JPS63194640A - Apparatus for measuring impedance of epithelial cell in body to be examined - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the detection of the presence of and inclination towards abnormal tissue growth, and more particularly to the detection of abnormal tissue and the detection of abnormal tissues in the examined tissue. The present invention relates to a probe for early indication of this and how to use this probe for such purpose.

As used herein, the term "abnormal tissue" refers to all types of tissue that have undergone malignant tumor induction such that they can effectively exhibit a loss of growth inhibition, often referred to as cancer or tumor growth. It means weaving. Detecting the presence of abnormal tissue is often difficult because such abnormal tissue is present in the body and the presence of abnormal tissue may not even be suspected until discomfort or other symptoms are felt. That's because there isn't. Furthermore, procedures for early detection are very expensive and complex, which can limit their use. Therefore, the presence of abnormal & II weave,
Ideally, it would be very beneficial to be able to quickly and easily detect possible abnormal tissue growth within the body's vagina, and in this case, the method would be beneficial to the human body's healthy &! It is preferred that 1Va be affected as little as possible.

Cancers and tumors often take a long time, in some cases years, to reach a size that is detectable or harmful to receptors (eg, the human body). Current treatments are reasonably effective when the abnormal tissue is in its early stages, long before it has grown sufficiently to cause discomfort or symptoms. It is true. Therefore, it would also be beneficial to be able to detect abnormal tissues while they are in their early stages or to detect the tendency of tissues to become abnormal.

Several research efforts have been made to find the relationship between the electrical impedance of a biological tissue and the condition or health of that tissue.For example, US Pat. It discloses that it can give a useful indication as to whether the disease is pathological or not. That is, the above US patent suggests that changes in the impedance of biological tissues can be used as a means for diagnosing certain cancers. According to the method of the above-mentioned US patent, a low level current is passed through the Mi weave to be inspected,
The voltage drop within the tissue can be measured, thereby providing a direct indication of the overall tissue impedance (ie, resistance and capacitance). Also, according to the above US patent, &
An increase in the impedance of a tissue is associated with an abnormal state of the cells that make up the tissue, and is indicative of a tumor, carcinoma, or other abnormal biological condition of the tissue.

According to the invention, a probe used to measure tissue impedance comprises first and second conductive rings, the first and second rings having an insulating member separating them. It is integrally constructed. Above 2
one of the two conductive rings is a measuring electrode and the other is a working electrode, generally coaxially arranged and to which individual leads are connected;
The leads extend from one end of the probe for connection to external processing and measurement equipment.

A second probe according to the invention may be constructed in a manner similar to the first probe described above, but comprising an annular conductor mounted within a substantially smaller elongate insulated tubular member and, in particular, for example It has an electrode sized and shaped to be inserted into a blood vessel.

In use, a first probe having a set of electrodes is inserted into an epithelial cavity (eg, the colon) and positioned at an examination location using an endoscope. The second probe then
The probe is moved along a suitable blood vessel adjacent to the tissue wall forming an epithelial cavity within which the probe is located.

In that case, the second probe is the skin (intradermal or subcutaneous)
It can be placed internally, on the external surface of the skin, or relatively distant within a blood vessel. An alternating current test signal is applied to the working electrode of each probe, and between the two sets of measuring electrodes the two
Measurements are made to determine the impedance of the buttress tissue between the two probes.

External measurement and processing equipment balances the measured impedance between the probes and transfers the resulting information to a cathode ray tube (CRT).
) or other suitable output display device, which automatically controls the programmable impedance (resistance and capacitance).

The AC input to the working electrode has a wide frequency range (IOH2
~7kHz) can be selected to any desired frequency value.

Embodiments of the present invention will be described below with reference to the drawings.
Referring specifically to FIG. 5, a probe 10 is shown that can be easily placed within an epithelial cavity 11 of a subject. In use, this probe 10 electrically interacts with a second probe 12 selectively placed within a blood vessel 13 to measure the impedance of the pair 114 between these two probes.

The basic premise of the present invention is that the magnitude of the electrical impedance of tissues provides a direct indication of whether their Mi tissues are in a healthy or pathological state. Therefore, the technology of the present invention can be applied to the lungs, for example.
Very useful for the diagnosis of most epithelial carcinomas such as colon/rectum, cervix, pancreas, pouch, oropharynx, nasopharynx, cavity, urethra, calyx, trachea, gallbladder, bile duct, and small intestine. It is believed that there is.

As best shown in FIG. 2, probe 10 includes first and second annular metal electrodes 16 and 17, which are connected to first and second insulating cylinders 18.
and 19, and is integrally assembled with the insulating tip 20. The insulating tip 20 is generally conical and is affixed to the circular side surface of the first electrode 16 . The opposite side surface of the first electrode is fixed to the end wall surface of the insulating cylinder 19. Similarly, the second electrode 17 has one side wall fixed to the end wall of the insulating cylinder 19 and the other side wall fixed to the end wall surface of the first insulating cylinder 18.

The electrodes 16 and 17 are assembled together with the insulating cylinder 18, 19 and the tip 20 into an integral cylindrical body;
The outer surface of this cylindrical body is smooth. A rod-shaped member 21 is inserted through the holes coaxially arranged in the insulating cylinder and the electrode, and the inner part of the rod-shaped member 21 is embedded in the tip part 20.

A first lead wire 22 extends along the rod-shaped member 21, and one end of the rod-shaped member 21 is electrically conductively fixed to the inner portion of the electrode 16. A member 21 is attached to the outer side of the cylindrical body 18.
0, a second lead wire 23 extends along the opposite side,
The inner end of this lead wire 23 is electrically conductively fixed to the inner surface of the electrode 17.

Leads 22 and 23 are wrapped with member 21 in a smooth insulating sheath 24 to protect the surrounding tissue when the probe is being inserted into and removed from the subject. Preferably.

Although other materials may be used to make the probe 10, to date the best method has been achieved by making the annular electrodes 16 and 17 from roots and coating them with silver chloride (AgCj!). Results are being obtained. This coating increases the surface area of the electrode by a factor of approximately 10,000, thereby
This reduces the problem sometimes referred to as ``electrolyte decentralization impedance'', which will be discussed in more detail below.

For this purpose, the barrel 18, 19 and the tip 20 are preferably made of molded or machined synthetic resin that is a good electrical insulator, non-toxic, and can be made very smooth. Suitable materials include nylon and a plastic sold under the trade name Delrin.

The second probe 12 is preferably made in the same manner as the probe 10, and has a pair of highly conductive cylindrical bodies separated by an insulating member.

Probes 10 and 12 have dimensions appropriate for their ultimate use. That is, the probe may be relatively small if placed intravenously, whereas it may be correspondingly large if placed, for example, in the colon.

Biological tissues, such as tissue 14, are generally comprised of semi-solids and liquids that act as electrolytes in terms of their electrical properties. The interface between the electrolyte and the electrodes gives rise to a so-called bridge polarization impedance in the event of a current flow, which can have a value that causes significant errors in the impedance measurements of the membrane, so its compensation or removal must be done. Silver chloride coating of the electrode substantially lowers the electrolyte impedance by increasing the surface area of the electrode (eg, by a factor of about 10,000). However, even with such a coating, the tissue impedance
In the case of electrode measurements (e.g., when measuring impedance by passing a current through the tissue between two electrodes), one technique for compensating for electrolyte impedance cannot satisfactorily solve the problem of electrolyte impedance. There is a method using a four-electrode method, and this general method is adopted in the present invention. For a detailed discussion of the theoretical aspects of this common technique, see
Biological Engineering 1972, No. 1
See the article entitled "Operational Amplifier Four-Electrode Impedance Bridge for Electrolyte Measurement" by C.D. Ferris and Donald Earl Rose in Vol. 0, pp. 647-654.

Reference is now made to FIG. 1 to describe the electrical controls and tissue impedance measuring device used with probe 10 and working electrodes 16,17. Programmable oscillator 25 may be selectively variable to provide a test voltage in the range of 10 Hz to 7 kHz. This oscillator 25
The AC output of is applied to the bridge transformer 26. This bridge transformer 26 is arranged between predetermined ones of the probe electrodes.
It is connected to apply a selected oscillation voltage signal via a switch circuit 27 and a bridge amplifier 28. This point will be explained in detail later.

Furthermore, the switch circuit and bridge amplifier connect the electrodes of the two probes 10 and 12 to first and second programmable impedances 29 and 30.

Since biological & II fabrics do not exhibit electrical impedance characteristics, their programmable impedance is R1/
It is represented by the symbols CI and R2/C2.

Figures 6A and 6B illustrate first and second circuit configurations, respectively, used to perform two-stage tissue impedance measurements. In the first stage circuit, the oscillating voltage signal from the bridge transformer 26 is applied to electrode 1 of the probe 10.
7 (which is what we call the "working" electrode), in which case electrode 16 (the "measuring" electrode) is supplied as one input to the differential amplifier 31. The other terminal of transformer 26 is connected to one common point of a parallel programmable resistance-capacitance arrangement, denoted rR1/CIJ, whose resistance-capacitance Me! Other common features of the structure are ground and connection to the working electrode of probe 12.

The other electrode of the probe 12, the measuring electrode, acts as a second input to the differential amplifier 31. The other terminal of the transformer is connected to another amplifier 32. The amplification factors of amplifiers 31 and 32 are the same. amplifier 31
The signal outputs of and 32 are fed to a differential amplifier, the Brifuji amplifier.

The first stage measurements give a first approximation of the tissue impedance, which is the programmed value of rR1/CIJ when the bridge circuit is balanced.

During this measurement, virtually no current flows through the m-weave 14, eliminating the possibility of errors arising from electrolyte polarization impedance.

When the first stage measurement is completed, the phycrocomputer 33
(FIG. 1) performs the replacement of a second set of programmable impedances R2/C2 for probes 10 and 12 via switch circuit 27, i.e., R2/C2.
One common point of C2 is connected to the ground point of R1/CI. The other common point of R2/C2 is connected to one input terminal of an amplifier 31, the other input terminal of which is grounded. R2/C2 is adjusted under the control of the microcomputer, and then R2/C2 is adjusted.
A value of 2 represents a precise measurement of tissue impedance after the bridge circuit is balanced.

The second step of balancing rR2/C2J relative to rR1/CIJ acts to neutralize the distributed impedance associated with wiring, external devices, and circuit power supplies.

To further discuss overall system operation, the unbalanced bridge amplifier signal is peak sensed at 38 and converted to digital form in an analog-to-digital converter 39 for input to the microcomputer. The computer continues to run the bridge until the bridge is balanced as indicated by the digital value returned by the A/D converter.
“Automatically adjust the value of R1/CIJ!11. Then, in the second step, the adjusted value of R1/CI is adjusted to balance the bridge, and the final value of R2/C2 is &
lI Ori Ifinpedance Ru.

As shown, the operations are preferably performed under the control of a microcomputer 33, which includes a disk drive 34, a cathode ray tube display 35 (CRT), a keyboard 36, a printer 37, etc. peripheral devices. The values of R2/C2 and R1/CI are changed automatically to achieve a highly accurate two-step measurement of tissue impedance. One output frequency can be selected or the computer program can specify another frequency or a continuous set of frequencies desired for impedance measurements. A graphical representation of the measured tissue impedance values can be displayed on the CRT 35 and printed out at 37 in the desired B format.

FIG. 7 is a graph showing a number of impedances obtained over an extended frequency range of test voltages for various test objects. The solid line shows the results of measurements made on test animals & tissues that have an innate resistance to abnormal tissue growth and are not found to be pathological; It was injected 14 times and was therefore concluded to be "healthy" tissue. On the other hand, the dashed line is
It shows tissue impedance values obtained from test animals that were injected with DMH (dimethylhydrazine), a known carcinogen, 14 times per week, in this case after the majority of these animals had been injected for 26 weeks. A tumor developed. As the graph clearly shows, the volume of healthy &11 tissue is substantially greater than the volume of &Il tissue, which would in fact develop a tumor. Measurements of electrical resistance alone taken at the same time interval showed no significant changes.

The use of DMH in laboratory animals is generally accepted as a model for colon cancer, which resembles naturally occurring cancers in humans. On this point, see N. Sanha in Cancer Research, Vol. 33, p. 940 (1973).
See comments by E.E. Deshna, E.H. Stonehill, and M. Rivkin.

The graph in FIG. 7 shows the average value (solid line) of the measurements for 10 different test subjects compared to the measurements obtained from the same number of test subjects injected with DMH. This result clearly shows that healthy tissue has a substantially larger and more defined volume than that of tissue that would be abnormal.

Microcomputer 33 used in the embodiment of the present invention
is a single-board microcomputer manufactured by Ampoule Computer Co., Ltd., which achieved the above functions under the control of the following program.

-Q ω d e d (se d (d d <(((((-
-ku-ichiro. (d (((k #Ro←Ro←Ro←
RO←RO←RO←RO←ROI+Σ←RORO ψψ−RO←RO←
←mouth
C11! +1 (se fJ gψ−ψ−Lee ← Ro Ro Ro 00 Ro Ro Ro Ro. Horn's W w MF w ′+ePw w Ma! Blue size ωC
JL) 0 mouths + 1 mouth! Roro (-(1)-to-coro
- In. The size of 17'3 Rolo 0 Rorororororo 0 Rorororo ■ Roro. (b)Q
of. 0χ
ΩCψ! -1, J -1<ce-111 (JC J 44
< e (e口X龜parentMM(-, J,!-0u ce
(H's ψmeψψ←mouthψiψmeichiro←ro←mouth←X(1)■
rroro←mouth ψsuψ−ro←mouthe m m se -ae
(ψ−se (g g L) dsu−ψ−ψ←−low 2−ψ−(<<<υbeψ−1 to the gate ωto cloud■low edge of the Qto~■to 0− Mak@to (1) ■Small hit to low-
Hehehe~hehe~he 0sososososososooriri! Masunbeak! Size!
! Size! Iriiri 17) -1+1 +m--+m--+
1-+1-+ +m-+-1-1-m-+-1+1-+
1 +-1+1 +1 +-1+-1-+1 +-1+
-1+-1- Ro Ro Ro 0 0 − Ro Ro 0 0 dimension Dimension Q ω L>
Ma beak! Ma.

In ■ Heguchi L) l - 曾TO Dimensions 1 a ■ ト
■Mouth.

e) 0 00 mouth Ro Ro Toro Q
-〇So JIQR-Gln III r9
1F1641υ4:tiU
loa enυXA BEQ NXT3 EX JMP AGN3 READ BRIDGE VALUE 0P LDA $C302 STA $4017 BRIDGE VA
LLIETS Ninety percent of human cancers originate in the epithelium.

Epithelial cells tend to line hollow organs or line tissue canals. Many of these organs can be examined endoscopically. For example, sac tissue can be accessed using a cytoscope, the lungs can be accessed using a bronchoscope, and the stomach can be accessed using a gastroscope. It is reasonable to expect that impedance studies could be performed with a simple modification of placing a probe at the end of these instruments, and that capacitance measurements could be made within the patient's body at the risk of developing cancer in different organs. sell. Therefore, the above-described devices and methods are of great significance for early detection of precancerous changes in many tissues, and have a significant impact on cancer mortality.

The techniques described above are of particular value in reducing mortality from colon cancer. A colonoscope or sigmoidoscope modified to implement the probe of the invention can measure the volume of the colonic or rectal mucosa within a patient, and recommendations can be made based on these studies. Currently, patients undergo colectomy (removal of the affected portion of the intestine) based on the presence of dysplasia (abnormal cells) or cancer. These changes often occur slowly, and advanced cancers that are incurable may be discovered at the time of surgery. Because changes in mucosal capacitance precede histological changes by months or years, secondary prevention may indeed be possible.

[Brief explanation of the drawing]

FIG. 1 is a schematic diagram showing a measuring electrode and a working electrode connected to a control and processing device; FIG. 2 is a cross-sectional view showing an impedance probe of the invention with two measuring electrodes and a connecting lead; 3 and 4 are cross-sectional end views taken along lines 3-3 and 4-4 of FIG. 2, respectively, and FIG. 5 shows the probe at a predetermined location within the body under test. FIGS. 6A and 6B are respectively schematic diagrams showing two stages for measuring tissue impedance; FIG. 7 is a fragmentary inverted view showing the electrodes; FIG. It is a graph showing the average value of the measured Mi weave impedance values. In the drawing, 10.12 is a probe, 14 is a tissue, 1
6.17 is an electrode, 22.23 is a lead wire, 25 is a programmable oscillator, 26 is a bridge transformer, 27 is a switch circuit, 28 is a bridge amplifier, 29.30 is a programmable impedance, R1, Cl5R2, and C2 are programmable resistors.・Capacitance circuit, 31 indicates a differential amplifier.

Claims (1)

[Scope of Claims] 1. An apparatus for measuring epithelial tissue impedance within a subject, comprising: first and second annular electrodes spaced apart by an intervening insulating member; a second probe having first and second lead wires each having one end connected to the first and second annular electrodes, and third and fourth electrodes having the lead wires connected to the first and second annular electrodes; and an epithelial tissue impedance within the body to be examined, comprising bridge circuit means connected to the lead wires of the first and second probe electrodes for measuring the electrical impedance of the epithelial tissue between the probes. A device for making measurements.