shown in FIGS. 1A to 1C, the detection accuracy of optical detection or optical imaging improve or increase reliability. As a method for reducing the optical noise, in this embodiment, at least the optical characteristics of either the irradiation light (first light) 12 or the detection light (second light) 16 are changed. As the optical properties to be changed,
(1) Reduces optical noise related to partial coherence (using optical property-altering members); (2) Only either wavefront aberration or partial heading change feedback due to the object 10. or a combination of both.

Regarding the above (2), the effect on the irradiation light 12 or the detection light 16 is measured in at least a part of the detection section 4 or 6 and the optical characteristics of the irradiation light 12 are changed via the feedback section 8 . Similarly, the insides of the detection units 4 and 6 may be controlled to change the optical characteristics of the detection light 16 (details will be described later in Chapter 6).

In Chapter 2, the principle of how partially coherent light generates optical noise will be described in Chapter 2, prior to describing a specific embodiment for (1) in Chapter 3.

In order to verify the reliability and credibility of knowledge obtained by optical detection or optical imaging, computer simulation using quantum chemical calculation software may be used together in this embodiment. The method of this embodiment for theoretically calculating the characteristics of the n-th overtone and combination tones limited to specific functional groups in the polymer will be described later in Chapter 7.

Section 2.2 Occasion of Partially Coherent White Light and Definition of Technical Terms
It is known that monochromatic laser light generated from a semiconductor laser element (Laser Diode Tip) or the like has cohetency. Correspondingly, white light emitted from a small light source 70, such as a Tungsten Halogen Lamp, is also partially coherent.

For example, as shown in FIG. 2A, take the case where the light (white light) emitted from the α point on the surface of the tungsten filament 50 (white light) and the light (white light) emitted from the β point are simultaneously observed at the γ point. . If the "Amplitude Correlation" between the two is very strong, or if the "Phase Shift Value" between the two is constant over time, the two lights are coherent. (Coherent Light). In this case, "interference" occurs between the two lights at the γ point.

Conversely, when there is no "amplitude correlation" between the two, or when the "phase difference changes completely irrelevantly" between the two, it is called incoherent light. In this case, no "interference" occurs between the two lights at the γ point. The light intensity observed at the γ point is obtained by simply adding the light intensity obtained independently from the α point and the light intensity obtained independently from the β point.

By the way, most of the light other than the steadily emitted laser light is in an intermediate state between the coherence state (Coherence) and the non-coherence state (Incoherence). This state of neither perfect coherence nor perfect non-coherence is generally called partial coherence. Light in such a state is called partially coherent light.

When this partially coherent light is scattered, reflected, or transmitted by an object to be detected, partial "interference" occurs in the subsequent optical path, causing speckle noise. Therefore, when using light to obtain a signal from an object to be detected (detecting a predetermined optical characteristic at a specific site within the object to be detected) or to obtain image information from the object to be detected, the "interference phenomenon of light" occurs. The resulting speckle noise degrades the quality and characteristics of detected signals and images.

In the present embodiment, as will be described later, "(A) mutual decoupling between different emission directions of light, between different light emitting regions, between different divided wavefronts, and between different divided amplitudes", " (B) We propose a unique method of synthesizing (mixing) multiple lights after decoherence. Therefore, in the explanation of this embodiment described later, the light used for signal detection and imaging is "partially decohered (not completely decohered, but decohered to some extent). The term "partial incoherence" is specially used in the sense that This clarifies the difference between the present embodiment and the prior art.

In the optical operation corresponding to (B) above, the operation of combining partial incoherent lights is expressed as "mix" in the description of this embodiment. The light obtained by the above mixing is called "mixed light".

On the other hand, in the description of this embodiment, "combine" is used to describe the operation of combining light that has passed through different optical paths regardless of the state of coherence. In other words, the light beams to be combined may have coherence (including partial coherence) or non-coherence (including partial non-coherence).

Depending on the optical manipulation method that combines broad-wavelength light that has passed through different optical paths, it is possible to have "partial incoherence in short wavelength components" and "partial coherence in long wavelength components". mixed characteristics may be exhibited. In this case as well, the combination operation is called "combining", and the light obtained as a result of combination is expressed as "combined light" in the description of this embodiment.

Further, the lights obtained by the synthesis (or mixing) described above may have the same or similar traveling directions or electric field vibration directions. As a result, the light before combining (or mixing), which passes through different optical paths, at least partially passes through the same optical path after combining (or after mixing).

First of all, the basic principle that causes the "coherence of light" explained so far will be explained. Here, for the sake of ease of explanation, the idea of "indefiniteness of the light emission time within the frequency width Δν (unique definition not possible within the time width Δt)" is used. However, as a general method for explaining the coherence of light, much of the explanation is given in the second half of this section (Section 2.2).

An optical narrowband bandpass filter that allows white light emitted from point α on the surface of tungsten filament 50 in FIG. 2A to pass only light within the wavelength range λ ₀ −Δλ/2 to λ ₀ +Δλ/2. Consider the case where the light reaches a point γ at a distance R after passing through (wavelength selection filter) 52 . At this time, the frequency (frequency) range of light that can pass through the narrow bandpass filter (wavelength selection filter) 52 is from ν ₀ +Δν/2 to ν ₀ -Δν/2.

The distance from this γ point to the β point on the surface of the tungsten filament 50 is defined as R+δ. Let C be the propagation speed of light in vacuum. The time when the lights arriving at the γ point at the same time depart from the β point is Δt=δ/C than the time when they depart from the α point (B・1)
It is natural to think that it is the fastest.

However, the following uncertainty principle also exists for light.
1 ≧ Δt・Δν …(B・2)
That is, it is difficult to identify the detailed temporal context between a plurality of optical phenomena (e.g., photon emission at a plurality of different positions) that occur within the time range Δt defined by the above formula (B.2). is interpreted as In other words, light emitted from a plurality of different positions occurring within the above time range Δt is regarded as "light emitted substantially at the same time".

By the way, between the central wavelength λ ₀ of light that can pass through the optical narrow-band bandpass filter (wavelength selection filter) 52, the wavelength range Δλ, the central frequency (frequency) ν ₀ and the range Δν,
(λ ₀ - Δλ/2) × (ν ₀ + Δν/2) = λ ₀ × ν ₀ = C (B・3)
Since the relationship holds, if we regard Δλ×Δν/4≈0 in the formula (B.3), then Δν ≈ Δλ×C/λ ₀ ² (B.4)
relationship is derived. Substituting equations (B.1) and (B.4) into equation (B.2) yields δ ≤ λ ₀ ² / Δλ (B.5)
is obtained. That is, in FIG. 2A, within a range in which the difference δ of the optical path length satisfies the formula (B.5), all the lights emitted from different positions (α point and β point) on the surface of the tungsten filament 50 are emitted almost simultaneously. It shall be construed as In particular, the length that satisfies the right side of equation (B.5) is called a coherence length. That is, the coherence length l _CL is
l _CL ≡ λ ₀ ² / Δλ … (B・6)
is expressed by the relational expression of

Therefore, the light beams within the range satisfying the above formula (B.5) have a relationship of partially coherent light beams. Also, the relationship between lights that does not satisfy the formula (B.5) but has a relationship close to the formula (B.5) is called low coherence. In particular, in the description of this embodiment (not used as a general term, but for the purpose of highlighting its uniqueness), the light controlled (operated) in a situation that deviates from the above formula (B 5) is described above. Specifically referred to as partially decoherent light.

In the example shown in FIG. 2A, an optical narrowband bandpass filter (wavelength selective filter) 52 was used to set the wavelength range Δλ in equation (B·6). However, it is not limited to this, and the wavelength range Δλ (wavelength resolution) that can be separated and detected within the detection unit 6 (FIGS. 1A to 1C) in this embodiment may be applied to the above equation (B.6).

For example, the above formula (B.6) can be used with Δλ being the wavelength range detectable by one detection cell in the one-dimensional line sensor 132 installed in the spectroscope 22 of FIG. 14E.

On the other hand, the value of the wavelength resolution (half width) of the spectroscope 22 itself in FIG. 14E may be applied to the above equation (B.6) as the wavelength range Δλ. Here, the wavelength resolution (half width) of the spectroscope 22 shown as an example in FIG. 14E is greatly affected by the width (or pinhole width) W of the slit 130 .

The diffraction angle θ when light with a wavelength λ near the center wavelength λ ₀ is incident on the blazed diffraction grating 126 is
θ ≒ χ・λ …(B・7)
is approximated as Here, χ represents the diffraction angle coefficient for the incident wavelength of the diffraction grating. Replacing λ with Δλ in the equation (B·7) yields the following equation.
Δθ ≒χ・Δλ …(B・8)
Further, when the distance between the condenser lens 134-2 and the one-dimensional line sensor 132 is represented by SL, the positional deviation amount ΔY on the one-dimensional line sensor 132 corresponding to Δθ is ΔY = SL Δθ ≈ SL χ Δλ ( B.9)
is obtained.

On the other hand, if the imaging magnification (horizontal magnification) of the condenser lens 134-2 is M, the width (or pinhole width) W of the slit 130 is ΔY = M·W/2 (B·10)
Since there is a relationship of (B 9) and (B 10),
Δλ ≒ M・W / (2SL・χ) …(B・11)
relationship is established. Substituting this equation (B.11) into the above equation (B.6) yields l _CL = 2SL.χ.λ ₀ ² /(M.W) (B.12)
is obtained.

Therefore, in this embodiment, various photodetectors (or the Speckle noise of the irradiation light (first light) 12 or the detection light (second light) 16 according to the characteristics of the optical element such as the optical narrow-band bandpass filter 10 (wavelength selection filter) The optical system structure in the light source section 2 or the detection section 6 may be devised so as to reduce the optical noise component (.delta.>l _CL ).

In the above, the optical system in the light source unit 2 or A specific embodiment has been described in which optical noise components such as speckle noise are reduced by devising the optical system in the detection unit 6 (where δ>l _CL ). However, not limited to this, in this embodiment, the characteristics (wavelength separation performance/resolution, etc.) of the monitor camera 24 shown in FIG. Ingenuity may be made to reduce optical noise components such as speckle noise (δ>l _CL ) in accordance with the optical characteristics of the optical element.

So far, a relatively narrow wavelength range Δλ has been described as an example. However, it is not limited to this, and the equations (B.5), (B.6), and (B.12) can be applied even when the wavelength range .DELTA..lambda. is very wide, such as "white light."

For example, if the wavelength range Δλ of white light emitted from a tungsten/halogen lamp is roughly estimated to be about 2 μm (0.5 μm to 2.5 μm) and the central wavelength λ ₀ is about 1.2 μm, then (B 6 ), the coherence length l _CL is 0.72 μm. That is, even among white lights emitted from a plurality of different light emitting points, interference occurs between the white lights whose optical path length difference δ to the measurement point (γ point) is 0.72 μm or less (a state of partial coherence occurs). )
The above phenomenon also occurs with white light emitted from any light source, not just the tungsten filament 50 as the light source. For example, for a light source that simultaneously emits white light from a wide area (that is, even if the light emitting region of the light emitting source is very wide), the amount of white light emitted from a minute light emitting region that satisfies the formula (B.5) is The same phenomenon (interference) occurs between them.

Instead of explaining the coherence length using the concept of "uncertainty of the occurrence (light emission) time within the time range Δt" as described above, in many cases, between different wave trains, is often described as the distance at which interference can occur.

For example, consider a case where white light emitted from a light emitting point propagates in the same direction (for example, z-axis direction) in space. It is assumed that the phases of all wavelength lights contained in the white light (the position in the z-axis direction where the electric field amplitude value reaches the "maximum value") match at t=0 and z=0. The electric field amplitude distribution region at all wavelengths localized within the range of the coherence length in this vicinity is defined as "wave train".

Citing the calculation example of the coherence length described above, when the wavelength range included in white light is 0.5 μm to 2.5 μm, the range in which one wave train is defined is −0.36 μm≦z≦0. 0.36 μm (=0.72 μm÷2). Since this 0.36 μm is shorter than the shortest wavelength of 0.5 μm, the phases of all wavelengths are substantially aligned within the same wave chain.

Therefore, when two wave trains adjacent to each other in the z-axis direction partially overlap, interference occurs in light of all wavelengths within the overlap region.

Section 2.3 Effects of Partially Coherent Light on Optical Imaging Within the range that satisfies equation (B.5), different positions (α point and β points) are all interpreted as being “emitted at approximately the same time”. Therefore, after passing through the optical narrow-band bandpass filter 10, the phases of the electric field amplitudes 54 (positions of ridges and troughs in the light traveling direction) are all considered to match, as shown in FIG. 2B.

FIG. 3 shows an example of an interference phenomenon that occurs when partially coherent light having this characteristic passes through "a light transmitting object 56 having a fine uneven structure on one side". In FIG. 3A, since there is no uneven structure on the surface of the light transmitting object 56, there is no canceling effect (based on interference caused by phase shift) between adjacent partially coherent beams 60. In FIG.

On the other hand, in FIG. 3B, the surface of the light transmitting object 56 has an uneven structure with steps d. Assuming that the refractive index of the light transmitting object 56 is n, the optical path length after passing through this interior by the mechanical distance d is "nd". On the other hand, the optical path length after passing the distance d in vacuum is d. Therefore, the optical path length between the light that has passed through the upper path (thickness d in vacuum) of FIG. The difference δ is δ = (n-1)d …(B・13)
becomes. Here, in the case of δ=λ ₀ /2, interference (cancellation) occurs between the partially coherent light beams that have passed through the upper and lower paths in FIG. . When this amount of transmitted light is detected by the detector 6, the difference (effect of interference) between FIGS. 3A and 3B appears as optical noise.

FIG. 3 shows an example of the influence of a fine concave-convex structure on optical imaging when light is transmitted in the middle of the optical path. interference) occurs.

In the explanation using FIG. 2A, the coherence length was explained as the range in which interference occurs between the “irradiation light 12 emitted (emitted) from the light source” (FIGS. 1A to 1C). However, it is not limited to this, and "light reflected or scattered (including transmitted) within a minute region within the object 10 (FIGS. 1A to 1C) to be observed, measured, and detected (partially coherent light)" Similar interference effects occur between

In FIG. 4, the illumination light 12 travels from right to left, and the light backscattered by part of the minute light scattering bodies 66 in the object 10 is used as the detection light 16 (see FIGS. 1A to 1C). Here is an example. Let us consider a case where the backscattered light at the points α and β in the minute light scatterer 66 is detected (measured) at the point γ. If the difference δ between the optical path length from the β point to the γ point and the optical path length from the α point to the γ point satisfies the relationship of the formula (B 5), the optical interference from the α point and the β point at the γ point (optical Interference) occurs.

Furthermore, if the surface of the target object 10 has a fine uneven structure, an interference phenomenon occurs in the same manner as described with reference to FIG. As a result, optical imaging is greatly affected. In addition to this, even if the refractive index inside the object 10 is non-uniform (has a refractive index distribution), an interference phenomenon (unnecessary density of the detected light amount in the detection direction) similarly occurs, resulting in optical imaging. have a significant negative impact on

Section 2.4 Effect of partially coherent light on measurement of spectral characteristics Section 2.3 explained why the effect degrades optical imaging. In addition to this, the reason why the detection signal obtained after photoelectric conversion and the measurement result of the spectral characteristics (light absorption characteristics, etc.) of the target object 10 itself are greatly adversely affected will also be explained.

FIG. 5 shows a light-transmitting object 58 having a fine concave-convex structure (a step of height d) on one side as an example of the structure of the object 10 shown in FIGS. 1A/B/C(a). As the incident light having partial coherence passing therethrough, the case of long wavelength light 68 in FIG. 5(a) and the case of short wavelength light 62 in FIG. 5(b) are considered.

Between the light passing through the upper part of the step d and the light passing through the lower part of the step d, a difference δ in optical path length corresponding to the formula (B.13) occurs. In the state of FIG. 5B, which satisfies the relationship "δ≈λ" with respect to the difference δ in optical path length and the wavelength λ of the incident light in vacuum, the light passing through the step d and the light passing through the lower step d phase match. Therefore, in this state, there is little decrease in the amount of transmitted light.

On the other hand, in the state of FIG. 5(a), when the relationship of "δ≈λ/2" is established, "canceling phenomenon of the amount of straight light due to interference" occurs between the light passing through the upper part of the step d and the light passing through the lower part of the step d. As a result, a reduction in the amount of straight light occurs.

If "the amount of straight light changes according to the wavelength of the incident light" in this way, a large error occurs in the measurement result of the spectral characteristics (light absorption characteristics, etc.) of the object 10 itself to be measured.

The characteristics of the light-transmitting object 58 in FIG. 5 have been described using an example having only a fine uneven structure on one surface. However, the optical interference phenomenon is not limited to this, and occurs inside the light transmissive object 58 as well. That is, in inorganic dielectrics, organic substances (polymerized polymers), and living organisms, which are objects that allow light to pass through with a predetermined thickness, light scattering occurs in minute regions. When multiple scattered lights with different traveling directions after being emitted from an object match, optical interference similar to that shown in FIG. 5 occurs.

FIG. 23A shows experimental results of measuring the wavelength change of the transmittance of a polyethylene sheet having a thickness of 30 μm and having both flat surfaces (detailed experimental conditions will be described later). In FIG. 23A(a), near-infrared light with high partial coherence is used for measurement, and near-infrared light with high partial incoherence is measured in FIG. 23A(c). 23A(a) to FIG. 23A(c), the transmittance at the wavelength of 1.360 μm increases from 85.3 to 85.80% and 87.2%. It is considered that the above-mentioned change in the same sample (object 10) and the same wavelength is caused by the partial incoherence difference of the near-infrared light used for the measurement.

That is, when light passes through the polyethylene sheet, multiple scattered light generated inside the polyethylene sheet also passes behind the polyethylene sheet. If the partial coherence of the detection light beams 16 after passing through the polyethylene sheet is high, the detection light beams 16 traveling in the same direction interfere with each other, reducing the intensity of the straight traveling light. On the other hand, if the partial incoherence of the detected light beams 16 is high, it is considered that the intensity of the straight traveling light is less reduced due to interference between the detected light beams 16 traveling in the same direction.

For ease of explanation, the example of FIG. 5 in which parallel light passes through the object 10 has been used to explain the effect on the spectral characteristic measurement results. However, the phenomenon described in section 2.4 or 2.3 also occurs in all the structures shown in FIGS. 1A to 1C as the measurement apparatus of this embodiment.

Furthermore, as described in Section 2.3 with reference to FIG. 4, the above phenomenon also occurs when spectral characteristics and light absorption characteristics are measured using reflected light from minute light scattering bodies 66 . Therefore, even in the near-infrared microscope apparatus for measuring minute light scattering bodies 66, in this embodiment, as shown in FIG. may be performed.

In the microscopic apparatus according to the present embodiment shown in FIG. 7, the illumination light (first light) 12 emitted from the light source 70 is converted into parallel light by the collimate lens 26, and then the inside of the object 10 is irradiated by the objective lens 25. Condensed at a specific location. The light reflected at this specific location forms an image on the spectroscope 22 and the monitor camera 24 as detection light (second light) 16 .

As a specific optical path, the detection light (second light) 16 obtained from the inside of the object 10 is converted into parallel light by the objective lens 25, and the light path of the irradiation light (first light) 12 is changed by the beam splitter 20. separated. Then, the beams are separated in different traveling directions by the beam splitter 18 in the detection unit 6 . The separated detection light (second light) 16 is focused on the monitor camera 24 and the spectroscope 22 (more specifically, on the pinhole or slit 130 shown in FIG. 14E) by the detection lenses 28-1 and 28-2, respectively. be done. Object lens 25 and detection lens 28-1 are provided between a specific location inside object 10 to be detected or measured by this microscope and the detection position (imaging surface, pinhole or slit 130) of spectroscope 22 and monitor camera 24. /2 forms an imaging optical system. As a result, it is possible to extract only characteristic signals at predetermined positions in the depth direction inside the object 10 .

In the microscopic apparatus of this embodiment, an optical noise reduction element or partial coherence reduction element 64 (detailed structure and operation will be described later in Chapter 3) may be inserted in the optical path. Thereby, the partial incoherence between the irradiation light (first light) and the detection light (second light) 16 is improved, and optical noise due to light interference is reduced.

Further, near-infrared light within the wavelength range defined in Section 2.5 may be used as the light used in the microscope. The microscopic device using the near-infrared light is particularly referred to as a "near-infrared microscopic device" in this embodiment.

Section 2.5 Mathematical Expression of Examples of Effect of Partially Coherent Light on Spectral Characteristics If partially coherent light is used to measure the spectral characteristics (absorbance characteristics, etc.) Section 2.4 explained qualitatively that the detection signal characteristics are degraded by the effect of the resulting speckle noise. Section 2.5 provides a quantitative (mathematical) explanation using a specific example model.

Tungsten-halogen lamps and xenon lamps are known as panchromatic light sources from the visible region to the near-infrared region (simultaneously emitting light of many different wavelengths over a wide panchromatic wavelength range). In these structures, a halogen-based gas (iodine or bromine compound) or xenon gas is enclosed around a tungsten filament. From an optical point of view (in terms of precision on the order of the wavelength of light), the thickness of the quartz glass vessel that encloses these gases is not uniform, and the thickness varies depending on the location. Therefore, in the course of the panchromatic light generated inside the tube passing through the tube, light interference occurs due to the uneven thickness of the tube.

This situation model is shown in FIG. It is assumed that divergent light emitted from the vicinity of the tungsten filament 50 of the light source 70 is collimated by the collimating lens 26 with the focal length F after passing through the tube 67 . Here, the radius of the opening (Pupil Area) of the collimating lens 26 is normalized to "1". The angle between the optical axis of the collimating lens 26 and the direction of travel of light generated from a point α in the vicinity of the tungsten filament 50 and passing through a point β on the surface of the tube is defined as η, and this light is collimated. Let r be the radius of the position passing through the aperture of lens 26 . Next, let n be the refractive index inside the tube (quartz glass) 67 of the tungsten/halogen lamp, and T be its thickness.

When the angle η is sufficiently small, the relationship between the angle ρ of the light traveling direction inside the tube (quartz glass) 67 of the tungsten/halogen lamp and the angle ρ is given by Snell's law as follows: ρ ≈ η/n (B ·14)
, the mechanical distance τ when passing through the bulb (quartz glass) 67 of the tungsten/halogen lamp is conveniently approximated as follows when the angle η is sufficiently small.
τ = T / cosρ ≒ T … (B・15)
Consider the case where the thickness of the tube (quartz glass) 67 of the tungsten/halogen lamp at the γ point on the tube surface is thinner than the surroundings by d. It is also assumed that the angle η is generated from the point α, passes through the point γ, exits the tube 67, and travels toward the collimating lens 26. In FIG. Since light passing through the β and γ points travels in the same direction, interference occurs due to the property of partial coherence.

The difference .delta. in the optical path length between the lights passing through the .beta. point and the .gamma. point is the same as the formula (B.13) when the approximation of the formula (B.15) is used. Then, the synthetic wave ψ after passing through the β point or γ point and passing through the tube (quartz glass) 67 of the tungsten/halogen lamp is given by ψ(r)= ^eikz +Ae ^{ik[z+(n−1)d]}
= ^{eik[z+(n-1)d/2]} {(1-A)e- ^ik(n-1)d/2 +2Acos[k(n-1)d/2]}
= ^{eik[z+(n-1)d/2]}
× { (1+A) cos[k(n-1)d/2]- i(1-A) sin[k(n-1)d/2) }…(B・16)
becomes. Here, the amplitude of light passing through the γ point is set to "1", and the amplitude of light passing through the β point is set to "A".

The distribution of the thickness deviation of the tube (quartz glass) 67 of the tungsten/halogen lamp is uneven, but the calculation model is simplified and the calculation is performed by assuming that "the thickness deviation d of the tube is uniformly distributed". proceed. Since the area of the radius r and the width dr on the aperture surface of the collimating lens 26 is 2πrdr, all the synthetic waves Ψ passing through the aperture of the collimating lens 26 are

becomes. Therefore, when the light intensity Ic of this composite wave Ψ is normalized by the maximum value, from k=2π/λ,

is obtained. The second term of the formula (B 18) states that “when light interference occurs in part during the measurement of spectral characteristics using partially coherent light, the amount of detected light changes cosinusoidally depending on the measurement wavelength. It means "to do".

A phenomenon similar to the above occurs when interference between partially coherent light beams occurs due to any cause other than uneven thickness of the bulb (quartz glass) 67 of the tungsten/halogen lamp. An optical path difference δ occurs for some reason in the light source unit 2 or the detection unit 6 (FIGS. 1A to 1C), and the composite wave ψ of different coherent lights traveling in the same direction (when the vibration directions are also the same) is ( B 16) ψ = e ^ikz + Ae ^{ik (z + δ)}
= eik ^[z+δ/2] {(1+A) cos(kδ/2) - i(1-A)sin(kδ/2)}…(B・19)
^{However , here | ψ |}
and

, the formula (B・19) is ψ = |ψ| ^{eik(z+δ/2+σ)} …(B・22)
and can be transformed. The formula (B.22) means that "a combined wave ψ obtained by synthesizing two plane waves having different phases becomes one plane wave having a phase of δ/2+σ". Furthermore, for the same reason, one plane wave can be obtained by synthesizing three or more plane waves having partial coherence.

Let _Ψ0 be the composite wave of all the light passing through the collimating lens 26 when there is no factor causing light interference (for example, when the tube 67 does not exist), and a new composite wave generated by the cause causing light interference. be _Ψ1 . When the respective composite waves Ψ ₀ and Ψ ₁ have partial coherence, from Ψ ₀ + Ψ ₁ further combining the two, the "detected light amount in the detection wavelength direction change” occurs.

Next, as a calculation model different from the above, let us consider the characteristics of the case where "the wall surface of the tube 67 of the tungsten/halogen lamp is regarded as a flat parallel plate through which divergent light directed toward the collimator lens 26 passes". Here, for the sake of simplification of calculation, it is assumed that "the amplitude distribution of the light passing through the collimating lens 26 is constant everywhere".

The NA (Numerical Aperture) value of the collimating lens 26 is represented by NA. Then from Figure 6,
r = η / NA … (B・23)
becomes. Although the formula (B.14) approximating Snell's law is used here, the following approximation formula with slightly improved precision is used for the formula (B.15).

The second term on the right side of equation (B.24) corresponds to "d" in equation (B.13) (or equation (B.16)).

As in the previous calculation model, the area of the radius r and the width dr on the aperture surface of the collimator lens 26 is 2πrdr.

is given by If v≡r2 is set here, from rdr=( ^1/2 )dv, the integration result of the formula (B·25) becomes the following formula.

Here, ψ in formula (B 16) is replaced with ψ, and "A = -1",
d = -T・NA ² /(2n ² ) …(B・27)
is proportional to the formula (B.26). Therefore, the light intensity Ic after normalization with respect to the composite wave Ψ is

is obtained. According to the second term on the right side of equation (B.28), the detected intensity changes periodically according to changes in the measurement wavelength λ. Also, the period of change in the detected intensity corresponding to the measurement wavelength λ changes depending on the thickness of the parallel plate (tube 67) or the NA value of the collimating lens 26. FIG.

After passing through the collimator lens 26 in FIG. 6, the parallel light passes through the target object 10 and enters the detection unit 6 as shown in FIG. 1B(a), for example. In the detection unit 6, for example, as shown in FIG. 14E, a signal including the characteristics of the formula (B.28) is detected or measured using the spectroscope 22 after being collected by the detection lens 28-2. However, the signal including the characteristic of the formula (B.28) can be detected or measured using any of the optical systems shown in FIGS. 1A to 1C. In other words, "In the middle of the optical path from the light source 70 to the photodetector 80 (FIG. 8B), if a transparent parallel plate (wall of a tube, etc.) is placed in the diverging or converging optical path of the partially coherent light, the light Equation (B.28) shows that, in principle, optical noise whose intensity changes periodically according to the change in wavelength λ can be generated due to the influence of interference.

In the formula (B.28), the amount of change in the periodically occurring optical noise is very large. Substituting the equation (B.27) into the equation (B.13), the maximum value δmax of the optical path length difference is δmax = -(n-1)TNA ² /(2n ² ) (B.29)
is given by In equation (B 29), when the thickness T of the parallel plate (such as the wall of the tube) increases,
δmax > _lCL (the calculated value of the actual coherence length _lCL will be described later in Section 2.7). In this state, no optical interference occurs inside the spectroscope 22 between light passing through the center and peripheral portions of the aperture of the collimating lens 26 .

The approximation of equation (B.24) holds only in the range where the value of ρ is sufficiently small. Furthermore, the uniformity of the thickness of the bulb 67 of the quartz glass tungsten/halogen lamp is not so high, and large thickness unevenness is expected. Also, the amplitude distribution at the opening of the collimating lens 26 is largely out of uniformity. As a result of these, an amount of optical noise that is much smaller than that of the formula (B.28) is actually observed.

In panchromatic light sources such as tungsten-halogen lamps and xenon lamps, differences in optical path length can occur within a tube placed around a tungsten filament. As a result, the panchromatic light emitted from the light source (including the tube) often contains an optical noise component as shown in equation (B.28).

Practically measured amounts of the optical noise component in the emitted light from the panchromatic light source are not as large as given by equation (B.28). Due to the various factors mentioned above, it is considered that the amount of the optical noise component is reduced according to the formula (B.28).

When the emitted light from multiple types of tungsten/halogen lamp light sources (including tubes) was actually examined, when the DC component (coefficient of the first term on the right side of equation (B 28)) was set to "1", was about 0.1 to 1.0%.

In comparison with the above, the amount of optical noise components allowed for a panchromatic light source will be described. When straight parallel light passes through a polyethylene film with a thickness of 30 µm, as shown in _FIG . (Details will be described later in Chapter 5, etc.).

Therefore, the optical noise component amount allowed for a panchromatic light source must be 0.5% or less on average (preferably 0.1% or less on average) at worst. There is also a need to measure samples (films) thinner than 30 μm, not limited to the experimental conditions of FIG. 23A. Therefore, the average amount of optical noise components must be 0.05% or less or 0.02% or less. Here, the optical noise component amount mentioned above is the optical noise component ( (equivalent to the coefficient value).

For the optical noise component of about 0.1 to 1.0% originally included in the panchromatic (non-monochromatic) light source light (due to the influence of the tube bulb, etc.), according to this embodiment described in Chapter 3, It can be reduced to an average of 0.5% or less (or an average of 0.1% or less, preferably an average of 0.05% or less or 0.02% or less). On the other hand, as explained in "Problems to be Solved by the Invention", the prior art such as Patent Document 1 has a limit to optical noise reduction, and the average is 0.5% or less (or average 0.1% or less, preferably It was difficult to reduce the optical noise to an average of 0.05% or less or an average of 0.02% or less. As shown in FIG. 9, the embodiment examples described later in Chapter 3 comprehensively present all methods for effectively reducing the optical noise generated by the influence of optical interference.

Therefore, as a result of applying some optical noise reduction processing to the illumination light 12 (or detection light 16) obtained from a non-monochromatic light source including a tube inside the light source, the illumination light 12 (or detection light 16) is When the amount of optical noise components achieves an average of 0.5% or less (or an average of 0.1% or less, preferably an average of 0.05% or less or an average of 0.02% or less), all (described in Chapter 3) ) can be considered to have implemented any of the embodiments or combinations thereof.

Section 2.6 Influence on detection/imaging using near-infrared light and its wavelength range ) and light scattering properties appear as relatively large changes. Therefore, the influence of optical noise does not pose much of a problem for signals obtained in the visible range and the mid/far infrared range. However, in the natural world, there are few substances that are transparent to visible light, and the types of measurement objects that can be measured from the surface to the inside with visible light are limited. In addition, since water molecules absorb mid-infrared light and far-infrared light well, mid-infrared light and far-infrared light are used to measure the internal characteristics of even slightly damp measurement targets and measurement targets with wet surfaces. hard to do.

In contrast, near-infrared light with a wavelength range of 0.7 to 2.5 μm has excellent transmission characteristics for dielectrics, organic substances, and living organisms. Therefore, the use of near-infrared light is suitable for measuring the internal characteristics of the measurement object 10 made of these substances. In particular, near-infrared light is called the “window of life” because of its excellent light transmission in the living body.

f-MRI (Functional Magnetic Resonance Imaging) is often used for visualization (imaging) of an active state inside a living body. Especially when dealing with imaging, Pulse Fourier Transform Spectroscope is often used for speeding up the processing speed. However, since the excitation pulse width (Pulse Width of Magnetical Excitation) in this method is on the order of microseconds, there is a drawback that changes faster than that cannot be detected.

On the other hand, in the activity inside the living body (biological reaction, biochemical reaction, or catalytic reaction), the reaction is often completed at a high speed of microseconds or less. Therefore, the above-mentioned f-MRI (or NRI) cannot detect activities occurring inside the body at high speed. On the other hand, if a high-speed photodetector (or imaging device) is used, near-infrared light can be used to detect high-speed changes inside the living body. Therefore, near-infrared light is suitable for detecting high-speed (microsecond or less) changes (activities) inside the living body.

However, as the near-infrared light transmission characteristics for dielectrics, organic substances, and living organisms are good, the absorption and scattering of near-infrared light in these substances is small. Therefore, the amount of change in the signal obtained by the near-infrared light from the specific region inside the object 10 to be measured is very small.

As a specific example, the experimental data in FIG. 23A shows that the light transmittance between the measured minimum value at a wavelength of 1.213 μm and the interpolated value (at the same wavelength position) estimated from the envelope connecting its periphery difference is as small as "0.5%".

Since the amount of signal change using near-infrared light is very small, it is necessary to reduce optical noise and obtain a sufficient S/N ratio (Signal to Noise Ratio). Therefore, the optical noise reduction method using this embodiment is particularly important when detecting or measuring a characteristic state or a change thereof in a specific region inside the object 10 using near-infrared light.

Especially when near-infrared light is used, the imaging described in Section 2.3, the signal detection (after photoelectric conversion) and spectral characteristics (for example, absorption characteristics and light scattering characteristics) described in Section 2.4 Optical noise reduction technology is important in the measurement of optical dependence).

However, the optical noise reduction method described in this embodiment is not unsuitable for detection signals obtained using the visible range and the mid/far infrared range. Applying the optical noise reduction method, which will be described later in Chapter 3 onwards, to the detection signals obtained using the visible region and the mid/far infrared region also reduces the amount of noise and further improves the S/N ratio.

In addition to the method of the present embodiment for optical noise reduction, which will be specifically described in Chapter 3 and later, the following limitation of the usable wavelength range may be used together. As a result, a sufficient S/N ratio can be obtained, and the accuracy and reliability of signal detection and measurement are enhanced.

The combination of the above is particularly effective when using near-infrared light to detect or measure the composition, structure, activity state, or change thereof inside a living body. This is because the living body contains many substances that absorb light in a specific wavelength range with respect to near-infrared light defined within the range of 0.7 to 2.5 μm. Therefore, a large amount of near-infrared light within the specific wavelength range absorbed by the above substances is absorbed in the living body, and the amount of detected signal is greatly reduced. Therefore, by using light with a wavelength that avoids the specific wavelength range for detection and measurement, it is possible to prevent an unnecessary decrease in the amount of detected signal.

Examples of substances that absorb light in a specific wavelength range in the near-infrared region include oxygen concentration indicators such as hemoglobin, myoglobin, cytochrome oxidase, and pyridine nucleotide (their light absorption characteristics are described in detail in Patent Document 2). ing). Hemoglobin and myoglobin (particularly in a deoxidized state) show a sharp increase in absorbance in the wavelength region below 850 nm. Therefore, it is desirable that the range of wavelengths to be used, which is limited in this embodiment, is from 875 nm to 2500 nm, including some margins.

On the other hand, the absorbance of oxygenated cytochrome oxidase slightly increases at 940 nm or less. Therefore, considering the absorbance characteristics of oxygenated cytochrome oxidase, the range from 950 nm to 2500 nm is more desirable, including some margins.

A water molecule exists as an in vivo substance that greatly absorbs near-infrared light. According to the description of Patent Document 3, the region with the highest absorption in the specific wavelength range related to water molecules has a center wavelength of 1.91 μm and a half-value range of absorbance of 1.894 to 2.061 μm. Therefore, the composition, structure, or activity state inside the living body can be detected by using light limited to the range of 875 nm or more and 1,890 nm or less, or the range of 950 nm or more and 1,890 nm or less, which avoids the absorption of oxygen concentration indicators and water molecules in the living body. and its change may be detected or measured.

Furthermore, absorption of water molecules also occurs in the region where the central wavelength is 1.43 μm and the absorbance half-value range is 1.394 to 1.523 μm. Therefore, by using light within the range of 875 nm or more and 1390 nm or less (or 950 nm or more and 1390 nm or less) and the range of 1530 nm or more and 1890 nm or less, which also avoids that region, the composition, structure, activity state, and changes thereof inside the living body are detected. Or you can measure.

Furthermore, absorption of water molecules (although the absorbance is relatively low) also exists in the region where the central wavelength is 0.97 μm and the half-value range of absorbance is 0.943 to 1.028 μm. Therefore, light in the range of 1028 nm or more and 1890 nm or less or 1028 nm or more and 1390 nm or less, which avoids the absorption range of water molecules, may be used to detect or measure the composition, structure, activity state, and changes thereof inside the living body.

Substituting the above wavelength range into the equation (B.6), the value of the coherence length l _CL is estimated. As described in section 2.2, in this embodiment, the value of the coherence length l _CL may be set in relation to (adapted to) the detection characteristics in the detection unit 6 . It is assumed that the wavelength resolution (half width) of the example spectroscope 22 shown in FIG. 14E is 5 nm for high performance and 50 nm for relatively low performance.

Therefore, when Δλ=5 nm, the coherence length l _CL ≈0.18 mm at λ ₀ =950 nm, the coherence length l _CL ≈0.21 mm at λ ₀ =1028 nm, and the coherence length l _CL ≈0.21 mm at λ ₀ =1890 nm. 0.71 mm.

On the other hand, when Δλ=30 nm, the coherence length l _CL ≈30 μm at λ ₀ =950 nm, the coherence length l _CL ≈35 μm at λ ₀ =1028 nm, and the coherence length l _CL ≈0.12 mm at λ ₀ =1890 nm. becomes.

Since the maximum value of the coherence length estimated above is 0.71 mm, it is possible to take some measures to reduce optical noise so that the coherence length l _CL is approximately 1 mm or more. good.

Chapter 3 Optical noise reduction method in this embodiment related to partial coherence
(Chapter 3] Optical Noise Reduction Method of Exemplary Embodiment regarding Partial Coherence)
Chapter 2 explained how partially coherent light emitted from a panchromatic light source, such as a tungsten-halogen lamp or a xenon lamp, can be contaminated with optical noise due to the effects of the tube surrounding the filament. A method of the present embodiment for reducing optical noise based on the optical interference will be described in Section 3.

Section 3.1 Basic Principles for Optical Noise Reduction
(Section 3.1) Basic Principle to Reduce Optical Noise
The basic principle of optical noise reduction in this embodiment will be described with reference to FIGS. 8A and 8B.
1A to 1C, from the light source 70 in the light emitting unit 2 through the object 10 (object to be detected or measured) to the photodetectors 80 in the detection units 4 and 6. (or at least part of the optical path starting from the light source 70 or at least part of the optical path reaching the photodetector 80) is composed of a plurality of optical paths. Then, the plurality of optical paths are combined or mixed at predetermined points in the optical paths.

Here, according to the definition of terms in Section 2.2, the mixed light generated immediately after "mixing" has partial incoherence (Partial Incoherent), and the partial coherence before mixing (Partial Coherence) has decreased significantly. On the other hand, the synthesized light generated immediately after the "synthesis" is allowed to be either "partially coherent" or "partially incoherent". Further, the combined light may be in an intermediate state between the two. For example, the short wavelength component in the combined light may have partial incoherence and the long wavelength component may have partial coherence.

Here, as shown in FIG. 8A or FIG. 8B, the above predetermined locations where a plurality of optical paths are synthesized or mixed are a photosynthesis (mixture) part 102 in the middle of the optical paths or a specific region (photosynthesis/mixing location) 200 in the target object 10, a light At least one inside the detector 80 may be used.

In particular, when there is a predetermined location (light combining (mixing) portion 102 in the middle of the optical path) in the middle of the optical path, the predetermined location exists in a local area in the optical axis direction of the combined light (mixed light) 78 ( That is, the predetermined location is localized at a specific position in the optical axis direction).

On the other hand, in the plane (optical cross-section) direction perpendicular to the optical axis direction, this predetermined location does not necessarily have to be localized. Therefore, the light 201, 202, 203 passing through each optical path may be combined or mixed simultaneously over the entire optical cross-section. Alternatively, the predetermined location (the light combining (mixing) section 102 in the optical path) may be arranged in a local area in a plane (optical cross section) direction perpendicular to the optical axis direction.

In addition, at the predetermined location where a plurality of optical paths are synthesized or mixed, it is preferable that at least either the direction of travel of light passing through different optical paths or the direction of vibration plane of the electric field approximately coincides (there is no need to strictly coincide with each other). ).

In particular, when there is a predetermined portion (photosynthesis (mixing) part 102 in the middle of the optical path) in the middle of the optical path, as shown in FIG. 8A(a) and FIG. . If the traveling directions of the lights 201, 202, and 203 that have passed through different optical paths at this predetermined location (the light combining (mixing) unit 102) do not match, the light 201, 202, 203 are separated again and partial incoherence is reduced.

Even when the optical path of the combined light (mixed light) 78 is short, the objective lens 25 and detection lenses 28-1 and 2 in FIG. light 201, 202, 203 are separated again. Therefore, when the traveling directions of the light beams 201, 202, and 203 passing through different optical paths are the same at the predetermined location (photosynthesis (mixing) section 102 in the optical path), detection signal accuracy and image sharpness are improved.

Similarly, when an analyzer or a polarizing beam splitter is arranged in the detection units 4 and 6 in order to measure the polarization characteristics of the detected light 16, the light passes through different optical paths at a predetermined location (optical combining (mixing) unit 102 in the optical path). By matching the vibration plane directions of the electric fields among the light beams 201, 202, and 203, detection signal characteristics are improved.

Further, the plurality of optical paths may be optically arranged so that the difference δ between the optical path lengths is greater than the coherence length _lCL . As a result, optical interference at the predetermined location between lights that have passed through different optical paths is inhibited, and optical noise can be reduced. Such an optical arrangement modifies the properties of the light that has passed through the multiple optical paths at the given location (that is, the partial coherence is reduced and the partial incoherence is increased). As a result, the light that has passed through the different optical paths is "mixed" at the given point.

Optical noise can be reduced because no optical interference occurs between light beams that have passed through different optical paths and become partially incoherent light beams. This effect will be described later in detail mathematically in Section 3.5. ) are intensity-added, and the optical noise characteristics are averaged (smoothed). Therefore, the greater the number of additions, the better the averaging (smoothing effect). Therefore, the larger the number of divisions N (corresponding to the number of additions) for dividing into a plurality of optical paths, the greater the effect of reducing the optical noise.

By reducing optical noise based on light interference in this way, the adverse effects on optical imaging described in Section 2.3 can be reduced. In addition, adverse effects on the measurement of spectral characteristics described in Section 2.4 and photodetection using general detection light 16 can be reduced.

As described above, in the present embodiment, optical characteristics are changed at the predetermined location or within the combined optical path by optically arranging such that the difference δ between the optical path lengths in the plurality of optical paths is greater than the coherence length _lCL . (reduced mutual partial coherence and increased partial incoherence). By the way, when partially coherent light beams passing through two different optical paths are combined at the above-mentioned predetermined location, if the direction of movement of the two at the predetermined location and the vibration plane direction of the electric field are greatly different, it is originally difficult to generate optical interference. . In that case, even if the method of the present embodiment is implemented, the optical noise reduction effect is weakened. Therefore, in order to exhibit the optical noise reduction effect according to the present embodiment, it is desirable that the direction of movement of both at the predetermined location and the direction of vibration plane of the electric field match to some extent.

In this embodiment, as shown in FIG. 8A or 8B, the value of the plurality of optical paths (the number of divisions of optical paths) N is set to "3 or more" (preferably 4 or more (examples such as FIG. 13A)). ing. However, it is not limited to this, and may be 8 or more or 9 or more as shown in FIG. 13B(a) or FIG. 12C(c).

By the way, the detector 80 described above includes all photodetection function units having a built-in photoelectric conversion function. Specific examples of this photodetection function unit are not limited to semiconductor type photodetectors composed of a single photodetection unit having a photoelectric conversion function, but also avalanche type (internal signal multiplier) detectors and photomultiplier detectors. Double tubes are also included. In addition, as a photodetector composed of a plurality of photodetection units (photodetection cells), a line sensor in which a plurality of detection cells are arranged in a one-dimensional direction, a surface sensor in which a plurality of detection elements are arranged in a two-dimensional direction, a predetermined It also includes a position sensor (position detection sensor) for detecting the position of the light spot irradiated within the plane area. Furthermore, the detector 80 described above also includes an imaging device (monitor camera 24 in FIG. 14D) and a spectroscope 22 in FIG.

Furthermore, it is desirable to use a panchromatic light source such as a tungsten/halogen lamp or a xenon lamp, or an incandescent lamp or a fluorescent lamp, as described in section 2.5, for the light source 70 described above.

In Section 2.5, using equation (B.28), when a transparent parallel plate is placed in the optical path of the divergent light emitted from the light source 70, the intensity distribution of the transmitted light changes according to the change in the measurement wavelength λ. explained that it can change periodically. This phenomenon occurs regardless of whether a panchromatic light source or a monochromatic light source (monochromatic single wavelength or narrow wavelength band) is used.

Another method of obtaining highly accurate spectral characteristics (or light absorption characteristics) by using this light in a spectroscope is to irradiate the target object 10 with light only in a narrow wavelength band at the same time, The irradiation wavelength may be swept in time series. When this method is adopted, the intensity of the narrow wavelength band light irradiated at the same time is monitored at the same time, and the result is fed back to the detected light amount to remove the irradiation light amount change component for each measurement wavelength λ. However, since the above method requires a "wavelength sweep time" for measuring spectral characteristics (or light absorption characteristics), it is difficult to detect and measure "rapid changes" in the object 10 .

In contrast, using a panchromatic light source for light source 70 (according to this embodiment) to illuminate target object 10 with partially incoherent light, for example, with spectroscope 22 of FIG. can be detected/measured at the same time, "high-speed detection/measurement" is possible. As a result, there is an effect that "high-speed change" inside the object 10 can be accurately detected and measured.

However, the light source 70 is not limited to this, and a monochromatic light source such as an LD (Laser Diode) or an LED (Light-emitting Diode) may be used.

FIG. 8A shows this embodiment example in which the optical paths in the light source unit 2 from the light source 70 to the specific region α in the target object 10 are composed of three optical paths. In this embodiment, it is not necessary to limit the number of optical paths to three, and as described above, more than three optical paths (four optical paths or more, eight optical paths or more, or nine optical paths or more) may be set (divided). Further, the optical path immediately after the light emitting source 70 does not necessarily have to be composed of a plurality of optical paths, and the optical path after the light emitting source 70 may be divided into a plurality of optical paths in the middle.

In the light source unit 2 shown in FIG. 8A, a plurality of optical paths having different optical path lengths are formed (FIG. 8B). Furthermore, a light combining (mixing) unit 102 that combines (or mixes) the light that has passed through the plurality of optical paths may be arranged in the light source unit 2 .

In the embodiment of FIG. 8A(a), a light combining (mixing) unit 102 is installed in the light source unit 2. In the embodiment shown in FIG. This light combining (mixing) section 102 corresponds to the above-described “predetermined portion” in the optical path in the light source section 2 . Also, the "predetermined location" (photosynthesizing (mixing) unit 102) in this state corresponds to "middle of the optical path (of the irradiation light 12)" as a synthesizing/mixing location in FIG. 9, which will be described later.

That is, in the embodiment of FIG. 8A(a), the optical path from the light emitting source 70 to the photosynthesis (mixing) unit 102 is composed of three optical paths: first, second, and third. 203 is synthesized (mixed) in the photosynthesis (mixing) unit 102 . After that, each light 201 , 202 , 203 is combined into a combined light (mixed light) 78 and irradiated within a specific region α inside the object 10 .

In the embodiment of FIG. 8A(b), all the optical paths in the light source unit 2 are composed of the first/second/third three optical paths, and are synthesized ( mixed). Therefore, in this case, the specific region (photosynthesis/mixing place) 200 within the object 10 corresponds to the "predetermined point" in the optical path.

In this state, the “predetermined location” (the specific region (photosynthesis/mixing location) 200 within the target object 10) is the “specific region within the target object 10 (to the detection surface 86, etc.)” as the synthesis/mixing location in FIG. including imaging)”.

In both FIGS. 8A (a) and (b), in this embodiment, the optical path length difference δ between the first/second/third optical paths satisfies δ>l _CL . Therefore, the partial coherence between the lights 201, 202 and 203 passing through the first/second/third optical paths is reduced, and the lights become partially incoherent with each other.

Therefore, as shown in FIG. 8A (a) or (b), the partial coherence of the irradiation light (first light) 12 (FIGS. 1A to 1C) is reduced (partially incoherent) within the light source unit 2. change to coherent light), imaging for a specific region α (200) in the target object 10, signal detection (after photoelectric conversion), spectroscopic measurement (for example, measurement of wavelength dependence of light absorption characteristics and light scattering characteristics) ) can be detected/measured more accurately and reliably.

That is, multiple scattering occurs inside the object 10, as will be described later in Section 5.3 using FIG. 23A. Therefore, if partially coherent light is used as the irradiation light (first light) 12 that irradiates the object 10, optical interference occurs between multiple scattered lights, which adversely affects imaging, signal detection, and spectroscopic measurement (large optical noise component is mixed). In addition, as described in section 2.3, there is also the adverse effect of optical interference caused by the fine uneven structure on the surface of the object 10 and the non-uniformity of the refractive index distribution inside the object 10 .

When the partial coherence of the irradiation light (first light) 12 is reduced (changed to partially incoherent light) as shown in FIG. 8A (a) or (b), the object 10 Reduces optical interference that can occur due to the interior or surface of the

FIG. 8B shows this embodiment example in which the optical paths in the detection units 4 and 6 from the specific region β in the object 10 to the photodetectors 80 in the detection units 4 and 6 are composed of three optical paths. In this embodiment, it is not necessary to limit the number of optical paths to three, and as described above, more than three optical paths (four optical paths or more, eight optical paths or more, or nine optical paths or more) may be set (divided). Further, the optical path immediately after the β region in the object 10 does not necessarily have to be composed of a plurality of optical paths, and the optical path after the object 10 may be divided into a plurality of optical paths in the middle.

In the embodiment of FIG. 8B(a), a photosynthesis (mixing) unit 102 is installed in the detection units 4 and 6 . This light combining (mixing) unit 102 corresponds to the "predetermined point" in the optical path in the detection units 4 and 6 described above. Also, the "predetermined location" (optical synthesis (mixing) unit 102) in this state corresponds to "midway of the optical path (of the detected light 16)" as a synthesis/mixing location in FIG. 9, which will be described later.

That is, in the embodiment of FIG. 8B(a), the optical path from the β region in the target object 10 to the photosynthesis (mixing) unit 102 is composed of three optical paths, first/second/third, and the light passing through each optical path 201 , 202 , and 203 are combined (mixed) in the photosynthesis (mixing) unit 102 . After that, each light 201 , 202 , 203 is combined into a combined light (mixed light) 78 and reaches the photodetector 80 .

In the embodiment of FIG. 8B(b), all the optical paths in the detectors 4 and 6 are composed of the first/second/third three optical paths, which are combined (mixed) on the photodetector. Therefore, in this case, the photodetector 80 corresponds to the "predetermined point" in the optical path.

The "predetermined location" (photodetector 80) in this state corresponds to the "detection surface 86 in the detector 80" as a combining/mixing location in FIG. 9, which will be described later.

In both FIGS. 8B(a) and (b), in this embodiment, the optical path length difference δ between the first/second/third optical paths satisfies δ>l _CL . Therefore, the partial coherence between the lights 201, 202 and 203 passing through the first/second/third optical paths is reduced, and the lights become partially incoherent with each other.

FIG. 9 shows a case-by-case list regarding the method for embodying the basic concept (basic principle) of this embodiment shown in FIGS. 8A and 8B.

Using FIGS. 8A and 8B, a structure/configuration for synthesizing/mixing the light that has passed through each optical path after configuring (at least part of) the optical paths in the light source unit 2 or the detection units 4 and 6 with a plurality of optical paths. is shown. However, not limited to this, in the present embodiment, "multiple optical paths ⇒ synthesis/mixing" may be performed across the light source unit 2 and the detection units 4 and 6, or "multiple optical paths ⇒ synthesis/mixing" may be performed by the light source unit 2. It may be performed both inside and inside the detection units 4 and 6 .

In addition to that, for example, like the near-infrared microscope apparatus shown in FIG. It may be arranged both inside and inside the detection unit 6 . Such a dual-purpose arrangement enables a significant reduction in the amount of optical noise caused by optical interference, and makes it possible to ensure high accuracy and high reliability of detection signals.

A column showing options for a method of forming a plurality of optical paths immediately after the light emitting source 70 in FIG. 8A corresponds to the column of "state of optical paths before synthesis/mixing" in FIG. That is, in the present embodiment, a method of forming a plurality of optical paths for the irradiation light (first light) 12 emitted from the light emitting source 70 by utilizing the “diversity of light emission states”; Either one of two methods (described in the column of optical path state/operation), or a combination of the two, can be employed to configure a plurality of optical paths by applying an "optical path splitting operation" to the light 12).

In addition, when constructing a plurality of optical paths using the above-mentioned "variety of light emission states", either different "light emitting regions" and "light emission methods" (described in the detailed content column), or A combination of both may be used.

For example, when the light is not emitted from only one point but has a “breadth in the light emitting area”, different lights emitted from different light emitting areas can be synthesized and used as the irradiation light (first light) 12 . On the other hand, when the emission direction of the emitted light from the light source 70 spreads, the light emitted in different directions is combined (considering the different light emission directions as a plurality of optical paths) to produce the irradiation light (first light ) 12.

For the detection light (second light) obtained from the β region in the target object 10 to be detected or measured shown in FIG. "Different light-emitting regions" (in the column of details) and "Optical path division operation" (in the column of optical path state/operation) are included as options in this embodiment. That is, in the present embodiment, either one of the above two methods or a combination of both may be performed.

For example, even if the target object 10 to be detected or measured has the microstructure of FIG. 4 (microscopic light scatterers 66), the optical path length difference δ is larger than the coherence length l _CL (δ>l _CL ) (Fig. 8B) (adapted to “different emission regions”), the partial coherence between them decreases and the optical noise can be reduced.

For both the irradiation light (first light) 12 in FIG. 8A and the detection light (second light) 16 in FIG. As a general "detailed content", either a method of "Wave Front Dividing" or a method of "Amplitude Dividing" or a combination of both can be selected.

"Wavefront splitting" means a method of spatially splitting a cross section of light on a cross section perpendicular to the optical axis along the direction of travel of light. After the wavefront splitting, the optical cross-sectional shape of each split beam is often deformed (compared to before the wavefront splitting). Further, when wavefront splitting is performed using a transparent parallel plate, the traveling directions of the individual split beams coincide with each other. Even if the traveling directions of the split lights match each other, in this embodiment, it is considered that "the individual split lights after wavefront splitting pass through different optical paths".

On the other hand, in the "amplitude division", the beam is divided into a plurality of optical paths with different traveling directions while maintaining the cross-sectional shape of the beam. Then, it is often amplitude-divided by an optical element such as a beam splitter or a polarizing beam splitter.

More specifically, the “method of photosynthesizing or light-mixing” a plurality of optical paths changes or controls the direction of travel of light for each of the plurality of optical paths. However, any method may be used as the "photosynthesis/mixing method" without being limited thereto.

First, we will describe the “photosynthesis/mixing method” that can be applied to all the states/operations in the “details” column. In FIGS. 8A and 8B, which illustrate the basic principle of optical noise reduction, light 201, 202, 203 passing through first/second/third optical paths with different optical path lengths converge toward a predetermined location. This predetermined location corresponds to the photosynthesis (mixture) unit 102 , the photodetector, or a specific region (photosynthesis/mixing location) 200 (α point) in the object 10 .

Therefore, including this optical path in general, it is described as "photosynthesis/mixing method" in FIG. In addition, as a supplementary explanation of the meaning of the "photosynthesis/mixing method", it is specified as a method related to [changing/controlling the course of each light path]. In the description of this embodiment, the generic term for optical members that change or control the course of each of a plurality of different optical paths is called an "optical property changing member". Therefore, all the optical elements described in the column of "Photosynthesis/Mixing Method" in FIG. 9 (for changing/controlling the course of each optical path) or a combination of these optical elements correspond to the "optical property changing member".

The functions that this optical property changing member can have include:
(A) A function of changing/controlling the optical path length for each of a plurality of optical paths (corresponding to the function of "optical path length change 76" in FIG. 10 described later) and (B) combining (or mixing) a plurality of optical paths at a predetermined location. Features included. In the description of this embodiment, an optical member that exhibits at least one of the above functions (may exhibit both functions at the same time) is referred to as an optical property changing member.

As for the physical structure of this optical characteristic changing member, it may be arranged integrally at one place in the optical path. Moreover, not limited to this, a plurality of members dispersedly arranged in the optical path may also be arranged as a combination. When distributed in this way, part of the optical property-changing member has the above function (B), and the remaining part, which is arranged at a different position, has the above function (A). may be separated into functions.
As an example of changing/controlling the light traveling direction for multiple light paths configured by any of the methods of “different light emitting regions”, “different light emission methods”, “wavefront splitting”, and “amplitude splitting”, a lens or the like is used. Refractive elements may also be used. In addition, in this embodiment, the "refractive element" may include not only a spherical lens but also an aspherical lens, a Fresnel lens, a prism, a transparent parallel plate, and the like.

In addition, it is also possible to use a diffraction-related element, an optical reflection element, or an optical phase conversion element. Here, the diffraction-related element includes a diffraction grating, a hologram element, and the like, and may be blazed with an inclined microplane.

An optical phase conversion element means an optical element that locally or entirely changes the phase of light (irradiation light 12 or detection light 16) after passing through or being reflected by this element. In order to realize this function, the optical phase conversion element has a fine refractive index distribution or a fine concave-convex structure on the surface. In this embodiment, the optical phase conversion element includes a random phase shifter or a diffuser having a surface with a specific periodic or random fine uneven structure, a sanding surface or a sanding surface (Sand Treatment Plate). ) are also included.

Also, a waveguide element that guides the traveling direction of light by forming or integrating optical guide paths on an optical fiber or a predetermined plate may be used for course change/control (photosynthesis/mixing method) for each of a plurality of light paths.

As another method, instead of changing/controlling the traveling direction of the light to the "predetermined location", only the light gathered in the "predetermined location" may be extracted from the light having a plurality of traveling directions. This method corresponds to "combined/mixed light extraction by detector 6" in FIG. For example, the photodetectors 80 in the detection units 4 and 6 of FIG. 8B perform "photodetection (photoelectric conversion) of only specific localized portions". Then, in the detection units 4 and 6, an imaging relationship (confocal relationship) is formed between the "specific localized location" on the photodetector 80 and the "predetermined location β" in the object 10. By doing so, it is possible to substantially detect/measure information only at the “predetermined location β” (details will be described later in Section 3.9 using FIG. 20).

Also, a prism or a special lens may be additionally used in the optical path of the light emitted from the "different light emitting areas" to collect the light emitted from the wide light emitting area. As explained in section _2.2 using FIG. , the partial coherence with each other is reduced (the partial incoherence is increased) and the amount of optical noise is reduced. For that purpose, it is desirable that the distance between the α point and the β point is large. Therefore, a prism or special lens may be used in the optical path to collect light emitted from a wide light emitting area (details will be described later in Section 3.9 using FIGS. 24A and 24B).

The special lens means an aspherical lens. Specifically, a lenticular lens, a cylindrical lens, a Fresnel lens, and the like may be included.

Then, as a method of "light combining/mixing" the light split into multiple optical paths by "amplitude splitting", a polarizing reflecting element, a polarizing transmitting element (such as a polarizing beam splitter), or a non-polarizing beam splitter can be used. May be used. Furthermore, a phase plate, an analyzer, or a polarizing beam splitter may additionally be used as a means for matching the directions of the electric field vibration planes between lights that have passed through different optical paths.

8A and 8B, and as will be described later using FIG. Combining/mixing light. In the process, an optical path length change 76 is generated to change the optical characteristics of the combined light (mixed light) 78 (decrease partial coherence and increase partial incoherence).

The "combining/mixing place" and "spatially identical area" in FIG. 9 and the "light combining (mixing) section 102" in FIGS. 8A and 8B correspond to the above-described "predetermined place". As a specific example of this embodiment in which the predetermined location is arranged in the middle of the optical path of the irradiation light 12 or the detection light 16, the core region 142 inside the optical fiber 100 may be adapted (see FIG. 14A for details). later in Section 3.4). In addition, in this embodiment, the position after passing through the optical phase conversion element may be adapted (details will be described later in Section 3.4 using FIG. 14B).

If the “predetermined region in which the light that has passed through a plurality of optical paths is synthesized or mixed” described at the beginning of Section 3.1 is set to the “specific region 200 within the target object 10”, for the reasons described above, the “detection surface 86 etc.” (details will be described later in Section 3.9 using FIG. 20). Therefore, in this case, the method "combination/mixing light extraction at detector 6" in the column "photosynthesis/mixing method" is used.

On the other hand, if the "predetermined area where light passing through a plurality of optical paths is synthesized or mixed" explained at the beginning of section 3.1 is set to "inside the photodetector 80", the "place of synthesis/mixing" in FIG. corresponds to "detection plane 86 in detector 80" in the . As described above, the “photodetector 80” in the present embodiment is not limited to a photodetector composed of only a single photodetector cell, but includes any photodetection functional unit having a built-in photoelectric conversion function. Therefore, when the imaging device is made to correspond, the imaging plane (detection plane) 86 in the monitor camera 24 shown in FIG. 14D corresponds to the above-mentioned "predetermined point".

In the spectroscope 22 shown in FIG. 14E as a kind of "photodetector 80", the pinhole or slit 130 corresponds to the above "predetermined point". And this example embodiment corresponds to "Pinholes or Slits 130" in the "Synthesis/Mixing Locations" column of FIG.

With reference to FIG. 10, the basic principle of the optical noise reduction method according to this embodiment will be explained from a different point of view. As shown in FIG. 10( a ), in this embodiment, basically, a portion 74 of light different from a portion 72 of light emitted from the light source 70 is subjected to an optical path length change 76 . The amount δ of the optical path length change 76 is desirably larger than the coherence length l _CL defined by the formula (B·6) (or the formula (B·12)). After that, both are mixed to generate a mixed light 78 (combined light may be used). This method thus modifies the optical properties of the mixed light 78 to reduce partial coherence and increase partial incoherence. Therefore, according to the basic principle of this embodiment shown in FIG. 10, synthetic light (mixed light) 78 is generated after changing the optical path length 76 when viewed along the optical path from the light source 70 .

By the way, the amount δ of the optical path length change 76 does not necessarily have to be larger than the coherence length l _CL at all wavelengths. This is because the coherence length l _CL defined by equation (B.6) (or equation ( _B.12 )) is varies greatly depending on Therefore, when panchromatic light is generated from the light source 70, the shortest wavelength to be used should be longer than the coherence length _lCL . In this case, partial coherence remains on the long wavelength side in the combined light 78 .

FIG. 10(b) shows an embodiment in which the optical operation of FIG. 10(a) is performed within the light source unit 2. As shown in FIG. In this case, the object 10 is irradiated with the combined light (mixed light) 78 as the irradiation light (first light) 12 .

On the other hand, FIG. 10(c) shows an embodiment in which the optical manipulation of FIG. 10(a) is performed within the detectors 4 and 6. That is, after a part 74 of the detection light (second light) 16 obtained from the object 10 is subjected to an optical path length change 76 , it is synthesized (mixed) with a part 72 of the remaining light. The resulting combined light (mixed light) 78 reaches the photodetector 80 .

FIG. 8A corresponds to FIG. 10(b), and FIG. 8B corresponds to FIG. 10(c). The optical path length change 76 that occurs in FIGS. 8A and 8B is clearly shown in FIG.

Also, as explained in the first part of Section 3.1, inside the optical path of the combined light (mixed light) 78 in FIG. It is desirable that the traveling direction of the light belonging to the part 72 (or the direction of vibration plane of the electric field) and the traveling direction of the light belonging to the part 74 of light (or the direction of the vibration plane of the electric field) coincide. As a result, re-separation inside the object 10 and on the photodetector 80 is suppressed, and a good image and a highly accurate detection signal can be obtained.

The material used for the above-mentioned optical property changing member or the material used for the substrate of the optical property changing member will be explained. In particular, when the near-infrared light described in Section 2.6 is used as the irradiation light 12 or the detection light 16, points to consider in material selection will be described below. The optical characteristic changing member here is premised on various optical members described in the column (column) of "Photosynthesis/mixing method [change/control of path for each light path]" in FIG. However, it is not limited to this, and may be applied to any optical element material.

It is desirable to select a material having high light transmittance for the portion through which the irradiation light 12 and the detection light 16 pass in the entire optical characteristic changing member or the entire base material thereof. Acrylic resin PMMA (Poly-Methyl-Metacrylate) and polycarbonate resin PC (Polycarbonate) are known as transparent plastic resins that are relatively inexpensively available. However, these plastic resins contain a large amount of functional groups (methyl groups, methylene groups, etc.) composed only of carbon atoms and hydrogen atoms.

The above functional groups have the property of absorbing near-infrared light as described in Section 2.6. The central wavelength light of the absorption band attributed to the first overtone of the stretching vibration generated in the functional group is particularly greatly absorbed. The central wavelength of this absorption band lies within the range of approximately 1710 nm to 1795 nm. For example, when the central wavelength light passes through a plate of transparent acrylic resin PMMA (Poly-Methyl-Metacrylate) having a thickness of 1 mm, the amount of light absorption is so large that the amount of transmitted light is halved. Therefore, when near-infrared light is used for the irradiation light 12 and the detection light 16, it is better to avoid using transparent plastic resin as the material for the optical characteristic changing member or its base material. In addition, it is desirable to use an inorganic material instead of an organic material as a material having high optical transparency to near-infrared light.

Optical glass, CaF ₂ , MgF ₂ , LiF, KBr, and the like are known as inorganic materials having high optical transparency. Therefore, these inorganic materials are compatible with the optical property-altering member (or the base material of the optical property-altering member).

By the way, for manufacturing reasons, a large amount of hydroxyl groups (--OH groups) are mixed in general optical glass. The center wavelength of the absorption band attributed to the first overtone of the stretching vibration of the hydroxyl group is within or near the range from 1395 nm to 1595 nm. Therefore, light passing through optical glass containing a large amount of hydroxyl groups is absorbed in the above wavelength range.

Therefore, when near-infrared light in the wavelength range described in section 2.6 is used as the irradiation light 12 or the detection light 16, the material of the optical property changing member (or the base material of the optical property changing member) is "hydroxyl group It is desired to select a material with a small amount of contamination. As a result obtained from the experiment, the specifically allowable amount of hydroxyl groups mixed in is "100 ppm or less" as a necessary condition. In particular, "1 ppm or less" is desirable when performing highly accurate near-infrared spectrum measurement. By selecting a material in which the amount of hydroxyl groups mixed in is within the above allowable range, light absorption in the wavelength range from 1395 nm to 1595 nm can be avoided, and high accuracy is achieved in the entire wavelength range of near-infrared light. An effect is produced that makes it possible to measure spectral characteristics.

As a specific method of obtaining a light-transmitting material within the above allowable range, when ordering materials, you may specify "a glass material with less hydroxyl group contamination and production control", "anhydrous quartz glass", or "anhydrous quartz". . In all of these, materials are manufactured while maintaining low humidity and temperature control in an environment with a low degree of cleanliness (inside a clean room). By manufacturing the raw material in a clean room set at low humidity, contamination of water vapor in the air is prevented, and the amount of contamination of hydroxyl groups is suppressed within the above allowable range. By adopting such a manufacturing method, it is possible to prevent the contamination of impurities that cause deterioration of the material, and to increase the purity of the produced material. As a result, the long-term storage stability of the light-transmitting material is guaranteed, so that there is an effect that the properties (performance) of the optical property-changing member produced using the light-transmitting material are maintained for a long period of time.

Section 3.2 Use of Emitted Light in Different Directions In section 3.1, a detailed list of optical noise reduction methods in this embodiment was outlined using the series of cases shown in FIG. Each detailed concrete example will be described in section 3.2 and later. This embodiment example described in section 3.2 and later is merely an example, and all combinations within FIG. 9 are included in this embodiment.

Using the "different light emission directions" in the "light path state before synthesis/mixing" column in FIG. FIG. 11 shows an example of a method of "synthesizing/mixing" different optical paths "on the way".

Emitted light is radiated in all directions from a tungsten filament 50 which is a kind of light source 70 in the light source section 2 . In many cases, only the forward emission light 84 (corresponding to the first optical path) is used as shown in FIG. 11(a).

On the other hand, in this embodiment, the rear mirror 82 of the light reflecting element is arranged on the rear side, and the backward emitted light 88 (corresponding to the second optical path) is returned to the inside of the tungsten filament 50 . The distance from the tungsten filament 50 to the back mirror 82 and back causes the optical path length change 76 . Compared with the calculation example in the second half of section 2.7, the difference δ in the optical path length that occurs here is much larger than the coherence length _lCL .

After passing through the tungsten filament 50, the backward emitted light 88 (the second optical path) follows the same optical path as the forward emitted light 84 (the first optical path). This mixes forward emitted light 84 (first optical path) and rearward emitted light 88 (second optical path).

In this embodiment shown in FIG. 11, the partial coherence of the mixed light is greatly reduced, so even if a transparent parallel plate is placed in the divergent optical path, the amount of optical noise can be kept relatively small. In addition, in the embodiment shown in FIG. 11, the effect that the emitted light from the tungsten filament 50 can be used effectively is produced.

Section 3.3 Optical Characteristic Changing Member Having Wavefront Splitting Function A specific example of this embodiment in which "wavefront splitting" is performed in the "optical path splitting operation" of FIG. 9 will be described in Section 3.3. Here, an example using a refractive element or a diffraction-related element as an optical element used to perform this "wavefront splitting" will be described. However, it is not limited to this, and an optical reflection element, an optical phase conversion element, or a waveguide element may be used. For example, as shown in FIGS. 12C to 13C, which will be described later, a light reflecting surface having different steps may be configured for each region, and the optical path length (after reflection) may be changed according to the reflection location within the light cross section 92. .

In addition, in the present embodiment described in Section 3.3, "middle of the optical path of the irradiation light 12 and the detection light 16" is set as the content in the column of "synthesis/mixing place" in FIG.

An example of this embodiment using "diffraction-related elements" or "refractive elements" as the "photosynthesis/mixing method" of FIG. 9 is shown in FIG. 12A. A blazed diffraction grating or prism 128 is arranged in a partial area of the light cross section (area through which the transmitted light 110-1 passes) in the middle of the optical path of the irradiation light 12 or the detection light 16, and the traveling direction of the transmitted light 110-1 is controlled. change.

After that, the transmission diffraction grating 120 synthesizes or mixes the transmission light 110-1 and the transmission light 110-2. At this time, the direction of travel of the first-order diffracted light of the transmitted light 110-1 and the zero-order light of the transmitted light 110-2 is matched.

The optical path length between blaze grating or prism 128 and transmission grating 120 differs between transmitted light 110-1 and transmitted light 110-2. As described above, in this embodiment shown in FIG. 12A, the optical characteristics of the combined light (mixed light) 79 are changed (by reducing the partial coherence) by using the change in the optical path length caused by the difference in the traveling paths of the light. increase partial incoherence).

FIGS. 12B to 13C show examples of this embodiment using transparent parallel plates as refractive elements used to realize the "wavefront splitting" of FIG. 9. FIG. Assuming that the refractive index in the transmissive parallel plate is n and the thickness is d, the first optical path goes straight through the transmissive parallel plate and the second optical path goes straight in a vacuum (air) of length d. A difference .delta.

12B to 13C, the optical characteristics of the combined light (mixed light) 78 are changed using the optical path length change δ of the passing light caused by the difference in the refractive index (partial coherence to increase partial incoherence). Therefore, the optical element combining the transparent parallel plates 94, 114, and 116 shown in FIGS. 12B to 13C is included in one type of the optical property changing member (or split wave optical path length conversion element 90).

As shown in FIG. 12B, the cut surface 95 of the parallel plate is parallel to the optical axis of the transmitted light with high accuracy. Therefore, the light passing through the optical characteristic changing member (divided wave optical path length conversion element 90) is wavefront-split at the boundary line 97 of the cross section (parallel plate) in the cross section 92 of the transmitted light. Since each wavefront-divided transmitted light has a different optical path length, it passes through a different optical path.

FIG. 12C shows another embodiment of the optical property changing member (divided wave optical path length conversion element 90) shown in FIG. 12B. First, the long side direction of a transparent parallel plate 114-2 having a thickness t is arranged in the X-axis direction. Then, as shown in FIG. 12C(a), a transparent parallel plate 114-1 with a thickness of 5t is superimposed (adhered) on a transparent parallel plate 114-2 with a thickness of t, with the long side direction being the X-axis direction. As a result, three regions with thicknesses of 0t, 1t, and 6t are formed along the Y-axis direction.

Next, a transparent parallel plate 114-3 having a thickness of 2t is arranged with the long side thereof in the Y-axis direction. Then, a transparent parallel plate 114-4 with a thickness of 2t is placed (adhered) under the transparent parallel plate 114-3 with a thickness of 2t as shown in FIG. As a result, three regions with thicknesses of 4t, 2t, and 0t are formed along the X-axis direction.

Next, as shown in FIG. 12(c), FIG. 12(b) and FIG. 12(a) are overlapped (adhered). Then, the transmission direction 96 of the partially coherent light is made to coincide with the Z-axis direction from bottom to top. As a result, when viewed in the cross-sectional direction of the light cut in the direction perpendicular to the light passage direction 96, the optical path is divided into nine regions. The thicknesses passing through the parallel plate 114 in each optical path are 10t, 8t, 6t, 5t, 3t, t, 4t, 2t, and 0t in order from the upper left. The optical path length difference δ for each optical path passing through each region is given by the formula (B·13).

In the first half of Section 3.1, it was explained that the optical noise reduction effect increases as the division number N (corresponding to the above addition number) for dividing the optical path increases. Therefore, at least one of all the items described in the "detailed contents" column in the "optical path state before combining/mixing" column of FIG. When light is divided into N different optical paths by an optical property changing member corresponding to amplitude division or different light emission directions, the difference δ in optical path length generated when passing through all the optical paths is different from each other. can be set to In the example of FIG. 12C, the above conditions are satisfied. That is, the difference δ in the optical path length generated in all the lights passing through the 9 regions divided on the light cross section (passing through 9 different optical paths) is different.

If the above contents are explained in another expression method, it will be as follows. That is, as an optical characteristic changing member, refractive elements (not limited to parallel plates, but also prisms and lenses) having different thicknesses are combined to divide into a plurality of optical paths. When the thickness of the refractive element in each optical path is mt (m is an integer), all divided optical paths have different values of m. Note that this characteristic as an optical property changing member is not limited to the structure of FIG. 12C, but also applies to the structures of FIGS. 13A to 13C. Furthermore, the above characteristics may correspond not only to the "wavefront distribution" in the "optical path state before synthesis/mixing" column of FIG. 9, but also to the "amplitude distribution" and "different light emission directions".

Furthermore, at least one of all the items described in the "detailed content" column in the "optical path state before combining/mixing" column in FIG. In this embodiment, the difference δ in optical path length between lights passing through different optical paths is given by equation (B·6) (or equation (B·12)). It is desirable that the optical arrangement is such that the coherence length _lCL is greater than the desired coherence length lCL. In the example embodiment of FIG. 9(c), the minimum thickness difference between the different regions is t. Therefore, considering the formula (B.13) for the above reasons,
(n−1) t > l _CL = λ ₀ ² / Δλ … (B・29)
The optical arrangement may be set so as to satisfy the following conditions. For example, when the refractive index of the refracting element is 1.5, the value of t may be set to 2 mm or more based on the calculation example in consideration of the margin in the second half of Section 2.7. On the other hand, it is also possible to set the upper limit of the wavelength to be used to less than 1.89 μm and set the value of t to 1 mm or more with the aim of miniaturizing the entire optical system. Furthermore, when the detectors 4 and 6 (or photodetectors) having a value of Δλ greater than 5 nm are used, the value of t may be set to 0.5 mm or more, preferably 0.3 mm or more.

Another way of expressing this content is as follows. That is, in an optical characteristic changing member that divides into a plurality of optical paths by combining refractive elements (including prisms and lenses as well as parallel plates) with different thicknesses, the thickness of the refractive element in each optical path is mt (m is an integer). , t satisfies the condition of formula (B.29). Note that the characteristics of this optical characteristic changing member are not limited to the structure of FIG. 12C, but also apply to the structures of FIGS. 13A to 13C. Furthermore, the above characteristics may correspond not only to the "wavefront distribution" in the "optical path state before synthesis/mixing" column of FIG. 9, but also to the "amplitude distribution" and "different light emission directions".

Furthermore, by combining the above as an application example of this embodiment, the characteristics of the optical characteristic changing member can be expressed as follows. That is, in an optical characteristic changing member that can be divided into N optical paths, if the thickness of the refractive element in each optical path is mt (or the optical path length generated when passing through each optical path is mδ) (m is an integer), then all N take different values of m in the optical path of , and satisfy the equation (B.29) (or δ>l _CL ).

The optical property changing member shown in FIG. 11C is divided into nine regions by combining (adhering) three divisions along the Y-axis direction and three divisions along the X-axis direction. Such a division method is called "XY division" in the description of this embodiment. This XY division is not limited to FIG. 11C, and if the number of divisions in one axis direction is 2 or more (for example, 2 divisions in the Y-axis direction x 2 divisions in the X-axis direction for a total of 4 divisions), any number of divisions can be selected. good.

In FIG. 11C, the X-axis and the Y-axis are orthogonal to each other, but the X-axis and the Y-axis may be obliquely crossed (the X-axis and the Y-axis intersect at an angle other than 90 degrees). Furthermore, as another wavefront splitting method, "X-axis splitting" that splits only along one axis (X-axis) direction may be performed. As another example, the optical characteristic changing member may be divided into a portion divided along the X-axis and a portion divided along the Y-axis, and may be dispersedly arranged at different positions on the optical path.

The “angle division” method, which is another wavefront division method, will be described with reference to FIGS. 13A and 13B. In this method, a (circular) transmitted light cross section 92 is angularly divided by dividing boundary lines 97 between optical paths with reference to the center of the circle. Even if angular division is performed in the middle of the optical path, deterioration of MTF (Modulation Transfer Function) characteristics does not occur in the imaging section, so there is an effect that good imaging characteristics can be obtained.

For example, as shown in FIG. 13A(a), a cut surface 95 of a transparent parallel plate 94-1 having a thickness Ta of 2t, for example, is arranged in the horizontal direction. Next, a transparent parallel plate 94-2 (FIG. 13A(b)) having a thickness Tb of, for example, 3 t and having a cut surface 95 arranged in the vertical direction is superimposed (adhered) to form the structure shown in FIG. 13A(c). and an optical property changing member. Then, a light transmission direction 96 is set so as to be parallel to the cutting plane 95 . As a result, the transmitted light cross section 92 is angularly divided into four quadrants in which the boundaries 97 of the cross section are orthogonal to each other.

In the optical property changing member of FIG. 13A(c), the thickness of the place (each region) through which each optical path passes when viewed from the light transmission direction 96 is Ta (eg, 2t), Ta+Tb (eg, 5t), Ta (eg, 5t), Tb (for example, 3t) and thickness "0". In this way, in the thickness mt, the value of m differs for each place (each region) through which each optical path passes (the value of m is 2, 5, 3, 0 in order from the first quadrant), and t is (B 29) satisfies the formula (for example, 0.3 mm or more).

In FIG. 13A(c), transparent semicircular parallel plates 94-1 and 94-2 are bonded together to form an integrated optical characteristic changing member. However, it is not limited to this, and a plurality of them may be distributed in the middle of the optical path. In this case, they may be arranged at a predetermined angle (for example, 45 degrees when two are distributed) so that the divided regions do not overlap each other.

An application example of FIG. 13A(c) is shown in FIG. 13B. The right side of FIG. 13B(a) shows a structure in which two pairs of optical property changing members having the structure of FIG. The thickness of this optical property changing member is 10t, 7t, 4t, 2t, 0, 3t, 6t, and 8t for each optical path (divided area).

The left end of FIG. 13B(b) shows an example in which the shift angle is set to 30 degrees instead of 45 degrees when two pairs of optical property changing members having the structure of FIG. On the other hand, a transparent semicircular parallel plate 94-5 with a thickness of 1t and a transparent semicircular parallel plate 94-6 with a thickness of 3t are overlapped (adhered) with a 90-degree shift (center view in FIG. 13B(b)), The right end of FIG. 13B(b) shows the optical property changing member formed by stacking (adhering) the left end group on top. In this structure, the transmitted light cross section 92 is equally divided into 12 areas (divided light path number N=12).

In the right end view of FIG. 13B, the transparent semicircular parallel plates 94-1 and 94-2 are bonded together to form an integrated optical property changing member. However, it is not limited to this, and a plurality of them may be distributed in the middle of the optical path. In this case, they may be arranged at a predetermined angle (for example, 22.5 degrees when two elements on the right end of FIG. 13B are distributed) so that the regions divided from each other do not overlap each other. .

A method of radially dividing the transmitted light cross section 92 (optical path division) into a circular shape is referred to as "radial division" in this embodiment. FIG. 13C shows an example of wavefront division of the transmitted light section 92 by this radial division and an example of combination with angle division.

Two transparent cylindrical parallel plates 116-1 and 116-2 with a thickness of 9t are superimposed on the right end structure of FIG. shown in

In the structure on the right side of FIG. 13C, the transmitted light section 92 is divided into 24 (3×8), and 24 different optical paths (the number of optical paths N=24) are simultaneously formed. Further, if the thickness of each optical path (divided area) is mt, all positive integer values included in the range of 0 to 28, excluding 1, 5, 14, 23, and 27, are used for each optical path (divided area). ).

In the right view of FIG. 13C, angle splitting and radial splitting are performed simultaneously within the integrated optical property-altering member. However, it is not limited to this, and a plurality of optical characteristic changing members that exhibit the same function may be distributed in the middle of the optical path. As an example, the angle-divided part and the radius-divided part may be separated from each other in the optical property changing member and dispersed on the optical path.

In the embodiment examples shown in FIGS. 12C to 13C, they are equally divided in the X/Y directions, angular directions, and radial directions. However, the present embodiment is not limited to this, and may be unequally divided for each divided optical path (for each divided area). Also, the number of optical paths N (or the number of divisions) generated by the optical property changing member may be set to an arbitrary value of 2 or more. Furthermore, in this embodiment, the transmitted light section 92 may be wavefront-divided by any other method.

As outlined in section 3.1 and explained in detail using formulas in section 3.5, the larger the number of optical paths N (or the number of divisions) generated by the optical property changing member, the higher the optical noise reduction effect. . In the wavefront splitting method that changes the thickness of the refractive element for transmitted light and the step amount for reflected light, the number of optical paths generated by the optical characteristic changing member is It can be arbitrarily set so as to increase N (or the number of divided regions). Furthermore, it becomes easy to achieve an optical arrangement in which the amount of light passing through each of the N-divided optical paths is substantially the same.

In contrast, with the amplitude division shown in FIG. 9, it is difficult to divide into many optical paths while ensuring the same intensity. Even if a plurality of amplitude splitting planes capable of splitting the amplitude are formed, the split light near the maximum intensity remains in only two optical paths. And the intensity of the other split optical paths tends to be greatly reduced.

As an optical property changing member having a wavefront splitting function, a prism having an inclination between the light incident surface and the light emitting surface may be used, or one surface may be non-flat. However, in this case, optical axis deviation is likely to occur for each optical path after transmission.

In contrast, as shown in FIGS. 12B to 13C, when a transparent parallel plate is used as a constituent element of the optical property changing member, and the light transmission direction 96 is set in the direction perpendicular to the plane thereof, "optical axis deviation after transmission" occurs. There is an effect that "all the optical paths after transmission (after emission) are kept parallel". This facilitates the combining (mixing) operation between different optical paths. Furthermore, even if the objective lens 25 and the detection lenses 28-1 and 2 are arranged after the synthesis (mixing) operation as shown in FIG. A detection signal is obtained.

When the wavefront splitting function is used to change the optical characteristics of the irradiation light (first light) 12 and detection light (second light) 16, the boundary lines (wavefront splitting boundaries) where the optical characteristics after the change are different from each other correspond to the light propagation. Appears in cross-sections perpendicular to the direction. A concrete example of this wavefront division boundary line corresponds to the boundary line 97 of the cross section shown in FIG. 12B and FIG. 13A.

By the way, in the light emitting source 70 (FIGS. 11 and 14A and 14B) using, for example, the tungsten filament 50, heat is generated during light emission. A mechanical fan is often used to cool the light source 70 . When this mechanical fan rotates, a minute mechanical vibration is generated, and this mechanical vibration may propagate to the "optical property changing member having a wavefront splitting function". As a result, the wavefront division boundary line may be slightly mechanically vibrated.

In the description of the materials used for the optical property changing member (or its base material) given at the end of Section 3.1, the existence of materials having large absorption bands in the near-infrared region was explained. Therefore, when a material having a large absorption band in the near-infrared region is used to create an "optical property changing member having a wavefront splitting function", the above absorption obtained from the detection units 4 and 6 (Figs. A noise component may be mixed in the detection signal of the in-band wavelength light. This noise component is generated in synchronization with the mechanical vibration of the wavefront division boundary. In order to remove this noise component, consideration should be given to material selection for the “optical characteristic changing member having a wavefront splitting function” as described at the end of Section 3.1.

That is, it is desirable to use an inorganic material instead of an organic material for the material of the "optical property changing member (or its base material) having a wavefront splitting function". Examples of inorganic materials include optical glass, CaF ₂ , MgF ₂ , LiF and KBr.

In particular, a low OH material that satisfies the condition that the amount of hydroxyl groups mixed in the material of the "optical property-changing member having a wavefront splitting function (or its base material)" is "100 ppm or less" (preferably "1 ppm or less"). Are suitable. Specific examples include "a glass material with less hydroxyl group contamination and production control", "anhydrous quartz glass", and "anhydrous quartz".

Considering the selection of the material for the "optical property changing member (or its base material) having a wavefront splitting function" in this way produces the effect of obtaining highly accurate spectral properties with less influence of mixing of mechanical vibrations.

Section 3.4 Synthesis (mixing) between split wavefronts
This Section 3.4 describes how light is combined/mixed after using the optical property modifying member described in Section 3.3. As described in Section 3.1 with reference to FIG. 10, after splitting the light into a plurality of optical paths using the optical property changing member, light that has passed through different optical paths is combined or mixed. The optical path state before synthesis/mixing described here is not limited to wavefront division, and any state (item) in the "optical path state before synthesis/mixing" column in FIG. 9 may be adapted. A combination of items may also be used, and FIGS. 14A and 14B show an example of a combination of "different light emission directions" and "wavefront splitting."

That is, the embodiment of FIGS. 14A and 14B utilizes the state (item) of the light emission direction that is different from the emission direction from the light source 70 (tungsten filament 50) directly to the collimating lens 26 and the emission direction to the rear mirror 82. ing. At the same time, an optical characteristic changing member that performs wavefront splitting by combining a transparent parallel plate 94-1 with a thickness Tb and a transparent parallel plate 94-2 with a thickness Ta is arranged in the middle of the optical path.

In addition, in the first half of Section 3.4, as items corresponding to the "synthesis/mixing place" column in FIG. In the second half of Section 3.4, the contents corresponding to "detection surface 86 in detector 80" and "pinhole or slit 130" will be explained. First, the description will start from the content corresponding to "in the middle of the optical path (of the irradiation light 12 and the detection light 16)".

In FIG. 14A, the optical system corresponding to the light combining (mixing) part in FIG. 8A(a) is composed of a combination of a condenser lens 98 and an optical fiber 100. In FIG. After passing through the optical characteristic changing member having this wavefront splitting function, the light passing through all the optical paths is all in a parallel state. When this light is condensed by the condensing lens 98, the equiphase planes of all the lights form a plane perpendicular to the optical axis on the condensing surface. This state is the state in which "the traveling directions of light passing through different optical paths are the same" as described in the first half of Section 3.1.

This condensing surface corresponds to the "predetermined location existing within a local area in the optical axis direction" described in the first half of Section 3.1. Then, the plane of incidence of the optical fiber 100 is aligned with this predetermined position. In the process of passing through the optical fiber 100, the light passing through each optical path wavefront-divided by the optical characteristic changing member is mixed. As a result, combined light (mixed light) 78 is emitted from the exit surface of the optical fiber 100 (combined light exit 108).

14A to the left entrance of the optical fiber 100 may be accommodated inside the light source unit 2 shown in FIGS. 1A to 1C or FIGS. 7, 8A, and 10B. The combined light exit 108 on the right side of the optical fiber 100 may then be placed near the object 10 .

The optical fiber 100 has very high flexibility, and the length of the optical fiber 100 can be set to any length (for example, 50 m or less). This has the effect of isolating the object 10 from the effects of heat and vibration generated in the vicinity of the light source 70 (tungsten filament 50).

In the column of "Photosynthesis/mixing method" in Fig. 9, "optical phase conversion elements" (random phase shifters, diffusers, sand (including sliding surfaces, etc.) are described. A specific example embodiment using this method is shown in FIG. 14B.

Similar to FIG. 14A, different light paths utilize light in different light emitting directions (forward and backward). Further, the optical characteristic changing member combining the transparent semicircular parallel plates 94-1 and 94-2 is not limited to the structure shown in FIGS.

The "optical phase conversion element" described in the "photosynthesis/mixing method" column in FIG. 9 corresponds to the transparent flat plate (lightsynthesis unit 102-2) 104 having a random fine uneven structure on one side. Light that has passed through any optical path is simultaneously diffused by this fine uneven surface and propagates in a wide range of directions. Due to this feature, a portion of the light diffused from every position on this micro-roughened surface also travels in the same specific direction. By the way, as explained in Section 3.3, in "wavefront splitting", the optical paths of light passing (or reflecting) at different positions on the transmitted light cross-section 92 (Fig. 12B or Fig. 13A) are different from each other. Therefore, the light extracted in a specific traveling direction after passing through the “optical phase conversion element” (or after being reflected) is “a state in which the traveling directions of the light that have passed through different optical paths are the same” (as described in the first half of Section 3.1). match).

As a specific method for extracting the light traveling in a specific direction after passing through (or after being reflected by) the “optical phase conversion element”, for example, as shown in FIG. You may extract only the light which passed through. Alternatively, as shown in FIG. 14D, the imaging surface (detection surface) 86 of the monitor camera 24 may be placed on the condensing surface of the detection lens 28-2, and the light irradiated only to specific pixels therein may be detected.

As described above, even if the light traveling in a specific direction after passing through (or reflecting) the "optical phase conversion element" is not extracted, one side of the transparent flat plate (light combining section 102-2) has a random fine concave-convex structure. Mixing (or combining) of light occurs in the wavefront 106 of the passing light at a predetermined distance or more from 104 . Light may be mixed (or synthesized) by utilizing the diffraction phenomenon of light in this manner.

When light is mixed (or synthesized) by using an "optical phase conversion element" in this way, mixing (or synthesis) occurs regardless of the traveling direction of light at a certain distance or more. Therefore, the generation of the combined light (mixed light) 78 does not require high-precision optical arrangement or optical axis alignment.

Further, as shown in FIG. 14B, an optical phase conversion element is directly adhered to a part (light exit) of an optical property changing member (consisting of transparent semicircular parallel plates 94-1 and 94-2), thereby forming an optical property changing member. An optical phase conversion element may be integrated. As a result, a single optical element has both an optical path separation (dividing) function and a photosynthesis/mixing function, making it easy to modify an existing measurement device (or microscopic device).

In FIG. 14B, an optical phase conversion element (transparent flat plate (light combining section 102-2) 104 having a random fine concave-convex structure on one side) or an integrated element with an optical property changing member is arranged in the light source section 2. FIG. However, it is not limited to this, and may be arranged in the detection section 6, or may be arranged in both the light source section 2 and the detection section 6 as shown in FIG. (In this case, the optical phase conversion element or the integrated element with the optical characteristic changing member corresponds to the optical noise reduction element or the partial coherence reduction element 64.)
FIG. 14C shows an example of a method using a "diffraction-related element" in the "photosynthesis/mixing method" column of FIG. Although the blazed diffraction grating 124 is used as the diffraction-related element in FIG. 14C, any optical element having a function of synthesizing (mixing) light using diffraction may be used.
Generally, diffraction-related elements are often used for splitting transmitted or reflected light. However, when viewed in reverse, the light path along which the light is split takes the form of light being combined (or mixed). Using this feature, the synthetic light (mixed light) 78 is generated.

The transparent parallel plates 114-1 and 114-2 are combined to form an optical characteristic changing member utilizing wavefront splitting. An optical element for changing the traveling direction of light, such as a Fresnel prism (blazed hologram) 122, is arranged at the exit of at least a part of this optical characteristic changing member. Note that the optical element for changing the light traveling direction and the optical characteristic changing member may be integrated by bonding.

Then, the passing light 110-1 whose traveling direction is changed is combined with the passing light 110-2 that has passed through only the transparent parallel plate 114-1 at the blazed diffraction grating 124. FIG. Therefore, the combined portion of the Fresnel prism (blazed hologram) 122 and the blazed diffraction grating 124 becomes a light combining (mixing) portion 102-3, which corresponds to the light combining (mixing) portion 102 in FIG. 8A(a) or FIG. 8B(a). .

Note that in this example embodiment of FIG. 14C, transmitted light 110-1, 2 is used. However, the combined light (mixed light) 78 may be generated using the reflected light.

An example embodiment corresponding to "Detection Plane 86 in Detector 80" in the "Synthesis/Mixing Location" column of FIG. 9 is shown in FIG. 14D. By using this embodiment, a magnified image of the minute light scatterer 66 can be clearly imaged.

An imaging plane (detection plane) 86 in the monitor camera 24 is an imaging plane for the minute light scatterers 66 by combining the objective lens 25 and the detection lens 28-2. A part of this imaging optical system (or confocal optical system) is used for light synthesis/mixing. In an imaging optical system (or a confocal optical system), light starting from one point converges to one point on the imaging plane regardless of the optical path. At the position of the focal point on the imaging plane, the lights passing through all the optical paths are combined/mixed.

Therefore, when an optical characteristic changing member that divides (separates) into a plurality of optical paths having different optical path lengths is arranged in the optical path of the imaging optical system, the optical arrangements shown in FIGS. 8B(b) and 10(c) are formed. 14D and the imaging surface (detection surface) 86 in the monitor camera 24 can be replaced with the light combining (mixing) unit 102-4 shown in FIG. 8B(a). You may make it correspond to the part 102. FIG.

The spectroscope 22 shown in FIG. 14E has a structure for measuring the spectral characteristics of only the light passing through the pinhole or slit 130 arranged at the entrance. That is, the light passing through the pinhole or slit 130 is returned to parallel light by the condenser lens 134-1, and is wavelength-separated using diffraction by the blazed diffraction grating 126. FIG. Then, the separated light of each wavelength is focused on the one-dimensional line sensor 132 by the condenser lens 134-2. The spectral characteristics are measured by detecting the distribution of the amount of light irradiated onto the one-dimensional line sensor 132 .

Also in another application embodiment example shown in FIG. 14E, an imaging optical system (or a confocal optical system) is used to synthesize (mix) light that has passed through a plurality of optical paths with different optical path lengths. In this case, only the light obtained from the optical axis of the objective lens 25 within the minute light scatterer 66 passes through the pinhole or slit 130 arranged at the imaging position (or confocal position). pass.

As a device for measuring the spectral characteristics of only a local region within the minute light scattering medium 66, a pinhole or slit 130 at the entrance of the spectroscope 22 is placed at the imaging position (or confocal position) of the local region. are matching. However, not limited to this, a single pinhole or slit 130 may be arranged at a predetermined position in the optical path (imaging position (or confocal position) corresponding to a small local area inside the light scatterer 66).

If the parallel plates 94-1 and 94-2 are arranged in the middle of the diverging optical path or the middle of the converging optical path in the imaging optical system, unnecessary light interference occurs as shown by the equation (B.28) in Section 2.5. In addition, as will be described later in Chapter 6, the formed image deteriorates due to the influence of spherical aberration. Therefore, in this embodiment shown in FIGS. 14D and 14E, an optical characteristic changing member composed of transparent semicircular parallel plates 94-1 and 94-2 is arranged in the middle of the parallel optical path. As a specific example of this embodiment, as shown in FIG. 22, the illumination light 12 is collimated between the collimator lens 26 and the condenser lens 98 . Transparent semicircular parallel flat plates 94-1 and 94-2, which are optical characteristic changing members, are arranged in the middle of the optical path in this parallel state. However, not limited to the above example, any form of optical property changing member described in the column of "light combining/mixing method" in FIG. As a result, unnecessary light interference is removed, optical noise is removed, and an effect is produced that makes it possible to sharpen the formed image.

14D and 14E, any member having the function of "wavefront splitting" or "amplitude splitting" in FIG.

So far in section 3.4, the explanation has focused on the method of mixing or synthesizing light that has passed through a plurality of optical paths divided mainly by "wavefront splitting". However, as described in the "detailed content" column of FIG. 9, the light that has passed through a plurality of optical paths divided by "amplitude division" may be mixed or synthesized.

In the case of mixing light that has passed through a plurality of optical paths divided by "amplitude division", in this embodiment, the direction of the vibration plane (of the electric field) in the mixed light may be matched. For example, if the vibration planes (of the electric field) of the light passing through the two optical paths divided by "amplitude splitting" are tilted (not completely matched), the vibration planes of both are may be aligned in the same direction. As a specific example of this method, an analyzer 496 or a polarizing beam splitter 492 shown in FIG. 33 may be used to extract (transmit) only light components having a predetermined plane of vibration.

When the direction of the plane of vibration in the mixed light is deviated using the analyzer 496 or the polarizing beam splitter 492, the mixed light becomes linearly polarized light. However, this embodiment is not limited to this, as long as the polarization characteristics in the mixed light match, and may be circularly polarized light or elliptically polarized light. The above operation is not limited to the case of mixing or synthesizing light that has passed through multiple optical paths divided by "amplitude division", and can be applied to any method described in the "details" column of FIG. Also good.

When signal detection/measurement (including spectral characteristic detection), imaging, or wavefront aberration characteristic detection/measurement is performed in the detection unit 6 (FIGS. 1A to 1C) using the mixed light, for example, as shown in FIG. In some cases, "polarization plane manipulation" (optical manipulation regarding the vibration plane of a specific electric field) is performed. If the polarization properties in the mixed light are different (between the different optical paths before mixing), the "polarization plane manipulation" inside the detector 6 may increase the partial coherence and increase the optical noise. . Therefore, when the polarization characteristics (or vibration plane direction) in the mixed light match, even if "polarization plane manipulation" is performed inside the detection unit 6, optical noise increase is suppressed and stable signal detection/measurement (spectral characteristic detection ), imaging, or wavefront aberration characteristic detection/measurement.

Section 3.5 Optical intensity mathematical expression when using partially incoherent light (optical noise reduction effect)
(Section 3.5) Light Intensity Formula of Partially Incoherent Light indicating Optical Noise Reduction Effect)
Section 3.1 qualitatively explained how the method of the present embodiment reduces optical noise. In Section 3.5, the effect of implementation is quantitatively explained using mathematical formulas.

Consider a case where the transmitted light cross section 92 is evenly divided into N (equally divided into N areas) by the angular division shown in the examples of FIGS. 13A and 13B. As already explained in Section 2.5, the uniformity of the thickness T of the bulb (quartz glass) 67 of the tungsten-halogen lamp of FIG. 6, for example, is low. Therefore, when the average thickness of each N-divided area is Tm, the average thickness Tm shows a different value for each different area m.

Due to the action of the optical property changing members of FIGS. 13A and 13B, the lights passing through different optical paths exhibit partial incoherence with each other. As a result, at the place where they are mixed, no synthesis (summation) occurs on the amplitude characteristic expressed by equation (B.19). Instead, at the mixing location, the transmitted light intensities (quantities) of the different optical paths are simply added.

From the above situation, the light intensity characteristic after mixing the partially incoherent light is

and transformed.

The second term on the right side of equation (B.30) indicates the amount of optical noise caused by optical interference. Since the numerator of the second term has a different average thickness Tm for each different optical path, the period of change according to the measurement wavelength λ is different. It is considered that the variation amplitude maximum value of the second term on the right side is reduced by averaging the cosine waves having different periods.

Comparing the expression (B-28) showing the detected intensity distribution of the partially coherent light and the expression (B-30) showing the detected intensity distribution of the partially incoherent light, it can be seen that by adopting the method of this embodiment, It can be seen that the amount of optical noise is greatly reduced. 13A and 13B are described as an example, but the results are similar to those described above for all the "optical path states before synthesis/mixing" in FIG.

As explained at the end of section 2.6, due to the influence of the tube inside the light source, the average An optical noise component of about 0.1 to 1.0% is included. In this embodiment, due to the effect of formula (B-30), the optical noise component amount is 0.5% or less on average (or 0.1% or less on average, preferably 0.05% or less on average or 0.02% or less on average). ). Here, the amount of optical noise component is the optical noise component (average amplitude value). Note that the experimental data of FIG. 23A(c) cited in Chapter 5 etc. shows that the optical noise component is greatly reduced (the above numerical value is satisfied).

If all the average thicknesses Tm for different optical paths match, the equation (B.30) completely matches the equation (B.28). ) does not appear. By the way, the formula (B.30) expresses a state in which the partial coherence decreases and the partial incoherence increases between lights that have passed through different optical paths. However, the method of the present embodiment for reducing optical noise is not an absolutely universal method, and the effect of reducing optical noise diminishes in situations where strong optical interference occurs in the optical system (for example, all Tm are the same). .

Also, even when the average thicknesses Tm for different optical paths do not all match, if the value of the number of divided optical paths N is small, a beat occurs in the second term of the right side of the equation (B.30). For simplification of explanation, the case of N=2 will be explained. Even in the situation where T ₁ ≠T ₂ , there are values of wavelength λ at which the value of the second term on the right side of equation (B·30) is 1/2 and wavelength λ at which it is −1/2. Since the interval (wavelength difference) between the two is much wider than the period of the formula (B.28), setting the detection/measurement wavelength range to a narrower range produces the effect of reducing optical noise. However, the configuration of the optical system in which the beat is hard to occur is preferred.

Therefore, in this embodiment, the value of the number of divided optical paths N is desirably "3 or more", more preferably 4 or more, 8 or more, or 9 or more. In order to increase the value of the divided number of optical paths N, in this embodiment, a plurality of items described in the "Details" column of FIG. 9 may be used in combination.

Section 3.6 Structural Ingenuity of the Optical Characteristic Changing Member This Section 3.6 describes the points to note and the details of the technical contrivance when using the optical characteristic changing member having the wavefront splitting function described in Section 3.3. As an example, a transparent semicircular parallel plate 94-1 with a thickness T and a transparent semicircular parallel plate 94-2 with a thickness of 2T are combined (adhered) to form an optical property changing member.

When light reflection occurs at the interface between the adhesive layer 112 and the transparent semicircular parallel plate 94-1 or 94-2 as shown in FIG. Noise increases. In addition, as shown in FIG. 15A, there is a risk that light reflection occurs at the interface between the transparent semicircular parallel plate 94-1 or 94-2 and the air, causing unnecessary light interference.

Furthermore, as shown in FIG. 15(c), when the cut surface 95 of the transparent semicircular parallel plate 94-2 is inclined with respect to the optical axis of the transmitted light 110-2, or when the boundary line 97 of the cut surface is widened, , that part becomes a shadow and causes an unnecessary loss of the amount of transmitted light. Further, when the parallelism between the parallel surfaces of the transparent semicircular parallel plate 94-2 decreases, the traveling angle ζ of the transmitted light 110-1 after passing through the transparent semicircular parallel plate 94-2 ( The angle formed with the direction of travel) becomes large, and the directions of travel tend to be inconsistent with each other after mixing (see the description in the first half of Section 3.1).

In order to prevent light reflection at the interface between the transparent parallel plates 114-1 and 2 and the adhesive layer 112, the interface between the two is aligned with the optical axis of the transmitted light 110-1 and 2 as shown in FIG. 16A(a). They may be arranged substantially parallel. As another method, in this embodiment, the refractive index of the adhesive layer 112 may be adjusted to the refractive index of the material to be bonded (that is, the glass material constituting the transparent parallel plates 114-1 and 114-2).

In addition, in order to prevent light reflection (and light interference caused thereby) on the front and back surfaces of the transparent semicircular parallel plates 94-1 and 94-2 shown in FIG. may be provided with antireflection coating layers 118-1 to 118-3. In other words, not only the “wavefront splitting” in the “detailed contents” of FIG. to prevent As a result, there is an effect that unnecessary optical interference can be prevented and an increase in optical noise can be prevented.

In order to prevent the light amount loss of the transmitted light due to the boundary line 97 of the cut surface and the cut surface 95 described with reference to FIG. That is, the width of the boundary line 97 of the cut surface in the optical property changing member is set to 1 mm or less (preferably 0.5 mm or less or 0.2 mm or less). Further, when the maximum thickness of the optical property changing member is T, and the inclination angle of the cut surface 95 with respect to the optical axis of the transmitted light 110-2 is η, the value of Ttanη is 1 mm or less (preferably 0.5 mm or less or 0.2 mm). below).

At the beginning of Section 3.1, it was explained that ``lights passing through a plurality of optical paths are combined or mixed at a predetermined location''. To make this possible, an allowable range of manufacturing accuracy of the optical property changing member (for example, parallel accuracy within the optical property changing member) is defined.

For example, in the embodiment of FIG. 14E, the pinholes or slits 130 are combined or blended. Therefore, it is necessary that the light passing only through the transparent semicircular parallel plate 94-1 and the light passing through the transparent semicircular parallel plate 94-2 also pass through the pinhole or slit 130 at the same time.

Let θ be the inclination angle between the two planes forming the transparent semicircular parallel plate 94-2 with the refractive index n. If the angle of inclination in the traveling direction of the light after passing through the transparent parallel plate is ζ, approximately ζ ≈ (n − 1) θ (B・31)
relationship is established. Let "F" be the focal length of the detection lens 28-2. A value of 1/2 of the pinhole radius/slit width W is defined as "a". Based on the position where only the transparent semicircular parallel plate 94-1 is passed and condensed on the surface of the pinhole or slit 130, the transparent semicircular parallel plate 94-2 on the surface of the pinhole or slit 130 was also passed. Assuming that the amount of deviation of the position where the light is condensed is D, it can be approximated as D≈Fζ. Since the condition that this light can pass through the pinhole or slit 130 is D<a, the above can be summarized as follows.

relationship is established. Therefore, the manufacturing accuracy of the optical property changing member (for example, the parallelism accuracy within the optical property changing member) is defined so as to satisfy the above conditions.

Section 3.7 Comparison with conventional technology using wavefront splitting
Here, the difference between the prior art described in [Patent Document 1] specified in [Prior Art Document] and the present embodiment will be described.

In [Patent Document 1], as shown in FIG. 17, the optical fiber 100-1 and the optical fiber 100-2 have different optical path lengths and are mixed by the collimating lens 136. FIG. However, in this prior art, the traveling directions of light after mixing do not match. That is, since the exits of the optical fibers 100-1 and 100-2 are arranged on the front focal plane of the collimating lens 136, the traveling directions of the light collimated by the collimating lens 136 are different from each other α and β. As a result, the equiphase planes (wavefronts) of the light traveling directions α and β after passing through the collimating lens 136 are tilted with respect to each other, and high-precision light synthesis or light mixing cannot be performed. Therefore, the partial coherence reduction effect becomes insufficient.

Furthermore, as shown in FIG. 8A or FIG. 10B, in this embodiment, after all the light traveling directions of the synthesized light (mixed light) 78 are matched (irrespective of the optical paths before synthesis/mixing), the target object 10 is irradiated to Accordingly, when the object 10 is irradiated with converged light as shown in FIGS. 1C and 7, all the light can efficiently irradiate the specific region α in the object. Then, for example, as shown in FIGS. 14D and 14E , especially for measurement and observation of a local specific region in a minute light scattering body 66, there is an effect that high signal detection accuracy, high imaging accuracy, and spectral characteristic measurement accuracy can be secured. There is

Section 3.8 Optical characteristic changing member with optical waveguide function An example embodiment will be described. In this embodiment, by making the length of the waveguide element longer than a predetermined distance, the optical path length is changed for each optical path of light passing through the waveguide element, thereby reducing the partial coherence. The optical path length of each optical path of light passing through the waveguide element may be longer than the coherence length given by the formula (B.6) or (B.12). That is, the above predetermined distance may correspond to the coherence distance.

The range of the maximum incident angle ε that enters from the entrance of the optical fiber 100-2 is defined by NA (strictly speaking, NA=sin ε in a vacuum (air)). When the value of ε is sufficiently small, NA≈ε. Also, the angle of incidence within the core region 142 of the optical fiber 100-2 at this time is represented by ξ. If the refractive index in the core region 142 of the optical fiber 100-2 is represented by n, Snell's law provides an approximation of ε≈n×ξ.

The optical path difference δ generated between the light passing through the optical path straight through the center of the core region 142 of the optical fiber 100-2 and the light passing through the optical path near the interface between the core region 142 and the clad layer 144 Estimate the value.

An optical path that also passes through the vicinity of the interface between the core region 142 and the clad layer 144 draws a curve as shown in FIG. 18(a). For simplicity of calculation, this curve is linearly approximated. That is, it is assumed that the optical path in the core region 142 travels straight and is totally reflected near the interface between the core region 142 and the clad layer 144 .

The optical path length difference δ ^* per unit length of the optical fiber 100-2 between this optical path and the optical path traveling straight through the central portion of the core region 142 is δ ^* ≈ {(1/cos ξ)-1}n... (B-33)
Therefore, when the total length of the optical fiber 100-2 is L, the total value δ=Lδ ^* of the optical path difference after passing through the optical fiber 100-2 is given by the formula (B.6) or (B.12). The condition for longer than the coherence length l _CL obtained from FIG.

is given by If the total length L of the optical fiber 100-2 is made longer than the length that satisfies this formula (B.34), the partial coherence of the light passing through the optical fiber 100-2 is reduced.

The above equation (B.34) is not a conditional expression that holds only for the optical fiber 100-2, but is also applicable to any waveguide element (for example, an optical waveguide formed (integrated and arranged) on a substrate). .

Section 3.9 Methods for Combining/Mixing Emissions from Different Regions An example embodiment using the "different emission regions" in FIG. 9 will now be described. This case also basically follows the basic principle explained in Section 3.1. That is, in this embodiment, the difference δ between the optical path lengths to the specific region (or measurement point) γ in the object 10 is the coherence length l Light emitted from a plurality of light emitting regions longer than _CL (eg, the α and β regions near the tungsten filament 50 in FIG. 2A) is mixed and irradiated onto the object 10 . Alternatively, the detected light 16 after passing through the object 10 (light detected by the photodetector 80 in FIG. 8B or FIG. 10) includes combined light or mixed light of the light generated from the α region and the β region. can be

19A and 19B, this Section 3.9 outlines a basic embodiment method in which the content already described in FIG. 8A is applied to "different light emitting regions" (FIG. 9). After that, a specific embodiment example thereof will be described with reference to FIGS. 20 to 21C and FIGS. 24A and 24B.

In section 3.9, the light emitting source 70 using the tungsten filament 50 will be described as an example of a different light emitting region. However, not limited to this, all light emitting sources 70 having characteristics of simultaneously emitting light from a relatively wide area may be adapted to the description. Also, here, an example of "the same light emitting source 70" having different light emitting regions is used for explanation. However, not limited to this, different light emitting regions may be distributed over different light emitting sources. That is, in this embodiment, light emitted from a plurality of different light emitting sources may be mixed and used as the irradiation light (first light) 12 (FIGS. 1A to 1C). In this case, a plurality of different light emitting sources are built inside the light source section 2 shown in FIGS. 1A to 1C. Also in this case, in the photosynthesis (mixing) unit 102 (FIG. 8A (a)), as described in Section 3.1, the traveling direction of light emitted from a plurality of different light emitting regions (or the vibration plane direction of the electric field) should be almost the same.

FIG. 19A shows a basic embodiment method applying what has already been described in FIG. 8A(b) to the “different emission regions” (FIG. 9). 19A(a), an optical path changing element 210 corresponding to a kind of optical property changing member is arranged between the light source 70 (tungsten filament 50) and the object 10. In FIG. On the other hand, in FIG. 19A(a), there is no such case, and the object 10 is directly irradiated with the light emitted from the light source 70 (tungsten filament 50).

In both FIGS. 19A (a) and (b), the α-region corresponding to the target in-vivo specific region 200 is the photosynthesis/mixing site. Here not all the light emitted from the light source 70 (tungsten filament 50) passes through the alpha region within the object 10. FIG. Only part of the light emitted from the light source 70 (tungsten filament 50) passes through the α region, and only the light that has passed through this α region is selectively extracted by the detector 6. FIG. This α area corresponds to the "particular area 200 within the object 10" or "(including image formation on the detection surface 86, etc.)" in the "Synthesis/Mixing Location" column of FIG. will be used later.

The differences δ ₁ and δ ₂ between the optical path lengths from the plurality of light emitting regions within the same light source 70 to the point α corresponding to the intra-subject specific region 200 are given by equation (B-6) or (B-12). longer than the coherence length l _CL provided, the partial coherence between the light emitted from each light emitting region is reduced.

Due to the geometric arrangement in FIG. 19A(a), the greater the distance between the light source 70 (tungsten filament 50) and the object 10, the smaller the values of the respective optical path length differences δ ₁ , δ ₂ . . Conversely, when the distance between the light source 70 (tungsten filament 50) and the object 10 is shortened, the values of the optical path length differences δ ₁ and δ ₂ become is reduced to a distance of

Therefore, when the distance between the light emitting regions on the same light source 70 is longer than the coherence length _lCL given by the formula (B.6) or (B.12), the light source 70 (tungsten filament 50) and Partial coherence always decreases regardless of the distance between objects 10 . Therefore, in this embodiment, the width (length) of the wide light emitting region in the light emitting source 70 may be set longer than the coherence length _lCL given by the equation (B.6) or (B.12). .

Especially when the tungsten filament 50 is used as the light emitting source 70, the width of the light emitting region differs between the vertical direction and the horizontal direction. In this case (when the width (length) of the wide light emitting region is different in the direction of the light emitting source 70), the length of the widest part of the light emitting region in the light emitting source 70 is determined from the coherence length l _CL You can make it longer.

By the way, when the distance between the light source 70 and the object 10 is sufficiently short and the widest width of the light emitting region in the light source 70 is the same as the coherence length _lCL , the light emitted from the light emitting regions at both ends in the light source 70 is Only partial incoherence can be obtained between the light beams. In this case, partial coherence is maintained between the lights emitted from the light-emitting regions near the center of the light-emitting source 70 .

It was explained in the first half of section 3.1 (or section 3.5) that the larger the value of the number of optical paths N at which the mutual optical path length difference δ is longer than the coherence length _lCL , the better. Therefore, from the viewpoint of the optical noise reduction effect, the width of the light emitting region in the light emitting source 70 should be wider. Therefore, as a condition that the optical noise reduction effect can always be exhibited regardless of the distance between the light source 70 and the target object 10, the length of the widest part of the light emitting region in the light source 70 is larger than N×l _CL . things are desirable. Here, the value of N is preferably "2 or more", more preferably 3 or more, 4 or more, or 8 or more.

In other words, the optical system may be arranged such that the object 10 is irradiated with light emitted from a wide-area light-emitting area wider than N×l _CL in the light-emitting source 70 . In addition to this, light emitted from a wide-area light-emitting region wider than N×l _CL in the light-emitting source 70 passes through the object 10 and passes through the photodetector 80 in the detection units 4 and 6 (FIG. 8B or FIG. 10 ( The optical system may be arranged to reach c)).

In Section 3.1, two types of functions that the optical property changing member can exhibit have been explained. An optical path changing element (optical property changing member) 210 used in FIG. change/control”.

That is, the traveling direction (optical path) of light emitted from a plurality of different light emitting regions on the light emitting source 70 (tungsten filament 50) is changed by the optical path changing element (optical property changing member) 210. FIG.

As the optical path changing element (optical property changing member) 210, an optical phase conversion element or a diffraction-related element described in the column "Method of light synthesis/mixing" in FIG. 9 may be used. As a result, the light passing through the optical path changing element (optical property changing member) 210 is diffused. A portion of the diffused light reaches the α-region within the target body 10 of the target body specific region (photosynthesis/mixing site) 200 .

As described above, the differences δ ₁ and δ ₂ between the optical path lengths from the plurality of light emitting regions in the same light emitting source 70 to the point α in the object 10 increase as the distance between the light emitting source 70 and the object 10 decreases. However, since the light source 70 (tungsten filament 50) generates a large amount of heat and vibration (rotational vibration of a heat dissipation fan, etc.), it is difficult to arrange the light source 70 and the object 10 at a short distance. As a countermeasure, an optical path changing element (optical property changing member) 210 is arranged between the light source 70 (tungsten filament 50) and the object 10. FIG. By bringing it closer to the object ₁₀ , the differences δ1 and δ2 between the optical path lengths from the plurality of light _- emitting regions in the light-emitting source 70 are increased, thereby making it easier to reduce the partial coherence.

Diverging light is actually emitted from each light-emitting region in the light-emitting source 70 . However, as will be described later, a specific region 200 within the target object 10 has a light path that matches the photosynthesis/mixing location. Consider the case where In this case, as in the description of FIG. 19A(a), if the width (length) of the wide light emitting region in the light emitting source 70 is longer than the coherence length _lCL , the partial coherence of the combined light tends to decrease. .

As in FIG. 19A(a), also in FIG. 19A(b), it is desirable that the length of the widest portion of the light emitting region in the light emitting source 70 is larger than N×l _CL (the value of N is “2 or more”, 3 or more, or 8 or more are also acceptable). Also in the method of FIG. 19A(b), the optical system may be arranged so that the target object 10 is irradiated with light emitted from a wide-area light-emitting area wider than N×l _CL in the light-emitting source 70 . Further, the light emitted from the wide-area light-emitting area wider than N×l _CL in the light-emitting source 70 passes through the object 10 and reaches the photodetector 80 (FIG. 8B or FIG. 10(c)) in the detection units 4 and 6. The optical system may be arranged as follows. Here, these conditions may be applied not only to FIG. 19A but also to FIGS. 19B(a) and 19B(b).

The method shown in FIGS. 19A (a) and (b) is to selectively extract only the light that has passed through the α region in the target body 10 in the detection units 4 and 6, so that the specific region 200 within the target body is photosynthesized/ Set to mixed location. 19B(a) and (b), a light combining (mixing) unit 102 is installed inside the light source unit 2 to generate combined light (mixed light) 78. In the method shown in FIGS. In this case, the differences δ ₁ and δ ₂ between the optical path lengths from a plurality of different light emitting regions in the light emitting source 70 to the photosynthesis (mixing) portion 102 are made longer than the coherence length l _CL , Reduces static coherence.

And FIG. 19B shows a basic embodiment method applying what has already been described in FIG.

In FIG. 19B(a), light emitted from a plurality of different light-emitting regions within light-emitting source 70 directly reaches photosynthesis (mixing) section 102 . On the other hand, in FIG. 19B(b), an optical path changing element (optical property changing member) 210 similar to that in FIG.

FIG. 20 shows a specific embodiment example of setting the α region of the intra-subject specific region 200 in FIGS. Here, FIG. 20(a) corresponds to FIG. 19A(a), and FIG. 20(b) corresponds to FIG. 19A(b). In both FIGS. 20A and 20B, the α region within the target object 10 corresponds to the “specific region 200 within the target object 10” in the “synthesis/mixing place” column of FIG. 9 .

A spectroscope 22 and a monitor camera 24 are installed in the detection unit 6 to detect detection light (second light) 16 obtained from the object 10 and measure the inside of the object 10 . Here, the position of the imaging surface (detection surface) 86 (see FIG. 14D) in the monitor camera 24 and the position of the pinhole or slit 130 (see FIG. 14E) in the spectroscope 22 are the α region (α point ) and imaging (confocal). Therefore, the monitor camera 24 and the spectroscope 22 selectively extract signals obtained from the α region (α point) within the object 10 . Arranging the detection planes in this manner corresponds to "(including imaging on the detection plane 86, etc.)" in the column "Synthesis/Mixing Place" in FIG.

On the other hand, the light emitted from a plurality of different light emitting regions in the light emitting source 70 (FIG. 20(a)) or the light after passing through the optical path changing element (optical property converting member) 210 spreads as diffused light. Part of the light emitted from all of the plurality of different light-emitting regions within the light-emitting source 70 passes through the α-region within the object 10 . Therefore, by using the imaging optical system in the detection unit 6, light emitted from a plurality of different light emitting regions in the light source 70 is substantially combined/combined within the α region (α point) in the object 10. mixed.

In FIG. 20, a monitor camera 24 and a spectroscope 22 are used for signal detection. However, not limited to this, in this embodiment, any signal detection means (broadly defined photodetector 80) may be arranged at the imaging position (confocal position).

A specific example embodiment for FIGS. 19B(a) and (b) is shown in FIG. 21A. Here, FIG. 21A(a) corresponds to FIG. 19B(a), and FIG. 21A(b) corresponds to FIG. 19B(b). As an example of the photodetector 80, the spectroscope 22 is used in FIG. 21A. However, the photodetector 80 having an arbitrary function may be used as means for detecting a signal obtained from the object 10 without being limited thereto.

In FIG. 21A(a), the collimating lens 26 performs part of the function of the light combining (mixing) section 102 in FIG. 19B(a). That is, the divergent light beams emitted from a plurality of light emitting regions (regions α, β, γ) in the light source 70 are partially synthesized (mixed) on the collimating lens 26 .

However, the equal phase plane (wavefront) after passing through the collimator lens 26 has a relationship in which the light emitting regions are inclined with respect to each of α, β, and γ (the traveling directions of the light do not match). Therefore, in this state, as in FIG. 17, they are not completely synthesized (mixed).

The light after passing through the collimating lens 26 is diffused by multiple scattering inside the object 10 . The detection unit 6 extracts and detects only parallel light beams "with the same traveling directions" from the detection light beam 16 that has passed through the object 10 by combining the detection lens 28 and the pinhole or slit 130 . Therefore, in the embodiment shown in FIG. 21A(a), the combination of the collimator lens 26 and the object 10 (multiple scattering inside) (strictly, the combination including the detection unit 6) allows the light combining (mixing) unit 102 to Configured.

As the optical path changing element 210, which is a kind of optical characteristic changing member in FIG. 19B(b), in FIG. The direction of travel of the light emitted from each of the light emitting regions α, β, and γ in the light source 70 is further diffused (the direction of travel of the light is changed to a direction in which it spreads further). As a result, the collimated light after passing through the collimating lens 26 contains the light emitted from the α, β, and γ light emitting regions (the light emitted from the α, β, and γ light emitting regions is included in the parallel light). (The direction of travel of light passing through different optical paths is the same).

21A(a) and FIG. 21A(b), the combination of the detection lens 28 and the pinhole or slit 130 in the detection unit 6 selectively detects only the parallel light component of the light that has passed through the object 10. be done.

Therefore, in FIG. 21A(b), the collimator lens (strictly speaking, the combination including the detection unit 6) corresponds to the light combining (mixing) unit 102 in FIG. 19B(b).

In FIG. 21A(b), the irradiation light 12 after passing through the collimator lens 26 also contains a large amount of non-parallel components. A beam expander is placed between the collimating lens 26 and the object 10 as a specific method for further improving the partial incoherence by matching the direction of travel of the combined light (mixed light) 78 irradiating the object 10 . , and a pinhole may be arranged in the condensing part on the way.

Another embodiment using the phase conversion element 212 as means for realizing the optical path changing element 210 that realizes "(A) the function of changing/controlling the optical path length for each of a plurality of optical paths" among the functions of the optical characteristic changing member is shown. Shown in FIG. 21B. In a panchromatic light source such as a tungsten-halogen lamp or a xenon lamp, a halogen-based gas (iodine or bromine compound) or xenon gas is sealed in the tube. Then, the inner wall or the outer wall of the tube 214 is formed with fine irregularities to have a phase conversion characteristic. As a result, the paths of light emitted from different light emitting regions on light source 70 (eg, tungsten filament 50) are varied, and the optical path length for each of the multiple light paths is varied/controlled.

Furthermore, the rear mirror 82 is used to synthesize (mix) the light that has passed through different optical paths. The use of a tube (and rear mirror 82) having phase conversion properties on the inner or outer wall as in FIG. 21B has the effect of producing light with reduced partial coherence at very low cost. Alternatively, the optical phase conversion element or the diffraction-related element described in the “Method of light synthesis/mixing” column of FIG. 9 may be arranged near the tube 214 .

Since the light reflected by the rear mirror 82 becomes parallel light, an optical characteristic changing member having a wavefront splitting function, such as 12A to 13C, which is not shown, may be arranged in the optical path of the parallel light. Alternatively, a light combining (mixing) section 102-1 composed of the condenser lens 98 and the optical fiber 100 shown in FIG. 14A may be arranged behind the optical characteristic changing member. Furthermore, as the optical fiber 100 used at this time, the bundle type optical fiber 300 used in FIG. 21C may be used.

Another embodiment of the optical path changing element (optical property changing member) 210 of FIG. 19B(b) will be described with reference to FIG. 21C. This optical path changing element (optical property changing member) 210 corresponds to a combination of an imaging lens 215, a collimating lens 26, and a bundle-type optical fiber group 300 (optical fibers 100).

In particular, the bundled optical fiber group 300 (optical fiber 100) collects emitted light from a very wide range of light emitting regions (α, β, γ regions (each point)) on the light source 70 to It has the ability to irradiate 10. Furthermore, the effect of blocking the influence of heat generated from the tungsten filament 50 of the light source 70 and vibration from the cooling fan between the inlet and outlet of the bundle type optical fiber group 300 (optical fiber 100) is exhibited.

Diffused light emitted from different light emitting regions (regions (each point) of α, β, and γ) on the light source 70 passes through the imaging lens 216 onto the incident surface of the bundle-shaped optical fiber group 300 (optical fiber 100). to form an image. Here, if the width of the light incident area of the bundle type optical fiber group 300 (optical fiber 100) is represented by "D" and the imaging magnification of the imaging lens 216 is represented by "M", the width of the wide area light emitting area on the light source 70 is , the light emitted within the range of D/M can pass through the bundle type optical fiber group 300 (optical fiber 100). where D/M>N・l _CL …(B・35)
(l _CL is given by formula (B-6) or (B-12), N is a positive number of 1 or more (however, N is preferably 2 or more, or 4 or more, and preferably 8 or more)) . In particular, when the bundle type optical fiber group 300 (optical fiber 100) is used, the value of "D" can be increased, so N can be increased. As a result, the partial coherence between the bundle optical fiber group 300 (optical fiber 100) passing light can be greatly reduced (the partial incoherence is greatly increased).

Light emitted from each region (each point) of α, β, and γ on the light source 70 reaches each point of ε, ζ, and η in the light incident region of the bundle optical fiber group 300 (optical fiber 100). imaged. Since the bundle-type optical fiber group 300 (optical fiber 100) carries the incident light as it is, each light is emitted from points ε, ζ, and η within the light emission region.

The lights emitted from the points ε, ζ, and η in the light emission region of the bundle optical fiber group 300 (optical fibers 100) become parallel lights after passing through the collimating lens 26. deviate from each other (equal phase surfaces (wavefronts) of parallel light are tilted with respect to each other).

A phase conversion element 212 is used as an optical characteristic changing member in order to match the traveling directions of the light emitted from the points ε, ζ, and η in the light emission region of the bundle type optical fiber group 300 (optical fiber 100). . The optical property changing member used here exhibits a function corresponding to "(B) combining (mixing) a plurality of optical paths" described in section 3.1. This phase conversion element (optical property changing member) 212 corresponds to the light combining (mixing) section 102 in FIG. 19B(b).

Since this phase conversion element (optical property changing member) 212 diffuses the transmitted light (parallel light is converted into diffused light when transmitted), a large amount of Non-parallel light components are included. On the other hand, the combination of the detection lens 28 and the pinhole or slit 130 selectively extracts only the parallel light component after passing through the object 10 for signal detection. Therefore, strictly speaking, in FIG. 21C, the combination of the phase conversion element (optical property changing member) 212 and detection lens 28 and the pinhole or slit 130 constitutes the light combining (mixing) section 102 .

A portion of the specific example embodiment of Figures 19A and 19B is shown in Figures 20-20C. However, any other specific method of implementing FIG. 19A or FIG. 19B may be used without being limited to the specific example embodiment described above. That is, in section 3.1, the functions that the optical characteristic changing member can have are (A) the function of changing/controlling the optical path length for each of a plurality of optical paths (corresponding to the function of "optical path length change 76" in FIG. 10 described later) and ( B) It has been explained that a function of synthesizing (or mixing) a plurality of optical paths at a predetermined location is included. Any form of optical characteristic changing member that realizes this “(B) combining (or mixing) of multiple optical paths” may be used as the light combining (mixing) section 102 in FIG. 19B. 19A(b) or FIG. 19B(b). may be used as Further, as this optical characteristic changing member, any optical element or combination thereof described in the column of "photosynthesis/mixing method" in FIG. 9 may be used.

In FIG. 20(b), FIG. 21A(b) or FIG. 21B/C, phase conversion elements 212 and 214 are used to change the optical path (advancing direction) of light. However, the optical phase conversion elements 212 and 214 having arbitrary characteristics cannot always efficiently reduce the partial coherence. FIG. 22 shows an experimental system used to measure the characteristics of the optical phase conversion element 212 and the effect of reducing partial coherence. The optical system of FIG. 22 also corresponds to another application example of this embodiment.

In the experiment, three types of items of "different light emitting regions", "different light emitting directions", and "wavefront splitting" are combined as the "optical path state before combining/mixing" in FIG.

Here, the radius of curvature of the rear surface mirror 82 is 19 mm, and the focal lengths of the collimator lens 26 and the condenser lens 98 are both 25.4 mm (imaging magnification M=1). The collimator lens 26, the condenser lens 98, the expand lens 218, and the detection lens 28 all have a parallel beam diameter of 25 mm.

The width D of the light incident area of the bundle-type optical fiber group 300 (optical fiber 100) was set to 5 mm. As a result, the value of the left side of the formula (B.35) is 5 mm. The spiral tungsten filament 50 used here has a length of about 5 mm, and the target object 10 can be irradiated with emitted light from almost the entire wide light emitting region of the light emitting source 70 . Also, the bundle type optical fiber group 300 (optical fiber 100) is set to 2 m in length, and the effects of heat generated from the tungsten filament 50 of the light source 70 and vibration from the cooling fan are evaluated. A break was made between the entrance and exit of the fiber 100).

For the combination of the transparent semi-circular parallel plates 94-1 and 94-2 and the combination of the transparent semi-circular parallel plates 94-3 and 94-4, two optical characteristic changing members that divide the angle by 45 degrees shown in FIG. used in combination. In order to increase the number of split optical paths, the two were installed at an angle rotated by 22.5 degrees with respect to each other. Here, the value of “t” shown in FIG. 13B(a) was set to 1 mm, and an optical glass generally called BK-7 was used. An adhesive having the same refractive index as BK-7 was used for the adhesion between the transparent semicircular parallel plates 94-1 and 94-2 and the adhesion between the transparent semicircular parallel plates 94-3 and 94-4.

The focal lengths of the expand lens 218 and the detection lens 28 are set to 50 mm and 250 mm. Also, the light is diffused (becomes diffused light) after passing through the optical phase conversion element (optical property changing member) 212 . However, by using a combination of the detection lens 28 and the pinhole or slit 130, only the parallel light component after passing through the object 10 is extracted and detected.

As the object 10, a polyethylene film with a thickness of 30 μm, which is transparent in the visible range, was used. The polyethylene film of the object 10 is not turbid even with near-infrared light. Therefore, by using the combination of the detection lens 28 and the pinhole or slit 130, substantially parallel light incident on the object 10 (emitted from the α region, the β region, and the γ region and having the same traveling direction) can be obtained. It is thought that only the component of the light incident on the target object in ) was selectively extracted and detected.

One side of the phase conversion element (optical property changing member) 212 is a sand treatment plate having different grain sizes. The other flat portion of the phase conversion element (optical property changing member) 212 is coated with an antireflection coating.

FIG. 23A shows the measured wavelength dependence of the detected light amount ratio (transmittance) before the insertion of the object 10 when the detected light amount before the insertion of the object 10 is standardized to be 100% uniform. In addition, the change in the measurement result when changing the grain size of the sand grains used for generating the sanded surface of the phase conversion element (optical property changing member) 212 is investigated. FIG. 23A(a) uses #1200 sand grains (average surface roughness Ra (Average Value of Roughness) is 0.35 μm). 23A(b) uses #800 sand grains (average surface roughness Ra is 0.48 μm), and FIG. 23A(c) uses #400 sand grains (average surface roughness Ra is 1.2 μm).

The difference value between the transmittance at the wavelength of 1.213 μm and the transmittance at the wavelength of 1.360 μm increases from FIG. 23A(a) to FIG. 23A(c). However, the change between FIG. 23A(a) and FIG. 23A(b) is relatively small (a large effect appears in FIG. 23A(c)).

On the other hand, the difference in light transmittance between the measured minimum value at a wavelength of 1.213 μm and the interpolated value (at the same wavelength position) estimated from the envelope connecting its periphery is shown in (a) and ( Both b) and (c) are almost the same level of "0.5%".

FIG. 23A shows the change in relative transmittance, but FIG. 23B shows the change in absorbance. Here, the absorbance indicates a value obtained by expressing the reciprocal of the transmittance as a common logarithm. It can be seen from FIG. 23B that the difference between the maximum absorption value at a wavelength of 1.213 μm and its surroundings shows substantially similar values regardless of the grain size of sand grains. On the other hand, the overall baseline height in FIG. 23B varies greatly with sand grain size. The origin of the absorbance maximum and overall baseline at 1.213 μm wavelength will be discussed in greater detail in Section 5 below.

In the absorbance characteristics of FIG. 23B, the measurement accuracy of the spectral characteristics (absorbance characteristics) is improved when the height of the baseline is low. Therefore, #400 (average surface roughness Ra is 1.2 μm) provides the highest measurement accuracy. On the other hand, the measurement accuracy slightly changes between #800 (average surface roughness Ra is 0.48 μm) and #1200 (average surface roughness Ra is 0.35 μm).

The above average surface roughness Ra represents the average amount of fine mechanical unevenness on the sanded surface. Therefore, the average amount .delta. of the phase difference occurring after transmission through the sanded surface can be obtained by substituting the value of "Ra" for "d" in the formula (B.13). Assuming that the refractive index n of BK-7 at a wavelength of 1.213 μm is about 1.5, δ=0.6 μm when Ra=1.2 μm. This value is about half the wavelength of 1.213 μm. Similarly, the average value of the phase difference corresponding to Ra=0.48 μm is 1/5, and the average value of the phase difference corresponding to Ra=0.35 μm is 1/7.

Therefore, when the phase conversion element (optical property changing member) 212 is used in this embodiment, the average value of the phase difference generated thereby is 1/6 or more (preferably 1/5 or more, or 1/6 or more) of the wavelength used. /4 or more), it can be said that the effect occurs.
also describes the use of diffraction gratings and diffusion plates to reduce optical noise. However However, there is no disclosure of the performance of the optical phase conversion element or the diffraction-related element that is necessary for actually exhibiting the effect. Also, the relationship with the optical characteristics/optical arrangement in the detection unit 6 is not disclosed.

Since the optical path length difference between the optical paths of the light emitted from the wide light-emitting regions (light-emitting points) separated from each other within the light-emitting source 70 becomes large, the “light emitted from the wide light-emitting regions (light-emitting points) within the light-emitting source 70 is , irradiate the object 10 or detect it with the photodetector 80,” was described in the first half of Section 3.9 of this book. An example application of an embodiment that implements the method is shown in FIGS. 24A and 24B.

FIG. 24A shows the irradiation light 12 emitted from a wide light emitting region (from the light emitting point β to γ) in the light source 70, and the light emitting region is reduced by an imaging lens with an imaging magnification M, and the incident region of the optical fiber 100 is shown. pass inside. The irradiation light 12 that has passed through the emission area of the optical fiber 100 is converted into parallel light by the collimating lens 26 and is irradiated onto the object 10 .

However, not limited to this, the collimator lens 26 may be used to converge the light on a local area within the object 10 (image is formed on the emission area of the optical fiber 100). In FIG. 24A, only one optical fiber 100 is depicted, but the present invention is not limited to this, and a group of bundled optical fibers may be used.

Furthermore, in FIG. 24A, the imaging system is configured with only one imaging lens 216, but the imaging system is not limited to this, and may be configured with a plurality of lenses. As a specific example thereof, as shown in FIG. 22, the collimating lens 26 and the condensing lens 98 may constitute an imaging system. Furthermore, as explained in the last part of Section 3.4, the wavefront splitting function (or other function) is applied to the parallel state (parallel beam) of the irradiation light formed by the collimator lens 26 and the condenser lens 98. You may arrange|position the optical characteristic change member which had. As an example of this optical property changing member, FIG. 22 shows an example of a combination of transparent semicircular parallel plates 94-1 and 94-2.

The imaging lens 216 in FIG. 24A fulfills the function of "(A) changing/controlling the optical path length for each of a plurality of optical paths" as an optical property changing member. Therefore, this imaging lens 216 is included in one type of the optical path changing element 210 described in FIG. 19B(b).

On the other hand, the optical fiber 100 in FIG. 24A performs the function of "(B) combining (or mixing) a plurality of optical paths" as an optical characteristic changing member. Also in FIG. 24B, the optical fiber 100 performs the same function. Therefore, this optical fiber 100 corresponds to the light combining (mixing) section 102 described in FIG. 19B(b).

As shown in FIG. 24A, the core diameter in the incidence area of the optical fiber 100 is represented by "ΔD". Further, the imaging magnification (horizontal magnification) of the imaging lens 216 is assumed to be "M". In this case also, if the condition of replacing D in the equation (B.35) with ΔD is satisfied, the combined light (mixed light) 78 (FIG. 10(b)) in the optical fiber 100 is partially incoherent. indicates

From yet another perspective, consider the optical path length difference δ between the light entering the optical fiber 100 . First, the α point (α region) on the light source 70 is arranged on the optical axis of the imaging lens 216 . Next, after being emitted from the β point (β region) on the light source 70, it passes through the center point of the imaging lens 216 and reaches the inner end of the incident region of the optical fiber 100 (the boundary position between the core region and the clad layer). Consider the optical path to The angle between this optical path and the optical axis of the imaging lens 216 is represented by η. Also, the distance from the light source 70 to the incident area of the optical fiber 100 is defined as "SF".

Since the distance between the α point (α region) and the β point (β region) on the light source 70 is ΔD/(2M),
When η is sufficiently small,

is approximated as On the other hand, the optical path length difference δ from the α point (α region) to the incident region of the optical fiber 100 and from the β point (β region) to the incident region of the optical fiber 100 is

is given by Therefore, the conditions under which partial coherence decreases (partial incoherence increases) due to mixing within optical fiber 100 are:

(N is a positive number equal to or greater than 1). Also, the above coherence length l _CL is given by the equation (B.6) or (B.12). Here, applying the same approximation formula as the formula (B.24) to the left side of the formula (B.38),

and transformed. Looking at the approximation formula (B.39), it can be seen that the ratio of the core diameter ΔD in the incident region of the optical fiber 100 to the imaging magnification (lateral magnification) M of the imaging lens 216 is an important factor. That is, it is desirable to minimize the imaging magnification (lateral magnification) M of the imaging lens 216 and to maximize the core diameter ΔD in the incident region of the optical fiber 100 . Furthermore, the shorter the distance SF from the light source 70 to the incident area of the optical fiber 100, the better.

That is, in the optical arrangement of FIG. 24A, if the formula (B.38) or (B.39) is set so as to satisfy the formula, the optical noise (for example, generated by the influence of the tube inside the light source 70) can be reduced. . The above imaging magnification M is not limited to the case where one imaging lens 216 is used. may be applied.

21A(b), FIG. 21C, and FIG. 22, the phase conversion element 212 is used as a means for realizing the function of "(B) combining (or mixing) multiple optical paths" that the optical property changing member has. However, in this method, the efficiency of the light used for signal detection within the detectors 4 and 6 is low. In contrast, by using the combination of the imaging optical system (confocal optical system) of FIG. 24A (or FIG. 24B) and the optical fiber 100, the target object 10 can be efficiently irradiated with partially incoherent light. In addition, there is an effect that the light can be efficiently guided to the photodetector 80 in the detection units 4 and 6 (signal detection by the photodetector 80).

The incident angle range of light that can enter the optical fiber 100 from the incident area of the optical fiber 100 is represented by the NA value. Many commercially available optical fibers 100 have a relatively small NA value, such as 0.22. Therefore, if the equation (B.38) or (B.39) is satisfied, only a part of the illumination light 12 emitted from the light source 70 passes through the imaging lens 216 . FIG. 24B shows a method of improving this to increase the utilization efficiency of the irradiation light 12 and to reduce the value of SF in the formula (B.38) or (B.39).

In the application example of this embodiment shown in FIG. 24B, an optical path changer 210 is arranged in (or in the vicinity of) the incident area of the optical fiber 100 to increase the substantial NA value of light that can enter the optical fiber 100. FIG. As a specific example of the optical path changing element 210, a micro concave lens 230 may be used. However, not limited to this, as the optical path conversion element 210, any optical element having a function of widening the incident angle range of light that can enter the optical fiber 100 may be used.

In addition, a concave lens or cylindrical concave lens 240 is arranged at a position close to the light source 70 to reduce the imaging magnification M of the imaging system from the light source 70 to the micro concave lens 230 (optical path changing element 210), and the mechanical mechanism therebetween. It simultaneously achieves the function of reducing the value of the distance SF.

In FIG. 24B, the collimator lens 26 and the condenser lens 98 are arranged between the light source 70 and the optical fiber 100, and the irradiation light 12 is made parallel between them. However, it is not limited to this, and only one imaging lens 216 may be arranged between the light source 70 and the optical fiber 100, and a concave lens or cylindrical concave lens 240 may be arranged in the middle of the optical path.

When using a light emitting source 70 such as a tungsten filament 50 whose width of the light emitting region is significantly different in the longitudinal direction and the width in the lateral direction, a cylindrical concave lens 240 or the like is arranged to change the imaging magnification in the longitudinal direction and the lateral direction of the light emitting region. M may be changed.

In the optical arrangement of FIG. 24B, astigmatism occurs in the vicinity of the incidence area of the optical fiber 100 . Here, in the vicinity of the incident area of the optical fiber 100 of the light emitted from the point α on the light emitting source 70, astigmatism is a phenomenon in which the light condensing positions in the longitudinal direction and the lateral direction of the light emitting area deviate on the optical axis. call. However, if the imaging magnification M is set smaller than "1", the amount of deviation can be set small. As a result, a large amount of light can be guided into the core region 142 in the optical fiber 100 without relying on astigmatism in the vicinity of the incident region of the optical fiber 100 .

As another method for changing the imaging magnification M in the longitudinal direction and the lateral direction of the light emitting area, instead of arranging the cylindrical concave lens 240 between the light emitting source 70 and the collimating lens 26, the collimating lens 26 and the condenser lens 98 are arranged. A beam expander may be formed by arranging two cylindrical concave lenses at a place between which the irradiation light 12 is parallel.

In FIG. 24B, transparent semicircular parallel flat plates 94-1 and 94-2, which are optical characteristic changing members having a wavefront splitting function, are arranged in the optical path of the irradiated light 12 in a parallel state, thereby partially allowing the irradiated light 12 to pass through. It reduces coherence (increases partial incoherence). However, it is not limited to this, and any optical property changing member (and combination thereof) described in the column of "photosynthesis/mixing method" in FIG. 9 may be arranged in the middle of the optical path.

24B (or FIGS. 24A and 24C) may be used as the internal structure of the light source unit 2 of FIG. 1A (or FIGS. 1B and 1C). In some cases, the light source 70 generates heat and uses a fan to cool it, which may become a source of vibration. Arranging the optical fiber 100 between the object 10 and the light source 70 as described above has the effect of protecting the object 10 from the effects of heat and vibration.

As another method of varying the imaging magnification M in the longitudinal and lateral directions of the tungsten filament 50 in the imaging (confocal) optical system shown in FIG. 24B, instead of using the spherical lens of FIG. A lens may be used, or a prism 220 or a lenticular lens 222 may be arranged in the optical path.

That is, in both (a) and (b) of FIG. 24C(a), the imaging lens 216 and the prism 220 are combined as the optical path conversion element 210. In FIG. As another application example of the embodiment, in FIG. 24C(b), a combination of an imaging lens 216 and a lenticular lens 222 is used for the optical path conversion element 210. FIG.

Section 3.10 Application Example for Synthesis/Mixing of Emitted Light from Different Regions Method of changing the optical path length between different optical paths when mixing (or synthesizing) light emitted from different regions within the same light source 70 was described in Section 3.9. Accordingly, it is possible to reduce the partial coherence (increase the partial incoherence) of light after mixing (combining). In this section, the technique is developed to explain a method of "expanding the optical path length difference between different optical paths" and a method of "more efficient mixing (synthesis)".

In both Figures 21C and 22, the entrance of the handle-shaped optical fiber group 300 (optical fiber 100) corresponds to the imaging position with respect to the light source 70 (tungsten filament 50). As a method of forming this imaging optical system, only one optical path changing element 210 (imaging lens 216) is used in FIG. 21C. In contrast, in FIG. 22, a combination of a plurality of optical path changing elements (collimating lens 26 and condensing lens 98) arranged at different spatial positions is used to form the imaging optical system. Rather than constructing an imaging optical system with a single optical path changing element 210 (imaging lens 216 in FIG. 21C), a plurality of optical path changing elements (collimating lens 26 in FIG. A combination of lenses 98) can be used to increase the "optical path length difference between different optical paths". As a result, there is an effect of "further reducing partial coherence" by configuring an imaging optical system by combining a plurality of optical path changing elements arranged at spatially different positions. Its basic principle is explained below.

FIG. 51 shows an imaging optical system for forming an image of light emitted from the light source 70 (tungsten filament 50) at the entrance of the optical fiber 100 (light combining (mixing) section 102). Here, in FIG. 51A, only one imaging lens 216 (optical path changing element 210) constitutes an imaging optical system. On the other hand, in FIG. 51(b), an imaging optical system is configured by combining a plurality of optical path changing elements (collimating lens 26 and condensing lens 98) arranged at spatially different positions.

The state of the illumination light 12 passing between the plurality of optical path changing elements (collimating lens 26 and condensing lens 98) may basically be either a diverging light state or a converging light state. For example, as shown in FIGS. 22 and 24B, a plurality of optical path changing elements (collimating lenses 26 and 26) are provided as optical characteristic changing members for changing the optical path length for each optical path divided by wavefront splitting of (the light cross section of) the irradiation light 12. Consider an optical system inserted between the condensing lenses 98). The examples shown in FIGS. 22 and 24B, in which this optical property changing member is composed of a combination of transparent parallel plates 94-1 to 94-4, will be examined. It is generally known that if the parallel plates 94-1 to 94-4 are arranged in the middle of the optical path of the divergent light or the middle of the light path of the converging light in the imaging optical system, aberration will occur in the imaging optical system. there is Therefore, it is desirable that the illumination light 12 passing between the plurality of optical path changing elements (collimating lens 26 and condensing lens 98) should be in a parallel light state. When the parallel light state is used in this manner, an accurate imaging pattern with little aberration for the light source 70 (tungsten filament 50) can be formed at the entrance of the optical fiber 100 (light combining (mixing) section 102).

Most of the core diameters ΔD of the optical fibers 100 made of generally available inorganic materials (for example, made of anhydrous silica glass) are 1.0 mm or less. On the other hand, the standard length of the tungsten filament 50 used in the tungsten-halogen lamp in the longitudinal direction (twice the distance ι between the α and β points) is 4 cm, which is more than 40 times the core diameter ΔD. Therefore, it is necessary to reduce the light emission image of the tungsten filament 50 to 1/40 or less and form the image at the entrance of the optical fiber 100 . Therefore, in order to form an image at a reduction of 1/40 or less with only one imaging lens 216 as shown in FIG.

The distance from tungsten filament 50 to the entrance of optical fiber 100 is denoted by SF. A light-emitting point on the light-emitting source 70 (tungsten filament 50) on the extension of the optical axis of the imaging lens 216 is defined as a point α. The α point is set so as to coincide with the longitudinal midpoint of the tungsten filament 50 . Consider the case where illumination light 12 emitted from point β located on the longitudinal end face of tungsten filament 50 passes through the center of the optical axis of imaging lens 216 . The angle between this irradiation light 12 and the optical axis of the imaging lens 216 is represented by η. Also, the distance between the α point and the β point is represented by ι.

When the imaging lens 216 is arranged near the entrance of the optical fiber 100 as described above,
η ≒ tan ^－１ (ι/SF) …(B・42)
can be approximated as

The optical path length for the irradiation light 12 emitted from the point β to pass through the imaging lens 216 and reach the entrance of the optical fiber 100, and the optical path length for the emitted light from the point α to reach the entrance of the optical fiber 100 is δ = SF{( cos η) ^-1 - 1 } ≈ SF η ² /2 (B 43)
can be expressed by an approximation of As shown by the equation (B.43), the optical path length difference δ changes with the square of the angle η. However, if the imaging optical system is configured with only one imaging lens 216 (optical path changing element 210), the angle η cannot be set large.

The coherence length l _CL and the natural number N ("1" or more are essential, but "2" or more or "4" or more and as large values as possible are desirable ) and the above optical path length difference δ ≧ N・l _CL (B・44)
holds, the partial coherence of the light passing through the light combining (mixing) section 102 (optical fiber 100) decreases (the partial incoherence increases).

However, in an imaging optical system composed of only one imaging lens 216 (optical path changing element 210), the value of the angle η is small, so the equation (B·44) cannot be satisfied for a sufficiently large N. As a result, it is difficult to sufficiently obtain the partial coherence reduction effect (the partial noncoherence increase effect).

Next, a description will be given of characteristics when an imaging optical system is configured by combining a plurality of optical path changing elements (collimating lens 26 and condensing lens 98) arranged at spatially different positions (FIG. 51(b)). . In this case, the focal length Fc of the optical path conversion element (collimating lens 26) arranged on the front side can be set to a value far smaller than SF (Fc<<SF). The relational expression regarding the angle η at this time is η ≒ tan ^-1 (ι/Fc) …(B・45)
becomes. Since Fc can be set sufficiently small (Fc<<SF) in the equation (B.45), the angle η becomes large. Therefore, since a large value of angle η can be substituted into the equation (B.43), a large optical path length difference δ can be obtained. Therefore, when a plurality of optical path changing elements arranged at different spatial positions are combined, the formula (B.44) holds for a sufficiently large N, so that a large partial coherence reduction effect (partial non-coherence effect of increasing coherence) is obtained.

The optical axis of the imaging optical system formed by combining a plurality of optical path changing elements (collimating lens 26, condensing lens 98, etc.) is indicated by an alternate long and short dash line in FIG. 51(b). The intersection of the extension line of this optical axis and the light source 70 (for example, the tungsten filament 70) is represented by the α point. A light emitting point in the light emitting source 70 located farthest from the point α is defined as a point β. Also, the distance between the α point and the β point is indicated by ι.

After being emitted from the points β and α, the optical path difference δc between the illumination light 12 and passing along the optical axis in the optical path changing element (collimating lens 26) arranged on the front side is δc = Fc{( cos η ) ^-1 - 1 } ≈ Fc η ² /2 … (B 46)
becomes. Here, the angle η satisfies the formula (B·45).

Next, let us consider the irradiation light 12 emitted from the point β and passing through the optical path changing element (condensing lens 98) disposed on the rear side. Here, the focal length of the optical path conversion element (collecting lens 98) arranged on the rear side is represented by Fo. Then, as shown in FIG. 51(b), the inclination angle from the optical axis of the traveling direction of this light is κ. The optical path length δo between the optical path until this light reaches the entrance of the optical fiber 100 after passing on the optical axis in the optical path conversion element (condensing lens 98) and the optical path passing on the optical axis is δo ＝ Fo{( cosκ) ^-1 - 1 } ≒ Fo・κ ² /2 …(B・47)
becomes.

Therefore, the sum of the optical path length differences from the points α and β to the entrance of the optical fiber 100 is δc + δo ≧ N·l _CL (B·48)
If the optical design satisfies , the effect of reducing partial coherence (effect of increasing partial incoherence) is exhibited. Note that the coherence length l _CL in the equation (B.48) is given by the equation (B.6) or the equation (B.12). The value of the natural number N must be "1" or more, but preferably "2" or more or "4" or more as large as possible.

In the embodiment shown in FIG. 51, an optical fiber 100 is used as a light combiner (or light mixer) 102. In the embodiment shown in FIG. However, as described above, most of the core diameters ΔD of the optical fibers 100 made of generally available inorganic materials (for example, anhydrous silica glass) are 1.0 mm or less. It is necessary to reduce and form an image.

Further, when the imaging magnification is reduced, an optical path is generated in which the incident angle η of the irradiation light 12 to the entrance of the optical fiber 100 is large. A maximum incident angle η that can penetrate into the core region 142 in the optical fiber 100 is defined by the NA value (NA=sin η). The standard optical fiber 100 has a relatively small NA value of 0.22. Therefore, if the imaging magnification at the entrance of the optical fiber 100 is reduced, part of the irradiation light 12 that has passed through an optical path with a large incident angle η cannot enter the core region 142, resulting in a significant reduction in light utilization efficiency. .

In order to solve the above problems, a light guide or light pipe (Light Guide/Light Pipe) 250 may be used as the light combiner (or light mixer) 102, as shown in FIGS. The light guide (light pipe) 250 is a kind of waveguide element shown in FIG. 9, and indicates a transparent optical element through which light can pass. That is, light (for example, irradiation light 12) is incident from the front-end boundary 252 of the light guide (pipe), and internally reflected (total internal reflection) at the side surface 254 while passing through the inside. It passes through and emerges from the Back-end Boundary 256 of the light guide (pipe).

Lights that have undergone different paths before entering the light guide (light pipe) 250 (for example, light emitted from different light emitting points α and β in the light source 70) pass through the light guide (light pipe) 250. and mix with each other (mixed or combined). The light guide (light pipe) 250 can take any shape as long as it has a structure in which the light passing through the light guide (light pipe) 250 (irradiation light 12) does not leak from the side surface 254 (total reflection is not blocked). As a specific shape example of the light guide (light pipe) 250, a prismatic shape or a cylindrical shape (or a shape similar to a pyramidal shape or a conical shape) may be taken.

The refractive index n inside the light guide (light pipe) 250 is always greater than the refractive index in air (in a vacuum). Therefore, the incident angle κ(η) of the irradiation light 12 on the front end face 252 of the light guide (light pipe) is allowed to be any value within the range of 0°≦κ≦90° (see FIG. 54(a) ). Therefore, there is an effect that the light loss when passing through the light incident surface (the front end surface 252 of the light guide (light pipe)) to the light guide (light pipe) 250 is small.

For example, light perpendicularly incident on flat glass having a refractive index n of 1.5 is reflected at the incident surface by about 4%. Therefore, both the front end 252 and the rear end 256 of the light guide (pipe) are coated with antireflection coatings (AR coatings) (reflectance is controlled to 1% or less, preferably 0.5% or less). ), to reduce light loss passing through the leading edge 252 and the trailing edge 256 .

Furthermore, the use of light guide (light pipe) 250 for light combining or mixing reduces the constraint on imaging magnification (between light source 70 and light guide (light pipe) front end face 252). This is because, for example, when using a rectangular parallelepiped light guide (light pipe) 250 made of, for example, a transparent inorganic material (made of anhydrous quartz glass, etc.), the light guide (light pipe) 250 can be easily created with arbitrary dimensions (light guide (light pipe) 250 has high dimensional freedom). Therefore, there is also an effect that the degree of freedom in designing the imaging optical system (using the optical path changing element 210) in the middle is improved.

As an example of a specific shape of the light guide (light pipe) 250, FIG. 54 shows a quadrangular prism. Also, in FIGS. 52 and 53, the shape is an intermediate shape between a quadrangular prism shape and a “shape obtained by cutting and removing the tip of a quadrangular pyramid”. However, it is not limited to this, and may be (a part of) a hexagonal prism or a hexagonal pyramid, or (a part of) a triangular prism or a triangular pyramid.

Also, for the reason explained at the end of Section 3.1, it is desirable to use an inorganic material instead of an organic material for the material of the light guide (light pipe) 250 . Examples of inorganic materials include optical glass, CaF ₂ , MgF ₂ , LiF and KBr.

In particular, a low OH material that satisfies the condition of "100 ppm or less" (preferably "1 ppm or less") for the mixed amount of hydroxyl groups contained in the material of the light guide (light pipe) 250 is suitable. Specific examples include "a glass material with less hydroxyl group contamination and production control", "anhydrous quartz glass", and "anhydrous quartz".

As shown in FIG. 52, the optical path changing element 210 (the imaging lens 216, or the combination of the collimating lens 26 and the condenser lens 98, etc.) forms an imaging optical system. When a plurality of optical path changing elements (collimating lens 26 and condensing lens 98) are arranged at different positions as shown in FIG. 52(b), an optical characteristic changing member (FIG. 9) is arranged between them. can be As an example of the function of the optical property changing member, "additional optical path length difference generation using wavefront splitting" may be performed. Specifically, any of the methods already described in Section 3.3 can be used. As an example of this, in FIG. 52(b), transparent semicircular parallel flat plates 94-1 and 94-2 are arranged in the parallel beam portion between the collimating lens 26 and the condensing lens 98. FIG.

By virtue of the imaging optics described above, an imaged pattern for the light emitting pattern on the light source 70 (eg, tungsten filament 50) is projected onto the front end face 252 of the light guide (pipe). The light that has formed this projected image (imaging pattern) enters the light guide (light pipe) 250 (the light combining (mixing) section 102) as it is, and is emitted from the rear end face 256 of the light guide (pipe).

FIG. 52 shows an example in which a reduced imaging pattern is projected (imaging magnification is less than 1). However, the pattern is not limited to this, and a pattern of arbitrary imaging magnification may be projected onto the front end surface 252 of the light guide (pipe). In this case, it is desirable that the area size of the light guide (pipe) front end face 252 is larger than the projected imaging pattern. Thereby, the utilization efficiency of the illumination light 12 entering the front end face 252 of the light guide (pipe) is increased.

In the embodiment shown in FIG. 52, the side surfaces 254-1 and 254-2 of the light guide (light pipe) 250 (light combining (mixing) section 102) have a slight inclination (taper) with respect to the optical axis. As a result, the area size of the rear end face 256 of the light guide (pipe) is smaller than the area size of the front end face 252 . The light density of the light (irradiation light 12 ) passing through the light guide (light pipe) 250 (the light combining (mixing) section 102 ) is higher at the rear end surface 256 than at the front end surface 252 .

As described above, the diameter ΔD of the core region 142 in the general optical fiber 100 is often around 0.6 mm. The side surfaces 254-1 and 254-2 may be slanted as described above to set the area size of the rear end surface 256 of the light guide (pipe) smaller. Consider, for example, the case where the light emitted from the rear end face 256 of the light guide (pipe) is passed through the optical fiber 100 . If the slanted side surfaces 254-1, 254-1, 2 are used to appropriately change the area size of the rear end surface 256, "improved light utilization efficiency during optical coupling between the light guide (light pipe) 250 and the optical fiber 100" ( prevention of significant optical loss at the optical junction) can be realized.

Note that in the example of the light guide (light pipe) 250 shown in FIG. 52, each of the side surfaces 254-1 and 254-2 is flat with a slight inclination (taper). However, the present invention is not limited to this, and only one of the four side surfaces 254 forming the light guide (light pipe) 250 may have a slope. In addition, the side surfaces 254-1 and 254-2 may be partially curved and partially inclined. However, in this case, as will be described later, the light passing through the light guide (light pipe) 250 maintains a shape in which it is reflected (total reflection) by the side surfaces 254-1 and 254-2, or is reflected by the side surfaces 254-1 and 254-2. It is necessary to have a structure (for example, forming a light reflecting layer on the side surfaces 254-1 and 254-2 so that the light is internally reflected).

Further, in the embodiment of FIG. 52, the cross-sectional shape of the light guide (light pipe) 250 (light combining (mixing) portion 102) is square. However, the cross-sectional shape may be circular or elliptical (in consideration of the efficiency of optical connection with the optical fiber 100, for example).

By appropriately changing the area size between the front end surface 252 and the rear end surface 256 using the inclined side surfaces 254-1 and 254-2 in this way, the "light emitting portion size of the light emitting source 70" and the "after photosynthesis (mixing) The effect of facilitating consistency with the region size of the rear end face 256 required by the optical system to be arranged is produced.

Note that the side surfaces 254-1 and 254-2 may be parallel to the optical axis (the area size between the front end surface 252 and the rear end surface 256 may be matched).

52 to 54 omit the optical path after passing through the rear end 256 of the light guide (pipe). When the area size of the rear end face 256 of the light guide (pipe) is reduced as described above, the light after passing through the rear end portion 256 of the light guide (pipe) can be treated as "divergence light from a pseudo point light source". . Then, the light emitted from the rear end portion 256 of the light guide (pipe) can be treated like "illumination light (first light) 12 emitted from the light source section 2 in FIG. 1A".

Further, as shown in FIG. 24A, a collimating lens 26 is arranged immediately after the rear end portion 256 of the light guide (pipe) to make a substantially parallel light state, and as shown in FIG. Irradiation may be performed.

Further, as shown in FIG. 1C, an objective lens 25 may be placed in the middle of the optical path of substantially parallel light, and the object 10 may be irradiated with substantially converged light. As an example of this substantially converged light irradiation, a part of the optical system shown in FIGS. 7, 14E, and 20 may be used.

That is, the light guide (light pipe) 250 may be arranged as the light combining (mixing) section 102 in the light source section 2 shown in FIGS. 1A to 1C. Further, an optical path changing element 210, which is a kind of optical characteristic changing member, is arranged in the light source unit 2 (before the light combining (mixing) unit 102), and an optical path length changer 76 (FIG. 10) is arranged for a part of the optical path. ) may be generated. 9 is placed in the light source unit 2 shown in FIGS. 1A to 1C, and described in Section 3.1 using FIGS. 8A and 10A and 10B. It is also possible to have a function that

In addition, the rear end 256 of the light guide (pipe) may be optically spliced to the optical fiber 100 and an optical system as shown in FIG. 24 may be arranged at the exit of the optical fiber 100 . Further, the rear end portion 256 of the light guide (pipe) may be optically joined to the bundle type optical fiber group 300, and an optical system as shown in FIG. 21C or FIG. good.

14A, 14E, 16B, 18, 21A, 21C, 22, 24A, 24B, and 24C, the optical fiber 100 and pinholes are formed in the optical path in the system of the present embodiment. Alternatively, a slit 130 may be installed. Further, not limited to this, if the region size of the rear end face 256 is narrowed in the light guide (light pipe) 250 (the light combining (mixing) portion 102), an optical effect equivalent to that provided with a pinhole or slit 130 can be obtained substantially. to be born. It is said that when these optical elements are installed in the optical path of "partially coherent light", spatial coherency increases. As a result, the partial coherence of the illumination light (first light) 12 or the detection light (second light) 16 increases, and optical noise tends to increase.

In contrast, when the irradiation light 12 is passed through the light guide (light pipe) 250 at a position near the light source 70 (inside the light source unit 2 or near the emission position from the light source unit 2) as in the system of this embodiment, Light emitted from different light emitting points within light source 70 is combined or mixed within light guide (light pipe) 250 . In this way, the partial coherence of the irradiation light 12 is reduced (the partial incoherence is increased) in advance at a position near the light source 70 (inside the light source unit 2 or near the emission position from the light source unit 2). . Then, even if the optical fiber 100, the pinhole, or the slit 130 is installed in the middle of the subsequent optical path, the partial coherence of the irradiation light 12 does not increase (the partial incoherence does not decrease). By arranging the light guide (optical pipe) 250 inside the light source unit 2 or in the vicinity of the position where light is emitted from the light source unit 2 in this way, there is an effect of reducing optical noise.

When the front end face 252 of the light guide is arranged at the imaging position of the light source 70 as shown in FIG. However, the present invention is not limited to this, and the front end surface 252 of the light guide may be arranged at the non-imaging position of the light source 70 . As a specific example, in FIG. 52(a), another optical element (such as another optical characteristic changing member shown in FIG. 9) other than the imaging lens 216 is placed between the light source 70 and the light guide (light pipe) 250. , or no optical elements need be placed between the light source 70 and the light guide (light pipe) 250 . Alternatively, a non-imaging optical system may be formed.

Another application example of the system of this embodiment is shown in FIG. The difference from the prior art shown in FIG. 17 was explained in Section 3.7. In FIG. 17, since the light traveling directions after passing through the collimating lens 136 do not match α and β, the partial coherence does not decrease (the partial incoherence increases) as it is.

On the other hand, in this application example, both lights from the optical fibers 100-1 and 100-2 are passed through the light guide (light pipe) 250. FIG. Both lights are combined or mixed with each other in a light guide (light pipe) 250 so that their light traveling directions match each other. Therefore, also in the application example shown in FIG.

In the explanation so far, the function of the photosynthesis (mixing) section 102 of the light guide (light pipe) 250 has been used. Here, the basic principle of the function of the photosynthesis (mixing) unit 102 will be described with reference to FIG. It has already been explained that incident light with a large angle of incidence η cannot penetrate into the core region 142 of the optical fiber 100 . Therefore, if the optical fiber 100 is placed in the middle of the optical path of (for example, the irradiation light 12), the loss of the amount of light at its entrance becomes a serious problem. FIG. 54(a) shows the reason why the light quantity does not decrease at the front end face 252 of the light guide (light pipe).

Light incident in air (or in vacuum) at an incident angle κ is refracted at an angle of refraction ξ in a transparent medium with a refractive index n. The approximation expression representing the relationship between the incident angle κ and the refraction angle ξ has already been explained in the equation (B·14). By the way, if we write the exact Snell's law without using approximations,
sinκ = nsinξ …(B・49)
becomes.

In the formula (B.49), "sin κ ≤ 1" must always hold. The maximum value of the refraction angle ξ at which "sinκ = 1" is called the angle of total internal reflection. For example, when "n=1.5", the angle of total reflection is "41.8 degrees" from the equation (B.49).

In FIG. 54( a ), the irradiation light 12 traveling in air (or in vacuum) passes through the front end surface 252 of the light guide (pipe) and enters the interior of the light guide (light pipe) 250 . View this optical path from the opposite direction. When the light passing through the light guide (light pipe) 250 reaches the front end face 252 of the light guide (pipe) at an angle ξ, it is refracted at an angle κ and travels through air (or vacuum). Here, when the angle at which the light reaches the front end face 252 of the light guide (pipe) becomes larger than "41.8 degrees", this light is totally reflected by the front end face 252 of the light guide (pipe), and in the air (or in the vacuum) ).

Although there are restrictions on the angle of arrival at the interface in the refracting body, there are no restrictions on the angle of arrival (angle of incidence κ) of the incident light (irradiation light 12) in air (or in vacuum). Therefore, within the range of "0 degrees ≤ κ ≤ 90 degrees", the illumination light 12 having any incident angle κ can pass through the front end surface 252 of the light guide (light pipe). As a result of strict optical calculations, a slight amount of light loss occurs due to minute light reflection when passing through the front end face 252 of the light guide (pipe). However, by applying an antireflection coating (AR coating (Antireflection Coatings)) to the front end face 252 of the light guide (light pipe), the loss of light quantity here can be greatly reduced. Therefore, if the light guide (light pipe) 250 is used in the light combining (mixing) unit 102 (see FIGS. 8A and 8B), the light passing through the light guide (light pipe) 250 (irradiation light 12) can be obtained with high light utilization efficiency. occurs.

The irradiation light 12 passing through the light guide (light pipe) 250 is reflected (total reflection) by the side surface 254 - 1 inside the light guide (light pipe) 250 . The reflection angle (total reflection angle) at this time is represented by φ. As shown in FIG. 54(a), when the side surface 254-1 of the light guide (light pipe) 250 and the front end surface 252 of the light guide (pipe) are perpendicular to each other, the refraction angle ξ and the reflection angle (total reflection angle) φ is ξ + φ = 90 degrees …(B・50)
is given by

The refraction angle ξ of the illumination light 12 entering the light guide (light pipe) 250 at an arbitrary incident angle κ with respect to the front end face 252 of the light guide (pipe) is always "41.8 degrees or less" as described above. Become. Therefore, from the equation (B.50), the angle φ is always "48.2 degrees or more". For the reason described above, the phenomenon of "φ≧48.2 degrees" is due to the fact that "the irradiation light 12 passing through the light guide (light pipe) 250 passes through the side surfaces 254-1 and 254-2 inside the light guide (light pipe) 250. Total reflection and no loss of light during reflection. In other words, if the light guide (light pipe) 250 is used to generate the combined light (mixed light) 78 (see FIG. 10), there is an effect that the light loss during photosynthesis (mixing) can be greatly reduced.

Examples of optical property changing members used to generate the combined light (mixed light) 78 include diffraction gratings 120 and 124 (FIGS. 12A and 14C), optical fiber 100 (FIGS. 14A, 24A, 24B and 24C), Usage examples of the phase conversion elements 102-2 and 212 (FIGS. 14B, 21A(b), 21C, and 22) have been described. By the way, when light passes through the above optical property changing member, some amount of transmitted light loss occurs in any of the optical property changing members. Compared to these optical property-altering members, the light guide (light pipe) 250 (which also belongs to the optical property-altering members) has a significantly lower amount of light loss during use.

The light guide (light pipe) 250 illustrated in FIG. 54 takes the shape of a rectangular parallelepiped. In contrast, in the structure of the light guide (light pipe) 250 illustrated in FIGS. 52 and 53, at least a portion of the sides 254-1,2 are sloped. Furthermore, a structure in which part of the side surfaces 254-1 and 254-2 has a curved surface shape and the amount of inclination is partially changed is also allowed. And in this case, the angle between the front end face 252 or the rear end face 256 of the light guide (pipe) and the side faces 254-1, 2 is different from 90 degrees (there may be locations at least locally). .

If μ is the slope angle in the (at least local) sides 254-1, 2, then ξ + φ + μ = 90 degrees for equation (B 50) (B 51)
relationship is established.

The maximum value that the refraction angle ξ can take (“41.8 degrees” when the refractive index n is “1.5”) and the critical angle at which total reflection occurs on the side surfaces 254-1 and 254-2 are “ Substituting φ=41.8 degrees into the equation (B·50) yields μ=6.4 degrees. In other words, in order for total reflection to occur on the side surfaces 254-1 and 254-2, the gradient angle μ on the side surfaces 254-1 and 254-2 must be "6.4 degrees or less".

Considering the angular error of the front end surface 252 and the rear end surface 256 of the light guide (light pipe) 250 during manufacturing and the change in the refractive index n due to the wavelength change of the irradiation light 12, the side surfaces 254- It is desirable to set the gradient angle μ at 1 and 2 to "6 degrees or less" (preferably "5 degrees or less").

As a premise of the above calculation, it was assumed that "the surfaces of the side surfaces 254-1 and 254-2 of the light guide (pipe) are exposed to the air (in a vacuum)". However, the present embodiment is not limited to the above conditions, and the inclination angle μ at the side surfaces 254-1 and 254-2 of the light guide (pipe) may be set to, for example, "5 degrees or more". In this case, the “conditions for total reflection on the side surfaces 254-1 and 254-2” are lost, so instead the surfaces of the side surfaces 254-1 and 254-2 of the light guide (pipe) may be coated with a light reflecting layer.

FIG. 54(b) shows a state in which light is synthesized (mixed) between the irradiation lights 12 traveling while repeating total reflection inside the light guide (light pipe) 250 in this way. The ε point on the front end face 252 of the light guide corresponds to the imaging point of the light emitting point α on the light source 70 (tungsten filament 50) in FIG. 52 or the exit of the optical fiber 100-2 in FIG. do. Similarly, the .zeta. point corresponds to the imaging point of the light emitting point .beta. on the light source 70 (tungsten filament 50) or the output opening of the optical fiber 100-1. As shown in FIG. 54(b), in the vicinity of the ε point and the ζ point, both lights pass through different optical paths.

However, after traveling a little through the light guide (light pipe) 250, the optical path 260 of the ε-point passing light and the optical path 270 of the ζ-point passing light overlap each other. A region where the two optical paths 260 and 270 overlap becomes a light mixing region 280, and the light is synthesized (mixed). Furthermore, while repeating total reflection on the side surfaces 254-1 and 254-2 inside the light guide (light pipe) 250, the synthesis (mixing) of both lights further progresses. Then, at the point of passage (emission) through the rear end face 256 of the light guide (pipe), it becomes combined light (mixed light) 78 (shown in FIG. 8A, FIG. 8B, and FIG. 10).

Diffraction gratings 120 and 124 shown in FIGS. 12A and 14C, which are examples of optical property changing members used to generate combined light (mixed light) 78, or FIGS. The described phase conversion element 102-2, 212 basically performs only one photosynthesis (light mixing) operation.

On the other hand, in the light guide (light pipe) 250, the process of superimposing the light paths (that is, photosynthesis/light mixing) is performed a plurality of times for each repetition of total reflection on the side surfaces 254-1 and 254-2. Therefore, the degree of mixing (synthesis) of light emitted from the light source 70 and passing through different optical paths is improved, and there is an effect of improving the efficiency of reducing partial coherence (efficiency of increasing partial incoherence). .

Section 3.11 Method of Reducing Partial Coherence for Electromagnetic Waves with Longer Wavelengths Than Infrared Light and Application Examples In the system of the present embodiment described in FIGS. The inside of the body 10 is irradiated, and the characteristics and conditions inside the target body 10 are measured using the detection light (second light) 16 obtained therefrom. Inside the object 10, the irradiation light (first light) 12 (and the detection light (second light) 16) repeat multiple light scattering. When the irradiation light 12 or the detection light 16 is partially coherent light, optical noise is generated in the detection light 16 as described later in Chapter 5, and the penetration distance of the irradiation light 12 into the object 10 is (Penetration Length) decreases.

This phenomenon occurs not only with near-infrared light and infrared light, but also with electromagnetic waves with longer wavelengths. By the way, in order to improve the directivity of electromagnetic waves in radar (Radar: Radio Detection and Ranging ), a method of flattening the wave front of electromagnetic waves is generally used. However, this technique increases the coherence of the electromagnetic waves, so that the penetration distance into the object 10 is reduced. (When a radar uses a single-frequency electromagnetic wave, it is coherent rather than partial coherent.) Experimental data using near-infrared light shown in Chapter 5 show similar results for electromagnetic waves with longer wavelengths. It suggests that something is happening. On the other hand, if the wavefront of the electromagnetic wave is disturbed in an attempt to reduce the partial coherence (or coherence) of the electromagnetic wave, the directivity is greatly reduced.

As an application example of this embodiment, a method of generating electromagnetic waves with low (partial) coherence while ensuring sufficient directivity will be described. Each electromagnetic wave source/receiving unit 292 in FIG. 55(a) is composed of an antenna common for transmitting/receiving electromagnetic waves, a transmitting circuit for generating electromagnetic waves, and a receiving circuit (detection circuit) for electromagnetic waves (not shown). there is Then, the electromagnetic waves 290-1 to -n (that is, electromagnetic waves traveling through different paths) emitted from different electromagnetic wave sources/receiving units 292-1 to -n (antennas inside) are spatially overlapped with each other. to mix electromagnetic waves. For this purpose, a plurality of independent electromagnetic wave generators/receivers 292 that radiate electromagnetic waves 290 with directivity are arranged close to each other and their radiation directions are made to match. Then, a mixed electromagnetic wave 294 having directivity is generated at a position sufficiently distant from the electromagnetic wave generating/receiving units 292-1 to -n.

The generation mechanism of the mixed electromagnetic wave 294 having directivity will be described in detail below. Electromagnetic waves 290-1 to -n radiated from electromagnetic wave sources/receiving units 292-1 to -n have directivities, respectively. However, the electromagnetic waves 290-1 to -n have a spatial spread (within a plane perpendicular to the traveling direction) at positions sufficiently distant from the electromagnetic wave source/receiving units 292-1 to -n. Therefore, when a plurality of electromagnetic wave generating/receiving units 292-1 to -n are densely arranged one-dimensionally or two-dimensionally, each electromagnetic wave 290- Spatial overlap between 1 and -n. Then, the electromagnetic waves 290-1 to -n are mixed at this overlapping portion to generate a mixed electromagnetic wave 294 having directivity. Since each of the electromagnetic waves 290-1 to -n has directivity, the directivity characteristics do not change even after mixing.

As described in Section 3.1 with reference to FIG. 10, if a portion 74 of light emitted from the same light source 70 is changed in optical path length 76 so as to satisfy the equation (B.44), the other No optical interference occurs with the part of the light 72 of the . Section 2.2 explained the cause of the occurrence of this optical interference using the Uncertainty Principle.

Based on the causes of optical (inter-electromagnetic wave) interference described above, no interference occurs between electromagnetic waves 290-1 to -n emitted from different electromagnetic wave sources/receivers 292-1 to -n. Therefore, the mixed electromagnetic wave 294 having directivity generated by the above method has low (partial) coherence (high (partial) non-coherence) although high directivity is maintained. The use of the mixed electromagnetic wave 294 with this directivity increases the penetration distance to the object 10 as will be described later in Chapter 5. Therefore, there is an effect that it is possible to measure the characteristics and conditions inside the object 10 up to a deep region. Furthermore, since the interference noise between the multiple scattered lights 370 within the object 10 is reduced, it is possible to detect characteristics with high accuracy.

By the way, not only the above application examples but also the electromagnetic waves in the frequency domain described in Section 3.11 can be applied by the method described in Sections 3.1 to 3.10 (combining electromagnetic waves via different paths (optical paths) ( mixing), or combining (mixing) after changing the optical path length of part of the electromagnetic waves.

At least one radar antenna is installed inside each of the electromagnetic wave source/receivers 292-1 to -n. Examples of this radar antenna structure include the Yagi Antenna structure, and the electromagnetic waves emitted spherically from one point are collimated using a hemispherical, elliptical, or parabolic reflecting mirror (Parabola Antenna). Any structure such as structure may be used. The frequency band of radio waves used in this embodiment suitable for the above antenna structure includes a low frequency band to a medium frequency band. Specifically, not only LF waves in the range of 30 kHz to 300 kHz (Low Frequency Wave: long waves), but also MF waves in the range of 300 kHz to 3 MHz (Middle Frequency Waves: medium waves), HF waves in the range of 3 MHz to 30 MHz (High Frequency Waves: short wave) VHF wave (Very High Frequency Wave: long wave) in the range of 30 MHz to 300 MHz may be targeted.

When an alternating current is passed through a single conductor, electromagnetic waves are emitted to the surroundings. In addition, an induced current flows when an electromagnetic wave passes through this conducting wire, and the electromagnetic wave can be detected. Therefore, when the electromagnetic wave generating transmission circuit and the electromagnetic wave receiving circuit (detection circuit) are connected, the same radar antenna can be used as the electromagnetic wave generating source as well as the electromagnetic wave receiving section.

Next, FIG. 55(b) shows an application example of this embodiment using an electromagnetic wave (standing wave) generation source 292 capable of emitting microwaves used in microwave ovens and radars. The frequency used in microwave ovens is standardized to 2.45 GHz (wavelength is 12.2 cm) as an international standard. However, use at 915 MHz (wavelength is 32.8 cm) is permitted only in the United States.

Waveguide antennas 298-1 to -n are installed at the exits of the microwaves in order to enhance the directivity of the microwaves emitted from the magnetron electromagnetic wave sources 296-1 to -n. A specific example of the shape of the waveguide antennas 298-1 to 298-n is a rectangular parallelepiped or cylindrical (or pyramidal or conical) cylinder with a hollow interior, and reflection is repeated on the inner wall of the hollow. However, microwaves with enhanced directivity are radiated to the outside.

The waveguide antennas 298-1 to 298-n serve as microwave radiation ports and can also be used as a part of receivers (microwave detectors) for microwaves entering from the outside. When the waveguide antennas 298-1 to -n are used as microwave receivers in this way, a preamplifier circuit (not shown) is connected to one end of each of the waveguide antennas 298-1 to -n. and a signal processing circuit may be connected.

The inside of the magnetron electromagnetic wave source 296 may have a thermionic tube structure installed in a strong DC magnetic field. A cathode (Cathode) installed in the center of the cavity of the tube (Vessel) is heated by a heater. Thermoelectrons emitted from the cathode move in vacuum toward the anode due to the action of the applied electrical field. At this time, thermoelectrons emit microwaves while drawing a cycloid curve under the influence of an external DC magnetic field.

The practical frequency range of this magnetron electromagnetic wave source 296 is said to be from 100 MHz to 200 GHz. Therefore, the term “microwave” referred to in this embodiment is used as a broad concept indicating the high frequency band side in the category of radio waves. That is, it is not limited to SHF waves (Super High Frequency Waves: microwaves in the narrow sense) in the range of 3 GHz to 30 GHz defined as microwaves in the narrow sense, but also includes a wider frequency range. In other words, VHF waves in the range of 30 MHz to 300 MHz, UHF waves (Ultra High Frequency Waves) in the range of 300 MHz to 3 GHz, and EHF waves (Extremely High Frequency Waves: millimeter waves) in the range of 30 GHz to 300 GHz are also included in the "broadly defined microwave frequency range". include.

Microwaves radiated to the outside of waveguide antennas 298-1 to -n become electromagnetic waves 290-1 to -n each having directivity. Even the electromagnetic waves 290-1 to -n having high directivity spread in a plane perpendicular to the traveling direction at a distance from the waveguide antennas 298-1 to -n as shown in FIG. 55(b). Also, as shown in FIG. 55(b), a plurality of sets each composed of a magnetron electromagnetic wave generating source 296 and a waveguide antenna 298 are densely arranged in one direction or in a planar direction. Then, at a distance from the waveguide antennas 298-1 to -n, the electromagnetic waves 290-1 to -n having directivity are spatially overlapped and synthesized (mixed) with each other. The mixed electromagnetic wave 294 having directivity generated by combining (mixing) in this way becomes an electromagnetic wave with low (partial) coherence.

By the way, there is known a phased array antenna in which waveguide antennas 298-1 to -n whose cavity has a rectangular (or square) cross-sectional shape are arranged two-dimensionally. It has a structure for optimizing the wavefronts of microwaves radiated from all waveguide antennas 298-1 to -n in order to increase the directivity of microwaves. When using this antenna, only the magnetron electromagnetic wave generator 296 is used. Therefore, the coherence of microwaves radiated from this antenna is very high.

The arrangement examples of the waveguide antennas 298-1 to -n are similar to each other, but the phased array antenna and the application example of this embodiment shown in FIG. different. That is, in a conventional phased array antenna that uses only one magnetron electromagnetic wave generator 296 to generate highly coherent microwaves, the penetration distance to the object 10 is short and the electromagnetic wave noise mixed into the detection signal is large. In contrast, if the application example of the present embodiment using a plurality of magnetron electromagnetic wave generation sources 296-1 to -n that are independent of each other is used, the penetration distance to the target object 10 becomes longer, and the electromagnetic wave noise mixed in the detection signal is reduced. There is an effect that can be greatly reduced.

The source of the "mixed electromagnetic wave 294 with high directivity and low (partial) coherence (high (partial) incoherence)" generated by the method of Fig. 55(a) or (b) is It will be called a directional electromagnetic wave generator/receiver 362 hereinafter. The directional electromagnetic wave generating/receiving unit 362 includes electromagnetic wave generating/receiving units 292-1 to -n or magnetron electromagnetic wave generating units 296-1 to -n and waveguide antennas 298-1 to -n. Multiple sets are arranged. The directional electromagnetic wave generating/receiving unit 362 also has a function of receiving (detecting) electromagnetic waves (or microwaves) from the outside.

Heating food in a microwave oven is based on the principle that "moisture" in food absorbs microwave energy and generates heat. The mechanism of absorbing the energy of electromagnetic waves differs depending on the wavelength band of the electromagnetic waves used. As will be described later in Section 5.2 with reference to FIG. 27, when irradiated with visible light, the "bias of electron orbits" that make up the molecule absorbs energy. Also, when irradiated with near-infrared light, energy is absorbed by "group vibration" within the functional groups (atomic groups) containing hydrogen atoms. When infrared light with a longer wavelength is irradiated, the constituent atoms in the molecule vibrate.

If the wavelength of the electromagnetic wave to be irradiated is longer than that, the vibration between constituent atoms in the molecule cannot absorb the electromagnetic wave, and the energy is absorbed by the "rotation and translational motion of the entire molecule". By the way, it is important to note that this “rotation and translational motion of the entire molecule” is likely to occur in “liquids” rather than “solids”. In other words, it can be said that water molecules in the "liquid" state (rather than solid) absorb electromagnetic waves in the frequency range described here (30 kHz to 300 GHz, or 30 MHz to 300 GHz). That is, the energy of electromagnetic waves of the above frequencies is much more absorbed by water molecules than by solids.

It is said that the frequency at which the absorption of electromagnetic wave energy is maximized due to the dielectric loss of water itself is in the range of 20 GHz to 80 GHz (the maximum frequency varies with temperature). However, even if the frequency of the electromagnetic wave is greatly changed, the "electromagnetic wave energy absorption efficiency of water" does not change much. Therefore, even if the frequency of the electromagnetic wave used in the microwave oven is 2.45 GHz (or 915 MHz), sufficient absorption of water molecules occurs and heating (of food) becomes possible. Furthermore, for the same reason, water molecules can absorb energy and generate heat even with electromagnetic waves whose frequencies are in the range of 30 MHz (or 3 MHz) to 300 GHz.

In the application example of the present embodiment, the above phenomenon may be used for "searching for water sources and metalliferous deposits 386". Specifically, the search location is irradiated with a mixed electromagnetic wave 294 having directivity. Then, the degree of interaction with the mixed electromagnetic wave 294 is compared for each measurement area.

If there is a water source 386 at the search location, the water source 386 will absorb the energy of the mixed electromagnetic wave 294 . Since the water source 386 absorbs electromagnetic waves (microwaves) to a large extent, the amount of electromagnetic waves reflected (backscattered amount) within the water source 386 is relatively reduced. A change in the amount of reflected electromagnetic waves (amount of backscattering) in the directional electromagnetic wave generating/receiving unit 362 is checked to find a decrease in the amount of reflected electromagnetic waves (amount of backscattering) in the water source 386 . Also, when the energy of electromagnetic waves (microwaves) is absorbed, the temperature in the water source 386 rises. The position of the water source 386 can also be searched by examining this temperature rise.

Also, the amount of reflection (scattering) of electromagnetic waves in the metal deposit 386 is greater than in other areas. Therefore, a region where the amount of reflection (scattering) of electromagnetic waves is greater than that of other regions suggests the possibility that a metal deposit 386 exists.

In recent years, it has been discovered that there is water on the moon. The solar cell panel 384 electrolyzes water on the moon with electricity obtained from sunlight to obtain oxygen molecules and hydrogen molecules. Rocket fuel can be made from the oxygen molecules and hydrogen molecules. Furthermore, if oxygen molecules are used, living things can live on the surface of the moon. In addition, if various metals can be extracted from the metal deposits buried inside the moon, they can be used as materials for manufacturing such as buildings on the moon, mobile objects, and rockets heading to other planets.

In the following, a method for searching for resources on the lunar surface will be described as an example of adaptation to an application. However, the following methods may be used to search for resources inside the earth or to search for resources in extraterrestrial regions (such as asteroids, planets, and satellites).

FIG. 56 shows an example of the structure of a water source/metal ore deposit searching device that can be used for position searching for water sources or metal ore deposits 386 on the surface of the moon (or for searching for resources in extraterrestrial regions other than the moon). A tank-like Caterpillar Tread 372 makes direct contact with the lunar surface. The transport wheels 374 then rotate to move the caterpillars to move the water source/metal deposit searcher over the lunar surface.

The central part of FIG. 56 shows the internal arrangement of the water source/metal deposit search device. A directional electromagnetic wave generator/receiver 362 having an internal structure shown in FIG. 55 emits a directional mixed electromagnetic wave 294 downward (i.e., to the underground interior of the lunar surface or the center of an extraterrestrial region other than the moon). It is positioned to radiate and receive (detect) mixed electromagnetic waves that are reflected (backscattered) back below (i.e., in the subsurface interior of the Moon or in the core of extraterrestrial regions other than the Moon).

Further, the directional electromagnetic wave generating/receiving section 362 is housed in a rotating mechanism 364 of the electromagnetic wave generating/receiving section and has a structure capable of tilting in any direction. Then, along with the rotation of the electromagnetic wave generating/receiving unit rotation drive unit 366, the entire electromagnetic wave generating/receiving unit rotating mechanism 364 slightly rotates in an arbitrary direction. Using this mechanism, a directional mixed electromagnetic wave 294 can be radiated in any direction inside the subsurface of the lunar surface. Similarly, it is possible to receive (detect) a mixed electromagnetic wave 294 that is scattered or reflected back from any direction inside the lunar underground.

As shown in FIG. 56, a far-infrared spectroscope 376 and an infrared spectroscope 376 are also mounted inside the water source/metal ore deposit exploration device. Here, the far-infrared spectrometer 376 itself does not have a light source, and has a structure capable of measuring the spectral characteristics (spectral spectrum) of far-infrared light emitted from the moon's underground. Within the infrared spectrometer 378, on the other hand, there is a unique infrared emission source. Infrared light emitted from this light source is irradiated toward the lunar surface or the air near the lunar surface. Then, the spectroscopic characteristics (spectral spectrum) of reflected light or scattered light in the air on or near the lunar surface are examined.

Power generated in a solar panel 384 mounted on top of the water source/metallic prospector is stored in a battery 388 to enable nighttime activity. A communication control unit 394 controls wireless communication with an external device via an antenna 396 . The search device internal control system 398 controls and manages the operations of these units in an integrated manner.

FIG. 57 shows an example of a method for searching for water sources and metal deposits inside the lunar surface (or searching for resources in extraterrestrial regions other than the moon) using this water source/metal deposit searching device. FIG. 57(a) shows an example of a water source position searching method using only one water source/metal ore deposit searching device. An example of a water source position searching method using a plurality of water source/metal ore deposit searching devices will be described in FIG. 57(b). In an application of this embodiment, first, the simple method of FIG. can be investigated in detail by the method of

In the simple search of FIG. 57(a), the directional electromagnetic wave generator/receiver 362 emits a directional mixed electromagnetic wave 294 directly below the water source/metal ore deposit search device. The radiated directional mixed electromagnetic wave 294 is reflected (backscattered) everywhere inside the earth's surface 392 and returns to the directional electromagnetic wave generator/receiver 362 . Depending on the reflection (backscattering) position of the mixed electromagnetic wave 294, the time from immediately after the mixed electromagnetic wave 294 is emitted until it returns to the directional electromagnetic wave generator/receiver 362 differs. Therefore, the mixed electromagnetic wave 294 having directivity is radiated in a short period of time, and the detected intensity change of the mixed electromagnetic wave 294 returning to the directional electromagnetic wave generating/receiving unit 362 is measured immediately after the radiation. By measuring the time change from immediately after the radiation in this way, it is possible to estimate some information in the depth direction below the ground surface 392 .

As will be described in section 5.1 using FIG. 26(b), actually, the detection accuracy in the depth direction is greatly reduced due to the influence of multiple scattered electromagnetic waves 294 . Furthermore, when interference occurs between this multiple scattered light 380 (electromagnetic waves) and the backscattered light 390 (electromagnetic waves) to be measured, the detection accuracy is further reduced. However, in the application example of this embodiment, the coherence of the mixed electromagnetic wave 294 having directivity is greatly reduced (the incoherence is dramatically improved), so that the multiple scattered light 380 (electromagnetic wave) and No interference between backscattered light 390 (electromagnetic waves) occurs. Therefore, an effect of improving search accuracy is produced.

When searching in this way, the amount of reflection (backscattering amount) of the mixed electromagnetic wave 294 from the region where the metal deposit 386 exists is large. Therefore, there is a possibility that the metal deposit 386 exists in the region where the detected intensity increases significantly immediately after the mixed electromagnetic wave 294 is emitted.

Large absorption of mixed electromagnetic waves 294 occurs in areas where strips and water sources 386 are present. Therefore, the amount of reflection (the amount of backscattering) of the mixed electromagnetic wave 294 from that area is greatly reduced.

By the way, the amount of reflection (the amount of backscattering) of the mixed electromagnetic wave 294 is greatly reduced not only from the water source 386 but also from the region where the cavity exists. How to distinguish between the water source 386 and the cavity region in this case can be understood by comparing the amount of reflection (the amount of backscattering) from deeper positions. That is, when a large amount of energy of the mixed electromagnetic wave 294 is absorbed by the water source 386, the reflected amount (backscatter amount) of the mixed electromagnetic wave 294 from deeper positions is small. On the other hand, since there is no energy absorption of the mixed electromagnetic wave 294 in the cavity region, the reflected amount (backscatter amount) of the mixed electromagnetic wave 294 from deeper positions is large.

Search accuracy is improved by using other physical parameters in addition to detection of changes in the amount of reflection (the amount of backscattering) of the mixed electromagnetic wave 294 . When the mixed electromagnetic wave 294 is irradiated inside the water source or metal ore deposit 386, the surface of the water source or metal ore deposit 386 absorbs energy and the temperature rises locally. This temperature rise may be detected to improve detection accuracy of water source or metal deposit 386 location.

Every substance emits light with a wavelength corresponding to its temperature. As an example of the relationship between wavelength and temperature at the maximum intensity position of black body radiation, the wavelength is 10.3 μm at 0° C., 8.05 μm at 50° C., and 7.75 μm at 100° C. Therefore, the far-infrared spectroscope 376 may be used to measure the spectral characteristics of the blackbody radiation emitted from the water source or the metal deposit 386 or its surroundings.

Further, instead of directly observing the far-infrared light 382, the temperature change near the earth's surface 392 may be measured using the conduction of heat 382 generated in water sources or metal deposits 386. FIG.

The temperature of the lunar ground surface 392 is 100° C. or higher during the day and -150° C. or lower at night. Therefore, if the temperature change is measured at night (150° C. below zero), high measurement accuracy can be obtained.

As explained using FIG. 55(b), the cathode in the magnetron electromagnetic wave generation source 296 is heated by the heater to emit thermal electrons. Therefore, heat generated when the directional electromagnetic wave generating/receiving unit 362 operates has an adverse effect on the temperature change described above. In order to eliminate the adverse effect, a plurality of water source/metal ore deposit search devices may be combined as shown in FIG. 57(b).

That is, when measuring the temperature change, the directional electromagnetic wave generating/receiving unit 362 in one water source/metal ore deposit search device is operated to irradiate the water source or metal ore deposit 386 with the mixed electromagnetic wave 294 having directivity. , the other heat-free water source/metal ore exploration device measures the temperature change.

Alternatively, as shown in FIG. 57(b), composite electromagnetic waves 294-1 and -2 having directivity may be emitted simultaneously from a plurality of directional electromagnetic wave generating/receiving units 362-1 and -2. A plurality of directional electromagnetic wave generating/receiving units 362-1 and 362-2 detect (receive) the composite electromagnetic wave 294. FIG. This has the effect of reducing the influence of the electromagnetic waves 294 multiple-scattered inside.

Also, when multiple directional electromagnetic wave generating/receiving units 362-1 and 362-2 arranged at different positions simultaneously irradiate composite electromagnetic waves 294-1 and 294-2 having directivity, the composite electromagnetic waves 294-1 and 294-2 can -2 energy is concentrated. This concentrated energy may be used to raise the temperature of a portion of water source 386 above 100°C. A portion of the water source 386 that has risen to 100° C. or higher boils and begins to diffuse. Part of the water vapor 368 diffused during the daytime (100° C. or higher) on the lunar surface is released to the outside of the earth's surface 392 . Observation of this released water vapor 368 with an infrared spectrometer 378 (FIG. 56) confirms the presence of a water source 386 in the energy concentration region.

By the way, water molecules strongly absorb infrared light in the vicinity of central wavelengths of 2.73 μm, 2.66 μm, and 6.27 μm. Therefore, if light absorption occurs commonly in the above wavelength band within the absorption characteristics obtained by the infrared spectrometer 378, it can be estimated that the water vapor 368 is released to the ground surface 392. FIG.

FIG. 58 shows a series of search procedures described so far. When the search for the location of the water source or metal deposit 386 is started (S101), as shown in S102, the water source/metal deposit search device detects the area to be searched (for example, the lunar surface 392 and extraterrestrial areas (sanitary, asteroid, planet, etc.) ). At the first search position, as shown in FIG. 57(a), a directional mixed electromagnetic wave 294 is radiated from the earth's surface 392 toward the underground (the lunar surface, a satellite, an asteroid, the center of a planet, etc.). As a method of searching for a water source or a metal deposit 386 using the radiated mixed electromagnetic wave 294 having directivity, the mixed electromagnetic wave 294 that is internally reflected (backscattered) and returned may be detected. At the same time, the far-infrared spectrometer 376 may be used to detect changes in the properties of the heat (far-infrared light) 382 generated inside (or near the surface of) the water source or metal deposit 386 .

As a result, is there a potential water source or metal deposit 386 at the original search location? is determined (S104). If there is no such possibility (No in S104), it moves to another search position (S102).

Thus, the first step is to map areas where water sources or metal deposits 386 may reside. Then, in the next step, the search accuracy is increased for possible areas (Yes in S104).

In the next step, as shown in FIG. 57(b), multiple water source/metal ore deposit searching devices are mobilized to start multifaceted investigation. As an example of this, as shown in S105, a mixed electromagnetic wave 294 having directivity is simultaneously irradiated from multiple directions to the candidate location of the water source or metal deposit 386 . Then, the mixed electromagnetic wave 294 obtained therefrom is detected (received). In parallel, a far-infrared spectrometer 376 may be used to measure the heat (or far-infrared light) 382 emitted from the region of interest.

If the result of this high-precision investigation is that the target water source or metal deposit 386 candidate is incorrect (No in S106), it moves to another mapping location (S105).

On the other hand, in areas where the possibility of water sources or metal deposits 386 has increased (Yes in S106), further corroborative investigations in S107 may be performed. Here, mixed electromagnetic waves 294-1, -2 with directivity are concentrated in one place from multiple directions to further increase the temperature of the water source or metal deposit 386. FIG. Then, the water vapor 368 diffused near the ground surface 392 and released onto the surface of the ground surface 392 may be detected using an infrared spectroscope 378 .

In this way, the water source/metal ore deposit search device continues to move on the earth's surface 392 until the end of the search (Yes in S108).

FIG. 55 shows a method of generating an electromagnetic wave (mixed electromagnetic wave 294 with directivity) with reduced partial coherence. As an application field example of this electromagnetic wave 294, the resource search method using FIGS. 56 to 58 has been described. Here, the water source/metal ore deposit searching device in FIG.

However, the present invention is not limited to this, and the mixed electromagnetic wave 294 having directivity may be radiated from the sky above the ground surface 392 . As a method of radiating the ground surface 392 from above, for example, the directional electromagnetic wave generating/receiving unit 362 may be mounted on a helicopter, an airplane, an artificial satellite, or the like. Alternatively, the directional electromagnetic wave generating/receiving unit 362 may be placed underground below the ground surface 392 and used for periodic measurement of changes.

Further, (a part of) the method shown in FIGS. 57 and 58 may be used for resource exploration of the earth. In particular, when the application example of the present embodiment is used for earth resource exploration, it may be specialized for metal ore deposit exploration.

Section 3.12 Simplified Explanation of Control Method for Partial Coherence of Light Up to Section 3.11 (previous section), we focused on a quantitative explanation using many mathematical formulas regarding the control method for partial coherence of light. As a result, although a certain degree of theoretical rigor was secured, the content tends to be difficult to understand. In order to eliminate the above-mentioned harmful effects, Section 3.12 will simply and intuitively explain the “method for controlling the partial coherence of light” in this embodiment. Therefore, the theoretical rigor in this section 3.12 is somewhat relaxed.

FIG. 59(a) is used to qualitatively show the conventional interference phenomenon with light having partial coherence. Light emitted from a light source 70 (eg, tungsten filament 50) travels straight with a relatively flat wavefront (equiphase front) 106 . When this light passes through a “transparent flat plate having a fine relief structure on one side” 104, distortion in a cotinually extended wave front 106 occurs.

Since the light travels in a direction perpendicular to the wavefront 106, the traveling direction of the light is bent in accordance with the distortion of the wavefront 106 described above. As a result, the amount of straight light is reduced. The thick hollow arrow in FIG. 59(a) indicates the traveling direction of the synchrotron radiation. As a result of light "interfering" due to the influence of this "transparent flat plate having a fine uneven structure on one side" 104,
1) As shown on the right side of FIG. 59(a), the intensity of light traveling in the direction of the thick hollow arrow increases,
2) The amount of straight light is reduced.

FIG. 59(b) shows incoherent light with reduced partial coherence obtained as a result of technical ingenuity in this embodiment. As in FIG. 59(a), the light immediately after being emitted from the light source 70 (for example, the tungsten filament 50) travels straight with a relatively flat Cotinually Extended Wave Front 106. FIG.

This light passes through the optical characteristic changing member 101 for generating multiple optical paths and the light combining (mixing) section 102 as in FIGS. 8A and 8B. Then, the continuously spreading wavefront 106 is "divided finely". However, the wavelength does not change even after passing through the optical characteristic changing member 101 for generating multiple optical paths and the light combining (mixing) section 102 . Therefore, the equal phase plane interval (Wave Front Interval) along the traveling direction of light is kept unchanged.

Since the wavefront 106 of this light is finely divided, even if it passes through the "transparent flat plate having a fine concave-convex structure on one side" 104, the distortion peculiar to the continuously expanding wavefront 106 does not occur. Therefore, since there is no inclination for each of the finely divided wavefronts 106, the wavefront 106 travels straight without being interfered with.

The method of "dividing the continuously spreading wavefront 106 finely" described here includes great technical novelty and technical inventive step in this embodiment. Because "simply spatially separating a portion of the continuously extending wavefront 106" does not reduce partial coherence.

That is, as explained when formula (B.22) in Section 2.5 was introduced, at a position a little behind the position where "a part of the wavefront 106 is spatially separated", "based on the separated wavefront "Synthesis of light" occurs. The synthesized light generated here inherits the original partial coherence.

Using FIG. 60, a simple explanation of the control method of the partial coherence of light in this embodiment will be given. Light immediately after being emitted from a light source 70 (eg, tungsten filament 50) travels straight with a relatively flat continuously extending wavefront 106 . This continuously expanding wavefront 106 is produced by the collection of light emitted "simultaneously" from the light source 70 .

FIG. 60 shows an easy-to-understand image of the internal functions of the optical property changing member 101 for generating multiple optical paths and the light combining (mixing) section 102 . FIG. 60 merely shows an easy-to-understand image. The specific technical contents are explained before Section 3.11.

A transparent parallel plate 114 is arranged in a part of the optical path through which the continuously expanding wavefront 106 passes.
Assuming that the refractive index in the transparent parallel plate 114 is n, the speed of light passing through it slows down by "1/n". As a result, the light 107 with a “radiation time different” from the surroundings exits the transparent parallel plate 114 . This 'different emission time' light 107 is then mixed with the remainder in the continuously expanding wavefront 106 .

Correspondence between the image diagram of FIG. 60 and FIGS. 8A and 8B will be described. When the transparent parallel plate 114 is arranged in a part of the optical path, differences in the optical paths 201 to 208 occur between the light passing inside and outside the transparent parallel plate 114 . Since the direction of travel of the light after passing through the transparent parallel plate 114 remains unchanged, mixed light 78 is generated behind the transparent parallel plate 114 .

10, an optical path length change 76 occurs between the light passing through the transparent parallel plate 114 (part of the light 74) and the light passing outside (the part of the light 72). ing.

As an image diagram of FIG. 60, an example of a "wavefront division method" for dividing a part of the continuously spreading wavefront 106 is described. However, generation of different optical paths 201 to 208 or generation of optical path length change 76 may be performed by any method other than wavefront division.

In order to "finely divide the continuously spreading wavefront 106", the radiation time difference between the time when the light source 70 radiates "simultaneously" and the time when the light 107 is radiated at "different radiation times" is important. . That is, when the time difference Δt between the two satisfies a condition that deviates from the formula (B·2) (section 2.2), "division" can be performed. Also, in relation to the expression (B.2), a conditional expression for the coherence length (expression (B.6) or expression (B.12)) is given.

According to the formula (B.2), when the frequency width Δν is short, Δt becomes extremely long. For example, there is an experimental method of photon counting, in which the light intensity of the irradiation light 12 is extremely reduced and the object 10 is irradiated with photons one by one in time series. Although each photon is emitted at different times, interference fringes are observed in the pattern obtained by accumulating the arrival locations of all photons.

Since the energy width (frequency width Δν) of each photon used in this experiment is very narrow, the shift Δt between the times when each photon is emitted satisfies the formula (B·2). Therefore, in this case, "breaking of the wavefront 106" does not apply.

OCT (Optical Computerized Tomography) technology is known as a three-dimensional pattern observation technology inside a living body. This divides the optical path of the coherent light into two amplitudes and irradiates the object 10 with only one light. The other light is used as reference light. Inside the detection unit 6, the detection light 16 obtained from the object 10 and the reference light are caused to interfere with each other. Using the incoherence when the optical path length difference between the detection light 16 obtained from the target object 10 and the reference light exceeds the coherence length, the signal noise component from other than the measurement target position is removed. there is

The differences between the above OCT technique and the present embodiment and the effects of the present embodiment are summarized below.
A] In OCT, coherent light is irradiated inside the object 10. As described later in Section 5.1 using FIG. There is interference between scattered lights 380 . The effect of this interference is to obtain only a detected image with a lot of optical noise. In contrast, in this embodiment, the object 10 is irradiated with "mixed light 78" with low partial coherence. As a result, a highly accurate detection signal can be obtained as will be described later in Chapter 5 with reference to FIGS. 61 and 63. FIG.
B] In OCT, the detection unit 6 synthesizes the detection light 16 having an optical path length difference and the reference light. and the multiple scattered light 370 generated inside the object 10 interfere with each other. Therefore, the penetration length of the coherent light entering the object 10 is shortened. On the other hand, in this embodiment, the target object 10 is irradiated with "mixed light 78" with low partial coherence. Therefore, as shown in FIG. 61, the penetration distance increases.
C] In OCT, no correction is made for changes in the unevenness of the surface of the object 10. On the other hand, reference light with a flat wavefront is used. Accordingly, positional deviation in the depth direction of the location where the detection image is obtained occurs according to the change in the unevenness of the surface of the object 10 . On the other hand, in the present embodiment, as will be described later in Chapter 6, it has a function of correcting changes in the uneven shape of the surface of the object 10 and changes in the internal refractive index. Therefore, it is possible to accurately set the depth direction inside the object 10 .

Chapter 4 Method of mixing/separating coherent light and partially incoherent light
(Chapter 5] Mixture and Separation between Normal and Partially Incoherent Light)
Section 3 described how to reduce the partial coherence and increase the partial incoherence of illumination light 12 or detection light 16 used for characterization/detection measurements of object 10 . However, coherent light is essential for, for example, OCT (Optical Computerized Tomography) measurement. Also, in the measurement of wavefront aberration, which will be described later in Chapter 6, detection accuracy increases when coherent light is used. Section 4 describes a measurement apparatus using both coherent and partially incoherent light.

Section 4.1 Structural Example in Measurement Apparatus Using Both Coherent Light and Partially Incoherent Light Both the light source section 322 for coherent light such as a laser light source and the light source section 302 for partially incoherent light An example embodiment of a measuring device with a is shown in FIG. The arrows in FIG. 25 indicate the optical path and traveling direction of light.

Here, the optical arrangement above the object 10 is similar to the optical arrangement in FIG. 1C(c). 1C(c), the light source unit 302 for partially incoherent light on the right side of the top of FIG. Corresponds to the configured region. Here, the specific structure of the light source section 302 for partially incoherent light corresponds to the structure inside the light source section 2 described in the first and third chapters. The light emitted from the light source unit 302 for partially incoherent light and the light source unit 322 for coherent light are mixed in the light mixing unit 340 (a specific mixing method will be described later in Section 4.2). .

Both the coherent light and the partially incoherent light mixed in the light mixer 340 are extracted as reference light in the reference light generator 320 . The reference light is divided into a coherent light portion and a partially incoherent light portion, and a wavefront aberration characteristic detector 306 for the partially incoherent reflected light and a wavefront aberration for the partially incoherent transmitted light are detected. It is used for wavefront aberration characteristic detection in the characteristic detector 316, the wavefront aberration characteristic detector 326 for coherent reflected light, and the wavefront aberration characteristic detector 336 for coherent transmitted light. The rest of the light that has become non-reference light in the reference light generation section 320 is sent to the optical path separation section 310 between the irradiation light and the detection light.

The entire optical path after the light separation section 312 on the upper left side of the object 10 corresponds to the detection section 6 in FIG. 1C(c). All the optical systems below the object 10 in FIG. 25 correspond to the detector 4 in FIG. 1C(a).

An optical path separation section 310 between the irradiation light and the detection light separates the optical path between the irradiation light 12 and the detection light 16 obtained by being reflected by the object 10 . As an example of this optical path separation method, the beam splitter 20 of FIG. 1C(c) may be used. Further, the lower side of the object 10 corresponds to the detection unit 4 in FIG. 1C(a).

In FIG. 25, the objective lens 308 may converge the illumination light 12 within the object 10 and the objective lens 318 may converge the light passing through this convergence point. Therefore, for example, as shown in FIG. 1C (a) or (c), let us consider the case where the irradiation light 12 is condensed at the α point (or α region) or γ point (γ region) in the object 10 . As will be described later in section 6.1, wave front aberration occurs along the optical path in which the irradiation light 12 reaches the α point (or α region) or γ point (γ region) in the object 10 . As a result, the detection light 12 is not condensed at the α point (or α region) or the γ point (γ region), and the condensed point is blurred. The amount of wavefront aberration until reaching this α point (or α region) or γ point (γ region) is predicted in advance, and wavefront aberration opposite to the above is added to the irradiation light 12 before entering the target object 10. back. As a result, the wavefront aberration characteristics generated inside the target object 10 are canceled, and the irradiation light 12 can be focused on the α point (or α region) or γ point (γ region) within the target object 10 .

In addition, with respect to the wavefront aberration characteristics generated in the detection light 16 that has left the α region inside the object 10 and has exited the object 10, the wavefront aberration characteristics that are opposite to those generated in the optical path in the detection unit 6 are generated. Add to detection light 16 . Thereby, a good imaging pattern is obtained on the detection surface of the photodetector 80 (FIG. 8B).

As described above, the wavefront aberration compensation process includes the process of preliminarily giving the irradiation light 12 the wavefront aberration characteristics to be corrected inside the light source unit 2 and the process of correcting the wavefront aberration characteristics in the detection light 16 obtained from the target object 10 . of Wave Front Aberration).

In the embodiment shown in FIG. 25, the wavefront aberration characteristics are measured separately for the reflected light and the transmitted light with respect to the object 10, and the wavefront aberration correction is performed for the irradiation light 12 and the detection light 16, respectively. Further, in order to increase the accuracy of wavefront aberration correction, wavefront aberration correction is performed in two stages of coarse movement (Course) and fine movement (Fine). Here, coarse wavefront aberration correction is performed by a wavefront aberration coarse motion correction unit 352 for irradiated light and a wavefront aberration correction coarse motion correction unit 358 for transmitted light. Further, wavefront aberration correction for fine movement is performed by a wavefront aberration correction unit 354 for irradiated light and a wavefront aberration correction fine movement correction unit 356 for transmitted light.

That is, for the wavefront aberration correction of the irradiation light, the wavefront aberration coarse correction unit 352 of the irradiation light is used to perform approximate wavefront aberration correction. Then, the wavefront aberration fine movement corrector 354 of the irradiation light corrects fine wavefront aberrations for the remaining wavefront aberration residual amount.

For wavefront aberration correction of the detection light 16 obtained after passing through the object 10 , the wavefront aberration coarse motion correction unit 356 of the detection light is utilized to perform rough wavefront aberration correction. Then, the wavefront aberration fine movement correction unit 358 of the detection light corrects fine wavefront aberration for the remaining wavefront aberration remaining there.

Wavefront aberration correction is independently performed for transmitted light from the object 10 (optical path below the object 10). Therefore, for the detection light 16 immediately after passing through the objective lens 318, the transmitted light wavefront aberration correction coarse motion correction unit 358 and the transmitted light wavefront aberration correction fine motion correction unit 356 are arranged in this order.

On the other hand, with respect to the reflected light from the target object 10 (optical path above the target object 10), the optical path of the irradiation light 12 and the optical path of the detection light 16 match. Therefore, the wavefront aberration characteristics generated in the irradiation light 12 when passing through the object 10 and the wavefront aberration characteristics generated in the detection light 16 returning after being reflected from the γ point (γ region) inside the object 10 are match.

Accordingly, wavefront aberration correction for the light source unit 2 and wavefront aberration correction for the detection units 4 and 6 are made common in the optical path above the target object 10 using reflected light. In the embodiment shown in FIG. 25, an irradiation light wavefront aberration rough movement correcting section 352 and an irradiation light wavefront aberration fine movement correcting section 354 are provided between the optical path separating section 310 between the irradiation light and the detection light and the objective lens 308 . are arranged in order.

In order to perform the above wavefront aberration correction, it is necessary to detect the wavefront aberration characteristics that actually occur within the object 10 . This characteristic is detected/measured in each wavefront aberration characteristic detector 306 , 316 , 326 , 336 .

These detectors compare the characteristics of light in an ideal state before wavefront aberration occurs and light containing wavefront aberration, and detect the differential characteristics as wavefront aberration characteristics. That is, by using the mixed light obtained in the light mixing section 340, the wavefront characteristic of the ideal state before wavefront aberration occurs is generated in the reference light generating section 320. FIG. Then, in each of the wavefront aberration characteristic detectors 306, 316, 326, and 336, the detected light containing the wavefront aberration and the reference light obtained by the reference light generator 320 are compared, and the difference between the two is determined. Consider the characteristic as a wavefront aberration characteristic to be detected.

In particular, in this embodiment, the wavefront aberration correction is performed by the coarse motion correction units 352 and 356 using the wavefront aberration characteristics obtained by the partially incoherent light. Further, wavefront aberration correction is performed in the fine motion correction units 354 and 358 by utilizing the wavefront aberration characteristics obtained by the coherent light.

That is, the detection/measurement result of the wavefront aberration characteristic detector 306 for the partially incoherent reflected light is fed back to the wavefront aberration coarse motion correction unit 352 of the irradiated light. Further, the detection/measurement result of the wavefront aberration characteristic detector 316 for the partially incoherent transmitted light is fed back to the wavefront aberration coarse motion corrector 356 for the transmitted light.

At the same time, the detection/measurement result of the wavefront aberration characteristic detector 326 for the coherent reflected light is fed back to the wavefront aberration fine movement corrector 354 of the irradiated light. Then, the detection/measurement result of the wavefront aberration characteristic detector 326 for the coherent transmitted light is fed back to the wavefront aberration fine movement correction unit 358 for the transmitted light.

As will be explained in Chapter 6, when the wavefront aberration characteristic is detected using partially incoherent light, the detection accuracy is low, but the detection range (dynamic range) is very wide. On the other hand, when the wavefront aberration characteristic is detected using coherent light, the detection accuracy is high, but the detection range (dynamic range) is very narrow. In the example of the measuring apparatus shown in FIG. 25, both are used together to efficiently draw out the advantages of both.

The coherent light and partially incoherent light mixed in the light mixer 340 are separated from each other in light separator sections 312 and 332 . Each light separated here is divided by light divider sections 342, 344, 346 and 368, respectively.

The light split here is used separately for signal detection and wavefront aberration characteristic detection. That is, the signal detector 304 for partially incoherent reflected light, the signal detector 314 for partially incoherent transmitted light, the signal detector 324 for coherent reflected light, and the coherent transmitted light Signal detection is performed by the signal detection unit 334 for .

A wavefront aberration characteristic detector 306 for partially incoherent reflected light, a wavefront aberration characteristic detector 316 for partially incoherent transmitted light, and a wavefront aberration characteristic detector 326 for coherent reflected light. A wavefront aberration characteristic detection unit 336 for coherent transmitted light detects the wavefront aberration characteristic.

Section 4.2 Method of Mixing and Separating Coherent Light and Partially Incoherent Light The method of mixing and separating with partially incoherent light is described in section 4.2.

In this embodiment,
A] Utilizing the orthogonality of the (electric field) vibration plane (using a polarizing beam splitter) and B) Utilizing the separation of the wavelength range used (using an optical element that has wavelength dependence in reflection/transmission)
At least one of is adopted, but both may be used together.

First, the method of using "A) orthogonality of vibration planes" will be described. Although not shown, an analyzer (which transmits/reflects only light having a specific vibration plane) is provided at the light exit of the light source unit 322 for coherent light and the light exit of the light source unit 302 for partially incoherent light in FIG. an optical element with specific characteristics). Then, the oscillation planes (of the electric field) between the coherent light and the partially incoherent light are set to be orthogonal.

In this case, a polarization beam splitter may be arranged in the light mixing section 340 to mix coherent light and partially non-coherent light. Polarizing beam splitters are similarly arranged in the light separation units 312 and 332 to separate the coherent light and the partially incoherent light by utilizing the orthogonality of the oscillation planes.

Next, the method "B" for separation by the difference in wavelength characteristics will be described. In this case, the light mixer 340 and the light separators 312 and 332 have the characteristic of "transmitting (or reflecting) only light within a specific wavelength range" and "reflecting (or transmitting) light of other wavelengths". An optical element (band-pass filter) is placed. Then, the coherent light and the partially incoherent light are mixed and separated by changing the wavelength used.

When detecting "absorption wavelength change of a functional group in which a carbon atom or a nitrogen atom is arranged at the center" described in Patent Document 3, partial incoherent light is used to detect the first or second overtone, the third It is desirable to detect changes in absorption wavelengths (changes in the central wavelength of the absorption band) attributed to stretching vibrations of overtones. In this case, coherent light having a wavelength outside the above wavelength range should be used.

Within the wavelength range of near-infrared light described in Section 2.6, there are absorption bands attributed to combination tones in addition to the absorption bands attributed to the n-th overtone of the stretching vibration. When identifying the attribution of these absorption bands, it is relatively easy to identify the absorption band attributing to the n-th overtone of the stretching vibration. Combining sounds are composed of a combination of factors that are more complicated than that. Therefore, it is difficult to estimate the attribution of the combination sound including the constituent factors. Therefore, in the optical detection method and the imaging method of this embodiment, the absorption band wavelength mainly attributed to the n-th overtone of the stretching vibration is selected as a detection/measurement target.

In this case, the lower limit wavelength value of the absorption band corresponding to the first overtone is 1440 nm, the upper limit wavelength value corresponding to the second overtone is 1210 nm, and the lower limit wavelength value is 970 nm. Also, the upper limit wavelength value corresponding to the third overtone is 920 nm. Therefore, the wavelength of the coherent light is preferably within the range of 930 nm to 960 nm or within the range of 1260 nm to 1390 nm.

The experimental basis for the above numerical values is shown in FIG. 23B. The absorption band around the wavelength of 1.213 μm is expected to belong to the second harmonic of the asymmetric stretching vibration due to the methylene group with the carbon atom arranged at the center. The absorption band wavelength of the second overtone of the functional group having a nitrogen atom at the center takes a slightly smaller value.

The absorption band within the 1.35 μm-1.50 μm wavelength region of FIG. 23B is expected to be attributed to the methylene group combination tone. A part of the wavelength range of 1260 nm to 1390 nm in which coherent light can be used includes an absorption band attributed to the combination tone. This means that the optical detection method or the imaging method of this embodiment may exclude the wavelength change of the absorption band attributed to the combination sound from the target.

Chapter 5 Interaction with Light Inside Object of Measurement Interaction with light that occurs inside object 10 (FIGS. 1A-1C) will be described.

Section 5.1 Influence of Light Scattering, Light Absorption, and Multiple Scattering Generated Inside the Subject When the subject 10 contains an inorganic compound or a polymer compound including a living body, light scattering and light absorption occur inside the subject 10. occurs.

The causes of light scattering and light absorption inside the target object 10 will be explained according to the quantum mechanical interpretation. When light (electromagnetic waves) passes through a local electric dipole moment inside the object 10, the vibration mode of the electric dipole moment changes from the ground state to the excited state due to light absorption. state).

Some of the excited states return to the ground state according to the principle of Induced Emission described in Quantum Mechanics. The light generated at this time becomes scattered light. On the other hand, when the energy in the excited state is converted into internal lattice vibration (atomic vibration), light absorption occurs.

A case in which scattered light is scattered in a direction close to the incident direction is called forward scattering. Scattering in the direction opposite to the direction of incidence is called Back Scattering, and scattering to the side is called Side Scattering. Light that is scattered multiple times inside the object 10 is called multi-scattered light.

Multiple scattered light generated inside the object 10 adversely affects signal detection characteristics (including spectral characteristic detection) and imaging characteristics. This situation will be described with reference to FIG. Here, the case of using partially coherent light as the irradiation light 12 is considered.

Straight light 360 is included in the light transmitted through the object 10 shown in FIG. In addition, there is also multiple scattered light 370 that has been scattered multiple times within the object 10 . Among them, the multiple scattered light 370 traveling in the same direction as the rectilinear light 360 interferes with the rectilinear light 360 . As a result of this interference, the total amount of light traveling straight may decrease.

It is considered that FIG. 23B expresses the above phenomenon. #1200 has the highest partial coherence (lowest partial non-coherence) and #400 has the lowest partial coherence (high partial non-coherence). Comparing the absorbance of the baseline represented by the wavelength range from 1.25 μm to 1.35 μm, #1200 has the highest absorbance (the total light amount of straight transmitted light is small). It is considered that the decrease in the total amount of light of the straight transmitted light is caused by partially coherent multiple scattered light.

FIG. 26(b) shows a situation in which the influence of multiple scattered light occurs also in the reflection direction. There is backscattered light 390 that undergoes backscattering only once inside the object 10 and returns in the direction of reflection. At the same time, there is also multiple scattered light 389 that is scattered multiple times within the object 10 and returns in the direction of reflection. When this multiple scattered light 389 returns in the same direction as the backscattered light 390, optical interference occurs between them. Therefore, it is desirable to use the partially incoherent light shown in this embodiment to improve the accuracy of signal detection (including spectral characteristic detection) and imaging accuracy using the backscattered light 390 .

Section 5.2 Relationship between Factors of Scattering/Absorption and Scattering Cross Section Section 5.1 explained that light absorption and light scattering occur where a local electric dipole moment exists. As a specific form of the electric dipole moment sensitive to near-infrared light described in Section 2.7,
1) Electron orbitals in polymer compounds (biased electron cloud distribution) and 2) Functional groups containing hydrogen atoms (group vibration between atoms that constitute them)
There are two types of

The interior of living organisms and organic chemical materials is composed of a large number of polymer compounds. In the interior of the polymer compound, a framework is formed by various atomic nucleus arrangements. In addition, an electron cloud (Electronic Orbital) 404 shown in FIG. 27 surrounds the periphery of the skeleton to connect the nuclei.

When the irradiation light 12 enters the object 10, the electron cloud distribution is induced by the electric field and biased. The deviation of the electron cloud distribution corresponds to the electric dipole moment. As shown in FIG. 27, the molecular size of the polymer compound 402 is relatively large, so the scattering cross-section is also relatively large.

In the state of the electron cloud distribution around each atomic nucleus that constitutes the functional group, the actual charge of each constituent atom has a positive or negative value. When the irradiation light 12 passes through this functional group 406, it vibrates (group vibration) between constituent atoms according to the positive or negative polarity of the effective charge of each constituent atom. Therefore, the difference in the net charge for each atom that constitutes this functional group 406 constitutes the electric dipole moment.

Since this functional group 406 is composed only of a central nucleus and 1 to 3 hydrogen nuclei arranged around it, the size of the functional group 406 itself is very small (compared to the polymer compound 402 described above). . Therefore, the scattering cross section of the functional group 406 is very small (compared to the polymer compound 402).

Section 5.3 Scattering cross section and characteristics of light scattering
According to Emil Wolf et al.'s textbook (Max Born and Emil Wolf: Principles of Optics (1975, PERGAMON PRESS LTD) Chapter 13), a light scatterer with a small scattering cross section as in the functional group 406 causes Rayleigh scattering. is likely to occur.

On the other hand, the above textbook describes that a different type of light scattering (Mie scattering) occurs in the polymer compound 402 having a large scattering cross section. In this type of light scattering, "Rayleigh scattered light generated at each point in the same polymer compound 402 interferes with each other".

That is, the two types of electric dipole moments (light scatterers) sensitive to near-infrared light described in section 2.7 have different scattering cross-sections, so that the light scattering states differ from each other.

Using the experimental data showing the absorbance in FIG. 23B, the relationship between the two types of light scatterers (electric dipole moments) described above will be considered. It has already been explained in section 4.2 that the absorption band around the wavelength 1.213 μm can be attributed to the second harmonic of the antisymmetric stretching vibration due to the methylene group with the centrally located carbon atom.

Since the methylene group belonging to the functional group 406 has a very small scattering cross-section, interference between scattered lights from the methylene group is difficult. 23B (or FIG. 23A), the absorbance difference from the baseline in the peripheral absorption band at a wavelength of 1.213 μm is considered to be substantially constant regardless of the partial coherence of the irradiation light 12 .

It is expected that the baseline absorbance represented in the wavelength region from 1.25 μm to 1.35 μm is greatly influenced by scattered light from the polymer compound 402 (FIG. 27). Since the Mie scattering characteristics are similar to "characteristics in which Rayleigh scattered light at each point in the polymer compound 402 interferes with each other", the difference in the partial coherence of the irradiation light 12 changes the absorbance of the baseline. It is possible.

Section 5.4 Detection Characteristics Using Backscattered Light (Reflected Light) According to the description in the above textbook, in Rayleigh scattering, the light intensity of forward scattered light and the light intensity of backscattered light are almost equal. On the other hand, in Mie scattering, the light intensity of backscattered light is much smaller than the light intensity of forward scattered light (depending on the case, it is on the order of 1/100 to 1/1000).

This difference is schematically shown in FIG. That is, the backscattered light intensity obtained from the polymer compound 402 is very small. In comparison, the relative backscattered light intensity within the total scattered light intensity received by functional group 405 is high (although the scattering cross section is small).

Decrease the partial coherence (increase the partial incoherence) of the illumination light 12 as described in Chapter 3, and as shown in FIGS. 1A-1C (b) and (c) Optical detection (including spectral characteristics) and imaging may be performed using reflected light (backscattered light). By doing so, it is possible to efficiently detect/measure signals and images from the functional group 406 while reducing the influence of scattered light from the polymer compound 402 .

In particular, when measuring the structure and state of the inside of the object 10 or its change using the reflected light (backscattered light) from the object 10, the penetration depth (Penetration Depth) of the irradiation light 12 that can penetrate deeply into the inside of the object 10 becomes a problem.

If the Lambert-Beer law holds, the intensity of the illuminating light 12 penetrating into the object 10 decreases exponentially with the penetration depth. The reduction coefficient at this time is proportional to the absorbance shown in FIG. 23B. As far as FIG. 23B is concerned, when #400 phase conversion element is used (when partial incoherence is increased), absorbance is 6 /7.

Therefore, the experimental data in FIG. 23B means that "reducing the partial coherence (increasing the partial incoherence) of the illumination light 12 increases the possible penetration distance into the object 10". do.

Even when #1200 is used here, as shown in FIG. 22, a rear mirror 82 is used and transparent parallel plates 94-1 to 94-4 are arranged in the optical path to reduce partial coherence. ing. Therefore, compared with the prior art, which does not reduce the partial coherence at all, the absorbance is expected to be much smaller than 6/7.

The difference in penetration depth of the irradiation light 12 into the object 10 can be explained as the influence of optical interference of the multiple scattered light 370 on the rectilinear light 360 shown in FIG. 26(a). That is, the relationship between the penetration intensity and depth of the straight light 360 when passing through the object (polyethylene sheet in the experimental data of FIG. 23B) 10 shown in FIG. be done. However, it is considered that the light 370 traveling straight after being multiple-scattered inside the object 10 causes optical interference with the straight traveling light 360 . As a result, the absorbance is greater than that of #1200, and the possible penetration distance within the object 10 is reduced.

The constituent molecular structures of cell membranes (lipid bilayers), internal membranes, and fat components (Fat) in vivo are similar to polyethylene described above. Therefore, the absorbance characteristics at the site are similar to FIG. 23B. Therefore, from the above phenomenon as well, light with reduced partial coherence (increased partial incoherence) can penetrate deeper regions in the body (structures and activities in deeper regions in the body). It has the effect of being able to observe the state or its change).

So far, only the influence of the multiple scattered light 370 inside the object 10 has been explained, but it is also necessary to consider the influence of the wavefront aberration mixed in the irradiation light 12 as well. The wavefront aberration mixed in the irradiation light 12 is
1. 2. Wavefront aberration generated inside the object 10; There are two types of wavefront aberrations that occur at the interface at the entrance of the object 10 (the interface between the air and the object 10).

In any case, the phase of the light affected by the wavefront aberration shifts with respect to the straight light 360 within the object 10 shown in FIG. 26(a). As a result, optical interference between the two reduces the possible penetration distance of the illumination light 12 into the interior of the object 10 .

Summarizing the above explanation,
(1) reduce the partial coherence (increase the partial incoherence) (Chapter 3 Embodiment), or (2) improve the wavefront aberration characteristics caused by the object 10 (Chapter 6 Example)
Then, an effect is produced that the possible penetration distance of the irradiation light 12 into the object 10 can be extended (measurement can be performed even in a deep region).

In relation to the above, the relationship between the depth of penetration of the irradiation light 12 into the object 10 and the wavelength used will be described. The Lambert-Beer law shows the relationship between the penetration depth inside the object 10 and the intensity of the irradiation light 12 in the straight-ahead state when the irradiation light 12 is caused to travel straight into the object 10 . Here, light absorption and light scattering inside the target object 10 can be considered as attenuation factors of the straight light intensity. Reflection of light is considered here as part of light scattering (backscattered light). Therefore, when light scattering occurs frequently inside the target object 10, the attenuation of straight light is increased (the penetration depth is shortened).

As explained in Section 5.3 with reference to FIG. 27, the light scattering form in the visible region to the near-infrared region includes scattering with a relatively small scattering cross section (Rayleigh scattering) and scattering with a relatively large scattering cross section ( Mie scattering, etc.).

In either case, the light scattering probability (substantial scattering cross section) increases rapidly as the wavelength used becomes shorter. Specifically, in Rayleigh scattering, the scattered light intensity (scattering probability/scattering cross section) is inversely proportional to the fourth power of the wavelength. Mie scattering also has a similar tendency.

All living organisms, including animals, plants, and microorganisms, have complex structures, and light scattering occurs in each individual structure. Therefore, when the inside of a living body is irradiated with light in the visible range to the near-infrared range, the depth of penetration sharply decreases as the wavelength used becomes shorter.

On the contrary, when near-infrared light with a long wavelength is used, the probability of light scattering (scattering cross section) inside the living body is greatly reduced. As a result, when near-infrared light is used as the irradiation light 12, the light can penetrate deep inside the living body. Therefore, near-infrared light is suitable for structural analysis, composition analysis, activity state and its change analysis in a relatively deep region inside the body.

Therefore, the method of using light (near-infrared light) in the wavelength range described in Section 2.6 as the irradiation light 12 and the method of reducing partial coherence (increasing partial incoherence) described in Chapter 3 ), the penetration distance of the irradiation light 12 inside the living body can be further increased.

In addition, the method of using light (near-infrared light) in the wavelength range described in Section 2.6 as the irradiation light 12 and the method of improving the wavefront aberration generated in the target object 10 described in Chapter 6 are also possible. Even if they are combined, an effect is produced in which the penetration distance of the irradiation light 12 inside the living body can be further increased.

Furthermore, the wavelength range described in Section 2.6, the method of reducing partial coherence (increasing partial incoherence) described in Chapter 3, and the method of improving wavefront aberration described in Chapter 6. You can combine all.

Section 5.5 Formulation of interactions with electromagnetic waves inside measurement object explained in detail. In order to be able to consider these interactions in more depth, this section 5.5 provides an interaction formulation. The range of application of the relational expressions introduced here is not limited to visible light and near-infrared light, and can be applied to a wide range of general electromagnetic waves from ultraviolet light to 30 kHz LF waves (Low Frequency Waves: long waves).

As part of Maxwell's equations

exists. The above formula (B.52) means "the electromagnetic field generated in the surroundings when the current J flows". Regarding the induced-current Ja generated by absorbing external electromagnetic waves ,

rewrite as Here, ε represents the dielectric constant in the dielectric.

Maxwell's equations in the absence of charge are also

exists.

Here, using the relationship of formulas (B.53) to (B.55),

A relational expression is derived.

A local electric dipole moment or dielectric polarization in a dielectric is denoted as Pε(r, t, ω). where ω represents the angular frequency of the electromagnetic wave. And εE=ε ₀ E+Pε(r, t, ω) with respect to the dielectric constant ε ₀ in vacuum (B・57)
relationship is established.

Also, in Sections 5.1 and 5.2, it was explained that absorption of electromagnetic waves occurs due to oscillation of the local electric dipole moment Pσ(r, t, ω). And between this local electric dipole moment Pσ(r, t, ω) and the induced-current Ja

There is a relationship of

Using equations (B・57) and (B・58), equation (B・56) is

A relational expression is derived. The left side of the equation (B.59) represents the wave characteristic of the electromagnetic wave in vacuum (that is, outside the object 10). That is, the behavior of the irradiation light (first light) 12 and the detection light (second light) 16 shown in FIGS. 1A to 1C is given by equation (B.59). Assuming that "Pε=Pσ=0", the equation (B·59) expresses the equation of an electromagnetic wave passing through a vacuum.

As explained in Sections 5.1 and 5.2, the light scattering and light absorption inside the object 10 are related to the oscillation of the local electric dipole moment. Pε on the right side of equation (B.59) is involved in the generation of scattered light, and Pσ is involved in light absorption.

In addition, as explained in Fig. 27 and section 5.2, the factors of interaction with near-infrared light are 1) electron orbitals in the polymer compound (bias of electron cloud distribution) and 2) functional groups containing hydrogen atoms. (Group vibration between atoms that make up)
There are two types of Therefore, the above two types of interaction factors are involved in the above electric dipole moments Pε and Pσ, respectively.

By the way, group vibrational (excitation) energy in a functional group is often diffused into interatomic vibrational energy in a polymer compound rather than emitted as scattered light. Therefore, the group vibration within the functional group contributes more to Pσ than to Pε (easily absorbs light). Therefore, part (one kind) of the electric dipole moment Pσ includes the “electric dipole moment μ _x in the functional group” (described later in Section 7.2) represented by the formula (C·7).

Electromagnetic waves E(r,t) of irradiation light (first light) 12 and detection light (second light) 16 passing through the outside of the object 10 are expressed as

, the electric dipole moments Pε and Pσ are respectively

and variables can be separated. By substituting the formulas (B.61) and (B.62) into the formula (B.59),

is obtained. Equation (B.63) shows that the scattered light intensity and the amount of light absorption are proportional to the square of the angular frequency (frequency) of the electromagnetic wave to be irradiated. It is also found that in a light scatterer or light absorber in which p _ε and p _σ are uniformly distributed, the intensity of scattered light and the amount of light absorption (when no light interference occurs) are proportional to their volume. These properties correspond to the Rayleigh Scattering described in Section 5.3.

And the solution of the equation of the form (B.63) is

is known to be given by Note that “r _s ” in the expression (B.64) represents a local position vector (Position Vector of Scattering Source) inside the object 10 . "r _d " represents the position vector of detecting destination of the measuring point (detecting unit 6 in FIGS. 1A to 1C) arranged outside the object 10 .

If the distribution of p _ε and p _σ is limited to a two-dimensional array, the formula (B·64) corresponds to the Fresnel-Kirchhoff' Formula described in general optics textbooks. Here, “p _ε (r _s , t)−p _σ (r _s , t)” in the equation (B·64) corresponds to the two-dimensional aperture function (Pupil Function) of the Fresnel-Kirchhoff equation. However, “p _ε (r _s , t)−p _σ (r _s , t)” in the formula (B·64) is unique in that it has a three-dimensional distribution.

The remaining terms excluding the portion corresponding to the above aperture function within the integrand region of equation (B.64) represent "spherical waves." Also, the right side of the equation (B.64) indicates integration over the entire internal region of the object 10 . Therefore, the "effect of interference between spherical waves" appears in the equation (B.64). Therefore, the equation (B.64) expresses interaction with electromagnetic waves having partial coherence (or coherence) inside the object 10 .

The method of formulating the interaction with electromagnetic waves with reduced partial coherence (or incoherence) aimed at in this embodiment is described in the textbook of Emil Wolf et al. (Max Born and Emil Wolf: Principles of Optics (1975, PERGAMON PRESS LTD) Chapter 10). Referring to the description there, the formulation of electromagnetic waves with reduced partial coherence (or incoherence) should be expressed in terms of "detected light intensity" instead of electric field amplitude.

The integrand in equation (B·64) represents the amplitude of the electromagnetic wave (electromagnetic field) scattered/absorbed from the local region inside the object 10 . Therefore, when the amplitudes (electromagnetic fields) of electromagnetic waves are "combined", interference between electromagnetic waves appears. On the other hand, for electromagnetic waves with reduced partial coherence (or incoherence), the intensity (light amount) of the electromagnetic waves scattered/absorbed from local regions inside the object 10 is integrated (mixed). Phase information is deleted from the intensity (light amount) itself. Therefore, the "interference effect" caused by the phase difference does not appear in the integration result.

(B 64) When formulating the above contents with reference to the formula,

corresponds to Here, the electromagnetic wave energy I(r _d ,t) carried by the electromagnetic wave in the vacuum is

It is known that Also, in the formula (B 66)

is ringing. Therefore, the coefficients of the formula (B.65) are set in consideration of the formulas (B.66) and (B.67).

(B-65), the detected intensity I(r _d ) obtained by the detection unit 6 (FIGS. 1A to 1C) can be calculated theoretically from the intensity considering the local scattering and absorption inside the object 10. reasonably predictable. In addition, such a method of expressing light intensity is well consistent with the formula (B.30) described in Section 3.5.

Here, if the intensity change of the irradiation light 12 in the depth direction inside the object 10 can be theoretically predicted, the theoretical calculation accuracy is further improved. From a macroscopic point of view, Lambert-Beer's law, in which the change in intensity of the illumination light 12 in the depth direction within the object 10 decreases exponentially, may be used approximately.

Combining the Lambert-Beer law and the theoretical calculation formula shown in formula (B 65) in this way, when using electromagnetic waves with low partial coherence (or non-coherence) The detection intensity I(r _d ) obtained by the detection unit 6 (FIGS. 1A to 1C) can be theoretically predicted. As a result, the local state and attributes inside the object 10 can be analyzed with high accuracy.

Section 5.6 Effect on measurement results due to difference in partial coherence of irradiation light and its consideration In Section 3.9, using FIGS. We have already explained the difference in measurement results depending on Section 5.6 presents further experimental results and discusses the results.

The same experimental system as in FIG. 22 was also used in the experiments in Section 5.6. #240 sand grains (average surface roughness Ra: 2.08 μm) are used to create a sanded surface of the phase conversion element (optical property changing member) 212 to generate “near-infrared light close to incoherence”. gone.

On the other hand, in the experiment using "conventional near-infrared light having partial coherence", the phase conversion element (optical property changing member) 212 was omitted. In order to match the amount of light detected by the spectroscope 22, an ND (Neutral-Density) filter of OD 1.5 (Optical Density) was arranged at the above position.

In each case, the average value of 250 repeated measurement results is calculated.

FIG. 61 shows spectral characteristics of light transmitted through a silk sheet with a thickness of approximately 100 μm. When compared with light with a wavelength of 0.9 μm, the light transmittance of “conventional near-infrared light with partial coherence” was a little over 2%. In comparison, the light transmittance of "near-infrared light close to incoherence" was a little less than 6%, a difference of a little less than 3 times. From this experimental data, it can be seen that the penetration distance to the target object 10 is longer with "near-infrared light with near incoherence" than with "conventional near-infrared light with partial coherence." .

In addition, the change in the amount of transmitted light in the wavelength direction in the "conventional near-infrared light with partial coherence" is linear (almost the same as the broken straight line added for reference), and the absorption No change in properties is observed.

On the other hand, the change in the amount of transmitted light in the wavelength direction for “near-infrared light that is nearly incoherent” shows characteristics that are significantly different from those described above. When the wavelength is 1.35 μm or more, the amount of light decreases significantly from the dashed straight line added for reference.

FIG. 62 shows the result of converting this transmitted light amount change characteristic into absorbance change. A plurality of peaks (maximum points) are observed in the absorbance of the silk sheet shown in FIG. "-log ₁₀ (It/Ii)" is defined as absorbance. Here, Ii represents the incident intensity of the irradiation light (first light) 12 . The transmission intensity of the detection light (second light) 16 obtained after passing through the silk sheet is represented by It.

For comparison, FIG. 63 shows the absorbance characteristics of light transmitted through a polyethylene sheet having a thickness of 30 μm. The molecular structure of polyethylene is shown in FIGS. 64(a) and (b). It has a simple structure in which two hydrogen atoms are bonded to each carbon atom that constitutes the principal chain. In addition, the center wavelength of the absorption band attributed to stretching vibration (Stretching) of this polyethylene is the position where the first overtone (First-Order Overtone) is longer than 1.7 μm, and the second overtone is around 1.21 μm, and the third It is known that overtones exist around 0.92 μm. It is also known that an absorption band attributed to a combination exists in the range from 1.39 μm to 1.42 μm.

Silk sheets have a more complex molecular structure than polyethylene. The silk sheet material is composed of a protein called fibroin. And this fibroin has a periodic structure every 6 amino acids (Hexapeptides), as shown in FIG. 64(c). And mainly Glycine G and Alanine A form this periodic structure. By the way, the amino residue (residue) of glycine has one hydrogen atom bonded to a carbon atom. A methyl group ( _-CH3 ) is attached to the carbon atom of the amino residue of alanine.

It is known that the "central wavelength of the absorption band attributed to stretching vibration" of the methyl group is slightly shorter than the central wavelength of the methylene group ( _-CH2 ). On the other hand, it is also known that the "central wavelength of the absorption band attributed to stretching vibration" of glycine residue (-CH) is almost similar to the central wavelength of methylene group (-CH ₂ ).

Therefore, the peak ₍ maximum) position indicated by the “Lower Direction Arrow” in the absorbance characteristic of FIG. It is possible. From the comparison with the absorption band in FIG. 63, these peaks may be the second overtone of the stretching vibration of the methyl group (—CH ₃ ), the coupling tone, and the first overtone of the stretching vibration in order of shortest wavelength.

On the other hand, the peak (maximum) positions indicated by the “White-Centered Bold Arrow of Higher Direction” in FIG. Amide II) may be involved.

As will be described later in Section 8.3 using FIG. 38, the β-sheet crystal part 602 is present in the fibroin. In the β-sheet crystal part 602, hydrogen bonds are formed between the secondary amides. Therefore, there is a possibility that any of the peak (maximum) positions indicated by the "upward bold arrow" is involved in this hydrogen bond.

As shown in the lower part of FIG. 61, it was impossible to analyze the molecular structure in the silk sheet with the “conventional near-infrared light with partial coherence”. However, by using the "near-infrared light that is nearly incoherent" realized in this embodiment, detailed structural analysis becomes possible even for aggregates with complex molecular structures such as silk sheets.

A detailed examination of the difference in the partial coherence of the illuminating light 12 on the absorbance characteristics obtained from the transmitted light of the polyethylene sheet reveals the difference between the interaction equations (B 64) and (B 65) comes into view. The lower side of FIG. 63 shows the case of using "near-infrared light that is nearly incoherent", and follows the vertical axis on the left side. On the other hand, the upper side of FIG. 63 is the case of using "conventional near-infrared light with partial coherence", and follows the vertical axis on the right side. Here, the scales of the left and right vertical axes are significantly different.

First, comparing (a) with (b) and (c) with (d), it can be seen that the height of the peak relative to the baseline slope indicated by the dashed line is significantly different. The apparent peak height is significantly higher in the case of using "near-infrared light close to incoherence". As can be seen by comparing Figures 23A and 23B, the absolute peak heights between (a) and (b) and between (c) and (d) are unchanged. The slope of the baseline is higher when measured with "conventional near-infrared light with partial coherence". However, the C/N ratio (Carrier to Noise Ratio) of the signal is clearly better when measured with "near-infrared light close to incoherence".

Next, attention is focused on the tail characteristics at wavelengths near the absorption band shown in (e) and (f). When measured with "near-infrared light close to incoherence", a large decrease in absorbance can be seen here. On the other hand, when "near-infrared light that is nearly incoherent" is used, the bottom of the absorption band becomes gentle. That is, the sharpness of the edge of the absorption band (edge portion of the absorption band) differs greatly.

The above difference is not seen around the absorption band ((g) to (i)) attributed to the second harmonic of the stretching vibration. However, since there is an absorption band derived from another stretching vibration here, there is a possibility that the above difference cannot be seen. The absorption band with a center wavelength of 1.21 μm is said to belong to the second harmonic of symmetrical stretching vibration of methylene group ( _-CH2 ). It is said that an absorption band attributed to the second overtone of the asymmetrical stretching vibration exists in the vicinity of the central wavelength of 1.19 μm, although the height is small. Therefore, at the positions (g) to (i), there is a possibility that the absorption band attributed to the second overtone of the antisymmetric stretching vibration is detected instead of the absorption band having a smooth bottom.

Furthermore, when measured with "near-incoherent near-infrared light", a large oscillation is seen at the position (j) associated with the combination tone. The vibration at position (j) is different from Fermi Resonance because the measurement results vary depending on the characteristics of the illuminating light 12 .

The changes that occur in the wavelength regions (e), (f), and (j) may be special phenomena that occur at the edge of the absorption band. For example, consider the case where methylene groups (-CH ₂ ) in polyethylene are irradiated with light having wavelengths corresponding to regions (e), (f), and (j). Absorbing this wavelength light, the methylene group tries to move to a vibrationally excited state. However, the methylene group cannot transition to a vibrationally excited state due to the quantum effect shown by the formula (A.60) in Section 7.2. Instead, it is assumed that the electron cloud around the methylene group absorbs the light of the above wavelength to make up for it (the value of "p _σ (r _σ , ω)" changes slightly locally).

When the value of "p _ε (r _ε , ω)" near the methylene group in polyethylene is small, the value of "p _σ (r _σ , ω)" in formula (B 65) changes slightly. However, it has little effect on the whole. However, in formula (B 64), between the scattered light near the methylene group and the scattered light at a location far from the methylene group (i.e., a location where the value of "p _ε (r _ε , ω)" is large) is cause optical interference. As a result, a minute value change of "p _ε (r _ε , ω)" near the methylene group is greatly amplified. It cannot be denied that this amplification result appears as a difference in each wavelength region of (e), (f), and (j).

In FIG. 63, the baseline profile is indicated by a dashed line. This baseline profile is considered to be related to the deviation of electron orbits localized around the polymer. The dashed line indicates that the absorbance value decreases as the wavelength increases. On the other hand, the dashed line (baseline) of the silk sheet shown in FIG. 62 increases the absorbance value as the wavelength increases. This difference in baseline properties may have something to do with macromolecular structure.

For example, in the case of a fibrous structure such as polyethylene polymer, a large amount of "biased electron trajectory" occurs with respect to short-wavelength light as shown in FIG. 64(a), and a large amount of energy is absorbed. On the other hand, as shown in FIG. 64(b), long-wavelength light may reduce the energy absorption efficiency of infrared light.

In addition, as shown in FIG. 64(c), the fibroin that constitutes the silk sheet has a periodic structure every six amino acids. An electron orbital with a periodic structure appears according to the periodic structure of this amino acid sequence. At the end faces of the blocks that make up the periodic structure, this electron trajectory is subject to boundary conditions. The energy required for the transition from the ground state 393 of the electron orbital to the excited state 399 corresponds to the maximum absorption amount (wavelength with high absorbance) (see equation (A.60) in section 7.2). As a result, it can be explained that the rising baseline (broken line) in FIG. 62 is formed.

Using the formula (B.65) in this way, there is also a method of explaining the baseline characteristic in the absorbance characteristic from the polymer structure. Therefore, from the absorption characteristics using "near-infrared near-incoherent light" obtained from unknown polymers and polymers that make up living organisms,
A] Estimation of polymer structure from baseline characteristics,
B) There is an effect that the functional group in the polymer can be estimated from the central wavelength of the absorption band. And not only that,
C] Real-time activity status (or change thereof) in the living body from the amount of wavelength shift from the standard value of the central wavelength of the absorption band
There is also an effect that can be estimated.

Chapter 6 Feedback Method for Wavefront Aberration Occurring in the Optical Path As a method for reducing optical noise mixed in the measuring apparatus 30, in this embodiment,
(1) reduction of optical noise related to partial coherence; .1 explained.

The above method (1) was mainly explained in Chapter 3. The following method (2) will be explained in Chapter 6.

Section 6.1 Principle of occurrence of wavefront aberration inside object (transparent parallel plate) First, the basic principle of occurrence of wavefront aberration inside object 10 will be described with reference to FIG.

As shown in FIG. 28(a), an objective lens 308 is used that converges the irradiation light 12 at a point α in a vacuum (air). For simplification of explanation, the object 10 is assumed to be a transparent parallel plate with a refractive index n. When a parallel plate (object 10) is placed in the middle of the optical path from the objective lens 308 to the focal point, refraction occurs at the interface between the vacuum (air) and the parallel plate with a refractive index of n. As a result, as shown in FIG. 28(b), the light is not focused at the β point, and the focus position shifts along the optical path. This phenomenon is called wavefront aberration.

In FIG. 28B, the surface of the object 10 is assumed to be optically flat for simplification of explanation (wavefront aberration occurs even if the surface is perfectly flat as described above). However, the surface of the object 10 actually has an uneven shape. Further wavefront aberration is generated according to the uneven shape.

Section 6.2 Wavefront Aberration Correction Method Before explaining the wavefront aberration correction method in Section 6.2, the reason why light is not focused on the β point in FIG. 28B will be explained.

In FIG. 28A, since the optical path length from each point divided on the objective lens 308 aperture plane (Pupil Plane) to the point α is the same, the light is condensed at the point α. On the other hand, in FIG. 28(b), the object 10 with the refractive index n is inserted in the middle of the optical path to the β point. As a result, an optical path difference .delta. according to the formula (B.13) is generated. Also, the value of the optical path length difference δ differs depending on the radial position on the aperture of the objective lens 308 . The difference in the optical path length difference δ impedes the collection of light at the point β.

Based on the above principle, the optical path difference opposite to the optical path difference .delta. This correction method corresponds to the wavefront aberration correction method. Further, it is desirable to correct the optical path length difference δ with parallel light immediately before (or immediately after) incidence on the objective lens 308 .

As a specific method for correcting the wavefront aberration, in this embodiment, the light cross section of the illumination light 12 or the detection light 16 in a parallel light state immediately before (or immediately after) entering the objective lens 308 is divided into meshes. The optical path length may be changed for each cell.

FIG. 29A shows a specific structural example of the wavefront aberration coarse motion corrector 352 for irradiated light and the wavefront aberration coarse motion corrector 356 for transmitted light in FIG. 25 . An optical cross section of the irradiation light 12 or the detection light 16 is divided into cells arranged two-dimensionally in the vertical and horizontal directions.

Light reflecting surfaces 416-1 to 416-6 are formed on the surface of each cell. Individual electrode portions 414-1 to 414-6 are provided below the light reflecting surfaces 416-1 to 416-6. Piezoelectric elements 418-1 to 418-6 are arranged between the individual electrode portions 414-1 to 414-6 and the common electrode portion 410, respectively.

For example, when a predetermined voltage with respect to the common electrode portion 410 is applied to the individual electrode portion 414-3, the thickness of the piezoelectric element 418-3 changes. The optical path length of the irradiation light 12 or detection light 16 reflected by the light reflecting surface 416-3 changes according to the thickness change of the piezoelectric element 418-3.

FIG. 29B shows a specific structural example of the wavefront aberration fine movement corrector 354 for irradiated light and the wavefront aberration fine movement corrector 358 for transmitted light in FIG. 25 . In FIG. 29B as well, the light cross section of the irradiation light 12 or the detection light 16 is divided into cells arranged two-dimensionally in the vertical and horizontal directions.

In the structure of FIG. 29B, the light reflecting surface and the common electrode portion 420 are shared. Then, the irradiation light 12 or the detection light 16 is reflected by the common electrode portion 420 which also serves as this light reflecting surface. Liquid crystal layers 428-1 to 428-3 are formed above the common electrode portion 420, which also serves as the light reflecting surface, and the optical path length changes according to the liquid crystal orientation inside the liquid crystal layers 428-1 to 428-3. A partition plate 422 separates the liquid crystal layers 428-1 to 428-3. Also, transparent electrode portions 424-1 to 424-3 for changing the liquid crystal orientation are formed on the upper portion.

In FIG. 29B, the irradiation light 12 or the detection light 16 is reflected to change the optical path length, but the irradiation light 12 or the detection light 16 may be transmitted to change the optical path length.

Section 6.3 Common Part of Wavefront Aberration Characteristics Detection Method Section 6.3 of this book begins with an explanation of the inside of the reference beam generator 320 shown in FIG.

FIG. 1C shows an example in which convergent irradiation light 12 is condensed at only one point (α/β/γ points) inside the object 10 . This is merely a description for simplification of explanation, and the light may be condensed at different points in the object 10 at the same time. Moreover, without being limited to this, in the present embodiment, the irradiation light 12 may form a predetermined three-dimensional shape in a local region inside the object 10 .

The control of the three-dimensional shape of the irradiation light formed inside the object 10, the plurality of condensing points, etc. is performed within the reference light generation unit 320. FIG. As its basic principle, the present embodiment forms "a plurality of imaging patterns in a confocal relationship along the optical axis direction".

The inside of the three-dimensional transmission pattern forming section 440 arranged inside the reference light generating section 320 has a structure in which a plurality of two-dimensional transmission image forming layers 442, 444, and 446 are stacked with a predetermined distance therebetween. The two-dimensional transmission image forming layers 442 , 444 , 446 have the function of extracting only specific region light in the cross section of the detection light 16 . The two-dimensional transmission image forming layers 442, 444, and 446 may be made of liquid crystal shutters, for example.

However, it is not limited to this, and any optical element that is arranged in the optical path of light and has a function of allowing light transmission (or light reflection) only within a predetermined pattern may be used. For example, a mechanical mask, pinholes, and slits having a predetermined two-dimensional pattern shape may be used, and the mechanical mask, pinholes, and slits may be taken out and replaced when the pattern shape is changed. Alternatively, a two-dimensional optical switch array that is arranged two-dimensionally and whose light transmission/reflection characteristics change locally according to electrical signals may be used.

Each layer of the two-dimensional transmission imaging layers 442 , 444 , 446 is in an imaging (confocal) relationship with different depth positions within the object 10 . Parallel light emitted from the light mixer 340 (FIG. 25) passes through the two-dimensional transmission image forming layers 442, 444, and 446, thereby forming an imaging pattern within the object 10. FIG.

For example, the two-dimensional transmission image forming layers 442 and 446 are set to transmit all the light (that is, the two-dimensional transmission image forming layers 442 and 446 are not blocked at all), and the two-dimensional transmission image forming layer 444 It is assumed that a pinhole structure is formed that transmits light only in the ε region of . In this case, the light is focused only on the α point within the object 10 .

Further, when a plurality of pinhole patterns through which only a plurality of points in the two-dimensional transmission image forming layer 444 can pass are formed, the light is condensed at a plurality of points on a corresponding plane (imaging plane) inside the object 10 accordingly.

A pinhole structure that allows light to pass through only the ε area of the two-dimensional transmission image forming layer 444 is formed, and a pinhole structure that allows light to pass through the η area of the two-dimensional transmission image forming layer 442 is provided, and the ε area and the η area are formed. Opens the optical path for the light that has passed through. Then, inside the target object 10, the light is condensed at points α and γ which are different in depth.

In this way, pinholes are formed in the ε region, the ζ region, and the η region, and the optical path of the light passing through them can be transmitted. Accordingly, light is focused only in the α region, β region, and γ region.

In FIG. 30, a plurality of two-dimensional transmission image forming layers 442, 444, and 446 are housed in the same three-dimensional transmission pattern forming section 440 together. However, not limited to this, the lights passing through the two-dimensional transmission image forming layers 442 , 444 , and 446 arranged at mutually different positions may be synthesized on the way to reach the object 10 .

FIG. 30 shows an example of forming an imaging pattern with a transmission pattern. However, not limited to this, the image forming pattern may be formed by reflected light. be. Although not shown in FIG. 30, the reference light 436 extracted here is separated into coherent light and partially non-coherent light in the reference light generator 320 .

The separated partially incoherent light reference beam 436 is then used as the reference beam 436 in FIG. 32B. Similarly, the reference beam 436 of the separated coherent beam is used as the reference beam 436 in FIG.

25 and the wavefront aberration fine movement correction unit 354 of the irradiation light are collectively referred to as a wavefront aberration correction unit 350 in FIG.

The situation in which multiple scattering of light occurs inside the measurement/detection object 10 and adversely affects detection characteristics and imaging characteristics has been described in section 5.1 using FIG. As explained in Section 3, increasing the partial incoherence of light reduces the effects of light interference with multiply scattered light 370 . However, the method of Chapter 3 cannot reduce the occurrence of multiple light scattering itself inside the object 10 .

For example, as shown in FIG. 30, when measuring the characteristics and images of only specific regions (α, β, γ regions) in the target object 10, the characteristics are used to reduce the influence of multiple scattered light 370. can.

That is, as is clear from FIG. 26, most of the multiple scattered light 370 is scattered at locations other than the α-region/β-region/γ-region within the object 10 . Therefore, an imaging optical system (or a confocal optical system) is used in the detection optical path to shield the light scattered in places other than the α region, β region, and γ region, and the majority of the multiple scattered light 370 is transferred to the detection system. can be removed from

In the example of the measurement apparatus shown in FIG. 25, the process of reducing the influence of multiple scattered light is performed in the light separating sections 312 and 332. In FIG. However, it is not limited to this, and any method for reducing the influence of multiple scattered light before entering the optical path of the signal detectors 304, 314, 324, 334 and the wavefront aberration characteristic detectors 306, 316, 326, 336 may be adopted. good.

As shown in FIG. 31 (partially modified from the original optical arrangement for explanation), the light separation units 312 and 332 in FIG. It is composed of a separating section 430 .

Inside the three-dimensional transmission pattern image forming unit 450, a plurality of two-dimensional transmission image forming layers 452, 454, and 446 are laminated with a predetermined distance therebetween, similarly to the three-dimensional transmission pattern image forming unit 440 shown in FIG. have structure. These two-dimensional transmission image forming layers 452 , 454 , 456 have the function of extracting only specific area light in the cross section of the detection light 16 . As a method of extracting only the light from the specific area, transmission or reflection of only the specific area may be used. That is, in the embodiment of FIG. 31, only the light passing through the part where the shutter is locally opened (or the light passing through the pinhole or specific pattern area) is extracted. Alternatively, the reflected light may be used to extract only the light from the specific area. The specific structures of the two-dimensional transmission image forming layers 452, 454, 456 are optical elements (light transmission/reflection elements) having a predetermined pattern, mechanical structures (masks and pinholes), or liquid crystal shutters. An active shutter or switch may also be used.

For convenience of explanation, the imaging lens 216 is arranged outside the light separating sections 312 and 332 in the current FIG. However, in practice (before modification for illustration) the imaging lens 216 is located inside the light separators 312 , 332 . In the optical arrangement shown in FIG. 25, the detection light 16 immediately after passing through the objective lenses 308 and 318 is in a parallel light state. When the detection light 16 in the parallel light state enters the light separating sections 312 and 332 , it actually becomes converging light by the action of the imaging lens 216 arranged at the entrance of the light separating sections 312 and 332 . Therefore, the combination of the objective lenses 308 and 318 and the image forming lens 216 is essentially the relationship between the light condensing regions (α, β, and γ regions) inside the object 10 and the image forming relationship inside the three-dimensional passing pattern forming unit 450 ( confocal relationship) is formed. However, for the sake of convenience of explanation, FIG. be.

In FIG. 31, the β region (β point) and the ζ region (ζ point) are considered to have an imaging relationship (confocal relationship). Then, the detection light 16 obtained from the β region (β point) within the object 10 is condensed into the ζ region (ζ point) within the light separating sections 312 and 332 .

In the two-dimensional transmission image forming layer 452, the shutter is locally opened so as to extract (light transmit) only the detection light 16 passing through the .zeta.-area (.zeta.-point). As a result, the detection light 16 component passing through a portion slightly away from the ζ region (ζ point) is blocked. By operating in this manner, the light multiple-reflected at a position slightly away from the β region (β point) in the object 10 cannot pass through the light separation sections 312 and 332 . On the other hand, the shutters of the two-dimensional transmission image forming layers 454 and 456 are set to open (light transmission becomes possible) along the optical path of the detection light 16 passing through the ζ region (ζ point). Only the 16 components of the detected light that have passed through the .zeta.-region (.zeta.-point) are selectively extracted (light-transmitted) by the three-dimensional transmission pattern forming section 450. FIG.

Similarly, the detection light 16 passing through the ε region (ε point) and η region (η point), which are imaging positions (confocal positions) for the α region (α point) and γ region (γ point) in the object 10 is also extracted (transparent). Then, the multiple scattered light scattered at positions apart from the α, β, γ regions (α, β, γ points) in the object 10 is shielded in the three-dimensional passing pattern forming section 450 . As a result, the adverse effects of multiple scattered light scattered outside the measurement or detection target area within the object 10 can be removed, enabling highly accurate detection/measurement, imaging, or detection of wavefront aberration characteristics.

The detection light 16 extracted (passed through) by the three-dimensional transmission pattern forming unit 450 is converted into substantially parallel light by the collimating lens 26 . Then, in this state of almost parallel light, the light is separated into partial non-coherent light and coherent light at the optical path separating section 430 . As for the separation method in this optical path separation section 430, the method already explained in Section 4.2 is used.

Section 6.4 Wavefront Aberration Characteristic Detection Method Using Partially Incoherent Light Wavefront Aberration Characteristic Detector 306 for Partially Incoherent Reflected Light and Wavefront Aberration for Partially Incoherent Transmitted Light in FIG. A wavefront aberration characteristic detection method using partially incoherent light inside the characteristic detection unit 316 will be described.

In this embodiment, partially incoherent light is used for a condensed spot 476 irradiated in a PSD (Position Sensitive Detector) cell 472 to reduce the effect of light interference. Then, the position of the condensed light spot 476 irradiated into the PSD cell 472 is detected to detect the local wavefront aberration condition.

FIG. 32A shows the detection principle of the above wavefront aberration characteristics. The reference beam 436 or the detection beam 16, which has passed through the light separation units 312 and 332 or the reference beam generation unit 320 (FIG. 25) described in Section 6.3 and has become substantially parallel, is transferred to a plane (the traveling direction of the reference beam 436 or the detection beam 16). The mini-lenses 474-1 to 474-4 are arranged two-dimensionally on an optical cross section obtained by cutting with a plane perpendicular to the direction). A two-dimensional PSD cell array 470 is arranged on the back focal planes of the mini-lenses 474-1 to 474-4. PSD cells 472-1 to 472-4 are arranged two-dimensionally on the surface of this two-dimensional PSD cell array 470, and light passing through one mini-lens 474 as part of the reference light 436 or the detection light 16 is individually A focused spot 476 is formed within the PSD cell 472 .

In the description example of FIG. 32A(a), the wavefront (equiphase plane) 480 of the reference light 436 or the detection light 16 passing through the mini-lenses 474-2 to 474-4 is planar and parallel to the optical axis. Go straight. Therefore, the lights passing through the mini-lenses 474-2-4 respectively form condensed spots 476-2-4 in the center of the PSD cells 472-2-4.

On the other hand, the wavefront (equiphase surface) 480 of the reference light 436 or the detection light 16 passing through the mini-lens 474-1 forms a curved surface and has an upward traveling direction with respect to the optical axis. Thus, when this light passes through mini-lens 474-1, it forms a focused spot 476-1 at the top within PSD cell 472-1.

By detecting the position of the condensed spot 476 formed in the PSD cell 472 in this way, the state of the wavefront (equiphase plane) 480 of the light passing through the corresponding mini-lens 474 can be known. By connecting the position detection signals from each PSD cell 472, the characteristics of the entire wavefront (equiphase plane) 480 can be predicted.

Problems when coherent light is used to detect wavefront aberration characteristics will be described below. Originally, it is desired to detect only the wavefront aberration characteristic included in the detection light 16 simultaneously obtained only from each region (each point) of α/β/γ in FIG. However, as explained in section 5.1 using FIG. Then, an optical interference pattern between the detection light 16 to be originally detected and the multiple scattered light 370, 380 appears in the PSD cell 472 as shown in FIG. 32A(b). As a result, the positions of the focused light spots 476-1 to 476-4 irradiated into the PSD cells 472-1 to 472-4 are erroneously detected.

As described above, in this embodiment, partially incoherent light is used for wavefront aberration characteristic detection, so condensed spots 476-1 to 476-4 with little light interference are formed in PSD cells 472-1 to 472-4. As a result, the position detection accuracy of the condensed spots 476-1 to 476-4 in the PSD cells 472-1 to 472-4 is improved, and the wavefront aberration characteristics can be detected with high accuracy.

In this embodiment, the wavefront aberration characteristic is detected by comparing the reference light 436 representing an ideal state in which no wavefront aberration occurs inside the target object 10 and the detection light 16 including the wavefront aberration occurring inside the target object 10. do. This is common both when partially incoherent light is used as the detection light 16 and when coherent light is used.

This embodiment is not limited to the method of detecting the wavefront aberration characteristics in the detection light 16 obtained only from one point (one region) within the object 10 . For example, as shown in FIG. 31, it is also possible to detect the wavefront aberration characteristics contained in the light simultaneously obtained from multiple regions (multiple points) of α/β/γ within the object 10 . Further, not limited to this, signal detection/measurement (including spectral characteristic detection/measurement) from the detection light 16 obtained from an arbitrary three-dimensional pattern localized in the target object 10 and wavefront aberration characteristics are detected in parallel with imaging. You can

In this case, the three-dimensional passing pattern forming section 440 of FIG. 30 artificially generates the above-mentioned localized arbitrary three-dimensional pattern. If wavefront aberration does not occur inside the target object 10, the three-dimensional pattern can be formed inside the target object 10 using imaging characteristics (confocal characteristics). By detecting/measuring in advance the wavefront aberration characteristics in the irradiation optical system, which is a factor that hinders the formation of a three-dimensional pattern inside the object 10, and giving the inversion characteristics to the wavefront aberration correction unit 350, the inside of the object 10 The above three-dimensional pattern can be formed with high accuracy.

In parallel with this, the ideal irradiation light 12 characteristic at the time of localized three-dimensional pattern generation in the three-dimensional passing pattern forming unit 440 is extracted as the reference light 436 . The reference light 436 extracted in FIG. 30 is in a mixed light state in which partially incoherent light and coherent light are mixed. The extracted reference beam 436, not shown, is separated in the manner described in Section 4.2. Therefore, the reference beam 436 used in FIG. 32B contains only the separated and extracted partial incoherent beam components.

FIG. 32B shows an electrical processing method for wavefront aberration characteristic detection using the reference beam 436 and the partially incoherent beam. The reference light 436 and the detection light 16 separately use the detection optical system shown in FIG. 32A(a).

A reference light condensed spot position detector 482 detects the condensed spot position of the reference light 436 on the PSD cell 472 . In parallel with this, the condensed spot position detector 484 of the detected light detects the condensed spot position of the detected light 16 on the PSD cell 472 .

Next, the positional deviation calculation unit 486 between the condensed spots calculates the difference in the position information between the two, and the deviation amount of the condensed spot position of the detection light 16 when the condensed spot position of the reference light 436 is used as a reference. Calculate In the example of FIG. 32A(a), the wavefront (equiphase plane) of the light passing through the mini-lens 474-1 is an upwardly inclined curved surface. Focused spot 476-1 in this case illuminates the upper portion within PSD cell 472-1. The amount of wavefront inclination of the light passing through the mini-lens 474-1 can be predicted from the amount of displacement of the position where the focused spot 476-1 is irradiated. Based on the principle described here, the positional deviation amount calculation unit 486 between the condensed spots outputs information on the local wavefront tilt amount 488 .

Only the tilt amount of the wavefront for the light passing through one mini-lens 474 can be obtained from the positional deviation amount calculation unit 486 between one focused spot. Therefore, it is necessary to individually detect the amount of tilt of the wavefront for the light passing through all the mini-lenses 474-1 to 474-4 in FIG. 32A.

As a specific method, positional deviation amount calculators 486 between different condensed spots corresponding to all mini-lenses 474-1 to 474-4 may be installed individually. As another method, if the wavefront aberration characteristic change speed with time is very slow, the minilens 474 that is the target of the local wavefront tilt amount 488 may be switched in time series. That is, when the condensed spot position detectors 482 and 484 are individually installed in the vicinity of each of the PSD cells 472-1 to 472-4, an input signal to the positional deviation amount calculation unit 486 between condensed spots (not shown) may be switched in chronological order.

As a result of the above, the wavefront tilt amount 488 and the tilt direction of the light passing through all the mini-lenses 474 - 1 to 474 - 4 are input into the overall wavefront aberration characteristic calculator 490 . In the wavefront aberration characteristic calculator 490, the wavefront inclination amount 488 of each of the mini-lenses 474-1 to 474-4 and information on the inclination direction are integrated to predict the overall wavefront aberration characteristic.

Section 6.5 Method for Detecting Wavefront Aberration Characteristics Using Coherent Light FIG. 33 shows a method for detecting wavefront aberration characteristics using coherent light. Of the reference light 436 extracted in FIG. 30, only the coherent light component separated by the method described in section 4.2 is used as the reference light 436 in FIG. As described in Section 4.1 with reference to FIG. 25, as a preliminary stage to detect the wavefront aberration characteristics using coherent light, the wavefront aberration coarse motion correction unit 352 of the irradiated light and the wavefront aberration coarse motion correction of the transmitted light It is assumed that the section 356 has been operated and the large wavefront aberration has already been corrected. Therefore, the amount of wavefront aberration to be detected in Section 6.5 is assumed to be within a small range less than or equal to the wavelength λ used for detection. This detection range is very small, but the detection accuracy is very high.

Signals of the amount of light detected for each of the two-dimensionally arranged pixels are obtained from the imaging planes in the imaging cameras 500-1 to 500-4. Taking the amplitude value of the reference light 436 irradiated to the specific pixel as a reference (when the amplitude value is "1"), the amplitude value of the detection light 16 is set to "A". The wavefront aberration amount at this specific pixel corresponds to the phase shift amount δ of the detection light 16 with respect to the reference light 436 . Therefore, the amount of detected light obtained from this specific pixel is given by the following equation obtained by substituting equation (B.13) into equation (B.18).

The problem with the formula (B.40) is that the calculation result of the formula (B.40) is the same regardless of whether .delta. is positive or negative. Therefore, by simply synthesizing the reference light 436 and the detection light 16 and detecting the amount of irradiation light for each pixel, it is not possible to obtain an accurate wavefront aberration characteristic for the detection light 16 .

In order to solve this problem, in the present embodiment, a predetermined amount of phase shift is added between the reference light 436 and the detection light 16, and then the combined light is measured for each pixel. As a specific example, for example, when the wavelength of the reference light 436 and the detection light 16 is λ, the wavelength λ is divided into N. Then, after adding a phase shift corresponding to m/N (m is a positive number), the reference light 436 and the detection light 16 are synthesized. The amount of light detected at a specific pixel at this time is

becomes.

Since there are three types of variables in the equation (B.41): "A", ".delta." and "polarity of .delta. (positive or negative?)", at least three simultaneous equations are required. Therefore, in this embodiment, it is desirable that N≧3.

In a generally well-known birefringent optical element, the refractive index n differs between the ordinary ray direction and the extraordinary ray direction. Therefore, from a principle similar to the formula (B.13), a phase shift occurs between the ordinary ray and the extraordinary ray after passing through the birefringent optical element. The phase shift amount m/N to be added in the formula (B.41) is generated using the birefringent optical element.

A specific arrangement example of the optical system is shown in FIG. The reference beam 436 and the detected beam 16 are mixed at a polarizing beam splitter 492 (see section 3.1 for a definition of the term "mixing"). The polarizing beam splitter 492 reflects only the S wave (Senkrecht Wave) component in the reference light 436 and transmits only the P wave (Parallel Wave) component in the detection light 16 . In the light mixed by the polarizing beam splitter 492, the vibration plane direction (S-wave direction) of the reference light 436 (electric field) and the direction of the detection light 16 (P-wave direction) are orthogonal to each other. Therefore, no optical interference occurs between the reference light 436 and the detection light 16 in the mixed light.

In the non-polarizing beam splitter 498-1, the light reflectance and the light transmittance of both the S wave component and the P wave component are substantially the same. Therefore, the reflected light from the non-polarizing beam splitter 498-1 contains the reference light 436 and the detection light 16 at the same ratio.

An analyzer 496-1 placed in the reflected light path of the non-polarizing beam splitter 498-1 detects the components of the oscillation direction (electric field) tilted 45 degrees with respect to the S-wave direction and the P-wave direction of the polarizing beam splitter 492. Extract (transmit) only Then, the reference light 436 contained in the light extracted by the analyzer 496-1 and the detected light 16 have the same vibration plane direction (electric field), so that optical interference occurs between them. As a result, the detected light amount signal obtained by one pixel in the imaging plane of the imaging camera 500-1 has the characteristic of "m=0" in the equation (B.41).

FIG. 33 uses a standard λ/4 plate (Quarter Wave Plate) 494 among the birefringent optical elements described above. However, any birefringent optical element may be used in this embodiment without being limited thereto. Then, the ordinary ray direction or extraordinary ray direction of the λ/4 plate 494 is matched with the S-wave direction or P-wave direction of the polarization beam splitter 492 .

Then, after passing through one λ/4 plate 494-1, the phases of the reference light 436 and the detection light 16 are shifted by 1/4 wavelength and added. Furthermore, after passing through the λ/4 plate 494-2, the phases of the reference light 436 and the detection light 16 are shifted by 1/2 wavelength and added. After that, when they pass through the λ/4 plate 494-3, the phases of the reference light 436 and the detection light 16 are shifted by a total of 3/4 wavelength and added.

Every time the phase between the reference light 436 and the detection light 16 is added by a predetermined value, the light is extracted by the non-polarization beam splitters 498-2 and 498-3 and passed through the analyzers 496-2 to 496-4 to form the reference light 436 component. The 16 detected light components are optically interfered.

As a result, the detected light amount signal obtained by one pixel in the imaging plane of the imaging cameras 500-2 to 500-4 has the characteristics of "m=1" to "m=3" in the formula (B.41). . By solving the simultaneous equations thus obtained, the "relative amplitude A of the detected light 16" and the "wavefront aberration amount δ" for each pixel can be calculated.

Similar to the overall wavefront aberration characteristic calculator 490 in FIG. 32B, the overall wavefront aberration characteristic can be calculated by combining the wavefront aberration amount δ for each pixel in the imaging camera 500 .

Chapter 7 Calculation method of n-th overtone characteristic limited to specific functional group in polymer Section 7.1 Optical noise reduction method and absorption band wavelength prediction attributed to group vibration in specific functional group In this embodiment system, The focus is on providing a method for accurately grasping the composition, structure, or activity state within the detection/measurement object 10 . Therefore, it is not limited to simply aiming at improving the accuracy of the detection signal and spectral characteristics obtained from the object 10 and improving the sharpness of imaging, but the composition, structure, or activity in the object 10 performed using the information obtained therefrom. It is possible to provide technical means to improve the accuracy of grasping the state.

As described in section 2.1, in this embodiment, optical noise is reduced by the following two methods.
(1) Chapter 3 explained how to reduce the optical noise associated with partial coherence. In addition, (2) the method of reducing the optical noise caused by the wavefront aberration generated inside the object 10 has been described in Chapter 6.

By the way, according to the method of the embodiment described in Chapters 3 and 6, it is possible to improve the accuracy of detection signals and spectral characteristics obtained from the object 10 and to improve the sharpness of imaging. However, in order to grasp the composition, structure, or activity state within the object 10 using the information obtained from it, it is necessary to understand the principle of interaction between the microstructures inside the object 10 and light. There is Therefore, in Chapter 5, an overview of the interaction between the light absorber or light scatterer occurring inside the object 10 and light was given.

That is, since the group vibration within the predetermined functional group has a small scattering cross-section, the frequency of occurrence of light interference between scattered lights therefrom is relatively low. Therefore, by using partially incoherent light as the irradiation light 12, it is possible to detect/measure the absorption band attributed to the group vibration in the predetermined functional group with relatively high accuracy.

Furthermore, by combining the wavefront aberration reduction technology (Chapter 6) generated in the object 10, the absorption band attributed to the group vibration in the functional group can be detected with higher accuracy.

Even if the absorption band characteristics of a specific region inside the object 10 are detected with high precision in this way, it is difficult to identify the vibration mode to which the absorption band belongs. If the vibration mode attributed to each absorption band can be predicted with high accuracy, it will be possible to accurately grasp the composition, structure, or activity state inside the object 10 in combination with the detection/measurement results.

The wavelength of the absorption band corresponding to the fundamental vibration can now be theoretically predicted using quantum chemical calculation software. However, until now, there is no method for simply predicting the wavelength of the absorption band corresponding to the n-th overtone of the group vibration.

Chapter 7 describes a solution to the above-mentioned problem that there is no simple method for theoretically predicting the wavelength of the absorption band attributed to the n-th overtone of group vibration generated in a specific functional group.

Section 7.2 Mathematical Expression for Group Vibration in Functional Group In introducing a mathematical formula for theoretically predicting the absorption band wavelength value corresponding to the n-th overtone of group vibration generated in a specific functional group, see Patent Document 3. Divert some of the formulas already described in . In order to clarify the difference between the formulas newly described in this specification and the above-mentioned diverted formulas, the formula numbers (A·&&) described in Patent Document 3 are used as they are. On the other hand, (C·$$) is set to the formula number for formulas newly described in this specification.

As shown in FIG. 34, let us consider a case where charged particles having a charge amount Q are arranged on the Z-axis. Let e _Z be the unit vector on the Z axis. The amount of work when the charged particle is moved by Z in the Z-axis direction against the external electric field Ee ^-i2πνt is represented by formula (A·1).

where (E·Z) represents the inner product of vectors E and Z; By the way, although the expression (A.1) does not include the interaction term with the magnetic field in the external electromagnetic wave, the term can be sufficiently ignored.

The Schrodinger equation when a polymer containing a specific functional group is placed in an external electromagnetic wave is given by equations (A.2) to (A.5) using equation (A.1).

However, h with a bar means [Planck's constant]/2π (Dirac constant), e ₀ is the elementary charge, and me is the mass of the electron. Further, N: number of atomic nuclei contained in the polymer, n: number of electrons contained in the polymer, t: time, Ma: mass of the a-th atomic nucleus, Ra: three-dimensional coordinates of the a-th atomic nucleus, Qa: Effective charge of the a-th atomic nucleus (charge amount based on the results of Mulliken's electron number analysis that also considers the shielding effect of electrons around the nucleus), rj: the three-dimensional coordinate of the j-th electron, σj: the spin coordinate of the j-th electron represent each.

Next, an equation representing only the relationship between nuclei using the Born-Oppenheimer approximation is extracted. First, by applying the Born-Oppenheimer approximation, it is assumed that the wave function that satisfies the equation (A.2) can be approximated as in the equation (A.6).

By substituting the formula (A.6) into the formula (A.2) and transforming the formula, the formula can be separated into the formula (A.7) consisting only of .psi.nucl and the formula consisting only of .psi.el.

If the value connected by the equal sign of both is represented by W( _{R 1} , . Equation (A.8) representing the relationship between nuclei is obtained as an included equation.

In equation (A.8), the effect of the optimized electron trajectory is summarized in W(R ₁ , . . . , R _N , t).

Next, the part of the relational expression corresponding to the normal vibration of the specific functional group that interacts with the external electromagnetic wave is extracted from the formula (A.8). Prior to this, a specific normal vibration portion is extracted in advance from the vibration analysis results by computer simulation using quantum chemical calculation software. As a result, it was found that the stretching vibration vibrating in the direction of bonding between the central nucleus C and the peripheral hydrogen nucleus H in the specific functional group corresponds to one kind of the normal vibration. Therefore, from equation (A.8), we extract an equation relating to group vibrations occurring within this specific functional group. As a calculation example of the group vibration, a relational expression for calculating the wavelength value of the absorption band belonging to the n-th harmonic of the stretching vibration will be derived below. However, not limited to this, for example, the derivation of relational expressions relating to deformation and combination sounds can also be performed in the same or similar manner as the content described below.

In the following description, the symbol "C" is used for the central atom within a particular functional group. This "C" stands for "Central Atom". Therefore, the central atom C in the specific functional group is not limited to a carbon atom, and may be a nitrogen atom or an oxygen atom. Also, as the structure of this specific functional group, a structure in which the central atom C and n hydrogen atoms arranged around it are individually covalently bonded is assumed. Also, not limited to this, one or more hydrogen atoms among the n hydrogen atoms may form a hydrogen bond with a predetermined atom (or ion) outside the target functional group. In addition, a predetermined atom (or ion) outside the target functional group may be close to one or more hydrogen atoms without forming a hydrogen bond.

FIG. 35 shows the position vector of each constituent atom in the specific functional group —CHn. Here, the position vector for the nuclear position of the central atom _C is indicated by RC, and the position vector for the nuclear position of the a-th hydrogen atom is indicated by Ra. Also, the mass of the central atom C is represented by M _C , and the mass of one hydrogen atom is represented by M _H . Here, as shown in FIG. 35, the vector from the nuclear position of the central atom C to the nuclear position of the i-th hydrogen atom is expressed as v _a ≡ Ra − R _C (C·1)
From formula (C 1),

get On the other hand, the position vector _RG indicating the center position of gravity of this specific functional group is

If we substitute formula (C.2) into formula (C.3), we get

relationship is derived.

Next, a vector directed from the nuclear position of the central atom C when the total energy of the entire specific functional group is minimum to the nuclear position of the a-th hydrogen atom is defined as "x _a ea" ( _{ea is a unit} vector). Then, from FIG. 35, the following relationships are defined.
v ₁ ≡ ( x ₁ + x ) e ₁ + s ₁ …(C・5)
v _a ≡ ( x _a ± x )e _a + s _a (2≦a≦n) …(C・6)
"x" in the formulas (C-5) and (C-6) is the distance from the nuclear position of the central atom C to the nuclear position of the a-th hydrogen atom, and the total energy of the entire specific functional group is the minimum. It represents the amount of deviation from time (Deviation).

In group vibration within a specific functional group, all hydrogen atoms belonging to this specific functional group vibrate in unison. In this embodiment, this linked state is approximated by the same parameter "x". From a classical mechanics point of view, the amount of displacement of the constituent hydrogen atoms during group vibration does not always match. In this case, the inconsistent component from “x” for each constituent hydrogen atom is internalized into “s _i ” in formulas (C·5) and (C·6).

As a calculation example of group vibration, in this explanation, a calculation formula for calculating the wavelength value of the absorption band attributed to the n-th overtone related to stretching vibration is introduced. Therefore, when the symbol "±" in the formula (C.6) is "+", it represents symmetrical stretching. "-" indicates Asymmetrical Stretching or Degenerate Stretching.

Sections 5.1 and 5.2 explained that the electric dipole moment localized inside the object 10 oscillates (or transitions to an excited state) to cause light scattering or light absorption. When all the hydrogen atoms move together by "x" from the state where each atomic nucleus is arranged at the position where the total energy of the entire specific functional group is minimum (that is, "s _a = 0”), the electric dipole moment in the functional group is based on the center of gravity position _RG in the functional group

is represented by Transforming this formula (C 7) (at "s _a = 0")

is substituted into the third term on the right side of equation (A.3), the interaction term between the functional group and the external electromagnetic field is

can be described as Here, the formula (C.9) represents an approximation under the condition of "s _a =0". Aiming to improve the approximation accuracy, a term including the vector “s _a ” described in the formulas (C.5) and (C.6) may be added to the formula (C.9). However, even if this is done, the effect will be incorporated into the potential function V(x) by the variable separation described later, and the finally derived relational expression will be the same. Therefore, in order to simplify the explanation, from now on, the transformation of the equation using the approximation equation (C.9) will be promoted.

In classical mechanics, the sum of the kinetic energies in the above specific functional groups is

becomes. Substituting formula (C.1) and formulas (C.4) to (C.6) into formula (C.10), we obtain

becomes.

In the second term on the right side of formula (C 11)

using the relationship of

By approximation, the formula (C 11) is

can be approximated as

By the way, the second term on the right side of formulas (C.5) and (C.6) to (C.14) is

becomes. According to the results of vibration analysis by computer simulation using quantum chemistry calculation software, group vibration corresponding to the normal vibration is often "e _a ·ds _a /dt≈0". Therefore, substituting this approximation into equation (C.15), equation (C.14) becomes

can be expressed as (The conditions under which this approximation holds are discussed in detail in Section 7.3.) Here

means the Reduced Mass for group vibrations in functional groups.

The first term on the right side of equation (C.16) represents the kinetic energy of the Center-of-mass Sustem _RG . The second term represents the kinetic energy corresponding to the approximated group vibration. And the last third term corresponds to the kinetic energy corresponding to the movement other than that. That is, the formula (C.16) shows that the sum of the kinetic energies of the constituent atomic nuclei of the specific functional group can be divided into the center-of-gravity system, group vibration, and other kinetic energies.

When quantizing the kinetic energy corresponding to the group vibration described by equation (C 16), part of the first term on the right side of equation (A 3) is

(The grounds for the above quantization are described in Patent Document 3).

Next, in the equations ⁽ _C.5 ) and (C.6), when approximating x _a >>|sa|

can be transformed/approximated as Furthermore, on the rightmost side of equation (A.7), W(R ₁ ,..., R _N , t) ≈ Wx(x) + W _OTHER (R ₁ ,..., R _N-n-1 , R _G , s ₁ ,... , s _n , t)…(C・20)
is approximated as

H _nucl + W ≈ Hx + H _OTHER on the right side of formula (A 8) (C 21)
From the equations (C 9), (C 18), and (C 19),

can be put. Also, the details of H _OTHER are given by the following equation.

(A 6) Regarding the wave function described in the formula

Assuming that

and variables can be separated. And in equations (C・22) and (C・25)

When approximating as, the Schrodinger equation describing the group vibration state from the equations (C 22) and (C 24) to (C 26) is as follows:

is guided.

When the group vibrational state in the specific functional group is given by the formula (A.27), the solution of the equation is derived below. A mathematical formula representing the wavelength value of the corresponding absorption band is also shown.

First, the wave function ψ _X when "κ ₃ =κ ₄ =E=0" is defined as follows.

Substituting this equation (A 28) and the condition of "κ ₃ =κ ₄ =E = 0" into equation (A27) yields the harmonic vibration equation

transformed into here

is defined, the solution of equation (A29) is as described in Patent Document 3

becomes.

No group vibration equation is derived in Patent Document 3. Conveniently, the calculation formula (mathematical expression) described in Patent Document 3 can be used as it is simply by changing the reduced mass Mx defined in Patent Document 3 to the formula (C·17). Therefore, regarding the solution of the equation (A.27), which is the Schrodinger equation describing the group vibration state, the contents of the description of Patent Document 3 are transcribed below.

Before deriving the final solution of Eq. (A27) showing anharmonic oscillation using Eq. Ask. Specifically, the term “κ ₃ x ³ +κ ₄ x ⁴ ” in equation (A27) is regarded as a sufficiently small perturbation term. Then, the perturbation solution is derived based on the equation (A30) showing the solution of the harmonic vibration equation.

As described in Patent Document 3, the energy eigenvalue _εm at the time of anharmonic vibration is given by equation (A38).

The energy eigenvalue (Energetic Eigen Value) ε _m during anharmonic vibration is affected only by the κ ₄ x ⁴ term in the equation (A27), but is not affected by the κ ₃ x ³ term (A38 ). Also, the wave function |m > at this time is

is given by here

(See Patent Document 3 for the detailed formula in the formula (A.39)).

Denoting the amount of energy required for the transition from energy level _ε0 to _εm by _hνm ,

is given by Therefore, from equation (A.60), when the frequencies of the reference tone and the first and second overtones are ν ₁ , ν ₂ and ν ₃ ,

relationship is established. Using the equations (A.60) to (A.62) derived here, from the frequencies ν ₁ , ν ₂ and ν ₃ of the reference tone and the first and second overtones based on the anharmonic vibration, the The value of the wavelength λ _m (frequency ν _m ) of the m−1 overtone can be predicted.

Comparing the calculation result using the above theoretical formula with the actual measured value, the theoretical calculation result tends to be slightly smaller (within the range of 10 to 30% as a wavelength value). Therefore, when comparing the theoretically predicted value and the experimental value with respect to the wavelength value of the absorption band attributed to the group vibration in the specific functional group, the theoretical value calculated above is multiplied by a predetermined correction factor, and then the experimental value is obtained. You can match with

Section 7.3 Significance of Group Vibrational Analysis in Functional Groups Anharmonic vibrational analysis methods in diatomic molecules (two systems) have been conventionally known. In one specific example, the motion within a diatomic molecule is separated into the motion of the center of gravity (Central Motion of Gravity) or Translation Motion and the Relative Motion. As for this relative motion, an equation similar to the equation (A.27) can be derived by setting the amount of deviation of the distance between two atoms as "x".

On the other hand, in group vibration, since the number of nuclei to be analyzed is three or more, the number of degrees of freedom (the number of variables required for analysis) increases significantly, making the analysis very complicated. There was Therefore, until now there has been no method for simply analyzing group vibration characteristics.

As explained in Section 5.2, in organic polymers and biosystem molecules that make up the inside of a living body, functional groups containing hydrogen atoms as constituent atoms (such as central atoms such as carbon atoms, oxygen atoms, and nitrogen atoms) and peripheral atoms structure covalently bonded between hydrogen atoms).

As described in Patent Document 3, in vivo activities (biological reactions, catalysis, etc.) are very often mediated by hydrogen bonds. It is theoretically predicted that when a hydrogen bond reaction occurs temporarily between a hydrogen atom in a specific functional group and another atom or another ion, the wavelength value of the corresponding absorption band will change temporarily. .

Therefore, the proposal of a simple theoretical analysis method for group vibrations in functional groups has the effect of increasing the theoretical prediction accuracy for the wavelength change in the above absorption band and increasing the consistency with experimental values.

As a result of analyzing the normal vibration in the functional group using quantum chemical calculation software, it is found that the multiple hydrogen atoms that make up the functional group are interlocked with each other. For example, bending vibrations, symmetrical stretching vibrations, antisymmetric stretching vibrations, degenerate stretching vibrations, etc. are all interlocked with each other by all the hydrogen atoms that constitute the functional groups.

As indicated by the “±” symbols in the formula (C.6), the directions of movement of the hydrogen atoms differ in the above vibration modes. However, the amount of deviation (absolute value) "x" from the position when the total energy is the minimum is approximated to be the same for all hydrogen atoms, and the amount of error from the approximation for each hydrogen atom actually generated is " _sa ". Notated. In other words, we did not make an easy approximation assumption, and considered the independent moving state of each hydrogen atom.

As shown in the result (C.16) of transforming (expanding) the relational expression including some approximation, the motion of all constituent atoms in the functional group is divided into "motion of the center of gravity" and "motion of only the common deviation amount x", It was discovered for the first time that the "motion of the error component s _a " can be independently separated (expressed in the form of linear addition of the terms including each variable). If the common deviation amount x and the error amount s _a of the movement of individual hydrogen atoms can be separated in the relational expression in this way, the separation of variables becomes possible as shown in the equation (C.25). As a result, a simple equation can be derived that describes the group vibrations within the functional groups shown in Eq. (A.27).

In addition to that, for the calculation target (polyatomic molecule), which originally requires multi-body motion analysis, analysis by "consolidating into a one-dimensional equation" of formula (A 27) greatly reduces the analysis effort. It also has a mitigating effect. In order to enable the consolidation into the one-dimensional analysis, the effect of the reduced mass relational expression shown in the formula (C.17) is very large. In other words, the information of the individual motion states in the many-body system is
1) “Number of hydrogen atoms n contained in the specific functional group” in formula (C 17) and 2) The sign of “±” in formula (C 6) specifying various vibration modes (positive and negative polarity)
3) These are summarized in the values of the second to fourth order coefficients κ ₂ to κ ₄ of the potential part in the equation (A·27).

The approximation of formula (C.16) must hold as a theoretical basis for the above "summarization into a one-dimensional equation". As a premise for this, it is important whether or not the condition "e _a ·ds _a /dt≈0" can be applied. The range that satisfies the condition is specified below. Regarding this condition, a] a state in which the structure of the functional group is unstable in water, b) a static state in which the functional group structure is stable and is not involved in any reaction (activity), and c) a time-series reaction such as reaction or biological activity Dynamic states that can be accompanied by state changes are explained separately.

First, [a] will be examined. Based on the experiment experience of the author (inventor), the functional group in which the oxygen atom is the central atom C is recognized to be relatively unstable in water. And from experimental experience, the hydrogen atoms in the "oxygen atom-hydrogen atom" bond have a high probability of being replaced with hydrogen atoms in water. A theoretical prediction value can be obtained by the method of section 7.4, but it is necessary to recognize that the reliability of the simulation result of the functional group having an oxygen atom as the central atom C is slightly lowered.

Similarly, based on experimental experience, there is a high possibility that one hydrogen atom H within a functional group having a structure of -NH ₃ ⁺ (N is a nitrogen atom) will be liberated. Therefore, the reliability of simulation results for the above structure is not so high.

Next, the functional group having the —NH _n structure where 1≦n≦2 will be examined. A search of past literature reveals many reports of experiments in which hydrogen atoms in the above structure are replaced with deuterium. However, it is stated that 1-2 days of standing is required to complete the replacement. Therefore, in short-term experiments, the —NH _n structure (1≦n≦2) is expected to be somewhat stable in water.

On the other hand, the structure of the functional group having a carbon atom at the central atom C is considered to be very stable.

As a conclusion, regarding [a], the reliability of the simulation results changes depending on the type of the central atom C of the functional group.

Next, consider [b]. A detailed examination of the results of vibrational analysis by computer simulation using quantum chemistry calculation software reveals that all hydrogen atoms belonging to specific functional groups vibrate together in group vibrations corresponding to a type of normal vibration inside the polymer. . Further, vibration amplitude values among all hydrogen atoms belonging to a specific functional group are often similar. The reason for this is considered to be that the H arrangement of the hydrogen atoms in the functional group having the structure -CHn (the central atom C corresponds to a carbon atom, a nitrogen atom, or an oxygen atom) has a relatively symmetrical structure.

As a very special example, it is possible that only the vibrational amplitude of a specific hydrogen atom differs from that of other hydrogen atoms within one functional group with a particular arrangement. As an example, it is conceivable that the bonding direction between one hydrogen atom H and the central atom C coincides with the vibration plane direction E (equation (A.3)) of the external electric field that induces vibration. However, there is generally no regularity in the orientation of the functional groups —CHn within the object 10, and they are arranged in random directions. Therefore, when the whole is averaged, it is natural to consider that all hydrogen atoms belonging to a specific functional group have similar vibration amplitude values.

Therefore, in the static state of [b] for the functional group having a stable structure in [a], it is considered that the reliability of the simulation result resulting from the condition of "e _a · ds _a /dt ≈ 0" is maintained to some extent. .

Next, consider [c]. As will be described later in Section 7.3, temporary hydrogen bonds may occur during activities in the body (biological reactions, biochemical reactions, catalytic reactions, etc.). In this case, a state occurs in which other atoms or ions are arranged in the vicinity of one hydrogen atom in the specific functional group.

In the functional group having a relatively stable structure in water described in [a] above, the central atom C and the surrounding hydrogen atoms H are covalently bonded, and the interatomic distance (bond length) is relatively short. Compared to that, the hydrogen bond distance between other atoms or ions arranged nearby is relatively long. Therefore, the effect of hydrogen-bonded hydrogen atoms H on atomic vibrations is limited to perturbative effects.

Therefore, when another atom or another ion approaches the vicinity of a specific functional group in the dynamic state of [c], the vibration amplitude value of each hydrogen atom in that functional group slightly changes (due to the perturbation effect described above). However, even in this case, the condition of "e _a ·ds _a /dt≈0" is generally satisfied.

The above study results are summarized. When theoretically analyzing a specific normal vibration (e.g. group vibration within a specific functional group) that occurs in a specific region within a very complex and huge polymer system or biological system, there is a The reliability of the theoretical analysis results changes depending on the types of atoms involved (that is, whether there are “bonds between oxygen atoms and hydrogen atoms” and “bonds between nitrogen atoms and hydrogen atoms”). On the other hand, the reliability of this theoretical analysis result is not greatly affected by whether the analysis target is a "static state" or a "dynamic state." From this result, the simple theoretical analysis results obtained from the simulation described later in Section 7.4 can be adapted to the state of activity in the living body that changes over time and its changes.

What is particularly important in this embodiment is that it has the effect of enabling the analysis of a complex structure of a macromolecule or a complex of a plurality of huge molecules. That is, a huge number of constituent atoms are allowed in the Hamiltonian H _nucl described in formula (A.3) or (A.8). A functional group to be analyzed can be arbitrarily selected from the giant molecule or the giant multi-molecular complex. Therefore, for the selected functional group, the values of the _second -order coefficient κ2 and the _fourth -order coefficient κ4 in the formula (A·27) can be calculated using the method described in Section 7.4. (A.32) and (A.38) alone can be used to predict the wavelength values of the relevant absorption bands (further using Eqs. (A.61) and (A.62) if necessary). can be done).

A situation in which other atoms or ions approach a specific functional group during biological activity (when a biological reaction, catalysis, or the like occurs) has been described above. In this way, when another atom or other ion approaches the specific functional group, the values of the _second -order coefficient κ2 and the _fourth -order coefficient κ4 in the equation (A 27) change as a perturbation effect, and the wavelength value of the corresponding absorption band changes. Therefore, even in this case, the method described in Section 7.4 can be used to theoretically predict the wavelength change of the corresponding absorption band. Therefore, the biological activity state can be predicted from the wavelength change of this absorption band.

In addition to this, there is an effect that it becomes possible to confirm the structure in the functional bioengineering product described in Chapter 8 and to control the manufacturing process.

As an explanation of this embodiment, the expansion of the formulas in Section 7.2 (especially the formulas (C 5) and (C 6)) mainly describes changes in the bond length between atomic nuclei. did. However, without being limited to this, in the present embodiment, the analysis may be simplified for any structural or shape change between constituent atoms in a molecule. In this case, instead of introducing Eq. (A 27), we expand (transform) the relational expressions similar to Section 7.2, and derive simplified equations corresponding to other changes (other variables). can be For example, in relation to bending vibrations that form the normal vibrations in the group vibrations, a one-dimensional equation (with one variable) in which the bond angles (torsional angles) between constituent atoms in the molecule are changed is derived and analyzed. You can try to simplify it.

Also, in Section 7.2, finally, the equation (A.27) containing only one variable x other than the time variable t was derived to simplify the analysis. However, it is not limited to this, and the variable separation method shown in the formula (C.25) may be frequently used to simultaneously derive a plurality of independent equations each containing only one variable other than the time variable t.

When a plurality of independent equations containing different variables are established at the same time, simultaneous transitions occur between a plurality of different vibration modes. This state corresponds to a combination tone. The energy eigenvalues of equation (A.27) with only one variable x are given by (A.38). In the case of this combination sound, the energy level is determined in the form of a linear combination of the energy eigenvalues corresponding to each vibration mode. Then, in a form similar to the formula (A.60), the center wavelength value of the absorption band corresponding to the combination tone can be theoretically predicted.

As an example of this embodiment, Section 7.2 described a method for simplifying analysis corresponding to stretching vibration. However, it is not limited to this, as described above, modification of the expansion (transformation) method of the formula explained in Section 7.2 (for example, changing the variable to be selected to "bond angle" instead of "bond length" between nuclei) derivation of analytical equations for angular vibration), or expansion (deformation) of equations (e.g., by deriving multiple independent equations containing different independent variables using variable separation, it is possible to analyze combined tones). can be

Section 7.4 Simulation method of absorption band wavelength attributed to group vibration Group vibration state can be simplified by combining quantum chemical calculation software with formulas (C 17), (A 27), and (A 60). This embodiment that can be analyzed will be described with reference to FIG.

When the analysis is started in S1, setting (S2) of the polymer structure (arrangement of each atom constituting the polymer) is performed using quantum chemical calculation software. Then, a structure optimization (S3) routine incorporated in general quantum chemical calculation software is executed.

As explained in Section 7.3, in this embodiment, even if a huge polymer structure or a complex composite (structure) thereof is constructed, the local region (around a specific functional group) in it It is possible to analyze the structure and reaction (activation state and its change). Therefore, as shown in S4, a region to analyze the local structure and reaction (activation state and its change) is specified. As an example, a functional group to be analyzed for group vibration characteristics may be set.

As this method, the user may directly specify the target area. Alternatively, the area selection (area setting) may be automatically performed. In this case, the user may specify the conditions for setting the regions in advance, and the quantum chemical calculation software may automatically determine the regions that match the conditions.

Specifically, for example, the user may specify in advance the "active area of a specific catalytic reaction or biological reaction" in the quantum chemical calculation software. In that case, quantum chemical calculation software may automatically extract a specific hydrogen atom and select a functional group containing that hydrogen atom. Here, the specific hydrogen atom may form a hydrogen bond with another atom or other ion during the catalytic reaction or biological reaction.

In S4, a predetermined functional group is set as the vibration characteristic analysis target region set here. However, not limited to this, in this embodiment, a local region related to any normal vibration in the polymer set in S2 may be set. For example, in Patent Document 3, two atoms involved in the normal vibration in the polymer are specified, and the formula (A 27) is derived as an equation representing the normal vibration between the two atoms (however, in this case, the analysis of the group vibration (C.17), the relational expression expressing the reduced mass is different from the formula (C.17).

The structures within the functional groups set in S4 have already been optimized in S3. In other words, the distance (bond length) between the central nucleus and the surrounding hydrogen nuclei in this functional group is optimized so that the total energy of the polymer is minimized. Therefore, the distance (bond length) between the central nucleus and the a-th hydrogen nucleus corresponds to “x _a ” (1≦a≦n) in the formulas (C·5) and (C·6).

Note that in FIG. 36, after the polymer structure is optimized (S3), local regions (functional groups, etc.) to be subjected to vibration characteristic analysis are set (S4). However, the present embodiment is not limited to this, and the order between the two (the order of S3 and S4) may be reversed.

As the next step, the analysis of the vibrational characteristics within the functional group specified in S4 (or within any local region involved in the normal vibration) is started. Here, a method for changing the bond length between two atoms (nuclei) according to the formula (A.27) in Section 7.2 will be explained. However, not limited to this, in this embodiment, the bond angle between two atoms (nuclei) sandwiching a central atom (nucleus) may be changed.

That is, according to the calculation model of the formulas (C.5) and (C.6), the bond lengths between all the hydrogen nuclei and the central nucleus constituting the functional groups set in S4 are uniformly changed by "x" ( smooth). Then, the total energy of the entire polymer at this time is calculated using quantum chemical calculation software (S5). Here, whether the bond length for the a-th (2 ≤ a ≤ n) hydrogen atom is added or subtracted by "x" (adopt the "+" side of the sign "±" in (C 6) or adopt the "-" side) changes depending on the selection of the vibration mode to be analyzed (for example, symmetrical stretching vibration, antisymmetric stretching vibration, or degenerate stretching vibration?).

Here, the absolute value of the shift amount x is preferably smaller than "x _a " (1≤a≤n) in the formula (C·5) or (C·6). Therefore, the shift amount x set in S5 should be set within the range of ±0.1 Å to ±1.5 Å (preferably within the range of ±0.1 Å to ±1.0 Å).

The values of the _second -order coefficient κ2 and the _fourth -order coefficient κ4 in the equation (A.27) in Section 7.2 are estimated from the variation characteristics of the total energy with respect to the variation x of the bond length. In order to determine these two coefficient values, the calculation result of only the total energy of only one point as the shift amount x is insufficient. Therefore, in this embodiment, as shown in S6, it is necessary to change the value of the shift amount "x" and calculate the total energy again.

With this calculation assumption, the total energy value may be calculated at two points having the same absolute value |x| of the amount of shift but with different positive and negative polarities. Furthermore, the total energy value may be calculated at additional two points where the positive and negative polarities are changed with respect to the absolute value |x| of the different shift amount.

The greater the number of samples of the shift amount x for calculating the total energy value (that is, the number of repeated calculations for calculating the total energy by changing the shift amount x), the more accurate the fitting performed in S7.

Then, from the change amount characteristics of the total energy with respect to the shift amount x calculated in S5 and S6, the values of the _second -order coefficient κ2 and the _fourth -order coefficient κ4 in the equation (A·27) are calculated/fitted (S7 ). As this fitting method, adaptation using the method of least squares may be performed, or adaptation may be performed by any other method.

Using the values of the second-order coefficient κ ₂ and the fourth-order coefficient κ ₄ obtained in S7, the wavelength of the corresponding absorption band is calculated using the relational expressions shown in formulas (A 61) and (A 62). is theoretically calculated (S8). Also, as described at the end of Section 7.2, there is a tendency for a constant rate of deviation to occur between the theoretical prediction results and experimental values. In order to correct it, it may be multiplied (multiplied) by a predetermined correction coefficient as described in S8.

After performing output processing (S9), such as displaying the calculation results on a display or saving them in a storage medium, the series of theoretical vibration analyzes is completed (S10).

A calculation example regarding the energy change when moving a hydrogen atom in a functional group with a specific hydrogen bond and the absorption wavelength change based on it will be briefly described later in Section 8.4 of Chapter 8.

Chapter 8 Functional Biomaterials This chapter 8 describes the contents of application examples regarding the object 10 in this embodiment shown in FIGS. 1A to 1C.

Section 8.1 What is a functional biomaterial? In the description in Section 2.4, inorganic dielectrics, organic substances (polypolymers) and living organisms are examples of the target object 10 described in FIGS. 1A to 1C. described. Before this chapter 8, as a specific example of the target object 10, the description was centered on the “existing object”. However, in this embodiment, a new substance may be included in the specific example (application example) of the object 10 without being limited to the category of the “existing substance”. From this point of view, Chapter 8 describes other application examples of the object 10 .

The light explained in Chapters 3 and 6 (light with low wavefront aberration characteristics, partial low coherence/high partial incoherence) is an object containing —CHn type functional groups inside. Situations that lend themselves to body 10 detection and measurement were described in Sections 5 and 7. Therefore, it is desirable that the novel substance described as an application example of the object 10 also contains the -CHn type functional group.

Also, during activities inside the body (biological reactions, biochemical reactions, catalytic reactions, etc.), other atoms or other ions temporarily come close to the hydrogen atoms in the specific functional groups, and the corresponding wavelength of the absorption band may change. The situation was described in section 7.3. Therefore, as a detection/measurement target using light described in Chapters 3 and 6, the detection/measurement of biological structures and biological activities is considered appropriate. From this situation, a functional bio-material is proposed as an application example of the object 10 .

A representative attribute of the functional bio-related substance in the application example of the present embodiment is "affinity with nature". The following contents can be listed as the specific attributes.
1) Each functional bio-related substance has a wide variety of unique functions 2) It did not exist alone in the existing natural world 4) Has little impact on existing ecosystems and the natural world (both substances themselves and their derivatives/products)
5) Neither the element nor its derivatives/products have self-sustaining viability in the existing natural environment.
(It also does not have the ability to multiply in a parasitic form to other living organisms)
6) Even when ingested by existing organisms, it does not exert a remarkable unique function other than nutritional supplementation in the body. In addition to the above attributes, at least one of the attributes described below may be included.
7) Possesses ease of decomposition after disposal (corresponds to the decomposition action of microorganisms, etc.)
8) As a specific form example of a functional bio-related substance with the above attributes, which does not involve the production of wastes that are difficult to decompose, such as carbon dioxide, at the time of production (manufacturing), it does not exist in the existing natural world (above [ Corresponding to the attribute of 2)) It may be used for new industrial materials (or raw materials), unique foodstuffs, or parts having unique functions.

There are already genetically engineered crops. However, since the seeds produced from these crops have self-proliferating power in the natural environment, they do not meet the attribute of [5] above. Therefore, even if the functional bio-related substance itself or its product (corresponding to seeds of genetically engineered crops) in this embodiment accidentally leaks into the natural environment, there is no risk of disturbing the existing ecosystem (the above It also matches the attribute of [4]).

On the other hand, the development of pharmaceuticals using biotechnology is progressing. Since these medicines have a unique function of "therapeutic (healing) effect" for the purpose of ingestion into the body, they do not correspond to the attribute of [6] above.

Existing industrial plastic materials often have a structure in which carbon atoms or silicon atoms linked to each other by covalent bonds are repeatedly linked to a principal chain part. Since the covalent bond between carbon atoms or between silicon atoms has a strong bonding force, it is difficult to be structurally decomposed.

On the other hand, since the binding force of peptide bonding parts in proteins is weaker than that of covalent bonds, they are easily decomposed by the action of microorganisms. Therefore, the protein structure has high decomposability after disposal (according to the attribute [7] above).

Details of the production method (or production method) of this functional bio-related substance will be described in detail in Chapter 9. Here, the effect will be briefly described in relation to the attribute described in [3] above.

For example, to obtain a large amount of wool, sheep breeding requires a great deal of labor and expense. In contrast, the production efficiency of functional bio-related substances can be greatly improved by using some (similar) systems and (similar) mechanisms of biological activities, such as culturing only specific sites and producing amino acids using microorganisms.

Such a technique for developing or producing functional bio-related substances by utilizing some (similar) systems and (similar) mechanisms of biological activity is called "bioengineering" in the system of this embodiment.

By the way, it is known that a wide variety of proteins exhibit various unique functions according to their three-dimensional structures (conformations) (conforming to the attribute of [1] above). . Therefore, an amino acid may be included in a part of the functional bio-related substance in the application form of this embodiment. Therefore, the functional bio-related substance in this application embodiment may be redefined as a substance (raw material, foodstuff, functional part) that contains amino acids at least in part and has a unique function.

The functional bio-related substance may be defined from another viewpoint without being limited to the above definition. It has been explained that an amino acid may be contained in a part of the functional bio-related substance. Taking this point of view further, the category of functional bio-related substances may be considered, and all artificial proteins may be included in functional bio-related substances. In this case, the amino acid selection, amino acid sequence, or conformation contained in the artificial protein is controlled to exhibit various unique functions.

In the present embodiment, a protein that differs in amino acid sequence by 0.1% or more (preferably 1.0% or more) from naturally occurring proteins is called an artificial protein. Many proteins have their own three-dimensional structures (conformations), and these three-dimensional structures greatly affect the performance of their own functions. A change of even 0.1% (at least 1.0%) in the amino acid sequence that constitutes the protein causes a drastic change in the three-dimensional structure. Therefore, as will be described later in Section 8.2 or Section 8.3, in this embodiment, the amino acid sequence of the naturally occurring protein is changed by 0.1% (at least 1.0%) to greatly change the three-dimensional structure. , it may be made to exhibit its own function as an artificial protein.

The above-described “functional bio-related substance containing amino acids in at least a part of the interior” and functional bio-related substances composed of artificial proteins do not necessarily have all of the above attributes [1] to [6]. You don't have to have it. However, it is desirable to have an affinity with nature.

By the way, in the present embodiment, functional bio-related substances may include not only final products such as industrial materials/raw materials, foodstuffs, or functional parts, but also originating substances for the products. A specific example of the producing substance contained in the functional bio-related substance may include a cell having, in its nucleus, a genome in which production information for the artificial protein is incorporated. This cell is known as a genome editing technology, for example, CRISPR (Clustered Regularity Interspaced Short Palindromic Reactions)/ Cas9 ( CRISPR - Associated Protein 9 ) or ZFN ( Zinc Finger Nuclease ). ), and TALEN (Transcription Activator - Like Effector Nuclease ).

In relation to [3] described above, this genetic information after genome editing is once transferred to mRNA ( Messenger Ribonucleic Acid ) and then transferred to tRNA (Transfer Ribonucleic Acid ) for protein synthesis. ) is done. Therefore, it may be included in the functional bio-related substance in the present embodiment in the sense that the genome of the above cell has a "memorization function of information necessary for production" of artificial proteins having various unique functions. In addition, the above cells not only have an "information storage function" in the genome, but also have an "intracellular production (manufacturing) function" of artificial proteins.

A cell having a genome in which the production information of the artificial protein is recorded in the cell nucleus does not necessarily have all of the attributes [1] to [6] described above. However, in order to satisfy the attribute of "[5] having no self-proliferative ability as a single body or parasite in a natural environment", it is desirable that the above-mentioned cell morphology does not take the seed, fertilized egg, or virus morphology.

Section 8.2 Classification of Functional Biomaterials Based on Unique Function Demonstration Method FIG. 37 shows the classification of functional biomaterials according to the unique function exhibition method in this embodiment. In any functional biomaterial, or bioengineering to produce it, there is a unique interaction between the illuminating light 12 or the detecting light 16 described in Sections 3 or 6. Each specific interaction site (and its content) is described in the column "Optical detection target site" in FIG. Therefore, using the above-described irradiation light 12 or detection light 16, structural analysis of the interior of the functional biomaterial and manufacturing control (using changes in detection characteristics) can be performed.

As the functional biomaterials shown in FIG. 37, examples of materials and parts exhibiting specific functions, food materials, enzymes, cells, etc. are described in line with the description in Section 8.1. However, not limited to this, in the present embodiment, [2] any substance that does not already exist in the natural world, and [3] any substance that is generated (manufactured) using a system or mechanism of (similar to) a part of existing biological activities can be

Fig. 37 and Section 8.3 show specific examples centering on the improvement of the fibroin structure, which has a fibrous shape and is contained in the hair, for ease of explanation. However, without being limited to this, in the present embodiment, any existing protein or polysaccharide may be improved.

As shown in FIG. 37, as a method for the functional biomaterial to exhibit its own function in this embodiment,
・Those that use three-dimensional structural features including changes in amino acid sequences ・Structures in which one type of monomer that constitutes a polymer is replaced with another monomer,
・Those in which a specific amino acid is inserted or substituted within a predetermined amino acid sequence,
・A product in which the structure of a predetermined active area (Active Area) in the protein is changed,
・ Enzymes that generate new active regions by hydrolyzing and dehydrating condensation of substrates, or high-speed/performance improvement of existing enzymes (degrading enzymes, etc.),
- A cell having a genome that records an amino acid sequence in the cell nucleus - A genome editing module and its carrier structure for efficient genome editing in large quantities - A cell that produces a fibrous protein.

Section 8.3 Examples of functional biomaterials exhibiting functions in amino acid sequence and steric structure A specific example corresponding to the contents of the list in FIG. 37 will be described below. In this Section 8.3, the method of exhibiting the unique function by the "stereostructural difference" and "amino acid sequence" in the column of "function exhibiting method" in FIG. The description in Section 8.3 is only an example, and may include any other method of exhibiting a unique function with "stereostructural difference" or "amino acid sequence" as a functional biomaterial.

First, we will explain functional biomaterials that exhibit unique functions by giving characteristics to their three-dimensional structures by partially changing the amino acid sequences of existing proteins.

Part of the three-dimensional structure of large proteins often has an α-Helix structure or a β-Sheet structure. Inside this α-helix, the main chain of amino acids (Principal Chain) draws a helical structure to form a columnar structure. A constant strength is maintained in the vicinity of the surface of the side wall of the cylinder due to hydrogen bonding along the direction of the cylinder.

In addition, the β-sheet has a structure in which folded paper is stacked many times like a folding screen, and a certain strength is maintained by hydrogen bonds generated in the direction in which the paper is stacked.

Absorption bands corresponding to the reference tone and the first/second overtones of stretching vibration centering on hydrogen atoms in these hydrogen bond regions are generated. From the wavelength of this absorption band and the amount of light absorption, the three-dimensional structure can be predicted to some extent. Specifically, the wavelength range of the absorption band generated at the hydrogen bonding portion is included in the range of 1.5 to 1.7 μm for the first harmonic and within the range of 1.0 to 1.2 μm for the second harmonic. be Here, since the hydrogen bond distance (length) in the α-helix is slightly longer than that in the β-sheet, the wavelengths of the corresponding absorption bands are slightly different between the α-helix and the β-sheet.

When some hydrogen bonds in the α-helix or β-sheet are broken under the influence of external pressure or mechanical vibration, the overall three-dimensional structure changes. This change is used for pressure sensors and vibration sensors. This content corresponds to the first line "dynamic conformational change" in FIG. Also, from the wavelength at which the light absorption amount changes within the absorption band at this time, it is possible to predict which hydrogen bond has been broken.

Also, functional biomaterials that are susceptible to changes in three-dimensional structure due to temperature can be used as thermal sensors. This corresponds to the second line "thermal conformational change" in FIG. For the same reason as above, changes in light absorption characteristics also appear due to changes in temperature.

Fibroin is known as a major component of silkworm silk and spider cocoon silk. It is a special protein in which the composition ratio of amino acids with small residues reaches 90%, of which glycine accounts for about 35% and alanine accounts for about 27%.

The structure of naturally occurring fibroin is composed of a β-sheet crystal portion 602 having a β-sheet structure and an amorphous portion 604 as shown in FIG. It is said that the ratio (crystallinity) of the β-sheet crystal part 602 to the whole fibroin existing in nature is about 40% to 50%. The curve in the non-crystalline portion 604 in FIG. 38 represents the main chain of peptide-bonded amino acids.

Information on natural fibroin can be found at
https://en.wikipedia.org/w/index.php?title=Fibroin&oldid=57333210
It is described in.

When the hydrogen bonding portion (constituting the β sheet) in the β sheet crystal portion 602 is irradiated with the irradiation light 12, the detection light 16 obtained from the irradiation light 12 indicates the hydrogen bonding of the β sheet (the reference tone of the stretching vibration and the Absorption bands corresponding to the first overtone, second overtone, combination tone) are detected at specific wavelengths. The measurement apparatus shown in FIGS. 1A to 1C may be used for wavelength measurement of this absorption band.

In addition, the amount of light absorption within the absorption band changes according to the above crystallinity. For example, if the crystallinity is less than 40%, the amount of light absorbed within the absorption band is reduced. On the other hand, when the degree of crystallinity is higher than 50%, the light absorption increases. Therefore, the crystallinity of fibroin can be quantitatively predicted from the amount of light absorption in the corresponding absorption band measured from the detected light 16 obtained from fibroin.

In particular, when the near-infrared light described in Section 2.6 is used as the irradiation light 12, the absorption band belonging to the first overtone of the stretching vibration at the hydrogen bond in the β-sheet and the second overtone of the stretching vibration belong to Both absorption bands can be detected simultaneously. The light absorption in both absorption bands increases as the crystallinity increases (the light absorption decreases as the crystallinity decreases).

Detecting an increase or decrease in the amount of light absorption in only one wavelength band has the risk of erroneous detection due to the influence of some disturbance noise. However, since it is possible to simultaneously measure the amount of light absorption within the absorption band in a plurality of different wavelength ranges (the wavelength value of the absorption band attributed to the second overtone is smaller than that of the first overtone), the measurement accuracy of the degree of crystallinity is improved. There is

An example embodiment of a functional biomaterial produced by modifying the natural fibroin described above is shown in FIGS. 39A and 39B. Both generation methods utilize the method briefly described at the end of Section 8.1. That is, the amino acid sequence in the artificial protein is partially changed by genome editing technology, and is generated by protein synthesis using tRNA via mRNA transcription (details will be described later in Section 8.5).

FIG. 39A(a) shows a structure in which the crystallinity in the improved fibroin is set to 40% or less (preferably 35% or less). corresponds to "decrease the Since the proportion of hydrogen bonds forming β-sheets is also low, the amount of light absorption (both first and second harmonics) within the corresponding absorption bands is relatively low.

Since the ratio of the strong (relatively hard) β-sheet crystal portion 602 is small and the ratio of the non-crystal portion 604 is high, the material has a good tactile sensation (feel) and is soft.

FIG. 39A (b) shows a structure in which the crystallinity in the improved fibroin is set to 50% or more (preferably 55% or more), and the fourth line in FIG. Corresponds to "Increase degree". Due to the high proportion of hydrogen bonds forming β-sheets, the amount of light absorption (both first and second harmonics) within the corresponding absorption bands is relatively high.

Since the ratio of the strong (relatively hard) β-sheet crystal portion 602 is high and the ratio of the non-crystal portion 604 is low, the material has high strength and rigidity and is suitable as a reinforcing material.

The method using the absorption band obtained from the hydrogen bond within the α-helix or within the β-sheet is not limited to functional biomaterials having the structure shown in FIG. It may be used for structural examination and detection/measurement of changes in any functional biomaterial having structure.

FIG. 39A(c) is a structure in which an amino acid having an acid residue is added to the non-crystalline portion 604 in the improved fibroin, and corresponds to the fifth line “containing acid residue” in FIG. . By the way, amino acids with acidic residues generally have a negative charge and tend to react with other substances. In this example, as shown in FIG. Cation is added (esterification). The cation is not limited to sodium ion, and any cation may be added.

The carboxyl group 616 contained in the acidic residual amino acid is highly hydrophilic. Therefore, by placing a cation-added acidic residual amino acid in the non-crystalline portion 604, a functional biomaterial with extremely high water absorbency can be obtained.

Whether or not the amorphous portion 604 contains an acidic residual amino acid to which a cation is added is determined by the presence of an absorption band at a wavelength value corresponding to (the second or first overtone of the stretching vibration of the carboxyl group 616). can be determined by whether or not The absorption band corresponding to the second harmonic of the esterified carboxyl group exists within the wavelength range of 1.8-2.0 μm. Therefore, for example, the detection light 16 obtained from the artificial protein created aiming at the structure of FIG. 39A(c) is examined to determine whether or not a specific absorption band is observed within the above wavelength range. If there is no absorption band in the above wavelength range, it is determined that no esterified acidic residual amino acid is contained (the desired artificial protein was not produced).

FIG. 39A(c) shows an example in which Aspartic Acid+cation 612 is incorporated as an amino acid having an acidic residue. However, it is not limited thereto, and for example, esterified (cationically added) glutamic acid may be incorporated.

In addition, the light in the above wavelength range may be used for structural analysis and changes in any functional biomaterial containing carboxyl groups, not limited to the structure shown in FIG. 39A(c).

Since fibroin is a protein composed of more than ten kinds of amino acids, application of fibroin to nutritional supplements has been developed. However, since the molecular weight of fibroin is as large as 350,000 to 370,000, there is a problem in digestibility. At present, it is possible to reduce the molecular weight of oligopeptides by enzymatic decomposition, but there is a problem that texture is impaired, such as the loss of chewing comfort due to powder.

FIG. 39B shows an example of this embodiment that solves the problem. This content corresponds to the content of the 6th line "oligopeptide bond" in FIG. In other words, the combination of low-molecular-weight oligopeptides and the powdery state, which is likely to occur, provides a chewing sensation close to that of meat, and exerts the effect of enhancing the satisfaction of users who ingest it.

Actin filaments and myosin filaments constitute some of the main components of meat. This actin filament has a structure in which actin dimers are bound by ADP and tropomyosin is reinforced on the outside. Here, the actin dimer itself is very small, and the isolated actin dimer is powdery.

FIG. 39B shows an example of the structure of a functional biomaterial that provides meat-like texture (feeling of chewing) to an improved low-molecular-weight fibroin product with reference to this actin filament structure. That is, an ADP ( Adenosine Diphosphate ) anchoring portion 626 and an ATPase active portion (Active Area of Adenosine Triphosphate Ase ) are formed at the end of the amino acid sequence in the molecular monomer 620 which is an improved fibroin having a low molecular weight. ) 622 .

A molecular monomer 620 modified from low-molecular-weight fibroin shown in FIG. 39B is polymerized through hydrolysis of ATP in an aqueous salt solution such as KCl. ATP initially immobilized on the ADP immobilization portion 626 contacts the ATPase active portion 622 together with magnesium ions. Then, ATP is hydrolyzed by the catalytic effect of the ATPase active part 622 . At that time, the γ-Phosphate Group is released, but ADP624 degraded from APT remains to form a polymer (multimer).

When a salt component such as KCl is removed from an aqueous solution in which the polymer (multimer) bound by ADP624 is added, it has a property of facilitating monomerization (monomerization). Thus, the non-rigidity of the multimeric (polymer) structure shown in FIG. 39B has the effect of promoting digestion/absorption within the human body.

Amino acids having basic residues such as arginine and lysine that constitute the APTase active portion 622 bind to ATP and magnesium ions. At this time, a hydrogen bond is generated between the basic residue and the phosphate group. The absorption band attributed to this hydrogen bond stretching vibration appears within the wavelength range of 1.4 to 1.6 μm for the first overtone and within the wavelength range of 0.95 to 1.1 μm for the second overtone. In particular, this absorption band is very special, and it is possible to distinguish from the wavelength of the absorption band the type of the basic residue of the hydrogen-bonding partner (arginine, lysine, or histidine?).

Further, when the polymer (multimer) state returns to the monomer (monomer) state, the hydrogen bond between the basic residue and the phosphoric acid group is broken. Therefore, when a hydrogen bond between a basic residue and a phosphate group is involved as shown in FIG. 39B, the detailed bonding state can be monitored from the absorption characteristics of the detection light 16 obtained therefrom.

Regarding the measurement of the structure or bonding state and its change using near-infrared light, it is not limited to the example of FIG. change in ).

An example of the potential sensor function described on the 6th line in FIG. 37 will be described. Patent Document 3 describes that a voltage-gated ion channel is composed of a plurality of α-helix structures having a length that penetrates the cell membrane. A portion of at least one transmembrane α-helix therein contains amino acids with charged polar residues (basic or acidic). When a DC electric field (potential difference) is applied from the outside, an electrostatic force acts on this charged polar residue. As a result, the three-dimensional structure of the voltage-gated ion channel is partially changed, and the gate is opened.

By applying the above principle, in the example described in the 7th line of FIG. Incorporates an amino acid with a positive or acidic residue). Electrostatic force acts on this charged polar residue to change its three-dimensional structure, thereby exerting the function of a voltage sensor.

In order to exhibit the function of the voltage sensor, it is necessary that ions of the opposite polarity are localized around amino acids having charged polar residues and are not electrically neutralized. Moisture (aqueous solution) in a living body contains a large amount of sodium ions and chloride ions. Amino acids with acidic residues such as aspartic acid and glutamic acid are esterified as shown in FIG. As described above, the wavelength of the absorption band changes before and after esterification. Therefore, from the wavelength of the absorption band appearing in the absorption spectrum of the detection light 16 obtained from the functional biomaterial as the voltage sensor, it can be determined whether or not the voltage sensitive part is esterified and neutralized in terms of charge.

Similarly, in the case of amino acids having basic residues such as arginine, lysine, and histidine, there is a risk that anions such as chloride ions will attach to the vicinity of the basic residues and neutralize the charge. When an anion is attached around a basic residue in this way, the wavelength of the absorption band changes (the wavelength becomes longer by a predetermined amount) in the same way as when a hydrogen bond occurs. Especially in this case, it is possible to predict the type of amino acid having a basic residue and the attached anion from the wavelength value of the absorption band attributed to the first or second overtone of the stretching vibration.

In this way, the functional stability of the functional biomaterial having the function of a voltage sensor and the cause of failure can be predicted from the wavelength of the absorption band appearing in the absorption spectrum of the detection light 16 . Moreover, the above method is not limited to voltage sensors, and may be applied to any functional biomaterial containing amino acids having basic residues. That is, from the wavelength of the absorption band appearing in the absorption spectrum of the detection light 16 obtained from any functional biomaterial containing an amino acid having a basic residue, confirm the functional stability related to the adhesion between the basic residue and the anion. and the cause of malfunction can be investigated.

In the first half of this section 8.3, it is said that "If the crystallinity in the improved fibroin is set to 50% or more (preferably 55% or more), the mechanical strength is improved and it is suitable for stiffening and reinforcing materials (Fig. 4th line in 37)”.

Thus, it is possible to increase the degree of crystallinity in the modified fibroin to (50% or more) to produce a structure having a predetermined shape. As an application example of the present embodiment, a method for producing a structure having excellent moldability will be described below. In the following, as an example of an embodiment, a method for constructing a structure by combining fibroin-based β-sheets will be described. However, it is not limited to this, and for example, a structure may be formed by combining α-helix structures. Furthermore, a structure may be constructed by combining an α-helix and a β-sheet.

A crystal part that has a β-sheet structure is used as a basic unit (monomer block), and a block is composed of aggregates (polymers) of these units. Then, the blocks are combined to form a structure. When a structure is created, a relatively large block (a size that is easy for humans to handle) is treated as a unit, so there is an effect of improving the convenience of creation.

In addition, since the basic units inside the aggregate are connected using a predetermined cohesive force such as electrostatic force, the aggregate is less likely to break. An example of using electrostatic force as the bonding force between basic units is shown below. That is, a structure having a "charged area" is given to a part of the outer wall (near side) of the basic unit. In this charge region, a "positive charge region" and a "negative charge region" may be mixed. Furthermore, the positions of regions having positive or negative charges may be matched between at least two basic units.

However, not only the electrostatic force but also Van der Waals force, hydrogen bonding force, ionic bonding force, covalent bonding force, etc. may be used as the bonding force between the basic units.

Also, as will be described later with reference to FIG. 49, instead of aggregating only with the basic unit (improved β-sheet crystal part (monomer block) 1602), some medium for aggregation may be used. For example, ADP624 may be used as a medium for assisting the aggregation, as shown in FIG. 39B.

In addition, when monomers are collected to form a polymer, or when blocks of polymers are collected and formed into a structure, the water quality of the aqueous solution mixed with the above is changed in order to bring out the cohesive force such as electrostatic force. . In this embodiment, pure water is used to reduce the concentration of anions (such as chloride ions) and cations (such as sodium ions) in the aqueous solution. However, the present embodiment is not limited to this, and for example, the pH value in the aqueous solution or the temperature of the aqueous solution may be changed.

For convenience of explanation, the structures described below are all composed of proteins. However, it is not limited to this, and a mixture of protein and existing engineering plastics or other materials may be mixed.

As a basic unit (monomer block) to be described below, as shown in FIG. 49(a), the starting point is the β-sheet crystal part in fibroin. Genome editing described later in Section 8.5 or Section 9.2 is performed on this existing β-sheet crystal part in fibroin to generate an improved β-sheet crystal part (monomer block) 1602 .

Among the 20 types of amino acids, alanine, which has neither charge nor polarity, as well as valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan, glycine, and cysteine are classified as “non-polar residues (Non- are called "amino acids with polar residues". Proteins composed only of amino acids with non-polar residues are highly hydrophobic.

Therefore, when it is desired to construct a structure that is difficult to dissolve in water in this embodiment, 50% or more (preferably 70% or more or 80% or more) of the amino acids constituting the protein have the above nonpolar residues. It may be composed of amino acids. Due to the above-mentioned hydrophobicity, it is difficult for water to penetrate into the gaps between the revised β-sheet crystal units (monomer blocks) 1602 in the crystal unit assembly (multimer) block 1604 (Fig. 49(b)). It has the effect of making it difficult to melt. Furthermore, when the above compositional conditions are satisfied, swelling due to absorption of water is less likely to occur, and the structural (dimensional) stability of the structure is improved.

On the other hand, when it is desired to produce a highly water-soluble structure such as a drug capsule, the content of amino acids having non-polar residues in the protein constituting the structure should be 50% or less (preferably 40% or less). or 30% or less). When the composition ratio is selected in this way, moisture enters the gaps between the improved β-type crystal parts (monomer blocks) 1602 (FIG. 49(b)) or the gaps between the crystal part assembly (multimer) blocks 1604. As a result, the cohesive force is reduced, and structural decomposition is likely to occur in water.

In the middle part of Section 8.3 of this book, it was explained that "when trying to apply existing fibroin to food, it is difficult to digest/absorb due to its large molecular weight". However, the basic unit (monomer block) in this embodiment handles only one crystal part with a relatively small molecular weight (FIG. 49(a)). Furthermore, the content of amino acids with non-polar residues in the protein is 50% or less (preferably 40% or less or 30% or less), and the improved β-sheet crystal part (monomer block) 1602 itself is Improving the water solubility will further improve the digestive/absorptive effect in the body. As a result, the suitability for foods, cosmetics, and the like is greatly improved.

FIG. 49(a) shows a state in which a linear protein is bent to form a β-sheet. Among the amino acids that constitute this protein, lysine, arginine, and histidine are all called "amino acids having basic residues". The place where the amino acids having this basic residue are arranged in the protein forms the place of the "positively charged region in the crystal part" indicated by the symbol "+".

That is, an amino acid having a basic residue is arranged in the amino acid constituting the improved β-sheet crystal part (monomer block) 1602 shown in FIG. 49(a). As a result, a positively charged region is formed in a portion of the outer wall (nearby) of the improved β-sheet crystal portion (monomer block) 1602 corresponding to the basic unit.

On the other hand, aspartic acid and glutamic acid, which are included in the 20 kinds of amino acids, are called "amino acids with acidic residues", and amino acids with these acidic residues in proteins were sequenced. A location forms the location of the "negatively charged region within the crystal" indicated by the "-" symbol.

That is, an amino acid having an acidic residue is arranged in the amino acid constituting the improved β-sheet crystal part (monomer block) 1602 shown in FIG. 49(a). As a result, a negatively charged region is formed in a portion of the outer wall (nearby) of the improved β-sheet crystal portion (monomer block) 1602 corresponding to the basic unit.

In this embodiment, an improved β-sheet crystal part (monomer block) 1602 corresponding to a basic unit has a structure in which a part of the outer wall (near) has a charge region, thereby forming a structure. An effect of increasing the cohesive force using the electrostatic force between the β-sheet crystal parts (monomer blocks) 1602 is produced. Therefore, the bonding strength between the monomers increases, and the mechanical strength of the entire structure increases.

As will be described later in detail with reference to FIG. 50A, a large amount of chloride ions and sodium ions are contained in an aqueous solution inhabited by secretory microorganisms that synthesize proteins in the body. Since each ion has a high degree of ionization in an aqueous solution, the ratio of forming a "salt" by ionic bonding with the above charge region is low. Therefore, even if a large amount of the improved β-sheet crystal part (monomer block) 1602 is dropped into this aqueous solution, no aggregation occurs.

However, if the concentration of chloride ions and sodium ions in the aqueous solution mixed with a large amount of the improved β-sheet crystal part (monomer block) 1602 is lowered and replaced with pure water and then dried, the improved β-sheet An electrostatic force acts between the charge regions arranged on the outer wall (near) of the crystal part (monomer block) 1602 to aggregate.

As a result of this aggregation, a crystallite assembly (multimer) block 1604 shown in FIG. 49(b) is produced. Here, in the outer wall of the crystal part assembly (multimer) block 1604, a "salt" between chlorine or sodium is generated in order to neutralize the amount of charge.

Further, when an aqueous solution containing a large amount of this crystal part assembly (multimer) block 1604 is substituted with pure water to remove chlorine ions and sodium ions and then dried, the final structure shown in FIG. 49(c) is obtained. is formed. Here, as shown in FIG. 49(c), a surface coat layer 1610 is applied to the surface of the molded structure. The surface coat layer 1610 serves to eliminate the adverse effects of the charge region remaining near the surface of the structure.

FIG. 50A shows an example of a molding procedure for a crystal part assembly (multimer) block 1604 having the structure of FIG. 49(b). First (S71), amino acid sequence design (nucleotide sequence design of DNA on which transcription into amino acids is based) is performed (S72) for genome editing described later in Section 8.5 or Section 9.2.

As a microorganism that synthesizes protein inside the body and secretes it to the outside of the body, Aspergillus oryzae or Corymebacterium Glutamicum, which produces glutamic acid, may be used. E. coli, which is suitable for crushing and extracting protein from the cells, may also be used.

When the monomer block (improved β-sheet crystal part) 1602 is generated (S74) using a bacterium (microorganism) that secretes the synthesized protein, FIG. 46 (details will be described later in Chapter 10) is shown The secretion amount of the monomer block (improved β-sheet crystal part) 1602 may be optically monitored (S75) using an optical management device (measuring device) 1020 .

In S78, this secreted improved β-sheet crystal part (monomer block) 1602 is extracted and purified. The aqueous solution used for this extraction and purification contains a large amount of chloride ions and sodium ions (a state similar to salt water).

Next, this aqueous solution is replaced with pure water to reduce the concentrations of chloride ions and sodium ions, and then dried to aggregate between the monomer blocks (improved β-sheet crystal units) 1602 (S78). As a result of its aggregation, a crystallite assembly (multimer) block 1604 is obtained.

Here, as shown in FIG. 49(c), in order to form the final structure, it is desirable that the size of the crystal part assembly (multimer) block 1604 is uniform. Filtration processing may be used for extraction (S79) of the crystal part aggregate (multimer) block 1604 having a size within the predetermined range. That is, the crystal part assembly (multimer) block 1604 is temporarily dispersed in pure water and passed through the filter paper multiple times. By changing the mesh size of this filter paper, it is possible to select only crystal part aggregates (multimers) blocks 1604 within a predetermined range.

In order to maintain the long-term stability of the crystal part assembly (multimer) block 1604, the selectively extracted crystal part assembly (multimer) block 1604 is stored for a long period of time in a dry atmosphere (S80).

With long-term storage in a dry atmosphere, the formation of the crystal part assembly (multimer) block 1604 itself ends (S81). The crystal part assembly (multimer) block 1604 produced here is in the form of powder or granules. Temporarily managing in such a shape has the effect of improving the ease of molding into the final structure.

A 3D printer method or a casting method may be used to form a structure using the powdery or granular crystal part assembly (multimer) block 1604 . Here, FIG. 50B shows an example of a procedure for forming a structure using the casting method. Moreover, FIG. 50C shows an example of a procedure for structure molding using a 3D printer method.
As shown in FIG. 49(b), the outer wall of the crystal part assembly (multimer) block 1604 is in a "salt" state in which sodium atoms and chlorine atoms are bonded. In any molding method, the powdered or granular crystal part assembly (multimer) block 1604 is once dispersed in water (S83 and S86) to remove the sodium atoms and chlorine atoms bound to the outer wall, and the crystal part assembly ( It is desirable to increase the cohesion between the multimer) blocks 1604 .

That is, in FIG. 49(b), when the sodium atoms and chlorine atoms covering the outer wall of the crystal part assembly (multimer) block 1604 are removed, the "charged region near the outer wall" is exposed. This electrostatic force between the exposed charge regions acts as a cohesive force between the crystallographic assembly (multimer) blocks 1604 within the structure.

Furthermore, dispersing the crystal part assembly (multimer) block 1604 in water greatly improves the ease of handling during molding. That is, in this state, it can be used as ink for 3D printers/inkjet printers. In addition, when the casting method is used in the state of being dispersed in water, there is an effect that a structure having a shape suitable for any fine mold shape can be produced.

For example, when molding an acrylic plate by a casting method, it takes one night to complete crosslinking by temperature control. In contrast, in the present embodiment, by promoting early drying, it is possible to aggregate (S84) in a very short period of time.

In the case of forming a structure by a 3D printer method, air may be blown (air jetting) to the upper part of the three-dimensionally laminated layers to accelerate drying (S88). The faster the drying, the faster the aggregation can be achieved.

In any molding method, after the structure is completed, it is completely dried (S85, S89),
Aggregation between crystallite assembly (multimer) blocks 1604 is strengthened.

After that, a surface coat layer is applied to the surface of the molded structure (S91), dried (S92), and the molding of the structure is completed (S93).

In the above description, cast molding and a 3D printer have been described as examples of molding. However, the present embodiment is not limited to this, and any other molding method may be adopted.

Section 8.4 Examples of functional biomaterials that exhibit functions as structures and enzymes in the active area Examples of how to implement unique functionality in a way that "works" are described in section 8.4. The description in Section 8.4 is only an example, and may include any other method of exhibiting a unique function as an "active domain structure" or an "enzyme" as a functional biomaterial.

FIG. 40A shows an example embodiment in which engineered proteins are used to perform the Conductive Function. This embodiment example corresponds to the ninth line "underwater conductive line" in FIG. Here, a plurality of intraprotein main chain regions 632 and 634 are present on the outer side, and the active region is arranged on the inner side. The inner active region 630 has a conducting structure.

In FIG. 40A, for the convenience of explanation, it is described in the form of a planar arrangement. However, it is not limited to this, and the intraprotein main chain regions 632 and 634 may have a double helix structure like the double helix structure of DNA (Deoxyribpnucleic Acid). Further, according to this, the active region 630 may have a helical structure instead of a planar shape.

When the active region 630 having a planar structure is exposed to water, electrical leakage occurs because it has some conductivity even in pure water. In particular, since the aqueous solution inside the living body contains a large amount of sodium ions and chloride ions, a large amount of electrical leakage occurs in the planar active region 630 .

Since the intraprotein main chain regions 632 and 634 have a double helix structure, they act as a film to the outside, and an insulating effect is generated to prevent leakage of electric current from the active region 630 to the outside.

In this embodiment shown in FIG. 40A, the inside of the twisted active region 630 is a localized molecular orbital area of π-electrons. Electrons of π orbital (Localized Molecular Orbital of π-Electron) are present in the 6-Atoms Cyclic Compound Part and the pentacyclic portion in the tryptophan Trp residue. In a region where these π orbitals are continuous, π electrons (π-Electrons) can move within a local range. Therefore, local π orbitals are connected in the active region 630 to provide a conductive function within the active region 630 .

In order to connect the π orbitals within the π electron localized region (active region) 630, FIG. 40A connects the π orbitals within the hexacyclic portion of the tyrosine Tyr residue. In addition, the π electrons in the carboxyl group of the aspartic acid Asp residue may also be linked to improve the conductive properties.

In particular, the carboxyl group in aspartic acid Asp and tryptophan Trp form a "CC=O...HN<" type hydrogen bond ("..." corresponds to the hydrogen bond portion). Thereby,
1. 2. Conductive properties in the active region 630 are improved due to the linkage of π electrons in the carboxyl groups. 3. The strength of the double helix bond between the intraprotein main chain regions 632 and 634 is improved. Numerous effects of securing the elasticity of the entire double helix using the flexibility of the distance between hydrogen bond atoms are produced.

In order for the functional biomaterial having conductive function shown in FIG. 40A to operate stably, the π-electron localized region (active region) 630 must be accurately formed. As one of the indicators for the correctness of the generation of this π-electron localized region (active region) 630, absorption spectrum observation using near-infrared light is performed for the above-mentioned “CC=O HN<” type hydrogen bonding state. you can go

A simple "C=O...HN" type hydrogen bond itself is frequently observed in general biological systems. However, as shown in FIG. 40A, the wavelength value of the absorption band attributed to hydrogen bonding within the π-electron localized region (active region) 630 slightly changes from the absorption band wavelength value generally obtained in vivo. It is also possible to monitor whether the formation of the π-electron localized region (active region) 630 is correct or not by measuring this absorption band wavelength value change. 1A to 1C may be used to measure the change in wavelength value of the absorption band.

According to Pauling's electronegativity, the hydrogen atom has a smaller value than the carbon, nitrogen, and oxygen atoms. Therefore, the actual charge of hydrogen atoms in the molecule takes a positive value.

Within the π-electron localized region (active region) 630, there are a large number of π-electrons that can move relatively freely. Therefore, in the "CC=O...HN<" type hydrogen bond site, the π electrons are more likely to be unevenly distributed around the nearest nitrogen nucleus than near the hydrogen nucleus. As a result, the effective charge amount of the nitrogen atom is greatly reduced (negative charge with a large absolute value), and the electrostatic attraction between the hydrogen atom and the nitrogen atom is increased. Therefore, the distance between the hydrogen nucleus and the nitrogen nucleus in the ground state (the lowest energy state of the entire molecule) becomes shorter than when there are not many π electrons.

As described in section 7.4, the total energy of the entire molecule when the hydrogen nucleus is moved is calculated in S5 and S6 of FIG. Since the distance between hydrogen nuclei and nitrogen nuclei in the ground state (the lowest energy state of the whole molecule) is shorter than when there are no π electrons, the total energy increases when the distance between hydrogen nuclei and nitrogen nuclei is shortened. quantity increases.

Due to the above influence, the value of _κ4 in the equation (A·27) or (A·38) calculated in S7 of FIG. 36 increases. And from equation (A 60), the wavelength values of the first and second overtones of the stretching vibration attributed to hydrogen bonding are slightly shorter in an environment with a large amount of π electrons than in the absence of π electrons. I understand. A simulation method similar to the above is described in Patent Document 3. However, Patent Document 3 does not disclose a method for calculating group vibrations in specific functional groups. Therefore, the content of Chapter 7, which explains the method of calculating group vibrations in specific functional groups, is original.

Amino acid residues forming the π-electron localized region (active region) 630 in the functional biomaterial having a conductive function will be described. The example embodiment of FIG. 40A shows an example composed of tryprophan Trp, tyrosine Tyr, and aspartic acid Asp residues. However, as an example of this embodiment, other residues such as histidine, glutamic acid Glu, asparagine, glutamine, and phenylalanine may be used. Further, the constitution of the π electron localized region (active region) 630 is not limited to that shown in FIG. On the other hand, arbitrary types may be extracted from the amino acid residues described above and combined in an arbitrary configuration.

As an example of an embodiment in which a unique function is generated in the "inside active region structure" of FIG. Structures within any active region may be generated based on catalytic function (Cataltsis) by a particular Enzyme. By the way, since the above-mentioned enzyme does not exist in the existing natural world, the above-mentioned enzyme itself is included in the functional biomaterial (described in the column of "Method of exhibiting function" in Fig. 37). In addition, even if the function of the enzyme itself exists in the existing natural world, the functional biomaterial of this embodiment also includes a novel enzyme that realizes an increase in speed of the existing enzyme.

In the following, the method of generating the active region 630 of the functional biomaterial having the conductive function shown in FIG. 40A will be described as an example, including the action of the enzyme.

As described at the end of Section 8.1, the amino acid sequence was determined by genome editing technology, and protein synthesis using tRNA via mRNA transcription resulted in the intraprotein main chain regions 632 and 634 having respective amino acid residues. pre-generated.

The first enzyme that catalyzes the dehydration condensation reaction binds between the tryprophan Trp residue and the tyrosine residue to connect the two intra-protein main chain regions 632 and 634 . Next, a second enzyme having a dehydrogenase function is used to bond between residues in the direction of the main chain (horizontal direction in FIG. 40A).

As for the order of catalysis, the dehydrogenative condensation reaction may be promoted by the second enzyme, and then the dehydration condensation reaction may be promoted by the first enzyme. Alternatively, the catalytic actions of the first enzyme and the second enzyme may be performed simultaneously.

As described in Patent Document 3, hydrogen bonding often occurs temporarily between part of the substrate and part of the enzyme during catalysis by the enzyme (during contact between the substrate and the enzyme). The wavelength value of the absorption band differs depending on the type of atoms (or anions or cations) on both sides that bond with the hydrogen atom in the hydrogen bond. From the difference in the absorption band wavelength values appearing in the absorption characteristics, in this embodiment, the state of the catalytic action may be monitored. In addition, the measurement apparatus shown in FIGS. 1A to 1C may be used to measure the absorption characteristics.

Another example of application of the functional biomaterial with conductive function shown in FIG. 40A is shown in FIG. 40B. This application example corresponds to the 8th line "FET switching" in FIG. FETs (Field-Effect Transistors), which are electronic components, have a power amplification function and a switching function. An example of realizing this function with a functional biomaterial is shown. Basically, this is a combination of the 8th line in FIG. 37 "charged polar residue / potential sensor: three-dimensional change at charged polar residue part" and the 9th line "underwater compatible conductive wire" in FIG. It is an embodiment.

Basically, the outer side is coated with the main chain regions 636 and 638 in the protein that spirally surround the outer side, and the π electron localized region (active region) 640 is arranged inside it so that it can be used in water and aqueous solutions. be done. Although FIG. 40B shows a flat surface for convenience of explanation, it may have a twisted structure in the longitudinal direction as in FIG. 40A.

This π-electron localized region (active region) 640 is not limited to the residues of tryprophan Trp, tyrosine Tyr, aspartic acid Asp, and glutamine Gln shown in FIG. may be used. Moreover, it may be composed of only one of the above residues, or may be composed of any combination of the above residues.

The parts in FIG. 40B that are common to FIG. 40A (including the generation method) are consistent with the description in FIG. 40A. Therefore, only the parts different from FIG. 40A will be described here.

Within the π-electron localized region (active region) 630 in FIG. 40A, all tryptophan Trp residues and tyrosine Tyr residues are covalently bonded. Therefore, the inside of the π-electron localized region (active region) 630 has a certain degree of rigidity.

In contrast, in FIG. 40B, one tyrosine Tyr is replaced with glutamine Gln. Conductive properties around the glutamine Gln residue are ensured because the π-electrons are contained within the bonding region between the carbon and oxygen atoms within the glutamine Gln residue.

On the other hand, as shown in FIG. 40B, a hydrogen bond is formed between the oxygen atom in the glutamine Gln residue and the hydrogen atom in the adjacent tryptophan Trp residue (the region marked with "..." in FIG. 40B). This hydrogen bond is weaker than the covalent bond (between tryptophan Trp and tyrosine Tyr residues). Therefore, this portion of the π-electron localized region (active region 640) allows elastic shape deformation.

In the other intraprotein main chain region 638, aspartic acid Asp with the charged polar residue protruding outside is bound. 8. When a voltage (potential difference) is applied from the outside in the same manner as the explanation corresponding to the 7th line “charged polar residue content” in FIG. Residues experience electrostatic forces.

In response to the external electrostatic force applied to this aspartic acid Asp, deformation occurs at the location where the binding force is the weakest (ie, the hydrogen bond portion of the glutamine Gln residue) within the π-electron localized region (active region) 640 .

When this deformation is the largest, the above hydrogen bonds are broken, and the conductivity in the π-electron localized region (active region) 640 is broken. Moreover, even if the deformation is small, the electric resistance value in the π-electron localized region (active region) 640 changes according to the change in bond distance in the hydrogen bond region.

When the electric resistance change in the π-electron localized region (active region) 640 corresponding to the external voltage (potential difference) received by the aspartic acid Asp residue is steep, it functions as a switching element (component). On the other hand, when the electrical resistance change with respect to the external voltage (potential difference) is gentle, it works as a power (current) amplifying element (part) like an FET element. This electrical resistance change characteristic changes depending on the amino acids constituting the functional biomaterial, the overall three-dimensional structure, and the like.

Although aspartic acid Asp was exemplified as the potential sensor portion in FIG. 40B, arginine, lysine, histidine, and glutamic acid having a charged polar residue may be used without being limited thereto.

"NIRFP" on the 10th line in FIG. 37 will be described with reference to FIG. GFP (Green Fluorescent Protein ) is known as a fluorescent indicator used for observing the state inside a living body. This luminophore absorbs near-ultraviolet light with a wavelength of 397 nm and emits green visible light with a wavelength of 509 nm. Recently, RFPs (Red Fluorescent Proteins) that emit red visible light during fluorescence have been commercialized.

As explained in the second half of Section 5.4, even red visible light has a short penetration distance into the living body. Therefore, even if RFP is used, there is a limit to observation in a deep region inside the living body.

In order to solve the above problems, it is desired to provide NIRFP ( Near Infra - Red Fluorescent Protein) having fluorescence wavelength characteristics in the wavelength range (near-infrared light) described in Section 2.6. By utilizing this, an effect is produced that enables observation in a deep region inside the living body.

The luminophore (active region) of existing GFP is spontaneously formed by cyclization and oxidation of three amino acid residues of Serine Ser65, Tyrosine Tyr66, and Glycine Gly67. The molecular structure within the finally formed luminophore (active region) is shown in the conventional GFP luminophore region 650 in FIG.

As suggested by the double bond (double line of bond) region in FIG. 41, the electrons of the π orbital (Localized Molecular Orbital of π-Electron) within the lumophore region 650 in the conventional GFP affect the fluorescence properties. It is thought that Then, the region in which the electrons in the π orbital are localized may be expanded to widen the fluorescence wavelength (increase the fluorescence wavelength value).

Although not shown in FIG. 41, in the existing GFP, a barrel structure (cylindrical structure made of β-sheet) surrounds the luminophore region 650 of the conventional GFP. A tyrosine Tyr extending inside the barrel may be inserted into a part of the amino acid sequence forming this barrel structure (if necessary, the amino acid sequences before and after the tyrosine Tyr may also be inserted).

Then, even if dehydration condensation reaction is caused using the enzyme developed for "new active region generation" on the 11th line of FIG. good. In this way, the region in which the π orbital electrons are localized within the luminophore region may be expanded to broaden the fluorescence wavelength (increase the fluorescence wavelength value).

During the above dehydration condensation reaction, hydrogen bonding may occur temporarily (to stabilize the structure) at the contact point between the substrate and the enzyme (see the description in Patent Document 3). Therefore, by observing the generation of the absorption band of the corresponding wavelength within the change in the absorption characteristics during the dehydration condensation reaction, it is possible to reliably determine whether the dehydration condensation reaction has occurred. Thereby, it is possible to manage whether or not to generate a functional biomaterial corresponding to NIRFP.

As an example of the NIRFP in FIG. 41, a tyrosine Tyr residue is additionally bound, but is not limited thereto, and any of histidine, aspartic acid Asp, glutamic acid, asparagine, glutamine Gln, phenylalanine, tryprophane Trp having π electrons, or The combination may be additionally combined.

Genome editing of CRISPR / Cas9 (and ZFN, TALEN, etc.) for patients and fertilized eggs may be applied to medical care of hereditary disease (disease caused by genetic characteristics). At this time, it is necessary to confirm whether or not the desired genome editing has been performed correctly.

During this genome editing, the above-mentioned NIRFP-generating gene may also be incorporated adjacent to the genome repair site of the genetic disease content. Whether or not the NIRFP emits near-infrared fluorescence has the effect of predicting whether or not the genome can be corrected (whether or not genetic disease treatment is successful). As described above, since near-infrared light penetrates into a living body over a long distance, non-contact and non-invasive observation of a patient or a pregnant woman from outside the body is possible. As a result, it is possible to confirm the correctness of genetic disease treatment without imposing a burden on patients and pregnant women.

Furthermore, by combining the near-infrared light with the technique of reducing partial coherence (increasing partial incoherence) in Chapter 3 or the aberration correction technique in Chapter 6, the penetration distance inside the living body can be further increased. spreads.

In addition, ingestion of a capsule in which a predetermined wavelength light-emitting element (light-emitting diode or the like) is inserted, an endoscope, or a catheter may be employed for irradiation of absorbed light before fluorescence.

Regarding "enzyme function" in the column "method of exhibiting function" in FIG. 37, examples of enzymes for novel substrates have been explained so far. However, the functional biomaterials may also include novel enzymes that exhibit the same enzymatic function as conventional enzymes on existing substrates, or that exhibit faster catalytic functions than conventional products.

For example, in line 12 of FIG. 37, "novel fast-degrading enzyme", the decomposition rate of cellulase, which is an enzyme that decomposes cellulose in plants at high speed to produce starch, may be increased.

In the cellulase active region, serine Ser, histidine, and glutamic acid form a catalytic triad. Within this histidine residue, there exists an absorption band with a unique wavelength (attributed to the first and second overtones of stretching vibration) between the hydrogen atoms bonded to the nitrogen atoms with π electrons. Therefore, in the present embodiment, the cellulose decomposition rate may be monitored by observing the absorption band within the absorption characteristics.

Section 8.5 Examples of functional biomaterials that exert their functions in the part related to the production process Functional biomaterials involved in the production process of functional biomaterials described in sections 8.3 and 8.4. Explain the substance.

The description of actin filaments has been simplified in Section 8.3 in the description with Figure 39B. Actin filaments, which are the main component in meat, are similar to FIG. 39B, and actin dimers are connected via ADP. As described in Section 8.3, removal of salt components such as KCl in the aqueous solution readily causes dissociation at the ADP624 portion.

On the other hand, tropomyosin is helically entwined around the actin filament and maintains a constant strength. The attachment of other molecules also increases the strength of the actin filaments. On the other hand, if the reinforcing effect of tropomyosin or the like is too strong, the meat will become too hard.

In the embodiment of “artificial meat” on line 13 of FIG. 37, some of the components that make up the multimer are replaced to simultaneously achieve both appropriate strength (crunchiness) and texture (softness) suitable for foodstuffs. You can

Specifically, it replaces tropomyosin, which is wrapped around the outer periphery of actin filaments, with another protein with an α-helical structure.

As described in Section 8.1, CRISPR / Cas9 (or TALEN or ZFN) may be used to perform genome editing and determine the unique amino acid sequence described from the center to the top of FIG. As a functional biomaterial having the function of storing amino acid sequence information, line 14 of FIG. Specifically, it may mean a cell itself having a cell nucleus containing DNA after genome editing.

Within the double helix of DNA, pairs are formed between specific bases, and ">NH...N<" type hydrogen bonds are formed between the pairs. This type of hydrogen bonding is a unique hydrogen bond that is rarely found in other cell regions. Therefore, an absorption band having a unique wavelength attributed to the second overtone, first overtone, and reference tone of the stretching vibration generated in the ">NH...N<" type hydrogen bond appears in the absorption characteristics.

By the method described in Section 7.4, the wavelength value of the absorption band corresponding to the stretching vibration generated in the “>N-H…N<” type hydrogen bonding region inside the double helix of DNA was theoretically simulated. made a prediction. After multiplication by the correction factors (Section 7.4), the values were 3408 nm for the reference tone, 1698 nm for the first harmonic, and 1172 nm for the second harmonic. Furthermore, assuming that the calculation error range of the simulation is ±20%, the wavelength values of the actual absorption bands are within the range of 4090-2726 nm for the reference tone, 2038-1358 nm for the first overtone, and 1406-938 nm for the second overtone. is expected.

Observation of the cell nucleus position in living cells is difficult with a general optical microscope. In many cases, the cell nucleus is dyed for observation, but this staining process damages the cell. On the other hand, it depends on whether or not the absorption band is observed at the unique wavelength position attributed to the second overtone, the first overtone, and the reference tone of the stretching vibration generated in the ">NH...N<" type hydrogen bond. , has the effect of determining the position of the cell nucleus in a living cell. This makes it possible to easily discover the "intracellular storage location of amino acid sequence information".

For example, the near-infrared microscope apparatus of FIG. 7 may be improved to provide another monitor camera at the position of the spectroscope 22, and a narrow-band bandpass filter (color filter) may be installed immediately before each monitor camera 24. FIG. Here, the transmission wavelength of one of these band-pass filters (color filters) is matched with the wavelength of the absorption band, and the transmission wavelength of the other is slightly shifted. The position of the cell nucleus may be detected by extracting a location where the intensity distribution in the imaging pattern is (slightly) different between the two. By using this method, the cell nucleus position can be determined accurately without damaging the cell nucleus.

In addition to the above amino acid sequence information, functional biomaterials having a “genome editing function” that promotes DNA base sequence editing in any genome are also included in this embodiment. An embodiment in which a vector carrier structure is devised in order to perform this genome editing simultaneously in large amounts and efficiently will be described in detail later in Chapter 9.

Alternatively, a gene regulator or gene regulation factor may be transported into the cell nucleus using the carrier into the cell nucleus shown in this embodiment. In that way, an efficient "gene regulatory function" can be realized.

As means for evaluating whether or not the carrier can be transported into the cell nucleus, the above-described near-infrared microscope apparatus may be used. Here, a substance whose position can be monitored by an optical method such as GFP is inserted in the inner packaging area. Then, while confirming the position of the cell nucleus by the above method, the position inside the carrier for delivery within the cell nucleus is monitored in real time. As a result, it becomes possible to confirm whether the inside of the carrier has been transported into the cell nucleus.

Cells that contain edited genome information in the cell nucleus have a unique function of "storing genome information including new amino acid sequence information", and furthermore, using that genome information to develop functional biotechnology. Cells themselves having a “generating function” to generate substances may also be included in functional biomaterials in this embodiment. This corresponds to the bottom line "produced/released in cells" in FIG.

Specifically, the genome information related to the production of various functional biosubstances described from the top to the center in FIG. and secrete the produced functional biomaterial outside the cell (secrete release).

Fermentation of glutamic acid corresponds to the above process example. Raw materials such as molasses extracted from sugar cane are placed in a fermentation tank, and glutamic acid-producing bacteria are cultured under appropriate conditions. In this way, various functional biomaterials described from the top to the center in FIG. 37 may be produced within the microorganism.

Instead of causing the above microorganisms to produce functional biomaterials, hair matrix cells having edited genomic information in their cell nuclei may be artificially cultured. In this case, functional biosubstances are produced instead of hair and released out of the hair matrix cells in a similar manner to the process of growing hair from the hair matrix cells.

Synthesis of artificial proteins using tRNA is frequently carried out in the above-mentioned hair matrix cells. Temporary hydrogen bonding occurs during this protein synthesis process. It is also possible to detect the unique absorption bands belonging to the second and first overtones of the stretching vibration at the hydrogen bonding sites that occur temporarily, and the reference tone from within the absorption characteristics, and to perform process control of the protein synthesis process. good. Note that the measurement apparatus shown in FIGS. 1A to 1C may be used for the measurement of this light absorption characteristic.

An example of a method for producing (manufacturing) a functional biomaterial by analogously using part of the existing ecological activity system and mechanism of organisms in this embodiment is shown. Namely, 1. 1. Harvesting hair matrix cells from the epidermis of an animal (eg sheep). Perform genome editing on the cell nucleus of the collected hair matrix cells (CRISPR / Cas9, TALEN, ZFN, etc. described in Section 8.1 may be used for the genome editing.)
3. Culturing the genome-edited hair matrix cells (before this, the cells were initialized by the method described in Patent Document 4 and Patent Document 5, and then grown into hair matrix cells under a specific environment. may be used)
4. Collecting functional biomaterials produced in hair matrix cells and grown therefrom like hair The form of functional biomaterials thus produced and collected is functional like hair pulled from the scalp. Hair matrix cells are attached to the ends of the biomaterial. If these hair matrix cells are left in the natural air from the culture environment, they will die due to cutoff of nutritional supply. Therefore, even if the hair matrix cells are left alone in a natural environment, they do not have a self-proliferation function, and thus there is no risk of adversely affecting the natural environment.

In the manufacturing process of producing (manufacturing) functional biomaterials by using part of the ecological activity system and mechanism of existing organisms, propagation of various bacteria (contamination) poses a very serious problem. The hair matrix cells themselves have a certain degree of disinfection resistance compared to microorganisms. Therefore, since sterilization and disinfection can be performed to a certain extent in the medium, there is an effect of facilitating countermeasures against propagation of various germs and contamination.

In addition, genome editing (or cell reprogramming) requires large-scale equipment, making it difficult to work in any location. On the other hand, transportation of functional biosubstance-producing cells (hair matrix cells, etc.) packed in a medium and cultivation of these functional biosubstance-producing cells (hair matrix cells, etc.) are relatively easy at any location.

Therefore, by delivering functional biomaterial-generating cells (such as hair matrix cells) generated at a specific location, it becomes possible to easily generate (cultivate) functional biomaterials in various parts of the world. Therefore, there is an effect that the generation (manufacturing) of the functional biomaterials shown in this embodiment can be easily spread all over the world.

As specific examples of "artificial protein synthesis" in the column "Method of exhibiting function" in FIG. not limited to, any other process may be used. For example, it is possible to use the ``spider thread-producing cells'' in the spider's body, or the ``silk-producing cells'' in the silkworm's body. Even in this case, the production process may be controlled by measuring the absorption band temporarily generated during protein synthesis in the production cell.

Chapter 9 Genome Editing Processing Using Functional Biomaterials Concrete structural examples and actual operation examples of the functional biomaterials having the “genome editing” function described in the second line from the bottom in FIG. to explain. A functional biomaterial having a "genome editing" function can be used as a starting point for producing a functional biomaterial having all the "functions" shown in FIG. A functional biomaterial having a “genome editing” function is also required for the method for producing a functional biomaterial described in Chapter 10.

The application of functional biomaterials with "genome editing" functions to humans and animals requires many secondary functions in order to ensure safety and ecosystem maintenance. Therefore, in Chapter 9, genetic diseases and cancer treatments are used as examples. However, the application of the functional biomaterial with the "genome editing" function is not limited to that, and may be used to generate any of the functional biomaterials described in FIG. Also, when used for other purposes, the secondary functions described in Chapter 9 may be appropriately excluded.

Section 9.1 Examples of dealing with affected areas related to DNA disorders and current problems In the treatment of cancers with oncogene addiction, a large number of molecular target medicines already exist. At present, their mechanism of effectiveness is damage to tumor cells (cell membrane disruption, etc.), phagocytosis, or inhibition of the pathway of signal transduction in tumor cells. (Inhibition of Tyrosine Kinase Activity, etc.). In other words, all of the above mechanisms of action work as negative effects on tumor cell activity, and there is a high risk of causing serious side reactions (Side Reactions). In other words, the main cause lies in the high risk of side effects that the inhibitory action on cell activity acts on normal cells by mistake and inhibits normal activity.

In contrast, the aim of this embodiment is to “transform into normal cells” of the tumor cells themselves, so it has the effect of reducing side effects (even if the original normal cells are normalized, problems are unlikely to occur). ). In other words, more than half of malignant tumors have been found to have abnormalities in the gene called p53. Therefore, normalization of the function of the p53 gene has the potential to cure many cancers.

In addition, c-kit gene mutations are involved in the development of gastrointestinal stromal tumors, and inhibition of KIT tyrosine kinase activity provides dramatic therapeutic effects.

As another example, the fusion gene EML4-ALK of EML4 ( Echinoderm Microtubule-Associated Protein - like 4 ) gene and ALK ( Anaplastic Lymphoma Kinase ) gene produced by inversion of chromosome 2 is also available. It is said to be the cause of tumorigenesis. It has been reported that tumorigenesis such as lung cancer occurs when gene expression from this occurs. ALK Blocking Medicine (tyrosine kinase inhibitor) was shown to be highly effective in patients with the disease.

KIF5B-RET has also been reported as another fusion gene example, and lung cancer develops due to gene expression here. Vandetanib, which inhibits RET, is considered effective against this.

As mentioned above, the administration of tyrosine kinase inhibitors is prone to the development of serious side effects. Therefore, as in this example, using a vector carrier, only the c-kit gene mutation site, the ALK fusion gene placement site, or the fusion gene KIF5B-RET placement site is directly genome-edited to restore the normal gene sequence. A cure with few side effects can be expected.

FIG. 42 shows an example of a treatment procedure using this embodiment. This formulation need not be restricted to the medical field only, but can also be applied to more general fields. Therefore, the processing procedure when applied to a general wide field is written together in parentheses in FIG. Furthermore, the procedure of FIG. 42 can be applied not only to the correction of defective parts, but also to the production of various functional biomaterials of FIG. 37, for example.

A basic coping procedure for a defective portion (affected part) in the present embodiment consists of “cause analysis→correction→result evaluation (diagnosis→treatment→confirmation)”.

In the diagnosis (problem cause analysis) related processing procedure 702, extraction of a section of the affected area (collection of information on the fault location) S22 and analysis of the extracted section (analysis of fault information content) S23 are performed. Here, in the section extraction (S22), surgical partial cutting using a knife is performed. If the affected area is internal to the body, an Endoscope or Catheter may be used.

In the analysis of the excised section (S23), it is determined whether the tumor is benign or malignant, and if malignant, the presence or absence of oncogene dependence is examined.

In the case of oncogene dependence, DNA analysis is performed to determine the DNA base sequence of the defective site corresponding to determination of the cause of the defect (S24). Next, in S25, using the result, optimization design of the DNA base sequence (design of the optimum correction method) is carried out. Then, based on the result of this optimization design (S25), the production of the "vector carrier" described in the second line from the bottom in FIG. )I do. Here, a DNA molecule that migrates to a chromosome (chromosome) within an affected area (defective site) for treatment (correction of the defective site) is called a vector.

As the treatment (correction of defective portion) related processing procedure 704, it is first necessary to transport the vector carrier to the vicinity of the affected area (defective portion) (S26). If the affected area (defective area) is exposed on the surface, it is sufficient to apply a drug containing a vector carrier. If the affected area (defective area) is localized deep inside the body, it may be transported nearby using an endoscope or a catheter.

At the stage of executing the genome editing process (S27) in the target cell, which will be described in detail in Section 9.2, it is very important to monitor the progress of the editing process in real time (S28). From a macroscopic point of view, not only are there large variations in the size and penetration depth of the affected area, but also the penetration speed into the affected area varies greatly depending on the transfer location of the vector carrier. In particular, when the affected area (defective site) is localized deep inside the body, it has been extremely difficult to grasp the state of diffusion of the vector carrier into the affected area using conventional existing techniques.

Applying near-infrared light with low optical noise (described in Chapters 3 and 6) to this optical monitor (S28) is very effective. As described in Section 2.6, near-infrared light with a wavelength range of 0.7 to 2.5 μm has excellent light transmittance in vivo. Therefore, the progress of genome editing can be monitored in real time by using the above-described measuring device using near-infrared light (FIGS. 1A to 1C).

As described later in Section 9.2, it occurs in response to the genome editing process (S27) in the target cell ○ Invasion of the genome editing module into the cell nucleus ○ DNA base sequence change ○ Gene expression
In each of the various processes such as, each unique form of "hydrogen bond" is (temporarily) generated. And, as explained in US Pat. No. 5,430,003, each unique hydrogen bonding configuration causes a corresponding wavelength change in the absorption band.

The progress of genome editing can be observed with high accuracy by measuring in real time the change in absorption spectrum of near-infrared light obtained from the diseased site (defective site) during the genome editing process on the optical monitor (S28). However, if near-infrared light is used for measurement within the scope of the prior art, sufficient detection accuracy cannot be obtained due to the optical noise described in Chapter 2. Therefore, highly accurate observation becomes possible only after applying at least one of the techniques described in Chapters 3 and 6 to the measuring apparatus (or microscopic apparatus) described in FIGS. 1A to 1C.

In the treatment (correction) result evaluation/confirmation related processing procedure 706, the above-mentioned "gene expression" result is used. At this time, the NIRFP described on the second line from the bottom in FIG. 37 may be used. As a specific method, the DNA base sequence for expressing NIRFP described in line 10 of FIG. 37 (and FIG. 41) and described in the second half of Section 8.4 is also arranged in the vector carrier. Then, the genome editing effect may be evaluated and confirmed based on whether or not NIRFP is also produced in the cell when the gene contained in the vector carrier is expressed.

In the step of inserting the tester around the affected area (corrected area) in S29, an endoscope or a catheter is used to guide visible light, and visible light is emitted around the affected area (corrected area) (inside the patient's body). Since NIRFP is produced in cells that have been successfully processed for genome editing, they absorb this visible light (excited by this visible light energy) and emit near-infrared light (fluorescence emission). Since near-infrared light has a high light transmittance inside the living body, a part of the near-infrared light passes through to the outside of the body.

As an analysis of the evaluation result (S30), it is analyzed whether or not the near-infrared light component emitted from the NIRFP is included in the spectral characteristics of the light emitted outside the body. If at least one of the techniques described in Chapters 3 and 6 is applied to the middle of the detection light 16 optical paths in this measurement device (or near-infrared microscope), the detection accuracy is improved.

Determination of the evaluation result (S31) is based on whether or not a predetermined amount or more of the near-infrared light component emitted from the NIRFP is included. That is, when the amount of the near-infrared light component is included in the spectral characteristics of the light emitted outside the patient's body at a predetermined threshold value or more, the judgment result (S31) of the evaluation result is considered to be good (Yes), A series of measures is terminated (S32). Conversely, when the near-infrared light component amount is less than the predetermined threshold value (No), it is considered that the effect of treatment (correction of the defective portion) is insufficient. In this case, the procedure 704 related to treatment (correction of defective parts) is started again.

Current problems in using existing genome editing technology for treatment or mass production of various functional biomaterials shown in FIG. 37 are mainly as follows.
1. 2. Scalability of replicating DNA and efficient selectivity of editing targets. Long-term safety in post-editing cells3. Nucleotide Sequence Management Before and After Editing and Prevention of Erroneous Editing The problems listed at the beginning will be explained. Low-molecular weight molecules and ions distributed outside the nuclear membrane can easily enter the cell nucleus by passing through the nuclear pore. On the other hand, transport of molecules with large molecular weights into the cell nucleus requires the help of carrier proteins. Therefore, as the molecular weight of the replicating DNA molecule that constitutes the vector increases, it becomes difficult to transport it into the cell nucleus using a carrier protein. In addition, the compatibility with the carrier protein greatly impairs the arbitrariness of the form of the genome editing module (the second line from the bottom in FIG. 37).

The next problem is that nuclease remains in the cell nucleus after genome editing. For genome editing, the nuclease is essential for cleaving a part of the existing double-helix structure of DNA. However, since the nuclease remains in the cell nucleus even after this genome editing, it is almost like leaving a scalpel in the body after surgery.

Viral infection of a former patient who completed the series of treatments shown in Figure 42 caused a change in the base sequence in the host cell or crRNA (CRISPR RNA), which will be described later, and remained in the cell. There is a risk that the nuclease will act and destroy the normal genome.

The above second problem becomes more serious in the application of genome editing technology to therapy and cell culture after genome editing.

For genome editing at the laboratory level, the last (third) problem is less critical. However, in a field where genome editing occurs frequently, measures to prevent artificial erroneous editing are important.

In the present embodiment described in Section 9.2 below, the above three problems are resolved.

Section 9.2 Structure and Operating Principle of Carrier for Delivery in Cell Nucleus Using the carrier for delivery in the cell nucleus shown as an example of this embodiment, efficient "genome editing function" and "gene regulation function" can be achieved. In addition, as one of application examples using the genome editing function, there is an example of coping with the defective portion described in Section 9.1 using FIG. 42 . Then, as one example of coping with the defective part, an example of treatment such as a malignant tumor was explained.

Section 9.2 describes an example of the structure and principle of operation of the intranuclear delivery carrier. As part of this explanation, we will also explain the mechanism for solving the three problems explained in the second half of Section 9.1. By the way, the application of the properties that solve this problem is not limited to treatment/coping with defective areas and mass production of various functional biomaterials, and may be applied to any application.

A case in which the genome editing module is contained in the carrier for delivery into the cell nucleus having a double packaging structure in this embodiment is called a vector carrier. In addition, when a gene regulatory factor enters, it is called a gene regulatory carrier. What is common to both is
○ It has a double packaging structure with an inner pack inside the carrier ○ The surroundings of the inner pack are covered with a membrane (membrane area inside the carrier) module or gene regulatory factor, etc.) ○ It is a place where the built-in material (genome editing module or gene regulatory factor) is delivered directly into the cell nucleus, so ○ the inner packaging membrane (outer membrane of the carrier inner package part) surface In addition, it has a selective junction with the surface of the cell nuclear membrane. be delivered. And not only that,
o A nuclear lamina may be present inside the carrier encapsulation,
FIG. 43(a) shows a structural example of the intranuclear transport carrier 800 in this embodiment. The outside of the intranuclear delivery carrier 800 is covered with a carrier envelope 840 . The material of the outer covering 840 of the carrier envelope may be a protein in which a large number of polypeptide chains are aggregated, or may be a lipid bilayer envelope.

When using the intranuclear transport carrier 800 as a vector carrier that is selectively transported into malignant tumor cells (cancer cells), a junction 846 to a selected cell is formed in a part of the envelope 840 of the carrier envelope. is set up. Part of a ligand that binds to a specific receptor present on the cell membrane of a malignant tumor cell (cancer cell) may be used as the joint 846 to this selected cell. You may use the antibody (Antibody) which specifies a cell.

As specific specific receptors, VEGFR ( Vascular Endothelial Growth Factor Receptor) or EGFR ( Epidermal Growth Factor Receptor) may be directly bound.

As an antibody that identifies a specific cancer cell, for example, a monoclonal antibody that identifies the above VEGFR may be used. Alternatively, an antibody that discriminately binds to the ligand itself that binds to the specific receptor may be used. In this case, the timing at which the ligand bound to the vector carrier binds to the receptor is used to transport the encapsulated portion in the vector carrier into malignant tumor cells (cancer cells).

The outer membrane 838 of the carrier encapsulation part and the inner membrane 836 of the carrier encapsulation part in the carrier for intranuclear delivery 800 are composed of lipid bilayers, and between them is a hydrophobic region 834 between the inner and outer membranes mainly composed of lipids. is formed.

Part of the outer membrane 838 of the carrier encapsulation (and the inner membrane 836 of the carrier encapsulation) is provided with a selective binding portion 830 (details will be described later) to the surface of the cell nuclear membrane. As a result, the genome editing module 808 and the gene regulatory factor 806 stored in the internal capsule can be stably transported into the cell nucleus.

By using this selective binding portion 830 to the surface of the nuclear membrane, the first problem described in Section 9.1, "1. Scalability of replicated DNA and efficient selectivity of editing targets" can be resolved. The outer membrane of the cell nucleus is directly connected to part of the endoplasmic reticulum (endoplasmic reticulum). Therefore, when the genome editing module 808 is released near the endoplasmic reticulum, genome editing cannot be performed. As a countermeasure, in this embodiment, the selective binding portion 830 to the cell nuclear membrane surface binds only to the cell nuclear membrane (including the nuclear lamina). As a result, the genome editing module 808 can be efficiently transported into the cell nucleus.

Then, with the binding of the selective binding portion 830 to the surface of the cell nuclear membrane and the cell nuclear membrane (including the nuclear lamina) as a trigger, the cell nuclear membrane and the inner membrane 836/outer membrane 838 of the carrier encapsulation part are fused to form the genome editing module 808. is transported into the cell nucleus. Therefore, since the genome editing module 808 of any size can be transported into the cell nucleus, there is an effect of greatly improving the flexibility of replicating DNA scalability.

A nuclear lamina 832 may be arranged inside the inner membrane 836 of the carrier encapsulating portion. The material of this nuclear lamina 832 may be similar to the nuclear lamina present in the cell nuclear membrane. This has the effect of improving the affinity between the carrier encapsulating portion and the cell nucleus and improving the fusibility between the two. In addition, there is also an effect of minimizing damage to the cell nuclear membrane when the both are fused and the genome editing module 808 or the gene regulatory element 806 invades the cell nucleus.

In addition, as will be described later, the selective bonding portion 830 protruding inward from the inner membrane 836 of the carrier encapsulating portion and protruding to the surface of the cell nuclear membrane enhances the bonding between the inner membrane 836 of the carrier encapsulating portion and the nuclear lamina 832 . As a result, the relative strength between the inner film 836 and the outer film 838 of the carrier encapsulating portion is increased, and there is also the effect of preventing film breakage during transportation.

When the gene regulatory factor 806 is stored inside the carrier encapsulation part, the inside of the carrier encapsulation part may be filled with the same nuclear fluid (Caryolymph) as in the cell nucleus. One or more gene regulatory factors 806, which will be described later, may be dispersed in the nuclear fluid. When the gene regulatory factor 806 is stored and the cell nucleus fuses with the carrier encapsulating part and the gene regulatory factor 806 enters the cell nucleus, if the nuclear fluid is present in advance, it has the effect of minimizing the damage to the inside of the cell nucleus. .

In contrast, when storing the genome editing module 808 inside the carrier encapsulation, a special nuclear fluid from which ATP (adenosine triphosphate) has been completely removed may be used. Phosphorylation of biopolymers often utilizes hydrolysis from ATP to ADP (Adenosine Diphosphate). Therefore, phosphorylation does not occur in an "ATP-free" environment in which ATP is completely removed.

Using this "ATP-free" state, the genome editing module 808 may enable genome editing for a predetermined period immediately after delivery into the cell nucleus. And after this validity period has passed, genome editing becomes impossible. By making it impossible to edit the genome after the validity period has passed, it is possible to avoid the "state in which the scalpel is left inside the body after surgery" explained in Section 9.1 (equivalent to the automatic destruction of the scalpel inside the body). . As a result, the effect of ensuring "2. long-term safety in post-editing cells" corresponding to the second problem presented in Section 9.1 is produced.

FIG. 43(b) shows a detailed internal structure example of the genome editing basic part 810 included in the genome editing module 808 shown in FIG. 43(a). For CRISPR / Cas9 described in Section 8.1, in this embodiment mCas partially modified Cas9 (modified CRISPR-associated System) 812-1, 2 is used. Here, the crRNA (CRISPR RNA) regions 816-1, 2 within mCas 812-1, 2 use the existing Cas9 equivalents or similar components.

The part modified with this mCas812-1, 2 is in the place where the "activity control mechanism" is added to the conventional Cas9. As an example of this activation mechanism, "activation by phosphorylation" is used. However, the activation control mechanism is not limited to this, and any other method may be used to provide the activation control mechanism. For example, as another example, when housed in a vector carrier, it may be individually separated and dispersed (monomer state), and polymerized immediately after moving into the cell nucleus to form mCas. .

That is, mCas812-1, 2 stored in the vector carrier are inactive in an ATP-free environment. When this migrates into the cell nucleus, it reacts with ATP present in the cell nucleus and activates the nuclease domain 814 . Regarding the phosphorylation that causes this activation, mCas812-1, 2 may be provided with an autophosphorylation function.

Alternatively, mCas control enzyme A_822 having kinase (phosphorylation) properties may be used. Under the ATP-free environment within the vector carrier, this mCas regulatory enzyme A_822 does not work. However, when this mCas regulatory enzyme A_822 moves into the cell nucleus, it phosphorylates mCas 812-1 and 2 using ATP present in the cell nucleus, and activates the nuclease domain 814. If the mCas812-1, 2 have a self-activating function based on autophosphorylation, the mCas regulatory enzyme A_822 becomes unnecessary.

Next, a method for exhibiting the function of the nuclease region 814 in mCas812-1, 2 only within a predetermined period (effective period) will be described. For this purpose, it is desirable to provide means for inactivating mCas 812-1, 2 (or the nuclease region 814 therein) or naturally inactivating properties.

In a state in which mCas812-1 and 2 are phosphorylated by ATP hydrolysis, the γ-phosphate group (γ-Phosphatic Group) in ATP is temporarily bound to part of mCas812-1 and 2. This bond generally does not last forever. When mCas812-1 and 2 do not have autophosphorylation function and mCas-regulating enzyme A_822 diffuses far, rephosphorylation becomes impossible and it returns to an inactive state. The active shelf life in this case corresponds to the period during which the γ-phosphate group is bound to a portion within mCas812-1,2. Therefore, adding an activation control mechanism (for example, a phosphorylation region) to mCas812-1 and 2 corresponds to giving them the property of being naturally inactivated.

As another application for inactivating the nuclease region 814, the mCas control enzyme B_824 may be used. When this mCas control enzyme B_824 is composed of a protein-degrading protease, the mCas812-1 and 2 are degraded upon activation.

Alternatively, instead of using the mCas control enzyme B_824, a "foreign marker that can be easily identified" may be provided in the genome editing basic part 810 by some method, and destroyed using phagocytosis.

Furthermore, as another application example, a phosphatase having a dephosphorylation function is built into the mCas control enzyme B_824 to remove the phosphate group bound to a part of mCas812-1, 2 and regenerate. Alternatively, a binding inhibitor (Anion) may be attached to prevent binding.

Then, a means for setting the period (effective period of genome editing) until the nuclease region 814 in mCas812-1, 2 is inactivated (activating the mCas control enzyme B_824) may be provided.

In this embodiment, a signal transduction pathway in the cell nucleus may be used as a timer that indicates the effective period of this genome editing. As a signal transduction pathway in the cell nucleus,
Calmodulin CALM (Calmodulin) ⇒ camkinase CaMIV (CaM KinaseIV) ⇒ CREB (cAMP Response Element Binding Protein) phosphorylation pathway,
A pathway of sequential phosphorylation in the order of p38MAPK (official name will be described later)->MSK1->CREB is known. Then, the time required for signal transmission between the paths may be used as a timer (effective period setting).

Therefore, as the intranuclear signal control enzyme 826, an enzyme such as calmodulin CALM or p38 MAPK, which is the starting point of the signal transduction pathway in the cell nucleus, is inserted. An enzyme such as CREB that is activated by being induced by phosphorylation of an enzyme near the terminal point of the signal transduction pathway in the cell nucleus is selected as mCas control enzyme B_824. Then, the mCas regulatory enzyme B_824 activated as described above acts to inactivate mCas 812-1, 2 (the nuclease region 814 therein).

Genome editing requires crRNA 816-1 for detecting the leading end of the DNA to be removed, crRNA 816-2 for detecting the terminal end, and DNA (vector) 818 to be replicated (newly replaced).

In this embodiment, as shown in FIG. 43(b) as a specific structure of the genome editing basic part 810, a replication DNA retention protein 817 that retains replication DNA (vector) 818 and mCas812-2 and mCas812-1 are It has a linked structure. By making it possible to store data in a linked form in this way, the third problem raised in section 9.1 is resolved. This not only facilitates the management of base sequence relationships before and after genome editing, but also has the effect of preventing artificial erroneous editing.

FIG. 43(b) shows an example in which the replication DNA (vector) 818 has a double helical structure and a nearly linear shape as a whole. However, not limited to that, as shown in FIG. 43(c), a histone (Histone) 819 wrapped with replicating DNA (vector) 818 may be ligated to mCas812-2.

Since the inside of the genome editing module 808 is ATP-free, the autophosphorylation protease 828 is in an inactive state. When the genome editing module 808 moves into the cell nucleus, the autophosphorylation protease 828 is phosphorylated (activated) using ATP in the cell nucleus. The resulting activated autophosphorylating protease 828 cleaves the cleavage site 820 of a protease with phosphorylating activity properties.

Alternatively, the replication DNA retention protein 817 may be provided with an autophosphorylation function. Inside the ATP-free inner capsule, a replicating DNA retaining protein 817 retains a replicating DNA (vector) 818 . When the entire genome editing module 808 enters a specific cell nucleus, ATP present in the cell nucleus binds to the autophosphorylation functional part described above, causing a conformational change in the replication DNA retention protein 817 to cause replication. DNA (vector) 818 is released. This facilitates incorporation of replicating DNA (vector) 818 into the genome to be edited.

In addition to this, the protein 817 for retaining replicated DNA undergoes a three-dimensional conformational change upon phosphorylation, but it is not necessary to have the self-phosphorylation function. In this case, mCas regulatory enzyme A_822 autophosphorylates to activate mCas812-1 and 2 (the nuclease region 814 therein), and at the same time phosphorylate the replication DNA retention protein 817 to cause a conformational change. You can let me.

Next, a description will be given of the gene regulatory factor 806 carried by the gene regulatory carrier. The gene regulatory factor 806 includes general substances involved in selection of genes to be expressed, control of gene transcription, and the like. Therefore, the gene regulatory factor 806 includes a repressor protein that suppresses genes and an activator protein that activates genes. In addition, the gene regulatory factor 806 may also include a substance involved in a signal transduction pathway (Pathway of Signal Transduction) inside the cell nucleus (inside the cell nuclear membrane).

Within a single cell, extremely complex signal transduction pathways exist even during the time that information given from the outside is transmitted to the inside of the cell nucleus. Therefore, when the gene regulatory factor 806 is inserted outside the cell nucleus, there is a high possibility of inducing unexpected signal transduction. Direct delivery of the gene regulatory factor 806 into the cell nucleus as shown in this embodiment has the effect of enabling efficient and reliable gene regulation.

Individual cells that make up each part of the body grow (cell fate is determined) through information exchange (mainly chemical signal exchange) with the surroundings during the growth process. . That is, each cell undergoes gene expression according to the constituent site in the body where it is arranged.

For example, in order to culture cells initialized by the method described in Patent Document 4 or Patent Document 5 (Initialized Cells) and grow them into cells that act at a specific site in vivo, conventionally, it is necessary to spend time under a predetermined environment. It was necessary to grow (long-term culture).

On the other hand, in the present example, there is an effect that the reprogrammed cells can be efficiently grown into the desired cells in a short period of time simply by mixing the gene regulatory carrier into the culture solution in which the reprogrammed cells are cultured. In this gene-regulating carrier, a gene-regulating element 806 is incorporated that promotes gene expression necessary for growing reprogrammed cells into desired cells.

In addition, in this embodiment, the vector carrier and the gene regulatory carrier may be given to the same cell, or may be administered multiple times. Alternatively, vector carriers with different content of genome editing module 808 may be administered multiple times, or gene regulatory carriers with different gene regulatory factors 806 may be administered multiple times.

When a vector carrier is administered and genome-edited cells are desired to grow and culture in large numbers, a gene regulatory carrier can be administered after administration of the vector carrier. At this time, mitogen-activated protein kinase MAPK (Mitogen-activated Protein Kinase) may be used as a gene regulatory carrier (gene regulatory factor 806).

So far, three types of MARK have been identified: ERK (Extracellular Signal-regulated Kinase), JNK (c-Jun N-terminal Kinase), and p38MARK, which are extracellular signal-regulated kinases. Here, the above-mentioned ERK has the function of "extracellular signal control", and its operation within the cell nucleus has been confirmed.

Activated (phosphorylated) ERK phosphorylates (activates) CREB (cAMP Response Element Binding Protein), Ets, Jun, Fos, Elk, HIF1, STAT3, etc. in the cell nucleus. to act on The action on this gene contributes not only to proliferation, but also to differentiation and growth.

In addition, the activated (phosphorylated) JNK phosphorylates (activates) c-Jun, AFT-2, ELK-1, p53 MAPK, NFAT, STAT3, etc. in the cell nucleus to act on genes. The action on this gene not only contributes to proliferation, but also participates in differentiation, apoptosis, and the like.

Activated (phosphorylated) p38MARK phosphorylates Ets-1, NFAT, Sap1, Stat1, Max, Myc, Elk1, p53MAPK, CHOP, MEF2, ATF-2, MSK1, MK2/3, etc. in the cell nucleus. to activate (activate) the gene. The action on this gene is involved in cytokine production, apoptosis, etc., in addition to proliferation.

The gene regulatory factor 806 to be included in the gene regulatory carrier is not limited to the above, and CREB, Ets, c-Jun, Fos, Elk, HIF1, STAT1 or 3, NFAT, Sap1, Max, Myc, CHOP, MEF2, ATF-2, MSK1, MK2/3, HMG-14, Smad, Co-Act, TF or combinations thereof may be used.

In addition, gene regulation of Aurora A/B, which regulates the activities of the centrosome, mitotic spindle, and kinetochore to promote normal mitosis It may be used as a factor 806. However, there is a risk that excessive intake may lead to carcinogenesis, so consideration must be given to the dosage.

FIG. 44(a) shows a structural example of the selective junction 830 to the cell nuclear membrane surface. A transmembrane portion 870 and a cell nucleus detection portion 850 are included in the selective junction 830 to the surface of the cell nucleus membrane in this embodiment. This transmembrane portion 870 serves to localize the selective joining portion 830 to the surface of the cell nuclear membrane in the membrane region covering the inside 842 of the carrier encapsulating portion in the intranuclear delivery carrier 800 . Hydrophobic regions 852-1 to 852-6 are present in at least part of the transmembrane portion 870. FIG. A cell nucleus detector 850 then detects or identifies the position of the cell nucleus within the cell.

When the cell nucleus detector 850 approaches the vicinity of the cell nucleus, the transmembrane portion 870 in the selective junction 830 to the surface of the cell nucleus drags the membrane region covering the inner side 842 of the carrier encapsulation portion, thereby moving the carrier encapsulation portion to the vicinity of the cell membrane. close to

As a specific example of the cell nucleus detection unit 850, an “antibody” may be used in this embodiment. However, not limited to this, in this embodiment, any method may be used as long as it is a method for detecting or identifying the position of the cell nucleus.

As an example of an antibody that identifies (or detects) a cell nucleus, an example using an antibody against the nuclear lamina 832 located inside the cell nucleus will be described. Therefore, as an example of the cell nucleus detection section, the case where the nuclear lamina identification antibody section 850 is used will be described. However, the present invention is not limited to this, and antibodies against any substance existing on the surface of the cell nucleus or inside the cell nucleus may be used.

Further, in FIG. 44, for convenience of explanation, the reaction (bonding) between the antigen showing the nuclear lamina 880 and the antibody is illustrated by the "fitting/matching relationship between the sides of the continuous triangular prism array". However, the joint shape of FIG. 44 does not actually exist.

Since the outer membrane 898 of the cell nuclear membrane is connected to the endoplasmic reticulum, it is necessary to prevent the cell nucleus detector 850 from erroneously detecting the position of the endoplasmic reticulum. The endoplasmic reticulum has a single-layer membrane structure, whereas the nuclear membrane has a two-layer membrane structure consisting of an inner membrane and an outer membrane. In other words, the nuclear lamina 880 is mostly distributed in the outer part of the cell nucleus. Therefore, the use of this feature has the effect of facilitating discovery of the cell nucleus position from the outside.

The transmembrane portion 870 penetrates the membrane region (at least one of the outer membrane 838 and the inner membrane 836 therein) covering the interior 842 of the carrier encapsulant on the outside one or more times. In the example shown in FIG. 44(a), the penetration is repeated six times. However, the present embodiment is not limited to this, and may be repeatedly pierced an arbitrary number of times (for example, 2 times, 4 times, 7 times, 24 times).

In the transmembrane portion 870, an example is shown in which the α-helix structure is maintained (in the form of forming the α-helix structure portion 860) and penetrates the membrane. However, it is not limited to this, and may be transmembrane in any form. That is, a transmembrane form with a random structure or a transmembrane form with a β-sheet structure may be used.

In the embodiment shown in FIG. 44(a), two of the six α-helical structures 860 are longer than the other four. The two long α-helix structure portions 860 are connected to the nuclear lamina identification antibody portion (cell nucleus detection portion) 850 at the ends thereof. If a structure is taken in which the transmembrane part 870 is connected to the cell nucleus detection part (nuclear lamina identification antibody part) 850 while being connected as the α-helix structure 860, the cell nucleus can be detected firmly inside the selective junction part 830 to the cell nuclear membrane surface. There is an effect that the portion (nuclear lamina identifying antibody portion) 850 can be retained.

However, the transmembrane portion 870 and the cell nucleus detection portion (nuclear lamina identification antibody portion) 850 may be connected in any form. As an example, a β sheet (crystal) portion may be arranged between the transmembrane portion 870 and the cell nucleus detection portion (nuclear lamina identification antibody portion) 850 .

Hydrophilic regions 856-1 to 8, 858-1 to 858-1 to 858-1 to 858-1 in the α-helix structural portion 860 constituting the α-helix are rich in asparagine, glutamine, serine, threonine, and tyrosine, which are amino acids having polar residues. included. In addition, within these hydrophilic regions 856-1 to 8 and 858-1 to 6, lysine, arginine, histidine, aspartic acid, and glutamic acid, which are amino acids containing charged residues, are partially present. Also good.

On the other hand, in the hydrophobic regions 852-1 to 6, 854-1, 2, the compounding ratio of the above amino acids is relatively small, and amino acids with non-polar residues (alanine or valine, leucine, isoleucine, proline) , phenylalanine, methionine, tryptophan, glycine, cysteine, and the like.

FIG. 44(b) shows an example of the location and function of the selective bonding portion 830 having the structure described in FIG.

The membrane region covering the inner capsule of the carrier for intranuclear transport 800 has a lipid bilayer structure composed of an outer membrane 838 of the carrier inner capsule and an inner membrane 836 of the outer carrier like the cell membrane of mammals. Between the outer membrane 838 of the carrier encapsulation and the inner membrane 836 of the carrier encapsulation, there is a hydrophobic region 834 between inner and outer membranes composed mainly of lipids.

Lipids are composed primarily of carbon and hydrogen atoms and thus have hydrophobic properties. And, like "oil droplets are separated and aggregated in water," hydrophobic substances gather in an aqueous solution (they are pushed out of the water molecule distribution region). Due to this characteristic, the hydrophobic regions 852-1 to 852-6 in the transmembrane portion 870 enter the hydrophobic region 834 between the inner and outer membranes.

As shown in FIG. 44(a), hydrophobic regions 854-1 and 854-2 are present in addition to the hydrophobic regions 852-1 to 852-6 in the selective junction 830 to the cell nuclear membrane surface. By the way, the surface areas of the hydrophobic regions 852-1 to 852-6 are larger than the surface areas of the hydrophobic regions 854-1 and 854-2. Therefore, not the hydrophobic regions 854-1 and 854-2, but the hydrophobic regions 852-1 to 852-6 enter the hydrophobic region 834 between the inner and outer membranes.

The cell nuclear membrane is also composed of a lipid bilayer consisting of an inner membrane 896 of the nuclear membrane and an outer membrane 898 of the nuclear membrane. Also between the inner membrane 896 of the nuclear membrane and the outer membrane 898 of the nuclear membrane, there is an inter-membrane hydrophobic region 894 composed mainly of lipids. A nuclear lamina 880 is arranged inside the inner membrane 896 of the cell nuclear membrane.

Therefore, the nuclear lamina identifying antibody portion (nucleus detecting portion) 850 in the selective junction 830 to the cell nuclear membrane surface needs to penetrate into the nuclear membrane to identify the existence of the nuclear lamina 880 . Hydrophobic regions 854-1 and 854-2 are provided in this embodiment as means for promoting the activity.

That is, as shown in FIG. 44(b), the hydrophobic regions 854-1 and 854-2 enter the hydrophobic region between the inner and outer membranes in the cell nuclear membrane. By establishing the foundation of the nuclear lamina identifying antibody portion (cell nucleus detecting portion) 850 in the cell nucleus in this manner, there is an effect of promoting the bonding of the nuclear lamina identifying antibody portion (cell nucleus detecting portion) 850 to the nuclear lamina 880. .

After being injected into the cell and before being absorbed into the cell nucleus, the intranuclear delivery carrier 800 moves freely within the cell. During this moving process, the hydrophobic regions 854-1 and 854-2 may temporarily enter, for example, the endoplasmic reticulum. However, since membranes such as the endoplasmic reticulum have a single-layer structure, their thickness differs from that of the cell nuclear membrane. Furthermore, since the nuclear lamina 880 does not exist inside the endoplasmic reticulum or the like, strong fixation by the nuclear lamina identification antibody section (cell nucleus detection section) 850 does not occur. Therefore, the intranuclear transport carrier 800 leaves the endoplasmic reticulum and the like in a short period of time, and begins searching for the cell nucleus.

As described later in section 9.3, the method of manufacturing the carrier for intranuclear transportation 800, a part of the carrier for intranuclear transportation 800 has a selective junction 830 with the surface of the cell nuclear membrane facing the inside 842 of the carrier encapsulating part. may be placed.

The nuclear lamina 832 located inside the carrier encasement 842 also has a relatively rigid structure. Therefore, by bonding the selective bonding portion 830 to the cell nuclear membrane surface facing the inside 842 of the carrier encapsulant with the nuclear lamina 832, the strength of the inner membrane 836 and the outer membrane 838 of the carrier encapsulant is improved. .

When the carrier 800 for intranuclear transport and the cell nuclear membrane are joined at the selective joining portion 830 to the cell nuclear membrane surface, as shown in FIG. be taken into As a result, the contents (genome editing module 808 or gene regulatory factor 806) of carrier 800 for intranuclear delivery are incorporated into cell nucleus interior 890. FIG.

Although detailed depiction in FIG. 44(c) is omitted, the inner membrane 836 of the carrier encapsulation part is incorporated as part of the inner membrane 896 of the cell nuclear membrane, and the outer membrane 838 of the carrier encapsulation part is part of the outer membrane 898 of the cell nuclear membrane. incorporated as a part. In parallel with this, the nuclear lamina 832 arranged inside 842 of the carrier encapsulating part is also incorporated as part of the nuclear lamina 880 in the cell nucleus.

Therefore, if at least one of the material, composition, structure, and thickness of the nuclear lamina 832 arranged in the inside 842 of the carrier encapsulating part is made to match or resemble the nuclear lamina 880 in the cell nucleus, the built-in contents of the carrier 800 for intranuclear transport ( An effect of minimizing damage to the cell nucleus when the genome editing module 808 or the gene regulatory factor 806) is delivered into the cell nucleus is produced.

Similarly, if at least one of the material, composition, structure, and thickness of the inner membrane 836 of the carrier encapsulating part matches or resembles the inner membrane 896 of the cell nuclear membrane, the effect of minimizing damage to the cell nucleus is produced.

Furthermore, if at least one of the material, composition, structure, and thickness of the outer membrane 838 of the carrier encapsulating part is matched with or similar to the outer membrane 898 of the cell nucleus membrane, the effect of minimizing damage to the cell nucleus is produced.

Section 9.3 Manufacturing method of carrier for intranuclear transport (suitable for mass production)
A G protein known as a membrane protein and an ion channel have a transmembrane portion 870 having an α-helical structure 860 . Therefore, referring to this amino acid sequence information, the amino acid sequence corresponding to the selective junction 830 to the cell nuclear membrane surface having the structure of FIG. 44(a) is first designed. Using this information, the genome of Aspergillus oryzae is edited, and a selective junction 830 to the cell nuclear membrane surface is created by the method shown in FIG. 45 or 47, for example.

As described in detail in reference 3, the phospholipid molecules that make up the nuclear membrane consist of a hydrophilic head and a hydrophobic tail made up of hydrocarbons. Therefore, when an appropriate amount of the above phospholipid molecules is injected into pure water in a petri dish, a monolayer film in which the phospholipid molecules are uniformly arranged on the pure water surface is formed.

In this single-layer membrane, the hydrophilic head faces downward toward the surface that comes into contact with pure water. The hydrophobic tails, on the other hand, are uniformly arranged upward and are located on the air contact side.

In this state, an injection needle is inserted into the pure water to inject the selective junction 830 to the cell nuclear membrane surface. As shown in FIG. 44(a), since there are hydrophobic regions 852-1 to 852-6 in the selective junction 830 to the cell nuclear membrane surface, they are pushed out by water molecules and move onto the pure water surface. Then, the nuclear lamina identification antibody portion (cell nucleus detection portion) 850 in the selective junction 830 to the cell nuclear membrane surface is directed downward and localized on the surface on which the monolayer membrane is formed. In particular, the hydrophobic regions 852-1 to 852-6 enter into regions where many hydrophobic tails are distributed within the monolayer membrane of phospholipid molecules.

A mesh or perforated plate previously placed in pure water is then slanted and moved out of the pure water to the top. The phospholipid molecular layer then enters into the interstices of the mesh or pores in the plate, forming a lipid bilayer.

Dispersed within this lipid bilayer are selective junctions 830 to the surface of the nuclear membrane. Here, the directions of the nuclear lamina identification antibody portions (cell nucleus detection portions) 850 in the selective junctions 830 to the surface of the cell nuclear membrane that are dispersed do not all match, and the selective junctions 830 to the surface of the cell nuclear membrane do not match. facing in opposite directions to each other.

When housing the genome editing module 808 in the carrier encapsulating part, an aqueous solution in which the nuclear lamina 832 and the genome editing basic part 810 are mixed in the ATP-free nuclear fluid is prepared in advance as shown in FIG. In this aqueous solution, mCas-regulating enzyme A_822, mCas-regulating enzyme B_824, intranuclear signal-regulating enzyme 826, and autophosphorylation protease 828 may be mixed, if necessary.

On the other hand, when the gene regulatory factor 806 is to be stored in the carrier encapsulating part, a nuclear fluid in which the nuclear lamina 832 and the predetermined gene regulatory factor 806 are mixed is prepared in advance.

This nucleus liquid (aqueous solution) is sprayed toward the pores in the mesh or plate blocked by the lipid bilayer. Then, the carrier encapsulating part is generated by the same principle as the soap bubble manufacturing principle. If an aqueous solution having the same components as the inside of the intracellular delivery carrier 800 is placed at the spray destination, the carrier encapsulating portion covered with the membrane region enters the aqueous solution.

As described above, the inner side of the inner film 386 of the carrier encapsulating portion is lined with the core lamina 832, so a predetermined strength is maintained. Therefore, by providing the inner film 386 of the carrier encapsulating portion with a structure lined with the core lamina 832, the effect of facilitating the handling of the carrier encapsulating portion is produced.

Next, a carrier 800 for intranuclear transport may be produced by a method similar to the procedure for producing the carrier encapsulating part.

By using the above method, the intranuclear delivery carrier 800 can be produced relatively easily. However, this embodiment is not limited to the above-described creation method, and may be created by any method.

Chapter 10 Production Method and Process Control of Functional Biomaterial In Chapter 10, the mass production method and process control method of the functional biomaterial in this embodiment will be described.

Section 10.1 Manufacturing method and basic procedure for process control In the production process of functional biomaterials shown in Fig. 37, changes in absorption characteristics in the near-infrared region described in Section 2.6 occur. In other words, in the process of producing functional biomaterials, the catalytic reaction of specific enzymes is utilized in some way. According to Patent Document 3, temporary hydrogen bonding occurs during this catalytic reaction, and the wavelength of the absorption band changes according to this hydrogen bonding form. Therefore, by measuring the wavelength change of this absorption band, it is possible to manage the state during production of the functional biomaterial. At this time, if at least the methods described in Chapters 3 and 6 are adopted, the accuracy of wavelength change measurement of the absorption band is greatly improved.

FIGS. 45 and 46 show a method for producing functional biomaterials while controlling the state using near-infrared light. In the method shown in FIG. 45, cells are expanded and cultured (S47) using gene regulation carriers after the genome editing treatment (S42) using vector carriers described in Chapter 9. On the other hand, the method of FIG. 46 performs genome editing (S66) using a vector carrier after performing cell culture (S64) using a gene regulatory carrier.

However, it is not limited to this, and only genome editing or proliferation culture may be performed, or both may be performed at the same time. Furthermore, both may be combined in random order.

In explaining the mass production method and the process control method using FIG. 45, as a specific example, an example of producing a functional biomaterial using a transgenic silkworm will also be explained.

Regarding the "fibroin deformation" described on the 3rd to 4th lines in FIG. 37 or the "acidic residue-containing fibroin" described on the 5th line in FIG. 37, it was explained in Section 8.3 using FIGS. .

Since cocoons expelled by silkworms contain a large amount of fibroin, transgenic silkworms can be used to produce the above-mentioned "fibroin variants" and "acidic residue-containing fibroin."

In the first step of starting production (S41), the vector carrier described in Section 9.2 is used to perform genome editing processing (S42) in target cells. At this time, hydrogen bonds between bases in nucleotides (Nucleotide) are temporarily generated. Therefore, at this time, the wavelength change of the absorption band described in section 8.5 occurs.

Not only that, but when using CRISPR/Cas9 for genome editing, DNA cleavage at the nuclease region 814 is performed. Since specific hydrogen bonds are also generated during this DNA cleavage, the corresponding wavelength change in the absorption band can be observed.

The optical monitoring in S43 means process control (control of genome editing state) based on observation of wavelength change in the absorption band using near-infrared light.

When transgenic silkworms are used, genome editing of S42 is performed on fertilized eggs of silkworms.

An evaluation is made as to whether or not the above genome editing has been properly performed (S45), and if not (No), the process returns to the genome editing process (S42). The evaluation of gene expression after genome editing and the functional biosubstance produced in the transgenic silkworm (S44) corresponds to the component analysis and characteristic analysis of the cocoon expelled by the grown silkworm.

If the evaluation result (S45) is good (Yes), the process proceeds to the next step of S46. At the stage when the fertilized egg after genome editing starts cell division, part of it is separated, extracted and stored frozen. Growth from remaining fertilized eggs to silkworm larvae and evaluation after transformation into pupae (S44). Cryopreserved eggs showing good results are initialized in S46. For this initialization, the method disclosed in Patent Document 4 or Patent Document 5 is used.

A gene regulation carrier is given to the reprogrammed cells to carry out proliferation culture (S47). As the gene regulatory factor used at this time, the MAPK family described in the second half of Section 9.2 may be used.

Here, when the gene regulatory factor acts on the DNA, temporary hydrogen bonding occurs between part of the gene regulatory factor and part of the DNA. The process of observing the wavelength change of the absorption band peculiar to this hydrogen bond and controlling the effect of the gene regulatory factor on DNA corresponds to the optical monitor S48.

In the next step S49, two methods can be selected in this embodiment as a method of terminal differentiation of cells after proliferation culture and harvesting functional biomaterials (S51). The first method is to extract only the cocoon after growing the fertilized egg into a silkworm larva and transforming it into a pupa.

Another method involves administering a gene-regulated carrier containing a gene-regulating factor that induces terminal differentiation to cells in culture. As a result, after growing into silk cells in the culture medium, the cell membrane is broken to extract fibroin (corresponding to harvesting of functional biomaterials in S51).

Here, temporary hydrogen bonds also occur when gene regulatory factors that promote terminal differentiation act on DNA. Therefore, the process of observing the wavelength change of the absorption band peculiar to this hydrogen bond and controlling the effect of the gene regulatory factor on DNA corresponds to the optical monitor S50.

Optical monitoring is also performed in steps S65 and S67 in FIG. 46, but since the specific contents are substantially the same as those described above, the description thereof will be omitted.

Regardless of which of the above two methods is adopted, the production is completed (S52) when the extraction of fibroin (harvesting of functional biomaterials S51) is completed. However, the cycle starting from cell reprogramming in S46 or proliferation culture in S47 may be repeated.

The above explanation was given taking the image of silk cells as an example of parent cells (original species) (Fig. 48) having the ability to produce functional biosubstances. As a method for mass-producing functional biomaterials in this embodiment,
A] Method of producing in a predetermined container without using cells B] Method of producing inside cells and collecting functional biomaterials by cell membrane disruption C] Functional biomaterials produced inside cells Method D] in which a functional biomaterial is secreted to the outside] A method in which a functional biomaterial is produced inside a cell and then extended outside the cell in a form linked to the cell may be used. However, the present embodiment is not limited to this, and any method may be used to produce a functional biomaterial.

The above [B] method is the same as E.I. Called the Coli method, proteins are produced inside Escherichia Coil. Since this method requires a process of "crushing to refining", the manufacturing process is complicated and the relative manufacturing cost tends to increase.

On the other hand, Aspergillus Oryzae and Corynebacterium Glutamicum are suitable for the method [C], which secretes proteins produced within the fungi. In particular, glutamic acid-producing bacteria have the characteristic of being able to secrete macromolecules while maintaining their three-dimensional structure by using a channel called TatABC. However, even in this case, since there is an upper limit to the molecular size (molecular weight) of secretable macromolecules, direct secretion of large-sized functional biomaterials is difficult.

In contrast, the method [A] can easily collect the produced protein of any size. As a specific method, protein synthesis is automatically performed only by dropping DNA into a specially shaped test tube containing an E. coli extract. In addition, by partitioning the inside of the special-shaped test tube with a special filter, gene expression using a microdialysis method is also possible.

However, since germs easily propagate in the Escherichia coli extract, it is desirable to manufacture the product only in a special environment (in a clean room) to avoid contamination with germs. When disinfection/sterilization treatment is performed for mass production under a general environment, the mRNA transcription system and protein synthesis system are likely to be seriously damaged.

As another application example of the present embodiment, the above method [D] may be used. Hair matrix cells extend wool and hair produced inside to the outside in a form that directly connects with hair matrix cells. In addition, compared to [A], the hair matrix cells are highly resistant to disinfection/sterilization. Therefore, by selecting appropriate disinfection/sterilization methods, production is highly facilitated in a general environment.

Using hair matrix-related cells 1000 as parent cells (original species) having the ability to produce functional biosubstances or daughter cells (daughter cells) obtained by growing and culturing them (seed species), by the method [D] above. FIG. 46 shows an image diagram of generating the functional biomaterial 1002 .

As shown in FIG. 46, a stirrer 1006 and an optical state control device (measuring device) 1020 are installed in a predetermined container 1010 in advance. This optical state management device (measuring device) 1020 is composed of a light source section 2 and a detection section 6, similar to the structure shown in FIGS. 1A to 1C.

Although not shown in FIG. 46, a pH adjuster for adjusting the pH value in the culture medium 1004 and an oxygen supply for supplying oxygen gas to the culture medium 1004 may be installed.

As shown in FIG. 46( a ), a container 1010 is filled with a predetermined medium 1004 and put into a container 1010 with hair matrix-related cells (parent cell/original seed or daughter cell/seed seed) 1000 in a state of constant stirring. In this environment, the hair matrix-related cells (parent cell/original seed or daughter cell/seed seed) 1000 are continued to be cultured for a predetermined period.

Then, hair matrix-related cells (parent cell/original seed or daughter cell/seed seed) 1000 to which the functional biomaterial 1002 is attached are obtained as shown in FIG. 46(b). This state becomes a form similar to hair with hair matrix cells attached.

Since the produced functional biomaterial 1002 can be collected by a very simple operation of removing it from the medium 1004, there is an effect that the mass production process can be greatly shortened.

FIG. 47 shows a production method for mass production of the parent cell (original strain) 1000 used here. As the first step S62 immediately after the start of production (S61), a large amount of cells of the same type are collected from the existing living body. Specifically, the epidermis of animals such as sheep may be collected.

Immediately after that, the collected cells are initialized by the method described in Patent Document 4 or Patent Document 5 (S63). Then, a gene regulatory carrier containing a gene regulatory factor such as the MAPK family is introduced to proliferate and culture cells immediately after reprogramming, and a gene regulatory carrier containing a predetermined gene regulatory factor is introduced to promote terminal differentiation. Since the contents of the optical monitors S65 and S67 are the same as or similar to those in FIG. 45, their description is omitted here.

Then, in step S66, a vector carrier is administered to carry out predetermined genome editing. After that, screening (S68) is performed to extract only cells in which the desired genome editing has been performed, and the cells are provided to the outside as parental cells (original species) 1000 (S69). Then the manufacturing is completed (S69).

A supplementary description will be given of the method for mass-producing the functional biomaterial described in [A] to [D] above. In each of the above methods [B] to [D], specific cells are used during mass production of functional biomaterials. The cells used here must be appropriately selected according to the type of functional biomaterial to be mass-produced.

For example, try to generate "Protein obtained from Higher Organism" in cells by genetic manipulation. From the point of view of cells belonging to primitive organisms, the above "proteins derived from higher organisms" appear to be invasion of foreign substances. Moreover, every cell possesses a protease that decomposes proteins inside. Therefore, when an attempt is made to produce "proteins derived from higher organisms" in cells that belong to primitive organisms, the synthesized proteins are degraded by the action of proteases, which is regarded as an invasion of foreign substances.

As a specific example, even if an attempt is made to produce fibroin (derived from insect species) in koji mold (derived from microorganisms), proteases act and the secretion efficiency of fibroin is greatly reduced. When protease activity is stopped to improve fibroin secretion efficiency, the production of other unnecessary foreign substances is increased.

For the above reasons, the mass production of "functional biomaterials derived from specific organisms" (including partially improved biomaterials directly produced by specific organisms) requires It is preferred to use cells.

As a specific example, it is desirable to use plant-derived cells for mass production of (substances constituting) artificial foods such as vegetables, rice, and wheat. In addition, when mass-producing artificial meat (or actin filament, which is a component thereof), it is desirable to use cells derived from mammals, birds, and fish instead of cells derived from insects (such as silkworm kinshin cells). .

As an example of using the above method [D], use of hair matrix-related cells 1000 was described above. For the reasons described above, it is desirable to use hair matrix-related cells 1000 derived from higher organisms (for example, derived from mammals such as sheep and humans).

Also in method [C] above, it is desirable to use cells derived from higher organisms (for example, mammals) for mass production. As an example of “cells (derived from higher organisms) that secrete internally produced functional biomaterials to the outside, we will explain the use of pancreas β cells (or improved cells thereof).

Human insulin secreted from pancreatic β cells has a protein structure comprising two monomers. Specifically, human insulin consists of two disulfides, the "A Chain" consisting of 21 amino acid linkages and the "B Chain" consisting of 30 amino acid linkages. Joined by Disulfide Bonds.

The insulin-secreting pancreatic β-cells used in this embodiment are not necessarily human-derived, and pancreatic β-cells existing in the body of other mammals may be used. Genome editing processing described in Chapter 9 is performed on the gene involved in insulin production in pancreatic β-cells. Then, for example, a portion of a muscle cell is transformed into a special cell that produces/secretes a functional protein suitable for foodstuffs or functional materials.

In the embodiment shown in FIG. 46, an example of using the hair matrix-related cells 1000 in accordance with the above method [D] has been described. On the other hand, in the above method [C], a functional protein is secreted from cells such as improved pancreatic β cells. In this case, the environment for producing/secreting the functional protein may use a culture medium 1004 and a manufacturing state control device (measuring device) 1020 as shown in FIG.

Section 10.2 Regionally Distributed Mass Production Process In the methods shown in FIGS. 45 and 47, the method of manufacturing the functional biomaterial 1002 at the same location was mainly described. However, without being limited to this, in the present embodiment, the place where each manufacturing process is performed may be divided and distributed over a wide area.

As the total volume of functional biomaterial 1002 produced increases, its transportation costs become very expensive. On the other hand, parent cells/original seeds from which functional biomaterials 1002 such as hair matrix-related cells are produced and daughter cells/seed seeds 1000 obtained by proliferating and culturing them are very small, so they are relatively inexpensive. can be shipped to

Therefore, if the functional biomaterial 1002 is transported in the form of parent cell/original seed or daughter cell/seed seed 1000 to the consumption area of the functional biomaterial 1002, and the functional biomaterial 1002 is produced in the consumption area, the total cost can be greatly reduced. can get.

On the other hand, if the vector carrier or gene regulatory carrier described in section 9.2 with reference to FIGS. 43, 44 and 37 is used, the genome editing module or gene regulatory factor directly penetrates into the cell nucleus. Therefore, from the necessity of protecting the natural environment and maintaining the ecosystem, it is desirable to limit the areas where vector carriers and gene regulation carriers can be used within specific areas.

Therefore, in this embodiment shown in FIG. 48, the production bases are hierarchized for each manufacturing process. Centralize the central headquarters 1130 to one location and limit the handling of gene regulatory carriers and vector carriers to this region. Then, the management within this core control center 1130 is strengthened to thoroughly prevent vector carriers and gene regulatory carriers from leaking to the outside. Adopting this method has the effect of preventing and controlling adverse effects on existing ecosystems and the natural world.

That is, genome editing, cell reprogramming, and gene regulation are performed only within the core control center 1130 . Then, parent cells (original species) 1000 having the ability to produce functional biomaterials are generated (mass produced). Then, the obtained parent cell (original seed) 1000 is provided to the distributed distribution base 1120 .

At each distributed distribution base 1120a to 1120c, the provided parent cell (original seed) 1000 is proliferated to generate daughter cells (seed seed). In addition, a growth factor is administered to increase the proliferation effect.

By the way, growth factors given to promote mitosis from parent cells (original seeds) 1000 and to promote growth of daughter cells (seed seeds) performed in each of the distributed distribution bases 1120a to 1120c are strictly extracellular. Limited to dosing. In other words, no gene-regulating carriers are used here that allow direct import into the cell nucleus.

In addition, a medium 1004 containing a sterilization/disinfectant (antibacterial growth inhibitor) that prevents the growth of bacteria in the medium 1004 under a general environment and does little damage to daughter cells (seed seeds) is also manufactured. Then, the daughter cells (seed seeds) produced here and the culture medium 1004 containing an antimicrobial agent are provided to final production sites 1100a to 1100j of functional biomaterials.

The final production area 1110 is located at the end of the distributed production hierarchy. And the final production site 1100a-1100j of each functional biomaterial is located near the consumption site of the functional biomaterial.

At the final production sites 1100a to 1100j of each functional biomaterial, the simple equipment described in FIG. Purchase from base 1120. As a purchase method, in addition to direct purchase, purchase via a network may be used.

And since the functional biomaterial 1002 is produced by the method shown in FIG. 46, there is an effect that the production can be easily performed by the general public under a general environment. Therefore, in this embodiment, production can be easily performed with the ease of homework.

Although several embodiments have been described above, these embodiments are presented as examples and are not intended to limit the scope of the invention. These novel embodiments can be implemented in various other forms, and various omissions, replacements, and modifications can be made without departing from the scope of the invention. These embodiments and modifications thereof are included in the scope and gist of the invention, and are included in the scope of the invention described in the claims and equivalents thereof.

Section 10.3 Estimation of functional biomaterials using incoherent near-infrared light Polyethylene having the molecular structure 408 described in FIG. 64(a) or (b) has the absorption characteristics shown in FIG. there is A partial amino acid sequence 400 in the silk sheet (fibroin) has the characteristics shown in FIG. 64(c). And it has the absorption characteristics shown in FIG.

Conventional straight light 360 having partial coherence causes optical interference with multiple scattered light 370 when passing through the silk sheet (see FIG. 26(a)). As a result, as shown in FIG. 61, conventional light with partial coherence did not provide the absorption characteristics of the silk sheet (fibroin). That is, with near-infrared light whose partial coherence is reduced (incoherent) by the method described in Chapter 3, highly accurate light absorption characteristics can be obtained.

In Section 10.1, an example of "manufacturing process control of functional biomaterials using the above-described incoherent light" was described. However, the findings obtained in FIGS. 62 and 63 may be utilized not only for the manufacturing process management described above but also for estimating (identifying) components, molecular structures, etc. of manufactured functional biomaterials.

Ingredients (excluding vitamins, minerals, etc.) can be roughly classified into protein-based, carbohydrate-based, and lipid-based. Therefore, not only functional biomaterials used in foodstuffs, but also functional biomaterials used as raw materials are classified into protein group, carbohydrate group, lipid group, and lipid group. Group).

A functional group containing a central nitrogen atom (-NHn) is not included in carbohydrate-based and lipid-based functional biomaterials (Fig. 65). On the other hand, functional groups (-CHn) containing a carbon atom at the center occupy the majority in lipid-based functional biomaterials. In addition, the content of hydroxyl groups (-OH) in lipid-based functional biomaterials is very low. In addition, the content of methyl groups (-CH ₃ ) is low in sugar-based functional biomaterials.

Any functional group can be contained within the protein-based functional biomaterial. Also, apart from the "-NH group", these functional groups are present in the "Amino Acid Residue". Therefore, in the absorption characteristics obtained from the functional biomaterial whose main component is the artificial protein, it is possible to estimate "the type and approximate composition of the amino acids that constitute the main component of the artificial protein" from the detected functional groups.

The numbers in parentheses at the bottom of the frame in FIG. 65 indicate values read directly from FIGS. In addition, the central part of the frame is reproduced from the literature of Ozaki et al.

As an example, in fibroin, glycine with a "-CH group" accounts for 46% of the total, and alanine with a "-CH ₃ group" accounts for 30% of the total. Therefore, it is considered that the peak (maximum) position indicated by the “Lower Direction Arrow” in FIG. 62 represents the alanine content of 30%.

On the other hand, in "Spider's Thread", it is said that most of the β-sheet crystal part 602 (Fig. 38) is occupied only by alanine. Therefore, when measuring the light absorption properties of spider silk, the peak amount (maximum value) at the "downward arrow" position is expected to increase significantly.

Further, when comparing FIG. 62 and FIG. 63, the central wavelength of the absorption band attributed to the first overtone of the stretching vibration exceeds 1.7 μm (from 1.81 μm to 1.70 μm) in the methyl group (-CH ₃ ). Within the range), the methylene group (-CH ₂ ) or "-CH group" is 1.7 µm or less. The positions indicated by the downward arrows in FIG. 62 were 1.683 μm and 1.177 μm. Therefore, when the central wavelength of the absorption band is observed near 1.683 μm (within the range from 1.80 μm to 1.67 μm) or near 1.177 μm (within the range from 1.23 μm to 1.12 μm), the presence of methyl groups is expected. Thus, the type of amino acid that is the main component can be determined by whether or not the central wavelength of the absorption band of the absorption characteristics obtained from the functional biomaterial exceeds 1.7 μm.

Although not shown, the center wavelength of the absorption band was observed at 1.7 μm or less for both PMMA (Poly-Methyl-Metacrylate) and epoxy resin having methyl groups.

In addition, when the central wavelength of the absorption band is observed in the range from 1.23 μm to 1.15 μm or in the range from 0.94 μm to 0.86 μm, a methyl group, a methylene group, or a “—CH group” likely to be included.

Further, from FIG. 65, it can be easily predicted whether or not the functional biomaterial to be measured contains a protein-based material. That is, when a protein-based material is included, the central wavelength of the absorption band exists within the range of 1.67 μm to 1.46 μm or within the range of 1.11 μm to 0.97 μm.

According to the measurement results of FIG. 62, the centers of the absorption bands are present near 1.570 μm, 1.538 μm, and 1.495 μm, respectively. A β-sheet crystal portion 602 (FIG. 38) is present within the fibroin. Therefore, if the protein has a β-sheet structure, an absorption band with a center wavelength at (or near) any of the above values can be detected.

For example, absorbance characteristics obtained from functional biomaterials that will be used (future) in foods and materials (measured using light with reduced partial coherence (or incoherence) described in Chapter 3) The method for estimating the composition (constituent material) of the functional biomaterial from the above is summarized below.

Among the group vibrations in functional groups, we begin by explaining the absorption bands attributed to the overtones of stretching vibrations. According to FIG. 65, the measurement wavelengths of 1.67 μm, 1.46 μm, 1.38 μm, 1.11 μm and 0.94 μm are the boundary values.

That is, if the central wavelength of the absorption band observed in the absorption characteristics is within the range of 1.67 μm to 1.46 μm or within the range of 1.11 μm to 0.97 μm, the target functional biomaterial is “ It may be interpreted as "protein-based" (at least part of which contains amino acids).

On the other hand, when the central wavelength of the absorption band is observed within the range of 1.46 μm to 1.38 μm or within the range of 0.99 μm to 0.94 μm, the functional biomaterial is “sugar-based” (e.g., oligo Polysaccharides such as oligosaccharides and cellulose (Cellulose) are included at least in part) or "proteins" (Amino acids are included in at least part).

Here, when the central wavelength of the absorption band does not exist within the range of 1.67 μm to 1.46 μm or within the range of 1.11 μm to 0.97 μm, it is assumed that the central composition is mainly composed of “sugars”. You can

On the other hand, when the central wavelength of the absorption band exists within the range from 1.67 μm to 1.46 μm or within the range from 1.11 μm to 0.97 μm,
There is a high possibility of either 1) a case where "protein-based" constitutes the central composition, or 2) a mixed system of "protein-based" and "sugar-based".

In FIG. 65, some of the "lipid-based" materials contain hydroxyl groups (-OH). However, in "lipid-based", the abundance ratio of methyl groups and methylene groups is overwhelmingly high. Therefore, the amount of hydroxyl groups (-OH) observed in "lipid systems" (that is, the strength of the absorption band) is often buried in measurement errors.

Similarly, the probability of existence of a methyl group ( _-CH3 ) present in the "sugar system" is very low. Therefore, when the central wavelength of the absorption band is at a position of 1.7 μm or more (as described above), it is included in either “lipid-based” or “protein-based”. Moreover, if the central wavelength of the absorption band is not within the range from 1.67 μm to 1.46 μm or within the range from 1.11 μm to 0.97 μm, it can be assumed that the central composition is composed of a "lipid system".

Next, how to distinguish between the absorption band attributed to the overtone of the stretching vibration and the absorption band attributed to the combination tone within the absorption characteristics will be explained. As shown in (a) and (c) of FIG. 63, the absorption bands attributed to harmonic overtones of stretching vibration are relatively narrow in width and high in intensity (height from the baseline to the center). In contrast, the absorption band attributed to the combination tone is relatively wide and low in intensity, as shown in the vicinity of FIG. 63(j).

Also, as explained in Section 5.6 for the part (j) of FIG. may be determined to belong to

As explained in Chapter 2 and shown in the measurement results of FIG. 61, the detection signal is buried in the optical noise in the conventional near-infrared light having partial coherence. As a result, in the prior art, it was difficult to characterize individual absorption bands attributed to group vibrations within functional groups. On the other hand, in this embodiment, light with low partial coherence (incoherence) can be generated by the method described in Chapter 3. Therefore, only by using that light is the effect of enabling the characteristics of individual absorption bands attributed to group vibrations in the functional groups to be produced.

Section 10.4 Optical Properties of Functional Biomaterial in this Embodiment The optical properties of the functional biomaterial prepared in this embodiment will be described. First, the optical properties of functional biomaterials that are structured using "protein-based" materials are described. Next, the optical properties of functional biomaterials that exhibit other unique functions will be explained.

In this embodiment, in the structure of a functional biomaterial using a protein-based material, A) a structure is formed using an α-Helix, β-Sheet, or Turned structure. B) to apply a composition that is optically easy to manage in the manufacturing process.

First, the above (B) will be explained. There are 20 kinds of amino acids in nature. Therefore, there is an option to use 20 types of amino acids in equal composition ratios as materials for functional biomaterials. However, in this case, the absorption properties obtained from the functional biomaterial are very complex. Suppose we want to manufacture a functional biomaterial with very complex absorption properties. If the material originally has complex characteristics, it is difficult to predict "what kind of problem has occurred?" even if the absorption characteristics change slightly during manufacturing process control.

In the functional biomaterial of the present embodiment, a functional biomaterial that forms a structure by increasing the composition ratio of characteristic amino acids is produced. As a result, there is an effect of facilitating the analysis of defective parts that occur during manufacturing. In addition, in this embodiment, instead of numerically limiting the compositional ratio of characteristic amino acids, the absorbance characteristics obtained from the manufactured functional biomaterial are defined (details will be described later). Moreover, as can be seen from FIG. 66, the above condition (A) is also satisfied when the composition ratio of characteristic amino acids is increased.

Section 8.3 used FIG. 49 to describe an example of forming a structure by combining improved β-sheet crystal parts 1602 . In FIG. 49, the structure was constructed from a plurality of crystallographic assembly (multimer) blocks 1604 .

A structure such as clothes may be constructed by twisting/knitting a fibriform protein without being limited to such a combination of blocks. Silk made from fibroin that already has a β-sheet structure corresponds to the fibrous protein described above. On the other hand, collagen and tropomyosin, which are classified as fibrous proteins, have an α-helical secondary structure.

Therefore, in the functional biomaterial of the present embodiment, structures such as α-helices, β-sheets, and folds are used to form structures. By giving the above-described structure to at least a part of the inside of the functional biomaterial in the present embodiment, not only is it easy to mold the macroscopic structure/shape of the functional biomaterial, but also the shape of the molded product during long-term storage. It has the effect of ensuring stability.

As a specific means for realizing this, in the present embodiment, a functional biomaterial is formed by increasing the composition ratio of amino acids that are likely to take structures such as α-helices, β-sheets, and folds.

FIG. 66 shows amino acids that tend to form the α-helical structure and amino acids that tend to form the β-seed structure. In FIG. 66, amino acids are classified according to the difference in the central atom of the functional group arranged at the tip of the amino acid residue. Most amino acids are classified into the Carbon Group, and the fewest are classified into the Nitrogen Group.

As can be seen from FIG. 66, all amino acids that tend to form an α-helical structure or a β-sheet structure contain a methyl group or a methylene group. Therefore, when combined with the contents described in FIG. The center wavelength of the absorption band exists within the range of .94 μm to 0.84 μm.

Next, the relationship between the composition ratio of those amino acids and the detection characteristics will be explained. In the absorbance characteristics of a silk sheet with a thickness of about 100 μm shown in FIG. 62, an absorption band related to alanine having a methyl group appears at the position of the downward arrow. The composition ratio of alanine is higher in spider silk. Therefore, in spider silk, it is expected that an absorption band with high absorption intensity (high height in terms of absorbance characteristics) will appear near the same downward arrow position.

In the present embodiment, instead of defining the composition ratio for each amino acid, the height of the absorption band attributed to the overtone of the stretching vibration of the methyl group and the methylene group (that is, the absorbance value at the center wavelength position of the absorption band and the dashed line) difference from baseline). Rather than specifying the composition ratio for each amino acid, specifying the height of the absorption band has the effect of facilitating handling during production or quality control of the finished product.

Most of the noise components in the incoherent light measurement results in FIGS. 62 and 63 are caused by electrical noise (dark current and shot noise) of the one-dimensional line sensor 132 (FIG. 22) in the spectroscope 22. . Each time immediately before measurement, the dark current of the one-dimensional line sensor 132 is measured and subtraction processing is performed. However, it is difficult to remove dark current components that change with time. In addition, the influence of shot noise is reduced by averaging 250 repeated measurements. However, there is a limit to the reduction. In particular, when the light intensity of the detection light 16 is low, the influence of electrical noise becomes relatively large.

The noise amplitude in absorbance in the incoherent light measurement results in FIG. 63 is estimated to be about "0.0003 p-p" at maximum. On the other hand, since the transmittance of the silk sheet on the long wavelength side is as low as about 5.3%, the influence of electrical noise is large. From FIG. 62, the noise amplitude is estimated to be about "0.003 p-p" at maximum.

Therefore, in this embodiment, the conditions under which signals can be stably detected are that the absorbance of the functional biomaterial in this embodiment is within the range of 1.81 μm to 1.67 μm, or within the range of 1.23 μm to 1.12 μm, The height of the absorption band observed in the range from 94 μm to 0.84 μm (difference value between the absorbance value at the center wavelength position of the absorption band and the baseline indicated by the dashed line) is 0.003 or more (preferably 0 .0003 or more).

The composition ratio of alanine in fibroin is said to be 30%. According to FIG. 62, the height of the absorption band attributed to the first overtone of the stretching vibration at this time (difference value from the baseline) is around "0.008". Also, the height of the absorption band attributed to the second overtone (difference value from the baseline) can be read to be around "0.002".

When detecting up to a composition ratio of about 10%, the results are "0.008/3=0.0027" and "0.002/3=0.00067". Therefore, when using the data of FIG. 62, the height of the absorption band observed in the range from 1.81 μm to 1.67 μm should be 0.0027 or more (preferably 0.008 or more). Similarly, the height of the absorption band observed within the range of 1.23 μm to 1.12 μm should be 0.00067 or more (preferably 0.002 or more).

As an application example of this embodiment, consider the case of producing a functional biomaterial from spider silk. In spider silk, the composition ratio of alanine is expected to be 45% or more. Then, "0.008×45/30=0.012" and "0.002×45/30=0.003" are obtained. Therefore, for example, when a functional biomaterial is produced using spider silk as a material, the height of the absorption band observed in the range of 1.81 μm to 1.67 μm is 0.012 or more, or 1.23 μm to 1 There is also a method of controlling the process so that the height of the absorption band observed within the range of 0.12 μm is 0.003 or more.

Next, the expected maximum height of the observable absorption band attributed to the methyl group (difference value from the baseline) is examined. If a synthetic protein with an alanine composition ratio of 100% is produced, it will be "0.008×100/30=0.027" and "0.002×100/3=0.0067". However, since the height of the absorption band changes depending on the measurement error and the way the baseline is taken, if the margin is doubled, the heights of the absorption bands attributed to the first and second overtones are 0.054 and 0.0134. is estimated.

This estimate assumes 100% alanine. As shown in FIG. 66, valine, isoleucine, and leucine each have two methyl groups in one residue. Therefore, when the composition ratio of these amino acids is 100%, the above values are doubled. Therefore, in this case, the height of the absorption bands attributed to the first and second overtones (difference value between the absorbance value at the center wavelength position of the absorption band and the baseline indicated by the dashed line) is 0.108. 0.0268.

From the above (also refer to FIG. 65), the absorbance characteristics obtained from the functional biomaterial of this embodiment are summarized. The difference between the absorbance value at the central wavelength position of the absorption band observed within the wavelength range of 1.80 μm to 1.67 μm and the baseline is within the range of 0.0027 to 0.108. Also, the difference value observed within the wavelength range of 1.23 μm to 1.12 μm is within the range of 0.00067 to 0.0268.

Next, the height of the observable absorption band attributed to the methylene group is examined. The abundance of methylene groups in polyethylene is sufficiently high. Therefore, the read value of 0.003 at position (a) in FIG. 63 is close to the value of the composition ratio of 100%. If the margin due to the measurement error and the accuracy error in taking the baseline is doubled, it is estimated to be 0.006 (=0.003×2). Assuming a composition ratio of 10% or more, 0.003×10/100=0.0003. Considering this with a margin of 2x, the minimum value is estimated at 0.0003/2=0.00015.

Therefore, considering the contents of FIG. 65, the difference between the absorbance value at the center wavelength position of the absorption band observed within the wavelength range of 1.23 μm to 1.15 μm and the baseline is 0.00015 to 0.00015. It is within the range up to 006.

Instead of forming a structure using the "protein system" described above, we describe the optical properties of functional biomaterials that perform unique functions. For example, as explained with reference to FIG. 39A(c) in Section 8.3, the presence of carboxyl groups 616 in the functional biomaterial improves water absorption. Before the cation 612 is bonded to the carboxyl group 616 in FIG. 39A(c), the hydroxyl group (—OH group) in FIG. 65 exists. Thus, when the functional biomaterial has a large amount of hydroxyl group (-OH group) or amino group (Amino Group, -NHn), the hydrophilicity (Hydrophilic Characteristic) is improved.

Therefore, for example, in a functional biomaterial having hydrophilicity, as shown in FIG. The manufacturing process may be controlled so that an absorption band with a difference value) of 0.003 or more (preferably 0.0003 or more) is observed.

Section 10.5 Methods for producing functional biomaterials produced in an extracellular environment The methods for producing functional biomaterials described in Sections 10.1 and 10.2 mainly involve the production of at least materials within a given cell. explained how. As an application example of the present embodiment, a method for producing functional biomaterials in an extracellular environment will be described.

A basic fabrication procedure is shown in FIG. 67A. That is, a step S110 of producing and extracting functional biomaterials, a refining step S120 of the functional biomaterials to improve the purity of the materials, a forming step S130 of the functional biomaterials, and finally a quality inspection step S140. configured and proceeded with the above procedure.

In step S110 for generating and extracting the material of the functional biosubstance, the functional biosubstance is produced using the Continuously Exchangeable Method with Dialysis and the Centrifugal Separation Method performed in S111. Material extraction (S112) is performed. In any of these steps, the monitoring S113 using the incoherent near-infrared light shown in the present embodiment (Chapter 3) is executed in parallel. Here, it is managed so that the optical characteristics described in Sections 10.3 and 10.4 are continuously obtained.

In addition, in the purification of the material of the functional biomaterial (S120), in order to improve the purity of the material, various methods are used to separate only the material used for the functional biomaterial. As a specific example, in FIG. 67A,
1] A method of separating and extracting only protein-based materials using the principle of optical tweezers (S121)
2) A method of applying an electric field to an aqueous solution to separate and extract only charged materials (S122)
3) A method of separating with a filter such as filter paper using the difference in material size (S124)
is applied. However, it is not limited to this, and a purification method other than the above may be employed. Also, any one of the above may be selectively employed.

In the various purification steps S121 and S122 described above, the incoherent near-infrared light shown in the present embodiment (Chapter 3) may be used (S123) to monitor the progress of the purification.

A description will be given of how to deal with the case where, as a result of monitoring in S113 or S123, the characteristics within the ranges described in Sections 10.3 and 10.4 cannot be obtained. If the frequency of failure to obtain the above properties is low, the material is selected and discarded. On the other hand, if the frequency is high, the production line is temporarily stopped to investigate the cause of the problem and deal with it.

In the functional biosubstance material production/extraction step of S110 and the functional biosubstance material purification step of S120, it is also necessary to monitor the states of the produced macromolecules S113 and S123. In particular, information on the bonding state in the polymer can be obtained from A) baseline profile characteristics and B) absorption band characteristics in the wavelength range from 1.67 μm to 1.46 μm (Fig. 65), as described in Section 5.6. . . . The peak (maximum) position indicated by “White-Centered Bold Arrow of Higher Direction” in FIG. 62 appears for reference. Therefore, it is desirable to evaluate these properties at the same time for process control.

FIG. 67B(a) shows an example of a method for producing functional biomaterials using the dialysis-type continuous exchange method performed in S111 above. The external liquid 1034 put in the transparent container 1010 is
○ Various amino acids that can be used as material manufacturers ○ Sugars that are active energy sources such as glucose ○ Nucleoside triphosphates
○ tRNA (Transfer Ribonucleic Acid)
○ Other substrates for transcription and translation
○ Growth factors for transcription/translation promotion
It consists of a mixture aqueous solution such as

In addition, the internal liquid 1032 put in the dialysis container 1036 contains
○ A cell-free protein synthesis system CF (Cell-Free Protein Synthesis System) reaction solution ○ Put in a linear DNA (Single Chaining Deoxyribonucleic Acid) fragment used as a template for protein production.

E. coli, rabbit, and wheat germ cell extracts (Solution Extracted from Wheat Cells with Embryo Buds) are conventionally used as the CF reaction solution. Recently, however, in addition to conventional systems, eukaryotic cell extracts (Solution Extracted from Eucaryote Cells) have been used.

As explained in Section 10.1, it is desirable to use organism-derived cells belonging to the same hierarchy or a higher hierarchy for "Protein obtained from higher organisms". Therefore, when producing a protein-based functional biomaterial, an "extract from an organism-derived cell equivalent to or higher than the target protein-derived organism" may be used as the CF reaction solution. Thereby, the productivity of functional biomaterial production is improved. Furthermore, the use of the "extract from the cells of the target protein-derived organism" further increases the affinity between the artificial protein to be produced and the CF reaction solution. In that case, the productivity of functional biomaterial production is further improved.

For example, when chicken is artificially produced as a food material, it is desirable to use "extract from chicken cells" or "cell extract from another bird species" as the CF liquid. Similarly, when beef or pork is artificially produced, an extract from bovine cells, pig cells, or other mammalian cells may be used as the CF reaction solution.

As another example of application, consider the case of transplanting a normal muscle to a patient in the treatment of muscular atrophy. When this muscle is artificially produced, an extract from human cells may be used as the CF reaction solution.

When artificially producing a functional biomaterial using silk or spider silk, CF liquid may be extracted from the cells of silkworms, spiders, or other insect species to produce the material. In addition, the use of human- or mammal-derived cell extracts in the CF reaction solution enables the production of artificial protein materials with relatively high versatility.

A linear DNA template for protein production may be artificially synthesized according to a predesigned nucleotide sequence (Nucleotide Sequence). Not limited to that, using the genome editing technology (CRISPR / Cas9, ZFN, TALEN, etc.) described in Sections 8.1 and 8.5, after editing the existing genome sequence, open and generate a double helix structure. can be

The dialysis container 1036 containing the internal fluid 1032 is put into the container 1010 containing the external fluid 1034 (FIG. 67B(a)) to start incubation. This incubation is held at 28° C.-40° C. for no less than 1 hour and no more than 32 hours.

A stirrer 1006 is arranged in the dialysis container 1036 . Then, the external magnetic field generating/rotating portion 1038 for inducing rotation of the stirrer rotates to rotate the stirrer 1006 and stir the inside of the internal liquid 1036 .

In addition, as shown in FIG. 1B(a), the detection unit 6 for detecting the detection light 16 obtained by passing through the light source unit 2 is arranged in the container 1010, and the material production status of the functional biomaterial (S111 in FIG. 67A ) are sequentially monitored (S113 in FIG. 67A). The incubation time is not limited to 1 to 32 hours as described above, and the incubation may be appropriately terminated when the material generation is completed in the monitoring of S113.

Then, the dialysis container 1036 is extracted from the container 1010, and the internal liquid 1032 is recovered in another container. Then, the internal liquid 1032 is left at a low temperature to complete the incubation. The temperature of the internal liquid 1032 at this time is desirably within the range of 0° C. to 10° C. (preferably around 4° C.).

In the extraction of the functional biosubstance shown in S112 of FIG. 67A, for example, centrifugation is performed by rotating at about 12000 rpm at about 4° C. for 5 minutes. The material of the produced functional biosubstance is mixed in the supernatant layer (Top Clear Layer) in the separated liquid obtained here.

Also, the range from the upper end of the separation liquid to which the produced functional biomaterial material is mixed can be found by monitoring using incoherent light in S133.

Next, FIG. 67B(b) shows an example of the functional biomaterial molding method described in S130 of FIG. 67A. FIG. 67B(b) shows a method of molding a fibrous functional biomaterial such as silk thread. A molding depression 1054 is carved on the surface of the molding die 1050 . When the purified internal liquid 1032 is dripped here, it concentrates in the molding recess 1054 .

When left in a dry environment, the moisture evaporates and a fibrous functional biomaterial is obtained. For example, fibroin containing a β-sheet crystal part 602 (FIG. 38), collagen having an α-helical structure, or tropomyosin alone has a relatively short fibrous structure. Then, when the water in the purified internal liquid 1032 evaporates, the individual fibers are entangled with each other to form a large fiber structure as shown in FIG. 67B(c). Clothing and food products may then be made from this fibrous functional biomaterial using conventional methods of weaving threads into cloth.

In the forming step (S130) of FIG. 67A, the method described in Section 8.3 using FIG. 49 may be used instead of the above method. Furthermore, you may shape|mold by arbitrary methods other than these.

An example of an apparatus used in the purification step (S120) of FIG. 67A is shown in FIG. 67C. Supernatant liquid 1096 obtained by centrifugation (S112) in FIG. 67A is placed in container 1090 for purification. Gravity is then used to move the supernatant liquid 1096 to the right.

In material separation of functional biosubstances using optical pressure shown in S121 of FIG. 67A, separation is performed using the principle of optical tweezers (optical pressure). As shown in FIG. 65, the protein-based functional biomaterial selectively absorbs near-infrared light in the wavelength ranges from 1.67 μm to μ1.46 μm and from 1.11 μm to 0.99 μm. Therefore, near-infrared light in the above wavelength range is used as the purification irradiation light 1060 in FIG. 67C.

A force is generated in the direction in which the intensity of the purification illumination light 1060 is low (upward on the page in FIG. 67C) to high (downward on the page). This force is used to move only protein-based functional biomaterials downward.

As shown in FIG. 67C, the irradiation light 12 emitted from the light source unit 2 passes through the optical fiber 100 and is irradiated to the passage position of the supernatant liquid 1096 after centrifugation. The detection light 16 obtained by passing through the supernatant liquid 1096 reaches the detection section 6 via the optical fiber 100 . This optical system monitors the absorbance characteristics of the supernatant liquid 1096 in real time (S123). This result is used to manage the material separation status of the functional biosubstance from the supernatant 1096 .

Next, a method for purification using an electric field applied to the aqueous solution shown in S122 of FIG. 67A will be described. Among amino acids, arginine, histidine, and lysine have a positive charge. Then, the nucleotide sequence in the template DNA is designed so that the generated amino acid sequence contains slightly more positively charged amino acids as described above. As a result, macromolecules, which are materials for functional biomaterials, have a positive charge in aqueous solution.

Then, voltage is applied from the purification variable voltage power supply 1074 to the purification voltage application electrode 1070, and material separation of protein-based functional biomaterials (S122 in FIG. 67A) is performed. This situation is also monitored by the combination of the power supply unit 2 and the detection unit 6 (S123).

In the above embodiment, the polymer that is the material of the functional biomaterial has a positive charge in the aqueous solution. However, if anions such as chloride ions are mixed into the above-mentioned purified aqueous solution, salts are generated in the forming process and the aqueous solution becomes electrically neutral.

The aqueous solution purified in this manner proceeds in the direction of (a) in FIG. 67C and is collected downward. Further, the aqueous solution containing other components proceeds in the direction of (b) and is discarded.

In addition, for example, a functional biomaterial extraction filter 1080 using filter paper or the like is used to purify the material of the functional biomaterial by utilizing the difference in molecular size.

Here, the explanation of the production method has been focused on protein-based functional biomaterials. However, the method of FIG. 67A may be used for the production of carbohydrate-based or lipid-based functional biomaterials.

For example, glucose can be polymerized to produce starch, which is used in foodstuffs. A portion of FIG. 67A may be used in this starch manufacturing process.

Although several embodiments have been described above, these embodiments are presented as examples and are not intended to limit the scope of the invention. These novel embodiments can be implemented in various other forms, and various omissions, replacements, and modifications can be made without departing from the scope of the invention. These embodiments and modifications thereof are included in the scope and gist of the invention, and are included in the scope of the invention described in the claims and equivalents thereof.

2 light source units 4 and 6 detection unit 8 feedback unit 9 wall 10 target object 12 illumination light (first light) (Illuminating Light (First Light))
16 Detection Light (Second Light)
18 beam splitter 20 beam splitter 22 spectrometer 24 monitor camera 25 objective lens 26 collimator lens 28-1, 2 detection lens 30 measuring device 32 reference sample column 34 measurement sample column 36 transparent glass container 38 movement direction of glass container 42 Note Inlet 44 Outlet 46 Lid 48 Mirror surface 50 Tungsten filament 52 Optical narrowband bandpass filter (wavelength selective filter)
54 Wavelength-selected light electric field amplitude 56, 58 Light transmitting object 60 having fine uneven structure on one side Incident light with partial coherence 62 Short wavelength light with partial coherence 64 Optical noise reduction element or partial coherence reduction element
(Optical Noise Reduction Element or Partial Coherency Reduction Element)
66 minute light scatterer 67 tube of tungsten/halogen lamp (quartz glass)
68 long wavelength light with partial coherence 70 light source 72, 74 part of light 76 optical path length change 78, 79 combined light (mixed light)
80 Photodetector 82 Rear mirror 84 Forward emitted light 86 Imaging surface (detection surface)
88 Rear emitted light 90 Optical property changing member 92 Transmitted light sections 94-1 to 6 Transparent semicircular parallel flat plate 95 Cutting surface 96 Light transmission direction 97 Boundary line 98 of cutting surface Condensing lenses 100, 100-1, 2 Optical fiber 101 Optical characteristic changing members 102, 102-1 to 102-1 to 5 for generating a plurality of optical paths Optical synthesis (mixing) unit 104 Transparent flat plate 106 having a random fine concave-convex structure on one side Wavefront of transmitted light 107 Light emitted at different times 108 Composite light exit 110 -1, 2 Transmitted light 112 Adhesive layers 114-1 to 4 Transparent parallel plates 116-1 to 2 Transparent cylindrical parallel plates 118-1 to 3 Antireflection coating layer 120 Transmission type diffraction grating 122 Fresnel prism (blazed hologram ) (Fresnel Prism / Blazed Hologram)
124, 126 Blazed Grating
128 Blazed diffraction grating or prism 130 Pinhole or slit 132 One-dimensional line sensor 134-1, 2 Condenser lens 136 Collimator lens 142 Core Area
144 Clad Layer
200 Target specific region in the body (location of photosynthesis (mixing))
201, 206 Light passing through the first optical path 202, 207 Light passing through the second optical path 203, 208 Light passing through the third optical path 210 Optical path changing element (optical property changing member)
212 phase conversion element (optical path changing element/optical property changing member)
214 tube 216 condensing lens 218 expanding lens 220 prism 222 lenticular lens 230 micro concave lens 240 concave lens or cylindrical concave lens 250 light guide (light pipe) )
252 Front-end Boundary of Light Guide / Light Pipe
254-1, -2 Side Surface
256 Back-end Boundary of Light Guide / Light Pipe
260 Optical path of light passing through ε point 270 Optical path of light passing through ζ point 280 Light mixing regions 290-1 to -n Directive electromagnetic waves 292-1 to -n Electromagnetic wave source/receiving section/receiving section 294-1, - 2 Directional Mixed Electromagnetic Waves 296-1 to -n Magnetron Electromagnetic Wave Sources/Receivers 298-1 to -n Waveguide Antenna 300 Bundle Optical Fiber Group 302 Partial Incoherent Light Source Part 304 Partial Signal detection section 306 for incoherent reflected light Wavefront aberration characteristic detection section 308 for partially incoherent reflected light Objective lens 310 Optical path separation section 312 between irradiation light and detection light Light separation section 314 Partial incoherence Signal detection section 316 for coherent transmitted light Wavefront aberration characteristic detection section 318 for partially incoherent transmitted light Objective lens 320 Reference light generation section 322 Coherent light source section 324 Signal detection for coherent reflected light Section 326 Wavefront aberration characteristic detection section 332 for coherent reflected light Light separation section 334 Signal detection section 336 for coherent transmitted light Wavefront aberration characteristic detection section 340 for coherent transmitted light Light mixing sections 342, 344, 346, 348 light splitting section 350 wavefront aberration correction section 352 wavefront aberration coarse movement correction section 354 for irradiation light wavefront aberration fine movement correction section 356 wavefront aberration coarse movement correction section 358 for transmitted light wavefront aberration fine movement correction section 360 for transmitted light Straight light 362-1, -2 Directional electromagnetic wave generating/receiving unit 364 Electromagnetic wave generating/receiving unit rotating mechanism 366 Electromagnetic wave generating/receiving unit rotation driving unit 368 Water vapor 370, 380 Multiple scattered light 372 Caterpillar 374 Moving wheel 376 Far Infrared spectroscope 378 Infrared spectroscope 382 Heat (far infrared light)
384 Solar cell panel 386 Water source or metal deposit 388 Battery 390 Backscattered light 392 Earth surface 393 Ground state electron orbital within 6 amino acid period 394 Communication control unit 396 Antenna 398 Control system in search device 399 Excited state electron within 6 amino acid period Orbit 400 Amino acid sequence of fibroin 402-1, 2 Polymer compound 404-1, 2 Electron cloud 406-1, 2 Functional group 408 Molecular structure of polyethylene 410 Common electrode parts 414-1 to 6 Individual electrode parts 416-1 to 6 Light reflecting surfaces 418-1 to 6 Piezoelectric element 420 Common electrode portion 422 also serving as a light reflecting surface Partition plates 424-1 to 3 Transparent electrode portions 428-1 to 3 Liquid crystal layer 430 Optical path dividing portion 436 Reference beams 440 and 450 Three dimensions Transmission pattern forming portions 442, 444, 446 Two-dimensional transmission image forming layers 452, 454, 456 Two-dimensional transmission image forming layer 460 Optical path separating portion 470 Two-dimensional PSD (Position Sensitive Detector) cell arrays 472-1 to 4 PSD (Position Sensitive Detector) ) Cell 474-1~4 Mini lens 476-1~4 Focused spot (no interference)
478-1~4 Focused spots (state where interference occurs)
480 wavefront (equal phase surface)
482 Condensed spot position detector 484 for reference light Condensed spot position detector 486 for detected light Position shift amount calculator 488 between condensed spots Local wavefront tilt amount 490 Overall wavefront aberration characteristic calculator 492 Polarization Beam splitter 494-1~3 λ/4 plate (1/4 phase plate)
496-1~4 Analyzer 498-1~3 Non-polarizing beam splitter 500-1~4 Imaging camera 602 β-sheet crystal part 604 Amorphous part 612 Aspartic acid + cation 616 Carboxyl group 620 Low-molecular-weight fibroin improving molecule monomer 622 ATPase activity 624 ADP
626 ADP fixed part 630, 640 π-electron localized region (active region)
632, 634, 636, 638 Main chain region in protein 650 Luminophore region in conventional GFP 702 Diagnosis (defect cause analysis) related processing procedure 704 Treatment (defect location correction) related processing procedure 706 Treatment (correction) result evaluation/confirmation Related processing procedure 800 carrier for intranuclear transport 806 gene regulatory factor 808 genome editing module 810 genome editing basic part 812-1, 2 (phosphorylation activity) mCas (modified CRISPR-Associated System)
814 nuclease region 816-1,2 crRNA (CRISPR RNA)
817 protein for retention of replicating DNA 818 replicating DNA (vector)
819 Histone 820 Cleavage site of protease with phosphorylating activity property 822 mCas control enzyme A (kinase)
824 mCas-regulated enzyme B (inhibitor/phosphatase)
826 cell nuclear signal control enzyme 828 autophosphorylation protease (self-activation by ATP addition with built-in kinase)
830 Selective junction to cell nuclear membrane surface 832 Nuclear lamina 834 Hydrophobic region between inner and outer membrane 836 Inner membrane of carrier enclosure 838 Outer membrane of carrier enclosure 840 Outer membrane of carrier enclosure 842 Interior of carrier enclosure 846 Selected cells Junction 850 to nuclear lamina identification antibody section (cell nucleus detection section)
852-1~6 Hydrophobic regions 854-1, 2 Hydrophobic regions 856-1~8 Hydrophilic regions 858-1~6 Hydrophilic regions 860 α helix structure portion 870 Transmembrane portion 880 Nuclear lamina 888 Nuclear membrane 890 Inside the nucleus 894 Between the inner and outer membrane Hydrophobic region 896 Inner membrane of cell nuclear membrane 898 Outer membrane of cell nuclear membrane 1000 Hair matrix-related cells (parent cell/original seed or daughter cell/seed seed)
1002 Produced functional biomaterial 1004 Culture medium 1006 Stirrer 1010 Container 1020 Optical condition control device (measuring device)
1032 Internal liquid 1034 External liquid 1036 Dialysis container 1038 External magnetic field generation/rotating part for stirring machine rotation induction 1040 Fibrous protein 1050 Mold for molding 1054 Molding depression 1060 Irradiation light for purification 1070 Voltage application electrode for purification 1074 Variable voltage for purification Power supply 1080 Functional biomaterial extraction filter 1090 Purification container 1096 Supernatant liquid after centrifugation 1100a ~ Final production site of functional biomaterial 1130 Central control base 1120a ~ 1120c Distributed distribution base 1602 Improved version β sheet type Crystal part (monomer block)
1604 crystal part assembly (multimer) block 1608 final molded structure 1610 surface coat layer

A amplitude of one side of the partially coherent light a half of the fiber core radius or pinhole radius/slit width
Asp Aspartic acid C Speed of light Cl ⁻ Chloride ion d Physical level difference D Width of the light incident area in the bundle type optical fiber group (or one optical fiber) or on the condensing surface of the light that has passed through the optical characteristic changing member Amount of deviation F Focal length of collimator lens 26/detection lens 28-2 G Position of center of gravity of specific functional group Gln Glutamine Gly Glycine k Wave number L Optical fiber total length l _CL coherence length
M imaging magnification (lateral magnification) or number of beam divisions corresponding to partial decoherence m individual suffix/subscript symbols (optical path numbers) of different optical paths
N Different number of optical paths in the measuring device (number of divisions into multiple optical paths)
n Refractive index NA in transparent medium through which light passes NA NA (Numerical Apperture) value Na ⁺ sodium ion R Distance from light emitting point/scattering point to measurement point Ra Average surface roughness in phase conversion element r Pupil of collimating lens 26 Surface radius Ser Serine SF Distance from light source to optical fiber incidence area SL Distance between condenser lens and line sensor T Tube thickness of tungsten/halogen lamp Trp Tryptophan Tyr Tyrosine t Time or thickness unit of parallel plate v r ²
W: Slit width or pinhole diameter z Distance in direction of light propagation α, β Emission point on tungsten filament, scattering point in a specific area within the object or pseudo-emission point in object γ Measuring point or on tungsten filament Light-emitting point or pseudo-light-emitting point within the object ΔD Optical fiber inner core diameter Δt Time width ΔY Position shift amount on the line sensor Δλ Selected wavelength width (wavelength range)
Δν Frequency width δ Optical path difference δmax Maximum value of optical path difference ε Incidence angle of incident light into optical fiber or imaging point ζ Traveling direction tilt angle of light after passing through a transparent parallel plate or imaging point η Traveling of light Inclination angle of corner or cut surface or image forming point θ Inclination angle or diffraction angle between two planes constituting a transparent parallel plate λ ₀ Center wavelength ν Frequency ξ Inclination of propagating light in optical fiber or light guide (optical pipe) Angle ρ Emission angle in quartz glass σ Phase amount or phase amount of composite wave τ Mechanical distance of optical path in tube of tungsten/halogen lamp χ Diffraction angle coefficient for incident wavelength of diffraction grating ψ Between partially coherent beams Synthetic wave Ψ Synthetic wave of the entire partially coherent light passing through the collimating lens + positively charged region (amino acid with basic residue) in the crystal part
- Negatively charged regions (amino acids with acidic residues) within the crystallites
ι Distance between α and β points along the longitudinal direction of the tungsten/halogen lamp κ Angle of incidence on the front end face of the light guide (light pipe) μ Angle of inclination of the side face of the light guide (light pipe) φ ) internal reflection angle

Claims (18)

In a light source unit composed of a light source and an optical property changing unit,
the light emitted by the light source comprises a plurality of different wavelengths of light within a wavelength range Δλ wider than 5 nm wide, the central wavelength of which is λ ₀ ;
the optical property changing unit allows the light to pass through a first optical path or a second optical path different from each other;
The optical property changing unit changes the optical path length difference between the first optical path and the second optical path by greater than λ ₀ ² /Δλ,
A light source unit that adds the intensity of the first optical path passing light and the second optical path passing light,
A first wavelength-dependent optical noise is generated from the light passing through the first optical path, and
When the second wavelength-dependent optical noise is generated from the light passing through the second optical path,
A light source section wherein said intensity summation smoothes said wavelength dependent optical noise. a light source unit that emits a first light that includes a plurality of different wavelength lights in a wavelength range wider than 5 nm to irradiate a target;
In a measuring device comprising a detection unit capable of measuring spectral characteristics using the second light obtained from the subject,
The wavelength resolution at the time of the spectral characteristic measurement at the wavelength λ ₀ included in the measurement target range of the detection unit is Δλ,
The light source unit configures a first optical path or a second optical path using wavefront division or amplitude division,
wherein the light source section changes the optical path length difference between the first optical path and the second optical path by greater than λ ₀ ² /Δλ,
A measuring device for adding the intensity of the first optical path passing light and the second optical path passing light,
A first wavelength-dependent optical noise is generated from the light passing through the first optical path, and
When the second wavelength-dependent optical noise is generated from the light passing through the second optical path,
A measurement device wherein said intensity summation smoothes said wavelength dependent optical noise. splitting a predetermined light with a central wavelength λ ₀ containing a plurality of light with different wavelengths within a wavelength range Δλ wider than 5 nm to pass through a first optical path or a second optical path different from each other;
changing the optical path length difference between the first optical path and the second optical path by more than λ ₀ ² /Δλ ;
A combined light generation method for adding intensity of the first light passing through the optical path and the second light passing through the optical path,
A first wavelength-dependent optical noise is generated from the light passing through the first optical path, and
When the second wavelength-dependent optical noise is generated from the light passing through the second optical path,
A method for generating combined light, wherein said intensity summation smoothes said wavelength dependent optical noise. irradiating the target with a first light containing a plurality of different wavelength lights in a wavelength range wider than 5 nm;
In the optical detection method for detecting the second light obtained from the object,
A wavelength λ ₀ is included in the wavelength range Δλ in which the second light can be detected ,
dividing at least part of the optical path of the first light into a first optical path or a second optical path different from each other;
changing the optical path length difference between the first optical path and the second optical path by more than λ ₀ ² /Δλ ;
An optical detection method for adding the intensity of the light passing through the first optical path and the light passing through the second optical path,
A first wavelength-dependent optical noise is generated from the light passing through the first optical path, and
When the second wavelength-dependent optical noise is generated from the light passing through the second optical path,
An optical detection method wherein said intensity summation smoothes said wavelength dependent optical noise. irradiating the target with a first light containing a plurality of different wavelength lights in a wavelength range wider than 5 nm;
In the imaging method for imaging using the second light obtained from the object,
a wavelength λ ₀ is included within the detectable wavelength range Δλ for utilizing the second light ;
wavefront splitting using angle splitting for at least part of the optical path of the first light to form a first optical path or a second optical path different from each other;
changing the optical path length difference between the first optical path and the second optical path by more than λ ₀ ² /Δλ ;
An imaging method for adding the intensity of the light passing through the first optical path and the light passing through the second optical path,
A first wavelength-dependent optical noise is generated from the light passing through the first optical path, and
When the second wavelength-dependent optical noise is generated from the light passing through the second optical path,
An imaging method wherein said intensity summation smoothes said wavelength dependent optical noise. In an optical property changing unit composed of an optical property changing unit for generating multiple optical paths and a light combining unit,
The optical characteristic changing unit for generating a plurality of optical _paths is set to the first optical path or the second split into optical paths of
The multiple optical path generation optical characteristic changing unit changes the optical path length difference between the first optical path and the second optical path by more than λ ₀ ² /Δλ ,
wherein the light combining unit is an optical characteristic changing unit that adds the intensity of the light passing through the first optical path and the light passing through the second optical path,
A first wavelength-dependent optical noise is generated from the light passing through the first optical path, and
When the second wavelength-dependent optical noise is generated from the light passing through the second optical path,
An optical property modifier wherein said intensity summation smoothes said wavelength dependent optical noise. 4. The synthetic light generation method according to claim 3, wherein the predetermined light is obtained from a panchromatic light source or a white light source. 5. The optical detection method of claim 4, wherein the first light is obtained from a panchromatic light source or a white light source. 8. The method of claim 7, wherein said light source comprises a filament. 4. The method of claim 3, wherein the intensity-added light corresponds to partially coherent light. 11. The combined light generation method according to claim 3, 7, or 10, wherein the phase of at least one of the light passing through the first optical path and the light passing through the second optical path is converted. converting the phase of at least one of the light passing through the first optical path and the light passing through the second optical path;
11. The synthetic light generation method according to claim 9, wherein the average value of the phase difference generated by converting the phase is 1/6 or more of the central wavelength _λ0 . In the division of the predetermined light,
13. The method of claim 3 or 12, wherein wavefront splitting is performed using at least one of angular splitting and radial splitting. 5. The optical detection method of claim 4, wherein said first light corresponds to partially coherent light. 15. The optical detection method according to claim 4, 8, or 14, wherein the second light is used to detect the spectral characteristics of the object. 16. The optical detection method according to claim 4 , 8, 14, or 15 , wherein phase conversion is performed in the optical path of the first light to the object. 17. The optical detection method according to claim 16 , wherein the average value of the phase difference generated after the phase conversion is 1/6 or more of the wavelength _λ0 . In the method for forming the first optical path or the second optical path,
17. An optical detection method according to claim 4, 15 or 16 , wherein wavefront splitting is performed using at least one of angular splitting and radial splitting.

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