Patent Description:
Embodiments of the present invention relate generally to medical diagnostic technology, and, more specifically, to techniques for detecting cancerous cells in excised tissue samples using impedance detection.

Mohs micrographic surgery (MMS) is a treatment for skin cancer that is used when removing basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). During MMS, a surgeon removes a layer of skin from a target area of a patient that is suspected to include some cancer cells. Immediately after removing the excised layer, frozen sections are prepared the surgeon examines slides under a microscope to determine the presence of cancer cells. According to the procedure, the surgeon successively removes and examines skin layers from the patient until the frozen sections are satisfactorily cleared of diseased tissue. MMS advantageously enables a surgeon to remove a minimal amount of tissue from the patient and preserve a maximal amount of healthy cells around the target excision.

One of the drawbacks of MMS is that excising, examining, and assessing the different layers of tissue suspected to contain cancer cells is quite time-consuming for surgeons. In particular, as alluded to above, for each excised layer of tissue, the surgeon must manually prepare frozen sections and then examine frozen sections under a microscope and assess whether the sample contains any cancer cells. Due to the time-consuming nature of MMS, this particular procedure is considered to be an expensive form of cancer treatment.

<NPL>, discloses a method for detecting cancerous cells in a sample of excised tissue using the Cole relaxation frequency.

<CIT> discloses a method for characterizing tissues within a subject as cancerous or non-cancerous, including determining the electrical properties of the subject. The electrical properties of the subject are fit to a model and a specific range of a set of characteristic frequencies of each tissue is then calculated.

<CIT> discloses an apparatus for diagnosis of a biological sample comprising a plurality of electrode elements thereby forming an electrode array where each electrode element is variably actuatable to apply an electrical signal to the biological sample.

As the foregoing illustrates, what is needed in the art are more effective techniques for analyzing and assessing excised tissue layers during Mohs micrographic surgery.

One embodiment of the present application sets forth a method for detecting cancerous cells in a sample of excised tissue. The method includes connecting an electrode array to a switching circuit, and a first subset of electrodes included in the electrode array measuring, at a first operating frequency, a first impedance of a first section of the sample. The method also includes computing a first Cole relaxation frequency for the first section of the sample based on the first impedance. The method also includes determining that the first section of the sample contains cancerous cells based on the first Cole relaxation frequency. This method also includes the switching circuit electrically connecting the first subset of electrodes and electrically disconnects all remaining electrodes in the electrode array when the first subset of electrodes measures the first impedance.

A major advantage of the disclosed tissue measurement system is that the system quickly and accurately detects the presence and location of cancer cells within a tissue excised from a patient, without involving the surgeon. Because the disclosed system is able to automatically analyze and assess successively excised tissue layers in an MMS procedure before the preparation of frozen sections, the time required to perform MMS is substantially reduced, thereby making MMS a more cost-effective form of cancer treatment.

So that the manner in which the above recited features of the invention can be understood in detail, a more particular description of the invention, briefly summarized above, may be had by reference to embodiments, some of which are illustrated in the appended drawings. It is to be noted, however, that the appended drawings illustrate only typical embodiments of this invention and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments.

In the following description, numerous specific details are set forth to provide a more thorough understanding of the present invention. However, it will be apparent to one of skilled in the art that the present invention may be practiced without one or more of these specific details.

As discussed above, conventional techniques for Mohs micrographic surgery (MMS) require a surgeon to excise and manually prepare frozen sections for microscopic evaluation of excised tissue to determine whether the excised tissue contains any cancer cells. Such a technique is time-consuming and expensive, as the lengthy process requires the surgeon or third party to perform assessments for several frozen sections of each of the excised layers during the surgery.

To address this problem, embodiments of the invention include a tissue measurement system that sends electrical currents to sections of an excised tissue sample. A diagnosis module connected to an electrode array receives electrical measurements and computes electrical properties, including impedances and Cole relaxation frequencies, based on the electrical measurements. The diagnosis module compares a computed Cole relaxation frequency to a cancer-detection threshold to determine whether cancerous cells are present in the corresponding section of the excised tissue sample. In some embodiments, the diagnosis module may determine the locations of the detected cancerous cells within the excised tissue sample.

Though the description discusses tissue samples excised during Mohs micrographic surgery, the disclosed techniques can be executed for other types of excised tissues cells. Further, the disclosed techniques can be executed independently from MMS procedures.

<FIG> illustrates a tissue measuring system configured to implement one or more aspects of the present invention. Tissue measurement system <NUM> includes a tissue measurement device <NUM>, a display <NUM>, and input/output (I/O) units <NUM>. Tissue measurement device <NUM> includes a diagnosis module <NUM>, a switching circuit <NUM>, and an electrode array <NUM>. Diagnosis module <NUM> includes an analyzer <NUM>, a controller <NUM>, and memory <NUM>.

Tissue measurement device <NUM> automatically measures impedances of a section of an excised tissue sample. Diagnosis module <NUM> causes switching circuit <NUM> to select different measuring subsets of electrode array <NUM> that measure the electrical properties of different sections of an excised tissue sample. In some embodiments, when performing measurements on the section of the excised tissue sample, diagnosis module <NUM> may perform a sweep of measurements within a range of operating frequencies. For example, a measuring subset of electrode array <NUM> may initially inject a current at an initial operating frequency between <NUM> and <NUM>, then measure and record the electrical properties of the section of the excised tissue sample. Tissue measurement device <NUM> may then sweep through range of operating frequencies. For example, tissue measurement device <NUM> may increase the operating frequency of the injecting current at steps of <NUM>.

Tissue measurement device <NUM> computes impedances for the electrical properties and subsequently computes a Cole relaxation frequency (Fcole) from the computed impedances. The Cole relaxation frequency for a section of the excised tissue sample reflects the rate at which a cell membrane discharges a stored electrical charge. In some embodiments, tissue measurement device <NUM> computes the Cole relaxation frequency as an average of electrical discharge rates for a plurality of cells included in the section of the excised tissue sample. In some embodiments, tissue measurement device <NUM> may determine the presence and/or location of cancerous cells based on computing Cole relaxation frequencies for one or more sections of the excised tissue sample. In some embodiments, tissue measurement device <NUM> may output measurement data to display <NUM> and/or I/O units <NUM>.

In some embodiments, tissue measurement device <NUM> may include diagnosis module <NUM>, switching circuit <NUM>, and electrode array <NUM> as separate physical components. In alternative embodiments, diagnosis module <NUM>, switching circuit <NUM>, and/or electrode array <NUM> may share a common housing. In some embodiments, tissue measurement device <NUM> may communicate wirelessly with display <NUM> and/or I/O units <NUM>.

Electrode array <NUM> includes multiple electrodes that are electrically isolated from each other by intervening channels. In some embodiments, electrode array <NUM> is planar, allowing an excised tissue sample to be placed directly on one or more electrodes of electrode array <NUM>. In some embodiments, one or more of the electrodes included in electrode array <NUM> are non-invasive and may have a surface configured to reduce electrical polarization between the individual electrodes of electrode array <NUM> and the excised tissue sample. For example, one or more of the electrodes in electrode array <NUM> may have a blackened platinum (BPt) surface that physically contacts a portion of the excised tissue sample, reducing the electrical polarization between the electrode array <NUM> and the excised tissue sample.

Switching circuit <NUM> connects electrical signals between electrode array <NUM> and diagnosis module <NUM>. In some embodiments, switching circuit <NUM> also includes components of measurement circuits, including a voltmeter and an ammeter. In such instances, switching circuit <NUM> connects a measuring subset of electrodes from electrode array <NUM> to the voltmeter and ammeter, respectively, to measure the voltage and current of the section of the excised tissue sample. As will be discussed in further detail below, switching circuit <NUM> includes an array of individual switches, such as micro-relay circuits, that each connect to a separate electrode in electrode array <NUM>. In some embodiments, the individual switches are controlled by controller <NUM> in diagnosis module <NUM> to connect the corresponding electrode to either a current-sensing circuit or a voltage-sensing circuit. Each of the current-sensing circuit and the voltage-sensing circuit may be components of a single measurement circuit. In some embodiments, switching circuit <NUM> may keep one or more micro-relays included in the micro-relay circuits open, where the connected electrode remains floating and provides a high impedance when a current is injected.

Diagnosis module <NUM> connects through switching circuit <NUM> to electrode array <NUM>. In some embodiments, diagnosis module <NUM> may use controller <NUM> to execute a program stored in memory <NUM> to conduct multiple electrical measurements on the excised tissue sample using multiple measuring subsets of electrode array <NUM>. In some embodiments, diagnosis module <NUM> may receive instructions from a user via I/O units <NUM> to store data or to perform specific electrical measurements via electrode array <NUM>. In some embodiments, diagnosis module <NUM> may store the measured electrical properties determined by the measurement circuit, such as the measured voltage and the measured current for an input signal at a specific operating frequency. In some embodiments, diagnosis module <NUM> can include a processing unit. The processing unit may be a single central processing unit (CPU), or combination of processing units. The processing unit may be any technically-feasible hardware unit capable of processing data and/or executing software code. In some embodiments, the processing unit of diagnosis module <NUM> may receive instructions from a user or from memory <NUM> and may execute instructions. In some embodiments, the processing unit may implement one or more techniques executed by analyzer <NUM> and/or controller <NUM>.

Analyzer <NUM> of diagnosis module <NUM> computes real and imaginary impedances for a section of the excised tissue sample based on the measured electrical properties. In some embodiments, diagnosis module <NUM> stores the computed impedances in memory <NUM>. Analyzer <NUM> computes the Cole relaxation frequency for the section of the excised tissue sample based on the computed impedances corresponding to the operating frequency. The Cole relaxation frequency for a section of the excised tissue sample reflects the rate at which a cell membrane discharges a stored electrical charge. In some embodiments, analyzer <NUM> determines whether the section of the excised tissue sample includes cancerous cells. Due to the contrasting electrical properties of malignant cells and non-malignant cells, malignant cells have a Cole relaxation frequency that is over one thousand times smaller than the Cole relaxation frequency of a non-malignant cell. Analyzer <NUM> compares the compute Cole relaxation frequency to a pre-determined cancer-detection threshold to determine whether the section of the excised tissue sample contains cancerous cells.

In some embodiments, analyzer <NUM> may determine a probability of malignant cancer cells based on one or more frequency ranges above the cancer-detection threshold. In such instances, each frequency range may indicate that the cancerous cells are more dangerous and may indicate a need for more aggressive treatment. For example, an initial cancer-detection threshold for breast cancer cells may be <NUM>. A Cole relaxation frequency occurring within a first critical range of <NUM> to <NUM> may indicate that the breast cancer may recur after treatment. A Cole relaxation frequency occurring within a second critical range above <NUM> may indicate a high likelihood of metastasis after treatment. The cancer-detection threshold and the number and thresholds for each of the critical ranges may vary for each type of cancer.

In some embodiments, analyzer <NUM> may generate an impedance spectrum for a set of computed impedances, which indicates the magnitude of impedances as a function of the operating frequency used during measurement. In such instances, analyzer <NUM> can compute the Cole relaxation frequency for the set of impedances by performing a regression analysis to find a best fit to pre-determined impedance spectrums stored in memory <NUM>. Analyzer <NUM> may determine the Cole relaxation frequency from the impedance spectrum by determining the frequency corresponding to the peak impedance of the impedance spectrum.

Controller <NUM> of diagnosis module <NUM> causes switching circuit <NUM> to select different measuring subsets of electrode array <NUM> that measure electrical properties of different sections of an excised tissue sample. Controller <NUM> also sets the operating frequency and amplitude of the injection current when initiating a measurement using the measuring subset of electrode array <NUM>. In some embodiments, controller <NUM> may load instructions stored in memory <NUM> and execute a measurement program using one or more measuring subsets of electrode array <NUM>. In some embodiments, controller <NUM> may generate and transmit one or more control signals to switching circuit <NUM> to open and/or close switches corresponding to different measuring subsets of electrode array <NUM>. Controller <NUM> may change to a different measuring subset by transmitting a control signal to switching circuit <NUM> that electrically connects electrodes of the measuring subset to the measuring circuit, while disconnecting all remaining electrodes in electrode array <NUM>.

Memory <NUM> is configured to store data and/or software applications. Memory <NUM> may include a random access memory (RAM) module, hard disk, flash memory unit, or any other type of memory unit or combination thereof. Diagnosis module <NUM> and I/O units <NUM> are configured to read data from memory <NUM>. Diagnosis module <NUM> and I/O units <NUM> are also configured to write data to memory <NUM>.

Display <NUM> displays data transmitted from tissue measurement device <NUM>. In an embodiment, display <NUM> displays one or more of the computed Cole relaxation frequency, the location(s) of cancerous cell regions, and the probability of cancer in the excised tissue sample. In some embodiments, display <NUM> may refresh the data received from tissue measurement device <NUM> while tissue measurement device <NUM> performs measurements on the excised tissue sample. In some embodiments, display <NUM> may display and image of the excised tissue sample with indications of the locations of probable cancerous cells.

I/O units <NUM> receive output signals from tissue measurement device <NUM> and transmit input signals from a user to tissue measurement device <NUM>. In some embodiments, I/O units <NUM> transmit program input signals to controller diagnosis module <NUM>, where diagnosis module <NUM> stores the program in memory <NUM>. In some embodiments, I/O units <NUM> may include devices capable of receiving one or more inputs, including a keyboard, mouse, input tablet, camera, and/or three-dimensional (3D) scanner. In some embodiments, I/O units <NUM> may also include devices capable of providing one or more outputs, such as a speaker or printer. I/O units <NUM> may also include devices capable of both receiving inputs and providing outputs, such as a touchscreen and a universal serial bus (USB) port.

<FIG> is a more detailed illustration of the electrode array of <FIG>, according to various embodiments of the present invention. Electrode array <NUM> includes a first column of electrodes 202a-I and a second column of electrodes 204a-I. In some embodiments, the physical distance between each of the electrodes in electrode columns 202a-I, 204a-I is constant. In some embodiments, the electrical paths of different electrode pairs are constant. For example, the physical distance between electrode 202a and electrode 202b may have a physical distance of <NUM>, which may be equal to a <NUM>-mm physical distance between electrode 204j and <NUM>. Similarly, an electrical path formed by connecting electrodes 202a, 202b to switching circuit <NUM> is equal to an electrical path formed by connecting electrodes 204j, <NUM> to switching circuit <NUM>. In some embodiments, controller <NUM> through switching circuit <NUM> selects a measuring subset of electrodes 206a-c where the measuring circuit includes electrodes that have the same path length. Selection of such measuring subset provides the advantage of avoiding synchronization issues by avoiding reflections and phase shifts when performing multiple measurements. In some embodiments, the physical path length and/or the electrical path length of electrodes 202a-I, 204a-I may not be equal, but may be fixed in time. In such instances, subsequent signal processing steps may be adjusted to compensate for unequal physical path lengths and/or unequal electrical path lengths.

During operation, controller <NUM> may measure the electrical properties of a section of an excised tissue sample located at section 208a by selecting measuring subset 206a of electrode array <NUM>, which includes electrodes 202a-d. Similarly, controller <NUM> may measure section 208b by selecting measuring subset 206b, which includes electrodes 204d-g. Controller <NUM> may measure section 208c by selecting measuring subset 206a, which includes electrodes 202f-i, 204f-i. In some embodiments, controller <NUM> may measure varying depths of the excised tissue sample by selecting a measuring subset with electrodes located further away from the section. For example, when measuring section 208c, controller <NUM> may measure a different depth of section 208c by selecting a measuring subset including each of electrodes 202c-I, 204c-I. When switching circuit <NUM> connects measuring subset 206a to the measuring circuit, one or more of electrodes 202a-d may be connected to a voltage-sensing device, one or more of electrodes 202a-d may be connected to a current-sensing device, while the remainder of electrodes 202e-I, 204a-I are disconnected from the measuring circuit.

In some embodiments, an electrode pair of 202a, 202d in measuring subset 206a forms a current-sensing circuit. In such instances, electrode 202a acts as an injection electrode that receives a current from a current generator. The injection electrode 202a receives an alternating current that has a frequency corresponding to the operating frequency specified by controller <NUM>. Electrode 202d acts as a return electrode that completes a current path by connecting to electrode 202a. In some embodiments, the return electrode 202d is connected to a current-sensing circuit or current-sensing device, such as an ammeter. Diagnosis module <NUM> may receive the current measurement provided by the current-sensing circuit or current-sensing device and associate the measured current with the operating frequency of the initial current.

In some embodiments, one or more electrodes in between the electrodes forming the current-sensing circuit may be part of a voltage-sensing circuit. For example, electrodes 202b, 202c of measuring subset 206a may act as voltage-sensing electrodes and be connected to a voltage-sensing circuit or a voltage-sensing device, such as a voltmeter. Voltage-sensing electrodes 202b, 202c may have a high impedance in order to avoid adding stray currents into the measuring circuit. Diagnosis module <NUM> may receive the voltage measurement provided by the voltage-sensing circuit or voltage-sensing device and associate the measured current with the operating frequency of the initial current.

Controller <NUM> may measure different sections of an excised tissue sample by switching to different measuring subsets 206a, 206b, 206c. For example, controller <NUM> may cause switching circuit <NUM> to switch from measuring section 208a to section 208b by disconnecting measuring subset 206a from the measuring circuit and connecting measuring subset 206b to the measuring circuit. In some embodiments, controller <NUM> may switch between sections 208a, 208b, 208c in a pre-defined pattern. For example, controller <NUM> may perform series of electrical measurements on section 208a for <NUM> to <NUM> seconds. Controller <NUM> may then cause switching circuit <NUM> to select a different measuring subset to perform a series of electrical measurements on a section of the excised tissue sample located between electrode 202c and 202d for <NUM> to <NUM> seconds. In some embodiments, controller <NUM> may perform electrical measurements all sections within electrode array <NUM> in under <NUM> to <NUM> seconds.

<FIG> is a more detailed illustration of the switching circuit of <FIG>, according to various embodiments of the present invention. Switching circuit <NUM> includes micro-relay circuits 302a-d connected to relay driver <NUM>. In some embodiments, relay driver <NUM> may receive one or more control signals from controller <NUM> and connect one or more electrodes to the voltage-sensing circuit of the measuring circuit and connect one or more electrodes to the current-sensing circuit of the measuring circuit.

Relay driver <NUM> may be a microcontroller or other electronic circuit that controls one or more micro-relay circuits 302a-d. In some embodiments, one or more relay drivers <NUM> may control each of the micro-relay circuits connected to the corresponding electrodes in electrode array <NUM>. In some embodiments, relay driver <NUM> may receive control signals from controller <NUM> to connect electrodes to the measuring circuit. Relay driver <NUM> may respond to the received control signal by sending one or more driving signals to micro-relay components included in each of micro-relay circuits 302a-d. The driving signal may close one of the pair of micro-relay components or open each of the micro-relay components. In some embodiments, relay driver <NUM> switches the measuring subset of electrodes 206a to a separate measuring subset of electrodes 206b by sending driving signals to each of micro-relay circuits 302a-d corresponding to the electrodes included in measuring subsets 206a, 206b.

Each of micro-relay circuits 302a-d is connected to a separate electrode in electrode array <NUM>. In some embodiments, micro-relay circuit 302a-d includes an amplifier and two separate micro-relay components at the input of the amplifier. In some embodiments, relay driver <NUM> may open both micro-relay components, configuring the circuit to perform voltage sensing at the corresponding electrode in electrode array <NUM>. Relay driver <NUM> may close the first of the two micro-relay components to connect micro-relay circuit 302a-d and the corresponding electrode to the current injection source. In some embodiments, relay driver <NUM> may close the second of the two micro-relay components to connect micro-relay circuit 302a-d and the corresponding electrode to the current-sensing circuit. In some embodiments, one or more of the remaining electrodes not in measuring subset 206a may be shorted to ground.

In some embodiments, a two electrode configuration may sense both the current and the voltage. In the two electrode configuration, one electrode in electrode array <NUM> configured for voltage sensing may simultaneously also be configured for current injection, while a second electrode configured for voltage sensing may simultaneously ale be configured for current sensing.

Micro-relay circuits 302a-d execute switching using one or more micro-relay components. The micro-relay components advantageously switch between connecting and disconnecting current injection and/or current-sensing circuits to the electrodes with a minimum of parasitic impedances or capacitances (<NUM>-<NUM> pF) added to the measuring circuit. By avoiding the addition of such parasitic impedances and capacitances, switching circuit <NUM> can switch between measuring subsets 206a-c quickly without sacrificing the accuracy of the collected electrical measurements. Micro-relay circuits 302a-d also provide the advantage of using electrical switches instead of slower mechanical rotary switches.

In some embodiments, micro-relay circuits 302a-d may include one or more correction techniques to minimize crosstalk caused by one or more electrodes in electrode array <NUM> when a measuring subset 206a is performing an electrical measurement. For example, one or more electrodes of electrode array <NUM> may be connected to a Reed relay, such as a <NUM> pF capacitor (not shown) to limit crosstalk for electrodes in electrode array <NUM> that are not included in the measuring subset 206a. In some embodiments, micro-relay circuits 302a-d may match impedances of.

<FIG> illustrates computed Cole relaxation frequencies for multiple sections of excised tissue, according to various embodiments of the present invention. Graphs <NUM> illustrate impedance spectrums indicating calculated impedances for a range of operating frequencies based on voltages and currents measured by electrode array <NUM>. Graph <NUM> illustrates impedance spectrum <NUM> for a section of an excised tissue sample that likely includes malignant cells. Graph <NUM> illustrates impedance spectrum <NUM> for a section of an excised tissue sample that likely does not include any malignant cells.

Graph <NUM> includes cancer-detecting threshold <NUM> and critical stage threshold <NUM>. Impedance spectrum <NUM> includes a Cole relaxation frequency <NUM> corresponding to the peak of impedance spectrum <NUM>. In some embodiments, analyzer <NUM> computes Cole relaxation frequency <NUM> by generating an impedance spectrum <NUM> and determining the frequency corresponding to the peak of the curve. In some embodiments, analyzer <NUM> may compare Cole relaxation frequency with cancer-detection threshold <NUM> and/or critical stage threshold <NUM>.

For example, analyzer <NUM> can compare Cole relaxation frequency <NUM> to cancer-detection threshold <NUM>. In some embodiments, cancer-detection threshold <NUM> can range from <NUM> to <NUM>. Analyzer <NUM> can determine that the section of the excised tissue sample likely contains malignant cells because Cole relaxation frequency <NUM> exceeds cancer-detection threshold <NUM>. In contrast, analyzer <NUM> may determine compare Cole relaxation frequency <NUM> for impedance spectrum <NUM> to cancer-detection threshold <NUM>. Analyzer <NUM> can determine that the section of the excised tissue sample likely does not contain malignant cells because Cole relaxation frequency <NUM> is less than cancer-detection threshold <NUM>. In some instances, Cole relaxation frequency <NUM> for a tissue sample containing malignant cancer cells is approximately <NUM> times larger than Cole relaxation frequency <NUM> for a tissue sample that does not contain any malignant cancer cells.

In some embodiments, analyzer <NUM> may compare Cole relaxation frequency <NUM> to a critical stage threshold <NUM>. In some embodiments, critical stage threshold <NUM> can range from <NUM> to <NUM>. Analyzer <NUM> can determine that the section of the excised tissue sample does not contain cells likely approaching a critical stage indicating more dangerous concentrations of cancer cells because Cole relaxation frequency <NUM> is below critical stage threshold <NUM>. Similarly, analyzer <NUM> may determine compare Cole relaxation frequency <NUM> to critical stage threshold <NUM>. Analyzer <NUM> can determine that the section of the excised tissue sample likely does not contain cells likely approaching a critical stage indicating more dangerous concentrations of cancer cells because Cole relaxation frequency <NUM> is less than critical stage threshold <NUM>. In some embodiments, analyzer <NUM> may compare Cole relaxation frequency <NUM> to multiple critical stage thresholds, where each critical stage threshold indicating a higher probability of cancer and/or a more dangerous diagnosis.

<FIG> illustrates tables showing the accuracies of cancer detection in a sample group of patients based on various computed Cole relaxation frequencies, according to various embodiments of the present invention. Tables <NUM> show tabulated results of diagnosis for squamous cell carcinomas (SCCs) <NUM>, basal cell carcinomas (BCCs) <NUM>, and combined results <NUM> for a group of patients using tissue measurement system <NUM>.

Table <NUM> shows that from a sample of <NUM> tests for basal cell carcinoma, tissue measurement system <NUM> accurately classified over <NUM> percent of the excised tissue samples. The accuracy of the tissue measurement system includes a high sensitivity rate, reflecting the rate at which tissue measurement system <NUM> correctly detected malignant cells in excised tissue that actually contained malignant cells. The accuracy of the tissue measurement system also includes a high specificity rate, reflecting the rate at which tissue measurement system <NUM> correctly detected no malignant cells in excised tissue that actually contained no malignant cells.

Table <NUM> shows that from a sample of <NUM> tests for squamous cell carcinoma, tissue measurement system <NUM> accurately classified each of the excised tissue samples. Table <NUM> shows that tissue measurement system <NUM> accurately detected the presence or absence of BCCs or SCCs in over <NUM> percent of excised tissue samples. Tissue measurement system <NUM> provides a technological improvement over prior devices in automatically detecting cancerous cells in an excised tissue sample quickly and with high accuracy.

<FIG> is a flow diagram of method steps for automatically analyzing and assessing samples of excised tissue for cancer cells, according to various embodiments of the present invention. Although the method steps described in conjunction with the systems of <FIG>, persons skilled in the art will understand that any system configured to perform the method steps, in any order, is within the scope of the invention.

As shown, a method <NUM> for automatically analyzing and assessing an excised tissue sample starts at step <NUM>, where diagnosis module <NUM> of tissue measurement device <NUM> selects a section of the excised tissue sample to measure. Controller <NUM> included in diagnosis module <NUM> sends a control signal to switching circuit <NUM> to connect a measuring subset 206a of electrode array <NUM> that surrounds the selected section. In some embodiments, controller <NUM> selects the section of the excised tissue sample based on an instructions from a program loaded from memory <NUM>. In some embodiments, controller <NUM> selects the section of the excised tissue sample based on a user input received via I/O units <NUM>.

At step <NUM>, tissue measurement device <NUM> measures at least one impedance of the section of the excised tissue sample. In some embodiments, controller <NUM> may cause switching circuit <NUM> to sweep through operating frequencies of a measurement circuit in order to measure voltages and currents for the section of the excised tissue sample. In some embodiments, diagnosis module <NUM> may store the measured voltage and current at each operating frequency in memory <NUM>. In some embodiments, analyzer <NUM> in diagnosis module <NUM> may compute an impedance for a given operating frequency as a ratio of the measured voltage and the measured current.

At step <NUM>, diagnosis module <NUM> of tissue measurement device <NUM> computes a Cole relaxation frequency <NUM>, <NUM> for the section of the excised tissue sample. In some embodiments, analyzer <NUM> of diagnosis module <NUM> may compute a Cole relaxation frequency <NUM>, <NUM> based on the one or more impedances computed for the section of the excised tissue sample. In some embodiments, analyzer <NUM> may calculate the Cole relaxation frequency <NUM>, <NUM> based on impedance at a single operating frequency. In some embodiments, analyzer <NUM> may generate an impedance spectrum from a set of impedances computed at multiple operating frequencies. Analyzer <NUM> may then compute the Cole relaxation frequency <NUM>, <NUM> by determining the peak of the impedance spectrum <NUM>, <NUM> and determining the frequency at which the peak occurs.

At step <NUM>, diagnosis module <NUM> of tissue measurement device <NUM> sends one or more of the computed results to display. In some embodiments, analyzer <NUM> may determine the presence or absence of cancerous cells based on the Cole relaxation frequency <NUM>, <NUM>. Analyzer <NUM> compares the Cole relaxation frequency <NUM>, <NUM> of the section of the excised tissue sample to a cancer-detection threshold <NUM>, <NUM> and generates an indication that the section contains cancerous cells when the Cole relaxation frequency <NUM>, <NUM> exceeds the cancer-detection threshold <NUM>, <NUM>. In some embodiments, analyzer <NUM> may generate a mapping image that identifies the location of the cancerous cells, corresponding to the sections of the excised tissue sample that analyzer <NUM> determined contain cancerous cells. Analyzer <NUM> may send the cancer detection indicator and/or mapping image to display <NUM>.

At step <NUM>, diagnosis module <NUM> of tissue measurement device <NUM> determines whether to measure another section of the excised tissue sample. Controller <NUM> may determine to measure another section of the excised tissue sample when executing instructions to measure multiple sections of the excised tissue sample in a pre-defined sequence. For example, controller <NUM> may execute instructions to measure consecutive sections of the excised tissue sample using a single column of electrodes 202a-I in electrode array <NUM>. When controller <NUM> determines to measure another section, diagnosis module <NUM> proceeds to step <NUM>, otherwise, method <NUM> ends at step <NUM>.

At step <NUM>, diagnosis module <NUM> of tissue measurement device <NUM> selects a different measuring subset 206b of electrode array <NUM> to measure a different section of the excised tissue sample. In some embodiments, controller <NUM> causes switching circuit <NUM> to disconnect one or more electrodes from previous measuring subset 206a and connect electrodes in measuring subset 206b to a measuring circuit. After switching to the new measuring subset 206b, tissue measurement device <NUM> returns to step <NUM>.

<FIG> is a flow diagram of method steps for detecting impedances for a section of excised tissue, according to various embodiments of the present invention. Although the method steps described in conjunction with the systems of <FIG>, persons skilled in the art will understand that any system configured to perform the method steps, in any order, is within the scope of the invention.

Method <NUM> occurs between step <NUM> and step <NUM> of method <NUM>. As shown, method <NUM> starts at step <NUM>, where controller <NUM> of diagnosis module <NUM> selects a group of electrodes to measure the select section of the excised tissue sample. Controller <NUM> causes switching circuit <NUM> to connect measuring subset 206a to measuring circuit. In some embodiments, controller <NUM> causes switching circuit <NUM> to short to ground all remaining electrodes in electrode array <NUM>.

At step <NUM>, controller <NUM> selects an operating frequency for a measuring alternating current. In some embodiments, controller <NUM> sends a control signal to switching circuit <NUM> that includes a signal generator. Controller <NUM> causes the signal generator in switching circuit <NUM> to generate a measuring signal that has an alternating current, where the frequency of the alternating current is the operating frequency.

At step <NUM>, switching circuit <NUM> injects the measuring signal at the operating frequency. In some embodiments, switching circuit <NUM> injects the measuring signal by connecting an electrode pair in measuring subset <NUM> to the signal generator to close a current path. In some embodiments, the current path may include a current-sensing circuit or a current-sensing device that measures the current of the measuring signal.

At step <NUM>, switching circuit <NUM> senses a voltage for the section of the excised tissue sample. In some embodiments, switching circuit <NUM> connects one or more electrodes 202b-c to a voltage-sensing circuit or device. The one or more electrodes 202b-c are physically located in between the electrode pair forming the current path. The one or more electrodes 202b-c provide a high-impedance voltage-sensing circuit that does not introduce stray currents into the current path carrying the measuring signal. In some embodiments, the voltage-sensing circuit measures the voltage of the section of the excised tissue sample located in between the one or more electrodes 202b-c included in the voltage-sensing circuit.

At step <NUM>, controller <NUM> in diagnosis module <NUM> determines whether to measure the electrical properties of the section of the excised tissue at another frequency. In some embodiments, controller <NUM> may change the operating frequency of the measuring signal as part of a frequency sweep to measure the same section of the excised tissue sample using multiple operating frequencies. In some embodiments, controller <NUM> may increase the operating frequency at a constant rate over a specified range of frequencies. For example, controller <NUM> may set an initial operating frequency of <NUM> and increase the operating frequency by <NUM> until reaching a final operating frequency of <NUM>. When controller <NUM> determines that the measuring circuit is to perform measurements at another frequency, controller <NUM> returns to step <NUM>, otherwise, controller <NUM> proceeds to step <NUM> of method <NUM>.

In sum, the tissue measurement system disclosed herein enables cancerous cells to be detected automatically within a sample of excised tissue based on the measured impedances of sections of the excised tissue. A controller in the tissue measurement system uses a switching circuit to select a first subset of electrodes in an electrode array, where the first subset of electrodes transmits a current through a given section of the excised tissue. As the current is transmitted through the given section of excised tissue, an analyzer included in the tissue measurement system measures the electrical impedance of the given section of excised tissue. The analyzer then computes a Cole relaxation frequency for the given section of excised tissue based on the measured electrical impedance. The Cole relaxation frequency for the given section of excised tissue reflects the rate at which cell membranes discharge stored electrical charges. The analyzer compares the computed Cole relaxation frequency given for the section of excised tissue to a threshold. If the computed Cole relaxation frequency for the given section of excised tissues exceeds the threshold, then cancerous cells are considered to be present in the given section of excised tissue.

In some embodiments, the switching circuit includes a separate micro-relay connected to each of the electrodes in the electrode array in order to prevent the electrode array from introducing crosstalk signals, stray impedances, or other parasitic electrical charges into the measured impedances of the different sections of excised tissue. In some embodiments, the controller causes the switching circuit to select different subsets electrodes in of the electrode array to determine impedances for different sections of the excised tissue. Accordingly, the analyzer can determine the presence of cancerous cells for each section of the excised tissue based on the respective impedances measured for those sections. The analyzer also indicates each location of detected cancerous cells based on the locations of the different sections determined to include cancerous cells.

A major advantage of the disclosed techniques is that the tissue measurement system enables a user to quickly detect the presence and location of cancer cells in a tissue with a high degree of accuracy based on the computed Cole relaxation frequency. Detecting cancerous cells based on the Cole relaxation frequency enables a surgeon to maintain high accuracy when assessing excised tissue during MMS without requiring frozen section preparation and microscopic evaluation of each excised tissue layer, greatly reducing the procedural time of MMS. The reduction in time of MMS also greatly reduces the cost of performing MMS as a treatment for skin cancer.

Another advantage of the disclosed techniques is that the tissue measurement system includes micro-relay components that advantageously switch between connecting and disconnecting the electrodes to the measure the electrical properties of the excised tissue sample without introducing parasitic impedances or capacitances. Avoiding the addition of parasitic impedances and capacitances enables the tissue measurement system switch connections to different electrodes quickly without sacrificing the accuracy of the collected electrical measurements.

Any and all combinations of the claim elements recited in any of the claims and/or any elements described in this application, in any fashion, fall within the contemplated scope of the present invention and protection.

Aspects of the present embodiments may be embodied as a system, method or computer program product. Accordingly, aspects of the present disclosure may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, micro-code, etc.) or an embodiment combining software and hardware aspects that may all generally be referred to herein as a "module" or "system. " Furthermore, aspects of the present disclosure may take the form of a computer program product embodied in one or more computer readable medium(s) having computer readable program code embodied thereon.

The flowchart and block diagrams in the Figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods and computer program products according to various embodiments of the present disclosure.

Claim 1:
A method for detecting cancerous cells in a sample of excised tissue, the method comprising:
connecting an electrode array (<NUM>) to a switching circuit (<NUM>);
measuring, by a first subset of electrodes (<NUM>) included in the electrode array (<NUM>) at a first operating frequency, a first impedance of a first section of the sample;
computing a first Cole relaxation frequency for the first section of the sample based on the first impedance; and
determining that the first section of the sample contains cancerous cells based on the first Cole relaxation frequency;
wherein the switching circuit (<NUM>) electrically connects the first subset of electrodes (<NUM>) and electrically disconnects all remaining electrodes in the electrode array when the first subset of electrodes (<NUM>) measures the first impedance.