Pre-analytical test modules, systems, and methods for using the same

Abstract

In some embodiments, a system is provided that includes a carousel configured to hold a plurality of test modules, each test module having an input port, an output port, and a channel region connected to the input port and the output port; an input station configured to transfer samples into channel regions of test modules of the carousel; a testing station configured to perform one or more tests on samples stored within channel regions of test modules of the carousel; and a washing station configured to clean channel regions of test modules of the carousel. The carousel is configured to rotate to transfer test modules between the input station, the testing station, and the washing station. Numerous other aspects are provided.

Description

PRE-ANALYTICAL TEST MODULES, SYSTEMS, AND METHODS FOR USING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 760,330, filed on February 19, 2025, the disclosure of which is hereby incorporated by reference herein in its entirety.FIELD

[0002] The present disclosure relates to diagnostic laboratories and more particularly to pre-analytical test modules, systems, and methods for using the same.BACKGROUND

[0003] Diagnostic laboratory systems conduct assays or tests to identify analytes or other constituents in biological samples such as blood serum, blood plasma, urine, interstitial liquid, cerebrospinal liquids, and the like. The biological samples are collected in sample containers, such as test tubes, by medical technicians and are then brought to a diagnostic laboratory system for testing. Each biological sample may have a number of test requirements, and each test requirement may require performing a different test within the diagnostic laboratory system.

[0004] A diagnostic laboratory system may include a plurality of instruments that are each configured to perform one or more tests. When a biological sample having test requirements is received in the diagnostic laboratory system, the biological sample is transferred to one or more instruments that are configured to perform the required tests.

[0005] In clinical laboratories, which may employ diagnostic laboratory systems, high throughput is vital for processing large numbers of patient samples. This efficiency isespecially important for diagnostic tests where timely results can influence patient care and treatment. Reliable, reproducible, and cost-effective result generation is crucial for diagnosis and patient health.

[0006] In clinical settings, whole blood, serum, and plasma are among the most analyzed sample types. However, the measurement of analytes in such samples can be influenced by several factors which can be hard to control. For example, a blood sample may be compromised by a patient's day-to-day condition, the form and quality of a blood draw, and comorbidities.

[0007] Some quality control entry tests, also referred to as pre-analytical screening tests, have been established for use before analysis for a specific clinical parameter. A goal of pre-analytical screening tests is to identify compromised samples that are unsuitable for testing so that more detailed, time consuming, and expensive analysis is not performed on such samples unnecessarily. However, many pre-analytical screening tests rely upon manual procedures which are prone to human error.

[0008] Accordingly, improved methods and apparatus for increasing testing throughput in diagnostic laboratories, such as through enhanced pre-analytic screening, are needed.SUMMARY

[0009] In some embodiments, a system is provided that includes a carousel configured to hold a plurality of test modules, each test module having an input port, an output port, and a channel region connected to the input port and the output port; an input station configured to transfer samples into channel regions of test modules of the carousel; a testing station configured to perform one or more tests on samples stored within channel regions of test modules of the carousel; and a washing station configured to clean channel regions oftest modules of the carousel. The carousel is configured to rotate to transfer test modules between the input station, the testing station, and the washing station.

[0010] In some embodiments, a method of testing samples includes obtaining a rotatable carousel having a plurality of test modules stored therein; rotating the carousel to position a test module of the carousel at an input station; transferring a sample into the test module using the input station; rotating the carousel to position the test module at a testing station; testing the sample within the test module at the testing station; rotating the carousel to position the test module at a washing station; and cleaning the test module with the washing station.

[0011] In some embodiments, a carousel system is provided that includes a rotatable carousel having a plurality of storage locations and configured to rotate between an input station, a testing station, and a washing station of a testing system; and a plurality of test modules stored within the carousel, each test module stored in a different one of the plurality of storage locations and having an input port, an output port, and a channel region connected to the input port and the output port.

[0012] Still other aspects, features, and advantages of this disclosure may be readily apparent from the following description and illustration of example embodiments. This disclosure may also be capable of other and different embodiments, and its several details may be modified in various respects, all without departing from the scope of the disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The drawings described below are provided for illustrative purposes and are not necessarily drawn to scale. Accordingly, the drawings and descriptions are to be regardedas illustrative in nature, and not as restrictive. The drawings are not intended to limit the scope of the disclosure in any way.

[0014] FIGS. 1A, 1B, 1C, and 1D illustrate a top perspective view, a bottom perspective view, a side view, and a side exploded view of a test module in accordance with one or more embodiments provided herein.

[0015] FIG. 1E illustrates an example flowcell in accordance with one or more embodiments provided herein.

[0016] FIG. 2A illustrates a carousel for housing a plurality of the test modules of FIGS. 1A and 1B in accordance with one or more embodiments provided herein.

[0017] FIG. 2B is a partial cut-away view of the carousel of FIG. 2A in accordance with one or more embodiments provided herein.

[0018] FIGS. 3A and 3B illustrate a side perspective view and a top view, respectively, of a first example testing system for testing samples using the carousel of FIG. 2A in accordance with one or more embodiments provided herein.

[0019] FIG. 3C illustrates a second example testing system for testing samples using the carousel of FIG. 2A in accordance with one or more embodiments provided herein.

[0020] FIG. 3D illustrates a third example testing system for testing samples using the carousel of FIG. 2A in accordance with one or more embodiments provided herein.

[0021] FIG. 4 illustrates a first workflow for testing samples in accordance with one or more embodiments provided herein.

[0022] FIG. 5 illustrates a second workflow for testing samples in accordance with one or more embodiments provided herein.

[0023] FIG. 6 is a flowchart of an example process for testing a sample in accordance with one or more embodiments provided herein.DETAILED DESCRIPTION

[0024] Independent of the grammatical term usage, individuals with male, female or other gender identities are included within the term.

[0025] As stated, some pre-analytical screening tests may rely upon manual procedures, which are prone to human error. For example, a visual inspection of sample integrity prior to processing with a high-throughput analyzer may detect hemoglobin, bilirubin, and intralipid (HIL) level status, sample inconsistency such as the presence of clots, or the like. However, visually inspecting a test tube for HIL level or sample inconsistency is often challenging due to inconsistent tube barcode labeling or sample filling levels, different curvatures of test tubes, or the experience of the examining technician. In large, fully-automated hospital facilities, samples are processed without human interactions and / or may be received from refrigerated storage without the benefit of human inspection.

[0026] Because of the difficulty associated with pre-analytical screening, some sample integrity tests may be performed only after a sample has been flagged due to an error or an unexpected result from the actual clinical diagnostic test. Example post-analytical sample integrity tests may detect micro-clots, hematocrit, and morphologic changes of red blood cells (RBCs) (e.g., as a result of hemoglobinopathies such as sickle cell disease). However, detection of morphological changes of a sample is often performed on different instruments or with different methods (e.g., using smears, whole blood, centrifuged blood, etc., ) that may not provide consistent results. Morphology, red blood count, clotting, coagulation, etc., may all be studied.

[0027] Embodiments provided herein provide advantages over current methods for pre-analytical screening tests and lead to more precise clinical diagnostic results. This may increasethe overall quality of customer results while reducing customer costs (e.g., by reducing errors during preanalytical screening and the number of retests). That is, embodiments provided herein may address an unmet need to deeply analyze patient samples prior to subsequent analysis on immunochemistry or chemistry systems to ensure and improve the efficacy of test results.

[0028] Beyond improvement of sample integrity determinations, embodiments provided herein provide opportunities for new diagnostic determinations. In some embodiments, apparatus and methods described herein may allow for 1) determination of hemoglobinopathies (e.g., prior to or immediately prior to measurement of hemoglobin Ale), 2) determination of microclots related to multiple disease states such as Post-Acute Sequelae of COVID (PASO) often referred to as long COVID, and 3) determination of micro-clots indicative of stroke risk and / or prognosis. Other diagnostic determinations may be performed.

[0029] Determination of hemoglobinopathies is of clinical importance because HbAlc determinations are not accurate (and not recommended) in cases where hemoglobinopathies such as sickle cell disease lead to reduced lifetime of RBCs. When this occurs, the meta-stable HbAlc concentration (which represents an average degree of hemoglobin glycosylation during the 3 -month lifetime of an RBC in a normal individual's circulation) will be reduced, degrading the clinical relevancy of the HbAlc value.

[0030] Micro-clot detection may provide a tool for prognostic evaluation of COVID patients during both the acute and postacute phases of the disease. Further, identification of microclots during evaluation of COVID patients may be used to direct treatment. It is hypothesized that micro-clots associated with COVID are a cause of the increased risk of ischemic stroke which is associated with COVID (see, forexample, Brown, Robert D., " What is a stroke? A Mayo Clinic expert explains, " www.mayoclinic. org, retrieved fromhttps: / / www.mayoclinic.org / diseases-conditions / stroke / symptoms-causes / syc-20350113 and Doctrow, Brian, " How SARS-CoV-2 contributes to heart attacks and strokes, " www.nih.gov, Oct. 24, 2023 retrieved from https: / / www.nih.gov / news-events / nih-research-matters / how-sars-cov-2-contributes-heart-attacks-strokes#:~:text=COVID%2D19%20is%20known%20to,contributes%20to%20this%20increased%20risk). If so, determination of micro-clots in advance of stroke symptoms (through routine monitoring of patients with elevated risk of stroke or patients that have already experienced a stroke) may enhance stroke prevention and management. Furthermore, detecting the presence of micro-clots more generally, whether related to COVID or another condition such as a clotting disorder, diabetes, an inflammatory disease, or the like, may enhance stroke prevention and management.

[0031] In some embodiments, a fully automated analysis system for pre-analytical screening of patient samples is provided that may transport test modules between different components such as an input station for supplying a sample to a test module, a testing station for analyzing the sample within the test module, and a washing station for cleaning the test module for subsequent reuse. This system provides opportunities for new diagnostic determinations unavailable by prior pre-analytical screening approaches.

[0032] These and other embodiments are described below with reference to FIGS. 1A-6.

[0033] FIGS. 1A, 1B, 1C, and 1D illustrate a top perspective view, a bottom perspective view, a side view, and a side exploded view of a test module 100 in accordance with one or more embodiments provided herein. With reference to FIGS. 1A-1D, in some embodiments, test module 100 may include a flowcell 102 coupled to a flowcell holder 104. Flowcell 102may include a channel region 106 formed therein through which a sample to be examined may flow and / or be stored. In some embodiments, channel region 106 may be a micro-channel configured to hold approximately 5 microliters or less of sample liquid such as whole blood, plasma, or another fluid. Other channel region sizes and / or storage volumes may be employed.

[0034] FIG. 1E illustrates an example flowcell 102 in accordance with one or more embodiments provided herein. In the embodiment of FIG. 1E, flowcell 102 may be formed from a first substrate material 108 having a slot 110 formed therethrough placed between a second substrate material 112 and a third substrate material 114. Second substrate material 112 may include an input opening 116 and an output opening 118 through which a sample may flow into and out of channel region 106 formed by slot 110 when second substrate material 112 and third substrate material 114 are attached to first substrate material 108. In some embodiments, the first, second, and third substrate materials may be formed from glass or another suitable (e.g., transparent) material and the first, second, and third substrate materials layers may be bonded, annealed, or otherwise coupled together. Thus, in some embodiments, channel region 106 of test module 100 may be transparent (e. g., have a transparent region capable of being optically analyzed). In other embodiments, flowcell 102 may be formed from a first substrate material having a channel region etched therein that is covered by a second substrate material. An input opening and an output opening may be formed through either the first substrate material or second substrate material. Other flowcell configurations may be employed.

[0035] As shown in FIGS. 1C and 1D, flowcell holder 104 may include an input port 120 that couples to input opening 116 of flowcell 102 and an output port 122 that couples to output opening 118 of flowcell 102 such that a sample input to inputport 120 may flow through channel region 106 of flowcell 102 and out of output port 122 of flowcell holder 104. As shown in FIGS. 1C and 1D, in some embodiments, the input port 120 and output port 122 of flowcell holder 104 may be oriented in line with channel region 106 of flowcell 102. Flowcell holder 104 may be formed from any suitable material such as a plastic or the like.

[0036] In some embodiments, a transducer 124 may be coupled to flowcell 102 and a printed circuit board (PCB) 126 may be provided for supplying electrical signals to and / or receiving electrical signals from transducer 124 (e. g., via one or more contact regions 128, a few labelled in FIG. 1B). For example, transducer 124 may be a piezo electric transducer configured to generate acoustic waves that alter the properties of any sample within channel region 106. Transducer 124 may be mounted to f lowcell 102 using a suitable adhesive and, in some embodiments, is mounted so as to not obstruct the optical path through channel region 106. In this manner, transducer 124 may modulate a sample and / or the properties of a sample within channel region 106 of flowcell 102 while allowing the sample to be optically probed.

[0037] In some embodiments, transducer 124 may be configured to generate ultrasonic waves within channel region 106 of flowcell 102. These ultrasonic waves may be employed to separate components (such as plasma from red blood cells) of a blood sample within channel region 106, to separate blood cells from one another, and / or to lyse blood cells (e.g., red blood cells) depending on the frequency and / or duration of the electrical signals applied to transducer 124. U.S. Patent No. 11,426,727 and PCT Publication W02024 / 005867, both of which are incorporated by reference herein in their entirety for all purposes, describe use of transducers to lyse samples.

[0038] FIG. 2A illustrates a carousel 200 for housing a plurality of the test modules 100 of FIGS. 1A and IB inaccordance with one or more embodiments provided herein. With reference to FIG. 2A, carousel 200 may include a plurality of storage locations 202 (a few labelled) each conf igured to store a test module 100. In some embodiments, the carousel 200 may include at least 10 storage locations, and in other embodiments, at least 20 storage locations. In general, the carousel 200 may include fewer or more storage locations.

[0039] Carousel 200 may be disposable (e. g., single use) or reusable (e. g., by replacing used test modules stored therein with new test modules ). In one or more embodiments, approximately 25 test modules may be stored in each carousel 200, with each test module capable of approximately 4,000 tests (e.g., approximately 100,000 tests per carousel ). After a predetermined number of tests ( e.g., 100,000 ) and / or predetermined time period (e.g., 28 days ), a carousel 200 may be replaced. Other numbers of tests per carousel and / or t ime periods for carousel exchange may be employed. The number of test modules 100 within a carousel 200 def ines a cadence for a system employing the carousel 200. In some embodiments, a single analysis may be performed in approximately 30 seconds (e. g., aspiration, analysis, sample discard, and test module washing) and each sample may be loaded in approximately 8 seconds. Other analysis times and / or loading times may be employed.

[0040] Carousel 200 may be formed from any suitable material such as a polymer material. Example materials include polypropylene, polyethylene, polystyrene, polycarbonate, or the like. Other materials may be employed. The size (e.g., diameter) of carousel 200 may depend on the size of test modules 100, the number of storage locations 202, etc.

[0041] FIG. 2B is a partial cut -away view of carousel 200 of FIG. 2A in accordance with one or more embodiments provided herein. As shown in FIG. 2B, in some embodiments, each test module 100 may be oriented in line with a central axis 204 ofcarousel 200 (e. g., vertically oriented in FIGS. 2A and 2B) as shown by test modules 100a and 100m. Other test module orientations may be employed. Carousel 200 with testing modules 100 stored therein may form a carousel system 206.

[0042] FIGS. 3A and 3B illustrate a side perspective view and a top view, respectively, of a first example testing system 300A for testing samples using carousel 200 of FIG. 2A in accordance with one or more embodiments provided herein. In the embodiments of FIGS. 3A and 3B, first example testing system 300A may include an input, testing, and washing (ITW) unit 302 to which carousel 200 may deliver test modules 100 as described below.

[0043] As shown in FIG. 3B, ITW unit 302 may include an input station 304, a testing station 306, and a washing station 308 to which carousel 200 may deliver test modules 100. For example, a test module 100a within a storage location 202a may be transferred to input station 304 of ITW unit 302 by rotating carousel 200 to align storage location 202a with input station 304 (as shown in FIG. 3B). Similarly, test module 100a may be transferred to testing station 306 of ITW unit 302 by rotating carousel 200 to align storage location 202a with testing station 306. Likewise, test module 100a may be transferred to washing station 308 of ITW unit 302 by rotating carousel 200 to align storage location 202a with washing station 308.

[0044] In some embodiments, carousel 200 may rotate clockwise, counterclockwise, or both clockwise and counterclockwise. For example, carousel 200 may rotate clockwise and / or counterclockwise to transfer test module 100a within storage location 202a of carousel 200 between input station 304, testing station 306, and washing station 308. As shown in FIG.3A, in some embodiments, a rotatable platform 310 (e.g., driven by a motor 312 or another mechanism) may be employed torotate carousel 200. Other rotation mechanisms may be employed.

[0045] Input station 304, testing station 306, and washing station 308 may be arranged in any order and / or may be spatially proximate or separate. Single or multiple input stations, testing stations, and / or washing stations may be employed. Additionally, in some embodiments, carousel 200 may be rotatably coupled to multiple ITW units 302 (e.g., 2, 3, 4, etc. ). While only a single input station 304, testing station 306, and washing station 308 are shown, it will be understood that more than one input station 304, testing station 306, and / or washing station 308 may be employed.

[0046] FIG. 3C illustrates a second example testing system 300B for testing samples using carousel 200 of FIG. 2A in accordance with one or more embodiments provided herein. In the second example testing system 300B, input station 304, testing station 306, and washing station 308 are separate components positioned so that carousel 200 may transfer test modules 100 between each of the stations 304, 306, and 308.

[0047] First and second testing systems 300A and 300B may include or be coupled to a control unit 314 (e. g., a microcontroller, a controller, a computer, or the like) configured to execute one or more programs and control operation of each testing system. For example, control unit 314 may be configured to communicate with input station 304, testing station 306, washing station 308, motor 312, and / or other components of the testing systems.

[0048] In some embodiments, control unit 314 may include a processor 316 coupled to a memory 318 having one or more programs 320 stored therein. The programs may be implemented in computer code, as computer executable instructions, or the like.

[0049] Memory 318 may be any suitable type of memory, such as, but not limited to, one or more of a volatile memory and / or anon-volatile memory. In one or more embodiments, memory 318 may be a non- transitory memory (e. g., a hard drive, a solid-state drive, a flash drive, another non- transitory computer-readable medium, etc. ). All or a portion of memory 318 may be local to or remote from control unit 314. Programs 320 may be computer code and / or instructions executable on or by processor 316. Such programs may control all or a portion of operation of testing system 300A and / or 300B as described below.

[0050] Control unit 314 may be coupled to a workstation 322 (shown in FIG. 3A only) that is configured to enable users to interface with testing system 300A and / or 300B. Workstation 322 may include a display 324, a keyboard 326, and other peripherals. Programs within memory 318 may cause display 324 to display information regarding processing of samples within testing system 300A or 300B.

[0051] As described further below, test modules 100 may be received within carousel 200 and used to store samples during pre-analytical testing within testing system 300A or 300B. During such pre-analytical testing, the samples may undergo a set of sequential operations or processes in a specific workflow that is defined by specif ic tests. Each type of test may have a unique sequence of operations. The workflow sequence may start with loading a sample into a test module 100 at input station 304, transferring of the test module 100 to testing station 306 (by rotating carousel 200), testing of the sample within the test module 100 at testing station 306, transferring of the test module 100 to washing station 308 (by rotating carousel 200), and cleaning of the test module 100 at washing station 308. Thereafter, in some embodiments, the test module 100 may be returned to carousel 200 and reused.

[0052] FIG. 3D illustrates a third example testing system 300C for testing samples using carousel 200 of FIG. 2A in accordance with one or more embodiments provided herein. Withreference to FIG. 3D, third example testing system 300C includes carousel 200 on rotatable platform 310, which rotatable couples a plurality of test modules 100 stored therein to input station 304, testing station 306, and washing station 308. Note that the spatial arrangement of the components in FIG. 3C is for convenience only. Carousel 200, input station 304, testing station 306, and washing station 308 may be otherwise arranged. For example, input station 304, testing station 306, and washing station 308 may be contained within a single unit (e. g., ITW unit 302 of FIGS. 3A and 3B) or spatially separated as shown in FIG. 3C.

[0053] In third example testing system 300C, input station 304 includes a pipettor 328 configured to aspirate a sample from a test tube or other sample container (e. g., sample 330 from sample container 332) and transfer the sample to the channel region 106 of a test module 100 via input port 120 of the test module 100. For example, a test module 100 may be positioned at input station 304 using carousel 200 and pipettor 328 may obtain (e. g., aspirate) a sample from a sample container (not shown) and transfer the sample (e. g., via a pipette 334) to the input port 120 of the test module 100. A pipette tip 336 may be coupled to the input port 120 of the test module 100 during sample transfer (e. g., drawing the sample through the pipette tip 336 and input port 120 and into channel region 106 of the test module 100). A removal tool 338 (e. g., a grasping device) may be provided for removing pipette tip 336 after sample transfer. Input station 304 may include a waste container 340 for storage of used pipette tips 336.

[0054] In some embodiments, samples may be transferred into test modules 100 while the test modules 100 remain within carousel 200. In other embodiments, to transfer a sample to a test module 100, the test module 100 may be removed from a storage location 202 of carousel 200 (e.g., via pipettor 328 or a gripper, a robot arm, or the like, not shown) duringsample transfer and / or removal of pipette tip 336 after sample transfer. For example, pipettor 328 (or a gripper or robot arm (not shown) ) may remove a test module 100 from carousel 200 and hold the test module 100 during sample transfer into the test module 100 with pipettor 328.

[0055] In the third example testing system 300C, testing station 306 may include a light source 342 for transmitting a light beam 344 through any sample within the channel region 106 of a test module 100. A detector 346 may be positioned to receive light beam 344 after it travels through the channel region 106 of the test module 100 and any sample stored therein. In this manner, optical properties of the sample within the channel region 106 may be measured at testing station 306. In one or more embodiments, a spectrophotometer, a microscopic camera, or another optical measurement device (not shown) may also be employed.

[0056] In some embodiments, light source 342 may be a light emitting diode (LED), an LED array, a laser, a white light source, etc., depending on the spectral wavelengths and / or spectral range to be analyzed. Detector 346 may be a photodiode, a charge -coupled device, a photomultiplier tube, or the like. Detector selection may be based on the type of information to be obtained such as the intensity of light beam 344, what wavelengths are absorbed by the sample within channel region 106, etc. Example sample properties that may be measured include concentration, chemical composition, etc. Other light sources and / or detectors may be employed and / or other sample properties may be measured.

[0057] In one or more embodiments, testing station 306 may include a power source 348 for delivering a time varying electrical signal to transducer 124 (e. g., via PCB 126) of test module 100. For example, the time varying electrical signal may be an ultrasonic frequency signal configured to generate acoustic standing waves within channel region 106.Other frequencies may be employed. These acoustic waves may be employed to separate components such as plasma and red blood cells of a blood sample within channel region 106 of a test module 100, to separate blood cells, and / or to lyse blood cells (e.g., red blood cells) depending on the frequency and / or duration of the electrical signals applied to transducer 124 by power source 348. Acoustic waves at several frequencies, such between about 300kHz to 400kHz depending on channel design, may be employed for electrical impedance sensing and / or optical detection.

[0058] As with input station 304, in some embodiments, testing station 306 may be configured to measure sample properties of a sample within a test module 100 while the test module 100 is positioned within carousel 200. In other embodiments, to test a sample within a test module 100, the test module 100 may be removed from a storage location 202 of carousel 200 (e. g., via a gripper, a robot arm, or the like, not shown). For example, a gripper or robot arm (not shown) may remove a test module 100 from carousel 200 and hold the test module 100 during sample testing and then return the test module 100 to carousel 200.

[0059] In the third example testing system 300C, washing station 308 may include a cleaning solution supply 350, a waste solution location 352, and a pump 354. After testing at testing station 306, carousel 200 may transport a testing module 100 to washing station 308 for cleaning. At washing station 308, pump 354 may supply cleaning solution from cleaning solution supply 350 to input port 120 of the test module 100 so that the cleaning solution travels through channel region 106 of the flowcell 102 of the test module 100. The cleaning solution may flush out and / or otherwise clean the channel region 106 of the flowcell 102 and waste cleaning solution and sample waste may be removed via output port 122 of the test module 100 and stored in waste solution location352 (and / or otherwise disposed). Any suitable cleaning solution may be employed, such as deionized water, a suitable surfactant solution, a dilute base (e. g., 0.1 N sodium hydroxide), a dilute acid (e. g., 0. 1 N acetic acid), an oxidizer (e. g., hypochlorite), a mixture of oxidizer and / or detergent with a dilute acid or base, or the like. Cleaning chemistry and / or cleaning duration may be varied based on the sample being cleaned from the test module 100. In some embodiments, a cleaning solution may be reused for multiple test modules.

[0060] As with input station 304 and / or testing station 306, in some embodiments, washing station 308 may be conf igured to clean a test module 100 while the test module 100 is positioned within carousel 200 or after the test module 100 is removed from carousel 200.

[0061] As stated, memory 318 of control unit 314 may include a number of programs 320 for controlling operation of one or more of carousel 200, input station 304, testing station 306, and washing station 308. For example, computer programs 320 may include computer program instructions executable by processor 316 including a carousel controller 360 for controlling rotation of carousel 200 between input station 304, testing station 306, and washing station 308. In some embodiments, carousel controller 360 may include program instructions that, when executed by processor 316, cause rotatable platform 310 to rotate (e.g., via electrical signals sent to motor 312 of FIG. 3A).

[0062] Transducer controller 362 may include program instructions that, when executed by processor 316, cause power source 348 to apply ultrasonic frequency electrical signals to transducer 124 (via PCB 126) so as to separate and / or lyse blood sample components within channel region 106 of a test module 100.

[0063] Optical detection controller 364 may include program instructions that, when executed by processor 316, cause light source 342 to emit light beam 344 and / or detector 346 to detect light beam 344 before, during, and / or after application of ultrasonic energy to channel region 106 of a test module 100 via transducer 124.

[0064] In one or more embodiments, optical detection controller 364, light source 342, and detector 346 may be employed to analyze absorbance spectra of a blood sample within a channel region 106 of a test module 100 initially and after transducer controller 362 and power source 348 are used to lyse the sample. Lysing the blood sample within the channel region 106 of a test module 100 may provide higher precision for a hemoglobin oxygenation- state determination due to reduced light scattering.

[0065] In additional embodiments, processor 316 and / or transducer controller 362 may employ transducer 124 (via PCB 126) to measure bulk impedance of a channel region 106 of a test module 100. This may allow processor 316 to analyze mechanical liquid properties of any sample within the flowcell 102 of a test module 100 being analyzed because such mechanical liquid properties contribute to the total impedance of the f lowcell 102.

[0066] Further, in some embodiments, processor 316 and / or transducer controller 362 may employ transducer 124 (via PCB 126) to perform electrical -acoustic impedance spectroscopy (EAIS) on a sample within the channel region 106 of a test module 100. In some embodiments, EAIS may be used for determination of hematocrit in a patient sample provided to the channel region 106 of a test module 100. For example, an algorithm may be developed for determination of hematocrit, with the constants and variables used in the algorithm determined via measurement of sample impedance as acoustic frequency applied to the sample in channel region 106 of testmodule 100 is varied. This type of determination may be carried out with hundreds of patient samples for which hematocrit was also determined via a reference method.Correlation coeff icients to relate the EAIS data to the reference method data may then be used to establish the algorithm for determination of hematocrit via EAIS. In addition to hematocrit determinations, EAIS may be employed for clinical diagnostics such as determination of long COVID risk or stroke risk. In some embodiments, artificial intelligence (Al) algorithms may be developed to add clinical value to EAIS results. For example, other risk factors such as obesity, diabetes, markers for inf lammation, etc., may be used in conjunction with EAIS to increase the clinical value of the EAIS data. Al may provide an efficient way to determine the parameters of such Al algorithms.

[0067] Pipettor controller 366 may include program instructions that, when executed by processor 316, cause pipettor 328 to aspirate a sample and transfer the sample to a test module 100 of carousel 200.

[0068] Likewise, wash controller 368 may include program instructions that, when executed by processor 316, cause washing station 308 to clean a testing module 100 of carousel 200. For example, processor 316 may direct pump 354 to rinse the channel region 106 of a test module 100 using cleaning solution from cleaning solution supply 350.

[0069] In some embodiments, one or more of programs 320 may be executed by other processors and / or stored in other memory locations (e.g., remote memory, local memory, combinations thereof, etc. ).

[0070] FIG. 4 illustrates a first workflow 400 for testing samples in accordance with one or more embodiments provided herein. First workflow 400 may be performed during pre-analytical screening or other testing with first, second, orthird example testing systems 300A-300C of FIGS. 3A-3D, for example.

[0071] Referring to FIG. 4, at block 402, test modules 100 are loaded into carousel 200 (e.g., in slots 202). As stated, in some embodiments, carousel 200 may store 10 or more, and in some embodiments 20 or more test modules. In other embodiments, carousel 200 may be preloaded with test modules 100. For example, carousel 200 with test modules loaded therein may be a disposable unit.

[0072] In block 404, carousel 200 may be rotated so as to transfer one of the test modules 100 (referred to as the "target test module 100" for convenience) to input station 304 (e. g., by rotatable platform 310 controlled by control unit 314). In some embodiments, control unit 314 may include processor 316, such as a microprocessor-based central processing unit (CPU), having suitable memory 318 and suitable conditioning electronics and drivers for operating the various system components relevant to carousel controller 360 and / or the other controllers / programs described herein.

[0073] In block 406, input station 304 may load a sample into the target test module 100 of carousel 200. For example, in some embodiments such as FIG. 3D, pipettor 328 may aspirate a sample (e. g., from sample container 332 ) into input port 120 of the target test module 100 (e. g., using pipettor controller 366). In one or more embodiments, pipette tip 336 may be attached to input port 120 of the target test module 100 during loading of the sample therein (e.g., during sample aspiration with pipettor 328). Pipette tip 336 may subsequently be removed using removal tool 338 and transferred into waste container 340.

[0074] In block 408, carousel 200 may be rotated to transfer the target test module 100 to testing station 306 (e.g., using processor 316 and carousel controller 360). Thereafter, in block 410, using optical detection controller 364, lightsource 342 may be energized so as to generate light beam 344 that passes through channel region 106 of the target test module 100. In response to light beam 344, detector 346 may record optical data such as absorption and / or spectrophotometric measurements. In one or more embodiments, transducer controller 362 may energize transducer 124 via power source 348 allowing impedance and / or electrical -acoustic impedance spectroscopy (EAIS) measurements of the sample and / or target test module 100.

[0075] In some embodiments, transducer controller 362 may energize power source 348 to generate one or more frequencies to lyse blood cells (e.g., red blood cells) within the sample stored in channel region 106 of the target test module 100. Optical detection controller 364 may then perform optical measurements on the lysed sample.

[0076] In block 412, carousel 200 may be rotated (via carousel controller 360) to transfer the target test module 100 to washing station 308. In some embodiments, in block 414, wash controller 368 may be employed to direct washing station 308 to wash the target test module 100 after testing, allowing for reuse of the test module. After the test module 100 is cleaned, it may be checked (in block 416) to determine if it is suitable for reuse, and if so, returned to carousel 200 for reuse. In some embodiments, test modules 100 may be removed from service after a predefined number of uses or after a failed inspection (e. g., failed optical inspection within testing station 306).

[0077] As described above, in some embodiments, carousel 200 may include a plurality of storage locations 202 for storing test modules 100 (e. g., 24 in some embodiments). Carousel 200 may rotate to transfer test modules 100 to different stations including an input station 304 (e. g., for pick-up and / or receipt of a sample into one or more test modules 100), a testing station 306 (e.g., for optical and / or electrical-acoustophoretic impedance spectroscopy (EAIS) of samples within test modules 100), and a washing station 308, where test modules 100 may be cleaned after use.

[0078] FIG. 5 illustrates a second workflow 500 for testing samples in accordance with one or more embodiments provided herein. Referring to FIG. 5, at block 502, test modules 100 are loaded into carousel 200 (e.g., in slots 202 ).

[0079] In block 504, carousel 200 may be rotated to transfer a target test module 100 to input station 304 (e. g., by rotatable platform 310 controlled by control unit 314 and / or carousel controller 360). In block 506, pipettor 328 may be attached to the target test module 100. For example, the target test module 100 may be removed from carousel 200 and pipette 334 may be attached to output port 122 of the target test module. In block 508, a standard pipette tip 336 may be connected at the bottom of the target test module 100 (e. g., to input port 120 of the target test module).

[0080] At block 510, a sample may be aspirated into the target test module 100 (e. g., via pipette 334 and input port 120 of the target test module). After aspiration, in block 512, a pipettor arm (not shown) may move into a sample pipette disposal position and ej ect the pipette tip 336 into waste container 340. Thereafter, the target test module 100 may be transported (e. g., with a pipettor arm) into a carousel module insert position and returned to carousel 200.

[0081] In block 514, carousel 200 may be rotated to transfer the target test module 100 to testing station 306 (e.g., using processor 316 and carousel controller 360). In this position, electrical connection may be made to PCB 126 of the target test module 100 (e. g., using pogo pins or another connection interface with clamping inside of testing station 306). In one or more embodiments, the target test module 100 may be slid from carousel 200 into testing station 306 via a motorized mechanical slider (not shown) within testing station 306, oranother suitable transfer mechanism. In some embodiments, the target module 100 may be completely removed from carousel 200 during testing so as to allow carousel 200 to rotate (e. g., for processing other test modules in parallel). That is, multiple test modules may be processed simultaneously.

[0082] Thereafter, with the target test module 100 at testing station 306, in block 516, one or more measurements may be conducted on the sample within the target test module 100. Example measurements that may be performed include optical spectrophotometric measurements using light source 342 and detector 346, digital image capture (with a digital camera, not shown) and digital image analysis of channel region 106 of the target test module, electrical -acoustic impedance spectroscopy, other impedance measurements, or the like.

[0083] In some embodiments, transducer 124 of the target test module 100 may be excited with a resonance frequency, or range of frequencies, and the resulting voltage and current signals may be recorded. Impedance spectra of the sample can be calculated from this data, and the impedance of a sample may reflect its density and modulus of elasticity. Transducer 124 may also be used to generate a range of resonance frequencies that lyse red blood cells (RBCs) within channel region 106 of the target test module 100. The specific frequency which will lyse the RBCs will be dependent upon the structural robustness of the RBCs, which will, in turn, be related to the RBC lifetime in a patient.

[0084] These features allow clinical diagnostic applications in a high throughput automation setting. Examples include hematocrit (HCT) determination. In some embodiments, EAIS may automatically provide HCT information which can support development of algorithms for detection and characterization of clinical markers including hemoglobinopathies and microclots. These markers have implications for differentialdiagnosis and monitoring of disease states including diabetes, long COVID, stroke risk, anemia, polycythemia, etc.

[0085] In further embodiments, hemoglobinopathies may be determined during pre -analytical testing (e.g., with testing system 300A, 300B, or 300C of FIGS. 3A-3D) prior to completing an assay for HbAlc. HbAlc is the primary automated clinical assay for diagnosis and monitoring of diabetes.Hemoglobinopathies (e.g., sickle cell disease) are present in a significant fraction of the world' s population and cause shortened RBC half -lives that may compromise the efficacy of HbAlc assays. Embodiments provided herein may provide a means of prescreening each patient' s whole blood sample for abnormal (e. g., fragile) RBCs prior to HbAlc testing. If abnormal RBCs are identified, inappropriate HbAlc testing would not only be prevented, but automated selection of tests for diabetes monitoring (e.g., fructosamine and glycated albumin) could be triggered.

[0086] EAIS may be able to identify micro-clots in acute and long COVID patients with implications for prognosis and direction of therapy. Further, depending on the impact of the micro-clot surface properties on the overall mechanical liquid properties of patient samples (e. g., impedance of the fluid) EAIS may be employed to differentiate COVID-specific microclots from micro-clots associated with other clinical conditions. More generally, determination of micro-clots during pre-analytic sample integrity testing has the potential to enhance assessment of risk and enhance preventive treatment selection for an initial, or subsequent, ischemic stroke. As such, a simple blood test analyzed via testing system 300A, 300B, or 300C may determine a more directly causative factor for stroke and provide significant clinical value.

[0087] In some embodiments, the testing systems and methods described herein may be applied to any sample derived from a patient with a clinical condition that affects the mechanicalliquid properties of the sample. Since the mechanical liquid properties of the sample will be affected by the size and concentration of sample particles, as well as the charge distribution on particle surfaces, there is a wide range of clinical and disease states which may benefit from application of the embodiments described herein. Regardless of whether micro-clots are causative or symptomatic of disease states, an effective, facile, and inexpensive diagnostic tool (e.g., such as testing systems 300A, 300B, and 300C) for characterization of micro-clots may provide great benefit by improving the understanding, diagnosis, and treatment of such disease states.

[0088] Following testing at testing station 306, the target test module 100 may be returned to carousel 200. For example, a mechanical slider (not shown) may transfer the target test module 100 into a slot 202 of carousel 200.

[0089] In block 518, carousel 200 may be rotated (e. g., via carousel controller 360) to transfer the target test module 100 to washing station 308. In some embodiments, in block 520, wash controller 368 may be employed to direct washing station 308 to wash the target test module 100 after testing, allowing for reuse of the test module.

[0090] In block 522, carousel 200 may rotate so the target test module 100 is positioned at testing station 306 and, in block 524, testing station 306 may verify that the test module 100 is still suitable for use. Example tests that may be performed on a test module 100 to confirm that it may continue to be employed include ultraviolet -visible (UV / VIS) spectroscopy, other spectrophotometric measurements, a bulk impedance measurement to confirm proper operation of transducer 124, or the like. In other embodiments, characterization studies may be conducted with clinical samples to determine how many times a test module 100 may be used, washed, and re-used. Design verification and / orvalidation studies may then be used to validate the number of times each test module may be used in a clinical or other diagnostic laboratory system. In this manner, in some embodiments, blocks 522 and 524 may be optional and each test module 100 may be used a predetermined number of times and / or for a predetermined time period without testing after washing.

[0091] In some embodiments, a test module check may be performed on each test module 100 within carousel 200 after washing, before washing, and / or after use. Such testing may be performed at testing station 306 or another location rotatably accessible by carousel 200. In one or more embodiments, test modules 100 may be disabled (e.g., no longer used) after a predefined usage period (e.g., after 5000 measurements or another number of uses). Once all test modules within carousel 200 have been disabled (e. g., used a predef ined number of times), carousel 200 may be replaced with another carousel having new test modules 100. In some embodiments, each carousel 200 may be used to process thousands, and in some cases, tens of thousands of samples.

[0092] Having multiple test modules 100 present in carousel 200 increases throughput, as a new test module 100 may be employed while a previously used test module 100 is being cleaned at washing station 308 and / or checked for continued use (e. g., at testing station 306 or another verification location).

[0093] FIG. 6 is a flowchart of an example process 600 for testing a sample in accordance with one or more embodiments provided herein. In some implementations, one or more process blocks of FIG. 6 may be performed by control unit 314 executing computer program instructions stored in memory 318 as computer program (s) 320.

[0094] As shown in FIG. 6, process 600 may include obtaining a rotatable carousel having a plurality of test modules stored therein (block 602 ). For example, rotatable carousel 200 (FIG.2A) having a plurality of test modules 100 stored therein may be obtained.

[0095] As also shown in FIG. 6, process 600 may include rotating the carousel to position a test module of the carousel at an input station (block 604 ). For example, control unit 314 and carousel controller 360 may cause carousel 200 to rotate to position a test module 100 of carousel 200 at input station 304, as described above.

[0096] As further shown in FIG. 6, process 600 may include transferring a sample into the test module using the input station (block 606). For example, control unit 314 and pipettor controller 366 may cause pipettor 328 (FIG. 3D) to transfer a sample into the test module, as described above.

[0097] As also shown in FIG. 6, process 600 may include rotating the carousel to position the test module at a testing station (block 608). For example, control unit 314 and carousel controller 360 may cause carousel 200 to rotate to position the test module at testing station 306, as described above.

[0098] As further shown in FIG. 6, process 600 may include testing the sample within the test module at the testing station (block 610). For example, control unit 314, transducer controller 362, and / or optical detection controller 364 may perform one or more measurements on the sample within the test module at the testing station, as described above. In some embodiments, this may include one or more of measuring absorption or absorption spectra of the sample, or otherwise optically probing the sample, in channel region 106 of the test module 100 before and / or after modulation of the sample using transducer 124 of the test module. Additionally or alternatively, transducer 124 of the test module may be employed to measure impedance spectra of the sample.

[0099] As also shown in FIG. 6, process 600 may include rotating the carousel to position the test module at a washingstation (block 612). For example, control unit 314 and carousel controller 360 may cause carousel 200 to rotate to position the test module at washing station 308, as described above.

[0100] As further shown in FIG. 6, process 600 may include cleaning the test module with the washing station (block 614). For example, control unit 314 and wash controller 368 may clean the test module with washing station 308 such as with a cleaning solution, as described above.

[0101] Although FIG. 6 shows example blocks of process 600, in some implementations, process 600 may include additional blocks, fewer blocks, different blocks, or differently arranged blocks than those depicted in FIG. 6. Additionally, or alternatively, two or more of the blocks of process 600 may be performed in parallel.ILLUSTRATIVE EMBODIMENTS

[0102] The following provides a non-limiting list of illustrative embodiments of this disclosure:

[0103] An illustrative system comprising: a carousel configured to hold a plurality of test modules, each test module having an input port, an output port, and a channel region connected to the input port and the output port; an input station configured to transfer samples into channel regions of test modules of the carousel; a testing station configured to perform one or more tests on samples stored within channel regions of test modules of the carousel; and a washing station configured to clean channel regions of test modules of the carousel; wherein the carousel is configured to rotate to transfer test modules between the input station, the testing station, and the washing station.

[0104] The illustrative system of any of the proceeding illustrative embodiments, wherein the carousel is configured to store at least 10 test modules.

[0105] The illustrative system of any of the proceeding illustrative embodiments, wherein the carousel is configured to store at least 20 test modules.

[0106] The illustrative system of any of the proceeding illustrative embodiments, further comprising the plurality of test modules.

[0107] The illustrative system of any of the proceeding illustrative embodiments, wherein each test module is reusable.

[0108] The illustrative system of any of the proceeding illustrative embodiments, wherein each test module has a transparent region that includes the channel region of the test module and wherein the testing station is configured to optically probe samples within the channel regions of test modules.

[0109] The illustrative system of any of the proceeding illustrative embodiments, wherein each test module includes a transducer configured to modulate a sample within the test module.

[0110] The illustrative system of any of the proceeding illustrative embodiments, further comprising a control unit having: a processor; a memory; and computer program instructions stored within the memory that, when executed by the processor, cause the processor to direct: rotation of the carousel to position a test module at the input station; transfer of a sample into the test module using the input station; rotation of the carousel to position the test module at the testing station; testing of the sample within the test module at the testing station; rotation of the carousel to position the test module at the washing station; and cleaning of the test module with the washing station.

[0111] The illustrative system of any of the proceeding illustrative embodiments, wherein the memory includes computer program instructions that, when executed by the processor,cause the processor to employ a transducer of the test module to lyse the sample within the test module at the testing station and optically probe the lysed sample.

[0112] The illustrative system of any of the proceeding illustrative embodiments, wherein the memory includes computer program instructions that, when executed by the processor, cause the processor to employ a transducer of the test module to measure impedance spectra of the sample.

[0113] An illustrative method of testing samples, comprising: obtaining a rotatable carousel having a plurality of test modules stored therein; rotating the carousel to position a test module of the carousel at an input station; transferring a sample into the test module using the input station; rotating the carousel to position the test module at a testing station; testing the sample within the test module at the testing station; rotating the carousel to position the test module at a washing station; and cleaning the test module with the washing station.

[0114] The illustrative method of any of the proceeding illustrative embodiments, wherein the carousel is configured to store at least 10 test modules.

[0115] The illustrative method of any of the proceeding illustrative embodiments, wherein the carousel is configured to store at least 20 test modules.

[0116] The illustrative method of any of the proceeding illustrative embodiments, wherein: each test module is reusable and includes a channel region; and the testing station is configured to optically probe samples within the channel regions of test modules.

[0117] The illustrative method of any of the proceeding illustrative embodiments, further comprising: employing a transducer of the test module to lyse the sample within the test module at the testing station; and optically probing the lysed sample.

[0118] The illustrative method of any of the proceeding illustrative embodiments, further comprising employing a transducer of the test module to measure impedance spectra of the sample.

[0119] An illustrative carousel system comprising: a rotatable carousel having a plurality of storage locations and configured to rotate between an input station, a testing station, and a washing station of a testing system; and a plurality of test modules stored within the carousel, each test module stored in a different one of the plurality of storage locations and having an input port, an output port, and a channel region connected to the input port and the output port.

[0120] The illustrative carousel system of any of the proceeding illustrative embodiments, wherein the carousel is configured to store at least 20 test modules.

[0121] The illustrative carousel system of any of the proceeding illustrative embodiments, wherein each test module is reusable and has a transparent region that includes the channel region of the test module.

[0122] The illustrative carousel system of any of the proceeding illustrative embodiments, wherein each test module includes a transducer configured to at least one of lyse a sample within the test module and characterize an impedance of the sample within the test module.

[0123] While the disclosure is susceptible to various modifications and alternative forms, specif ic method and apparatus embodiments have been shown by way of example in the drawings and are described in detail herein. It should be understood, however, that the particular methods and apparatus disclosed herein are not intended to limit the disclosure.

Claims

WHAT IS CLAIMED IS:

1. A system comprising:a carousel configured to hold a plurality of test modules, each test module having an input port, an output port, and a channel region connected to the input port and the output port;an input station configured to transfer samples into channel regions of test modules of the carousel;a testing station configured to perform one or more tests on samples stored within channel regions of test modules of the carousel; anda washing station configured to clean channel regions of test modules of the carousel;wherein the carousel is configured to rotate to transfer test modules between the input station, the testing station, and the washing station.

2. The system of claim 1, wherein the carousel is configured to store at least 10 test modules.

3. The system of claim 2, wherein the carousel is configured to store at least 20 test modules.

4. The system of claim 1 further comprising the plurality of test modules.

5. The system of claim 4, wherein each test module is reusable.

6. The system of claim 4, wherein each test module has a transparent region that includes the channel region of the test module and wherein the testing station is configured to optically probe samples within the channel regions of test modules.

7. The system of claim 4, wherein each test module includes a transducer conf igured to modulate a sample within the test module.

8. The system of claim 1 further comprising a control unit having:a processor;a memory; andcomputer program instructions stored within the memory that, when executed by the processor, cause the processor to direct:rotation of the carousel to position a test module at the input station;transfer of a sample into the test module using the input station;rotation of the carousel to position the test module at the testing station;testing of the sample within the test module at the testing station;rotation of the carousel to position the test module at the washing station; andcleaning of the test module with the washing station.

9. The system of claim 8, wherein the memory includes computer program instructions that, when executed by the processor, cause the processor to employ a transducer of the test module to lyse the sample within the test module at the testing station and optically probe the lysed sample.

10. The system of claim 8, wherein the memory includes computer program instructions that, when executed by theprocessor, cause the processor to employ a transducer of the test module to measure impedance spectra of the sample.

11. A method of testing samples, comprising:obtaining a rotatable carousel having a plurality of test modules stored therein;rotating the carousel to position a test module of the carousel at an input station;transferring a sample into the test module using the input station;rotating the carousel to position the test module at a testing station;testing the sample within the test module at the testing station;rotating the carousel to position the test module at a washing station; andcleaning the test module with the washing station.

12. The method of claim 11, wherein the carousel is configured to store at least 10 test modules.

13. The method of claim 12, wherein the carousel is configured to store at least 20 test modules.

14. The method of claim 11, wherein:each test module is reusable and includes a channel region; andthe testing station is configured to optically probe samples within the channel regions of test modules.

15. The method of claim 11, further comprising:employing a transducer of the test module to lyse the sample within the test module at the testing station; and optically probing the lysed sample.

16. The method of claim 11, further comprising employing a transducer of the test module to measure impedance spectra of the sample.

17. A carousel system comprising:a rotatable carousel having a plurality of storage locations and configured to rotate between an input station, a testing station, and a washing station of a testing system; anda plurality of test modules stored within the carousel, each test module stored in a different one of the plurality of storage locations and having an input port, an output port, and a channel region connected to the input port and the output port.

18. The carousel system of claim 17, wherein the carousel is configured to store at least 20 test modules.

19. The carousel system of claim 17, wherein each test module is reusable and has a transparent region that includes the channel region of the test module.

20. The carousel system of claim 17, wherein each test module includes a transducer configured to at least one of lyse a sample within the test module and characterize an impedance of the sample within the test module.

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