JPH07250837A - Tissue type recognition and device for that - Google Patents

Abstract

PURPOSE: To enable to discriminate types of pathogenic tissue, by giving multiple different stimulation to tissue, detecting a response of the tissue in proportion to each stimulation, classyfing the tissue by processing a combination of each response, and discriminating the tissue in comparison with a known list of an expected tissue type. CONSTITUTION: When cervical cancer is to be detected, a vaginal wall 31 of a patient is opened by a microscopic examination 30 at first, and the tip end of a probe 1 is exposed. The tissue of the cervixuteri 32 is stimulated by probe 1, the responce of the stimulation is processed by a control device 20. That is to say, a first electrode 3 of an electric wire is placed at the center of a bound of optical fiber 4 in an outside tube 2, and the other three electrodes 5, 7 are placed at an inner surface adjacent to the outside tube 2 on the probe 1. Electrical responces obtained by stimulating tissue with these electrodes 3, 5, 7 are measured, and the measured electric signals are compared with measured and received radiation, and then compared with known values to discriminate the tissue by the comparison results.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method and apparatus for identifying different tissues, including tissues showing lesions associated with pre-cancerous or cancerous stages, pathological tissues, and tissues in the transition stage.

Identification of different tissue types is done through a set of measurements of the physical properties of the tissue. The invention relates in particular to the identification of different types of tissue, including the epidermis and what can be examined by such means as an endoscope to allow direct access to the body. A particular application of the invention relates to cervical examination.

[0003]

2. Description of the Related Art Early detection of tissues showing precancerous or cancerous lesions is important for successful treatment.
The detection techniques currently used are inaccurate, error prone to operators and time consuming. A good example of this is the Pap smear for cervical cancer. X-ray diagnostics, which can also be used to detect advanced cancer lesions, can be adversely affected by radiation exposure.

The positive results produced by the Pap smear test are generally due to a visual examination using a colposcop which allows a magnified view of the cervix. The suspicious area of the cervix is evaluated by a trained physician who then makes a subjective judgment about the tissue observed. There are numerous tissue types in the cervix, some of which exhibit similar appearance, including visual and histological properties, which make clinical diagnosis very difficult and misleading.

Similar subjective assessments play an important role in the localization and treatment of other preneoplastic and neoplastic activity, eg malignant melanoma.

[0006] Several methods and devices have been developed in an attempt to distinguish between cancerous and non-cancerous tissue using measurements of physical properties of the tissue. Electrical measurements of skin or tissue have been used. Such electrical measurements alone do not provide the information needed for effective diagnosis.

US Pat. No. 4,537,203 discloses an abnormal cell detecting device having a pair of electrodes attached to a part of the human body. In this patent, two voltages at different frequencies are applied between a pair of electrodes. Capacitance measured at two frequencies indicates the presence of abnormal cells.

US Pat. No. 4,955,383 discloses a method and apparatus for determining the presence or absence of pathological conditions in tissue. In this patent, an electrode array is used to measure epidermal potential.

US Pat. No. 5,143,079 discloses a device for detecting tumors in tissue. The device includes means for determining the dielectric constant of human tissue. The impedance of a particular area depends on the permittivity and conductivity of the tissue. Impedance fluctuations occur when there are foreign parts in the tissue.

It is also known to measure physical properties of tissue by optical measurements. For example, US Pat.
The device described in 853 is used to identify cervical tissue suspected of being physiologically altered as a result of neoplastic or preneoplastic activity of a cervical rash.
In this configuration, the probe device must be properly positioned with respect to the surface of the cervix to avoid false measurements. The device described in this patent cannot guarantee correct positioning.

The above arrangement has a number of drawbacks. Specifically, each configuration is generally configured for use with a particular type of cancer and is presented to a physician under almost the same conditions. Thus, such devices cannot be effectively used for multiple tissue types and cancer types such as cervical, skin, colon, or conveniently used where such cancers are found.

[0012]

SUMMARY OF THE INVENTION One object of the present invention is to enable its use in various locations within or around the human body,
It is an object of the present invention to provide a tissue type recognition method and device capable of rapidly performing objective discrimination of a tissue type including the presence of pre-cancer activity and cancer activity.

[0013]

SUMMARY OF THE INVENTION In accordance with one aspect of the present invention, an apparatus is disclosed for identifying different tissue types, including those exhibiting precancerous or lesions containing cancerous activity.
The apparatus includes a probe having one end having a shape facing the tissue and at least two paths for electromagnetic radiation, at least one of the paths for electromagnetic radiation reaching the one end and heading toward the one end. And at least one other is configured to carry the electromagnetic radiation in a second direction away from the one end and away from the one end, the at least one first First along said directional path, said electromagnetic radiation
A first electromagnetic generator means connected to said at least one first direction path for transmitting at a wavelength of, or associated with a first wavelength, and said electromagnetic along said at least one first direction path. Second electromagnetic generator means connected to the at least one first directional path for delivering radiation at a second wavelength different from the first wavelength; and the first and backscattered backscattered by the tissue. Receiving means connected to said at least one second direction path for receiving said radiation of a second wavelength;
At least one electrode means for applying an electrical signal to the tissue, an electrical measuring means for measuring the electrical response obtained from the tissue, and comparing the measured electrical signal with the measured and received radiation and comparing them Comparison means for comparing with a known value and thereby identifying the tissue type.

It should be noted that when the term "wavelength" is used with respect to a source of electromagnetic radiation, the spectral bandwidth of such source is finite.

In accordance with another aspect of the present invention, a method of identifying tissue suspected of being physiologically altered as a result of precancerous or cancerous activity is disclosed. The method is
Irradiating the tissue with electromagnetic radiation of wavelength
Irradiating the tissue with electromagnetic radiation of a second wavelength different from the first wavelength, receiving radiation of the first and second wavelengths backscattered by the tissue, and applying an electrical signal to the tissue. And measuring the resulting electrical response of the tissue, and mathematically transforming the received radiation and electrical response signals,
Identifying the condition of the tissue by comparing a list of the main features of normal and abnormal tissue types with the result of the mathematical transformation. Note that backscattered radiation includes reflected radiation.

In accordance with another aspect of the invention, a method of identifying tissue suspected of being physiologically altered as a result of pre-cancerous or cancerous activity is disclosed. The method is
(A) subjecting the tissue to a plurality of different stimuli;
(B) detecting a tissue response corresponding to each stimulus, (c) combining and processing each response to categorize the tissue, and (d) a known list of expected tissue types. And comparing the categories of the organization to identify the organization.

According to another embodiment of the present invention, an apparatus for identifying tissue suspected of being physiologically altered as a result of precancerous or cancerous activity is disclosed. The apparatus detects a plurality of energy sources configured to strike or contact tissue with a plurality of different stimuli and a response of the tissue to each or more of the stimuli, and A detector configured to couple the response to a controller, the controller comprising:
A processor unit configured to process the responses in combination to categorize the organization; a memory unit comprising a list of expected tissue types; and a list from the list for identifying the organization. A comparison device is provided to compare the expected tissue type with the categorization of the tissue, and an indicating device for indicating the identified tissue type or its probability to the user of the device.

[0018]

[Example] Cancer detection by optical detection is generally performed by a sensor
Image the tissue region of interest onto the array. Such techniques impose a number of restrictions. First, for cancer detection,
Optical transmission sensors are primarily responsive to surface reflections, although transmission and scattering in and around the tissue is more important than surface reflections from the tissue. Second, the sensed image is usually greatly affected by the interference properties of the tissue surface such as surface reflectance, emissivity, specular reflection, surface fluid, ambient light.
Third, the optical signal received by each pixel of the sensor array is generally spectrally decomposed into a very small number of wavelength regions, similar to a Red Green Blue (RGB) camera system.
Fourth, electrical, magnetic, or acoustic measurements cannot be made on each projected pixel of tissue at the same time. It may be of utmost importance to combine such measurements with optical information, as we have discovered, to identify the tissue type of an area. Also, the area of interest is not always sufficiently accessible to be illuminated and detected by an imaging system such as a camera.

When viewing tissue with the naked eye or with an imaging system, what is seen as an image is the illumination light reflected by each fine region of tissue. It mainly represents the surface reflected light and has a large, if not a dominant effect, by the dominant fluid on the surface, the oxidant or other chemicals present on the surface or the pH phenomenon, the surface temperature, the type and angle of illumination. May receive a. Therefore,
Light from cells or tissues at or near the surface
In general, there is less identifying information about cancer or precancer compared to light from cells or tissues that are slightly deeper. However, light from the inside is visually obscured primarily by surface reflections. Therefore, a system that accesses the optical properties of such deeper cells as a signal while eliminating reflections from surface cells is highly desirable. The means used in the embodiments described herein to make such an identification include "controlled spatial and optical separation of the area of tissue being irradiated and the area of tissue being examined for radiation. It is.

There is no comparable process for observing with the naked eye or conventional optical imaging systems the local migration characteristics of each "pixel" of tissue as described above. This is a result of complex mechanics between transmission, absorption, scattering and retroreflection, where the final effect allows for better tissue discrimination than surface reflection. This process, referred to herein as backscattering, constitutes the basic mechanism used in the preferred embodiment described below.

The information obtained from all of the adjacent regions where the backscattering power was measured is reconstructed as an optical image (ie reconstructed in the same spatial order in which the measurements were made).
And forms an "image" of the backscattered values on the reconstructed surface. Such images are referred to herein as "backscatter images" and allow mappings useful for identifying cell and tissue types in an area. One embodiment of the invention provides a means for producing such a backscatter image. Also, the inclusion of electrical measurement data regarding locally dominant dielectric and impedance properties of the tissue of each pixel of the image provides a multi-dimensional imaging mechanism.
The backscatter imaging mechanism described herein includes electrical, magnetic, and acoustic parameters for each pixel region.
It includes the concept of measuring any one or more of physical parameters such as ultrasonic parameters, thermal parameters, optical parameters. Therefore, the backscatter image can include characterizations of multiple energy types and physical features at each pixel region.

Thus, the backscatter image can include a characterization of multiple energy types and physical features at each pixel region. The backscatter signal variables are primarily stimulus / receive transfer, but are included in the system,
Self-characteristics in each pixel area (such as dominant temperature and electrostatic potential)
Is included within the definition of backscatter image herein.

Since it is particularly important in cancer detection to approach zero false negative results, it is often desirable to use as many independent discriminators (identifiers) as possible to determine a large number of cell types. For example,
A given mechanism involving independent stimulus / received energy forms (eg, magnetic) provides only 1% additional statistical contribution to the discrimination of many cell types, while other energy forms used (eg, optical energy). And the sum of electrical energy) allows a statistical accuracy of 98% to be distinguished, by adding a magnetic contribution of 1%, [100% to 98%] = 2% From [1
The system inaccuracy can be halved (00% to 99%] = 1% (for optical, electrical and magnetic energies). Thus, the contribution of the apparently low statistical discriminant function can greatly improve the performance of the overall system, possibly ensuring that this energy form is included in the system. For this reason, multiple measurements involving a number of different energy forms and mechanisms (although cumbersome to implement and difficult to incorporate into a single miniature probe that requires microminiaturization techniques) are desirable for the preferred embodiment. Represents a feature.

Therefore, it is desirable to use a properly configured probe that allows access to the surface of the tissue and avoids some or all of the limitations discussed above. For cancer detection near the area entered by the physical probe, it is important to access the tissue surface while allowing substantial visual feedback and allowing the clinician the best positioning. Therefore, an example in which the probe is used is
It should be configured to maximize visibility and minimize ambiguity while at the same time stimulating the sensor to follow the contours of the tissue of interest. The accuracy of determining tissue type near the surface is highly dependent on such function. Controlling orientation toward the surface, pressurizing against the surface, and eliminating unwanted instrument noise sources such as background lights, fluids, parasitic electromagnetic vibrations, and parasitic mechanical vibrations are important for making precise measurements.

Further, whether the stimulus is electric,
Whether optical, acoustic, magnetic, thermal, or ultrasonic, these limitations on measurement accuracy carry the stimulation energy to and from the tissue surface. It is interdependent with the method used to.

In the imaging probe of the embodiments described herein, the data for each such spatial region is such that the decision for each spatial region is based on multiple N readings rather than a single reading. Are preferably cumulatively accumulated. With such a sampling process, the statistical accuracy improves in proportion to √N. It would also be convenient to be able to see the resulting “picture” of each cell or tissue type in the region of interest, which is similar to the pictures on the computer screen that can be guided through the imaging system.

Thus, the design of a pre-cancer / cancer detection system that measures physical variables has a data acquisition system adapted to multiple probe types that is specifically configured to address the applications involved. Is reasonable. Therefore, the probe should be interchangeable with the automatic calibration upon replacement. It is also important to provide the clinician conducting the test with feedback to read misuse, misplacement, or inappropriate or prevailing conditions that could invalidate the test in progress.

Such information should be readily or immediately available, along with other warning alarms regarding the instantaneous proximity of the sensing probe to cancerous or pre-cancerous tissue. During use, the clinician tends to be immersed in manipulating the probe onto the tissue area of interest, thus
You cannot focus your attention on the computer screen, other conventional displays or pointing devices (hereinafter also called indicators). Therefore, a configuration that provides appropriate real-time feedback to the clinician's operator while at the same time storing important measurement data is a relevant element of cancer measuring instruments.

Since probes are typically used in environments containing fluids that have variable optical and electrical properties, transmissive, transmit and receive sensors, to address this variability,
And calibrating electrical performance is more difficult. Optical measurement is not the surface reflection but the transmission, absorption of the material by the human body,
It is preferably based on backscattering. Placing the probe tip perpendicular to the reflectance standard for calibration produces a response primarily due to the surface reflectance of this reference. In such a calibration, the emission / reception rate is not monotonic with the distance from the reflectance reference to the probe plane, but is very dependent on that distance. Therefore, simulating the actual measurement conditions in this calibration process is a difficult problem.

Semiconductors and other components are used in probes that are manipulated by the operator and are in intermittent contact with the tissue surface and change in temperature due to the difference between room temperature and tissue temperature. Especially for components with semiconductor junctions on the probe face, variations in performance can have serious consequences for temperature changes. Therefore, it is desirable for the data processing system to compensate for the instantaneous temperature of such components while making measurements.

At present, the underlying mechanisms leading to physically measurable differences between normal and pre-cancerous and cancerous tissue types are only understood in terms of phenomenological models. The significance of each discriminant parameter cannot be exactly predicted for any type of cancer. As a result, the process of calibrating such a cancer detection instrument is directly interconnected to the identification algorithm used and the underlying measurements underlying the algorithm. This ensures that the design algorithm can be truly optimized by using a stable and repeatable probe design with appropriate shape, efficiency, and (for example) electro-optic performance to ensure that it is relevant for cancer and its pre-cancerous state. It means only when collecting accurate data. Therefore, the means for optimizing the algorithm through successive iterations and the means for achieving the results obtained by the various embodiments are part of the calibration process.

One or more electrodes can be used to provide multiple discriminants that can be used to identify tissue type. When using a single electrode, the patient is grounded by some form of contact with other parts of the body. For example, using the electrodes used in electrocardiograph (ECG) readings, or soaking one hand in saline, or wearing a conductive wrist band on one hand, such as an electronics worker. By using multiple electrodes, their relative readings can additionally be used to establish other measurements. For example, optical measurements are successfully established via optical transducers that are properly placed in contact with the tissue surface. The asymmetry of the readings taken from symmetrically located electrodes indicates the asymmetry of the probe tip with respect to the tissue surface.

The electrodes may take the form of a metal disc covered by the surface of said insulator obtained by using a truncated insulated wire. The electrode is one of a number of shapes that can include a circle, an ellipse, a square, a rectangle, a triangle, a segment of a circle or a segment of a ring 1
The orientation of the electrodes can be symmetrical or asymmetric about the center of gravity of the tissue portion under examination.

The electrode surface itself may be metallic or non-metallic.
For example, the electrodes can be composed of a semiconductor such as silicon, carbon, or titanium dioxide bonded onto titanium.

The electrodes can also consist of an electrolytic cell (eg silver / silver chloride or mercury / mercuric chloride) which is bound to the tissue by a salt bridge. A salt bridge in the form of an electrolyte containing a gel or sponge or pore plug can also be used with a metal electrode.

The electrodes can be used to measure a number of electrical properties such as: conductivity. The common-mode current that flows when a sinusoidal voltage is applied to the electrodes at a series of frequencies is determined. The complex impedance of the system at a range of frequencies The current to the electrodes on the tissue when a voltage is applied. The current is
It can be analyzed by its time or frequency components (eg Fourier analysis). The time analysis may be by the shape of the current versus time curve, by the parameters in the equation of that curve, or by the values of the components in the equivalent electrical circuit. The current from the tissue after the application of voltage pulses to the electrodes is stopped. The analysis, as described above,
It may be temporal or frequency related. Voltage decay without shunt current (step-down to very high impedance) after step removal of applied voltage that was held constant for a time sufficient for the system to reach equilibrium before being eliminated.

The electronic circuits used to perform the above measurements may be hard-wired or under software control by a computer. In the latter case, the type of measurement performed may change depending on the results of the previous measurement.

This feature is important to allow the probe to be accurately placed on the tissue so that the electrical, optical or other reading is reliable. If the probe orientation is outside the acceptable range, then the data should be rejected. Various electrode configurations and signal analysis circuits can be selected to meet software needs. Depending on the type of organization,
The computer may not be able to make a clear diagnosis using standard measurement methods. In that case, the circuit can be changed by software or the like to make a supplementary determination.

The probe may also be manipulated across the surface of the human body using a reflector or other assistive device that provides the clinician with an unobstructed view of the tissue under examination,
Alternatively, it should be possible to operate it in the body. There should also be sufficient gaps to allow for high levels of illumination, especially when making optional video recordings of data sampling. For many internal applications, the dimensions of the area where the probe should be able to respond may be as small as 2 mm in diameter. Therefore, the resolution of the probe must be sufficient to resolve pre-cancerous tissue of that size.

Having described various preferred criteria useful in performing pre-cancerous and cancerous tissue detection, a number of specific examples can now be described.

FIG. 1 shows a device for detecting pre-cancerous and cancerous tissue comprising probe 1 coupled to a control device 20 via a cable 9 connected to the probe 1 itself via a coupling 8. . Probe 1 in this example
Is used to detect cervical cancer and FIG. 1 further shows a speculum 30 used to open the wall of the patient's vagina 31 to expose the tip of the probe 1. Cervix 32
Is the end of the birth canal 33 that forms the path to the uterus 34. The probe 1 is capable of stimulating the tissue of the cervix 32 and moving across the surface of the cervix 32 in order to obtain a response to the stimulus that can be processed by the controller 20.

As shown in FIG. 2, the probe 1 comprises an outer tube 2 which serves for electrical insulation and mechanical strength.
Within the tube 2 is located a first electrode 3 in the form of a flat end of an electric wire positioned in the center of a bundle of optical fibers 4. The other three electrodes 5, 6, 7 are shaped adjacent to the inner surface of the outer tube 2 and form part of a cylindrical metal tube positioned to join.

A second embodiment 2 useful in the configuration of FIG.
Probe 10 is shown in FIG. This embodiment of the probe 10 shows a smaller design, which is realized using only three electrodes 15, 16, 17 having a different shape than the electrodes 5, 6, 7. Due to the shape of the electrodes 15, 16, 17 electrical and optical measurements are made on the same area of tissue. The electrodes 15, 16, 17 are adjacent to and joined to the outer tube 12, with a bundle of three optical fibers 14 positioned between the electrodes.

Using the probe 1 of the first embodiment, three initial electrical measurements are made between the central first electrode 3 and the other electrodes 5, 6, 7. The results of these measurements are compared, and if the results are significantly different, it indicates that the tip of the probe 1 is not in uniform contact with the tissue, so the measurement values are discarded.

In the preferred embodiment, pulse measurements are used for both optical and electrical properties as a way to reduce noise and mutual interference between measured signals. For this reason,
As described with respect to FIGS. 4 and 5, examples of the invention include the use of a sequence of electrical pulses.

A graph of a sequence of electrical pulses for using the probe 1 of FIG. 2 is shown in FIG. The electrodes 6 and 7 are cut off and a voltage pulse U ₃ , ₅ between electrodes 3 and 5 is applied.
Is applied. Following this pulse, electrodes 5 and 7 are shut off and pulses U ₃ and ₆ are applied between electrodes 3 and 6.
Then, the electrodes 5 and 6 are cut off to separate the electrodes 3 and 7 from each other.
During this period, pulses U ₃ and ₇ are applied. Each pulse U ₃ , ₅ ,
During and immediately after U ₃ , ₆ and U ₃ , ₇ , the system measures the electrical response, which is then stored and compared. This will be described below. If the result is significantly different, it means that the tip of the probe 1 does not uniformly contact the tissue, and the result is discarded. In order to be able to take multiple readings, the pulse and sequence durations are relatively short, typically tens or hundreds of microseconds within the millisecond sequence range, providing useful real-time information. . Measured value is probe 1
, The electrodes are symmetrically connected, ie a voltage pulse U _{3 (5, 6, 7)} is applied between electrode 3 and electrodes 5, 6, ₇ To execute.

FIG. 5 shows a similar sequence of electrical pulses used in the arrangement shown in FIG. In this example,
The symmetry of the electric field at a given time is no longer realized. U ₁₅ applied between the electrode 15 and connected electrodes 16 and _{17 (16,17), U 16 (} 17,15) applied between the electrodes 17 and 15 connected to the electrode 16, and the electrode U applied between electrodes 15 and 16 connected to 17
Three electrical pulses of _{17 (15, 16)} are used. The relative magnitude of the measured response indicates whether the probe is positioned correctly or incorrectly.

In another form of the invention, only one electrode needs to be used on the probe and the skin can be removed using any one of a number of convenient methods, for example using a conductive pad to a body part. Or a second connection to the tissue can be made.

The probes 1 and 10 of the above example can be used to determine the electrical properties of tissue in a number of ways. For example, a rectangular electrical pulse can be applied to the electrodes as described above and the temporally different currents flowing between the electrodes and the tissue following the pulse measured as currents in the circuit or as temporally different potential differences. it can. The shape of this time-varying signal is indicative of the electrical properties of the tissue. Electrical signals of various frequencies can also be used to measure electrical properties of tissue. The magnitude of the voltage applied to the tissue during the measurement should be great enough that the signal being measured exceeds any ambient noise signals that may be present, but generally to avoid patient discomfort. Must not exceed 2V.

The optical properties of tissue can be measured over the wavelength range from ultraviolet to infrared. One optical fiber in the probes 1 and 10 emits electromagnetic radiation,
It is used to guide the radiation from one or more sources to the surface of the tissue where it is absorbed and scattered. A second fiber, which may be adjacent to the first fiber or separated by a short distance, again directs radiation from the tissue to one or more detectors (not shown). The magnitude of the signal from the detector is indicative of the optical properties of the tissue.

The source of electromagnetic radiation may be a light emitting diode (not shown) or a solid state laser (not shown). Several wavelengths can be guided on the fibers 4, 14 or separate fibers 4, 14 can be used for each wavelength. Wavelengths known to be highly characteristic are 540 nm, 650 nm, 660 nm, 940
nm and 1300 nm.

The controller 20 is a dedicated computer shown in FIG. 6 which is capable of monitoring the preferred embodiment apparatus.
The system 21 is included. The system 21 provides an analog block 23 for the appropriate synchronization of the electrical signals applied to the electrodes 3, 5, 6, 7, 15, 16, 17 of the probes 1 and 10 and the optical radiation source (not shown). Included is a microprocessor block 22 which is controlled via. The signals from the electrical and optical detectors can be processed in the microprocessor block 22 and the results shown on the display 24, or said results
Other visual indicators, audible indicators, or print indicators can also be activated. The keyboard 25 can be used by an operator to provide commands to the computer system 21.

The data collected by computer system 21 is processed and compared to the data stored in the memory of computer system 21 in the form of data patterns specific to each tissue type. FIG. 7 shows a typical graph of tissue type as a function of three discriminants resulting from electrical and optical measurements.

The three discriminants used in creating FIG. 7 are two measurements of the backscattered light (dsc1, dsc2 at the corresponding wavelengths respectively),
It was a measured value (dsc3) of the shape of the electrical relaxation curve derived by Fourier analysis. Figure 7 shows normal tissue type original squamous epithelium (OSE1, OSE2, OSE
3), columnar epithelium (COL1, COL2), and premature metaplasia (P), abnormal, precancerous tissue type
Papilloma virus (HPV), variant (ATYP),
And whether to distinguish from pre-cancer (D1, D2, D3).

The results of this comparison are communicated to the operator via the display 24 or other suitable means. The result is a microprocessor block 2 for a particular patient.
2 and can be retrieved or printed out later.

In the embodiment of FIGS. 1-7, a flexible shaft is optionally provided with the elongated straight outer tube probes 1 and 10, or the probe is encapsulated, thereby permitting insertion using a catheter configuration. It can be carried out.

FIG. 8 shows a specially configured probe 40 that can sample the tissue type on the patient's cervix 32. Specifically, the cervical probe 40 includes an elongated shaft 41 that can be held by a clinician and interconnected with a cable (not shown) that provides a signal to a controller. The shaft 41 ends in a body 42, from which a central probe part 43 extends to the birth canal 33. Body 42
Has an annular recess 44 configured to receive the cervix 32 therein. The probe portion 43 and the depressions 44 have a repeating array of stimulating / receiving elements 45 as sensors arranged on the surface configured to sample the physical properties of the tissue along the entire shape of the cervix 32. The sensor 45 is interconnected with the controller via the shaft 41. Multiple stimulation / received energy types can be provided in multiple continuous regions along the entire shape of the probe surface so that the operator can twist shaft 41 once.
You can see the composite backscatter picture.

FIG. 9 shows a flexible probe 50 configured for specific application to the skin, in this case on the patient's arm 36. This probe 50
Includes a flexible printed circuit planar substrate 51 composed of a number of sensors 52. The sensor 52 is connected to the cable 54 via a number of print connectors 53. The cable 54 links the probe 50 to the controller, as in the previous embodiment. In this configuration, the probe 50 is formed on a curved or flat surface so that a relatively large area can be accessed in a substantially shorter time than required with the probe of the embodiment of FIG. 2, 3 or 8. it can.

FIG. 10 illustrates the extension of the detector assembly 60 of the configuration of FIG. 9, but with full integration. The detector assembly 60, like the probe 50, includes a flexible substrate 61 configured with a plurality of sensors 62. The substrate 61 is a controller 65 for the detector assembly 60.
It is supported by a support body 63 made of an open-cell foam connected to a housing 64 in which is formed. Support 63
Thus, while the substrate 61 is supported by the control device 65, the substrate 61 can be flexed to conform to the shape of the tissue. The controller 65 is connected to the sensor 62, and the controller 65 incorporates the processing functions required for external tissue type determination into a small handheld package.
The controller 65 includes a process module 67, a sensor 6
It includes an integrated battery supply 66 with an input / output 68 connected to the two and a control / display module 69. Connected to the control / display module 69 are a number of indicators 70 that provide the operator with visual or audible feedback indicative of tissue type when the probe assembly 60 is placed on the surface of the human body.

FIG. 11 shows a shaft housing 72 and
A ball refraction probe 71 with a transparent (transmissive) spherical refraction ball 73 formed at its tip is shown. Within the shaft housing 72 are a plurality of light sources 74 (only one shown), such as light emitting diodes covering different spectral bands, a light dependent resistor, a PIN diode,
Complementary photosensors 75 (again, only one is shown for clarity), such as other optical sensors. The probe 71 refracts the light emitted from each light source 74 in a substantially spherical pattern, and
3 is configured to act to stimulate a large area of tissue 76 that contacts 3 itself. In contrast, the backscattered light from the tissue 76 is refracted within the ball 73 onto the sensor 75. An optional opaque barrier 77 prevents direct illumination of light source 74 to sensor 75. Two electrodes 78 are positioned on the ball 73 to contact the tissue 76 for providing electrical stimulation. A number of wire conductors 79 carry signals between the probe 75 and a controller (not shown). As shown, region 80 of tissue 76 is illuminated by light source 74 and region 81 of tissue is observed by sensor 75, thus tissue 76 between regions 80 and 81.
The light transmission through is shown.

FIG. 12 includes four electrical sensors 87 formed on the shaft 86 and configured similarly to the previous embodiment. Specifically, the probe 85 is provided with four ultrasonic transducers 88, each of which can be separately activated to stimulate contacted tissue. If any one transducer 88 is stimulated, the remaining three can be used to receive the transmitted ultrasonic pattern. The patterns received can be processed to determine various features related to tissue density and any changes in density throughout the tissue that are indicative of blood flow. This can be done using time-of-flight measurements such as those used in sonar and audiovisual systems known for medical ultrasound. A number of temperature sensors 89 are provided in the probe 8 to compensate for changes in acoustic coupling.
5 is provided on the surface. The temperature sensor can be used to detect the temperature of the tissue and compensate for changes in ultrasonic velocity within the tissue in the sample.

13A and 13B show a thermal / optical probe 90 including a tubular casing 91. Three optical fibers 92 are arranged along the tubular casing 91.
Fiber 92 is used to illuminate the tissue in the sample and receive the light reflected from the tissue. Probe 9
0 also includes a resistance heater 93 configured to selectively heat the tissue under examination and a temperature sensor 94 configured to measure the temperature of the tissue in response to operation of the heater 93. There is. This allows the thermal response time of certain tissue types to be determined by the controller and to indicate blood flow through the tissue, which can indicate growth of pre-cancerous and cancerous cells.

In FIGS. 14A and 14B, the magnetic probe 1
00 is the tubular casing 101 as in the above-described embodiment.
It is shown to be configured within. Probe 100
Is a multiplicity of electrodes 102 configured similarly to the previous embodiment.
including. 1300 nm, 440 nm, 565 nm, 66
Also included are four optical transmitters 103, such as light emitting diodes configured to send light at different wavelengths, such as 0 nm. The two optical receivers 104 are 1300 nm, 500
To 1000 nm, it is configured to receive light at different wavelengths. A magnetic transmitter 105 located at the center of the probe 100 and three magnetic receivers 106 surrounding it.
Is also available. The magnetic transmitter 105 and the magnetic receiver 106 include a ferromagnetic core and corresponding windings so that the magnetic transmitter 105 establishes a small magnetic field extending from the end of the probe 100. Changes in the magnetic field can be detected and compared by the receivers 106, whereby the imbalance between the signals received by each receiver 106 is
Indicates magnetic anomaly of tissue.

At the time of this writing, the exact significance of magnetic stimulation is unknown, but local abnormalities in the magnetic response of tissue are a result of changes in the intracellular partitioning of the tissue, the charge. It is thought to be due to the disturbance of. Specifically, the nucleus of a cell is surrounded by a large number of distribution layers, and communication between these layers is thought to limit normal cell growth. However, in cancer cells, the only limitation is the communication between layers, which is thought to be directly related to the growth of cancer cells without limitation. Thus, an unbalanced distribution of charge that can be detected or magnetically modified can be indicative of limited communication and thus cancer activity.

It is preferable to use a common control mechanism for many different probe types. Therefore, such a control mechanism is reasonable if the probes are interchangeable and the probe and / or the control device can be calibrated by conventional methods to provide reliable and consistent tissue sampling. Is. The increasing miniaturization will increase the number of the above mentioned energy stimulation / reception modes performed within the tip of a single probe, increasing the number of discriminant parameters needed to detect cancer and precancer. ing.

A first calibration device 120 is shown in FIG. 15 by which a probe 122 connected to a controller 121 is in contact with a synthetic tissue substitute 123. The material 123 simulates known tissue properties that are well-defined for backscattering and other energy emitting / receiving properties such as electrical properties. In this way, the controller 121 can verify that the stimulation pulse output from the probe 122 and the received signal are acceptable or can be adjusted to match within predetermined limits. The automatic blanking mode can be set. After proper calibration, probe 1
22 is used. The synthetic alternative material 123 is sterilized, thereby preventing biological hazards.

FIG. 16 shows a proactive second device 12
5 is shown. To the contrary, the embodiment of FIG. 15 is semi-active. In FIG. 16, the tip of the probe 126 is shown in contact with a complementary probe array 127 forming part of the controller 128 to which the probe 126 is connected. In this way, the probe tip 12
And transmitter and receiver in 6 and probe array 127.
And can be simulated. Since the response of the probe array 127 is known and stable via a precisely calibrated drive mechanism 129, the drive mechanism 12
9 response may be detected by the calibration controller 130, which in turn may detect the probe tip 12
Six drive arrangements 131 can serve to modify.

A third calibration device 135 is shown in FIG. In this figure, a probe 136 having a configuration of conductive leads 137 from a transducer (not shown) is interconnected with a controller 141. Inside the probe 136,
A programmable read only memory (PROM) 138 is configured that is programmed with specific calibration values for the transducers in probe 136. PROM13
8 is directly connected to the calibration module 140 via a number of leads 139. The calibration module 140 outputs a number of gain control outputs 142. These outputs feed an array of amplifiers 143 connected to leads 137 to and from the transducer. In this way, the gain of each amplifier 143 is adjusted to compensate for variations between transducers of different probes 136.
Adjusted in response to a value in 38. The network of PROMs 138 allows digital electronic sterilization of the probe and keeps track every time the probe is used with a computer. Inclusion of the PROM 138 in the probe 136 allows the probe 136 to be electronically identified and recorded each time the probe 136 is used, thereby automatically proactively probing the number of repeated uses of the probe, as appropriate. Can be restricted.

Referring now to FIG. 18, there is shown schematically a preferred configuration of detection system 150 which includes probe 151 connected to processor board 153 via analog board 152. Processor board 1
53 outputs to the display 154 and has user input obtained via a number of control keys 155 and a numeric keypad 156. Computer type communication
It is available via RS232 type connection 157, or IEEE 488 port or COM # port, or direct memory access (DMA). AC mains power is supplied directly via input 158.

The probe 151 includes a device for providing a plurality of different physical stimuli. Specifically, multiple light emitting diodes (LEDs) 159 provide optical stimuli.
The multiple electrodes 160 also provide electrical stimulation to the tissue to determine the discriminant value and determine the alignment of the probe 151 with respect to the tissue. Additional components (not shown) for additional stimulation / reception discriminants may also be included as described above. To complement the array of probes 151, a number of strain gauges 161 indicate the orientation of the probes 151 with respect to the tissue. The probe 151 also includes a number of indicators 162, which may include audible and / or optical indicators that provide the physician with feedback as to the type of tissue when accessed in real time. The number of photodiodes 163 is L
Electro-optical detection of the light emitted from the ED 159 and reflected by the tissue is performed. In order to amplify the output from the photodiode 163, the preamplifier 16 is connected to the probe 151.
4 is included. The probe 151 is an analog circuit that includes a drive amplifier and a control amplifier coupled to each of its elements.
It is connected to the board 152.

The processor board 153 has a digital input / output block 176 and a serial input / output block 178a.
A microprocessor controller using a CPU 178 is installed. The CPU 178 starts the stimulus output to the digital-analog converter 174 via the input / output block 178a. D / A converter is L
Output to the ED drive controller 165. The LED drive controller 165 is used to drive the LED 159,
Also, a digital signal is input via the digital input / output 176. The digital input / output 176 also outputs an electrode stimulation pulse to an electrode driver 166 coupled to the electrode 160 to deliver tissue. The amplifier 167 is
Protective device 172 for evaluation by CPU 178
Amplify the output of electrode 160 that is routed to analog-to-digital converter 177 via. The output of the preamplifier 164 of each photodiode is the optical detector amplifier 171.
The output of the optical detector amplifier 171 is provided to the CPU.
Digitized using A / D converter 177 as referenced by 178. An alternative stimulation / received energy transducer 160a can also be included if desired. The strain gauge drive mechanism 168 uses the DC signal from the DC power conditioner 180 to drive the strain gauge 161 that outputs to the strain gauge amplifier 169. The amplifier 169 is connected to the A / A via the protection device 172.
It is output to the D converter 177 and the magnitude of the force applied to the tissue by the probe is measured. Further, the digital input / output 176 outputs to the indicator driving mechanism 170 which drives the indicator 162 by a known method. The CPU 178 includes a reset device 181 and a clock 182, and also outputs to the test socket 183.

As mentioned above, the probe 151 can be equipped with a PROM (not shown) to facilitate calibration, facilitate sterilization, and record the number of times the probe has been used. If a PROM is used, it can be directly connected to the digital I / O block 176.

In operation, the basic simulation pattern is programmed by the CPU 178 or selected from the memory 179 and the LE is used using the pattern.
D159 and electrode 160 are stimulated. Raw data is C
Recorded by PU 178 and stored in memory 179, thereby being treated as a different discriminant. For each related series of samples obtained,
Multiple discriminants are calculated by argism to categorize the tissue type. The categorization is then compared to the known categorization stored in the non-volatile portion of memory 179, and if a match occurs, the former categorization is normal tissue, pre-cancerous tissue, or cancerous. The tissue is identified and displayed to the doctor as appropriate. If the tissue type is unknown, a corresponding indication is provided to the physician, who can order the next exam for that particular portion of the tissue.

When processing the sensed raw data, it is reasonable to select properties that are relatively unrelated to normal patient-to-patient variations. This can include processing physical parameters such as electrical and optical properties in both frequency and time domains to obtain frequency and time descriptions of electrical behavior. The frequency components are
It can be obtained by Fourier transform or measurement at different frequencies. The time response relates to the amplitude of the response to the energy applied to the tissue. Sweeping the frequency stimulus provides a spectral response, each performing a tissue-type complex impedance study consisting of nine or more separate parameters, including the corresponding spectral curves. The electrical time response can be determined by sequentially monitoring the observed response to known electrical stimuli, which are usually step functions or impulses.

In the optical device, the absolute backscatter of the sample, as well as the slope and rate of change of the response, can be determined as described above, whereby the first and second respectively in the case of spectral or temporal characterization, respectively. The difference versus wavelength or time is obtained as a variable.

In the case of ultrasound, the transmission density changes after the amplitude and Doppler effects, as well as various combinations thereof, and can be analyzed by image analysis techniques. In the case of magnetic stimulation, abnormalities at a particular frequency or series of frequencies can be determined.

Various combinations of stimuli can be used for each different tissue type. For example, in the case of cervical cancer, the preferred stimulation types are optical and electrical. For skin tissue, optical, electrical, magnetic, acoustic, and thermal stimuli may be important.

Once the physical data and various discriminants have been obtained, they can be mathematically combined to determine the particular type of tissue under examination. This can be done using discriminant analysis techniques, linear programming, cross-correlation, or neural networks. The discriminant analysis techniques of the preferred embodiment are used to correlate data to optimize discriminant values using expert opinion or empirically derived correlations. Basically, the various coefficients for each variable are evaluated to determine what modification the variable requires to map to a particular categorization type.

The preferred embodiment for detecting cervical cancer uses eight discriminants based on electrical and optical sensing. Those discriminants are 540 nm, 660 nm, 940 nm, and 13
There are four shape features of the backscatter of light at 00 nm and the voltage decay curve.

The method of categorizing tissues using discriminants is algorithmic, and in the case of cervical cancer and precancer detection using discriminants identified above, the combinations are as follows: is there.

[Equation 1] Where VAR _j is the real-time variable associated with position j in the linear equation, A _ij is the constant coefficient of variable i, and P _i is the relative probability of the i th tissue category.

A large database is required to obtain accurate test results. Such a database allows correlating known responses to specific types of cancer and precancers. For example, the present inventor has searched for an example relating to the detection of cervical cancer, and
More than 0 subjects were surveyed. Each subject was analyzed by a specialized colposcopist and, where appropriate, a tissue physiologist provided reference data on significant tissue categories. Also, each of these subjects used probes and systems according to the preferred embodiment to enable cross-correlation of the preferred embodiment's response to a particular manually categorized tissue type with the manual categorization. Was inspected. This in turn allows the probe to be applied to other patients so that after processing through discriminant analysis, the response from that patient can be cross-correlated with the database to identify a particular tissue type. A database is created for the cancer types of

The inventor has also performed similar experiments,
Databases for breast, skin, colon, and prostate cancer are under development. However, each different cancer type presents a different type of problem to the development of the database. Specifically, in the case of cervical cancer, an in-vivo test can be performed, but in the case of breast, colon, and prostate cancer, biopsy results are needed, so the database is in terms of "reactive system" information. To be developed. For skin cancer, skin tests and biopsy results can be used.

All samples are determined by correlating the probe results with in vivo and biopsy identifications that provide reference features for each tissue type when the results are detected by the probe.

Our investigation of the performance of the preferred embodiment has revealed a detection system 150 for cervical cancer.
However, between colposcopy / histophysiology and probe diagnosis, 85% or more depending on low-grade abnormalities (changes in fully grown human papillomavirus, mild atypia, or cervical intraepidermal tumor grade 1) 99%,
It was shown to give 90% concordance for high grade abnormalities (cervical intraepithelial tumor grade 2 or 3) and 99% for invasive cancer. Statistical analysis and extrapolation of these results show a false positive to false negative ratio of about 10% using the probe of the preferred embodiment, and thus for cervical cancer:
It is shown that the probe configuration of the present invention is a substantial improvement over the accuracy of about 50% to 60% that is considered suitable for conventional pap smear tests.

The foregoing describes only a few embodiments of the present invention, which may be modified by those skilled in the art without departing from the scope thereof.

[Brief description of drawings]

FIG. 1 is a partial cross-sectional view of an example probe system in use.

FIG. 2 is a schematic view of the probe of the first embodiment.

FIG. 3 is a schematic diagram of a probe of a second embodiment.

4 is a graph of a sequence of electrical pulses used in the embodiment shown in FIG.

5 is a graph of a sequence of electrical pulses used in the embodiment shown in FIG.

FIG. 6 is a schematic block diagram of a detection system according to an embodiment.

FIG. 7 is an example of a graph showing a panel of tissue types as a function of three discriminants resulting from electrical and optical measurements.

FIG. 8 illustrates the use of one example of a probe specifically configured to detect pre-cervical cancer.

FIG. 9 illustrates another embodiment of a sensor specifically configured to detect skin cancer and the like.

FIG. 10 is a partial cutaway view of another embodiment of the present invention for detecting skin cancer and the like.

FIG. 11 is a side view of an optical sensor including a ball refracting head.

FIG. 12 is a diagram of another embodiment including an ultrasonic transducer.

FIG. 13 is a front and side view of a probe embodiment incorporating thermal and optical stimuli.

FIG. 14 is a front view of a probe embodiment including electrical stimulation, optical stimulation, and magnetic stimulation, and a side view of a probe embodiment including electrical stimulation, optical stimulation, and magnetic stimulation.

FIG. 15 shows a configuration for probe calibration.

FIG. 16 shows a configuration for probe calibration.

FIG. 17 shows another embodiment of probe calibration.

FIG. 18 is a schematic block diagram of a detection device according to a preferred embodiment.

[Explanation of symbols]

2 external tubes, 3 electrodes, 8 couplings,
9 cable, 10 probe, 20 control device, 21 computer system, 24 display, 25 keyboard, 30 speculum, 32 cervix, 34 uterus, 41 shaft, 42 body,
44 annular recess, 45 sensor

Front Page Continuation (72) Inventor Bivan Leslie Raid 2577 New South Wales, Wellei (Via Moss Vale) Greenhill Road (no street number) “Greenhills” (72) Inventor Victor・ Nikelovich Skladnev Australia 2022 New South Wales Bondi Junction Rasven Street 89

Claims (20)

[Claims] 1. A method of identifying tissue suspected of being physiologically altered as a result of pre-cancer activity or cancer activity, comprising: (a) applying a plurality of different stimuli to the tissue; (b) each stimulus. Detecting the response of the tissue corresponding to, (c) combining and processing each response to categorize the tissue, and (d) a known list of expected tissue types and the categorization of the tissue. And comparing to identify tissue. 2. The method of claim 1, wherein the stimulus is selected from the group consisting of electrical stimulus, light stimulus, acoustic stimulus, magnetic stimulus and thermal stimulus. 3. The one or more of the stimuli is selected from the class consisting of continuous stimulation signals, pulse continuous stimulation signals, frequency modulated stimulation signals and phase modulated stimulation signals. The method described in 2. 4. The photostimulation signal comprises a sequence of a plurality of pulsed optical signals, each of which has a different spectral bandwidth, and the sequence is repeated so fast that tissue responses are obtained at substantially the same time. The method according to claim 3, wherein 5. A quantum sample response is detected,
The method of claim 2, wherein all the stimuli are applied to the tissue at substantially the same time. 6. Step (c) processes each said response by one or more predetermined process steps,
The method according to claim 1, wherein the processed results are obtained for each of the process steps, and the processed results are combined in a predetermined method to classify the tissue. 7. The method according to claim 6, wherein at least N stimuli (N ≧ 2) are used and the response is processed as at least N + 1 results of the processing. 8. The method of claim 7, wherein the stimulus comprises an electrical stimulus and an optical stimulus that provides eight of the processing results. 9. The weighting value for each processing result is a predetermined value, and based on the organization type in the list and a specific association of each processing result with the list, the processing result The method according to claim 6, wherein the processing results are combined by a weighted sum. 10. The process step includes amplitude response, frequency response, absolute amplitude determination, phase response, spectral response, a first differential response with respect to time, and a second differential with respect to time in the case of the electrical stimulation and magnetic stimulation. Response The method according to claim 6, characterized in that in the case of the optical stimulus, it is selected from the group consisting of an amplitude response and a frequency response in the case of the acoustic stimulus. 11. The method of claim 6, wherein the processing results are combined by an algorithmic method using one of linear programming, cross-correlation, and neural networks. 12. The tissue type of a sample in which the list of tissue types is manually examined and pathologically classified and identified from the sample in steps (a), (b),
Obtained by cross-reference with the processed responses obtained in (c), whereby those responses are obtained by using said method in the absence of manual examination or pathological classification of said tissue The method of claim 1, wherein the method is expected to be. 13. The tissue is suspected of being altered in one or more of a cervical tissue category, a breast tissue category, a skin tissue category, a prostate tissue category, and a colon tissue category. The method of claim 1. 14. The method of claim 1, wherein the processing and comparing steps are performed in real time, and the identifying comprises a statistical comparison of the categories and tissue types in the list. 15. The method of claim 1, wherein the tissue forms part of a living body. 16. An apparatus for identifying a tissue suspected of being physiologically altered as a result of pre-cancer activity or cancer activity, the apparatus comprising striking the tissue and stimulating the tissue with a plurality of different stimuli. A plurality of energy sources, and a plurality of detectors configured to detect a response of the tissue to each of the stimuli and couple the response to a controller, the controller comprising the tissue A processor configuration configured to combine and process the responses to categorize the response, a memory configuration comprising a list of expected organization types, and a list obtained from the list to identify the organization. A comparison arrangement for comparing the categories of the expected tissue type and the tissue, and an indicating device for indicating the identified tissue type to the user of the device. Device according to claim. 17. The energy source and the detector are configured in a probe operable by an operator to contact the tissue within or on the exterior surface of the body under examination. The device according to claim 14. 18. A probe that carries a stimulus to a tissue via electronic identification is numerically serialized and recorded automatically each time the probe is used, the number of repeated uses of a given probe. 18. The device according to claim 17, characterized in that is automatically pre-limited. 19. A tissue-facing end, at least one being configured to carry electromagnetic radiation in a first direction towards and at one end, and at least one other A probe comprising at least two electromagnetic radiation paths configured to carry the electromagnetic radiation in a second direction away from the one end and away from the one end; and along the at least one first direction path, First electromagnetic generator means connected to said at least one first directional path for sending said electromagnetic radiation at a first wavelength or in association with said first wavelength; and said at least one first directional path Along said electromagnetic radiation,
Second electromagnetic generator means connected to the at least one first directional path for transmitting at a second wavelength different from the first wavelength; the first and second wavelengths backscattered by the tissue Receiving means connected to the at least one second directional path for receiving the radiation, at least one electrode means for applying an electrical signal to the tissue, and an electrical response resulting from the tissue. Characterized in that it comprises electrical measuring means for measuring the measured electrical signal and comparing means for comparing the measured electrical signal with the received radiation and comparing them with known values, thereby identifying the tissue type. And
An apparatus for identifying different tissue types, including those indicative of precancerous or lesions involving cancerous activity. 20. Irradiating the tissue with electromagnetic radiation of a first wavelength, irradiating the tissue with electromagnetic radiation of a second wavelength different from the first wavelength, and backscattered by the tissue. Receiving radiation at the first and second wavelengths, providing an electrical signal to the tissue and measuring the resulting electrical response of the tissue; and mathematically receiving the received radiation and electrical response signal. Pre-cancer activity or cancer, comprising the step of performing a transformation and identifying the state of said tissue by comparing said mathematical transformation with a list of the main features of normal and abnormal tissue types. A method of identifying tissue suspected of being physiologically altered as a result of activity.