Probe and method of use for detecting abnormal tissues
This is a division of application Ser. No. 790,491, filed Oct. 23, 1985. 
    
    
     The present invention pertains generally to the detection of the presence of and tendency toward abnormal tissue growth and, more particularly, to a probe and method of use of the probe for the detection of abnormal tissue and an early indication that tested tissue will become abnormal. 
     BACKGROUND 
     The term &#34;abnormal tissue&#34; as used herein refers to all forms of tissues which have undergone malignant induction such that these tissues may eventually show loss of growth control which is frequently referred to as cancerous or tumorous growth. The detection of the presence of such abnormal tissues is often made difficult because they are located within the body so that until discomfort or other symptoms are experienced by the individual, the existence of the abnormal tissues may not even be suspected. Additionally, procedures for early detection can be so expensive and complex as to make their use restricted. Therefore, it would be highly advantageous to be able to detect quickly and simply the presence of abnormal tissue or ideally the eventuality of abnormal tissue growth within a body cavity of the host, for example, and preferably the technique should be minimally invasive. 
     Many forms of cancers or tumors require extended periods of time to achieve a size detectable or injurious to the host, and in some cases this may take many years. Treatment at the present time is considerably more effective when the abnormal tissues are in their early phases and long before they have achieved growth sufficient to cause discomfort or produce symptoms. It would, therefore, also be advantageous to be able to detect the presence of abnormal tissues in their early phases or to detect the tendency for tissues to become abnormal. 
     Several research efforts have been directed toward discovering the relationship between the electrical impedance of biological tissue and its condition or health. For example, U.S. Pat. No. 3,949,736 discloses that the impedance of biological tissues can provide a useful indication as to whether tissues are healthy or diseased. Specifically, this patent suggests that changes in impedance of biological tissues can be used as a technique for diagnosis of certain carcinomas. According to this patented technique, a low level electric current is passed through the investigated tissue with measurement of the voltage drop across the tissue providing an indirect indication of the overall tissue impedance (i.e., resistance and capacitance). Also, according to this patent, increase in the impedance of the tissue is associated with an abnormal condition of the cells composing the tissue and indicative of a tumor, carcinoma, or other abnormal biological condition of the tissue. 
     SUMMARY OF THE DISCLOSURE 
     A probe for use in effecting measurements of tissue impedance consists of first and second conductive rings unitarily arranged with an insulative member separating the rings. The conductive rings, one a measuring and the other a working electrode, are generally coaxially arranged and have individual lead wires connected thereto which extend from one end of the probe for connection to external processing and measuring equipment. 
     A second probe, which may be constructed in the same manner as the first probe, has electrodes each consisting of annular conductors mounted within an elongated insulative tubular member substantially smaller than the probe, and, in particular, are of a size and shape enabling their receipt within a blood vessel, for example. 
     In use, the first probe containing one set of electrodes is inserted within an epithelial cavity (e.g., the colon) and located at a test position through the use of an endoscope. Then the second probe is passed along a suitable blood vessel which may be located adjacent to the wall of the tissue defining the epithelial cavity within which the first probe is located. Optionally, the second probe may be located in the skin (either intradermal or subcutaneous), on the skin outer surface, or within a relatively remote blood vessel. An alternating test signal is then applied to the working electrodes of each probe and measurements are taken between the two sets of measuring electrodes determining the impedance of the cavity wall tissue lying between the two probes. 
     The external measuring and processing system consists of a microcomputer which automatically controls a programmable impedance (resistance and capacitance) for balancing with the measured impedances between the probes, and displaying onto a CRT or other suitable output display device the information obtained. The AC input to the working electrodes is selectable to any desired frequency value over an extensive frequency range (10 Hz-7 KHz). 
    
    
     DESCRIPTION OF THE DRAWING 
     FIG. 1 is a schematic view of the measuring and working electrodes shown interconnected with control and processing equipment. 
     FIG. 2 is a side elevational, sectional view of an impedance probe of the present invention having two measuring electrodes and interconnecting lead wires. 
     FIGS. 3 and 4 are end elevational, sectional views taken along the lines 3--3 and 4--4 of FIG. 2, respectively. 
     FIG. 5 is a side elevational, partially fragmentary view showing the probe and working electrodes in place within the body of the individual. 
     FIGS. 6A and 6B show, respectively, electrical circuit schematics of the two stages for measuring tissue impedance. 
     FIG. 7 is a graph of average tissue impedance measurements taken with the described probe and control and processing equipment. 
    
    
     DESCRIPTION OF A PREFERRED EMBODIMENT 
     Turning now to the drawings and particularly FIG. 5, there is shown a probe 10 to be more particularly described which can be readily located within an epithelial cavity 11 of a test subject. The probe 10 in use electrically interacts with a second probe 12 selectively positioned in a blood vessel 13 to measure the impedance of the tissues 14 lying between the two probes. 
     As has been alluded to generally, and as will be more particularly described later herein, it is a basic premise of the present invention that the magnitude of electrical impedance of the tissues provides a direct indication as to the health or diseased condition of these tissues. It is believed, therefore, that the described techniques will be highly useful in the diagnosis of most epithelial carcinomats such as lung, colon/rectum, cervix, pancreas, bladder, oro-pharynx, naso-pharynx, vagina, urethra, renal calyx, trachea, gall bladder, bile ducts, and small bowel, for example. 
     As can be seen best in FIG. 2, the probe 10 includes first and second annular metallic electrodes 16 and 17 unitarily assembled with first and second insulative cylinders 18 and 19 and an insulative nose 20. The nose is generally conical and is affixed onto a circular side of the first electrode 16, the opposite side of this electrode being secured to the end wall surface of insulative cylinder 19. Similarly, the second electrode 17 has one side wall affixed to the end wall of cylinder 19 and the other side wall secured to the first insulative cylinder end wall surface. 
     The electrodes 16 and 17 along with the insulative cylinders 18, 19 and the nose 20 are assembled into a unitary cylindrical affair, the outer surface of which is smooth. A rod-like member 21 extends through the axially arranged bores of the insulative cylinders and electrodes and has its inner end embedded within the nose 20. 
     A first lead wire 22 extends along the member 21 and has one end conductively secured to an inner part of the electrode 16. A second lead wire 23 extends along the opposite side of member 21 through the bore of cylinder 18 and has its inner end conductively secured to an inner surface of electrode 17. Preferably, the cable wires 22 and 23 are enclosed with the member 21 by a smooth insulative covering 24 to protect surrounding tissues when the probe is being inserted into and removed from the body of a test subject. 
     Although other materials may be found suitable for constructing a probe 10, best results to date have been obtained by making annular electrodes 16 and 17 from silver which is coated with silver chloride (AgCl 2 ). This coating increases the electrode surface area approximately 10,000 times which reduces a problem sometimes referred to by the term &#34;electrolytic polarization impedance&#34; to be discussed in detail later herein. 
     The cylinders 18, 19 and the nose 20 are preferably constructed of a molded or machined synthetic plastic which is non-toxic, a good electrical insulator and can be brought to a highly smooth condition. Suitable materials for this purpose are nylon or the plastic sold under the commercial designation Delryn. 
     The second probe 12 is preferably constructed in the same manner as probe 10 with a pair of highly conductive cylinders separated by insulative members. The probes 10 and 12 are of a size commensurate with their ultimate use location. Thus, if contemplated for intravenous disposal, they are relatively small, whereas if considered for emplacement within, say, the colon, they can be correspondingly larger. 
     Biological tissue such as tissue 14 consists generally of semisolids and liquids which from the standpoint of their electrical characteristics act as electrolytes. The interface between the electrolyte and an electrode produces a so-called electrode-polarization impedance on the passage of an electric current therethrough, which can be of such magnitude as to impose a serious error in any tissue impedance measurement, and, therefore, compensation or elimination must be provided. The electrode silver chloride coating by increasing the electrode surface area (e.g., approximately 10,000 times) substantially reduces the electrolytic impedance. However, even with this coating the electrolytic impedance problem cannot be satisfactorily solved in 2-electrode measurement of tissue impedance (i.e., measuring the impedance by passing current through tissues lying between two electrodes). One approach to compensating for electrolytic impedance is to adopt a 4-electrode system, and this general scheme is adopted here. For a detailed discussion of theoretical aspects of this general approach reference is made to the article entitled, &#34;An Operational Amplifier 4-Electrode Impedance Bridge for Electrolyte Measurements&#34; by C. D. Ferris and Donald R. Rose in Medical Biological Engineering, Volume 10, pages 647-654, 1972. 
     For the ensuing discussion of the electrical control and tissue impedance measurement equipment used with the probe 10 and work electrodes 16, 17, reference is now made to FIG. 1. A programmable oscillator 25 is selectively variable to provide test voltage in a range from 10 Hz-7 KHz. The alternating current output of oscillator 25 is applied to a bridge transformer 26 which is interconnected through a switch network 27 and bridge amplifier 28 to apply the selected oscillating voltage signal across certain of the probe electrodes as will be discussed in detail later. In addition, the switch network and bridge amplifier interconnect the electrodes of the two probes 10 and 12 with first and second programmable impedances 29 and 30. Biological tissues do not exhibit electrical inductance characteristics, and, therefore, the programmable impedances are further identified by the schematic representations &#34;R1/C1&#34;, &#34;R2/C2&#34;. 
     FIGS. 6A and 6B depict, respectively, first and second circuital arrangements used to accomplish what is a two stage tissue impedance measurement. In the first stage circuit, one side of the oscillating voltage signal from the bridge transformer 26 is applied to electrode 17 of probe 10 (which may be termed a &#34;working&#34; electrode) while the electrode 16 (a &#34;measuring&#34; electrode) is fed as one input to a differential amplifier 31. The other terminal of transformer 26 is connected to a common point of the parallel programmable resistance-capacitance arrangement identified as &#34;R1/C1&#34; the other common point of which connects with electrical ground and a working electrode of probe 12. The other, a measuring electrode of probe 12, serves as a second input to differential amplifier 31. The transformer other terminal is fed to a further amplifier 32. The amplification factors of amplifiers 31 and 32 are the same. The signal outputs of amplifiers 31 and 32 feed into bridge amplifier 28, also a differential amplifier. 
     The first stage measurement provides a first order approximation of the tissue impedance which is the programmed value of &#34;R1/C1&#34; when the bridge circuit is balanced. It is of particular importance to note that in making this measurement virtually no current passes through the tissue 14 and, therefore, the possibility of an error from electrolytic polarization impedances is obviated. 
     On conclusion of the first stage impedance measurement, the microcomputer 33 (FIG. 1) effects via switch network 27 a substitution of a second set of programmable impedances, R2/C2, for the probes 10 and 12. More particularly, one common point of R2/C2 is connected to the grounded common of R1/C1. The remaining common point of R2/C2 is fed into amplifier 31, the other input being grounded. Adjustment of R2/C2 is then made under control of the microcomputer following which the value of R2/C2 represents a precise measurement of the tissue impedance after the bridge circuit is balanced. 
     The second stage of balancing &#34;R2/C2&#34; against &#34;R1/C1&#34; acts to neutralize distributed impedances associated with cabling and internal equipment and circuit sources. 
     Still further as to overall system operation, unbalanced bridge amplifier signals are peak detected at 38, and converted to digital form in the analog-to-digital converter 39 for insertion into the microcomputer. The computer, in turn, automatically adjusts the values of &#34;R1/C1&#34; until the bridge is balanced as indicated by the digital value returned by the A/D converter. Then, in the second stage the adjusted value of R1/C1 is maintained and R2/C2 is adjusted to bridge balance with the final value of R2/C2 being the tissue impedance. 
     As shown, operation is preferably under the control of a microcomputer 33 which may have a conventional set of peripherals, such as disc drive 34, cathode ray tube display 35 (&#34;CRT&#34;), key board 36, and printer 37. The values of R2/C2 and R1/C1 are automatically changed to achieve the highly accurate two-stage measurement of tissue impedance. A single output frequency of oscillator 25 can be selected by inserting a proper command via keyboard 36, for example, or the computer program can specify another frequency or consecutive set of frequencies desired for impedance measurement. Also, a graphical representation of tissue impedance values measured can be displayed at the CRT 35 and printed out in desired manner at 37. 
     FIG. 7 is a graph showing a number of impedance traces taken of various test subjects and over an extended frequency range of test voltage. The straight line traces are measurements made of test animal tissues with inbred resistance to abnormal tissue growth not otherwise known to be diseased, and which animals had been given fourteen (14) weekly injections of physiological saline, and, therefore, are concluded to be &#34;healthy&#34; tissues. The dotted line traces, on the other hand show tissue impedance values obtained from test animals which had received 14 weekly injections of DMH (dimethylhydrazine) a known carcinogen, the majority of which animals develop tumors after twenty-six (26) weeks of injections. As the graph clearly shows, the capacitance of healthy tissues is substantially greater than that of tissues which will eventually develop tumors. Measurements of electrical resistance alone at the same intervals have shown no significant change. 
     The use of DMH in laboratory animals is generally accepted as a model of large bowel cancer similar to spontaneously occuring cancer in man. See in this connection the comments of N. Thurnherr, E. E. Deschner, E H. Stonehill, M. Lipkin, in Cancer Research, Volume 33, page 940 (1973). 
     The graph of FIG. 7 depicts the average values of ten (10) different test subject measurements (straight line) as compared with traces taken for the same number of test subjects injected with DMH. The results clearly show that healthy tissue has a substantially greater and definable capacitance than that of the tissues which will become abnormal. 
     A microcomputer 33 used in a practical construction of the invention is a single-board microcomputer manufactured by Apple Computer and accomplished the described functions under control of the following program: ##SPC1## 
     Ninety (90) percent of human cancers are of epithelial origin. Epithelial cells tend to line hollow organs or line the ducts of glandular tissue. Many of these organs are amenable to examination with endoscopes. For example, the bladder is accessible by a cytoscope, lungs by a bronchoscope, stomach by a gastroscope and so on. It is reasonable to expect that impedance studies can be carried out by simple modifications of these instruments placing a probe at the end of the instrument, so that measurements of capacitance can be made in patients at risk for cancer development in the different organs. The described apparatus and technique, therefore, has far reaching implications in the early detection of premalignant changes in many tissues and, as a result, have a major impact on cancer death rates. 
     The described techniques would be especially valuable in reducing death rates from large bowel cancer. A colonscope or sigmoidoscope modified to carry a probe of this invention can measure the capacitance of the colonic or rectal mucosa in vivo (inside the patient) and make recommendations based on these studies. At the present time, a patient undergoes colectomy (removal of the diseased bowel) based on the presence of dysplasia (abnormal cells) or cancer. These changes often occur late and advanced cancers not amenable to cure may be found at surgery. It is believed that the altered electrical capacitance of the mucosa antecede the histologic changes by many months, or even years making secondary prevention in these patients a real possibility.