Noninvasive measurements in a human body

[0001] The present invention generally relates to the field of medical devices, and relates to a method and system for non-invasive measurements in the human body. The invention is particularly useful for monitoring parameters of the human body such as oxygen saturation (blood) and / or blood concentration of the analyte (s).

BACKGROUND OF THE INVENTION [0002] Monitoring the oxygenation level of a tissue area is required to determine whether the tissue is viable or necrotic. Measuring the level of oxygen saturation allows, for example, to determine whether a patient who has suffered a stroke should undergo therapeutic treatment, whether the procedure is not necessary, or whether certain procedures involve a high risk. These measurements are also necessary to determine the effectiveness of the treatment.

[0003] Near infrared radiation has been used for non-invasive examination of the patient's brain, based on various absorption properties of oxygen-saturated and deoxidized hemoglobin. Nevertheless, near infrared spectroscopy (NIRS) has several disadvantages, for example due to the fact that the differential scattering of two different wavelengths used in the measurements results in uncertainty in the path length that the wavelengths of each wavelength pass; the inherent inability to locate the sampled volume, which requires intensive calculations performed by tomographic devices and algorithms to be solved; the analysis of the detected signal depends on the model used to characterize the structure of the tissue being examined. This makes it difficult to use NIRS in real-time medical applications.

[0004] Patent US5293873 discloses a measuring system for optical examination of patient tissue using visible light, infrared (IR) or near infrared (NIR). According to this technique, coherent light and ultrasound are directed at the patient along parallel propagation paths. Ultrasound causes a Doppler shift of the light emitted by the examined object, associated with specific tissue features.

The emitted light is detected, a suitable signal is provided to the assessment stage in which the intensity of those parts of the detected light that passed through the non-ultrasound tissue and those parts of the detected light that passed through the ultrasound tissue are calculated in an absolute or relative way. Patent US 6002958 also discloses NIR spectroscopy. To identify the type of pathology in the tissue, the effect of the simultaneously used modulated ultrasound beam on the detected NIR radiation is recorded.

BACKGROUND OF THE INVENTION [0005] There is a need in the art to facilitate non-invasive measurements in the human body, by providing a new method and system capable of monitoring blood or other fluid and / or tissue parameters in the human body, e.g., analyte concentration in blood, fluid reservoirs or tissue regions. The technique of the present invention is capable of quantitatively monitoring brain oxygenation or blood volume in such a way as to provide e.g.

continuous information on the state of brain tissue in patients at risk of neurological trauma.

[0006] The present invention uses the principles of ultrasonic light marking. According to the present invention, acoustic light marking is used to allow distinguishing between the optical response of an area of ​​interest (e.g. brain tissue, blood vessels) and regions outside the area of ​​interest, and / or significantly improve oximetry and pulse oximetry measurements.

[0007] A part of the body is illuminated with light of at least one wavelength and is irradiated with acoustic radiation (preferably ultrasound), so that acoustic radiation is applied to the illuminated area of ​​the body (this amount of application is referred to as "labeled volume"). The light scattered from the body is properly detected. Scattered light contains photons labeled and unlabeled by acoustic radiation.

[0008] According to the invention, the acoustic device operates in at least two different operating conditions, thereby irradiating a particular area of ​​the body part (area of ​​interest) with acoustic radiation of at least one variable characteristic of acoustic radiation. At least one variable feature is selected to provide at least two different optical paths for labeled photons scattered in the area of ​​interest. The relationship between the measured data corresponding to different acoustic radiation conditions (for example resulting in different effective optical path lengths) is an indicator of the properties of the tissue in the area of ​​interest.

[0009] At least two different operating states of the acoustic device (at least two different values ​​of the characteristics of the acoustic radiation) are chosen such that irradiation is for different volumes of the area of ​​interest (i.e. different labeled volumes basically coincide in space) and / or in to provide different labeling performance. Irradiation of different volumes can be achieved by generating pulses of acoustic radiation of different length and / or generating acoustic radiation of different beam width. Different labeling efficiencies can be obtained by generating pulses of acoustic radiation with different amplitudes and / or frequencies and / or "chirping" gradient (changes in carrier frequency due to keying).

[0010] It should be noted that the term "tissue property" as used herein means at least one parameter of the medium or centers in the area of ​​interest where the medium may include liquid or other tissues.

[0011] The term "effective optical path length" means the length of the optical path from the lighting set (its light output port) to the detection set (its light input port) resulting from tissue scattering.

[0012] The term "labeling efficiency" means the number of labeled photons relative to the number of unlabelled photons scattered by the scattering centers within the labeled volume.

[0013] The term "different volumes" or "different labeled volumes" refers to volumes in substantially the same position relative to the acoustic transducer system, i.e. volumes that substantially coincide in space, so that the average optical and acoustic properties of the labeled volumes are such same over time and between individual measurements, so the relative change in labeled volume between two measurements is less than the labeled volume.

[0014] Preferably, the body part (e.g., human head) comprising the area of ​​interest (e.g. brain tissue) is irradiated with light (e.g. at least two different wavelengths) and irradiated with acoustic radiation such that provide optimal working conditions for measurements. Optimal operating conditions are when light and acoustic radiation coincide in the region of interest, and thus the light scattering and from the area of ​​interest is "marked" with acoustic radiation (light is modulated by the frequency of the acoustic radiation), while they generally do not coincide area of ​​interest.

In addition, optimal operating conditions are selected to ensure that the detected light contains parts of the light scattered by the area of ​​interest and labeled by acoustic radiation, and part of the unlabeled light scattered in regions outside the area of ​​interest. This allows a distinction to be made between the light responses of the region of interest and its surroundings (e.g.

brain and extracranial tissue; vascular cavity and surrounding tissues, or blood and surrounding tissues).

[0015] It should be understood that acoustic radiation may be in the form of a continuous wave or pulses.

[0016] The technique of the present invention can be used in pulse oximetry measurements to determine the level of oxygen saturation in an area of ​​interest. Comparison of the technique of the present invention to pure pulse oximetry measurements, which are very sensitive to small body movements, shows that the measured data obtained by the technique of the present invention, e.g. in the form of the power spectrum of the labeled light and the responses from the area of ​​interest, are practically insensitive to movements of regions outside the area of ​​interest.

[0017] Preferably, the measurement data is obtained in the form of a change of the marked light signals depending on the time and / or wavelength, for at least two wavelengths of incident light.

The present invention allows non-invasive determination of parameters such as the level of oxygen saturation in the area of ​​interest, the concentration of the substance (e.g. hemoglobin) or structures in the area of ​​interest, the presence and concentration of platelet bodies in the amniotic fluid to determine the level of fetal lung maturity, the presence and / or concentration of meconium in the amniotic fluid, the presence and / or concentration of blood in the amniotic fluid, as well as for non-invasive monitoring the optical properties of other extravascular fluids such as pericardial, peritoneal (peritoneal and pelvic) fluids and joint fluids.

[0019] The acoustic radiation (ultrasound) used for measurements may or may not be focused because the measurements use ultrasonic marking to distinguish light responses from the area of ​​interest and its surroundings and / or to increase the signal to noise ratio, and not necessarily to imaging. The invention can also be used for imaging body parts, in particular for mapping the optical attenuation of human tissues. This is carried out through the appropriate operation of optical and acoustic devices.

[0020] The present invention, according to a preferred embodiment, can use oximetry principles to process measurement data. For this purpose, lighting is used using at least two different wavelengths. In some embodiments, light response signals collect more than heart rate, and pulse oximetry principles are used to determine the level of oxygen saturation.

[0021] The present invention can be used to measure the concentration of a substance in a body region using light at least one wavelength. In some embodiments, the wavelength is selected to correspond to a characteristic wavelength that is selectively absorbed or scattered by the substance. For example, the redox status of cytochrome-c oxidase may be monitored at a wavelength (or wavelength selection) that indicates oxygen availability and metabolic activity of the tissue. Hypoxia depolarization is another example. Therefore, measuring the optical changes associated with potassium is an indirect indicator of changes in oxygenation. Contrast agents such as indocyanine green (ICG) can also be monitored using the technique of the present invention, where the contrast agent is administered through blood vessels passing through the region of interest, thereby determining both the dynamics of the change in the concentration of the contrast agent and its absolute concentration. . Other tissue analytes such as glucose, bilirubin and urea can be monitored by selecting the appropriate wavelength of illumination. [0022] Preferably, the measurement unit (lighting assembly, light detection assembly and acoustic transducer system) is placed in close contact with a suitable part of the body (e.g. skin covering the skull). As indicated above, the lighting assembly is configured and adapted to illuminate body parts with at least two wavelengths of light. The acoustic transducer system is configured and adapted to transmit acoustic radiation to the same volume from which the light detector collects diffused light.

[0023] The light detection assembly may be set to collect both forward scattered light and back scattered light.

[0024] The present invention preferably uses imaging of the area of ​​interest before or simultaneously with the use of its measurements, to facilitate the determination of the optimal positioning of the measuring system (its probe), which results in optimal working conditions for measurements. Imaging can be performed using ultrasound, magnetic resonance imaging (MR), computed tomography (CT) or positron emission tomography (PET). Ultrasound-based imaging can be performed using the same ultrasonic transducer system that is used for measurement, or using a different transducer.

[0025] Preferably, the invention also relates to the use of ultrasonic radiation to determine such blood parameters in the area of ​​interest as blood flow, tissue velocity profile etc. To this end, the reflections of the ultrasonic radiation from the irradiated area are analyzed by any known suitable Doppler technique. . Ultrasonic radiation can be used in the form of a continuous wave or pulses (gates).

[0026] Thus, the present invention provides a device according to claim 1. The invention further provides a method according to claim 1. 17.

[0028] Also provided is a probe for use in a system for monitoring tissue properties in the human body, comprising: the support structure configured to contact the body part, the support structure carries a system of at least two light output ports, spaced apart, connected to the light source assembly, at least two light input ports, spaced apart, connected to the light detection assembly, and at least one acoustic device output, the arrangement of light ports and the acoustic port allows selection of at least one of the light output ports, at least one of the light input ports and at least one of the acoustic output ports so that acoustic radiation of a specified frequency range from at least one selected acoustic output port and illuminating light from at least one selected light output port, overlap in the area of ​​interest in the body, and at least one input port receives diffused light from the overlapping area of ​​light and sound and diffused light from outside the area of ​​interest.

BRIEF DESCRIPTION OF THE DRAWINGS [0029] In order to understand the invention and to show how it can be implemented in practice, preferred embodiments will be described by way of non-limiting examples, with reference to the accompanying drawings, in which:

Figures 1A to 1C schematically show three different examples of the monitoring system of the invention, respectively, for monitoring an area of ​​interest in a human or animal body;

Fig. 1D is a block diagram of a method according to the invention;

Fig. 1E is a block diagram of an example of a measurement technique according to the present invention;

Figures 2A and 2B schematically show the principles of a measurement system according to an embodiment of the invention;

Fig. 2C illustrates another possible example of affecting the effective optical path length of labeled photons scattered from an area of ​​interest;

Fig. 3 is a block diagram of an embodiment of the method of the invention using the measuring system of Figs. 2A and 2B;

Figures 4A and 4B schematically show two examples of the configuration of a monitoring system suitable for monitoring saturation in the human internal jugular vein;

Figures 5A and 5B schematically show two examples of the configuration of a measuring unit suitable for use in the system of the present invention for performing detection of required parameters of the area of ​​interest, using the local oscillator method;

Figures 6A and 6B schematically show two examples of the configuration of a measuring unit suitable for use in a system according to the invention using the phase arrangement of an acoustic transducer assembly;

Figures 7A, 7B and 8A-8B illustrate various configurations of the support structure (probes) carrying at least part of the measurement assembly.

Detailed description of the invention [0030] Figs. 1A-1C illustrating schematically three specific but non-limiting examples of a measurement system, generally designated 100, configured and adapted in accordance with the invention for non-invasively measuring one or more parameters (properties of tissue components) in an area of ​​interest 200 in the human or animal body. The measured parameter may be oxygen saturation levels, or various other parameters, such as analyte concentration in the patient's blood, or analyte / metabolite perfusion in tissues. To facilitate understanding, the same references are used to identify elements that are common to all embodiments of the invention.

[0031] The system 100 includes a measurement unit 101 and a control unit 120. The measurement unit 101 includes: an optical unit 101C formed by lighting assembly 101A and a light detection assembly 102A and an acoustic unit formed by the transducer system 110. The control unit 120 is configured to control operation measuring unit 101, processing and analyzing the measurement data generated by the measuring unit 101.

[0032] Lighting assembly 101A may include one or more lighting units associated with one or more locations, respectively, in the area of ​​interest. Similarly, detection assembly 102a may include one or more detectors associated with one or more sites in the area of ​​interest, respectively. The lighting unit may include one or more lighting elements, similarly the detection unit may include one or more light detection elements. The lighting element is formed by a light emitter and optionally a light guide element (e.g. optical fiber or fiber bundle), the light detection element is formed by a light sensor and optionally a light guide element (e.g. optical fiber or fiber bundle).

[0033] In the example of Fig. 1A, lighting assembly 101A includes one lighting unit and light detection assembly 102A includes one detector. This does not necessarily mean one illuminating element and / or a single detector, but may refer to the arrangement of illuminating elements, provided that they are associated with the same place, in relation to the area of ​​interest and / or the arrangement of detecting elements associated with the same place, in relation to the area of ​​interest.

[0034] The optical unit 101C and the acoustic unit 110 are connected to the control unit 120 via wires or wirelessly. The controller 120 is typically a computer system including, but not limited to, a power supply (not shown), a control panel with I / O functions, a data presentation tool (display) 120A; 120B memory tool and 120C data processing and analyzing tool (e.g. CPU). The control unit 120 also includes a signal generator (e.g. function generator and phase control) 122 configured and adapted to control the operation of the transducer system

110 and appropriate tools 123 configured to operate the 101C optical unit. The CPU 120C is programmed to receive measured MD data from detection unit 102A and process this data to determine the appropriate parameter (s) in the region of interest, e.g., oxygen saturation level.

[0035] In the present example, the measuring device 101 is configured as a probe having a supporting (preferably flexible) structure 403 placed on the part of the body to be measured. The 403 supporting structure carries at least part of the lighting assembly

101A (at least one light output port - single OP output port in the example of Fig. 1A and multiple ports in the examples of Figures 1B-1C) and at least part of the detection assembly 102A (at least one light input port - single IP input port on example of Fig. 1A and many ports in the examples of Figs. 1B-1C).

[0036] It should be understood that the OP light output port can be made integrally with the light-emitting element or can be located at the distal end of the optical fiber system connected with its other end to the light-emitting element outside the support structure (e.g. on the unit control). Similarly, the IP light input port can be made integrally with the light detection element or it can be placed at the distal end of the optical fiber system, connected with its other end to the light emitting element, located outside the supporting structure (e.g. on the control unit).

[0037] In general, lighting assembly 101A may be configured to emit light of one wavelength. Preferably, lighting assembly 101A is configured to generate light of at least two different wavelengths. To this end, the lighting assembly may comprise at least two light emitters (e.g., laser diodes), e.g. one emitting a narrow band of photons with a wavelength in the range of 605nm to 805nm and the other emitting a photon with a wavelength in the range of 800nm down

1300nm, or it may contain broadband light sources. The lighting assembly 101A may, for example, be pre-programmed to produce waves with different components at different times, or simultaneously produce wave components with different frequencies and / or phase modulation. Accordingly, the control unit 120 is programmed to determine, in the signal generated by the detection unit 102A, the corresponding wavelength of light by means of time and / or phase and / or frequency analysis. The detection assembly may include a suitable frequency filter.

[0038] Thus, the lighting assembly 101A may include a light emitter carried by the support structure 403 and communicating with the control unit 120 via wires 106 or wireless signal transmission. Alternatively, the light emitter (s) may be located outside the support structure 403 (e.g. in the control unit 120) and the connector 106 formed by the light guide elements (e.g. the optical fibers) directing the light to the light output port OP located on the support structure 403 .

[0039] The detection assembly 102A includes one or more light detectors. The detector can be a photomultiplier, photodiodes, avalanche photodiodes, or preferably an image pixel matrix, e.g. CCD or photodiodes matrix. The detectors can be located outside the supporting structure (probe) 403, they can, for example, be in the control unit 120, and the returning light (light response) can be guided from the IP input port of the detection assembly through the light guide elements 105 (e.g.

fiber). Alternatively, the detector (s) may be located on the support structure and the connector 105 configured to connect the electrical output of the detector (s) indicating the measured MD data to the control unit 120.

[0040] It should also be understood that connectors 105 and 106 may be electric wires connecting the control unit 120 to the lighting assembly and detection assembly located on the probe 403, or the connection may be wireless.

[0041] Thus, in general, the "lighting assembly" and "detection assembly" are carried by a support structure which contacts the measured body part and are formed at least by the leading and receiving light ports.

[0042] It should be noted that for the purposes of the present invention, the light input port of the detection assembly 102A may be larger than that used for imaging with scattered light. In diffused light imaging, location is achieved through small input ports, otherwise large-volume light is collected. According to the invention, it is desirable to collect light from a large volume, since the location is achieved by ultrasonic marking. Therefore, the input port of the detection assembly 102A is optimized to collect light from substantially large tissue and / or blood volumes, for example using large area detectors or a CCD camera or a matrix of detectors comprising one input port.

[0043] As mentioned above, the detection assembly 102A may include two separate detectors or a detector array. Each detector can be coupled with a bandpass filter configured to transmit light of the appropriate wavelength, produced by the lighting unit 101A. Bandpass filters may include optical high-pass, low-pass and band-pass filters. Alternatively, narrow-band detectors may be used.

[0044] The transducer system 110 may be placed on the support structure 403 and connected to the control unit 120 (its signal generator 122 and processor 120 C) by means of cables and / or optical fibers 107 and / or by wireless means. Alternatively, connector 107 may be an acoustic guide unit connecting the transducer (s) located outside the support structure (e.g., on the control unit 120) to the acoustic output port 245 on the support structure.

[0045] In this case, the light detectors are placed on a flexible support structure (probe) 403, the detectors are preferably mechanically and electronically insulated so that the acoustic waves propagating from the acoustic output port 245 minimally affect the collection of photons by the detectors and the processing of light signals on electrical signals. If the ultrasonic transducer system 110 is also located on the probe 403, then the configuration is such that it prevents RF and other electronic signals generated by the transducer system from interfering with the photon collection of detectors and the conversion of light signals into electrical signals. This is accomplished by means of a shielding system, for example containing electrical insulation of the sensors by means of suitable materials, which are poor conductors, or by creating a Faraday cage around detectors (detection elements), or by creating mechanical insulation using appropriate materials that suppress the propagation of pure waves acoustic through a probe or through body tissues. As indicated above, the detectors can be connected to the 403 probe through connection ports (possibly detachable). The connection ports are configured to isolate mechanical and electrical signals in the frequency range generated by the ultrasonic transducer system and for other frequencies.

[0046] The transducer system 110 may be made as a single acoustic element configured and operating to emit a focused or unfocused acoustic beam or to emit acoustic pulses; or as a piezoelectric phase matrix capable of producing an acoustic beam with variable direction, focus, time and phase, or it can be a matrix of silicone units or other pressure generating units, configured as a single element or matrix of elements (phase matrix), or a full ultrasound probe containing transmission and reception units. The transducer system may be connected to an amplifier (not shown) located in the control unit 120 and capable of amplifying the electronic signals generated by the signal generator 122. The control unit is pre-programmed to operate the transducer system 110 (using the signal generator 122) in a set from top way, as will be described below.

[0047] In addition, the transducer system 110 may include a matrix of laser generated ultrasound elements (JST) coupled to a laser source capable of emitting short light pulses (for example, from 10nsec to 100μsec). These short light pulses are transmitted to the transducer system 110 via optical fibers to produce acoustic waves of a certain frequency, time and duration. In the group of light pulses emitted in each element, there may be a relative delay between the elements. This delay creates phase delays between the generated acoustic waves in each element and can be used to focus or mix the generated beam towards the desired location (i.e. area of ​​interest 200). Elements of laser manufactured ultrasonic transducers are known in the art, for example as disclosed in PCT WO03057061. Using such a transducer system, you will be able to get a cheaper 403 probe, because the elements of the probe are optical fibers. When LGU elements are used, the controller unit 120 controls the activation of laser sources emitting short pulses to create acoustic waves, in accordance with an embodiment of the present invention, with respect to starting the signal generator. For example, the control unit 120 may activate the lasers so that they emit a series of consecutive short pulses to produce a specific duration of the acoustic pulses, or the control unit 120 may control the amplitude of the laser pulses so that the amplitude of the acoustic waves generated by the LGU elements is determined in accordance with a specific embodiment of the invention as will be described below.

[0048] The detection assembly 102A generates electrical signals in response to the amplitude and phase of the photons reaching the IP input port. These electronic signals can be filtered by analogue or digital filters, for example bandpass filters, respectively connected to the data processing tool 120C of the control unit 120 or being part of this data processing tool. The bandwidth of these filters can be set or changed by the control unit 120. Band tuning can be done optically by heterodyne detection or by using multiple filters having different bandwidths, or tuned filters coupled to each detector. Alternatively, the filters can be electronic. Preferably, before actual measurements are taken, the optimal arrangement of the optical and acoustic units in relation to the area of ​​interest 200 is determined so that it meets the operating conditions of the measurements. The operating conditions are such that both illuminating light 250 (at least part of it) and acoustic radiation 255 radiate to the same area (volume) simultaneously, while they do not substantially overlap each other and that the detection assembly detects light scattered by the area of ​​interest 200 and the area outside of it. In general, the positioning of the optical module and transducer system relative to area of ​​interest 200 is such as to allow the distinction between scattered photons collected from area 200 and areas 11 outside this area, using acoustic light marking. As will be described later, the area of ​​interest can be identified by the control unit 120.

[0049] As mentioned above, pre-positioning can be carried out by means of ultrasound. An imaging system of any known suitable configuration may be used that can use the same transducer system 110 used for the measurement process or another ultrasonic transducer. The ultrasound images of the body part covering the area of ​​interest 200 are recorded and analyzed by the control unit 120 (which in this case is installed together with the appropriate image processing device) or other suitably programmed computer system in order to determine the optimal positioning of the optical unit 101 (i.e. 101A lighting unit and detection unit 102A) relative to the area of ​​interest and relative to the acoustic unit 110.

[0050] The lighting assembly 101A is preferably positioned as close as possible to the area of ​​interest 200.

Preferably, the lighting assembly 101A is arranged such that the optical path between the lighting assembly 101A and the area 200 causes the least attenuation at the wavelength selected for measurement compared to other paths. The distance between lighting assembly 101A and detection unit 101B is preferably determined to be at least equal, and preferably greater than the distance between lighting assembly 101A and area 200.

[0051] Preferably, the support structure 403 is configured to define different attachment locations of the detection assembly 102a and / or lighting assembly 101A so as to maintain appropriate distances between them. For example, these positions can be determined by means of a sliding strip (not shown) which is attached to the light detection assembly 102A and can be attached to the supporting structure 403 by means of a small screw or latch. Alternatively, multiple output ports and / or multiple light input ports are provided with a supporting structure 403 and the control unit 120 operates to select the appropriate light source (s) and detector (s) (output port and light input port) for measurement. This selection is made based on the signals generated by each detector and the geometry of the body part and the location of the area of ​​interest in it.

[0052] Furthermore, the lighting assembly 101A and 102A and the detection assembly are arranged such that the light output OP port of the lighting assembly and the light input IP port of the detection assembly are in close contact with the outer shell of the body part. Optionally, oil or glue 10 is used to reduce light reflection from the outer shell. An adhesive can be used to attach the 403 to a specific location on body parts. Alternatively or additionally, a belt may be used to prevent the supporting structure 403 from moving.

[0053] After determining the position of the lighting and detection assemblies, the acoustic transducer system 110 is arranged such that the acoustic waves

255 generated by the transducer system 110 are coupled to the respective parts of the body, propagate in them and reach the area of ​​interest 200. In the case where the lighting and detection assemblies are arranged to illuminate and collect the light scattered by the area 200, the transducer system 110 is placed so that the acoustic waves 255 propagate in the same part of the area 200 from which the scattered photons 250 detected by the detection unit 102A are collected. The transducer system 110 can be attached to a suitable location using an ultrasonic adhesive or acoustic coupling material (e.g., gel or hydrogel glue or ultrasonically compatible adhesive) and, optionally, a belt to secure the transducer in one place. The ultrasonic transducer system 110 may be configured as a transducer phase matrix producing a focused beam that is scanned on the skin area 10 covering the body part.

[0054] After the lighting and detection assemblies and the acoustic transducer assembly are optimally positioned, measurements are made by the appropriate actions of the measuring unit 101. The control unit 120 actuates the lighting assembly 101A to produce photons 250 (preferably at least two different wavelengths). The lighting assembly 101A can be configured and adapted to produce a continuous stream of photons 250 (CW) or a stream modulated in time (at a certain frequency W) or subsequent pulses. The photons 250 propagate through a part of the body and reach the area of ​​200. Part of the photons 250 are absorbed by the area of ​​200 and part of the photons 250 are scattered by this area 200 and its surroundings 11. Part of the scattered photons

250 propagates through a part of the body (around the area of ​​interest) and reaches detection unit 102A. The latter collects at least some of these photons and generates MD measurement data indicating photons, i.e. an electrical signal in response to the number of photons that are collected by the detection input IP port at a specified time for each illuminating wavelength generated by lighting assembly 101A. [0055] It should be noted that in the event that the detection assembly 102A is at a distance from the lighting assembly 101A equal to or greater than twice the minimum distance between the area 200 and the lighting assembly 101a, the detection assembly 102A collects both scattered photons back and forth. In the case where the lighting assembly 101A includes a laser with a coherence length greater than the optical path of the scattered photons in the tissue, an interference image is generated at the IP input port of the detection assembly resulting in a spot image. For detection and analysis of the macular image, the detection assembly 102A may include a matrix of detectors, each of a size comparable to a single spot.

[0056] Fig. 1D is a diagram of the main steps of the measurement method in the human body according to the present invention. Optical and acoustic units are properly attached to the body. The optical system is operated (by the control unit) so that it illuminates the body with at least one wavelength. When the photons 250 illuminate the area 200, the transducer system 110 operates under at least two different operating conditions determined by changing at least one of the characteristics of the acoustic radiation 255. Acoustic radiation propagates through the body to irradiate the volume of the area 200 from which the scattered photons 250 are detected by detection unit 102a. The labeled volume corresponds to the acoustically irradiated volume during the measurement.

The interaction of acoustic waves 255 with photons 250 results in a shift of photon frequency 250 by the frequency of acoustic waves

255. In addition, photons 250 dispersed in the labeled volume experience modulation of the optical path length resulting in modulation of the density of the scattering centers and in their acoustically forced movement. Acoustic radiation works with at least two different irradiation conditions for the volume being labeled. These two conditions correspond to two different effective optical path lengths of labeled photons, scattered in the labeled volume. The effective optical path length depends on the labeled volume and / or changes in the labeling efficiency of the photons dispersed in the labeled volume. The detection unit 102A detects modulated photons ("labeled photons") and unmodulated photons with original frequency ("unlabeled photons") under two measurement conditions, for each of the wavelengths of light. The detection unit 102A generates MD measurement data (electrical signals) indicating the photons detected. The measured portion of the data corresponding to the labeled photons is referred to as the "labeled signal".

[0057] The control unit 120 processes the measured MD data to determine the relationship between the data portions corresponding to different labeled photons, i.e. labeled photons with different effective optical path lengths as a result of different acoustic radiation characteristics. This relationship between the data portions indicates the difference in optical attenuation, and thus indicates the properties of the tissues in the illuminated and acoustically irradiated area of ​​the body. Examples of operation of an acoustic unit providing different characteristics of acoustic radiation will be described below with reference to Figs. 2A-2C.

[0058] Data processing includes a suitable algorithm depending on the type of detection used. For example, for one (large surface) detector, known heterodyne detection techniques (e.g.

described in Lev A. and BG Sfez Optics Letters (2002) 27 (7) 473-475) to extract from the measurement data a portion of the data indicating the signal of the labeled photons. Another known suitable technique, described for example by Leveque-Fort et al. in Optics Communication 196 127-131 (2001) can be used to determine the optical signal of photons scattered from a given volume, marked by acoustic waves when using a CCD camera that detects a macular image. Other possible algorithms are described below.

[0059] As indicated above, more than one IP light input port and more than one OP 100 light output port can be placed in the measurement system. This is illustrated in Fig. 1B. In this arrangement, measurement system 100 uses a pair of IP1 and IP2 light input ports and a pair of OP1 and OP2 light output ports. It should be understood that more than two I / O ports can be used. In addition, each port can serve as a dual light input and output port, using a fiber optic adder / splitter that couples light to and from one fiber. The ports can be arranged in a one-dimensional matrix or two-dimensional matrix to improve flexibility of use.

[0060] Fig. 1C illustrates a measurement system 100 with a slightly different arrangement of input and output ports (or light sources and detectors) within the flexible probe 403. In this arrangement, the OP1 light port acts as an output port (associated with the lighting unit), OP2 ports and IP1 act as ports for output and input (associated with the lighting unit and detection unit), and the IP2 port acts as the input port (associated with the detection unit).

[0061] In the examples of Figs. 1A-1C, the audio output port 245 (or transducer system) is located between the input ports and the light output ports. However, it should be understood that the 245 audio port can be located anywhere on the flexible 403 probe (i.e., to the right of the OP light output port or to the left of the IP light input port). Several acoustic output ports can be used, located at different locations along the 403 flexible probe, in combination with the same transducer system or other transducer systems. It should also be understood that the acoustic port 245 can be located outside the flexible probe 403 on its own support structure adapted to be attached to a part of the body (e.g. skin).

[0062] When different acoustic transducer systems are used, then the transducer systems may generate acoustic waves with the same frequency modulation, or each of them may generate a different frequency modulation. When different frequencies are generated, the control unit 120 controls the modulation in each transducer system, according to the spatial position of each output port associated with each transducer system, so that the light propagates in the same volume in which the propagation of acoustic waves occurs, it is collected by one or more light input ports and analyzed based on the appropriate frequency modulation of the appropriate transducer system (as will be described below in relation to one transducer system). Different transducer systems can generate acoustic waves at the same or different time intervals.

[0063] As indicated above, the area of ​​interest can be identified by measuring system 100. This is done while the system is in calibration mode. The acoustic radiation generated by the transducer system or many such systems is directed to many areas of the body part under the 403 probe, for example by means of a phase matrix to scan various regions. At the same time, photons are introduced by the lighting unit to illuminate the body parts.

The scattered photons are detected by the detection unit. The control unit 120 analyzes the tagged and unmarked light signals associated with each area, as described above and as will be illustrated in more detail below. The processed signals are then used to determine the parameter of each area.

The determined parameters can be compared to reference data to identify the area of ​​interest. For example, the threshold value for a blood clot or haemorrhage occupying a predetermined volume within an area is first determined (before actual measurements are taken). The measured parameters are then compared to the threshold value. The area of ​​interest is identified as an area having a fixed parameter with a higher value (or less or equal to a certain margin) relative to the threshold value. As another example, a different threshold value may be defined that is defined for local ischemia in the area of ​​interest. The specified parameters are then compared to the threshold value to determine the area of ​​interest.

[0064] Measuring system 100 can be used to determine an area of ​​interest with a fixed scattering factor. Optimal arrangement of lighting, detection and acoustic assemblies having multiple input and output ports can be determined by scanning the acoustic beam at various locations inside the body and determining, for example, the autocorrelation or power spectrum of the signals generated by each detection unit in response to scattered photons from different volumes in the area of ​​the body where the lighting coincides with the acoustic beam. Because the width of the autocorrelation spectrum line or the power spectrum of the labeled signals (modulation frequency) around the frequency of the acoustic radiation depends on the scattering coefficient of the labeled volume, the control unit can monitor the spectrum line widths when using ultrasound beams for optimal volume labeling with fixed diffusing properties ( e.g. a fluid reservoir such as accumulated blood or extravascular fluid).

[0065] The area of ​​interest may also be defined by the system operator (e.g., by defining the area boundaries), and the indicator parameters of this area may be recorded by the control unit 120. The control unit 120 determines the distances between the area of ​​interest and the acoustic output port 245 and light input and output port. In this way, the control unit 120 determines the appropriate distance to be provided between the light output port and the light input port, so that photons 250 from the light output port will propagate in the area of ​​interest 200 before reaching the IP input port. The control unit 120 can choose which input and output ports from among many light ports located at different locations are used, such that at least one input port collects photons emitted from at least one output port that propagate in the volume of tissue through which propagate acoustic waves 255. With reference to Fig. 1B or Fig. 1C, the control unit 120 also determines which of the other light input ports (e.g. light input / output port PO2) collect photons propagating through the surrounding tissues 11, not in the area of ​​tissue 200.

[0066] In addition, in calibration mode, the control unit 120 determines the desired frequency bandwidth Af to be used during the measurements. As indicated above, the control unit 120 may determine the desired frequency band Af₁, used during measurements as corresponding to the bandwidth of the frequency optimally filtered by analogue or electronic digital filters, connected to detectors.

The bandwidth optimally transferred through these filters is constant or changed by the control unit 120 during system operation. The control unit 120 controls a portion of the frequency band generated by the function generator 122 so that it corresponds to the bandwidth that is optimally transferred by electronic filters connected to light detectors. Alternatively, the filter band is changed by the control unit 120 to correspond to a portion of the frequency band generated by the function generator.

[0067] After calibration mode, the control unit 120 controls the operation of selected, fixed light input and output ports by modulating (including time gating) light sources connected only to selected output ports, or modulating the output ports themselves and analyzing the signals generated by coupled sensors with selected input ports.

[0068] The control unit 120 controls the time-dependent generation of frequency-modulated acoustic waves. The control unit 120 further determines the time Δ (needed to collect the signal to obtain the optimal signal-to-noise ratio (SNR) as a result of the measurements to determine the required parameter (e.g. oxygen saturation). If pulse oximetry is used for data analysis, the period Δ ( is shorter than the interval between the patient's heartbeats. The control unit 120 also determines the frequency modulation parameters such that the desired frequency bandwidth Δ ^ (or phase) propagates through the volume of tissue 200 over a period of time At₁. The beginning of the period Δ (occurs at the moment t₁approximately equal to the moment at which the pulse generated at port 245 reaches a tissue volume of 200. Time t2 is given by the formula t₂= t₁ + Δ (.

[0069] In the examples of Figs. 1B-1C, operation of the device 100 in "monitor" mode or in measurement mode is shown. In the example of FIG. 1B, the control unit, 120 in monitoring mode, activates the light source (a) associated with the OP1 output port to emit 250 and 251 photons and activates the light source (a) associated with the OP2 output port to emit 252 photons. Light ports can be associated with different light sources or with one or more common light sources. A single light source, and preferably two light sources, emitting light with at least two different wavelengths, are connected to the output ports, wherein one light source can be connected to more than one output port. Light sources connected to different output ports, and the output ports themselves, can be activated at different times and / or with different characteristics (e.g. with different frequency or phase modulation), so that the control unit

120 can distinguish between measured data indicating the detected photons 251 and 252 collected by the IP1 and IP2 input ports of the detection unit. [0070] The control unit 120 also activates the signal generator 122, which in turn activates the acoustic transducer system 110 to generate the acoustic waves 255 transmitted through the acoustic output port 245. The frequency (or phase) of the acoustic wave generated by the function generator 122 is modulated by the control unit 120 so that the acoustic waves reaching the area of ​​interest 200, illuminated by photons 250, will have a specified frequency bandwidth Af_rWhen the Af band is set₁, the control unit 120 determines the frequency modulation of the generator of the function controlling the generation of acoustic waves 255, such that the acoustic waves 255 with a frequency modulated in the Af band₁ reach a tissue volume of 200 during t₁. In addition, acoustic waves with a frequency in the Af range₁. they generally do not propagate through other tissues during the period of time At₁ following t1. Accordingly, the control unit controls the detection assembly 102a so that the light sensors associated with the IP1 and IP2 input ports start collecting photons at time t1 and complete the collection process at time t2. Alternatively or additionally, the control unit 120 controls the activation of the light sources associated with the output ports OP1 and / or OP2 at time t1 and completes their activation at time t2. During the At1 period, the IP2 input port and / or the IP1 input port collects photons 250 propagate through the same tissues through which the acoustic waves 255 propagate (delay in photon propagation by tissues, on the order of nanoseconds, is ignored). Photons 251 generally do not propagate in the same area of ​​tissue in which acoustic frequencies within Af1 spread at At1.

[0071] Fig. 1E shows in more detail an example of a system maintenance procedure and data processing procedure, taking into account the system configuration of Figures 1B or 1C. The IP2 input port collects photons

250, including labeled and unlabelled photons scattered by surrounding tissues 11 and labeled photons scattered by volume of tissue of interest 200, while the IP1 input port collects mainly only unlabelled photons 251 scattered by surrounding tissues 11. Signal generated by detection unit 102A in response to the 250 photons collected on the IP2 input port, it is referred to as the "signal

A ". The signal generated by the detection unit 102A in response to the photons 251 collected on the IP1 input port is referred to as" signal B ". [0072] According to this example, to describe the spread of light in multiple layers of body tissue, and selected two models.Such models are described, for example, by Keinle et al in Physics in Medicine and Biology

44: 2689-2702 (1999). One model (Model A) contains parameters representing some tissues through which 251 photons propagate from the OP1 exit port through the medium until reaching the IP1 input port, and another model (Model B) contains parameters representing some tissues in the medium through which they propagate 250 photons marked up to IP2 input port. These models include known parameters such as molar absorption and blood cell scattering coefficients, oxygenated hemoglobin and deoxygenated hemoglobin, for each photon light wavelength. In addition, models may include layer thicknesses, presence and amount of fluid by light beam and other parameters that are measured during operation of the device 100. In models A and B, some tissue parameters in the model can be averaged, other transformations of known or measured parameters of real tissues can also be performed. [0073] For the known amplitude of illuminating light and known distances between the OP1 light output port and the IP1 input port, model A is used to calculate the expected time-dependent photon flux, i.e. the light intensity at the input port of the detection unit 102A. The expected time-dependent photon flux or light intensity is used to calculate the expected signal (referred to as "C signal") that can be generated by the detection unit 102A in response to such a photon flux. Signal C actually shows theoretical data for unlabeled photons at the site of detection unit 102A, while signal B shows real measurement data for unlabeled photons collected by detection unit 102A.

[0074] The parameters of model A are adapted (optimized) such that the signal C is equal to or close to the signal B (best fit). Signal processing techniques based on optimization algorithms, such as a neural network, can be used to optimally determine A parameters. Model parameters are used to calculate the optical properties of some tissues through which photons 251 propagate.

[0075] It is generally assumed that the optical properties of tissues outside the area of ​​interest (i.e. in areas 11) through which both photons 250 and 251 pass are similar. Alternatively, it can be assumed that by determining the parameters and optical properties of the tissues through which 251 photons pass, one can deduce, with a reasonable error, the optical properties of the respective tissues through which photons 250 pass. The parameters calibrated by the B signal and the optical properties of the tissues through which the 251 photons pass are then used to calibrate (optimize) the B model, which describes the propagation of 250 photons in surrounding tissues.

[0076] The time-dependent signal amplitude for all photon wavelengths 250 is processed by the control unit 120 using techniques known in the art, such as Fourier digital transformation and analogue or digital filtering, to extract a portion of the signal from the entire signal A corresponding to labeled photons 155. This part of the signal is referred to as "labeled signal A". The tagged A signal is modulated at the acoustic frequency generated by the 110 converter system. The amplitude of the power spectrum of the tagged A signal at acoustic frequency (or associated with the acoustic frequency), modulation of the width of its power spectrum or other features of the tagged A signal, such as its phase, are collectively referred to as "processed tagged A signal" This processed tagged A signal actually Cie indicates both responses of surrounding tissues and area of ​​interest labeled by acoustic radiation. In addition, signal A contains information that is not modulated in audio frequency, referred to as "unlabelled signal A".

[0077] According to this particular embodiment, the unlabeled A signal can also be used in the data processing and analysis procedure, for example to determine some unknown parameters of model B and further optimize the model.

[0078] As mentioned above, the control unit 120 processes the measurement data (using a suitable algorithm, depending on the type of detection used) to extract the measured portion of data indicating the labeled photons and processes this portion of data to identify the light response of the area 200 (diffuse photons in the area of ​​200) by determining the relationship between labeled signals corresponding to different effective optical path lengths of labeled photons.

[0079] Using the above-mentioned or other suitable technique, it is possible to determine the effective attenuation of photons propagating through the area of ​​interest. To this end, the acoustic radiation can be used such that the acoustic waves 255 pass through different tissue depths (e.g., by displacing the transducer system relative to the bodies a, or by means of a phase transducer). Therefore, it is possible to isolate the absorption coefficient and the reduced scattering coefficient for two wavelengths selected for lighting. For example, using an equation similar to the equation of 4 mentioned above in Lev et al.

<img file="PL1863387T3_D0001.tif" />

it is possible to determine the level of oxygen saturation in the area of ​​interest. x is the fraction of deoxyhemoglobin, γ is the molar extinction coefficients of oxyhemoglobin (O) and deoxyhemoglobin (H) for both wavelengths (in the referenced article, means 690nm and 8 means 820nm), and μ_{β /}ξ₆ and μ_{β /}ξ₈ are the measured damping factors at 690 and 820nm, respectively.

[0080] The acoustic transducer system 110 (or its output port) is maintained in a certain position that is optimal for the propagation of acoustic waves through the same volume of tissue from which the scattered photons are detected by the detection unit. The transducer beam size 110 is such that the cross-sectional volume between photons and acoustic waves is determined by the control unit 120 to obtain a high signal-to-noise ratio (SNR).

[0081] The control unit 120 analyzes the labeled photons scattered both backwards and forwards to determine the optical attenuation of the light passing through the area of ​​interest. Therefore, the control unit 120 does not need to perform high resolution imaging of the area of ​​interest, but analyzes the collected photons scattered in a significant volume of target tissues.

[0082] The control unit 120 processes the portion of the measurement data associated with the labeled photons 250 scattered from the area of ​​interest to determine the corresponding parameter in the area of ​​interest - oxygen saturation in this example. Two methods can optionally be used to determine oxygen saturation, one based on the measurement of average oxygen saturation (known as oximetry) and the other based on the measurement of oxygen saturation correlated with changes in blood volume during the cardiac cycle (known as pulse oximetry).

[0083] Oxygen saturation (saturation), S is the ratio of oxygenated hemoglobin [HBO] to total hemoglobin [HBT] in the blood:

<img file="PL1863387T3_D0002.tif" />

where [Hb] is the deoxygenated hemoglobin concentration.

[0084] The saturation value S can be obtained from the attenuation factor measured for at least two wavelengths λ1 and λ2, the molar absorption coefficients and HB and HBO scattering for each wavelength are known from the literature. Note that more than two wavelengths can be used to improve measurement sensitivity.

[0085] When the arteries dilate, blood volume [HBT] is increased by [AHbT], therefore absorption changes periodically. Optical attenuation at λ1 and λ2 is measured at predetermined points (e.g., maximum and minimum power spectrum of the tagged signal or processed tagged signal as defined below) generated by the detection unit 102a during the cardiac cycle. Saturation S can be calculated based on differences in light attenuation (AOD ^ for each wavelength between maximum and minimum.

ΔΟΏ^λ = (γ ^ ΙΔ ^ &amp; Ο] + γ ^ [Δ / β]) Ζ^λ = (γ ^ 5 + γ ^ (1 - Sy) [AHbT] L^k [3] where

<img file="PL1863387T3_D0003.tif" />

are the molar suppression coefficient of oxygenated and deoxygenated hemoglobin, respectively, at wavelength λ (λ = λ₁, λ₂), L^AND means the effective length of the optical path from the lighting unit (its light output port) to the detection unit (its light input pore) associated with the dispersion by tissues. L factor^AND can be determined by solving the photon diffusion equation for the appropriate measurement geometry (for example, as disclosed in A. Zourabian et al. "Transabdominal monitoring of fetal arterial blood oxygenation using pulse oximetry" Journal of Biomedical Optics 5 (4), 391-405 ( 2000)).

[0086] Determining the R ratio between ΔOD^λ for each wavelength λ₁and λ₂, assuming that, L^K1 essentially equals L^K2, we get:

_ ΔΟ £>^{Λ |} _ [7 // 60 ^ + 7 // 6 0 - ^) 3 than ^ OD^kl [7 ^ + 7 ^ 0-5) 3 where saturation S is obtained from equation [4] when ΔOD^λ1 and ΔOD^λ2 are measured and molar attenuation coefficients are known. In the case where L^K1 essentially does not equal L^K2, can be determined empirically (see above reference to A. Zourabian et al), or the wavelength selection is determined such that the two parameters are essentially equal.

[0087] When monitoring the tissue area, or with a negligible pulsation, ΔOD^λ is determined as the difference between the optical signal parameter under two different measurement conditions, as defined below.

[0088] In accordance with an embodiment of the present invention, the control unit analyzes the signals generated by the detection assembly in response to each wavelength λ1, λ2 generated by the lighting assembly. The labeled signals corresponding to the collected, labeled photons are selected by the detection assembly using the interference principle with a local oscillator, or by the control unit 120 by means of frequency analysis and / or spot imaging. The time-dependent amplitude and / or phase of the labeled signals for each wavelength λ1, λ2 is stored in the memory of the control unit 120, at a time determined to optimize the output signal, e.g.

increase SNR. To determine the level of oxygen saturation in the area of ​​interest, the control unit 120 determines the time-dependent changes in attenuation of labeled signals for each wavelength.

[0089] To determine oxygen saturation in area of ​​interest 200 based on oximetry, time-averaged signals generated by the detection unit in response to labeled photons of at least two light wavelengths collected by the light input port are used. Time averaging can be performed over periods longer than the duration of the heart cycle.

[0090] When pulse oximetry is used to determine the level of oxygen saturation, periodic changes (due to the heart cycle) of blood volume are monitored by the control unit 120 by monitoring low frequency changes (0.5-2.5 Hz) of signals generated by the unit detection light entering the input port. Because the frequency of ultrasound is orders of magnitude higher than heart rate, in order to improve SNR measurement, it is possible to average signals responding to labeled photons from a fraction of the heart's cycle. Using oxygen oximetry, both oxygen saturation and heart rate are determined simultaneously.

[0091] The control unit 120 displays the set oxygen saturation level, along with the heart rate, as a function of time. The heart rate is determined by low-frequency analysis of labeled signals. The control unit 120 optionally warns, by means of a suitable tool (e.g. sound and / or light signal, when the oxygen saturation level falls below a certain threshold (e.g. 50% or 70%) [0092] In an embodiment of the present invention, the optical module is configured as a pulse oximeter, i.e. includes an lighting assembly

101 A generating light at least two different wavelengths and light detection assembly 102A; is used in conjunction with the 110 acoustic transducer system to significantly improve pulse oximetry measurements. The measuring system can be configured to operate in transmission mode (light transmission detection), just like a conventional pulse oximeter on a finger or earlobe. In this case, the support structure 403 is positioned so that the lighting assembly 101A is collinear with the detection assembly 102A: the lighting assembly 101A is located on one side of the tissue, and the detection assembly 102A is located on the opposite side of this tissue, thereby both transmitted light, as well as diffuse emitted by lighting assembly 101A is detected by detection assembly 102A. The transducer system 110 is positioned such that the acoustic waves coincide with the illuminated area of ​​interest from which the scattered light reaches the detection assembly 102A, preferably the area includes a blood vessel (e.g., an artery) or a collection of arterial vessels. In other applications requiring reflection based reflection of interest ("reflection mode"), the measurement system 100 is positioned as described above, wherein the area of ​​interest preferably includes blood vessels (e.g., an artery) or a collection of arterial vessels. This arrangement is better than a conventional pulse oximeter, because it is not affected by inconsistent ambient light, and more importantly, the relative movement of the tissue relative to the detection unit and the lighting unit has less effect, as long as the area of ​​interest is illuminated and propagates through him acoustic waves.

[0093] It should be understood that the use of acoustic light marking in pulse oximetry measurements significantly improves the measurement results, because the measured tagged light signal is practically insensitive to movements of the area of ​​interest within the measurements, which is a common problem in typical, pure pulse oximetry measurements.

[0094] As indicated above, due to the appropriate operation of the acoustic transducer system, at least two different optical paths of dispersed, labeled photons are obtained under at least two different measuring conditions (corresponding to two different values ​​of the acoustic radiation characteristics). When measuring oxygen saturation, this ensures that the oxygen saturation level in the area of ​​interest is determined, regardless of the pulsating volume of the blood. This is especially important for measuring local oxygenation of tissues or blood vessels or when pulsation is negligible. The control unit 120 controls the measurement conditions by controlling at least one activation parameter of the transducer system 110, such that the transducer system 110 emits at least two different acoustic signals having two different activation parameters when illuminating an area of ​​interest with a light of one wavelength, or at least two different wavelengths of light (or vice versa). At least one activation parameter includes, among others, the following parameters: duration of the acoustic pulse or wave, amplitude, frequency, number of elements activated in phased matrices, focal length of the transducer system, focal length dimensions (e.g. acoustic beam width at a distance equal to the focal length) of the transducer system or a peep gradient at the frequency of the acoustic waves.

[0095] The measurement conditions are determined such that the labeled volume in each measurement is within the area of ​​interest and that the average optical and acoustic characteristics of the labeled volume are approximately the same during and between these two measurements. Of course, two or more measurement conditions can be changed between measurements. For example, two sets of measurements are made for two different pulse durations, with the first set having one acoustic wave amplitude and the second set having the second acoustic wave amplitude. All measurements are then used to determine the parameter for the area of ​​interest.

[0096] Consider the signal generated by the detection unit 102A indicating the light response of the labeled volume:

<img file="PL1863387T3_D0004.tif" />

where C is the proportionality constant, depending on the efficiency of the detection unit and the surface of the IP light input port, EU is the absolute amplitude of the unlabelled electromagnetic field, ET is the absolute amplitude of the labeled electromagnetic field, ω ^ is the light frequency, φ_υ and Φ? means the phases of unlabelled and labeled electromagnetic fields respectively and Ω ^ is the acoustic frequency.

[0097] Because the labeling efficiency (the number of labeled photons relative to the number of unlabelled photons scattered by the scattering centers within the labeled volume) is low (e.g. Iu = | EU |² >> | ET |²= IT), the detected signal It (t) can be written as:

<img file="PL1863387T3_D0005.tif" />

[0098] The first component means a constant component while the second component is modulated in acoustic frequency. Amplitude of the second component, sampled at the acoustic frequency, divided by

<img file="PL1863387T3_D0006.tif" />

[0099] Optical attenuation OD^λ light with a specific wavelength λ is defined by the modified Beer-Lambert law as:

<img file="PL1863387T3_D0007.tif" />

where /^λ is the light output intensity and f is the light input intensity, α^λ is the absorption at the wavelength λ (which depends on the concentration of chromophores), L^h is the effective optical path length which is responsible for scattering and G is the geometric measuring factor.

[0100] For labeled and unlabelled signals, we can write using the equation:

<img file="PL1863387T3_D0008.tif" />

iu =^c2^;oexp [-aMv - gJsC₂/₀k ^ exp [- Ć7] [9b] ​​where C₁ and C.₂ are constants and L^hT and Lf are effective optical path lengths of labeled and unlabeled photons, respectively. Assuming that the effective path length changes of labeled photons ^ L_T) in the labeled volume depend primarily on changes in the characteristics of acoustic radiation and are essentially independent of the wavelength of light:

^ y- = - [Aa / Zr + α^λΔΐ_Γ]. [10a] κ_Γ ^ - = -Δα^λζ £, [10b] [0101] Formulas 10a and 10b assume that the effective optical path length in the labeled volume changes, while the effective optical path length in unlabeled volume does not change, and the marked volume is much smaller than the unlabelled volume and thus a change in the effective length of the labeled optical path has little effect on the unlabelled signal. Because Δα^λ presents changes in the concentration of chromophores in the medium, it can be omitted during the measurement when there are slight changes in their concentration (i.e. in the absence of pulsation in the case of blood-related measurements, or when changes in the concentration of chromophores occur over a much longer period than used in conditions measurement).

[0102] In this way, by introducing changes in at least one of the characteristics of the acoustic radiation (for example, as a result of a change in the effective optical path length in the labeled volume) in two successive measurements, the chromophore absorption coefficient in the labeled volume can be determined.

[0103] The tagged signal obtained from the signal measured during the first measurement is designated IT1, and the marked signal during the second measurement is designated IT2. Thus:

J_T}-1_T2 __αλ ^ [11]

Λί κ £, [0104] For oxygenated and deoxygenated hemoglobin

<img file="PL1863387T3_D0009.tif" />

for two different wavelengths λ 1 and λ 2 we get:

_ α^λ1ΔΖ · Γ __ (Υ + Υ Ο ~ α Δ £ τ "(Υ⁺ ΥHb ^ ~ [12] [0105] Therefore, eq. 12 is equivalent to 4. Therefore, causing small changes (ĄLt &lt;&lt; L^kt) in the effective optical path length of labeled photons, in order to determine the level of oxygen saturation in the determined volume, it corresponds to a change in the concentration of chromophore.

[0106] The following are non-limiting examples of making changes to at least one acoustic radiation property.

[0107] The control unit controls the production of acoustic radiation to create a labeled volume of VT, such that small variations in VT correspond to small variations in the effective optical path length of labeled photons. According to the present invention, different labeled volumes substantially overlap in space.

[0108] For example, the control unit controls the activation of the signal generator (122 in Fig. 1A), such that the signal generator transmits two series of pulses at the same or different repetition rate for each series. This is illustrated in Figs. 2A and 2B; an example of the measurement method is shown as a block diagram in Fig. 3. For clarity, Figs. 2A-2B show only significant components of the measurement system 100 applied to area of ​​interest 200.

[0109] A control unit (not shown) activates an acoustic signal generator to produce a series of specified amplitude, frequency f and phase Φ. The generated pulse activates the transducer system at t100 for the duration of T1. This pulse, referred to as the "T1 pulse", propagates through surrounding tissues in a part of the body and reaches the area of ​​interest 200 at time t0. The control unit activates the lighting unit 101A emitting light with at least one wavelength λ 1. The control unit activates the set of signals of the detection unit 102A at t 0 following t 100. The detection unit 102A collects marked and unlabeled light from a part of the body at time To. During time To (following time t0), the sound waves propagate at a distance D from the acoustic output port 245. The spatial length, d1 of the T1 pulse is equal to the product of T1 · Cs, where Cs is the velocity of propagation of acoustic waves (e.g. sound velocity) in the area of ​​interest. Volume 266, which has been marked by the pulse T1 at any time in time, is equal to d1 times the cross section A 'of the acoustic beam. For example, for a flat acoustic wave with a uniform cross section A 'it can be assumed that the volume 266 is equal to V₁T =₁C_s-AND'. The control unit analyzes the measured data (marked and unlabelled signals detected) to determine the signal parameter corresponding to the optical attenuation (e.g. the amplitude of the power spectrum of the detected signal in the frequency of the acoustic wave). The determined parameters are stored in the device's memory [0110] The control unit activates the signal generator to generate a second series having the same amplitude, frequency f and phase Φ.

The generated pulse activates the transducer system at t 200 for the period T2 (T2 is different from T1). This impulse, referred to as the "T 2 impulse", propagates through the surrounding tissues in a part of the body and reaches the area of ​​interest 200 at t 0.

[0111] It is clear that many T1 pulse series can be emitted sequentially before the emission of many T2 pulse series, until the optical and acoustic properties of the tissues change during the two pulse series. The signal series corresponding to the T1 and T 2 series will be analyzed as a long series. In such cases, it is advantageous if the series of acoustic pulse pulses is phase synchronized to improve SNR. The signals are combined to form a long-time signal and then analyzed as the effect of one long series.

[0112] Pulse T2 propagates to the same distance D at time T0 following time t0. Impulse T2 occupies a volume of 267 equal to:

V₂T =₂CsA '. For a flat acoustic wave, the difference in labeled volume is: Δν ^ νΊ-νϊ ^ ΓΊ-Τύ ^ Α '. The control unit also activates the lighting unit 101A emitting light with at least one wavelength λ 1. The control unit activates the set of signals of the detection unit 102A at the moment 1₀ following 1 ₂₀₀, [0113] The control unit activates the detection assembly 102A to collect labeled and unlabelled light signals over a period T0, preferably shorter than the shortest duration of the pulse series (i.e. shorter than T1 or T2). As the labeled volume changes, the number of labeled photons reaching the detector's input port will change. The control unit analyzes the relevant measured data to determine the same signal parameter corresponding to optical attenuation (as for the T1 series) and stores this parameter in the device's memory. Thus, for each T1 and T2 series, the control unit stores the tagged and unlabelled signals and stores them in memory.

[0114] The above technique is repeated for each wavelength λ1, λ2 and for each wavelength the difference of the tagged signal (IT1-IT2) is calculated based on the difference of the tagged signal parameters (e.g., the amplitude of the power spectrum of the tagged signal in acoustic frequency, normalized or not by the corresponding parameter of the unlabelled signal) between the T1 and T2 series, equation 12 is used to determine the level of oxygen saturation.

[0115] In another example, different operating conditions for the generation of acoustic radiation (providing different optical path lengths) are obtained by controlling the width of the acoustic beam. The control unit determines the width of the acoustic beam by adjusting the beam opening or several acoustic elements activated in the transducer system 110, forming the phase matrix. The focal length of the matrix is ​​immutable between series, only the beam dimensions in both series change (i.e. one series has a beam width BW1 and the other has BW2). As in the example described above with different pulse durations, the tagged signal is specified for each BW1 and BW2 width, and the relative difference in parameters of the tagged signal is determined for each series. The process is repeated for each of at least two illuminating light waves, which determines the tissue parameter. [0116] Labeling efficiency, defined as the number of labeled photons relative to the number of unlabeled photons scattered by the dispersion media within the labeled volume, depends, as is known, on the frequency of the acoustic beam, the speed of the acoustic wave in the tissue and the amplitude of the acoustic radiation in the labeled volume. Therefore, changes in the frequency of the acoustic radiation, the intensity (or power) of the acoustic beam and the speed of the acoustic wave (sound) in the tissue, cause changes in the effective length of the optical path of the labeled photons.

[0117] Assuming constant labeling efficiency under both measurement conditions, as explained above, the normalized amplitude at the acoustic frequency corresponds to the optical attenuation of the medium. Assuming that the average optical and acoustic properties of the illuminated medium are almost the same in both measurements, the difference or ratio between optical attenuation t in two measurement conditions corresponds to the optical properties of the area of ​​interest. [0118] The effective optical path length can also vary between measurements by changing performance markings.

[0119] For example, the amplitude of the acoustic waves can be changed between two or more acoustic pulses. For example, the transducer system produces one pulse with an A1 amplitude and another pulse with an A2 amplitude different from A1. Since the labeling performance depends on the amplitude of the acoustic waves, the measurement data indicates two different labeled signals generated by the detection unit in response to the collected photons of each acoustic wave pulse of A1 and A2 amplitude. The difference or relative difference between the two signals corresponds to the effect of the amplitude of the acoustic waves on the marked signals, and can therefore be determined by this measurement.

[0120] In yet another example, the frequency of the acoustic waves is changed between two pulses (or two series of pulses), one pulse has the frequency F1 and the other has a different frequency F2. In the case of a focused acoustic beam, assuming the absence of chromatic aberration of the acoustic lens assembly used in the transducer system, the dimensions of the focal volume (i.e. beam diameter and focal length) are known to depend on the frequency of the acoustic radiation. Therefore, different frequencies will be focused in different volumes, and the size of the labeled area will be different for each frequency. In addition, the marking efficiency depends on the frequency of the acoustic waves. Both effects lead to different effective optical path lengths. The control unit starts the signal generator to emit pulses of the same amplitude, phase and duration, but with two different frequencies F1 and F2. This measurement system is repeated for each wavelength λ1 and λ 2 of illuminating light and for each wavelength, based on the difference in the parameters of the tagged signal (e.g. the amplitude of the power spectrum of the tagged signal at acoustic frequency) the attenuation difference between the series with frequency F 1 is calculated and F 2. Equivalent 12 is used to determine the level of oxygen saturation.

[0121] In yet another example, the acoustic frequency of each pulse can be modulated (e.g. by tweet) so that the signal generator continuously generates modulated signals (i.e., "pulse" refers to one tweet cycle). The control unit sets the frequency range Af1 as described above, to propagate then through tissue volumes 200 at At1. As shown in Fig. 2C, during one cycle of tweet modulated cycles (cycle 1), the tweet gradient (df / dt) is equal to GC₁, and during the second cycle of tweet modulated cycles (cycle 2), the tweet gradient (df / dt) is equal to GC2.

[0122] The control unit activates the lighting assembly 101A with light of at least one wavelength λ1. The control unit activates the collection of signals from the detection unit 102a at time t0. This process is repeated for different optical wavelengths for each GC1 a and GC2 set, and the processed signals (e.g., the power spectrum of the tagged signal) are stored in memory. Again, for each GC1 and GC2 cycle, the parameter of the tagged and unlabeled signal is determined and stored. For each wavelength, the difference between the normalized labeled signals is determined, for each wavelength, as the difference in the value of this parameter for each wavelength, for two cycles.

[0123] Since the labeling performance depends on the acoustic properties, but the total signal labeling depends on both the optical and acoustic properties of the labeled volume, various measurement conditions can be used to separate these effects on the labeling performance of the total signal. This can be achieved, for example, by making four different measurements, one pair for two different pulse durations with one amplitude and the other for the same pulse durations with different amplitude of acoustic waves. Δα is determined for each pair of measurements^λ as indicated above, then the difference between the specified values ​​(if any) is taken into account in the changes in marking efficiency. Once this relationship is established, it can then be used to determine the effect of acoustic parameters on the measured signals. Alternatively, three different optical wavelengths can be used to determine the relative state of measurement, the acoustic properties are the same between measurements. The measurement is repeated for each of the three wavelengths, in two different measuring conditions, and the acoustic parameters are separated from the set signals. The following is an example of the use of the system according to the present invention for imaging the tissue region in the body, namely the optical attenuation mapping (i.e. determining the optical attenuation parameter at each location). The control unit 120 controls the arrangement of the ultrasonic transducer 110 to scan various volumes of tissues. The intensity of each pixel or voxel in the image is determined as follows:

Step 1: Signal generator 122 is activated to send a signal to transducer system 110 to generate one T1 audio pulse.

Step 2: The lighting unit and detection unit are activated with a specific delay time td, such that the T1 acoustic pulse propagates over distance D_d from the 245 sound port, determined by the formula D_d= C_s-t_d. In the case where the transducer system 110 is a phased array, the control unit 120 also determines the angle Θ_d between the 245 acoustic port and the propagation direction of the acoustic beam. The control unit 120 processes and analyzes the signals (measurement data) generated by the detection unit 102A at T0 (as defined above) and stores the parameters of the processed signals in memory.

Step 3: Step 1 and Step 2 are repeated using the same time delay parameter t_d (and angle parameter Θ ^ if needed) ultrasonic pulse T 2 is generated by the acoustic system 110.

Step 4: The control unit 120 then analyzes the recorded parameters of the light signals generated during pulses T1 and T2 to determine the property of the volume of tissue labeled by acoustic radiation at distance D_d (and angle Θ ^ where applicable) from the sound port. Then, a certain value is assigned to such a property (for example, the degree of oxygen saturation of this volume).

Step 5: The assigned value is displayed as an image with two or three dimensions on the screen where the pixel / voxel position corresponds to the distance D_d and angle Θ_d from the 245 sound port (the 245 sound port position can be used as the "zero position" on the screen, and all distances are calculated relative to this zero position).

[0124] Steps 1-5 are repeated for different delays td (and different angles Θ

d) and a full image is displayed when the value of each pixel is translated into a color scale, gray scale or numeric scale representing a parameter value (e.g. hemoglobin or saturation). [0125] The method of the present invention can be used to determine blood concentration or blood volume or other chromophores in an area of ​​interest. In order to determine the blood volume, one wavelength corresponding to the isosbestic point of oxygenated and deoxygenated hemoglobin may be used, but preferably two or three light wavelengths are used, with at least one corresponding to the isosbestic point. In order to determine the volume or concentration of blood in the labeled volume, the transducer system generates two characteristic impulses of acoustic waves (as described above for oxygen saturation). Marked and unlabelled signals are detected for each pulse, and the corresponding measurement data is collected by the control unit over a period of time corresponding to the propagation of acoustic waves within the area. These signals are recorded and stored in memory for each wavelength of light. For isbestos point Y_HbO= Y_hb= γ_ΗΤ and from equation 12 above, we get:

&amp;FROM^l=/_HBT[HBT] AL_T . [13] [0126] Total blood volume in labeled volume can be calculated if Δ L is known_T. Preferably, two or more wavelengths are used to determine hemoglobin concentration in the area of ​​interest, as explained above.

[0127] It is known that the optical properties of a clot or internal hemorrhage can be determined by near infrared spectroscopy [B. Chance et al "Optical investigations of physiology: a study of intrinsic and extrinsic biomedical contrast" Phil. Trance. R. Soc. Lond. B (1997) 352, pp. 707-716]. Therefore, by monitoring changes in labeled signals of interest in the hematoma or bleeding, the control unit can determine the hemorrhagic event and the possible time interval of the hemorrhage, or changes in the blood volume of the existing hemorrhage.

[0128] According to another embodiment of the invention, the area of ​​interest is a blood vessel or a blood-filled cavity such as the chamber, sinuses and pad. Blood oxygenation within the area of ​​interest is monitored by the measuring system of the present invention. For example, venous blood oxygen saturation is measured in the jugular vein bulb, using a modified probe. The jugular vein pad is at the base of the skull, about 2-3 cm behind the ear. Therefore, it is preferable to place the acoustic transducer system inside the external auditory canal so that its output surface forms acoustic contact (using gel or oil) with the outer wall of the external auditory canal. The transducer system is configured and positioned so that the acoustic waves pass through the auditory canal and are focused on the jugular vein bulb.

Such configuration may include phase matrix elements or other elements adapted to work in any direction, phase and delay time. To determine the exact location of the jugular vein pad in relation to the auditory canal, the operator can use radiological images obtained before the operation of the image processing device or the back-reflected Doppler signals from the pad. If Doppler signals are used, the transducer may include, but is not limited to, an acoustic transducer capable of generating and collecting acoustic signals at a frequency and duration appropriate to perform Doppler measurements (e.g., by means of 2MHz ultrasonic waves). The control unit analyzes the Doppler shift of the signals to determine the distance from the probe head located in the ear canal to the jugular vein pad during calibration mode, as well as between actual measurements to check that the acoustic transducer has not changed its position relative to the jugular vein pad .

[0129] Figs. 4A-4B illustrate the use of a measurement system 100 according to the present invention for measuring the level of oxygen saturation in the area of ​​interest of external brain tissues. The area of ​​interest is the internal jugular vein, in some cases the pad of the internal jugular vein is located near the middle cavity of the ear. The location of the area of ​​interest is preferably determined using a Doppler imaging system that recognizes the direction of blood flow and the distance from the vessel. Such a Doppler system may form part of the transducer system 110 of the measurement system 100. When the location of the jugular vein (pad or other area) of interest is determined, the transducer system 110 is attached with glue from the bottom of the output port or with a belt. A flexible probe (supporting structure) 403 is attached to the area of ​​skin covering the area of ​​interest. The flexible probe 403 includes a lighting assembly

101A (at least its light output ports) and detection unit 102A (at least its light input ports) and with appropriate optical indicator matching adhesives, used to attach the light input and output ports. The flexible probe 403 is connected to the control unit 120 by means of cables, optical fibers or wirelessly.

[0130] In the arrangement shown in Fig. 4A, the transducer arrangement 110 is located such that at least its exit port is on the supporting structure 403 between the light inlet and outlet ports. The control unit 120 operates to determine the distance between the input and output ports so that the light propagating through the area of ​​interest is collected by the detection unit 102A.

In the system configuration of Fig. 4B, the transducer system 110 is located outside the support structure 403 in an optimal location for subjecting the jugular vein or jugular vein to acoustic radiation. The optimal site may be the ear canal as described above.

The control panel (not shown) then determines the optimal position of the lighting unit and detection unit, such that the scattered light from the area of ​​interest reaches the input port of the detection unit 102A. The control unit controls the operation of the optical system placed on the supporting structure 403 and the functioning of the acoustic transducer system so as to enable the determination of oxygen saturation of blood passing through the jugular vein. In addition, the control unit may collect acoustic signals containing a Doppler shift, reflected from the blood flowing inside the jugular vein to determine blood flow parameters as well as to adapt to movements or changes within the probe head relative to the area of ​​interest.

[0131] It will be understood by those skilled in the art that the acoustic transducer assembly may be inserted through other tracks or lumens in the human body so as to form acoustic contact with the inner wall of the track.

[0132] According to yet another embodiment, one of the detection or lighting assemblies may be inserted through the same path or lumen as the transducer system, or through another path or lumen, so as to ensure optimal positioning of the system relative to the area of ​​interest. This configuration may include a catheter placed in the track or lumen, or an endoscope containing optical and acoustic elements for imaging the inner part of the body.

[0133] It should also be noted that other blood vessels (veins or arteries) can be monitored with this device and the measurement method is not limited to the jugular vein, which is given by way of example only. Other examples include, but are not limited to, monitoring of other blood analytes in blood vessels (e.g. glucose, urea and bilirubin) and monitoring of other vessels (e.g. femoral artery in the hip joint or other locations near the skin). In each embodiment, the position of the blood vessels is determined using an imaging system (preferably a Doppler imaging system), and the system of the present invention is used to monitor the blood vessel.

[0134] Fig. 5A shows a modified probe (measuring unit) 101 for measuring in the area of ​​interest. Lighting assembly

101A includes one or more light emitters (not shown) and a light conducting unit, including optical fibers, optical fibers or optical fiber bundles 810 and 814 optically connected to each other by a connector 850. The light from the light emitter is connected to the 810 fiber at one end thereof and propagates through this optical fiber towards the optical connector 850 to another connected optical fiber 814. The distal end of optical fiber 814 includes an output port

OP lighting unit. An optical fiber 850 or fiber bundle 811 is also attached to the optical connector 850. The detection assembly 102A includes one or more light detectors (not shown) and a light guide unit, including the optical fiber or beam 812 optically coupled to the optical fiber or bundle 813 via optical connector 851, which is also connected to the 811 fiber or bundle.

[0135] The optical connector 850 is configured to couple some first portion (e.g., 1% of the propagating light intensity) input light propagating through the fiber 810 to the optical fiber 811 and couple the second portion of the input light (e.g., 99%) to the fiber 814 This second portion of fiber light 814 illuminates, through the OP light output port, the skin region 10 covering area of ​​interest 200. The 813 fiber provides the light collected by the IP light input port towards the light detector.

[0136] The connector 851 combines light from fiber 813 and fiber 811 to fiber 812. The connector 851 is designed to provide maximum light transmission from fiber 813 to fiber 812, which means that coupling losses are minimal. The coupling efficiency of the connector 851 from fiber 811 to fiber 812 should preferably be constant.

[0137] It should be understood that the fiber portions 810 and 814 or the fiber portions 813 and 812 may be the same physical fibers, they need not be separate fibers. It should also be understood that the optical unit (i.e., the length of the fiber portion 811 and the location of connectors 850 and 851 along the fibers 810 and 813) is configured in such a way that the light passing through the 811 fiber is consistent with the light collected by the IP input port and reaching the 851 to meet the interference condition. This requirement is in line with the requirement that the coherence length of the light source is longer than the length of the light path inside the tissue as explained above. connectors

850 and 851 may be included in flexible probe 403.

[0138] Photons 820 from fiber 811 interfere with labeled and unlabelled photons 250 propagating in fiber 813, the intensity of light incident on the detector (s) is modulated over time.

[0139] The interference signal of the three electromagnetic fields is read by the detection assembly. This can be saved as:

1, (/) = C | £ y exp [/ ((u_;/ + Φν)] + Ε_τ εχρ [; ((ω_£ + Ω_μί) / + «Ί_Γ)] + E_L0 exp [z (&lt;yj + φ_ι0)}² [14] where C is the proportionality constant, depending on the performance of the detection assembly and the surface of the light input port, EU is the absolute amplitude of the unlabeled electromagnetic field, and ET is the absolute amplitude of the labeled electromagnetic field, ωι.

is the frequency of the light, φ_υ and φτ denote the phases of unlabelled and labeled electromagnetic fields, respectively, Ω US means the acoustic frequency, E LO means the absolute amplitude of the electromagnetic reference field and φ LO means its phase.

[0140] The signal may be divided into three components:

f = |^£t / | + NW^{+ 2E}AT ^ELO ^C0S($ U - ΦΐΐΑ

<img file="PL1863387T3_D0010.tif" />

<img file="PL1863387T3_D0011.tif" />

[0141] The first component I1, in most cases, will be constant and will have a certain line width, which depends, e.g., on the breathing rhythm of the body and Brownian movement of the distraction centers. The second and third interference patterns are modulated in time by the acoustic wave frequency

255 emitted by the transducer system 110. The control unit 120 analyzes the signal generated by the detection assembly to determine the parameters of the area of ​​interest and the tissues surrounding the area of ​​interest. All three components can be analyzed simultaneously. In addition, each of the components can be separated by blocking the transmission of 820 photons or 250 photons, or by analyzing the signals detected when the sound waves do not propagate (no "marking").

[0142] For example, photons 820 may be used to determine light source characteristics by the control unit during system operation. The control unit may instruct the connector 851 to block light transmission from fiber 813 to fiber 812 at specific time intervals. During these periods, only 820 photons will be detected, which can serve as a reference point for the properties of illuminating light (e.g. intensity, length of source coherence). According to another possibility, the control unit activates the detection of photons 250 when the acoustic waves 255 do not radiate at all to the tissues. Thus, during these periods all photons 250 are unlabelled ("no labeling"). The signals detected during these periods are the result of interference of unlabeled 250 photons and 820 photons. This signal depends, for example, on Brownian motion of the scattering centers and on the breathing rhythm. Thus, these two parameters can be determined and used during these periods to optimize the measurement conditions (for example, to reduce breathing artifacts). The control unit activates photon detection 250 when acoustic waves 255 radiate to the area of ​​interest ("normal marking"). During labeling, there are an increase in components two and three compared to the periods of "no labeling". These relative changes can help determine parameters of the area of ​​interest and surrounding tissues.

[0143] According to yet another option, when acoustic radiation is used to mark an area of ​​interest (normal marking), the control unit may block photon collection 820, blocking their transmission through switch 851, thereby sampling photons

250 (i.e. only unlabeled light and component three). This signal is used to separate the I2 input into an audio-modulated signal (i.e., I2 + I3) when photons 820 and 250 interfere (referred to as "coupled signal") and thereby extract the I3 input.

[0144] In order to separate the I2 and I3 input into the coupled signal simultaneously, it is preferred to introduce a frequency shift into the reference arm formed by the fiber 811.

[0145] Fig. 5B illustrates a similar configuration of the measuring device 101, but using a light modulator (e.g., acousto-optical modulator or photorefractive crystal) 815 in the optical path of light passing through the fiber 811. Light propagating through the fiber 811 is attached to this light modulator through its input surface 811A and disconnected from the light modulator 815 through its output surface 816a to another optical fiber 816, which in turn is optically coupled to port 851. Connector 851 connects light from the fiber optical 816 and 813 in 812 fiber. Because the light propagates through the 815 light modulator, its frequency is shifted at a certain frequency Ω_αο defined by the control unit (not shown) in relation to the characteristic frequency Ω ^ of acoustic radiation generated by the transducer system 110. Modulation frequency Ω _AO is optimally selected so that it differs from the characteristic Ω US frequency. In this regard, photons 820, after exiting the modulator 815, have a shifted frequency and are designated as modulated photons 821. Photons 250, collected at the IP light input port and connected through a connector 851 from fiber 813 to fiber 812, interfere with photons 821. Interference signal:

I, (i) = - ύ \ Ε_υ εχρ [ι (ω £ ί + 4 ^) 1+ ^ET exp [i ((in jr. + &amp; Us) &lt;+)] + ^elo ^exp [ '(( "i ⁺ ^ aol¹ + ΦLO) J |² [16] _ _ has four important frequency components:

<img file="PL1863387T3_D0012.tif" />

<img file="PL1863387T3_D0013.tif" />

<img file="PL1863387T3_D0014.tif" />

<img file="PL1863387T3_D0015.tif" />

[0146] The number of photons 821 can be monitored, for example by blocking the transmission of photons 250 through the connector 851 and detecting the number of photons 821 reaching the detection module, the contribution of unlabeled photons to the first component I'1, can be isolated assuming, as before, | EU |²>> | ET |². The signals generated at three different frequencies represent, respectively, the interference between 821 photons and 250 unlabelled photons (I'2) the interference between 821 photons and 250 labeled photons (I'3), and the interference of labeled and unlabelled 250 photons (I'4). Because 821 photons do not pass through the body, the control unit can separate the effects associated with the general propagation of light in tissues from the light source to the detector separately from the local effects of labeled volume.

[0147] For example, using the configuration of Fig. 5B, there are two independent measurements for labeled and unlabelled photons, allowing the correlation of spots or Brownian motion of the scattering centers to be separated from the components I'2 and I'4. In addition, after separating the labeled and unlabelled signals, they can be used to calibrate tissue models A and B described above.

[0148] Thus, for example, the line width of the I'2 component can be used to determine the tissue dispersion factor. Therefore, the scattering factor of tissue models A and B can be determined and used to calibrate and explain light propagation through surrounding tissues. The control unit 120 then determines the absorption coefficient of the area of ​​interest, separated from the scattering coefficient, by measuring the light attenuation of the tissues.

[0149] Furthermore, the relative amplitudes of the components I'2 and'3 and I'4 can be used to isolate the contribution of each signal. For example, to optimize the modulation of the amplitude of the I'3 component, the ratio of the amplitudes of the I'2 and I'3 components can be used by controlling the percentage of photons

820 that are connected to fiber 811 via a connector 850, or by controlling the efficiency of the transfer to modulator 815, resulting in the control of the amount and phase of photons 821. The number of photons 821 can, for example, be roughly equated with the number of labeled photons 250, for each length wave by optimizing the amplitude of the I'3 component. When this condition is reached, the I'3 component will provide maximum sensitivity to signal changes in the labeled photons.

[0150] Since the width of the autocorrelation spectrum line or power spectrum of the labeled signals around the frequency of the acoustic radiation is different when the marking is carried out at different centers, the control unit can determine, by monitoring the line width, when an ultrasound beam is used for optimal marking of the volume of the area of ​​interest .

[0151] Additionally or alternatively, other parameters of labeled and unlabelled signals, such as amplitude and frequency, are used to determine one or more parameters indicating an area of ​​interest. For example, blood volume can be determined at any location as described above. The control unit then displays the blood volume at each location scanned by the acoustic beam. The image can be superimposed on the morphological image of the monitored organ, e.g. CT or MRI image of the brain. The system of the present invention can monitor cerebral hemorrhage, subarachnoid hemorrhage or other blood clots in the brain. Alternatively, the oxygen saturation corresponding to each location of the acoustic beams can be determined and displayed. The system can be used to monitor tissue ischemia, in particular brain ischemia.

[0152] In another embodiment of the invention, the measurement system may be used to monitor changes in the concentration of analyte (s) in the area of ​​interest during therapeutic or surgical procedures (e.g., when using high-power pulses or ultrasonic waves, laser ablation, or chemical procedures) ). For example, the transducer system can be used to ablate tumors or distortions in tissue. When using high-power ultrasonic pulses, light is emitted and collected by the lighting unit and detection unit, respectively, to determine the concentration of the analyte characteristic of therapy in the ablation area. Alternatively, low-power ultrasonic pulses (which do not cause ablation) radiate intermittently to the area of ​​interest, while low-power pulses of light are emitted and collected by the lighting unit and detection unit to determine the concentration of the analyte characteristic of the therapy. Oxygenation, for example, is monitored. Such information is used to control and monitor therapy when using ultrasound radiation.

[0153] Figs. 6A-6B illustrate specific designs of the respective transducer system 110. To create a focused ultrasonic beam, a phased array 410 containing multiple elements is used. Various configurations of a phased array, known for having a large effective surface without loss of flexibility, are known for positioning lighting and detection assemblies.

[0154] Fig. 6A schematically shows a top view of a transducer system 410 comprising a chamfered annular matrix in a system comprising a central bore. The number and dimensions of the 410A-410D acoustic ring elements are determined to correspond to a particular focal depth and F # of the matrix. The transducer system 410 is placed in acoustic contact with the skin 401 covering the area of ​​interest. Optical elements, preferably optical fibers, associated with the lighting unit and detection unit are placed inside a circular hole in the transducer system. Five such elements 420A-420E are shown in Fig. 6A. Each of these elements may serve as an input or output light port in accordance with an embodiment of the present invention. This configuration allows for deeper beam focusing and a smaller focal depth than achieved with a single transducer element or a phased array placed between the light input and output ports. The phased array elements 410A-410D, activated by a control unit (not shown) deliver a focused ultrasound beam to the area of ​​interest, or outside the area. The focal plane of the phase system can be scanned by introducing an appropriate delay between the activation of each ring element.

[0155] In the example of Fig. 6B, a partially annular beveled matrix 415 is shown. The matrix 415 is generally shaped similar to the matrix 410 described above differs from the matrix 410 in that the acoustic transducers do not form closed ring elements 415A-415A, but only partially concave. The 415 matrix has a similar focal depth and F # as the matrix 410 described above (assuming that both matrices have the same number of transducer elements and dimensions). When comparing matrix 415 to matrix 410, matrix 415 provides greater flexibility when positioned on the skin surface, required, for example, when bones are present under skin area 401.

[0156] Figs. 7A, 7B and 8A-8B show examples of different support structure configurations (probe) 403 suitable for use in the present invention. In the example of Fig. 7A-7B, flexible probe 403 includes a flexible structure 301, for example made of electrically insulating material (s), carrying light ports 303-316 (fiber ends in a suitable housing, or light sources and / or light detectors as described above) and 302 audio output port (or audio transducer system). Fig. 7A is a bottom view of the flexible probe 403 viewed from the side from which it is attached to the skins, and Fig. 7B is a schematic side view of a flexible probe 403.

[0157] Optical fibers or 330-336 and 340-346 electric wires connect light ports 310-316 and 303-309, respectively, to common connector 320. An insulated electric wire (or acoustic waveguides) connects output 302 to the same connector 320. The sound port 302 is preferably coupled to the sound transducer system 327 connected to the flexible support structure 301 by means of vibration controls. The connector 320 is associated with the control unit (not shown), namely, it connects the optical fibers and wires connected to the flexible support structure 301 with the optical fibers and electric wires connected to the control unit. The connector 320 may consist of several connecting elements. On the underside of the support structure 301, adhesive 325 is applied, so that the probe 403 can be attached to the skin with adhesive 325. Adhesive 325 is preferably transparent and causes minimal dispersion in the wavelength range used for measurement (i.e., emitted by light sources). Alternatively or additionally, the adhesive 325 may be an optical level matching factor between light ports and skin. Alternatively, adhesive 325 may not cover light ports at all or may partially cover them. Adhesive 325 may contain pigments, chromophores or other materials to control the transmission of different wavelengths of light. Below the 302 acoustic port is 326 adhesive gel.

The 326 adhesive gel is made of the same or different material as the 325 adhesive and is designed for optimal acoustic coupling between the 302 acoustic port and the skin. Materials that can be used to make adhesives 325 and 326 include hydrogel based adhesives.

[0158] Individual flexible elements of probe 603 may be mounted in various ways. For example, the complete 603 probe is assembled prior to operation, and the user only needs to remove the thin layer covering the bottom side of the adhesives 325 and 326. In yet another example, the adhesive 326 is attached to the acoustic output port 302 (preferably including the acoustic transducer system) that it is not attached to the 403 probe prior to operation. The user first fastens the flexible support structure 301 to the skin using adhesive 325, and then inserts the acoustic port 302 through the appropriately provided opening 301, in the structure, the transducer 327 is optionally connected to the support structure 301 by conventional means and is attached to the skin by adhesive 326, which can be part of the adhesive 325, only acoustic output port 302 is inserted and attached to the top of adhesive 326 (which is double-sided adhesive). The user first glues the adhesive 325 and 326 to the skin, and then attaches the acoustic port 302 to the adhesive 326, and then connects the supporting structure 301 to the upper adhesive layer of the adhesive 325 (which is double-sided adhesive). Finally, the connector 320 is connected to the wires and fibers of the control unit to allow the probe to operate. Each of the components of the flexible probe 403 and probe 403 as a whole can be used only once and then discarded (i.e., it is disposable), or reused.

[0159] Figs. 8A and 8B show, respectively, a bottom and side view of the probe 403 whose support structure 301 carries light ports (or sources) and several acoustic ports 302, 319 and 319a (or acoustic transducer systems). Each of the acoustic ports 302, 319 and 319a is connected to connector 320 via wires 338, 339 and 339A, respectively. For attaching acoustic parts 302, 319 and 319A, adhesive gels 326, 329 and 329A are used, respectively. Similarly, each of the acoustic ports can be separated from the 403 probe when not in use, and inserted by the user in preparation for operation.

[0160] Those skilled in the art will readily recognize that various modifications and changes may be made to the embodiments of the present invention described above without departing from the scope thereof as defined in the appended claims.