TWI673497B - Monitor for monitoring organisms, control method thereof and health management system - Google Patents

Abstract

A monitor (10) for monitoring the internal state of a living body from the surface of the living body is provided. The monitor (10) has: a probe (23), which contains an observation window (21) and is worn on the surface of a living body (2); a unit (25), which accesses the access via the observation window (21) At least a part of the observation area (3) on the surface of the living body (2) is irradiated with laser light; a unit (27) detects from each observation point of the plurality of observation points dispersed in a two-dimensional manner in the observation area (3), The scattered light 28 caused by laser irradiation; the Doppler analysis unit (51) and the SORS analysis unit (52) are based on the scattered light 28 obtained from a plurality of observation points, and from among the plurality of observation points, it is determined that A first observation point to obtain scattered light containing information on a target portion inside a living body; and a CARS analysis unit (53) to obtain a spectroscopic spectrum of at least one component from the first observation point or observation points around it, The first information indicating the internal state of the living body is output according to its intensity.

Description

Monitor for monitoring living body, control method thereof and health management system

The present invention relates to a monitor for monitoring the internal state of a living body, and a system for giving biologically active substances based on information from the monitor.

Japanese Patent Application Laid-Open No. 2007-192831 discloses a diagnostic kit that can avoid the necessity of performing an invasive test on the measurement of blood glucose regulation or the use of blood support indicators. This diagnostic kit contains a predetermined amount of blood glucose and exhalation collection containers with an additional ¹³ C. It is a diagnostic set for controlling blood glucose in a subject. In one embodiment, it includes a plurality of exhalation collection containers. In another embodiment, it is used for diagnosing diabetes, and in another embodiment, it is used for diagnosing insulin resistance.

[Advanced technical literature] [Patent Literature] [Patent Document 1]

JP 2007-192831

Breath analysis is not invasive, but it is difficult to continuously monitor the state of the organism.

One aspect of the present invention is a monitor for monitoring the internal state of a living body from the surface of the living body. The monitor has: a probe that contains an observation window and is worn on the surface of a living body; a unit that irradiates a laser on at least a part of an observation area on the surface of the biological body accessed through the observation window; a unit, It detects scattered light due to laser irradiation from a plurality of observation points formed intermittently in the observation area as a two-dimensional dispersion or scanning the observation area continuously formed; a unit, which is based on a plurality of observation points The scattered light obtained at the observation point defines, from among the plurality of observation points, a first observation point which is judged to obtain scattered light containing information on a target portion inside the organism; and a unit which is at the first observation point or Observation points around it obtain a spectroscopic spectrum of at least one component, and output first information indicating the internal state of the organism according to its intensity.

Preferably, the monitor has a unit which is located at or around the first observation point, and obtains the spectral spectrum of the first component of a plurality of parts at different depths from the surface of the living body, and the intensity of the spectral spectrum of the first component , And then limit or update the first observation point.

Another aspect of the present invention is a control method of a system including a monitor for monitoring the internal state of a living body from the surface of the living body. The monitor includes: a probe, which sets a plurality of observation points in a two-dimensional dispersion on the surface of the living body at a first interval; a unit, which irradiates the surface of the living body with laser light, and scans each observation point of the plurality of observation points Output scattered light; and a unit which Detecting scattered light from a plurality of observation points, the control method includes the following steps.

1. Obtain scattered light from the observation points of each observation point of the plurality of observation points, and use the laser Doppler effect to obtain the first observation point associated with the subcutaneous blood vessel from the plurality of observation points.

2. At or around the first observation point, obtain the spectroscopic spectrum of the first component of a plurality of sections at different depths from the surface of the biological body, and determine the target portion under the surface of the biological body based on the intensity of the spectral component of the first component. .

3. The first information indicating the internal state of the organism is output according to the intensity of the spectral spectrum of at least one component of the target portion.

Ideally, this control method further includes the following steps.

4. At or around the first observation point, obtain the spectroscopic spectrum of the first component of a plurality of parts at different depths from the surface of the living body. Based on the intensity of the spectroscopic spectrum of the first component, define or update the first observation point.

Using near-infrared spectroscopy, Raman spectroscopy, and other spectroscopic analysis techniques can analyze compounds or subcutaneous tissues that are present in bodily fluids such as blood, and can analyze biochemicals and cell components in bodily fluids based on the analysis results. Therefore, biological information should be obtained by spectroscopic analysis. However, the concentration of biochemical substances and cell components in each part of the organism are different. Therefore, the obtained information includes information of various structures under the surface of the organism, so that the target information is buried by other information or noise, and it is difficult to estimate the state of the organism.

Regarding the above-mentioned monitor and control method, a plurality of observations are set in an observation area on a surface of a living body accessible through an observation window of a probe. point. Then, instead of using all the data of the plurality of observation points, a limited unit is used to lock and obtain a spectroscopic spectrum at a part of the plurality of observation points, and the first information representing the internal information of the organism is output based on the data. Therefore, it is possible to selectively obtain information related to a limited portion below the surface of a living body, so that the target information can be suppressed from being covered by other information or noise.

1‧‧‧ system

2‧‧‧ surface (skin)

3‧‧‧ observation area

5,5a‧‧‧ observation point (the first observation point)

7‧‧‧ organism (human body)

8‧‧‧ microvascular

10‧‧‧Monitor

11‧‧‧Raman spectroscopic analysis unit

20‧‧‧ Optical Engine

21‧‧‧observation window

23‧‧‧ Probe

23a‧‧‧output unit

23b‧‧‧input unit

25‧‧‧Unit

25‧‧‧laser irradiation unit (primary optics)

25a‧‧‧First light path

25b‧‧‧ 2nd optical path

27‧‧‧Unit

27‧‧‧detection unit (secondary optics)

27a‧‧‧Light Path

28‧‧‧ scattered light (secondary light)

30‧‧‧laser engine

31‧‧‧Stokes Light

32‧‧‧Pu Guang

40‧‧‧ Detector

45‧‧‧ diffuse porous membrane

50‧‧‧Signal Processing Engine

51‧‧‧laser Doppler analysis unit

51‧‧‧ Doppler Analysis Unit

52‧‧‧SORS analysis unit

53‧‧‧CARS analysis unit

54‧‧‧3D profile unit (3D profiler)

55‧‧‧Memory

56‧‧‧Biological information generating unit

57‧‧‧Three-dimensional section

58‧‧‧The first information

58‧‧‧ Information

59‧‧‧Biological Information

P‧‧‧Polarizer

HWP‧‧‧Half Wave Plate

QWP‧‧‧1 / 4 wave plate

BC‧‧‧Two-way beam coupler

L‧‧‧ lens

[Figure 1] A block diagram showing a health management system.

[Fig. 2] A block diagram showing a monitor.

[Fig. 3] A diagram showing observation areas and observation points.

[Fig. 4] A diagram showing a Raman spectroscopic spectrum.

[Fig. 5] A block diagram showing an event recognition module.

Fig. 6 is a graph showing changes in blood glucose.

[FIG. 7] A flowchart showing the operation of the health management system.

In the following, an event in which subcutaneous microvessels are used as a target portion, and information including components that circulate in the blood vessel, such as the amount of blood glucose, is obtained by acquiring its spectroscopic spectrum will be described as an example.

In the monitor of the present invention, a plurality of observation points are set in an observation area on the surface of a living body accessible through the observation window of the probe. The limiting unit is: first, based on the scattered light obtained from a plurality of observation points, restrict or lock the observation points within the organism that should obtain the information of the target portion It is designated as the first observation point. If the target portion is a microvessel inside a living body, the spectrum of the laser Doppler effect contained in the scattered light can be focused on, and locked to the first observation point depending on whether it is an observation point for observing blood flow. The target part is not limited to microvessels. For example, if it is a lymph gland, the spectrum of the component detected with the maximum intensity when the component contained in the lymph gland is analyzed spectroscopically is determined based on whether it is an observation point for observing its component. Locked to the first observation point.

When the unit to be limited is locked to the first observation point, it is not only a quadratic element profile, but also a cubic element cross section including a depth direction cross-section. In the case of microvessels, a mathematical model can be used to obtain a profile in the depth direction from the blood flow components contained in the laser Doppler effect. For Raman spectroscopy, Spatially Offset Raman Spectroscopy (SORS) can be used.

The first observation point for observing the blood flow of the microvessels is located on or near the microvessels. The unit for outputting the first information that becomes the biological information is to lock the first observation point or the observation points around it, obtain a spectral spectrum of at least one component, and output the first information indicating the internal state of the organism according to its intensity. .

In this monitor, set at or around the first observation point to obtain the spectroscopic spectrum of the first component of a plurality of parts at different depths from the surface of the living body. Based on the intensity of the spectroscopic spectrum of the first component, the first The unit of 1 observation point is valid. The spectrum of a plurality of sections at different depths from the surface of the living body is obtained by a spectroscopic method, and the intensity of the first component contained in the spectrum can be used to determine whether it is the spectrum of the target section. For example, when you want to detect the concentration of biochemicals in blood vessels, in the case of humans, the surface of a living body The vicinity of is formed by the skin (epidermis), dermis, and subcutaneous tissue that forms the surface, and most of the blood vessels exist in the dermis or subcutaneous tissue. However, the distance from the surface to the blood vessel varies from site to site, from patient to patient, and may vary depending on the posture at the time.

With regard to this monitor, it is possible to determine the spectrum of blood by judging the most intense spectrum of the most components present in blood among the spectra of different depths. Then, by determining the intensity of one or a plurality of components contained in the blood spectrum, the first information indicating the internal state of the living body based on the concentration in the blood can be output. The target part is not limited to blood vessels, but may be subcutaneous fat or lymph nodes, and the first information representing the internal state of the organism may also be generated according to the composition of a plurality of target parts of different depths. Typical values for clinical biochemical analysis that can be obtained from blood spectra are fasting blood glucose (cholesterol), blood glucose (glucose), HbA1c, glycated hemoglobin, transglutamin (AST), and serum Transamine (ALT), triglycerol, binding protein (G-GTP), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), adiponectin (ADIPONECTIN), etc.

One of the spectroscopic analysis methods whose depth can be easily adjusted is confocal Raman analysis. By using one or more confocal Raman analysis units, it is also possible to obtain three-dimensional information of the components or cells present in the target portion. The incident light used for spectroscopic analysis can also be LED or other wide band, but laser light with narrow band is ideal. When a tunable laser with a switchable wavelength is used as the light source, the depth adjustment becomes easy. Furthermore, by using resonance Raman spectroscopy, a more accurate spectrum of the target portion can be obtained.

Another method of spectroscopic analysis that can produce a profile in the depth direction One is spatially shifted Raman spectroscopy (SORS). In addition, as for a method capable of generating a depth profile with high accuracy, the present inventors advocate using a Coherent Anti-stokes Raman Spectroscopy (SCattering) method by controlling The angle of illumination of the pump light or the Stokes light to obtain a spatially offset CARS spectrum.

The plurality of observation points can also be set by selectively irradiating the laser on the plurality of observation points, and it is also possible to selectively obtain scattered light from each observation point of the plurality of observation points. Therefore, the probe may also include an output unit that selectively guides the laser from the unit that is irradiated to each of the plurality of points. The probe may also include an input unit that directs scattered light from each observation point of the plurality of observation points to a detection unit. An example of the output unit and the input unit is a mirror (MD, Micro-mirror Device) formed by a MEMS or a micromechanical. Within the observation area, one or a plurality of laser points can be formed intermittently or continuously, and a plurality of observation points can be formed.

Other examples of the output unit and the input unit are multi-focus optical members such as photonic crystal fiber (PCF), micro-structured fiber, holey fiber, and bundle fiber, and A shutter matrix formed by MEMS or micromechanics, or a combination with MD. In the observation area, one or a plurality of points can be formed intermittently, and a plurality of observation points can be formed.

Preferably, the output unit and the input unit can set a plurality of observation points at an interval of 1 to 1000 μm in the observation area. It is more preferable that the plurality of observation points can be set at an interval of 10 to 100 μm in the observation area. The average size of the subcutaneous tissue ranges from several μm to several 10 μm. Resolution of 100 μm or less.

Preferably, the probe is closely attached to the skin. It can also be installed on the skin through fluids such as colloids. However, considering the convenience and wearability of the user, it is ideal to closely attach the observation window to the surface of the living body through a diffusing porous membrane. An example of a diffusive porous film is a PDMS (polydimethylsiloxane) and a thin film made of mixed silicon.

By combining this monitor with a distribution unit that imparts a biologically active substance to a living body based on the first information obtained from the monitor, a drug delivery system can be provided. This system is used in patient treatment, health status management, home rehabilitation, etc. A biologically active substance is a substance or a group of chemical substances, which is a biological substance or a synthetic substance, whether it is a biological substance or a synthetic substance. Bioactive substances include vitamins, minerals, enzymes, hormones, etc. One example of a hormone is insulin.

Ideally, this system has an action monitoring unit that obtains or predicts the external state of the organism. Preferably, the system has a unit for controlling the amount or type of biologically active substance to be given to the organism from the distribution unit based on the information (second information) from the mobile monitoring unit in addition to the first information. By predicting the patient's living conditions in the near future from the patient's living pace and action patterns, and predicting future changes in the living body from actual meals and exercise, the current living body conditions can be controlled in advance to be given to them Type or amount of biologically active substance. Therefore, the type and amount of biologically active substances can be controlled so that the patient's condition is in a state consistent with his actions.

Furthermore, it is preferable that the system includes a unit that outputs the operation status of the first information and delivery unit to the outside. Through this system, the physician or The caregiver can monitor the patient remotely.

The control method of the system including the above-mentioned monitor described in this manual can be recorded on a suitable recording medium as a program or a program product or provided through the Internet. In addition, the control method of this system can also be provided by a method including monitoring the internal state of a living body from the surface of the living body by spectrometry. This method can also be provided by a method of treating a patient, a method of managing a user's health status, and a method of preventing seizures.

Preferably, when the system is a distribution unit having a biologically active substance to the organism, the control method includes a step of selecting the biologically active substance and the amount to be distributed by the distribution unit based on the first information.

Ideally, in the case where the system is an action monitoring unit that obtains or predicts the external state of the organism, the selection step includes the use of external state information in addition to the first information to select the biologically active substance to be distributed by the distribution unit. Amount or kind.

FIG. 1 is a block diagram showing a schematic configuration of a non-invasive health / vital control platform (control or adjustment system). This system 1 includes: a sensor platform 10; an analysis engine 120; a medicine delivery unit 130; and an event tracking unit 140. In addition, the following will take as an example a system 1 that maintains the life of a diabetic patient, and enables the patient to lead a healthy and active life, and manages the patient's health as an example. For diabetes.

The sensor platform (monitor) 10 is for a diabetic patient to continuously monitor the amount of blood glucose in a non-invasive manner. Sensor platform An example of 10 is a FTIR-Raman spectroscopic analysis unit with a switchable wavelength type. The sensors mounted on the sensor platform 10 are not necessarily one type, and may be a plurality of types, and may also include a plurality of sensors of the same type. For example, it may be any one of an infrared spectroscopic analysis device, a near-infrared spectroscopic analysis device, a mass analysis device, an ion mobility sensor, or a plurality of types of sensors that are commonly worn on the surface of a living body. Installers are scattered on the surface of the living body.

The sensor included in the monitor 10 is based on technologies such as MEMS, and is compact and lightweight to the extent that it is not easy to cause obstacles to life or activities when mounted on a human body or a living body. Long-time operation with a lightweight battery pack. The power source can be a small battery pack, or it can generate electricity from external energy sources such as solar cells, or it can also generate electricity based on body temperature, other biological reactions, or even biological activities. Of combination.

The monitor 10 is required to have high accuracy and have an automatic correction function. The automatic correction function includes a function of automatically discovering a measurement target portion inside the organism from the surface of the organism, and automatically tracing or rediscovering information from the target portion regardless of the activity of the organism.

The ideal information (biological information) 150 for measuring diabetic patients using the monitor 10 is related to blood glucose concentration, glycated hemoglobin concentration (HbA1c concentration), glycated albumin concentration, blood pressure, blood oxygen level, and cancer indicators. And other elements related to health and life support.

FIG. 2 shows a Raman spectroscopic analysis unit 11 as an example of the monitor 10. This unit 11 includes an optical engine 20, a tunable laser engine 30, a detector 40, and a signal processing engine 50, all of which are chipped and formed into other components. It can be worn on the surface (skin) 2 of the living body (human body) 7 in a laminated state.

The optical engine 20 includes a probe 23 containing an observation window 21, which is a MEMS optical chip and is worn on the skin 2; and a unit 25, which irradiates at least a part of the observation area 3 of the skin 2 accessed through the observation window 21 Laser; unit 27 detects scattered light due to laser irradiation from each observation point of a plurality of observation points formed intermittently like a two-dimensional dispersion in the observation area 3 or continuously like a scanning observation area.

The laser irradiation unit (primary optical system) 25 includes a first optical path 25a corresponding to the CARS and guiding a Stokes light 31 having an angular frequency ω s obtained from the tunable laser engine 30; a second optical path 25b, The pump light 32 is guided at an angular frequency ω p. The first optical path 25a and the second optical path 25b include a polarizing plate P, a half-wavelength plate HWP, and a quarter-wavelength plate QWP. The laser irradiation unit 25 combines the Stokes light 31 and the pump light 32 by a dichroic beam coupler BC, and then irradiates the laser light to the observation area 3 through the probe 23.

The laser engine 30 is a wafer-type laser chip or LED unit that outputs a plurality of wavelengths of laser light. As the laser engine capable of changing wavelengths, a Littrow laser engine, a Littman laser engine, or the like can be used. The laser engine 30 is preferably one capable of supplying Stokes light 31 having a switchable wavelength and pump light 32 having a switchable wavelength. An example of the wavelength range of the Stokes light 31 is 1000 to 1100 nm, and more preferably 900 to 1450 nm. An example of the wavelength range of the pump light 32 is 700 to 800 nm. The laser engine 30 may also use a combination of a plurality of light source units to generate laser light in these wavelength ranges.

The detection unit (secondary optics) 27 includes: a beam separator BS, which separates anti-Stokes light at an angular frequency ω as supplied by the probe 23; an optical path 27a, which will be observed from The scattered light (secondary light) 28 obtained from the plurality of observation points in the area 3 formed in a two-dimensional dispersion manner is supplied to the photodetector 40. The detection unit 27 may also include a lens L, a laser blocking filter, a diffraction grating, and the like for focusing the scattered light 28 on the detector 40. The detection unit 27 may also include different types of detectors, such as a scattered mirror 28 that divides the scattered light 28 and supplies it to the CCD and the photodiode.

The photodetector 40 may also be a sensor having a two-dimensional arrangement of detection elements such as a CCD or a CMOS. The photodetector 40 may also be a photodiode, which is suitable for an InGaAs photodiode with fast response speed, low noise, and excellent frequency characteristics. In particular, when the probe 23 has a high-resolution selection function with an observation point, the light-detector 40 side does not need to have an observation point selection function or a low-resolution selection function. Therefore, the detector 40 can be applied to a photodiode and can output a signal with low noise.

The probe 23 includes an output unit 23a that forms a plurality of observation points in an observation area 3 accessible via an observation window 23 (21) , and an input unit 23b that can selectively obtain scattered light 28 from the plurality of observation points. The output unit 23a of this probe 23 uses an MD unit with a MEMS-type polygon mirror, and the input unit 23b uses a combination of an MD unit and a multi-fiber, so that it can be selectively obtained without interference from a plurality of observation points. Scattered light 28.

FIG. 3 shows a state where a plurality of observation points 5 are set in the observation area 3. In this example, it is in the observation area 3 of 600μm × 600μm, The μm interval is set to 12 × 12 observation points 5. The size of the observation area 3, the interval, and the number of observation points 5 are examples and are not limited thereto. The observation points 5 may not be constant intervals, or may be set continuously using an MD unit. The position of each observation point 5 is expected to have high reproducibility. Further, it is preferable that the interval between the observation points 5 is a person who can sufficiently detect the size of the microvessels 8 which is a detection target having a diameter of several μm to several 10 μm, and selectively obtain information of the microvessels 8. Therefore, the interval between the observation points 5 is preferably about 1 to 1000 μm, and more preferably about 10 to 100 μm.

The optical engine 20 may be a person having a function as a 3D confocal Raman microscope.

The signal processing engine 50 that controls the optical engine 20 includes: a laser Doppler analysis unit 51; a SORS analysis unit 52; a CARS analysis unit 53; a 3D profile unit (3D profiler) 54; a memory 55; and Biological information generating unit 56. The Doppler analysis unit 51 and the SORS analysis unit 52 are based on the scattered light 28 obtained from the plurality of observation points 5, and it is determined from the plurality of observation points 5 to obtain an internal target including the belonging organism 7 The unit of the first observation point 5a of the scattered light 28 of the information of the partial microvessels 8 functions.

The 3D profile survey system 54 is based on the output of the laser Doppler analysis unit 51 and the SORS analysis unit 52, and locks the first observation point 5a covering the microvessel 8 with a second element to form a depth direction corresponding to the first observation point 5a. Profile. Thereby, a three-dimensional cross section 57 of the microvessel 8 related to the observation area 3 is formed and accumulated in the memory 55. The three-dimensional section 57 of the microvessel 8 is not limited to one. Also, every time the probe is replaced, the three-dimensional section 57 will not Same, and after wearing time, there will be different situations due to changes in posture.

The CARS analysis unit 53 functions as a unit that obtains a spectral spectrum of at least one component from the first observation point 5a and / or surrounding observation points, and outputs the first information 58 indicating the internal state of the living body 7 according to its intensity. Further, the CARS analysis unit 53 obtains the spectroscopic spectrum of the first component of a plurality of parts at different depths from the surface 2 of the living body at the first observation point 5a and / or its surroundings, and the intensity of the spectroscopic spectrum of the first component is used as the basis. , The unit that verifies the first observation point 5a and re-limits or updates as necessary to perform its function.

The biological information generating unit 56 generates and outputs biological information 59 containing information 58 obtained from the CARS analysis unit 53.

The CARS analysis unit 53 of this example is provided with a function as a SORS, and irradiates one of the Stokes light 31 and the pump light 32, for example, the Stokes light 31 to any one of the first observation points 5a, Any angle of the DM of the output unit 23a is controlled so that the Stokes light 31 is irradiated with the pump light 32 at different angles. The scattered light 28 of the laser light is obtained by using the input unit 23b having excellent position selectivity (resolution) at the observation point 5 whose position is shifted from the incident position of the laser light. Thereby, CARS spectra of structures from positions in different depth directions can be obtained.

In the case where the laser engine 30 is a confocal Raman Spectrometer, the focal position of the laser can also be changed in the depth direction. Therefore, a 3D Raman spectrum of the inside of the organism, that is, the subcutaneous tissue, can be obtained from the surface of the organism (skin surface) 2.

If Raman spectra of blood flowing in a blood vessel are included in Raman spectra having different depth directions, the 3D section 57 obtained in advance can be verified. Whether the blood is a Raman spectrum can be determined by selecting the Raman spectral component (spectral peak) of the component that has the highest concentration in the blood or the lowest concentration in the blood. For example, compared with the subcutaneous tissue and the dermis, the blood glucose in the blood vessel is the highest. Analyzing the CARS spectrum or the 3D Raman spectrum according to the blood glucose concentration can determine the position of the blood vessel. Instead of blood glucose, or in addition to blood glucose, pay attention to the Raman spectrum of blood vessels (white blood cells, red blood cells) containing hematocrit or albumin and other components mainly contained in blood vessels to determine the position of blood vessels.

If the position of the blood vessel (vessel depth) can be determined, the Raman spectrum at that position is a reflection of blood components. From the Raman spectrum with a clear position, the other contained in the blood can be obtained immediately or continuously at the minimum sampling time interval. Component concentration, for example, blood component information such as glycated red blood cell concentration (blood component information, internal body information, first information). The distance (depth) and position (angle) of the monitor (sensor platform) 10 and the microvessel 8 mounted on the surface of the living body will change depending on the posture or activity of the human body. Therefore, it is desirable to periodically and repeatedly perform the process of finding the position of a blood vessel.

Figure 4 shows a comparison of the Raman spectrum (dashed line) of blood glucose with the Raman spectrum (solid line) obtained from bovine blood. The Raman shift of blood glucose is expressed around 400cm ^-1 and 1100cm ^-1 . It is also observed in bovine blood. Therefore, it was understood that the blood glucose concentration can be measured by Raman spectroscopy. The spectrum shown in FIG. 4 is spontaneous Raman scattering.

Preferably, when the probe 23 is mounted on the surface (skin) 2 of the living body, the observation window 21 is closely adhered to the surface of the living body as much as possible without gaps. There is no moisture between skin 2 and skin 2 as much as possible. Even if there are gaps or moisture, the laser power can still be measured by adjusting the laser power, but it is ideal to obtain information with high accuracy, and to eliminate it as much as possible.

In this example, the probe 23 is closely adhered to the skin 2 via a diffusing porous film 45. Moisture (sweat) exists with skin respiration, but it prevents the acquisition of a Raman spectrum containing information inside the organism, but a diffusive porous membrane (permeable membrane) 45 is provided between the probe 23 and the probe. Between the skin 2, moisture can be continuously discharged to the outside. Since the laser light 31 and 32 and the scattered light 28 penetrate the diffusive porous film 45, they hardly affect the above-mentioned observation. In addition, since the diffusive porous film 45 has elasticity, it is possible to prevent a gap between the probe 23 and the skin 2 even if a person moves. The diffusive porous film 45 may be attached to the probe side or the skin side. Examples of the diffusive porous film 45 include PDMS (polydimethylsiloxane), mixed silicon, and the like.

PDMS is a kind of polymer membrane material with large distance between polymer chains and high gas permeability coefficient. Therefore, it has been reported that PDMS has the function of a fine-diameter porous membrane, is hydrophobic, has high affinity for organic liquids, and has excellent selective permeability. Hybrid silicon based silica-based microporous organic-inorganic composite film, with an average pore diameter of 0.1 to 0.6 nm, stable in hot water at least up to 200 ° C in several media, can be used for short Manufactured by sol-gel treatment of chain bridge silanes. It has been reported that mixed silicon is suitable for gas separation and separation of water and other small molecular compounds from various organic compounds such as low molecular weight ethanol. In addition, it has high heat resistance to PDMS and is suitable for applications at high temperatures, such as concentration applications such as low temperature accumulation and high temperature release. The diffusive porous film 45 is not limited to these. It can also be changed Instead of the diffusive porous membrane 45, a semi-fluid such as colloid or the like having equivalent functions is used.

The monitor 10, which belongs to the sensor platform, can also replace the Raman spectroscopic sensor 11 or in addition to the Raman spectroscopic sensor 11, and an ion mobility sensor for analyzing the components of skin respiration can also be mounted. (IMS) or mass analysis sensor (MS). Moreover, if it is a distributed sensor platform 10, an ion mobility sensor and a mass analysis sensor for breath analysis may be mounted near or in the nostril. Information from multiple sensors in a distributed configuration can be collected wirelessly or wiredly.

Returning to FIG. 1, the analysis engine 120 analyzes the internal information of the organism obtained through the monitor (sensor platform) 10 together with the external information of the organism obtained in the event tracking unit 140, and uses the drug delivery unit 130 to analyze the biological information. The active substance is injected into a living body (human body).

The drug delivery unit (distribution unit) 130 is ideal because it is automated, non-invasive, and has a plurality of drug injection channels (channels) and can be simply worn or attached to a living body (human body) 7. One example is the use of non-invasive insulin pumps or syringes using MEMS ultrasound, field effect transistors, and nanojets. One example of the prescription 152 for diabetics is basal insulin and bolus insulin.

The drug delivery unit 130 may also be mounted on the surface of the human body side by side with the monitor 10. The biologically active substance injected into the human body by the drug delivery unit 130 may affect the internal information of the living body obtained through the monitor 10 before the human body absorbs or diffuses it as intended. In this case, the drug delivery unit 130 is worn away from the monitor 10, for example, on the opposite side of the human body. Drug Transmission The information path between the sending unit 130, the analysis engine 120, and the monitor 10 may be wired or wireless, and furthermore, it may be directly or indirectly connected through a computer network.

The event tracking unit 140, which provides external information of the living body to the analysis engine 120, can also be worn on the human body, it can also be used to observe the movement of the human body from the outside, and it can also be included in the server that manages the patient's schedule. May be a combination of these. The event tracking unit 140 typically has a sensor or a sensor group that can be worn on the body. The event tracking unit 140 includes determining whether a patient has a meal or a meal by using information obtained from an image sensor or the like, or determining a patient's action by using information obtained from an acceleration sensor, or the like Exercise, or work, or sleep or rest.

The event tracking unit 140 may be provided with sensors for obtaining the body temperature of the patient, the humidity of the skin surface, the temperature, humidity, wind volume, wind direction, and air pressure outside the patient. Ideally, the event tracking unit 140 is more capable of learning the movements of past patients and predicting the near future, for example, the movements of patients after an hour, 30 minutes, or minutes, such as eating, exercising (training), Functions (learning functions) for daily business, bedtime, and rest.

The analysis engine 120 has a function as a control unit of the system 1. The analysis engine 120 further includes: based on the external information of the organism obtained from the event tracking unit 140, the function of anticipating an event that will happen dynamically in the patient itself or around the patient in the future (event predictive function); consider the ordinary (daily, static ) The function of the occurrence of the event (static event analysis function); and the event recognition module 60.

The analysis engine 120 further includes: in addition to the internal information of the human body obtained from the sensor platform 10, the external information of the human body including the predicted event is also considered to determine and control the bioactive substance injected from the drug delivery unit 130, such as The function of the types and amounts of hormones such as insulin, prescription drugs, minerals, and nutrients (estimated dose function). The analysis engine 120 further includes a function for determining the type and amount of a biologically active substance, a function for obtaining prescription contents, a body size characteristic, and a body parameter of a case (a body parameter monitoring function) and a correction function (for example, from a database). Check function).

The dose estimation function for determining the type and amount of biologically active substances to be injected or supplied to the human body includes: a closed-loop function that determines the type and amount based on the internal information of the organism; based on the output of the closed-loop function based on The predictive function containing external information of the organism is added to the modified open-loop function.

FIG. 5 shows an outline of the event recognition module 60. The event recognition module 60 may be provided by the analysis engine 120 or may be provided by the event tracking unit 140. The event recognition module 60 uses event prediction information 62 to process real-time GCM (Continuous Glucose Monitoring) information 61 obtained from the monitor 10 to generate event recognition 63 for controlling the dosing (drug delivery) unit 130. . The event prediction information 62 is generated based on the information 65 of meals and foods obtained by the event tracking unit 140 and the like, information 66 for exercise or daily life (daily business), and information 67 during bedtime.

The analysis engine 120 further has a function of determining the type and amount of the biologically active substance by a third person using an application provided by the online store 154 or the like 68. An example of an application provided by the online store 154 is, diabetes Programs for patients, programs for diet management, programs for palpitations, programs for stress monitoring, programs for lifestyle management, programs for preventive diagnosis, programs suitable for diagnosis. Regarding the diseases that can be judged by the sensor platform 10 and treated according to the bioactive substance or urgently treated, myocardial infarction, cerebral infarction, liver dysfunction, renal dysfunction, hyperlipidemia, etc. can be mentioned.

The analysis engine 120 further includes a function 69 for information exchange with the cloud service 156. Cloud service 156 includes the services of online monitoring of patients by doctors or caregivers, and even family members, and includes online monitoring, rewriting events to determine the type or amount of medicine to be administered, the function of generating an event database, and the function of Monitoring services.

The analysis engine 120 may also be implemented using a computer resource including a CPU and a memory, may be an LSI or an ASIC, and may also be implemented using a chip capable of reconfiguring a circuit.

Fig. 6 shows an example of changes in blood glucose. The solid line shows how the blood glucose was checked and insulin was given. In the case where the blood glucose concentration in the blood is measured using a puncture-type sensor, a measurement lag may be used. Therefore, since the insulin supply 77 is too late, too early, and the amount of insulin is too much or too little, there may be a case where the blood sugar amount 76 may become a hyperglycemic state 78 or a hypoglycemic state 79. The worst cases are irreversible damage to the human body or death. In order to avoid this, it is necessary for patients with diabetes to prevent conditions that are prone to changes in blood glucose levels, and it is necessary to carry out various restricted lives such as avoiding strenuous exercise and regular meals and intake of a predetermined amount of calories.

In this regard, in the health management system 1 of this example, The sight device 10 continuously and immediately measures the blood glucose in the blood. Therefore, it is possible to finely control the insulin supply amount with respect to the continuously measured blood glucose concentration. Furthermore, the event recognition module 60 detects the occurrence of events such as sports or meals (patient's activities), and then uses the daily schedule or the output of various sensors to predict the patient's activities. The analysis engine 120 determines the type and amount of insulin to be supplied in a manner corresponding to the predicted state. Therefore, the blood glucose concentration in the blood can be controlled within a narrow range 75 that has little health impact. Therefore, even a diabetic can exercise and eat like a healthy person.

FIG. 7 shows a main operation of the health management system 1 in a flowchart. In step 81, the observation window 21 of the probe 23 of the monitor 1 is worn on the surface of the skin 2 via the PDMS 45. In step 82, the moisture of the skin 2 of the observation area 3 visible in the observation window 21 is measured by Raman spectroscopy. For example, by the confocal method, the amount of water on the surface and inside of the skin can be measured, and even the distance from the skin can be measured. In step 83, using the moisture content on the skin surface and the distance from the skin surface, the laser output used for subsequent measurements is adjusted. Because the surface of the skin 2 has a lot of water, and the laser penetrating power changes when there is a gap between the skin 2 and the observation window 21, it is ideal to adjust the laser output. The amount of water on the surface of the skin 2 can also be determined by measuring the electrical conductivity (conductivity).

In step 84, the laser Doppler analysis unit 51 is used to determine the observation point 5a of the blood flow using the observation point 5 in the observation area 3 by the laser Doppler method. By limiting the observation point 5a where the blood flow is being detected, the position of the microvessels 8 in the observation area 3 can be specified, and the observation points 5a located on or near the microvessels 8 can be identified. For example, the entire observation area 3 is irradiated with laser light 32 for pumps having a wavelength of about 800 nm, and the observation point 5 is obtained. The spectrum (Rayleigh scattering) of the diffused light 28 is obtained, and if the frequency range of the Doppler shift of the light scattered by the red blood cells can be seen, the presence or absence of blood flow can be determined. The DM module 23a may be used to irradiate the laser light 32 to each observation point 5 individually.

In step 85, after that, the observation point (first observation point) 5a to be the measurement target is defined, and the measurement target is locked. In step 86, the 3D profile surveying system 54 generates the depth profile of the microvessel 8 under the locked observation point 5a according to the mathematical model from the Doppler shift data obtained at the locked observation point 5a.

Next, in step 87, the profile survey system 54 further uses the SORS analysis unit 52 to verify the profile in the depth direction of the observation point 5a. Regarding spatially shifted Raman spectroscopy (SORS), the observation point 5a is irradiated with laser light, and the scattered light 28 is obtained from the observation point 5 around the observation point 5a leaving the observation point 5a. The deep tissue from the skin 2 can be obtained. Raman spectrum. It is also possible to adjust the irradiation angle of the laser to obtain a Raman spectrum for cross-section generation in the depth direction.

In step 88, when the 3D profile 57 including the depth profile of the locked observation point 5a is obtained, the profile survey system 54 determines the position in the depth direction of the measurement object (target portion) where the microvessel 8 should be present. . With this, the three-dimensional position of the target portion is determined.

In step 89, the CARS analysis unit 53 obtains a CARS spectrum from the position of the measurement object by coherent anti-Stokes Raman spectroscopy (CARS). The CARS analysis unit 53 is based on the locked observation point 5a or the observation points 5 around it, and selectively irradiates a convertible wavelength laser as the Stokes light 31 and / or the pump light 32 in a set depth crossing manner. . Take this from the locked The observation point 5a can obtain anti-Stokes Raman scattered light 28 from a component existing at a set depth and a component that is consistent with the wavelength conditions set by the Stokes light 31 and the pump light 32. Therefore, the detector 40 can detect a CARS spectrum from a tissue at a position under the skin where the microvessels 8 should be present. Therefore, it is possible to obtain low-noise information without weakening and averaging the information of the microvessels 8 due to Raman spectrum from other tissues.

In order to supply the scattered light 28 from each observation point 5a to the detector 40, an input unit 23b having a combination of a multi-fiber capable of forming a multi-focus and a DM or MEMS type shutter is used to block the light coming from The scattered light 28 of the observation point 5 is ideal.

Furthermore, by setting the Stokes light 31 and the pump light 32 to convert wavelengths, the irradiation position is limited to the locked observation point 5a or its surroundings, so that the position analysis of the detector 40 becomes unnecessary. Degree and wavelength selectivity. Therefore, a light detector with a fast response speed and high accuracy can be used. Therefore, the Stokes light 31 and the pump light 32 can be supplied as pulsed light for a short period of time, for example, pulsed light can be supplied in units of picoseconds or femtoseconds.

Therefore, the skin 2 can be prevented from being damaged by the laser light, the influence on the human body can be suppressed, and the information from the microvessels 8 can be continuously obtained for a long time. In addition, by sandwiching a porous film such as PDMS45 between the skin 2 and the skin 2, the influence of the laser light on the skin 2 can be further reduced.

In step 90, the CARS analysis unit 53 extracts information such as blood glucose, hemoglobin HbA1c, etc. from the CARS spectrum and supplies the first information 58 to the biological information generation unit 56. The biological information generating unit 59 generates the 3D information by combining the first information 56 in the blood with the profile survey system 54 if necessary. The information collected during the sectioning process is provided to the analysis engine 120 as the internal body information 59.

In step 91, the CARS analysis unit 53 obtains a CARS spectrum that changes the depth of the measurement target (target portion) at a certain interval. From the blood glucose concentration contained in the Raman spectrum that changes in the depth direction (vertical direction), it is determined whether the spectrum at the depth of the target portion is a spectrum suitable for blood vessels relative to the spectrum at portions with different depths. This allows the depth profile 57 to be verified at all times. In step 92, the information obtained from the target portion is not suitable for the blood vessel, and returns to step 84 to update and regenerate the 3D section 57.

The Raman spectrum component used in the verification of the depth profile 57 is not limited to blood glucose, but may also be a component of hematocrit, albumin, etc. that exists in the blood vessel at a higher concentration than the surrounding.

When the CARS spectrum is obtained by changing the depth direction, the CARS analysis unit 53 changes the angle of the Stokes light 31 or the pump light 32, and can also obtain the CARS spectrum at a position offset from a predetermined observation point 5a. By obtaining the CARS spectrum (SOCARS spectrum) after spatial migration, the accuracy of the profile in the depth direction can be further improved.

Can also replace CARS, or use CARS together with CARS to obtain spectra. The data of the plurality of Raman spectroscopic sensors 11 can also be combined to obtain a 3D Raman spectrum.

In step 90, the analysis engine 120 is not limited to the internal information of the blood glucose-containing organism, and can also obtain chemical components other than blood glucose contained in blood flowing through the blood vessels, cells containing red blood cells, albumin, and other proteins. Of blood components and all components that can be estimated from Raman spectroscopy Information inside the organism.

In step 93, the analysis engine 120 obtains external information of the organism from the event tracking unit 140, and in step 94, determines the type and amount of the biologically active substance to be administered by the administration unit 130 according to the internal information of the organism and the external information of the organism. Then, in step 95, the dosing unit 130 supplies a predetermined biologically active substance, such as insulin, according to the analysis result of the analysis engine 120.

As explained above, the health management system 1 is a continuous closed loop and non-invasive health / life control platform. It contains a non-invasive wavelength-programmable spectroscopic device. In addition, the body's mobility and event tracking unit and control unit It is integrated with the drug administration unit (drug delivery unit) and is an automatic adjuster capable of automatically performing the measurement portion. Non-invasive optical mass analysis techniques are used for blood-based measurements. The monitor 10, which is a sensor platform, has a MEMS-based optical device capable of tunable lasers, and a part that contacts the human body uses a highly penetrable film structure (thin film).

This system 1 is used as a platform, and includes the scalability of downloading new methods (treatment methods) or processing methods.

Claims (13)

A monitor is a monitor for monitoring the internal state of a living body from the surface of the living body, comprising: a probe, which contains an observation window and is worn on the surface of the living body; and a unit, which is accessed through the observation window At least a part of the observation area on the surface of the living body is irradiated with a laser, the laser has a wavelength of a pump light and a wavelength of a Stokes light; a unit that is Dimensions are scattered intermittently, or each observation point of a plurality of observation points formed continuously like the aforementioned observation area is scanned to detect coherent anti-Stokes Raman spectroscopic scattered light (referred to as CARS light) due to laser irradiation A unit that restricts the first observation point of the CARS light determined to obtain information including the target portion inside the organism from among the plurality of observation points based on the CARS light obtained from the plurality of observation points ; And a unit that obtains a spectroscopic spectrum of at least one component at or above the first observation point, and outputs first information indicating the internal state of the organism according to its intensity, wherein The probe includes an output unit that selectively directs the laser from the aforementioned laser irradiating unit to each of the plurality of points to cross the Stokes light and the light at a depth inside the organism. Pump light, and change the depth of the intersection to obtain a depth profile of the organism. For example, the monitor of claim 1 has a unit which obtains the same information as the aforementioned first observation point or its surroundings. The spectroscopic spectra of the first component of the plurality of parts at different depths on the surface of the living body are further limited or updated according to the intensity of the spectroscopic spectrum of the first component. For example, the monitor of claim 1 or 2, wherein the probe includes an input unit that directs scattered light from each observation point of the plurality of observation points to the detection unit. For example, the monitor of claim 1 or 2, wherein the plurality of observation points are set in the observation area at intervals of 1 to 1000 μm. For example, the monitor of claim 1 or 2, wherein the plurality of observation points are set in the observation area at intervals of 10 to 100 μm. The monitor according to claim 1 or 2, wherein the probe is configured to closely adhere the observation window to the surface of the living body through a diffusing porous membrane. A health management system includes the monitor according to any one of claims 1 to 6, and a distribution unit that imparts a biologically active substance to a living body based on the aforementioned first information. For example, the system of claim 7, further comprising: an action monitoring unit that acquires or predicts the external state of the organism; and a unit that uses information from the aforementioned action monitoring unit in addition to the aforementioned first information to control the slave The amount or type of the biologically active substance to be imparted to the organism by the aforementioned distribution unit. If the system of item 7 or 8 is requested, it further has a unit that outputs the aforementioned first information and the operation status of the aforementioned delivery unit to the outside. A control method of a system including a monitor for monitoring the internal state of a living body from the surface of the living body. The monitor includes: a probe, which contains an observation window, and is worn on the surface of the living body; and a unit, which passes through the observation At least a part of the observation area on the surface of the biological body accessed by the window irradiates a laser, the laser having a wavelength of a pump light and a wavelength of a Stokes light; and a unit which The observation area is discontinuous like a two-dimensional dispersion, or each observation point of a plurality of observation points formed continuously is scanned as the observation area, and a coherent anti-Stokes Raman spectroscopy scattered light due to laser irradiation is detected. (Referred to as CARS light); the control method includes: based on the CARS light obtained from the foregoing plurality of observation points, from the foregoing plurality of Among the observation points, the first observation point that is determined to obtain CARS light containing information on the target portion inside the organism is limited; and the first observation point obtained from the first observation point or the surrounding observation points is used to obtain at least one component. Spectroscopy spectrum, crossing the Stokes light and the pump light at a depth inside the organism, and changing the depth of the intersection to obtain a depth profile of the organism, representing the interior of the organism according to its intensity output The first information of the state. The method according to claim 10, comprising: obtaining the spectroscopic spectrum of the first component of the plurality of parts at different depths from the surface of the biological body at or around the first observation point, and based on the spectroscopic spectrum of the first component Intensity, the first observation point is limited or updated. For example, the method of claim 10 or 11, wherein the aforementioned system further has a distribution unit that imparts a biologically active substance to the organism, and the method includes selecting the biologically active substance and amount to be distributed by the distribution unit according to the aforementioned first information. The method of claim 12, wherein the aforementioned system further has an action monitoring unit that obtains or predicts the external state of the organism, and the aforementioned selection includes the use of the aforementioned external state information in addition to the aforementioned first information to select the aforementioned The quantity or type of biologically active substance to be distributed by the distribution unit.