System and method for calculating the voltage to be applied to wound tissue

Abstract

This disclosure provides a method. The method includes the steps of applying one or more electrical signals to wound tissue and collecting electrical measurements from an array of electrodes. The method also includes the step of processing the collected electrical measurements to generate one or more impedance maps of the wound tissue that represent the heterogeneous electrical properties measured across a region of the wound tissue. The method further includes the step of calculating at least two voltages, each targeting the wound tissue, based on the spatial distribution of electrical measurements in the impedance maps of the wound tissue. A system is also provided, including an array of electrodes, a circuit functionally connected to the array of electrodes, and a processor. In addition, a device for application to wound tissue is provided, which includes an array of electrodes configured to be placed on the wound tissue and a circuit functionally connected to the array of electrodes.

Description

[Technical Field] 【0001】 Epithelial cells can be directed to move in the direction of an applied electric field. This phenomenon can be utilized to promote wound re-epithelialization if electrical stimulation can be applied in an effective manner. Further development of electrical stimulation for re-epithelialization is desirable. [Overview of the project] 【0002】 In a first embodiment, a method is provided. The method includes the steps of applying one or more electrical signals to wound tissue via an array of electrodes, and collecting electrical measurements from the array of electrodes via a circuit functionally connected to the array of electrodes. The method further includes the steps of processing the collected electrical measurements via a processor to generate one or more impedance maps of the wound tissue representing the heterogeneous electrical characteristics measured over a region of the wound tissue, and calculating at least a first voltage and a second voltage, each targeting the wound tissue, based on the spatial distribution of electrical measurements of the one or more impedance maps of the wound tissue. 【0003】 In a second embodiment, a system is provided, comprising: an array of electrodes configured to apply one or more electrical signals to wound tissue; a circuit functionally connected to the array of electrodes for collecting electrical measurements from the array of electrodes; and a processor. The processor is configured to process the collected electrical measurements to generate one or more impedance maps of the wound tissue representing the heterogeneous electrical characteristics measured across a region of the wound tissue, and to calculate at least a first voltage and a second voltage, each targeting the wound tissue, based on the spatial distribution of the electrical measurements of the one or more impedance maps of the wound tissue. 【0004】 In a third embodiment, a device for application to wound tissue is provided. The device includes an array of electrodes configured to be placed on wound tissue and having at least two electrodes configured to apply one or more electrical signals to the wound tissue, and a circuit functionally connected to the array of electrodes for collecting electrical measurements from the array of electrodes and transferring the collected electrical measurements for processing. 【0005】 These embodiments advantageously provide a calculated voltage that is tailored to a specific wound tissue based on the impedance map of the wound tissue. 【0006】 The above summary of this disclosure is not intended to describe each embodiment or all implementations disclosed herein. The following description more specifically illustrates exemplary embodiments. Guidance is provided in several places throughout this application through lists of examples, and these examples can be used in various combinations. In each example, the enumerated list serves only as a representative group and should not be interpreted as an exclusive list. [Brief explanation of the drawing] 【0007】 [Figure 1] This is a flowchart illustrating an exemplary method according to one embodiment. [Figure 2] This is a schematic diagram showing an exemplary electrode arrangement according to one embodiment. [Figure 3A] These are photographs and maps related to the estimation of wound boundaries according to one embodiment. [Figure 3B] These are photographs and maps related to the estimation of wound boundaries according to one embodiment. [Figure 4A] This is a schematic diagram showing the application of an electric field to wound tissue according to one embodiment. [Figure 4B] This is a schematic diagram showing the application of an electric field to wound tissue according to one embodiment. [Figure 4C] This is a schematic diagram showing the application of an electric field to wound tissue according to one embodiment. [Figure 5]This embodiment demonstrates how an inwardly oriented E-field can be achieved near the wound boundary of wound tissue. [Figure 6] This is a schematic diagram showing an exemplary system according to one embodiment. [Figure 7A] This image shows a photograph of wound tissue on the back of a pig and an electrical impedance tomography (EIT) map of the conductivity of the wound tissue, according to one embodiment. [Figure 7B] This image shows a photograph of wound tissue on the back of a pig and an electrical impedance tomography (EIT) map of the conductivity of the wound tissue, according to one embodiment. [Figure 7C] This is a schematic diagram showing a system applicable to the wound tissue shown in Figures 7A and 7B, according to one embodiment. [Figure 8] This is a flowchart of one embodiment of the present disclosure. [Figure 9A] This figure shows the relative conductivity and topographic map of a wound in progress according to one embodiment. [Figure 9B] This figure shows the relative conductivity and topographic map of a wound in progress according to one embodiment. [Figure 9C] This figure shows the relative conductivity and topographic map of a wound in progress according to one embodiment. 【0008】 The figures identified above illustrate some embodiments of this disclosure, but other embodiments are also contemplated, as mentioned in the description. The drawings are not necessarily drawn to scale. In all cases, this disclosure presents aspects of the invention representatively, rather than limitingly. [Modes for carrying out the invention] 【0009】 Glossary The terms "preferred" and "preferably" refer to embodiments of the present disclosure that can provide certain benefits under certain circumstances. However, in the same or other circumstances, other embodiments may also be preferred. Furthermore, the description of one or more preferred embodiments does not mean that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the present disclosure. 【0010】 In this application, terms such as "a", "an", and "the" are not intended to refer only to a single entity, but include the entire class for which a particular example may be used for illustration. The terms "a", "an", and "the" are used interchangeably with the term "at least one". The phrases "at least one of" and "including at least one of" following a list refer to any one of the items in the list and any combination of two or more of the items in the list. 【0011】 As used herein, the term "or" is generally used in its ordinary sense, including "and / or", unless the context clearly indicates otherwise. The term "and / or" means one or all of the recited elements, or any combination of two or more of the recited elements. 【0012】 Also, in this specification, all numbers are assumed to be modified by the term "about", preferably by the term "exactly". When used herein in connection with a measured quantity, the term "about" refers to the variations in the measured quantity that would be expected by one of ordinary skill in the art who takes due care in making the measurement and in view of the purpose of the measurement and the accuracy of the measuring device used. 【0013】 Where used herein as a modifier for a characteristic or attribute, the term “generally” means, unless otherwise specifically defined, that the characteristic or attribute is readily recognizable to a person skilled in the art, but does not require absolute precision or perfect agreement (e.g., within + / - 20% for quantifiable characteristics). The term “substantially” means, unless otherwise specifically defined, a high degree of approximation (e.g., within + / - 10% for quantifiable characteristics), but again, does not require absolute precision or perfect agreement. Terms such as “same,” “equal,” “uniform,” “constant,” and “strictly” are understood to mean within the range of normal tolerances or measurement errors applicable to a particular situation, rather than requiring absolute precision or perfect agreement. 【0014】 As used herein, the term “impedance” refers to an electrical property that is a complex quantity, including what are called “real” and “imaginary” quantities, for example, Z = R + iX, where Z is impedance, R is the so-called real component, resistance, and X is the so-called imaginary component, reactance. In addition, as used herein, the term “conductivity” is used, which is the mathematical reciprocal of resistance R. The term “relative conductivity” refers to conductivity relative to some measured or algorithmically estimated baseline value. 【0015】 The term "electrical measurement" refers to one or more measurements of electrical properties at one or more frequencies, such as conductivity, resistivity, complex impedance, impedance magnitude, admittance, impedance phase angle, and reactance. 【0016】 The term "impedance map" refers to a representation(s) of the spatial distribution of one or more electrical measurements, which may exist in the form of a map(s) or other suitable data structure. 【0017】 The term "wound tissue" refers to both peri-wound tissue and wound bed tissue. The term "wound bed tissue" refers to tissue with damage to the epithelial layer, damage to the subcutaneous tissue, and / or tissue with at least one of bruise, rash, or infection. The term "peri-wound tissue" refers to tissue within the peri-wound area and can be defined as the area of ​​skin extending beyond the wound bed to a certain distance (a few centimeters, e.g., 4 cm) or the surrounding skin extending from the wound bed. 【0018】 The term "boundary" in relation to wound tissue refers to at least one of the area, volume, or line between the wound bed and the surrounding tissue. Wound tissue may have two or more enclosed boundaries. 【0019】 The terms “tissue characteristic map” or “clinical metrics” refer to a representation(s) of the spatial distribution of one or more tissue characteristics, including, for example, wound margins / boundaries, wound depth information (e.g., a wound topography map with depth relative to x and y coordinates), presence of granulation tissue, thickness of granulation tissue, wound healing stage (e.g., congestion, inflammation, proliferation, remodeling stage), epithelial coverage, epithelial thickness, biomass, bioburden, infection level, infection type, necrotic tissue, and healing tissue. Tissue characteristics may exist in the form of a map(s) or other preferred data structure. In some cases, the tissue characteristic representation or map may include healing metrics. 【0020】 The term "healing metrics" refers to a global assessment of a wound, which may include calculations performed on tissue characteristic data. Healing metrics may include wound length, wound width, wound depth (e.g., maximum, minimum, mean), wound area, wound volume, granulation tissue thickness (e.g., maximum, minimum, mean), total epithelial coverage (e.g., percentage of the wound bed covered with new epithelium), epithelial thickness (e.g., maximum, minimum, mean), total bioburden, biofilm thickness (e.g., maximum, minimum, mean), and biofilm volume. 【0021】 method In the first aspect, a method is provided. Referring to Figure 1, the method is Step 110 involves applying one or more electrical signals to wound tissue via an array of electrodes, Step 120 involves collecting electrical measurements from the electrode array via a circuit functionally connected to the electrode array, Step 130 involves processing the collected electrical measurements via a processor to generate one or more impedance maps of the wound tissue that represent the heterogeneous electrical characteristics measured across the area of ​​the wound tissue, The procedure includes step 140, which calculates at least first and second voltages, each targeting the wound tissue, based on the spatial distribution of electrical measurements from one or more impedance maps of the wound tissue. In some cases, the first and second voltages are different from each other, while in other cases, the first and second voltages are the same. In a selected embodiment, at least four voltages are calculated, each targeting the wound tissue, based on the spatial distribution of electrical measurements from one or more impedance maps of the wound tissue. 【0022】 The electrodes are not particularly limited. Exemplary preferred electrode arrangements include, but are not limited to, a 15-pin electrode on a rigid printed circuit board (PCB), a 15-pin electrode on a flexible Kapton PCB, a 64-pad electrode on a flexible Kapton PCB, a 16-pin electrode on a flexible transparent composite, or a 3M RED DOT 2670 skin electrode attached to a flexible Kapton PCB via a snap connector. Referring to Figure 2, an exemplary 8-electrode device 2000 was fabricated on a soft, flexible substrate 2100. The electrode 2200 was a 3M RED DOT 2360 electrode (3M Company, St. Paul, MN). The device includes a UV-curable silicone encapsulant protective layer 2300 and a urethane film 2150 that is laser-etched and silver-bladed to function as electrical leads 2400 and contacts 2500, with the electrode 2200 embedded within the cured silicone encapsulant 2300. The substrate 2100 defines an opening region 2600 which can be suitably positioned on a desired portion of the wound tissue. 【0023】 Electrical impedance tomography (EIT) is used to measure and determine the spatial distribution of electrical impedance in a continuous two-dimensional (2D) or three-dimensional (3D) space. Typically, impedance measurements are obtained from electrical contacts sparsely distributed in a continuous 2D / 3D space, and the continuous 2D / 3D impedance map is reconstructed by solving an inverse problem of a finite element model (FEM) for the space. In the methods described herein, an array of electrodes is placed on the wound tissue to spatially map the resistance / conductivity profiles of the wound tissue and surrounding tissues. In some cases, one or more of the electrodes are placed on the peri-wound tissue surrounding the wound bed, one or more of the electrodes are placed on the wound bed, or both. 【0024】 Electronic equipment for performing EIT mapping of wound tissue may include electrodes, a microcontroller for control and data acquisition measurements, a low-noise, high-precision current source as a power supply, an analog-to-digital (ADC) preamplifier for noise filtering and signal amplification, and an input / output multiplexer for switching electrodes for current supply and voltage measurement. 【0025】 One or more signal generators may be electrically connected to an array of electrodes and may be configured to generate alternating current electrical signals, such as electrical waveforms. These electrical signals may be sine waves, square waves, pulse waves, triangle waves, sawtooth waves, etc. The signal generators may be configured to generate electrical signals containing one or more frequencies within any range including 1kHz–2kHz, 2kHz–4kHz, 4kHz–55kHz, and 55kHz–120kHz. In some embodiments, the signal generators may be configured to generate electrical signals in a frequency range that may be greater or less than the exemplary ranges described above. In some embodiments, the electrical signal generators may be configured to generate electrical signals at a predetermined frequency, such as approximately 85kHz (e.g., 85kHz ± 10kHz). In some cases, the signal generators are configured to generate electrical signals. 【0026】 Impedance maps can be acquired at a single frequency or multiple frequencies. In some embodiments, impedance can be measured relative to different baselines established through different estimation methods. The baseline may refer to a map of conductivity values ​​representing the tissue before wounding. Relative conductivity may refer to a current conductivity map of the tissue subtracted from the baseline map. 【0027】 In some embodiments, baseline measurements of non-wound tissue may include homogeneous measurements to capture the background conductivity of intact tissue and heterogeneous measurements to capture the conductivity of wound tissue. Methods for baseline estimation may include, for example, frequency-difference EIT (fdEIT), measurement-scale feature (MSF), best homogeneous (BH) estimators, data-driven estimators, or a combination thereof. Data-driven estimators may include machine learning and deep causal learning methods using database lookups. Useful database lookups may be based on patient history or patient demographics. Alternatively, it is also possible to reconstruct the conductivity map of wound tissue using methods that do not require baseline measurements of non-wound tissue. Since biological tissues may have unique frequency responses, the impedance distribution of wound tissue can be imaged by the fdEIT reconstruction method, with measurements taken at least two frequencies on the wound tissue. Measurements at a first frequency (i.e., a reference frequency) can serve as a proxy for baseline measurements, while measurements at a second frequency (i.e., a measurement frequency) act as heterogeneous measurements. Thus, in some embodiments, one or more impedance maps of wound tissue are algorithmically estimated using frequency difference electrical impedance tomography (fdEIT), measurement scale features (MSF), best homogeneity (BH) estimators, data-driven estimators, or a combination thereof. 【0028】 Different methods can be used when reconstructing conductivity maps. Exemplary methods include the one-step Gauss-Newton (GN) method and the iterative total variation (TV) method, each applying suitable hyperparameters. These hyperparameters can be heuristically determined to optimize the degree of contrast between anomalies and the background. It should be noted that this heuristic selection can be replaced by automatic selection based on any predetermined strategy. The one-step GN method can provide real-time reconstruction results with acceptable quality of anomaly shape and size. The iterative TV method tends to be computationally slower compared to the GN method, but can also provide higher resolution of phase features. 【0029】 As a further alternative, baseline measurement estimation techniques can be applied to calculate a uniform conductivity distribution in non-injured tissue. TdEIT can then take the estimated baseline and heterogeneous measurements to reconstruct the conductivity map of the injured tissue. For example, either the best homogeneous approximation or a predefined MSF can be used to estimate the baseline measurements. E In an EIT system with multiple electrodes, the baseline measurement value U baseline n under the setting of adjacent simulation patterns E (n E -3) Represents the vector of voltage measurements. 【0030】 In one embodiment, U baseline This is estimated by the following steps: First, a finite element model (FEM) is generated that reflects the geometry of the wound tissue and electrode placement. Second, a simulated baseline measurement U0 is obtained from the FEM with a uniform conductivity distribution, where the baseline conductivity σ0 = 1. Third, the heterogeneous measurement U meas This is obtained from the wound tissue. Finally, U0 is scaled by the ratio parameter μ to estimate the baseline measurement. Thus, the baseline vector is expressed as follows: 【0031】 【number】 【0032】 When using the BH method for baseline estimation, the ratio parameter μ can be expressed as follows: 【0033】 【number】 【0034】 When using the MSF operator for baseline estimation, the ratio parameter μ can be expressed as follows: 【0035】 【number】 In the formula, f is defined as a feature operator that maps measured values ​​to feature values. Exemplary MSF operators include the arithmetic mean, range, midrange, electrode-based mean range, and electrode-based mean midrange. Their respective mathematical representations are shown below. 【0036】 MSF1: Arithmetic mean 【0037】 【number】 MSF2: Range 【0038】 【number】 MSF3: Midrange 【0039】 【number】 MSF4: Electrode-based average range 【0040】 【number】 MSF5: Electrode-based average midrange 【0041】 【number】 【0042】 In some embodiments, a new impedance map may be arithmetically calculated from an impedance map at a given frequency and from maps generated from different baseline estimation methods. The measured impedance may vary due to variations in electrical properties between tissue sites of an individual, e.g., between different tissue locations on the same patient and / or animal, variations in tissue properties over different times, and variations between individuals, e.g., between patients and / or animals. For example, the electrical properties of a tissue may vary based on tissue composition and thickness, tissue water content and / or tissue hydration, ambient relative humidity at the time of measurement, etc. In addition, the electrical properties of a tissue may depend on which particular tissue type is present at that location. For example, variations may be observed with respect to muscle tissue versus fat accumulation tissue, and variations may be observed with respect to wound tissue versus wound, non-wound, well-epithelialized tissue versus open wound areas having various types and amounts of healing tissue within them (e.g., different amounts of granulation tissue filling in the wound bed and / or different degrees of epithelial coverage on the wound bed). 【0043】 In some embodiments, a map of wound tissue impedance can be converted into quantitative metrics of healing. In other words, a spatial map of impedance (e.g., conductance or resistance) obtained via EIT can be converted into a quantitative map of healing, such as wound shape, depth, size (e.g., area or volume), amount of granulation tissue, epithelial coverage, and wound stage. 【0044】 In some embodiments, one or more impedance maps can be transformed into spatial maps of clinical metrics by calibrating the impedance maps using a calibration model. Clinical metrics may include various wound information data for the (x,y) coordinate in a Cartesian coordinate system (x,y,z) where the z-axis corresponds to the depth direction of the wound tissue. Exemplary clinical metrics include wound depth d(x,y) and granulation tissue thickness t. g (x,y), epithelial coverage c(x,y), biofilm thickness t b This may include (x,y), bioburden (i.e., the number of contaminating organisms found in a given amount of material) b(x,y), infection level i(x,y), healing stage (e.g., inflammation, proliferation, or remodeling stage) index h(x,y), etc. Preferred calibration methods also include those described in detail in international application PCT / IB2022 / 062138 (Zhu et al.), which are incorporated herein by reference in their entirety. 【0045】 In some embodiments, the obtained impedance maps can be used to determine the wound boundary and other wound tissue features. For example, in certain embodiments, one or more impedance maps of wound tissue identify at least one boundary between the wound bed and the peri-wound tissue. As stated above, “boundary” refers to at least one of area, volume, or line between the wound bed and the peri-wound tissue. For example, referring to Figure 3, the location of the wound boundary can be estimated by thresholding using an impedance map of the relative conductivity of the wound site. Figure 3A shows a photograph 3100 of a tissue-mimicking wound phantom model of a wound that has begun to re-epithelialize inward from the wound boundary, which may benefit from E-field accelerated epithelialization. Point 3110 indicates the location of electrode placement, and circle 3120 indicates the location of the wound boundary (in this case, the boundary enclosing the non-epithelialized open wound tissue and excluding the epithelialized tissue). An EIT acquisition map 3200 of the relative conductivity of the wound phantom is also provided. Figure 3A further includes contour maps 3300 of the relative conductivity of wound phantoms with thresholds of -0.05, -0.06, -0.08, -0.10, -0.12, and -0.15. Note that the threshold contour of -0.06 follows the wound boundary 3320 relatively well. Photograph 3400 of a wound phantom with a relative conductivity threshold of -0.06 highlights how this threshold predicts the location of the wound boundary 3420 relatively well. Figure 3B shows a threshold contour map 3500 with a threshold of -0.06 3520 as a 3D contour. Here, various mathematical methods can be applied to wound edge detection based on changes in material properties (such as relative conductivity). Various methods for edge detection (such as the Canny edge detector, Deriche method, Sobel method, Prewitt method, Laplacian of Gaussian, and determinant of the Hessian matrix) have been presented in the literature, and these are generally classified into two groups: "exploratory" and "zero-crossing" methods. In this case, one method is to find the wound edge by applying an exploratory method, such as the Canny edge detector or Sobel method, based on the magnitude of the conductivity gradient, and exploring the direction of the gradient.Another approach is to apply a zero-crossing method to search for zero crossings in the second derivative representation (e.g., the Laplacian). Alternatively, edge detection methods can be combined, such as a combination of conductivity and gradient evaluation, to determine the wound boundary. 【0046】 For example, referring to Figure 4, epithelial cells 4100 can be directed to move in the direction D of the applied electric field (e.g., Figure 4A). This phenomenon can be utilized to promote wound re-epithelialization if electrical stimulation can be applied to form an electric field (E field) at a target therapeutic intensity (e.g., Figure 4B). An array of electrodes providing voltages v1~v8 and interfaced with wound tissue 4200 can theoretically produce a sculpted E field profile (e.g., an inwardly directed E field profile as shown in Figure 4C), however, the electrical properties of actual wounds are spatially heterogeneous and tend to change over time (e.g., as the wound heals). 【0047】 Advantageously, the method according to at least certain embodiments of the present disclosure generates a calculated voltage designed to achieve a predetermined electric field targeting the wound tissue, based on a near real-time determination of the impedance map of the wound tissue. If the electrical properties of a particular wound tissue change over time, the calculation may be updated accordingly. Thus, referring back to Figure 1, the method optionally further includes step 160, which repeats each of the collecting step, the processing step, and the calculating step after applying a first voltage and a second voltage to the wound tissue. In addition, ground (i.e., 0 voltage) may also be applied to the wound tissue. In some cases, the collecting step, the processing step, and the calculating step are repeated at predetermined intervals after applying the first voltage and the second voltage to the wound tissue. Typically, these processes can be performed on a short time scale, such as seconds (or even faster), and thus the predetermined interval may be selected based on other criteria (e.g., the amount of time required for a measurable change in one or more electrical properties of the wound tissue). The specified time is not particularly limited and may include any one or more of the following: 1 to 60 minutes, 1 to 24 hours, 1 to 7 days, or 1 to 52 weeks. 【0048】 One way to calculate the voltage is described herein. Voltage optimization calculations can be performed to select an appropriate voltage at specific electrodes placed around the wound tissue (e.g., at location 3110 in FIG. 3A). In these examples, for the sake of rationalizing the calculations, the two electrodes at the 12 o'clock position are tied to the same voltage (v1), the two electrodes at 3 o'clock are tied to a voltage (v2), and the electrodes at 6 o'clock (v3), 9 o'clock (v4), and the central electrode are tied to ground (0V). However, note that the method described can instead apply eight independent voltages to each of these eight electrodes and can use any number of electrodes and applied voltages. The voltage is calculated using a mapping of the electrical inhomogeneity of the wound tissue (e.g., from EIT mapping), whereby an E-field profile is formed in the tissue around the wound boundary at a target intensity of 30 V / m, which is also mapped using the EIT method. In some embodiments, the E-field profile is designed to provide an inwardly directed E-field direction. 【0049】 This method utilizes the principle of superposition. That is, the voltage distribution that appears on the wound tissue is the sum of the voltage distributions formed from the voltage contributions of each single electrode. The algorithm applies a voltage (v i ) to each individual electrode (i.e., i may be equal to [1, 2, 3, 4]). To find the wound boundary voltage distribution and the negative gradient, a finite element simulation performed in COMSL's AC / DC module is applied. The electric field, 【0050】 【Number】 This must be separated into x and y components. Thus, for the i-th electrode, 【0051】 【Number】 where i = [1, 2, 3, 4]. 【0052】 Using superposition, field E becomes as follows: 【0053】 【number】 And so, In the formula, A i This is the scale factor for each individual electrode, which can be algorithmically weighted. 【0054】 The voltage gradient norm is calculated as follows: 【0055】 【number】 【0056】 These weighted scalar factors A i To solve this, an optimization program based on MATLAB's optimization function is used, where the error e is: e=Σ(VGN-VG critical ) 2 And in the formula, VG critical This is the target E field intensity, which in this embodiment is 30 V / m. 【0057】 It should be noted that this target E-field intensity can be any value determined to optimize epithelial cell migration and may be informed by experiments, databases, algorithms, machine learning, deep causal learning, and physician / patient input (patient demographics, medical records, etc.). The optimal applied electrode voltage is then determined to be scaled by the following formula: For electrodes i=[1,2,3,4], A i V i . 【0058】 Referring again to Figure 1, the method optionally further includes step 150 of applying at least a first voltage and a second voltage to wound tissue via an array of electrodes. The array of electrodes includes a minimum of two electrodes, but any number can be used. For example, the array of electrodes may include 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more electrodes. Regardless of how many electrodes are present in the array, each electrode may be configured to operate independently and / or have any positive or negative voltage. 【0059】 In some cases, the steps of applying at least a first voltage and a second voltage generate an electric field directed at least partially inward from the boundary into the wound bed. For example, referring to Figure 5, an inwardly directed E-field can be achieved near the wound boundary of a particular wound tissue. Photo 5200 is of a wound phantom showing the locations of each electrode v1-v8 and the grounded v0. Figure 5300 is a diagram of the E-field lines when the electrodes are excited with the optimized voltages described above. Note that the E-field lines (i.e., lines with arrows) generally point inward, starting at least from the wound boundary 5100. Figure 5400 shows the E-field distribution when the electrodes are excited with the optimized voltages. Note that a target E-field intensity of approximately 30 V / m is achieved along the wound boundary. 【0060】 However, the magnitude of the electric field is not particularly limited. In some cases, the step of applying a voltage (for example, at least first and second) may be 0 volts / meter (V / m) or more, 2 V / m, 5 V / m, 10 V / m, 15 V / m, 20 V / m, 25 V / m, 30 V / m, 35 V / m, 40 V / m, 45 V / m, 50 V / m, 55 V / m, 60 V / m, 65 V / m, 70 V / m, or 75 V / m or more, and 1,000 V / m or less, 950 V / m, 900 V / m, 850 V / m, It generates electric fields with magnitudes of 800V / m, 750V / m, 700V / m, 650V / m, 600V / m, 550V / m, 500V / m, 450V / m, 400V / m, 350V / m, 300V / m, 250V / m, 200V / m, 175V / m, 150V / m, 125V / m, 100V / m, 90V / m, 85V / m, 80V / m, 75V / m, 70V / m, 65V / m, 60V / m, 55V / m, or 50V / m or less. In a particular embodiment, the E-field strength is in the range of 10V / m to 100V / m. 【0061】 Referring again to Figures 4C and 5, in some embodiments, the application step includes applying a 0-volt (V) ground to an electrode placed on the wound bed. In selected embodiments, including the example shown in Figure 5, the electrode placed on the wound bed is substantially centered on the wound bed. 【0062】 Systems and Devices In a second aspect, a system is provided. This system is An array of electrodes configured to apply one or more electrical signals to wound tissue, To collect electrical measurements from the electrode array, a circuit functionally connected to the electrode array is used, The processor includes, and the processor is The collected electrical measurements are processed to generate one or more impedance maps of the wound tissue, which represent the heterogeneous electrical properties measured across the area of ​​the wound tissue. The system is configured to calculate at least a first voltage and a second voltage that target the wound tissue, based on the spatial distribution of electrical measurements from one or more impedance maps of the wound tissue. 【0063】 In a third aspect, a device for application to wound tissue is provided. This device is An electrode array comprising at least two electrodes configured to be placed on wound tissue and configured to apply one or more electrical signals to the wound tissue, The system includes a circuit functionally connected to the electrode array for collecting electrical measurements from the electrode array and for transferring the collected electrical measurements for processing. 【0064】 Figure 6 is a schematic diagram showing an exemplary system 6000 according to one embodiment. In the illustrated embodiment, system 6000 includes device 6102 and computing device 6106. In some cases, device 6102 is a diagnostic or monitoring device. In some cases, device 6102 is a dressing. Device 6102 may be communicatively coupled to computing device 6106, for example, by a wired or wireless connection. Computing device 6106 may include a processing circuit 6216 coupled to a display 6218, an output 6221, and a user input 6222 of a user interface 6228. In some embodiments, display 6218 may include one or more display devices (e.g., a monitor, PDA, mobile phone, tablet computer, any other suitable display device, or any combination thereof). For example, display 6218 may be configured to display physiological information and information showing epithelial tissue characteristics determined by system 6000. 【0065】 The device 6102 may be of any type of structure. In some embodiments, the device 6102 may include a bandage comprising a flexible backing material, an adhesive for adhesion to the patient's 614 skin, and an electrode 6130. In some embodiments, the device 6102 may include a foam dressing material comprising the electrode 6130. In some embodiments, the device 6102 may include a material that is, for example, attached to tissue via an adhesive or held in place physically. In other embodiments, the device 6102 may be a diagnostic patch, for example, a material comprising one of the electrodes 6130. In some embodiments, additional materials such as sterile saline-containing gauze, gel, etc., placed between the device 6102 and the tissue site 6150 may be applied to the patient 614 for wound measurement / monitoring. 【0066】 Device 6102 includes an array of electrodes 6130. When device 6102 is placed on the wound tissue to be tested, the array of electrodes can apply an electrical signal from a signal generator to a first tissue site 6152 located outside the second tissue site 6150. The second tissue site 6150 may correspond to wound tissue or wound bed, for example, tissue with damage to the epithelial layer and / or subcutaneous tissue. The second tissue site 6150 may also correspond to tissue with a bruise, tissue with a rash, tissue with an infection, etc. The second tissue site 6150 may also correspond to currently undamaged tissue that needs to be monitored for damage (for example, for a venous ulcer (VLU) or pressure ulcer (PU)) in the case of an observable open wound. The first tissue area 6152 can optionally be defined as a region of skin that corresponds to the tissue in the peri-wound area and extends beyond the wound bed to a certain distance (several centimeters, e.g., 4 cm), or as the surrounding skin extending from the wound bed. In some embodiments, the additional material may include therapeutic agents such as drugs and / or be at least partially conductive to improve conductivity between the electrode 6130 and the first tissue area 6152. 【0067】 One or more signal generators may be electrically connected to the array of electrodes 6130 and may be configured to generate AC electrical signals, such as electrical waveforms. The electrical signals may be as described in detail above with respect to the first embodiment. 【0068】 In the embodiment shown in Figure 6, device 6102 further includes a processing circuit 6116 and a memory 6124. In some embodiments, device 6102 may process electrical signals without transferring them to a computing device 6106. For example, the processing circuit 6116 may further include a signal monitor for detecting electrical signals applied to a first tissue site 6152 adjacent to a second tissue site 6150. In other embodiments, electrical signals, or information corresponding to electrical signals, may be transferred to the computing device 6106 for processing, for example, by a wired or wireless connection between device 6102 and the computing device 6106. 【0069】 Memory 6116 and memory 6224 may include any volatile or non-volatile medium, such as random access memory (RAM), read-only memory (ROM), non-volatile RAM (NVRAM), electrically erasable programmable ROM (EEPROM), or flash memory. Memory may also be a storage device or other non-temporary medium. Memory may be used by processing circuits 6216 or 6124 to store reference information or initialization information corresponding to physiological monitoring, such as wound monitoring. In some embodiments, processing circuits 6216 or 6124 may store data previously received from physiological measurements or electrical signals in memory for later retrieval. In some embodiments, processing circuits may store determined values, such as information indicating epithelial tissue characteristics, or any other calculated values ​​in memory for later retrieval. 【0070】 Figures 7A and 7B are photographs of tissue sites in which the system may be used, according to one embodiment. Figure 7C is a schematic diagram showing the system 7000 applied to wound tissue sites, such as the wound tissue sites in Figures 7A and 7B. As shown in the examples in Figures 7A and 7B, the tissue site 7150 corresponds to at least partially open wound tissue. The peri-wound tissue site 7152 corresponds to the area surrounding the open wound tissue 7150. 【0071】 In this embodiment, the system 7000 includes an array of electrodes 7210 positioned on a peri-wound tissue site 7152. The array of electrodes 7210 is supported by a substrate 720. In the illustrated embodiment, the substrate 720 includes a central portion 7202 that substantially covers (e.g., open) wound bed tissue 7150, and a peripheral portion 7204 of the central portion 7202. The array of electrodes 7210 is positioned on the inner surface of the dressing periphery 7204. 【0072】 Using the EIT method described above, the wound sites shown in Figures 7A and 7B can be mapped in a manner that characterizes the spatial distribution of the conductivity of the wound bed relative to the intact skin observed in the peri-wound tissue of the wound site. To collect this data, one euthanized Yorkshire pig was prepared by first shaving the animal's dorsal right flank (where the wound bed would be generated and the peri-wound electrode would be placed) and abdomen (where a single large reference electrode would be placed). On the animal's dorsal right flank, two 5 cm diameter circular wound bed sites were outlined with a pen, spaced 15 cm apart from center to center of the wound. One wound bed was generated in a semi-circular shape via a full-thickness surgical excision (i.e., cut down to the dorsal fascia) (Figure 7A, left), and the other wound bed was generated in a circular shape in full thickness (Figure 7B, left). A large adhesive return electrode was placed on the animal's shaved abdomen, connected to the electrical ground of the EIT electronic equipment. Eight 3M Red Dot 2670 electrodes were cut into circles and placed at equal intervals around each of two wound beds on intact peri-wound tissue (eight electrodes per wound) (Figures 7A and 7B, left photograph). These electrodes were snap-connected to the input terminals of an EIT electronic device via electrocardiogram (ECG) leads. The EIT electronic device injected sinusoidal current into the electrode pairs rotating at 40 kHz using a Keithly 6211 current source, while simultaneously measuring voltage from other electrodes in the array. This tomographic mapping scheme yielded a spatial map of the conductivity of the wound tissue, shown here against the intact skin of the peri-wound tissue (Figures 7A and 7B, right conductivity map). For the semicircular wound beds, the generated relative conductivity map can be seen to show areas of modified conductivity values ​​in the area of ​​the map corresponding to the semicircular wound bed (Figure 7A, right: non-zero color in the dashed semicircular area). Similarly, for a circular wound bed, the generated relative conductivity map shows the region of modified conductivity values ​​in the area of ​​the map corresponding to the circular wound bed (Figure 7B, right: non-zero color in the dashed circular region). This embodiment demonstrates the ability to capture impedance maps in animal tissue, which can later be used to generate wound boundary maps.The impedance map and wound boundary map can then be fed into an algorithm that determines the optimal voltage to be applied to the system's electrodes to generate a targeted therapeutic E-field intensity around the wound boundary. 【0073】 It should be understood that in some embodiments, additional electrodes may be placed on the wound tissue, such as on an open wound bed. In some embodiments, electrodes may be present only on the peri-wound tissue, or on both the wound bed tissue and the peri-wound tissue. In some embodiments, electrodes present around the wound are desirable because (i) they are less invasive as they do not need to contact sensitive wound bed tissue, and (ii) the electrical interface with the intact peri-wound tissue is likely to be more stable than that with the wound bed tissue because it changes over time (e.g., as it heals). 【0074】 In some embodiments, electrodes are provided for 4-probe measurements, with two electrodes for current sources and two electrodes for voltage measurements, and the minimum number of electrodes is 4. In some embodiments, eight or more electrodes are provided to obtain mapping results. A larger number of electrodes may allow for higher resolution and accuracy. 【0075】 It should be understood that any suitable form of electrode device can be used to enable the placement of electrode arrays in a predetermined pattern on a tissue site. In some embodiments, electrode arrays can be placed around dressings, such as on the drape of a negative pressure wound therapy (NPWT) dressing. In some embodiments, electrode arrays can be integrated into a non-dressing device. In one embodiment, a flexible circuit board may be decorated with snap connectors that can connect multiple electrodes. In one embodiment, the device may include an internal array of metal pin electrodes that can interact with the wound bed, or a flexible printed circuit board (PCB) having multiple metal pin electrodes that interact with the peri-wound tissue surrounding the wound. Similar configurations can also be implemented in a rigid PCB format. Additional suitable electrodes are those described above with respect to the first embodiment. Electrodes can be placed anywhere on the wound tissue, such as inside the wound bed, outside the wound bed, or both. 【0076】 Referring again to Figure 7C, the system 7000 further includes electronic components 7220 electrically connected to the array of electrodes 7210. The electronic components 7220 may include various control circuits, processors, memories, power supplies, etc. For example, the electronic components 7220 may include one or more of the processing circuit 6116, memory 6124, processing circuit 6216, and memory 6224 as shown in Figure 6. 【0077】 The electronic component 7220 is configured to apply an electrical signal to a tissue site via an electrode array 7210, collect electrical measurements from the electrode array 7210, process the collected electrical measurements to generate one or more impedance maps of the wound bed (e.g., open wound tissue 7150 and subcutaneous wound tissue 7154) representing the heterogeneous electrical characteristics measured across the area of ​​wound tissue, and calculate at least a first voltage and a second voltage targeting each wound tissue based on the spatial distribution of electrical measurements in the one or more impedance maps of the wound tissue. As described above, the one or more impedance maps may also include a baseline map representing non-wound tissue. 【0078】 In certain preferred embodiments, the circuit is further functionally connected to an array of electrodes to deliver a voltage through this array of electrodes, for example, to wound tissue. In selected embodiments, the array of electrodes includes a first electrode configured to apply a first voltage to wound tissue and a second electrode configured to apply a second voltage to wound tissue. Having the option to use the same electrodes for both collecting electrical measurements and delivering voltage to wound tissue is advantageous because it simplifies the overall device, rather than requiring different sets of electrodes or separate devices to create an impedance map and apply electrical stimulation to wound tissue. 【0079】 Referring to Figure 8, a schematic diagram illustrating a flowchart of one embodiment of the present disclosure is provided. In such a case, the device (for example, according to the third embodiment) is placed on the wound tissue 810, and then conductivity processing 820 of the electrical measurements is performed based on the electrical measurements collected from the device. The processing generates a conductivity map 830 of the wound tissue and, optionally, also generates a wound boundary map 832 which can be used when calculating the voltage 840. Furthermore, this embodiment also optionally includes applying the calculated voltage to the wound tissue 850. In some cases, advantageously, after applying the voltage to the wound tissue 850, the process is repeated to collect new electrical measurements from the device on the wound tissue 810 to capture differences in electrical measurements due to changes in the conductivity of the wound tissue over time, for example, due to increased epithelialization as the wound tissue heals. 【0080】 Referring to Figures 9A to 9C, schematic diagrams of tissue-mimicking phantoms used in conductivity mapping experiments are provided from the side view (top row). Each phantom represents a progressively healed wound as it moves from Figure 9A to Figure 9B and Figure 9C. Top view photographs of the tissue-mimicking wound phantoms are also provided (second row). In addition, Figures 9A to 9C show EIT acquisition maps of the relative conductivity of the wound phantoms (third row) and overlays of the phantom photographs onto the EIT maps (bottom row). In these cases, the relative conductivity represents the difference between the conductivity of the wound bed and the conductivity of the epithelialized skin surrounding the wound (for example, the conductivity of the skin surrounding the wound is 2 × 10⁻⁶). -6 It is S / m and is considered to have a relative conductivity of 0, and a relative conductivity of 0.2 is 2.4 × 10⁻⁶ -6 With a density of 20% greater than skin in S / m and a relative conductivity of -0.2, the result is 1.6 × 10⁻⁶. -6 (S / m is 20% smaller than skin.) 【0081】 Embodiment In a first embodiment, the present disclosure provides a method. The method includes the steps of applying one or more electrical signals to wound tissue via an array of electrodes, and collecting electrical measurements from the array of electrodes via a circuit functionally connected to the array of electrodes. The method further includes the steps of processing the collected electrical measurements via a processor to generate one or more impedance maps of the wound tissue representing the heterogeneous electrical characteristics measured over a region of the wound tissue, and calculating at least a first voltage and a second voltage, each targeting the wound tissue, based on the spatial distribution of electrical measurements in one or more impedance maps of the wound tissue. 【0082】 In a second embodiment, the disclosure provides a method according to the first embodiment, wherein the first voltage and the second voltage are different from each other. 【0083】 In a third embodiment, the disclosure provides a method according to the first or second embodiment, further comprising the step of applying at least a first voltage and a second voltage to wound tissue via an array of electrodes. 【0084】 In a fourth embodiment, the disclosure provides a method according to a third embodiment, wherein the applying step includes applying a 0-volt (V) ground to an electrode placed on a wound bed. 【0085】 In a fifth embodiment, the disclosure provides a method according to a fourth embodiment, wherein the electrode placed on the wound bed is located in the center of the wound bed. 【0086】 In the sixth embodiment, the disclosure provides a method according to any one of the second to fifth embodiments, further comprising the steps of applying a first voltage and a second voltage to wound tissue, and then repeating each of the steps of collecting, processing, and calculating. 【0087】 In the seventh embodiment, the disclosure provides a method according to the sixth embodiment, wherein the steps of collecting, processing, and calculating are repeated at predetermined intervals after the first and second voltages have been applied to the wound tissue. 【0088】 In the eighth embodiment, the disclosure provides a method according to any one of the second to seventh embodiments, wherein the step of applying at least a first voltage and a second voltage generates an electric field having a magnitude of 0 to 1,000 volts / meter (V / m). 【0089】 In the ninth embodiment, the disclosure provides a method according to any one of the first to eighth embodiments, wherein one or more impedance maps of wound tissue identify at least one boundary between the wound bed and the peri-wound tissue. 【0090】 In a tenth embodiment, the disclosure provides a method according to a ninth embodiment, wherein the step of applying at least a first voltage and a second voltage generates an electric field directed at least partially inward from the boundary into the wound bed. 【0091】 In the eleventh embodiment, the disclosure provides a method according to any one of the first to tenth embodiments, in which at least four voltages are calculated, each targeting the wound tissue, based on the spatial distribution of electrical measurements of one or more impedance maps of the wound tissue. 【0092】 In the twelfth embodiment, the Disclosure provides a method according to any one of the first to eleventh embodiments, wherein one or more impedance maps of wound tissue are algorithmically estimated without requiring baseline measurements of non-wound tissue, and one or more impedance maps of wound tissue are algorithmically estimated using frequency difference electrical impedance tomography (fdEIT), measurement scale features (MSF), best homogeneity (BH) estimators, data-driven estimators, or a combination thereof. 【0093】 In a thirteenth embodiment, the disclosure provides a system comprising: an array of electrodes configured to apply one or more electrical signals to wound tissue; a circuit functionally connected to the array of electrodes for collecting electrical measurements from the array of electrodes; and a processor. The processor is configured to process the collected electrical measurements to generate one or more impedance maps of the wound tissue representing the heterogeneous electrical characteristics measured across a region of the wound tissue, and to calculate at least a first voltage and a second voltage, each targeting the wound tissue, based on the spatial distribution of the electrical measurements in the one or more impedance maps of the wound tissue. 【0094】 In a fourteenth embodiment, the disclosure provides a system according to a thirteenth embodiment, the electrode arrangement comprising a first electrode configured to apply a first voltage to wound tissue and a second electrode configured to apply a second voltage to wound tissue. 【0095】 In a 15th embodiment, the Disclosure provides a device for application to wound tissue. The device includes an array of electrodes comprising at least two electrodes configured to be placed on wound tissue and configured to apply one or more electrical signals to the wound tissue, and a circuit functionally connected to the array of electrodes for collecting electrical measurements from the array of electrodes and transferring the collected electrical measurements for processing. 【0096】 In the sixteenth embodiment, the disclosure provides a device according to the fifteenth embodiment, wherein the circuit is further functionally connected to the array of electrodes to pass a voltage through the array of electrodes. 【0097】 While the present invention has been described with reference to preferred embodiments, those skilled in the art will recognize that modifications can be made in form and detail without departing from the spirit and scope of the invention.

Claims

[Claim 1] The steps include applying one or more electrical signals to wound tissue via an array of electrodes, The steps include: collecting electrical measurements from the electrode array via a circuit functionally connected to the electrode array; The steps of processing the collected electrical measurements via a processor in order to generate one or more impedance maps of the wound tissue that represent the non-uniform electrical characteristics measured over the region of the wound tissue, A step of calculating at least a first voltage and a second voltage, each targeting the wound tissue, based on the spatial distribution of the electrical measurements of one or more impedance maps of the wound tissue, Methods that include... [Claim 2] The method according to claim 1, wherein the first voltage and the second voltage are different from each other. [Claim 3] The method according to claim 1 or 2, further comprising the step of applying at least the first voltage and the second voltage to the wound tissue via the array of electrodes. [Claim 4] The method according to claim 3, wherein the step of applying the voltage includes the step of applying a 0-volt (V) ground to an electrode placed on a wound bed. [Claim 5] The method according to claim 4, wherein the electrode placed on the wound bed is located at the center of the wound bed. [Claim 6] The method according to any one of claims 2 to 5, further comprising the step of repeating each of the steps of collecting, processing, and calculating after applying the first voltage and the second voltage to the wound tissue. [Claim 7] The method according to claim 6, wherein the steps of collecting, processing, and calculating are repeated for a predetermined time after the first voltage and the second voltage are applied to the wound tissue. [Claim 8] The method according to any one of claims 2 to 7, wherein the step of applying at least the first voltage and the second voltage generates an electric field having a magnitude of 0 to 1,000 volts / meter (V / m). [Claim 9] The method according to any one of claims 1 to 8, wherein the one or more impedance maps of the wound tissue identify at least one boundary between the wound bed and the peri-wound tissue. [Claim 10] The method according to claim 9, wherein the step of applying at least the first voltage and the second voltage generates an electric field directed at least partially inward from the boundary into the wound bed. [Claim 11] The method according to any one of claims 1 to 10, wherein at least four voltages are calculated, each targeting the wound tissue, based on the spatial distribution of the electrical measurements of the one or more impedance maps of the wound tissue. [Claim 12] The method according to any one of claims 1 to 11, wherein the one or more impedance maps of the wound tissue are algorithmically estimated without requiring baseline measurements of non-wound tissue, and the one or more impedance maps of the wound tissue are algorithmically estimated using frequency difference electrical impedance tomography (fdEIT), measurement scale features (MSF), best homogeneity (BH) estimators, data-driven estimators, or a combination thereof. [Claim 13] An array of electrodes configured to apply one or more electrical signals to wound tissue, To collect electrical measurements from the electrode arrangement, a circuit functionally connected to the electrode arrangement is provided. Processor and The processor includes, The collected electrical measurements are processed to generate one or more impedance maps of the wound tissue that represent the heterogeneous electrical properties measured across the region of the wound tissue. Based on the spatial distribution of the electrical measurements of one or more impedance maps of the wound tissue, each calculates at least a first voltage and a second voltage that target the wound tissue. system. [Claim 14] The system according to claim 13, wherein the electrode arrangement includes a first electrode configured to apply the first voltage to the wound tissue and a second electrode configured to apply the second voltage to the wound tissue. [Claim 15] A device for application to wound tissue, An array of electrodes comprising at least two electrodes configured to be positioned on the wound tissue and configured to apply one or more electrical signals to the wound tissue, A circuit functionally connected to the electrode array to collect electrical measurements from the electrode array and to transfer the collected electrical measurements for processing, A device that includes this. [Claim 16] The device according to claim 15, wherein the circuit is further functionally connected to the electrode array in order to pass a voltage through the electrode array.

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