Measurement of edema

APPLIANCES TO EVALUATE PRE-ECLAMPSY, HYPOOVOLEMIA AND COMPARTMENTAL SYNDROME, AND METHODS TO DETECT PRE-ECLAMPSY, HYPOOVOLEMIA AND COMPARTMENTAL SYNDROME.

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This patent application claims the priority benefit of US Provisional Application 62 / 454,467, filed on February 3, 2017, and US Provisional Application 62 / 521,890, filed on June 19, 2017 , each of which is incorporated herein by reference in its entirety.

FIELD OF APPLICATION [0002] The present patent application provides apparatus and methods for measuring subepidermal moisture (SEM) in patients as an indication of tissue damage associated with elevated or reduced levels of moisture in the tissue.

DESCRIPTION OF RELATED TECHNIQUE [0003] Many physical conditions and illnesses cause a patient's tissue structure to degrade, allowing fluid to leak into the interstitial spaces between cells, causing swelling known as edema. Other conditions reduce the amount of extracellular fluid (ECF) in certain tissues.

[0004] Pre-eclampsia is a potentially life-threatening condition that affects about 5 percent of pregnant women. It ranges in impact from mild to severe, in which case it can cause serious or even life-threatening problems. One effect of pre-eclampsia is that blood vessels compress, thereby causing high changes in

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2/32 blood flow in capillaries that allow fluid to leak into the surrounding tissue, thereby causing edema. This swelling can occur on the face, hands, or feet or ankles.

[0005] Dehydration can cause a reduced level of moisture in the body, which can result in low blood volume which reduces the amount of oxygen distributed to the tissue. Local dehydration on the surface of a wound, which can be caused by a patient's general dehydration or local damage, can reduce cell migration and delay the healing process.

[0006] Another condition associated with edema is compartment syndrome. Groups of organs or muscles are organized in areas called compartments. Strong membranes of connective tissue called fascia form the walls of these compartments. After an injury, blood or fluid can accumulate in the compartment. The fascia cannot expand easily and therefore the pressure in the compartment increases, preventing adequate blood flow to the tissues within the compartment which can result in tissue damage. When this condition occurs in a limb, such as a tibia, the increase in pressure can cause swelling of the affected limb. SUMMARY [0007] In one aspect, the present application for a patent provides, and includes, an apparatus for evaluating preeclampsia, the apparatus comprising: a sensor comprising at least a first electrode and at least a second electrode, where the sensor is configured to be placed against a patient's skin; a circuit electronically coupled to the first and second electrodes and configured to measure an electrical property between the first and second electrodes

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3/32 and provide information regarding electrical property; a processor electronically coupled to the circuit; and a non-transitory, computer-readable medium electronically coupled to the processor and comprising instructions stored therein, which, when executed on the processor, perform the steps of: receiving circuit information, converting the information into a first subepidermal humidity (SEM) value, and determining a difference between the first SEM value and a reference value, where the magnitude of the difference exceeding the reference value is indicative of pre-eclampsia.

[0008] One aspect of the present patent application provides, and includes, an apparatus for assessing hypovolemia, the apparatus comprising: a sensor comprising at least a first electrode and at least a second electrode, where the sensor is configured to be placed against a patient's skin; a circuit electronically coupled to the first and second electrodes and configured to measure an electrical property between the first and the second electrodes and provide information regarding the electrical property; a processor electronically coupled to the circuit, and non-transitory, computer-readable media electronically coupled to the processor and comprising instructions stored in the same that, when executed on the processor, perform the steps of: receive the circuit information, convert the information into a first SEM value, and determine a difference between the first SEM value and a reference value, where the magnitude of the difference less than the reference value is indicative of hypovolemia.

[0009] In one aspect, the present patent application

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4/32 of the invention provides, and includes, a method for detecting preeclampsia at a first location on a patient's skin, the method comprising: obtaining a subepidermal moisture value (SEM) at the first location; and determining that the SEM value is greater than a reference value to indicate preeclampsia.

[00010] In one aspect, the present application for a patent provides, and includes, a method for detecting hypovolemia at a first location of a patient's skin, the method comprising: obtaining a subepidermal moisture value (SEM) at the first location ; and determine that the SEM value is less than a reference value to indicate hypovolemia.

[00011] One aspect of the present patent application provides, and includes, an apparatus for assessing compartmental syndrome, the apparatus comprising: a sensor comprising at least a first electrode and at least a second electrode, where the sensor is configured to be placed against a patient's skin, a circuit electronically coupled to the first and second electrodes and configured to measure an electrical property between the first and second electrodes and provide information regarding electrical property, a processor electronically coupled to the circuit, and a non-transitory, computer-readable medium electronically coupled to the processor and comprising instructions stored therein, which, when executed on the processor, perform the steps of: receiving circuit information, converting the information into a first subepidermal humidity (SEM) value, and determine a difference between the first SEM value and a reference value,

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5/32 where the magnitude of the difference exceeding a predetermined amount is indicative of compartment syndrome.

[00012] In one aspect, the present application for a patent provides, and includes, a method for detecting compartment syndrome at a first location of a patient's skin, the method comprising: obtaining a first subepidermal moisture (SEM) value at first location; obtaining a second SEM value at a second location on the patient's skin; and determining whether the difference between the first SEM value and the second SEM value exceeds a predetermined amount indicative of compartment syndrome.

BRIEF DESCRIPTION OF THE DRAWINGS [00013] Aspects of the present application for a patent are described herein, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is emphasized that the particularities shown are by way of example and are for the purpose of illustrative discussion of aspects of the description. In this regard, the description and drawings, considered alone and together, make it apparent to those versed in the technique

<td>as aspects of this</td><td>request</td><td>patent</td><td colspan="2">of invention can</td>

<td>be practiced.</td><td></td><td></td><td></td><td></td>

<td>[00014] Figure</td><td>IA</td><td>reveals</td><td>a sensor</td><td>in</td>

<td>toroidal bioimpedance.</td><td></td><td></td><td></td><td></td>

<td>[00015] Figure</td><td>IB</td><td>reveals a</td><td>device</td><td>in</td>

SEM scan comprising the sensor of Figure IA.

[00016] Figure 2 is a first exemplary array of electrodes.

[00017] Figure 3 is an exemplary array of electrodes in accordance with the present patent application.

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6/32 invention.

[00018] Figure 4A illustrates a first example of how the electrode array disclosed in Figure 3 is configured to form a bioimpedance sensor in accordance with the present application for a patent.

[00019] Figure 4B illustrates a second example of how the electrode array disclosed in Figure 3 is configured to form a bioimpedance sensor in accordance with the present application.

[00020] Figure 5A illustrates exemplary measurement locations for evaluating preeclampsia-related edema in the hand in accordance with the present invention patent application.

[00021] Figure 5B illustrates exemplary measurement locations for evaluating edema related to preeclampsia in the upper ankle region according to the present application for an invention patent.

[00022] Figure 5C illustrates exemplary measurement locations for evaluating edema related to preeclampsia on the face according to the present application for an invention patent.

[00023] Figure 6 reveals an exemplary measurement location for assessing dehydration on the back of a hand according to the present application for an invention patent.

[00024] Figure 7A illustrates an exemplary measurement location for assessing compartmental syndrome in the forearm area in accordance with the present application.

[00025] Figure 7B illustrates an exemplary measurement location for assessing compartment syndrome in the

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Ί / 32 calf area according to the present patent application.

DETAILED DESCRIPTION [00026] The present patent application describes applications of the measurement of various electrical characteristics and derivation of SEM values ​​for physical conditions and diseases associated with accumulation or depletion of extracellular fluid (ECF), also referred to as intercellular fluid. Examples allow application to particular conditions, including pre-eclampsia, dehydration, compartment syndrome, and burns and other open wounds. These examples are not limiting and the principles demonstrated can be applied to a wider scope of injuries and conditions beyond the specific example. For example, apparatus and methods revealed in relation to a burn of 3^O grade can be used just as effectively in an open cut, gangrene, an ulcer, or other similar injury.

[00027] Women are susceptible to pre-eclampsia during pregnancy, with one of the symptoms being swelling in areas such as the face, hands, feet, or ankles. Providing a quantitative assessment of the degree of swelling would be beneficial, compared to subjective assessment methods currently in use to assess the possibility of a patient having pre-eclampsia.

[00028] Patients who lose a significant amount of ECF are often considered dehydrated, whereas, in fact, ECF depletion is caused by hypovolemia, which is a decrease in the volume of blood plasma. As the intravascular volume is controlled by sodium regulation while the water content of the total body is not, it is important to differentiate the two conditions in a way

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8/32 to select the appropriate treatment.

[00029] Compartment syndrome occurs when excessive pressure builds up in a closed muscle space in the body. Compartmental syndrome can result from internal bleeding or swelling after an injury. The dangerously high pressure in the compartment syndrome prevents blood flow to and against the affected tissues, which leads to tissue death if the blood flow is impeded for a sufficient amount of time. It may be an emergency, requiring surgery to prevent permanent injury and a quick and accurate assessment of this condition is vital in determining when to intervene.

[00030] This description should not be a detailed catalog of all the different ways in which the description can be implemented, or all of the features that can be added to the present invention patent application in question. For example, resources illustrated with respect to one modality can be incorporated into other modalities, and resources illustrated with respect to a particular modality can be deleted from that modality. Accordingly, the present invention patent application contemplates that, in some embodiments the present invention patent application, any resource or combination of resources presented here can be excluded or omitted. In addition, countless variations and additions to the various modalities suggested here will become apparent to those skilled in the art in the light of the present patent application, which do not escape the description in question. In other cases, well-known structures, interfaces and processes have not been shown in detail in order not to unnecessarily overshadow the present invention patent application. It is intended that no party

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9/32 of this specification is to be interpreted for the purpose of contradicting any part of the general scope of the present invention patent application. Consequently, the following descriptions are to illustrate some particular embodiments of the invention, and do not exhaustively specify all permutations, combinations and variations thereof.

[00031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning normally understood by those skilled in the art to which this patent application relates. The terminology used in describing the invention here is for the purpose of describing particular aspects or modalities only and is not intended to limit disclosure.

[00032] All publications, patent applications, patents and other references cited here are incorporated by reference in their entirety to the teachings relevant to the sentence and / or paragraph in which the reference is presented. References to techniques employed here are to refer to techniques in the manner normally understood in the art, including variations in these techniques or substitutions of equivalent techniques that would be apparent to those skilled in the art.

[00033] US Patent Application 14 / 827,375 discloses an apparatus that uses radiofrequency (RF) energy to measure the subepidermal capacitance that corresponds to the moisture content of a patient's target skin region. The '375 order also reveals an arrangement of these bipolar sensors of various sizes.

[00034] US Patent Application 15 / 134,110 discloses an apparatus for measuring subepidermal moisture (SEM) using a

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10/32 RF signal at a frequency of 32 kHz to generate a bioimpedance signal, then convert this signal to a SEM value.

[00035] Both US Patent Applications 14 / 827,375 and 15 / 134,110 are incorporated herein by reference in their entirety.

[00036] Unless the context indicates otherwise, it is specifically intended that the various characteristics of the disclosure described here can be used in any combination. In addition, the present invention patent application also contemplates that, in some aspects of the invention, any feature or combination of features presented here can be excluded or omitted.

[00037] The methods disclosed here include comprise one or more steps or actions to carry out the described method. The steps of the method and / or actions can be interchanged with each other without departing from the scope of the present invention patent application. In other words, unless a specific order of steps or actions is required for the correct operation of the modality, the order and / or use of specific steps and / or actions can be modified without departing from the scope of this invention patent application.

[00038] As used in the description of the invention and in the appended claims, the singular forms one, one and o, a should include plural forms equally, unless the context clearly indicates otherwise.

[00039] As used herein it refers to any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (or).

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11/32 [00040] The terms about and approximately in the form used here when referring to a measurable value such as a length, frequency, or SEM value and the like, should encompass variations of ± 20%, ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified quantity.

[00041] As used here, expressions such as between X and Y and between about X and Y should be interpreted to include X and Y. As used here, expressions such as between about X and Y mean between about X and about Y and expressions such as about X to Y mean about X to about Y.

[00042] As used here, the term subepidermal moisture or SEM refers to the increase in tissue fluid and localized edema caused by vascular permeability and other changes that modify the underlying structure of damaged tissue in the presence of continued pressure in the tissue, apoptosis, necrosis , and the inflammatory process.

[00043] As used here, a system can be a collection of devices in physical or wireless communication with each other.

[00044] As used here, interrogation refers to the use of radio frequency energy to penetrate a patient's skin.

[00045] As used here, a patient can be a human or animal subject.

[00046] As used here, total body water or TBW refers to the total water content in a subject's body including intravascular fluid and extracellular fluid.

[00047] As used here, intravascular volume refers to the fluid contained in the cells.

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12/32 [00048] As used here, extracellular fluid or ECF refers to the body fluid contained outside the cells, including plasma, interstitial fluid, and transcellular fluid.

[00049] As used here, interstitial fluid refers to the fluid that surrounds the tissue cells of a multicellular subject.

[00050] As used here, skin fold refers to the slow return of the skin to its normal position after being pinched.

[00051] Figure IA reveals a toroidal bioimpedance sensor 90. In one aspect, a central electrode 110 is surrounded by a ring electrode 120. Without being limited to a particular theory, the gap between the two electrodes affects the depth of penetration of substrate field below sensor 90. In one aspect, a ground plane (not visible in Figure IA) is parallel and separate from the plane of the electrodes and, in one aspect, extends beyond the outer diameter of the ring electrode 120. Without being limited to a particular theory, a ground plane can limit the field between electrodes 110 and 120 to a single side of the electrode plane which is on the opposite side of the electrode plane from the ground plane.

[00052] Figure 1B provides top and bottom views of a SEM 170 scanning device that comprises electronic components that drive sensor 174, which is similar to sensor 90 in Figure 1, and measures a capacitance between electrodes 110 and 120 This capacitance is converted to a SEM value that is displayed on monitor 176.

[00053] Aspects of sensor 90 and SEM 170 scanning device are disclosed in International Publication No. WO 2016/172263, of which US Patent Application 15 / 134,110

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13/32 was deposited as an entry into the national phase, all of which are hereby incorporated by reference in their entirety.

[00054] Figure 2 represents an exemplary electrode array 290, in accordance with the present application for a patent. Arrangement 290 is composed of individual electrodes 300 arranged, in this example, in a regular pattern on a substrate 292. In one aspect, each electrode 300 is separately coupled (through conductive elements not shown in Figures 2 to 4B) to a circuit, as described with reference to Figure 4A, which is configured to measure an electrical parameter. In one aspect, a virtual sensor is created by selective connection of predetermined subsets of electrodes 300 to a common element of a circuit. In this example, a particular electrode 310 is connected as a central electrode, similar to electrode 110 in Figure IA, and six electrodes 320A-320F are connected together as a virtual ring electrode, similar to electrode 120 in Figure IA. In one aspect, two individual electrodes are individually connected to a circuit to form a virtual sensor, for example, electrodes 310 and 320A are respectively connected as two electrodes from a sensor. In one aspect, one or more electrodes 300 are connected together to form one or the other of the electrodes of a two-electrode sensor.

[00055] Any pair of electrodes, whether composed of individual electrodes or a set of electrodes coupled together to form virtual electrodes, is coupled to electronic components that are configured to measure an electrical property or parameter that comprises one or more of the selected electrical characteristics of the group that

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14/32 consists of a resistance, capacitance, inductance, impedance, reluctance, or other electrical characteristic with one or more of sensors 90, 174, 290, 430, 440, or another two-electrode sensor.

[00056] Figure 3 represents another exemplary array 400 of electrodes 410, in accordance with the present application for a patent. In this example, each of the electrodes 410 is an approximate hexagon that is separated from each of the surrounding electrodes 410 by a gap 420. In one aspect, electrodes 410 are in the shape of circles, squares, pentagons, or other regular or irregular shapes. In one aspect, the clearance 420 is uniform across all 410 electrodes. In one aspect, the gap 420 varies between several electrodes. In one aspect, the gap 420 has a width that is less than the cross section of each of the electrodes 410. The electrodes 410 can be interconnected to form virtual sensors as described below with respect to Figures 4A and 4B.

[00057] Figure 4A represents an array 400 of electrodes 410 which are configured, for example, connected to a measuring circuit, to form an exemplary sensor 430, in accordance with the present application for an invention patent. A single hexagonal electrode 410 that is labeled with a 1 forms a central electrode and a ring of electrodes 410 that is marked with a 2 is interconnected to form a ring electrode. In one aspect, electrodes 410 between the center electrode and ring are electrically floating. In one aspect, electrodes 410 between the center electrode and the ring are grounded or connected to a floating earth. In one aspect, electrodes 410 that are outside the ring electrode are electrically fluctuating. In one aspect, electrodes 410

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15/32 that are outside the virtual ring electrode are grounded or connected to a floating earth.

[00058] Figure 4B represents an alternative aspect where the array 400 of electrodes 410 has been configured to form a virtual sensor 440, in accordance with the present application for an invention patent. In one aspect, multiple electrodes 410, indicated by a 1, are interconnected to form a central electrode while a double width electrode ring, indicated by a 2, is interconnected to form a ring electrode. In one aspect, various numbers and positions of electrodes 410 are interconnected to form virtual electrodes of a variety of sizes and shapes.

[00059] Figure 5A reveals exemplary measurement locations 510 and 520 on hand 500 for evaluation of edema related to preeclampsia, in accordance with the present application for an invention patent. Location 510 is generally located on the left hand tenar, while location 520 is generally located on the hypotenar eminence of a left hand. Similar locations exist in the same areas as a right hand. Other locations where edema related to pre-eclampsia can be observed are known to those skilled in the art. In one aspect, a measured SEM value can be compared to a predetermined reference value, where the measured SEM value being above or below a threshold is indicative of edema. In one aspect, multiple measurements made at multiple locations are averaged or compared to an average, where a difference between a reading and the average is indicative of edema at the respective location. In one aspect, a maximum SEM value and a minimum SEM are identified

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16/32 in a set of measurements, where a characteristic of the comparison such as the difference between the maximum and the minimum is compared to a predetermined threshold. In one aspect, a SEM value measured at a first predetermined location is compared to a SEM value measured at a second predetermined location, where a feature of the comparison such as a difference greater than a threshold is indicative of edema at one of the locations.

[00060] Figure 5B reveals exemplary measurement locations 552 and 562 for evaluating edema in the upper ankle region 550 and foot 560 that are related to preeclampsia, according to the present application for an invention patent. In one aspect, SEM values ​​derived from measurements taken at one of more locations 552 and 562 are compared to each other, a parameter calculated from one or more of the measurements, for example, a mean SEM value, or with predetermined thresholds.

[00061] In one aspect, a SEM sensor as described herein, for example, sensor 90 or sensor 400, is embedded in a band 554 that can be wrapped around a calf as shown in Figure 5B. In one aspect, band 554 comprises sensors configured to measure one or more of tissue oxygenation, which may comprise measurement of one or both of oxyhemoglobin and deoxyhemoglobin, temperature of one or more points on the skin, pulse and blood pressure in a patient. In one respect, the combination of measurements made by the 554 range provides information regarding blood flow and edema in a patient's tibia.

[00062] Figure 5C reveals exemplary measurement locations 572, 574, 576 for evaluation of edema on face 570

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17/32 which is related to pre-eclampsia, according to the present invention patent application. Swelling can occur at one or more of the location 572 near the eyes, location 574 in the infraorbital triangle, location 574 on the malar bone, or other locations between and around the locations in a patient as identified in Figure 5C. SEM values ​​derived from measurements at one or more of these locations can be assessed as discussed in relation to Figures 5A and 5B.

[00063] In general, edema caused by pre-eclampsia is a systemic condition and is expected to be present at the same level at equivalent locations in a patient's body. For example, it is expected that the swelling of a left hand is approximately the same as that of the corresponding right hand, and vice versa. In one aspect, a SEM scanning device comprises two electrodes, a circuit electronically coupled to the electrodes and configured to measure electrical property between the electrodes and provide information regarding electrical property to a processor that is configured to convert the information into a SEM value. . In one respect, multiple measurements of electrical property are used to generate an average SEM value. A processor of an SEM scanning device then compares the SEM values ​​derived from measurements at similar locations and calculates one or more of an average, a difference, a percentage difference, or another computational characteristic of the SEM value set. In one aspect, a determination that the SEM values ​​at two corresponding locations are both above a predetermined threshold and are also within a predetermined range of one another is indicative of pre-eclampsia. In one respect, a single SEM value exceeding a value of

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18/32 reference, which can be predetermined or derived from other SEM measurements, is indicative of pre-eclampsia.

[00064] In one aspect, a predetermined reference value for pre-eclampsia can range from 0.1 to 8.0, such as from 0.1 to 1.0, from 1.1 to 2.0, from 2, 1 to 3.0, 3.1 to 4.0, 4.1 to 5.0, 5.1 to 6.0, 6.1 to 7.0, 7.1 to 8.0 , from 0.1 to 7.5, from 0.5 to 8.0, from 1.0 to 7.0, from 1.5 to 6.5, from 2.0 to 6.0, from 3.0 to 5.5, from 3.5 to 5.0, or from 4.0 to 4.5. In one aspect, a predetermined reference value for preeclampsia can range from 0.1 to 4.0, such as from 0.5 to 4.0, from 0.1 to 3.5, from 1.0 to 3.5 , from 1.5 to 4.0, from 1.5 to 3.5, from 2.0 to 4.0, from 2.5 to 3.5, from 2.0 to 3.0, from 2.0 to 2.5, or 2.5 to 3.0. In one respect, a predetermined reference value for

<td>pre eclampsia</td><td>can range from 4.1 to 8.0, as</td><td>in</td><td>4.5 to</td>

<td>8.0, from 4.1 to</td><td>7.5, from 5.0 to 7.5, from 5.5 to 7.0, from</td><td>5.5 to</td><td> 7,5,</td>

<td colspan="2">from 6.0 to 8.0, from 6.5 to 7.5, from 6.0 to 7.0, from 6.0 to</td><td> 6,5,</td><td>or of</td>

<td>6.5 to 7.0.</td><td>In one respect, a value of</td><td colspan="2">reference</td>

<td>predetermined</td><td>for preeclampsia can be about</td><td> 0,3,</td><td> 0,35,</td>

<td> 0,4, 0,45, 0,5</td><td> , 0,55, 0, 6, 0, 65, 0,7, 0,75, 0, 8,</td><td> 0,85,</td><td> 0, 9,</td>

<td> 0,95, 1,0, 1,1</td><td> , 1,2, 1,3, 1,4, 1,5, 1,6, 1,7, 1,8,</td><td> 1, 9,</td><td> 2,0,</td>

<td> 2,1, 2,2, 2,3,</td><td> 2,4, 2,5, 2,6, 2,7, 2,8, 2,9, 3,0,</td><td> 3,1,</td><td> 3,2,</td>

<td> 3,3, 3,4, 3,5,</td><td> 3,6, 3,7, 3,8, 3,9, 4,0, 4,1, 4,2,</td><td> 4,3,</td><td> 4,4,</td>

<td> 4,5, 4,6, 4,7,</td><td> 4,8, 4,9, 5,0, 5,1, 5,2, 5,3, 5,4,</td><td> 5,5,</td><td> 5, 6,</td>

<td> 5,7, 5,8, 5,9,</td><td> 6,0, 6,1, 6,2, 6,3, 6,4, 6,5, 6,6,</td><td> 6,7,</td><td> 6,8,</td>

<td> 6,9, 7,0, 7,1,</td><td>7.2, 7.3, 7.4, or 7.5. In one aspect</td><td>, one</td><td>value</td>

<td>of reference</td><td>predetermined for preeclampsia</td><td>podí</td><td>s be</td>

increased by a factor or a multiple based on the values ​​provided here.

[00065] One or more regions can be defined in a body. In one respect, measurements made in a region are

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19/32 considered to be comparable to each other. A region can be defined as an area on the skin of the body where measurements can be taken anywhere in the area. In one aspect, a region corresponds to an anatomical region (for example, heel, ankle, lower back). In one aspect, a region can be defined as a set of two or more specific points relating to anatomical features in which measurements are made only at specific points. In one aspect, a region can comprise a plurality of non-contiguous areas in the body. In one aspect, the set of specific locations can include points in multiple non-contiguous areas.

<td></td><td> [00066]</td><td>In</td><td>one</td><td>aspect,</td><td>a region is defined</td><td>through the</td>

<td>area</td><td>superficial.</td><td>In</td><td>one</td><td>aspect,</td><td>a region can be,</td><td>per</td>

<td colspan="2">example, between 5 and</td><td colspan="3">200 cm², in between</td><td>5 and 100 cm², between 5</td><td>and 50</td>

<td>cm²,</td><td>or between 10 and</td><td> 50</td><td>cm²,</td><td>between 10</td><td>and 25 cm², or between 5</td><td>and 25</td>

<td>cm².</td><td> [00067]</td><td>In</td><td>one</td><td>aspect,</td><td colspan="2">measurements can be made</td>

in a specific pattern or portion of it. In one aspect, the pattern of readings is done in a pattern with the target area of ​​interest in the center. In one aspect, measurements are made in one or more circular patterns of increasing or decreasing size, T-shaped patterns, a set of specific locations, or randomly across a fabric or region. In one aspect, a pattern can be located on the body by defining a first measurement location of the pattern with respect to an anatomical feature with the other defined pattern measurement locations offset from the first measurement position.

[00068] In one aspect, a plurality of measurements are made across a fabric or region and the difference between the

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20/32 lowest measurement value and highest measurement value of the plurality of measurements is recorded as a delta value of that plurality of measurements. In one aspect, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more measurements are made through a fabric or region.

[00069] In one respect, a threshold can be established for at least one region. In one aspect, a threshold of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or another value can be established for at least one region . In one aspect, a delta value is identified as significant when the delta value of a plurality of measurements made in a region meets or exceeds a threshold associated with that region. In one respect, each of a plurality of regions has a different threshold. In one respect, two or more regions may have a common threshold.

[00070] In one aspect, a threshold has both a delta value component and a chronological component, where a delta value is identified as significant when the delta value is greater than a predetermined numerical value for a predetermined portion of a time interval . In one aspect, the predetermined portion of a time interval is defined as a minimum of X days, in which a plurality of measurements taken on that day produces a delta value greater than or equal to the predetermined numerical value in a total of Y contiguous measurement days . In one aspect, the predetermined portion of a time interval can be defined as 1, 2, 3, 4, or 5 consecutive days in which a plurality of measurements made on that day produce a delta value that is greater than or equal to the predetermined numerical value . In one aspect, the predetermined portion of a time interval can be defined as

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21/32 some portion of a different specific time period (weeks, month, hours, etc.).

[00071] In one aspect, a threshold has a tendency aspect in which changes in the delta values ​​of consecutive pluralities of measurements are compared to each other. In one aspect, a trend threshold is defined as a predetermined change in the delta value over a predetermined length of time, in which a determination that the threshold has been reached or exceeded is significant. In one respect, a determination of significance will cause an alert to be issued. In one aspect, a trend line can be computed from a portion of the individual measurements from the consecutive pluralities of measurements. In one aspect, a trend line can be computed from a portion of the delta values ​​of the consecutive pluralities of measurements.

[00072] In one aspect, the number of measurements taken in a single region may be less than the number of measurement locations defined in a standard. In one respect, a delta value will be calculated after a predetermined initial number of readings, which is less than the number of measurement locations defined in a standard, has been taken in one region and after each additional reading in the same region, in which readings no additional changes are made since the delta value meets or exceeds the threshold associated with that region.

[00073] In one aspect, the number of measurements taken in a single region can exceed the number of measurement locations defined in a standard. In one respect, a delta value will be calculated after each additional reading.

[00074] In one aspect, a quality metric can be generated for each plurality of measurements. On a

Petition 870190039765, of 26/04/2019, p. 10/279

22/32 aspect, this quality metric is chosen to assess the repeatability of measurements. In one aspect, this quality metric is chosen to assess the skill of the clinician making the measurements. In one aspect, the quality metric can include one or more statistical parameters, for example, an average, an arithmetic mean, or a standard deviation. In one aspect, the quality metric can include one or more of a comparison of individual measurements with a predefined range. In one aspect, the quality metric may include comparing individual measurements against a standard of values, for example, comparing measurement values ​​at predefined locations with ranges associated with each predefined location. In one respect, the quality metric can include determining which measurements are made on healthy tissue and one or more consistency assessments in this healthy measurement subset, for example, a range, standard deviation, or other parameter.

[00075] In one aspect, a measurement, for example, a threshold value, is determined by SEM Scanner 200 Model (Bruin Biometrics, LLC, Los Angeles, CA). In another aspect, a measurement is determined by another

<td rowspan="2">device</td><td rowspan="2">in [00</td><td colspan="2">SEM scan.</td><td colspan="2" rowspan="2">value of</td><td rowspan="2">measurement</td><td rowspan="2">is</td>

<td>07 6] In one</td><td>aspect, one</td>

<td>based on</td><td>an</td><td>measurement of</td><td>capacitance</td><td>per</td><td colspan="2">reference to</td><td>one</td>

<td>device</td><td>in</td><td>reference</td><td colspan="2">In one respect,</td><td>an</td><td>measurement</td><td>in</td>

Capacitance can depend on the location and other aspects of any electrode in a device. Such variations can be compared to a reference SEM device such as a Model 200 SEM Scanning Device (Bruin Biometrics, LLC, Los Angeles, CA). Experienced in the technique understand that

Petition 870190039765, of 26/04/2019, p. 10/28

23/32 measurements presented here can be adjusted to accommodate a different capacitance range by reference to a reference device.

[00077] Figure 6 reveals an exemplary measurement location for assessing dehydration, in accordance with the present application for an invention patent. Dehydration is often used to describe both true dehydration, which is a reduction in total body water, and as a substitute for hypovolemia, which is a decrease in the volume of blood plasma. Total body water is not controlled by sodium regulation, while intravascular volume is controlled by sodium regulation, and so this distinction is important to guide therapy. Patients who lose a significant amount of ECF are often considered dehydrated, whereas, in fact, ECF depletion is caused by hypovolemia. The provision of guideline needs how the amount of interstitial, or extracellular, fluid is therefore an important guideline for a clinician treating the patient.

[00078] A current method of assessing hydration is to pull up a skin fold 610 on an area of ​​loose skin and assess how the skin fold 610 relaxes, where a slow return or inability to return completely is considered indicative of dehydration.

[00079] The measurement of capacitance, or other electrical characteristic of a patient's local tissue, using sensors such as sensor 90 or 440, will detect a reduction in the amount of ECF. An exemplary location for assessing dehydration is location 620 over the junction of the second and third compartments of a hand. The comparison of values

Petition 870190039765, of 26/04/2019, p. 10/29

24/32

SEM derived from such measurements with predetermined thresholds will provide a quantitative indication if a patient is suffering from hypovolemia. In one respect, using an SEM measurement to assess the amount of ECF in combination with a measurement that is responsive to a tissue's total water content, which includes both ECF and fluid in the cells, and comparing the two measurements with thresholds, or with each other, will provide an indication of true dehydration. In one respect, multiple measurements of electrical property are used to generate an average SEM value to assess the amount of ECF. In one respect, a single SEM value being less than a reference value, which can be predetermined or derived from other SEM measurements, is indicative of hypovolemia.

[00080] In one aspect, a predetermined reference value for hypovolemia can range from 0.1 to 8.0, such as from 0.1 to 1.0, from 1.1 to 2.0, from 2.1 to 3.0, from 3.1 to 4.0, from 4.1 to 5.0, from 5.1 to 6.0, from 6.1 to 7.0, from 7.1 to 8.0, from 0.1 to 7.5, 0.5 to 8.0, 1.0 to 7.0, 1.5 to 6.5, 2.0 to 6.0, 3.0 to 5 , 5, from 3.5 to 5.0, or from 4.0 to 4.5. In one aspect, a predetermined reference value for hypovolemia can range from 0.1 to 4.0, such as from 0.5 to 4.0, from 0.1 to 3.5, from 1.0 to 3.5 , from 1.5 to 4.0, from 1.5 to 3.5, from 2.0 to 4.0, from 2.5 to 3.5, from 2.0 to 3.0, from 2.0 to 2.5, or

2.5 to 3.0. In one respect, a predetermined reference value for hypovolemia can range from 4.1 to 8.0, such as from 4.5 to 8.0, from 4.1 to 7.5, from 5.0 to 7.5 , from 5.5 to 7.0, from 5.5 to 7.5, from 6.0 to 8.0, from 6.5 to 7.5, from 6.0 to 7.0, from 6.0 to 6.5, or 6.5 to 7.0. In one aspect, a predetermined reference value for hypovolemia can be about 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0, 6, 0, 65, 0.7 , 0.75, 0, 8,

Petition 870190039765, of 26/04/2019, p. 10/30

25/32

<td> 0, 85,</td><td> 0, 9,</td><td> 0, 95</td><td>, i, o,</td><td> 1,1, 1,2, 1,3,</td><td> 1,4,</td><td> 1,5,</td><td> 1,6, 1,7,</td><td> 1,8,</td>

<td> 1, 9,</td><td> 2,0,</td><td> 2,1,</td><td> 2,2,</td><td> 2,3, 2,4, 2,5,</td><td> 2, 6,</td><td> 2,7,</td><td> 2,8, 2,9,</td><td> 3,0,</td>

<td> 3,1,</td><td> 3,2,</td><td> 3,3,</td><td> 3,4,</td><td> 3,5, 3,6, 3,7,</td><td> 3,8,</td><td> 3, 9,</td><td> 4,0, 4,1,</td><td> 4,2,</td>

<td> 4,3,</td><td> 4,4,</td><td> 4,5,</td><td> 4, 6,</td><td> 4,7, 4,8, 4,9,</td><td> 5,0,</td><td> 5, 1,</td><td> 5,2, 5,3,</td><td> 5,4,</td>

<td> 5,5,</td><td> 5, 6,</td><td> 5,7,</td><td> 5,8,</td><td> 5,9, 6,0, 6,1,</td><td> 6,2,</td><td> 6,3,</td><td> 6,4, 6,5,</td><td> 6, 6,</td>

<td> 6,7,</td><td> 6,8,</td><td> 6, 9,</td><td> 7,0, 7</td><td> ,1, 7,2, 7,3, 7,</td><td>4, or</td><td> 7,5.</td><td colspan="2">In one respect,</td>

a predetermined reference value for hypovolemia can be extended by a factor or a multiple based on the values ​​provided here.

[00081] Figures 7A and 7B reveal exemplary measurement locations for assessing compartment syndrome, in accordance with the present invention patent application. Compartment syndrome is defined as a complex symptom resulting from an increase in tissue pressure in a limited space that compromises the circulation and function of the contents in that space. This occurs when intramuscular pressure is raised to a level and for a period of time sufficient to reduce capillary perfusion. Muscles and nerves can tolerate ischemia for up to 4 hours and irreversible damage occurs in 8 hours. There are numerous compartments in a human body, including three forearm compartments and ten separate osteofascial compartments in the hand. Symptoms of compartment syndrome include pain in the affected region, passive stretching of the muscles involved, localized swelling, paresthesia (eg, tinnitus) in the nerve distribution involved, and muscle paresis (eg, weakness). Current practice for quantifying the degree of compartment syndrome for a limb is to measure the circumference of the limb in sequential times. This method is slow and depends on the length of time between the injury and the initial measurement. a

Petition 870190039765, of 26/04/2019, p. 10/31

26/32 A new method for quantifying edema in a compartment and tracking changes in the degree of edema on a time scale of minutes would provide important information to a clinician.

[00082] Compartmental syndrome swelling is considered to be triggered primarily by ECF. Measuring tissue capacitance in a compartment will respond to the increase in ECF. Since compartment syndrome typically affects only one region of the body, for example, a single leg, SEM values ​​can be derived from capacitance measurements at corresponding locations on both the affected leg and the other leg, and compared, with a difference greater than a threshold predetermined being indicative of compartment syndrome. In one respect, the magnitude of the difference between measurements of an affected and an unaffected body part is indicative of the severity of the compartment syndrome and the associated urgency of the condition.

[00083] In one aspect, a predetermined threshold indicative of compartment syndrome can range from 0.1 to 8.0, such as from 0.1 to 1.0, from 1.1 to 2.0, from 2.1 to 3.0, from 3.1 to 4.0, from 4.1 to 5.0, from 5.1 to 6.0, from 6.1 to 7.0, from 7.1 to 8.0, from 0.1 to 7.5, 0.5 to 8.0, 1.0 to 7.0, 1.5 to

6.5, 2.0 to 6.0, 3.0 to 5.5, 3.5 to 5.0, or 4.0 to

4.5. In one aspect, a predetermined threshold indicative of compartment syndrome can range from 0.1 to 4.0, such as from 0.5 to 4.0, from 0.1 to 3.5, from 1.0 to 3.5 , from 1.5 to 4.0, from

1.5 to 3.5, 2.0 to 4.0, 2.5 to 3.5, 2.0 to 3.0, 2.0 to 2.5, or 2.5 to 3, 0. In one aspect, a predetermined threshold indicative of compartment syndrome can range from 4.1 to 8.0, such as from 4.5 to 8.0, from 4.1 to 7.5, from 5.0 to 7.5 , in

5.5 to 7.0, 5.5 to 7.5, 6.0 to 8.0, 6.5 to 7.5, 6.0

Petition 870190039765, of 26/04/2019, p. 10/32

27/32 to 7.0, from 6.0 to 6.5, or from 6.5 to 7.0. In one aspect, a predetermined threshold indicative of compartment syndrome can be

<td>fence</td><td>in</td><td> 0,3,</td><td> 0,35,</td><td> 0,4,</td><td> 0,45, 0,5, 0,</td><td> 55, 0, 6, 0, 65,</td><td> 0,7,</td>

<td> 0,75,</td><td> 0,8,</td><td> 0,85</td><td> , 0, 9</td><td> , 0, 95</td><td> , 1,0, 1,1, 1,2</td><td> , 1,3, 1,4, 1,5,</td><td> 1, 6,</td>

<td> 1,7,</td><td> 1,8,</td><td> 1, 9,</td><td> 2,0,</td><td> 2,1,</td><td> 2,2, 2,3, 2,4,</td><td> 2,5, 2,6, 2,7,</td><td> 2,8,</td>

<td> 2, 9,</td><td> 3,0,</td><td> 3,1,</td><td> 3,2,</td><td> 3,3,</td><td> 3,4, 3,5, 3,6,</td><td> 3,7, 3,8, 3,9,</td><td> 4,0,</td>

<td> 4, 1,</td><td> 4,2,</td><td> 4,3,</td><td> 4,4,</td><td> 4,5,</td><td> 4,6, 4,7, 4,8,</td><td> 4,9, 5,0, 5,1,</td><td> 5,2,</td>

<td> 5,3,</td><td> 5,4,</td><td> 5,5,</td><td> 5, 6,</td><td> 5,7,</td><td> 5,8, 5,9, 6,0,</td><td> 6,1, 6,2, 6,3,</td><td> 6,4,</td>

<td> 6,5,</td><td> 6, 6,</td><td> 6,7,</td><td> 6,8,</td><td> 6, 9,</td><td> 7,0, 7,1, 7,2,</td><td>7.3, 7.4, or 7,</td><td>5. In</td>

one aspect, a predetermined threshold indicative of compartment syndrome can be increased by one factor or a multiple based on the values ​​provided here.

[00084] In Figure 7A, the forearm 642 of the arm 640 is swollen as indicated schematically by the envelope in dashed lines 642A. A measurement at a location 644 that is selected to be directly coupled to one of the compartments on the forearm 642 will provide an SEM value that is related to the degree of edema in that compartment. Comparing this SEM value with a second SEM value derived from a measurement at an equivalent location (not shown in Figure 7A) on the other arm will provide information regarding the degree of edema and the severity of the condition. In one aspect, the SEM value is associated with a pressure in the measured compartment.

[00085] Figure 7B represents a situation for a 650R right leg that is similar to the situation in Figure 7A. the tibia 660 is swollen as indicated by the envelope in dashed lines 660A. A SEM value derived from a capacitance measurement at location 670, which has been selected to be coupled to one of the compartments in the 650R tibia, will provide an indication of edema in that compartment. As in Figure 7A, a

Petition 870190039765, of 26/04/2019, p. 33/109 SEM value of a corresponding location (not shown in Figure 7B) in the left 650L tibia provides a baseline, where a comparison of the two readings provides an indication of the degree of edema and the urgency of the compartment syndrome.

[00086] From the foregoing, it is understood that the present application for a patent for invention can be conceived in several ways, which include, but are not limited to, the following:

[00087] Mode 1. A device for assessing pre-eclampsia, the device comprising: a sensor comprising at least a first electrode and at least a second electrode, where the sensor is configured to be placed against a patient's skin, a circuit electronically coupled to the first and second electrodes and configured to measure an electrical property between the first and second electrodes and provide information regarding electrical property, a processor electronically coupled to the circuit, and a non-transitory, computer-readable medium electronically coupled to the processor and comprising instructions stored therein, which, when executed on the processor, perform the steps of: receiving circuit information, converting the information into a first subepidermal humidity (SEM) value, and determine a difference between the first SEM value and a reference value, where the magnitude of the difference exceeding the reference value is indicative of pre-eclampsia.

[00088] Mode 2. The device of mode 1, where the reference value is predetermined.

[00089] Mode 3. A device for assessing hypovolemia, the device comprising: a sensor comprising at least one first electrode and at least one

Petition 870190039765, of 26/04/2019, p. 10/34

29/32 second electrode, where the sensor is configured to be placed against a patient's skin, a circuit electronically coupled to the first and second electrodes and configured to measure an electrical property between the first and second electrodes and provide relative information electrical property, a processor electronically coupled to the circuit, and a non-transitory, computer-readable medium electronically coupled to the processor and comprising instructions stored in the sameue, when executed on the processor, perform the steps of: receiving circuit information, converting the information into a first subepidermal humidity (SEM) value, and determine a difference between the first SEM value and a reference value, where the magnitude of the minor difference which the reference value is indicative of hypovolemia.

[00090] Mode 4. The device of mode 3, where the reference value is predetermined.

[00091] Mode 5. A method for detecting preeclampsia at a first location of a patient's skin, the method comprising: obtaining a subepidermal moisture value (SEM) at the first location; and determining that the SEM value is greater than a reference value to indicate preeclampsia.

[00092] Mode 6. The method of mode 5, where the reference value is predetermined.

[00093] Mode 7. A method for detecting hypovolemia in a first location of a patient's skin, the method comprising: obtaining a subepidermal humidity (SEM) value in the first location; and determine that the SEM value is less than a reference value to indicate

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30/32 hypovolemia.

[00094] Mode 8. The method of mode 7, where the reference value is predetermined.

[00095] Mode 9. An apparatus for assessing compartment syndrome, the apparatus comprising: a sensor comprising at least a first electrode and at least a second electrode, where the sensor is configured to be placed against a patient's skin, a circuit electronically coupled to the first and second electrodes and configured to measure an electrical property between the first and second electrodes and provide information regarding electrical property, a processor electronically coupled to the circuit, and a non-transitory, computer-readable medium electronically coupled to the processor and comprising instructions stored therein that, when executed on the processor, perform the steps of: receiving circuit information, converting the information to a first subepidermal humidity (SEM) value, and determining a difference between the first SEM value and a reference value, where the magnitude of the difference exceeding a predetermined amount is indicative of compartment syndrome.

[00096] Mode 10. The device of mode 9, where: the first SEM value is derived from a measurement made at a first location of the patient's skin; the reference value is a second SEM value derived from a measurement taken at a second location on the patient's skin.

[00097] Mode 11. The device of mode 10, where the first and second locations are symmetrical with respect to a center line of the patient's body.

[00098] Mode 12. The apparatus of the mode

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10, where the first SEM value exceeding the second SEM value in the predetermined quantity is indicative of compartment syndrome at the first location.

[00099] Mode 13. The device of mode 10, where the second SEM value exceeds the first SEM value by the predetermined quantity is indicative of compartment syndrome in the second location.

[000100] Mode 14. A method for detecting compartment syndrome at a first location of a patient's skin, the method comprising: obtaining a first subepidermal humidity (SEM) value at the first location; obtaining a second SEM value at a second location on the patient's skin; and determining whether the difference between the first SEM value and the second SEM value exceeds a predetermined amount indicative of compartment syndrome.

[000101] Mode 15. The method of mode 14, where the first and second locations are symmetrical with respect to a center line of the patient's body.

[000102] Mode 16. The method of mode 14, where the first SEM value exceeding the second SEM value by the predetermined quantity is indicative of compartment syndrome at the first location.

[000103] Mode 17. The method of mode 14, where the second SEM value exceeding the first SEM value by the predetermined quantity is indicative of compartment syndrome in the second location.

[000104] Although the present invention patent application has been described with reference to particular aspects, those skilled in the art will understand that various changes can be made and equivalents can be used in

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32/32 replacement of the elements of the same without departing from the scope of the present invention patent application. In addition, many modifications can be made to a particular situation or material according to the precepts of the invention without departing from the scope of the invention. Therefore, it is intended that the present invention patent application is not limited to the particular aspects disclosed, but that the present invention patent application includes all aspects that fall within the scope and spirit of the appended claims.