WO2021183678A1

WO2021183678A1 - Devices and methods of urinalysis for real-time monitoring of organ health

Info

Publication number: WO2021183678A1
Application number: PCT/US2021/021763
Authority: WO
Inventors: Prajakta KULKARNI
Original assignee: Kulkarni Prajakta
Priority date: 2020-03-10
Filing date: 2021-03-10
Publication date: 2021-09-16
Also published as: EP4118424A4; CA3171291A1; EP4118424A1; AU2021233839A1

Abstract

A non-invasive system and method for disease detection and real-time monitoring of organ health wherein the changes in the electrical properties of urine samples are studied over time in the presence or absence of interacting electrochemicals for qualitative and quantitative estimation of urinary analytes. The system has two components – a test platform and a reader. The test platform is integrated with electrodes and electrochemicals, which interact with urine to detect the biomarker of the disease and quantify the analyte. The changes in the electrical properties serve as an electrical signature for a particular analyte. This electrical signal from the test platform is relayed to an electronic reader that receives, processes, and analyzes the data for single test detection or continuous monitoring. The reader stores the information that can then be coupled to a readout system or transmitted by wired or wireless mechanisms to any electronic platform in real-time.

Description

DEVICES AND METHODS OF URINALYSIS FOR REAL-TIME MONITORING OF

ORGAN HEALTH

BACKGROUND

[0001] Field

[0002] This disclosure relates to devices and methods for disease detection and real-time monitoring of organ health wherein the changes in the electrical properties of urine samples are studied over time in the presence or absence of interacting electrochemicals.

[0003] Description of the Related Art

[0004] The urinary biomarkers are analyzed to detect diseases and monitor health at home, in clinics, and the pathology labs. Home-based tests that are currently available for use are mostly qualitative or semi-quantitative in nature. But more precise and reliable information about the disease and overall health can be gathered with quantitative urinalysis.

[0005] The quantitative urine analysis conducted in the pathology labs requires skilled personnel to operate the instrument and does not perform real-time organ health monitoring. Hence, smart toilets have been developed to detect urine [CN109870565], monitor fluid body volume in the predetermined time [CA3094993], and sense biomarkers using aptamers [US20180321218]. But the technologies need further development to be able to handle the extensive tests that come under the umbrella of urinalysis.

[0006] Systems for monitoring the medical status of patients at home from a care center are also advancing, which can transmit the information from the patient at a remote location to the doctors’ clinic. [WO1994024929] A kidney health monitoring system was also developed in a similar manner [US20180110455]. [0007] Instruments for automated urine analysis often use optical sensors to conduct colorimetric, fluorometric, infrared, and turbidimetric analysis. However, these technologies are restricted in practice due to the nature of the tests and the cost associated with the devices. Electrochemical tests are highly precise, and some tests have shown lower limits of detections as compared to colorimetric and fluorometric methods. However, there is no home-based device that can conduct automated, quantitative urinalysis due to the lack of a usable test platform and method for integrating existing setups with advancing technologies. This invention describes the use of test platforms integrated with electrodes and electrochemicals for sensing the electrical behavior of urinary analytes in the presence of reactive electrochemicals.

SUMMARY OF THE INVENTION

[0008] According to exemplary embodiments, a device for conducting automated urine analysis for detecting and monitoring organ health is provided.

[0009] The exemplary kidney health monitor in this invention is designed for continuous, real time monitoring of kidney health. It analyses biomarkers in the urine by employing electrochemical tests and detects the onset of kidney disease earlier than widely used kidney function tests. It also monitors kidney health to determine the stage of kidney disease. This device has a disposable part that interacts with urine, carries out a test, records signature behaviors of analytes in the form of an electrical signal, and relays information to a non disposable receiver. This receiver can then transmit the information to other devices for analysis. [0010] Other features and characteristics of the present invention, as well as the methods of operation, functions of related elements of structure and the combination of parts, and economies of manufacture, will become more apparent upon consideration of the following description and the appended claims with reference to the accompanying drawings, all of which form a part of this specification, wherein like reference numerals designate corresponding parts in the various figures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a schematic diagram of the components in an exemplary system for kidney health monitoring system.

[0012] FIGS. 2A, 2B and 2C are several configurations of an exemplary test platform with multiple test wells.

[0013] FIGS. 3 A, 3B and 3C are several embodiments of a single use cup comprising electrodes.

[0014] FIG. 4 shows a number of test containers or test wells for recording multiple reactions in series or parallel.

[0015] FIG. 5 is a flow chart for a one-time point, single parameter test using the device.

[0016] FIG. 6 is a flow chart for a single parameter continuous monitoring.

[0017] FIG. 7 is a flow chart for a multiple parameter one-time test.

[0018] FIG. 8 is a flow chart for continuous monitoring of multiple parameters.

DETAIFED DESCRIPTION

[0019] Unless defined otherwise, all terms of art, notations, and other technical terms or terminology used herein have the same meaning as is commonly understood by one of ordinary skilled in the art to which this disclosure belongs. All patents, applications, published applications, and other publications referred to herein are incorporated by reference in their entirety. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications, and other publications that are herein incorporated by reference, the definition set forth in this section prevails over the definition that is incorporated herein by reference.

[0020] Unless otherwise indicated or the context suggests otherwise, as used herein, “a” or “an” means “at least one” or “one or more.”

[0021] This description may use relative spatial and/or orientation terms in describing the position and/or orientation of a component, apparatus, location, feature, or a portion thereof. Unless specifically stated, or otherwise dictated by the context of the description, such terms, including, without limitation, top, bottom, above, below, under, on top of, upper, lower, left of, right of, in front of, behind, next to, adjacent, between, horizontal, vertical, diagonal, longitudinal, transverse, etc., are used for convenience in referring to such component, apparatus, location, feature, or a portion thereof in the drawings and are not intended to be limiting.

[0022] Furthermore, unless otherwise stated, any specific dimensions mentioned in this description are merely representative of an exemplary implementation of a device embodying aspects of the invention and are not intended to be limiting.

[0023] Device for Automated, Real-Time Urine Analysis

[0024] The device records the signature electrical behaviors of analytes in the presence of specific electrochemical to detect and quantify the biomarker and processes the data for the purpose of diagnosis or monitoring organ health. A kidney health monitoring test platform is developed as an example of the present invention.

[0025] The device has two major components -

[0026] 1. Disposable test platform - interacts with urine, pumps in the urine for a transient period using tubing and microfluidic channels distribute the collected sample to different test wells. It is equipped with electrodes and electrochemicals to carry out the analysis. The disposable part has conductive traces or is connected to PCB to relay the information to the electronic non-disposable part.

[0027] 2. Non-disposable Reader - The electrical signal collected from the disposable test platform is stored and processed in the reader in the predetermined format and is transmitted by a wired or wireless mechanism to any electronic platform.

[0028] Exemplary Development of Kidney Health Monitoring Device [0029] The present application provides an exemplary development of a non-invasive device to monitor renal health. This device detects and quantifies analytes excreted by kidneys to determine the stage of renal failure and other diseases associated with renal function impairment. The device can conduct a simultaneous estimation of multiple analytes by employing electrochemical tests and records the electrical behavior of the biomarkers in healthy and disease conditions. The device acts as a 24-hour (or continuous) urine sample analyzer to perform the kidney function tests, quantifies proteins (microalbumin, protein biomarkers), proteases and gelatinases, creatinine, urea, ions (calcium, potassium, sodium), a ratio of protein to creatinine and creatinine to urea to estimate the extent of kidney function impairment or renal failure.

[0030] The Device Can Be Made as a Single-Use Device

[0031] Figure. 1 is a schematic diagram of the components for and use of an exemplary system for kidney health monitoring. The device can be installed on a toilet bowl (A). The disposable part of the test platform is placed on or under the toilet seat (B) designed explicitly with electrodes and conductive traces (B). It is then connected to the non-disposable electronic device (wirelessly or wired) to record, monitor, and save the data (C). This device then transmits the electrical conductivity data to an electronic device (D) such as a smartphone or tablet that can then further analyze or transmit the data to another electronic device to estimate the stage of the kidney disease and other urine tests required for the determination of kidney function. (Steps B, C, and D can be combined in the same device) The C and D are separate in this example. However, the functionality can be combined in one part. The test platform in the form of collection basket shaped to fit in a toilet or urinal may be disposable, such as made of paper with the electrodes and conductive traces printed on the paper, and the entire the collection basket is flushable. Alternatively, the collection basket is made of a non-flushable material and the basket is configured to remain in the toilet bowl over a period of time and perform multiple tests and record changes in the electrical behavior of the urine analytes.

[0032] Figures 2A, 2B, 2C describe scenarios in which multiple tests are conducted on one disposable test platform (A) equipped with electrodes and fluid detectors (B) which are placed on a conductive platform to detect the electrical signatures of the analytes. The test platform has a number of microfluidic distribution channels for uneven distribution of the urine sample to different locations for simultaneous determination of multiple analytes using one urine sample test wells for the purpose of conducting tests simultaneously. The device in the figure has five test wells comprising a pair of electrodes in each test well. The test platform includes test wells for collecting urine, and each test well is composed of Polydimethylsiloxane (PDMS), but any other water repellant material can be used. The test wells are made with different diameters to accommodate different volumes of the test samples on the same platform. Each test well is attached to the fluid inlet by microfluidic channels of depth 500m, and widths of lOOpm, 200pm, 250 pm, 350 pm, and 500 pm for uneven distribution of the fluid to respective test wells in a given time. The number, length, width and/or height (dimensions) of microfluidic distribution channels that are open for urine flow can be increased or decreased based on test requirements.

In this example, the smallest well of volume 0.2 mL was used for estimation of ions and the largest well of volume 0.8 mL was used for quantitative estimation of total proteins. The test wells are either coated with an electrochemical, and a conductive polymer or electrochemical is introduced into the device through the fluid inlet port. A level detector is attached to the device to further calculate the volume of the sample in each well of the known radius. Each well contains pair of electrodes inside the well, which are connected to the reader interface by conductive traces. The fluid inlet port is located at the center of the device to distribute the fluid to all the test wells via covered micro fluidic channels. As the fluid is filled in the wells, the conductivity of the sample is tested, and the information is transferred to the reader interface.

The conductivity of the fluid in each well is monitored and recorded such as after every 20 seconds, and the data is recorded for a predetermined time which is a minimum of 20 seconds up to 24 hours. The data is then analyzed by the reader based on the signal ranges stored on the device. As an example, the test platform is composed of PDMS, and the electrodes are immersed in the test wells during the process of curing. The electrochemicals are introduced to the wells through the fluid inlet. The device is then bonded on the PCB to align electrodes with the conductive traces. The PCB is then attached to a multi-probe conductivity analyzer to record the changes in the electrical properties of the sample over time. The data is then analyzed by the reader and is processed to learn linear relationships in changes in conductance over time. The conductance values are converted to the amount of analyte present in the sample. The information is then correlated to the normal ranges of the analytes and stages of the renal disease to detect the disease and estimate the extent of renal function impairment.

[0033] Figures 3A, 3B, 3C illustrate alternative forms of the disposable tester. The disposable barrier on this device is the container wall. The cap of the device (A) or the bottom of the device (C) is equipped with electrodes to record the electrical signature of the analytes for qualitative and quantitative estimation of biomarkers. The barrier is divided (B) to create separate environments in the same device. The position of the reader may be changed with respect to the position of the electrodes in the device. In an example, a urine collection cup was used with titanium and platinum electrodes. The lid or the bottom of the container was cut in 1 inch diameter to install the electrodes printed on the PCB. The PCB is physically glued to the container using water-repellant silicon-based glue. The electro chemicals were added to the container, and the baseline conductance is recorded using a multi-probe conductivity measurement device. To this device, urine sample was added, and the conductance was recorded as a function of time. The electrochemical mixtures added to the device vary based on the test. For example, for determination of total urinary proteins, a mixture of NaCl, functionalized PVA, L-arginine were added to the well in molar ratios 2:1:1, and the change is conductance was recorded over time. The reader then processed these electrical signals by subtracting the baseline conductance values from each reading and defining relationship between the conductance over time. We observed linear decrease in the conductance over time in response to the presence of urinary proteins. Similarly, when the tests were conducted for determination of ions, the increase in conductance over time was observed. In all the tests, the rate of reaction determines the duration of the test. For example, the total ions can be estimated within 30 seconds. But the test for total proteins may require recording times longer than 2 minutes. The data is then collected by the reader for further processing.

[0034] Figure 4 depicts another alternative scenario for the test platform where larger volumes of the test sample are needed for the test. The primary reservoir, in this case, maybe a toilet bowl, urinal, or another container or equipment. The fluid is pumped into the test containers or test wells equipped with the electrolytes and connected to the reader. The tests can be conducted simultaneously or in series.

[0035] Simultaneous Measurements

[0036] The devices in Figures 2, 3, and 4 are used for conducting multiple tests or repeats of the same test. The electrochemical composition for each test is based on the time required to obtain the results. The device conducts measurements in sequence for each parameter based on time to reduce the errors in interpretation. For example, the results for the volume and temperature are obtained instantaneously. The results for total urinary proteins can be obtained in 2 minutes while we wait for 5 minutes to detect the presence of proteolytic enzymes. The computation for the test results for each test occurs at once. But the data for each test is stored as recorded. The system is developed for the measurement of six parameters simultaneously. But it can be designed and used for measuring a single parameter.

[0037] Figure 5 shows the signal pathway from the device to the diagnostic outcome when a single test is to do for a single parameter. Figure 6 gives the process of monitoring a single parameter continuously over a predetermined time. Figure 7 shows the signal path for the scenario where multiple parameters are being analyzed at the sample time for a one-time sample. Figure 8 shows the process of monitoring multiple parameters at multiple time points or for the purpose of continuous monitoring. In an example, this method is used for simultaneous estimation of urinary protein, creatinine, and calcium over a 24-hour urine sample. The cumulative values were compared with the normal ranges of the analytes to diagnose a disease condition.

[0038] Computation of Individual Test Results [0039] The time-dependent changes in the electrical signal detect and quantify the analytes in the urine. The tester runs single or multiple tests simultaneously. The receiver saves the data as it is generated with respect to time. However, the computation takes place for each test in a sequential manner. This helps in the estimation of multiple components from the same tester and also allows time-dependent estimation of analytes as required in 24- hour urine tests or for continuous analysis. The sequence of computation is dependent on the required test panel. For example, for the determination of protein creatinine ratio, the signal from the protein test is recorded and computed for 3 minutes. The signal from the channel for the creatine test is recorded and computed after 1 minute. In both, the test time starts when the urine sample fills into the respective test wells. The computation of the test starts after 3 minutes when the electrical signals for both the tests are available. The data is then processed to find the linear relationship between electrical signal and time. The electrical signal is then converted to values in mg/dl, and then the ratio of the amounts is computed. In some cases, filters can be employed to reduce the noise. Every sample can be measured with an on-off switch or a proximity sensor, and then the device can add the values over 24 hours to give a reading for a 24-hour urine test. [0040] Data Interpretation

[0041] The data interpretation is made based on the available known values for the analytes in the urine samples. The data is then presented using an electronic platform in the form of values of each analyte and stage of kidney disease. The presence of microalbumin more than 30 mg in 24 hours urine sample was considered an early sign for renal disease, and more than 300 mg in 24 hours was considered as advanced renal disease. The amounts less than 30mg were considered as a normal range. For a single point determination, the values of microalbumin were correlated with values obtained from the urinary creatinine test to estimate the extent of renal function impairment. The universally used normal ranges were used in all the tests performed. On the multi-test platform, if only one analyte is outside the normal range, the stage of renal failure is not calculated, but the information is highlighted on the reader, indicating requirements for further analysis. For example, matrix metalloproteinases are increased in other chronic diseases and may not necessarily indicate advanced kidney disease. In these cases, the abnormalities in the values will be indicated, but other tests will be suggested to complete the diagnosis.

[0042] Transmission of the Data

[0043] The data can be transmitted directly from the disposable part of the device or the non disposable reader. For reliable results, data is transmitted from the reader to an electronic platform. The data can be transferred by a wired connection, Bluetooth, or by a wireless connection to store on a cloud-based platform or a server using any means of existing or novel data transfer protocols.

[0044] The intended application of the device

1. Urinalysis using electrical and electrochemical methods.

2. Monitoring organ health using electrochemical methods of urinalysis in the toilet bowl, urinals, or urine collection containers where electrodes are integrated with the surface or within an accessory.

3. Early detection of diseases with urinalysis when biomarkers show changes in electrical behavior in the presence of a specific electrochemical.

4. Continuous real-time monitoring of organ health in clinics and at home using the electrode embedded devices for urine analysis. [0045] Closing Comments.

[0046] While the present invention has been described and shown in considerable detail with reference to certain illustrative embodiments, including various combinations and sub combinations of features, those skilled in the art will readily appreciate other embodiments and variations and modifications thereof as encompassed within the scope of the present invention. [0047] Moreover, the descriptions of such embodiments, combinations, and sub-combinations are not intended to convey that the invention requires features or combinations of features other than those expressly recited in the claims. Accordingly, the present invention is deemed to include all modifications and variations encompassed within the spirit and scope of the following appended claims.

[0048] Throughout this description, the embodiments and examples shown should be considered as exemplars, rather than limitations on the apparatus and procedures disclosed or claimed. Although many of the examples presented herein involve specific combinations of method acts or system elements, it should be understood that those acts and those elements may be combined in other ways to accomplish the same objectives. With regard to flowcharts, additional and fewer steps may be taken, and the steps as shown may be combined or further refined to achieve the methods described herein. Acts, elements, and features discussed only in connection with one embodiment are not intended to be excluded from a similar role in other embodiments.

[0049] As used herein, “plurality” means two or more. As used herein, a “set” of items may include one or more of such items. As used herein, whether in the written description or the claims, the terms “comprising”, “including”, “carrying”, “having”, “containing”, “involving”, and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’, respectively, are closed or semi-closed transitional phrases with respect to claims. Use of ordinal terms such as “first”, “second”, “third”, etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements. As used herein, “and/or” means that the listed items are alternatives, but the alternatives also include any combination of the listed items.

Claims

CLAIMS It is claimed:

1. A device for urinalysis to record the electrical behavior of urine analytes for disease diagnosis and organ monitoring, comprising: a) a test platform in the form of a fluid collection basket configured to be installed in a toilet bowl or urinal, the collection basket containing electrodes, conductive traces and electrochemicals which generate an electrical signal over time that is specific to the analyte in the urine; and b) an electronic reader that receives the signal and converts the signal to data, and is configured to collect, store, analyze and transmit the data to an external recipient.

2. The device of claim 1, wherein the collection basket is made of paper with the electrodes and conductive traces printed on the paper, and the entire the collection basket is flushable.

3. The device of claim 1, wherein the collection basket is made of a non-flushable material and the basket is configured to remain in the toilet bowl over a period of time and perform multiple tests and record changes in the electrical behavior of the urine analytes.

4. The device of claim 1, wherein the test platform is integrated into a stand-alone unit.

5. The device of claim 1, wherein the test platform comprises individual parts that may be assembled prior to usage.

6. The device of claim 1, wherein a position of the electrodes on the collection basket can be varied.

7. The device of claim 1, wherein the collection basket contains multiple test wells connected to a common urine inlet by channels.

8. A device for urinalysis to record changes in the electrical behavior of urine analytes for disease diagnosis and organ monitoring, comprising: a) a test platform in the form of multiple test wells connected to a common source of urine by channels, each test well containing electrodes, conductive traces and electrochemicals which generate an electrical signal over time that is specific to the analyte in the urine; and b) an electronic reader that receives the signal and converts the signal to data, and is configured to collect, store, analyze and transmit the data to an external recipient.

9. The device of claim 8, wherein each test well has a capacitance sensor mounted therein to measure fluid level in the test well.

10. The device of claim 8, wherein the test platform is configured to be fit within an existing urine collection cup.

11. The device of claim 8, wherein there are differently sized test wells.

12. A method of urinalysis using a disposable test platform containing electrodes, conductive traces and electrochemicals which generate an electrical signal over time that is specific to the analyte in the urine, including the steps of - collecting a sample of urine, distribution to electrode embedded devices, recording the electrical signal, converting the electrical signal to a biochemically relevant unit, relaying the electronic signal to a reader for analysis, disease diagnosis and monitoring, wherein, the changes in the electrical behavior of urine analytes are recorded for disease diagnosis and organ monitoring.

13. The method of claim 12, including monitoring urine over a pre-determined time period which is a minimum of 20 seconds up to 24 hours.

14. The method of claim 12, wherein the test platform has multiple test wells connected to a common source of urine by channels, each test well containing electrodes, conductive traces and electrochemicals, and the method includes recording electrical signals generated by each test well.

15. The method of claim 14, wherein data obtained from the multiple test wells are processed sequentially, simultaneously or continuously using algorithms in a processor.