Title: Short-Wave Infrared Imaging and Spectroscopy

Technique for Inflammation Classification and Tumor and Inflammation Differentiation in Human Tissues

Inside the Body.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to optical measurement techniques and methods for inflammation classification and differentiation between inflammation and tumor in human tissues inside the body. More particularly, the invention relates to an optical method and device for in-vivo diagnosing of body cavity conditions (ear, colon, etc.) that includes obtaining a Short- Wave IntraRed (SWIR) spectrum together with a visible (VIS) - SWIR image of reflected light from a tissue.

The biochemical composition of a cell is a complex mix of biological molecules including, but not limited to, proteins, nucleic acids, lipids, and carbohydrates. The composition and interaction of the biological molecules determines the metabolic state of a cell. The metabolic state of the cell will dictate the type of cell and its function (i.e., red blood cell, epithelial cell, etc.). Tissue is generally understood to mean a group of cells that work together to perform a function.

Imaging and spectroscopic techniques may provide information about the optical properties of cells and tissues. As the tissue's metabolic state changes from the normal state to a diseased state (including inflammation or tumor), imaging and spectroscopic techniques can provide information to indicate the change and therefore serve to diagnose a disease state.

For example, colonic polyps appear as two major types, neoplastic and non-neoplastic. Non-neoplastic polyps are benign with no direct malignant potential and do not necessarily need to be resected. Hyperplastic polyps, juvenile polyps, mucosal prolapse and normal mucosal polyps are examples of non-neoplastic polyps. Conversely, neoplastic polyps are pre-malignant, a condition requiring resection and further surveillance. Examples of premalignant neoplastic polyps are tubular adenoma, villous adenoma and tubulovillous adenoma.

Conventional laser-induced fluorescence emission and diffused reflectance spectroscopy can distinguish between neoplastic and non-neoplastic tissue with accuracies approaching about 85%. However, typically these methods require that the full spectrum be measured with algorithms dependent on many emission wavelengths.

Endoscopy video imaging in body cavities ordinarily utilizes back- scattered white light applied through the endoscope to form a low-resolution color image of the internal surfaces of these cavities. Physicians often use the changes in shapes and in local apparent color (which are often due to changes in blood distribution) to recognize disease states, such as malignant tumors or inflammation. Unfortunately, these clues are frequently not sufficient, especially for detection of the early onset of disease.

Diagnostic improvements have been made by quantitative measurements of the light scattering and of tissue fluorescence emission. The fluorescence is excited by absorption of ultraviolet light of about 300-400 nm wavelength or sometimes slightly longer wavelength of visible light. A problem with this method is that this UV light is strongly absorbed by hemoglobin and oxyhemoglobin in the blood, which are not fluorescent, so that penetration of the illumination into the tissue depends on the concentration and distribution of the hemoglobin and oxyhemoglobin.

In a further example, a wide variety of diseases associated with the human ear have been identified. In children, otitis media is one of the most common pathologies. By itself, otitis media is a significant affliction, which can lead to serious long-term hearing and learning disabilities if not promptly diagnosed and treated. Two major medical conditions are mistakenly diagnosed as otitis media: The first mistaken diagnosis is a healthy ear, in which no medical therapy is of need. The second mistaken diagnosis is serous otitis media (SOM) which is an allergic reaction or which is caused by a virus. These ear pathologies are generally diagnosed using common diagnostic techniques, such as tympanometry or visual otoscopy.

Relating to otoscopy, it is quite clear that physicians should not rely solely on the otoscope to diagnose the medical condition of the ear. Otoscopy is largely subjective because it is a visual examination. Therefore, it usually results in over diagnosis of otitis media.

The technique of near infrared spectroscopy (NIRS, ~750- 1,000 nm) has been increasingly used to monitor blood and tissue oxygenation in patients, especially the status of the brain.

The relative good transparency of biological tissues to Red-NIR light (i.e., 600-1,000 nm) allows the absorption properties of intact organs to be monitored non-invasively. In the NIR, absorption due to hemoglobin and cytochrome oxidase can be observed, making it possible to monitor changes in blood and tissue oxygenation. The method was applied to the brains of newborn infants and adults.

In the NIR spectrum, the primary absorbers of light are hemoglobin, oxyhemoglobin, water, and lipids. With knowledge of accurate spectra of these chromophores over the desired wavelengths, it becomes possible to non- invasively assess their concentration (Delpy and Cope 1997) and, hence, total hemoglobin (HbT) and tissue oxygen saturation (StO2). Delpy, D. T. & Cope, M. (1997) Philos. Trans. R. Soc. London B 352, 649-659.

A pressure ulcer (PU), also known as a bedsore, develops at the bony prominences of the body (heel, elbows, shoulders bones, sacrum) for people with limited mobility. Pressure ulcers (PUs) are currently diagnosed visually by clinicians by matching characteristic features of defined stages of PUs to a lesion at a bony prominence. A stage I of PU, the lowest grade PU, is diagnosed specifically with the blanch test - the application of pressure to the site to observe the whitening of the skin (blanch response) - the clinical standard. However as the melanin content in the skin increases, it becomes more difficult for clinicians to accurately diagnose stage I of PUs. PUs are the easiest to treat and heal at an early stage.

Pressure ulcers cost the US health care system $1.3 billion every year

(Cuddigan et.al. 2001). [J. Cuddigan, D. R. Berlowitz, and E. A. Ayello, "Pressure Ulcers in America: Prevalence, Incidence, and Implications for the Future: An Executive Summary of the National Pressure Ulcer Advisory Panel Monograph," Advances in Skin and Wound Care, vol. 14, pp. 208-215, July/August 2001.]

There are currently no commercially available devices specifically designed to diagnose PUs. Analytical spectrometers are commercially available (the Mexameter, Courage & Khazaka, Koln, Germany, and the Erytha Meter, Diastron, Andover, UK) that can quantify skin color and the changes in skin color. These devices however are designed for cosmetology/dermatology research, are not simple to use for an untrained professional, and they are not suited for the detection of pressure ulcers.

The patents for PU diagnostic devices describe methods for early PU diagnosis based on tissue reflectance spectroscopy using a combination of LEDS, processors, and photodetectors.

Tissue reflectance spectroscopy can be used to identify early stage pressure ulcers by analyzing the reflected spectrum of the skin from an incident light beam to observe the transient changes in blood (oxyhemoglobin and deoxyhemoglobin) concentration. Though the patented devices using tissue reflectance spectroscopy were prototyped and tested, neither of the devices successfully passed clinical trials due to poor ergonomic design or difficulty of use.

Lung cancer is the second most common cancer in humans and is the most common cause of cancer deaths in the world. Because early lung cancers or pre-cancers such as dysplasia and carcinoma in situ (CIS) are only a few cell layers thick (0.2-1 mm), they can be very difficult to visually detect by conventional diagnostic methods.

Tissue fluorescence spectroscopy has been successfully used in vivo to diagnose early lung cancers. Fluorescence point spectra may be collected in less than a second, and fluorescence imaging is possible due to the relatively high tissue auto-fluorescence that occurs in the lung. Nevertheless, tissue auto- fluorescence spectral features are broad and show less specific differences between normal and pathologic tissues.

Near-infrared (NIR) Raman spectroscopy has certain advantages, such as relative insensitivity to tissue water contents and deeper penetration depth into the tissue. NIR Raman spectroscopy has been investigated for in vitro diagnosis of malignant tissue from various organs (e.g., brain, breast, bladder, colon, larynx, cervix and skin). These studies show that specific features of tissue Raman spectra can be related to the molecular and structural changes associated with neoplastic transformations. However, Raman spectroscopy has not yet been applied to the bronchus to date.

Raman scattering from tissue is inherently very weak. It is very difficult to achieve measurements rapidly in vivo with a high signal-to-noise (S/N) ratio while avoiding interference from tissue auto-fluorescence and Raman signals from the silica fiber optics. This is because the fiber-optic probes used to collect in vivo signals exhibit strong silica Raman scattering in the so-called fingerprint region (500 -1,800 cm-1). Moreover, data acquisition times and irradiance powers for in vivo use must be limited for practical and safety reasons.

The present invention is directed to overcoming these diagnostic deficiencies in the art.

There is therefore a need to facilitate optical measurements inside the patient's body, especially, but not limited, for determining the patient's body cavity condition (ear, colon, etc), by providing a novel optical method and system that enable detection, classification and differentiation of inflammation and tumor inside in body tissue, such as, for example the existence of otitis media of the ear such as, but not limited to, acute otitis media (AOM) and serous otitis media (SOM)) or colon diseases such as, but not limited to, inflammation or tumor and in general the present state of tissue inside in body.

SUMMARY OF THE INVENTION The present invention is an optical method and system that enable detection, classification and differentiation of inflammation, tumor, abnormalities and/or the present state of tissue inside in body.

According to the teachings of the present invention there is provided, a method for detection, classification and differentiation of the present state of tissue inside an animal body, the method comprising: (a) illuminating a region of interest with incident light beams of at least two different wave-bands each of which is in a range in which at least one of the scattering and the absorbing properties of tissue of the region of interest are sensitive to light radiation; (b) sensing, with a sensor unit, reflected light of the least two different wave-bands that is reflected from the region of interest; and (c) determining a presence of irregular tissue in the region of interest based upon identification of at least one local absorbance data in at least one of the least two different wave-bands that is indicative of the present state of tissue inside in body.

According to a further teaching of the present invention, the at least two different wave-bands are implemented in VIS and S WIR ranges.

According to a further teaching of the present invention, the VIS waveband is implemented at 350-700 nm for color imaging (RGB) and the SWIR wave-band is implemented at 1200-2500 nm for SWIR spectroscopy and SWIR imaging.

According to a further teaching of the present invention, the SWIR wave-band is implemented as at least three discrete SWIR wavelengths, 1200- 1350 nm, 1400 -1500 nm and 1500-2500 nm. According to a further teaching of the present invention, there is also provided determining the existence of inflammation with liquid behind at least a portion of the tissue of the region of interest.

According to a further teaching of the present invention, the illuminating, the sensing and the determining are implemented as providing substantially continuous illumination, sensing and determining over a predetermined period of time.

According to a further teaching of the present invention, there is also provided an optical fibers arrangement suitable for insertion into a cavity of an animal body.

There is also provided according to the teachings of the present invention, a device for detection, classification and differentiation of the present state of tissue inside an animal body tissue, the device comprising: (a) an illumination unit configured to generate illumination of at least two different wave-bands each of which is in a range in which at least one of the scattering and the absorbing properties of tissue of the region of interest are sensitive to light radiation; (b) transmission/receiving unit configured to transmit the illumination so as to illuminate a region of interest with incident light beams of the at least two different wave-bands and to receive reflected light of the least two different wave-bands that is reflected from the region of interest; (c) a detection unit configured to sense the reflected light of the least two different wave-bands that is reflected from the region of interest; and (d) a processing unit programmed to determine a presence of irregular tissue in the region of interest based upon identification of at least one local absorbance data in at least one of the at least two different wave-bands that is indicative of the present state of tissue inside in body.

According to a further teaching of the present invention, the least two different wave-bands are in VIS and SWIR ranges.

According to a further teaching of the present invention, the VIS wave- band is in a range of 350-700 nm for color imaging (RGB) and the SWIR wave-band is in a range of 1200-2500 nrn for SWIR spectroscopy and SWIR imaging.

According to a further teaching of the present invention, the SWIR wave-band is configured as at least three discrete SWIR wavelengths, in a range of 1200-1350 nm, in a range of 1400 -1500 nm and in a range of 1500- 2500 nm.

According to a further teaching of the present invention, the illuminating, the sensing and the determining are substantially continuous illumination, sensing and determining over a predetermined period of time.

According to a further teaching of the present invention, the transmission/receiving unit includes an optical fibers arrangement suitable for insertion into a cavity of an animal body.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein:

FIG. 1 is FIG 1 illustrates plots of SWIR absorption spectra of the principal components in tissue;

FIG. 2 illustrates SWIR water transmission spectra for the depth of water of 0.3 mm and 5 mm, theoretically calculated from the water absorption coefficient spectra;

FIG. 3 illustrates SWIR spectroscopy of a 0.6 mm tissue thickness of animal tissue sample with and without water behind;

FIG. 4 is a black and white photo of showing the tissue of FIG. 3 in the Visual wavelength;

FIG.5 shows an image of the tissue of FIG. 3 in the SWIR wavelength;

Fig. 6 is a block diagram of a first preferred embodiment of an optical system constructed and operational according to the teaching of the present invention; Figs 7 and 8 are a cross-section and an end view of a first preferred embodiment of an optic fibers arrangement suitable to be used in the system of FIG. 6;

Fig. 9 is a block diagram of a second preferred embodiment of an optical system constructed and operational according to the teaching of the present invention; and

FIG. 10 is an end view of an optic fibers arrangement suitable to be used in the system of FIG. 9.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is an optical method and system that enable detection, classification and differentiation of inflammation, tumor, abnormalities and/or the present state of tissue inside in body tissue.

The principles and operation of an optical method and system that enable detection, classification and differentiation of inflammation, tumor, abnormalities and/or the present state of tissue inside in body, according to the present invention may be better understood with reference to the drawings and the accompanying description.

It will be readily understood that abnormalities include inflammatory and non-inflammatory tissues, such as non-inflammatory cysts for example. Another abnormality the present invention is able to detect and monitory is the presents of foreign material in the blood stream such as, but not limited to pharmaceuticals.

By way of introduction, the present invention may overcome the limitations of the prior art by providing combination of imaging and spectroscopy in visual (VIS) and short wave infra-red (SWIR) wave-bands for rapid, non-invasive, and nondestructive detection and differentiation between inflammation and tumor in complex environments such as a human body cavity such as, but not limited to, the ear and colon. While the combination of VIS and SWIR has been used to find bruises in some thin skinned fruits and vegetables, historically SWIR has not been used in conjunction with scanning the human body because of the high percentage of fluid (water) in body tissue. In fact, SWIR is generally filtered out as producing background "noise".

The present inventors, however, have discovered that relevant and useful data may be obtained by the use of SWIR scanning, especially when combined data obtained by VIS scans and spectral analysis of the SWIR.

More specifically, the proposed technology provides for use of elastic scattering VIS-SW1R spectroscopic and imaging techniques including hyperspectral imaging to detect and classify inflammations and to differentiate between inflammation and tumor in biological tissues inside human body. It will be appreciated that analysis of the spectroscopic images allows the present invention to analyze the chemical makeup of the liquid behind the tissue of the region of interest (ROI). The term "region of interest" or "ROI" is used herein to refer to a region of tissue to be studied such as, for example, a middle ear cavity between the tympanic membrane and the external inner ear wall or a part of colon tissue.

It will be further appreciated that the method and device of the present invention may be used to equal benefit for obtaining both spontaneous single event "snapshots" of the ROI and substantially continuous imaging/spectral analysis over a period of time. It will be readily understood that during such substantially continuous imaging/spectral analysis, the illumination unit will provide substantially continuous illumination over a predetermined period of time. It should be noted that the substantially continuous imaging/spectral analysis is produced over all wavelengths being monitor such as, but not limited to VIS, SWIR and SWIR spectral monitoring.

The combination of chemical analysis of the liquid behind the tissue of the ROI and substantially continuous imaging/spectral analysis over a period of time allows to present invention to monitor changes in the condition of the tissue of the ROI in real time. While reference is made herein to detection within bodily cavities such as the ear and colon, these are used as non-limiting examples. It will also be appreciated that a device constructed and operational according to the teaching of the present invention that is configured to practice the method of the present invention on tissue surfaces that are not inside a bodily cavity but rather behind thin tissues on the outer surface of the body is within the scope of the present invention.

It should be noted that the inventors have found that the present invention provides the ability to differentiate inflammatory load (severity of inflammation), especially in bone tissue. This is due to the varying amounts of liquid associated with the severity of the inflammation. Further, the present invention provides information regarding the depth of the inflammation, as well.

It should also be noted that as used herein the term "reflected light" refers to substantially any electromagnetic energy emanating from the ROI, reflected and otherwise transmitted from the ROI.

In a first broad aspect, the present invention provides a measurement technique for detecting the condition of a patient's ear indicative of a particular disease. The method of the present invention provides for detecting the existence of SOM or AOM condition, and for distinguishing between these conditions. Either one or both of the SOM and AOM conditions can be detected as a condition of the existence of fluid (mainly water) in the ROI. As for distinguishing between the SOM and AOM, this can be based on a difference in the fluid density at the location of the SOM or AOM conditions of the ear 3. The ear drum itself is becoming opaque because it may take part in the inflammatory process, causing reduced to minimal visibility through ear drum. The ear drum is transparent to VIS light if not inflamed or calcificated. The SOM-related fluid is a transparent blue or clear fluid, while the AOM- related fluid is opaque for visible-range light and is relatively highly scattering for the SWIR range. Hence, the fluid which accumulates in the middle ear differently scatters the propagating light, thus a different amount of light is detected at the SOM and AOM condition sights.

Elastic scattering spectroscopy and imaging is based on irradiation of a region of interest and detection of scattered radiation at the same wave-band, and it can be employed to analyze biological tissues in-vivo. Thus, no tissue preparation is required.

Hyperspectral imaging (or multispectral imaging) of biological tissue or human tissue relates to the images at discrete (narrow) wave-bands. The optical sensor (the SWIR camera or focal-plane array) records a two-dimensional (2D) image of an area of the tissue of the region of interest at a specific waveband or wave bands, which may be chosen on the basis of known optical properties (spectral signatures) of the tissue. The optical sensor collects information as a set of images (frames) at a specific waveband for each frame. These frames are then combined and form three-dimensional hyperspectral data for processing and analysis.

Conventional imaging and spectroscopic devices operate over a limited range of wavelengths due to the operation ranges of the detectors or tunable filters possible. This enables analysis in visible ("VIS"), near infrared ("NIR"), short-wave infrared ("SWIR") wavelengths, and to some overlapping ranges. These correspond to wavelengths of approximately -380-750 nm ("VIS") and -750-2500 nm ("NIR-SWIR" or "SWIR").

Generally, at least one selected range of the predetermined light spectrum is defined depending on the patient's condition to be detected.

For the purpose of determining the inflammation existence (redness level), the predetermined light spectrum preferably includes a range -380-750 nm (Visual range).

An example of an algorithm to determine the presence of inflammation (redness) is carried out through use of RGB imaging data fields as a ratio: R /(R+G); (R-G)/(R+G); R / (R+G+B) wherein R, G, B are the detected radiance of light within the wavelength sub-region coming from the ROI. The term "RGB" is used herein with respect to visual imaging where RGB corresponds to colors in terms of wavelength sub-ranges: Red (-orange) ~ 590-750 nm; Green (-yellow) ~ 490-590 nm; Blue (-violet) ~ 390-490 nm.

For the purposes of determining the existence of inflammation with liquid substance (e.g. otitis media condition), the predetermined light spectrum includes additionally a range of 1200-2500 nm (SW1R).

For the purpose of differentiation between inflammation and tumor, the predetermined light spectrum is preferably selected to be within both VIS and SWIR regions of -350-750 nm and -1200-2500 nm, respectively.

The detectable light response depends on the tissue condition, i.e., the incident light wavelength is differently absorbable/transmittable or scattered by the tissue in the ROI based on the existence of a certain disease (or lack thereof) such as, but not limited to inflammation or tumor. Further, the features of the tissue such as, but not limited to, the concentration of substances within the tissue are changed in the ROI, as compared to a normal, healthy tissue.

SWIR absorbance spectra of three major constituents of tissue are shown overlaid in Figure 1. Specifically, the absorbance spectra of water 10, protein 12, and lipid 14 are shown. As can be seen, the absorbance spectra of water 10 and protein 12 have spikes near 1450 nm, while the lipid 14 plot is relatively flat. The water absorption band is centered at -1450 nm.

To classify inflammation (otitis media etc.) and to differentiate between inflammation and tumor (e.g. in colon) at least two wave-bands are chosen for the scan.

These two wave-bands include one reference wave-band and the second an operating wave-band. The reference wave-band is either substantially absorbable or scattered (transmittable) by the ROI irrespective of whether a specific object (substance) exists or its features has changes in the ROL The reference wave-band, therefore, is preferably in the wavelength range of -1400-1500 nm. The operating wave-band is differently absorbable/transmittable or scattered by the ROI when a disease is present in the tissue or the features of the tissue have changed in the ROI.

The operating wave-band is in at least one of the following ranges: -1200-1350 nm and 1550-2500 nm.

This allows for determining tissue properties by detecting a change in scattering of the operating wavelength such as increased scattering or lower intensity of the detected light.

Preferably, the wavelengths also include an additional wave-band in visual range: 400-750 nm. The system is therefore operable to detect inflammation condition via detection of a change in the redness level based on image RGB analysis.

It should be noted that the terms "substantially absorbable," "transmittable" and "scattered" may or may not refer to full absorption or full scattering / transmission of the specific wavelengths, rather they are used herein as relative terms meaning that the specific wavelengths are absorbed or scattered by the ROI at a relatively higher rate as compared to other wavelengths.

Therefore, the measurement method of the present invention for use in detecting a condition of a patient's ear indicative of a certain disease is as follows.

1 - Illuminating the ROI with incident light beams of at least two different wave-bands in a range where the scattering or absorbing properties of tissue are sensitive to light radiation (e.g. in VIS and SWIR range);

2 - Sensing with a sensor unit reflected light from the ROI in VIS and SWIR wavelength region; and

3 - Determining whether inflammation is present in the ROI based upon the identification of at least one local absorbance maximum or minimum in the SWIR wave-length that is indicative of the presence of liquids (otitis media). VIS-SW1R digital imaging provides a means to obtain optical (i.e., spatial— morphological, topographical or textural etc.) information about a tissue. By combining the spatial information obtained from SWIR digital imagery and the spectral information obtained from SWIR spectroscopy, the region of interest can be mapped out in both two and three spatial dimensions.

Instruments for performing VIS-SWIR hyperspectral imaging and spectroscopy can typically comprise an illumination source, image gathering optics (lenses, fibers, filters, polarizers), focal plane array imaging detectors (such as cameras) and dispersive spectrometers.

In general, the diagnostic channel size determines the choice of image gathering optic. A flexible fiberscope or endoscope with fibers can be employed for the analysis of sub millimeter spatial dimension tissues located within relatively inaccessible environments like the colon for example.

A region of interest is illuminated to produce scattered light in VIS- SWIR wavelengths. Including the SWIR spectral regions along with the visible provides for a more robust identification and mapping of tissue disease than using visible imaging spectroscopy alone.

The scattered photons are detected to generate a color (RGB) VIS and SWIR spectroscopic data set representative of the tissue, wherein the VIS- SWIR data set includes SWIR spectra of the tissue and a spatially accurate wavelength resolved VIS-SWIR image of the tissue. The cross-polarization method can be used to reject a spectrurai reflection and enhance a signal of the diffusive backscattering from the region of interest.

The VIS-SWIR spectroscopic data set is evaluated using a chemometric (principal component or multivariate analysis, etc.) or other technique to classify the tissue state as inflammation or tumor (acute, chronic, incipient, or none).

The analysis may include comparing at least one SWIR spectrum or RGB-SWIR image representative of the ROI. This comparison is accomplished using a signal processing or image processing technique. The device and method of the present invention use Color (RGB) and SWTR imaging, SWIR spectroscopy, including RGB-SWIR hyperspectral imaging. The device may include an endoscope, color (RGB) and SWIR cameras (or FPA detectors), SWIR spectrometer, a tunable filter, polarizers, fiber bundles and one or more illumination source such as, but not limited to, LED, Halogen lamp, etc.

The device may be configured in different embodiments:

In a first preferred embodiment of the present invention, as illustrated in Figure 6, the region of interest is illuminated by wide wave-band source which overlaps VIS-SWIR range of wavelengths from -380 to -2500 nm. Backscattered light from the tissue (colon, ear of a subject etc) is separated into narrow wave-bands using optical filters and collected by the detector for analysis.

In a second preferred embodiment of the present invention, as illustrated in Figure 9, a number of discrete (narrow) waveband light sources are used for illumination.

The processing unit 68 (software) translates the obtained spectrum of reflected light to one or more output values related to the condition of the tissue. The method of the invention is able, for example, to determine whether the ear is healthy, or is infected with either otitis media, or serous otitis media.

Further, the present invention may be configured to determine the inflammation (or the redness degree) of the tissue (e.g. tympanic membrane compared to a healthy ear, colon conditions, etc.).

The present invention may also be configured to determine the effusion degree (water) in the middle ear compare to a healthy ear.

A further configuration the present invention provides a method for detecting and classification (diagnosing) tissue related conditions (inflammation etc) comprising the steps of illuminating inside the body; inserting a device to the canal (ear, colon etc) capable of conveying at least one spectrum and/or image from said tissue to a processing unit; or activating a number of single detectors at chosen wavelengths, or spectrometer, or imager.

In a second broad aspect of the present invention, there is provided a measurement system and method based on measured SWIR spectra for use in inflammation classifying and inflammation / tumor differentiation, in which the system includes:

(a) an optical measuring device operable for applying spectral measurements to the ROI in a patient's body with predetermined SWIR spectrum and producing measured spectral data indicative thereof; and

(b) a device for receiving and processing the measured data to generate output data indicative of measurement results; a software for processing and analyzing the measured data by selecting a certain part of the measured spectra within at least one range of the predetermined SWIR spectrum and applying a predetermined model to the selected part of the measured data to determine a corresponding value for the disease identification and to generate output data indicative of association between the determined parameter value and the reference data.

Preferably, the processing of the measured spectral data comprises normalizing the measured spectral data to thereby obtain a relative spectrum. The predetermined model is then applied to the relative measured spectrum.

The normalization of the measured spectral data includes normalization by a reference SWIR spectrum, normalization by a certain wavelength from the predetermined SWIR spectrum, and preferably also normalization by the predetermined light source spectrum. The result of normalizing the measured data by the reference spectrum is a normalized reflectivity/absorption spectrum.

The reference spectrum is indicative of the light intensity illuminating the ROI as a function of wavelengths of the predetermined incident light.

Generally, this can be implemented by operating the measuring unit to apply spectral measurements to a highly reflective (highly diffusely reflective) surface. Preferably, this is achieved by appropriately configuring the measuring unit. For example, by providing a plug that has a highly diffusely reflective surface and is mounted on the measuring unit such that it is shiftable from its operative position when said surface is located in the optical path of light propagating through the measuring unit and an inoperative position of the plug when said surface is out of the optical path. Hence, the measuring unit can be operated to selectively obtain the reference spectrum or the measured data.

The data processing with the predetermined model preferably includes: applying a Likelihood Algorithm to the relative measured spectrum, calculating a feature vector as a function of wavelength within the selected range, calculating a ratio between the feature vector of the relative measured spectrum and that of the reference data, etc.

Preferably, the software can be configured as an expert system capable of analyzing the calculated measurable parameters and optimizing the model accordingly.

Preferably, the processing of the relative measured spectrum allows for determining measurable parameters indicative of the existence of inflammation, tumor or both, and differentiates between them. It allows classifying the inflammation, for example, in the patient's ear for otitis media (SOM or AOM).

Additionally, the method of the present invention allows for conducting qualitative measurements at the same time as allowing the user (physician) to observe the target tissue itself. This is implemented by configuring the measuring unit (an optical probe) for transmitting light emanating from a target tissue (ROI) along at least two separate optical channels: a VIS channel and a SWIR channel. Both channels also allow quantitative analysis of said light emanating from the target tissue.

The present invention may also be configured to provide a method and device for use in detecting and differentiation between inflammation and tumor inside patient's body (colon, etc). When thusly configured, the system includes: (a) an optical measuring unit configured and operable for irradiating a region of interest in patient's body (colon, ear, lungs, an area of the surface of the skin in which the ROI includes the skin surface and the tissue below, etc) with incident light including at least two different wave-bands;

(b) detecting light responses of the ROI to said at least two different wave-bands, and generating measured data indicative thereof, with the at least two different wave-bands being selected such that the light response of the ROI to a first wave-band is substantially independent of the predetermined condition and the light response to a second wave-band is affected by the predetermined condition.

When classifying inflammation and tumor/inflammation differentiation, present invention utilizes the following:

Inflammation detection is accomplished in the VIS wavelengths using the RGB scale.

Inflammation classification is accomplished using SWIR imaging and

SWIR spectroscopy.

Differentiation between inflammation with or without infusion or liquids is based on the amount of SWIR absorption, with highly absorbed SWIR indicative of liquids. Referring to Figures 2-5, Figure 2 illustrates SWIR water transmission spectra for the depth of water of 0.3 mm 20 and 5 mm 22, theoretically calculated from the water absorption coefficient spectra. Figure 3 is a graph showing comparative SWIR spectroscopy of a sample of tissue having a 0.6 mm thickness with water 30 behind the tissue and without 32.

Figure 4 is a photograph taken in the VIS range of the sample of tissue 40 having a 0.6 mm thickness covering a container partially filled with water.

Figure 5 is the SWIR image of the tissue 40 of Figure 4. However, here the water level 42 is clearly visible.

Differentiation between inflammation and tumor is based on data from

RGB and SWIR imaging and SWIR spectroscopy, with low SWIR absorption and increased scattering indicative of tumor. Ordinarily, the light at predetermined wave-bands is delivered through an optical fiber or fiber bundle that is inserted through a small tube into the endoscopic pipe to accommodate a mechanical biopsy wire. Small optical fibers or fiber bundles can be passed easily through the same tube.

Referring now to the drawings, Figure 6 illustrates, in a block diagram, a first preferred embodiment of a device 50 of the present invention which provides illumination of the ROI with a wide wave-band source 52.

Illuminating an ROI so as to generate a first plurality of interacted with tissue photons. These interacted with photons may include photons scattered, reflected (spectural reflection) or absorbed by the tissue, and combinations thereof.

The light source 52 may include a halogen lamp that produces visible light at 350-700 nm for color imaging (RGB) as well as SWIR radiation (1200- 2500 nm) for SWIR spectroscopy and imaging. A polarizer 54 and/or neutral density (ND) filter with or without a beam splitter (BS) may he provided in front of the light source to obtain desired illumination light intensity and polarization.

Figures 7 and 8 illustrate a cross-sectional and end views respectively of a possible preferred embodiment of a fibers arrangement that includes a transceiver fiber bundle 56a having illumination and receiving fibers, a VIS image fiber 56b and as SWIR imaging fiber 56c.

The detection of photons may be accomplished using optical fibers 56 (or fiber bundles) and additional collection optics 58 such as, but not limited to, beam splitters, polarizers, filters, cameras, SWIR spectrometers and lenses.

In one embodiment, the invention is practiced by illuminating tissue with broad-band (350-2500 nm) excitation light delivered via a single optical fiber. The back-scattered / reflected light is collected with a plurality of optical fibers surrounding the illumination fiber. In one embodiment, signals from the individual collection fibers can be averaged into a single spectrum thereby increasing sensitivity. In an alternative embodiment, the signals from the individual collection fibers can be analyzed as discrete signals. The scattered photons are passed through a polarizer 58a and band-pass optical filter 58b or tunable filter, and directed to dispersive SWIR spectrometer 56c and VIS-SWIR imaging detectors 58d (FPA or cameras).

The tunable filter may comprise, for example, an electro-optical tunable filter, a liquid crystal tunable filter (LCTF), or an acousto-optical tunable filter (AOTF). A tunable filter may be a band-pass or narrow band filter that can sequentially pass or "tune" scattered photons into a number of predetermined wavelength bands. These predetermined wavelength bands may include specific wavelengths or ranges of wavelengths characteristic of the tissue undergoing analysis. The organic material in tunable filters is actively aligned by applied voltages to produce the desired band-pass and transmission function. The spectra obtained for each pixel of such an image thereby forms a complex data set referred to as a hyperspectral image which contains the intensity values at number of wavelengths.

Detectors may include VIS-SWIR cameras or optical signal collection device such as, but not limited to, an image focal plane array (FPA) detector, which may be a charge coupled device (CCD) detector, or a CMOS (Complementary Metal Oxide Semiconductor) array sensor. Detectors measure the intensity of scattered / reflected light incident upon their sensing surfaces at multiple discrete locations or pixels, and transfer received information for storage and analysis. The optical region employed to characterize the tissue of interest governs the choice of two-dimensional array detector. For example, a two-dimensional array of silicon charge-coupled device (CCD) detection elements can be employed with visible wavelength scattered / reflected photons, while gallium arsenide (GaAs) and indium gallium arsenide (InGaAs) FPA detectors can be employed for image analysis at SWIR wavelengths.

The photons may be detected so as to generate at least one VIS-SWIR data set representative of the region of interest. This VIS-SWIR data set may include: a SWIR spectrum, a spatially accurate wavelength resolved (hyperspectral) RGB-SWIR image, and combinations thereof. This data set may be analyzed to determine the presence or absence of inflammation or tumor in the tissue of the ROI.

In one configuration, the analyzing may be achieved by comparing the SWIR data set to one or more reference data sets. These reference data sets may be located in a reference database and each reference data set may correspond to a known spectral response for inflammation or tumor. This comparing may be achieved by applying a chemometric technique. This technique may be substantially any known in the art, including but not limited to, principal component analysis (PCA), multivariate curve resolution (MCR), partial least squares discriminant analysis (PLSDA), k-means clustering, cosine correlation analysis ("CCA"), partial least squares regression (PLSR), a spectral information divergence metric, etc., and any possible combinations thereof.

Additional or optionally, the method may further include fusing data using multiple modalities to thereby determine the presence or absence of inflammation or tumor in a tissue. Such fusion holds the potential for increasing the accuracy and reliability of tissue analysis.

The SWIR image may also be fused with a color (RGB) image representative of the tissue. The SWIR image may be fused also with a SWIR spectroscopic data set.

In one configuration, this SWIR data set may include at least one of: an

SWIR spectrum, a spatially accurate wavelength resolved SWIR image and combinations thereof.

In another configuration, this SWIR data set may include at least one hyperspectrai RGB-SWIR image.

The data analysis may include, for example, comparing said fused data with one or more reference data sets by applying a chemometric technique or other method such as, by non-limiting example, Bayesian fusion. In addition, the use of intensity ratios at different wavelengths may be analyzed to further assess the spectral and hyperspectrai data. The use of these intensity ratios may hold potential for reducing the influences from diverse tissue samples; therefore, it could be universally applied for fast, accurate, specific, and routine screening of inflammations and tumors.

Classifying or comparing normalized intensities into one or more groups may be performed by any acceptable means. There are numerous acceptable approaches to such classifications. By non-limiting example, one general method of grouping the two normalized intensities is a Bayesian-based classifier using Mahalanobis distances. A specific Bayesian Mahalanobis-based classifier can be selected from linear discriminant analysis, quadratic discriminant analysis, and regularized discriminant analysis. As those familiar with statistical analysis will recognize, linear discrimination analysis and quadratic discriminant analysis are methods that are computationally efficient. Regularized discriminant analysis uses a biasing method based on two parameters to estimate class co variance matrices.

Figure 6 illustrates, in a block diagram, a second preferred embodiment of a device 60 of the present invention that includes an illumination unit 62 which provides illumination of the ROI with a plurality of discrete (narrow) wave-band sources. Figure 10 illustrates a possible preferred fiber arrangement for use with the embodiment of Figure 9.

To irradiate the ROI a polarized quasi-monochromatic light source in combination with a wide-band (white) light source can be used. Light sources can include LEDs (light emitting diodes) at SWIR wavelengths 62a, and white LED 62b irradiating in visual band.

The quasi-monochromatic and visual-band radiation reaching the ROI illuminates the tissue, and produce scattered photons. The scattered photons are detected to generate VIS-SWIR imaging data set representative of the tissue.

The detector unit 66 may include detectors selected from the groups described above with reference to the embodiment 50. The imaging data set includes a spatially accurate wavelength-resolved VIS-SWIR hyperspectral images. The images are analyzed using appropriate image processing techniques to thereby classify a disease state of the tissue (inflammation or tumor).

It will be understood that solid-state LEDs are now available over a spectral range that substantially covers most SWIR wavelengths, including key wavelengths for water. The operating temperature and smaller size of LEDs allows placement of the source closer to the object being imaged or using optical fiber for illumination. LEDs also provide diffuse and even illumination and enable rapid switching between key wavelengths. This is valuable for looking at the difference or ratio of images taken at two wavelengths, which enables the mapping of moisture uniformity while ignoring surface variations. Switching times for LEDs are fast enough to be cycled on a frame-by-frame basis.

An additional benefit of the availability of LEDs over a wide spectral range is the ability to simultaneously image an object with visible and SWIR cameras without one interfering with the other.

For example, inflammation detection could be performed with white LEDs (RGB-ratio approach) while the inflammation classification and inflammation / tumor differentiation is performed with the SWIR camera using ϊ,45-μηι LED illumination (for the best contrast of water-based substance).

In an exemplary embodiment, three emitting diodes (LEDs) operating in three different spectral regions are implemented to provide separate measurements. Specifically, at:

(a) 1400 -1500 nm - strong water absorption wave-band;

(b) 1200-1350 nm and 1500-2500 nm - outside of strong water absorption wave-band.

The LEDs are selected to have a spectral bandwidth of approximately 75-80 nm or less.

The light that is scattered and reflected by the tissue is detected by a number of single detectors or FPA for image evaluation. In this preferred embodiment 60, a system of the present invention includes a fibers arrangement 64 having an optical fiber 64 as the illumination source. The detector(s) may receive light from the tissue by way of a plurality of optical fibers configure to receive VIS 64b and specific SWIR wavelengths 64c.

In one configuration, an in-line (coaxial) system can be implemented. In such a system, the probe comprises a beam splitter arrangement for splitting light traveling in a proximal direction from probe-end into said first channel and said second channel. The term "beam splitter arrangement" refers herein to any optical arrangement capable of splitting a light beam into at least two beams, i.e., two channels or directions, substantially unaffecting the intensity or wavelength of the light.

The probe is configured for directing at least a portion of light traveling from the probe-end there through along the first and second channels toward the objectives. The latter may comprise suitable cameras (FPA) mean for recording said image.

The reference data may be indicative of a relation between the light responses of the normal (healthy) tissue to the at least two different wavelengths (wave-bands). The measured data may be in the form of a relation between light responses of the ROI in the patient's body (ear, colon, gastric) to the at least two different wavelengths (wave-bands).

Alternately or additionally, the reference data may be indicative of the light response for the operating wavelength as a function of the light response for the reference wavelength corresponding to the healthy condition.

The system may be configured and operable to process the measured data using a processing unit 68 to determine the light response for the operating wavelength (wave-band) as a function of the light response for the reference wavelength (wave-band), and determine a difference between the reference and measured data indicative of whether fluid media exists in the ROI (e.g., inflammation or SOM condition). It will be appreciated that the methods and device of the present invention may be used to equal benefit to distinguish between healthy tissue and tissues in which an abnormality has begun to for such as, but not limited to, pressure ulcers and lung cancer.

When configured for substantially continuous imaging over a period of time, it will be readily understood that the present invention may be used to monitor blood and tissue oxygenation or the presence of other tissue abnormalities in atients.

The relative good transparency of biological tissues to Red-NIR light (i.e., 600-1,000 nm) allows the absorption properties of intact organs to be monitored non-invasively. Therefore, changes in the concentration levels of injectable materials (drugs), which are administrated by infusion, can be estimated by using the present invention configured to include SWIR spectroscopy .

For example, propofol is a widely used intravenously administered hypnotic agent. It is a short-acting intravenous anesthetic drug for controlled sedation, surgical procedures, and maintenance of anesthesia when administered by infusion. However there are only indirect methods for controlling anesthesia. The direct continuous detection of propofol during anesthesia promises a better understanding of its pharmacokinetics and allows better control by the anesthesiologist.

Propofol has strong absorption bands in SWIR bandwidth at 1420 nm and 1691 nm, weaker bands can be observed at 1193 nm, 1546 and 1930 nm.

It should be noted that In the current invention, we define difference in signal response by the following parameter C for the SWIR spectral regime, which is defined as a normalized difference of the reflectance from the tissue obtained at different frequency bands, described above, that is:

This parameter is used as an indicator of tissue properties. It will be appreciated that the above descriptions are intended only to serve as examples and that many other embodiments are possible within the spirit and the scope of the present invention.