Matrix droplet extruder, sample holder, and sample analysis system

Abstract

To quickly obtain a plurality of diagnostic results in point-of-care testing.SOLUTION: A matrix droplet extruder comprises: a casing; one or a plurality of reagent containers; a plurality of pneumatic connectors on the casing that are each configured to be connected to a pneumatic actuator to provide controlled pneumatic pressure to one or more of the plurality of the pneumatic connectors; a droplet matrix extrusion surface with one or a plurality of printing zones, each printing zone comprising an array of perforations; and a liquid management chip for dispensing one or more reagents from the one or a plurality of reagent containers through the array of perforations of the one or a plurality of printing zones, so as to repeatedly generate a matrix of droplets when applying the pneumatic pressure to the one or more reagents.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a system and method for analyzing a sample. [Background technology]

[0002] Receiving test results quickly is often important for timely medical diagnosis. Various approaches have been used to facilitate timely results. Large-scale, automated laboratories allow for rapid testing of large numbers of samples. However, test samples (e.g., blood, saliva, or other test materials) must be transported from a local clinic or other facility to the laboratory. Point-of-care (POC) testing generally refers to diagnostic testing that is performed outside a central laboratory, for example, at a medical clinic or other facility where the patient is present. Over the years, the increasing availability of portable, mobile, and sometimes handheld devices has led to the migration of POC testing from the hospital environment to various medical settings, including workplaces, homes, disaster care facilities, and community clinics.

[0003] The use of POC testing is impacting many types of diagnoses, including infectious diseases, autoimmune conditions, allergies, cancer, heart disease, and bowel disease. Summary of the Invention [Problem to be solved by the invention]

[0004] A typical POC testing device provides a single diagnostic test for a single sample. However, in many scenarios, a panel of diagnostic tests is required. Thus, the use of such a single-test typical POC testing device may require a clinic to acquire and maintain a wide variety of different POC devices. [Means for solving the problem]

[0005] The following embodiments and aspects thereof are described and illustrated with reference to systems, tools, and methods that are intended to be exemplary and illustrative, and not limiting in scope.

[0006] Thus, according to one embodiment of the present invention, there is provided a matrix droplet extruder, which may include a casing, one or more reagent containers, and a plurality of pneumatic connectors on the casing, each connected to a pneumatic actuator and configured to provide a controlled pneumatic pressure to one or more of the plurality of pneumatic connectors. The matrix droplet extruder also includes a droplet matrix extrusion surface having one or more print zones, each print zone comprising an array of perforations, and a liquid management chip for dispensing one or more reagents from the one or more reagent containers through the array of perforations in the one or more print zones and for repeatedly generating a matrix of droplets upon application of pneumatic pressure to the one or more reagents.

[0007] In some embodiments of the invention, the droplet matrix extrusion surface comprises a pattern to allow mixing of two or more droplets.

[0008] In some embodiments of the present invention, the matrix droplet extruder may further include a washer for cleaning said one or more print zones.

[0009] In some embodiments of the invention, the cleaner is configured to move between an idle waiting position away from the one or more print zones and a cleaning position above the one or more print zones.

[0010] In some embodiments of the invention, the cleaner comprises an inlet port for introducing a cleaning agent to and discharging the cleaning agent from said one or more print zones.

[0011] In some embodiments of the present invention, the matrix droplet extruder may further include a pneumatic actuator, a controller for controlling the pneumatic actuator, and a docking station having a plurality of pneumatic docking station connectors connected to the pneumatic actuator.

[0012] In some embodiments of the invention, the controller is configured to control a duration for which pressure is applied to one of the plurality of pneumatic connectors by the pneumatic actuator.

[0013] In some embodiments of the invention, the controller is configured to control pressure applied by the pneumatic actuator to one of the pneumatic connectors.

[0014] In some embodiments of the invention, a sample holder may include a casing having a pocket, a removable sample slide having one or more substrate patches configured to be inserted into or removed from the pocket, and a sample channel for introducing a liquid sample into one or more enclosed spaces between the sample slide and a section of the casing for absorbing the sample liquid into the one or more substrate patches.

[0015] In some embodiments of the present invention, the substrate patch comprises a membrane.

[0016] In some embodiments of the invention, the membrane comprises a material selected from the group of materials consisting of nitrocellulose, fiberglass, nanomesh, plastic and glass.

[0017] In some embodiments of the invention, the sample holder includes a plurality of pneumatic connectors on a casing, each of the plurality of pneumatic connectors configured to be connected to a pneumatic or vacuum actuator to provide a controlled air pressure or vacuum to one or more of the plurality of pneumatic connectors to obtain a laminar flow of sample or other liquid into the one or more enclosed spaces.

[0018] In some embodiments of the invention, the sample holder includes one or more liquid containers that contain one or more other liquids.

[0019] In some embodiments of the invention, the sample holder includes a lock for locking the sample slide when fully inserted into the pocket.

[0020] In some embodiments of the present invention, a sample analysis system is provided that includes a pneumatic actuator; one or more sample holders comprising a casing having a pocket, a liquid container, a removable sample slide having a substrate with one or more substrate patches configured to be inserted into or removed from the pocket, and a sample channel for introducing a liquid sample into one or more enclosed spaces between the sample slide and a section of the casing to absorb the sample liquid into the one or more substrate patches; a controller configured to control the pneumatic actuator to sequentially flow one or more liquids from one or more of the liquid containers to or from the sample slide in the sample holder; and an analysis module for examining the sample slide after the sample contacts multiple dots of one or more reagents printed on the substrate.

[0021] In some embodiments of the invention, the analysis system also includes a transport mechanism configured to sequentially transport each of the one or more sample holders to one of a plurality of stations along the transport mechanism, and the controller is further configured to control the transport mechanism to cause the transport mechanism to move the one or more sample holders such that each of the one or more sample holders moves sequentially from a current station of the plurality of stations to a next station of the plurality of stations.

[0022] In some embodiments of the invention, the transport mechanism comprises a rotatable carousel, with a plurality of pneumatic connectors arranged to enable connection of each of said one or more sample holders at positions on the periphery of the carousel.

[0023] In some embodiments of the invention, a plurality of pneumatic connectors are positioned to allow connection of said one or more sample holders at equally spaced positions along the circumference of the carousel.

[0024] In some embodiments of the present invention, the multiple stations include at least one docking station to which a matrix droplet extruder can be attached, the docking station including multiple docking station connectors for connecting to multiple docking pneumatic connectors of the matrix droplet extruder, and the docking station is controllable by the controller to selectively apply pressure to each of the docking station connectors to control the extrusion of droplets from one or more reagent containers of the matrix droplet extruder onto a droplet matrix extrusion surface of the matrix droplet extruder to form a plurality of reagent droplets.

[0025] In some embodiments of the invention, the at least one docking station comprises a mechanism for emptying a reagent canister into one of the one or more reagent vessels.

[0026] In some embodiments of the invention, the analytical system includes a mechanical system controlled by a controller to manipulate a substrate of each of one or more sample holders to place the substrate in contact with a droplet matrix extrusion surface to enable a plurality of reagent dots to be extruded onto the substrate and to expose the substrate to an analytical module.

[0027] In some embodiments of the invention, the mechanical system is pneumatically controlled.

[0028] In some embodiments of the invention, the machine system comprises a rinse chamber configured to be positioned relative to the droplet matrix extrusion surface to enable cleaning of the droplet matrix extrusion surface.

[0029] In some embodiments of the invention, the analysis module comprises an optical system for acquiring images of the substrate or an electronic system for measuring electrical properties of the substrate.

[0030] In some embodiments of the invention, the substrate comprises said dots of one or more reagents pre-extruded onto the substrate.

[0031] In some embodiments of the invention, the analytical system further includes a matrix droplet extruder for printing a plurality of dots of one or more reagents, the matrix droplet extruder including a casing, one or more reagent containers, a second plurality of pneumatic connectors on the casing, each of the second plurality of pneumatic connectors connected to a pneumatic actuator and configured to provide a controlled pneumatic pressure to one or more of the second plurality of pneumatic connectors, a droplet matrix extrusion surface having one or more print zones, each print zone comprising an array of perforations, and a liquid management chip for dispensing one or more reagents from the one or more reagent containers through the array of perforations in the one or more print zones and repeatedly generating a matrix of droplets upon application of pneumatic pressure to the one or more reagents.

[0032] In some embodiments of the present invention, the one or more print zones comprise two print zones.

[0033] In some embodiments of the invention, the analysis system further includes a transport mechanism for transporting each of the one or more sample holders to and from a position facing the matrix droplet extruder and for positioning a sample slide of each of the one or more sample holders above one of the one or more print zones.

[0034] In some embodiments of the invention, the analytical system further comprises a waste container for disposing of used ones of said one or more sample holders.

[0035] In order to better understand the present invention and appreciate its practical applications, the following drawings are provided and reference is made to them. It should be noted that the drawings are given by way of example only and are not intended to limit the scope of the present invention in any way. Similar elements are provided with similar reference numerals. [Brief description of the drawings]

[0036] [Figure 1] 1 shows a schematic representation of a multi-sample analysis device according to a possible embodiment of the invention; [Diagram 2] FIG. 2 is a block diagram of a multi-sample analyzer generally similar to that shown in FIG. [Figure 3A] 3 shows a schematic diagram of an example of a transport and analysis system for a multi-sample analysis device, possibly similar to that shown in FIG. 2; [Figure 3B] FIG. 3B is a schematic exploded view of the transport and analysis system shown in FIG. 3A. [Figure 4] FIG. 3B is a schematic top view of the transport and analysis system shown in FIG. 3A. [Diagram 5] 4 shows a schematic diagram of an example of a carousel of the transport analysis system shown in FIG. 3. [Figure 6A] 4 shows a schematic diagram of an example of a sample holder of a multi-sample analysis device such as that shown in FIG. 3. [Figure 6B]6B illustrates a schematic diagram of a chamber for applying suction to a slide in a sample holder as shown in FIG. 6A. [Figure 7A] 3B shows a schematic diagram of an example matrix droplet extruder inserted into an example docking station, possibly suitable for use in a delivery analysis system such as that shown in FIG. 3A. [Figure 7B] 7B illustrates a schematic diagram of the docking station shown in FIG. 7A. [Figure 7C] 7B shows a schematic diagram of the rear side of a matrix droplet extruder such as that shown in FIG. 7A. [Figure 7D] 7D is a schematic cross-section of an example of a matrix droplet extruder as shown in FIG. 7C. [Figure 7E] 7B shows a schematic of an example of a slide onto which reagent dots have been extruded, perhaps by a matrix droplet extruder as shown in FIG. 7A. [Figure 8] 3B shows a schematic diagram of possible stations for sample holders in an example of a transport analytical system as shown in FIG. 3A. [Figure 9] 2 is a flow chart illustrating a possible method of operation of a multi-sample analysis device, in accordance with one embodiment of the present invention. [Figure 10] 1 illustrates a schematic diagram of an example reagent dot printing system. [Figure 11] 1 illustrates a schematic of an example of a stand-alone sample processing system. [Figure 12A] FIG. 12 is a front view of a sample holder 1200 of a multi-sample analysis device according to some embodiments of the present invention, with a sample slide inserted therein. [Figure 12B] FIG. 12 is a front view of sample holder 1200 of a multi-sample analysis device with sample slides removed according to some embodiments of the present invention. [Figure 13A] 1 shows a matrix droplet extruder configured to perform a dual printing assay, according to some embodiments of the present application, with a sample slide in a first printing position. [Figure 13B]1 shows a sample slide in a second print position with a matrix droplet extruder configured to perform a dual print assay, according to some embodiments of the present application. [Figure 13C] 1 illustrates a rear view of a matrix droplet extruder according to some embodiments of the present invention. [Figure 13D] FIG. 13C is a front view of a cleaner for the matrix droplet extruder shown in FIGS. 13A and 13B. [Figure 14] 1 is a schematic diagram of a sample analysis system having dual printing assay capabilities, according to some embodiments of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] It will be understood that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, dimensions of some elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate similar elements.

[0038] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, modules, units and / or circuits have not been described in detail so as not to obscure the present invention.

[0039] For example, discussions utilizing terms such as "processing," "calculating," "computing," "determining," "establishing," "analyzing," "checking," and the like, may refer to operations and / or processes of a computer, computing platform, computing system, or other electronic computing device that manipulates and / or transforms data represented as physical (e.g., electronic) quantities in the registers and / or memory of the computer into other data similarly represented as physical quantities in the registers and / or memory of the computer, or in other information storage media (e.g., memory) that may store instructions that perform the operations and / or processes. For example, the terms "multiple" and "plurality," as used herein, may include "multiple" or "two or more." The terms "multiple" or "multiple" may be used throughout this specification to describe two or more components, devices, elements, units, parameters, and the like. Unless expressly stated, method embodiments described herein are not bound to a particular order or sequence. Additionally, some of the described method embodiments or elements thereof may occur or be performed simultaneously, contemporaneously, together. Unless otherwise indicated, the conjunction "or" as used herein should be understood to be inclusive (any or all of the listed alternatives).

[0040] Some embodiments herein may include articles such as computer or processor readable media or computer or processor non-transitory storage media, e.g., memory, disk drives, USB flash memory, etc., that encode, include, or store instructions, e.g., computer executable instructions, that when executed by a processor or controller, perform the methods disclosed herein.

[0041] According to at least certain embodiments of the present invention, an analytical or diagnostic system (e.g., a point-of-care system) may be configured to allow for non-automated or automated sequential, chemical, biochemical, and / or other analysis and / or testing of one or more (e.g., a plurality) samples. For example, the samples may include substances derived from a human or animal patient (e.g., blood, saliva, urine, feces, or other types of substances extracted, excreted, or secreted from a human or animal patient), substances derived from the environment (e.g., water or other liquids, rainfall, mud or soil, substances extracted or secreted from plants, or other materials found in the environment), substances derived from industrial products (food, fuels, lubricants, pharmaceuticals, cleaning and maintenance products, beauty products, substances manufactured for industrial products, or other industrial products), and / or substances derived from other types of substances or purified liquids.

[0042] It should be noted that POC applications, systems, devices, and methods are referred to herein as examples only. The systems, devices, or methods described herein may be used or applied in settings other than medical clinics or similar settings. For example, the devices, systems, and methods described herein may be used in central laboratories, factories (e.g., industrial or manufacturing applications), in the field (e.g., environmental, geological, biological, resource exploration, or other applications), police laboratories (e.g., forensic applications), or other locations. Thus, references to point-of-care herein should be understood as being equally applicable to any other settings or applications.

[0043] For a testing system to effectively function as a point-of-care diagnostic system, the system can follow an approved standard analytical protocol, for example, meeting Clinical Laboratory Improvement Act (CLIA) standards, enzyme-linked immunosorbent assay (ELISA) protocols, DNA / RNA testing protocols, or another approved protocol, and meeting standards for preventing mixing of samples from different patients.

[0044] Additionally, the system may be configured to prevent misuse by a user (e.g., improper insertion of a sample or improper application of a test to a sample). Tests that may be performed by the system may not necessarily require an excessive amount of time (e.g., 10-20 minutes or less). In many cases, a qualitative (e.g., yes / no, positive / negative, present / absent, or the like) response may be sufficient and, in some cases, may be preferred over a quantitative response.

[0045] Each sample can be spread on a substrate, such as a membrane, on a possible slide in a separate sample holder. The sample holder can be a single-use device that can be disposed of or discarded after subjecting the sample to a testing protocol.

[0046] For example, a sample holder can include one or more openings through which a liquid sample can be introduced into the sample holder. For example, each opening may open into an internal capillary to draw a liquid sample, such as a drop of blood, or another liquid sample, into the sample holder. A user, such as a medical professional or laboratory technician, a patient trained for self-testing, or other user, can identify the sample holder and match it with an inserted sample (e.g., a patient identifier), for example, by scanning a barcode, radio frequency identification (RFID) tag, or other method. The user can also input or otherwise specify a testing protocol into the system to apply to a particular sample in an identified sample holder.

[0047] The sample holder may be configured to apply one or more steps of a processing protocol to the sample. Typically, the protocol may include contacting the sample with a droplet matrix extrusion surface of a matrix droplet extruder. For example, the slide may be mechanically removed from the sample holder and pressed against the droplet matrix extrusion surface.

[0048] When or before the droplet matrix extrusion surface is in contact with the sample, the matrix droplet extruder extrudes a matrix of reagent dots onto the droplet matrix extrusion surface through an array of corresponding perforations opening from the matrix droplet extruder at the droplet matrix extrusion surface. The selection of reagents in each matrix of extruded reagent droplets can be specific to a particular test protocol. The matrix droplet extruder may be configured to include multiple liquid reservoirs.

[0049] The matrix droplet extruder may include a microfluidic channeling system that may be controllable to direct liquid from one or more liquid reservoirs to specific openings of an array of micro-openings or perforations in the droplet matrix extrusion surface, where the directed liquid may be extruded through the openings to predetermined locations on the droplet matrix extrusion surface to form reagent dots that are brought into contact with samples on the slide substrate of the sample holder.

[0050] The processing protocol can typically be configured to produce an optically or electronically detectable result indicative of the outcome of the application of the analytical protocol (e.g., the presence of a particular substance, such as an antigen, in the sample). For example, the analytical protocol can be configured to change the color or fluorescence of areas of the sample slide in contact with one or more reagent dots, the color being indicative of the composition of the sample. Alternatively or additionally, areas of the sample slide in contact with one or more of the reagent dots may fluoresce with a particular color indicative of the composition of the sample.

[0051] Alternatively or additionally, areas of the sample slide in contact with one or more of the reagent dots may be characterized by one or more changes in electrical properties indicative of the composition of the sample. For example, the processing protocol may include an immunoassay protocol (e.g., an enzyme-linked immunosorbent assay (ELISA) protocol) in which the sample is exposed to one or more antibodies or enzymes to detect the presence of one or more antigens in the sample.

[0052] In at least some examples, a multi-sample diagnostic system can be provided that may include an integrated transport control mechanism for transporting a plurality of sample holders, each to one or more of a plurality of stations. The transport control mechanism may be configured to simultaneously transfer all of the sample holders from one station to the next station in succession. For example, the transport mechanism may include a linear or circular conveyor or carousel. In the case of a circular carousel, the sample holders may be arranged along the periphery of the carousel. In some cases, such a carousel may be configured to simultaneously transport up to eight sample holders (e.g., corresponding to the maximum number of processing steps in a typical ELISA protocol), or another number of sample holders.

[0053] Each sample holder may include a number of pneumatic connectors that may be arranged to connect with corresponding connectors on the transport mechanism when the sample holder is inserted into the transport mechanism. The connectors may typically be connected to a source of pressurized air pressure or a vacuum pump or other suction source via an arrangement of pneumatic channels and valves. Each sample holder may also include one of one of one or more filters, one or more materials, typically a reservoir of liquid, and / or other structures.

[0054] When the sample holder is placed in several stations, the valves may be actuated to cause the movement of a certain amount of liquid in the sample holder. For example, a sample of blood may be drawn through a filter device to obtain plasma or serum suitable for testing. Liquid may be drawn from one or more reservoirs to the sample on the substrate of the slide to perform the wet method steps of the protocol (e.g., washing, blocking, or other steps).

[0055] The transport mechanism may be configured such that each sample holder remains at each station for a period of time sufficient to allow completion of the steps of the processing protocol on each sample. For example, in many cases a period of one minute may be sufficient to perform the longest steps of a typical analytical protocol.

[0056] The diagnostic system may include one or more (e.g., two) docking stations, to each of which a matrix droplet extruder may be connected (e.g., at the start of the working day or otherwise). During the operation of some protocol, when a sample holder is led to a processing station that includes a matrix droplet extruder, the sample substrate of that sample holder may be pressed against the droplet matrix extruding surface of that matrix droplet extruder (e.g., after possible removal of the sample slide from the sample holder). Thus, the sample may be brought into contact with the array of reagents such that the reagents are printed on the sample at known positions.

[0057] When all steps of an analytical protocol are completed for a sample in the sample holder, application of the protocol may result in one or more optically assessable results. For example, the color of an area of ​​the sample contacted with a dot of reagent at a known location on the matrix droplet extruder may be changed, or the fluorescence of the sample may be changed. In some cases, an electrical property of the sample may be changed, for example, the resistance or conductivity, dielectric constant, or another electrical property of the sample.

[0058] Note that in this manner, the composition of each reagent dot is known by its location, and therefore each type of reagent does not need to be distinguished from the others by a clearly detectable effect (e.g., by a different detectable color or electrical property), as would be required in a system in which the reagents are not spatially separated from one another and / or are not formed in a predetermined scheme, perhaps determined by an array of predetermined perforations opening from a matrix droplet extruder at the droplet matrix extrusion surface.

[0059] After all steps of the analysis protocol are completed on the sample in the sample holder, the transport mechanism can transport the sample holder to a station that includes an analysis module. For example, the analysis module can include an imaging device (e.g., a camera), an illumination source, and appropriate optics for detecting any optical effects of the processing protocol on the sample in the sample holder, such as staining or fluorescence.

[0060] An image of the sample can be acquired (e.g., in a display area of ​​the analysis module after removal of the sample slide from the sample holder) and the image, or analysis results of the image, can be displayed or otherwise output or communicated to a user. In some cases, the image or results can be stored or transmitted to another device for later review, analysis, or comparison. The analysis module can include electronic components to measure electrical properties of the processed samples.

[0061] After imaging or analysis by the analysis module, the ejection mechanism can remove the sample holder from the transport mechanism. For example, the ejection mechanism can be configured to decouple the sample holder from the transport mechanism. A tilted slide or other structure can be configured to allow removal of the ejected sample holder a sufficient distance away to ensure that the ejected sample holder does not interfere with the function of the transport mechanism or other components of the diagnostic system.

[0062] The transport mechanism may cooperate with a loading mechanism for loading the sample holders onto the transport mechanism. In some cases, the loading mechanism may be configured to hold one or more sample holders until a space becomes available on the transport mechanism. For example, the loading mechanism may include a rotatable turntable or another mechanical structure capable of holding one or more sample holders (e.g., capable of holding three sample holders, or another number of sample holders) and configured to successively position sample holders on vacant positions on the transport mechanism as such vacant positions become available.

[0063] In some cases, the reagent dot printing system can operate as a stand-alone system rather than as part of a POC diagnostic device. For example, such a reagent dot printing system can include a docking station, an associated controller, and one or more pneumatic pressure sources (e.g., pressure actuators or pressure sources). The matrix droplet extruder can be connected to the docking station of the reagent dot printing system. The reagent dot printing system can be configured to operate the liquid management chip of the matrix droplet extruder to controllably extrude an array of dots onto a droplet matrix extrusion surface of the matrix droplet extruder, the matrix extrusion surface facing outward from the matrix droplet extruder. In some embodiments of the present invention, the matrix droplet extruder can be configured to controllably extrude more than one array of dots (e.g., two or more arrays) onto a droplet matrix extrusion surface of the matrix droplet extruder, the matrix extrusion surface facing outward from the matrix droplet extruder.

[0064] The reagent dot printing system may be operated to print the reagent dots on the slide prior to incorporation into the sample holder. For example, the reagent dot printing system may be operated by a central laboratory or by a manufacturer of slides for a stand-alone sample analysis system. The reagent dot printing system may include a mechanical system for automatically positioning the slide against the droplet matrix extrusion surface or may allow manual manipulation of the slide against the droplet matrix extrusion surface.

[0065] Slides printed with arrays of reagent dots may be stored under conditions that preserve the reagent properties of the dots until use. For example, the storage conditions may include one or more of controlled temperature, controlled humidity, limited exposure to light, or other controlled conditions.

[0066] Prior to use, slides can be inserted into a sample holder. Such sample holders with pre-printed slides can be utilized in stand-alone sample analysis systems. For example, a sample analysis system can include a sample holder device configured to hold one or more sample holders. The sample holder device can include a controller and one or more air pressure sources (e.g., suction pumps).

[0067] The controller may cause the flow of one or more samples or other liquid substances to filter the sample, to spread the sample on a slide, to expose the sample to one or more liquid substances (e.g., wet methods), or otherwise cause liquid flow within the sample holder. The sample holder apparatus may be configured to control liquid flow within a single sample holder at any given time, or may be configured to control liquid flow within two or more sample holders simultaneously.

[0068] For example, the sample holder device may be smaller, simpler, and less expensive than the POC diagnostic system, in which case a physician, field worker, or other user may use such a sample holder device, along with a sample holder having pre-printed slides, in a simple and efficient manner (albeit at a low throughput rate) using a reagent dot printing system at a location remote from a clinic or other facility equipped with the POC diagnostic system.

[0069] FIG. 1 shows a schematic diagram of a multi-sample analytical diagnostic device according to a possible embodiment of the present invention.

[0070] The multi-sample analyzer 10 may be configured to analyze multiple samples simultaneously. Each sample may be contained within and / or attached to a sample holder 18. The components of the multi-sample analyzer 10 may be enclosed within a housing 11. The multi-sample analyzer 10 may be utilized as a POC device.

[0071] Multiple sample holders 18 may be sequentially inserted or mated into the multi-sample analysis device 10 via the sample holder opening 16. Once analysis of the samples in a sample holder 18 is complete, that sample holder 18 may be ejected from the multi-sample analysis device 10 via the ejection opening 20.

[0072] Prior to analysis of the samples in the sample holder 18, one or more (e.g., one or two) matrix droplet extruders 14 may be inserted or fitted into the multi-sample analysis device 10. For example, one or more matrix droplet extruder openings 12 may be provided to allow for the insertion or coupling of the matrix droplet extruders 14. Alternatively or additionally, a cover of the housing 11 may be openable to allow for the insertion or coupling of one or more matrix droplet extruders 14.

[0073] The matrix droplet extruder 14 can be operated to generate an array of droplets of reagents at or on the outward facing surface of the extruder 14, which can be contacted with a sample loaded into the sample holder 18. For example, a single extruded droplet can have a volume between 100 pL and 2 nL, a diameter between 20 pm and 500 pm, and an inter-dot spacing between 100 pm and 300 pm (e.g., 200 pm between dots of a single type of reagent and 300 pm between different reagents), or other values.

[0074] The multi-sample analyzer 10 may include one or more user controllers 22 that may be operable to control the operation of the multi-sample analyzer 10. The multi-sample analyzer 10 may include one or more output devices 24 for communicating status (e.g., the number of sample holders 18 currently inserted, whether another sample holder 18 may be inserted, error messages, and / or other conditions), analysis results, and / or other information to a user of the multi-sample analyzer 10. For example, the output devices may include one or more display screens, indicator lights, speakers and / or other audible signal generators, and / or other output devices.

[0075] The multi-sample analysis apparatus 10 may be configured to communicate via a wired or wireless connection with an external device 28. For example, the external device 28 may include a computer, terminal, or other device that may allow for the input of instructions or data (e.g., patient or other identification data associated with the samples in the sample holders 18, an analytical or testing procedure or protocol to be performed on the samples in a particular sample holder 18, or other instructions) or the output of data or messages (e.g., the results of an analysis or test).

[0076] Power for operating the multi-sample analysis apparatus 10 may be supplied via a power connector 26. Typically, power may be supplied by a direct current (DC) power source. A DC power source may include an adapter that connects to an alternating current power source (e.g., mains power), a battery or battery pack, a solar cell, or another DC power source (e.g., having a voltage of 24V, or another voltage).

[0077] FIG. 2 is a block diagram of the multi-sample analyzer shown in FIG.

[0078] The transport analytical system 40 can be configured to transport the sample holder 18 to a number of predefined stations within the transport analytical system 40. At each station, one or more steps of an analytical process can be performed. After completion of the analytical process, the matrix droplet extruder 14 can be ejected from the multi-sample analytical device 10.

[0079] The operation of the transportation analysis system 40 may be controlled by a controller 36. The controller 36 may be configured to operate one or more components of the transportation analysis system 40 according to instructions generated by the processor 34. The processor 34 may communicate with other units or devices via an input / output (I / O) unit 32. For example, the processor 34 may communicate with one or more of the user controller 22, the output device 24, and the external device 28 via the I / O unit 34.

[0080] The transport and analysis system 40 can include a transport mechanism 70 , an analysis module 54 , and a mechanical system 50 , each of which can be controlled by a controller 36 .

[0081] Power for operating the different components of the transport analytical system 40 and the multi-sample analytical device 10 may be provided via a DC / DC converter circuit 38. The DC / DC converter circuit 38 can convert the input voltage from the power connector 26 to an operating voltage suitable for each component of the transport analytical system 40 or the multi-sample analytical device 10.

[0082] Fig. 3A shows a schematic diagram of an example of a transport and analysis system of a multi-sample analysis device generally similar in principle to that shown in Fig. 2. Fig. 3B shows a schematic exploded view of the transport and analysis system shown in Fig. 3A. Fig. 4 shows a schematic top view of the transport and analysis system shown in Fig. 3A. Fig. 5 shows a schematic diagram of a carousel of the transport and analysis system shown in Fig. 3.

[0083] The components of the transport analysis system 40 of the multi-sample analysis apparatus 10, in this optional example, may be mounted to a system base 41. Mounting to the system base 41 may allow the components of the transport analysis system 40 to be placed in predetermined positions and orientations relative to one another. The transport analysis system 40 may be connected to a controller 36, which may in turn be configured to control the operation of the components of the transport analysis system 40.

[0084] In the illustrated example, the transport mechanism 70 includes a carousel 42. A carousel motor 74 can be operated to rotate the carousel 42 about its axis. The carousel 42 can be configured to transport a number of sample holders 18 arranged around the carousel 42, and in the illustrated example, is configured to transport up to eight sample holders in eight locations. Each sample holder 18 can be held by a sample holder holding structure 19. Continuous rotation of the carousel 42 can lead each sample holder 18 to each of an equal number of stations (e.g., eight in the illustrated example) distributed around the carousel 42. The carousel 42 can be operated such that each sample holder 18 remains at each station for a predetermined period of time (e.g., one minute, or another period of time). Thus, in the illustrated example, rotation of the carousel 42 through a rotation angle of 45° can lead each sample holder 18 from one of the stations to the next.

[0085] The loading mechanism 47 may be configured to load one or more sample holders 18 onto the carousel 42. The loading mechanism 47 may include one or more sample holder slots 48. In the illustrated example, the loading mechanism 47 includes three sample holder slots 48. For example, a sample holder 18 that may be inserted or mated or coupled to a sample holder opening 16 (as shown in FIG. 1 or FIG. 5 ) may be placed in a sample holder slot 48 that may be aligned or biased to match the sample holder insertion opening 16.

[0086] If the loading mechanism 47 includes one or more empty sample holder slots 48, the loading mechanism 47 can be rotated to align one of the sample holder slots 48 with the sample holder opening 16 to allow another sample holder 18 to be inserted or coupled to the sample holder opening 16. When a sample holder 18 is removed from the carousel 42 and an empty sample holder retaining structure 19 is rotated into a station including the loading mechanism 47, the sample holder 18 can be loaded from one of the sample holder slots 48 into the sample holder retaining structure 19 on the carousel 42. Thus, the loading mechanism 47 can function as a buffering mechanism to allow efficient loading of the sample holder 18 into the multi-sample analysis device 10.

[0087] The sample holder 18 can be loaded into a sample holder holding structure 19 on a holder platform 45 and connected to a holder platform pneumatic connector set 43 . The number of sets of holder platform pneumatic connectors 43 on the holder platform 45 can, in some examples, define the maximum number of sample holders 18 that can be loaded onto the carousel 42 at one time (eight in the illustrated example).

[0088] Once a sample holder 18 is loaded onto the carousel 42, one or more identification markings on the sample holder 18 may be read by an identification reader 62. For example, the identification reader 62 may include a barcode scanner, an RFID reader, or other sensor or device capable of reading identification markings on the sample holder 18. The processor 34 may be configured to associate the identified sample holder 18 with the source of the sample in the sample holder 18 (e.g., a patient or other source) and with possible analytical procedures that may be performed on or for the sample.

[0089] Each sample holder 18 may be configured to hold a sample of liquid for analysis. Each sample holder may include a group of pneumatic connectors (e.g., nine, or another number) that may be configured to connect (e.g., mate) at each sample holder position on the carousel 42 to a pneumatic connector set 43, which may include as many pneumatic connectors as there are groups of connectors on the holder.

[0090] The carousel 42 may include one or more pneumatic actuator systems 44 (e.g., in the illustrated example, one pneumatic actuator system 44 for actuating up to two sample holders 18). Each pneumatic actuator system 44 may include a vacuum pump and an arrangement of conduits and valves. The number of valves in one possible example may be equal to the number of sample holder positions on the carousel 42 multiplied by the number of pneumatic connectors at each sample holder position (e.g., 72 for an arrangement of eight sample holder positions and nine pneumatic connectors).

[0091] The valves can be selectively actuated, for example, by the controller 36 to cause the flow of one or more liquids (e.g., sample liquid or liquid from a liquid reservoir of the sample holder 18) through the sample holder 18. A conduit connecting a pneumatic actuator system 44 with the holder platform pneumatic connector 43 can be incorporated into the holder platform 43.

[0092] The delivery analysis system 40 may include one or more (two in the illustrated example) docking stations 56. The matrix droplet extruder 14 may be connected to one or more of the docking stations 56. The docking stations 56 may include a set of interfaces to the matrix droplet extruders 14 connected to that docking station 56. The interfaces may include a set of pneumatic connectors for connecting a microfluidic channeling assembly in the matrix droplet extruder 14 to a pneumatic actuator assembly 58.

[0093] The matrix droplet extruder 14 may include a perforated droplet matrix extrusion layer 57 (see FIG. 3B) having an exterior droplet matrix extrusion surface 571 facing outward from the extruder 14. Typically, the droplet matrix extrusion layer 57 may be formed from a flat slab of stainless steel or another material that may be substantially non-absorbent and washable. Each matrix droplet extruder 14 may be configured to extrude a matrix of reagent droplets onto the droplet matrix extrusion surface 571 of the droplet matrix extrusion layer 57 through an array of perforations.

[0094] The matrix droplet extruder 14 may be configured to hold a number of reagent containers that can be separately inserted into the matrix droplet extruder 14 (e.g., at a facility for preparation of the matrix droplet extruder 14 or by a user of the transport analysis system 40). A particular reagent can be guided from one of the reagent containers (or a reagent reservoir emptied of its contents) by a microfluidic channeling assembly to a particular perforation on the droplet matrix extrusion surface 571. The configuration of the microfluidic channeling assembly can then be controlled by the controller 36 via the docking station 56, for example, according to the current step of a particular analysis to be performed on a sample in a particular sample holder 18.

[0095] For example, the delivery analytical system 40 may include a pressure actuator 60 configured to generate pneumatic pressure to effect and control the flow of reagents (through a microfluidic channeling assembly) to the droplet matrix extrusion surface 571. For example, the pressure actuator 60 may include one or more pressure pumps and one or more pressure regulating valves or structures.

[0096] The mechanical system 50 may be configured to manipulate the sample holder 18 and other manipulable components of the transport analytical system 40. For example, the mechanical system 50 may include one or more mechanical arms 51 that can grasp and manipulate the sample holder 18. The components of the mechanical system 50 may be pneumatically actuated. For example, the mechanical system 50 may include a pressure pump 66. A number of internal valves may be operated to control the movement of the mechanical arms 51 or other components of the mechanical system 50.

[0097] Rotation of the carousel 42 can bring a sample holder 18 into a station where a matrix droplet extruder 14 is located. When a sample in that sample holder 18 is placed in contact with a droplet matrix extruding surface 571 of the matrix droplet extruder 14, the controller 36 operates the mechanical arm 51 to lift the sample slide in that sample holder 18 from the sample holder 18 and press the sample slide against the droplet matrix extruding surface 571. For example, the gripping structure 72 of the mechanical arm 51 can be configured to grip and manipulate the slide, for example, using structures 79 ( FIG. 6A ) of the sample slide 80.

[0098] Typically, the reagent may be extruded through perforations in the droplet matrix extrusion surface 571 when the slide of the sample holder 18 is in contact with the droplet matrix extrusion surface 571. In this way, evaporation of the reagent droplets prior to contact with the sample may be prevented.

[0099] After a sample is contacted with droplet matrix extrusion surface 571, droplet matrix extrusion surface 571 can be washed to remove traces of the sample before another sample is contacted with droplet matrix extrusion surface 571. For example, mechanical arm 51 can include a rinse chamber 68. Rinse chamber 68 can include a shallow (e.g., having a depth of about 100 pm) recess whose rim contains a gasket (e.g., an O-ring or other gasket).

[0100] After removing the slide from the droplet matrix extrusion surface 571, the mechanical arm 51 can press the rinse chamber 68 against the droplet matrix extrusion surface 571. For example, a gasket of the rinse chamber 68 can form a seal between the rinse chamber 68 and the droplet matrix extrusion surface 571. The matrix droplet extruder 14 can then be operated to fill the rinse chamber 68 with rinse liquid via a rinse inlet opening of the droplet matrix extrusion surface 571. After the rinse chamber 68 is filled, the matrix droplet extruder 14 can be operated to remove the rinse liquid from the rinse chamber 68, for example, via a rinse outlet opening of the droplet matrix extrusion surface 571.

[0101] As an alternative or in addition to rinse chamber 68, mechanical system 50 or mechanical arm 51 may include one or more brushes, pads, wipers, or other structures to facilitate cleaning of droplet matrix extrusion surface 571.

[0102] Typically, after all steps of an analysis protocol have been applied to the sample in the sample holder 18, the sample holder 18 can be rotated to a station including an analysis module 54. For example, the analysis module 54 may include one or more imaging devices, optical sensors, e.g., cameras 54a, illumination sources, e.g., light sources 54b, or other components that allow for optical evaluation of the sample in the sample holder 18, e.g., after contacting an array of reagents at the droplet matrix extrusion surface 571. The analysis module 54 may include one or more electrical contacts, voltage or current sources, voltmeters or ammeters, electronic circuits, integrated circuits, or other components for electronic evaluation of the sample in the sample holder 18, e.g., after contacting an array of reagents at the droplet matrix extrusion surface 571.

[0103] For example, once the sample holder 18 is positioned in a station that includes the analysis module 54, the mechanical arm 51 can be manipulated to lift the sample slide from the sample holder 18 and place it in a viewing position relative to the analysis module 54. For example, the analysis module 54 can include a light-tight chamber that can allow for imaging of light reflected or fluoresced by the sample without interference from ambient light. The captured image of the slide, or other data, can be communicated to the processor 34, the external device 28, both, or another destination.

[0104] Typically, the sample holder 18 is removed from the carousel 42 after its samples have been examined by the analysis module 54. For example, an ejection mechanism can remove the sample holder 18 from the carousel 42 such that the sample holder 18 exits the multi-sample analysis device 10 via the ejection opening 20. For example, the ejection mechanism can include or cooperate with a ramp that allows the sample holder 18 removed from the carousel 42 to slide away from the carousel 42 and out through the ejection opening 20. Typically, the ejected sample holder 18 may be discarded. In some cases, the ejected sample holder 18 may be stored for further analysis.

[0105] Figure 6A shows a schematic of the sample holder of the multi-sample analysis device shown in Figure 1. Figure 6B shows a schematic of a chamber for applying suction to slides in the sample holder shown in Figure 6A.

[0106] The components of the sample holder 18 may be enclosed in a holder casing 76. The holder casing 76 may be configured to connect to the holder platform 45 of the carousel 42. A pneumatic connector 78 of the sample holder 18 may connect to a holder platform pneumatic connector 43 on the holder platform 45 and thus to the pneumatic actuator system 44.

[0107] During application of some steps of an analytical process to a sample in the sample holder 18, the pneumatic actuator system 44 can apply suction to one or more pneumatic connectors 78, while one or more other pneumatic connectors 78 can be connected to atmospheric pressure via breather vents. The pneumatic connectors 78 can be connected to various structures within the sample holder 18 via a conduit system 88. Selective application of suction and / or atmospheric pressure to the pneumatic connectors 78 can cause one or more liquid substances to flow between various components of the sample holder 18.

[0108] A sample may be introduced into the sample holder 18 via one or more (e.g., two or more or another number) openings into the sample channel 82. In the illustrated example, the sample channel 82 may be in the form of a capillary. For example, a sample chamber 82 in the form of a capillary may be suitable for samples including blood. For other types of samples, other forms of sample channels may be provided. For example, other types of sample channels or holders may include a strip or mass of adsorbent or adhesive material, a direct opening into a widened chamber, or other types of channels or openings.

[0109] After removing the holder cover 87, a sample can be introduced into the sample channel 82. For example, the sample may include a drop of blood from a pricked finger (typically the third or fourth drop after a previous drop has been wiped off, e.g., to avoid contamination of the sample), or another liquid of biological or other origin. Once the sample is loaded into the sample channel 82, the holder cover 87 can be replaced. Typically, after loading the sample into the sample channel 82 (or sometimes before loading), a barcode, RFID tag, or other identifier of the sample holder 18 can be scanned and associated with the origin of the sample (e.g., a particular patient) and the analytical procedure to be performed on the sample by the multi-sample analyzer 10.

[0110] In some cases, for example, when the sample is a blood sample, separation may be required. For example, blood analysis may require separating blood cells from the blood in the sample channel 82 to obtain plasma. For example, suction may be applied to the sample channel 82 by the pneumatic actuator system 44 via the pneumatic connector 78, the plasma chamber 83, and the blood separator 89 to draw blood from the sample channel 82 through the blood separator 89 and into the plasma chamber 83. For example, the blood separator 89 may include a filter, a microchannel, or other technology.

[0111] Structures within the holder cover 87 can function as breather vents to allow blood to flow through the blood separator 89 and into the plasma chamber 83. The suction (negative pressure) applied may be weak enough to avoid hemolysis (rupture of blood cells). If the sample contains a liquid or solution that does not contain biological cells or other types of suspended particles that may be removed by the blood separator 89, the sample may be aspirated through the blood separator 89 without substantially affecting the sample. In some cases, the sample holder 18 may be designed for such other types of samples, for example, without the blood separator 89.

[0112] The sample holder 18 may include a sample slide 80. The sample may be applied to a substrate 81 of the sample slide 80. For example, the substrate 81 may include a membrane, which may be composed of or include nitrocellulose, fiberglass, nanomesh, plastic, glass, or another suitable material for absorbing samples and other substances that may be applied to the substrate 81. If the substrate 81 is an adsorbent, the sample or applied reagents may be absorbed into the substrate 81 orthogonal to its surface, so that the concentration of absorbed sample or reagents per unit area may be higher than would be possible for a non-adsorbent surface. The membrane may be placed on a web of hydrophilic / hydrophobic mesh, where the hydrophobic side of the mesh faces the membrane and the hydrophilic side of the mesh faces away from the membrane. Wax, or other hydrophobic material, may be used to coat the top side of the membrane.

[0113] A substance to be applied to the substrate 81, e.g., a sample in the sample channel 82, the plasma chamber 83, or a liquid substance held in one or more liquid containers 84, can be drawn into an enclosed space 861 between a section of the holder casing 76 bounded by a sealing gasket 86 and a section of the sample slide 80 that contains the substrate 81. The dimensions of the enclosed space 861 can be designed to promote laminar flow of the sample or other liquid (e.g., to facilitate uniform application of the liquid to the substrate 81).

[0114] In some cases, suction is applied to the enclosed space 861 while the source of the applied substance is both open to a breather vent via pneumatic connector 78. Once the enclosed space 861 is filled with the substance, suction can be applied via chamber 77 (see FIG. 6B) to the side of the substrate 81 opposite the side exposed to the enclosed space 861 while the enclosed space 861 is open to a breather vent via pneumatic connector 78. This allows the substance filling the enclosed space 861 to be drawn into the substrate 81, facilitating absorption of the substance into the substrate 81.

[0115] In some cases, as shown diagrammatically in FIG. 7E, the surface of the substrate 81 may be divided into two or more substrate sections 8G. For example, each substrate section 8G may be provided with a separate sealing gasket. Alternatively or additionally, the substrate 81 itself may include one or more partitions 75. For example, the partitions 75 may be made of a material that inhibits or prevents the diffusion of liquid from one substrate section 8G to another. For example, different wet method steps may be applied to two or more different substrate sections 8G. In some cases, one or more substrate sections 8G may serve as a reference or control section, for example, where one or more process steps are not applied or where no sample is applied.

[0116] A variety of liquid substances can be held within the sample holder 18. Typically, the sample holder 18 can include between four and seven liquid containers 84. The number of pneumatic connectors 78 can be selected to allow transfer of liquid from the liquid containers 84 to the substrate 81, with additional pneumatic connectors 78 connected to a breather vent. In a non-bonded example, a sample holder 18 having seven liquid containers 84 can include nine pneumatic connectors 78. Similarly, a sample holder 18 having four liquid containers 84 can include six pneumatic connectors 78.

[0117] A particular sample holder 18 may be configured for application of a particular analytical procedure or family of similar analytical procedures, e.g., to a particular type of sample. For example, some or all of the sample holders 18 may be provided (e.g., by the manufacturer or user of the sample holder 18) with a selection of liquid substances, each sealed within a blister pack 85 (which should be understood to include any type of sealed package insertable into the sample holder 18). Sealing of the liquid substances within the blister pack 85 allows for storage of the liquid substances for extended periods of time, e.g., months or years.

[0118] The sample holder retaining structure 19 of the carousel 42, or the stations along the periphery of the carousel 42, may include one or more pins or protrusions (e.g., similar to the protrusions 61 of the docking stations 56, as described below) that are configured to be pressed (e.g., by the mechanical system 50) to puncture the blister pack 85 and empty its contents into a liquid container 84 for application to the substrate 81 during analysis of the sample in the sample holder 18 (the "wet method").

[0119] The sample slide 80 may be removed from the holder casing 76, for example, by the mechanical arm 51 or another component of the mechanical system 50. For example, the substrate 81 of the sample slide 80 may be positioned against the droplet matrix extrusion surface 571 of the matrix droplet extruder 14 or may be positioned in the analysis module 54. The sample slide 80 (see FIGS. 6A and 6B ) may include alignment structures 79 to facilitate precise alignment with the droplet matrix extrusion surface 571 or the analysis module 54.

[0120] For example, the alignment structures 79 may include mechanical structures (e.g., holes, depressions, pins, protrusions, or other mechanical structures), optical structures (e.g., mirrors, colored lines, bars, dots, patterns, or other optical structures), electromagnetic structures, or other structures to enable precise alignment of the sample slide 80 with, for example, a droplet matrix extrusion surface 571, a matrix droplet extruder 14, an analysis module 54, or a cooperating structure elsewhere.

[0121] Figure 7A shows a schematic representation of a matrix droplet extruder inserted into a docking station that may be used in the transport analysis system shown in Figure 3A. Figure 7B shows a schematic opposite view of the docking station shown in Figure 7A. Figure 7C shows a schematic representation of the rear side of the matrix droplet extruder partially seen in Figures 7A and 7B. Figure 7D is a schematic cross-section of the matrix droplet extruder shown in Figure 7C.

[0122] The docking station 56 in this example includes an insertion space 67 into which the matrix droplet extruder 14 can be inserted. For example, the matrix droplet extruder 14 can be handled using the puck handle 15 (e.g., without contaminating the droplet matrix extrusion surface 571).

[0123] The casing 91 (see FIG. 7C) of the matrix droplet extruder 14 may include a number of docking pneumatic connectors 92 that may be connectable to docking station connectors 65 (see FIG. 7B) in the insertion space 67 of the docking station 56. The internal structure of the matrix droplet extruder 14 may be controlled, for example, within the casing 91 by the pneumatic actuator assembly 58 via the docking pneumatic connectors 92.

[0124] The matrix droplet extruder 14 may include a plurality of reagent containers 93 (see FIG. 7D ), each for holding a liquid reagent or other liquid (e.g., a cleaning fluid, a hydraulic fluid, or other liquid, all of which are referred to herein as reagents for convenience and clarity). The reagent liquid may be provided in a reagent canister 94. For example, the reagent canister 94 may include a blister pack or other sealed container that may be emptied into the reagent container 93.

[0125] Prior to attachment to docking station 56, a reagent canister 94 may be placed into each of some or all of the reagent containers 93, e.g., by a manufacturer, distributor, or user of matrix droplet extruder 14. The selection of reagent canisters 94 (e.g., each housing a particular liquid reagent) for insertion into reagent containers 93 may be configured for a particular facility or type of facility (e.g., a clinic, mobile facility, hospital, or other type of facility), or for a particular purpose (e.g., blood testing or other clinical testing, chemical evaluation of a substance, or other purpose), or otherwise.

[0126] Liquid reagents may be stored in reagent canisters 94 for extended periods of time (e.g., months or years) (it should be understood that references herein to reagent vessels, canisters, conduits, or other reagent components or structures should be understood to mean components or structures for holding or directing the flow of any liquid utilized during operation of the matrix droplet extruder 14).

[0127] After inserting the matrix droplet extruder 14 into the insertion space 67, the activation plate 59 of the docking station 56 may be operated to prepare the matrix droplet extruder 14 for operation, for example, at the start of a work period (e.g., a work day) or otherwise after insertion of the matrix droplet extruder 14 but prior to operation of the matrix droplet extruder 14. A mechanism may push the activation plate 59 forward, toward the rear side of the matrix droplet extruder 14 (e.g., the side opposite to the side including the droplet matrix extrusion surface 571). In the illustrated example, the activation plate 59 can be urged forward by applying air pressure to the plate movement pneumatic connector 63 .

[0128] The activation plate 59 may include a plurality of protrusions 61, for example cylindrical pins or other protrusions. When the activation plate 59 is pressed into the matrix droplet extruder 14, the protrusions 61 may be inserted into the reagent canisters 94. When the protrusions 61 are inserted, a portion of each reagent canister 94 may burst or otherwise force the contents of that reagent canister 94 into the reagent vessel 93 in which the reagent canister 94 was inserted.

[0129] Typically, liquid reagents may be stored in the reagent containers 93 for a typical operating period (e.g., one day). In some cases, the multi-sample analyzer 10 may be provided with either internal refrigeration (e.g., a refrigeration structure enclosed within the housing 11) or external refrigeration (e.g., a refrigeration case into which the multi-sample analyzer 10 or matrix droplet extruder 14 may be inserted) to extend the usable life of the liquid reagents (e.g., for use in facilities with low daily sample throughput).

[0130] In some cases, docking station 56 may be configured to separately insert subsets of protrusions 61 into subsets of reagent canisters 94. For example, docking station 56 may include multiple separately operable activation plates 59 or may include mechanisms for selectively extending, retracting, or otherwise actuating individual protrusions 61 or groups of protrusions 61.

[0131] In addition to emptying the contents of the reagent canisters 94, pushing the activation plate 59 into the matrix droplet extruder 14 may also cause each of the docking station connectors 65 to connect to a corresponding docking pneumatic connector 92 (see FIG. 7C ) on the matrix droplet extruder 14. Thus, the pneumatic actuator assembly 58 may be actuated to supply air pressure to the matrix droplet extruder 14 via the docking pneumatic connector 92.

[0132] When the matrix droplet extruder 14 prints a pattern of reagent dots via the droplet extrusion surface 571, the pneumatic actuator assembly 58 can be operated to extrude liquid reagent from the reagent reservoir 93, through the reagent channels of the channel arrangement 96 (see FIG. 7D ), and into or towards the liquid management chip 98. The liquid management chip 98 may be controllable via a number of pneumatic control channels 97 of the channel arrangement 96 connecting each of the one or more docking pneumatic connectors 92 to one or more pneumatically operable gates 95 of the liquid management chip 98.

[0133] The liquid management chip 98 may include an internal arrangement of control conduits and distribution channels 99 to control and direct the flow of liquid reagent from the reagent reservoir 93, via the channel arrangement 96, to a particular perforation 69 of the droplet matrix extrusion surface 571. For example, the channel arrangement 96 and distribution channels 99 may be arranged to connect a particular reagent reservoir 93 to one perforation of the droplet matrix extrusion surface 571, or more typically to a plurality of particular perforations 69. Reagent may be distributed, for example, when air pressure is applied to the reagent at the reagent reservoir 93. Closing of the pneumatically operable gate 95 may prevent extrusion through a particular perforation 69.

[0134] In some cases, two or more reagent containers 93 may be connected to a single perforation 69. For example, one of the two or more reagent containers 93 may be filled first, while another reagent container is filled when the first reagent container is emptied or has been open for a predetermined period of time. In some cases, wash fluid may be pushed through perforation 69 during the sequential pushing of reagents from different reagent containers 93.

[0135] In some cases, extrusion of two or more different reagents through a single perforation 69 may enable the formation of droplets that include a mixture or other combination of both reagents. For example, the perforation 69 may be elongated to enable connection to two or more distribution channels 99. As another example, the droplet matrix extrusion surface 571 may include grooves or other structures that enable or facilitate mixing (e.g., via one or more channeling effects) between different reagents extruded by two or more separate but adjacent perforations 69.

[0136] The liquid management chip 98 can be controlled by a pneumatic actuator assembly 58 (shown in FIGS. 3 and 4 ) to direct a particular liquid reagent from a selected reagent reservoir 93 to one or more selected perforations 69 on the droplet matrix extrusion surface 571. The liquid reagent can be extruded through the perforations 69 to print the reagent, for example, onto a sample on the substrate 81 of the sample slide 80.

[0137] FIG. 7E shows a schematic of an example of a slide with extruded reagent dots.

[0138] In the illustrated example, the reagent dots 71 are printed on a substrate 81. In the illustrated example, the substrate 81 is divided into a plurality of substrate sections 8G by partitions 75, although the substrate 81 may be a single undivided surface (e.g., a membrane). In the illustrated example, the reagent dots 71 are organized into dot rows 73, where the separation between adjacent dot rows 73 is, optionally, greater than the separation between adjacent reagent dots 71 within a single dot row 73. For example, each dot row 73 may include reagent dots 71 of a single reagent (e.g., where any mixing between adjacent reagent dots 71 is unlikely to affect the results), or different dot rows 73 may be of different reagents where mixing should be avoided.

[0139] As an alternative or in addition to organizing the reagent dots 71 into separate dot rows 73, groups of reagent dots 71 may be organized into separate columns, clusters, or otherwise, or may be organized without separation between groups. In another example, portions of the substrate 81 may be coated or infused (e.g., using a solid ink printer) with a repellent agent to limit absorption to predetermined areas of the substrate 81 (e.g., to create separate assay areas on the substrate 81).

[0140] FIG. 8 shows diagrammatically the transport of a sample holder to a station of the transport and analysis system shown in FIG.

[0141] Stations A-H are distributed around the circumference of the carousel 42. A transport mechanism 70 may be configured to rotate in the direction indicated by the arrow to transport each loaded sample holder 18 from one of stations A-H to the subsequent station B-A. After a sample holder 18 is transported to the next station, the carousel 42 remains stationary (e.g., does not rotate) for a predetermined period of time.

[0142] FIG. 9 is a flow chart illustrating a possible method of operation of a multi-sample analysis device, in accordance with one embodiment of the present invention.

[0143] With respect to any flowcharts referenced herein, it should be understood that the division of the illustrated method into separate operations represented by flowchart blocks has been chosen for convenience and clarity only. It is possible to divide the illustrated method into separate operations with equivalent results. Such alternative divisions of the illustrated method into separate operations should be understood as representing alternative embodiments of the illustrated method.

[0144] Similarly, unless otherwise noted, it should be understood that the illustrated order of performance of the operations represented by any flowchart blocks referenced herein has been chosen for convenience and clarity only. The operations of the illustrated method may be performed in alternate orders, or simultaneously, with equivalent results. Such reordering of the operations of the illustrated method should be understood as representing alternative embodiments of the illustrated method.

[0145] The POC sample analysis method 100 may be performed by a processor, such as processor 36 of the multi-sample analysis apparatus 10 , or by another processor in communication with processor 36 or the multi-sample analysis apparatus 10 .

[0146] A sample holder 18 may be received (block 110). For example, the sample holder 18 may be loaded into the multi-sample analyzer 10 via the sample holder insertion opening 16 and may be loaded onto a transport mechanism 70, e.g., the carousel 42. In the example shown in Figure 8, the sample holder 18 is loaded onto the carousel 42 at station D, e.g., via the loading mechanism 47.

[0147] Each sample holder 18 is transported by the transport mechanism 70 to the next station (block 120), where the sample holder 18 remains for a predetermined period of time (e.g., one minute, or another suitable period of time). For example, the sample holder 18 loaded onto the carousel 42 at station D is transported to station E. The other sample holders 18 on the carousel 42 are similarly transported to the next stations.

[0148] Actions may be performed on the sample holders 18 remaining at each station for a predetermined period of time (block 130). The actions taken may depend on the current step of the analytical process being performed on the samples held in each sample holder 18.

[0149] For example, steps of an ELISA protocol can begin to be applied to the sample in sample holder 18 when sample holder 18 is in station A. Subsequent steps of the ELISA protocol can be performed at each subsequent station B-G (depending on the type or ELISA protocol, e.g., indirect or sandwich ELISA protocol). In this case, if the sample is a blood sample, blood can be flowed from sample channel 82 through blood separator 89 at each of stations E-H between the loading of sample holder 18 at station D and the application of the first step of the ELISA protocol at station A.

[0150] In some cases, the actions taken may include waiting at a station without processing a sample held in sample holder 18. In some cases, waiting at a station may provide an incubation step of an ELISA protocol.

[0151] In some cases, this action may include placing the sample in contact with an array of reagent droplets on the droplet matrix extrusion surface 571 of the matrix droplet extruder 14, in the illustrated example at station B or F. When the sample holder 18 is transported to station B or F, the mechanical arm 51 may lift the sample slide 80 from the sample holder 18 and bring the substrate 81 into contact with the droplet matrix extrusion surface 571. For example, if the sample contains or is suspected to contain one or more specific antigens, the array of reagent droplets may include one or more specific detection antibodies to which detection molecules (e.g., fluorescent or other dyes such as horseradish peroxidase) are attached. Typically, the particular contents of each reagent droplet are replicated, for example, in adjacent rows or columns of reagent droplets.

[0152] After removing the slide 80 from the droplet matrix extrusion surface 571, the machine system 50 can position the rinse chamber 68 on the droplet matrix extrusion surface 571. The pneumatic actuator assembly 58 can then be actuated to cause the wash fluid to flow from the wash fluid reservoir of the matrix droplet extruder 14 into the rinse chamber 68 via the wash fluid inlet. After a predetermined period of time has elapsed, the pneumatic actuator assembly 58 can be actuated to drain the wash fluid from the rinse chamber 68 via the wash fluid outlet into the waste fluid reservoir of the matrix droplet extruder 14. The machine system 50 can remove the rinse chamber 68 from the droplet matrix extrusion surface 571.

[0153] At least in some stations, the sample may be subjected to one or more wet methods. For example, the substrate 81 on which the ELISA protocol is applied may be subjected to one or more coating, washing, blocking or other steps. In particular, the coating step may include coating with the sample or coating with a capture antibody before coating with the sample.

[0154] When the sample holder 18 is transferred to a station that includes an analysis module 54 (station H in the illustrated example), e.g., after some or all processing steps have been applied to the sample, the sample may be inspected by the analysis module 54. For example, the machine system 50 may be controlled to lift the sample slide 80 from the sample holder 18 such that the sample slide 80, or at least the substrate 81, is inserted into the analysis module 54, e.g., into a light-tight chamber of the analysis module 54.

[0155] The analysis module 54 may then be operated to acquire one or more images of the substrate 81, for example, under various types of illumination or under fluorescence of the substrate 81. Alternatively or additionally, the analysis module 54 may apply electronics to measure one or more electrical properties of locations on the substrate 81. The analysis may include determining a correspondence between the results at each location on the substrate 81 and a reagent that the substrate 81 was placed in contact with at that location.

[0156] The analysis may include mapping measured properties of the substrate within the reagent dots (which may have, for example, irregular shapes). The analysis may include combining measurements at different points on the reagent dots, or different reagent dots of the same reagent, to calculate statistically significant results. The analysis may include preparing a report summarizing the results of the analysis.

[0157] When all actions for the sample holder 18 have been completed (block 140), the mechanical system 50 may be operated to remove the sample holder 18 from the carousel 42 and eject it from the multi-sample analyzer 10 (block 150). Typically, the final action performed on the sample holder 18 is inspection of the sample slide 80 by the analysis module 54.

[0158] If additional actions remain to be performed on the sample holder 18 (block 140), the sample holder 18 is transported to the next station (block 120) where the additional actions can be performed (block 130).

[0159] The matrix droplet extruder 14 can be incorporated into a stand-alone reagent dot printing system for pre-printing reagent dots onto a sample slide 80. Similarly, the pre-printed slides may be incorporated into a sample holder 18 for use with a stand-alone sample analysis system.

[0160] FIG. 10 illustrates a schematic diagram of an example of a reagent dot printing system.

[0161] The reagent dot printing system 200 can be utilized to print an array of reagent dots 71 onto a surface. In particular, the reagent dot printing system 200 can be operated to print an array of reagent dots 71 onto a slide to generate a pre-printed sample slide 204 in which the reagent dots 71 are pre-extruded. As used herein, pre-extrusion means extruding reagent droplets onto the substrate 81 prior to introducing a sample onto the substrate 81.

[0162] For example, the dot-printing device 202 can incorporate the docking station 56. The dot-printing device 202 can include one or more pneumatic actuators 203 and conduits for operation of the matrix droplet extruder 14 that are connected to the docking station 56. The dot-printing device 202 can incorporate or communicate with a controller 201 to control the operation of the pneumatic actuators. For example, the controller 201 can be configured to control the pressure generated by the pressure actuator 60 (not shown in FIG. 10 ) of the pneumatic actuator 203 and applied to one or more docking pneumatic connectors 92 of the matrix droplet extruder 14, or the operation time of the pressure actuator 60, or the duration for which the pressure is applied to one or more docking pneumatic connectors 92.

[0163] In some cases, the dot-printing device 202 can include a user-operable controller to control the operation of the dot-printing device 202. In some cases, the operation of the dot-printing device 202 may be controlled via an external device 28 (e.g., a computer, a smartphone, or other device) that communicates with the dot-printing device 202 via a wired or wireless connection.

[0164] For example, the dot-printing device 202 may be operated (e.g., by a pharmacist, physician, or other trained user) to generate pre-printed sample slides 204. Typically, the dot-printing device 202 may be operated to generate a plurality of pre-printed sample slides 204 designed for use by a particular user (person or institution) under particular conditions (e.g., for application of a particular protocol or for detection of a particular physiological disorder, toxin, contaminant, or other component of a liquid sample), in a geographic location (e.g., where particular conditions prevail), or under other particular applications.

[0165] The pre-printed sample slide 204 may be immediately inserted into the sample holder 18 or may be stored separately for later insertion into the sample holder 18 or for other use. Storage of the pre-printed sample slide 204, or the sample holder 18 with the pre-printed sample slide 204 inserted, may be under controlled conditions designed to preserve the integrity of the reagent dots printed on the pre-printed sample slide 204.

[0166] FIG. 11 shows a schematic of an example of a stand-alone sample processing system.

[0167] The sample processing system 210 is configured to perform one or more processing steps, in particular wet method steps, on a sample introduced to the sample holder 18. For example, the sample processing device 212 may include a pneumatic actuator that induces liquid flow of one or more samples or other liquids in the sample holder 18 that is inserted into the sample processing device 212.

[0168] If the sample holder 18 includes a pre-printed sample slide 204, the processed sample may interact with the reagent dots on the pre-printed sample slide 204 to produce an optically assessable result (e.g., color change or fluorescence). Typically, the sample processing device 212 includes an analysis module 54 for optically or electronically inspecting the pre-printed sample slide 204 after processing occurs in the sample holder 18 inserted into the sample processing device 212. In some cases, the sample processing device 212 may include a mechanical system (e.g., having some components of the mechanical system 50 as described above) for removing the pre-printed sample slide 204 from the sample holder 18. In other cases, a user may remove the pre-printed sample slide 204 from the sample holder 18 for analysis by the analysis module 54.

[0169] For example, the sample processing device 212 may be utilized by a private user (e.g., a patient) or other user who does not need to analyze a large number of samples. Thus, a user of the sample processing device 212 may purchase pre-printed sample slides 204 for a particular test, or for a limited number of tests, and utilize an appropriate sample holder 18 to perform the appropriate wet method steps on the samples.

[0170] According to some embodiments of the invention, the sample analysis device can include a sample holder and a matrix droplet extruder configured to controllably extrude two or more arrays of dots onto a droplet matrix extrusion surface of the matrix droplet extruder, the matrix extrusion surface facing outward from the matrix droplet extruder. The sample holder in such an embodiment can include a sample slide having two or more isolation zones, and the sample analysis device can be configured to manipulate the sample slide to perform, for example, a primary printing of an array of droplets of one or more first antibody agents onto the two or more isolation zones, followed by a secondary printing of one or more second antibody agents onto the two or more isolation zones on the sample slide. According to some embodiments of the invention, various preparation steps, for example washing, blocking, and other steps, can be performed between the two printings.

[0171] Figure 12A is a front view of a sample holder 1200 of a multi-sample analysis device according to some embodiments of the present invention, with a sample slide inserted therein, and Figure 12B is a front view of a sample holder 1200 of a multi-sample analysis device according to some embodiments of the present invention, with a sample slide removed.

[0172] The components of the sample holder 1200 may be enclosed within a holder casing 76a. The holder casing 76a may be configured to connect to a holder platform 45 of the carousel 42 or another platform and may be movable or fixed in place. The pneumatic connector 78a of the sample holder 1200 may be connected to a pneumatic actuator system via a holder platform pneumatic connector.

[0173] During application of some steps of an analytical process to a sample in the sample holder 1200, the pneumatic actuator system may apply suction to one or more pneumatic connectors 78a while one or more other pneumatic connectors 78a may be connected to atmospheric pressure via a breather vent. The pneumatic connectors 78a may be connected to various structures within the sample holder 1200 via a conduit system 88a. Selective application of suction and / or atmospheric pressure to the pneumatic connectors 78a may cause one or more liquid substances to flow between various components of the sample holder 1200.

[0174] A sample may be introduced into the sample holder 1200 via one or more (e.g., two or another number) openings into one (or more) sample channels 82a. The sample channel 82a may be in the form of a capillary, e.g., suitable for blood-containing samples. For other types of samples, other forms of sample channels may be provided. For example, other types of sample channels or holders may include a strip or mass of adsorbent or adhesive material, a direct opening into a widened chamber, or other types of channels or openings.

[0175] A sample can be introduced into the sample channel 82a. For example, the sample can include a drop of blood from a pricked finger (typically the third or fourth drop after a previous drop has been wiped off, e.g., to avoid contamination of the sample), or another liquid of biological or other origin. Once the sample is loaded into the sample channel 82a, a holder cover 87a can be placed over the inlet of the sample channel 82a to seal it. Typically, after loading the sample into the sample channel 82a (or possibly before loading), a barcode, RFID tag, or other identifier of the sample holder 1200 can be scanned and associated with the origin of the sample (e.g., the identity of a particular patient) and the analytical procedure to be performed on the sample by the multi-sample analyzer.

[0176] In some cases, for example, when the sample is a blood sample, separation may be required. For example, blood analysis may require separating blood cells from the blood in the sample channel 82a to obtain plasma. For example, suction can be applied to the sample channel 82a via the pneumatic connector 78a, the plasma chamber 83a, and the blood separator 89a by a pneumatic actuator system to draw blood from the sample channel 82a through the blood separator 89a and into the plasma chamber 83a. For example, the blood separator 89a can include a filter, a microchannel, or another device using other separation techniques.

[0177] The holder cover 87a may include a breather vent that allows blood to flow through the blood separator 89a and into the plasma chamber 83a. In some other embodiments, the sample holder 1200 may be designed for such other types of samples.

[0178] The sample holder 1200 can include a sample slide 80a configured to be inserted into or removed from a pocket 1201 in the sample holder 1200. A sample can be applied to two or more substrate patches 81a and 81b of the sample slide 80a. For example, the substrate patches 81a and 81b can each include a membrane, which can be composed of or include nitrocellulose, fiberglass, nanomesh, plastic, glass, or another suitable material for absorbing samples and other substances that can be applied to the substrate patches 81a and 81b. If the substrate patches 81a and 81b are adsorbents, the sample or applied reagents can be absorbed into the substrate patches 81a and 81b at right angles to their surfaces, so that the concentration of absorbed sample or reagents per unit area can be greater than would be possible for a non-adsorbent surface.

[0179] When the sample slide 80a is inside the pocket 1201 of the sample holder 1200, substances to be applied to the substrate patches 81a and 81b, e.g., samples in the sample channel 82a, the plasma chamber 83a, or liquid substances held in one or more liquid containers 84a, can be drawn into the enclosed spaces 861a and 861b between the section of the holder casing 76a bounded by the sealing gasket 86a and either the section of the sample slide 80a that contains the substrate patch 81a or the substrate patch 81b. The dimensions of the enclosed spaces 861a and 861b can be designed to obtain a laminar flow of the sample or other liquid (e.g., to facilitate uniform application of the sample or one or more types of other liquid to the substrate patches 81a and / or 81b).

[0180] In some cases, suction can be applied to the sealed spaces 861a and 861b, while the sources of the applied substance are both open to the breather vent via the pneumatic connector 78a. Once the sealed spaces 861a and / or 861b are filled with the substance, suction can be applied to the side of the substrate 81a opposite the side exposed to the sealed spaces 861a and 861b via the chamber 77 (see FIG. 6B), while the sealed spaces 861a and 861b are open to the breather vent via the pneumatic connector 78a. The substance filling the sealed spaces 861a and 861b can be drawn into the substrate patches 81a and 81b, respectively, thus facilitating absorption of the substance into the substrate patches 81a and 81b.

[0181] A variety of liquid substances can be held in the sample holder 1200. Typically, the sample holder 1200 can include multiple liquid containers 84a. The number of pneumatic connectors 78a can be selected to allow transfer of liquid from the liquid containers 84a to the substrate patches 81a and 81b, with the additional pneumatic connectors 78a connected to breather vents.

[0182] A particular sample holder 1200 may be configured for application of a particular analytical procedure or family of similar analytical procedures, e.g., to a particular type of sample. For example, some or all of the sample holders 1200 may be provided (e.g., by the manufacturer or user of the sample holder 18) with a selection of liquid substances, each sealed within a blister pack 85a (which may include any type of sealed package insertable into the sample holder 1200).

[0183] The sample slide 80a may include a locking mechanism that locks the sample slide 80a in place when the sample slide 80a is fully inserted inside the sample holder 1200. For example, a lock 1220 may be included that, when the sample slide 80a is fully inserted inside the sample holder 1200, is operated, e.g., by a mechanical arm, to secure the sample slide 80a in position, and when it is desired to remove the sample slide 80a from the sample holder 1200, is released, e.g., by a mechanical arm, to release the sample slide 80a for removal from the sample holder 1200.

[0184] FIG. 13A shows a sample slide in a first printing position with a matrix droplet extruder configured to perform a dual printing assay according to some embodiments of the present application.

[0185] FIG. 13B shows a sample slide in a second print position with a matrix droplet extruder configured to perform a dual print assay according to some embodiments of the present application.

[0186] The matrix droplet extruder 1300 may be used in a sample analysis system according to some embodiments of the present invention.

[0187] FIG. 13C shows a rear view of a matrix droplet extruder 1300 according to some embodiments of the present invention.

[0188] The casing 91a of the matrix droplet extruder 1300 may include a number of docking pneumatic connectors 92a that may be connectable to docking station connectors (e.g., docking station connector 65, see FIG. 7B) of a docking station (e.g., docking station 56). For example, the internal structure of the matrix droplet extruder 1300 within the casing 91a may be controlled by a pneumatic actuator assembly (e.g., pneumatic actuator assembly 58 via the docking pneumatic connectors 92).

[0189] Matrix droplet extruder 1300 may include multiple reagent containers (e.g., containers 93a), each for holding a liquid reagent or other liquid (e.g., cleaning fluid, hydraulic fluid, or other liquid, all of which are referred to herein as reagents for convenience and clarity). The reagent liquid may be provided in various types of reagent containers, e.g., canisters. For example, the reagent canisters may include blister packs or other sealed containers that may be emptied into the reagent containers.

[0190] The matrix droplet extruder 1300 may include a liquid management chip having an internal arrangement of control conduits and distribution channels to control and direct the flow of liquid reagent from a reagent reservoir to a particular perforation 69a of the droplet matrix extrusion surface 571a via a channel arrangement, which may be arranged to connect a particular reagent reservoir to one perforation, or more typically to a plurality of particular perforations 69a of the droplet matrix extrusion surface 571a. The reagent may be distributed, for example, when air pressure is applied to the reagent at the reagent reservoir. Closing a pneumatically operable gate may prevent extrusion through a particular perforation 69a.

[0191] The extrusion surface 571a of the extrusion matrix extrusion device 1300 can include two (or more) separate print zones 1302a and 1302b, each of which can include a plurality of perforations 69a. The separate print zones can be useful for analytical processes that require printing a reagent onto a sample on a sample slide more than once.

[0192] A cleaner 1304 may be provided for cleaning the print zones 1302a and 1302b on the matrix extrusion surface 571a. The cleaner may be located in a waiting (idle) position (as shown in Figures 13A and 13B) when the sample slide 80a is positioned above the print zone. If cleaning of the print zone is required, the cleaner may be transported (e.g., by a mechanical arm or by another transport mechanism) to a position above the print zones 1302a and 1302b of the matrix extrusion surface 571a to perform the cleaning.

[0193] The cleaner 1304 can include an inlet port 1306 for introducing a cleaning material (eg, a cleaning fluid) onto the print zone and for expelling the cleaning material from the print zone.

[0194] When the sample slide 80a is not above the print zone, a washer 1304 can be positioned above the print zone to maintain a moist enclosure bounded by gaskets 1308a and 1308b over perforations 69a to prevent the perforations from becoming blocked by dried material.

[0195] Matrix droplet extruders such as those shown in Figures 13A and 13B are suitable for use in sample analysis systems that require dual (or more) printing. For example, an analysis protocol (e.g., ELISA) may require introducing a first antibody to a sample, followed by introducing a second antibody to the sample. Such protocol steps may include printing a first set of antibodies onto a sample slide, binding the first antibody, washing away any remaining unbound first antibody, and printing a second set of secondary antibodies.

[0196] In some embodiments of the present invention, the sample analysis system can include one or more matrix droplet extruders, such as those shown in Figures 13A and 13B. Having two or more matrix droplet extruders, such as those shown in Figures 13A and 13B, can facilitate the execution of various analysis protocols that require a combination of printing options. Thus, for example, it may be possible to perform an analysis protocol for each patient sample that has two or more overlapping printed assays, or multiple different tests (e.g., to test for multiple biomarkers, an upper print zone of a first matrix droplet extruder for testing for biomarker test panel A, a lower print zone of that first matrix droplet extruder for testing for biomarker test panel B, an upper print zone and a lower print zone of a second matrix droplet extruder for testing for biomarker test panel C that requires a dual print assay, etc.).

[0197] A sample analysis system according to some embodiments of the present invention can include a matrix droplet extruder as shown in Figures 13A and 13B. The sample slide 80a can be removed from the sample holder 1200 and placed on a first print zone 1302a, and printing of a first array of a first antibody is performed on the sample slide (e.g., sample membrane). The sample slide 80a can then be removed from the first print position, returned to the sample holder 1200, and subjected to additional processing (e.g., washing), before being removed from the sample holder 1200 again and placed on a second print zone 1302b, and printing of a second array of a second antibody is performed on the printed first array of the first antibody. Once placed on one of the print zones, the holes 1227 in the sample slide 80a (see Figure 12B) can be used in cooperation with matching pins to properly align (register) the sample slide 80a over the appropriate print zone.

[0198] Some embodiments of the present invention may be used in performing a variety of assays (eg, direct assays, indirect assays, sandwich assays, etc.).

[0199] FIG. 13D is a front view of the cleaner 1304 of the matrix droplet extruder shown in FIGS. 13A and 13B.

[0200] The cleaner 1304 may include two (or more) insulated cleaning enclosures 1310a and 1310b that are separated from one another, for example, by gaskets 1308a and 1308b that insulatingly surround the cleaning enclosures 1310a and 1310b, respectively.

[0201] A cleaning agent (e.g., liquid) can be introduced into cleaning enclosures 1310a and 1310b and discharged from these enclosures in one or more cycles to clean print zones 1302a and 1302b when the cleaner is positioned over these print zones and operated. The cleaner may be connected to a first container for containing the cleaning liquid and a second container for containing the cleaning agent after it has been used to clean the print zones.

[0202] FIG. 14 is a schematic diagram of a sample analysis system 1400 according to some embodiments of the present invention.

[0203] The sample analysis system 1400 can include a housing 1420 that houses the matrix droplet extruder 1300, a linear displacement mechanism 1404 for moving the sample holder 1200 on the movable docking station 1415 from the input port 1402 to a position facing the matrix droplet extruder 1300 or for moving the sample holder 1200 to the docking station 1415 facing the matrix droplet extruder 1300, and a transport mechanism that can include a lifting mechanism 1406 for engaging the sample slide 80a and lifting it to at least one printing position on the extrusion surface of the matrix droplet extruder 1300. In some embodiments, the lifting mechanism 1406 is configured to engage the sample slide 80a and lift it to a first printing position and / or a second printing position on the extrusion surface of the matrix droplet extruder 1300. After printing is completed, the lifting and / or displacement mechanism 1404 positions the sample slide 80a in front of an imaging device 1416 (e.g., a camera) for capturing an image of the sample slide 80a with the imaging device. After capturing the image, the sample holder 1200 with the sample slide 80a is discarded through a port 1422 into a waste container 1424 and retained therein. A controller 1410 is provided and configured to control the operation of the displacement mechanism 1404, the lifting mechanism 1406, the docking station 1415, and the imaging device 1416.

[0204] The transport mechanism (e.g., the displacement mechanism and / or lifting mechanism) may include one or more tracks, motors and transmissions, chains and / or belts, and / or any other known mechanism or mechanisms for displacing and / or lifting objects.

[0205] The sample analysis system 1400 may be used at the point of care to perform various tests on patient biological samples (e.g., blood, urine, saliva, etc.), according to some embodiments of the present invention. Each patient may be assigned a single sample holder that is loaded with the sample to be tested for that patient. Each patient's sample slide may undergo various test stages, for example as described above, and when the test is completed, the sample holder with the patient's sample slide may be disposed of in a waste container. From time to time, or when the waste container is filled, the waste container may be emptied via port 1426, or the entire waste container may be replaced with a new empty waste container. The used sample holder with the used sample slide may preferably be treated for biological waste according to appropriate medical standards.

[0206] Various embodiments are disclosed herein. The features of a particular embodiment can be combined with the features of other embodiments, and therefore a particular embodiment can be a combination of features of more than one embodiment. The above description of the embodiments of the present invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. Those skilled in the art should appreciate that many modifications, variations, substitutions, changes, and equivalents are possible in light of the above teachings. It is therefore to be understood that the appended claims are intended to cover all such modifications and variations as fall within the true spirit of the invention.

[0207] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. It is therefore to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

1. 1. A matrix droplet extruder comprising: A casing; one or more reagent containers; a plurality of pneumatic connectors on the casing, each configured to be connected to a pneumatic actuator to provide controlled air pressure to one or more of the plurality of pneumatic connectors; a droplet matrix extrusion surface having one or more print zones, each print zone comprising an array of perforations; a liquid management tip for dispensing one or more reagents from the one or more reagent reservoirs through an array of perforations in the one or more print zones and for repeatedly generating a matrix of droplets upon application of air pressure to the one or more reagents; A matrix droplet extruder comprising:

2. 10. The matrix droplet extruder of claim 1, wherein the droplet matrix extrusion surface comprises a pattern to enable mixing of two or more droplets.

3. The matrix droplet extruder of claim 1 , further comprising a washer for cleaning the one or more print zones.

4. 4. The matrix droplet extruder of claim 3, wherein the cleaner is configured to move between an idle waiting position away from the one or more print zones and a cleaning position above the one or more print zones.

5. 5. The matrix droplet extruder of claim 4, wherein the washer comprises an inlet port for introducing a washer to the one or more print zones and discharging the washer therefrom.

6. A pneumatic actuator; A controller for controlling the pneumatic actuator; a docking station having a plurality of pneumatic docking station connectors connected to the pneumatic actuator; 2. The matrix droplet extruder of claim 1, comprising:

7. 7. The matrix droplet extruder of claim 6, wherein the controller is configured to control a duration for which pressure is applied by the pneumatic actuator to one of the plurality of pneumatic connectors.

8. 7. The matrix droplet extruder of claim 6, wherein the controller is configured to control a pressure applied by the pneumatic actuator to one of the plurality of pneumatic connectors.

9. A sample holder, a casing having a pocket; (9) a removable sample slide having one or more substrate patches configured to be inserted into or removed from the pocket; a sample channel for introducing a liquid sample into one or more enclosed spaces between the sample slide and the casing section, for absorbing the sample liquid into the one or more substrate patches; A sample holder comprising:

10. The sample holder of claim 9 , wherein the substrate patch comprises a membrane.

11. 11. The sample holder of claim 10, wherein the membrane comprises a material selected from the group of materials consisting of nitrocellulose, fiberglass, nanomesh, plastic and glass.

12. 10. The sample holder of claim 9, further comprising a plurality of pneumatic connectors on the casing, each of the plurality of pneumatic connectors being connected to a pneumatic or vacuum actuator and configured to provide controlled air pressure or vacuum to one or more of the plurality of pneumatic connectors to obtain laminar flow of the sample or other liquid into the one or more enclosed spaces.

13. 13. The sample holder of claim 12, further comprising one or more liquid containers containing one or more of said other liquids.

14. The sample holder of claim 9 , further comprising a lock for locking the sample slide when fully inserted into the pocket.

15. 1. A sample analysis system comprising: A pneumatic actuator; One or more sample holders, a casing having a pocket; A liquid container; a removable sample slide having a substrate with one or more substrate patches configured to be inserted into or removed from the pocket; a sample channel for introducing a liquid sample into one or more enclosed spaces between the sample slide and the casing section, for absorbing the sample liquid into the one or more substrate patches; one or more sample holders comprising: a controller configured to control the pneumatic actuators to sequentially flow one or more liquids from one or more of the liquid containers to or from the sample slide in its sample holder; an analysis module for examining the sample slide after the sample has contacted a plurality of dots of one or more reagents printed on the substrate; A sample analysis system comprising:

16. 16. The sample analysis system of claim 15, further comprising a transport mechanism that transports each of the one or more sample holders sequentially to one station of a plurality of stations along the transport mechanism, and the controller is further configured to control the transport mechanism to cause the transport mechanism to move the one or more sample holders such that each of the one or more sample holders moves sequentially from a current station of the plurality of stations to a next station of the plurality of stations.

17. 17. The sample analysis system of claim 16, wherein the transport mechanism comprises a rotatable carousel, and the plurality of pneumatic connectors are positioned to enable connection of each of the one or more sample holders at positions on the periphery of the carousel.

18. 20. The sample analysis system of claim 17, wherein the plurality of pneumatic connectors are positioned to allow connection of the one or more sample holders at equally spaced locations along a circumference of the carousel.

19. 17. The sample analysis system of claim 16, wherein the plurality of stations comprises at least one docking station to which a matrix droplet extruder can be attached, the docking station comprising a plurality of docking station connectors for connecting to a plurality of docking pneumatic connectors of the matrix droplet extruder, the docking station being controllable by the controller to selectively apply pressure to each of the docking station connectors to control the extrusion of droplets from one or more reagent containers of the matrix droplet extruder onto a droplet matrix extrusion surface of the matrix droplet extruder to form the plurality of reagent droplets.

20. 20. The sample analysis system of claim 19, wherein the at least one docking station comprises a mechanism for emptying a reagent canister into one of the one or more reagent vessels.

21. 20. The sample analysis system of claim 19, further comprising a mechanical system controlled by the controller to manipulate the substrate of each of the one or more sample holders to place the substrate in contact with the droplet matrix extrusion surface to enable the plurality of reagent dots to be extruded onto the substrate and to expose the substrate to the analysis module.

22. 22. The sample analysis system of claim 21, wherein the mechanical system is pneumatically controlled.

23. 22. The sample analysis system of claim 21, wherein the mechanical system comprises a rinse chamber configured to be positioned relative to the droplet matrix extrusion surface to enable cleaning of the droplet matrix extrusion surface.

24. 16. The sample analysis system of claim 15, wherein the analysis module comprises an optical system for acquiring an image of the substrate or an electronic system for measuring an electrical property of the substrate.

25. The sample analysis system of claim 15 , wherein the substrate includes the dots of one or more reagents pre-extruded onto the substrate.

26. 11. The sample analysis system, further comprising a matrix droplet extruder for printing a plurality of dots of the one or more reagents, the matrix droplet extruder comprising: A casing; one or more reagent containers; a second plurality of pneumatic connectors on the casing, each of the second plurality of pneumatic connectors connected to the pneumatic actuator and configured to provide controlled air pressure to one or more of the second plurality of pneumatic connectors; a droplet matrix extrusion surface having one or more print zones, each print zone comprising an array of perforations; a liquid management tip for dispensing one or more reagents from the one or more reagent reservoirs through an array of perforations in the one or more print zones and for repeatedly generating a matrix of droplets upon application of air pressure to the one or more reagents; The sample analysis system of claim 15 .

27. 27. The sample analysis system of claim 26, wherein the one or more print zones comprise two print zones.

28. 27. The sample analysis system of claim 26, further comprising a transport mechanism for transporting each of the one or more sample holders to and from a position facing the matrix droplet extruder and for positioning a sample slide of each of the one or more sample holders above one of the one or more print zones.

29. The sample analysis system of claim 15 , further comprising a waste container for disposing of used ones of the one or more sample holders.

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