An apparatus for assessing biological tissue

Abstract

An apparatus (100) for performing an assessment of a biological tissue in an oral cavity of a patient, the apparatus adapted to be wearable by a medical professional during examination of the patient, which apparatus comprises: a probe interface unit (112); and a probe (110) having a proximal end and a distal end, the proximal end connectable to said probe interface unit (112) and the distal end adapted to be positioned within a distal phalanx region of a finger of the medical professional, and wherein said distal end comprises an electrode arrangement adapted for performing electrical impedance spectroscopy on said biological tissue when the medical professional positions the distal phalanx region of the finger on the biological tissue in the oral cavity of the patient, thereby bringing the distal end of the probe into contact therewith.

Description

[0001] aratus for performing an assessment of biological tissue in the oral cavity of a patient, the apparatus adapted to be wearable by a medical professional during examination of the patient. The assessment may be performed on a visible abnormality in the oral mucosa of the patient to determine whether the abnormality is likely to be dysplasia or oral pre-cancer. In certain embodiments the apparatus may be suitable for assessing the depth information of an abnormality visible on the surface of a biological tissue in the oral cavity, including the depth to which it has grown. Embodiments may relate to a probe for performing an assessment of biological tissue in the oral cavity of a patient. Some embodiments may relate to a probe interface unit for use in performing an assessment of a biological tissue in the oral cavity of a patient by a medical professional during examination of the patient, the probe interface unit being wearable by a medical professional.

[0002] BACKGROUND OF THE INVENTION

[0003] Oral (mouth) cancer is among the 10 most common cancers worldwide. The incidence of oral cancer has been rising for men and women, both young and old, with current figures indicating that new cases of mouth cancer in the UK have now reached 8,302 annually. This has increased by 49% in the last decade and by 135% compared with 20 years ago. Most oral cancers are linked to lifestyle, with smoking and alcohol being the biggest avoidable risk factors. However, a subgroup of oral cancers arising on the back of the mouth (oro-pharyngeal cancer) is caused by infection with the Human Papilloma Virus (HPV), which has been increasing at an epidemic rate over the past two decades (225% increase). In 2015, oro-pharyngeal cancer surpassed cervical cancer as the most common HPV-associated cancer in the US. Prognosis of oral cancer is poor, with more than 50% of affected individuals dying of their disease within five years of diagnosis. Despite advances in the detection and treatment of many other malignancies, prognosis rates have remained disappointingly low and relatively constant during the last few decades. For those who survive, quality of life is often permanently compromised: treatment often produces dysfunction and distortions in speech, dental health, mastication and swallowing, and even in the ability to interact socially. Consequently, oral cancer is considered amongst the most debilitating and disfiguring of all cancers.

[0004] Oral cancer is often preceded by long-term visible changes of the oral mucosa (the lining of the mouth), including for example white (leukoplakia) and red (erythroplakia) patches. Prompt identification of these abnormalities can prompt a surgical biopsy, which can in turn translate into diagnosis of early-stage oral cancer or pre-cancer (oral epithelial dysplasia, herein simply ‘dysplasia’). Both dysplasia and early-stage oral cancer are is highly curable and associated with much more favourable prognosis than advanced oral cancer. Indeed, the oral cavity is an anatomical region that lends itself to routine screening and clinical examination, and considering that oral cancer arises and develops on an accessible and visible surface, it should be relatively easy to detect it in its early stages or at the pre-cancer stage (oral dysplasia). However, current data suggests that referral to cancer clinics is often delayed until the disease progresses to a more advanced stage, when it is easier to detect but more difficult to cure.

[0005] This trend partly accounts for the high mortality rates of oral cancer. Paradoxically, the percentage of oral cancers diagnosed in the early stages is similar to that of colon cancers (-35%), even though the mucosa of the colon requires endoscopic examination for evaluation.

[0006] Early diagnosis of dysplasia and oral cancer is known to decrease both the associated morbidity and mortality, as well as the treatment costs. Effective treatment of dysplasia can prevent oral cancer development and is therefore associated with no notable mortality. The 5-year survival rate of early oral cancer (stage I) is 70-80% as opposed to 10-20% of stage IV. Furthermore, making a diagnosis of oral cancer diagnosis stage I rather than stage IV in 1,000 patients would achieve a reduction in treatment costs in the UK alone of about £8,600,000 (the cost of treating one patient with stage IV and I disease is £13,513 and £4,914 respectively (see Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, Augustovski F. The cost-effectiveness of screening for oral cancer in primary care. Health Technol Assess. 2006 Apr; 10(14): 1-144, iii-iv. doi: 10.3310 / htal0140. PMID: 16707071); multiplied by 1000 patients the total treatment costs are £13,513,000 and £4,914,000 respectively, with a different of about £8,600,000).

[0007] However, there remains no effective means at present to help primary care doctors and dentists identify dysplasia and early oral cancer, and to refer affected patients promptly to cancer clinics. The diagnostic gold standard (histopathology assessment of a specimen collected via a surgical biopsy) is not normally performed in primary care, and practitioners (both dental and medical) typically assess changes to the oral mucosa via visual inspection. Current UK data indicates that not only are most cases of oral cancer identified and referred too late, but also only a small proportion (-10%) of the patients referred for suspected oral cancer via the urgent 2- week pathway to NHS cancer clinics are actually found to have cancer. Similar problems exist in may countries around the world (see for example Lima AM, Meira IA, Soares MS, Bonan PR, Melo CB, Piagge CS. Delay in diagnosis of oral cancer: a systematic review. Med Oral Patol Oral Cir Bucal. 2021 Nov I;26(6):e815-e824. doi: 10.4317 / medoral.24808. PMID: 34704975, and Gigliotti J, Madathil S, Makhoul N. Delays in oral cavity cancer. Int J Oral Maxillofac Surg. 2019 Sep;48(9): 1131-1137. doi: 10.1016 / j.ijom.2019.02.015. Epub 2019 Mar 13. PMID: 30878273). This large quantity of inappropriate referrals (-90%) carries notable negative consequences as it drains NHS resources and causes unnecessary concern to patients. It also suggests that a simple visual inspection of the lining of the mouth performed by general practitioners does not seem to accurately distinguish oral cancer from benign disease of the lining of the mouth.

[0008] The use of adjuncts that aid visual inspection may improve the ability of primary care doctors and dentists to differentiate oral cancer and dysplasia from benign lesions, increase the number of oral cancers detected at an early stage, reduce the diagnostic delay, and ultimately improve survival rates. Ideally, a detection system for early oral cancer and pre-cancer (dysplasia) should consist of a non-invasive, sensitive, specific and quick test that can be easily performed in the primary care setting, such as a GP surgery or dental practice. Unfortunately, previous attempts to develop diagnostic aids for oral cancer (e.g. VELscope, Toluidine blue, Vizilite, OralCDx Brush Test) have failed to identify an effective instrument that could be used by GPs and dentists to identify, with robust sensitivity and specificity, the oral mucosal changes that are likely to represent oral cancer or dysplasia. The ability to make an early diagnosis of, or to differentiate between, dysplasia and early oral cancer in primary care without performing a surgical biopsy therefore remains a challenging and unmet need.

[0009] SUMMARY OF PREFFERED EMBODIMENTS

[0010] According to some embodiments there is provided an apparatus for performing an assessment of a biological tissue in an oral cavity of a patient. The apparatus may be adapted to be wearable by a medical professional during examination of the patient. The apparatus may comprise a probe interface unit. The apparatus may comprise a probe having a proximal end and a distal end. The proximal end may be connectable to said probe interface unit. The distal end may be adapted to be positioned within a distal phalanx region of a finger of the medical professional. The distal end may comprise an electrode arrangement adapted for performing electrical impedance spectroscopy on said biological tissue when the medical professional positions the distal phalanx region of the finger on the biological tissue in the oral cavity of the patient, thereby bringing the distal end of the probe into contact therewith.

[0011] In an embodiment the probe may comprises an elongate body. The elongate body may be of a size so that, in use, said probe reaches from the distal phalanx of the medical professional, along the finger, and so that said proximal end of the probe is located within a region between a base of the finger and a wrist of the medical professional.

[0012] In an embodiment the probe may comprise a material which permits the medical professional to move the finger and associated wrist substantially without restriction. The material may be flexible. The material may be elastic. The material may be both flexible and elastic.

[0013] In an embodiment the material may comprise a biomaterial that is suitable for interaction with the human or animal body. The material may be suitable for printing a biocompatible conductive material onto its surface, for example.

[0014] In an embodiment the material may comprise one or more of: polyethylene terephthalate (PET), polyamide, thermoplastic polyurethane (TPU) and silicone. In an embodiment the material may be between about 25 pm and about 75 pm in thickness.

[0015] In an embodiment the probe may comprise an elongate body generally in the form of a strip.

[0016] In an embodiment the probe may be adapted to be worn over a medical examination glove on the hand of the medical professional. The probe may of a size such that it is useable by medical professionals with different hand sizes.

[0017] In an embodiment the apparatus may further comprise at least one adhesive portion for adhering the probe to the medical examination glove on the finger.

[0018] In an embodiment the at least one adhesive portion may be located at said distal end of said probe. In use the medical professional may adhere the distal end of the probe to the finger and hold the electrode arrangement in place during the assessment.

[0019] In an embodiment said at least one adhesive portion may comprises a tab. The tab may be at least partially folded around the finger to hold the probe in place.

[0020] In an embodiment the electrode arrangement may have a substantially planar configuration. The probe may further comprise a stiffened portion for inhibiting movement of said electrode arrangement away from said substantially planar configuration during use.

[0021] In an embodiment the probe may further comprise an electrical interface at said proximal end. There may be a plurality of electrical interconnects between said electrode arrangement and said electrical interface. The electrical interface may be adapted to be electrically connected by the medical professional to the probe interface unit before said tissue assessment is performed. In use, the electrical interconnects may enable the probe interface unit to deliver a current through said electrode arrangement and measure a voltage at said electrode arrangement.

[0022] In an embodiment the electrical interface may comprise a plurality of electrical contacts. Each electrical contact electrically connected with a respective one of said electrical interconnects, a number of the electrical contacts being equal to a number of electrodes in the electrode arrangement.

[0023] In an embodiment each electrical interconnect of said plurality of electrical interconnects may comprise a conductive track.

[0024] In an embodiment the conductive track may have a width of between about 200 pm and 2 mm.

[0025] In an embodiment the conductive track may have a thickness measured from a top surface of the probe of between about 10 pm and 17 pm.

[0026] In an embodiment a spacing between adjacent conductive tracks may be between about 20 pm and 200 pm.

[0027] In an embodiment the electrical interface and the plurality of electrical interconnects may comprise at least one of silver, carbon, gold and platinum.

[0028] In an embodiment the probe interface unit may be adapted to deliver a current to said probe having a magnitude of between a few microamps and a few hundred microamps.

[0029] In an embodiment the probe interface unit may comprise a housing wearable by the medical professional on the wrist or hand.

[0030] In an embodiment the apparatus may further comprise a strap for retaining said housing to the wrist or hand.

[0031] In an embodiment the housing may comprise a pair of arms closed together at a first end but left open at a second end opposite the first end. In this way the housing may form a shape approximating a U or C. The second end may be adapted to receive the wrist or a part of the hand of the medical professional such that the pair of arms may be slid on to the wrist or the part of the hand and worn thereon during the tissue assessment, and slid off the wrist or the part of the hand after completion of the tissue assessment.

[0032] In an embodiment the apparatus may further comprise a retainer on said pair of arms for helping to retain the housing on the wrist or part of the hand.

[0033] In an embodiment the housing may be adapted to slide on and off the hand between the thumb and index finger. It may be that, in this way, when slid on to the hand, a first arm of said pair of arms may be positioned adjacent the back of the hand, and a second arm of said pair of arms may be positioned adjacent the palm of the hand, and the first end of the housing may bridge the webbing between the thumb and index finger.

[0034] In an embodiment the apparatus may further comprise an actuator on said first end of said housing. The actuator may be actuatable by the thumb of the hand of the medical professional on which the housing is worn.

[0035] In an embodiment the probe interface unit may further comprise an electrical connector to which said proximal end of said probe is connectable. The probe interface unit may further comprise a computer processor and a memory. The memory may store computer-executable instructions that, when executed, cause the probe interface unit to perform the electrical impedance spectroscopy.

[0036] In an embodiment the probe interface unit may further comprise a power supply for powering said computer processor and said memory.

[0037] In an embodiment the probe interface unit may further comprise a waveform generator for generating an input voltage waveform. The probe interface unit may further comprise a voltage-to-current converter for generating an input current corresponding to said input voltage waveform, the input current to be delivered to said electrode arrangement for performing the electrical impedance spectroscopy.

[0038] In an embodiment the probe interface unit may further comprise a first device that is controllable by said computer processor for switching the input current waveform between different pairs of electrodes in the electrode arrangement. In an embodiment the first device may be a first multiplexer. In an embodiment the probe interface unit may further a second device that is controllable by said computer processor for switching between pairs of electrodes of the electrode arrangement to measure a voltage across the selected pair of electrodes. In an embodiment the second device may be a second multiplexer.

[0039] In an embodiment the computer-executable instructions may be adapted to cause said probe interface unit to perform the electrical impedance spectroscopy. The electrical impedance spectroscopy may be performed by delivering input currents at different frequencies to said probe. The input currents may pass through electrode arrangement and the biological tissue. The electrical impedance spectroscopy may be performed by measuring voltages between a pair of electrodes of the electrode arrangement. The measured voltages may be induced by the input currents in the biological tissue. The measured voltages may be at the different frequencies of the input currents. The electrical impedance spectroscopy may be performed by storing in the memory a plurality of values indicating the trans-impedance of the biological tissue at the different frequencies.

[0040] In an embodiment the computer-executable instructions may be adapted so that the step of storing in the memory comprises storing a first set of complex values indicating the magnitude and frequency of the input currents. The computerexecutable instructions may be adapted to store a second set of complex values indicating the magnitude and frequency of the measured voltages. In this way, each one of the first complex values may be mapped to a respective one of the second complex values.

[0041] In an embodiment the probe interface unit may further comprise a wireless transmitter. The computer-executable instructions may be adapted to transmit said first and second sets of complex values to a remote computing device using the wireless transmitter.

[0042] In an embodiment the computer-executable instructions may be adapted so that the step of storing in the memory comprises using said first set of complex values and said second set of complex values to determine a plurality of trans-impedance values. The computer-executable instructions may also be adapted to cause the plurality of trans-impedance values to be stored in the memory.

[0043] In an embodiment the probe interface unit may further comprise a wireless transmitter. The computer-executable instructions may be adapted cause said trans- impedance values to be transmitted to a remote computing device using the wireless transmitter.

[0044] In an embodiment the probe interface unit may further comprise a button for enabling the medical professional to start the electrical impedance spectroscopy.

[0045] In an embodiment the electrode arrangement may comprise one or more group of electrodes. In an embodiment each group may have four electrodes.

[0046] In an embodiment a first pair of electrodes in each group may be for injecting a current into said biological tissue. In an embodiment a second pair of electrodes of the group may be for recording a voltage induced in the biological tissue by said current.

[0047] In an embodiment each electrode of said first pair of electrodes may be spaced apart a first distance in a first direction. Each electrode of said second pair of electrodes may be spaced apart said first distance in said first direction. The first pair of electrodes may be spaced apart from said second pair of electrodes a second distance in a second direction different to said first direction.

[0048] In an embodiment each group of said one or more group of electrodes may be arranged at the vertices of a rectangle.

[0049] In an embodiment the second direction may be substantially perpendicular to said first direction.

[0050] In an embodiment the at least one group of electrodes may comprise a first group of electrodes. There may be a second group of electrodes. There may be a third group of electrodes. Each group of electrodes may be spaced apart a different first distance so that: the first group of electrodes may have the smallest first distance; the second group of electrodes may have a larger first distance than the first group of electrodes; and the third group of electrodes may have a larger first distance than the second group of electrodes. In this way, current injected by the third group of electrodes may spread deepest into said biological tissue. Current injected by the second group of electrodes may spread less deep than current of said third group of electrodes. Current injected by said first group of electrodes may spread less deep than said second group of electrodes.

[0051] In an embodiment there may be a non-linear increase in first distance from:

[0052] (i) the first group of electrodes; to

[0053] (ii) the second group of electrodes; to

[0054] (iii) the third group of electrodes. In this way there may be an approximately linear spacing between the maximum current spread depth of the first, second and third groups of electrodes.

[0055] In an embodiment the second distance may be substantially the same for each of the first, second and third groups of electrodes.

[0056] In an embodiment each electrode of each group of electrodes may have a surface area. The surface area of each electrode of the first group may be substantially the same as the surface area of any other electrode of the first group. The surface area of each electrode of the second group may be substantially the same as the surface area of any other electrode of the second group. The surface area of each electrode of the third group may be substantially the same as the surface area of any other electrode of the third group.

[0057] In an embodiment the surface area of each electrode of the first group may be different to the surface area of any other electrode of the second group and the third group. The surface area of each electrode of the second group may be different to the surface area of any other electrode of the first group and the third group. The surface area of each electrode of the third group may be different to the surface area any other electrode of the first group and the second group.

[0058] In an embodiment there may be a non-linear increase in surface area from: (i) the first group of electrodes; to

[0059] (ii) the second group of electrodes; to

[0060] (iii) the third group of electrodes.

[0061] In an embodiment each electrode may comprise a substantially circular region of conductive material on a top surface of said probe. Each electrode may comprise an outwardly facing surface of the electrode for bringing into contact with the biological tissue by the medical professional under control of the finger.

[0062] In an embodiment each electrode of said first pair of electrodes may be substantially collinear. In this way one electrode of said second pair of electrodes may at least partially surround a respective one electrode of said first pair.

[0063] In an embodiment each electrode of said second pair of electrodes may be substantially collinear with said first pair of electrodes.

[0064] In an embodiment each electrode of said first pair of electrodes may comprise a substantially circular region of conductive material on a top surface of said probe. Each electrode may comprise an outwardly facing surface of the electrode forbringing into contact with the biological tissue by the medical professional under control of the finger. Each electrode of said second pair may comprise an annular sector.

[0065] In an embodiment each annular sector may be oriented so that, in use, a zone of zero and near-zero electrical potential between each electrode of the first pair of electrodes is located in an open region of the respective annular sectors of the second pair of electrodes.

[0066] In an embodiment the open region may have an angle 6. The angle 6 may be between 0° and about 90°. The angle 6 may be smaller the larger a distance between the first pair of electrodes.

[0067] In an embodiment each electrode of said first pair of electrodes may be spaced apart a first distance in a first direction.

[0068] In an embodiment said one or more group of electrodes may comprise: a first group of electrodes, a second group of electrodes, and a third group of electrodes. Each group of electrodes may be spaced apart a different first distance so that the first group of electrodes may have the smallest first distance. The second group of electrodes may have a larger first distance than the first group of electrodes. The third group of electrodes may have a larger first distance than the second group of electrodes. In this way current injected by the third group of electrodes may spread deepest into said biological tissue. Current injected by the second group of electrodes may spread less deep than current of said third group of electrodes. Current injected by said first group of electrodes may spread less deep than said second group of electrodes.

[0069] In an embodiment there may be a non-linear increase in first distance of the first pair of electrodes from:

[0070] (i) the first group; to

[0071] (ii) the second group; to

[0072] (iii) the third group. In this way there may be an approximately linear spacing between the maximum current spread depth of the first, second and third groups of electrodes.

[0073] In an embodiment each electrode of each first pair of electrodes of the first, second and third groups of electrodes may have a surface are. The surface area of each electrode of the first pair of electrodes of the first group may have substantially the same surface area. The surface area of each electrode of the first pair of electrodes of the second group may have substantially the same surface area. The surface area of each electrode of the first pair of electrodes of the third group may have substantially the same surface area.

[0074] In an embodiment the surface area of each electrode of the first pair of electrodes of the first group may be different to the surface area of any other electrode of the second group and the third group. The surface area of each electrode of the first pair of electrodes of the second group may be different to the surface area of any other electrode of the first group and the third group. The surface area of each electrode of the first pair of electrodes of the third group may be different to the surface area any other electrode of the first group and the second group.

[0075] In an embodiment there may be a non-linear increase in the surface area of each electrode of the first pair of electrodes from:

[0076] (i) the first group; to

[0077] (ii) the second group; to

[0078] (iii) the third group.

[0079] In an embodiment the probe may be a single-use probe.

[0080] In some embodiments there is provide a probe for use in performing an assessment of a biological tissue in an oral cavity of a patient by a medical professional during examination of the patient. The probe may comprise a proximal end and a distal end. The proximal end may be connectable to a probe interface unit. A distal end may be adapted to be positioned within a distal phalanx region of a finger of the medical professional. The distal end may comprise an electrode arrangement adapted for performing electrical impedance spectroscopy on said biological tissue when the medical professional positions the distal phalanx region of the finger on the biological tissue in the oral cavity of the patient, thereby bringing the distal end of the probe into contact therewith.

[0081] In some embodiments there is provided a probe interface unit for use in performing an assessment of a biological tissue in an oral cavity of a patient by a medical professional during examination of the patient. The probe interface unit may comprise an electrical connector to which a proximal end of a probe as set out above may be connectable. The probe interface unit may comprise a computer processor and a memory. The memory may store computer-executable instructions that, when executed, cause the probe interface unit to perform an electrical impedance spectroscopy on the tissue of the patient.

[0082] In some embodiments there is provided a kit for performing assessments of biological tissue, which kit comprises a probe interface unit as set out above or as described or claimed anywhere herein and a plurality of single-use probes, each probe as set out above or as described or claimed anywhere herein.

[0083] In some embodiments there is provided a computing device for generating an assessment of depth of an abnormality visible on the surface of a biological tissue in an oral cavity. The computing device may comprise a processor and a memory. The memory may store computer-executable instructions that when executed cause the computing device to perform the steps of receiving and storing data representing measured trans-impedance of the abnormality, the measured trans-impedance obtained by an apparatus as set out above, or as described or claimed anywhere herein. The computer-executable instructions may be adapted to cause the computing device to process the data to determine an estimated depth of the abnormality. The computerexecutable instructions may be adapted to cause the computing device to output the estimated depth of the abnormality.

[0084] In an embodiment the computer-executable instructions may be adapted so that the computing device determines said depth deterministically or statistically.

[0085] In an embodiment the computer device may comprise a server computer remote from said apparatus.

[0086] BRIEF DESCRIPTION OF THE DRAWINGS

[0087] Figs. 1A and IB are schematic drawings of an apparatus according to an embodiment of the invention in use on the hand of a medical professional;

[0088] Fig. 2A is a schematic plan view of a probe according to an embodiment of the invention;

[0089] Fig. 2B is a schematic side view of a probe of Fig. 2A;

[0090] Fig. 3 is a schematic block diagram of a probe interface unit according to an embodiment of the invention;

[0091] Fig. 4 is a flowchart showing the steps of operation of the wearable device of Fig. 3;

[0092] Fig. 5 is a schematic diagram of the human oral cavity;

[0093] Fig. 6A is a schematic diagram of a linear electrode arrangement;

[0094] Fig. 6B is a schematic diagram of the linear electrode arrangement of Fig. 6A at the tip of a probe showing connections to conductive tracks;

[0095] Fig. 6C is a schematic diagram of a non-linear electrode arrangement;

[0096] Fig. 6D is a schematic diagram of the non-linear electrode arrangement of Fig. 6C at the tip of a probe showing connections to conductive tracks;

[0097] Figs. 7A and 7B are graphs showing how measured impedance of a biological tissue may change with increasing electrode spacing;

[0098] Fig. 7C is a schematic cross-section illustrating current flow though a surface region of a biological tissue for a linear electrode arrangement;

[0099] Fig. 7D is a graph of normalised impedance versus depth of surface perturbation;

[0100] Fig. 7E is a graph of normalised impedance versus normalised diameter of electrode as determined in a finite element modelling experiment;

[0101] Fig. 7F is a schematic cross-section illustrating current flow through a surface region of a biological tissue for a non-linear electrode arrangement;

[0102] Fig. 8A is a graph of impedance versus frequency for an experiment using a linear electrode array;

[0103] Fig. 8B is a graph of impedance versus frequency for an experiment using a non-linear electrode array;

[0104] Fig. 9A is a schematic diagram of a tetrapolar electrode array;

[0105] Fig. 9B is a schematic diagram of an electrode array according to an embodiment;

[0106] Fig. 10 is a schematic diagram of a non-linear electrode array according to an embodiment of the invention;

[0107] Fig. 11 is a schematic side view of an embodiment of an apparatus according to an embodiment of the invention;

[0108] Figs. 12 and 13 are schematic perspective views of the apparatus of Fig. 11 being inserted into and a battery charger;

[0109] Fig. 14 is a schematic perspective view of the apparatus of Fig. 11 in use on the hand of a medical professional, with a probe positioned along the side of finger;

[0110] Fig. 15 is a schematic perspective view of the apparatus of Fig. 11 in use on the hand of a medical professional, with a probe positioned along the underside of finger;

[0111] Fig. 16 is a perspective view of the apparatus of Fig. 11 in use on the wrist of a medical professional and connected to a probe.

[0112] Figs. 17A and 17B are schematic perspective views showing the apparatus of Fig. 11 A in use on a patient; and

[0113] Figs. 17C and 17D are schematic perspective views showing activation of a button on the apparatus of Fig. 11. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0114] Referring to Figs 1 A and IB an apparatus 100 for performing an assessment of a biological tissue in an oral cavity of a patient is shown in use on a hand 102 and wrist 104 of a user. The apparatus 100 may be in the form of a wearable device. The user may be a medical professional intending to perform an examination of the oral cavity on a patient (not shown). The patient may be a human or an animal. For performing the examination, the user wears a glove 106. The glove 106 may be a disposable medical glove that is intended to protect the patient from cross-contamination from the hand 102 of the user. The glove 106 may be a close fit with the user’s hand 102 and may be made from an elastic material that stretches to accommodate the hand 102, while maintaining sufficient dexterity and feel for the user whilst in use. The glove 106 may be made from a range of polymers to achieve these functions including, but not limited to, latex, nitrile rubber, polyvinyl chloride and neoprene. The glove 106 may comprise a cuff 108 that is intended to be a close fit with the wrist 104. In this embodiment, the glove 106 is of a size such that the cuff 108 is positioned on the user’s wrist 104. The glove 106 may be of a longer shape such that the cuff is positioned further up the user’s forearm (not shown).

[0115] The wearable device 100 comprises two main parts: a probe 110 and a probe interface unit 112. The probe interface unit 112 may comprise a housing 114 and a strap 116. The strap 116 enables the user to removably attach the probe interface unit 112 to the wrist 104, in a similar fashion to a wristwatch. The strap 116 may comprise a material that is easy to clean and which does not absorb fluids, such as a silicone or rubber material. Further details of the probe interface unit 112 will be described in greater detail below.

[0116] The housing 114 may comprise an injection moulded thermoplastic polymer, such as Acrylonitrile Butadiene Styrene (ABS) and High Impact Polystyrene (HIPS). The overall weight of the probe interface unit 112 may be in the range between about 0.075 kg and about 0.2 kg, and may be about 0.1 kg.

[0117] An advantage of the apparatus 100 is that the probe 110 may be worn over the glove 106, and does not need to be manufactured as part of the glove 106. Accordingly, one length of probe 110 may be used by users with different hand sizes. For example, when a user with a smaller hand size wears the probe 110, the spare length may be taken up in a ‘hump’ in the probe that stands up above the user’s hand. In the example shown in Fig. 1A, the size of the user’s hand is close to the maximum that the probe 110 can accommodate (whilst still permitting the required dexterity), and so the probe 110 follows the contour of the user’s hand quite closely.

[0118] Referring also to Figs. 2A and 2B, the probe 110 comprises a proximal end 118 and a distal end 120. In use, the distal end 120 of the probe 110 may be removably connected to the probe interface unit 112, as will be described in greater detail below. The probe 110 has a length so that it may reach from the probe interface unit 114, over the back of the hand 102, wrap over the end of the index finger 122 and terminate in the distal phalanx region 124. Alternatively, the probe may be adapted so that it is routed under the hand 102, across the palm, terminating in the distal phalanx region 124. In this way, either across the back of the hand or the palm, the distal end 120 of the probe 110 may be positioned at the fingertip of the user. It may be preferable to route the probe 110 over the back of the hand for oral examination. In particular, if routed across the palm of the hand, the probe 110 may tend to bend outward away from the palm causing an undesirable obstruction to the examination or the patient’s mouth.

[0119] The probe 110 comprises an elongate body 126 having a top surface 127 and a bottom surface 128. The elongate body 126 may be between about 125 mm and about 250 mm in length, about 10 mm in width and may have a thickness in the range about 25pm to about 75pm. A pair of tabs 129a, 129b extend at right angles from the side of the elongate body 126. The elongate body 126 and pair of tabs 129a, 129b may be formed as a single substrate (for example cut or stamped from a sheet of material). Each tab 129a, 129b may be about 25 mm in length and about 10 mm in width. The pair of tabs 129a, 129b may be positioned approximately four fifths along the length of the elongate body from the proximal end 118. In this way, the tabs 129a, 129b will be located somewhere along the user’s index finger 122 in use (see Fig. IB). The bottom surface 128 of each tab 129a, 129b may comprise first self-adhesive portions 130a, 130b that may be folded around the index finger 122 and adhered to the glove 106.

[0120] There may be sufficient length between the pair of finger tabs 128a, 128b and the proximal end 118 so that, in use when connected to the probe interface unit 112, the user is able to articulate the wrist 104 without restriction of movement. For example, the length may be sufficient so that the user may move the wrist 104 in the full range of normal movements: flexion, extension, adduction and abduction.

[0121] At the distal end 120 of the elongate body 126 there may be a second self- adhesive portion 131 on the bottom surface 128. The second self-adhesive portion 131 may be arranged so that, when the distal end 120 is folded over the end of the index finger 122 as shown in Fig. IB, the self-adhesive portion 132 may adhere to the glove 106 in the distal phalanx region 124 of the index finger 122. In this way, the top surface 127 of the probe 110 may face outwardly from the fingertip.

[0122] The elongate body 126 of probe 110 may comprise a material that is flexible and / or elastic. The flexibility and / or elasticity may be sufficient to allow the elongate body 126 to flex and / stretch from a substantially flat configuration in Fig. 2 to a configuration similar to that shown in Fig. IB where the elongate body 126 follows a path from the wrist 104 to the tip of the index finger 122, the pair of tabs 129a, 129b are folded around the index finger 122 and the distal end 120 is folded around the tip of the finger. The material may be any material that is engineered to interact with biological systems for a medical purpose, either therapeutic or diagnostic. The material may also be biocompatible, that is not having toxic or injurious effects on human or animal biological systems. For example, the biomaterial may be chosen to comply with IEC 60601, or other similar or equivalent standards. The apparatus 100 as a whole may conform to any appropriate medical regulation such as the EU Medical Device Regulation and / or FDA regulation. The apparatus 100 as a whole may also comply with any appropriate medical device standard such as, IEC 60601, related general and specific sections. It may be that the material is selected for biocompatibility with biological surfaces, such as a mucosal membrane (e.g. oral mucosa). Useful flexible biomaterials for the elongate body 126 may include, but are not limited to, polyethylene terephthalate (PET), polyamide, thermoplastic polyurethane (TPU) and silicone.

[0123] The bottom surface 128 of the probe 110 may comprise a stiffened portion 132 at the distal end 120. The stiffened portion may comprise a separate piece of material that is incorporated into the probe 110. The stiffened portion 132 may be located on the probe 110 so that, in use, it is positioned within the distal phalanx region 124 of the index finger 122. The stiffened portion 132 may be positioned so that it supports an electrode region 138 of the probe 110 (described in greater detail below). In particular, the stiffened portion 138 may help the electrode region 138 to remain in a substantially planar configuration during use when brought into contact with a tissue of the patient in the oral cavity. The stiffened portion 132 may comprise a material that is stiffer than the material of the elongate body 126. The stiffened portion 132 may comprise a sheet of a polyester such as thermoplastic polymer, e.g. polyethylene terephthalate (PET). The stiffened portion 132 may be about 125 pm in thickness and may be about 8 mm in diameter. The stiffened portion 132 may be laser cut or stamped from a large sheet and then adhered to the bottom surface 128 using an adhesive, such as a pressure-sensitive adhesive. In some embodiments the stiffened portion may be formed integrally with the elongate body 126 rather than as a separate part.

[0124] The second self-adhesive portion 131 may overlay the stiffened portion 132. The second self-adhesive portion 131 may be larger in size than the stiffened portion 132 and may be of a size that helps the distal end 120 of the probe 110 to adhere to the part of the glove 106 overlaying the distal phalanx region 124 of the index finger 122.

[0125] The top surface 127 of the probe 110 may comprise electrically conductive features including an interface region 134 at the proximal end 118, an interconnect region 136 between the proximal end 118 and the distal end 120, and the electrode region 138 at the distal end 120. These electrically conductive features may be produced on the top surface 127 by a variety of methods including, but not limited to, printing, depositing and etching. The top surface 127 may comprise a flexible and stretchable screen-printed resist over the interconnect region 138 to provide electrical insulation for that region. The interface region 134 is exposed to permit electrical connection of the probe 110, and the electrode region 138 is exposed to permit contact between electrodes and a patient, as described in greater detail below.

[0126] In an embodiment an electronics printing process may be used to make the probe 110. The electronics printing process may use screen printing to directly deposit onto the elongate body 126 consecutive layers of (i) a flexible and stretchable conductor, such as silver, to form conductive tracks and the base of electrodes (these features being described in greater details below); and (ii) dielectric (insulating) materials, also in a flexible form over the conductive tracks whilst leaving a portion of each electrode base exposed for the next layer; and (iii) a tissue-interface conductor (such as silver or silver chloride), covering the electrode bases. Alignment of the layers may be achieved using optical fiducial registration. The printing order of layers (ii) and (iii) may be reversed. In an embodiment a screen printing machine from Microtec Co., Ltd, Japan, may be used to fabricate the probe 110. Other processes may be used to manufacture the probe 110 including, but not limited to: ink-jet printing; and a transfer printing process in which the various layers are printed onto a transfer with a final outer layer of adhesive. The transfer is then pressed on to the elongate body 126 so that the layers are adhered to it by the adhesive. An example of such a transfer process is described in GB-A-2 555 592, the contents of which is incorporated herein for all purposes.

[0127] The interface region 134 may comprise four electrical contacts 140 that are adapted to be inserted into and removed from a corresponding connector on the probe interface unit 112. Insertion of the interface region 134 into the connector puts the probe 110 in electrical connection with the probe interface unit 112.

[0128] The interconnect region 136 comprises four conductive tracks 142. Each conductive track may have a width (as viewed in plan in Fig 2) of between about 200 pm to 2 mm and a thickness (perpendicular to the plane of the page in Fig. 2) of between about 10 pm to 17 pm. The spacing between two adjacent conductive tracks may be greater than about 200 pm. In some embodiments without any ground plane, this range of spacing size has been found to reduce crosstalk between conductive tracks 142 to an acceptable level. It may be possible to reduce this spacing to about 20 pm in some embodiments (for example using a screen print and laser ablation process). The probe 110 may or may not comprise one or more ground planes. In some embodiments there may be a ground plane between each conductive track 142, or a ground plane(s) above and / or below the conductive tracks 142, to mitigate crosstalk.

[0129] The four electrical contacts 140 and the four conductive tracks 142 may comprise at least one of silver, carbon (e.g. graphite), gold and platinum.

[0130] The electrode region 138 may comprise four electrodes 144 formed on the top surface 127 of the probe 110. The stiffened portion 132 may be positioned on the bottom surface 128 so that it is underneath the electrode region 138 to provide support to the four electrodes 144 as described above. In particular, the stiffened portion 132 may help the maintain the four electrodes 144 substantially in the same plane during use of the probe 110 when the electrode region is pressed into contact with a biological surface such as the oral mucosa.

[0131] The purpose of the four electrodes 144 is to facilitate assessment of the biological tissue in the oral cavity by electrical impedance spectroscopy (EIS). This functionality may be performed and controlled by the probe interface unit 112, as described in greater detail below. To perform EIS the four electrodes are controlled in a tetrapolar configuration. In a tetrapolar configuration, current is applied over a range of frequencies through a first pair of electrodes and the induced voltage in the sample is recorded across a second pair of electrodes in the vicinity (note that there may be more than four electrodes, and that ‘tetrapolar configuration’ refers to the way measurements are taken, i.e. a pair of current injecting electrodes and a pair of voltage recording electrodes at any one time). The ratio of the latter and the former is the transfer impedance, or trans-impedance, of the biological tissue where the measurements were taken. The characteristics of the impedance profile over the applied range of current frequencies enables information to be derived about the biological tissue, for example whether it is dysplasia and early oral cancer .

[0132] The four electrodes 144 form a tetrapolar channel: at any one time, two of the electrodes may be used to inject a current and the other two electrodes may be used to record voltage. Although the embodiment of the probe 110 shown in Figs. 2A and 2B shows only one tetrapolar channel (which has been developed as a prototype for experimental purposes), it is intended that the probe 110 has multiple tetrapolar channels, preferably three or more, with electrode arrangements described in greater detail below. Utilisation of multiple tetrapolar channels enables a structural assessment of the abnormality on the surface, including the depth to which it has grown, which may lead to higher sensitivities and specificities in cancerous / pre-cancerous tissue detection.

[0133] There is electrical continuity between each electrode 144 and a corresponding one of the four conductive tracks 142. In this way there is electrical continuity between each electrode and a corresponding one of the four electrical contacts 140. Each electrode 144 may comprise silver / silver chloride, although other materials are possible, such as gold or other biocompatible conductive materials that are suitable for printed electronics manufacturing processes. Each electrode 144 has dimensions 1.0 mm diameter. The centres of the four electrodes 144 may be arranged at the corners of a rectangle of sides 1.4 mm by 1.4 mm. However, it is noted that other sizes and arrangements of electrodes are possible, some of which are described in greater detail below.

[0134] A pressure sensor may be located behind the electrode array. This would be a capacitive pressure sensor, with plates printed from a conductive ink and a printed, or deposited, dielectric. The connections are the made from two additional interconnects that run down the reverse side of the electrode substrate, that both use ‘vias’ adjacent to the lead connector 146.

[0135] Referring to Fig. 3, the probe interface unit 112 comprises the housing 114 (note the strap 116 is not shown). The housing 114 may comprise a plastic material and / or metal material to protect the electronic components inside the housing in a way the permits repeated use of the probe interface unit 112 with different probes 110. The probe interface unit 112 may comprise an electrical connector 146 into which the interface region 134 of the probe 110 may be inserted and from which it may be removed after the probe 112 has been used. A shield 147 may be included to provided noise and crosstalk suppression. There may be a control unit 148 in the housing 114, which may receive power from a battery / power management unit 150. The control unit 148 may be implemented using a microcontroller or a FPGA, for example. The control unit 148 may comprise a memory 151 and a processor 152. The memory 151, which may be in the form of a solid-state memory, may store executable-instructions for performing at least some of the functions described herein. The memory 151 may also store data taken from the probe 110. The control unit 148 may also provide the function of demodulation of signals received from the probe 110. The control unit 148 may also provide communication via a network interface 153 and an antenna 154.

[0136] In order to apply current into the probe 110, the probe interface unit 112 may comprise an arbitrary waveform generator (‘ AWG’) 156 for generating an appropriate voltage signal, such as multisine, chirp, frequency sweep and wideband random signal. A voltage-to-current converter 158 may be provided for converting the voltage signal from the AWG 156 to an input current. A first multiplexer 160 may be provided for switching the input current between different pairs of electrodes 144, and the switching may be controlled by the control unit 148. It is noted that it is not essential to uses a multiplexer, and alternatives are described elsewhere herein. The current signal (e.g., multisine, chirp, frequency sweep, wideband random signal) may be applied to one pair of electrodes. The induced voltage signal may be recorded across the other pair of electrodes. Depending on the current signal applied, a method may be used to calculate the magnitude and phase of the transfer impedance signal (i.e., voltage signal / current signal) for the target range of frequencies, as described below.

[0137] To read output voltages between pairs of electrodes 144 a second multiplexer 162 may be provided. The control unit 148 may use the second multiplexer 162 to control switching between different pairs of electrodes 144. An output from the second multiplexer 162 may be sensed by a variable gain amplifier 164. An output from the variable gain amplifier 164 may be conditioned by a signal conditioning unit 166, for example by filtering to remove any unwanted signal. An output from the signal conditioning unit 166 may be received by the control unit 148. The control unit 148 may be adapted to process the output signal to derive a complex trans-impedance between the pair of electrodes 144. Depending on the applied current signal, the control unit 148 may use analogue or digital techniques, including but not limited to coherent demodulation and fast Fourier transform, to extract the complex trans- impedance. This extraction process may be referred to herein as demodulation. In use, the control unit 148 may repeat this process for different channels (i.e. different pairs of electrodes) and for different input currents. The complex trans-impedance data for all channels may be stored in the memory 152 of the control unit 148. The complex trans-impedance data may be transmitted from the probe interface unit 112 to a remote computer (not shown) using the antenna 154, either as the data is gathered and processed, or once all of the data has been gathered and processed.

[0138] It may be that each channel (i.e. pair of electrodes 144, either input or output) comprises a dedicated source and preamplifier. It may be that the first multiplexer 160 and / or the second multiplexer 162 is omitted and included in the probe 110. For example, the first multiplexer 160 and / or the second multiplexer 162 may be located in the interconnect region 136.

[0139] The electronic components in the housing 114 may be implemented on a printed circuit board (PCB), on a bare die, as a system on a chip, or as an application specific integrated circuit (ASIC), either in whole or in part.

[0140] Although not shown in Fig. 3 the probe interface unit 112 may further comprise a power button enabling the user to switch the device on an off. The probe interface unit 112 may also comprise a display by which the user may operate the device. The display may be a touchscreen. In other embodiments the probe interface unit 112 may not have a display, but may have one or more indicator (e.g. LED) for indicating to the user the status of the device. The probe interface unit 112 may also comprise a port for charging the battery / power management unit 150, or the device may be chargeable wirelessly.

[0141] Referring to Fig. 4, a flowchart of at least some of the steps of operation of the probe interface unit 112 is generally indicated by reference numeral 400. It is assumed that a probe 110 is connected to the probe interface unit 112, that the device has been switched on, and is ready to start the tissue assessment process.

[0142] The medical professional may have a patient with an oral cavity that is to be inspected as part of a routine dental check-up for example. Referring to Fig. 5 a schematic diagram of the human oral cavity is generally identified by reference 410. The oral cavity 410 generally comprises a moist mucous membrane which is distinct from the skin which has an epidermis that is generally regarded as dry (at least compared to the moist mucous membrane of the mouth). The lips are generally regarded as the division between the moist mucous membrane of the mouth and the epidermis of the skin. The oral cavity 410 is divided into several anatomical sub-sites, including: an upper lip 412 and a lower lip 414; a tongue 416 (anterior two-thirds shown); floor of the mouth 418; upper gingiva 420 and lower gingiva 422; buccal mucosa 424; retromolar trigone 426; hard palate 430; soft palate 432; and teeth 434. The oral cavity 410 extends from the vermilion border of the upper and lower lips 412, 414 to the circumvallate papillae of the tongue 416 inferiorly and the junction of the hard palate 430 and soft palate 432 superiorly. Dysplasia and oral cancer may present anywhere on the moist mucous membrane inside the mouth including on the upper or lower lips 412, 414, upper or lower gingiva 420, 422, tongue 416, buccal mucosa 424, hard palate 430, and soft palate 432. It is assumed for the purposes of this example that there is an abnormality on the surface of the oral mucosa. The abnormality may have been discovered by the medical professional during a routine dental examination.

[0143] After the medical professional has attached the probe 110 to the finger 122, the tip of the finger 122 (and thereby electrode region 138) may be brought into contact with the abnormality in the oral cavity 410 of a patient. An advantage of the apparatus 100, and in particular the nature of the probe 110, is that the medical professional may utilise the ordinary dexterity of their hand to reach an abnormality in the oral cavity and bring the electrode region 138 into contact therewith. In this way the medical professional may rely on the skills of touching and feeling parts of the oral cavity that have been developed over many years.

[0144] Once the electrode region 138 is in contact with the abnormality, the medical professional activates the assessment process at step SI. This may be done by pressing a start button on the probe inspection device 112. Additionally or alternatively, this may be done via a remote control device (wired or wireless), or using voice activation if the device has a microphone or wireless capability which may permit voice activation through an external device. At step S2 the probe interface unit 112 may turn all indicators off. At step S3, the probe interface unit 112 may check for a sufficient contact between the electrodes 144 and the abnormality identified in the patient’s oral cavity 410. Sufficient contact may be determined using a pair of electrodes 144 to measure the impedance between them across the abnormality. The moist mucous membrane inside the mouth provides a lower contact impedance than the epidermis of the skin for example, and this permits safe currents to be more readily injected by the electrodes. If the measured impedance is out of range (i.e. open circuit), insufficient contact is detected. If the impedance value is not at the expected value, the device 112 may switch a first indicator on to inform the medical professional at step S4, and the medical professional may re-position the probe 110 or press more firmly for example.

[0145] If the expected impedance value is measured at step S3, the device 112 may switch a second indicator on to inform the user at step S5. Step S5 may further comprise sequential selection of each channel of a set of pre-programmed channels (stored by the control unit 148), where each channel corresponds to a first pair of electrodes 144 for inputting current and a second pair of electrodes 144 for measuring voltages. As each channel is selected, a current at a particular frequency is input across the first pair of electrodes 144 and voltage is measured across the second pair of electrodes, and a trans-impedance determined and recorded. This process is repeated until the set of pre-programmed channels is completed for that frequency. Another frequency is selected for the current and the process repeated for the set of preprogrammed channels. The process continues until a range of frequencies has been input and trans-impedance data generated and stored by the control unit 148.

[0146] Once the process is complete, the device 112 may switch the second indicator off at step S6 in order to inform the medical professional that the assessment process is complete. Once completed, the medical professional may remove the probe 110 from the mouth. At this point, the probe interface unit 112 may wait at step S7 for the medical professional to press a ‘send’ button. When the user presses the ‘send’ button the probe interface unit 112 may transmit the trans-impedance data to a remote device via the antenna 154 using any suitable wireless network and communication protocol including, but not limited to, a wireless Local Area Network (LAN) such as Wi-Fi, a wireless Personal Area Network (PAN) such as Zigbee or Bluetooth, and a cellular communication network using 4G or 5G for example. It may be that the device 112 has a wired connection to a remote device via which data transmission may take place. A third indicator may be switched at step S8 to indicate to the medical professional that data transmission is taking place. Once data transmission is complete, the device 112 may switch all indicators off and enters a standby mode at step S9.

[0147] — Channels and multi-frequency interrogation

[0148] At step S5 described above, the wearable apparatus 100 scans a frequency range and measures a number of voltage values using different channels, each channel comprising a pair of current-carrying (or input) electrodes and a pair of voltagerecording (or output) electrodes. To scan a given frequency range using the wearable device 100, it may be that a sinusoidal current signal of a given frequency is applied to the current-carrying electrodes, and the induced voltage may be recorded across the voltage-recording electrodes. The frequency may be changed in discrete steps and the process repeated at each step. The steps may be selected logarithmically to sample the target frequency range with a reasonable number of data points. An example frequency range may be from a few tens or hundreds of Hz to a few MHz. Further information about suitable frequency ranges for biological tissue can be found in Gabriel, Camelia, Sami Gabriel, and Y. E. Corthout. "The dielectric properties of biological tissues: I. Literature survey." Physics in medicine & biology 41.11 (1996): 2231, which is incorporated herein by reference.

[0149] However, for a specific application a given frequency range may be found to present the largest contrast in the impedance between normal tissue and abnormal tissue which is to be detected, and the probe interface unit 112 may be configured to use that frequency range for applying current to the electrodes.

[0150] To speed up the process, multifrequency signals (such as multi sine, chirp and random signal) may be applied to the current-carrying electrodes by the probe interface unit 112.

[0151] For inter-channel sweep, one may sequentially switch from one tetrapolar channel to another. Alternatively, to speed up the process, methods such as frequency division multiplexing may be used in which slightly frequency shifted signals are applied to the channels, all at the same time. Owing to the orthogonality of the signals applied to the channels the associated trans-impedance data for each channel may be extracted and distinguished by the control unit.

[0152] Input current amplitude

[0153] Preferably, the amplitude of the applied signal should not exceed a few hundred microamps, to ensure safety and linearity of impedance in the biological tissue.

[0154] — Trans-impedance data determination

[0155] Depending on the current signal applied, different methods may be used to calculate the trans-impedance data. Generally, the complex ratio of the recorded voltage and the applied current yields the complex trans-impedance. One method that may be used to extract complex trans-impedance data is to multiply the recorded voltage signal with in-phase and 90-degrees-phase-shifted versions of the input current signal to extract real and imaginary components of trans-impedance. Other methods may involve using methods such as magnitude / phase and fast Fourier transform (FFT) analysis for example. Whichever method is used to determine the impedance data, there are several possibilities for where the determination is performed and where data is stored. For example, all data storage and calculation may be performed on the apparatus 100 and the final output impedance values could be transmitted to one or more remote computing device for further processing. Another possibility is that the analogue input current values and output voltage values taken during step S5 are digitised and stored in the memory 151 of the apparatus 100. Once the assessment process is completed, the digitised current values and voltage values may be transmitted to one or more remote computing device (such as a server) for further processing. This further processing may include the steps of: determining trans-impedance values and either returning the trans-impedance values to a computing device (such as a computing device accessible to the medical professional), or storing the trans-impedance values for further processing. In a multi-channel electrode arrangement the further processing may include the step of using the trans-impedance values to determine a structural assessment of the abnormality under inspection (as described in greater detail below), and which may include an estimate of the depth of the abnormality and / or other information such as conductivity. Data representing the structural assessment may be transmitted back to a computing device (such as a computing device accessible to the medical professional). The structural assessment may comprise: a value indicating a depth; a range of values within which the actual depth is expected to be found; or may be in the form of a binary indication either to refer or not refer the patient for specialist advice.

[0156] — Electrode arrangements

[0157] Fig. 6A shows a linearly-spaced electrode arrangement 600 comprising electrodes 602 that may be used in the probe 110. The electrodes 602 are shaded to illustrate how they may be divided into groups of four for tetrapolar measurement. Each group of four may comprise a tetrapolar channel. Pairs of current-carrying electrodes 604 may inject current into the biological tissue and pairs of voltagerecording electrodes 606 may take voltage measurements. As is shown, each member of the pair of current-carrying electrodes 604 and each member of the pair voltagerecording electrodes is spaced a distance ± x from a centre line 608 (for the centre line x = 0) of the electrode arrangement 600. It can be seen that the electrodes of each channel are progressively further from the centre line 608. Considering just the pairs of current-carrying electrodes 604 it can be seen that each channel may be spaced an increasing distance x from the centre line 608. It may be that the increase is linear, so that each channel is spaced apart evenly along x. It may be that the linear increase is determined as a multiple of the electrode radius. The pairs of voltage-measuring electrodes 606 may be arranged in the same way. Fig. 6B illustrates how such a linear array of electrodes 600 may be arranged in the electrode region 138 of the probe 112, and how they may be connected to conductive tracks 142.

[0158] A larger spacing between current injecting electrodes leads to a larger current spread, implying that the recorded impedance progressively receives contributions from deeper layers of the biological tissue as the electrodes 602 are placed further and further apart. In order to investigate this a model was developed in COMSOL Multiphysics. Two disk electrodes of a set diameter were placed on top of a medium. The spacing between the disk electrodes were increased in multiples of their radii. The quasi-static approximation of Maxwell’s equations was solved using finite element methods. In each case induced voltage on the electrodes were simulated upon application of a set current level. Fig. 7A shows a graph 700 of distance x versus the magnitude of the measured trans-impedance Z, and Fig. 7B shows a graph 702 of distance x versus the rate of change of the measured trans-impedance, Z. Electrode contact impedance is ignored in the model. As can be seen in Fig. 7A the impedance measured using two electrodes on the surface of the biological tissue changes nonlinearly as the electrode spacing increases, indicating a nonlinear change in current spread in the tissue. For smaller electrode spacing distance x, Fig. 7B shows that this nonlinear change decays quickly as a function of interelectrode spacing. In other words, as electrode spacing increases, impedance measurements tend toward the same value making it harder to distinguish information from deeper layers of tissue. Of course, for practical applications it is not possible to increase electrode spacing indefinitely, and the electrodes should be spaced in a sufficiently localised way that they can be positioned on top of an abnormality.

[0159] This effect is shown in an alternative way in Fig. 7C which is a schematic cross section through a biological tissue 710 having a surface region of cancerous tissue 712 over a region of normal tissue 714. The linearly spaced electrode arrangement 600 has been placed on a surface 715 of the cancerous tissue 712 and current is being injected between pairs of electrodes (note only the current carrying electrodes 604 are shown). The surface 715 on which the electrode arrangement 600 is placed may be the oral mucosa for example and the depth of the biological tissue 710 shown in Fig. 7C may be of the order of several hundred microns. Current paths 716a, 716b, 716c are shown passing through the biological tissue 710. It is noted that this is a purely schematic representation of the current paths, but which does indicate the general pattern however. The maximum depth of current path 716a between a first, closest pair of electrodes 718 is near the surface of the biological tissue 710 (for example a few microns). In this way the transimpedance measurements from the corresponding pair of voltage recording electrodes (not shown) would indicate impedance of only a very shallow depth of the cancerous region 712 and contains no information from deeper layers. Since the second, next closest pair of electrodes 720 is spaced further apart than the first pair, current is able to penetrate deeper into the biological tissue 710 from the surface 715 (perhaps tens to a few hundred microns), as shown by the current path 716b. In this example, the maximum depth of the current path 716b is close to a boundary between the cancerous tissue 712 and the normal tissue 714. The corresponding pair of voltage recording electrodes would therefore include some information about the impedance of this boundary. The third pair of electrodes 722, being spaced further apart on the surface 715, is able to inject current deeper than the second pair 720 as shown by the current path 716c.

[0160] However, as shown by the pattern of the current paths 716 in the Fig. 7C, the increase in maximum depth penetration of current is non-linear and diminishing as a function of linear increase in electrode spacing on the surface 715. The maximum depth of current penetration may be considered as the depth range over which any given electrode pair is sensitive. As shown in Fig. 7C, the second pair of electrodes 720 has a very similar depth range to the third pair of electrodes 722. This means that there is limited benefit (in terms of additional depth range) in using the third pair of electrodes 722.

[0161] This is the same effect as shown in Figs 7A and 7B, in which the measured impedance tends towards a plateau with increasing spacing between a pair of electrodes.

[0162] Fig. 7D shows a graph 704 of normalised impedance versus depth of surface perturbation (e.g. cancerous tissue). These results were obtained using the aforementioned model in COMSOL Multiphysics. To model the surface perturbation there were two media beneath electrodes. The conductivity of a thinner superficial medium (representing the surface perturbation) was set to be 10 times lower that the deeper substrate (representing the normal tissue). The disk electrodes of set diameter, d, were placed at different distances away from each other (2d, Ad and 6d respectively) on the surface perturbation The depth of surface perturbation th was changed in multiples of the electrode radius r. To allow a better comparison between electrode pairs with different spacings, the results were normalised. In particular, the impedance traces were shifted down as much as their value at Z / =1.2r (|Z01) in each case and normalised to the maximum impedance Z (Z@6d and th= ) to better show the sensitivity irrespective of the actual impedance value. The results in graph 704 illustrate the non-linearity of the depth penetration of a linearly spaced set of electrodes, and that the second and third spacings (Ad and 6d) produce very similarly impedance results.

[0163] Fig. 6C shows a non-linearly spaced electrode arrangement 620 comprising electrodes 622 that may be used in the probe 110. The electrodes 622 are shaded to illustrate how they may be divided into groups of four for tetrapolar measurements. Each group of four may comprise a tetrapolar channel, 622a, 622b, 622c respectively. Pairs of current-carrying electrodes 624 may inject current into the biological tissue and pairs of voltage-recording electrodes 626 may take voltage measurements. As is shown, each member of the pair of current-carrying electrodes 624 and each member of the pair voltage-recording electrodes is spaced a distance ± x from a centre line 628 (for the centre line x = 0) of the electrode arrangement 600. It can be seen that the electrodes of each channel are progressively further from the centre line 628. Considering just the pairs of current-carrying electrodes 624 it can be seen that each channel may be spaced an increasing distance x from the centre line 628. It may be that the increase is non-linear, so that each channel is spaced apart non-evenly along x. The non-linearity may be defined as a function of x, for example as a power of x or as an exponent of x. The pairs of voltage-measuring electrodes 606 may be arranged in the same way. Fig. 6D illustrates how such a non-linear array of electrodes 602 may arranged in the electrode region 138 of the probe 112, and how they may be connected to conductive tracks 142. In one embodiment, each pair of current carrying electrodes 624 of channel 622a may be spaced apart 0.8mm (i.e. ±0.4mm from centre line 628); each pair of current carrying electrodes 624 of channel 622b may be spaced apart 2.4mm (i.e. ±1.2mm from centre line 628); and each pair of current carrying electrodes 624 of channel 622c may be spaced apart 6.5mm (i.e. ±3.25mm from centre line 628).

[0164] It is also noted in Fig. 6C that the diameter of each electrode pair may increase as the distance x from the centre line 628 increases, although it is noted that this is not essential. Fig. 7E is a graph 706 of normalised impedance versus normalised diameter in the modelling experiment described above with reference to Fig. 7D. For current carrying electrodes, as shown in Fig 7E, larger electrodes lead to lower measured transimpedance. In the absence of any practical consideration, smaller electrodes are favoured due to localisation of the screening as well as the increase in the amplitude of the recorded voltage signal. However, smaller electrodes suffer from poorer contact which leads to a noisy recorded signal. Therefore, a trade-off should be reached depending on the target depth and the above. Larger current levels may be applied to larger electrodes to mitigate the issue with the reduction of voltage signal level.

[0165] Fig. 7F shows the change in current paths that the non-linear electrode arrangement 620 may have (recalling that Figs. 7C and 7F are simplified conceptual for the purposes of illustration). Fig 7F is similar to Fig. 7C with like numerals indicating like parts. However, instead of the linear arrangement of electrodes 600 on the surface 715, the non-linear arrangement of electrodes 620 has been placed in contact with the surface 715. Maximum current spread 726a, 726b, 726c for each electrode pair is shown passing through the biological tissue 710. It is noted that this is a purely schematic representation of the current spread, but which does indicate the general pattern however. In contrast to Fig. 7C it can be seen how the maximum depth of each current path 726a, 726b, 726c of the non-linear electrode arrangement 620 may be more linearly spaced through the biological tissue 710, and the maximum depth of penetration of the second pair of electrodes 730 is different to the third pair of electrodes 732. By more evenly spacing the depth of maximum penetration through the biological tissue, an improved discrimination of the depth the cancerous tissue 712 may be achieved compared to the linear array of electrodes 600.

[0166] An experiment was carried out to investigate how the two different electrode arrangements performed with different depths of the cancerous tissue 712, also called ‘surface perturbation’. Four discs of a porous polystyrene scaffold (Alvetex™), each disc 200pm thick, were dipped in alcohol momentarily and then soaked momentarily in a growth medium (Sigma-Aldrich Minimum Essential Medium M4655 comprising Earle’s salts, L-glutamine and sodium bicarbonate). A substrate was formed by stacking the four discs on top of one another to represent the normal tissue 714. In order to model different depths of cancerous tissue 712, 200pm thick layers of a type of cultured cell (4 weeks old) were placed on top of the substrate to mimic the expected bilayer and to build up depth on the surface of the perturbation in increments of 200pm, forming a sample for testing. As each layer was added the sample was tested using EIS. In a first part of the experiment the linear electrode arrangement 600 shown in Fig. 6A and 6B was used to perform the EIS measurements. For the experiment a precision impedance analyser 6500B series (Wayne Kerr Electronics) was used. The current level was set to 200pA.

[0167] Fig. 8A is a graph 800 of input current frequency versus measured impedance using the linear electrode arrangement 600, for the sample described above. In Fig. 8A CHx (x = 1, 2, 3) indicates the channel number where CHI has the smallest interelectrode spacing. Ly (y = 0, 1, 2, 3) indicates the 200 pm increments of surface perturbation, where L0 indicates no surface perturbation (only the Alvetex™ substrate), and L3 indicates a 600 pm perturbation on the surface. CHI measurements 802 are well separated from the other two channels. However, CH2 and CH3 measurements 804 are not well separated over the whole frequency range. This is as expected from Fig. 7C in which the maximum depth of current penetration for CH2 (second pair 720) and CH3 (third pair 722) is broadly similar. Furthermore, it can be seen that the CH2L0 and CH2L1 measurements are criss-crossing the CH3L2 and CH3L3 measurements across the frequency range. For any given sample of unknown depth, this makes it difficult to determine whether impedance measurements indicate a cancerous tissue having a depth of L0 (0pm), LI depth (200 pm), L2 (400 pm) or L3 (600 pm).

[0168] In the second part of the experiment, the non-linear electrode arrangement 620 was used to perform the EIS measurements in place of the linear electrode arrangement 600. Fig. 8B is a graph 810 of input current frequency versus measured impedance using the non-linear electrode arrangement 620, for the sample described above. The key for CHx and Lx is the same as in Fig. 8A. CHI impedance measurements 812 are broadly similar to CHI measurements 802 of Fig. 8A. However, in contrast to the results shown in Fig. 8A, the inter-channel separation, i.e. between CH2 impedance measurements 814 and CH3 impedance measurements 816, is greater. This result supports the shape of current paths 726b and 726c shown in Fig. 7D in which the maximum depth penetration of the currents is more separated than in Fig. 7C. By improving the separation of the impedance measurements of each channel, there is a reduced chance that two channels will indicate conflicting depths of the cancerous tissue 712 (as described above with reference to Fig. 8A). Furthermore, intra-channel separation of impedance measurements within CH2 and within CH3 respectively is greater than in Fig. 8A, especially in the zone of frequency above about 1MHz to about 8MHz. This improved intra-channel separation of impedance measurements enables a more accurate indication of the depth of the cancerous tissue 712 to be made as there is greater certainty in selecting, for each channel, the closest matching impedance profile (e.g. CH2L1 or CH2L3) in Fig. 8B to the impedance measurements from an unknown abnormality in the patient’s mouth. The identification of the closest matching impedance profile provides an indication of the depth of the abnormality. It is noted that the inter-channel separation of impedance measurements may not always be in the range 1 MHz - 8 MHz, and that this range may be particular to this sample in this experiment. For example, inter-channel separation has been observed at lower frequencies than this range, but the separation was not as clear as shown in Fig. 8B. Experiments may be performed on a number of samples of the same tissue type to provide better reference data for use on patients with abnormalities of unknown depth.

[0169] As described above a tetrapolar impedance measurement system may comprise four electrodes in a rectangular format. An example of a tetrapolar electrode arrangement 900 is shown in Fig. 9A. A pair of circular current-carrying electrodes 902 are arranged in a rectangular format with a pair of circular voltage-recording electrodes 904. The lateral spacing dxbetween the two pairs is less than the spacing dybetween individual electrodes in each pair. In one example where each electrode has a diameter of 1 mm, dxis 200pm and dyis 750pm. In use, the tetrapolar electrode arrangement 900 facilitates measurement of a trans-impedance. The measured transimpedance can be significantly smaller than the actual impedance as current spread is in all directions, but voltage is measured on one side only. Also, the lateral size in direction dxof the electrode arrangement is relatively large and not suitable where multiple lateral channels should perform dense spatial sampling.

[0170] Fig. 9B shows an electrode arrangement 910 comprising a pair of circular current-carrying electrodes 912. A pair of voltage-recording electrodes 914 may be arranged to at least partly surround the pair of current-carrying electrodes 912. In particular, each one of the pair of voltage-recording electrodes 914 may comprise an open or closed annular sector shape (bearing some resemblance to a horseshoe shape) that may be arranged at least partly around one the current-carrying electrodes 912. By ‘open’ it may be meant that that annular sector shape does not form a complete circle around a current-carrying electrode 912, and there may be an angle 6 left open. By ‘closed’ it may be meant that the annular sector shape does form a complete circle (i.e. an annulus), thereby entirely surrounding a current-carrying electrode 912. The annular sector shape of each voltage-recording electrode 914 may have a width wr.

[0171] Each one of the pair of current-carrying electrodes 912 may have a corresponding one of the voltage-recording electrodes 914 around it. If each of the voltage-recording electrodes 914 has an open annular sector shape it may be that the open parts of each of the voltage-recording electrodes face one another, as shown in Fig. 9B. We have realised that the open annular sector shape is important for the following reason. In the middle of the line joining the centres of the current-carrying electrodes 912 there is a region of zero and near zero electrical potential. As the distance dybetween the pair of current-carrying electrodes 912 becomes smaller a portion of the voltage-recording electrodes will intersect this region. This is not desirable as this will reduce the overall recorded voltage. Using the open annular sector shape and arranging the voltage-recording electrodes 914 as shown in Fig. 9B, the recorded voltage may be increased.

[0172] In one example where each current-carrying electrode 912 has a diameter of 1mm, dxis 200 pm, dyis 750 pm and wris 200 pm.

[0173] By arranging electrodes in this way, it may be possible to improve the sensitivity and low current performance of tetrapolar measurements. In particular, recorded trans-impedance values may be brought closer to the actual impedance of the tissue. Furthermore, it is noted that the lateral size (in the direction dx) of the electrode arrangement 910 is smaller than the lateral size of the electrode arrangement 900 of Fig. 9A which may be advantageous in applications where space is restricted. For example, an arrangement like the electrode arrangement 910 may be used in the electrode region 138 of the probe 110, and replace the four electrodes 144 of Fig. 2. Fig. 10 shows an electrode arrangement 1000 based on the principles explained with reference to Fig. 9B, and on the principles of non-linear electrode spacing described with reference to Fig. 6C. The electrode arrangement 1000 may comprise three tetrapolar channels: a first channel 1002 comprising a first pair of currentcarrying electrodes 1004 and a first pair of voltage-recording electrodes 1006; a second channel 1008 comprising a second pair of current-carrying electrodes 1010 and a second pair of voltage-recording electrodes 1012; and a third channel 1014 comprising a third pair of current-carrying electrodes 1016 and a third pair of voltage-recording electrodes 1018. In use, the ring-like shape of the voltage-recording electrodes enables sampling of the current spread at least some, and possibly, all directions around the current-carrying electrodes.

[0174] The electrodes of the three channels may be spaced in a non-linear way, for example as described above with reference to Fig. 6B. Furthermore, the size and shape of the electrodes may be varied. For example, the size (e.g. diameter) of the electrodes may increase non-linearly with distance from a centre line 1020. This may be to allow greater currents to injected between further apart electrodes. Furthermore, the thickness of the annular sector shape of the voltage-recording electrodes 1006, 1012, 1018 may increase non-linearly with distance from the centre line 1020, but this is not essential.

[0175] The shape of the first and second pairs of voltage-recording electrodes 1006, 1012 may be in the form of an open annular sector as described above. Since the region of zero electrical potential between the current-carrying electrodes becomes smaller with increasing distance from the centre line 1020, the angle 6 of the open annular sector may decrease as the distance from the centre line 1020 increases. The open area of each annular sector shape may be oriented toward the centre line 1020, i.e. along a perpendicular line including the region where electrical potential is close to zero in use. However, each one of the third pair of voltage-recording electrodes 1018 may be in the form of an annulus shape and completely surround a corresponding one of the current-carrying electrodes 1016. This is because, at a greater distance from the centre line 1020, the electrical potential around the current-carrying electrodes will not be close to zero and therefore these potentials should be included in the voltage measurements. In an embodiment, only the first pair of electrodes 1006 has the form of an open angular sector and the remaining pairs (e.g. second pair 1012, third pair 1018) may be like the third pair 1018 shown in Fig. 10, with one voltage-recording electrode completely surrounding one current-carrying electrode.

[0176] An arrangement like the electrode arrangement 1000 may be used in the electrode region 138 of the probe 110 and replace the four electrodes 144 of Fig. 2.

[0177] — Designing a non-linear electrode array

[0178] The exact size and spacing of a nonlinear electrode array (e.g. as shown in Fig. 6C and in Fig. 10) may be determined having regard to the expected depth of cancer at different stages. Inter-electrode spacing may be designed to best capture those target depths. Reference is made again to Fig. 7F which illustrates how changing interelectrode spacing changes current penetration depth. Additionally, electrodes that are placed further apart may be made larger for more reliable contact. As discussed, above, it is noted that a larger electrode will reduce measured impedance, which may also lead to a reduction in signal to noise ratio (SNR). This may be compensated by a larger applied current, which may be safely delivered as the electrodes are larger and the ensuing current densities lower and within safe limits. Larger current levels will also help in resolving smaller impedance variations. Note that the lateral spacing between the current carrying electrode and voltage recording electrode does not contribute to resolving depth information.

[0179] For each application finite element methods may be used to assist the design of a non-linear electrode arrangement. Alternatively, finite element modelling may be used to derive non-linear electrode arrangements.

[0180] — Alternative Probe Interface Unit

[0181] Referring to Figs. 11 to 17 another embodiment of a probe interface unit is generally indicated by reference numeral 1100. One difference between the probe interface unit 1100 and the probe interface unit 112, is that the probe interface unit 1100 may be worn on either the hand 1112 of the user or the wrist as shown in Figs. 14 - 16, rather than only the wrist, as described in greater detail below. However, the internal electrical components and functionality of the probe interface unit 1100 are mostly the same as the probe interface unit 112, and reference is specifically made to Fig. 3 and the accompanying description which is incorporated into the present embodiment.

[0182] The probe interface unit 1100 may comprise a housing 1114 which may be formed in two or more parts that are assembled during manufacture to form the whole shown in Figs. 11 - 17. The housing 1114 may comprises a plastics material such as acrylonitrile butadiene styrene (ABS) or High Impact Polystyrene (HIPS). Once assembled, the housing 1114 may be generally C or U-shaped and may be substantially rigid as shown in Fig 11 A. In particular, the housing 1114 may comprise a pair of arms 1116 including a first arm 1118 and a second arm 1120. The first arm 1118 and second arm 1120 are each slightly curved and are closed together at a first end 1122 of the probe interface unit 1100. Although described as closed together, it is noted that the housing 1114 forming this section may be constructed from a single piece or may be constructed with multiple pieces. At a second end 1124 of the probe interface unit 1100 the pair of arms 1116 may form an opening 1126. The opening 1126 may be sized so that the thickness of hands 1112 (and / or wrists) of various users may fit between the pair of arms 1116, as shown in Fig. 14 and Fig. 16. In particular, the probe interface unit 1100 may be pushed on to the hand 1128 in the thenar space (between the thumb and index finger) so that the first arm 1118 lies adjacent the back of the hand 1128 and the second arm 1120 lies adjacent the palm of the hand.

[0183] To help the probe interface unit 1100 to fit a range of hand and / or wrist thicknesses, a retainer 1130 may be provided. The retainer 1130 may comprise a pair of removable rubberised polymer inserts, one insert mounted on each arm near the second end 1124. The probe interface unit 1100 may be supplied with a range of different sizes of the removable rubberised inserts so that a user may try different sizes to find the pair that is most comfortable for them. The retainer 1130 may be provided as a single removable piece that is sized and shaped to be retained around the inner edge 1132 of the housing 1114, i.e. extending from the second end 1124 on the first arm 1118 to the first end 1122 and then to the second end 1124 on the second arm 1120. In other embodiments the probe interface unit 1100 could be manufactured in different sizes to fit a normal population range of users. In another embodiment (shown in Fig. 1 IB) a probe interface unit is generally identified by reference numeral 1110b. The probe interface unit 1100b is generally the same as the probe interface unit 1100 except that at least one of the pair of arms 1116 is pivotably mounted to the first end 1122 of the housing 1114, for example by a sprung hinge (not shown). In this embodiment the second arm 1120 of the probe interface unit 1100b is pivotably mounted to the first end of the housing 1114. The second arm 1122 may be rotatable about an axis that is perpendicular to the page showing Fig. 1 IB. The sprung hinge may tend to bias the second arm 1120 into the space 1126 (so that the space 1126 becomes smaller), as shown by the dashed outline of the second arm 1120. In use, the user may rotate the second arm 1122 against the bias of the sprung hinge to allow the probe interface unit 1100 to be pushed onto the hand or wrist (see Figs. 14 and 16). Once on the hand or wrist, the sprung hinge may bias the second arm 1122 toward the position shown by dashed outline in Fig. 1 IB, thereby gently gripping the user’s hand or wrist.

[0184] Returning to Fig. 11 the first end 1122 of the housing 1114 may comprise two electrical connection ports 1134, either one of which may receive a proximal end of a probe 1137. One electrical connection port 1134 may be positioned on each side of the first arm 1118 (see Figs. 11 and 15 for example) so that the probe interface unit 1100 may be worn on either the right hand or the left hand. The first end 1122 of the housing 1114 may comprise a data capture button 1136. The data capture button 1136 may be positioned on the first end 1122 so that it may be reached and operated by the thumb 1138 of the hand 1112 on which the probe interface unit 1110 is worn (see e.g. Fig. 14). In particular, the inside region 1139 of the thumb (which generally faces the index finger 1140) in the zone of the proximal and distal phalanges may be rotated toward the data capture button 1136 to operate it. The data capture button 1136 may be operated in a similar way if the probe interface unit 1100 is worn on the left hand.

[0185] Referring also to Figs. 12 and 13, the first end 1122 of the housing 1114 may comprise a visual interface 1142. The visual interface may be positioned on the first end 1122 so that, in use, it is generally visible by the user. The probe interface unit 1110 may be adapted so that the visual interface communicates information to the user in a relatively simple way. For example, the probe interface unit 1110 may be configured to cause the display to show a colour to indicate its present status (the entire display may show the colour for example). Communicating device status in a simple way may be useful when the probe interface unit 1110 is being used by the medical professional to examine an abnormality in the oral cavity of the patient. During the examination, the index finger 1140 may be in contact with a tissue in the oral cavity of the patient. In order to do that, the medical professional may be concentrating on maintaining the index finger 1140 in position. Therefore, it may be more difficult to look at a visual display that shows more detailed information, such as text. By showing only a colour the medical professional may more easily determine the device status by using peripheral vision for example.

[0186] Figs. 12 and 13 illustrate the probe interface unit 1100 and a charging cradle 1144. The charging cradle 1144 may comprise a body 1146 which may be formed using a plastics material similar to the housing 1114. For example, the body 1146 may be formed from ABS. The charging cradle 1144 may be of a generally rectangular cuboid shape with five closed sides, one open side 1148 and a generally hollow interior. The size of the charging cradle 1144 may be sufficient to accommodate the pair of arms 1116 of the probe interface unit 1100, but leave the first end 1122 of the housing 1114 at least partly exposed (as shown in Fig. 14) when the pair of arms is pushed fully into the body and reaches a base side 1150.

[0187] The charging cradle 1144 may comprise a charging port (not shown, which may be a USB charging port) and a primary coil inside the body 1146 for providing an inductive charging function. The pair of arms 1116 of the probe interface unit 1100 may comprise a secondary coil positioned so that it is brought generally into alignment with the primary coil of the charging cradle when the probe interface unit 1100 is fully inserted into the body 1146 (see Fig. 13). In this position, the charging cradle may wirelessly charge the battery in the probe interface unit 1100.

[0188] The charging cradle 1144 may be configured to trigger the probe interface unit 1100 to wirelessly transfer data (e.g. WiFi, Bluetooth, Zigbee, NFC) once pushed back into the charging cradle 1144. For example, the charging cradle 1144 may comprise an internal microswitch, magnetically operated switch, or other proximity sensor (e.g. optical, inductance) for this purpose. The probe interface unit 1100 may be adapted to display a colour on the visual interface 1142 to indicate charging or data transfer is in progress, or both. Figs. 14, 15 and 16 show some different ways in which the probe interface unit 1100 may be worn. In Figs. 14 and 15, the probe interface unit 1100 may be worn on the hand as described above. Figs. 14 and 15 also two different arrangements of the probe 1137 on the index finger 1140: in Fig. 14, the probe 1137 is positioned so that it runs along the side of the index finger 1140 and the distal end is located within the distal phalanx, and in particular at the tip of the index finger; in Fig. 15, the probe 1137 runs under the index finger 1140 and the distal end of the probe 1137 is positioned within the distal phalanx. In the latter case, the probe 1137 may not have to bend around the tip of the finger 1140.

[0189] In Fig. 16, the probe interface unit 1100 may be worn on the wrist, and the probe 1137 routed along the index finger 1140 generally as described with reference to Fig. 1

[0190] In Figs. 14 and 15, since the probe interface unit 1100 may be worn over the palm and back of the hand (with the first end 1122 positioned between the thumb 1138 and index finger 1140 as shown in Fig. 15), the probe 1137 may be shorter than an embodiment where the probe interface unit 1114 is worn over the wrist (e.g. Fig. 16). This is possible because the two electrical connection ports 1134 are closer to the distal phalanx of the index finger than in the embodiment shown in Fig. 16. The probe 1137 is arranged differently in Figs. 14 and 15 resulting in different lengths. In Fig. 14 the length of the probe 1137 may be between about 80 mm and 120 mm, for example. In Fig. 15 the length of the probe 1137 may be between about 70 mm and 90 mm, for example. The exact range of lengths may depend on the size range of hands of the intended users. An advantage of the shorter probe 1137 of Figs. 14 and 15 is that the resistance of the conductive tracks may be reduced compared to the resistance of the tracks in Fig. 16 for example.

[0191] Additionally or alternatively, the probe interface unit 1100 may comprise a haptic device (not shown). The haptic device may be adapted to apply vibration to the hand 1112, for example via the second arm 1120 that is positioned adjacent the palm of the hand during use. The probe interface unit 1110 may be adapted to control the haptic device to indicate status to the user. In use, the medical professional may remove the probe interface unit 1100 from the charging cradle 1144 and place it on the right or left hand, between the thumb 1138 and index finger 1140 (as shown in Fig. 15 for example). If necessary, the retainer 1130 may be changed for a smaller or larger retainer to make the probe interface unit a comfortable friction-fit on the hand. The probe 1137 may be connected to the electrical connection port 1134 that faces the index finger, and the probe held in place on the examination glove as described elsewhere herein. Fig. 17 shows the probe interface unit 1100 on the hand 1112 ready for use. If the probe interface unit 1100 has a haptic device, a low intensity pulse or vibration 1152 may be emitted to indicate to the medical professional that the probe interface unit 1100 is ready.

[0192] Referring to Fig. 17B, the medical professional may bring the electrode region of the probe into contact with an abnormality 1154 on a biological tissue in the oral cavity of a patient, which in this example is the oral mucosa. If the probe interface unit 1100 determines there is sufficient contact between the electrode region and the abnormality 1154, a high intensity or continuous vibration 1156 may indicate this to the medical professional. The medical professional may start capture of voltage measurements by pressing the data capture button 1136 with the thumb (see Fig. 17C). The probe interface unit 1100 may indicate that the device is taking voltage measurements via a signal 1141 on the visual interface 1142 (see Fig. 17D). At this point voltage data may be captured and stored in a similar way to that describe above with reference to Fig. 4. The visual interface 1142 may also be used to indicate that data capture is complete. Once data has been captured and stored by the probe interface unit 1100, it may be returned to the charging cradle where data may be transferred via the charging cable to a remote computer (not shown).

[0193] — Depth information assessment

[0194] In embodiments utilising electrode arrangements comprising two or more tetrapolar channels (where each channel may comprise a group of four electrodes) depth information may be derived from the trans-impedance data for characterisation of the surface perturbation. Depth information may be derived deterministically by considering the “expected” impedance values for tetrapolar channels with further apart electrodes (e.g. CH2, CH3) based on the impedance recorded from the most central channel (e.g. CHI, which is expected to measure the impedance of the surface perturbation only). Additionally or alternatively, depth information may be determined statistically using algorithms such as those based on machine learning and artificial intelligence which depend on training on a large number of cases through unsupervised or supervised learning.

[0195] In this way it is possible to provide an indication of the likely depth information of the abnormality to the medical professional. The depth information may be provided as a likely depth, or a range of likely depths. The depth information may be provided via the probe interface unit, and / or may be provided to a computing device accessible to the medical professional. The determination of depth information may be performed locally on a computing device accessible to the medical professional. Alternatively, impedance or voltage data may be sent to a remote computing device for further processing and the depth information returned to a local computing device accessible to the medical professional. In some embodiments the depth information may be made accessible to the medical professional via the Internet, for example via a web browser.

Claims

CLAIMS1. An apparatus for performing an assessment of a biological tissue in an oral cavity of a patient, the apparatus adapted to be wearable by a medical professional during examination of the patient, which apparatus comprises: a probe interface unit; and a probe having a proximal end and a distal end, the proximal end connectable to said probe interface unit and the distal end adapted to be positioned within a distal phalanx region of a finger of the medical professional, and wherein said distal end comprises an electrode arrangement adapted for performing electrical impedance spectroscopy on said biological tissue when the medical professional positions the distal phalanx region of the finger on the biological tissue in the oral cavity of the patient, thereby bringing the distal end of the probe into contact therewith.

2. An apparatus as claimed in claim 1, wherein said probe comprises an elongate body of a size so that, in use, said probe reaches from the distal phalanx of the medical professional, along the finger, and so that said proximal end of the probe is located within a region between a base of the finger and a wrist of the medical professional.

3. An apparatus as claimed in claim 1 or 2, wherein said probe comprises a material which permits the medical professional to move the finger and associated wrist substantially without restriction. The material may be flexible. The material may be elastic. The material may be both flexible and elastic.

4. An apparatus as claimed in claim 3, wherein said material comprises a biomaterial that is suitable for interaction with the human or animal body. The material may be suitable for printing a biocompatible conductive materials onto its surface.

5. An apparatus as claimed in claim 4, wherein said material comprises one or more of: polyethylene terephthalate (PET), polyamide, thermoplastic polyurethane (TPU) and silicone.

6. An apparatus as claimed in claim 5, wherein the material is between 25 pm and 75 pm in thickness.SUBSTITUTE SHEET (RULE 26)7. An apparatus as claimed in any preceding claim, wherein said probe comprises an elongate body generally in the form of a strip.

8. An apparatus as claimed in any preceding claim, wherein the probe is adapted to be worn over a medical examination glove on the hand of the medical professional, and the probe is of a size such that it is useable by medical professionals with different hand sizes.

9. An apparatus as claimed in claim 8, further comprising at least one adhesive portion for adhering the probe to the medical examination glove on the finger.

10. An apparatus as claimed in claim 9, wherein said at least one adhesive portion is located at said distal end of said probe whereby, in use, the medical professional may adhere the distal end of the probe to the finger and hold the electrode arrangement in place during the assessment.

11. An apparatus as claimed in claim 8, 9 or 10, wherein said at least one adhesive portion comprises a tab that can be at least partially folded around the finger to hold the probe in place.

12. An apparatus as claimed in any preceding claim, wherein said electrode arrangement has a substantially planar configuration, the probe further comprising a stiffened portion for inhibiting movement of said electrode arrangement away from said substantially planar configuration during use.

13. An apparatus as claimed in claim 12, wherein said probe further comprises an electrical interface at said proximal end, and a plurality of electrical interconnects between said electrode arrangement and said electrical interface, wherein said electrical interface is adapted to be electrically connected by the medical professional to the probe interface unit before said tissue assessment is performed, and wherein, in use, said electrical interconnects enable said probe interface unit to deliver a current through said electrode arrangement and measure a voltage at said electrode arrangement.SUBSTITUTE SHEET (RULE 26)14. An apparatus as claimed in claim 13, wherein said electrical interface comprises a plurality of electrical contacts, each electrical contact electrically connected with a respective one of said electrical interconnects, a number of the electrical contacts being equal to a number of electrodes in the electrode arrangement.

15. An apparatus as claimed in claim 13 or 14, wherein each electrical interconnect of said plurality of electrical interconnects comprises a conductive track.

16. An apparatus as claimed in claim 15, wherein said conductive track has a width of between about 200 pm and 2 mm.

17. An apparatus as claimed in claim 15 or 16, wherein said conductive track has a thickness measured from a top surface of the probe of between about 10 pm and 17 pm.

18. An apparatus as claimed in claim 15, 16 or 17, wherein a spacing between adjacent conductive tracks is between about 20 pm and 200 pm.

19. An apparatus as claimed in claim 15, 16, 17 or 18, wherein said electrical interface and the plurality of electrical interconnects comprise at least one of silver, carbon, gold and platinum.

20. An apparatus as claimed in any preceding claim wherein said probe interface unit is adapted to deliver a current to said probe having a magnitude of between a few microamps and a few hundred microamps.

21. An apparatus as claimed in any preceding claim, wherein said probe interface unit comprises a housing wearable by the medical professional on the wrist or hand.

22. An apparatus as claimed in claim 21, further comprising a strap for retaining said housing to the wrist or hand.

23. An apparatus as claimed in claim 21, wherein said housing comprises a pair of arms closed together at a first end but left open at a second end opposite the first end, whereby the housing forms a shape approximating a U or C, the second end adaptedSUBSTITUTE SHEET (RULE 26)to receive the wrist or a part of the hand of the medical professional such that the pair of arms may be slid on to the wrist or the part of the hand and worn thereon during the tissue assessment, and slid off the wrist or the part of the hand after completion of the tissue assessment.

24. An apparatus as claimed in claim 23, further comprising a retainer on said pair of arms for helping to retain the housing on the wrist or part of the hand.

25. An apparatus as claimed in claim 23, wherein said housing is adapted to slide on and off the hand between the thumb and index finger so that, when slid on to the hand, a first arm of said pair of arms is positioned adjacent the back of the hand, and a second arm of said pair of arms is positioned adjacent the palm of the hand, and the first end of the housing bridges the webbing between the thumb and index finger.

26. An apparatus as claimed in claim 25, further comprising an actuator on said first end of said housing, the actuator actuatable by the thumb of the hand of the medical professional on which the housing is worn.

27. An apparatus as claimed in any of claims 21 to 26, wherein said probe interface unit further comprises: an electrical connector to which said proximal end of said probe is connectable; a computer processor and a memory, the memory storing computer-executable instructions that, when executed, cause the probe interface unit to perform the electrical impedance spectroscopy.

28. An apparatus as claimed in claim 27, wherein said probe interface unit further comprises a power supply for powering said computer processor and said memory.

29. An apparatus as claimed in claim 27 or 28, wherein said probe interface unit further comprises a waveform generator for generating an input voltage waveform, and a voltage-to-current converter for generating an input current corresponding to said input voltage waveform, the input current to be delivered to said electrode arrangement for performing the electrical impedance spectroscopy.

30. An apparatus as claimed in claim 29, wherein said probe interface unit furtherSUBSTITUTE SHEET (RULE 26)comprises a first device, such as a first multiplexer, that is controllable by said computer processor for switching the input current waveform between different pairs of electrodes in the electrode arrangement.

31. An apparatus as claimed in claim 30, wherein said probe interface unit further comprises a second device, such as a second multiplexer, that is controllable by said computer processor for switching between pairs of electrodes of the electrode arrangement to measure a voltage across the selected pair of electrodes.

32. An apparatus as claimed in any of claims 27 to 31, wherein said computerexecutable instructions are adapted to cause said probe interface unit to perform the electrical impedance spectroscopy by: delivering input currents at different frequencies to said probe, the input currents passing through electrode arrangement and the biological tissue; measuring voltages between a pair of electrodes of the electrode arrangement, the measured voltages induced by the input currents in the biological tissue, and the measured voltages at the different frequencies of the input currents; and storing in the memory a plurality of values indicating the trans-impedance of the biological tissue at the different frequencies.

33. An apparatus as claimed in claim 32, wherein said computer-executable instructions are adapted so that the step of storing in the memory comprises storing a first set of complex values indicating the magnitude and frequency of the input currents, and storing a second set of complex values indicating the magnitude and frequency of the measured voltages, whereby each one of the first complex values is mapped to a respective one of the second complex values.

34. An apparatus as claimed in claim 33, wherein said probe interface unit further comprises a wireless transmitter, and wherein said computer-executable instructions are adapted to transmit said first and second sets of complex values to a remote computing device using the wireless transmitter.

35. An apparatus as claimed in claim 33, wherein said computer-executableSUBSTITUTE SHEET (RULE 26)instructions are adapted so that the step of storing in the memory comprises: using said first set of complex values and said second set of complex values to determine a plurality of trans-impedance values; and storing the plurality of trans-impedance values in the memory.

36. An apparatus as claimed in claim 35, wherein said probe interface unit further comprises a wireless transmitter, and wherein said computer-executable instructions are adapted to transmit said trans-impedance values to a remote computing device using the wireless transmitter.

37. An apparatus as claimed in any of claims 27 to 35, wherein said probe interface unit further comprises a button for enabling the medical professional to start the electrical impedance spectroscopy.

38. An apparatus as claimed in any preceding claim, wherein said electrode arrangement comprises one or more group of electrodes, each group having four electrodes.

39. An apparatus as claimed in claim 38, wherein a first pair of electrodes in each group is for injecting a current into said biological tissue, and a second pair of electrodes of the group is for recording a voltage induced in the biological tissue by said current.

40. An apparatus as claimed in claim 39, wherein each electrode of said first pair of electrodes is spaced apart a first distance in a first direction, and each electrode of said second pair of electrodes is spaced apart said first distance in said first direction, and said first pair of electrodes is spaced apart from said second pair of electrodes a second distance in a second direction different to said first direction.

41. An apparatus claimed in claim 38, wherein each group of said one or more group of electrodes is arranged at the vertices of a rectangle.

42. An apparatus as claimed in claim 40 or 41, wherein said second direction is substantially perpendicular to said first direction.SUBSTITUTE SHEET (RULE 26)43. An apparatus as claimed in Claim 40, 41 or 42, wherein said at least one group of electrodes comprises: a first group of electrodes; a second group of electrodes; and a third group of electrodes; each group of electrodes spaced apart a different first distance so that: the first group of electrodes has the smallest first distance; the second group of electrodes has a larger first distance than the first group of electrodes; and the third group of electrodes has a larger first distance than the second group of electrodes; whereby, in use, current injected by the third group of electrodes spreads deepest into said biological tissue, current injected by the second group of electrodes spreads less deep than current of said third group of electrodes, and current injected by said first group of electrodes spreads less deep than said second group of electrodes.

44. An apparatus as claimed in claim 43, wherein there is a non-linear increase in first distance from:(i) the first group of electrodes; to(ii) the second group of electrodes; to(iii) the third group of electrodes; whereby, in use, there is an approximately linear spacing between the maximum current spread depth of the first, second and third groups of electrodes.

45. An apparatus as claimed in any of Claims 40 to 44, wherein said second distance is substantially the same for each of the first, second and third groups of electrodes.

46. An apparatus as claimed in any of claims 40 to 45, wherein each electrode of each group of electrodes has a surface area, wherein: the surface area of each electrode of the first group is substantially the same as the surface area of any other electrode of the first group; the surface area of each electrode of the second group is substantially the same as the surface area of any other electrode of the second group; and the surface area of each electrode of the third group is substantially the sameSUBSTITUTE SHEET (RULE 26)as the surface area of any other electrode of the third group.

47. An apparatus as claimed in claim 46, wherein: the surface area of each electrode of the first group is different to the surface area of any other electrode of the second group and the third group; the surface area of each electrode of the second group is different to the surface area of any other electrode of the first group and the third group; and the surface area of each electrode of the third group is different to the surface area any other electrode of the first group and the second group.

48. An apparatus as claimed in claim 47, wherein there is a non-linear increase in surface area from:(i) the first group of electrodes; to(ii) the second group of electrodes; to(iii) the third group of electrodes.

49. An apparatus as claimed in any of claims 36 to 48, wherein each electrode comprises a substantially circular region of conductive material on a top surface of said probe, an outwardly facing surface of the electrode for bringing into contact with the biological tissue by the medical professional under control of the finger.

50. An apparatus as claimed in claim 39, wherein each electrode of said first pair of electrodes is substantially collinear, and wherein one electrode of said second pair of electrodes at least partially surrounds a respective one electrode of said first pair.

51. An apparatus as claimed in claim 50, wherein each electrode of said second pair of electrodes is substantially collinear with said first pair of electrodes.

52. An apparatus as claimed in claim 50 or 51, wherein each electrode of said first pair of electrodes comprises a substantially circular region of conductive material on a top surface of said probe, an outwardly facing surface of the electrode for bringing into contact with the biological tissue by the medical professional under control of the finger, and wherein each electrode of said second pair comprises an annular sector.

53. An apparatus as claimed in claim 52, wherein each annular sector is orientedSUBSTITUTE SHEET (RULE 26)so that, in use, a zone of zero and near-zero electrical potential between each electrode of the first pair of electrodes is located in an open region of the respective annular sectors of the second pair of electrodes. E.g. IV recording, near-zero would be a microvolt.

54. An apparatus as claimed in claim 53, wherein said open region has an angle 0, between 0° and about 90° and wherein said angle 6 is smaller the larger a distance between the first pair of electrodes.

55. An apparatus as claimed in any of claims 50 to 54, wherein each electrode of said first pair of electrodes is spaced apart a first distance in a first direction.

56. An apparatus as claimed in claim 55, wherein said one or more group of electrodes comprises: a first group of electrodes a second group of electrodes; and a third group of electrodes; each group of electrodes spaced apart a different first distance so that: the first group of electrodes has the smallest first distance; the second group of electrodes has a larger first distance than the first group of electrodes; and the third group of electrodes has a larger first distance than the second group of electrodes; whereby, in use, current injected by the third group of electrodes spreads deepest into said biological tissue, current injected by the second group of electrodes spreads less deep than current of said third group of electrodes, and current injected by said first group of electrodes spreads less deep than said second group of electrodes.

57. An apparatus as claimed in claim 56, wherein there is a non-linear increase in first distance of the first pair of electrodes from:(i) the first group; to(ii) the second group; to(iii) the third group; whereby, in use, there is an approximately linear spacing between the maximum current spread depth of the first, second and third groups of electrodes.SUBSTITUTE SHEET (RULE 26)58. An apparatus as claimed in claim 56 or 57, wherein each electrode of each first pair of electrodes of the first, second and third groups of electrodes has a surface area, wherein: the surface area of each electrode of the first pair of electrodes of the first group has substantially the same surface area; the surface area of each electrode of the first pair of electrodes of the second group has substantially the same surface area; the surface area of each electrode of the first pair of electrodes of the third group has substantially the same surface area.

59. An apparatus as claimed in claim 58, wherein: the surface area of each electrode of the first pair of electrodes of the first group is different to the surface area of any other electrode of the second group and the third group; the surface area of each electrode of the first pair of electrodes of the second group is different to the surface area of any other electrode of the first group and the third group; and the surface area of each electrode of the first pair of electrodes of the third group is different to the surface area any other electrode of the first group and the second group.

60. An apparatus as claimed in claim 59, wherein there is a non-linear increase in the surface area of each electrode of the first pair of electrodes from:(i) the first group; to(ii) the second group; to(iii) the third group.

61. An apparatus as claimed in any preceding claim, wherein said probe is a singleuse probe.

62. A probe for use in performing an assessment of a biological tissue in an oral cavity of a patient by a medical professional during examination of the patient, which probe comprises a proximal end and a distal end, the proximal end connectable a probe interface unit and a distal end adapted to be positioned within a distal phalanx regionSUBSTITUTE SHEET (RULE 26)of a finger of the medical professional, and wherein said distal end comprises an electrode arrangement adapted for performing electrical impedance spectroscopy on said biological tissue when the medical professional positions the distal phalanx region of the finger on the biological tissue in the oral cavity of the patient, thereby bringing the distal end of the probe into contact therewith.

63. A probe interface unit for use in performing an assessment of a biological tissue in an oral cavity of a patient by a medical professional during examination of the patient, which probe interface unit comprises: an electrical connector to which a proximal end of a probe as claimed in claim 60 is connectable; a computer processor and a memory, the memory storing computer-executable instructions that, when executed, cause the probe interface unit to perform an electrical impedance spectroscopy on the tissue of the patient.

64. A kit for performing assessments of biological tissue, which kit comprises a probe interface unit as claimed in claim 61 and a plurality of single-use probes, each probe as claimed in claim 60.

65. A computing device for generating an assessment of depth of an abnormality visible on the surface of a biological tissue in an oral cavity, which computing device comprises a processor and a memory, the memory storing computer-executable instructions that when executed cause the computing device to perform the steps of:(i) receive and store data representing measured trans-impedance of the abnormality, the measured trans-impedance obtained by an apparatus as claimed in any of claims 1 to 60;(ii) process the data to determine an estimated depth of the abnormality; and(iii) output the estimated depth of the abnormality.

66. A computer device as claimed in claim 65, wherein said computer-executable instructions are adapted so that in step (ii) the computing device determines said depth deterministically or statistically.

67. A computer device as claimed in claim 65 or 66, wherein said computer deviceSUBSTITUTE SHEET (RULE 26)comprises a server computer remote from said apparatus.SUBSTITUTE SHEET (RULE 26)

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