A DEVICE AND METHOD FOR CANCER DETECTION, DIAGNOSIS AND TREATMENT GUIDANCE USING ACTIVE THERMAL IMAGING

FIELD OF THE INVENTION

[1] The present invention relates to cancer detection, diagnosis and treatment, and more specifically the present invention relates to cancer detection, diagnosis and treatment guidance through the use of thermal imaging technology.

BACKGROUND OF THE INVENTION

[2] Tumor cells are distinct from their surrounding normal tissue by several properties, one of which is a thermo-physical property referred to as thermal diffusivity, which is expected to be different in cancerous cells compared to healthy cells. Thermal diffusivity is the combined property of density, heat capacity and thermal conductivity which are expected to be noticeably different in cancer cells. Importantly, even precancerous tissues or very young tumors appear to have distinct thermal diffusivity properties due to an enlarged nucleus, elevated crowdedness and so on.

[3] Lung cancer is considered the most deadly cancers in men and women worldwide. Lung cancer is the leading cause of cancer death among both men and women in the United States.

[4] Statistical data regarding the extent of lung cancer states that lung cancer results in about 1.6 million deaths a year worldwide, being the leading cause of cancer death, at a total of 27% of all cancer related deaths. In the U.S alone 228,190 new cases are diagnosed, and 160,000 deaths occur annually. In Israel 1,900 new cases are diagnosed and 1,600 deaths occur annually. Only 5% of lung cancers cases are diagnosed in stages that allow healing.

[5] This extremely low survival rate of lung cancer is not due to lung tumors being more aggressive than other malignant tumors types, but in fact is due to the lack of early detection. Since the lung contains no 'pain sensing' mechanism and its gas volume is much greater than its tissue volume, a tumor would hardly be noticed at early stages. Usually when the patient starts feeling any discomfort and turns to a physician, the tumor will already have exceeded the treatable size. Therefore breathing difficulties and coughing which usually leads to the diagnosis of the cancer means the tumor is large enough to be noticed and is probably untreatable. At this stage the cancer is progressive and usually metastatic and a targeted healing therapy cannot be considered, resulting in the five years survival rate which is very low. [6] In addition, oncologists treating the cancer have great difficulty in monitoring the treatment progress, and even cataloging the different stages of the disease. Many times, after a relatively long treating period, the physician would find the treatment had little to no effect. Treatment methods would then be changed, losing valuable time. In other cases cancer cells would successfully be destroyed, and turn into necrotic cells, however, traditional scans would not differentiate them from cancer cells. Usually in this case, an invasive lung biopsy is needed.

[7] According to the World Health Organization (WHO), cervical cancer is the second most commonly prevalent cancer and the third greatest cause of death in women, with 530,000 new cases discovered each year.

[8] Increasing incidences of weakened immune system, rapid spread of human papillomavirus (HPV) infection among the female population and long-term use of oral contraceptive pills are the primary factors responsible for the growth of cervical cancer.

[9] Currently, cervical cancer screening includes a cytology-based screening, known as the Pap test or Pap smear. The main purpose of screening with the Pap test is to detect precancerous abnormal cells that may develop into cancer if left untreated, specifically Cervical Intraepithelial Neoplasia (CIN). In regularly screened populations, the Pap test identifies most abnormal cells before they become cancer. However, the Pap test should be taken with caution, as it is approximated that test incidence of false negatives can be as high as 20%- 45%. Moreover, Pap test is expensive and requires 14-30 days of waiting for the cytology testing.

[10] US patent 8774902 discloses a device and method to diagnose an internal abnormality in a living subject by sensing a passively occurring electromagnetic radiation signal associated with the abnormality and inside an orifice of the subject, and US patent 7513876 discloses a system for passively detecting thermal discrepancies in vessel walls. However, the use of passively occurring radiation only renders '902 to be incompetent in detecting minor differences in cell structure, which are already found in the precancerous stage.

[11] US patent 8864669 discloses a method for detecting abnormal tissue using ultrasound backscattered from the background. The detection is manifested through different tissues absorbing ultrasound differently.

[12] US patent 8923954 discloses an IR detection system for identifying malignant tumors by identifying areas of increased metabolic activity, and by assuming that malignant tumors have increased metabolic activity due to increased blood supply. However, patent '954 only identifies tumors which have grown in mass to such extent as to provide evidence of increased metabolic activity and blood supply.

[13] Therefore, a long felt need still exists for a screening system and method which will provide early pre-cancerous diagnosis, assuring early and highly effective treatments.

SUMMARY OF THE INVENTION

[14] Therefore, detection of cancer cells using a thermal diffusivity imaging method is disclosed.

[15] It thus an object of the present invention to provide a method for detecting, diagnosing and guiding treatment of cell irregularities in an examined tissue, characterized by the steps of: applying thermomodulating means to at least a portion of the examined tissue; collecting at least one thermal data of at least a portion of the tissue over time; and calculating at least one heat transfer index of the thermal data over time; thereby detecting, diagnosing and guiding treatment of cell irregularities according to the at least one heat transfer index; wherein the heat transfer index is calculated according to a derivative of the thermal data over time.

[16] It is another object of the present invention to provide the above mentioned method, further comprising the step of selecting the derivative to be from the group consisting of first derivative, second derivative, third derivative and any combination thereof.

[17] It is another object of the present invention to provide the above mentioned method, further comprising the step of normalizing the heat transfer index to a predetermined scale.

[18] It is another object of the present invention to provide the above mentioned method, wherein the scale is a numerical scale between 1 and 10, further wherein a higher value indicates a higher severity of the medical condition of the cell irregularities.

[19] It is another object of the present invention to provide the above mentioned method, further comprising the step of correlating the heat transfer index with associated cell irregularities selected from the group consisting of malignant tumors, precancerous tumors, benign tumors, infections, pneumonia, necrotic cells and any combination thereof.

[20] It is another object of the present invention to provide the above mentioned method, further comprising the step of collecting the thermal data using a sensor selected from the group consisting of an IR sensor, a mercury-in-glass thermometer, pill thermometer, liquid crystal thermometer, thermocouple, thermistor, resistance temperature detector, silicon bandgap temperature sensor and any combination thereof.

[21] It is another object of the present invention to provide the above mentioned method, wherein the at least one thermal data is a temperature measurement of the at least a portion of the tissue over time. [22] It is another object of the present invention to provide the above mentioned method, further comprising the steps of: collecting thermal image data of at least a portion of the tissue over time; calculating heat transfer index of the thermal image data over time; constructing a heat transfer map comprising, optionally spatial (i.e. three-dimensional), locations of the heat transfer index over time; and identifying a designated location in the heat transfer map having distinctive heat transfer index from surrounding spatial locations.

[23] It is another object of the present invention to provide the above mentioned method, further comprising the step of producing a thermal image of the at least a portion of the tissue prior to the applying thermomodulating means to the tissue.

[24] It is another object of the present invention to provide the above mentioned method, further comprising the step of deeming a designated spatial location of the heat transfer map suspect of cell irregularities if the designated spatial location has the heat transfer index falling within a predetermined heat transfer index range.

[25] It is another object of the present invention to provide the above mentioned method, wherein the spatial location is selected from the group consisting of one pixel, a plurality of pixels, a sub-pixel and any combination thereof.

[26] It is another object of the present invention to provide the above mentioned method, further comprising the step of comparing the heat transfer map to a spatial image of the examined tissue's area.

[27] It is another object of the present invention to provide the above mentioned method, wherein the collecting thermal data of at least a portion of the tissue over time is operated at a time interval of between about 10 ns and about 10 s.

[28] It is another object of the present invention to provide the above mentioned method, wherein during the step of applying thermomodulating means to the tissue, the method further comprises the steps of: collecting thermal data of at least a portion of the tissue over time, for tracking the thermoregulation; and calculating heat transfer index of the thermal data in realtime.

[29] It is another object of the present invention to provide the above mentioned method, further comprising the step of constructing a heat transfer map comprising spatial locations of the real-time heat transfer index.

[30] It is another object of the present invention to provide the above mentioned method, further comprising normalization steps selected from the group consisting of correcting to ambient temperature, correcting to ambient humidity, correcting to ambient electromagnetic radiation and any combination thereof. [31] It is another object of the present invention to provide the above mentioned method, further comprising the steps of providing access to a cervix area by a mechanical speculum; applying the heating and/or cooling to the cervix area; and correlating the heat transfer index with Cervical Intraepithelial Neoplasia (CIN).

[32] It is another object of the present invention to provide the above mentioned method, further comprising the step of deriving the examined tissue from a mammal selected from the group consisting of human, monkey, rodent, sheep, goat, cow, horse and swine.

[33] It is another object of the present invention to provide the above mentioned method, wherein the examined tissue is selected from the group consisting of lungs, skin, cervix, ear, nose, throat, oral cavities, esophagus, stomach, intestine, colon, rectum, kidney, uterus, urinary tract, bladder, prostate, eyes, and any part of the human body.

[34] It is another object of the present invention to provide the above mentioned method, further comprising the step of selecting the thermomodulating means to operate in a manner selected from the group consisting of advection, convection, conduction, radiation and any combination thereof.

[35] It is another object of the present invention to provide the above mentioned method, wherein the thermomodulating means is selected from the group consisting of heating means, cooling means and any combination thereof.

[36] It is another object of the present invention to provide the above mentioned method, further comprising the step of applying the heating and/or cooling means by a method selected from the group consisting of hot and/or cold fluid inhalation, hot and/or cold fluid application, halogen lamp exposure, xenon lamp exposure, flash lamp exposure, incandescent lamp exposure, IR emission, radiation, electromagnetic and/or mechanical vibration heating, hot and/or cold solid positioning, hot and/or cold patch positioning, pharmaceutical heat modification, chemically induced heating and/or cooling and any combination thereof.

[37] It is another object of the present invention to provide the above mentioned method, wherein the step of collecting thermal data of at least a portion of the tissue over time is conducted by a thermal sensor positioned in a position selected from the group consisting of mounted outside the body, inserted to the body in an invasive procedure, inserted to the body in a semi-invasive procedure and any combination thereof.

[38] It is another object of the present invention to provide the above mentioned method, further comprising the step of calculating the heat transfer index according to the thermal sensor resolution and sampling rate. [39] It is another object of the present invention to provide the above mentioned method, wherein the examined tissue is a biopsy sampling of a suspected tissue area.

[40] It is another object of the present invention to provide the above mentioned method, further comprising the steps of applying the method to a second examined tissue being a biopsy sampling of a healthy tissue area, and obtained heat transfer index is compared between the suspected tissue area and the healthy tissue area.

[41] It is another object of the present invention to provide the above mentioned method, further comprising the steps of using the heat transfer index for at least one of the following: detecting and mapping tumor boundaries for tumor removal operations; determining medical severity and/or malignancy status of the cell irregularities; and determining an appropriate treatment procedure.

[42] It is another object of the present invention to provide the above mentioned method, further comprising the step of normalizing the heat transfer index with patient parameters selected from the group consisting of sex, age, smoking habits, drinking habits, number of births, height, weight, blood pressure, diabetes state, medical history, relatives medical history, patient's previous heat transfer index and any combination thereof.

[43] It is another object of the present invention to provide the above mentioned method, further comprising the steps of: applying thermomodulating means to a second tissue; collecting second thermal data of at least a portion of the second tissue over time; calculating a baseline heat transfer index of the second thermal image data over time; comparing the baseline heat transfer index to the heat transfer index of the examined tissue; and detecting, diagnosing and guiding treatment of cell irregularities according to a difference between the baseline heat transfer index of the second tissue to the heat transfer index of the examined tissue.

[44] It is another object of the present invention to provide the above mentioned method, wherein at least one of the following is being held true: the second tissue is healthy; the second tissue comprises cell irregularities;

[45] It is another object of the present invention to provide the above mentioned method, further comprising the step of obtaining the baseline heat transfer index from a database comprising heat transfer index obtained from at least one second tissue deriving from an examined individual and/or from at least one second examined individuals.

[46] It is another object of the present invention to provide the above mentioned method, further comprising the step of deriving a ratio between the heat transfer index of the examined tissue and a second heat transfer index of a second examined tissue, and comparing the ratio to at least one second ratio between a third heat transfer index of a third examined tissue, and a fourth heat transfer index of a fourth examined tissue.

[47] It is another object of the present invention to provide the above mentioned method, wherein the second examined tissue is tissue surrounding the first tissue.

[48] It is another object of the present invention to provide the above mentioned method, further comprising the step of obtaining the third distinctive heat transfer index and fourth heat transfer index from a database comprising heat transfer index obtained from a plurality of tissues deriving from an examined individual and/or a plurality of examined individuals.

[49] It is another object of the present invention to provide the above mentioned method, further comprising the step of storing the baseline heat transfer index in a storing means selected from the group consisting of a computer readable medium, a server, a cloud-like server and any combination thereof.

[50] It is another object of the present invention to provide the above mentioned method, further comprising the steps of applying the thermomodulating means according to a manner selected from the group consisting of according to a pre-determined protocol, in a continuous manner, in a pulse manner and any combination thereof.

[51] It is also an object of the present invention to disclose a system for detecting, diagnosing and guiding treatment of cell irregularities in an examined tissue, comprising: a thermomodulating means for applying heating and/or cooling to at least a portion of the examined tissue; a thermal sensor for collecting at least one thermal data of at least a portion of the examined tissue over time; and a processor adapted to read a computer readable medium with instructions for calculating at least one heat transfer index of the thermal data over time; thereby detecting, diagnosing and guiding treatment of cell irregularities according to the at least one heat transfer index; wherein the heat transfer index is calculated according to a derivative of the thermal data over time.

[52] It is still an object of the present invention to disclose the aforementioned system, wherein the derivative is selected from the group consisting of first derivative, second derivative, third derivative and any combination thereof.

[53] It is still an object of the present invention to disclose the aforementioned system, wherein the processor is further adapted to normalize the heat transfer index to a predetermined scale.

[54] It is still an object of the present invention to disclose the aforementioned system, wherein the scale is a numerical scale between 1 and 10, further wherein a higher value indicates a higher severity of the medical condition of the cell irregularities. [55] It is still an object of the present invention to disclose the aforementioned system, wherein the processor is further adapted to read a computer readable medium with instructions for correlating the heat transfer index with associated cell irregularities selected from the group consisting of malignant tumors, precancerous tumors, benign tumors, infections, pneumonia, necrotic cells and any combination thereof.

[56] It is still an object of the present invention to disclose the aforementioned system, wherein the thermal sensor is selected from the group consisting of an IR sensor, a mercury-in-glass thermometer, pill thermometer, liquid crystal thermometer, thermocouple, thermistor, resistance temperature detector, silicon bandgap temperature sensor and any combination thereof.

[57] It is still an object of the present invention to disclose the aforementioned system, wherein the at least one thermal data is a temperature measurement of the at least a portion of the tissue over time.

[58] It is still an object of the present invention to disclose the aforementioned system, wherein the thermal sensor is configured for collecting thermal image data at a time interval of between about 10 ns and about 10 s.

[59] It is still an object of the present invention to disclose the aforementioned system, wherein the processor is further adapted to read a computer readable medium with instructions for: calculating heat transfer index of a thermal image data obtained over time; constructing a heat transfer map comprising, optionally spatial, locations of the heat transfer index over time; and identifying a designated spatial location in the heat transfer map having distinctive heat transfer index from surrounding spatial locations.

[60] It is still an object of the present invention to disclose the aforementioned system, wherein, if a designated spatial location of the heat transfer map has the heat transfer index falling within a predetermined slope, the designated spatial location is deemed suspect of cell irregularities.

[61] It is still an object of the present invention to disclose the aforementioned system, wherein the spatial location is selected from the group consisting of one pixel, a plurality of pixels, a sub- pixel and any combination thereof.

[62] It is still an object of the present invention to disclose the aforementioned system, wherein the thermal sensor is adapted to collect thermal data of at least a portion of the tissue over time, while the thermomodulating means is applied, thereby enabling the processor to calculate the heat transfer index in real-time. [63] It is still an object of the present invention to disclose the aforementioned system, further comprising at least one sensor selected from the group consisting of a thermometer, a hygrometer, a photodetector and any combination thereof.

[64] It is still an object of the present invention to disclose the aforementioned system, further comprising a spatial positioning means selected from the group consisting of a visible light imaging means, a CCD camera, an ultrasound scanner, a thermal camera, a laser rangefinder and any combination thereof.

[65] It is still an object of the present invention to disclose the aforementioned system, further comprising a mechanical speculum.

[66] It is still an object of the present invention to disclose the aforementioned system, wherein the distinctive heat transfer index is correlated with Cervical Intraepithelial Neoplasia (CIN).

[67] It is still an object of the present invention to disclose the aforementioned system, wherein the examined tissue is derived from a mammal selected from the group consisting of human, monkey, rodent, sheep, goat, cow, horse and swine.

[68] It is still an object of the present invention to disclose the aforementioned system, wherein the examined tissue is selected from the group consisting of lungs, skin, cervix, ear, nose, throat, oral cavities, esophagus, stomach, intestine, colon, rectum, kidney, uterus, urinary tract, bladder, prostate, eyes, and any part of the human body.

[69] It is still an object of the present invention to disclose the aforementioned system, further comprising a display means for presenting a graphical representation of a feature selected from the group consisting of a user interface, the heat transfer map, the heat transfer index analysis, the marking of cell irregularities, border lines of the marking of cell irregularities, a visual image of the examined tissue's area, the thermal data, the thermal image data and any combination thereof.

[70] It is still an object of the present invention to disclose the aforementioned system, wherein the display is adapted to further display data relating to patient parameters selected from the group consisting of sex, age, smoking habits, drinking habits, number of births, height, weight, blood pressure, diabetes state, medical history, relatives' medical history, patient's previous heat transfer index analysis and any combination thereof.

[71] It is still an object of the present invention to disclose the aforementioned system, wherein the thermomodulating means are adapted to provide and/or draw heat in a manner selected from the group consisting of advection, convection, conduction, radiation and any combination thereof. [72] It is still an object of the present invention to disclose the aforementioned system, wherein the thermomodulating means are adapted to heat the at least a portion of the examined tissue, or cool the at least a portion of the examined tissue, or both.

[73] It is still an object of the present invention to disclose the aforementioned system, wherein the thermomodulating means are selected from the group consisting of hot and/or cold fluid inhalation, hot and/or cold fluid application, halogen lamp exposure, xenon lamp exposure, flash lamp exposure, incandescent lamp exposure, IR emission, radiation, electromagnetic and/or mechanical vibration heating, hot and/or cold solid positioning, hot and/or cold patch positioning, pharmaceutical heat modification, chemically induced heating and/or cooling and any combination thereof.

[74] It is still an object of the present invention to disclose the aforementioned system, wherein the thermal sensor position is selected from the group consisting of mounted outside the body, inserted to the body in an invasive procedure, inserted to the body in a semi-invasive procedure and any combination thereof.

[75] It is still an object of the present invention to disclose the aforementioned system, wherein the heat transfer index is calculated according to the thermal sensor's resolution, sampling rate and camera sensitivity.

[76] It is still an object of the present invention to disclose the aforementioned system, wherein the examined tissue is a biopsy sampling of a tissue area suspected of having cell irregularities.

[77] It is still an object of the present invention to disclose the aforementioned system, wherein a second examined tissue is a biopsy sampling of a healthy tissue area, and obtained heat transfer index is compared between the suspected tissue area and the healthy tissue area.

[78] It is still an object of the present invention to disclose the aforementioned system, wherein the heat transfer index is used for at least one of the following: detecting and mapping tumor boundaries for tumor removal operations; determining medical severity and/or malignancy status of the cell irregularities; and determining an appropriate treatment procedure.

[79] It is still an object of the present invention to disclose the aforementioned system, further comprising a database containing at least one heat transfer index of at least one second tissue, and further wherein the processor is adapted to: compare between the at least one baseline heat transfer index of at least one second examined tissue and the at least one heat transfer index of at least one examined tissue, and detect, diagnose and guide treatment of cell irregularities according to a difference between the baseline heat transfer index of the second tissue to the heat transfer index of the examined tissue. [80] It is still an object of the present invention to disclose the aforementioned system, wherein the second examined tissue is selected from the group consisting of a healthy tissue, a tissue containing cell irregularities and any combination thereof.

[81] It is still an object of the present invention to disclose the aforementioned system, further comprising a storing means for storing the database, selected from the group consisting of a computer readable medium, a server, a cloud-like server and any combination thereof.

[82] It is still an object of the present invention to disclose the aforementioned system, wherein the processor is in operative communication with the storing means, optionally wirelessly.

[83] It is also an object of the present invention to provide a computer readable medium (CRM), or electronics component, having instructions which, when implemented by one or more computers cause the one or more computers to: process thermal data derived from a thermal sensor collected over time; calculate at least one heat transfer index of the thermal data over time; wherein the heat transfer index is calculated according to a derivative of the thermal data over time.

[84] It is still an object of the present invention to disclose the aforementioned CRM or electronics component, wherein the derivative is selected from the group consisting of first derivative, second derivative, third derivative and any combination thereof.

[85] It is still an object of the present invention to disclose the aforementioned CRM or electronics component, further wherein the instructions which, when implemented by one or more computers cause the one or more computers to normalize the heat transfer index to a predetermined scale.

[86] It is still an object of the present invention to disclose the aforementioned CRM or electronics component, wherein the scale is a numerical scale between 1 and 10, further wherein a higher value indicates a higher severity of the medical condition of the cell irregularities.

[87] It is still an object of the present invention to disclose the aforementioned CRM or electronics component, further wherein the instructions which, when implemented by one or more computers cause the one or more computers to correlate the distinctive heat transfer index with associated cell irregularities; thereby detecting, diagnosing and guiding treatment of cell irregularities.

[88] It is still an object of the present invention to disclose the aforementioned CRM or electronics component, further wherein the instructions which, when implemented by one or more computers cause the one or more computers to correlate distinctive the heat transfer index with associated cell irregularities selected from the group consisting of malignant tumors, precancerous tumors, benign tumors, infections, pneumonia, necrotic cells and any combination thereof.

[89] It is still an object of the present invention to disclose the aforementioned CRM or electronics component, further wherein the instructions which, when implemented by one or more computers cause the one or more computers to: construct a heat transfer map comprising, optionally spatial, locations of the heat transfer index over time; and present on a display unit a designated spatial location in the heat transfer map having distinctive heat transfer index from surrounding spatial locations.

[90] It is still an object of the present invention to disclose the aforementioned CRM or electronics component, wherein the instructions which, when implemented by one or more computers cause the one or more computers to present on a display unit a designated spatial location in the heat transfer map having distinctive heat transfer index from surrounding spatial locations, further wherein the spatial location is selected from the group consisting of one pixel, a plurality of pixels, a sub-pixel and any combination thereof.

BRIEF DESCRIPTION OF THE PREFERRED EMBODIMENTS

[91] The novel features believed to be characteristics of the invention are set forth in the appended claims. The invention itself, however, as well as the preferred mode of use, further objects and advantages thereof, will best be understood by reference to the following detailed description of illustrative embodiment when read in conjunction with the accompanying drawings, wherein:

[92] Fig. 1 presents a top level scheme of the method disclosed by the present invention.

[93] Fig. 2 schematically presents high level overview of a preferred embodiment of the system disclosed by the present invention.

[94] Fig. 3 schematically presents a high level overview of a preferred embodiment of the method disclosed by the present invention.

[95] Fig. 4 presents the cell types examined under the present invention and their index numbers.

[96] Fig. 5A-B illustrates a first experimental setup using six cell types for examination. Fig. 5A illustrates the cell types and their experimental configuration. Fig. 5B illustrates a visual demonstration of the heat transfer map of the six cell types illustrated in Fig. 5A.

[97] Fig. 6 graphically illustrates temperature decay profiles of the examined cell populations presented in Fig. 5 A and B.

[98] Fig. 7 graphically illustrates the first derivative of the data presented in Fig. 7. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[99] The following description is provided, alongside all chapters of the present invention, so that to enable any person skilled in the art to make use of the invention and sets forth the best modes contemplated by the inventor of carrying out this invention. Various modifications, however, will remain apparent to those skilled in the art, since the generic principles of the present invention have been defined specifically to provide a method for detection, diagnosis and treatment of cell irregularities in a healthy tissue.

[100] The term "cell irregularities" refers hereinafter to malignant tumors, precancerous tumors, benign tumors, infections, pneumonia infected cells, necrotic cells, infected cells and any other cell type exhibiting distinctive thermal transfer properties from healthy standard tissue.

[101] The term "camera sensitivity" refers hereinafter to the capacity to have the signal stand out from the surrounding noise, i.e. the signal-to-noise ratio acquired by the camera, and in the case of a thermal sensor, this translates to the capacity to detect minute temperature differences.

[102] The term "radiation" refers hereinafter to the use of any visible or non-visible radiation which has the capacity to elevate the temperature of the target tissue, such as emitted by, in a non-limiting manner, halogen lamp, incandescent lamp, IR emission, and pertaining to any such electromagnetic wave and non-ionizing radiation.

[103] The term "hot" or "heating" refers hereinafter to a temperature higher than the examined tissue, or an object having a temperature higher than the examined tissue.

[104] The term "cold" or "cooling" refers hereinafter to a temperature lower than 37°C, or an object having a temperature lower than 37°C.

[105] The term "fluid" refers hereinafter to a liquid or a gas, which may be hot or cold, and may refer to in a non-limiting example to air, nitrogen, helium, hydrogen, carbon dioxide, steam, water or oil.

[106] The term "spatial positioning means" refers hereinafter to any imaging device providing information with regards to the physical position of the examined tissue, and may include visible-light imaging means, such as a CCD camera, a laser rangefinder, an ultrasound scanner and so forth, resulting in a spatial image of the examined tissue's area. Spatial positioning means may give out results in a one dimensional output, two dimensional or three dimensional output.

[107] The term "thermal data" refers hereinafter to any numerical or image-like data depicting the temperature of at least a portion of an examined tissue. [108] The term "thermal image data" refers hereinafter to a visual representation of thermal data in the form of a digital image.

[109] The term "heat transfer map" refers hereinafter to a thermal image data depicting the change in temperature of at least a portion of an examined tissue over time.

[110] The term "heat transfer index" refers hereinafter to the rate of heat transfer exhibited by at least a portion of an examined tissue after being exposed to active thermoregulation.

[I l l] The term "tissue" refers hereinafter to any of a tissue culture, a cell line, a biopsy sampling, an in situ tissue (i.e. in the examined animal) and the like.

[112] The term "thermomodulating means" refers hereinafter to any means or method for heating or cooling a tissue.

[113] The present invention exploits active thermography to identify minute variations between healthy tissues as compared to tissues undergoing cancerous/precancerous stages, or any other cell irregularity. Active thermography is the induction of a heat flow by energetically exciting a test object. The heat flow is influenced by interior material layers and defects. These inhomogeneities can be captured on the surface by high-precision thermal sensors. The inventors of the present invention have discovered that even a minor differentiation of tissue cells, such as in precancerous conditions, results in biomechanical-thermal differences which lead to differences in heat flow, and therefore to a distinctive thermal diffusivity and heat transfer.

[114] Reference is now made to Fig. 1 illustrating a top level overview of the core technological features of the present invention's system 100. Thermal excitation source 101, or thermomodulating means, is first used on an examined tissue. The thermal excitation may be through transferring heat to the tissue by any energy inducing device or through drawing heat from the tissue through exposure to cold objects, or by any pharmaceutical administration altering body temperature, or by any chemical reaction configured to induce temperature alterations in any part of the body. After such thermal excitation, heat transfer is induced throughout the tissue. The heat transfer is dependent on the thermal diffusivity properties of the tissue, such that healthy tissue has certain thermal diffusivity properties and tissues having cell irregularities exhibit distinctive thermal diffusivity properties. Heat transfer may be the result of advection, convection, conduction, radiation and may be carried out by any device or means such as, in a non-limiting example, hot and/or cold fluid inhalation, hot and/or cold fluid application, halogen lamp exposure, xenon lamp exposure, flash lamp exposure, incandescent lamp exposure, IR emission, radiation, electromagnetic and/or mechanical vibration heating, hot and/or cold solid positioning, hot and/or cold patch positioning, pharmaceutical heat modification, chemically induced heating and/or cooling and any combination thereof.

[115] In various embodiments of the present invention, the examined tissue may be at least a section of a tissue in an examined individual. Such individual may be any mammal, such as in a non-limiting example, human, monkey, rodent, sheep, goat, cow, horse and swine, and may be derived from any body part, including in a non-limiting example, lungs, skin, cervix, ear, nose, throat, oral cavities, esophagus, stomach, intestine, colon, rectum, kidney, uterus, urinary tract, bladder, prostate and eyes. Preferably, the examined body part is of a kind that is accessible to thermal excitation and thermal sensing.

[116] In other embodiments of the present invention, the examined tissue may be an in vitro examined biopsy sample taken from at least a section of a tissue of an examined individual. The biopsy sample may be healthy tissue or tissue suspected of having cell irregularities. And yet in other embodiments, the examined tissue may be an extracted cell line or cell culture grown on a dish.

[117] In preferred embodiments the examined tissue is human cervix tissue examined in situ i.e. in the patient himself, and the resultant identified cell irregularities are Cervical Intraepithelial Neoplasia (CIN). However, cell irregularities may also refer to any cancerous or precancerous tissues found in any other part of the examined body.

[118] The heat transfer is monitored with thermal sensor 102, which is preferred to be an JR camera or JR sensor, but may be any sensor which could provide thermal data, which is preferably temperature values. Other sensors which may be used are a mercury-in-glass thermometer, pill thermometer, liquid crystal thermometer, thermocouple, thermistor, resistance temperature detector, silicon bandgap temperature sensor and any combination thereof. In some embodiments, the thermal sensor produces thermal data which consists of a series of time-resolved temperature measurements. In other embodiments, thermal sensor 102 may produce a plurality of time-resolved thermal image data, or thermal digital images, preferably at a time interval of about 10 ns and about 10 s. Thermal sensor 102 may be mounted outside the body or inserted into the body in an invasive procedure, or in a semi-invasive procedure.

[119] Thermal data, or thermal image data is then transferred to a processor comprising thermal analysis software 103. This processor is found in operative communication with thermal sensor 102, optionally through wireless communication. Thermal analysis software 103 contains instructions for calculating the heat transfer index, i.e. the rate in which the heat transferred through the examined tissue, according to the thermal data, or thermal image data taken over time. These calculations include deriving the derivative of the change in the thermal data detected over time. The derivative may be a first derivative, a second derivative or a third derivative of the thermal data, or thermal image data (through spatial location intensity derivation), and any combination thereof. A plurality of such heat transfer indexes may be then used to construct a heat transfer map exhibiting these temporal heat transfer indexes through spatial locations, which may be at a single pixel resolution, a plurality of pixel resolution or sub-pixel resolution, which is less than one pixel, i.e. super-resolution. Optionally, binning is used to illustrate the heat transfer indexs, i.e. through spatial locations which comprise a plurality of pixels. Cell irregularities are identified by identifying a designated spatial location having a distinctive heat transfer index from its surrounding spatial locations. Cell irregularities may also be detected or diagnosed through suspected heat transfer index, or heat transfer index which is found within a known heat transfer range to be suspected of cell irregularities.

[120] In preferred embodiments, thermal analysis software 103 calculates the heat transfer index through an algorithm comprising first measuring the intensity of each of the spatial locations, followed by determining a first derivative of the measured intensity over time, and finally determining the heat transfer index according to the first derivative. In an embodiment of the present invention, a second or third derivative of the intensity over time may be used to calculate the heat transfer index. In various embodiments the heat transfer index is calculated in accordance with the thermal sensor's resolution, sampling rate and sensitivity.

[121] In some embodiments, thermal sensor 102 is operated during the heating and/or cooling applied by thermal excitation source 101, and consequently, thermal analysis software 103 is configured to calculate the thermal diffusion through the examined tissue, as a consequence of the application of thermal sensor 101, in real-time.

[122] In various embodiments, the heat transfer index is normalized against personal patient parameters such as, in a non-limiting example, sex, age, smoking habits, drinking habits, number of births, height, weight, blood pressure, diabetes state, medical history, relative's medical history, the patient's own previous heat transfer index analysis and any combination thereof.

[123] In an embodiment of the present invention, the heat transfer map's emerging markings of distinctive heat transfer indexes is used for detecting and mapping the cell irregularities' borders and for surgical removal of the markings findings.

[124] Results of thermal analysis software 103 are then displayed on display means 104 comprising a user interface. The display means may be a monitor which is part of the system, or of a personal computer or the screen of any other electronic device such as a personal tablet, smartphone, smart TV and the like. The electronic device may comprise the thermal analysis software 103 in itself or may be in operative communication with the processor comprising thermal analysis software 103, wirelessly or through wire communication.

[125] Cell irregularities may be recognized by correlating the emerging heat transfer index with associated cell irregularities, which may be selected from the group consisting of malignant tumors, precancerous tumors, benign tumors, infections, pneumonia, necrotic cells and any combination thereof. Cell irregularities may also be recognized by comparing the emerging heat transfer indexes to a predetermined range of slopes which are suspected to be the result of irregular biomechanical-thermal properties in a tissue. In other embodiments, the heat transfer indexes may be compared to a baseline of healthy tissues or other tissues comprising cell irregularities, whether extracted from the same patient or from a plurality of other examined individuals.

[126] In several embodiments, thermal analysis software 103 is configured to calculate a ratio between the distinctive heat transfer index of the suspected area to the heat transfer index of the surrounding tissue area. This ratio can then be compared to other ratios taken from other examined individuals.

[127] Display means 104 may illustrate a numerical or graphical presentation of the gradient temperatures, the heat transfer maps, the thermal data images, cell irregularities markings, cell irregularities border, the patient's personal parameters and the like.

[128] The procedure includes heating and/or cooling application to the examined area, forcing the tissue to transfer heat, followed by monitoring the tissue's heat transfer and cooling by a thermal sensor screening sampling of multiple thermal images, until full coverage of examined tissue surface is reached, and finally constructing temperature profile in relation to time and location, as measured during the test (marking any irregularities).

[129] In some embodiments, the device is directed to examining the lungs. In such an embodiment, heat convection by inhalation of hot air would supply a heat application to at least a portion of the lung area, from the symphonies to the alveolus. The thermal potential created between the surface lung tissues and the internal ones would transfer heat to the inner tissues. There, it would be absorbed and spread by the internal layers. This is done due to several heat transfer mechanisms found in biological tissues and conduction. This process would eventually balance at steady state. Since cancerous tissues vary in thermal properties from healthy ones and specifically the thermal diffusion, it would stand out of the healthy environment. Using the thermal camera images taken throughout the procedure, heat transfer index analysis is made. Area temperature mapping (According to the camera's resolution), at different times (according to the camera's sampling rate - FPS) is depicted. This maps the diffusion properties, revealing the abnormal areas. Finally a three dimensional map of the examined tissue or organ is constructed, marking the suspected areas.

[130] Reference is now made to Fig. 2, illustrating a high level overview of a preferred embodiment of the system disclosed by the present invention. The system disclosed by the present invention may comprise mechanical speculum 110, in order to gain access to examined tissue 10 which me be an inner tissue area, such as the cervix. After gaining access to examined tissue 10, scanner module 120 is operated. The module comprises a heat/cool source 121, scan unit 122, thermal sensor 123, and may further comprise spatial positioning means 125, which could be in a non-limiting example a CCD camera, a thermal camera, a laser rangefinder, or an ultrasound scanner, and may also comprise at least one environmental sensor adapted to measure various parameters of the ambient environment where the examination takes place, and this sensor may be, in a non-limiting example a thermometer, a hygrometer, a photodetector and any combination thereof.

[131] In an embodiment of the present invention, the heat/cool source 121 could be any device which is configured to apply heat to the surface area of an examined tissue in a manner of advection, convection, conduction, radiation or any combination thereof. In a similar manner, cooling may be conducted by using a device which is configured to remove heat from the surface area of the tissue, in the manner of advection, convection, conduction, radiation or any combination thereof. Radiation may be applied in any wave length.

[132] Thermal sensor 123 refers to any device providing detection of thermal energy in a resolution of time and space, and producing thermal images data. Preferably, thermal sensor 123 is an IR sensor, but not limited to it, and thermal sensor 123 may also be a mercury-in-glass thermometer, pill thermometer, liquid crystal thermometer, thermocouple, thermistor, resistance temperature detector, silicon bandgap temperature sensor and any combination thereof.

[133] Thermal image data and any other data is then communicated to the software module 130, which comprises data collector submodule 131, data analyzer submodule 132 and results submodule 133. Software module 130 comprises the thermal analysis software 103 and results in temperature measurements which are subjected to mathematical manipulations including deriving a first, second or third derivative of the change in temperature over time, resulting in the heat transfer index. This index may further be used to construct the heat transfer map exhibiting the suspected areas of cell irregularities. Data collector 131 is found in operative communication with scanner module 120, and comprises all the data available from module 120. Data analyzer 132 is found in communication with data collector 131 and extracts the relevant data required for the heat transfer index analysis. Results 133 is found in communication with data analyzer 132 and contains analyzed data from cervical scanner 120.

[134] The results 133 data, the analysis data of data analyzer 132 and the raw data of data collector

131 are then preferably transferred to database 140. This database may be found in the same electronic device as software module 130, or may be in a different device, and even possibly, the data is wirelessly transmitted to database 140 which is found at a different location. Database 140 may comprise various submodules, and in the illustrated embodiment it comprises personal data submodule 141, global data submodule 142, update submodule 143 and extract submodule 144.

[135] Personal data 141 comprises personal patient parameters which may contain sex, age, smoking habits, drinking habits, number of births, height, weight, blood pressure, diabetes state, medical history, relatives' medical history, patient's previous heat transfer index and any combination thereof.

[136] Global data 142 may comprise data relating to examined tissues or organs in other tissues and/or in other individuals. Preferably global data 142 contains a database of examinations of a plurality of tissues (a plurality of tissues from a single individual, or a plurality of tissues from a plurality of individuals whose data has been recorded), according to the method as recited in the present invention. This database collectively provides a heat transfer index baseline according to which an immediate examination is referred to. Global data 142 may comprise raw data taken from the scanner module, at least partially analyzed data and/or results data. It may also contain personal information related to the examined individuals participating in the baseline database. Preferably, global data provides the ratio between healthy tissues and tissues exhibiting cell irregularities. The ratio may then be compared between the patient and a database containing such ratios from other examinees. The comparison between the patient's ratio and the global data's ratios will enable a better identification of the cell irregularities, as well as the severity of the medical condition and the malignancy status.

[137] Update 143 provides an updated analysis of the heat transfer index results 133 derived from scanner module 120, in view of the baseline data of global data 142. Extract 144 provides the finalized analysis of the heat transfer index results, after being compared to the baseline data. The baseline gradient temperature may refer to healthy tissues, or may refer to any tissue having cell irregularities. Global data 142 may comprise a plurality of databases relating to various tissue conditions, and comparison to the appropriate database may be determined, inter alia, according to personal data 141.

[138] The final results of the analyzed tissue heat transfer provided by database module 140 are then transferred to the user interface module 150, which preferably comprises processor 151 and display 152. User interface 150 enables both data representation and data input by a user, where user of the system provided by the present invention enters any data which is relevant to the analysis of the heat transfer index. In addition, the user may decide which output will be presented to him on the display and in which manner.

[139] Reference is now made to Fig. 3, illustrating a high level overview of a preferred embodiment of the method disclosed by the present invention. Preferably the method is conducted on the examined individual, if needed by creating access 210 to the suspected tissue, using device such as, in a non-limiting example, a mechanical speculum. After gaining access to the suspected area, at least a portion of its surface undergoes heating and/or cooling 220. The elevation/reduction in tissue temperature is monitored and if the temperature has not reached the desired value 230, then a better access 210 and/or re-heating/cooling 220 is repeated. If the temperature has reached the desired value, then thermal scanning 240 is conducted next.

[140] Thermal scanning 240 includes the use of a thermal sensor, such as preferably an IR sensor, but could also include a mercury-in-glass thermometer, pill thermometer, liquid crystal thermometer, thermocouple, thermistor, resistance temperature detector, silicon bandgap temperature sensor and any combination thereof, and the heat transfer index analysis, resulting in a heat transfer map. If no distinctive heat transfer indexes emerge 250, i.e. the heat transfer map is homogenous and normal tissue status is displayed 30, showing a numerical or graphical representation of healthy results. If on the other hand, inhomogeneous regions are suspected to be in the heat transfer map, the data is preferably compared to a database 260. The database comprises a baseline derived from various examinations of other tissues and/or other examined individuals, as depicted in Fig. 2. According to the comparison 260, it can be determined if the tissue is cancerous/precancerous 270, in addition to providing an estimate of the severity of the medical condition, the extent of the cell irregularities or the malignancy status of the tumor. Such a comparison may be to the heat transfer index itself, or to the ratio between the heat transfer index exhibited by the healthy tissue to the heat transfer index exhibited by the suspicious tissue. If it is, then marking is displayed for the cancerous region 20. If the comparison does not result in cancer suspicious tissue, other pathologies may be diagnosed 280, might be with the use of other baselines. If other pathologies are identifies, then markings of the found pathological region is displayed 21. If no cancer, and no other pathology are found, then normal tissue status is displayed 31.

[141] According to an embodiment of the present invention, the method can also be applied to diagnosing and determining appropriate treatments based on comparison of the analyzed results to a baseline. This baseline could be any tissue which was processed using the method proposed in the present invention, i.e. any healthy or malignant tissue, which has been applied with heating or cooling, and been scanned for temperature gradient profiling. The temperature gradient profile, and the resulting heat transfer index, of the examined tissue can be compared with the temperature gradient profile, and the resulting heat transfer index, of the baseline tissue. Identification of similar patterns will enhance the likelihood of correct diagnosis and suitable treatment routines.

[142] In various embodiments of the present invention, the heat transfer index is normalized to provide a scale, preferably a numerical scale, which has a range between 1 and 10, wherein a higher value indicates a higher severity of the medical condition of the cell irregularities, or a later cancer stage. A value of 0 may indicate healthy tissue.

[143] Reference is now made to Figs. 4-7, demonstrating results of a first experimental set up which includes six experiments conducted on six cell types cultures. Various cell types are compared with regards to their thermal properties.

[144] The tested tissue is thermally excited by heating or cooling the tissue surface, and is then carefully monitored for heat spread and absorption. Using infrared sensors, thermal surface images are obtained in various time intervals. Analyzing the temperature variation from the images, in relation to time and position can reveal points of irregularities, which suggest pathological tissue.

[145] Without wishing to be bound by theory, the concept of using thermal analysis based on thermal diffusivity changes for finding irregularities is already successfully implemented in the field of material analysis. Industrial and research facilities apply non-destructive tests (NDT) for a variety of materials (such as metals, polymers, concrete, composite materials and others) using infrared active analysis. The tested material is thermally excited by heating the surface, and carefully monitored for heat conduction. Using infrared sensors, thermal surface images are obtained for different sampling times. Analyzing the temperature profile from the images, in relation to time and position can reveal irregularities. These might be cracks or any other flaws in the material, which are discovered due to differences in their thermal properties compared to homogenic material. [146] Hereby is the "Penne's equation", a widely accepted temperature profiling equation for biological tissues: pC ^ = V (kV T ) + q + A ₀ - b (T - T _b )

dt

Whereas:

w w_

External heat source; m ³ -Metabolic heat source

W

rn °C Heat loss due to blood perfusion , ·; T„ ^fc [ ^L °C] ^J -Blood temperature

kg

T[°C] — Tissue temperature; Density

j w

C l ^k g° ^c \ - Heat capacity; ^ L m°c J - Thermal conductivity factor

[147] Biological tissues behave much like a homogenous solid whose thermal properties are defined mostly by its water content. In addition, there is a dependency of the properties on tissue temperature.

[148] Different studies have shown that there is a temperature rise of approximately 1 degree Celsius in cancer tumor compared a healthy neighboring tissue. This is due to enhanced metabolic activity, accelerated growth mechanisms and massive blood vessel usage of the tumor. It is therefore expected to find a temperature of 38 degrees Celsius in a lung tumor opposed to normal 37 degrees Celsius in normal lung tissue. This change of temperature supports the premises that cancer cells have different thermal properties. This of course enables the diagnostic of such cells using active thermal imaging.

[149] studies include "Modeling Temperature in a Breast Cancer Tumor for Ultrasound-Based Hyperthermia Treatment" by Brian Ho et al.; Strom et al., Cancer research, 1979; "Introduction to NDT by Active Infrared Thermography" by X. Maldague; "Thermal Properties" by Holmes; and "Tissue Thermal Properties and Perfusion" by Jonathan W. Valvano, which are incorporated herein as a reference.

[150] The thermal conductivity factor "k" for human tissues has been tested before, however, it was not categorized to different lung tissues groups. Moreover the data that do exist does not mention the lung tissue type tested. As in many human tissues, the lung tissue contains a large amount of water. This makes its thermal properties very close to those of water and in particular the conductivity factor.

[151] According to Mcintosh and Anderson's literature survey taken in 2010, in which several conductivity factor where tested (Mcintosh and Anderson, Biophysical Reviews and Letters, 2010, incorporated herein as a reference), average values can be calculated for the factor. It is hereby presented:

Maximum value: 0.28 L ^m ° ^c

Minimum value: 0.48 L ^m ° ^c

Γ w

Average value: 0.38L ^m ° ^c J

[152] The lung's "K" factor varies significantly according to the subject's age. Values could change from 0.3 in a child's to 0.55 in a grown man with a lung disease.

[153] The thermal diffusion is a property subjected to changes according to the three previously mentioned properties in this manner:

K

a

pC Whereas:

kg

P Γ J 1 w

-Density; cL ^¾ ° ^c J- Heat capacity; ^ L m°cJ - Thermal conductivity factor

[154] The experiment is to prove the differences in thermal diffusion between a healthy tissue and a cancer one, and that it is large enough to be successfully identified as an irregularity.

Example 1

[155] The experimental set up used to evaluate the invention is comprised of two stages. The second stage is designed to achieve greater accuracy and elaboration of the results obtained in the first stage, in addition to handling experimental issues and difficulties arising in the first experimental stage. The second stage was conducted in view of the results obtained in the first. Experimental design goes as follows:

Image capturing of all cell cultures; Laboratory conditions take into account: (a) Neutralizing disturbances; (b) Constant temperature, registration of any alterations, (c) Registration of humidity values.

Camera set up: Control set up - heating; Control set up - cooling; Conduct experiments using heating; Conduct experiments using cooling

[156] While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and the above detailed description. It should be understood, however, that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.