Title of Invention	METHOD AND PROBE FOR MEASURING THE IMPEDANCE OF HUMAN OR ANIMAL BODY TISSUE
Abstract	The method for determining whether a probe for measuring the impedance of human or animal body tissue has been placed over a boundary between different tissue types is described. The probe used in the method comprises at least a first (16), a second (22), third (18) and a fourth (20) electrode arranged such that the third (18) and fourth (20) electrodes are each located substantially the same distance from both the first (16) and second (22) electrodes. The method comprises: driving a current between the first (16) and the second (22) electrodes; measuring a first value of an electrical parameter between the third (18) and the fourth (20) electrode; and determining whether the probe has been placed over a boundary between different tissue types based on the first value. A probe for carrying out the method is also described.

Title of Invention

METHOD AND PROBE FOR MEASURING THE IMPEDANCE OF HUMAN OR ANIMAL BODY TISSUE

Abstract

The method for determining whether a probe for measuring the impedance of human or animal body tissue has been placed over a boundary between different tissue types is described. The probe used in the method comprises at least a first (16), a second (22), third (18) and a fourth (20) electrode arranged such that the third (18) and fourth (20) electrodes are each located substantially the same distance from both the first (16) and second (22) electrodes. The method comprises: driving a current between the first (16) and the second (22) electrodes; measuring a first value of an electrical parameter between the third (18) and the fourth (20) electrode; and determining whether the probe has been placed over a boundary between different tissue types based on the first value. A probe for carrying out the method is also described.

Full Text	WO 2006/129108 PCT/GB2006/002026 -1- METHOD AND PROBE FOR MEASURING THE IMPEDANCE OF HUMAN OR ANIMAL BODY TISSUE The present invention relates to a probe which can measure the impedance of human or animal body tissue. More particularly it relates to a probe which can determine when the probe is placed over a boundary between two different tissue types and a corresponding method. It has been proposed to use measurements of tissue impedance in medical diagnosis applications. An example of a probe suitable for measuring the tissue impedance is discussed in WO-A-01/67098 and is depicted in Figure 1. The probe comprises four 1mm diameter gold electrodes 2 which are mounted flush with the end race 4 of the probe and spaced equally on a circle of 1.65mm radius. Figure 2 depicts the way in which the probe is used to calculate a transfer impedance when it has been placed in contact with a tissue to be measured. An ac current I, of 10 uA peak- to-peak is passed between two adjacent electrodes 6,8 and the real part of the resulting potential V, between the two remaining electrodes 10,12 is measured. The current path used for measuring the impedance is depicted in Figure 2 by broken line 14, it runs from electrode 6 to electrode 10 to electrode 12 to electrode 8. The ratio of the measured potential to the amplitude of the current determines the transfer impedance. Measurements are made at eight frequencies by doubling the frequency in steps between4.8 kHz and 614 kHz. Measurements may also be made at frequency ranges with an upper limit of up to 1.5 MHz. The transfer impedance so measured can then be analysed for use m cancer screening because the value will vary according to the type of cells and their arrangements which make up the tissue. The transfer impedance can also be used in screening for pre-term birth. WO 2006/129108 PCT/GB2006/002026 -2- However, the method can give inaccurate results when the probe is positioned over a tissue boundary. When the probe is used for cervical cancer screening the two major normal tissue types are normal squamous epithelium and columnar tissue. These two tissues are well separated in their impedance spectrums. However, if the probe is placed close to the uterine canal on the border between these two tissue types the resulting measured impedance can look like premalignant tissue. (The impedance spectrum of premalignant tissue lies between that of normal squamous epithelium and columnar tissue,) Therefore, misplacement of the probe may lead to a false positive result. It is desirable to reduce the occurrence of false positive results. Accordingly, the present invention provides a method and a probe which can determine whether the probe has been placed over a tissue boundary. Thus an operative can be alerted to reposition the probe slightly to reduce the likelihood of a raise positive result According to a first aspect of the present invention, there is provided a method for determining whether a probe for measuring the impedance of human or animal body tissue has been placed over a boundary between different tissue types, the probe comprising at least a first, a second, a third and a fourth electrode arranged such that the third and fourth electrodes are each located substantially the same distance from both the first and second electrodes; the method comprising: driving a current between the first and the second electrode; measuring a first value of an electrical parameter between the third and the fourth electrode; and detennining whether the probe has been placed over a boundary between difrerent tissue types based on the first value. The electrical parameter may be the potential difference between the third and fourth electrodes, the transfer impedance between the first and second electrodes and the third and fourth electrodes or the current flowing between the third and fourth electrodes. The third and fourth electrodes are each substantially the same distance from the first and second electrodes. Therefore, if the probe has been placed over substantially homogenous tissue WO 2006/129108 PCT/GB2006/002026 -3- the current path through the third electrode will be the same as the current path through the fourth electrode, the system will be balanced and the first value will indicate this. As the system is balanced the first value can be expected to be low or close to zero. Therefore, in one embodiment, in the step of determining whether the probe has been placed over a boundary between different tissue types, if the first value is not substantially equal to zero it is determined mat the probe has been placed over a boundary between different tissue types. The method can be used with several different arrangements of electrodes, however it is preferred that the first, second, third and fourth electrodes are arranged at the corners of a square with the first and second electrodes diagonally opposite each other. This arrangement is advantageous because it can be used to measure the tissue impedance and also determine whether the apparatus has been placed over a tissue boundary with the same set of four electrodes. It has also been found that a comparison of the first value with a value of the parameter obtained when measuring the impedance of the tissue is effective at identifying a tissue boundary. Thus, in one preferable embodiment, the step of deterrnining whether the probe has been placed over a boundary between different tissue types comprises: comparing the first value to a predetermined value, wherein the predetermined value is that expected to be obtained when a current is driven between the first and third electrodes and the electrical parameter is measured between the second and fourth electrode; and wherein if the first value is greater than half the predetermined value it is determined that the probe has been placed over a boundary between different tissue types. More preferably if the first value has a value greater man 20% of the predetermined value it is determined that the probe has been placed over a boundary between different tissue types. Still more preferably, if the first value has a value greater than 10% of the predetermined value it is determined that the probe has been placed over a boundary between different tissue types. WO 2006/129108 PCT/GB2006/002026 -4- The poredetennined value may be provided based on an assumption of a particular tissue type or be an average across all likely tissue types. In an alternate embodiment, the method may further comprise: driving the current between the first and third electrodes; and measuring a second value of the electrical parameter between the second and fourth electrodes; wherein said step of determining whether the probe has been placed over a boundary comprises comparing the first value to the second value and wherein if the first value is greater than half the second value it is determined that the probe has been placed over a boundary between different tissue types. More preferably if the first value has a value greater than 20% of the second value it is determined that the probe has been placed over a boundary between different tissue types. Still more preferably, if the first value has a value greater than 10% of the second value it is determined that the probe has been placed over a boundary between different tissue types. This method has the advantage that the actual parameter being measured by the probe may be used in the determination of whether the probe is placed over a tissue boundary. Although unlikely to happen, h is possible that the method above might not detect a tissue boundary which passes between the first and second electrodes or the third and the fourth electrodes because in mat case the system will still be balanced. The system will also be balnced if the boundary is parallel to a line drawn between the first and second electrodes or parallel to a line drawn between the third and fourth electrodes. To avoid this problem the method may further comprise rotating the probe slightly, preferably by an angle of less than 45°, and repeating the measurement of the first value of die electrical parameter. A rotation of less than 45° is preferable because of the rotational symmetry of a square electrode arrangement In an alternate embodiment, the probe may be provided with more than four electrodes to enable a tissue boundary passing through two of the electrodes to be detected without requiring rotation of the probe. WO 2006/129108 PCT/GB2006/002026 -5- According to a second aspect of the present invention, there is provided a probe for measuring the impedance of human or animal body tissue, the probe comprising: at least a first, a second, a third and a fourth electrode arranged such that the third and fourth electrodes are each located substantially the same distance from both the first and second electrodes; a current source for driving a current between the first and second electrodes; a measurement circuit for measuring a first value of an electrical parameter between the third and fourth electrodes; and a controller for controlling the current source; and a processor for determining whether the probe has been placed over a boundary between different tissue types based on the first value. The controller and processor may be implemented in several ways, tor example as an application specific integrated circuit (ASIC), a microprocessor, microcontroller or a programmable logic array. The measurement circuit may be a voltmeter or any other circuit which is capable of measuring the potential difference between two points, or an ammeter for measuring the current flowing between two points. In one embodiment the current source, measurement circuit, controller and processor may be integrated into a single integrated circuit In one embodiment the processor determines that the probe has been placed over a boundary between different tissue types if the first value is not substantially equal to zero. Preferably, the first, second, third and fourth electrodes are arranged at the comers of a square with the first and second electrodes diagonally opposite each other. The same electrodes can men be used for impedance measurement and for detecting placement of the probe over a tissue boundary. In one preferable embodiment, the processor is also tor comparing the first value to a predetermined value, wherem me predetermined value is that expected to be obtained when a current is driven between the first and third electrodes and the electrical parameter is measured between the second and fourth electrodes; and wherein if the first value is greater WO 2006/129108 PCT/GB2006/002026 -6- than half the predetermined, value it is determined that the probe has been placed over a boundary between different tissue types, More preferably if the first value has a value greater than 20% of the predetermined value the processor determines that the probe has been placed over a boundary between different tissue types. Still more preferably, if the first value has a value greater than 10% of the predetermined value, the processor determines that the probe has been placed over a boundary between different tissue types, In another preferable embodiment, the current source is also for driving a current between the first and third electrodes; and the measuring circuit is also for measuring a second value of the electrical parameter between the second and fourth electrodes; wherein the processor determines whether the probe has been placed over a boundary by comparing the first value to the second value, and wherein if the first electrical parameter is greater than half the second value it is determined mat the probe has been placed over a boundary between different tissue types. More preferably if the first value has a value greater than 20% of the second value the processor determines that the probe has been placed over a boundary between different tissue types. Still more preferably, if the first value has a value greater man 10% of the second value, the processor determines that the probe has been placed over a boundary between different tissue types. According to a third aspect of the invention, there is provided a computer program comprising code means that, when executed on a computer system, instructs the computer system to perform the method of the first aspect of the invention. This allows the method of detecting placement of a probe over a tissue boundary to be provided as a retro-fit upgrade. The term computer system is used to encompass bom an external computer system connected to the probe and also an internal controller or microprocessor located within the probe which executes instructions to operate the probe. According to a fourth aspect of the present invention, there is provided a computer program product comprising a computer readable medium bearing a computer program according to the above described third aspect. WO 2006/129108 PCT/GB2006/002026 -7- Embodimentg of the invention will now be described by way of example only with reference to the accompanying drawings, in which: Figure 1 depicts a probe for measuring the impedance of tissue; Figure 2 depicts a method for using the probe depicted in Figure 1 to measure the impedance of tissue; Figure 3 depicts a method according to the present invention for detecting placement of the probe depicted in Figure 1 across a tissue boundary; and Figure 4 depicts a probe which has been placed over a tissue boundary. In a first embodiment, depicted in Figure 3, a probe is provided with four electrodes 16,18, 20,22 are arranged at the comers of a square, as described for example in WO-A- 01/67098. The probe includes a controller and a processor (not shown) which are both implemented by a microprocessor in this embodiment but may also be a microcontroller, an application specific integrated circuit (ASIC), or a programmable logic array. The controller controls the way in which the electrodes are driven. There are two modes of operation. In the first mode, the probe measures the tissue impedance by driving the electrodes in the same way as that described in WO-A-01/67098. That is, an alternating current supplied from a current source (not shown) is driven between two adjacent electrodes and the resulting potential difference is measured by a measurement circuit (not shown) between the other two electrodes. The ratio of the amplitude of the alternating current to the resulting potential difference can then be used to calculate the tissue impedance. The amplitude of the alternating current may be in the range 1 μAto 1mA. Measurement is taken at several values in the range of 1 kHz up to an npper limit of 500 kHz to 3 MHz. In the second mode of operation the electrodes are driven to enable the placement of the probe over a tissue boundary to be detected. The controller controls the current source to drive a current between diagonally opposite electrodes 16,22 rather than between adjacent electrodes as is the case when measuring tissue impedance. The potential is measured by WO 2006/129108 PCT/GB2006/002026 -8- the measurement circuit between the other two electrodes 18, 20. The same currents and frequencies ate used as in the first mode of operation. This driving arrangement results in two effective current paths which are depicted with broken lines in Figure 3. The first current path 24 runs from electrode 16 to electrode 22 via electrode 18. The second current path 26 tuns from electrode 16 to electrode 22 via electrode 20. By measuring the potential difference across electrodes 18,20 the probe electrodes now function in a similar way to a bridge circuit, If the tissue on which the probe has been placed is homogenous the effective impedance of path 24 will be the same as the effective impedance of path 26. The geometry of the arrangement is such that the electrodes IS and 20 are each located the same distance from both electrode 16 and electrode 22. Therefore, in a theoretically ideal situation, the potential measured across electrodes IS and 20 with homogenous tissue will be substantially equal to zero because the system is balanced. Figure 4 depicts the situation in which the probe has been placed over a tissue boundary 28. In this embodiment the probe is used for cervical cancer screening and therefore the two major tissue types are normal squamous epithelium and columnar tissue. These two tissues are well separated in their impedance spectrums. Therefore, when the current is driven between electrodes 16 and 22, me impedance in the path through electrode IS is not the same as the impedance in the path through electrode 20. As a result a non-zero potential difference will be measured between electrodes IS and 20, indicating that the probe is placed on a tissue boundary. The processor determines from the measured potential difference whether the probe has been placed on a tissue boundary, m the event mai it is detemiined that the probe is located on a tissue boundary a visual or audio warning may be communicated to alert the operative to remove the probe. This warning may be transmitted from the probe itself, for example from a light or buzzer in the handle, or from a connected computer system. The square arrangement of this embodiment has the added benefit that the same electrodes can be used both for tissue impedance measurements and to check that the probe is not WO 2006/129108 PCT/GB2006/002026 -9- located over a tissue boundary. If the probe is located over a tissue boundary any impedance measurements will not be reliable and it is therefore preferable to drive the electrodes to check for a tissue boundary prior to driving them to measure the tissue impedance. It has been found that the difference between the impedance of tissue types likely to be encountered in cancer screening is most different at lower frequencies. Therefore, the detection of a tissue boundary can be improved by driving the current at generally lower frequencies man those used for tissue impedance measurement It is possible that a tissue boundary which passes diagonally under the probe, coincident with either electrodes 16 and 22 or electrodes 18 and 20 will not be detected because the resulting system will still be balanced. Likewise, the system will also be balanced if the tissue boundary is parallel to the line between electrodes 16 and 22 or parallel to the line between electrodes 18 and 20. To avoid lack of detection because of this, the operator may rotate the probe slightly about its central axis before the probe repeats the boundary detection. An angle of rotation of less than 45 ° is preferred because of the rotational symmetry of the square electrode arrangement In a second embodiment of the present invention, which i$ the same as first save as described below, the measured value of potential difference obtained when operating the electrodes to detect atissue boundary is compared with another value to determine the presence of a tissue boundary. The present inventors have found that if the probe has been placed over a tissue boundary, the potential difference measured between electrodes 18 and 20 when a current is driven between electrodes 16 and 22 (the second mode of operation) is similar to that obtained when a current is driven between electrodes 16 and 18 and a potential measured between electrodes 20 and 22 (the first mode of operation), Therefore, in mis embodiment a comparison method is used to detect a tissue boundary, litis can give more accurate results because the theoretically ideal situation of a completely balanced system resulting in a zero potential difference may rarely occur in practice. WO 2006/129108 PCT/GB2006/002026 -10- The potential difference measured between electrodes 16 and 22 in the second mode of operation may be compared to a predetermined value representative of likely values of potential difference obtained when the probe is used for impedance measurement in the first mode of operation. Alternatively, the probe may first be used for impedance measurement, and the tissue boundary detection may make a comparison with the results obtained from operation in the first mode. If no tissue boundary is present, the value of potential difference measured in the second mode will be less than that of the first mode. The processor determines a tissue boundary is present if the potential difference measured in the second mode is greater than 50% of the value of the predetermined value or the value measured in the first mode. Changing this value can alter the sensitivity to a tissue boundary. In alternate embodiments which are more sensitive to a tissue boundary, it is determined that a tissue boundary is present if the potential difference meausured in the second mode is greater than 20 %, or alternatively greater than 10% of the predetermined value or the value measured in the first mode. In an alternate embodiment, the electrodes can be arranged other than in a square, providing that there are first and second electrodes for driving a current between and third and fourth electrodes for measuring a potential difference arranged such that the third and fourth electrodes are each located substantially the same distance from bom the first and second electrodes. An example of such an arrangement is where the electrodes are placed at the corners of a kite shape (a quadrilateral which is symmetrical about one diagonal). In alternate embodiments more than tour electrodes can be provided. In these embodiments there must be two electrodes between which a current can be driven between and two electrodes for measuring potential spaced an equal distance from both of the two electrodes through which a current is driven. An example of an arrangement suitable for use with more than four electrodes is a regular hexagon. All of the above embodiments could be adapted to use the measured potential to calculate the transfer impedance between the electrodes 18 and 20 and the electrodes 16 and 22. This can be calculated from the ratio of the measured poteritial between electrodes 18 and WO 2006/129108 PCT/GB2006/002026 -11- 20 to the amplitude of the current between electrodes 16 and 22. Likewise, the embodiments can be adapted to measure the current flowing between the electrodes 18 and 20. In these cases, because the system is balanced, the value of the parameter measured will be zero or close to zero in an ideal theoretical situation. The method of comparing the values will also work in the same way as described for potential difference. WO 2006/129108 PCT/GB2006/002026 -12- CLAIMS 1. A method for determining whether a probe for measuring the impedance of human or animal body tissue has been placed over a boundary between different tissue types, the probe comprising at least a first, a second, a third and a fourth electrode arranged such that the third and fourth electrodes are each located substantially the same distance from both the first and second electrodes; the method comprising: driving a current between the first and the second electrode; measuring a first value of an electrical parameter between the third and the fourth electrode; and determining whether the probe has been placed over a boundary between different tissue types based on the first value. 2. A method according to claim 1 for use with a probe wherein the first, second, third and fourth electrodes are arranged at the corners of a square with the first and second electrodes diagonally opposite each other, 3. A method according to claim 2, wherein the step of determining whether the probe has been placed over a boundary between different tissue types comprises: comparing the first value to a predetermined value, wherein the predetermined value is that expected to be obtained when a CTirrent is oMven between me first and mhxl electrodes and the electrical parameter is measured between the second and fourth electrode; and wherein if the first value is greater than half the predetermined value it is determined that the probe has been placed over a boundary between different tissue types. 4. A method according to claim 2, the method further comprising: driving the current between the first and third electrodes; and measuring a second value of the electrical parameter between the second and fourth electrodes; wherein said step of detennining whether the probe has been placed over a boundary comprises comparing the first value to the second value and wherein if the first WO 2006/129108 PCT/GB2006/002026 -13. value is greater than half the second value it is determmed that the probe has been placed over a boundary between different tissue types. 5. A method according to claim 1 or 2, wherein in the step of determining whether the probe has been placed over a boundary between different tissue types, if the fust value is not substantially equal to zero it is determined that the probe has been placed over a boundary between different tissue types. 6. A probe for measuring the impedmre of hum comprising: at least a first, a second, a third and a fourth electrode arranged such that the third and fourth electrodes are each located substantially the same distance from both the first and second electrodes; a current source for driving a current between the first and second electrodes; a measurement circuit for measuring a first value of an electrical parameter between the third and fourth electrodes; and a controller for controlling the current source; and a processor for determining whether the probe has been placed over a boundary between different tissue types based on the first value. 7. A probe according to claim 6, wherein the first, secorKi, third and fourth electrodes are arranged at the corners of a square with the first and second electrodes diagonally opposite each other. 8. A method according to claim 7, wherein the processor is also for comparing the first value to a predetermined value, wherein me predetenru^ed value is that expected to be obtained when a current is driven between the first and third electrodes and the electrical parameter is measured between the second and fourth electrodes; and wherein if the first value is greater than half the predetermined value it is determined that the probe has been placed over a boundary between different tissue types. 9. A method according to claim 7, wherein: WO 2006/129108 PCT/GB2006/002026 -14- the current source is also for driving a current between the first and third electrodes; and the measuring circuit is also for measuring a second value of the electrical parameter between the second and fourth electrodes; wherein the processor determines whether the probe has been placed over a boundary by comparing the first value to the second value, and wherein if the first electrical parameter is greater man half the second value it is determined that the probe has been placed over a boundary between different tissue types. 10. A probe according to claim 6 or 7, wherein the processor determines that the probe has been placed over a boundary between different tissue types ifthe first value is not substantially equal to zero. 11. A computer program comprising code means that, when executed on a computer system, instructs the computer system to perform the method according to any one claims 1 to 5. 12. A computer program product comprising a computer readable medium bearing a computer program according to claim 11. The method for determining whether a probe for measuring the impedance of human or animal body tissue has been placed over a boundary between different tissue types is described. The probe used in the method comprises at least a first (16), a second (22), third (18) and a fourth (20) electrode arranged such that the third (18) and fourth (20) electrodes are each located substantially the same distance from both the first (16) and second (22) electrodes. The method comprises: driving a current between the first (16) and the second (22) electrodes; measuring a first value of an electrical parameter between the third (18) and the fourth (20) electrode; and determining whether the probe has been placed over a boundary between different tissue types based on the first value. A probe for carrying out the method is also described.

Full Text

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METHOD AND PROBE FOR MEASURING THE IMPEDANCE OF HUMAN OR
ANIMAL BODY TISSUE
The present invention relates to a probe which can measure the impedance of human or
animal body tissue. More particularly it relates to a probe which can determine when the
probe is placed over a boundary between two different tissue types and a corresponding
method.
It has been proposed to use measurements of tissue impedance in medical diagnosis
applications. An example of a probe suitable for measuring the tissue impedance is
discussed in WO-A-01/67098 and is depicted in Figure 1. The probe comprises four 1mm
diameter gold electrodes 2 which are mounted flush with the end race 4 of the probe and
spaced equally on a circle of 1.65mm radius.
Figure 2 depicts the way in which the probe is used to calculate a transfer impedance when
it has been placed in contact with a tissue to be measured. An ac current I, of 10 uA peak-
to-peak is passed between two adjacent electrodes 6,8 and the real part of the resulting
potential V, between the two remaining electrodes 10,12 is measured. The current path
used for measuring the impedance is depicted in Figure 2 by broken line 14, it runs from
electrode 6 to electrode 10 to electrode 12 to electrode 8.
The ratio of the measured potential to the amplitude of the current determines the transfer
impedance. Measurements are made at eight frequencies by doubling the frequency in
steps between4.8 kHz and 614 kHz. Measurements may also be made at frequency ranges
with an upper limit of up to 1.5 MHz.
The transfer impedance so measured can then be analysed for use m cancer screening
because the value will vary according to the type of cells and their arrangements which
make up the tissue. The transfer impedance can also be used in screening for pre-term
birth.

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However, the method can give inaccurate results when the probe is positioned over a tissue
boundary. When the probe is used for cervical cancer screening the two major normal
tissue types are normal squamous epithelium and columnar tissue. These two tissues are
well separated in their impedance spectrums. However, if the probe is placed close to the
uterine canal on the border between these two tissue types the resulting measured
impedance can look like premalignant tissue. (The impedance spectrum of premalignant
tissue lies between that of normal squamous epithelium and columnar tissue,) Therefore,
misplacement of the probe may lead to a false positive result.
It is desirable to reduce the occurrence of false positive results. Accordingly, the present
invention provides a method and a probe which can determine whether the probe has been
placed over a tissue boundary. Thus an operative can be alerted to reposition the probe
slightly to reduce the likelihood of a raise positive result
According to a first aspect of the present invention, there is provided a method for
determining whether a probe for measuring the impedance of human or animal body tissue
has been placed over a boundary between different tissue types, the probe comprising at
least a first, a second, a third and a fourth electrode arranged such that the third and fourth
electrodes are each located substantially the same distance from both the first and second
electrodes; the method comprising:
driving a current between the first and the second electrode;
measuring a first value of an electrical parameter between the third and the fourth
electrode; and
detennining whether the probe has been placed over a boundary between difrerent
tissue types based on the first value.
The electrical parameter may be the potential difference between the third and fourth
electrodes, the transfer impedance between the first and second electrodes and the third and
fourth electrodes or the current flowing between the third and fourth electrodes. The third
and fourth electrodes are each substantially the same distance from the first and second
electrodes. Therefore, if the probe has been placed over substantially homogenous tissue

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the current path through the third electrode will be the same as the current path through the
fourth electrode, the system will be balanced and the first value will indicate this.
As the system is balanced the first value can be expected to be low or close to zero.
Therefore, in one embodiment, in the step of determining whether the probe has been
placed over a boundary between different tissue types, if the first value is not substantially
equal to zero it is determined mat the probe has been placed over a boundary between
different tissue types.
The method can be used with several different arrangements of electrodes, however it is
preferred that the first, second, third and fourth electrodes are arranged at the corners of a
square with the first and second electrodes diagonally opposite each other. This
arrangement is advantageous because it can be used to measure the tissue impedance and
also determine whether the apparatus has been placed over a tissue boundary with the same
set of four electrodes.
It has also been found that a comparison of the first value with a value of the parameter
obtained when measuring the impedance of the tissue is effective at identifying a tissue
boundary. Thus, in one preferable embodiment, the step of deterrnining whether the probe
has been placed over a boundary between different tissue types comprises:
comparing the first value to a predetermined value, wherein the predetermined
value is that expected to be obtained when a current is driven between the first and third
electrodes and the electrical parameter is measured between the second and fourth
electrode; and wherein if the first value is greater than half the predetermined value it is
determined that the probe has been placed over a boundary between different tissue types.
More preferably if the first value has a value greater man 20% of the predetermined value it
is determined that the probe has been placed over a boundary between different tissue
types. Still more preferably, if the first value has a value greater than 10% of the
predetermined value it is determined that the probe has been placed over a boundary
between different tissue types.

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The poredetennined value may be provided based on an assumption of a particular tissue
type or be an average across all likely tissue types.
In an alternate embodiment, the method may further comprise:
driving the current between the first and third electrodes; and
measuring a second value of the electrical parameter between the second and
fourth electrodes;
wherein said step of determining whether the probe has been placed over a
boundary comprises comparing the first value to the second value and wherein if the first
value is greater than half the second value it is determined that the probe has been placed
over a boundary between different tissue types. More preferably if the first value has a
value greater than 20% of the second value it is determined that the probe has been placed
over a boundary between different tissue types. Still more preferably, if the first value has
a value greater than 10% of the second value it is determined that the probe has been
placed over a boundary between different tissue types.
This method has the advantage that the actual parameter being measured by the probe may
be used in the determination of whether the probe is placed over a tissue boundary.
Although unlikely to happen, h is possible that the method above might not detect a tissue
boundary which passes between the first and second electrodes or the third and the fourth
electrodes because in mat case the system will still be balanced. The system will also be
balnced if the boundary is parallel to a line drawn between the first and second electrodes
or parallel to a line drawn between the third and fourth electrodes. To avoid this problem
the method may further comprise rotating the probe slightly, preferably by an angle of less
than 45°, and repeating the measurement of the first value of die electrical parameter. A
rotation of less than 45° is preferable because of the rotational symmetry of a square
electrode arrangement
In an alternate embodiment, the probe may be provided with more than four electrodes to
enable a tissue boundary passing through two of the electrodes to be detected without
requiring rotation of the probe.

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According to a second aspect of the present invention, there is provided a probe for
measuring the impedance of human or animal body tissue, the probe comprising:
at least a first, a second, a third and a fourth electrode arranged such that the third
and fourth electrodes are each located substantially the same distance from both the first
and second electrodes;
a current source for driving a current between the first and second electrodes;
a measurement circuit for measuring a first value of an electrical parameter
between the third and fourth electrodes; and
a controller for controlling the current source; and
a processor for determining whether the probe has been placed over a boundary
between different tissue types based on the first value.
The controller and processor may be implemented in several ways, tor example as an
application specific integrated circuit (ASIC), a microprocessor, microcontroller or a
programmable logic array. The measurement circuit may be a voltmeter or any other
circuit which is capable of measuring the potential difference between two points, or an
ammeter for measuring the current flowing between two points. In one embodiment the
current source, measurement circuit, controller and processor may be integrated into a
single integrated circuit
In one embodiment the processor determines that the probe has been placed over a
boundary between different tissue types if the first value is not substantially equal to zero.
Preferably, the first, second, third and fourth electrodes are arranged at the comers of a
square with the first and second electrodes diagonally opposite each other. The same
electrodes can men be used for impedance measurement and for detecting placement of the
probe over a tissue boundary.
In one preferable embodiment, the processor is also tor comparing the first value to a
predetermined value, wherem me predetermined value is that expected to be obtained when
a current is driven between the first and third electrodes and the electrical parameter is
measured between the second and fourth electrodes; and wherein if the first value is greater

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than half the predetermined, value it is determined that the probe has been placed over a
boundary between different tissue types, More preferably if the first value has a value
greater than 20% of the predetermined value the processor determines that the probe has
been placed over a boundary between different tissue types. Still more preferably, if the
first value has a value greater than 10% of the predetermined value, the processor
determines that the probe has been placed over a boundary between different tissue types,
In another preferable embodiment, the current source is also for driving a current between
the first and third electrodes; and
the measuring circuit is also for measuring a second value of the electrical
parameter between the second and fourth electrodes;
wherein the processor determines whether the probe has been placed over a
boundary by comparing the first value to the second value, and wherein if the first
electrical parameter is greater than half the second value it is determined mat the probe has
been placed over a boundary between different tissue types. More preferably if the first
value has a value greater than 20% of the second value the processor determines that the
probe has been placed over a boundary between different tissue types. Still more
preferably, if the first value has a value greater man 10% of the second value, the processor
determines that the probe has been placed over a boundary between different tissue types.
According to a third aspect of the invention, there is provided a computer program
comprising code means that, when executed on a computer system, instructs the computer
system to perform the method of the first aspect of the invention. This allows the method
of detecting placement of a probe over a tissue boundary to be provided as a retro-fit
upgrade. The term computer system is used to encompass bom an external computer
system connected to the probe and also an internal controller or microprocessor located
within the probe which executes instructions to operate the probe.
According to a fourth aspect of the present invention, there is provided a computer program
product comprising a computer readable medium bearing a computer program according to
the above described third aspect.

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Embodimentg of the invention will now be described by way of example only with
reference to the accompanying drawings, in which:
Figure 1 depicts a probe for measuring the impedance of tissue;
Figure 2 depicts a method for using the probe depicted in Figure 1 to measure the
impedance of tissue;
Figure 3 depicts a method according to the present invention for detecting placement of the
probe depicted in Figure 1 across a tissue boundary; and
Figure 4 depicts a probe which has been placed over a tissue boundary.
In a first embodiment, depicted in Figure 3, a probe is provided with four electrodes 16,18,
20,22 are arranged at the comers of a square, as described for example in WO-A-
01/67098. The probe includes a controller and a processor (not shown) which are both
implemented by a microprocessor in this embodiment but may also be a microcontroller,
an application specific integrated circuit (ASIC), or a programmable logic array. The
controller controls the way in which the electrodes are driven.
There are two modes of operation. In the first mode, the probe measures the tissue
impedance by driving the electrodes in the same way as that described in WO-A-01/67098.
That is, an alternating current supplied from a current source (not shown) is driven between
two adjacent electrodes and the resulting potential difference is measured by a
measurement circuit (not shown) between the other two electrodes. The ratio of the
amplitude of the alternating current to the resulting potential difference can then be used to
calculate the tissue impedance. The amplitude of the alternating current may be in the
range 1 μAto 1mA. Measurement is taken at several values in the range of 1 kHz up to an
npper limit of 500 kHz to 3 MHz.
In the second mode of operation the electrodes are driven to enable the placement of the
probe over a tissue boundary to be detected. The controller controls the current source to
drive a current between diagonally opposite electrodes 16,22 rather than between adjacent
electrodes as is the case when measuring tissue impedance. The potential is measured by

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the measurement circuit between the other two electrodes 18, 20. The same currents and
frequencies ate used as in the first mode of operation.
This driving arrangement results in two effective current paths which are depicted with
broken lines in Figure 3. The first current path 24 runs from electrode 16 to electrode 22
via electrode 18. The second current path 26 tuns from electrode 16 to electrode 22 via
electrode 20. By measuring the potential difference across electrodes 18,20 the probe
electrodes now function in a similar way to a bridge circuit, If the tissue on which the
probe has been placed is homogenous the effective impedance of path 24 will be the same
as the effective impedance of path 26. The geometry of the arrangement is such that the
electrodes IS and 20 are each located the same distance from both electrode 16 and
electrode 22. Therefore, in a theoretically ideal situation, the potential measured across
electrodes IS and 20 with homogenous tissue will be substantially equal to zero because
the system is balanced.
Figure 4 depicts the situation in which the probe has been placed over a tissue boundary 28.
In this embodiment the probe is used for cervical cancer screening and therefore the two
major tissue types are normal squamous epithelium and columnar tissue. These two tissues
are well separated in their impedance spectrums. Therefore, when the current is driven
between electrodes 16 and 22, me impedance in the path through electrode IS is not the
same as the impedance in the path through electrode 20. As a result a non-zero potential
difference will be measured between electrodes IS and 20, indicating that the probe is
placed on a tissue boundary.
The processor determines from the measured potential difference whether the probe has
been placed on a tissue boundary, m the event mai it is detemiined that the probe is
located on a tissue boundary a visual or audio warning may be communicated to alert the
operative to remove the probe. This warning may be transmitted from the probe itself, for
example from a light or buzzer in the handle, or from a connected computer system.
The square arrangement of this embodiment has the added benefit that the same electrodes
can be used both for tissue impedance measurements and to check that the probe is not

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located over a tissue boundary. If the probe is located over a tissue boundary any
impedance measurements will not be reliable and it is therefore preferable to drive the
electrodes to check for a tissue boundary prior to driving them to measure the tissue
impedance.
It has been found that the difference between the impedance of tissue types likely to be
encountered in cancer screening is most different at lower frequencies. Therefore, the
detection of a tissue boundary can be improved by driving the current at generally lower
frequencies man those used for tissue impedance measurement
It is possible that a tissue boundary which passes diagonally under the probe, coincident
with either electrodes 16 and 22 or electrodes 18 and 20 will not be detected because the
resulting system will still be balanced. Likewise, the system will also be balanced if the
tissue boundary is parallel to the line between electrodes 16 and 22 or parallel to the line
between electrodes 18 and 20. To avoid lack of detection because of this, the operator may
rotate the probe slightly about its central axis before the probe repeats the boundary
detection. An angle of rotation of less than 45 ° is preferred because of the rotational
symmetry of the square electrode arrangement
In a second embodiment of the present invention, which i$ the same as first save as
described below, the measured value of potential difference obtained when operating the
electrodes to detect atissue boundary is compared with another value to determine the
presence of a tissue boundary.
The present inventors have found that if the probe has been placed over a tissue boundary,
the potential difference measured between electrodes 18 and 20 when a current is driven
between electrodes 16 and 22 (the second mode of operation) is similar to that obtained
when a current is driven between electrodes 16 and 18 and a potential measured between
electrodes 20 and 22 (the first mode of operation), Therefore, in mis embodiment a
comparison method is used to detect a tissue boundary, litis can give more accurate
results because the theoretically ideal situation of a completely balanced system resulting in
a zero potential difference may rarely occur in practice.

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The potential difference measured between electrodes 16 and 22 in the second mode of
operation may be compared to a predetermined value representative of likely values of
potential difference obtained when the probe is used for impedance measurement in the
first mode of operation. Alternatively, the probe may first be used for impedance
measurement, and the tissue boundary detection may make a comparison with the results
obtained from operation in the first mode.
If no tissue boundary is present, the value of potential difference measured in the second
mode will be less than that of the first mode. The processor determines a tissue boundary
is present if the potential difference measured in the second mode is greater than 50% of
the value of the predetermined value or the value measured in the first mode. Changing
this value can alter the sensitivity to a tissue boundary. In alternate embodiments which are
more sensitive to a tissue boundary, it is determined that a tissue boundary is present if the
potential difference meausured in the second mode is greater than 20 %, or alternatively
greater than 10% of the predetermined value or the value measured in the first mode.
In an alternate embodiment, the electrodes can be arranged other than in a square,
providing that there are first and second electrodes for driving a current between and third
and fourth electrodes for measuring a potential difference arranged such that the third and
fourth electrodes are each located substantially the same distance from bom the first and
second electrodes. An example of such an arrangement is where the electrodes are placed
at the corners of a kite shape (a quadrilateral which is symmetrical about one diagonal).
In alternate embodiments more than tour electrodes can be provided. In these
embodiments there must be two electrodes between which a current can be driven between
and two electrodes for measuring potential spaced an equal distance from both of the two
electrodes through which a current is driven. An example of an arrangement suitable for
use with more than four electrodes is a regular hexagon.
All of the above embodiments could be adapted to use the measured potential to calculate
the transfer impedance between the electrodes 18 and 20 and the electrodes 16 and 22.
This can be calculated from the ratio of the measured poteritial between electrodes 18 and

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20 to the amplitude of the current between electrodes 16 and 22. Likewise, the
embodiments can be adapted to measure the current flowing between the electrodes 18 and
20. In these cases, because the system is balanced, the value of the parameter measured
will be zero or close to zero in an ideal theoretical situation. The method of comparing the
values will also work in the same way as described for potential difference.

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CLAIMS
1. A method for determining whether a probe for measuring the impedance of human
or animal body tissue has been placed over a boundary between different tissue types, the
probe comprising at least a first, a second, a third and a fourth electrode arranged such that
the third and fourth electrodes are each located substantially the same distance from both
the first and second electrodes; the method comprising:
driving a current between the first and the second electrode;
measuring a first value of an electrical parameter between the third and the fourth
electrode; and
determining whether the probe has been placed over a boundary between different
tissue types based on the first value.
2. A method according to claim 1 for use with a probe wherein the first, second,
third and fourth electrodes are arranged at the corners of a square with the first and second
electrodes diagonally opposite each other,
3. A method according to claim 2, wherein the step of determining whether the probe
has been placed over a boundary between different tissue types comprises:
comparing the first value to a predetermined value, wherein the predetermined
value is that expected to be obtained when a CTirrent is oMven between me first and mhxl
electrodes and the electrical parameter is measured between the second and fourth
electrode; and wherein if the first value is greater than half the predetermined value it is
determined that the probe has been placed over a boundary between different tissue types.
4. A method according to claim 2, the method further comprising:
driving the current between the first and third electrodes; and
measuring a second value of the electrical parameter between the second and
fourth electrodes;
wherein said step of detennining whether the probe has been placed over a
boundary comprises comparing the first value to the second value and wherein if the first

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-13.
value is greater than half the second value it is determmed that the probe has been placed
over a boundary between different tissue types.
5. A method according to claim 1 or 2, wherein in the step of determining whether
the probe has been placed over a boundary between different tissue types, if the fust value
is not substantially equal to zero it is determined that the probe has been placed over a
boundary between different tissue types.
6. A probe for measuring the impedmre of hum
comprising:
at least a first, a second, a third and a fourth electrode arranged such that the third
and fourth electrodes are each located substantially the same distance from both the first
and second electrodes;
a current source for driving a current between the first and second electrodes;
a measurement circuit for measuring a first value of an electrical parameter
between the third and fourth electrodes; and
a controller for controlling the current source; and
a processor for determining whether the probe has been placed over a boundary
between different tissue types based on the first value.
7. A probe according to claim 6, wherein the first, secorKi, third and fourth electrodes
are arranged at the corners of a square with the first and second electrodes diagonally
opposite each other.
8. A method according to claim 7, wherein the processor is also for comparing the
first value to a predetermined value, wherein me predetenru^ed value is that expected to be
obtained when a current is driven between the first and third electrodes and the electrical
parameter is measured between the second and fourth electrodes; and wherein if the first
value is greater than half the predetermined value it is determined that the probe has been
placed over a boundary between different tissue types.
9. A method according to claim 7, wherein:

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the current source is also for driving a current between the first and third
electrodes; and
the measuring circuit is also for measuring a second value of the electrical
parameter between the second and fourth electrodes;
wherein the processor determines whether the probe has been placed over a
boundary by comparing the first value to the second value, and wherein if the first
electrical parameter is greater man half the second value it is determined that the probe has
been placed over a boundary between different tissue types.
10. A probe according to claim 6 or 7, wherein the processor determines that the
probe has been placed over a boundary between different tissue types ifthe first value is
not substantially equal to zero.
11. A computer program comprising code means that, when executed on a computer
system, instructs the computer system to perform the method according to any one claims 1
to 5.
12. A computer program product comprising a computer readable medium bearing a
computer program according to claim 11.

The method for determining whether a probe for measuring the impedance of human
or animal body tissue has been placed over a boundary between different tissue types
is described. The probe used in the method comprises at least a first (16), a second
(22), third (18) and a fourth (20) electrode arranged such that the third (18) and
fourth (20) electrodes are each located substantially the same distance from both the
first (16) and second (22) electrodes. The method comprises: driving a current between
the first (16) and the second (22) electrodes; measuring a first value of an electrical
parameter between the third (18) and the fourth (20) electrode; and determining
whether the probe has been placed over a boundary between different tissue types
based on the first value. A probe for carrying out the method is also described.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=EJB5cxsV0oE8Qp3wy98miw==&loc=wDBSZCsAt7zoiVrqcFJsRw==

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Patent Number

269099

Indian Patent Application Number

4592/KOLNP/2007

PG Journal Number

40/2015

Publication Date

02-Oct-2015

Grant Date

30-Sep-2015

Date of Filing

28-Nov-2007

Name of Patentee

THE UNIVERSITY OF SHEFFIELD

Applicant Address

WESTERN BANK, SHEFFIELD S10 2TN

Inventors:

#	Inventor's Name	Inventor's Address
1	TIDY, JOHN, ANTHONY	120 RINGINGLOW ROAD, SHEFFIELD S11 7PR
2	BROWN, BRIAN, HILTON	16, CARTLEDGE LANE, HOLMESFIELD, DERBYSHIRE S18 7SB

PCT International Classification Number

A61B 5/053

PCT International Application Number

PCT/GB2006/002026

PCT International Filing date

2006-06-02

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0511289.1	2005-06-03	U.K.