CA2093922C - A device for measurement of electrical impedance of organic and biological materials - Google Patents
A device for measurement of electrical impedance of organic and biological materials Download PDFInfo
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- CA2093922C CA2093922C CA002093922A CA2093922A CA2093922C CA 2093922 C CA2093922 C CA 2093922C CA 002093922 A CA002093922 A CA 002093922A CA 2093922 A CA2093922 A CA 2093922A CA 2093922 C CA2093922 C CA 2093922C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
- A61B5/053—Measuring electrical impedance or conductance of a portion of the body
- A61B5/0531—Measuring skin impedance
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
- A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
- A61B3/16—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for measuring intraocular pressure, e.g. tonometers
Abstract
A device far depth-selective, non-invasive, local measurement of electrical impedance of organic and biological materials such as tis-sues from vegetable or animal origin comprising a probe (Fig. l-3; 9a, 9b) with a number of electrodes (A, B, C) driven from an electronic control unit (F) in such a way that the electric current path defining the actual tissue under test is dependent upon a control signal. The probe is pressed toward the surface of the body part under test and by varying the control signal, it is possible to select the region under test within limits determined by the shapes, sizes and distances of the elec-erodes and the properties of the tissue under test. By means of combin-ing results obtained with different control signals, it is possible to compute local impedance profiles.
Description
V6'0 92/06b34 PCT/S E91 /00703 ,..~
A DEVICE FOR I~ASU1E2F3~t~T OF ~3~DCrF~ICAL IMPEDANCE
OF ORGANIC AND BIOLOGICAL MATERIALS.
BACKGROUND OF THE INVENTION
The present invention relates to a device for non-invasive depth-selective detection and characterizeition of surface phenomena in organic and biological systerns such as tissues by surface measurement of the electrical impedance of said mate-rial with said device as well as a method for said surface characterization.
Electrical impedance is a very sensitive .indicator of minute changes in organic and biological material and especially tissues such as mucous membranes, skin and integuments of ,."~~
organs, including changes due to irritation caused by diffe-rent reactions, and scientists all over the world have worked hard to find a convenient way to measure variations and alte-rations in different kinds of organic and biological material to be able to establish the occurrence of such alterations - .
A DEVICE FOR I~ASU1E2F3~t~T OF ~3~DCrF~ICAL IMPEDANCE
OF ORGANIC AND BIOLOGICAL MATERIALS.
BACKGROUND OF THE INVENTION
The present invention relates to a device for non-invasive depth-selective detection and characterizeition of surface phenomena in organic and biological systerns such as tissues by surface measurement of the electrical impedance of said mate-rial with said device as well as a method for said surface characterization.
Electrical impedance is a very sensitive .indicator of minute changes in organic and biological material and especially tissues such as mucous membranes, skin and integuments of ,."~~
organs, including changes due to irritation caused by diffe-rent reactions, and scientists all over the world have worked hard to find a convenient way to measure variations and alte-rations in different kinds of organic and biological material to be able to establish the occurrence of such alterations - .
which are due to different states, characteristic of irrita- ' tions from e.g. diseases.
Much of the fundamental knowledge within the current area stems from the field of electrochemistry. 1?otentiostats have for a long time been in use for studies of e.g. corrosion, and AC (alternating current) methods have gradually evolved and are well documented, cf. Claude Gabriella: Identification of electrochemical processes by frequency response analysis.
Solartron Instruments technical report number 004/83, 1984 and F.B. Growcock: What's impedance spectroscopy. Chemtech, sep-tember 1989, pp 564-572.
Excellent tools for work in this field are available, e.g.
the 1286 Electrochemical Interface,_Solartz~on Instruments, UK and the Model 378 Electrochemical Impedance Systems, EG&G
Princeton Applied Research, HJ, USA.
Characteristic features of these systems are that they are intended for use with specimens mounted in appropriate elec-trochemical cells.
It is well known that certain parameters in living tissues are reflected by electrical impedance of said tissues:
U.S.P. 4,038,975 (Aug. 2;1977) to Vrana et al. relates to an electrically instrumented method of diagnosing the presence of a neoplast in mucuos membrane samples wherein the electrical impedance of the sample has resistive and capacitive compo-1~0 92/06634 PCT/SE91 /00703 ' 2093922 nents and wherein the relative values of raid components are indicative of the presence or absence of raid neoplast by associating the sample with the terminals of a series circuit including in succession a grounded, amplitude-modulated high-frequency generator and first and second Equal-valued resis-tors wherein the impedance of the generator and the resistance of both resistors are low relative to the impedance of the sample. Said association being made by connecting a test spot on the sample to the terminal of the second resistor remote from the junction of the first and second resistors and by connecting the bulk of the sample to the grounded terminal of the generator, simultaneously measuring the amplitudes of the potentials of the test spot and of the junction of the first and second resistors with respect to a reference value es-tablished at the junction of the generato:c and the first resistor, and computing from the measured values and from the reference value the resistive and capacit:ive portions of the impedance of the test spot.
By EP 0 315 854 (Appln. No. 88118083.0) to Honna is previously known a method and a system for measuring moisture content in skin by passing "weak" low frequency electric current through the keratinous layer between two electrodes abutted upon the skin, amplifying the electric voltage appearing on the layer, rectifying and taking out signals of the .amplified output, and measuring the amplitude of the signal, which is characterized in that the voltage appearing on the keratinous layer is the voltage appearing between either one of said two electrodes V1~0 92/06b34 PCT/S E9 t /00703 whichever is closer to another electrode w',hich is abutted upon said skin at a location outside said two electrodes.
The system comprises a measuring electrode structure of triple concentric circles including a central electrode, an inter-mediate electrode and an outer electrode a:11 of which can be abutted on the skin, a generator which used one of said elec-trodes as a common electrode and supplies :Low frequency signal between this common electrode and another of said three elec-trodes; an amplifier which converts the re:~ulting current into a voltage appearing between said common elE~ctrode and yet another of said three electrodes, and a means to display the output voltage of the amplifier which is characterized in that a circuit means is provided for switching between a first cir-cuit using said intermediate electrode as common electrode and a second circuit which uses the outer electrode as a common electrode.
Further prior art is disclosed in e.g. Yamamoto, T. & Yamamo-to, Y.: Analysis for the change of skin impedance. Med. &
Biol. Eng. & Comp., 1977, 15, 219-227; Sal.ter, D.C:: Quanti-fying skin disease and healing in vivo using electrical impe-dance measurements. In: Non-invasive physiological measure-menu, Vol l, 1979, Peter Rolfe ed. , pp 21-~64; Leveque, J. L.
& De Rigal, J.: Impedance methods for studying skin moisturi-zation. J.Soc.Cosmet.Chem., 1983, 34, 419-4:28; and Morkrid, L.
& Qiao, Z.-G.: Continuous estimation of parameters in skin electrical admittance from simultaneous measurements at two Vy0 92/06634 2 0 9 3 9 ~ G PCl'/SE9l/00703 ._ ._ different frequencies. Med. & Biol. Eng. & Comp., 1988, 26, 633-640.
Characteristic of existing technology in this field is that either: a) a biopsy would have to be excised in order to well define the actual tissue under test, i.e. not suit-able for in vivo measurements; or b) electrodes are applied to the skin at separate sites, directing the electric test: current right through the skin and regarding the: inner part of the skin and deeper lying tissue as are almost ideal short circuit between the contact sites, i.e. no discrimi-nation between the layers of the rather complicated anatomy of the skin.
There are devices for measuring the water content in the outermost layers of the skin (such as the Corneometer CM820PC, Courage + Khazaka Electronic GmbH, FRG) u:>ing interdigitated electrode patterns. A device called DPM9003 from NOVA Tech-nology Corporation, Mass., USA employs a :simple coaxial elec-trode. These devices have no means for controlling the measu-rement depth except for the limitations sEa by physical size.
Indeed, they are applications of the well known principle of moisture measurement using fringing field, (tiles: Electronic sensing devices, Newnes, London, 1966/68, pp 80-81).
A device for measuring conductance of the fluids in mucous WO 92/06634 2 0 9 3 g G 2 P~/SE91/00703 membranes of the airways has been published (Fouke, J M et al:
Sensor for measuring surface fluid conductivity in vivo. IEEE
Trans. Biomed. Eng., 1988, Vol 35, No 10, pp 877-881). This paper shows, backwards, the problem encountered while measu-ring on wet surfaces without a control elecarode to enforce depth penetration.
It is possible to use Applied Potential Tomography/Electrical Impedance Tomography to obtain tomographic images of e.g.
thorax or gastric regions, employing a large number of elec-trodes around the body and computing with reconstruction algorithms an image representing changes of conductivity in the body (Seagar, A.D. & Brown, H.H.: Limitations in hardware design in impedance imaging. Clin. Phys. Physiol. Meas., 1987, Vol. 8, Suppl. A, 85-90).
According to the present invention depth selectivity is achie-ved by controlling the extension of the electric field in the vicinity of the measuring electrodes by means of a control electrode between the measuring electrodes, the control electrode being actively driven with the same frequency as the measuring electrodes to a signal level, taken from one of the measuring electrodes but also multiplied by a complex number, in which the real and imaginary parts are optimized for each application depending upon the desired depth penetra-tion. The function of the controlling field is analogous to that of a field effect transistor, well knoian from solid state physics. In biological tissue or "wet state"', conduction WO 92/06634 2 0 9 3 .9. ~ P~T/SE91 /00703 mechanisms are complicated involving a number of ions, polari-zation effects, charged or polarizable organelles, etc. How-ever, no reconstruction algorithms are needed to achieve depth selectivity, although consecutive measurements at different depths must be recorded in order to obtain a profile.
The principle is basically frequency independent, and works from DC to several MHz. Simple impedance measurements at one or a few frequencies, as well as impedance spectroscopy in this range can thus be done depth selective on e.g. skin.
In mucous membranes the fluid on the surface would normally short circuit measuring electrodes placed on the same surface;
however, by use of the control electrode 'the test current is forced down into the mucous membrane rather than taking the shortest way and local definition of the Factual tissue under test is thus achieved. These advantages a:re directely appli-cable while measuring impedance as an indicator of irritation during tests of irritants on skin and oral mucous membranes.
It was also possible to measure impedance on kidneys while at the same time measuring the blood pressure within the kidney in the main artery, and it was found that impedance descripti-ve parameters correlated well with blood ;pressure. This opens the possibility to measure pressure, as mell as microcircula-tion non-invasively in many organs during surgery by applying a probe to the surface of the organ. Another application is the measuring of pressure in the eye (diagnosis of glaucoma).
7a The invention provides a device for depth-selective measurement of electrical impedance of organic and biological material comprising:
a probe with measuring electrodes and a virtual control electrode, positioned between at least two of the measuring electrodes;
a voltage and impedance measuring means for applying an electrical potential to the measuring electrodes and for measuring the electrical impedance of the organic or biological material between the measuring electrodes;
an amplifier having a transfer function and a high-impedance input and a low impedance output, said amplifier connected between one of the measuring electrodes and the virtual control electrode to actively drive said virtual control electrode, via the transfer function of the amplifier, with a signal from said measuring electrode, wherein said transfer function is adapted to control the extension of an electrical field from the virtual control electrode and thereby the depth of the impedance measurement for all subjects under examination.
The invention also provides a generalized probe as described above, wherein the control electrode is a number of electrodes which are switchable to function as the control electrode or the measuring electrode according to the desired physical size of the active probe area so that coarse depth penetration is achieved by switching the electrodes into different functions, and fine adjustment as well as the possibility to measure on wet surfaces is achieved by driving the virtual control electrode to the proper potential.
The invention also provides a probe for measuring of electrical impedance comprising concentric or topologically 7b equivalent arrangements of electrodes in which measuring electrodes are separated by a control electrode, the distance between the measuring electrodes corresponding to desired maximum depth penetration, one of the measuring electrodes being a central electrode, and said central electrode surrounded by a control electrode, and the control electrode surrounded by a second measuring electrode; the potential of the control electrode is following the potential of the central electrode or the second measuring electrode by multiplying said potential in an adjustable amplifier by a complex number in which the real and imaginary parts are optimized for each application; the essential part of the probe, except for contact surface, is surrounded by conductive material at signal ground or following the potential at the central electrode by a factor of one, and all conductive parts 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 invention further provides a method for depth-selective, non-invasive surface characterization of organic or biological material, wherein the impedance of organic or biological materials is measured from the surface of said material by application of a device as described above.
SHORT DESCRIPTION OF THE DRAWINGS.
Fig. 1 is a block diagram illustrating the principle of measu-rement employed in an embodiment of the preaent invention;
Fig. 2a is a plane topview of the tip of a probe with two measuring electrodes separated by a control electrode;
Fig. 2b is a cross-sectional view along plane S - S of Fig.
2a;
Fig. 3a is a cross-sectional view of a probe with linear, iterated structure;
Fig. 3b is a perspective view of the tip of the probe with a linear, iterated structure, electrically eq~uvivalent to Fig.
3a;
Fig. 3c is a perspective view of the tip of a simplified structure of a similar arrangement, sufficient in some appli-cations.
Fig. 4a is an illustration of a normal tissue with closed packed cells;
Fig. 4b is an illustration of an irritated tissue showing increased intercellular space;
V1V0 92/06634 ~ p 9 3 9 2 P~/SE9i/00703 ,, Fig. 5 is a plot showing mean values in $ obtained with prior technique in measurement of irritation on oral mucosa for NaCl, H3P04, SLS;
Fig. 6 is a plot showing values in $ for one person obtained with the technique according to the inveni:ion in the measure-ment of irritation on oral mucosa;
Fig. 7 is a plot showing irritation index results of measure-ment of irritation on skin with the technique according to the invention for one person with 20 hours of exposure of material and additionally 24 hours;
Fig. 8 is a plot showing absolute value of electrical impedan-ce at 20 kHz measured on intact surface of rat kidney at consecutive values of blood pressure by stepwise choking and releasing supporting artery in vivo;
Fig. 9a is a plane topview of a generalized probe switchable into different configurations;
Fig. 9b is a cross-sectional view along plane S - S of Fig. 9a showing also switchable electrical pathways.
DESCRIPTION
The essential features of the invention are a probe with two measuring electrodes separated by a control electrode, sui-table equipment for measuring the electr~:c impedance in the ",:.'T'/S E91 /00703 W02/06634 2 0 9 3 9 2 .
desired frequency range, and an amplifier with adjustable amplification capable of maintaining the chosen control sig-nal, derived from the potential of one of tlhe measuring elec-trodes at the control electrode without loading said measuring electrode, i.e. the amplifier must have higlh 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 ampli-fier with a complex number in which the real and imaginary parts are optimized for each application. W:Cth the amplifica-tion factor set to zero, the system assumes the special case of signal ground at the control electrode. :Cn this special case the system behaviour is similar to the system in the prime case of Fig. 1 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 amp7.itude supplied to the measuring electrodes) will modify the dE:pth 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.
i~VO 92/06634 F 2 0 9 3 _9 . 2 PCT/SE9l /00703 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 regula-tions.
It is important to limit excitation amplitude in order to minimize non-linearities inherent in living tissues. The amplitude supplied to the electrodes shou7.d be no more than a few tens of millivolts, preferably below '_i0 millivolts and more preferably about 25 millivolt. Higher amplitudes produce unreliable results. Working on wet mucous membranes does not require any special preparations. If deepf:r layers of the skin (stratum corneum and down) are to be investigated, the dry surface of the skin is preferably inundated with a salt solu-tion of physiological concentration.
The capability of the control electrode to vary depth penetration is, as stated above, limited lby 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 WO 92/06634 2 0 9 3 9 2 . P~/S E9l/00703 according to Fig. 9b. The dominating factor determining depth penetration is distances between electrodes; the basic theory has been expanded by Roy et al (Roy, A. & Apparao, A.: Depth of investigation in direct current methods. Geophysics, Vol.
36, No. 5, 1971, pp 943-959; Roy, K.K. & Rao, K.P.: Limiting depth of detection in line electrode system:a. Geophysical Prospecting, 25. 1977, pp 758-767) for a nunnber 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. ste:pwise increase of penetration with a fixed factor. With the generalized probe coarse depth penetration is thus selected by switching elec-trodes 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 ~W0 92/06634 . PCfI S E91 /00703 Zo939_ electrodes and using the rings in between, connected together, as a control electrode, and driving this virtual control electrode with a potential derived from tine 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 most 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 aecond electrode, connected together, as the control electrode.
PREFERRED EMBODIMENT
In Fig. 1 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. Said control electrode B will be actively held at a given potential by a controllable amplifier F, said 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.
Said measuring electrodes A and C are connected to a standard instrument for impedance measurement IM.
WO 92/06634 2 0 9 3 9. 2 2 Iris E9 ~ ioo~o3 Fig. 2a and Fig. 2b 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 consiats of the electrodes A, B and C, each electrically isolated from the other, in a coaxial arrangement and present, as depicted in Fig 2a. a plane surface containing respective electrodes A, B
and C and the isolating material 1.
Fig. 3b and Fig. 3c are showing the respective embodiments of an open linear, iterated structure which can be used according to the invention. The structure of Fig. 3c involves a simpli-fied feature, within the scope of the invenl~ion 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 electrode,, the size of which is depending upon desired maximum depi~h penetration. The electrodes comprise a central electrode being one of two measuring electrodes, and the central electrode being sur-rounded by a control electrode which is following the poten-tial 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 i:or each applica-Lion. The control electrode is surrounded by a second measuring electrode. The essential part of l:he probe, except WO 92/06634 ~ 9 3 .9 2 G. PCT/SE91/00703 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 dlevice 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 frequen-cies and plotting of Nyquist or Bode graphs.
For measurement of irritation, impedance values at two frequ-encies, one in the range several hundred l~;Hz 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 Fig 4: 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 po:~sible for the transfer function of the amplifier F in the used frequency a W ,92/06634 2 0 ~ 3 9 2 - ~T/S E91/00703 range.
APPLICATIONS
SIMPLE IRRITATION MODEL, FIG. 4 Fig. 4a shows normal tissue with close packed cells.
Fig. 4b shows irritated tissue with increased intercellular space.
High frequency (HF) is coupled capacitively through cell membrane to cell interior.
Low frequency (LF) is confined to extracell.ular/intercellu-lar space.
Conductivity is essentially the same in int:ra- och extracellu-lar liquid.
IRRITATION ON ORAL MUCOSA, FIG. 5.
Prior Technology 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 H3P04 (-5 to 0 in graph) and 10 minutes for SLS (however plotted between -5 and 0 in graph, for unii:ormity of nominal value). Electrical impedance was measured l:hrough the cheek, with a small electrode on the inside of then cheek at the site of irritation, and a large electrode on thf: outside of the cheek, thus creating a conical field yield~Lng highest elec-tric current density at the inside. Impedance information is ~WO 92/06634 0 9 3 2 G P~/SE91/00703 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 pur-poses, since averages from a number of test persons are necessary to obtain significant results.
With said 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. said prior method is not suitable for diagnostic purposes, and indeed not many mucous membranes are available from two sides non-invasibly.
IRRITATION ON ORAL MUCOSA, FIG. 6.
According to the invention 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 diagnos-tic 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 W92/06634 0 9 3 9 7 P~'~s E9l /00703 measure non-invasibly from the surface of any mucous membrane which can be reached from one side. In the case of oral muco-sa, artifacts from skin or muscular tissue are eliminated, and it is possible to follow irritation processes on single per-sons with high accuracy.
IRRITATION ON SKIN, FIG. 7.
According to the invention 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 FIG 7).
PRESSURE IN KIDNEY IN VIVO, FIG. 8.
According to the invention 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 pres-sores were induced by choking and releasing the supporting WO 92/06634 ~ ~ ~ PCT!SE91/00703 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 int~sct kidney of rat in vivo, the kidney being exposed to changea in blood circulation and pressure. There is significant correlation between pressu-re and value of measured impedance, the correlation being higher at 20 kHz (FIG 8) 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.simila:r to the kidney when it comes to tissue changes in the surface due to internal pressure, the invention may be useful fo:r diagnosis of glauco-ma.
Much of the fundamental knowledge within the current area stems from the field of electrochemistry. 1?otentiostats have for a long time been in use for studies of e.g. corrosion, and AC (alternating current) methods have gradually evolved and are well documented, cf. Claude Gabriella: Identification of electrochemical processes by frequency response analysis.
Solartron Instruments technical report number 004/83, 1984 and F.B. Growcock: What's impedance spectroscopy. Chemtech, sep-tember 1989, pp 564-572.
Excellent tools for work in this field are available, e.g.
the 1286 Electrochemical Interface,_Solartz~on Instruments, UK and the Model 378 Electrochemical Impedance Systems, EG&G
Princeton Applied Research, HJ, USA.
Characteristic features of these systems are that they are intended for use with specimens mounted in appropriate elec-trochemical cells.
It is well known that certain parameters in living tissues are reflected by electrical impedance of said tissues:
U.S.P. 4,038,975 (Aug. 2;1977) to Vrana et al. relates to an electrically instrumented method of diagnosing the presence of a neoplast in mucuos membrane samples wherein the electrical impedance of the sample has resistive and capacitive compo-1~0 92/06634 PCT/SE91 /00703 ' 2093922 nents and wherein the relative values of raid components are indicative of the presence or absence of raid neoplast by associating the sample with the terminals of a series circuit including in succession a grounded, amplitude-modulated high-frequency generator and first and second Equal-valued resis-tors wherein the impedance of the generator and the resistance of both resistors are low relative to the impedance of the sample. Said association being made by connecting a test spot on the sample to the terminal of the second resistor remote from the junction of the first and second resistors and by connecting the bulk of the sample to the grounded terminal of the generator, simultaneously measuring the amplitudes of the potentials of the test spot and of the junction of the first and second resistors with respect to a reference value es-tablished at the junction of the generato:c and the first resistor, and computing from the measured values and from the reference value the resistive and capacit:ive portions of the impedance of the test spot.
By EP 0 315 854 (Appln. No. 88118083.0) to Honna is previously known a method and a system for measuring moisture content in skin by passing "weak" low frequency electric current through the keratinous layer between two electrodes abutted upon the skin, amplifying the electric voltage appearing on the layer, rectifying and taking out signals of the .amplified output, and measuring the amplitude of the signal, which is characterized in that the voltage appearing on the keratinous layer is the voltage appearing between either one of said two electrodes V1~0 92/06b34 PCT/S E9 t /00703 whichever is closer to another electrode w',hich is abutted upon said skin at a location outside said two electrodes.
The system comprises a measuring electrode structure of triple concentric circles including a central electrode, an inter-mediate electrode and an outer electrode a:11 of which can be abutted on the skin, a generator which used one of said elec-trodes as a common electrode and supplies :Low frequency signal between this common electrode and another of said three elec-trodes; an amplifier which converts the re:~ulting current into a voltage appearing between said common elE~ctrode and yet another of said three electrodes, and a means to display the output voltage of the amplifier which is characterized in that a circuit means is provided for switching between a first cir-cuit using said intermediate electrode as common electrode and a second circuit which uses the outer electrode as a common electrode.
Further prior art is disclosed in e.g. Yamamoto, T. & Yamamo-to, Y.: Analysis for the change of skin impedance. Med. &
Biol. Eng. & Comp., 1977, 15, 219-227; Sal.ter, D.C:: Quanti-fying skin disease and healing in vivo using electrical impe-dance measurements. In: Non-invasive physiological measure-menu, Vol l, 1979, Peter Rolfe ed. , pp 21-~64; Leveque, J. L.
& De Rigal, J.: Impedance methods for studying skin moisturi-zation. J.Soc.Cosmet.Chem., 1983, 34, 419-4:28; and Morkrid, L.
& Qiao, Z.-G.: Continuous estimation of parameters in skin electrical admittance from simultaneous measurements at two Vy0 92/06634 2 0 9 3 9 ~ G PCl'/SE9l/00703 ._ ._ different frequencies. Med. & Biol. Eng. & Comp., 1988, 26, 633-640.
Characteristic of existing technology in this field is that either: a) a biopsy would have to be excised in order to well define the actual tissue under test, i.e. not suit-able for in vivo measurements; or b) electrodes are applied to the skin at separate sites, directing the electric test: current right through the skin and regarding the: inner part of the skin and deeper lying tissue as are almost ideal short circuit between the contact sites, i.e. no discrimi-nation between the layers of the rather complicated anatomy of the skin.
There are devices for measuring the water content in the outermost layers of the skin (such as the Corneometer CM820PC, Courage + Khazaka Electronic GmbH, FRG) u:>ing interdigitated electrode patterns. A device called DPM9003 from NOVA Tech-nology Corporation, Mass., USA employs a :simple coaxial elec-trode. These devices have no means for controlling the measu-rement depth except for the limitations sEa by physical size.
Indeed, they are applications of the well known principle of moisture measurement using fringing field, (tiles: Electronic sensing devices, Newnes, London, 1966/68, pp 80-81).
A device for measuring conductance of the fluids in mucous WO 92/06634 2 0 9 3 g G 2 P~/SE91/00703 membranes of the airways has been published (Fouke, J M et al:
Sensor for measuring surface fluid conductivity in vivo. IEEE
Trans. Biomed. Eng., 1988, Vol 35, No 10, pp 877-881). This paper shows, backwards, the problem encountered while measu-ring on wet surfaces without a control elecarode to enforce depth penetration.
It is possible to use Applied Potential Tomography/Electrical Impedance Tomography to obtain tomographic images of e.g.
thorax or gastric regions, employing a large number of elec-trodes around the body and computing with reconstruction algorithms an image representing changes of conductivity in the body (Seagar, A.D. & Brown, H.H.: Limitations in hardware design in impedance imaging. Clin. Phys. Physiol. Meas., 1987, Vol. 8, Suppl. A, 85-90).
According to the present invention depth selectivity is achie-ved by controlling the extension of the electric field in the vicinity of the measuring electrodes by means of a control electrode between the measuring electrodes, the control electrode being actively driven with the same frequency as the measuring electrodes to a signal level, taken from one of the measuring electrodes but also multiplied by a complex number, in which the real and imaginary parts are optimized for each application depending upon the desired depth penetra-tion. The function of the controlling field is analogous to that of a field effect transistor, well knoian from solid state physics. In biological tissue or "wet state"', conduction WO 92/06634 2 0 9 3 .9. ~ P~T/SE91 /00703 mechanisms are complicated involving a number of ions, polari-zation effects, charged or polarizable organelles, etc. How-ever, no reconstruction algorithms are needed to achieve depth selectivity, although consecutive measurements at different depths must be recorded in order to obtain a profile.
The principle is basically frequency independent, and works from DC to several MHz. Simple impedance measurements at one or a few frequencies, as well as impedance spectroscopy in this range can thus be done depth selective on e.g. skin.
In mucous membranes the fluid on the surface would normally short circuit measuring electrodes placed on the same surface;
however, by use of the control electrode 'the test current is forced down into the mucous membrane rather than taking the shortest way and local definition of the Factual tissue under test is thus achieved. These advantages a:re directely appli-cable while measuring impedance as an indicator of irritation during tests of irritants on skin and oral mucous membranes.
It was also possible to measure impedance on kidneys while at the same time measuring the blood pressure within the kidney in the main artery, and it was found that impedance descripti-ve parameters correlated well with blood ;pressure. This opens the possibility to measure pressure, as mell as microcircula-tion non-invasively in many organs during surgery by applying a probe to the surface of the organ. Another application is the measuring of pressure in the eye (diagnosis of glaucoma).
7a The invention provides a device for depth-selective measurement of electrical impedance of organic and biological material comprising:
a probe with measuring electrodes and a virtual control electrode, positioned between at least two of the measuring electrodes;
a voltage and impedance measuring means for applying an electrical potential to the measuring electrodes and for measuring the electrical impedance of the organic or biological material between the measuring electrodes;
an amplifier having a transfer function and a high-impedance input and a low impedance output, said amplifier connected between one of the measuring electrodes and the virtual control electrode to actively drive said virtual control electrode, via the transfer function of the amplifier, with a signal from said measuring electrode, wherein said transfer function is adapted to control the extension of an electrical field from the virtual control electrode and thereby the depth of the impedance measurement for all subjects under examination.
The invention also provides a generalized probe as described above, wherein the control electrode is a number of electrodes which are switchable to function as the control electrode or the measuring electrode according to the desired physical size of the active probe area so that coarse depth penetration is achieved by switching the electrodes into different functions, and fine adjustment as well as the possibility to measure on wet surfaces is achieved by driving the virtual control electrode to the proper potential.
The invention also provides a probe for measuring of electrical impedance comprising concentric or topologically 7b equivalent arrangements of electrodes in which measuring electrodes are separated by a control electrode, the distance between the measuring electrodes corresponding to desired maximum depth penetration, one of the measuring electrodes being a central electrode, and said central electrode surrounded by a control electrode, and the control electrode surrounded by a second measuring electrode; the potential of the control electrode is following the potential of the central electrode or the second measuring electrode by multiplying said potential in an adjustable amplifier by a complex number in which the real and imaginary parts are optimized for each application; the essential part of the probe, except for contact surface, is surrounded by conductive material at signal ground or following the potential at the central electrode by a factor of one, and all conductive parts 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 invention further provides a method for depth-selective, non-invasive surface characterization of organic or biological material, wherein the impedance of organic or biological materials is measured from the surface of said material by application of a device as described above.
SHORT DESCRIPTION OF THE DRAWINGS.
Fig. 1 is a block diagram illustrating the principle of measu-rement employed in an embodiment of the preaent invention;
Fig. 2a is a plane topview of the tip of a probe with two measuring electrodes separated by a control electrode;
Fig. 2b is a cross-sectional view along plane S - S of Fig.
2a;
Fig. 3a is a cross-sectional view of a probe with linear, iterated structure;
Fig. 3b is a perspective view of the tip of the probe with a linear, iterated structure, electrically eq~uvivalent to Fig.
3a;
Fig. 3c is a perspective view of the tip of a simplified structure of a similar arrangement, sufficient in some appli-cations.
Fig. 4a is an illustration of a normal tissue with closed packed cells;
Fig. 4b is an illustration of an irritated tissue showing increased intercellular space;
V1V0 92/06634 ~ p 9 3 9 2 P~/SE9i/00703 ,, Fig. 5 is a plot showing mean values in $ obtained with prior technique in measurement of irritation on oral mucosa for NaCl, H3P04, SLS;
Fig. 6 is a plot showing values in $ for one person obtained with the technique according to the inveni:ion in the measure-ment of irritation on oral mucosa;
Fig. 7 is a plot showing irritation index results of measure-ment of irritation on skin with the technique according to the invention for one person with 20 hours of exposure of material and additionally 24 hours;
Fig. 8 is a plot showing absolute value of electrical impedan-ce at 20 kHz measured on intact surface of rat kidney at consecutive values of blood pressure by stepwise choking and releasing supporting artery in vivo;
Fig. 9a is a plane topview of a generalized probe switchable into different configurations;
Fig. 9b is a cross-sectional view along plane S - S of Fig. 9a showing also switchable electrical pathways.
DESCRIPTION
The essential features of the invention are a probe with two measuring electrodes separated by a control electrode, sui-table equipment for measuring the electr~:c impedance in the ",:.'T'/S E91 /00703 W02/06634 2 0 9 3 9 2 .
desired frequency range, and an amplifier with adjustable amplification capable of maintaining the chosen control sig-nal, derived from the potential of one of tlhe measuring elec-trodes at the control electrode without loading said measuring electrode, i.e. the amplifier must have higlh 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 ampli-fier with a complex number in which the real and imaginary parts are optimized for each application. W:Cth the amplifica-tion factor set to zero, the system assumes the special case of signal ground at the control electrode. :Cn this special case the system behaviour is similar to the system in the prime case of Fig. 1 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 amp7.itude supplied to the measuring electrodes) will modify the dE:pth 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.
i~VO 92/06634 F 2 0 9 3 _9 . 2 PCT/SE9l /00703 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 regula-tions.
It is important to limit excitation amplitude in order to minimize non-linearities inherent in living tissues. The amplitude supplied to the electrodes shou7.d be no more than a few tens of millivolts, preferably below '_i0 millivolts and more preferably about 25 millivolt. Higher amplitudes produce unreliable results. Working on wet mucous membranes does not require any special preparations. If deepf:r layers of the skin (stratum corneum and down) are to be investigated, the dry surface of the skin is preferably inundated with a salt solu-tion of physiological concentration.
The capability of the control electrode to vary depth penetration is, as stated above, limited lby 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 WO 92/06634 2 0 9 3 9 2 . P~/S E9l/00703 according to Fig. 9b. The dominating factor determining depth penetration is distances between electrodes; the basic theory has been expanded by Roy et al (Roy, A. & Apparao, A.: Depth of investigation in direct current methods. Geophysics, Vol.
36, No. 5, 1971, pp 943-959; Roy, K.K. & Rao, K.P.: Limiting depth of detection in line electrode system:a. Geophysical Prospecting, 25. 1977, pp 758-767) for a nunnber 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. ste:pwise increase of penetration with a fixed factor. With the generalized probe coarse depth penetration is thus selected by switching elec-trodes 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 ~W0 92/06634 . PCfI S E91 /00703 Zo939_ electrodes and using the rings in between, connected together, as a control electrode, and driving this virtual control electrode with a potential derived from tine 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 most 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 aecond electrode, connected together, as the control electrode.
PREFERRED EMBODIMENT
In Fig. 1 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. Said control electrode B will be actively held at a given potential by a controllable amplifier F, said 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.
Said measuring electrodes A and C are connected to a standard instrument for impedance measurement IM.
WO 92/06634 2 0 9 3 9. 2 2 Iris E9 ~ ioo~o3 Fig. 2a and Fig. 2b 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 consiats of the electrodes A, B and C, each electrically isolated from the other, in a coaxial arrangement and present, as depicted in Fig 2a. a plane surface containing respective electrodes A, B
and C and the isolating material 1.
Fig. 3b and Fig. 3c are showing the respective embodiments of an open linear, iterated structure which can be used according to the invention. The structure of Fig. 3c involves a simpli-fied feature, within the scope of the invenl~ion 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 electrode,, the size of which is depending upon desired maximum depi~h penetration. The electrodes comprise a central electrode being one of two measuring electrodes, and the central electrode being sur-rounded by a control electrode which is following the poten-tial 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 i:or each applica-Lion. The control electrode is surrounded by a second measuring electrode. The essential part of l:he probe, except WO 92/06634 ~ 9 3 .9 2 G. PCT/SE91/00703 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 dlevice 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 frequen-cies and plotting of Nyquist or Bode graphs.
For measurement of irritation, impedance values at two frequ-encies, one in the range several hundred l~;Hz 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 Fig 4: 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 po:~sible for the transfer function of the amplifier F in the used frequency a W ,92/06634 2 0 ~ 3 9 2 - ~T/S E91/00703 range.
APPLICATIONS
SIMPLE IRRITATION MODEL, FIG. 4 Fig. 4a shows normal tissue with close packed cells.
Fig. 4b shows irritated tissue with increased intercellular space.
High frequency (HF) is coupled capacitively through cell membrane to cell interior.
Low frequency (LF) is confined to extracell.ular/intercellu-lar space.
Conductivity is essentially the same in int:ra- och extracellu-lar liquid.
IRRITATION ON ORAL MUCOSA, FIG. 5.
Prior Technology 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 H3P04 (-5 to 0 in graph) and 10 minutes for SLS (however plotted between -5 and 0 in graph, for unii:ormity of nominal value). Electrical impedance was measured l:hrough the cheek, with a small electrode on the inside of then cheek at the site of irritation, and a large electrode on thf: outside of the cheek, thus creating a conical field yield~Lng highest elec-tric current density at the inside. Impedance information is ~WO 92/06634 0 9 3 2 G P~/SE91/00703 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 pur-poses, since averages from a number of test persons are necessary to obtain significant results.
With said 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. said prior method is not suitable for diagnostic purposes, and indeed not many mucous membranes are available from two sides non-invasibly.
IRRITATION ON ORAL MUCOSA, FIG. 6.
According to the invention 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 diagnos-tic 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 W92/06634 0 9 3 9 7 P~'~s E9l /00703 measure non-invasibly from the surface of any mucous membrane which can be reached from one side. In the case of oral muco-sa, artifacts from skin or muscular tissue are eliminated, and it is possible to follow irritation processes on single per-sons with high accuracy.
IRRITATION ON SKIN, FIG. 7.
According to the invention 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 FIG 7).
PRESSURE IN KIDNEY IN VIVO, FIG. 8.
According to the invention 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 pres-sores were induced by choking and releasing the supporting WO 92/06634 ~ ~ ~ PCT!SE91/00703 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 int~sct kidney of rat in vivo, the kidney being exposed to changea in blood circulation and pressure. There is significant correlation between pressu-re and value of measured impedance, the correlation being higher at 20 kHz (FIG 8) 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.simila:r to the kidney when it comes to tissue changes in the surface due to internal pressure, the invention may be useful fo:r diagnosis of glauco-ma.
Claims (19)
1. A device for depth-selective measurement of electrical impedance of organic and biological material comprising:
a probe with measuring electrodes and a virtual control electrode, positioned between at least two of the measuring electrodes;
a voltage and impedance measuring means for applying an electrical potential to the measuring electrodes and for measuring the electrical impedance of the organic or biological material between the measuring electrodes;
an amplifier having a transfer function and a high-impedance input and a low impedance output, said amplifier connected between one of the measuring electrodes and the virtual control electrode to actively drive said virtual control electrode, via the transfer function of the amplifier, with a signal from said measuring electrode, wherein said transfer function is adapted to control the extension of an electrical field from the virtual control electrode and thereby the depth of the impedance measurement for all subjects under examination.
a probe with measuring electrodes and a virtual control electrode, positioned between at least two of the measuring electrodes;
a voltage and impedance measuring means for applying an electrical potential to the measuring electrodes and for measuring the electrical impedance of the organic or biological material between the measuring electrodes;
an amplifier having a transfer function and a high-impedance input and a low impedance output, said amplifier connected between one of the measuring electrodes and the virtual control electrode to actively drive said virtual control electrode, via the transfer function of the amplifier, with a signal from said measuring electrode, wherein said transfer function is adapted to control the extension of an electrical field from the virtual control electrode and thereby the depth of the impedance measurement for all subjects under examination.
2. The device according to claim 1, wherein the amplifier has a frequency response that is sufficiently wide to avoid introduction of phase or amplitude errors in the output signal.
3. The device according to claim 1, wherein the amplitude applied to the measuring electrodes is no more than 50 millivolts.
4. The device according to claim 3, wherein the amplitude applied to the measuring electrodes is no more than 25 millivolts.
5. The device according to any one of claims 1 through 4, wherein the transfer function of the amplifier is externally controllable.
6. The device according to claim 5, wherein the externally controllable transfer function of the amplifier is manually selectable or continuously variable.
7. The device according to any one of claims 1 through 6, wherein the amplifier is stepwise or continuously controlled by the measuring means.
8. The device according to claim 1, wherein the potential of the control electrode is following the potential of one of the measuring electrodes by multiplying the signal at said measuring electrode with an adjustable amplifier by a complex number, in which real and imaginary parts are optimized for each application, and feeding tie control electrode from said amplifier.
9. The device according to claim 8, wherein the control electrode for measurement of irritation has the real part set between 0.01 - 10 corresponding to a chosen penetration depth and the imaginary part set as close to zero as possible in the frequency range used.
10. The device according to claim 1, said probe having a contact surface and said device further comprising:
an isolating material between the measuring electrodes and the control electrode;
said electrodes and said isolating material being in one plane with one another at the contact surface;
whereby any residual liquid layer between the probe and the test site during operation of the device is minimized so that the control electrode facilitates a deeper penetration than the thickness of the remaining liquid layer.
an isolating material between the measuring electrodes and the control electrode;
said electrodes and said isolating material being in one plane with one another at the contact surface;
whereby any residual liquid layer between the probe and the test site during operation of the device is minimized so that the control electrode facilitates a deeper penetration than the thickness of the remaining liquid layer.
11. The device according to claim 1, wherein the voltage and impedance measuring means applies the electrical potential over the measuring electrodes at a first and a second frequency for measurement of irritation impedance values in the test site.
12. The device according to claim 11, wherein the first frequency is greater than 100 kHz and the second frequency is less than 100 kHz, the electrical potential when at the first frequency forming a normalizing signal corresponding to the geometry of the test site.
13. The device according to claim 1, wherein the equipment for measuring impedance further measures impedance at a limited number of frequencies, said frequencies determined in pretests.
14. The device according to claim 1, wherein the virtual control electrode comprises a number of electrodes between the measuring electrodes connected together to form the virtual control electrode.
15. A probe for measuring of electrical impedance comprising concentric or topologically equivalent arrangements of electrodes in which measuring electrodes are separated by a control electrode, the distance between the measuring electrodes corresponding to desired maximum depth penetration, one of the measuring electrodes being a central electrode, and said central electrode surrounded by a control electrode, and the control electrode surrounded by a second measuring electrode; the potential of the control electrode is following the potential of the central electrode or the second measuring electrode by multiplying said potential in an adjustable amplifier by a complex number in which the real and imaginary parts are optimized for each application; the essential part of the probe, except for contact surface, is surrounded by conductive material at signal ground or following the potential at the central electrode by a factor of one, and all conductive parts 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.
16. A generalized probe according to claim 1, wherein the control electrode is a number of electrodes which are switchable to function as the control electrode or the measuring electrode according to the desired physical size of the active probe area so that coarse depth penetration is achieved by switching the electrodes into different functions, and fine adjustment as well as the possibility to measure on wet surfaces is achieved by driving the virtual control electrode to the proper potential.
17. A method for depth-selective, non-invasive surface characterization of organic or biological material, wherein the impedance of organic or biological materials is measured from the surface of said material by application of a device as claimed in any one of claims 1 through 16.
18. The method according to claim 17, wherein the impedance due to irritation effects or other changes in the organic or biological material such as skin or mucous membranes or other integuments is measured.
19. The method according to claim 17, wherein the impedance due to irritation effects or other changes in the kidney or the eye is measured.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9003336A SE466987B (en) | 1990-10-18 | 1990-10-18 | DEVICE FOR DEEP-SELECTIVE NON-INVASIVE, LOCAL SEATING OF ELECTRICAL IMPEDANCE IN ORGANIC AND BIOLOGICAL MATERIALS AND PROBE FOR SEATING ELECTRICAL IMPEDANCE |
| SE9003336-6 | 1990-10-18 | ||
| PCT/SE1991/000703 WO1992006634A1 (en) | 1990-10-18 | 1991-10-18 | A device for measurement of electrical impedance of organic and biological materials |
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|---|---|
| CA2093922A1 CA2093922A1 (en) | 1992-04-19 |
| CA2093922C true CA2093922C (en) | 2001-07-31 |
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|---|---|---|---|
| CA002093922A Expired - Lifetime CA2093922C (en) | 1990-10-18 | 1991-10-18 | A device for measurement of electrical impedance of organic and biological materials |
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| US (1) | US5353802A (en) |
| EP (1) | EP0553187B1 (en) |
| JP (1) | JP3320413B2 (en) |
| KR (1) | KR100201178B1 (en) |
| AT (1) | ATE167794T1 (en) |
| AU (1) | AU659111B2 (en) |
| CA (1) | CA2093922C (en) |
| DE (1) | DE69129698T2 (en) |
| DK (1) | DK0553187T3 (en) |
| ES (1) | ES2120419T3 (en) |
| FI (1) | FI110304B (en) |
| HU (1) | HU216496B (en) |
| NO (1) | NO307863B1 (en) |
| SE (1) | SE466987B (en) |
| WO (1) | WO1992006634A1 (en) |
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| AUPM851694A0 (en) * | 1994-09-30 | 1994-10-27 | Barsamian, Sergei T | New methods for diagnosis, detection of cell abnormalities and morphology of living systems |
| NO180024C (en) * | 1994-10-11 | 1997-01-29 | Oerjan G Martinsen | Measurement of moisture in the skin |
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| US4951683A (en) * | 1989-01-19 | 1990-08-28 | Davis Jeffrey P | Device for detecting keratoconjunctivitis sicca |
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1990
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- 1991-10-18 WO PCT/SE1991/000703 patent/WO1992006634A1/en active IP Right Grant
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- 1991-10-18 CA CA002093922A patent/CA2093922C/en not_active Expired - Lifetime
- 1991-10-18 JP JP51777291A patent/JP3320413B2/en not_active Expired - Lifetime
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- 1991-10-18 HU HU9301109A patent/HU216496B/en not_active IP Right Cessation
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1993
- 1993-04-16 FI FI931730A patent/FI110304B/en not_active IP Right Cessation
- 1993-04-16 NO NO931415A patent/NO307863B1/en not_active IP Right Cessation
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| AU8849991A (en) | 1992-05-20 |
| FI931730A0 (en) | 1993-04-16 |
| ES2120419T3 (en) | 1998-11-01 |
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| WO1992006634A1 (en) | 1992-04-30 |
| HUT66173A (en) | 1994-09-28 |
| NO307863B1 (en) | 2000-06-13 |
| ATE167794T1 (en) | 1998-07-15 |
| DE69129698D1 (en) | 1998-08-06 |
| JPH06502323A (en) | 1994-03-17 |
| HU216496B (en) | 1999-07-28 |
| JP3320413B2 (en) | 2002-09-03 |
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