the essential features of the invention are a probe with two measuring electrodes separated by a control electrode , suitable equipment for measuring the electric impedance in the desired frequency range , and an amplifier with adjustable amplification capable of maintaining the chosen control signal , derived from the potential of one of the measuring electrodes at the control electrode without loading said measuring electrode , i . e . the amplifier must have high input impedance and low output impedance in the frequency range used . the control electrode is following the potential of one of the measuring electrodes by multiplying the signal of the amplifier with a complex number in which the real and imaginary parts are optimized for each application . with the amplification factor set to zero , the system assumes the special case of signal ground at the control electrode . in this special case the system behaviour is similar to the system in the prime case of fig1 described in the ep publication no . 0 315 854 ( application no . 88118083 . 0 ), where one electrode is always connected to signal ground . however , the intermediate electrode of said system is not actively driven by an amplifier as in the present invention but is galvanically connected to signal ground . according to the present invention any control signal different from zero ( the amplitude may be less than , equal to , or larger than the amplitude supplied to the measuring electrodes ) will modify the depth penetration within a range determined by the shapes , sizes and distances of the electrodes and the properties of the tissue under test . the present amplifier of course can also be set to signal ground whereby the function signalwise corresponds to the previously known apparatus . however , said feature is outside the scope of the present invention . the electrodes may be configured in concentric , linear , iterated linear or any topological way compatible with the essential features . additional electrodes carrying guard , signal ground , driven guard , etc . may be required to optimize operation depending on the application . cabling and shielding must be in accordance with established engineering practice in order to minimize electromagnetic interference . for use on humans , design may have to conform to local safety regulations . it is important to limit excitation amplitude in order to minimize non - linearities inherent in living tissues . the amplitude supplied to the electrodes should be no more than a few tens of millivolts , preferably below 50 millivolts and more preferably about 25 millivolt . higher amplitudes produce unreliable results . working on wet mucous membranes does not require any special preparations . if deeper layers of the skin ( stratum corneum and down ) are to be investigated , the dry surface of the skin is preferably inundated with a salt solution of physiological concentration . the capability of the control electrode to vary depth penetration is , as stated above , limited by the shapes , sizes and distances of the electrodes as well as the properties of the tissue under test . for a large range of depths a variety of probes of different sizes may thus seem necessary . however , a generalized probe can be achieved by adding a number of electrodes which are switched into different functions according to fig9 b . the dominating factor determining depth penetration is distances between electrodes ; the basic theory has been expanded by roy et al ( roy , a . & amp ; apparao , a . : depth of investigation in direct current methods . geophysics , vol . 36 , no . 5 , 1971 , pp 943 - 959 ; roy , k . k . & amp ; rao , k . p . : limiting depth of detection in line electrode systems . geophysical prospecting , 25 . 1977 , pp 758 - 767 ) for a number of electrode configurations . it is , of course , still essential that the path of the measured test current is kept from the immediate surface of the probe by driving the virtual control electrode according to the present invention . when choosing a certain pair of measurement electrodes , i . e . the center electrode and the most distant of the activated rings , all ( minimum one ) electrodes in between are connected together to form the virtual control electrode . distances between electrodes may be the same or vary in a non - linear way to achieve e . g . stepwise increase of penetration with a fixed factor . with the generalized probe coarse depth penetration is thus selected by switching electrodes of the probe , and fine adjustment of penetration as well as facilitating measurements on wet surfaces are achieved by driving the virtual control electrode to the proper potential . the switches may be mechanical or electronic and may be manually operated or under computer control . for achieving maximum penetration depth , the best mode is thus to use the center electrode and outermost ring as measurement electrodes and using the rings in between , connected together , as a control electrode , and driving this virtual control electrode with a potential derived from the potential of one of the measurement electrodes in the same way as described above . if the application is such that optimum results would come from a lesser depth penetration , the best mode would be to use another ring as one of the measurement electrodes , leaving the outer ring or rings unconnected and using the ring or rings between the outer electrode and selected second electrode , connected together , as the control electrode . in fig1 is shown a block diagram illustrating the principle of measurement employed in a preferred embodiment of the present invention . two measuring electrodes a and c are separated by a third electrode , the control electrode b . control electrode b will be actively held at a given potential by a controllable amplifier f , amplifier f also receiving an input reference signal from electrode a using a high impedance input terminal and supplying said control electrode b via a low impedance output terminal so that said control electrode b will track said electrode a but with a signal level ensueing from the transfer function of the amplifier f . measuring electrodes a and c are connected to a standard instrument for impedance measurement im . fig2 a and fig2 b illustrates a preferred embodiment of the tip end of a measurement probe for studies of irritation on i . e . oral mucosa and skin . said probe consists of the electrodes a , b and c , each electrically isolated from the other , in a coaxial arrangement and presents as depicted in fig2 a , a plane surface containing respective electrodes a , b and c and the isolating material 1 . fig3 b and fig3 c are showing the respective embodiments of an open linear , iterated structure which can be used according to the invention . the structure of fig3 c involves a simplified feature , within the scope of the invention sufficient in some applications . the invention relates to a device for depth - selective , non - invasive , local measurement of electric impedance in tissues such as preferably skin , mucous membranes and integuments of organs in or from humans or animals in vivo or in vitro comprising a probe with concentric electrodes , the size of which is depending upon desired maximum depth penetration . the electrodes comprise a central electrode being one of two measuring electrodes , and the central electrode being surrounded by a control electrode which is following the potential of the central electrode by multiplying the signal of one of the measuring electrodes by a complex number in which the real and imaginary parts are optimized for each application . the control electrode is surrounded by a second measuring electrode . the essential part of the probe , except for the contact surface , is surrounded by conductive material at signal ground or following the potential at the central electrode by a factor of one . all conductive parts are separated by stable isolating material and all electrodes and isolating material on the contact surface arranged in one plane , concave or convex surface to fit the surface of the test site with minimum liquid wedge . the device is further provided with suitable equipment for measuring impedance at a limited number of frequencies , these frequencies determined in pretests for a certain application by a wide scan of frequencies and plotting of nyquist or bode graphs . for measurement of irritation , impedance values at two frequencies , one in the range several hundred khz to several mhz , and one in the range 1 khz to 100 khz , will work . the major information comes with the lower frequency , the impedance at the higher frequency is used to normalize the geometrical definition of the tissue under test . for convenience , an irritation index defined as the quotient between the absolute value at 20 khz and the absolute value at 1 mhz has been introduced . phase is not included in this irritation index . see fig4 : simple irritation model . a decrease in irritation index means increased irritation . for depth selectivity the signal of the control electrode is optimized when the real part is a number between 0 . 01 - 10 and the imaginary part as close to zero as possible for the transfer function of the amplifier f in the used frequency range . high frequency ( hf ) is coupled capacitively through cell membrane to cell interior . ten voluntary test persons were exposed to three different liquid substances ( sodium chloride , sodium lauryl sulphate and phosphoric acid ). exposure time was 5 minutes for nacl and h 3 po 4 (- 5 to 0 in graph ) and 10 minutes for sls ( however plotted between - 5 and 0 in graph , for uniformity of nominal value ). electrical impedance was measured through the cheek , with a small electrode on the inside of the cheek at the site of irritation , and a large electrode on the outside of the cheek , thus creating a conical field yielding highest electric current density at the inside . impedance information is thus dominated by events at the inside , however somewhat occluded by artifacts occurring in intercepted regions of muscular tissue and skin . not suitable for diagnostic purposes , since averages from a number of test persons are necessary to obtain significant results . with the method impedance from the skin of the cheek as well as muscular layers are involved , and averages of data from ten or more test persons are required to see any significant changes , i . e . the prior method is not suitable for diagnostic purposes , and indeed not many mucous membranes are available from two sides non - invasibly . by the measurement according to the invention artifacts from muscular tissue and skin are eliminated , since the device measures to a controlled depth of the oral mucosa . the results are stable and it is easy to follow the course of events on one single person , i . e . the method is well suited for diagnostic purposes . the graph shows result from 30 minutes exposure (- 30 to 0 in graph ) to sodium lauryl sulphate , with a pause of approximately 15 seconds half way ( at - 15 in graph ) to measure that point . after 12 hours irritation index is back at normal levels . maximum irritation of this substance on this test person was reached 15 minutes after cessation of exposure . with the device according to the invention it is possible to measure non - invasively from the surface of any mucous membrane which can be reached from one side . in the case of oral mucosa , artifacts from skin or muscular tissue are eliminated , and it is possible to follow irritation processes on single persons with high accuracy . voluntary test persons were exposed to patch test on back . sodium lauryl sulphate of different concentrations was applied for 24 hours in finn chambers . irritation was measured according to the invention and assessed according to standard procedures by a trained dermatologist ( scale 0 .. 3 , interior labels in graph ). there is good correlation between irritation index and concentration for all concentrations , despite the fact that the trained dermatologist could not discern any irritation at the lower concentrations ( marked 0 in the graph ). with the claimed invention it was possible to detect irritation effects not visible to a trained dermatologist ( points marked 0 in fig7 ). absolute value of electrical impedance at 20 khz was measured on the intact surface of a rat kidney , still in function . at the same time arterial pressure was measured with a sensor implanted in the supporting vessel . consecutive blood pressures were induced by choking and releasing the supporting artery . impedance correlated well with pressure , with a delay of approximately 15 seconds . graph shows sequence of events . autoregulatory mechanisms of the kidney are not demonstrated explicitly with this type of plot . the device according to the invention has been tried for measurement of electric impedance on intact kidney of rat in vivo , the kidney being exposed to changes in blood circulation and pressure . there is significant correlation between pressure and value of measured impedance , the correlation being higher at 20 khz ( fig8 ) than at 100 khz . thus , the device according to the invention may be useful to detect ischemic states during e . g . transplantational surgery . as the behaviour of the eye seems similar to the kidney when it comes to tissue changes in the surface due to internal pressure , the invention may be useful for diagnosis of glaucoma .
a device and method for noninvasive depth - selective detection and characterization of surface phenomena in organic and biological material such as tissues by surface measurement of the electrical impedance of the material . the device includes a probe with a plurality of measuring electrodes separated by a control electrode . measuring equipment measures impedance in a desired frequency range . an adjustable amplifier maintains a chosen control signal derived from the potential of one of the measuring electrodes at the control electrode without loading the measuring electrode . depth selectivity is achieved by controlling the extension of the electric field in the vicinity of the measuring electrodes by the control electrode actively driven with the same frequency as the measuring electrodes .