SYSTEM AND METHOD FOR MEASURING OXYGENATED BLOOD VOLUME IN BIOLOGICAL TISSUE - Patent application

Abstract

A system and method for monitoring oxygenation in biological tissue are provided. The system includes a controller configured and operable to receive data indicative of optical responses from an area of ​​biological tissue illuminated and / or collected at two different wavelengths within two selected wavelength ranges, and to process the data by comparing the data indicative of each selected wavelength range to determine the oxygenation / deoxygenation state of the biological tissue. The two wavelength ranges include a first wavelength range in which the absorbance of deoxyhemoglobin in the tissue is higher than that of oxyhemoglobin, and a second wavelength range in which the absorbance of oxyhemoglobin in the tissue is higher than that of deoxyhemoglobin (or vice versa). The two wavelengths within the two wavelength ranges include the first wavelength and the second wavelength that, for each of the identified first and second wavelengths, satisfy a predetermined ratio condition between the absorbance of deoxyhemoglobin and the absorbance of oxyhemoglobin. [Selected Figure] Figure 1

Description

[Technical field]

[0001] The present invention relates to a method for measuring oxygenated blood volume in biological tissue, in particular for tissue oxygenation mapping. [Background technology]

[0002] In many medical situations, it is useful to measure the amount of oxygenated blood in biological tissues. Local oxygen delivery plays a key role in maintaining tissue function. Hypoxia in individual tissues or organs, associated with the destruction of local microcirculation caused by capillary dysfunction, leads to a decrease in the global (systemic) peripheral blood oxygen saturation (SpO 2 ) measurements. A variety of chronic and even acute medical conditions (e.g., peripheral vascular disease, diabetes mellitus, hypercholesterolemia, hypertension, chronic renal failure, chronic obstructive pulmonary disease, abdominal aortic aneurysm, venous insufficiency, and various surgeries) are associated with impaired local tissue oxygenation.

[0003] In plastic surgery, for example flap surgery, a tissue segment is at least partially removed from the blood vessels responsible for blood flow in the tissue segment, and the tissue is moved to a new location in the body, often connected to new blood vessels near the new location. If the connection to the new blood vessels is successful and present, if the connection to the original old blood vessels remains good and the healing process is going well, the tissue segment will receive a sufficient supply of oxygenated blood from the arteries and deoxygenated blood will be carried away by the veins, making the tissue segment viable. However, if something goes wrong and for some reason the tissue segment does not contain a sufficient amount of oxygenated blood, for example if the arteries do not supply enough oxygenated blood or the veins do not carry away enough deoxygenated blood, the result is that the tissue segment will not be viable. If the fact that the tissue segment does not contain enough oxygenated blood can be detected early enough, measures can be taken to salvage the tissue segment. If the fact that the tissue segment does not contain enough oxygenated blood is not detected early enough, necrosis will occur and the tissue segment will have to be excised.

[0004] For example, in emergency care, a patient may arrive for medical care with extensive body parts severely damaged, including partial amputations, and medical personnel are unable to determine which body parts are viable and which are not. In order to treat such a patient, it would be useful to be able to quickly determine which body parts contain sufficient oxygenated blood volume and are viable and which are not. Body parts identified as viable are then treated first to ensure survival, and for those parts that are not immediately viable, medical personnel can determine whether reconnecting the blood supply or amputating the body parts can improve the patient's survival and recovery rate. Summary of the Invention

[0005] There is a need in the art for a non-invasive method that allows the identification of said dysfunctions, allowing clinicians to identify patients at high risk for peripheral and cardiovascular diseases. It would also be beneficial to have a method that would be useful in qualitatively and / or quantitatively measuring the amount of oxygenated blood in tissues. To this end, the present invention provides a novel method for providing an indication of tissue oxygenation. More specifically, the system is configured for the measurement of biological tissues, for measuring the oxygenated / deoxygenated blood present in the tissue. The present invention provides a method for measuring oxygen saturation in tissue capillaries, based on the spectral analysis of characteristic wavelengths that distinguish oxygenated from deoxygenated hemoglobin. The method can serve as the basis for various systems for various clinical applications.

[0006] According to a broad aspect of the invention, there is provided a system for monitoring oxygenation in biological tissue, comprising a controller configured and operable to receive data indicative of light responses from the same area of ​​biological tissue illuminated and / or collected at two separate wavelengths within two selected wavelength ranges, and to perform data processing by comparison of the data indicative of each selected wavelength range to determine an oxygenation / deoxygenation state of the biological tissue, the two wavelength ranges of illumination and / or collection including a first wavelength range in which deoxyhemoglobin in the tissue has a higher absorbance than oxyhemoglobin and a second wavelength range in which oxyhemoglobin in the tissue has a higher absorbance than deoxyhemoglobin (or vice versa), and the two wavelengths within the two wavelength ranges include a first wavelength and a second wavelength that satisfy a predetermined ratio condition between the absorbance of deoxyhemoglobin and the absorbance of oxyhemoglobin for each of the identified first and second wavelengths.

[0007] Such a predetermined condition corresponds to a relatively high ratio between the absorbance of deoxyhemoglobin and the absorbance of oxyhemoglobin for each of the first and second wavelengths specified. In this connection, it should be noted that said relatively high ratio between the absorbance of deoxyhemoglobin and the absorbance of oxyhemoglobin is preferably substantially / approximately the highest / maximum ratio and corresponds to a condition where the absorbance characteristics (intensities) of deoxyhemoglobin and oxyhemoglobin for each of these two wavelengths are significantly (maximally) different from each other.

[0008] In some embodiments, the first wavelength range is selected such that the data is indicative of tissue portions located at the surface of the tissue region being monitored, and the second wavelength range is selected such that the data is indicative of tissue portions located deep within said tissue region. In this case, the first and second wavelength ranges are located in different spectral bands, the blue and red spectral bands. The first wavelength may be near / around 415 nm within a first wavelength range of about 400 nm to about 420 nm, and the second wavelength may be near / around 650 nm within a second wavelength range of about 600 nm to about 800 nm. In another possible example, the first wavelength is near / around 470 nm within a first wavelength range of 450 to 500 nm, and the second wavelength is near / around 650 nm within a second wavelength range of 600 to 800 nm.

[0009] In some other embodiments, which may be used instead of or in addition to the above embodiments, the first and second wavelength ranges are substantially in the same spectral band, and the first and second wavelength ranges are selected such that the measurement data is indicative of a superficial tissue portion of the tissue region being monitored. The first wavelength may be near / around approximately 415 nm in a first wavelength range of 400-420 nm, and the second wavelength may be near / around approximately 435 nm in a second wavelength range of 420-450 nm. Another possible example of these embodiments is the use of a first wavelength near 435 nm in a first wavelength range of 420-450 nm, and a second wavelength near 470 nm in a wavelength range of 450-500 nm.

[0010] In some embodiments, the controller is configured and operable to process the data by calculating a relationship (e.g., ratio) between two average intensities indicative of light response from the same area of ​​biological tissue illuminated and / or collected at two separate selected wavelength ranges. This relationship is indicative / descriptive of the oxygenation / deoxygenation state of the biological tissue. It is understood that such relationship (ratio) between the light responses measured at the selected wavelengths may be a certain normal value, which may be individual-specific and / or measurement location (body part) specific. This normal value may be determined by calibration methods or preliminary machine learning methods. That is, what is actually measured / detected is the change in the relationship (ratio) from the normal value.

[0011] In some embodiments, the controller is configured and operable to determine the oxygenation / deoxygenation state of the biological tissue in real time.

[0012] In some embodiments, the tissue is illuminated using two electromagnetic beams having different wavelength ranges (e.g., a blue wavelength range and a red wavelength range). Two reflected and backscattered beams of light corresponding to the different wavelength ranges are then collected using a detector (imaging or non-imaging). The system may include an imaging unit configured and operable to receive the light response and generate at least two pixelated images thereof.

[0013] As used herein, the term "image capture unit" refers to any device capable of producing pixelated digital image data (still or moving image). The data may include at least two pixelated images. As used herein, for clarity, the term "image" refers to an image that is visible to the naked eye (e.g., when displayed on a permanent medium such as printed paper or on an electronic medium such as a display screen (LED, LCD, CRT)), and also refers to image data (especially electronic data) representing said image, including data stored on a magnetic or electrical medium (e.g., flash memory, magnetic disk, magnetic tape), and the like.

[0014] Processing the data may include identifying pixels in each image that are indicative of a particular area of ​​the region; performing a pixel-by-pixel comparison of the at least two pixelated images for each of the particular areas; determining the oxygenation / deoxygenation state of the biological tissue for each pixel, and generating a processed image as a map indicative of tissue oxygenation / deoxygenation state. As used herein, for clarity, the term "pixel" refers to an element that makes up a pixelated image (displayed or stored as data) and, where context dictates, to the value of the pixel. The controller may be configured and operable to generate a processed image of the tissue region that is indicative of the oxygenation state of tissue portions at the tissue surface compared to the oxygenation state of tissue portions deeper in the tissue.

[0015] If an imaging unit is used, image data representing the two reflected and backscattered rays are compared pixel by pixel as described above to determine the oxygenated / deoxygenated blood present in the tissue. An image can then be obtained by performing a pixel by pixel comparison of the first image data with the second image data to generate blood-oxygenated tissue status map data. Full color mapping is performed by sampling the appropriate wavelength ranges selected.

[0016] In some embodiments, the imager comprises a spectral imager configured and operable to receive the light response and generate at least two pixelated spectral images thereof. Thus, the data may include at least two pixelated spectral images. Processing the data includes extracting at least two monochromatic images from said at least two pixelated spectral images, each corresponding to a selected wavelength range of illumination and / or collection, performing a pixel-by-pixel comparison for each specific range of said at least two monochromatic images, and generating a processed image indicative of a spectrally resolved tissue oxygenation / deoxygenation mapping.

[0017] In some embodiments, the imaging portion comprises at least two imaging portions, each configured and operable to detect at least one electromagnetic beam within a different selected wavelength range.

[0018] In some embodiments, the system comprises at least two crossed polarizing elements coupled to the illumination source and the imaging component, the crossed polarizing elements configured and operable to remove specular reflections from the tissue.

[0019] In some embodiments, the system includes a non-imaging light detector configured and operable to acquire non-image data. The non-imaging light detector is configured and operable to receive light responses of the same area of ​​the biological tissue illuminated and / or collected at two separate selected wavelength ranges and generate at least two average intensities of the area. Thus, the data may include non-image data indicative of at least two average intensities in the two separate wavelength ranges. Processing the data may include calculating a ratio between the two average intensities. Any suitable detector or combination of detectors may be used to measure the intensity of the light response (e.g., diffuse reflected light). For example, detection units including optoelectronic components may be used, such as photoelectric detectors (e.g., photodiodes, phototransistors, photomultipliers, optosolators, and optical integrated circuits), photoconductive detectors (e.g., photoresistors, photoconductive image pickup tubes, charge-coupled devices), induced emission detectors (e.g., injection laser diodes, quantum cascade lasers), radiative recombination detectors (light emitting diodes, organic light emitting diodes), and photoemissitivy detectors (photoemission image pickup tubes).

[0020] In some embodiments, the system comprises an illumination source configured and operable to illuminate the biological tissue with electromagnetic beams in two separate wavelength ranges.

[0021] In some embodiments, the above methods allow for quantification and monitoring of therapies designed to inhibit or enhance microcirculatory function. In addition, assessment of microcirculatory functionality and monitoring of local tissue oxygenation both aid in various surgical procedures (e.g., plastic surgery, tissue transplantation) to ascertain tissue vitality and to determine therapeutic endpoints and post-therapeutic tissue viability. In this regard, it should be appreciated that assessment of local tissue oxygenation is very challenging, as systemic hemodynamic variables provide only a crude assessment of organ perfusion. Systemic SpO 2 The parameter has low sensitivity and is a non-specific indicator of safe oxygenation at the local tissue level.

[0022] The surface of the biological tissue is any suitable surface. In some embodiments, the region of biological tissue may be a two-dimensional matrix overlaid on the surface of the biological tissue. In some embodiments, the surface is skin, particularly human skin. In some embodiments, the surface is the inner surface of the intestinal tract. In some embodiments, the surface is neural tissue of the brain. In some embodiments, the surface is the dura mater that covers the brain. In some embodiments, the surface is muscle tissue. In some embodiments, the surface is the surface of the retina that faces the inside of the eye.

[0023] According to another broad aspect of the invention, there is provided a method for use in monitoring oxygenation in biological tissue, the method comprising: determining operational data for use in one or more measurement sessions to enable collection of data indicative of an oxygenated / deoxygenated tissue state of the biological tissue, the determining comprising selecting two separate wavelengths (wavelengths for illumination and / or collection of light responses) within two wavelength ranges for use in the one or more measurement sessions to enable creation of data indicative of a light response of a region of the biological tissue to the two wavelengths, the two wavelength ranges being selected by identifying a first wavelength range in which deoxyhemoglobin in the tissue has a higher absorbance than oxyhemoglobin and a second wavelength range in which the absorbance of oxyhemoglobin in the tissue is higher than deoxyhemoglobin (or vice versa), and selecting a first wavelength and a second wavelength from the first wavelength range and the second wavelength range that satisfy a condition in which, for each of the identified wavelengths, the ratio between the absorbance of deoxyhemoglobin and the absorbance of oxyhemoglobin is relatively high (preferably highest).

[0024] The method may further include analyzing measurement data obtained in one or more measurement sessions using the operational data, the measurement data being indicative of optical responses from the same region of the biological tissue in the two separate selected wavelength ranges; and determining an oxygenation / deoxygenation state of the biological tissue.

[0025] In some embodiments, the method includes performing the one or more measurement sessions while reducing specular reflection from tissue.

[0026] In some embodiments, the method comprises illuminating the biological tissue with at least two electromagnetic beams having different selected wavelength ranges.

[0027] In some embodiments, the method includes collecting image or non-image data indicative of a light response from the same region of biological tissue in two separate selected wavelength ranges.

[0028] In some embodiments, the method includes displaying the oxygenation / deoxygenation tissue status of the region of interest. [Brief description of the drawings]

[0029] In order to provide a better understanding of the inventive subject matter disclosed herein and to illustrate how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the attached drawings in which: [Figure 1] FIG. 1 shows typical absorption spectra of hemoglobin (Hb) and oxyhemoglobin (HbO2). [Figure 2A] FIG. 2A shows a schematic of the display screen of a light detection device (photodetector, oscilloscope) used to measure the change in intensity of two preselected wavelengths as a function of time before and during the blood flow occlusion procedure. [Figure 2B] FIG. 2B shows a schematic of the display screen of the light detection device (photodetector, oscilloscope) used to measure the change in intensity of two preselected wavelengths as a function of time before and during the blood flow occlusion procedure. [Figure 2C] Figures 2C-2E show the experimental results more specifically, with Figure 2C showing the raw light response data measured at two wavelengths, λ1 and λ2, on a human arm under normal conditions (i.e., no vascular occlusion). [Figure 2D] FIG. 2D shows the individual light responses measured on a human arm at the onset of the occlusion mode. [Figure 2E] FIG. 2E shows the change in each light response during the 2-minute occlusion mode. [Diagram 3] FIG. 3 is a block diagram illustrating a data processing system (controller) for implementing monitoring of the oxygenation state of biological tissue. [Figure 4] FIG. 4 is a photograph illustrating a system for monitoring oxygenation in biological tissue according to some embodiments of the present invention. [Figure 5A]FIG. 5A is a graphical illustration of tissue oxygen saturation (StO2) monitoring before and during a blood flow occlusion procedure using a standard TC-PO2 system (PERIMED) and the method of the present invention. [Figure 5B] FIG. 5B is a three graph illustration of tissue oxygen saturation (StO2) monitoring before and during the blood flow occlusion procedure using a conventional pulse oximeter and the method of the present invention. [Figure 5C] FIG. 5C is a three graph illustration of tissue oxygen saturation (StO2) monitoring before and during the blood flow occlusion procedure using a conventional pulse oximeter and the method of the present invention. [Figure 5D] FIG. 5D is a three graph illustration of tissue oxygen saturation (StO2) monitoring before and during the blood flow occlusion procedure using a conventional pulse oximeter and the method of the present invention. [Figure 6] FIG. 6 shows a graph comparing the amount of oxygenated blood in tissue as determined by a blood oxygenation sensor according to the teachings herein with the amount of oxygenated blood in tissue as determined by a commercially available prior art device for determining blood oxygenation, the amount of oxygenated blood being measured during a pulmonary lavage procedure, the device being placed on the arm of a severely burned patient suffering from burn-induced pulmonary failure. [Figure 7] 7A-7E are schematic block diagrams illustrating possible optical imaging setups for monitoring oxygenation in biological tissue in some embodiments of the present invention. [Figure 8] FIG. 8 is a flow chart illustrating a method for monitoring oxygenation in biological tissue. [Figure 9] 9A-9C are three images obtained using the method of the present invention of a finger under three different clamping regimes: normal (FIG. 9A), 2 minutes of ischemia (FIG. 9B), and after reperfusion (FIG. 9C). [Figure 10] FIG. 10 is a schematic block diagram illustrating a possible optical setup for monitoring oxygenation in biological tissue in some embodiments of the present invention. [Figure 11]FIG. 11 illustrates a schematic diagram of an embodiment of a device that includes a computer processor operatively connected to a spectral imaging camera. [Figure 12] 12A-12D show the teachings herein used to assess oxygenation of a skin flap transplant in mice. [Figure 13] 13A-13B show the teachings herein used to assess oxygenation of a flap created by frontal-to-nasal transposition. [Figure 14] 14A-14B show the teachings herein used to determine tissue oxygenation during nasal reconstruction. [Figure 15] 15A-15D show the teachings herein employed for real-time monitoring of brain function. [Figure 16] 16A-16C show the teachings herein used to monitor cancer treatment using photothermal therapy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, shall control.

[0031] As used herein, the terms "comprising," "including," "having," and grammatical variations thereof are to be construed as specifying the stated features, integers, steps, or components, but not excluding the addition of one or more additional features, integers, steps, components, or groups thereof. These terms encompass the terms "consisting of" and "consisting essentially of."

[0032] As used herein, the indefinite articles "a" and "an" mean "at least one" or "one or more," unless the context clearly indicates otherwise.

[0033] As used herein, when a numerical value is preceded by the term "about," the term "about" is intended to represent + / - 10%.

[0034] As used herein, a phrase of the form "A and / or B" means a selection from the group consisting of (A), (B), or (A and B). As used herein, a phrase of the form "at least one of A, B, and C" means a selection from the group consisting of (A), (B), (C), (A and B), (A and C), (B and C), or (A and B and C).

[0035] Method and / or system embodiments described herein may include performing or completing selected tasks manually, automatically, or a combination thereof. Some methods and / or systems described herein are implemented using components that include hardware, software, firmware, or a combination thereof. In some embodiments, some components are general-purpose components, such as a general-purpose computer, a general-purpose digital processor, or a general-purpose oscilloscope. In some embodiments, some components are dedicated or custom components, such as circuits, integrated circuits, or software.

[0036] It will be understood that certain features of the invention that are for clarity described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention that are for brevity described in the context of a single embodiment may also be provided separately or in any suitable subcombination or, where suitable, in any other described embodiment of the invention. Certain features described in the context of various embodiments are not considered essential features of those embodiments unless the embodiment is inoperable without those components.

[0037] Referring to FIG. 1, oxyhemoglobin (HbO 2 Typical absorbance spectra of (deoxy)hemoglobin (Hb) and (deoxy)hemoglobin (Hb) are shown. The inventors have found that by selecting two different wavelengths of illumination and / or collection, and in some embodiments by selecting two wavelengths in different wavelength ranges, such that there is a first wavelength at which the absorbance of deoxyhemoglobin in tissue is higher than oxyhemoglobin, and a second wavelength at which the absorbance of oxyhemoglobin in tissue is higher than deoxyhemoglobin (and vice versa), and the two wavelengths include a first wavelength and a second wavelength that satisfy the condition that the ratio between the absorbance of deoxyhemoglobin and the absorbance of oxyhemoglobin is relatively high (substantially / approximately highest) for each of the first and second wavelengths specified. This unique selection of two different wavelengths provides a special contrast. 2 ) and (deoxy)hemoglobin (Hb). Importantly, this unique, choice of two distinct wavelengths allows for the determination of biological tissue state and the measurement of changes in biological tissue state.

[0038] It will be appreciated that this method is entirely different from pulse oximetry, where StO2 hemoglobin measurement relies on a cardiac pulse signal. This particular contrast allows for obtaining data indicative of a superficial tissue portion of the tissue being monitored, and in some embodiments, data indicative of a first tissue portion located at the surface of the tissue being monitored, and data indicative of a second tissue portion located deeper within the tissue being monitored.

[0039] It should also be noted that an advantage of the method of the present invention is that it does not require the use of fluorescence techniques (which are expensive, require the injection of potentially allergenic substances into the patient, and are time consuming), and furthermore does not require the injection of potentially allergenic substances (e.g., contrast agents) into the patient.

[0040] Thus, this novel method of the present invention provides a tissue oxygenation map without injecting any substance into the patient. Arteries and veins are clearly differentiated in the image. For example, pixels with higher oxygenated blood volume (Ioxy) values ​​are associated with arterial identifications. These may be displayed in red (qualitatively indicating more oxygenated blood in the tissue underlying the surface corresponding to the pixel). Pixels with intermediate Ioxy values ​​associated with venous identifications may be displayed in blue (qualitatively indicating less oxygenated blood in the tissue underlying the retinal surface corresponding to the pixel). Pixels with low Ioxy values ​​associated with blood-deprived neural and connective tissue identifications may be displayed in white (qualitatively indicating no blood in the tissue underlying the retinal surface corresponding to the pixel).

[0041] Thus, in some embodiments, a first wavelength range is selected such that data is indicative of tissue condition of a tissue portion near the surface of the biological tissue, while a second wavelength range provides data indicative of tissue condition of a tissue portion deeper within the biological tissue being monitored. Using this novel method, an indication of tissue condition is achieved that indicates whether the volume of biological tissue contains sufficient / insufficient oxygenated blood to be considered viable. Furthermore, the method provides a predictive tool that allows for the assessment of tissue viability upon transplantation.

[0042] For example, according to the above principles, the lower range of the first wavelength (of blue light) can be 400 nm or 405 nm or 410 nm or 412 nm. The upper range of the first wavelength can be 418 nm or 420 nm. Alternatively, the lower range of the first wavelength (of blue light) can be 450 nm or 460 nm or 465 nm or 468 nm. The upper range of the first wavelength can be 472 nm or 475 nm or 480 nm or 500 nm.

[0043] For example, following the above principles, the lower range of the second wavelength (of red light) can be 600 nm or 630 nm or 640 nm, and the upper range of the first wavelength can be 660 nm or 670 nm or 800 nm.

[0044] In a specific, non-limiting example, the first and second wavelengths are designated as 415 nm and 650 nm (a narrow specific range, not a broad range), where the ratio between oxygenated and deoxygenated Hb is maximized.

[0045] The amount of oxygenated blood in the volume of biological tissue underlying the region may be determined qualitatively. The oxygenated blood may be determined to be sufficient if it is relatively high (large percentage of oxygenated blood) or may be determined to be insufficient if it is relatively low (small percentage of oxygenated blood). Hereinafter, the intensity (per pixel or average of the measured area) of the light response (i.e., backscattered) from at least one region of the surface of the biological tissue of interest illuminated and / or collected with a first wavelength range is referred to as the "first intensity (Ifirst)". As defined above, the term "first intensity" as used herein is the measured intensity of light diffusely reflected (i.e., backscattered) from at least one region of the surface of the biological tissue of interest in a first wavelength range (e.g., blue light) as a result of illuminating the at least one region with light having a wavelength within a first wavelength range, the first wavelength range being as defined above. The intensity (per pixel or average of the measured area) of light diffusely reflected (i.e., backscattered) from the same region of the surface of the biological tissue of interest when illuminated and / or collected with a second wavelength range is referred to as the "second intensity (Ifirst)". As defined above, the term "second intensity" as used herein refers to the measured intensity of light diffusely reflected from at least one region of the surface of the biological tissue in a second wavelength range (e.g., red light) as a result of illuminating the at least one region with light having a wavelength within the second wavelength range, the second wavelength range being as defined above. It has been found that a high second intensity accompanied by a low first intensity indicates that a volume of biological tissue underlying a region of the surface of the biological tissue contains relatively more oxygenated blood, whereas a low second intensity accompanied by a high first intensity indicates that a volume of biological tissue underlying the region contains relatively less oxygenated blood.

[0046] In this regard, with reference to Figures 2A-2E, a specific, non-limiting example is illustrated of measuring the change in intensity of two preselected wavelengths as a function of time before and during a blood flow occlusion procedure using a photodetector / oscilloscope device.

[0047] Traces 20 and 22 in Figures 2A and 2B correspond to the time evolution of the measured signal (light response intensity) for the first and second wavelengths.

[0048] Figures 2C-2E show more specific raw data of the light responses measured at two wavelengths, λ1 and λ2, on a human arm in a normal state (i.e., without vascular occlusion) (Figure 2C), the light responses measured on the human arm at the start of the occlusion mode (Figure 2D), and the change in each light response during the two minutes of occlusion mode (Figure 2E).

[0049] In this non-limiting example, both the first and second intensities are repeatedly measured using one or more photodetectors (e.g., 60 Hz) and input to an oscilloscope, which displays the first and second intensity values ​​as a function of time as traces on the oscilloscope screen. An external signal amplifier or amplifier may be part of the oscilloscope and used to simultaneously display both the first intensity trace 20 and the second intensity trace 22 on the oscilloscope screen with similar values ​​to allow comparison.

[0050] As long as the distance (difference on the Y-axis) between the first and second intensity traces 20 and 22 remains substantially constant as in Figure 2A, the comparison provides evidence supporting the conclusion that the volume of biological tissue underlying the region of the biological tissue surface contains sufficient oxygenated blood to be considered viable (e.g., healthy). If it is noted that the intensity values ​​of the second intensity trace 22 become progressively lower while the intensity values ​​of the first intensity trace 20 become progressively higher as in Figure 2B, the comparison provides evidence supporting the conclusion that the volume of biological tissue underlying the region of the biological tissue surface contains insufficient oxygenated blood to be considered viable (e.g., pre-necrotic or necrotic).

[0051] For example, when monitoring the amount of oxygenated blood in a tissue over time using a blood oxygenation monitor with a comparator to perform the comparison, both the second intensity and the first intensity are repeatedly measured (e.g., at 1 Hz) using one or more photodetectors. While the second intensity value>the first intensity value, the comparator outputs an indication that the comparison provides evidence supporting a conclusion that the volume of biological tissue underlying the region of the surface of the biological tissue contains sufficient oxygenated blood to be considered viable. If the second intensity value<the first intensity value, the comparator outputs an indication that the comparison provides evidence supporting a conclusion that the volume of biological tissue underlying the region of the surface of the biological tissue contains sufficient oxygenated blood to be considered viable, providing an indication of tissue condition that allows monitoring of oxygenation in the biological tissue.

[0052] Referring to FIG. 3, a block diagram illustrating the main elements of a system of the present invention is shown. The system 100 is intended for monitoring oxygenation in biological tissue. The system 100 detects at least two distinct wavelengths λ within two selected wavelength ranges. 1 and λ 2 and a controller 202 configured and operable to receive data indicative of a light response from the same region R of the biological tissue illuminated and / or collected at the selected wavelength ranges and perform data processing by comparing the data indicative of each selected wavelength range to determine the oxygenation / deoxygenation state of the biological tissue. The two wavelength ranges of illumination and / or collection are a first wavelength range λ where deoxyhemoglobin in the tissue has a higher absorbance than oxyhemoglobin. 1 and a second wavelength range λ in which the absorbance of oxyhemoglobin in tissue is higher than that of deoxyhemoglobin. 2and vice versa), where the two wavelengths in the two wavelength ranges include a first wavelength and a second wavelength, each of which satisfies a relatively high ratio (preferably at or substantially / approximately at the highest / maximum ratio) between the absorbance of this wavelength by deoxyhemoglobin and the absorbance of this wavelength by oxyhemoglobin. In some embodiments of the method of the present invention (appropriate selection of the first and second wavelengths that penetrate to different depths within the tissue), the controller 202 is configured and operable to generate a processed image of the tissue indicative of the oxygenation state near the surface of the tissue compared to the oxygenation state at the depth of the tissue.

[0053] In some embodiments, the oxygenated blood status within the volume of biological tissue underlying the region is quantitatively determined. It has been found that the first intensity and the second intensity together may correlate with a numerical value of tissue oxygenation for a given tissue. A numerical value may be determined by comparing the first intensity to the second intensity, as described below.

[0054] In some embodiments, the controller 202 is configured and operable to process the data by calculating a ratio between two average intensities indicative of a light response from the same region of biological tissue illuminated and / or collected at two separate selected wavelength ranges.

[0055] For example, the tissue status can be calculated as follows: TIFF0007624218000001.tif36170In the formula, A and B are independently any suitable positive numbers other than 0, including 1; x and y are independently any suitable numbers, including 1; and m and n are independently any suitable numbers, including 0.

[0056] For example, the tissue status can be calculated as follows: TIFF0007624218000002.tif12170

[0057] In some embodiments, the control unit 202 includes a computer processor for performing the comparison, such as those present in processor devices such as desktop computers, laptop computers, handheld computers, tablets, smartphones, digital cameras, medical equipment controllers, etc. As used herein, a computer processor is an electronic device that can be programmed to perform mathematical functions and data processing. As used herein, a processor is an electronic device configured to receive two electronic signals as inputs and then output an electronic signal that constitutes a comparison of the two electronic signals. Non-limiting examples of the term processor include a comparator, a division circuit, an oscilloscope, and a computer processor. Non-limiting examples of the term processor include a microprocessor, a digital signal processor (DSP), a microcontroller, a field programmable gate array (FGPA), an application specific integrated circuit (ASIC), and devices such as computers, personal computers, servers, smartphones, and tablets. To carry out the teachings herein, such computer processors are typically programmed, for example with software instructions, to perform the functions and methods described herein.

[0058] The control unit 202 may be part of a digital video camera or part of a blood oxygenation monitor. In some embodiments where the control unit 202 is part of a digital video camera, the system of the present invention thereby displays a series of images as a real-time movie of the blood oxygenation of tissue underlying the surface of the biological tissue, the output being a blood oxygenation tissue status map. In some embodiments where the system is a blood oxygenation tissue status monitor, the control unit 202 may indicate evidence that the flap has sufficient oxygenated blood volume to be considered viable, and outputs a separate "warning" signal if the flap has insufficient oxygenated blood volume to be considered viable.

[0059] In some embodiments, the control unit 202 does not include a computer processor for performing the comparison, but includes another processor suitable for performing the comparison, such as an oscilloscope, digital and analog comparators, digital division circuits, and analog division circuits.

[0060] The controller 202 is in data communication with the detector 104 (e.g., optoelectronic components, digital camera) directly or indirectly (e.g., the detector 104 acquires data and stores the data on a storage component, and then the data is retrieved from the storage component and provided to the controller 202). When the detector 204 is placed at a certain distance from the subject, the raw data received by the controller 202 may be, for example, the intensity of a large number of pixels at various target wavelengths over a wide range of interest. When the detector 204 is placed in contact with the subject, the raw data collected may be the intensity of various target wavelengths at the smallest range. When a standard imager 104A (configured and operable to receive the light response and generate at least two pixelated images thereof) is used, once the imager collects the image data, the controller 202 may perform a pixel-by-pixel comparison of the at least two images to determine the oxygenation / deoxygenation state of the biological tissue for each pixel and generate a processed image showing tissue oxygenation / deoxygenation mapping. In the case where a spectral imager (configured and operable to receive the light response and generate at least two pixelated spectral images thereof) is used, once the imager collects the image data, the controller 202 may extract monochromatic image data from the at least two pixelated images, each corresponding to the illumination and / or collection wavelength range, perform a pixel-by-pixel comparison of the at least two monochromatic images, determine the oxygenation / deoxygenation state of the biological tissue for each pixel, and generate a processed image indicative of a spectrally resolved tissue oxygenation / deoxygenation mapping. As used herein, the term "monochromatic image data" refers to digital data representing a pixelated image, in which the value of each pixel is a single intensity value representing only the amount of light, i.e., contains only intensity information.When a non-imaging light detection unit 104B (configured and operable to receive a light response and generate at least two average intensities of the region) is used, the control unit 202 may receive from the light detection unit first and second average intensities of light diffusely reflected from at least one region of the surface of the biological tissue in a first wavelength range and a second wavelength range as a result of illuminating and / or collecting the at least one region with light having wavelengths in the first wavelength range and the second wavelength range, respectively.

[0061] Typically, the controller 202 may be a processor, controller, microcontroller, or any type of integrated circuit. The controller 202 is typically configured as a computing / electronic utility, including, among other things, utilities such as a data input module / utility 202A and a data output module / utility 202B, a storage utility 202C (i.e., a non-volatile computer readable medium), and an analyzer / data processing utility 202D. Thus, the utility of the controller 202 may be implemented by suitable circuitry and / or software and / or hardware components including computer readable code configured to receive data indicative of at least two pixelated images of the same region of biological tissue and process the data to generate a processed image indicative of a spectrally resolved tissue oxygenation / deoxygenation mapping. Aspects of the present invention may include general purpose or special purpose computer systems with various computer hardware components. Aspects within the scope of the present invention also include computer readable media for carrying or storing computer executable instructions, computer readable instructions, or data structures. Such computer readable media may be any available media accessible by a general purpose or special purpose computer system. By way of example, and not limitation, such computer-readable media may include physical storage media such as RAM, ROM, EPROM, flash disks, CD-ROM, or other optical disk storage, magnetic disk storage, or other magnetic storage devices, or may include any other medium that can be used to carry or store desired program code means in the form of computer-executable instructions, computer-readable instructions, or data structures and that can be accessed by a general-purpose or special-purpose computer system. Computer-readable media may include computer programs or computer applications that are downloadable to a computer system over a network, such as a wide area network (WAN) (e.g., the Internet).

[0062] In this specification and the claims that follow, a "controller" is defined as one or more software modules, one or more hardware modules, or a combination thereof that work together to perform operations on electronic data. For example, the definition of a controller encompasses software modules, such as the operating system of a personal computer, as well as the hardware components of a personal computer. The physical location of the modules is not important. A computer system may include one or more computers linked via a computer network. Similarly, a computer system may include a single physical device whose internal modules (such as memory and processor) work together to perform operations on electronic data. The controller 202 may be comprised of an internal or external processor that executes a computer program. The computer program product may be embodied in one or more computer readable media having computer readable program code embedded therein. The computer readable media may be a computer readable signal medium or a computer readable storage medium. The computer program code for performing operations in each aspect of the invention may be written in any combination of one or more programming languages. The program code may be executed entirely on the user's computer, partially on the user's computer as a stand-alone software package, partially on the user's computer and partially on a remote computer, or entirely on a remote computer or server, where the latter may be connected to the user's computer through any type of network including a Local Area Network (LAN) or a Wide Area Network (WAN), or said connection may be to an external computer (e.g., through the Internet using an Internet Service Provider).These computer program instructions can be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to create a machine such that the instructions executed by the processor of the computer or other programmable data processing apparatus create means for performing the functions / actions specified in one or more blocks of the flowcharts and / or block diagrams. Certain functions of the processor can be performed by a dedicated hardware-based system that performs the particular functions or actions, or a combination of dedicated hardware and computer instructions. In some embodiments, the implementation includes a user interface, typically comprising one or more of an input device (e.g., allowing for input of instructions and / or parameters) and an output device (e.g., allowing for reporting of parameters and results of operations).

[0063] For example, a table of correspondence between the intensities of different wavelengths and tissue oxygenation values ​​may be stored in a database. Such a table may be stored in memory 202C. Alternatively, the storage may be separate from the server (e.g., SAN storage). If separate, the storage location may be in one body location or in multiple locations and connected through any type of wired or wireless information and communication infrastructure. The database may be based on any type of method or platform for storing digital data. The database may include, for example, traditional SQL databases such as Oracle Server and MS SQL Server, file systems, big data, NoSQL, in-memory database devices, parallel computing (e.g., Hadoop clusters), etc. The memory 202C, when configured as a storage medium for the database, may include any standard or proprietary storage medium such as magnetic disks or tapes, optical storage, semiconductor storage, etc.

[0064] In some embodiments, the system 100 is configured in a cloud-based configuration and / or utilizes Internet-based computing, such that portions of the processing utility 202D and / or memory 202C may reside in multiple distinct geographic locations. After receiving the THz response signal, the data processing utility 202D may process the signal. The results of the signal processing steps may be displayed by a display component and / or stored in a storage component and / or transmitted to a data communication unit via a transmission component, a signal generation component, and combinations thereof.

[0065] More specifically, the data output 202B of the control unit 202 may be output using at least one of the following actions: Displaying what the processing represents using a display component that generates a temporary or permanent image for a human to view (such as a display screen (e.g., LED, CRT, LCD), or a printer); storing the results on a storage component (e.g., on a magnetic medium such as a magnetic disk, flash memory, solid state memory, computer memory, laser disk, floppy disk, magnetic tape, etc.); Transmitting the results to a remote device using a transmission component (e.g., wirelessly using a transmitter such as a Wi-Fi or Bluetooth transceiver, a cellular transmitter, a dimming transmitter, a radio frequency transmitter, or by hard-wired connection to a remote device such as a computer, server, smartphone, phone, tablet, etc.); and Using a signal generation component, generating a signal indicative of a result perceptible by a human (e.g., generating a visual signal that a human can see, an audible signal that a human can hear, or a tactile signal that a human can feel to indicate an all-or-noise signal if the process provides evidence that supports a conclusion that the volume of biological tissue contains sufficient oxygenated blood, and / or to indicate a warning signal if the process provides evidence that supports a conclusion that the volume of biological tissue contains insufficient oxygenated blood).

[0066] Examples of human perceptible signals can be one or more of the following: an audible signal (i.e., perceived by hearing), such as a gentle sound when the process provides evidence supporting a conclusion that the volume of biological tissue contains sufficient oxygenated blood, and / or a warning sound as a warning signal when the process provides evidence supporting a conclusion that the volume of biological tissue contains insufficient oxygenated blood; a visual signal (i.e., perceived by sight), such as a gentle sound when the process provides evidence supporting a conclusion that the volume of biological tissue contains sufficient oxygenated blood, and / or a warning sound as a warning signal when the process provides evidence supporting a conclusion that the volume of biological tissue contains insufficient oxygenated blood; a green light if the process produces evidence that supports a conclusion that the volume of biological tissue contains insufficient oxygenated blood, and / or a flashing red light if the process produces evidence that supports a conclusion that the volume of biological tissue contains insufficient oxygenated blood; and a tactile signal (i.e., perceived by the sense of touch), such as a gentle vibration if the process produces evidence that supports a conclusion that the volume of biological tissue contains sufficient oxygenated blood, and / or a strong and sustained vibration if the process produces evidence that supports a conclusion that the volume of biological tissue contains insufficient oxygenated blood.

[0067] Each pixel of the image data corresponds to a particular area i of the region of the surface of the biological tissue. In some embodiments, the controller 202 identifies the particular area i of each image. More specifically, the controller 202 is configured to identify a corresponding pixel P1(i) in the first image data and identify a corresponding pixel P2(i) in the second image data. The controller 202 then compares the value of P1(i) with the value of P2(i) to calculate the Ioxy value for pixel P3(i) in the blood oxygenation tissue status map data corresponding to the region i. The resulting blood oxygenation tissue status map data represents a pixelated distribution of oxygenated blood status in tissue underlying the surface of the biological tissue.

[0068] In some embodiments, the blood oxygenation tissue status map data is displayed as a visually monochromatic monochrome image, i.e., the displayed blood oxygenation tissue status map data comprises a single color, with each pixel having a different intensity or shade of color based on the Ioxy value of that pixel. Typical of such visually monochromatic images are grayscale (e.g., black being the lowest pixel value, white being the highest pixel value, and shades of gray being intermediate values), sepia, and green.

[0069] For example, in some embodiments, when the result of the comparison includes blood oxygenation tissue status map data, the output component is configured to display an image visible to the human eye, where tissue portions with good oxygenated blood tissue status are displayed differently from tissue portions with poor oxygenated blood tissue status. For example, in some embodiments, the processor and output component are configured to issue a particular output, such as an alarm disarming signal, when the comparison provides evidence supporting a conclusion that a volume of biological tissue contains sufficient oxygenated blood to be considered viable.

[0070] In some embodiments, the blood oxygenation tissue status map data is displayed as a visible colorized monochromatic image. In such embodiments, each pixel has only a single intensity value Ioxy, but each such intensity value may be displayed as a combination of two or more colors. For example, in one such embodiment, each pixel of the blood oxygenation tissue status map data having an intensity value Ioxy between 0 and 255 is represented in the visible colorized monochromatic image by a pixel having a red light intensity Ireddisplay=Ioxy and a blue light intensity Ibluedisplay=255-Ioxy.

[0071] In the displayed image of this exemplary embodiment, pixels with high intensity values ​​are displayed as red, pixels with low intensity values ​​are displayed as blue, and pixels with intermediate intensity values ​​are displayed as various shades of purple. For example, in a different such embodiment, each pixel of blood oxygenation tissue status map data having intensity values ​​Ioxy between 0 and 255 is represented in a visible colorized monochrome image by pixels with Ioxy values ​​between 0 and 100 being increasingly lighter shades of blue, Ioxy values ​​between 101 and 149 being increasingly lighter shades of green, and Ioxy values ​​between 150 and 255 being increasingly lighter shades of red.

[0072] In some embodiments, one or more of the resulting outputs are performed in real time, for example, displaying images resulting from representative processing on an electronic display screen, such as to aid a surgeon in determining the relative oxygenated blood volume of various parts of a patient during surgery.

[0073] Additionally or alternatively, the control unit 202 may continuously output the generated blood oxygenation tissue status map data: for example, if a series of image data is continuously acquired using a digital video camera and a corresponding series of blood oxygenation tissue status map data is continuously generated therefrom by the processor, the resulting series of blood oxygenation tissue status map data may be continuously displayed on a screen to assist a medical professional during surgery (e.g., brain surgery) and identify areas of the cerebral cortex that are activated when a particular stimulus is applied to the patient.

[0074] For example, in some embodiments, an alleviation or warning signal is issued immediately after the action is performed.

[0075] For example, in some embodiments, the controller 202 may store the results locally in real time, and / or wirelessly transmit the results to storage (e.g., to an electronic medical file) in real time, and / or activate an alarm (e.g., to a nurse's station) to provide evidence to medical personnel that the underlying tissue is non-viable. In some embodiments, the controller 202 activates a signal in real time to alert medical personnel to the results. In some embodiments, the signal is not issued in real time. The blood oxygenation tissue status map data stored in the storage component is thereby retrievable for transfer, storage, recording, display, study, and automated analysis, among other things. The storage component is any suitable data storage component. In some embodiments, the storage component is one or more storage components selected from the group consisting of optical storage components (e.g., laser disks, CDs, DVDs), magnetic storage components (e.g., hard disks, flash memory, magnetic tapes, floppy disks), magneto-optical storage components (e.g., mini disks), and electronic storage components (e.g., flash memory, solid state drives).

[0076] The memory 202C may include instructions executable by the data processing utility 202D. The instructions may operate to enable the data processing utility 202D to receive data indicative of the light response, process the data, determine the oxygenation / deoxygenation state of the biological tissue, and output notifications regarding the oxygenation / deoxygenation tissue state via the data output utility 202B. The notifications may be relayed to a central database via a wireless or wired connection by an external device.

[0077] In some embodiments, the system 100 may include a detector 104. The detector 104 may be integrated into or be an integral part of one of the following devices: a probe for determining the oxygenation state of biological tissue, a device for performing angiography, a device for performing retinal angiography, a spectral imaging camera, a medical digital camera, an ingestible endoscope, an endoscope, an ophthalmoscope, a fundus camera, a flexible endoscope, an upper gastrointestinal endoscope, an enteroscope, a cholangiopancreatoscope, a colonoscope, a sigmoidoscope, a nasal mirror, a bronchoscope, a cystoscope, a gynoscope, a hysteroscope, a salpingoscope, an amnioscope, a gastroscope, an otoscope, a laparoscope, a pan-endoscope, and a fetoscope. In this case, the present invention provides an imaging device with analysis software that shows the ability to map hemoglobin oxygenation of large tissue areas remotely or in contact. In some embodiments, the detector 104 determines a first intensity and a second intensity. In some embodiments, the detector for determining the first intensity and the detector for determining the second intensity are different detectors, each detector configured and operable to detect at least one electromagnetic beam within a different selected wavelength range. In some embodiments, each detector determines the first intensity and the second intensity simultaneously. In some embodiments, each detector does not determine the first intensity and the second intensity simultaneously.

[0078] In some embodiments, the imager 104A is a camera configured and operable to acquire pixelated monochromatic image data of a surface of the biological tissue. The camera may be a monochrome camera.

[0079] In some embodiments, the system 100 comprises an illumination source 102 configured and operable to illuminate the biological tissue with electromagnetic beams of two separate wavelength ranges. The illumination source 102 comprises at least one light source that illuminates with coherent or incoherent light, light within a narrow wavelength range such as an LED, a laser, or a broadband light source (e.g., a xenon lamp) with an optical filter configured to illuminate exclusively with a particular one of the two wavelength ranges. For example, the illumination source 102 is configured to alternately illuminate the surface of the biological tissue with a first light having wavelengths exclusively within a first range or a second light having wavelengths exclusively within a second range. The illumination source 102 can be a single physical device or multiple physically separated devices that can operate together or independently. The controller 202 can be configured for powering and activating other components of the system 100 based on the teachings herein. More specifically, the controller 202 may be configured and operable to control (eg, activate) the illumination source 102 and select a wavelength range of the illumination.

[0080] In some embodiments, the diffusely reflected light (one or both of the two wavelength ranges) is guided to a detector with a light guide. For example, at least one region of the tissue surface is illuminated with light emitted by the illumination source 102 and guided near the surface with a light guide. Alternatively, in some embodiments, the diffusely reflected light (one or both of the two wavelength ranges) reaches the detector 104 without a light guide. The illumination of the at least one region with light having a wavelength in the first wavelength range and light having a wavelength in the second wavelength range may or may not be simultaneous.

[0081] In some such embodiments, system 100 further comprises at least one optical filter (e.g., replaceable) configured to transmit only a first wavelength to the detector in a first state, where the detector is configured to determine only data in the first wavelength range, and to transmit only a second wavelength range to the detector in a second state, where the detector is configured to determine only data in the second light. In some such embodiments, the detector comprises a first detector configured to detect only the first wavelength range, and a second detector configured to detect only the second wavelength range.

[0082] In some embodiments, the system 100 includes components that allow the photodetector to detect only diffusely reflected light, for example by preventing detection of specularly reflected light. Components for allowing only diffusely reflected light to be detected are known to those skilled in the art. In some embodiments, the detector 104 is operatively connected to a polarizing filter, for example a polarizing filter that is cross-polarized with respect to the polarized illuminator. In some embodiments, the system 100 includes at least two cross-polarizing elements connected to the illumination source 102 and the detector 104 that are configured and operable to remove specular reflections from tissue.

[0083] 4, an example of a system 200 of the present invention is shown. In this specific, non-limiting example, a control unit 202 is in data communication with a detection unit 204, which in this example is an RGB sensor, and with an illumination source 302. In this specific, non-limiting example, the illumination source 302 includes three blue LEDs and three white LEDs.

[0084] Referring to Figures 5A-5D, a clinical study conducted using the teachings of the present invention is shown. The clinical trial was aimed at validating the method of the present invention compared to whole body StO2 monitoring at the finger with a standard pulse oximeter and tcpO2 device. In this study, vascular occlusion was performed using a pneumatic cuff that simultaneously reduces StO2 at the finger and the skin of the arm. With reference to Figure 5A, the inflatable cuff was inflated to reduce the flow of oxygenated blood to the forearm, and after 3 minutes, the inflatable sleeve was deflated. Figure 5A shows the correlation between a standard TC-PO2 system (Perimed) and simultaneous measurements performed with the system of the present invention. These two devices were placed on the patient's left arm. Measurements were taken before, during, and after hemostatic suppression by blood pressure cuff inflation. In Figure 5A, it can be seen that the reduction in blood flow to the arm due to cuff inflation resulted in a measurable reduction in the amount of oxygenated blood in the arm. Importantly, the close correlation between the absolute measurements achieved using the teachings herein (lower graph) and tcpO2 (upper graph) indicates that the teachings herein can be calibrated (e.g., calibrated against a tcpO2 sensor) to achieve quantitative measurements of oxygenation status in biological tissue.

[0085] 5B-5D show monitoring of tissue oxygenation in three healthy subjects during vascular occlusion achieved by pneumatic cuff inflation. Concurrent measurements using the teachings of the present invention and a standard pulse oximeter (finger probe) were compared. More specifically, FIG. 5B shows uncalibrated measurements of tissue oxygenation at the skin of the arm using the system of the present invention and at the finger using the pulse oximeter during a vascular occlusion procedure with a blood pressure (BP) cuff. When there is no pulse (inattentive), no signal is observed from the pulse oximeter. FIG. 5C and FIG. 5D show calibrated measurements of tissue oxygenation at the skin of the arm using the system of the present invention and at the finger using the pulse oximeter during a vascular occlusion procedure with a BP cuff. When there is no pulse (inattentive), no signal is observed from the pulse oximeter. A good correlation was shown between the data at both the beginning and end of the measurement. 5B-5D, it can be seen that during the absence of a pulse, the pulse oximeter was unable to determine oxygenated blood volume (curves 51, 52, 54), while the tissue oxygenation sensor according to the teachings herein continued to operate without interruption (curves 50, 56, 58). The difference in dynamics between systemic and local tissue oxygen saturation is clearly shown.

[0086] Reliable and reproducible results showing significant correlation have been confirmed between the measurements of the system of the present invention and standard pulse oximeter measurements in clinical trials on volunteers and patients with pulmonary insufficiency. Patients admitted to burn units usually present with pulmonary insufficiency and acute respiratory failure and are placed on mechanical ventilation. Patients require pulmonary lavage by liquid aspiration (a method to remove mucus from the lungs). During this procedure, patients are required to use a respirator and systemic StO2, depending on the extent of lung damage. 2 During the pulmonary lavage procedure, the whole-body StO 2Simultaneously with the recordings, several measurements were made in the patient using the system of the present invention. The detector of the system of the present invention was attached to the skin of the patient's leg. Monitoring of tissue oxygenation in patients in a burn unit was performed using the system of the present invention and a pulse oximeter during a lung lavage procedure.

[0087] In this regard, reference is made to FIG. 6, which shows the monitoring of tissue oxygenation of a patient in a burn unit using a system utilizing the tissue oxygenation sensor of the present invention at 508 and a pulse oximeter at 510 during a lung lavage procedure. The tissue oxygenation sensor and pulse oximeter of the present invention were placed on the arm of a severely burned victim with pulmonary insufficiency. The figure shows the measurement of tissue oxygenation in a patient in a burn unit using the system of the present invention (b) and a pulse oximeter (a) during a lung lavage procedure. More specifically, trace "a" corresponds to the value of blood oxygenation determined by the pulse oximeter, and trace "b" corresponds to the absolute value of the measurement according to the teachings of the present invention. As can be seen, there is a good correlation between the data at both the beginning and the end of the measurement. This shows that by calibrating the teachings of the present invention (e.g., calibrating to the pulse oximeter), a quantitative measurement of blood oxygenation status in the tissue is possible. Importantly, tracking began when the oxygen supply to the burn victim was stopped and the victim was breathing normal air, causing the victim's oxygenated blood volume to decrease. Both sensors showed an immediate increase in oxygenated blood volume at 300 seconds, when the victim was once again given oxygen to breathe.

[0088] 7A, a possible optical configuration of the system 300 of the present invention is depicted. The controller 202 is in data communication with the detector 104 and the illumination source 402. In this specific, non-limiting example, the illumination source 402 comprises two narrowband light sources (e.g., LEDs or lasers). Each LED emits a different selected wavelength λ 1 and λ 2The object is illuminated with light. The detector 104 (e.g., a digital camera) is used to collect the optical response of the tissue being measured / monitored. In this non-limiting example, the detector 104 comprises a single photodetector (e.g., a photosensor, a monochrome digital camera, a monochrome digital video camera) that functions as both the first wavelength photodetector and the second wavelength photodetector. The different wavelengths λ 1 and λ 2 Different beam splitters 610 and 620 are used in the system 300 to split the illumination and collection.

[0089] Alternatively or additionally, it will be appreciated that the same light source (e.g., LED or laser) can be used (e.g., equipped with one or more appropriate spectral filters) to perform two or more measurement sessions with a first and a second wavelength in first and second distinct but spectrally close wavelength ranges (e.g., both in the blue spectrum). In this case, the measurements / imaging with the two different wavelengths may be combined into sessions separated in time. This embodiment is described in more detail below.

[0090] Referring to Figure 7B, a possible optical configuration of the system 400 of the present invention is depicted. The control unit 202 is in data communication with the detection unit 304 and the illumination source 502. In this specific, non-limiting example, the illumination source 502 comprises a light source (e.g., an LED). The detection unit 104 (e.g., a digital camera) comprises two detectors for collecting the light response. Each detector detects two selected separate wavelengths λ 1 and λ 2 The light source is configured and operable to collect light responses at different wavelengths λ 1 and λ 2 A beam splitter 610 is used in the system 400 to split the collection of.

[0091] 7C, a possible optical configuration of the system 500 of the present invention is depicted. The controller 202 is in data communication with the detector 404 and the illumination source 502. In this specific, non-limiting example, the illumination source 502 comprises two light sources (e.g., LEDs). Each LED emits a different selected wavelength λ 1 and λ 2 The object is illuminated with light. The detector 404 (e.g., a digital camera) includes two detectors for collecting the light response. Each detector emits light at two selected separate wavelengths λ 1 and λ 2 The light source is configured and operable to collect light responses at different wavelengths λ 1 and λ 2 A beam splitter 620 is used in the system 500 to split the collection of.

[0092] Referring to FIG. 7D, a possible optical configuration of a system 600 of the present invention is depicted. In some embodiments of the system 600, the illumination source 36 comprises a broadband component light source (e.g., a xenon lamp) for emitting light having both wavelengths in a first wavelength range and wavelengths in a second wavelength range. The light emitted by the light source is directed to the biological tissue surface 40 through an interchangeable optical filter 44, which comprises a first optical filter 46a that transmits only light having wavelengths in the first wavelength range and a second optical filter 46b that transmits only light having wavelengths in the second wavelength range. The optical filters 46a and 46b are mounted on a rotating plate 48. The controller 38 may activate an electric motor 50 to rotate the plate 48, so that the optical filters 46a and 46b alternately filter the light from the broadband component light source, thereby alternately illuminating the biological tissue surface 40 with only light having wavelengths in the first range or only light having wavelengths in the second range.

[0093] In some embodiments, the illumination source 102 may include at least two light sources, each configured and operable to illuminate the biological tissue at a different selected wavelength range. Alternatively, the tissue may be illuminated using two light beams having different wavelength ranges. Alternatively, the tissue is illuminated using a broadband light source having two different filters that allow for the transmission of the selected wavelength ranges. For example, the illumination source comprises a broadband component light source (e.g., a xenon lamp) with operatively connected interchangeable optical filters, including an optical filter that transmits only light having wavelengths within a first wavelength range and a different optical filter that transmits only light having wavelengths within a second wavelength range, mounted, for example, on a rotating plate.

[0094] 7E, a possible optical system configuration of the present invention system 650 is depicted. System 650 comprises two optical light guides (fiber optic cables): optical light guide 54 for directing the light response from the biological tissue surface 40 to the photodetector 34 and optical light guide 56 for directing illumination light from illumination source 36 to illuminate the biological tissue surface 40.

[0095] Referring to FIG. 8, a flow chart 700 illustrating the method of the present invention is shown.

[0096] The method 700 includes, at 702, determining the operating data (i.e., wavelengths of illumination and / or collection) to be used in one or more measurement sessions to enable collection of data indicative of oxygenation / deoxygenation tissue status of the biological tissue. This is done by selecting two separate wavelengths within two wavelength ranges to enable generation of data indicative of the optical response of an area of ​​the biological tissue to the two wavelengths. The two wavelength ranges include a first wavelength range in which the absorbance of deoxyhemoglobin in the tissue is higher than oxyhemoglobin and a second wavelength range in which the absorbance of oxyhemoglobin in the tissue is higher than deoxyhemoglobin (and vice versa), and the two wavelengths within the two wavelength ranges include a first wavelength range and a second wavelength range in which the absorbance of oxyhemoglobin in the tissue is higher than deoxyhemoglobin (and vice versa), where the ratio between the absorbance of deoxyhemoglobin and the absorbance of oxyhemoglobin is relatively high (preferably substantially / approximately the highest ratio) for the wavelength ranges identified above. The method performs an analysis of the light response data measured in one or more measurement sessions using the two wavelengths in steps 704 and 706. The measurement data is received from a measurement data providing device, which may be the measuring / imaging unit itself (online mode) or from a storage device where the measurement data is already stored (offline mode). That is, measurement data indicative of light responses from the same area of ​​the biological tissue in two separate selected wavelength ranges is received and processed to determine the oxygenated / deoxygenated tissue state of the biological tissue.

[0097] In some embodiments, the processing at 704 includes a comparison of data indicative of each selected wavelength range at 704A. If non-image data is received, the comparison may be performed by calculating a ratio between two average intensities indicative of light response from the same region of biological tissue in two separate selected wavelength ranges. Alternatively, if image data is received, the comparison may be performed by identifying pixels in each image indicative of a particular range of the region; and performing a pixel-by-pixel comparison of at least two pixelated images for each particular range. Alternatively, if spectral image data is received, the comparison may be performed by extracting at least two monochromatic images from the at least two pixelated images, each corresponding to a selected wavelength range of illumination and / or collection; and performing a pixel-by-pixel comparison of each of the particular ranges of the at least two monochromatic images.

[0098] In some embodiments, the method 700 includes generating, at 708, a processed image indicative of tissue oxygenation / deoxygenation mapping. The processed image of the tissue is indicative of the oxygenation state at the surface of the tissue compared to the oxygenation state deeper in the tissue. In some embodiments, the method 700 includes generating, at 708, a processed image indicative of the oxygenation state of a first tissue portion and a second tissue portion, both located near the surface of the tissue being monitored.

[0099] In some embodiments, the method 700 includes, at 710, selecting different selected wavelength ranges λ 1 and λ 2 The method includes illuminating the biological tissue with at least two electromagnetic beams having

[0100] In some embodiments, the method 700 includes, at 712, collecting image data or non-image data indicative of light responses from the same region of the biological tissue in two separate selected wavelength ranges.

[0101] In some embodiments, the method 700 includes, at 714, displaying the oxygenation / deoxygenation status of the region of interest.

[0102] In some such embodiments, the method further includes illuminating the at least one region with light having a wavelength within the first wavelength range while measuring the intensity of light diffusely reflected from the at least one region of the surface of the biological tissue in the first wavelength range; and illuminating the at least one region with light having a wavelength within the second wavelength range while measuring the intensity of light diffusely reflected from the at least one region of the surface of the biological tissue in the second wavelength range.

[0103] For example, in some embodiments, the method is performed by a controller 202 that is part of a pen-like tissue oxygenation probe used to assist a medical practitioner in determining whether a portion of tissue is receiving sufficient oxygenated blood. The medical practitioner contacts the probe with the surface of the tissue (e.g., a graft flap) and activates the system of the present invention. The system reports whether the process provides evidence that the flap has a sufficient amount of oxygenated blood to be considered viable.

[0104] The monitoring may be performed repeatedly for any suitable period of time. For example, when the teachings herein are implemented to videotape the blood oxygenation status of a tissue during surgery, the period of time may be as long as the medical practitioner deems useful, typically the duration of surgery. For example, when the teachings herein are implemented to continuously monitor the blood oxygenation status of a tissue flap in a recovering patient, the period of time may be as long as the medical practitioner deems useful, typically several days until the medical practitioner deems the flap to have sufficient blood supply and no longer requires monitoring. In particular, the teachings of the present invention may provide quantitative and continuous monitoring of tissue oxygenation at the surface of the tissue, independent of the systemic hemodynamic status traditionally provided by pulse oximetry.

[0105] The repetition rate is any suitable rate determined in each case of a particular embodiment by what is useful to the medical practitioner. The rate can be 100Hz, since the amount of data collected and processed is very small, or it can be more frequent if this proves useful. In some embodiments, slower rates are sufficient, for example, in some embodiments where the teachings herein are implemented to monitor blood oxygenation of tissue flaps in recovering patients, the repetition rate is typically not faster than 1Hz, for example, once per minute, or even once every 5 minutes.

[0106] Referring to Figures 9A-9C, three images are shown acquired using the method of the present invention of a finger under three different clamping regimes: normal (Figure 9A), 2 minutes of ischemia (Figure 9B), and after reperfusion (Figure 9C). Figure 9A shows the finger clamping tissue ischemia model under normal finger conditions. In this specific, non-limiting example, the finger was illuminated with a broadband light source (cold white) and acquisitions were made simultaneously in the blue (λ1) and red (λ2) wavelength ranges. Image processing included conversion of the grayscale image to a pseudocolor image using a 16-color LUT. EXAMPLES

[0107] Example 1A To monitor the oxygenated blood tissue status of the tissue flap, the system includes two oxygenation sensors 82, shown diagrammatically in Figure 10. Each oxygenation sensor 82 has a hermetically sealed waterproof sensor body 84 with a contact surface 86 having a 0.5 mm radius illumination window 64 that is transparent to light wavelengths in the range of at least 405 nm to 670 nm.

[0108] Inside the sensor body 84 are: a. A power source 66 (battery) for powering the other components of the oxygenation sensor; b. an LED configured to emit light having a wavelength of 405 nm to 420 nm as a first illuminator 42a and to emit the emitted light through an illumination window 64; c. an LED configured to emit light having a wavelength of 630 nm to 670 nm and to emit the emitted light through the illumination window 64 as the second illuminator 42b; d. single photodetectors 34 configured to determine the intensity of light in the range of at least 405 nm to 670 nm as a first (blue) and second (red) detector; e. Bluetooth® wireless transceiver 68; and f. A controller 38 including a computer processor, a timer, and solid state memory on a printed circuit board operatively associated with the other components of the oxygenation sensor and configured to: i. receiving a wake-up command sent by a user via transceiver 68; ii. after receiving the command, alternately activating the first illuminator 42a and the second illuminator 42b to illuminate an area of ​​the surface of the biological tissue in contact with the surface 86 at a rate and for a duration received from the user via the transceiver 68; iii. receiving and storing, from the photodetector 34, in a memory of the controller 38, a first intensity (the intensity of light diffusely scattered from the surface of the biological tissue when the first illuminator 42a is activated) and a second intensity (the intensity of light diffusely scattered from the surface of the biological tissue when the first illuminator 42b is activated); iv. comparing the received first and second intensities by calculating Ioxy=second intensity / first intensity; and v. Transmitting the calculated Ioxy at a user selected rate via wireless transceiver 68 to a remote device with which oxygenation sensor 82 is in wireless communication via wireless transceiver 68. Oxygenation sensor 68 does not include a lens.

[0109] For ease of use, the first of the two provided oxygenation sensors 82 is attached to the earlobe of the human subject by adhesive applied to the border of the contact surface 86. The second of the two provided oxygenation sensors 82 is attached to a flap of tissue of the human subject created during flap surgery by adhesive applied to the border of the contact surface 86.

[0110] A Bluetooth® piconet is formed including a Bluetooth® enabled smartphone as a master and two oxygenation sensors 86 as slaves, and the smartphone is programmed as necessary to carry out the teachings herein. Once per second, the smartphone receives Ioxy (reference) from the earlobe sensor 86 and Ioxy (flap) from the flap sensor 86.

[0111] For the first minute after piconet formation, the smartphone calculates the ratio OxContent(0)=Ioxy(flap) / Ioxy(baseline) as a baseline value indicating that the flap is receiving sufficient oxygenated blood from the blood supply maintained and / or newly created during flap surgery.

[0112] The two oxygenation sensors then communicate two Ioxy values, and the smartphone calculates the corresponding OxContent(t) value. As long as OxContent(t) remains within 80% of OxContent(0), the smartphone only stores OxContent(0) in the smartphone memory. If OxContent(t) falls below 80% of OxContent(0), the smartphone sends an alarm to the resident physician, who can then choose to consider whether the flap is still viable.

[0113] Returning to FIGS. 7A-7C, which are schematic illustrations of optical systems suitable for implementing the present invention, it should be noted that the first and second different wavelengths may be relatively close to each other. Also, the light source may be a laser. In other words, considering the configuration of FIG. 6A, for example, LED λ 1 and LED λ 2The elements labeled with may constitute two different lasers or two successive actions of the same laser, respectively. The control unit (202 in FIG. 6A) may thus be configured and operable to process first and second image data corresponding to / collected in imaging sessions separated in time. This may be performed, for example, by illuminating the tissue with a first wavelength (e.g., using a first illumination source) in a first time frame and illuminating the tissue with a second wavelength (e.g., using a second illumination source) in a second time frame. Working with alternating data (i.e., performing imaging sessions with measurement / imaging sessions separated in time) while using different illumination wavelengths obviates the need for spectrally selective filters 610, 620, which may be replaced, for example, by crossed polarizers. That is, the reference numbers 610, 620 in the figure may constitute polarizers. Alternatively, the same illumination source may be used with different first and second spectral filters activated in the first and second time frames, respectively. A further advantage of using such an alternating measurement mode is that illumination of different but close wavelengths can be performed without interference between the collected signals. Crossed polarizers 610, 620, if used, may be configured to eliminate specular reflections from the tissue surface, thus providing a high SB ratio. It should also be noted that laser units emitting polarized light may be used, and this configuration provides higher energy efficiency when used in conjunction with the cross-polarized approach. Furthermore, the use of different but close wavelengths is advantageous since it eliminates the need to correct for chromatic aberration.

[0114] More specifically, in such an embodiment utilizing illumination having different but spectrally close first and second wavelengths, the wavelengths may be about 415 nm (415±5 nm) and about 430-440 nm (e.g., 435 nm). Note that since the backscattered light signals are actually from the same depth within the tissue, the imaging system would not require optics to correct for differences in depth, and alternating measurements at different wavelengths would be simplified. Diode lasers for such an embodiment are readily available and may also be controlled to give short pulses to reduce energy consumption and increase safety. Thus, the use of such spectrally close light sources may allow for monitoring tissue oxygenation separately and independently from large vessel oxygenation information, which is readily available. It should be emphasized that tissue oxygenation information collected in this manner is independent of large vessel oxygenation information, since blue light is primarily reflected and scattered from and very close to the tissue surface, whereas large vessels reside deep within the tissue.

[0115] Example 1B As in Example 1A, the surfaces monitored are: graft tissue (e.g., a big toe transplanted as a thumb); A flap from the forehead used to reconstruct the nose; breasts reconstructed from abdominal tissue; Breasts after breast reduction surgery; and Some of the patients who were involved in the accident and it is unclear whether they will survive.

[0116] Example 1C A tissue oxygenation sensor similar to that described in Example 1A was used. The body of the sensor was a plastic disk with a diameter of 2 cm. An RGB light sensor (S9706, Hamamatsu Photonics, Shizuoka, Japan) was placed in the center of the disk. This light sensor was found to detect the intensity of red light at 650 nm and blue light at 413 nm. Within the circle, around the light sensor, eight LEDs were placed as illumination sources for the sensor: four warm white LEDs (ASMT-UWB-1-NX3J2, Broadcom, Irvine, CA, USA) and four blue LEDs (found to emit 413 nm light, OCU-400 411 OS, Osa Opto Light GmbH, Berlin, Germany).

[0117] A standard inflatable cuff was placed on the patient's upper arm. A tissue oxygenation sensor and a standard commercial tcpO2 sensor (Perimed AB, Järfälla, Sweden) were placed near each other on the underside of the patient's forearm, and the outputs of these two sensors were directed to a laptop computer, which received and analyzed the data received from the two sensors: from the tcpO2 sensor, a blood oxygenation measurement was displayed in mmHg, and from the tissue oxygenation sensor, it was displayed as second intensity / first intensity. The results of this experiment are shown above in Figure 5A.

[0118] It should be noted that similarly highly correlated measurement results were obtained between the tissue oxygenation sensor of the present invention and a standard pulse oximeter, and these results are shown in Figures 5B to 5D and 6 above. These figures show a close correlation between the blood oxygenation values ​​measured with a standard pulse oximeter and the absolute values ​​measured using the tissue oxygenation sensor of the present invention.

[0119] Example 2A 11 shows a schematic diagram of an embodiment of a system 98 based on the teachings herein, in which a computer processor 76 was a component of a commercially available laptop computer 100. Through an input port 12, the computer processor 76 was operatively connected to a spectral imaging camera 102 and a broadband illumination source 36 (a commercially available SD-300 spectral imaging camera from ASI (Migdal Haemek, Israel) fitted with a halogen lamp illumination source and a cross-polarizing filter set). Through an evidence output port 14, the processor 76 was also operatively connected to output components (a display screen 104a and a printer 104b as display components, an external hard disk 104c as storage components, and a Bluetooth transceiver 104d as a transmission component).

[0120] Image processing software connected to the camera 102 is programmed to execute on the computer 100 automatically extracting first pixelated monochromatic image data (blue image data) and second pixelated monochromatic image data (red image data) based on the teachings herein from the acquired spectral image received from the camera 102, and then automatically generating a third pixelated monochromatic image data as tissue oxygenation map data based on the teachings herein using pixel-by-pixel division (Ioxy=second intensity / first intensity for each pixel).

[0121] Using the arrangement described in FIG. 11, a spectral image of the surface of a body part is obtained and blood oxygenation tissue status map data of the body part is automatically generated, indicating the state of oxygenation in tissues below the surface of the body part.

[0122] Specifically, once every 30 seconds after the patient placed the forceps on the base of the finger, a spectral image of the finger was acquired using the camera 102 as described above, and the acquired spectral image was fed to the processor 76 to generate a third pixelated monochromatic image data as a blood oxygenation tissue status map. Corresponding blood oxygenation tissue status map data was generated and stored on the hard disk 104c, and a colorized version was displayed on the screen 104a and, if desired, printed on paper using the printer 104b. If necessary, the blood oxygenation tissue status map data was transferred to the smartphone using the transceiver 104d.

[0123] The displayed blood oxygenation tissue status map was pseudocolorized using publicly available software implementing a 16-color lookup table (LUT) known in the art of digital photography, with pixels having the highest values ​​displayed as dark red (qualitatively indicating more oxygenated blood in the tissue underlying the skin corresponding to that pixel) and pixels having the lowest values ​​displayed as dark blue (qualitatively indicating less oxygenated blood in the tissue underlying the skin corresponding to that pixel). Intermediate intensity values ​​were assigned one of 14 different colors, progressing from dark red to orange, orange to yellow, yellow to green, green to blue, and finally to dark blue.

[0124] The displayed colorized blood oxygenation tissue status map showed how the finger's oxygenated blood volume gradually decreased. After 3 minutes, the forceps were removed from the finger and the displayed colorized blood oxygenation tissue status map showed how the finger's oxygenated blood volume gradually increased back to normal.

[0125] Example 2B Using this system, blue image data and red image data of a human retina were simultaneously acquired. A set of simultaneously acquired images, blue image data from the first camera and red image data from the second camera, were input into a suitably configured (using image processing software) general-purpose laptop computer as a processor, and a pixel-by-pixel division of the red image data by the blue image data (for each pixel, Ioxy=second intensity / first intensity) was performed to generate third pixelated monochromatic image data constituting retinal blood oxygenation tissue status map data. The computer output the third pixelated monochromatic image data by displaying the data as a grayscale image on the computer screen and by storing the data on the computer hard disk.

[0126] The displayed grayscale image was processed to identify intensity values ​​associated with each portion of the image that clearly corresponded to an artery, vein, and retina. A colorized third image was generated in pseudocolor using publicly available software implementing a 16-color lookup table (LUT) known in the art of digital photography, with pixels having high Ioxy values ​​associated with identifying arteries displayed as red (qualitatively indicating a high amount of oxygenated blood in the tissue underlying the retinal surface corresponding to the pixel), pixels having intermediate Ioxy values ​​associated with identifying veins displayed as blue (qualitatively indicating a low amount of oxygenated blood in the tissue underlying the retinal surface corresponding to the pixel), and pixels having low Ioxy values ​​associated with identifying bloodless neural and connective tissue displayed as white (qualitatively indicating a lack of blood in the tissue underlying the retinal surface corresponding to the pixel).

[0127] The angiographic images obtained not only exhibited exceptionally high resolution, but also showed even the smallest arteries and veins, making it possible to clearly distinguish between arteries and veins by examining the images.

[0128] Example 2C In some embodiments, an optical waveguide (e.g., an optical waveguide that is part of an endoscope) is connected to an objective lens of an imaging camera (e.g., a spectral camera), and the optical waveguide directs light reflected from the surface of the biological tissue to the objective lens for detection. In some such embodiments, the tip of the endoscope comprises an illumination source (e.g., a white light source). In another such embodiment, the optical waveguide is operatively connected to an illumination source (e.g., a white light source, a xenon lamp) such that the illumination source directs light from the illumination source to illuminate the surface of the biological tissue.

[0129] Example 2D A physician cares for a subject with a foot ulcer as a result of diabetes. Blue and red image data of the foot ulcer are acquired in a similar or identical manner as described above, and blood oxygenation tissue status map data of the foot ulcer is generated. The physician prescribes treatment of the patient with a vasodilator. One week after the patient takes the vasodilator, blue and red image data of the foot ulcer are acquired, and post-treatment blood oxygenation tissue status map data of the foot ulcer is generated as described above. The physician visually displays and compares the two blood oxygenation tissue status map data to determine whether the vasodilator treatment was effective in treating the ulcer.

[0130] Example 2E Using the teachings herein, the viability of flaps after several surgical procedures is monitored. In the surgical procedures, subjects with tissue flaps (flaps formed during flap surgery) or grafts were monitored, and the patients were in-hospital patients. In a similar or identical manner to the above, blue image data and red image data were acquired, and blood oxygenation tissue status map data of the flaps and surrounding tissues was generated as necessary, where the blue image data wavelength was 405 nm to 420 nm, the red image data wavelength was 630 nm to 670 nm, and P3(i)=P1(i) / P2(i). The generated blood oxygenation tissue status map data was output by storage in a digital memory (e.g., a solid-state hard disk). The generated blood oxygenation tissue status map data was displayed and examined to confirm whether the flap / graft received sufficient blood supply to be viable or required surgical procedures. In a first example, using a common rodent skin flap model in experimental surgery, a dorsal-based fascial flap was created in a mouse by partial tissue dissection. Figure 12A (RGB image) and Figure 12B (blood oxygenation tissue status map generated from the spectral image) are of the flap 1 hour after surgery, and Figure 12C (RGB image) and Figure 12D (blood oxygenation tissue status map generated from the spectral image) are of the same flap 72 hours after surgery, showing necrosis due to insufficient blood supply to the base of the flap.

[0131] In a second example, the results of a frontal to nasal transposition were monitored in a patient. In such a procedure, a skin flap from the frontal region is transferred to the nasal region while still receiving blood from the frontal artery. After the flap has developed a sufficient blood supply from tissue in the nasal region, the frontal artery can be severed from the flap.

[0132] Figure 13A shows a blood oxygenation tissue status map generated from a spectral image of the flap 3 days after surgery. In the upper right-hand corner of the image, you can see the surgical clamp used to stop blood flow to the flap from the frontal artery. The dark color of the flap (indicated by the black arrow) indicates that the flap is receiving insufficient oxygenated blood from the nasal region and is dependent on blood from the frontal artery to survive.

[0133] Figure 13B shows a similar blood oxygenation tissue status map generated from the spectral image of the flap 10 days after surgery. The white color of the flap indicates that the blood supply to the flap from the nasal region is sufficient to ensure the survival of the flap and the frontal artery can be safely severed from the flap.

[0134] In a third example, the results of a nasal reconstruction surgery 14 days after the surgery was performed were evaluated using embodiments of the teachings herein. FIG. 14A shows a complete image of the patient's face. FIG. 14B shows a blood oxygenation tissue status map generated from the spectral images. The dark color of the reconstructed nose in the blood oxygenation tissue status map in FIG. 14B indicates that the reconstructed nose has a sufficient blood supply to be viable. The above experiment was repeated, with blue image data for wavelengths between 460 nm and 480 nm and red image data for wavelengths between 630 nm and 670 nm. The results obtained are substantially the same as those above.

[0135] Example 2F In a similar or identical manner to that described above, blue and red image data of injured limbs and organs of a human involved in a car accident were acquired, and corresponding blood oxygenation tissue status map data was generated. The blood oxygenation tissue status map data was displayed on a screen (in color, if desired) and, if desired, saved on a hard disk or the like and output. The displayed blood oxygenation tissue status map data was examined by a treating physician to determine which tissues could be salvaged, for example by surgery, and which tissues required resection.

[0136] Example 2G The teachings herein were used for real-time monitoring of brain function during stimulation.An imaging system similar to that described above was provided, in which the digital cameras are video cameras and an associated processor is configured to continuously simultaneously acquire a set of red image data (wavelengths between 630 nm and 670 nm) and blue image data (wavelengths between 405 nm and 420 nm) from each camera in real time at a desired rate (e.g., 1 Hz, 20 Hz, 60 Hz) according to the teachings herein, generate corresponding blood oxygenation tissue status map data using pixel-by-pixel division (Ioxy=second intensity / first intensity), and then output the generated blood oxygenation tissue status map data by storing to disk and displaying the real-time animated blood oxygenation tissue status map of the surface of the biological tissue from which the image was acquired.

[0137] During brain surgery on the subject, image data pairs were acquired of the exposed cortical surface of the right hemisphere of the subject's brain, and a real-time video of the blood oxygenation tissue status map of the cortical surface was displayed on a screen viewable by the operating surgeon. When the surgeon stimulated an extremity (e.g., the left hand) of the subject, the portion of the cortical surface that experienced a higher volume of oxygenated blood as a result of the stimulation indicated that portion of the cortical surface was associated with the stimulated extremity.

[0138] FIG. 15A shows an RGB image of a portion of the right hemisphere of the brain of a human subject. FIG. 15B, FIG. 15C, and FIG. 15D show blood oxygenation tissue state maps of a portion of the cortical surface generated in accordance with the teachings herein for the left hand, FIG. 15B for no stimulation, FIG. 15C for low stimulation, and FIG. 15D for high stimulation. FIG. 15C and FIG. 15D show a portion of the brain that exhibited an increase in oxygenated blood volume as a result of stimulation. The above experiment was repeated, with blue image data for wavelengths between 460 nm and 480 nm, and red image data for wavelengths between 630 nm and 670 nm. The results obtained were substantially the same as those described above.

[0139] Example 2H The teachings herein were used to monitor cancer treatment using photothermal therapy. Nude mice were subcutaneously inoculated with human colon cancer H29. After 3 weeks, the tumor was exposed and photothermal therapy was performed using an IPL (intense pulsed light) device manufactured by ESC Medical Systems (Yokneam, Israel) essentially as described in Kostenich G et al., "Photothermic treatment of pigmented B16 melanoma using a broadband pulsed light delivery system," Cancer Letters, Vol. 157, No. 2, (p. 161), (2000). During the treatment, full-spectrum image data of the tumor was acquired using a spectral imaging camera. Blue image data with wavelengths of 460 nm to 480 nm and red image data with wavelengths of 630 nm to 670 nm were extracted from the full-spectrum image data. The pixel-wise division (P3(i)=P1(i) / P2(i)) produced the blood oxygenation tissue status map described herein. FIG. 16A shows the generated blood oxygenation tissue status map of the tumor before photothermal therapy. It can be seen that the tumor is intact. FIG. 16B shows the generated blood oxygenation tissue status map of the tumor before photothermal therapy. The tumor is shown to be intact after 40 J / cm 2 FIG. 16C shows the generated blood oxygenation tissue status map of the tumor after receiving multiple light pulses equivalent to 80 J / cm. The decrease in oxygenated blood at the base of the tumor indicates vascular occlusion and ischemia caused by light exposure. FIG. 16D shows the generated blood oxygenation tissue status map of the tumor after receiving multiple light pulses equivalent to 80 J / cm. The decrease in oxygenated blood at the base of the tumor indicates vascular occlusion and ischemia caused by light exposure. 2 4 shows the generated blood oxygenation tissue status map of a tumor after receiving multiple light pulses equivalent to 1000 s. The complete lack of oxygenated blood throughout the tumor indicates that substantially all of the tumor blood vessels have been occluded by the light exposure, resulting in tumor cell death. The above experiment was repeated and blue image data with wavelengths between 405 nm and 420 nm and red image data with wavelengths between 630 nm and 670 nm were extracted from the full spectrum image data. The results obtained were substantially the same as those above.

Claims

1. 1. A system for monitoring oxygenation in biological tissue, comprising: a controller configured and operable to receive and process data indicative of collected light responses of a region of the biological tissue, the controller irradiating the biological tissue with a wavelength range that is absorbable by oxyhemoglobin and deoxyhemoglobin; processing the received data includes comparing data representative of two selected wavelength ranges of collected light responses from the region to determine an oxygenation / deoxygenation state of the biological tissue; the two selected wavelength ranges include a first wavelength range in which the absorbance of deoxyhemoglobin in the biological tissue is higher than the absorbance of oxyhemoglobin and a second wavelength range in which the absorbance of oxyhemoglobin in the biological tissue is higher than the absorbance of deoxyhemoglobin, or include a first wavelength range in which the absorbance of oxyhemoglobin in the biological tissue is higher than the absorbance of deoxyhemoglobin and a second wavelength range in which the absorbance of deoxyhemoglobin in the biological tissue is higher than the absorbance of oxyhemoglobin, the two selected wavelength ranges having first and second wavelengths, providing a maximum or highest ratio of absorbance of deoxyhemoglobin to absorbance of oxyhemoglobin in the biological tissue such that the absorbance intensities of deoxyhemoglobin and oxyhemoglobin are maximally different from each other at each of the first and second selected wavelengths; the first wavelength is within the first wavelength range of 400 nm±10% to 420 nm±10%, or 450 nm±10% to 500 nm±10%, and the second wavelength is within the second wavelength range of 420 nm±10% to 450 nm±10%, or 600 nm±10% to 800 nm±10%, The system is characterized in that comparing the data indicating the two selected wavelength ranges includes determining the oxygenation / deoxygenation state of the biological tissue by utilizing a correspondence between a numerical value of a ratio or difference between data indicating the light response intensity of the first wavelength range and the second wavelength range and a numerical value of tissue oxygenation data.

2. 2. The system of claim 1, wherein the first wavelength range is selected such that the data represents a first tissue portion located at a surface of the tissue being monitored, and the second wavelength range is selected such that the data represents a second tissue portion located at a second tissue portion deeper in the tissue being monitored.

3. 2. The system of claim 1, wherein the first wavelength range and the second wavelength range are in the blue spectral band, and the first wavelength range and the second wavelength range are selected such that the data is indicative of a superficial tissue portion of the tissue being monitored.

4. 4. The system of claim 3, wherein the first wavelength range is from 400 nm ± 10% to 420 nm ± 10% and the second wavelength range is from 420 nm ± 10% to 450 nm ± 10%; or, the second wavelength range is from 420 nm ± 10% to 450 nm ± 10% and the first wavelength range is from 450 nm ± 10% to 500 nm ± 10%.

5. 5. The system of claim 1, wherein the controller is configured and operable to process the data by calculating a ratio comparing two average intensities of the two selected wavelength ranges in the collected light response.

6. The system of any one of claims 1 to 5, wherein the control unit is configured and operable to determine the oxygenation / deoxygenation state of the biological tissue in real time.

7. 7. The system of claim 1, wherein the data indicative of collected light responses in the two selected wavelength ranges includes at least two pixelated images; and processing the data comprises: identifying pixels in each image indicative of a particular area of ​​the region; performing a pixel-by-pixel comparison of the at least two pixelated images for each of the particular areas; determining the oxygenation / deoxygenation state of the biological tissue for each pixel; and generating a processed image indicative of tissue oxygenation / deoxygenation tissue state mapping.

8. 8. The system of claim 7, wherein the control unit is configured and operable to generate processed images of the tissue being monitored, the processed images indicative of oxygenated tissue status at a surface of the tissue linked to oxygenated tissue status deeper within the biological tissue.

9. The system of any one of claims 1 to 8, further comprising a detector configured and operable to collect the light response.

10. 10. The system of claim 9, wherein the detection unit comprises an imaging unit configured and operable to receive the light response and generate at least two pixelated images thereof.

11. 11. The system of claim 10, wherein the imager comprises a spectral imager configured and operable to receive the light response and generate at least two pixelated spectral images thereof.

12. 12. The system of claim 11, wherein the data comprises at least two pixelated spectral images; and processing the data comprises extracting from the at least two pixelated spectral images at least two monochromatic images corresponding to the two selected wavelength ranges of illumination and / or acquisition, respectively, performing a pixel-by-pixel comparison for each specific range of the at least two monochromatic images, and generating a processed image indicative of a spectrally resolved tissue oxygenation / deoxygenation mapping.

13. 13. The system of any one of claims 10 to 12, wherein the imaging portion comprises at least two imaging portions, each imaging portion configured and operable to detect at least one electromagnetic beam within a different selected wavelength range.

14. 13. The system of claim 10, further comprising at least two crossed polarizing elements connected to an illumination source and to the imaging unit, the crossed polarizing elements configured and operable to remove specular reflections from the tissue.

15. 10. The system of claim 9, wherein the detector comprises a non-imaging optical detector configured and operable to receive optical responses of a same region from the biological tissue illuminated and / or collected at the two selected wavelength ranges and generate at least two average intensities of the region.

16. The system of any one of claims 1 to 15, further comprising an illumination source configured and operable to illuminate the biological tissue with electromagnetic beams of the two selected wavelength ranges.

17. The system of claim 16 , wherein the controller is configured and operable to control the illumination source and select a wavelength range of illumination.

18. 18. The system of claim 16 or 17, wherein the illumination source comprises at least two light sources, each light source configured and operable to illuminate the biological tissue at a different selected wavelength range.

Images