WO2017074378A1 - Apparatus, system and method employing impedance measurements and images for disease detection - Google Patents

Apparatus, system and method employing impedance measurements and images for disease detection Download PDF

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Publication number
WO2017074378A1
WO2017074378A1 PCT/US2015/057965 US2015057965W WO2017074378A1 WO 2017074378 A1 WO2017074378 A1 WO 2017074378A1 US 2015057965 W US2015057965 W US 2015057965W WO 2017074378 A1 WO2017074378 A1 WO 2017074378A1
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plurality
electrodes
set
impedance
fiducial
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PCT/US2015/057965
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French (fr)
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Arthur A. AARON
Michael E. Beach
Christopher W. CAHILL
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Aaron Arthur A
Beach Michael E
Cahill Christopher W
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/44Detecting, measuring or recording for evaluating the integumentary system, e.g. skin, hair or nails
    • A61B5/441Skin evaluation, e.g. for skin disorder diagnosis
    • A61B5/444Evaluating skin marks, e.g. mole, nevi, tumour, scar
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/0059Detecting, measuring or recording for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0077Devices for viewing the surface of the body, e.g. camera, magnifying lens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/05Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radiowaves
    • A61B5/053Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0531Measuring skin impedance
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/06Devices, other than using radiation, for detecting or locating foreign bodies ; determining position of probes within or on the body of the patient
    • A61B5/061Determining position of a probe within the body employing means separate from the probe, e.g. sensing internal probe position employing impedance electrodes on the surface of the body
    • A61B5/064Determining position of a probe within the body employing means separate from the probe, e.g. sensing internal probe position employing impedance electrodes on the surface of the body using markers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/684Indicating the position of the sensor on the body
    • A61B5/6842Indicating the position of the sensor on the body by marking the skin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2560/00Constructional details of operational features of apparatus; Accessories for medical measuring apparatus
    • A61B2560/04Constructional details of apparatus
    • A61B2560/0443Modular apparatus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2560/00Constructional details of operational features of apparatus; Accessories for medical measuring apparatus
    • A61B2560/04Constructional details of apparatus
    • A61B2560/0462Apparatus with built-in sensors
    • A61B2560/0468Built-in electrodes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/04Arrangements of multiple sensors of the same type
    • A61B2562/046Arrangements of multiple sensors of the same type in a matrix array
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6843Monitoring or controlling sensor contact pressure

Abstract

An impedance measurement apparatus is employed to collect information concerning a region of the skin of a subject. The apparatus includes a set of electrodes employed in impedance measurements and a housing. The housing includes a body configured to be gripped by a user when the set of electrodes are applied to the subject and a head located at a distal end of the body. The set of electrodes are configured for removable attachment to the head. A first plurality of fiducial markers is included as a part of the apparatus. A second plurality of fiducial markers is located on the subject adjacent the region. The first plurality of fiducial markers is configured to allow the user, while applying the impedance probe to the subject, to confirm that the set of electrodes is in a location determined when the first plurality of fiducial markers are aligned in a known alignment relative to the second plurality of fiducial markers.

Description

APPARATUS, SYSTEM AND METHOD EMPLOYING IMPEDANCE MEASUREMENTS AND IMAGES FOR DISEASE DETECTION

BACKGROUND OF INVENTION

1. Field of Invention

Embodiments of the invention generally relate to impedance measurements employed in health care, more specifically, at least one embodiment relates to apparatus, systems and methods for impedance measurements and images employed together for diagnosis of surface lesions.

2. Discussion of Related Art

Electrical impedance measurements are employed in various diagnostic approaches in health care today. For example, electrical impedance measurements are used to characterize tissue such as lesions located on the surface of a patient's skin or within the patient' s body. Imaging systems including cameras are also used by medical professionals to characterize tissue. Some approaches employ both impedance measurements and other images in a dual modality. These approaches can provide a wider range of information for use in making a diagnosis.

However, approaches that employ a combination of electrical impedance measurements and images together are rarely attempted. One challenge to the preceding is in finding an effective process to align the impedance measurements with locations in the image. In summary, an efficient and clinically effective process for collecting and evaluating a combination of these two forms of data has not been identified. For example, some prior approaches include the use of fiducial markers to assist in the alignment process of the impedance measurements and digital images. However, where a camera is used to capture images, these approaches generally locate the fiducial marker on the impedance measurement probe and require that the probe remain in place on the patient while the photographs or video images are recorded. Images of the patient with the probe removed are employed in combination with the images that include the probe with fiducials. Consequently, these approaches are somewhat slow and tedious. Other approaches combine impedance measurements with x-ray imaging. These approaches describe that x-ray absorbing alignment marks are used.

Mechanical means such as x-ray absorbing brackets, straight edges and rims are also described for use in aligning an impedance probe with an x-ray imager. However, even where the preceding approach is employed it relies on the user trying to position the impedance probe using fiducials or mechanical means only located on the patient. Some larger impedance measurement equipment forces the user to try to locate the fiducials by looking around the bulky impedance measurement equipment. Thus, the approach is not suitable for widespread use because it can be difficult and time consuming.

While older style equipment is oversized for practical use, newer impedance probes have measurement areas that are so small that most sets of impedance measurements do not provide measurements of both healthy tissue and unhealthy tissue when applied at a single measurement location. Instead, the small overall area covered with the impedance probe located at a single location requires that the practitioner take measurements at a series of different locations as the probe is relocated along the surface of the skin. Only by this time-consuming approach is the practitioner able to capture impedance data for both an area where the lesion appears and an area of healthy tissue in the vicinity of the lesion. The lack of easily obtainable reference measurements for healthy skin makes accurate diagnosis more difficult. The slow process required to capture such data makes the approach more costly.

Consequently, these approaches are not widely adopted in the field of dermatology.

SUMMARY OF INVENTION

According to the various apparatus, system and methods described herein, impedance measurements are taken using a handheld impedance measurement device that is small enough to easily use with a single hand while also employing an electrode array that is large enough to provide sufficient impedance information when applied at a single location on a patient's skin. In particular, in some embodiments described herein, the electrode array is sized such that information is collected for both a lesion and reference area in the vicinity of the lesion with the array applied at one location. Further, a single set of fiducial markers are employed for use with both impedance measurement apparatus and digital imaging apparatus. The preceding allows the approaches described herein to provide a diagnosis through automatic analysis of the information provided by both the digital image and the impedance measurement apparatus. In some embodiments, a first set of fiducial markers are applied to a patient and a second set of fiducial markers included in the impedance measurement apparatus are employed in combination therewith.

In one aspect, an impedance measurement apparatus is employed to collect information concerning a region of the skin of a subject. The apparatus includes a set of electrodes employed in impedance measurement, a housing and a first plurality of fiducial markers. The housing includes a body configured to be gripped by a user when the set of electrodes are applied to the subject and a head located at a distal end of the body. The head is configured for a removable connection of the set of electrodes. A second plurality of fiducial markers are located on the subject adjacent the region being measured. The first plurality of fiducial markers are configured to allow the user, while applying the impedance probe to the subject, to confirm that the set of electrodes is in a location determined when the first plurality of fiducial markers are aligned in a known alignment relative to the second plurality of fiducial markers.

In one embodiment, the head includes the first plurality of fiducial markers. In a further embodiment, the head includes a plurality of viewing elements, each viewing element including at least one of the first plurality of fiducial markers.

According to another embodiment, a size of a total area covered by the plurality of measurement electrodes is selected based on the surface area of a target lesion. According to further embodiments, a first impedance measurement corresponds to a location of a lesion and a second impedance measurement corresponds to a location that does not include the lesion. In a further embodiment, a size of individual electrodes included in the plurality of measurement electrodes, a quantity of electrodes included in the plurality of measurement electrodes and a distribution of electrodes included in the plurality of measurement electrodes are selected such that the first impedance measurement and the second impedance measurement are available for any single electrode location such that a portion of the surface area of the target lesion is located within the total area. According to one embodiment, the preceding design considerations concerning the measurement electrodes are selected to achieve the respective first and second measurements where the portion of the target lesion has a diameter of substantially 2 mm or greater.

According to another aspect, a method of diagnosing a condition of a region of the skin of a subject using an impedance measurement device and imaging equipment is provided. The impedance measurement device includes a first plurality of fiducial references and the region of the skin includes a lesion. In one embodiment, method includes acts of applying a second plurality of fiducial references on the subject in a vicinity of the region, placing the impedance measurement device in contact with the skin at a location such that the first plurality of fiducial references are aligned with corresponding ones of the plurality of fiducial references on the subject, respectively, taking a plurality of impedance measurements of the region of the skin with the impedance measurement device at the location, and taking at least one image showing a surface of the skin including the region. In further embodiments, the second plurality of fiducial references appear in the at least one image. The method also includes determining, using the second plurality of fiducial references appearing in the at least one image, locations in the at least one image corresponding to respective ones of the plurality of impedance measurements, respectively, and providing a diagnosis of the condition of the region of the skin based on a visual condition of the surface of the skin in at least a part of the region appearing in the at least one image and respective values of the plurality of impedance measurements.

According to one embodiment, the method includes providing a diagnosis including a determination of whether the lesion is benign or malignant following automatic analysis of the plurality of impedance measurements and the at least one image by the impedance measurement device.

According to another embodiment, the method includes wirelessly

communicating data concerning the plurality of impedance measurements to a device employed to automatically categorize the lesion as malignant or benign based on the data and information determined from the at least one image. According to still another aspect, a method of providing an impedance measurement apparatus for an automated diagnosis of lesions is provided. According to one embodiment the method includes acts of determining a maximum surface area of the lesions that qualify as a target lesion, determining a minimum surface area of the lesions that qualify as the target lesion, and providing a set of measurement electrodes in the impedance measurement apparatus that are sized to provide a measurement area such that a plurality of impedance measurements taken by the apparatus at any one location, with a surface area of the target lesion within the measurement area being at least as large as the minimum surface area, includes at least a first impedance measurement and a second impedance measurement.

According to this embodiment, the first impedance measurement corresponds to a location of the target lesion, and the second impedance measurement corresponds to a location that does not include the target lesion.

According to a further embodiment, the method includes configuring the impedance measurement device as a handheld device sized and configured to grip with a single hand while the handheld impedance probe is applied to a subject.

As used herein when referring to "contact" between an impedance

measurement electrode and a subject, the term "contact" refers to an electrically conductive path established between the electrode and the skin of the subject. As will be recognized by those of ordinary skill in the art in view of the preceding, where a gel is employed on the surface of the electrode and/or skin of the subject an electrode is "in contact" with the skin where the conductive path is established even if the surface of the electrode is not in direct contact with the skin (i.e., where a layer of conductive gel is located between the contact and the skin).

As used herein, the term "reference area(s)" refers to an area of the skin that does not include a lesion. As is appreciated by those of skill in the art, a reference area can be located immediately adjacent a lesion or elsewhere on the body.

The term "surface area" as used herein when referring to a lesion refers to the two dimensional area covered by the lesion when viewed from a location orthogonal to the lesion. As is appreciated by those of skill in the art, in this context, surface area does not include vertical area created by changes in the surface elevation of the lesion. BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures is represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. In the drawings:

FIG. 1 is a schematic diagram of a set of impedance measurement electrodes and associated circuitry in accordance with one embodiment;

FIG. 2 illustrates discrete impedance elements superimposed on the electrode array illustrated in FIG. 1 ;

FIG. 3 illustrates a digital image of a lesion in accordance with one embodiment;

FIG. 4 illustrates the digital image of FIG. 3 superimposed on the plan view illustrated in FIG. 2 in accordance with one embodiment;

FIG. 5 is an isometric view of a portion of an impedance measurement instrument in accordance with one embodiment;

FIG. 6 is a side elevation view of a distal end of the impedance measurement instrument illustrated in FIG. 5 ;

FIG. 7 is a side elevation view of the impedance measurement instrument illustrated in FIG. 6 applied to a subject;

FIG. 8 is a plan view of a region of a subject's skin with locations of a set of electrodes superimposed on the region in accordance with one embodiment;

FIG. 9 is a plan view of a region of a subject's skin and fiducial markers in accordance with one embodiment;

FIG. 10 is a plan view of fiducial markers applied in a region of a subject's skin including a lesion in accordance with one embodiment;

FIG. 11 is a plan view of a portion of an impedance measurement instrument in accordance with another embodiment;

FIGS. 12A and 12B illustrate respective alignments of fiducial markers in accordance with one embodiment; FIGS. 13A and 13B illustrate respective alignments of fiducial markers in accordance with another embodiment;

FIG. 14 is a block diagram of a system including an impedance measurement system in accordance with one embodiment;

FIGS. 15A and 15B illustrate an electrode assembly in accordance with one embodiment; and

FIG. 16 illustrates a flow diagram of a process in accordance with an embodiment. DETAILED DESCRIPTION

This invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," "having," "containing," "involving," and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

Figure 1 illustrates a system 10 including an electrode array 12 employed in an apparatus used for impedance measurements. In the illustrated embodiment, the electrode array 12 is applied to the surface of a subject's skin, for example, to measure the impedance in the vicinity of a lesion or other abnormality. The system 10 also provides impedance measurements for regions of the skin that are void of any lesions, for example, regions of the healthy skin immediately adjacent a lesion. The system 10 includes a first multiplexer 14, a second multiplexer 16, a third multiplexer 18 and a fourth multiplexer 20. In the illustrated embodiment, the electrode array 12 includes a first set of drive electrodes 22, a second set of drive electrodes 24, a third set of drive electrodes 26, a fourth set of drive electrodes 28 and a set of measurement electrodes 30. Depending on the embodiment, a drive electrode can be employed as a signal source or a signal return. The first multiplexer 14 is connected to the first set of drive electrodes 22 and the second set of drive electrodes 24. The second multiplexer 16 is connected to the third set of drive electrodes 26 and the fourth set of drive electrodes 28. Each of the third multiplexer 18 and the fourth multiplexer 20 are connected to the measurement electrodes 30.

According to the illustrated embodiment, the electrode array 12 is organized into rows and columns. In one embodiment, each electrode included in the array 12 is manufactured from a material including silver and silver chloride. However, other materials with high electrical conductivity can be employed, for example, aluminum, copper, gold, platinum and various alloys including combinations of the preceding can be used. In some embodiments, the electrode array 12 is located on a substrate common to all the electrodes included in the array 12, for example, a printed circuit board.

For purposes of the description herein, rows are labeled from one to four, top to bottom while columns are labeled from one to four, left to right. Using the preceding methodology, measurement electrodes 30 are individually identified using row-column numbers for purpose of the description herein. The four corner electrodes 1-1, 1-4, 4-1 and 4-4 are identified in FIG. 1 for reference.

Additional circuitry (described below) is provided for operation of the electrode array 12. In general, an impedance measurement is initiated by selecting a particular row/column to drive current along the skin of the subject and beneath the skin of the subject at varying depths. A differential voltage measurement on two nodes that are located within the current path (for example, located between a location of the two active drive electrodes) is performed for each impedance measurement. A measurement of the drive current is also performed in the device and the impedance of the segment of skin is calculated as Z = V/I. According to the illustrated embodiment, a first electrode selected from among the electrodes included in the sets of drive electrodes 22, 24, 26, 28 is energized to source a low level alternating current. For example, the current levels at each of a variety of frequencies are maintained within the safety limits defined in IEC-60601. A second electrode selected from among the electrodes included in the sets of drive electrodes 22, 24, 26, 28 is energized to provide a return current path to the impedance measurement apparatus. Electrodes included in the set of measurement electrodes 30 are employed to measure voltage produced by the drive current.

According to one embodiment of the apparatus 10 illustrated in FIG. 1, the multiplexers 14, 16 selectively operate a pair of electrodes in a selected row or column where current is driven from a first electrode to a second electrode at the opposite end of the row or column. For example, a first electrode among the first set of drive electrodes 22 can be activated along with a second electrode selected from among the third set of drive electrodes 26. Thus, the first multiplexer 14 can operate in one measurement sequence by selecting each of the drive electrodes in the first set of drive electrodes 22 in col. 1 - 4, in turn. At the same time, the second multiplexer 16 operates to select each of the drive electrodes in the third set of drive electrodes 26 in col. 1-4 when the opposing electrode among the first set of drive electrodes is active.

The above described pairing of electrodes is employed to apply current to the subject. The measurement electrodes 30 included in the array 12 are employed to measure a resulting voltage found at various points along the current path. According to one embodiment, each available electrode pairing in a given row and a given column of the measurement electrodes 30 is employed in the impedance

measurements. For example, when the drive electrodes at opposing ends of row 1 are energized the following electrode pairs are employed for impedance measurement: the pair of electrodes 1-1 and 1-2; the pair of electrodes 1-1 and 1-3; the pair of electrodes 1-1 and 1-4; the pair of electrodes 1-2 and 1-3; the pair of electrodes 1-2 and 1-4; and the pair of electrodes 1-3 and 1-4. A similar approach can also be employed in each column of the measurement electrodes 30. Thus, when the drive electrodes at opposing ends of column 4 are energized, the following electrode pairs are employed for impedance measurement: the pair of electrodes 1-4 and 2-4; the pair of electrodes 1-4 and 3-4; the pair of electrodes 1-4 and 4-4; the pair of electrodes 2-4 and 3-4; the pair of electrodes 2-4 and 4-4; and the pair of electrodes 3-4 and 4-4.

Further, in some embodiments, the low level alternating drive current is provided at a plurality of different frequencies, respectively. In these embodiments, a series of measurements are taken for a plurality of different drive currents each provided at a different frequency, respectively. According to one embodiment, drive current is applied at a plurality of frequencies that range from 500Hz to lMHz.

According to another embodiment, drive current is applied at a plurality of frequencies that range from approximately 100Hz to 5MHz. According to still another embodiment, drive current is applied at a plurality of frequencies that range from approximately 100Hz to 10MHz.

In some embodiments, an impedance measurement operation includes sequentially operating pairs of drive electrodes for each row and each column of the electrode array 12. The drive current is also sequentially applied at a plurality of frequencies to adjust a depth at which impedance measurements are performed. A full set of measurements is taken using all possible combinations of measurement electrodes in each of the respective rows and columns. Referring again to the above example and the electrode array 12, when drive electrodes at opposing ends of row 1 are energized at the various frequencies the following electrode pairs are employed for impedance measurements at each of the frequencies: 1-1 and 1-2; 1-1 and 1-3; 1-1 and 1-4; 1-2 and 1-3; 1-2 and 1-4; and 1-3 and 1-4. A full set of measurements can include the same form of measurements as the preceding for each row and each column in the electrode array 12.

Referring now to Fig. 2, an electrode assembly 31 includes the electrode array 12 located on a substrate 33. As illustrated, the substrate includes a first corner 34, a second corner 36 and a third corner 38. In some embodiments, an electrical connector (not shown) is located on a rear of the substrate such that the electrode array 12 can be removably connected to a corresponding electrical connection in the impedance measurement device, for example, plugged into a handheld impedance measurement device. In further embodiments, the electrode array 12 includes a flexible cable including a connector employed to connect to the electrodes in the array to additional circuitry located external to the array 12. In one embodiment, the electrode array 12 is located on a flexible substrate.

FIG. 2 schematically illustrates a set of impedance measurements according to one embodiment. As illustrated, the impedance measurements are taken between adjacent electrodes by row and by column. In column 1, an impedance Zi is measured between the electrode 1-1 and the electrode 2-1, an impedance Z2 is measured between the electrode 2-1 and the electrode 3-1, and an impedance Z3 is measured between the electrode 3-1 and the electrode 4-1. As described above, these three impedance values Zi - Z3 are sequentially measured by selective activation of pairs of measurement electrodes 1-1, 2-1, 3-1 and 4-1. The measurement operations are performed with the electrode array 12 in contact with the subject while current is driven between the drive electrode located at the top of column 1 and the drive electrode located at the bottom of column 1.

A similar set of measurements can be made in each of columns 2-4, and each of rows 1-4. For example, in row 1, an impedance Z4 is measured between the electrode 1-1 and the electrode 1-2, an impedance Z5 is measured between the electrode 1-2 and the electrode 1-3, and an impedance Z6 is measured between the electrode 1-3 and the electrode 1-4.

Different and/or additional impedance measurements can be made in addition to those illustrated in FIG. 2. As just two examples of the additional measurements possible with the array 12, an impedance Z7 and an impedance Z8 can be measured along with the impedances measured between the electrode 1-4 and an electrode 3-4 in column 4. In general, the diagnostic value of the impedances measured by the array can be improved by taking measurements using electrodes separated by different distances because the voltage along the current path is measured at different depths as the distance between electrodes changes. Different sequencing can be employed in different embodiments.

Embodiments described herein employ fiducials applied to the subject to provide a known alignment between a location of measurement electrodes 30 during the impedance measurements and locations within an image taken of the lesion and surrounding skin. In various embodiments, the approaches described herein allow an accurate mapping of impedance measurements to locations within the image. In general, these approaches, facilitate an evaluation of the lesion by providing impedance measurements at various depths in: 1) regions where the lesion appears in the image; 2) reference regions, e.g., regions free of a visible evidence of the lesion; and 3) border regions, e.g., regions in the vicinity of an outer border of a lesion at a transition to a reference region. In various embodiments, algorithms are employed to process the impedance information as well as the appearance of the lesion in the image to determine whether a lesion is benign or malignant. Further, approaches described herein can be employed to determine a risk level for malignant lesions by evaluating the combination of impedance measurements and image data.

Referring now to FIG. 3, a digital image 40 of a lesion 42 and its surroundings is illustrated in accordance with one embodiment. The image 40 includes a first fiducial 44, a second fiducial 46 and a third fiducial 48. In various embodiments, the fiducials were applied to the skin of the subject using one of a variety of approaches. As two examples, the fiducials can be applied directly to the skin in advance of impedance measurements or concurrently with the impedance measurements. In one embodiment, the latter approach is achieved by including a fiducial stamp in a portion of an impedance measurement device that contacts the skin of the subject when the impedance measurements are taken. In this embodiment, the stamp leaves stamped- marks on the skin of the subject. The marks are visible when the impedance measurement device is removed. According to another embodiment, the fiducials are included on a substrate that is temporarily affixed to the skin of the subject, for example, an adhesive-backed substrate. In according to another embodiment, fiducials are manually applied by pen and ink when the impedance measurement array is located at a measurement location on the skin.

In various embodiments, the fiducials provide a fixed reference from which coordinates can be established for an accurate alignment of the impedance measurements with locations within the image. Further, multiple fiducials are employed to assure that these coordinates are accurately established. For example, the use of at least three fiducials provides a coordinate system that eliminates error that might otherwise result from image rotation and image tilt, that is, rotation about an axis perpendicular to the skin and rotation about an axis parallel to the surface, respectively. Other image processing techniques can be employed as needed to align the impedance measurement data with locations in the image. For example, scaling or more complex image transformation processes can be employed, as necessary. Depending on the embodiment, various imaging techniques can be employed in combination with impedance measurements. In one embodiment, digital photographs are employed where the image provides a 2D image including the lesion.

Referring now to FIG. 4, the electrode array 12 is shown with the corners 34, 36, 38 aligned with the fiducials 44, 46, 48 illustrated in FIG. 3. The alignment provides a coordinate system with known locations of the set of measurement electrodes 30 relative to the fiducials 44, 46, 48. FIG. 4 also includes the image 40 illustrated in FIG. 3 superimposed on the electrode array. The image includes the lesion 42. The alignment of the image 40 with the electrode array is readily achieved because alignment of the three corners 34, 36, 38 of the electrode assembly 31 with the corresponding fiducials 44, 46 and 48, respectively, places the electrodes at known coordinates relative to the fiducials. The image 40 can be processed to provide a scale and rotation that place the lesion (and the surrounding reference regions) at known coordinates relative to the fiducials. With a known alignment, known overall dimensions of the set of measurement electrodes 30 and known spacing between electrodes included in the set of measurement electrodes 30 a precise mapping of the impedance measurements to locations in the image can be made. Thus, the use of fiducials allows a location of impedance measurements to be mapped relative to pixel coordinates within the image.

Referring now to FIG. 5 a portion of an impedance measurement instrument

60 is illustrated in accordance with one embodiment. The instrument 60 includes a housing 62, the electrode array 12 and a plurality of pins. The housing 62 includes an outside edge 63. According to the illustrated embodiment, the plurality of pins include a first pin 64, a second pin 66, a third pin 68 and a fourth pin 70. The housing 62 is employed to house the various other elements of the instrument 60 including additional components, different components and different combinations of components as illustrated.

According to some embodiments, the housing 62 includes a distal region at which the electrode array 12 is located, for example, a head 65. In the illustrated embodiment, a proximate region of the housing 62, a body 67, is employed by the user to grip the instrument 60. In one embodiment, the electrode array 12 is included as a part of a cartridge suitable for removable attachment to the head 65.

As described in detail below, approaches optimize the sizing of the electrode array 12 such that it is sufficiently large to measure the impedance of both a lesion and an adjacent reference region of any lesion within a target lesion size. By identifying the maximum size of lesions for some of the most common malignancies, these same approaches can assist in maintaining a form factor suitable for a handheld instrument.

According to various embodiments, the electrode array 12 includes both drive electrodes and measurement electrodes, for example, the first set of drive electrodes 22, the second set of drive electrodes 24, the third set of drive electrodes 26, the fourth set of drive electrodes 28 and the set of measurement electrodes 30 illustrated in FIG. 1. Alternatively, other electrode- array configurations can be employed.

According to some embodiments, the plurality of pins 64, 66, 68, 70 include a plurality of different shapes to allow each to be uniquely identified relative to the others. For example, each of the plurality of pins 64, 66, 68, 70 can be a selected geometric shape relative to the others. Alternatively, or in combination with the preceding, each of the plurality of pins 64, 66, 68, 70 can be a unique color relative to others of the pins. The preceding approaches can be employed where for example the pins are aligned with fiducials on the subject and the fiducials also have unique shapes corresponding to various ones of the pins 64, 66, 68, 70, respectively. Both shape and color coding are beneficial if the plurality of pins 64, 66, 68, 70 appear in the digital image. As described in greater detail below, one or more of the plurality of pins 64, 66, 68, 70 can be employed to sense when the instrument 60 is applied to the subject such that the electrode array 12 is in contact with the subject's skin. Further, while referred to as "pins" these elements include flat surfaces at their distal ends in the illustrated embodiments. In other embodiments, the pins 64, 66, 68, 70 can include curved or pointed surfaces to engage the subject's skin.

Referring to FIG. 6, a side elevation view of the impedance measurement instrument 60 is illustrated in accordance with one embodiment. This view is from the left side given the perspective of the practitioner operating the instrument 60. Accordingly, the second pin 66 and the third pin 68 are visible in this view. The housing 62 also includes a surface 72. The electrode array 12 is also visible in profile in FIG. 6. However, according to other embodiments, the housing 62 encloses the electrode array 12 such that it is flush with the surface 72 and only exposed in a direction perpendicular to the surface 72.

According to some embodiments, the plurality of pins 64, 66, 68, 70 are employed to sense when the instrument 60 is located against the subject's skin such that the electrode array 12 is in contact with the skin. FIG. 7 illustrates one such embodiment illustrating a portion of a subject 76 including a surface 78 of the subject's skin. In FIG. 7, the impedance measurement instrument 60 is pressed against the surface 78 such that the electrode array 12 is in contact with the surface 78. With the electrode array 12 in contact with the surface 78, the second pin 66 and the third pin 68 are moved to a recessed position within the housing 62. According to one embodiment, each of the plurality of pins 64, 66, 68, 70 is spring-loaded to maintain the respective pin in the extended position illustrated in FIG. 5 before the instrument 60 is applied to the surface 78. According to this embodiment, the limited amount of force required to place the electrode array 12 against the surface 78 overcomes the spring pressure to allow the plurality of pins 64, 66, 68, 70 to be depressed into the housing 62.

According to various embodiments, the plurality of pins are employed to provide the instrument 60 with feedback concerning a position of the instrument 60 relative to the surface 78. In one embodiment, a depression of one or more of the plurality the pins 64, 66, 68, 70 changes the state of a limit switch when the electrode array 12 is placed in contact with the surface 78. However, the position sensing of the pins can be provided in a variety of configurations depending on the embodiment. According to one embodiment, a conventional mechanical switch is operated by movement of the corresponding pin or pins. In other embodiments, a magnetically operated (for example, a Hall effect) switch is employed. In still other embodiments, the plurality the pins 64, 66, 68, 70 are replaced by a different style sensing element. For example, the plurality the pins 64, 66, 68, 70 can be replaced by contact surfaces that are coupled to sensing circuitry in the instrument 60. For example, the contact surfaces can be located at the same depth as the contact surfaces of the electrode array 12. When the contact surfaces make contact with the surface 78, the sensing circuitry within the instrument 60 signals that the electrode array 12 is in position to perform impedance measurements. According to another embodiment, the pins 64, 66, 68, 70 are replaced by capacitive touch sensors located within the instrument to

automatically detect when the electrode array is placed in contact with the subject.

Referring now to FIG. 8, the lesion 42 and the fiducials 44, 46, 48 are illustrated with a location of the electrode array 12 superimposed on the region of the skin where the lesion 42 is located. In particular, the location of the electrode array 12 appears where the sets electrodes 22, 24, 26, 28, 30 make contact with the skin when the instrument 60 is aligned with the fiducials 44, 46, 48. For example, where a plurality of fiducials included in the instrument 60 are aligned with respective ones of the fiducials 44, 46, 48.

As can be seen from FIG. 8, the area covered by the set of measurement electrodes 30 includes the lesion 42, a region of healthy skin 80 and a border region 82 found at the border between the lesion 42 and the region of healthy skin 80. In the illustrated embodiment, the size the electrode array 12 and the location at which the instrument is placed on the skin result in the entire lesion 42 being located within the area covered by the set of measurement electrodes 30. As a result, the edge region 82 appears for 360 degrees around a circumference of the lesion in the set of

measurements. In addition, a region of healthy skin 80 is measured immediately adjacent the lesion 42 for 360 degrees around a circumference of the lesion. However, the results of the diagnosis processes described herein can be provided where only a portion of the lesion 42 is covered by the measurement electrodes 30.

As is described in more detail herein, fiducials can be included as a part of the instrument 60. FIG. 9 illustrates such an approach in accordance with one

embodiment. In FIG. 9, the fiducials are illustrated as they appear relative to one another when properly aligned. For clarity, the instrument 60 is not illustrated in FIG. 9.

In one embodiment, a set of fiducials located on the skin of the subject include a first fiducial 83, a second fiducial 85 and a third fiducial 87. Further, two styles of fiducials are illustrated. The first fiducial 83 and the third fiducial 87 are provided as an object with two straight lines that meet to form a right angle. The second fiducial 85 is a circular object with an unmarked central region. Depending on the

embodiment, other geometric shapes and geometric relationships can be employed to form a fiducial provided that they can be used with a corresponding geometric shape included in a fiducial on the instrument 60. The set of fiducials is applied to the skin as described elsewhere herein.

In FIG. 9, a set of fiducials provided in the instrument 60 include a fourth fiducial 84, a fifth fiducial 86 and a sixth fiducial 88. As illustrated, the fourth fiducial 84 and the sixth fiducial 88 are provided as an object with two straight lines that meet to form a right angle. An interior of the right angle formed by the lines faces in a direction opposite the direction of an interior of the right angles formed by the first fiducial 83 and the third fiducial 87, respectively. The fifth fiducial 86 is a circular object that has a diameter smaller than a diameter of the second fiducial 85. Thus, when the instrument 60 is properly aligned with the set of fiducials on the skin, a point formed by the fourth fiducial 84 meets a point formed by the first fiducial 83, a point formed by the sixth fiducial 88 meets a point formed by the third fiducial 87 and the fifth fiducial 86 is centrally located within the second fiducial 85.

According to an alternate embodiment, the fourth fiducial 84, the fifth fiducial 86 and the sixth fiducial 88 are included in the set of fiducials located on the skin of the subject. In this embodiment, the first fiducial 83, the second fiducial 85 and the third fiducial 87 are included in the set of fiducials included in the instrument 60. Thus, the circular fiducial included in the set of fiducials on the skin of the subject has a smaller diameter than the circular fiducial included in the instrument in contrast to the embodiment described above.

Referring now to FIG. 10, an applicator 90 is illustrated according to one embodiment. In this embodiment, the applicator 90 includes a substrate 92 including a set of fiducials including a first fiducial 94, a second fiducial 96 and a third fiducial 98. In some embodiments, the substrate 92 is an adhesive -backed substrate, for example, a piece of tape. In various embodiments, the fiducials 94, 96, 98 are preprinted on the substrate 92. For example, each of the individual fiducials 94, 96, 98 is provided on the substrate 92 in advance of the substrate 92 being applied to the subject. Typically, the shape and size of the fiducials 94, 96, 98 is selected for use with the complementary fiducials, respectively, included in the instrument 60.

The shape, style and orientation of fiducials 94, 96, 98 included in a set of fiducials can be the same. Alternatively, a mix of shapes, styles and orientations can be used in combination in a single set of fiducials. For example, in FIG 10 the first fiducial 94 and the third fiducial 98 are two lines that meet to form a 90 degree angle, respectively. However, the two fiducials 94, 98 are facing in the opposite direction from one another. Further, the quantity and type of shapes, and the relative placement of the individual fiducials 94, 96, 98 included in the set of fiducials located on the substrate 92 can be used can improve the accuracy of the alignment. For example, the proper rotational alignment can be unambiguously determined with the relative placement of the three fiducials 94, 96, 98 illustrated in FIG. 10.

Referring to FIG. 11 an impedance measurement instrument 160 is illustrated in accordance with one embodiment. The instrument 160 includes a housing 162 having an edge 163 and a surface 164, an electrode array 112, a first viewing element 102, a second viewing element 104 and a third viewing element 106. In various embodiments, the viewing elements 102, 104 and 106 include sighting holes or ports employed to view fiducials located on the subject, for example, the fiducials 94, 96, 98 illustrated in FIG. 10. Further, the viewing elements 102, 104, 106 are used to align the instrument 160 with the fiducials on the subject when impedance measurements are taken. The alignment fixes a location of the impedance

measurements relative to the location of the fiducials located on the subject. In the illustrated embodiment, the surface 164 of the impedance measurement instrument 160 faces the subject when the electrode array 112 is placed in contact with the subject's skin.

According to some embodiments, the viewing elements 102, 104, 106 are through-holes included in the instrument 160 such that they are enclosed for a full 360 degrees about the viewing element by the housing 162. Thus, these embodiments employ "interior" viewing elements that allow the user to "see through" the housing 162. In various embodiments, the viewing elements 102, 104, 106 extend from a first side of the housing which faces the user during operation to a second side of the housing which faces the subject during impedance measurements. According to one embodiment, the interior viewing elements are oriented to place them such that central longitudinal axis of respective viewing elements are substantially perpendicular to the surface of the electrode array used for impedance measurements.

According to other embodiments, one or more viewing elements can be provided at the outside edge 163 of the housing 162. For example, in some embodiments, a viewing element 108 is formed as a shape in the outside edge 163 of the housing 162. Examples of these "exterior" viewing elements 108 include semicircles, and other angled cutouts formed at one or more locations along the outside edge 163. In some embodiments, one or more "exterior" viewing elements 108 are employed in combination with "interior" viewing elements such as one or more of the viewing elements 102, 104, 106.

In some embodiments, the viewing elements 102, 104, 106 include fiducials. When impedance measurements are taken, the fiducials included in the viewing elements are aligned with the corresponding fiducials, respectively, located on the skin of the subject. As one example, the surface 164 of the impedance measurement instrument 160 is facing a subject with the applicator 90 and corresponding fiducials 94, 96 and 98 oriented as shown in FIG. 9 already applied to the subject's skin. To align the impedance measurement instrument 160 with the fiducials 94, 96, 98, a user can move the instrument such that the first viewing element 102 is located above the third fiducial 98, the second viewing element 104 is located above the second fiducial 96 and the third viewing element 106 is located above the first fiducial 94. Further, each of the viewing elements 102, 104, 106 can include a fiducial having a style similar to the fiducial 94, 96, 98 with which they are to be aligned.

FIG. 12A illustrates a fiducial 114 included in the third viewing element 106. In FIG. 12A, the fiducial 114 and the first fiducial 94 are not properly aligned.

Therefore, the user operating the impedance measurement instrument 160 is aware that impedance measurements should not be taken with the instrument 160 in that location. FIG.12B illustrates the fiducial 114 and the first fiducial 94 are properly aligned. Here, the user understands that the alignment involving the third viewing element is satisfactory.

FIG. 13A illustrates a fiducial 116 included in the second viewing element 104. In FIG. 13A, the fiducial 116 and the second fiducial 96 are not properly aligned. FIG. 13A provides another example in which the user operating the impedance measurement instrument 160 is aware that impedance measurements should not be taken with the instrument 160 in that location. FIG.13B illustrates the fiducial 116 and the first fiducial 96 are properly aligned. Here, the user understands that the alignment involving the second viewing element is satisfactory.

According to the preceding example, where the three viewing elements 102,

104, 106 are employed together in an alignment process, the user of the instrument 160 can begin an impedance measurement sequence when the fiducials are aligned as shown in FIG.12B and 13B provided that the third fiducial 94 is properly aligned with a fiducial included in the first viewing element 102.

Referring again to FIGS.12A, 12B, 13A and 13B, the fiducials 114, 116 can be provided as fiducial marks on a lens or other transparent surface located within the viewing element 106, 104, respectively. However, in other embodiments, the viewing element 102, 104, 106 can form a fiducial reference. In one embodiment, the fiducial 116 is provided by the walls of the viewing element 104 where, for example, the viewing element is a through hole in the housing 162 having a circular shape. In this example, an operator of the impedance measurement instrument 160 aligns the fiducial 116 with the second fiducial 96 by centering the second fiducial 96 within the fiducial 116 formed by the through-hole style viewing element.

Referring now to FIG. 14, a block diagram of system 250 including a computer 251 and an impedance measurement device 260 is illustrated in accordance with one embodiment. Depending on the embodiment, the computer 251 can be a portable computing device such as a tablet computer or smartphone, a laptop computer or a desktop computer. In general, the impedance measurement device 260 operates to measure and store impedance values taken for one or more regions of the skin of a subject. According to some embodiments, the information concerning the impedance measurements is wirelessly transmitted to the computer 251 for storage and or processing. In further embodiments, one or more images provided by imaging equipment external to the impedance measurement device 260 are also provided to the computer 251. The computer 251 is used to align the impedance measurements with the image or images. The computer 251 employs algorithms to process the impedance measurements and the image data and generates a diagnosis of whether a lesion being evaluated is benign or malignant. In some embodiments, a diagnosis is automatically generated when the algorithms are applied to the impedance measurements and the image data.

In the illustrated embodiment, the impedance measurement device 260 includes a power source 262, a microcontroller 264, a communication system 266, current drive and impedance measurement circuitry 268, a memory 270, a switch matrix 272 and an electrode assembly 274. Optionally, the device 260 can also include a user interface 276 and/or an imaging system 278.

Power and communication buses are included in the device 260 to connect the various components for operation. The communication buses can be used for the communication of instructions/commands and data between the illustrated components and between the illustrated components and other components included in the device depending on the embodiment. The power buses connect the power source 262 to the various components to provide operating power as required.

As illustrated, the memory 270 is external to the microcontroller 264, however, the device 260 can include the memory 270 in the microcontroller 264, or a combination of a memory integral to the microcontroller 264 and a memory external to the microcontroller employed together. The memory 270 can be configured to store software instructions 280, for example, software instructions that when executed by the microcontroller 264 cause the device 260 to perform impedance measurements. Further, the memory 270 can also be employed to store impedance measurement values or other information concerning the impedance measurements.

Depending on the embodiment, the power source 262 can be a battery power source integral to the device 260. For example, the power source 262 can include an alkaline battery power source or a lithium ion battery power source. In general, the communication system 266 can include either or both of local- area networks (LANs), wide area networks (WANs), wireless communication, wired communication and may include the Internet. According to a further embodiment, the communication system 266 provides access "over-the-cloud" to one or more remote devices, servers, and/or data storage systems. For example, the communication system can allow communication between any of the impedance measurement device 260, the computer 251 with one another and/or with any of the other resources and devices coupled to the communication system 266. Communication can occur using any of Wi-Fi networks, Bluetooth™ communication, cellular networks, satellite

communication, and peer-to-peer networks available either alone or in combination with one another via the communication system 266. Other communication protocols and topologies can also be implemented in accordance with various embodiments.

The communication system 266 is employed to communicate information concerning the impedance measurements to the computer 251 and/or remote servers. According to one embodiment, the information includes a matrix of impedance measurement values that includes the association of each measurement value with a location within the set of electrodes. In various embodiments, wireless

communication 267 is employed for bi-directional data communication between the computer 251 and the impedance measurement device 260.

According to one embodiment, a server remote from the impedance measurement device 260 receives the information including the matrix of impedance measurement values that includes the association of each measurement value with a location within the set of electrodes. The server also receives digital images and/or information concerning a lesion included in one or more digital images. Further to this embodiment, the server stores the information and/or generates the diagnosis regarding the lesion.

The impedance measurement device 260 includes the current drive and impedance measurement circuitry 268. According to one embodiment, a 4-wire system that operates to take impedance measurements with a positive drive polarity and a negative drive polarity is employed. According to this embodiment, the circuitry 268, along with a defined measurement sequence that switches polarity, provide improved accuracy for electrical impedance measurements across a wide range of frequencies by removing error terms that would otherwise affect the measured values. In a further embodiment, the approach is suitable for high accuracy measurement at frequencies up to 10MHz or more. In further embodiments, the measurement electrodes are also switched between a positive polarity and a negative polarity.

The switch matrix 272 provides an interface between the current drive and impedance measurement circuitry 268 and the electrode assembly 274. The switch matrix 272 operates to provide the correct current path by connecting the drive electrodes in pairs and in sequence by row and column as described above. In addition, the switch matrix 272 operates to sequence through each of the impedance measurements via the appropriate pairs of measurement electrodes. According to some embodiments, analog switches or multiplexors are included in the switch matrix to select the electrode pair that is connected to the impedance measurement circuitry. For example, the first multiplexer 14, the second multiplexer 16, the third multiplexer 18 and the fourth multiplexer 20 are included in the switch matrix 272 according to one embodiment.

The electrode assembly 274 can include impedance measurement electrode arrays in any of a variety of configurations provided they are suitable to apply to the skin of a subject. The electrode assembly 274 includes both drive electrodes and measurement electrodes. The electrode assembly 274 is connected to the switch matrix 272 by a connector 282. In various embodiments, the electrode assembly 274 is removable. For example, a first set of electrodes can be used with a first patient. The electrode assembly is then replaced before the device 260 is used with a different patient. The connector can include a plug and/or cable that can easily be disconnected. According to some embodiments, the electrode assembly 274 is provided as a cartridge that includes the electrode assembly 274, a housing for the electrode assembly 274 and an electrical connector configured to couple to an electrical connector located in the impedance measurement device (for example, referring to FIG. 5 an electrical connector located in the head 65).

Various forms of the user interface 276 can be included in the impedance measurement device 260 to allow a dermatologist, technician or other user to control operation of the device 260 and receive feedback concerning the impedance measurement process. According to one embodiment, a relatively simple user interface provides the user with an ability to select the start of a measurement sequence by pressing a button or selecting a switch once the user has the impedance measurement device 260 properly aligned with the fiducials located on the subject. One or more LEDs can also be provided to give an indication of the operating status of the device 260, for example, a first LED lit when the device 260 is ready, a second LED that is lit during the impedance measurement process and a third LED that is lit when the communication system 266 is actively sending or receiving information. The LEDs can also be placed in more than one state to provide additional feedback. For example, the LEDs can blink or blink at different rates to provide feedback. According to other embodiments, the user interface 276 can include a display. In one embodiment, the user interface 276 includes a graphical user interface. In a further embodiment, the user interface provides feedback concerning the diagnosis to the user, for example, an indication of whether a lesion is benign or malignant. According to one embodiment, the device 260 includes a beeper or other audio output device to provide feedback to the user.

While standalone imaging equipment can be employed with the impedance measurement devices 60, 160, 260 described herein, some embodiments can include the imaging system 278 as an integral part of the device. In one embodiment, the imaging system 278 includes a digital camera. The imaging system is used to capture the region of the skin including the location at which the measurement electrodes 30 were applied in a manner that allows alignment between the locations of the measurements included in a set of measurements and locations in the image. In some embodiments, the imaging system captures the fiducials which are used to provide a common point of reference with which to align the impedance measurements with the visual representation presented in the image.

In one embodiment, the imaging system can be included as part of a rotary head suitable to move through at least two positions including a first position at which the electrode assembly 274 is positioned for impedance measurements and a second position at which the imaging system 278 is positioned to capture an image of the skin in the measurement region. Alternatively, the imaging system 278 can be included in the device 260 such that the device is moved as a whole (for example, flipped over or swapped on end) to switch from an impedance measurement position to an imaging position.

Referring now to FIGS. 15A and 15B, an electrode assembly 274 is illustrated in accordance with one embodiment. The electrode assembly 274 includes a first set of drive electrodes 222, a second set of drive electrodes 224, a third set of drive electrodes 226, a fourth set of drive electrodes 228 and a set of measurement electrodes 230. The electrodes 222, 224, 226, 228, 230 are located on a substrate 240. The electrode assembly 274 includes a first spacer 242, a second spacer 244, a third spacer 246 and a fourth spacer 248. A conductive gel 249 is included at least in the regions in which the electrodes 222, 224, 226, 228, 230 are located. For example, referring to the cross-sectional view presented in FIG. 15B, the conductive gel 249 is located in the region of the second set of drive electrodes 224, the set of measurement electrodes 230 and the fourth set of drive electrodes 228. According to one embodiment, the substrate 240 includes a printed circuit board.

The spacers 242, 244, 246, 248 are insulating spacers employed to provide electrical isolation between each of the respective regions where the electrodes 222, 224, 226, 228, 230 are located. For example, the spacer 242 isolates the second set of drive electrodes 224 from the set of measurement electrodes 230, and the spacer 248 isolates the third set of drive electrodes 226 from the set of measurement electrodes 230. Each spacer 242, 244, 246, 248 has a height that is greater than the depth to which the conductive gel 249 is applied. Consequently, the conductive nature of the gel 249 does not create a conductive path between the various regions where the electrodes 222, 224, 226, 228, 230 are located. According to one embodiment, the conductive gel 249 is a hydro-gel.

The spacing of the measurement electrodes 230 provides a distance x between adjacent electrodes located in separate columns and a distance y between adjacent electrodes located in separate rows. According to one embodiment, the distance x equals the distance y. Referring to FIG. 15B, the conductive gel 249 is applied to a depth 254 sufficient to cover the face of each of the electrodes 222, 224, 226, 228, 230. For example, for an electrode having a height 252 the conductive gel 249 is applied to a minimum depth that is greater than the height 252. The result is a layer of gel having a thickness 253 on the face of the electrodes. An improved conductive path between the electrode and the subject is created with application of the gel 249 to this minimum depth. However, because the conductive gel 249 is located in regions between adjacent electrodes care must be taken to apply an amount of conductive gel 249 that improves the impedance measurement process without significantly influencing the impedance measurements taken between adjacent electrodes. That is, the resistance of the conductive path created by the gel between adjacent electrodes must be kept at a minimum while the thickness on the face of each electrode must be sufficient to allow the impedance measurement device to quickly establish a measurement via the subject. Applicant finds that the results are improved when the depth 254 of the gel is precisely controlled to keep the thickness 253 at a maximum that is a fraction of the spacing between measurement electrodes.

In particular, Applicant finds that results can be improved where the depth of the gel 249 has the depth 254 provided such that the thickness 253 is no greater than 25% of the minimum value of the distances x and y. Further improvement in the speed at which measurements can be taken and the accuracy of results is achieved when the depth 254 is provided such that the thickness 253 is no greater than 20% of minimum value of the distances x and y. For example, where the minimum value of the distances x and y is 2 mm the depth 254 is provided such that the thickness 253 is .381 mm to achieve a ratio of thickness/electrode spacing of approximately 0.19 or 19%.

In further embodiments, a total area of the set of measurement electrodes 230 is optimized based on the size of a target lesion. Referring again to FIG. 15 A, the set of measurement electrodes 230 are located in a region having a length 255, a width 256 and a total area defined by the length times the width. Applicants find that the speed of impedance measurements and the speed at which the associated diagnosis is provided can be greatly improved where the total area of the set of measurement electrodes 230 is selected based on the surface area of the target lesion. In particular, some embodiments provide a measurement area that is large enough to record impedance measurements at a lesion and at one or more areas of healthy skin in the vicinity of the lesion with the electrode assembly 274 placed at a single location on the subject.

Because the human body has any number of locations at which a lesion might appear a compact size of the electrode assembly is beneficial. Accordingly, results are improved where the proper balance is struck between the size of the electrode assembly and the ability to capture impedance data for both a lesion and surrounding reference area at a single measurement location. According to one embodiment, a size of a total area covered by the set of measurement electrodes, when placed at a single location on the skin, is selected such that each of a first impedance measurement and a second impedance measurement are recorded at the single location for any region of the skin that includes a lesion having a surface area no smaller than 2% of the total area and no greater than 80% of the total area. In addition, embodiments achieve the preceding so long as at least a portion of the lesion less than the entirety is located in the measurement location.

According to this embodiment, the first impedance measurement corresponds to a location of the lesion in the region, and the second impedance measurement corresponds to a location in the region that does not include the lesion. In one embodiment, a set of measurement electrodes having dimensions of 6.1 mm by 14.3 mm (a total area of 87.2 mm2) is provided to evaluate target lesions with the preceding dimensions. In a further embodiment, the preceding set of measurement electrodes is include as part of the electrode assembly 274 having dimensions of 25.9 mm by 17.8 mm (a total area of 461 mm2). This embodiment can be employed with lesions that have a diameter that ranges in size from 2 mm to 12 mm. Other embodiments can use larger electrode assemblies for use with lesions that have a diameter that ranges in size from 2 mm to 20 mm and still provide the first impedance measurement and the second impedance measurement for a single location. In each case, a single measurement location can be employed to quickly provide all the impedance measurements needed for diagnosis of a lesion having a selected target size. Referring again to FIG. 15B, the substrate 240 includes a surface 258 and the electrode assembly 274 includes an electrical connector 257 connected to the surface 258. Various types of connectors can be employed to suit the requirements of a particular application. For example, the connector 257 can include a low profile construction that locates a set of contact pads on the surface 258. In other

embodiments, the connector includes a set of pins. In either embodiment, the connector 257 is configured to engage corresponding structure included in the impedance measurement device 260. The electrode assembly 274 can employ a connector configured to removably attach the electrode assembly 274 to the impedance measurement device 260, for example, to plug the electrode assembly into the head of the device 260. According to some embodiments, the electrode assembly 274 is provided in the form of a disposable cartridge that quickly and easily plugs into an impedance measurement device. In these embodiments, the cartridge can include a housing to house the electrode assembly 274 including the electrical connector 257. According to a further embodiment, each cartridge is a single use cartridge that is disposed after use.

Referring now to FIG. 16, a flow diagram 300 of a process using impedance measurements and digital imaging for diagnosis of skin lesions is illustrated in accordance with one embodiment. The process begins at act 302. At act 304 fiducials are applied to the subject in a vicinity of the region that includes a lesion. At act 306 fiducials included as part of an impedance measurement device are aligned with the fiducials that were applied to the subject. At act 308 impedance measurements are taken using the impedance measurement device in the aligned-position. At act 310 a digital image of the region of the subject including the lesion and the fiducials applied to the subject is taken. At act 312 the image data and the impedance data are analyzed using one or more algorithms. At act 314 a diagnosis is provided. The process ends at act 316.

The process described above can include different combinations of acts and different sequences of acts depending on the embodiment. For example, the process can be modified to include additional acts or fewer acts. Further, the activities performed at each act can vary depending on the embodiment. For example, where the impedance measurement device includes some form of fiducial applicator (for example, a stamp) the act of taking impedance measurements places the fiducial on the subject. Further, the alignment of the impedance measurement device and the fiducials occurs automatically because the relationship between the fiducials and the measurement electrodes is fixed. Thus, in these embodiments, acts 304, 306 and 308 can be combined.

In some embodiments, locations of the impedance measurements are aligned with locations in the image at act 312. According to other embodiments, the preceding correlation occurs in a separate step distinct from the act 312.

Further, while the process illustrated in the flow diagram 300 describes digital imaging, different imaging modalities can be employed depending on the

embodiment. For example, a digital camera, digital video recorder or other electronic imaging technology can be employed at act 310.

According to further embodiments, the process includes an act of

communicating the impedance measurement data and/or digital images from the device(s) that recorded the data to a different device for processing. For example, the impedance measurements can be wirelessly communicated to a tablet computer. The image data can be recorded with the tablet or with another device and transmitted to the tablet. Thus, the process can include the act or acts of communicating. According to another embodiment, impedance measurements are communicated to a remote server from the tablet. In this embodiment, the server can also receive the image data.

The act 312 of analyzing the data can also be performed in a variety of ways depending on the embodiment. For example, the image data can be evaluated using the Asymmetry, Border, Colors and Dermoscopic (ABCD) score. According to this approach: asymmetry is assessed after the lesion is bisected and in regard to the shape, color and dermoscopic structures in the sections; the border is assessed based on the changes in pigment pattern along sections of the border; colors are assessed based on the typical association with a melanoma; and dermoscopic evaluation focuses on five structural features - network features, homogeneous area, branched streaks, dots and globules. The preceding is currently employed for digital images to categorize lesions as: benign, melanocytic lesions; suspicious lesions that require close monitoring or recommended excision and lesions highly suggestive of melanoma.

However, in accordance with some embodiments, act 312 includes a combination of an ABCD image analysis with that addition of impedance measurements precisely located relative to the location of the lesion in the image. These embodiments can result in a significant improvement of the sensitivity and specificity of the diagnosis relative to prior approaches. Thus, in various

embodiments, the process is employed as a non-invasive approach for pre-operative skin cancer assessment.

Although the sets of electrodes are illustrated as an array including a matrix of identically sized electrodes other configurations can be employed. For example, other geometric configurations of the overall set of electrodes can be employed, other shapes of electrode contact surface can be employed and other distributions of electrodes can be employed. For example, the set of electrodes can be structured as concentric rings, a series of rectangles, or a series of shapes other than circles and square.

Further, the face of the electrode that contacts the subject can vary in different embodiments. Electrodes can include a substantially flat surface to be placed in contact with the skin. Conically shaped electrode faces and spherically shaped electrode faces can also be employed.

Having thus described several aspects of at least one embodiment of this invention, it is to be appreciated various alterations, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description and drawings are by way of example only.

Claims

WHAT IS CLAIMED IS
1. An impedance measurement apparatus employed to collect information concerning a region of the skin of a subject, the apparatus comprising:
a set of electrodes employed in impedance measurement; and
a housing including:
a body configured to be gripped by a user when the set of electrodes are applied to the subject;
a head located at a distal end of the body and configured for a removable connection of the set of electrodes; and
a first plurality of fiducial markers included as a part of the apparatus and configured to allow the user, while applying the impedance probe to the subject, to confirm that the set of electrodes is in a location determined when the first plurality of fiducial markers are aligned in a known alignment relative to a second plurality of fiducial markers located on the subject and adjacent the region.
2. The apparatus of claim 1, wherein the head includes the first plurality of fiducial markers.
3. The apparatus of claim 2, wherein the head includes a plurality of viewing elements, each viewing element including at least one of the first plurality of fiducial markers.
4. The apparatus of claim 3, wherein the plurality of viewing elements comprise a plurality of viewing ports.
5. The apparatus of claim 4, further comprising a first surface oriented to face the user with the apparatus applied to the skin of the subject, and
a second surface oriented to face the subject with the set of electrodes applied to the skin of the subject, wherein the viewing ports include through-holes that extend orthogonally between the first surface and the second surface.
6. The apparatus of claim 1, further comprising a substrate to which the set of electrodes is coupled, and
at least one insulation segment coupled to the substrate and extending substantially perpendicular to the substrate,
wherein the at least one insulation segment is located such that the set of electrodes is divided into a plurality of electrically isolated regions each including at least one electrode included in the plurality of electrodes.
7. The apparatus of claim 6, further comprising:
circuitry located in the housing; and
an electrical connector coupled to the substrate,
wherein the substrate is configured for removal attachment to the head via the electrical connector, and
wherein a connection is completed between the circuitry and the set of electrodes when the substrate is attached to the head via the electrical connector.
8. The apparatus of claim 6, further comprising:
a set of measurement electrodes included in the set of electrodes;
a set of signal delivery electrodes included in the set of electrodes; and a conductive gel applied to the substrate,
wherein the conductive gel has a thickness determined by a spacing between adjacent electrodes in the set of measurement electrodes.
9. The apparatus of claim 8, wherein the thickness of the conductive gel is less than 25% of a distance between a location of adjacent electrodes in the set of measurement electrodes.
10. The apparatus of claim 2, wherein the housing includes a set of walls that form an exterior of the head, and
wherein designated locations along the wall are employed as the first plurality of fiducial markers.
11. The apparatus of claim 1, further comprising at least one pressure sensitive device located in the head,
wherein the pressure sensitive device is employed to detect when the set of electrodes is in contact with the skin.
12. The apparatus of claim 1, wherein the head is sized and configured to allow the user viewing the apparatus along an axis orthogonal to the region of the skin to view at least one of the second plurality of fiducial markers with the set of electrodes applied to the skin of the subject with the first plurality of fiducial markers aligned with the second plurality of fiducial markers.
13. The apparatus of claim 1, wherein the set of electrodes includes a plurality of measurement electrodes,
wherein a size of a total area covered by the plurality of measurement electrodes, when placed at a single location on the skin, is selected such that each of a first impedance measurement and a second impedance measurement are recorded at the single location for any region of the skin that includes a lesion having a surface area no smaller than 2% of the total area and no greater than 80% of the total area, wherein the first impedance measurement corresponds to a location of the lesion in the region, and
wherein the second impedance measurement corresponds to a location in the region that does not include the lesion.
14. The apparatus of claim 13, wherein the size is selected based on a target lesion having a diameter of at least 2 mm and less than or equal to 20 mm.
15. The apparatus of claim 14, wherein a size of individual electrodes included in the plurality of measurement electrodes, a quantity of electrodes included in the plurality of measurement electrodes and a distribution of electrodes included in the plurality of measurement electrodes are selected such that the first impedance measurement and the second impedance measurement are available for any single location that locates the set of electrodes such that a portion of the surface area of the target lesion having a diameter of substantially 2 mm or greater is located within the total area.
16. A method of diagnosing a condition of a region of the skin of a subject using an impedance measurement device and imaging equipment, the impedance measurement device including a first plurality of fiducial references, the region of the skin including a lesion, the method comprising:
applying a second plurality of fiducial references on the subject in a vicinity of the region;
placing the impedance measurement device in contact with the skin at a location such that the first plurality of fiducial references are aligned with
corresponding ones of the plurality of fiducial references on the subject, respectively; taking a plurality of impedance measurements of the region of the skin with the impedance measurement device at the location;
taking at least one image showing a surface of the skin including the region, the second plurality of fiducial references appearing in the at least one image;
determining, using the second plurality of fiducial references appearing in the at least one image, locations in the at least one image corresponding to respective ones of the plurality of impedance measurements, respectively; and
providing a diagnosis of the condition of the region of the skin based on a visual condition of the surface of the skin in at least a part of the region appearing in the at least one image and respective values of the plurality of impedance
measurements.
17. The method of claim 16, wherein the impedance measurement device includes a plurality of viewing elements, and wherein the method further comprises aligning the first plurality of fiducial references and the second plurality of fiducial references using the plurality of viewing elements.
18. The method of claim 17, wherein the plurality of viewing elements each includes a fiducial reference included in the first plurality of fiducial references, and wherein the method further comprises aligning each fiducial reference included in the first plurality of fiducial references with a respective one of the second plurality of fiducial references.
19. The method of claim 16, further comprising providing the diagnosis and including a determination of whether the lesion is benign or malignant following automatic analysis of the plurality of impedance measurements and the at least one image by the impedance measurement device.
20. The method of claim 16, further comprising removing the impedance measurement device from the location before taking the at least one image.
21. The method of claim 16, wherein the impedance measurement device includes a set of electrodes, wherein the method further comprises selecting the location such that a portion of a surface area of a lesion located in the measurement area has a diameter of substantially 2 mm or greater.
22. The method of claim 16, wherein the act of complying further comprises including the second plurality of fiducial references on an adhesive-backed substrate configured for a temporary attachment to the skin.
23. The method of claim 16, further comprising including a plurality of shapes in each of the first plurality of fiducials and the second plurality of fiducials, respectively.
24. The method of claim 16, further comprising wirelessly communicating data concerning the plurality of impedance measurements to a device employed to automatically categorize the lesion as malignant or benign based on the data and information determined from the at least one image.
25. The method of claim 24, further comprising communicating the data to the device via a wide area network.
26. The method of claim 16, further comprising placing the impedance measurement device in contact with the skin and taking the plurality of impedance measurements with the impedance measurement device operated using a single hand.
27. A method of providing an impedance measurement apparatus employed to provide an automated diagnosis of lesions, the method comprising:
determining a maximum surface area of the lesions that qualify as a target lesion;
determining a minimum surface area of the lesions that qualify as the target lesion; and
providing a set of measurement electrodes in the impedance measurement apparatus that are sized to provide a measurement area such that a plurality of impedance measurements taken by the apparatus at any one location, with a surface area of the target lesion within the measurement area being at least as large as the minimum surface area, includes at least a first impedance measurement and a second impedance measurement,
wherein the first impedance measurement corresponds to a location of the target lesion, and
wherein the second impedance measurement corresponds to a location that does not include the target lesion.
28. The method of claim 27, further comprising selecting a spacing of electrodes included in the plurality of measurement electrodes based on a diameter of lesions having the minimum surface area.
29. The method of claim 28, further comprising selecting a quantity of electrodes included in the plurality of measurement electrodes based on a diameter of lesions having the maximum surface area.
30. The method of claim 27, further comprising providing a plurality of viewing elements including fiducial references in the impedance measurement apparatus.
31. The method of claim 27, further comprising including a fiducial applicator in the impedance measurement apparatus, the fiducial applicator configured to apply an ink- stamp fiducial to a subject when the impedance measurements are taken.
32. The method of claim 27, further comprising a communication system in the impedance measurement device, the communication system configured to wirelessly transmit data concerning the impedance measurements to a device employed to categorize the lesion as malignant or benign based on the data and information determined from a digital image of the lesion.
33. The method of claim 32, further comprising configuring the impedance measurement device as a handheld device sized and configured to grip with a single hand while the handheld impedance probe is applied to a subject.
PCT/US2015/057965 2015-10-29 2015-10-29 Apparatus, system and method employing impedance measurements and images for disease detection WO2017074378A1 (en)

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