Magnet assembly for preventing extraction particle retention

Abstract

This document discloses embodiments of a fixed magnet assembly that can be implemented in an automated platform for performing polynucleotide extraction from biological samples and preparing polynucleotides into amplification-ready forms. The fixed magnet assembly can be used to provide magnetic energy to a container containing magnetic particles and polynucleotides, causing the magnetic particles to separate from the reaction mixture. This can prevent or reduce the retention of magnetic particles in the prepared amplification-ready sample, thereby improving amplification results.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 948,003, filed December 13, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to an automated platform for performing polynucleotide extraction from biological samples and preparing polynucleotides into PCR-ready forms. More specifically, this disclosure relates to a stationary magnet assembly that can be used with such an automated platform to provide magnetic energy to a container containing magnetic particles and polynucleotides, thereby separating the magnetic particles from the reaction mixture. Background Technology

[0004] The medical diagnostics industry is a critical element of today's healthcare infrastructure. However, diagnostic analysis is currently a bottleneck in patient care, regardless of routine procedures. There are several reasons for this. First, many diagnostic analyses can only be performed using expensive, highly specialized equipment that can only be operated by trained clinicians. Such equipment is found in only a few locations—typically only one in any given urban area. This means that most hospitals need to send samples to these locations for analysis, resulting in freight costs and delivery delays, and potentially even sample loss or mishandling. Second, the equipment in question is often not used "on demand" but rather in batches, delaying the processing time of many samples as they must wait for the machines to fill up before they can run.

[0005] Understanding that sample flow consists of several key steps will lead to consideration of methods to automate these steps as much as possible. For example, once a biological sample is extracted from a patient, it must be placed into a suitable processing regime, which typically involves amplification using methods including, but not limited to, polymerase chain reaction (PCR), TMA, SDA, NASBA, LCR, and rolling cycle amplification to amplify the vector of interest. Once amplified, the presence of the nucleotide of interest in the sample needs to be definitively determined. While not requiring specialized skills and can be effectively automated, preparing samples for PCR is currently a time-consuming and labor-intensive step. In contrast, steps such as PCR and nucleotide detection are generally only within the scope of specially trained personnel with access to specialized equipment.

[0006] Sample preparation is laborious, partly because most samples must be heated in one or more stages, and partly because the target polynucleotides are often captured by some type of retention device and then must be effectively isolated from the surrounding environment. Therefore, even when various liquid transfer operations can be optimized or even automated, controlled application of heat and efficient in-situ capture of the extracted polynucleotides remain essential.

[0007] The discussion of the background art included herein is intended to illustrate the context of the invention described herein. This should not be construed as an admission that any material mentioned prior to the priority date of any claim had been published, known, or was part of the general public.

[0008] Throughout the description and claims, the word “comprising” and its variations, such as “containing” and “including”, are not intended to exclude other additives, components, integers or steps. Summary of the Invention

[0009] The systems, methods, and apparatuses described herein each have several aspects, and no single aspect is solely responsible for their desired properties. Without limiting the scope of this disclosure, several non-limiting features will now be briefly discussed.

[0010] This document discloses embodiments of a fixed magnet assembly that can be implemented in an automated platform for performing polynucleotide extraction from biological samples and preparing polynucleotides into PCR-ready forms. The fixed magnet assembly can be used to provide magnetic energy to a container containing a reaction mixture of magnetic particles and polynucleotides, causing the magnetic particles to separate from the reaction mixture. This can prevent or reduce magnetic particle carryover in the prepared PCR-ready samples, thereby improving PCR results.

[0011] In various embodiments, a system for analyzing nucleic acids is envisioned, and the system may include a receiving rack configured to receive a plurality of lysis tubes aligned along a lysis axis and a plurality of mixing tubes aligned along a mixing axis generally parallel to the lysis axis. The receiving rack may include one or more first magnets aligned along a first magnet axis (generally parallel to the lysis and mixing axes), and one or more second magnets aligned along a second magnet axis (generally parallel to the first magnet axis). The one or more first magnets may be configured to move between a position below the plurality of lysis tubes and a position adjacent to the plurality of lysis tubes when the plurality of lysis tubes are received in the receiving rack. The one or more first magnets may be configured to apply a first magnetic force to the contents of the plurality of lysis tubes when the plurality of lysis tubes are received in the receiving rack and the one or more first magnets are positioned adjacent to the plurality of lysis tubes. The one or more second magnets may be configured to remain stationary when the plurality of mixing tubes are received in the receiving rack, and the one or more second magnets may be configured to apply a second magnetic force to the contents of the plurality of mixing tubes when the plurality of mixing tubes are received in the receiving rack.

[0012] In some embodiments, one or more second magnets are included in a fixed magnet assembly, which may include: a mounting plate; a support plate having a height relative to the mounting plate; and a first plurality of fasteners mechanically connecting the support plate to the mounting plate. The first plurality of fasteners allows the height of the support plate relative to the mounting plate to be adjustable by a user. In some cases, each of the first plurality of fasteners may include a lifting screw.

[0013] In some embodiments, when a plurality of pyrolysis tubes and a plurality of mixing tubes are received in a receiving rack, a first magnetic force is applied to the contents of each of the plurality of pyrolysis tubes in a direction substantially perpendicular to the pyrolysis axis, and a second magnetic force is applied to the contents of each of the plurality of mixing tubes in a direction substantially parallel to the mixing axis. In some embodiments, when a plurality of pyrolysis tubes and a plurality of mixing tubes are received in a receiving rack, a first magnetic force is applied to the contents of each of the plurality of pyrolysis tubes in a direction substantially perpendicular to the pyrolysis axis, and a second magnetic force is applied to the contents of each of the plurality of mixing tubes in a direction substantially perpendicular to the mixing axis. In some embodiments, the receiving rack is further configured to receive a processing apparatus comprising a plurality of pyrolysis tubes and a plurality of mixing tubes. In some embodiments, the axes of a first magnet and a second magnet are spatially spaced apart by a distance such that when a plurality of mixing tubes are received in the receiving rack, one or more first magnets do not apply a first magnetic force to the contents of the plurality of mixing tubes, and when a plurality of pyrolysis tubes are received in the receiving rack, one or more second magnets do not apply a second magnetic force to the contents of the plurality of pyrolysis tubes.

[0014] In some embodiments, the system may further include a plurality of second magnets enclosed within a plurality of housings aligned along the axes of the second magnets, wherein each of the housings encloses two of the plurality of second magnets. In some embodiments, when the plurality of mixing tubes are received in a receiving rack, a first magnet of the two magnets in each housing is configured to apply a second magnetic force to the contents of the first mixing tube at a first position of the first mixing tube, and wherein a second magnet of the two magnets in each housing is configured to apply a second magnetic force to the contents of a second mixing tube adjacent to the first mixing tube, and a second magnet of the two magnets is configured to apply a second magnetic force at a second position of the second mixing tube, the second position of the second mixing tube being approximately 180° or less than 180° from the first position of the second mixing tube. In some embodiments, when the plurality of mixing tubes are received in a receiving rack, the ratio of mixing tubes to housings is two to one.

[0015] In some embodiments, the system may further include a plurality of first magnets aligned along the axis of the first magnet, and the ratio of the pyrolysis tubes to the first magnets is one to one when the plurality of pyrolysis tubes are received in the receiving rack. In some embodiments, each housing may include two faces, each face at a different angle relative to the axis of the second magnet, and each of the two second magnets (enclosed in the housing) is positioned adjacent to the inner wall of one of the angled faces of the housing.

[0016] In some embodiments, the system may further include an integral structure comprising multiple housings. In some embodiments, the multiple housings are spaced apart by multiple connectors.

[0017] In some embodiments, the system may include a second magnet formed of a magnetic material, wherein the second magnet includes a plurality of magnet structures aligned along the axis of the second magnet. Each magnet structure may include two angled magnet faces, each magnet face forming a different angle relative to the axis of the second magnet. In some embodiments, when a plurality of mixing tubes are received in a receiving holder, a first angled magnet face of each magnet structure is configured to apply a second magnetic force to the contents of the first mixing tube at a first location of the first mixing tube, and a second angled magnet face of each magnet structure is configured to apply a second magnetic force to the contents of a second mixing tube adjacent to the first mixing tube. The second angled magnet face may be configured to apply the second magnetic force at a second location of the second mixing tube, the second location of the second mixing tube being approximately 180° or less than 180° from the first location of the second mixing tube.

[0018] In some embodiments, when multiple mixing tubes are received in the receiving frame, the ratio of mixing tubes to magnet structures is 2:1. In some embodiments, the system may further include a plurality of first magnets aligned along the axis of a first magnet, and when multiple splitting tubes are received in the receiving frame, the ratio of splitting tubes to first magnets is 1:1. In some embodiments, the receiving frame may further include a support plate located between one or more second magnets and a cover of the receiving frame. In some embodiments, the support plate includes a plurality of recesses, each recess configured to receive the bottom of one mixing tube when multiple mixing tubes are received in the receiving frame.

[0019] In some embodiments, the system may further include a plurality of second magnets enclosed within a plurality of housings aligned along the axes of the second magnets, and the housings are movable relative to a support plate when the plurality of mixing tubes are not received in a receiving frame. In some embodiments, the system may further include a plurality of pyrolysis tubes and a plurality of mixing tubes received in a receiving frame.

[0020] In various embodiments, a system for analyzing nucleic acids is envisioned, and the system may include: a receiver configured to receive a device having lysis tubes and mixing tubes aligned along each of a plurality of parallel processing axes. The receiver may include one or more first magnets aligned along first magnet axes substantially perpendicular to the plurality of processing axes, and the receiver may also include one or more second magnets aligned along second magnet axes substantially perpendicular to the first magnet axes. The one or more first magnets may be configured to move between a position below and adjacent to the plurality of lysis tubes when the device is received in the receiver. The one or more first magnets may be configured to apply a first magnetic force to the contents of the plurality of lysis tubes when the device is received in the receiver and the one or more first magnets are positioned adjacent to the plurality of lysis tubes. The one or more second magnets may be configured to remain stationary when the plurality of mixing tubes are received in the receiver. The one or more second magnets may be configured to apply a second magnetic force to the contents of the plurality of mixing tubes when the device is received in the receiver.

[0021] In some embodiments, when the device is received in a receiving rack, a first magnetic force is applied along the respective processing axis of each of the plurality of pyrolysis tubes, and a second magnetic force is applied at a point offset from the respective processing axis of each of the plurality of mixing tubes. In some embodiments, when the device is received in a receiving rack, a first magnetic force is applied along the respective processing axis of each of the plurality of pyrolysis tubes, and a second magnetic force is applied along the respective processing axis of each of the plurality of mixing tubes.

[0022] In some embodiments, the axes of the first magnet and the second magnet are spatially separated by a distance such that when the device is received in the receiving rack, one or more first magnets do not apply a first magnetic force to the contents of the plurality of mixing tubes, and when the device is received in the receiving rack, one or more second magnets do not apply a second magnetic force to the contents of the plurality of pyrolysis tubes.

[0023] In some embodiments, the system may further include a plurality of second magnets enclosed within a plurality of housings aligned along the axes of the second magnets, and each of the housings encloses two of the plurality of second magnets. In some embodiments, when the device is received in a receiving rack, a first magnet of the two magnets in each housing is configured to apply a second magnetic force to the contents of the first mixing tube at a first position of the first mixing tube. A second magnet of the two magnets in each housing may be configured to apply a second magnetic force to the contents of a second mixing tube adjacent to the first mixing tube, and the second magnet of the two magnets may also be configured to apply a second magnetic force at a second position of the second mixing tube, the second position of the second mixing tube being approximately 180° or less than 180° from the first position of the second mixing tube.

[0024] In some embodiments, when the device is received in the receiving rack, the ratio of the mixing tube to the housing is 2:1. In some embodiments, the system may further include a plurality of first magnets aligned along the axis of the first magnets, and when the device is received in the receiving rack, the ratio of the splitting tube to the first magnets is 1:1. In some embodiments, each housing includes two faces, each face being angled relative to an adjacent processing axis, and each of the two second magnets is positioned adjacent to the inner wall of one of the angled faces.

[0025] In some embodiments, the system may further include an integral structure comprising a plurality of housings. In some embodiments, the receiving rack further includes a support plate located between one or more second magnets and a cover of the receiving rack. In some embodiments, the support plate includes a plurality of recesses, each recess configured to receive the bottom of a mixing tube when the device is received in the receiving rack. In some embodiments, the system may further include a plurality of second magnets enclosed within a plurality of housings aligned along the axes of the second magnets, wherein the plurality of housings are movable relative to the support plate prior to the device being received in the receiving rack. In some embodiments, the system may further include the device received in the receiving rack.

[0026] Additional embodiments of the present disclosure are described below with reference to the appended claims, which may be used as additional inventive content to the present disclosure. Attached Figure Description

[0027] Figure 1AAn image of a device (e.g., a microfluidic cartridge) for PCR amplification according to an embodiment disclosed herein is shown, which is mechanically clogged by residual magnetic extraction particles.

[0028] Figure 1B A schematic diagram of an automated diagnostic or preparation apparatus for automating the preparation of multiple samples in parallel, according to embodiments disclosed herein, is shown.

[0029] Figure 2A An isometric view of an exemplary reagent holder according to an embodiment disclosed herein is shown.

[0030] Figure 2B A side profile view of an exemplary reagent holder according to an embodiment disclosed herein is shown.

[0031] Figure 2C A top view of an exemplary reagent holder according to an embodiment disclosed herein is shown.

[0032] Figure 2D A side profile view of an exemplary reagent holder according to an embodiment disclosed herein is shown.

[0033] Figure 2E A top view of an exemplary reagent holder according to an embodiment disclosed herein is shown.

[0034] Figure 3A An isometric view of an exemplary heater assembly and a magnetic separator according to embodiments disclosed herein is shown.

[0035] Figure 3B Isometric views and side profiles of an independently controllable heater unit of a heater assembly according to embodiments disclosed herein are shown.

[0036] Figure 3C A side profile view of an independently controllable heater unit of a magnetic separator and heater assembly according to an embodiment disclosed herein is shown, illustrating the interaction between the magnetic separator and the heater unit.

[0037] Figure 4A A perspective view of a stand for holding a reagent holder according to an embodiment disclosed herein is shown.

[0038] Figure 4B An isometric view of a stand for holding a reagent holder according to an embodiment disclosed herein is shown.

[0039] Figure 5A An isometric view of an empty loading rack (or receiving rack) of an automated diagnostic or preparation apparatus according to embodiments disclosed herein is shown.

[0040] Figure 5BA front perspective view of an example automated diagnostic apparatus according to an embodiment disclosed herein is shown, the example automated diagnostic apparatus having two loading racks occupied by corresponding sample racks.

[0041] Figure 6A A top view concept diagram of a set of reagent holders in a loading rack or receiving rack of a diagnostic or preparation device according to an embodiment disclosed herein is shown.

[0042] Figure 6B Examples according to the disclosure herein are shown. Figure 6A A top-view conceptual diagram showing the position of certain components of a reagent holder relative to a magnet in a diagnostic or preparation device.

[0043] Figure 6C A top view concept diagram of another set of reagent holders in a loading rack or receiving rack of a diagnostic or preparation device according to an embodiment disclosed herein is shown.

[0044] Figure 6D Examples according to the disclosure herein are shown. Figure 6C A top-view conceptual diagram showing the position of certain components of a reagent holder relative to a magnet in a diagnostic or preparation device.

[0045] Figure 6E A side profile concept diagram showing the position of certain components of a reagent holder relative to a magnet in a diagnostic or preparation device according to embodiments disclosed herein.

[0046] Figures 7A-7B A perspective view is shown of an embodiment of a fixed magnet assembly that can be implemented in an automated diagnostic or preparation device according to the embodiments disclosed herein.

[0047] Figure 7C A side profile view showing the dimensions of an embodiment of a fixed magnet assembly located between certain components of a reagent holder, according to an embodiment disclosed herein.

[0048] Figure 8A An isometric view is shown of an embodiment of a fixed magnet assembly that can be implemented in an automated diagnostic or preparation device according to the embodiments disclosed herein.

[0049] Figure 8B An isometric view is shown of an embodiment of a fixing magnet assembly for fixing to an automated diagnostic or preparation device according to an embodiment disclosed herein.

[0050] Figure 9 An isometric view is shown of an embodiment of a fixed magnet assembly that can be implemented in an automated diagnostic or preparation device according to the embodiments disclosed herein.

[0051] Figure 10AAn isometric view is shown of an embodiment of a fixed magnet assembly that can be implemented in a diagnostic or preparation device according to embodiments disclosed herein.

[0052] Figure 10B A transparent perspective view is shown of a reagent holder that interacts with an embodiment of a fixed magnet assembly according to an embodiment disclosed herein.

[0053] Figure 11 An isometric view of the interior of some embodiments of an automated diagnostic or preparation apparatus according to embodiments disclosed herein is shown.

[0054] Figure 12A An isometric view of a processing board used in some embodiments of a diagnostic or preparation apparatus according to embodiments disclosed herein is shown.

[0055] Figure 12B A top view is shown of an arrangement of two processing boards received in a receiver rack in some embodiments of a diagnostic or preparation apparatus according to embodiments disclosed herein.

[0056] Figure 13A Isometric views of the interior of some embodiments of a diagnostic or preparation apparatus according to embodiments disclosed herein are shown.

[0057] Figure 13B A side profile view of the processing board and interior of a diagnostic or preparation apparatus according to embodiments disclosed herein is shown.

[0058] Figure 14A A top view concept diagram of a processing board used in some embodiments of a diagnostic or preparation device according to embodiments disclosed herein is shown.

[0059] Figure 14B A top view concept diagram showing the position of certain components of a processing board relative to a magnet in some embodiments of a diagnostic or preparation device, according to embodiments disclosed herein.

[0060] Figure 14C A side profile concept diagram showing the position of certain components of a processing board relative to a magnet in some embodiments of a diagnostic or preparation device, according to embodiments disclosed herein.

[0061] Figures 15A-15D An isometric view of a fixed magnet assembly used in some embodiments of a diagnostic or preparation device according to embodiments disclosed herein is shown.

[0062] Figures 16A-16C An isometric view of an embodiment of a stationary magnet assembly used with an automated diagnostic or preparation device, according to embodiments disclosed herein.

[0063] Figure 16DA perspective view is shown of a fastening mechanism used in an embodiment of a fixed magnet assembly according to an embodiment disclosed herein.

[0064] Figure 16E A side sectional view of a fastening mechanism used in an embodiment of a fixed magnet assembly according to an embodiment disclosed herein is shown.

[0065] Figure 16F An isometric view is shown of an embodiment of a fixing magnet assembly for fixing to an automated diagnostic or preparation device according to an embodiment disclosed herein.

[0066] Figures 17A to 17D An isometric view of an embodiment of a bridge for mounting a fixed magnet assembly within an automated diagnostic or preparation device, according to embodiments disclosed herein. Detailed Implementation

[0067] Automated platforms (which may also be referred to as automated diagnostic or preparation devices) exist for processing biological samples for diagnostic or preparation purposes. For example, these automated platforms can be used to perform polynucleotide extraction from biological samples and prepare polynucleotides into PCR-ready forms.

[0068] Some embodiments of these automated platforms perform polynucleotide extraction and preparation by mixing cells from a biological sample with a lysis reagent in a processing tube and heating the tube (which lyses the cells and releases the polynucleotides contained within them). To isolate the polynucleotides from the remainder of the mixture, magnetic extraction particles (e.g., surface-modified magnetic beads) configured to bind to those polynucleotides can be added to the mixture. Magnetic extraction particles are also referred to herein as magnetic matrix or magnetically bound particles. Magnetic extraction particles can include, for example, beads modified with PAMAM, dendritic polyamines, poly(allylamine) (PAA), polypropyleneimine tetraamine dendritic macromolecules (DABAM), or any other suitable material. Once the polynucleotides are bound to the magnetic extraction particles, a magnet can be used to apply magnetic force to hold the magnetic extraction particles in place and separate them from the remainder of the mixture. Some embodiments of these automated platforms may have a magnetic separator that can move up and down relative to the processing tube to lift and remove the magnetic extraction particles from the remainder of the mixture.

[0069] Once the magnetically extracted particles are isolated in the processing tube, a chemical elution buffer can be added to the tube to separate the polynucleotides from the magnetically extracted particles. Some embodiments of automated platforms may reuse the magnetic separator to capture and hold the magnetically extracted particles in place as the polynucleotides are extracted from the processing tube and transferred to a separate mixing tube. The polynucleotides can then be added to a mixture of primers and sample for PCR amplification, which can then be loaded into a device for PCR amplification (e.g., a microfluidic cartridge).

[0070] However, certain chemical components may be present in the cell matrix of the sample, or other substances may be present during sample collection, which could prevent sufficient magnetic trapping of the magnetically extracted particles to separate them from other contents in the processing tube. Some examples of substances present during sample collection can include medical lubricants, antifungal creams, antibacterial creams, contraceptive gels and foams, vaginal moisturizers, etc. Any chemical components present can interact with the modified surface of the magnetically extracted particles, the cell matrix, the trapped polynucleotides, or any combination thereof, and disrupt the magnetic trapping of the magnetically extracted particles. As a result, when the polynucleotides are extracted from the processing tube and transferred to the mixing tube, magnetically extracted particles may be left behind in the mixing tube and thus end up in the equipment used for PCR amplification (e.g., microfluidic cartridges). This “residual” magnetically extracted particles can cause mechanical or chemical failure of PCR amplification, triggering assay failures such as non-reportable (NR). Mechanically, the residual particles can clog the loading port or microfluidic fluid in PCR amplification equipment (e.g., microfluidic cartridges). Examples of this are... Figure 1A As shown in the figure, Figure 1A An image shows an apparatus (e.g., a microfluidic cartridge) used for PCR amplification that is mechanically clogged by residual magnetic extraction particles. Chemically, problematic components of the cell matrix or other interfering substances bound to the residual magnetic extraction particles may interfere with or inhibit the PCR reaction and subsequent detection of the amplification products.

[0071] To reduce and prevent the retention of such undesirable magnetic extraction particles, various embodiments of a fixed magnet assembly that can be implemented using these automated platforms are envisioned and disclosed herein. In some embodiments, the fixed magnet assembly may include a set of magnets within a housing positioned adjacent to a mixing tube. In some such embodiments, the individual magnets may be 0.25 x 0.25 x 0625” NdFeB, Grade The N52 square magnet has a pulling force of 1.77 psi and a field strength of 3032 gauss. However, for other embodiments, suitable magnets may include magnets of various materials, sizes, and / or strengths, as long as the selected magnet configuration, combined with the positioning of the magnet in relation to the mixing tube, enables the magnet to capture some or all of the magnetically extracted particles left in the mixing tube. The magnet can be positioned close enough to the mixing tube to generate a magnetic field of sufficient strength to retain or “capture” the leftover magnetically extracted particles in the mixing tube, particularly close to the inner wall of the mixing tube. Thus, the fixed magnet assembly of the disclosed technique can provide a set of auxiliary magnets (attached to the first set of magnets in the magnetic separator) that can be positioned in a fixed location near the mixing tube to provide auxiliary magnetic capture of any unwanted magnetically extracted particles left in the mixing tube (e.g., extracted particles not captured during early steps of the workflow), preventing these magnetically extracted particles from being left into the PCR amplification equipment.

[0072] Embodiments of the disclosed technology can be advantageously implemented in any device that receives a holder for processing and manipulating the substrate within the holder's container. Embodiments of the fixed magnet assembly according to the disclosed technology can be placed in a very small, predefined volume or housing between the cover of the receiving rack and the processing device received in that rack. As a result, existing diagnostic or preparation devices with specific receiving racks configured to receive specific processing devices can be retrofitted with the fixed magnet assembly without redesigning the processing device (such as a reagent holder or processing plate) or eliminating the need for components that snap into the device (such as a reagent tube or container). Although retrofitted to devices already implemented in many locations with some component variations, the magnets of the fixed magnet assembly still effectively and consistently apply magnetic force to the contents of the processing device received by these field-deployed systems. A further significant advantage of the disclosed technology is that it can be implemented very quickly in field-deployed systems with minimal downtime for customers or laboratories employing the device.

[0073] The installation of the fixed magnet assembly according to the disclosed technology can be adjusted for site-specific characteristics and constraints. As will be described in detail below, a fixed magnet assembly with a shim can be installed between the assembly and the cover of the receiver rack, wherein the height of the shim is selected based on site-specific considerations. This can be particularly advantageous when retrofitting the fixed magnet assembly into existing preparation and diagnostic devices in the art, taking into account minor dimensional differences and tight tolerances associated with the receiver rack and processing equipment implemented in the apparatus.

[0074] As another example of the advantageous adjustability and versatility of the disclosed technology, some embodiments of the fixed magnet assembly include a spring-mounted support plate that is movable in the z-direction relative to a mounting plate fixed to a cover of a receiving rack. The mounting plate can be secured using any suitable mechanism, including but not limited to screws or tape (including double-sided tape). The support plate can move up or down in the z-direction within the receiving rack before and during insertion of the processing equipment into the receiving rack. This feature allows for accurate and consistent positioning of the tube or container of the processing equipment relative to the magnets in the fixed magnet assembly on each of a plurality of devices in which the fixed magnet assembly is mounted, without requiring accurate and consistent reproduction of precise magnet positioning (e.g., via a fixed magnet assembly designed, constructed, and positioned with very tight tolerances).

[0075] As another example of the advantageous adjustability and versatility of the disclosed technology, some embodiments of the fixed magnet assembly include a support plate mechanically coupled to a mounting plate using a plurality of adjustable fasteners. This allows the support plate to be movable relative to the mounting plate in the z-direction by adjusting the fasteners. The support plate can be mechanically coupled to the mounting plate using any suitable fasteners that can be adjusted to change the distance between the support plate and the mounting plate. For example, the support plate can be mechanically coupled to the mounting plate using a plurality of jacking screws that can be turned clockwise or counterclockwise to increase or decrease the distance between the support plate and the mounting plate, respectively (e.g., raise or lower the height of the support plate in the z-direction). The mounting plate can be secured to the cover of the receiver using any suitable mechanism, including but not limited to screws or tape (including double-sided tape). This feature allows installers of the fixed magnet assembly (e.g., users of the system, including but not limited to) to manually adjust the height of the support plate based on the specific device in which the fixed magnet assembly is installed, so that the tubes or containers of the processing equipment are accurately and consistently positioned relative to the magnets in the fixed magnet assembly without having the fixed magnet assembly pre-configured for precise magnet positioning (e.g., by designing, building and positioning a fixed magnet assembly with very tight tolerances), and thus enabling the fixed magnet assembly to be used with a variety of devices that may have inconsistent sizes.

[0076] Embodiments of the fixed magnet assembly according to the disclosed technology may include multiple magnet housings or structures. As will be described in detail below, the magnet housings and structures may include faces that are advantageously oriented to be very close to (e.g., within 1-2 mm) aligned with the tube or container containing the magnetic structure, while also avoiding interference with the tube (or features around the tube) when the tube is inserted into the receiving rack. These faces may be angled relative to the processing axis where the tube is located, while still remaining close to the tube. In the case of the magnet housing, the magnets connected to the inner walls of the faces may be advantageously oriented. In the case of the magnet structure formed of a magnetic material, the faces may be advantageously oriented at an angle. The shape and size of the magnet housing / structure, as well as the shape and size of the connecting structures connecting the magnet housing / structure, may be advantageously customized so that they do not interfere with the skirt or flange on the underside of the processing device receiving the snap-in reagent tube or container. Thus, the magnet housing / structure can avoid undesirable physical interference with the tube containing the magnetic substrate and nearby tubes that do not contain a magnetic substrate, while still positioning the magnet physically very close to the tube containing the magnetic substrate.

[0077] Embodiments of the fixed magnet assembly according to the disclosed technology may include a magnet housing / structure configured to simultaneously apply magnetic force to two different tubes or containers arranged on parallel processing axes. For example, in the case where the magnet housing encloses two magnets, one magnet housed in the magnet housing can apply magnetic force to one side of a first container of the processing device, and the other magnet housed in the magnet housing can apply magnetic force to the opposite side of a second container of the processing device, wherein the first and second containers are located on parallel processing axes. In other words, the magnets in the magnet housing can apply magnetic force to the opposite sides of containers on adjacent processing axes. In a non-limiting example where reagent holders are received in a rack inserted into a receiving rack, the magnets within a single magnet housing can apply magnetic force to the opposite sides of the snap-in containers of adjacent reagent holders. Although the magnetic force is applied to different sides of the snap-in container depending on which magnet is adjacent to it, magnetic extraction particle residue is still effectively and consistently resolved for each reagent holder. Advantageously, this embodiment avoids the need to place magnets in a very tight space (e.g., between a snap-in container containing magnetic particles and another snap-in container aligned along the same processing axis). Alternatively, the magnets of the disclosed technology can be advantageously arranged at an angle relative to the processing axis of each reagent holder, rather than arranged on the processing axis.

[0078] As described above, the fixed magnet assembly can be designed for rapid and efficient implementation, even in existing automated diagnostic or preparation devices, without requiring any hardware modifications. Different embodiments of the fixed magnet assembly of the disclosed technology can be designed, configured, and customized for use with specific embodiments of automated diagnostic or preparation devices. Several specific examples of various embodiments of the fixed magnet assembly are shown and discussed herein.

[0079] For example, Figure 1B , Figures 2A-2E , Figures 3A-3C , Figures 4A-4B , Figures 5A-5B A scenario is provided for a first embodiment of an automated diagnostic or preparation device. Figures 6A-6C A conceptual overview is provided regarding how to configure, position, and implement a fixed magnet assembly relative to this first embodiment of an automated diagnostic or preparation device to reduce or prevent the retention of magnetically extracted particles. Figures 7A-7B , Figures 8A-8B , Figure 9 , Figures 10A-10B and Figures 16A-16F Various embodiments of the fixed magnet assembly are shown, demonstrating the combination of Figures 6A-6C Additional features and concepts outlined. References Figures 6A-6C The described example fixed magnet assembly can be implemented in a first embodiment of an automated diagnostic or preparation device to prevent the retention of magnetically extracted particles. It should be understood that these are non-limiting examples, and other suitable configurations and implementations are also compatible with the disclosed technology.

[0080] in addition, Figure 11 , Figures 12A-12B and Figures 13A-13B A second embodiment of an automated diagnostic or preparation apparatus is provided, in which a fixed magnet assembly of the disclosed technology can be implemented. Figures 14A-14C A conceptual overview is provided regarding how to configure, position, and implement a fixed magnet assembly relative to this second embodiment of an automated diagnostic or preparation device to prevent the retention of magnetically extracted particles. Figures 15A-15D An embodiment of the fixed magnet assembly is shown, demonstrating the combination of... Figures 14A-14C Additional features and concepts outlined. References Figures 15A-15D The described example fixed magnet assembly can be implemented using a second embodiment of an automated diagnostic or preparation device to prevent the retention of magnetically extracted particles. It should be understood that these are non-limiting examples, and other suitable configurations and implementations are also compatible with the disclosed technology.

[0081] Examples of the disclosed technologies include automated devices, reagent holders, and benches.

[0082] Figure 1BA schematic diagram of an apparatus 181 for automating the preparation of multiple samples in parallel, according to steps exemplified elsewhere herein, is shown. The geometric arrangement of the components of system 181 is exemplary and not intended to be limiting. The apparatus may additionally include (in...) Figure 1B The device (not shown) is located in a receiving rack and is configured to perform diagnostic tests on samples, such as by detecting the presence of amplified polynucleotides in a cartridge. The device may include, for example, a microfluidic cartridge configured to receive polynucleotides already placed in a PCR-ready form. Such additional features are also described in U.S. Patent Application Serial No. 12 / 173,023, filed July 14, 2008 (attributed to Williams et al., entitled “Integrated Apparatus for Performing Nucleic Acid Extraction and Diagnostic Testing on Multiple Biological Samples”). Unless specifically stated otherwise, the use of the term “PCR” herein is intended to cover any variant of PCR, including but not limited to real-time and quantitative PCR, and any other form of polynucleotide amplification.

[0083] As shown in the figure, a processor 180, such as a microprocessor, is configured to control the functions of various components of the system and thereby communicate with each such component that needs to be controlled. It should be understood that many of these control functions can optionally be performed manually, rather than under the control of the processor. Furthermore, the order in which the various functions are described below is not limited to the order in which the processor executes instructions during operation of the device. Thus, the processor 180 can be configured to receive data about a sample to be analyzed from, for example, a sample reader 190, which can be a barcode reader, an optical character reader, or an RFID scanner (radio frequency tag reader).

[0084] Processor 180 may be configured to accept user instructions from input device 184, wherein such instructions may include instructions to begin analyzing samples and selection of operating conditions. Processor 180 may also be configured to communicate with display 182 to, for example, transmit information about the analysis to the display and thereby to the user of the system. Such information includes, but is not limited to: the current status of the device; the progress of the PCR thermal cycle; and warning messages in the event of system or cartridge failure. Additionally, processor 180 may transmit one or more questions to be displayed on display 182, prompting the user to provide input in response. Thus, in some embodiments, input 184 and display 182 are integrated with each other. Processor 180 may optionally be further configured to transmit the results of the analysis to output device 186, such as a printer, visual display, display utilizing holographic projection, or speaker, or a combination thereof. Processor 180 may further optionally be connected to computer network 188 via a communication interface, such as a network interface.

[0085] The processor 180 can be further configured to control various aspects of sample preparation and diagnosis as outlined below. Figure 1B In this configuration, device 181 is configured to operate in conjunction with complementary test bench 170. Device 181 may be able to receive multiple test benches, such as 1, 2, 3, 4, or 6 test benches.

[0086] Embodiments of the stand 170 are further described in U.S. Patent Application Serial No. 12 / 173,023 (filed July 14, 2008, entitled "Integrated Apparatus for Performing Nucleic Acid Extraction and Diagnostic Testing on Multiple Biological Samples" by Williams et al.) and U.S. Patent Application Serial No. 12 / 178,584 (filed July 23, 2008, entitled "Rack For Sample Tubes And Reagent Holders" by Duffy et al.), the entire contents of which are incorporated herein by reference. The stand 170 itself is configured to receive multiple biological samples 196 in a form suitable for examination and diagnostic analysis, and to receive multiple holders 172, such as those further described herein, including those for combination. Figure 2A-2C The multiple holders 172 are equipped with various reagents, pipette tips, and receivers. The stand is configured to allow samples to be processed in the respective holders during sample examination, the processing including individual heating and cooling via heater assembly 177.

[0087] The heating function of heater assembly 177 can be controlled by processor 180. Heater assembly 177 operates in conjunction with separator 178 (such as a magnetic separator), which can also be controlled by processor 180 to move to one or more processing chambers adjacent to or not adjacent to the holder 172, where particles such as magnetic particles are present. Assembly 177 and separator 178 are further described herein.

[0088] Liquid dispenser 176 (which may be similarly controlled by processor 180) is configured to perform various aspiration and dispensing operations on corresponding samples, fluids, and reagents in holders 172 to extract nucleic acids from samples. Liquid dispenser 176 can perform this operation on multiple holders simultaneously.

[0089] Sample reader 190 is configured to transmit identification tags about samples (in some cases, holders) to processor 180. In some embodiments, the sample reader is attached to a liquid dispenser and can therefore read tags about samples above the liquid dispenser. In other embodiments, the sample reader is not attached to a liquid dispenser and is independently movable under the control of the processor. Liquid dispenser 176 is also configured to aliquot a sample containing nucleic acids extracted from one or more samples and direct it to a potentially cooler storage area 174. Storage area 174 may contain, for example, PCR tubes corresponding to each sample. Additionally or alternatively, liquid dispenser 126 may be configured to aliquot a sample containing nucleic acids extracted from one or more samples and direct them to a device configured to receive and amplify nucleic acids. This device may include, for example, microfluidic cartridges received in a receiver rack (not shown) of device 181.

[0090] As with other exemplary embodiments described herein, Figure 1B The embodiments of the apparatus outlined herein are advantageous because they do not require a properly configured location within the apparatus for storing reagents. Therefore, Figure 1B The device is independent and operates in conjunction with a holder 172, which is pre-filled with reagents, such as in a location dedicated to reagent storage.

[0091] Figure 1BThe devices can be configured to operate in a single location (such as a laboratory environment) or be portable so that they can accompany doctors or other healthcare professionals who may visit patients in different locations. The devices are typically equipped with a power cord so that they can accept AC power from mains or a generator. The devices can also be configured to operate using one or more batteries and are therefore usually equipped with a battery charging system, as well as various warning devices that alert the user if the battery power becomes too low to reliably start or complete diagnostic analysis.

[0092] In other embodiments, Figure 1B The apparatus can be further configured for multiplexed sample analysis and / or analysis of multiple batches of samples, wherein, for example, a single benchtop holds a single batch of samples. Therefore, Figure 1B Each component shown may exist as many times as the sample batch, although various components can be configured in a common housing.

[0093] The device described herein can be used for any application that analyzes samples containing nucleic acids for any purpose, including but not limited to genetic testing and clinical testing for various human infectious diseases.

[0094] The apparatus described in this paper can be configured to operate on a benchtop or similar environment and, when running continuously throughout a normal workday, can test approximately 45 samples per hour. Results for each raw sample are typically available in less than one hour.

[0095] Figure 2A An exemplary retainer described herein is shown (e.g., Figure 1B The image shows an isometric view of the holder 172. The holders described herein are reagent holders for holding and transporting reagents for various purposes, including but not limited to sample preparation in clinical settings, and are configured to be received by the benches described herein. Reagent holders typically also provide a container in which various reagents can be mixed with each other and / or with a sample. Holders are also configured for use in automated devices that can simultaneously prepare samples in more than one holder.

[0096] This exemplary holder, as well as other holders compatible with the written description herein, though not shown as a particular embodiment, are now described. Further details of the reagent holder can be found in U.S. Patent Application Serial No. 12 / 218,416 (titled “Reagent Tube, Reagent Holder, and Kits Containing Same”), filed July 14, 2008, in the name of Wilson et al., which is incorporated herein by reference.

[0097] Figure 2A An exemplary retainer 200 includes a connecting member 210 having one or more of the following characteristics. The connecting member 210 is used to connect the various components of the retainer together. The connecting member 210 has an upper side 212 and a lower side (not shown) opposite to the upper side.

[0098] The reagent holder 200 will now be described to illustrate certain features of the disclosed technique. It should be understood that the disclosed technique can be implemented with any suitable holder that receives a magnetic matrix, such as magnetically bound particles. This particular non-limiting embodiment... Figure 2A The reagent holder 200 includes a processing tube 220 having an orifice 222 in a connecting member; two or more reagent tubes 240 disposed on the underside of the connecting member, each reagent tube having an inlet orifice 242 in the connecting member; and one or more receivers 250 located in the connecting member, wherein each of the one or more receivers 250 is configured to receive a complementary container 254, such as a reagent tube, inserted from the upper side 212 of the connecting member. Figures 2A to 2C In the illustrated embodiment, the reagent holder 200 includes four receivers 250, each receiver being configured to receive a snap-in container 254. See below for reference. Figure 2D and Figure 2E In another non-limiting embodiment described, the reagent holder includes three receivers 250, each configured to receive a snap-in container 254. Implementations of the disclosed technology can be carried out in holders having any suitable number of receivers, as well as in holders having a container 254 integrally formed with, rather than snap-in into, the connecting member. The reagent holder 200 may optionally include at least one support located in the connecting member and at least one pipette sheath configured to receive disposable pipette tips. In this non-limiting embodiment, the reagent holder includes four supports and four pipette sheaths. The bench described herein has channels designed with sufficient depth and width to accommodate the various reagent tubes, receivers, processing tubes, and pipette sheaths of a given reagent holder, and to position the processing tubes in communication with the heater / separator unit.

[0099] Containers 254 have been inserted into their corresponding receptors 250. One or more receptors 250 are configured to receive a reagent tube containing an amount of one or more reagents for performing nucleic acid extraction from a sample associated with the retainer. The reagents may be in solid form, such as lyophilized form. Receptors may all be the same size and shape, or may be different in size and shape from one another. Receptors 250 are shown as having an open bottom, but are not limited to this topology, and may be closed except for the inlet 252 in the upper side of the connecting member 210. Preferably, receptors 250 are configured to receive containers commonly used in the field of laboratory analysis, or suitably configured to be used with the retainers described herein. For example, container 254 may be a 0.3 ml tube.

[0100] An embodiment of the reagent holder 200 is shown configured with a waste chamber 260, which has an inlet port 262 on the upper side of the connecting member 210. The waste chamber 260 is optional, and in embodiments where it is present, it is configured to receive waste liquid reagents. In other embodiments, where a waste chamber is absent, the waste liquid reagents can be transferred to and disposed of outside the holder, for example, in a sample tube containing the contents of the original sample being analyzed.

[0101] The processing tube 220 can be configured as a snap-in tube similar to container 254, or it can be integrally formed in the connecting member 210. The processing tube 220 can be used for various mixing and reaction processes that occur during sample preparation. For example, cell lysis can occur in the processing tube 220, and nucleic acids, such as DNA or RNA from a patient and DNA or RNA from a pathogen, can be extracted. The processing tube 220 can be advantageously positioned in a location that minimizes overall pipette tip movement operations involving the transfer of liquid to the processing tube 220. The processing tube 220 is also positioned in a holder such that, when the holder is inserted into a stand as further described herein, the processing tube is exposed and accessible to the heater and separator, as further described herein.

[0102] Some reagents contained in the holder are provided as liquids, while others may be provided as solids. In some embodiments, liquids are stored using containers or tubes of a different type than those used for storing solids.

[0103] Reagent wells 240 are typically configured to hold one liquid reagent per well. For example, in reagent holder embodiment 200, three reagent wells are shown, each containing a wash buffer, a release buffer, and a neutralization buffer, each used in a sample preparation protocol. Other numbers and configurations of reagent wells may be suitably implemented in embodiments of the disclosed technology.

[0104] The reagent holder 200 has a connecting member configured such that at least one support, one or more receivers, and corresponding holes in the processing tubes, as well as two or more reagent tubes, are all arranged linearly relative to each other (i.e., their midpoints are on the same axis). See below for reference. Figures 6A-6B More specifically, this axis can be the processing axis along which the features of the retainer are aligned. It should be understood that, in embodiments of the disclosed technology, the features of the retainer can be aligned in a substantially linear arrangement such that the midpoints of the features are not precisely located on a common processing axis. Furthermore, the retainer described herein is not limited to a specific configuration of receivers, processing tubes, holders, reagent tubes, and waste chambers (if present). For example, if some orifices are staggered and occupy “off-axis” positions, the retainer can be shorter. Various receivers, etc., also do not need to occupy relative to each other with respect to the processing axis. Figure 2A The same location as shown.

[0105] It should be understood that alternative configurations of the various parts of the retainer 200 only result in changes of form and can be accommodated within other variations of the described apparatus, including but not limited to alternative sets of instructions for liquid dispensing pipette tips, heater assemblies, and magnetic separators, as further described herein. Each such configuration of the reagent retainer can be adapted by corresponding changes in the form of the bench described herein that receives one or more such retainers.

[0106] In some embodiments, the retainer 200 includes a registration member, such as a mechanical key. Typically, such a key is part of the connecting member 210. The mechanical key ensures that the retainer is received by a complementary member in, for example, a support frame as described herein (e.g., Figure 1B The holder is located in the receiving rack of a device (170) or a device for controlling the pipetting operation of reagents in the holder. Therefore, embodiment 200 has a mechanical key 292, which includes a pair of rectangular cutouts at one end of the connecting member. As shown, this feature also provides a label that allows the user to determine the appropriate purchase when inserting or removing the holder from the holder into or from the holder. The illustrated embodiment of holder 200 also has a mechanical key 290 at the other end of the connecting member 210. Key 290 is an angled cutout that facilitates insertion of the holder into the holder and ensures good alignment therein when adjacent to a complementary angled cutout in a recessed area configured to receive the holder.

[0107] As described herein, reagent holders used with racks are typically made of plastics such as polypropylene. As further described herein, this plastic provides a degree of flexibility to facilitate placement within the rack. However, the plastic generally possesses sufficient rigidity to prevent the holder from sagling or bending significantly under its own weight, and to prevent easy deformation during routine handling and transport, thus preventing reagent leakage.

[0108] The retainer 200 typically comprises the connecting member 210, the processing tube 220, two or more reagent tubes 240, and the waste chamber 260 (if present) as a single piece made of a material such as polypropylene. It should be understood that other configurations of the retainer 200 may be suitably implemented in the disclosed art.

[0109] The illustrated embodiment of the reagent holder 200 has four receivers 250 and corresponding containers 254. Figure 2B A side profile view of this embodiment of the reagent holder 200 is shown, and Figure 2C A top view of this embodiment of the reagent holder 200 is shown. It can be seen that four receptors 250 (e.g., receptors 250-1, 250-2, 250-3, and 250-4) are configured to receive corresponding containers 254 (e.g., containers 254-1, 254-2, 254-3, and 254-4). Some containers 254 may contain a quantity of one or more reagents, typically in solid form, such as lyophilized form, for use in extracting nucleic acids from a sample associated with the holder.

[0110] In other embodiments, such as Figure 2D and Figure 2E The embodiment of the retainer 202 shown may have a different number of receivers 250 and containers 254. For example, Figure 2D A side profile view of an embodiment of the retainer 202 is shown, while Figure 2E A corresponding top view of an embodiment of the retainer 202 is shown. In this embodiment of the reagent retainer 202, there are three receptors 250 (e.g., receptors 250-1, 250-2, and 250-3) configured to receive corresponding containers 254 (e.g., containers 254-1, 254-2, and 254-3). Some containers 254 may contain an amount of one or more reagents, typically in solid form, such as lyophilized form, for use in extracting nucleic acids from a sample associated with the retainer. Although example retainers 200 and 202 are described as containing reagents for extracting nucleic acids from a sample, it should be understood that the disclosed techniques are not limited to retainers containing such reagents and can be implemented on any retainer in which a magnetic matrix (such as magnetically bound particles) in solution is manipulated or processed.

[0111] Now refer to Figures 3A-3C Example heater and magnetic separator assemblies are described, capable of applying thermal and magnetic energy to the processing tubes of multiple retainers. It should be understood that embodiments of the disclosed technology can be suitably implemented in other heater and magnetic separator assemblies. Figure 3A An isometric view of an exemplary heater assembly 300 having an independently controllable heater unit and a magnetic separator 370 is shown. Figure 3B An isometric view and side profile of one of these independently controllable heater units 301 are provided. Figure 3C A side profile view of the interaction between the magnetic separator 370 and the independently controllable heater unit of the heater assembly 300 is provided.

[0112] More specifically, Figure 3A The heater assembly 300 shown may include one or more independently controllable heater units 301, each heater unit including a heating block 303. Each heating block 303 is configured to align with and transfer heat to the processing tube 302. Each heating block 303 may optionally be secured and connected to the remainder of the device using one or more fasteners (such as one or more screws 307 or one or more other adhesive devices). The securing mechanism is not limited to this configuration.

[0113] In some embodiments, the heater assembly 300 contains 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 25, 30, 32, 36, 40, 48, or 50 heater units. Other numbers of heater units (such as any number between 6 and 100) are compatible with the description herein. One or more heating blocks 303 may be made of a single sheet of metal or other material, or may be made separately from each other and mounted independently or connected to each other in some way. Thus, the term heater assembly refers to a collection of heater units, but does not require that the heater units or their corresponding heating blocks be directly or indirectly attached to each other. The heater assembly 300 may be configured, for example, by allowing each of the one or more heating blocks to be independently controllable, such that each heater unit 301 independently heats each of the one or more processing tubes 302 (e.g., the processing tube of a reagent holder, such as...). Figure 2A The processing tube 220 of the holder 200 shown herein is as further described herein.

[0114] In some embodiments, a magnetic separator 370 may be present. The magnetic separator 370 may be configured to move one or more magnets 304 relative to one or more processing tubes 302 and to separate magnetic particles within the processing tubes 302. In some embodiments, the magnets 304 may be moved adjacent to the processing tubes 302 (e.g., each magnet 304 has a facet distance of less than 2 mm, between 2 mm and 1 mm, or less than 1 mm from the outer surface of the corresponding processing tube 302 without contacting the processing tube 302). The magnets 304 of the magnetic separator 370 may be aligned on a common axis (e.g., the common axis may pass through the midpoint of each magnet 304). This common axis may be located behind the processing tubes 302 and extend parallel to the processing tubes 302 (more specifically, when the processing tubes 302 are disposed in the heating block 303, it extends parallel to the common axis passing through all the processing tubes 302). In some cases, this common axis passing through the magnets 304 of the magnetic separator 370 may be referred to as a first magnet axis, such as... Figure 3B An example of the first magnet axis 380 is shown. Magnetic particles can be microparticles, beads, or microspheres capable of binding one or more biomolecules, such as polynucleotides, and are often used as retention components. When in solution, separating particles typically involves collecting and concentrating or aggregating the particles at a location inside one or more processing tubes 302.

[0115] Structurally, the magnetic separator 370 may include: one or more magnets 304 fixed to a support member; an electric mechanism configured to move the support member such that the one or more magnets move back and forth along a fixed axis, and during at least a portion of the movement, the one or more magnets remain in close proximity to one or more receptors containing magnetic particles in the solution; and a control circuit for controlling the electric mechanism. The support member and the electric mechanism are not... Figure 3A As shown in the figure, but combined Figure 3C It was described in more detail.

[0116] The magnetic separator 370 can operate in conjunction with the heater assembly 300 to allow continuous heating and separation operations on liquid material in one or more processing tubes without transporting the liquid material or processing tubes to different locations for heating or separation. This operation is also advantageous because it means that the functions of heating and separation (although independent of each other, both used for sample preparation) can be performed in a compact and efficient device.

[0117] In some embodiments, the heater assembly 300 and the magnetic separator 370 may be controlled by electronic circuitry, such as on a printed circuit board 309. The electronic circuitry may be configured to allow the heater assembly 300 to independently apply heat to the processing tube 302 to minimize heating and sensing costs. It may also be configured to repeatedly move the magnetic separator 370 relative to the processing tube 302. The electronic circuitry may be integrated into a single printed circuit board (PCB).

[0118] In some cases, the magnetic separator 370 may be integrated with the heater assembly 300, and they may be collectively referred to as an integrated magnetic separator and heater assembly. Thus, the integrated magnetic separator and heater may include: a heater assembly comprising a plurality of independently controllable heater units, each heater unit having a heating block configured to receive and heat one of a plurality of processing tubes; one or more magnets fixed to a support member; an electric mechanism configured to move the support member such that the one or more magnets move back and forth along a fixed axis, and during at least a portion of the movement, the one or more magnets remain in close proximity to one or more processing tubes in the heater assembly, wherein the one or more processing tubes contain magnetic particles; and control circuitry for controlling the electric mechanism and controlling the heating of the heater units.

[0119] Despite Figure 3A Not shown, but a housing may cover the magnetic separator 370 and heater assembly 300 for protection of the underlying sub-assemblies and for aesthetic purposes. The housing may also be designed to space the heating blocks 303 apart to ensure efficient heating and cooling. The housing may be configured to allow sufficient airflow around the processing tube 302 without significantly inhibiting the cooling rate. The housing may have a gap between itself and the heating blocks 303 to facilitate cooling. Alternatively, the magnetic separator 370 and heater assembly 300 may be enclosed by separate housings. For example, the heater assembly 300 may optionally be contained within a housing surrounding the heater unit 301 and the heating blocks 303. One or more housings may be made of plastic, but are not limited to this. One or more housings may be configured for aesthetic appeal to the user.

[0120] exist Figure 3A In the specific configuration shown, the heater assembly 300 includes twelve heating blocks 303 aligned parallel to each other. Each heating block 303 is made of aluminum and has an L-shaped configuration with a U-shaped inlet for receiving a processing tube 302. The magnetic separator 370 includes twelve magnets 304 aligned parallel to each other. Each magnet 304 can be a rectangular neodymium block (or other permanent rare earth material with a magnetic field), disposed behind each heating block 304 and mounted on a support member. The magnets 304 can be configured to move vertically relative to the processing tube 302 in the heater assembly 300. Figure 3CPlease describe the agency in further detail.

[0121] As further described herein, some embodiments of the automated diagnostic or preparation apparatus described herein have more than one independently controllable heater unit 301 in a single heater assembly 300. For example, a single heater assembly 300 may be configured to independently heat 6 or 12 processing tubes, and the apparatus may be configured with two or four such heater assemblies 300. It should be understood that embodiments of the disclosed technology may be implemented in heater assemblies that do not independently heat each processing tube, or that can apply heat to a subset of multiple processing tubes received in the heater assembly.

[0122] Despite Figure 3B The right panel shows a cross-sectional view of a heating block 303, but it should be understood that this is compatible with aligning multiple heating blocks parallel to each other and ensuring that their geometric midpoints all lie on a single linear axis (e.g., as shown in the diagram). Figure 3A (As shown), however, its configuration is not limited to this. Therefore, one or more heating blocks can be positioned at different heights, either grouped or alternating, individually or from left to right, grouped or alternating, or individually relative to each other. Additionally, in other embodiments, the heating blocks are not aligned parallel to each other, but are arranged at an angle relative to each other, which is not 180°. Furthermore, although... Figure 3B The heating block 303 shown may be one of several heating blocks of the same size, but in accordance with the technology herein, one or more heating blocks may be configured to receive and heat processing tubes of different sizes.

[0123] Figure 3B The exemplary heating block 303 in the right panel is configured to have an internal cavity partially surrounding the lower portion of the processing tube 302. In the heating block 303, the internal cavity surrounds the lower portion of the processing tube 302 on both sides, but not on the front side (facing away from the magnet 304) or the back side (adjacent to the magnet 304). In other embodiments, the heating block 303 is configured to surround the bottom of the processing tube 302 on three sides, including the front side. Other configurations of the heating block 303 are also feasible, which is compatible with the goal of achieving rapid and uniform heating of the contents of the processing tube 302. In some embodiments, the shape of the heating block is designed to fit closely to the shape of the processing tube 302 to increase the surface area of ​​contact between the heating block and the processing tube during heating. Thus, although the exemplary heating block 303 is shown as having a tapered, curved-bottom cavity in which the complementary processing tube is disposed, other embodiments of the heating block 303 have, for example, a cylindrical cavity with a flat bottom. Other embodiments of the heating block 303 may have a linear internal cavity, such as one that can accommodate a cuvette.

[0124] Furthermore, despite Figure 3B The heating block 303 is shown in an L-shape, which helps to transfer heat away from the heating element 351 and helps to secure one or more heating blocks to the rest of the device, but this is not necessary, as further described herein. For example, in some embodiments, the heating element 351 may be positioned directly below the processing tube 302.

[0125] In one embodiment, the heating block 303 has a mass of ~10 grams and is configured to heat liquid samples with volumes between 1.2 ml and 10 μl. A 1 ml biological sample can be heated from room temperature to 65°C in less than 3 minutes, and a 10 μl aqueous liquid (such as a release buffer) can be heated to 85°C (starting from 50°C) in less than 2 minutes. The heating block 303 can be cooled from 85°C to 50°C in less than 3 minutes. The heating block 303 can be configured to have a temperature uniformity of 65 ± 4°C for heating a 1 ml sample and a temperature uniformity of 85 ± 3°C for heating a 10 μl release buffer. These ranges are exemplary, and the heating block can be appropriately scaled to heat other volumes of liquid at rates slower and faster than described. This aspect of the technology is one that facilitates rapid nucleic acid extraction from multiple samples by combining liquid processing steps, rapid heating for lysis, DNA capture and release, and magnetic separation, as further described herein and elsewhere, such as U.S. Patent Application Serial Nos. 12 / 172,208 and 12 / 172,214, both of which are incorporated herein by reference.

[0126] like Figure 3B As shown, the independently controllable heater unit 301 may also include one or more heating elements (e.g., power resistors) 351, each configured to thermally engage with and dissipate heat from the heating block 303. For example, in one embodiment, the power resistor may dissipate up to 25 watts of power. Although the heating element 351 is shown positioned at the bottom of the heating block 303, it should be understood that other configurations are compatible with the components described herein: for example, the heating element 351 may be positioned on top or side of the heating block 303 or directly below the processing tube 302. In other embodiments, the heating element has other shapes, and its cross-section may not be rectangular but may be curved, such as spherical or elliptical. Additionally, the heating element may be molded or shaped such that it fits closely or approximately in contact with the bottom of the processing tube.

[0127] exist Figure 3BIn the illustrated embodiment, the independently controllable heater unit 301 may further include one or more temperature sensors 352, such as resistive temperature detectors, to sense the corresponding temperature of each heating element 303. Although the temperature sensors 352 are shown as being placed at the bottom of the heating element 303, it should be understood that other configurations are compatible with the components described herein: for example, the temperature sensors may be placed on the top or side of each heating element 303, or closer to the bottom of the processing tube 302, but not too close to avoid hindering its uniform heating.

[0128] A printed circuit board (PCB) 309 is also shown, which enables the heater assembly 300 to independently apply heat to each processing tube 302 upon receiving appropriate instructions.

[0129] Figure 3C A cross-sectional profile view of the magnet 304 of the independently controllable heater unit 301 and the magnetic separator 370 is provided to illustrate the interaction between the magnetic separator 370 and the independently controllable heater unit of the heater assembly 300.

[0130] although Figure 3C The magnet 304 shown is depicted as a rectangular block, but its shape is not limited to this. Furthermore, Figure 3C The configuration is compatible with the following structures: a single magnet extending across all heating blocks 303 in the heater assembly 300, or magnets cooperating and aligned (e.g., collinearly aligned on support members) across a subset of heating blocks 303. The magnet 304 may be made of neodymium and may have a magnetic strength of 5,000-15,000 Gauss (Brmax). An example magnet is from K&J Magnetics. Other suitable magnets may be implemented. The poles of the magnet 304 may be arranged such that one pole faces the heating block 303 and the other pole faces away from the heating block 303.

[0131] Magnet 304 is mounted on support member 372, which can be raised and lowered along a fixed axis using an electric shaft 305. The fixed axis can be vertical. Magnetic separator 370 may have a gear 306 that transmits rotational energy from motor 375 to the electric shaft 304 to raise and lower magnet 304 relative to the heating block. This gear arrangement allows motor 375 to be placed perpendicular to shaft 305, thus saving space in the device in which magnetic separator 370 is located. In other embodiments, motor 375 is positioned below shaft 305. It should be understood that other configurations are compatible with the movement of magnet 304 relative to processing tube 302, including but not limited to moving magnet 304 from one side to the other or lowering magnet 304 from above.

[0132] Motor 375 can be computer-controlled to operate at a specific speed; for example, a rotational speed that causes magnet 304 to move vertically in the range of 1-20 mm / s. Therefore, magnetic separator 370 can be configured to repeatedly move (e.g., up and down, from one side to the other, or back and forth) along the same axis multiple times. In some embodiments, there is more than one electrically controlled shaft 305. The presence of at least a second shaft serves to smooth the movement of separator 370 and acts as a guide member. In some embodiments, support member 372 rides on one or more guide members to ensure that support member 372 does not tilt, twist, or yaw or undergo other internal movements during movement (other than controlled movement along the axis), thereby reducing the separation effect.

[0133] The support member 372 can also be configured to position the magnet 304 away from the processing tube 302 in a first position (e.g., as shown in the image). Figure 3C (on the left side) and the second position immediately adjacent to the processing tube 302 (e.g., as Figure 3C It moves between the right side of the first position and the second position, and is further configured to move near the second position by a certain amplitude, wherein the amplitude is less than the distance between the first and second positions measured along axis 305.

[0134] Figure 4A and Figure 4B Various views of the rack are shown, which can hold multiple reagent holders (e.g., Figure 2A The retainer 200 shown is held in a predefined position to ensure that when the bench is loaded into the automated diagnostic or preparation apparatus described herein, the processing tube of the reagent retainer (e.g., Figure 2A The processing tube 220 of the holder 200 shown is precisely positioned in the heater block of the heater assembly (e.g., Figure 3A In the heater block 303 of the heater assembly 300 shown. More specifically, Figure 4A A perspective view of the back of the stand is shown, while Figure 4B An isometric view of the platform is shown. Figure 4A and 4B Let's describe them together.

[0135] An embodiment of a bench 400 is shown, which is configured to be inserted into and removed from a loading rack (or alternatively, a receiving rack) of automated devices (such as the automated diagnostic device or automated preparation device described herein). Figure 5AAn example of a loading rack for an automated apparatus is shown. Additional details of this apparatus are provided in U.S. Patent Application Serial No. 12 / 173,023, filed July 14, 2008 (attributed to Williams et al., entitled “Integrated Apparatus for Performing Nucleic Acid Extraction and Diagnostic Testing on Multiple Biological Samples”), which is incorporated herein by reference. The automated apparatus may have multiple loading racks, allowing samples to be processed simultaneously on multiple racks.

[0136] Each stand can be configured to receive multiple reagent holders. In some examples, the stand is also configured to receive multiple sample tubes. The device is configured to receive multiple reagent holders and multiple sample tubes, such that there is a one-to-one correspondence between the reagent holders and sample tubes, and wherein each reagent holder contains sufficient reagents to extract polynucleotides from the sample and place the polynucleotides in a PCR-ready form. In embodiments where the stand receives multiple sample tubes, the stand can accept any number of sample tubes containing the sample (e.g., 2, 4, 6, 8, 10, 12, 16, or 20 sample tubes) and a corresponding number of reagent holders. The stand can be configured to hold the reagent holders in place, thereby allowing access to the reagents stored in the holders on the lab bench, or in a dedicated area of ​​the device, thereby allowing access to one or more other functions of the device (such as automated pipetting, heating of the processed tubes, and magnetic separation of affinity beads) to the holders. The reagent holder may have at least one processed tube and one or more reagent containers. In this document (e.g., in conjunction with...) Figures 2A to 2E The reagent holder is described in further detail, and additional details of the reagent holder are provided in U.S. Patent Application Serial No. 12 / 218,416 (filed on July 14, 2008, entitled "Reagent Tube, Reagent Holder, and Kits Containing Same" by Wilson et al.), which is incorporated herein by reference.

[0137] For example, in Figure 4A and Figure 4B In the illustrated embodiment, the bench 400 is configured to receive 12 sample tubes 416 and 12 corresponding reagent holders 404 in 12 channels 402. As used herein in the context of bench 400, the channels 402 are dedicated areas of bench 400 designed to receive sample tubes and corresponding reagent holders 404. In some cases, the reagent holders 404 may be... Figure 2AThe reagent holder 200 shown has a processing tube 220 at one end. The channel 402 of the stand 400 can be configured to receive the reagent holder 404 in a specific orientation. For example, in order to slide each reagent holder 404 into the channel 402, it may be necessary to point the end of the reagent holder 404 with the processing tube toward the channel 402.

[0138] For example, in the embodiment shown here, at least the first and second channels are parallel to each other, a configuration that increases pipetting efficiency. Typically, when parallel to each other, pairs of adjacent sample channels 402 are spaced 24 mm apart at their respective midpoints. Other distances are also possible, such as 18 mm or 27 mm apart. As further described herein, the distance between the midpoints depends on the nozzle spacing in the liquid dispensing head. Maintaining the spacing as a multiple of 9 mm facilitates loading from the bench into 96-well plates (typically these wells are spaced 9 mm apart). Typically, the bench should also ensure that multiple reagent holders in the multiple channels are held at the same height relative to each other.

[0139] Channels 402 of the stand 400 can be configured to receive a given reagent holder 404 such that the reagent holder 404 reversibly snaps into or locks into place, and thus the reagent therein remains stable in a timely manner and while the stand 400 is being moved from one place to another or being inserted into or removed from a diagnostic or preparation device. Channels 402 of the stand 400 can be configured such that the reagent holder 404 is aligned when positioned in the stand 400 for proper pipette tip pickup using a liquid dispenser, as further described herein. Furthermore, in examples where the reagent holder accommodates one or more pipette tips, the second position of each channel can be deep enough to accommodate one or more pipette tips, such as those contained within a pipette tip sheath.

[0140] The stand 400 may include a sample tube holder 410 configured to receive a plurality of sample tubes 416 (one for each channel 402). Therefore, in Figure 4A and Figure 4B In the illustrated embodiment, the sample tube holder 410 can be configured to accept up to 12 sample tubes 416. For each sample tube 416 to which the sample tube holder 410 is configured to hold, the sample tube holder 410 may have a first slot 412 and a second slot 414 through which the sample tube 416 is inserted. Each first slot 412 may have a corresponding second slot 414, and each first slot 412 and its corresponding second slot 414 may be positioned to receive and hold the sample tube 416 at a location adjacent to a channel 402 (e.g., on the same axis as the channel 402, such that the holder 404 inserted into the channel 402 is aligned with the sample tube 416). It should be understood that implementations of the disclosed technology are not limited to those shown. Figures 4A-4BThe table shown includes a sample tube holder 410, and embodiments of the disclosed technology can be suitably implemented using a table that does not include the sample tube holder 410 and does not receive sample tubes 416.

[0141] Figure 5A An isometric view of an empty loading rack 500 (or receiving rack) for an automated diagnostic or preparation device is shown.

[0142] The loading rack 500 can be a recessed area of ​​the device, which is configured to receive, for example, Figure 4A and Figure 4B The apparatus may have any number of loading racks 500 for receiving a corresponding number of racks 400. For example, Figure 5A An embodiment of an apparatus with two loading racks 500 positioned side-by-side is shown, the side-by-side positioning allowing two separate racks 400 to be loaded simultaneously. Figure 5A The diagram also shows a first magnet axis 580, which can be a common axis of magnets aligned with the magnetic separator (e.g., a common axis of magnets passing through the magnetic separator). This first magnet axis 580 (similar to...) is positioned such that when the platform 400 is inserted into the loading rack 500 and extends parallel to those processing tubes (more specifically, parallel to the common axis passing through the processing tubes), it... Figure 3B The first magnet axis 380 shown can be located behind the processing tube of the reagent holder in the stand 400.

[0143] Figure 5B A front perspective view of an example automated diagnostic apparatus is shown, having two loading racks 500 occupied by corresponding sample stages 400. These loading racks 500 are shown relative to two microfluidic cartridges 510, which can be configured to amplify appropriately prepared samples, as further described in U.S. Patent Application Serial No. 12 / 173,023, filed July 14, 2008 (attributed to Williams et al., entitled “Integrated Apparatus for Performing Nucleic Acid Extraction and Diagnostic Testing on Multiple Biological Samples”). Recessed areas for receiving other appropriately configured stages of different shape, appearance, and form, but not functional differences, are compatible with the description herein.

[0144] Also shown is a liquid dispensing head 520, which can be an automated pipette tip for performing liquid handling operations. An exemplary automated pipette tip is described in U.S. Patent Application Serial No. 12 / 173,023, filed July 14, 2008 (under the name of Williams et al., entitled "Integrated Apparatus for Performing Nucleic Acid Extraction and Diagnostic Testing on Multiple Biological Samples").

[0145] The liquid dispensing head 520 can pick up a pipette tip (e.g., from one or more holders in a reagent holder (such as a reagent holder 404 in the rack 400)) and then return the pipette tip (e.g., after use, to such a holder in the reagent holder); after use or in case of an error, detach and discard the pipette tip; and precisely move the pipette tip from one position to another in a given holder so that, for example, liquid reagents can be positioned and added to solid reagents to prepare solutions, and various liquid reagents can be mixed with each other during sample preparation protocols. Furthermore, it is desirable that such a liquid dispensing head 520 be able to operate on several holders (e.g., 2, 3, 4, or 6) in the rack 400 simultaneously, and thus perform certain operations in parallel. The liquid dispensing head 520 can move in three degrees of freedom.

[0146] Fixed magnet assembly according to examples of the disclosed technology

[0147] Figures 6A to 6E Various conceptual diagrams are shown that relate to implementations of a stationary magnet assembly for preventing the retention of extraction particles, according to the disclosed technology. These conceptual views provide contextual details that help to understand how the addition of the stationary magnet assembly prevents the retention of extraction particles in embodiments of the disclosed technology.

[0148] Figure 6A A top view of a set of three reagent holders 602 in a loading rack or receiving rack 600 of a diagnostic or preparation device. Figure 6A The diagram illustrates how the reagent holder 602 is arranged relative to a first magnet axis 612 (e.g., an offset magnetic separator) and a second magnet axis 614 (according to the disclosed technology of a fixed magnet assembly). See above for reference. Figures 3A-3COne or more magnets of the magnetic separator can be aligned along the axis 612 of the first magnet. A set of three sample tubes 604 associated with the reagent holder 602 is also shown, adjacent to the reagent holder 602. In practice, there can be more than three reagent holders 602 (and more than three corresponding sample tubes 604) in the receiving rack 600, such as the 12 reagent holders held in the rack 400. For each reagent holder 602, some of its associated components are shown, including a processing tube 606 (e.g., Figure 2A The processing tube 220 shown) and a set of containers 608 (e.g., Figure 2A (See container 254 shown). Each reagent holder 602 and its corresponding sample tube 604 can be aligned along a processing axis 610, wherein the diagnostic or preparation device is configured to perform processing and operations (e.g., transfer of liquids) along each processing axis 610. Thus, a total of n processing axes 610 can be conceptualized – each reagent holder 602 and its corresponding sample tube 604 corresponds to one processing axis.

[0149] It should be understood that in some embodiments, the processing axis 610 does not include the sample tube 604 (e.g., if the sample tube 604 is received in a different part of a device not associated with the reagent holder 602). In such an example, the processing axis 610 may be defined by the location of the processing tube 606 and the location of the container (container 608-3 in the illustrated embodiment) that receives magnetic energy from a magnet aligned along the second magnet axis 614.

[0150] In some embodiments, each reagent holder 602 may be similar to Figures 2A-2C The reagent holder 200 is shown. In other words, the reagent holder 602 can be a container with four snap-fit ​​containers 608 (e.g., Figure 2A In an embodiment of container 254, the snap-in container includes containers 608-1, 608-2, 608-3, and 608-4 (numbered in order from closest to furthest from processing tube 606). In this case, processing tube 606 may alternatively be referred to as reaction tube or lysis tube, container 608-1 may alternatively be referred to as extraction tube, and container 608-3 may alternatively be referred to as mixing tube. It should be understood that alternative reagent holders 602 may be implemented in embodiments of the disclosed technology. For example, multiple reagent holders 602 may be combined or formed into a single integral processing device configured to be received in a receiving rack. As another example, an integral device including multiple reagent holders 602 may be received in a receiving rack.

[0151] The first magnet axis 612 may extend horizontally behind the processing tube 606 of the reagent holder 602. The first magnet axis 612 may be a magnet of a magnetic separator (e.g., Figure 3A and Figure 3C The axis on which the magnet 304 of the magnetic separator 370 shown is located. The first magnet axis 612 can be positioned such that when the magnetic separator is lifted, the magnet of the magnetic separator is in close proximity to the processing tube 606 (e.g., within 2 mm of the processing tube 606).

[0152] According to embodiments of the fixed magnet assembly of the disclosed technology, the second magnet axis 614 may extend horizontally through the container 608-3 of the reagent holder 602. Alternatively, the second magnet axis 614 may extend behind or in front of the container 608-3, in either case being sufficiently close to apply a magnetic force to the contents of the container 608-3. The second magnet axis 614 may be the axis along which the magnet of the fixed magnet assembly is located. The second magnet axis 614 may be positioned such that the magnet of the fixed magnet assembly is sufficiently close to the container 608-3 (e.g., a mixing tube) of the reagent holder 602 to apply a magnetic force to the contents of the container 608-3. The magnetic force may be strong enough to, for example, hold magnetically bound particles in the solution in the container 608-3 against the inner wall of the container 608-3 when transferring the solution from the container 608-3 during a pipetting operation. Furthermore, the second magnet axis 614 can be spaced sufficiently far from the first magnet axis 612 so that the magnets of the fixed magnet assembly do not interfere with the magnets of the magnetic separator. For example, the first magnet axis 612 can be spatially separated from the second magnet axis 614 by a distance "D" such that one or more magnets aligned along the first magnet axis 612 do not apply magnetic force to the contents of the container 608-3, and one or more magnets aligned along the second magnet axis 614 do not apply magnetic force to the contents of the processing tube 606.

[0153] The first magnet axis 612 and the second magnet axis 614 are in Figure 6B The figure further illustrates a top-view conceptual diagram of the positioning of certain components of the reagent holder 602 relative to magnets on the first magnet axis 612 and magnets on the second magnet axis 614.

[0154] More specifically, Figure 6B The diagram shows four reagent holders, including processing tubes 606, snap-fit ​​containers 608-3, and the location of a processing axis 610 associated with each reagent holder. It can be seen that the magnetic separator 620 includes a plurality of magnets 622 aligned on a first magnet axis 612, and each magnet 622 is positioned adjacent to the processing tube 606 of the reagent holder. In this example embodiment, each magnet 622 corresponds one-to-one with a processing tube 606. In practice, when the magnetic separator 620 is raised to bring the magnets 622 close to the processing tube 606, the magnets 622 apply a magnetic force to the contents of the processing tube 606 (in...). Figure 6B (shown as a vertical vector).

[0155] exist Figure 6B The diagram also illustrates a magnet 632 of a fixed magnet assembly according to the disclosed technology. In this example embodiment, a single magnet 632 applies magnetic force to two containers 608-3, such that the magnet 632 does not correspond one-to-one with the container 608-3. In some embodiments, the magnets 632 of the fixed magnet assembly may be arranged in pairs. Each pair of magnets 632 may be located within a housing or structure 630. The fixed magnet assembly may include multiple housings 630. In one non-limiting embodiment, the multiple housings 630 are formed as a single structure, and each housing is configured to receive or enclose two magnets 632. In another non-limiting embodiment, the fixed magnet assembly includes a single structure formed of magnetic material, the single structure including multiple magnet structures 630 configured to apply magnetic force to the container 608-3. Pairs of magnets 632 can be positioned within the diagnostic or preparation device such that, when the reagent holders are in the receiving rack of the diagnostic or preparation device, each pair of magnets 632 is located between the containers 608-3 of two adjacent reagent holders (as shown in the figures). One magnet 632 can be present for each reagent holder, and each magnet 632 can be adjacent to the container 608-3 of the reagent holder when the reagent holder is in the receiving rack of the diagnostic or preparation device. All magnets 632 of the fixed magnet assembly can be aligned (or substantially aligned) on the second magnet axis 612. Each magnet 632 can apply a magnetic force to the contents of the adjacent container 608-3 (in... Figure 6B (shown as a horizontal vector).

[0156] Implementations of the fixed magnet assembly according to the disclosed technology may include magnets of any suitable configuration. In a non-limiting example, each magnet 632 is a 0.25 x 0.25 x 0625” NdFeB Grade N52 square magnet with a pull force of 1.77 psi and a field strength of 3032 gauss. It should be understood that the materials, dimensions, and pull forces are not limited to this particular example of the disclosed technology. Suitable magnets may include a variety of magnets of different materials, sizes, and / or strengths, provided that the selected magnet configuration, combined with the positioning of the magnets by the mixing tube, enables the magnets to adequately capture magnetically extracted particles in the mixing tube.

[0157] Figure 6C Similar to Figure 6A ,in Figure 6C A top conceptual view of a set of three reagent holders 602 in a loading or receiving rack 600 of a diagnostic or preparation device is shown. However, in Figure 6CIn the illustrated embodiment, the second magnet axis 614 does not extend through the midpoint of the container 608-3 of each reagent holder 602. Instead, the second magnet axis 614 lies on an eccentric chord of each container 608-3. For example, this could correspond to... Figure 6D The example shown.

[0158] Figure 6D Similar to Figure 6B ,in Figure 6D A top-view conceptual diagram shows the positions of certain components of the reagent holder 602 relative to magnets on the first magnet axis 612 and magnets on the second magnet axis 614. However, in Figure 6D In the illustrated embodiment, the second magnet axis 614 does not extend through the midpoint of the container 608-3 of each reagent holder 602. This second magnet axis 614 differs from the mixing axis 616, which passes through the midpoint of the container 608-3 of each reagent holder 602. The magnet 632 is aligned along the second magnet axis 614, which is generally parallel to the first magnet axis 612 and also generally parallel to the mixing axis 616 (but does not coincide with it). However, the second magnet axis 614 can be close enough to the mixing axis 616 that the magnet 632 (located on the second magnet axis 614) can be considered to apply a magnetic force to the contents of each container 608-3 in a direction generally parallel to the mixing axis 616. Figure 6E The additional context provided can better illustrate the function of the magnet 622 in the magnetic separator 620 and the magnet 632 in the fixed magnet assembly. Figure 6E This is a side profile concept diagram showing the positions of the reagent holder 602 and the corresponding sample tube 604 relative to the first magnet 622 (e.g., from the magnetic separator) and the second magnet 632 (e.g., from the fixed magnet assembly) when the reagent holder 602 and the corresponding sample tube 604 are in the receiving rack of the diagnostic or preparation device.

[0159] More specifically, Figure 6E A reagent holder 602 is shown, comprising a processing tube 606, a set of four snap-fit ​​containers 608 (e.g., containers 608-1, 608-2, 608-3, and 608-4), a set of reagent tubes (e.g., reagent tubes 640, 642, and 644), a waste chamber 646, and a set of pipette tips (e.g., pipette tips 648, 650, 652, and 654) disposed within a pipette sheath. Although the illustrated embodiment of the reagent holder 602 has four snap-fit ​​containers 608, it should be noted that embodiments of the disclosed technology can be used with reference to 2D- Figure 2E The reagent holder described is a reagent holder with three snap-fit ​​containers 608 (e.g., without containers 608-4) to be properly implemented.

[0160] Typically, a processing tube 606 (similar to) can be used during sample preparation. Figure 2A The processing tube 220 shown is used for cell lysis and nucleic acid extraction, such as the extraction of DNA or RNA from patients and pathogens. The processing tube 606 can be positioned at a location at the distal end of the reagent holder 602 that minimizes overall pipette tip movement associated with transferring liquid to the processing tube 606 when the reagent holder 602 is in the receiving rack of the diagnostic or preparation device. The processing tube 606 is also positioned such that, when the reagent holder 602 is in the receiving rack of the diagnostic or preparation device, the processing tube 606 is positioned within the heater block 660 of the heater assembly (e.g., as shown in the image). Figure 3A and 3B (As shown). The first magnet 622 of the magnetic separator can be raised to a position adjacent to the processing tube 606 to apply a magnetic force to the contents of the processing tube 606.

[0161] Some containers 608 may contain lyophilized reagents (e.g., desiccant) to which fluids can be added. In some embodiments, container 608-1 may alternatively be referred to as an extraction tube. In some embodiments, container 608-3 may alternatively be referred to as a mixing tube. In some embodiments, containers 608-2 and 608-4 may alternatively be referred to as master mixing tubes. Reagent tubes 640, 642, and 644 may contain liquid reagents, one liquid reagent per tube. In some embodiments, reagent tube 640 may contain a wash buffer. In some embodiments, reagent tube 642 may contain an elution buffer. In some embodiments, reagent tube 644 may contain a neutralization buffer. The wash buffer, release buffer, and neutralization buffer may each be used in a sample preparation protocol. Used liquid reagents may be transferred to waste chamber 646 and disposed of there.

[0162] A set of four pipette tips (e.g., pipette tips 648, 650, 652, and 654) may be housed within a pipette sheath. Diagnostic or preparation devices may use the pipette tips (e.g., via liquid dispensing tip 520) to perform procedures and operations (e.g., transfer of liquids). The pipette sheath may be used to capture drops from the pipette tips in use, thereby preventing cross-contamination of samples, preventing the use of one holder for another in similar locations, and / or any supports in which the holder is positioned. The pipette sheath may be permanently or removably attached to the reagent holder 602, or may be formed (e.g., molded) as part of a single-piece assembly for the holder 602.

[0163] The process of preparing a sample using the additional immobilizing magnet assembly is as follows. It should be noted that the following description of an example workflow is provided to offer context for understanding the role of the immobilizing magnet assembly, and these steps are not applicable to all assays, which may use other workflows with different processing steps or sequences of operations. In some embodiments, the liquid dispensing tip of the diagnostic or preparation device may first pick up the first pipette tip 648 and use it to pierce the various components of the reagent holder 602 (e.g., to make them accessible), including container 608-1, waste chamber 646, and reagent tubes 640, 642, and 644 (containing wash buffer, release buffer, and neutralization buffer, respectively).

[0164] The liquid dispensing tip of the diagnostic or preparation device can use a first pipette tip 648 to transfer some of the raw sample from sample tube 604 and add it to processing tube 606. The amount of raw sample transferred can depend on the type of assay or procedure. Some sample (e.g., the remainder of the sample not transferred to processing tube 606) can be added to container 608-1 (e.g., extraction tube), which may contain magnetic particles (e.g., beads), lyophilized extraction reagent (e.g., dried lysis reagent), and an internal control. The magnetic particles can be configured to bind specific molecules (e.g., DNA / RNA) in the sample. The contents of container 608-1 are rehydrated using the added sample and given time to dissolve in solution. The liquid dispensing tip can then use the first pipette tip 648 to transfer the contents of container 608-1 to processing tube 606 (which contains the remainder of the transferred sample from sample tube 604) and mix the contents of processing tube 606. Afterward, the liquid dispensing head can return the first pipette tip 648 to its pipette sheath.

[0165] The contents of a processing tube 606 (e.g., the processing tube 606 is received within the heater block 660) located in the heater unit of the heater assembly of the diagnostic or preparation device are heated by the heater block 660. The temperature and duration of heating are determined by the type of assay or procedure. Heating and lysis reagents cause cells from the sample to rupture, and certain target nucleic acids (e.g., DNA or RNA) contained within the cells, as well as internal controls, can attach to or bind to magnetic particles (e.g., magnetically bound particles or magnetic beads).

[0166] The first magnet 622 of the magnetic separator can be raised until it is adjacent to the processing tube 606. Magnet 622 can apply a magnetic force to the magnetic particles in the processing tube 606, thereby attracting the magnetic particles and attached nucleic acids to the side of the processing tube 606. A liquid dispensing head can extract liquid from the processing tube 606 using a first pipette tip 648, while magnet 622 continues to attract the magnetic particles and attached nucleic acids to the side of the processing tube 606. Ideally, under normal operation, the liquid should not contain magnetic particles and attached nucleic acids, and when extracting the liquid, the magnetic particles and attached nucleic acids are kept close to the inner wall of the processing tube 606. The liquid dispensing head can dispense the extracted liquid into the waste chamber 646 and return the first pipette tip 648 to its pipette sheath.

[0167] The first magnet 622 of the magnetic separator can be lowered to remove the magnetic force holding the magnetic particles and attached nucleic acids to the side of the processing tube 606. A liquid dispensing tip can be used with a second pipette tip 648 to transfer washing buffer from the reagent tube 640 to the processing tube 606. A second pipette tip 650 can also be used to mix the added washing buffer with the nucleic acid-bound magnetic particles in the processing tube 606. Afterward, the first magnet 622 of the magnetic separator can be raised until it is flush with the processing tube 606. The magnet 622 can then apply a magnetic force to the magnetic particles in the processing tube 606, thereby again attracting the magnetic particles and attached nucleic acids to the side of the processing tube 606.

[0168] If magnetic particles move to the side of the processing tube 606, the liquid dispensing head can use the second pipette tip 650 to extract the liquid contents (e.g., primarily added wash buffer) of the processing tube 606 and transfer the liquid to the waste chamber 646. Ideally, under normal operating conditions, the liquid should not contain magnetic particles and attached nucleic acids, which are held close to the inner wall of the processing tube 606 during liquid extraction. Afterward, the liquid dispensing head can return the second pipette tip 650 to its pipette sheath and lower the first magnet 622 of the magnetic separator, thereby removing the magnetic force holding the magnetic particles and attached nucleic acids to the side of the processing tube 606.

[0169] Then, the dispensing tip can use the third pipette tip 652 to transfer release buffer from reagent tube 642 to processing tube 606, which contains magnetic particles and attached nucleic acid. The release buffer allows the magnetic particles to separate from the nucleic acid and internal control. The dispensing tip can then use the third pipette tip 652 to transfer neutralization buffer from reagent tube 644 to an empty snap-in container 608-3 (e.g., a mixing tube). The dispensing tip can then return the third pipette tip 652 to its pipette sheath. At this point, processing tube 606 will contain magnetic particles, extracted nucleic acid (e.g., DNA / RNA extracted from cells and attached to magnetic particles), and an internal control. Snap-in container 608-3 (e.g., a mixing tube) contains neutralization buffer.

[0170] The heater block 660 is activated a second time to heat the contents of the processing tube 606. The temperature and duration of heating will depend on the assay or procedure being performed. The first magnet 622 of the magnetic separator can be raised again until it is flush with the processing tube 606. Magnet 622 can apply a magnetic force to the magnetic particles in the processing tube 606, thereby attracting the magnetic particles to the inner wall of the processing tube 606 (but not to nucleic acids, such as DNA / RNA molecules, which no longer attach to the magnetic particles). While the magnetic particles are attracted to and held flush with the inner wall of the processing tube 606 by magnet 622, the liquid dispensing tip can be used with the third pipette tip 652 to extract the liquid contents (e.g., a nucleic acid mixture) from the processing tube 606 without extracting the magnetic particles. The nucleic acid mixture can be transferred to a container 608-3 (e.g., a mixing tube) that now contains a neutralization buffer. The neutralization buffer is configured to lower the pH of the nucleic acid mixture to a neutral pH. The third pipette tip 652 can return to its pipette sheath, and the first magnet 622 of the magnetic separator can be lowered.

[0171] In this embodiment, for a reagent holder 602 having four snap-in containers 608, the liquid dispensing tip can be used with a fourth pipette tip 654 to pierce containers 608-2 and / or 608-4 (e.g., to make them accessible). Containers 608-2 and 608-4 can alternatively be referred to as master mixture tubes, and which of these containers is used may depend on the assay or procedure being performed. A first master mixture tube (e.g., container 608-2) may contain primers and a sample for testing a first analyte of interest, and a second master mixture tube (e.g., container 608-4) may contain primers and a sample for testing a second analyte of interest.

[0172] As a very specific example, in some embodiments, reagent holder 602 can be used to perform an assay of enterobacteria, and both container 608-2 and container 608-4 can be used. In this case, container 608-2 can be referred to as an enterobacteria master mixture tube containing an enterobacteria master mixture for identifying one group or one plate of enterobacteria, and container 608-4 can be referred to as an extended bacterial master mixture tube containing an extended bacterial master mixture for identifying a second group or a second plate of enterobacteria. Thus, some neutralized DNA / RNA mixture from container 608-3 can be transferred to both master mixture tubes.

[0173] In some embodiments, reagent holder 602 can be used to extract polynucleotides (e.g., DNA or RNA) from a sample and place the polynucleotides in a PCR-ready form. In this case, snap-in container 608-4 or snap-in container 608-2 can be used as a PCR master mixture tube containing a PCR master mixture (e.g., primers, sample, and other PCR reagents for the PCR reaction). For example, if snap-in container 608-2 is a PCR master mixture tube containing a PCR master mixture, a dispensing tip can first puncture container 608-2 (e.g., to make it accessible) using a fourth pipette tip 654. The dispensing tip can then extract the neutralized nucleic acid mixture from container 608-3 (e.g., a mixing tube) and transfer it to container 608-2. When reagent holder 602 is inserted for processing by a diagnostic or preparation device, container 608-3 can be in close proximity to a second magnet 632 (e.g., a fixed magnet assembly). Figure 6B Additional context is provided regarding the possible location and orientation of the second magnet 632. The second magnet 632 can apply a magnetic force to the contents of container 608-3 as the liquid dispensing head extracts the neutralized nucleic acid mixture from container 608-3. Specifically, some magnetic particles (e.g., beads) may be present and transferred from processing tube 606 into container 608-3, although efforts are made to prevent this (e.g., using the first magnet 622 to retain the magnetic particles in processing tube 606). The second magnet 632 can be used as part of an additional filtration step to remove any residual magnetic particles (e.g., “residual” magnetic particles) left from processing tube 606 from the neutralized nucleic acid mixture when it is extracted from container 608-3.

[0174] The extracted, neutralized nucleic acid mixture is then transferred to container 608-2 (e.g., a PCR master mixture tube). In some embodiments, the PCR master mixture in container 608-2 may be in the form of lyophilized pellets. Adding neutralized RNA / DNA mixture can dissolve the PCR master mixture pellets. Dissolution of the PCR master mixture pellets may be permitted, and the liquid dispensing tip can use the fourth pipette tip 654 to mix the contents of container 608-2 together. The liquid dispensing tip can then use the fourth pipette tip 654 to aspirate the mixture (now amplification-ready sample) from container 608-2 and transfer it to a device (including a storage device in which samples are stored or a microfluidic cartridge in which amplification is performed, e.g., Figure 5B The microfluidic cartridge 510 shown in the figure).

[0175] It should be noted that this sample preparation process for extracting and preparing polynucleotides into a PCR-ready form can be used with other embodiments of reagent holders (such as reagent holders with only 3 snap-in containers, e.g., similar to...). Figure 2D and Figure 2E The reagent holder 202 shown is used together. In the absence of a fourth snap-in container (e.g., container 608-4), a second snap-in container (e.g., container 608-2) is used as the master mixing tube, which will hold the prepared PCR-ready solution, which will be transferred to a storage device or microfluidic cartridge.

[0176] Figure 7A and Figure 7B Two perspective views are shown of an embodiment of a fixed magnet assembly according to the disclosed technology, which can be implemented in an automated diagnostic or preparation device. Figure 7C It shows Figures 7A-7B A side profile view of the dimensions of the fixed magnet assembly 700 relative to the dimensions of the snap-in container of the reagent holder received in a diagnostic or preparation device.

[0177] Specifically, the magnet 732 of the fixed magnet assembly 700 is shown positioned to engage with a third snap-fit ​​container 708-3 (e.g., a third snap-fit ​​container, such as...) received in a reagent holder in a diagnostic or preparation device. Figures 6A-6E The container 608-3 is adjacent to it. In this non-limiting example, for each reagent holder, the magnet 732 is positioned behind the third snap-fit ​​container 708-3 (e.g., between the third snap-fit ​​container 708-3 and the location where the second snap-fit ​​container will reside (if shown)). Furthermore, in this embodiment of the fixed magnet assembly 700, the magnets 732 are oriented at an angle such that they are parallel to the inclined wall of the snap-fit ​​container 708-3 (e.g., generating a magnetic force perpendicular to the inclined wall).

[0178] like Figure 7A As shown, the fixed magnet assembly 700 (and its magnet 732) can be configured to fit between the second snap-fit ​​container (not shown) and the third snap-fit ​​container once the fixed magnet assembly 700 is installed and the stand with the loaded reagent holder is received in the receiving rack of the diagnostic or preparation device (e.g., in...). Figure 6E (between containers 608-3 and 608-2). Although the dimensions vary across the diagnostic or preparation device, and the precise placement of each fixed magnet assembly 700 within the receiver rack of the diagnostic or preparation device differs, the fixed magnet assembly 700 can still be configured to fit within a very small volume between the snap-in containers. In a non-limiting example, the fixed magnet assembly 700 can be positioned such that the magnet is only 0.01 inches away from the sloping wall of the container, and the fixed magnet assembly 700 can have dimensions that allow it to be positioned in the space between the containers. For example, the fixed magnet assembly 700 can have a width ranging from 0.15 to 0.3 inches and a height of less than 0.4 inches. The ability to fit the fixed magnet assembly 700 into such a small volume advantageously allows for the retrofitting of existing diagnostic or preparation devices with the fixed magnet assembly 700 without having to redesign the reagent holder or snap-in container, while also enabling the magnet 732 of the fixed magnet assembly 700 to effectively and consistently apply magnetic force to the snap-in container 708-3.

[0179] This advantage of the fixed magnet assembly 700 is that Figure 7C To better visualize, Figure 7C A side profile of the retaining magnet assembly 700 located between the third retaining container 708-3 and the second retaining container 708-2 is shown. In some embodiments, the distance 750 between the inclined wall of the third retaining container 708-3 and the magnet 732 of the retaining magnet assembly 700 may be 0.011 inches or less, the horizontal distance 752 between the walls of the third retaining container 708-3 and the second retaining container 708-2 may be 0.152 inches or less, and the length 754 of the inclined wall of one retaining container may be approximately 0.407 inches. The size and shape of the retaining magnet assembly 700 may be configured to fit within the space between the third retaining container 708-3 and the second retaining container 708-2 when the test strip is loaded into a rack received in a diagnostic or preparation device.

[0180] although Figure 7A and Figure 7BThe example fixed magnet assembly 700 is shown as being configured to apply a magnetic force to a third snap-in container, but it should be understood that they can be appropriately positioned to apply a magnetic force to any other snap-in container, depending on the specific measurement or process performed and which container may contain residual particles.

[0181] It should be noted that it can be considered that Figure 7A and Figure 7B The magnet 732 of the embodiment of the fixed magnet assembly 700 shown is arranged along a single linear axis (e.g., an axis perpendicular to the longitudinal axis of the reagent holder and an axis perpendicular to the processing axis of the reagent holder). Therefore, although the magnet 732 of the fixed magnet assembly 700 is arranged with... Figure 6B The magnets 632 shown are arranged in different ways, but if... Figure 6A and Figure 6B If the second magnet axis 614 is adjusted to extend between the second and third snap-fit ​​containers, then the magnet axis will still be applicable (magnet 732 will reside on this axis, similar to magnet 622 residing on the first magnet axis 612), and a magnetic force will be applied to the third snap-fit ​​container, which will preferably be... Figure 6B (represented as a vertical vector in the middle).

[0182] Figure 8A An isometric view of an embodiment of a fixed magnet assembly is shown, which can be implemented in an automated diagnostic or preparation device according to the disclosed techniques. More specifically, Figure 8A An embodiment of a fixed magnet assembly 800 having a fixed height when implemented in a diagnostic or preparation device is shown. Figure 8B A receiver rack for diagnostic or preparation devices (such as in a reference) is shown. Figures 5A-5B The implementation in the described receiver rack 500) Figure 8A Fixed magnet assembly.

[0183] The fixed magnet assembly 800 may include a support plate 802, the size of which may be adapted to accommodate a specific diagnostic or preparation device in which the fixed magnet assembly 800 is implemented. In some embodiments, the support plate 802 may be a machined aluminum plate. The support plate 802 may include a set of notches or holes 806, each notch or hole 806 being configured to receive a container (e.g., a mixing tube) (such as...). Figures 7A-7B The container shown is 708-3 or Figures 6A-6E The bottom end of container 608-3 shown. For example, in Figure 6B The indicated position of container 608-3 shown in the concept diagram can coincide with the position of hole 806 on support plate 802.

[0184] The fixed magnet assembly 800 may also include a magnet retainer 804, the size of which may be similarly adapted to a specific diagnostic or preparation device in which the fixed magnet assembly 800 is implemented. In some embodiments, the magnet retainer 804 may be made of a chemically detergent-resistant material. The magnet retainer 804 may include a set of magnet housings 812 and connectors 814. The magnet housings 812 and connectors 814 may be integrally formed as a single piece. In another example, the magnet housings 812 and connectors 814 are coupled to form the magnet retainer 804. Other configurations may be implemented as appropriate. In some embodiments, each magnet housing 812 may have a trapezoidal shape when viewed from above. In this example, each magnet housing 812 accommodates two magnets (not shown), which are positioned adjacent to a first face 820 and a second face 822 of the magnet housing 812, respectively. This arrangement may be similar to Figure 6B The arrangement of a pair of magnets 632 within the housing 630 is shown.

[0185] In one non-limiting example, the fixed magnet assembly 800 is a single integral piece comprising a plurality of magnet housings 812 separated by connectors 814. In some cases, the fixed magnet assembly is an integral structure comprising a plurality of magnet housings 812. The integral fixed magnet assembly 800 may be formed of, for example, a magnetic material. In another non-limiting example, the integral fixed magnet assembly 800 is formed of one or more non-magnetic materials, and the magnetic material is coupled to the inner wall of the housing adjacent to a first surface 820 and a second surface 822 of each magnet housing 812. Other configurations are also possible.

[0186] The magnet retainer 804 may have a mounting hole 816 (e.g., in a connector 814) for attaching the magnet retainer 804 to a support plate 802. For example, fasteners (e.g., screws) may be inserted into the mounting hole 816 to secure the magnet retainer 804 to the support plate 802 and form a fixed magnet assembly 800. The support plate 802 of the fixed magnet assembly 800 can then be mounted (e.g., fixed to) a diagnostic or preparation device using any suitable mechanism. In some embodiments, the fixed height (e.g., up / down position) of the magnet retainer 804 relative to the support plate 802 and the remainder of the diagnostic or preparation device can be adjusted by adding a shim of a desired height, measured in the z-direction, between the magnet retainer 804 and the support plate 802. Mounting the fixed magnet assembly 800 may include selecting one of a plurality of shims of different heights from a mounting kit, mounting the selected shim in a receiver, and mounting the fixed magnet assembly 800 over the shim in the z-direction. Given the minor differences in size and the tight tolerances associated with the receiver rack and bench implemented in the device, this can be particularly advantageous when retrofitting the stationary magnet assembly into existing preparation and diagnostic devices in the art.

[0187] Therefore, the mixing tube of the reagent holder (e.g., container 608-3 or container 708-3) can be received in the hole 806 of the support plate 802, such that each mixing tube is adjacent to a magnet in an adjacent magnet housing 812 (e.g., a magnet located behind a first face 820 or a second face 822 of an adjacent magnet housing 812). In some embodiments, the first face 820 and the second face 822 of each magnet housing 812 can be oriented at an angle such that when the mixing tube is positioned in the hole 806, the first face 820 and the second face 822 are parallel to the inclined wall of the mixing tube (e.g., container 608-3 or container 708-3). Therefore, the magnet located behind each first face 820 or second face 822 of the magnet housing 812 can also be oriented parallel to the inclined wall of the adjacent mixing tube, thereby generating a magnetic force perpendicular to the inclined wall of the mixing tube.

[0188] The shape and size of the magnet housing 812 and the connector 814 connecting the magnet housing 812 can be advantageously customized such that when the fixing magnet assembly 800 is installed in the diagnostic or preparation device and the rack containing the reagent holder is loaded into the receiving rack of the diagnostic or preparation device, they do not interfere with the skirt or flange of the receiver (e.g., receiver 250) of the reagent holder that receives the second or third snap-in container (e.g., containers 608-2 and 608-3, respectively). For example, the connector 814 may have a selected depth (measured in the y-direction) and height (measured in the z-direction) in the portion near the hole 806, such that the connector 814 fits between the second and third snap-in containers of the reagent holder housed in the rack in the insertion receiving rack. This allows the magnet housing 812 to apply magnetic force to the third snap-in container without physically interfering with the second snap-in container, which would otherwise be pushed past its receiver and pushed out from the top of the reagent holder when the stand housing the reagent holder is inserted into the receiver rack if the magnet housing 812 and connector 814 are not sized correctly.

[0189] As shown in the embodiment, the fixed magnet assembly 800 may advantageously include a magnet housing 812 configured to simultaneously apply magnetic force to the snap-fit ​​containers of two different reagent holders (e.g., as...). Figure 6B (Similar to the magnet housing 630 in the example). More specifically, the magnet housing 812 of the fixed magnet assembly 800 may include two magnets (not shown), one of which can apply magnetic force to one side of the snap-in container of the reagent holder, and the other magnet can apply magnetic force to the opposite side of another snap-in container of a different reagent holder. In other words, the magnet in the magnet housing 812 can apply magnetic force to the opposite side of the snap-in tube of an adjacent reagent holder; adjacent magnets in the fixed magnet assembly 800 apply magnetic force to the opposite side of the snap-in tube of an adjacent reagent holder. Although the magnetic force is applied to different sides of the snap-in container depending on which magnet is adjacent to the snap-in container (e.g., ...). Figure 6B (as shown), however, for each reagent holder, the problem of magnetic extraction particles remains effectively and consistently solved. This implementation avoids the need to place the magnet in a very compact space (e.g., as shown). Figures 7A-7B As in the example, between the third and second snap-in containers of the reagent holder. Alternatively, the magnet can be arranged at an angle relative to the processing axis of each reagent holder, rather than being arranged on the processing axis. Figure 6B The arrangement of each pair of magnets 632 in the magnet housing 630 is shown to illustrate an example.

[0190] In some embodiments, the fixed magnet assembly 800 can be implemented in a particular diagnostic or preparation device by securing the support plate 802 to the device cover 850 using fasteners (such as using very high adhesive tape). This method allows the fixed magnet assembly 800 to be implemented in-situ in a particular device (e.g., at the location of the diagnostic or preparation device) inexpensively and quickly, but there may be unknown component variations between different devices, and variations also exist among all possible personnel installing the fixed magnet assembly 800 into different devices. Figure 8B The cover 850 attached to the diagnostic or preparation device is shown. Figure 8A The same fixed magnet assembly 800 shown includes a support plate 802 and a magnet retainer 804.

[0191] More specifically, Figure 8B This illustrates how the fixed magnet assembly 800 can be implemented in the receiver rack of a diagnostic or preparation device (such as...). Figures 5A-5B The receiving rack 500 of the diagnostic or preparation device shown is configured such that when the receiving rack receives a rack with reagent holders inserted into the rack, the processing tubes of these reagent holders are received in holes 806 in the support plate 802 of the fixed magnet assembly 800. Additionally, one or more movable magnets of the magnetic separator (not shown in the figure, but referenced above) Figures 3A-3C (As described) a magnetic force can be applied to each processing tube of the reagent holder in the bench. Additionally, with the fixed magnet assembly 800 installed in this position, a constant, consistent magnetic force from the magnets of the fixed magnet assembly 800 (e.g., the magnets in the magnet housing 812) is also applied to each third snap-fit ​​container of the reagent holder in the bench.

[0192] Figure 9 An isometric view of an embodiment of a fixed magnet assembly according to the disclosed technology is shown, which can be implemented in an automated diagnostic or preparation device. More specifically, Figure 9 An embodiment of a fixed magnet assembly 900 compliant in the z-direction is shown (e.g., when implemented in a receiver rack of a diagnostic or preparation device, it may move up or down in the z-direction).

[0193] The fixed magnet assembly 900 may include a support plate 902, the size of which may be adapted to accommodate a specific diagnostic or preparation device in which the fixed magnet assembly 900 is implemented. In some embodiments, the support plate 902 may be a machined aluminum plate. The support plate 902 may include a set of notches or holes 808, each notch or hole 806 configured to receive a container (e.g., a mixing tube) (such as...). Figures 7A-7B The container shown is 708-3 or Figures 6A-6E The bottom end of container 608-3 shown. For example, in Figure 6BThe indicated position of container 608-3 shown in the concept diagram can coincide with the position of hole 908 on support plate 902.

[0194] The fixed magnet assembly 900 may further include a magnet retainer 904, the size of which may be similarly adapted to a specific diagnostic or preparation device in which the fixed magnet assembly 900 is implemented. In some embodiments, the magnet retainer 904 may be made of a chemically detergent-resistant material. The magnet retainer 904 may include a set of magnet housings 912 and connectors 914. In some embodiments, each magnet housing 912 may have a trapezoidal shape when viewed from above. In this example, each magnet housing 912 accommodates two magnets (not shown) positioned adjacent to a first face 920 and a second face 922 of the magnet housing 912, respectively. This arrangement may be similar to Figure 6B The arrangement of a pair of magnets 632 within the housing 630 is shown.

[0195] The fixed magnet assembly 900 includes a mounting plate 906 located below a support plate 902. The fixed magnet assembly includes a set of springs 924 (not visible in this view), one end of each spring attached to the mounting plate 906, and the opposite end of each spring attached to a magnet holder 904 and / or the support plate 902. Additional biasing mechanisms may be suitably implemented by adding to or replacing the springs 924. The springs 924 apply a biasing force to the support plate 902 to create a desired spacing between the mounting plate 906 and the support plate 902 when the springs are uncompressed. To assemble the fixed magnet assembly 900 of this non-limiting embodiment, the magnet holder 904 is secured to the support plate 902. In some embodiments, the magnet holder 904 may be mechanically coupled to the support plate 902 using fasteners 919, which may be received in mounting holes 918 in the magnet holder 904 and corresponding mounting holes (not shown) in the support plate 902. Next, the support plate 902 is secured to the mounting plate 906. The support plate 902 can be secured using a spring 924 coupled to the support plate 902 and the mounting plate 906, allowing the support plate 902 to move up and down relative to the mounting plate 906 in the z-axis (e.g., by compressing or decompressing the spring 924). In some embodiments, the support plate 902 can be additionally mechanically coupled to the mounting plate 906 via a fastener 919. The fastener 919 can be inserted through a mounting hole (e.g., mounting hole 918) in the magnet retainer 904 and a corresponding mounting hole (not shown) in the support plate 902 to secure the support plate 902 to the mounting plate 906. In some embodiments, the fastener 919 can be a screw or a shoulder bolt, and they can limit the maximum spacing between the mounting plate 906 and the support plate 902. The fastener 919 can provide an upward limit on the upward movement of the support plate 902 away from the mounting plate 906 in the z-direction, but does not limit the downward movement of the support plate 902 toward the mounting plate 906 in the z-direction. In some embodiments, fastener 919 may further restrict movement of support plate 902 on the x and y axes. The retaining magnet assembly 900 can then be secured to the receiver of the diagnostic or preparation device, such as by using fasteners (e.g., very high adhesive tape or fasteners received in mounting plate 906) to secure mounting plate 906 to the cover of the diagnostic and preparation device. Other fasteners may be appropriately implemented according to the disclosed techniques.

[0196] Advantageously, because the spring 924 allows the support plate 902 to move in the z-direction relative to the mounting plate 906 fixed to the cover, the support plate 902 of the installed fixed magnet assembly 900 can move up or down in the z-direction within the receiver before and during insertion of the stage into the receiver. This feature allows the mixing tube of the reagent holder (e.g., container 608-3 or container 708-3) to be properly positioned relative to the magnet in the magnet holder 904 without accurately and consistently reproducing the precise magnet positioning on each of the multiple devices in which the fixed magnet assembly is mounted (e.g., via designing, constructing, and positioning the fixed magnet assembly with very tight tolerances). For example, when the stage is inserted into the receiver, the bottom surface of the stage can contact the top surface of the magnet holder 904. In a non-limiting example, this contact occurs between the bottom surface of the stage and the top surface of one or more magnet housings 912. This contact causes the magnet holder 904 and the support plate 902 to lower in the z-direction, thereby compressing the spring 924 located between the support plate 902 and the mounting plate 906. As the stage continues to be inserted into the receiving frame, the magnet holder 904 and the support plate 902 continue to lower in the z-direction until they reach a position that precisely positions the magnet housing 912 relative to the mixing tube of the reagent holder and precisely positions the mixing tube of the reagent holder in the hole 908 of the support plate 902. In a non-limiting embodiment, as the spring 924 is compressed, the support plate 902 lowers relative to the mounting plate 906 until the support plate 902 reaches a point where the stage has reached its lowest position within the receiving frame, at which point the bottom of the mixing tube of the reagent holder will be reliably and accurately positioned in the hole 908 of the support plate 902. This arrangement causes each mixing tube to be in close proximity to a magnet in an adjacent magnet housing 912 (e.g., behind a first face 920 or a second face 922 of an adjacent magnet housing 912), independent of specific dimensional variations in the pedestal used to insert the retainer into the receiving frame, and independent of specific dimensional variations in the receiving frame for receiving the retainer. Therefore, this arrangement for providing magnetic energy to the mixing tubes of multiple retainers using a z-direction adjustable support plate 902 can be reliably and accurately reproduced on many different devices, independent of dimensional and tolerance variations between the receiving frame and the pedestal of the device.

[0197] In some embodiments, the first face 920 and the second face 922 of each magnet housing 912 may be oriented at an angle such that when the mixing tube is disposed in the hole 908, the first face 920 and the second face 922 are parallel to the inclined wall of the mixing tube (e.g., container 608-3 or container 708-3). Therefore, a magnet positioned adjacent to each of the first face 920 or the second face 922 inside the magnet housing 812 may also be oriented parallel to the inclined wall of the adjacent mixing tube, thereby generating a magnetic force perpendicular to the inclined wall of the mixing tube.

[0198] Advantageously, embodiments of the fixed magnet assembly 900 according to the disclosed technology can allow the fixed magnet assembly 900 to be implemented in situ in a particular diagnostic and preparation device (e.g., at the location of the diagnostic and preparation device) using nominal magnet positioning.

[0199] Figure 10A An isometric view of an embodiment of a fixed magnet assembly is shown, which can be implemented in an automated diagnostic or preparation device according to the disclosed techniques. More specifically, Figure 10A An embodiment of a fixed magnet assembly 1000 compliant in the z-direction is shown (e.g., when implemented in a receiver rack of a diagnostic or preparation device, it can move up or down in the z-direction). Figure 10B It shows the relationship with Figure 10A A transparent perspective view of the reagent holder interacting with the fixed magnet assembly 1000 to show how the third snap-in container 1030 of the reagent holder can be placed in the hole 1008 of the support plate 1002 of the fixed magnet assembly 1000 once the fixed magnet assembly 1000 is installed and the stand containing the reagent holder is loaded into the receiving rack of the diagnostic or preparation device.

[0200] The fixed magnet assembly 1000 may include a support plate 1002, the size of which may be adapted to accommodate a specific diagnostic or preparation device in which the fixed magnet assembly 1000 is implemented. In some embodiments, the support plate 1002 may be a machined aluminum plate. The support plate 1002 may include a set of notches or holes 1008, each notch or hole 806 configured to receive a container (e.g., a mixing tube) (such as...). Figures 7A-7B The container shown is 708-3 or Figures 6A-6E The bottom end of container 608-3 shown. For example, in Figure 6B The indicated position of container 608-3 shown in the concept diagram can coincide with the position of hole 1008 on support plate 1002.

[0201] The fixed magnet assembly 1000 may further include a set of magnet housings 1012. In some embodiments, the magnet housings 1012 may be made of a chemically detergent-resistant material. Each magnet housing 1012 may have a trapezoidal shape when viewed from above. In this example, each magnet housing 1012 accommodates two magnets (in... Figure 10A Not shown in the text, but in Figure 10B As can be seen in the image, the two magnets are positioned adjacent to the first surface 1020 and the second surface 1022 of the magnet housing 1012, respectively. This arrangement can be similar to... Figure 6B The arrangement of a pair of magnets 632 within the housing 630 is shown.

[0202] The fixed magnet assembly 1000 includes a mounting plate 1006 located below a support plate 1002. The fixed magnet assembly includes a set of springs 1024, one end of each spring attached to the mounting plate 1006, and the opposite end of each spring attached to the magnet housing 1012 and / or the support plate 1002. Additional biasing mechanisms can be suitably implemented by adding to or replacing the springs 1024. A gap may exist between the support plate 1002 and the mounting plate 1006 when the springs 1024 are in an uncompressed state.

[0203] Spring 1024 applies a biasing force to support plate 1002 to create a desired gap between mounting plate 1006 and support plate 1002 when the spring is uncompressed. In some embodiments, support plate 1002 may additionally be mechanically coupled to mounting plate 1006 via fasteners 1019. The maximum gap between mounting plate 1006 and support plate 1002 may be limited by fasteners 1019 (e.g., screws or shoulder bolts) inserted through mounting holes 1018 in support plate 1002. These fasteners 1019 are inserted into mounting holes 1018 to secure support plate 1002 to mounting plate 1006 to form fixed magnet assembly 1000. In this example, the head of the fastener 1019 inserted into mounting hole 1018 provides an upward limit on upward movement of support plate 1002 away from mounting plate 1006 in the z-direction, but does not limit downward movement of support plate 1002 toward mounting plate 1006 in the z-direction. In some embodiments, fastener 1019 may further restrict movement of support plate 1002 on the x and y axes. Mounting plate 1006 may then be secured to the cover of the diagnostic and preparation device, such as by using fasteners (such as very high adhesive tape or other suitable fasteners), to secure the fixed magnet assembly 1000 to the diagnostic or preparation device.

[0204] Advantageously, because the spring 1024 allows the support plate 1002 to move in the z-direction relative to the mounting plate 1006 fixed to the cover, the spring-loaded support plate 1002 of the installed fixed magnet assembly 1000 can move up or down in the receiving rack in the z-direction before and during insertion of the rack into the receiving rack. This feature allows the mixing tube of the reagent holder (e.g., container 608-3 or container 708-3) to be accurately and consistently positioned relative to the magnet in the magnet housing 1012 without having to accurately and consistently reproduce the precise magnet positioning on each of the multiple devices in which the fixed magnet assembly is installed. For example, the mixing tube of the reagent holder can be received in the hole 1008 of the support plate 1002, and the mixing tube (or another portion of the rack in contact with the compliant support plate 1002) can be pressed down on the support plate 1002 in the z-direction, thereby compressing the spring 1024 located between the support plate 1002 and the mounting plate 1006. As spring 1024 is compressed, support plate 1002 lowers relative to mounting plate 1006 until support plate 1002 reaches a point where the stage has reached its lowest position within the receiving rack, at which point the bottom of the mixing tube of the reagent holder will be reliably and accurately positioned in the hole 1008 of support plate 1002. This arrangement results in each mixing tube being in close proximity to a magnet in the adjacent magnet housing 1012 (e.g., behind the first face 1020 or the second face 1022 of the adjacent magnet housing 1012), independent of specific dimensional variations of the stage for inserting the holder into the receiving rack, and independent of specific dimensional variations of the receiving rack for receiving the holder. Therefore, this arrangement for providing magnetic energy to the mixing tubes of multiple holders using a z-direction adjustable support plate 1002 can be reliably and accurately reproduced on many different devices, independent of dimensional and tolerance variations between the receiving rack and the stage of the device.

[0205] In some embodiments, the first face 1020 and the second face 1022 of each magnet housing 1012 may be oriented at an angle such that when the mixing tube is disposed in the hole 1008, the first face 1020 and the second face 1022 are parallel to the inclined wall of the mixing tube (e.g., container 608-3 or container 708-3). Therefore, a magnet positioned adjacent to each of the first face 1020 or the second face 1022 inside the magnet housing 1012 may also be oriented parallel to the inclined wall of the adjacent mixing tube, thereby generating a magnetic force perpendicular to the inclined wall of the mixing tube.

[0206] from Figure 10B This makes it easier to understand. Figure 10BA transparent view of the fixed magnet assembly 1000 is shown to more easily illustrate the features of the disclosed technology. Embodiments of the fixed magnet assembly, mixing tube, and retainer need not be transparent. The mixing tube 1030 of the retainer (e.g., a container in a third position starting from the processing tube at the distal end of the retainer) is shown as located in the aperture 1008 of the fixed magnet assembly 1000. In this position, the mixing tube 1030 is positioned immediately adjacent to the magnet housing 1012 having a first surface 1020 and a second surface 1022. From Figure 10B It can be seen that magnet 1040 is located behind the first surface 1020, and magnet 1042 is located behind the second surface 1022. When the mixing tube 1030 is located in the hole 1008 of the fixing magnet assembly 1000, magnet 1042 is adjacent to the mixing tube 1030 (within about 2 mm), and it can be seen that magnet 1042 has an angled tilt orientation that matches the tilted wall of the mixing tube 1030.

[0207] Advantageously, the magnet housing 1012 is sized such that it does not interfere with the second snap-fit ​​container of the reagent holder (not shown, but similar). Figure 6E (See container 608-2 shown). Furthermore, the size of the magnet housing 1012 can be advantageously configured so as not to interfere with the skirt or flange of the second or third receiver, which respectively receives the second or third snap-fit ​​container 1030.

[0208] It should be understood that embodiments of the disclosed technology are not limited to applying a fixed magnetic force to the above-mentioned reference. Figures 2A-10B The aforementioned retainer. Similarly, it should be understood that embodiments of the disclosed technology are not limited to applying a fixing magnetic force to the above reference. Figure 1B The discussion concerns a retainer in an automated diagnostic or preparation apparatus. The disclosed technique can be advantageously implemented in any device that receives a retainer for handling and manipulating a magnet substrate within the retainer's container. Reference will now be made to... Figures 11-15D A non-limiting example automated apparatus configured to apply a fixed magnetic force to a non-limiting example holder according to the disclosed technology is described to further illustrate certain advantageous features of the disclosed technology. Figure 11 Isometric views of the interior 1100 of some embodiments of a diagnostic or preparation device.

[0209] The illustrated embodiment of the diagnostic or preparation device can be similarly used to extract polynucleotides from samples and prepare them into PCR-ready forms. This diagnostic or preparation device can be similar to the device disclosed in PCT application WO2017 / 184244 ( entitled “Automated Diagnostic Analyzer and Method for its Operation”), filed February 17, 2017, the entire disclosure of which is incorporated herein by reference.

[0210] It is worth noting that this embodiment of the diagnostic or preparation device may not use a reagent holder containing pre-packaged reagents for sample preparation, such as... Figure 2A-2C The reagent holder shown is loaded into a rack for reception by a diagnostic or preparation device. Alternatively, the diagnostic or preparation device may receive a processing plate 1140 excluding pre-packaged reagents, and reagents for sample preparation may be stored separately in different locations on the processing platform 1116. Figures 12A-12B The processing board 1140 is described in more detail.

[0211] For example, a drying reagent plate 1150 may be present, comprising a plurality of drying reagent compartments sealed by a permeable membrane placed above each drying reagent compartment. In some embodiments, a total of 96 drying reagent compartments may be present in the drying reagent plate 1150, and each reagent compartment within the same plate 1150 may be loaded with the same reagent, such that the reagent plate is specific to the assay. However, depending on the assay or procedure, multiple drying reagent plates 1150 may be used, and separate reagent plates, each with reagents specific to the assay, may be utilized. For example, to prepare a sample into a PCR-ready form, a first drying reagent plate (e.g., an extraction reagent plate) containing lysis buffer and magnetic particles (e.g., extraction beads) and a second drying reagent plate (e.g., an amplification reagent plate) containing a master mixture of reagents may be present. In other embodiments, different reagents may be combined on a single drying reagent plate 1150 (e.g., an extraction reagent plate and an amplification reagent plate may be combined).

[0212] The device may also include a liquid reagent plate 1160. The liquid reagent plate 1160 may include multiple reagent compartments organized into four processing rows, and each processing row may include four compartments, each compartment holding reagents for a sample processing step. For example, each processing row may include a first compartment for a reconstitution buffer, a second compartment for a wash buffer, a third compartment for an elution buffer, and a fourth compartment for a neutralization buffer. These compartments may be arranged in the order they are used. However, they may be arranged in other ways. Additionally, each compartment holds enough reagent to process an entire batch of samples, such as a batch of 24 samples in total. A permeable membrane (not shown) is placed over each of these compartments and sealed to the liquid reagent plate 1160 such that if the membrane is permeated to make access to one compartment, the remaining compartments remain sealed. This allows the liquid reagent plate 1160 to be stored until another batch of samples is needed.

[0213] In some embodiments, the processing plate 1140 may have an aperture for holding pipette tips, and an elongated opening 1117 may be present on the processing platform 1116, allowing reusable pipette tips held in the processing plate 2040 to extend through it. In some embodiments, the processing platform 1116 may include a pipette tip groove 1135 in which used pipette tips can be disposed. In some embodiments, the interior 1100 of the diagnostic or preparation device may include a rack configured to receive an amplification cartridge 1170, which includes a microfluidic channel and an amplification chamber for performing amplification of the processed sample.

[0214] Figure 12A For reference Figure 11 An isometric view of an example processing board 1240 used in some embodiments of the described diagnostic or preparation apparatus. Figure 12B This is a top view of the arrangement when two processing boards 1240 are inserted into the receiver rack for use in some embodiments of the diagnostic or preparation device. This arrangement of the two processing boards 1240 allows for the processing of 24 samples (12 samples from each processing board 1240). Figure 12A and Figure 12B They will be described together. Processor board 1240 can be referenced above. Figure 11 The processing board 1140 described is the same as or substantially similar to the example processing board 1240. It should be understood that the disclosed technology is not limited to the specific features of the example processing board 1240, and other appropriately configured processing boards can be implemented in the disclosed technology.

[0215] The processing plate 1240 may include a plate body 1241, which may partially define a plurality of processing tubes 1244, mixing tubes 1246, and pipette tip holding stage 1247. The plate body 1241 may have a circular opening for each of the processing tubes 1244, mixing tubes 1246, and pipette tip holding stage 1247. The processing tubes 1244 may have a tube body 1245 extending from the bottom of the plate body 1241, and the tube body 1245 may have a conical surface of revolution. The mixing tubes 1246 may also have a tube body (not shown, but...) extending from the bottom of the plate body 1241. Figure 13B As can be seen in the image, the tube body can also have a conical surface of revolution. The pipette tip holder 1247 can have a sleeve extending from the bottom of the plate body 1241 (not shown, but in the image). Figure 13B (See image). Even if the processing plate 1240 moves, the sleeve can keep the pipette tip stationed in the pipette tip holding stage 1247 stable.

[0216] In some embodiments, the processing tube 1244 may alternatively be referred to as the extraction tube or the pyrolysis tube. In some embodiments, the mixing tube 1246 may alternatively be referred to as the mixing well. The processing tube 1244 may be positioned closer to the center of the plate body 1241 than the mixing tube 1246, and the mixing tube 1246 may be positioned closer to the center of the plate body 1241 than the pipette tip holding stage 1247. Other configurations may be suitably implemented in the disclosed art.

[0217] In some embodiments, the processing plate 1240 may include two rows of processing tubes 1244, mixing tubes 1246, and pipette tip holders 1247 arranged parallel to each other. In the illustrated embodiment, the processing plate 1240 includes two rows of six processing tubes 1244, two rows of six mixing tubes 1246, and two rows of six pipette tip holders 1247. However, more or fewer may be considered (e.g., the processing plate 1240 may include two rows of twelve processing tubes 1244, mixing tubes 1246, and pipette tip holders 1247, or even a single row like this). The processing of a single sample may involve one of the processing tubes 1244 and its corresponding mixing tube 1246 and pipette tip holder 1247 aligned with it in the same column. Thus, a single processing plate 1240 may allow for the processing of 12 samples.

[0218] In some embodiments, the processing plate 1240 may include an engagement member 1249 on the top surface of the processing plate 1240. The engagement member 1249 may include an engagement notch 1242. The engagement member 1249 and the engagement notch 1242 may allow the processing plate 1240 to be grasped and moved by features (e.g., a robotic arm) of a diagnostic or preparation device for sample processing.

[0219] Figure 13A Isometric views of the interior of some embodiments of a diagnostic or preparation device. Figure 13B A side profile view of the interior of some embodiments of a diagnostic or preparation device, wherein a processing plate is positioned for sample processing. Figure 13A and Figure 13B Let's describe them together.

[0220] As in Figure 13A As can be seen, the first extractor 1340 and the second extractor 1350 are visible as part of a single assembly, which, among other components, may also include a housing 1342, a printed circuit board 1347 (“PCB”), a motor 1344, a plurality of heater assemblies 1348, and a plurality of magnetic separators 1341. Any number of heating assemblies 1348 and magnetic separators 1341 may be present. In some embodiments, the heater assemblies 1348 and magnetic separators 1341 may be controlled by electronic circuitry, such as on the PCB 1347 (e.g., to allow the heater assemblies 1348 to independently apply heat to the processing tubes of the processing plate(s)). The magnetic separators 1341 may also be configured to move up and down relative to the processing tubes of the processing plate(s).

[0221] Similar to Figures 3A-3C The heater assembly 300 shown, heater assembly 1348, may include one or more independently controllable heater units, each heater unit including a heating block 1349. Heating blocks 1349 may be made of a single sheet of metal or other material, or may be made separately and mounted independently of each other or connected to each other in some way. Therefore, heater assembly 1348 may include an assembly of heater units, but it is not necessary for the heater units or their respective heating blocks 1349 to be directly or indirectly attached to each other. As further described herein, each heating block 1349 may be configured to align with and transfer heat to the processing tubes 1314 of the processing plate 1310 (similar to...). Figure 12A The processing tubes 1244 of the processing plate 1240 shown are illustrated, and the heater assembly 1348 can be configured such that each heater unit independently heats each of the one or more processing tubes 1314 of the processing plate 1310, for example by allowing each of the one or more heating blocks 1349 to be independently controllable. A heater assembly 1348 can have any number of independently controllable heater units. In various embodiments, the heater assembly 1348 can have 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 25, 30, 32, 36, 40, 48, or 50 independently controllable heater units. Any number of heating assemblies 1348 can be used in diagnostic or preparation devices.

[0222] Similar to Figures 3A-3C The magnetic separator 370 shown, magnetic separator 1341 can be configured to move one or more magnets 1354 relative to one or more processing tubes 1314 of processing plate 1310 (similar to processing tubes 1244 of processing plate 1240). Magnetic separator 1341 can move the magnets 1354 close to the processing tubes 1314 (e.g., without contacting the processing tubes, the face of each magnet 1354 of magnetic separator 1341 is less than 2 mm, between 2 mm and 1 mm, or less than 1 mm from the outer surface of the adjacent processing tube) to separate magnetic particles in the processing tubes.

[0223] Structurally, the magnetic separator 1341 may include: one or more magnets 1354 fixed to a support member 1352; an electric mechanism (e.g., see motor 1344) configured to move the support member 1352 such that the one or more magnets 1354 move back and forth along a fixed axis, and during at least a portion of the movement, the one or more magnets 1354 remain in close proximity to one or more processing tubes 1314 containing magnetic particles in the solution; and control circuitry (e.g., PCB 1347) for controlling the electric mechanism. The magnetic separator 1341 may operate in conjunction with a heater assembly 1348 to allow continuous heating and separation operations of liquid material in one or more processing tubes 1314 without transporting the liquid material or processing tubes to different locations to perform heating or separation. Such operation is also advantageous because it means that the functions of heating and separation (although independent of each other, both used in sample preparation) can be performed with a compact and efficient device.

[0224] In the illustrated embodiment, there are four heating assemblies 1348, each having six independently controllable heater units, each heater unit including a heater block 1349. Up to two processing plates 1310 can be used at a time, and each processing plate 1310 involves the use of two heating assemblies 1348, with a magnetic separator 1341 between the two heating assemblies 1348. The magnetic separator 1341 may have two rows of six magnets (e.g., one row of six magnets on each side of the magnetic separator 1341), thereby forming six pairs of adjacent magnets facing the two heating assemblies 1348 across the magnetic separator 1341. This side-by-side pairing of magnets, relative to a single magnet, can enhance the magnetic attraction of magnetically extracted particles within the processing tube 1314 of the processing plate 1310. When the magnetic separator 1341 is in the raised position, each magnet in the magnetic separator 1341 can be positioned adjacent to the heater block 1349 of one of the two heating assemblies 1348. Each of the 12 heating blocks 1349 in these two heating assemblies 1348 can be specifically positioned to receive the 12 processing tubes 1314 of the processing plate 1310 (e.g., Figure 12AOne of the two rows of six processing tubes 1244 shown. When the motor 1344 is running, the magnet row in the magnetic separator 1341 can move upward into the space between the two rows of heating blocks 1349 to be adjacent to the processing tube 1314 disposed therein.

[0225] As previously mentioned, in some cases, the magnetic separator 1341 can be integrated with the heater assembly 1348 (e.g., one magnetic separator in the magnetic separator 1341 and two heating assemblies 1348 across it), and they can be collectively referred to as the integrated magnetic separator and heater assembly. Additionally, although not mentioned in... Figure 13A and Figure 13B As shown, however, the housing may cover the interior of the diagnostic or preparation device (including the magnetic separator 1341 and heater assembly 1348) for the purpose of protecting the sub-assemblies and for aesthetic purposes.

[0226] Figure 14A A top-view conceptual diagram of a processing board used in some embodiments of a diagnostic or preparation device is shown. More specifically, Figure 14A An example processing board 1400 (similar to) is shown. Figure 12A and 12B The processing board 1240 shown can be used with some embodiments of automated diagnostic or preparation devices (e.g., Figure 11 , Figure 13A and Figure 13B (Those described in the text) can be used together. The treatment plate 1400 may have two rows of treatment tubes 1442, two rows of mixing tubes 1444, and two rows of pipette tip holders 1446.

[0227] Each processing tube 1442 can be associated with a mixing tube 1444 and a pipette tip holding stage 1446, and they can be aligned along processing axes 1410, wherein diagnostic or preparation devices are configured to perform processing and operations (e.g., transfer of liquids) along each processing axis 1410. Thus, a total of n processing axes 1410 can be conceptualized—one processing axis for each processing tube 1442 in the processing plate 1400.

[0228] When the automated diagnostic or preparation device uses the processing board 1400, a magnetic separator (e.g., magnetic separator 1341) with two rows of magnets can be placed between the two rows of processing tubes 1442. This allows for... Figure 13B As seen in [the text], each row of magnets in a magnetic separator can be aligned on a common axis (e.g., a common axis passing through the midpoints of the magnets in that row), which can be referred to as the first magnet axis. Therefore, a magnetic separator with two rows of magnets can have a first magnet axis for each of the two rows, which... Figure 14AThe first magnet axis 1412 represents the magnetic separator. Each first magnet axis 1412 may extend horizontally parallel to an adjacent row of processing tubes 1442. Each first magnet axis 1412 may be positioned such that when the magnetic separator is lifted, the magnet of the magnetic separator aligned on the first magnet axis 1412 is adjacent to the processing tubes 1442 in the adjacent row of processing tubes 1442 (e.g., within 2 mm of each processing tube 1442 in the row).

[0229] In some embodiments, two separate fixed magnet assemblies can be implemented in an automated diagnostic or preparation device. Each fixed magnet assembly may include a row of magnets aligned on a common axis (e.g., a common axis passing through the midpoint of all the magnets). This common axis associated with the fixed magnet assembly may be referred to as the second magnet axis. The second magnet axes of the two fixed magnet assemblies are located at... Figure 14A The second magnet axis 1414 is indicated in the middle. Two fixed magnet assemblies can be positioned such that each second magnet axis 1414 is close to one of the two rows of mixing tubes 1444, such that the magnet of the fixed magnet assembly is sufficiently close to the adjacent row of mixing tubes 1444 to apply a magnetic force to any magnetically extracted particles contained in those mixing tubes 1444. The magnetic force can be strong enough to hold the magnetically extracted particles in the solution in the mixing tube 1444 against the inner wall of the mixing tube 1444, for example, when transferring the solution from the mixing tube 1444 during a pipetting operation. Using two separate fixed magnet assemblies, each second magnet axis 1414 can extend horizontally through one of the two rows of mixing tubes 1444. Alternatively, the second magnet axis 1414 can extend behind or in front of a row of mixing tubes 1444, in either case sufficiently close to apply a magnetic force to the contents of the mixing tube 1444 and capture any magnetically extracted particles contained therein. Additionally, each second magnet axis 1414 can be spaced sufficiently far from the nearest first magnet axis 1414 so that the magnets of the fixed magnet assembly do not interfere with the magnets of the magnetic separator. For example, each first magnet axis 1412 can be spatially separated from the corresponding second magnet axis 1414 by a distance "D" such that one or more magnets aligned along the first magnet axis 1412 do not apply magnetic force to the contents of the mixing tube 1444, and one or more magnets aligned along the second magnet axis 1414 do not apply magnetic force to the contents of the processing tube 1442.

[0230] The first magnet axis 1412 and the second magnet axis 1414 are in Figure 14B The text further illustrates that, Figure 14B Additional context can be provided for understanding the first magnet axis 1412 and the second magnet axis 1414. Figure 14BA top-view conceptual diagram shows the position of certain components of a processing board relative to a magnet in some embodiments of a diagnostic or preparation device, according to one configuration of a fixed magnet assembly.

[0231] More specifically, Figure 14B The positions of the two rows of processing tubes 1442 and mixing tubes 1444 of the processing plate are shown, along with the processing axis 1410 associated with each processing tube 1442. A magnetic separator 1420 with two rows of magnets 1422 is located between the two rows of processing tubes 1442. It can be seen that there are two distinct first magnet axes 1412, corresponding to each row of magnets in the two rows of magnets 1422 of the magnetic separator 1420. In this example embodiment, the magnets 1422 correspond one-to-one with the processing tubes 1442. In practice, when the magnetic separator 1420 is raised so that the magnets 1422 are close to the processing tubes 1422, the magnets 1422 apply a magnetic force to the contents of the processing tubes 1442 (in... Figure 14B (shown as a vertical vector).

[0232] Figure 14B The figure also shows magnets 1432 of two separate fixed magnet assemblies according to the disclosed technology. In some embodiments, the magnets 1432 of the fixed magnet assembly may be arranged in pairs. Each pair of magnets 1432 may be located within a housing 1430. The fixed magnet assembly may include multiple housings 1430. The pairs of magnets 1432 may be positioned within a diagnostic or preparation device such that, when the processing board is located in the receiving rack of the diagnostic or preparation device, each pair of magnets 1432 is located between two adjacent mixing tubes 1444 of the processing board (as shown in the figures). For each mixing tube 1444 in the processing board, one magnet 1432 may be present, and each magnet 1432 may be adjacent to the adjacent mixing tube 1444 when the processing board is located in the receiving rack of the diagnostic or preparation device. All magnets 1432 of the fixed magnet assembly may be aligned (or substantially aligned) on a second magnet axis 1414. In the case of two separate fixed magnet assemblies, there are two separate second magnet axes 1414, each second magnet axis 1414 corresponding to a row of magnets 1432 in one of the two fixed magnet assemblies. In this example embodiment, the magnets 1432 correspond one-to-one with the mixing tubes 1444, and each magnet 1432 can apply a magnetic force to the contents of the adjacent mixing tube 1444 (in... Figure 14B (shown as a horizontal vector).

[0233] Figure 14C A side profile concept diagram showing the position of certain components of a processing board relative to a magnet in some embodiments of a diagnostic or preparation device, according to embodiments disclosed herein.

[0234] More specifically, Figure 14CA processing tube 1442, a mixing tube 1444, and a pipette tip holder 1446 associated with a processing axis 1410 of a processing plate 1400 are shown. The processing tube 1442 can be used during sample preparation for cell lysis and nucleic acid extraction, such as DNA or RNA from a patient and DNA or RNA from a pathogen. The processing tube 1442 can be positioned such that when the processing plate 1400 is in the receiving rack of a diagnostic or preparation device, the processing tube 1442 is positioned within the heater assembly (e.g., Figure 13A The heater assembly 1348 shown is located within the heater block 1460. A first magnet 1422 of the magnetic separator can be raised to a position adjacent to the processing tube 1442 to apply a magnetic force to the contents of the processing tube 1442. A mixing tube 1444 can be positioned adjacent to a second magnet 1432 of the fixed magnet assembly, such that the second magnet 1432 applies a magnetic force to the contents of the mixing tube 1444.

[0235] The process of preparing a sample using the added immobilized magnet assembly is as follows. In some embodiments, the diagnostic or preparation device may puncture an extraction tube (e.g., a sealed desiccant compartment of a desiccant plate 1150) containing extraction reagents, which may include magnetic extraction particles, lyophilized extraction reagents (e.g., desiccant lysis reagents), and an internal control. The magnetic particles may be configured to bind specific molecules (e.g., DNA / RNA) in the sample. The diagnostic or preparation device may also puncture an associated reagent compartment of a liquid reagent plate 1160. The diagnostic or preparation device may then transfer some of the raw sample into a processing tube 1442. The amount of raw sample transferred may depend on the type of assay or procedure. The diagnostic or preparation device may then transfer some extraction reagents (e.g., extraction buffer) from the extraction tube of the extraction plate into the processing tube 1442.

[0236] The contents of the processing tube 1442, located in the heater block 1460 of the heater unit, are then heated by the heater block 1460. The heating temperature and duration depend on the type of assay or procedure. Heating and lysis reagents cause cells from the sample to rupture, and certain target nucleic acids (e.g., DNA or RNA) contained in the cells and internal controls may attach to or bind to magnetic particles (e.g., magnetically bound particles or magnetic beads).

[0237] The first magnet 1422 of the magnetic separator can be raised until it is adjacent to the processing tube 1442. The magnet 1422 can apply a magnetic force to the magnetic particles in the processing tube 1442, thereby attracting the magnetic particles and attached nucleic acids to the side of the processing tube 1442. While the magnet 1422 is still attracting the magnetic particles and attached nucleic acids to the side of the processing tube 1442, the diagnostic or preparation device can extract liquid from the processing tube 1442. Ideally, under normal operation, the liquid should not contain magnetic particles and attached nucleic acids, and during liquid extraction, the magnetic particles and attached nucleic acids are held close to the inner wall of the processing tube 1442. The diagnostic or preparation device can dispense the extracted liquid.

[0238] The first magnet 1422 of the magnetic separator can be lowered, thereby removing the magnetic force that holds the magnetic particles and attached nucleic acids to the side of the processing tube 1442. A diagnostic or preparation device can transfer washing buffer into the processing tube 1442 (e.g., from the reagent compartment of the liquid reagent plate 1160) to mix with the magnetic particles of nucleic acids bound to the processing tube 1442. Afterward, the first magnet 1422 of the magnetic separator can be raised again until it is close to the processing tube 1442. The magnet 1422 can then apply a magnetic force to the magnetic particles in the processing tube 1442, thereby again attracting the magnetic particles and attached nucleic acids to the side of the processing tube 1442.

[0239] If the magnetic particles move to the side of the processing tube 1442, the liquid contents (e.g., mainly added washing buffer) can be extracted from the processing tube 1442 and processed. Ideally, under normal operating conditions, the extracted liquid should not contain magnetic particles and attached nucleic acids, and the magnetic particles and attached nucleic acids are held close to the inner wall of the processing tube 1442 during liquid extraction. Afterwards, the first magnet 1422 of the magnetic separator can be lowered, thereby removing the magnetic force that holds the magnetic particles and attached nucleic acids to the side of the processing tube 1442.

[0240] Elution or release buffer (e.g., from the reagent compartment of liquid reagent plate 1160) can be added to processing tube 1442, which contains magnetic particles and attached nucleic acids. Release buffer allows the magnetic particles to separate from the nucleic acids and internal controls. A diagnostic or preparation device can transfer neutralization buffer (e.g., from the reagent compartment of liquid reagent plate 1160) to a mixing tube 1444, which has been empty until now. At this point, processing tube 1442 will contain magnetic particles, separated nucleic acids (e.g., DNA / RNA), and an internal control. Mixing tube 1444 contains neutralization buffer.

[0241] The heater block 1460 is activated a second time to heat the contents of the processing tube 1442. The heating temperature and duration will depend on the assay or procedure being performed. The first magnet 1422 of the magnetic separator can be raised again until it is flush with the processing tube 1442. The first magnet 1422 can apply a magnetic force to the magnetic particles in the processing tube 1442, thereby attracting the magnetic particles to the inner wall of the processing tube 1442 (but not to nucleic acids, such as DNA / RNA molecules, which no longer attach to the magnetic particles). While the magnetic particles are attracted by the first magnet 1422 and held flush with the inner wall of the processing tube 1442, the liquid contents (e.g., a nucleic acid mixture with added release buffer) are extracted from the processing tube 1442 without extracting the magnetic particles. The nucleic acid mixture can be transferred to a mixing tube 1444 containing a neutralization buffer. The neutralization buffer is configured to lower the pH of the nucleic acid mixture to a neutral pH. The first magnet 1422 of the magnetic separator can be lowered.

[0242] In some embodiments, the drying reagent compartment of the amplification reagent plate may be accessible, containing PCR master mixture reagents, which contain samples and primers for PCR amplification. The PCR master mixture reagents may be in the form of lyophilized beads. A diagnostic or preparation device may transfer the contents of mixing tube 1444 into the compartment of the amplification reagent plate containing the PCR master mixture reagents, and the neutralized nucleic acid mixture from mixing tube 1444 may dissolve the PCR master mixture beads. However, when the contents are extracted from mixing tube 1444, a second magnet 1432 of the immobilizing magnet assembly may apply a magnetic force to the contents of mixing tube 1444. In particular, some magnetic particles (e.g., beads) may be transferred from processing tube 1442 into mixing tube 1444, although efforts are made to prevent this from happening (e.g., using a first magnet 1422 to retain the magnetic particles in processing tube 1422). The second magnet 1432 can be used as part of an additional filtration step to remove any residual magnetic particles (e.g., “residual” magnetic particles) left from the processing tube 1422 when the neutralized nucleic acid mixture is extracted from the mixing tube 1444.

[0243] The resulting mixture (containing rehydrated PCR master mixture reagents and neutralized nucleic acid mixture) in the dry reagent compartment of the amplification reagent plate can be transferred to a device that includes a storage device for storing samples therein or a microfluidic cartridge (e.g., for amplification therein) for performing amplification. Figure 11 The microfluidic cartridge shown is 1170.

[0244] Figures 15A to 15D An isometric view of a stationary magnet assembly used in some embodiments of a diagnostic or preparation device according to the disclosed technology is shown.

[0245] An embodiment of the fixed magnet assembly 1500 is shown, which can be used for... Figure 11 Figure 13- Figure 13B and Figures 14A-14C The embodiments of the diagnostic or preparation device shown and described herein are implemented. As shown, four separate fixed magnet assemblies 1500 can be mounted, each fixed magnet assembly including a support plate 1502, the support plate 1502 being sized to accommodate a specific diagnostic or preparation device in which the fixed magnet assembly 1500 is implemented. In some embodiments, the support plate 1502 can be a machined aluminum plate. The support plate 1502 may include a set of notches or holes 1508, each notch or hole 1508 being configured to receive a mixing tube 1546 (similar to) of a processing plate 1540. Figure 13B The mixing tube 1316 shown or Figures 14A-14C The bottom end of the mixing tube 1444 shown.

[0246] The fixed magnet assembly 1500 may further include a set of magnet housings 1512. The magnet housings 1512 may be integrally formed as a single piece. The magnet retainer 1500 may include a set of magnet housings 1512 and connectors 1514. The magnet housings 1512 and connectors 1514 may be integrally formed as a single piece. In another example, the magnet housings 1512 and connectors 1514 are coupled to form the magnet retainer 1500. Other configurations may be implemented suitably. In some embodiments, each magnet housing 1512 may have a trapezoidal shape when viewed from above. In this example, each magnet housing 1512 accommodates two magnets (not shown), which are positioned adjacent to a first face 1520 and a second face 1522 of the magnet housing 1512, respectively. This arrangement may be similar to... Figure 14B The diagram illustrates a manner in which a pair of magnets 1432 are arranged within a housing 1430. The magnet mounting assembly 1500 may include mounting holes 1518 for attaching a magnet housing 1512 to a support plate 1502. For example, fasteners (e.g., screws) may be inserted into the mounting holes 1518 to secure the magnet housing 1512 to the support plate 1502 and form the magnet mounting assembly 1500. The support plate 1502 of the magnet mounting assembly 1500 can then be mounted (e.g., fixed to) a diagnostic or preparation device using any suitable mechanism.

[0247] In one non-limiting example, the fixed magnet assembly 1500 is a single integral piece comprising a plurality of magnet housings 1512 separated by connectors 1514. In some cases, the fixed magnet assembly is an integral structure comprising a plurality of magnet housings 1512. The integral fixed magnet assembly 1500 may be formed of, for example, a magnetic material. In another non-limiting example, the integral fixed magnet assembly 1500 is formed of one or more non-magnetic materials, and the magnetic material is coupled to the inner wall of the housing adjacent to the first surface 1520 and the second surface 1522 of each magnet housing 1512. Other configurations are also possible.

[0248] In some embodiments, the magnet housing 1512 of each fixed magnet assembly 1500 may have a fixed height (e.g., an up / down position) relative to the support plate 1502 and the rest of the diagnostic or preparation apparatus. This fixed height can be adjusted by adding a shim of the desired height, measured in the z-direction, between the magnet housing 1512 and the support plate 1502. Mounting the fixed magnet assembly 1500 may include selecting one of a plurality of shims of different heights from a mounting kit, mounting the selected shim in the receiver rack, and mounting the fixed magnet assembly 1500 over the shim in the z-direction. This can be particularly advantageous when retrofitting fixed magnet assemblies into existing preparation and diagnostic apparatuses in the art, taking into account minor dimensional differences and tight tolerances associated with the receiver rack and bench implemented in the apparatus. In some other embodiments, Figure 9 and Figures 10A-10B The spring-based mechanism shown can be used to secure the magnet assembly 1500, allowing the support plate 1502 of the mounted magnet assembly 1500 to move up or down in the z-direction.

[0249] Therefore, the mixing tubes 1546 of the processing plate 1540 can be received in the holes 1508 of the support plate 1502, such that each mixing tube 1546 is in close proximity to a magnet in an adjacent magnet housing 1512 (e.g., a magnet located behind a first face 1520 or a second face 1522 of an adjacent magnet housing 1512). In some embodiments, the first face 1520 and the second face 1522 of each magnet housing 1512 can be oriented at an angle such that when the mixing tube is disposed in the hole 1508, the first face 1520 and the second face 1522 are parallel to the inclined wall of the mixing tube.

[0250] Figures 16A-16B An isometric view of another embodiment of a fixed magnet assembly is shown, which can be implemented in an automated diagnostic or preparation device according to the disclosed techniques. More specifically, Figures 16A-16B An embodiment of a fixed magnet assembly 1600 with a user-adjustable height is shown. Figure 16C It shows Figures 16A-16BThe fixed magnet assembly, wherein the magnet housing 1612 and connector 1614 are omitted for illustrative purposes only. Figure 16D It shows the result of Figures 16A-16C A perspective view of the fastening mechanism implemented for the fixed magnet assembly, and Figure 16E A side sectional view of the fastening mechanism is shown. Figure 16F The receiving rack of the diagnostic or preparation device is shown (such as in the reference). Figures 5A-5B The described receiving rack (within 500) is implemented Figures 16A-16C An isometric view of the fixed magnet assembly.

[0251] The magnet retainer assembly 1600 may include a mounting plate 1602, a support plate 1606, and a magnet holder 1604. The mounting plate 1602 may be sized to accommodate specific diagnostic or preparation devices for the magnet retainer assembly 1600. In some embodiments, the mounting plate 1602 may be a machined aluminum plate. In some embodiments, the mounting plate 1602 may include a plurality of mounting brackets 1640 on one side. For example, in the embodiment shown in the figures, two mounting brackets 1640 are present on the front side of the mounting plate 1602, extending upward (e.g., along the z-axis) from the mounting plate 1602. Each mounting bracket 1640 may have a vertical slot 1644 through which a fastener 1642 may be configured. The fastener 1642 may be configured to pass through the vertical slot 1644 and into a corresponding recess (not shown) in the support plate 1606, which is configured to receive the fastener 1642. In some cases, the fastener 1642 may be a screw, and tightening the fastener 1642 clamps the mounting bracket 1640 between the fastener 1642 and the support plate 1606, thereby mounting the support plate 1606 to the mounting bracket 1640 to prevent repositioning of the support plate 1606. In some embodiments, the mounting plate 1602 may also include fastener housings 1630, and fasteners 1632 may be disposed in each fastener housing 1630. In the embodiment shown in the figures, there are three fastener housings 1630 spaced apart along the length of the mounting plate 1602, with two fastener housings 1630 each at each longitudinal end of the mounting plate 1602. It should be understood that other numbers, spacings, and configurations of the fastener housings 1630 are possible. Each fastener 1632 may be configured to pass through a notch in the fastener housing 1630, and may also be configured to pass through a corresponding notch in the support plate 1606 (e.g., ...). Figure 16E (As shown). In some cases, the fastener 1632 can be a screw, and tightening the fastener 1632 can make them penetrate deeper into those notches of the support plate 1606 to lift the support plate 1606 relative to the mounting plate 1602.

[0252] As will be described in further detail herein, the mounting bracket 1640 (and its vertical slot 1644), fastener 1642, fastener housing 1630, and fastener 1632 may be components configured to work together to allow a user to adjust the height (relative to mounting plate 1602) of the support plate 1606 and / or magnet retainer 1604 of the fixed magnet assembly 1600. Once the mounting plate 1602 is secured in place, the support plate 1606 and / or magnet retainer 1604 can be moved up and down relative to the stationary mounting plate 1602 within a limited range (e.g., along the z-axis) using a user-adjustable height function. In some embodiments, the support plate 1606 may be a component that moves up and down (e.g., along the z-axis) relative to the mounting plate 1602 when the user-adjustable height function is used, such as when the fastener 1632 (located in the fastener housing 1630) is rotated clockwise and / or counterclockwise.

[0253] A support plate 1606 may be located on top of a mounting plate 1602, sandwiched between the mounting plate 1602 and a magnet holder 1604. The magnet holder 1604 may include a set of magnet housings 1612 and connectors 1614. The magnet housings 1612 and connectors 1614 may be integrally formed as a single piece, or they may be coupled to form the magnet holder 1604. Other configurations may be implemented as appropriate. The dimensions of the support plate 1606 and the magnet holder 1604 may be adapted to accommodate a specific diagnostic or preparation device in which the fixed magnet assembly 1600 is implemented. In some embodiments, the magnet holder 1604 may be made of a chemically resistant cleaning agent material. In some embodiments, each magnet housing 1612 may have a trapezoidal shape when viewed from above. In this example, each magnet housing 1612 can accommodate two magnets (not shown), which are positioned adjacent to a first surface 1620 and a second surface 1622 of the magnet housing 1612, respectively. This arrangement can be similar to... Figure 6B The arrangement of a pair of magnets 632 within the housing 630 is shown.

[0254] In one non-limiting example, the fixed magnet assembly 1600 is a single integral piece comprising a plurality of magnet housings 1612 separated by connectors 1614. In some cases, the fixed magnet assembly is an integral structure comprising a plurality of magnet housings 1612. The integral fixed magnet assembly 1600 may be formed of, for example, a magnetic material. In another non-limiting example, the integral fixed magnet assembly 1600 is formed of one or more non-magnetic materials, and the magnetic material is coupled to the inner wall of the magnet housing 1612 adjacent to a first surface 1620 and a second surface 1622 of each magnet housing 1612. Other configurations are also possible.

[0255] The magnet retainer 1604 may have a mounting hole 1616 (e.g., in connector 1614) for mechanically coupling the magnet retainer 1604 to a mounting plate 1602. For example, in some embodiments, a fastener 1617 (e.g., a screw or shoulder bolt) may be inserted into the mounting hole 1616 (and also through a corresponding mounting hole in a support plate 1606, not shown) to mechanically couple the magnet retainer 1604 to the support plate 1606 and / or the mounting plate 1602. In some embodiments, the fastener 1617 may limit the maximum spacing between the support plate 1606 and the mounting plate 1602. The fastener 1617 may provide an upward restriction on upward movement of the support plate 1606 away from the mounting plate 1602 in the z-direction, but does not restrict downward movement of the support plate 1606 toward the mounting plate 1602 in the z-direction. In some embodiments, the fastener 1617 may additionally restrict movement of the support plate 1606 in the x-axis and y-axis. With these fasteners 1617 in place, the magnet retainer 1604 can be secured to the support plate 1606, allowing both to move together as a single unit. These fasteners 1617, inserted through the mounting holes 1616, should not be mistaken for fasteners 1632 located in the fastener housing 1630; they can be used for various purposes (e.g., enabling the user to adjust the height of the magnet assembly 1600, such as the z-axis position of the magnet retainer 1604 and support plate 1606 relative to the mounting plate 1602). With the magnet retainer 1604, support plate 1606, and mounting plate 1602 mechanically connected, the mounting plate 1602 of the magnet assembly 1600 can then be mounted (e.g., secured to) a diagnostic or preparation device using any suitable mechanism. In some embodiments, the magnet assembly 1600 can be secured in a particular diagnostic or preparation device by using fasteners (such as very high adhesive tape) to secure the mounting plate 1602 to the device's cover 1650.

[0256] In some embodiments, the fixed height (e.g., up / down position) of the magnet retainer 1604 and / or support plate 1606 relative to the mounting plate 1602 and the rest of the diagnostic or preparation device can be adjusted by the user, such as by using the following technique or procedure. First, the fastener 1642 in the mounting bracket 1640 can be loosened (e.g., by turning the fastener 1642 counterclockwise). Once the correct height is determined (e.g., by securely fastening the magnet retainer 1604 to the mounting bracket 1640), the fastener 1642 can be used to lock that height; loosening the fastener 1642 allows the height to be adjusted. The fastener 1642 can remain loose during height adjustment and can then be tightened to ensure that the support plate 1606 remains in the correct position.

[0257] After loosening fastener 1642, fasteners 1632 in the fastener housing 130 can be adjusted individually or simultaneously to adjust the height of the support plate 1606. For example, in some cases, each fastener 1632 can be a jacking screw, configured to pass through a recess in the fastener housing 1630 and threaded through a recess in the support plate 1606. Therefore, as the jacking screw is further screwed in or out of the support plate 1606, the support plate 1606 can move up and down accordingly. For example, turning the jacking screw clockwise can further screw the jacking screw into the support plate 1606 and move that portion of the support plate 1606 toward the fastener housing 130, thereby raising that portion of the support plate 1606. Turning the jacking screw counterclockwise can unscrew the jacking screw from the support plate 1606 and move that portion of the support plate 1606 away from the fastener housing 130, thereby lowering that portion of the support plate 1606.

[0258] In some embodiments, when the retaining magnet assembly 1600 is installed into a particular diagnostic or preparation device and height adjustment is performed, an alignment device (e.g., a separate device not shown in the figures) that can be loaded into the same hole will occupy the same hole when the stand is placed in the receiving rack of the device. The alignment device can serve as a guide during height adjustment to determine when the support plate 1606 and / or the magnet holder 1604 are at the correct height for that particular diagnostic or preparation device. Advantageously, the height adjustment described above can be a one-time adjustment, performed only once, and not repeated once the system is put back into service.

[0259] Once the support plate 1606 and / or the magnet retainer 1604 are adjusted to the desired height, the fasteners 1642 can be tightened to maintain those heights. In some embodiments, an additional device (e.g., another separate device not shown in the figures) may be present, which allows for checking the adjusted height of the support plate 1606 and / or the magnet retainer 1604 to confirm that they are within + / - 1 mm of the expected nominal position, which can indicate whether readjustment is required during this installation process. This particular configuration of the retaining magnet assembly 1600 allows for its inexpensive and rapid on-site implementation in a particular device (e.g., at the location of a diagnostic or preparation device), despite any unknown component variations that may exist between different devices. Figure 16F The cover 1650 attached to the diagnostic or preparation device is shown. Figures 16A-16C The same fixed magnet assembly 1600 shown includes a support plate 1602 and a magnet retainer 1604.

[0260] More specifically, Figure 16FThis illustrates how the fixed magnet assembly 1600 can be implemented in the receiver rack of a diagnostic or preparation device (such as...). Figures 5A-5B The receiving rack 500 of the diagnostic or preparation device shown is arranged such that when the receiving rack receives a rack with reagent holders inserted into the rack, the processing tubes of these reagent holders rest on a mounting plate 1602 of the fixed magnet assembly 1600 adjacent to the magnets in the magnet holder 1604. Additionally, one or more movable magnets of the magnetic separator (not shown in the figure, but referenced above) Figures 3A-3C (As described) a magnetic force can be applied to each processing tube of the reagent holder in the bench. In addition, with the fixed magnet assembly 1600 installed in this position, a constant and consistent magnetic force from the magnets of the fixed magnet assembly 1600 (e.g., the magnets in the magnet holder 1604) is also applied to each third snap-fit ​​container of the reagent holder in the bench.

[0261] Figures 17A to 17D An isometric view is shown of an exemplary structure for mounting and implementing the fixed magnet assembly 1710 into an automated diagnostic or preparation device. More specifically, Figure 17A An embodiment of a bridge 1700 for supporting a fixed magnet assembly 1710 is shown. Figures 17B to 17D It shows Figure 17A The bridge 1700 and the fixed magnet assembly 1710 can be mounted and implemented within the receiving rack of an automated diagnostic or preparation device according to this non-limiting embodiment. It will be understood that this disclosure is not limited to mounting the fixed magnet assembly according to this embodiment, and other configurations may be suitably implemented.

[0262] In a non-limiting example, bridge 1700 may include multiple portions, such as a first bridge portion 1702 and a second bridge portion 1706, which can be used to support the fixed magnet assembly 1710. For example, the first bridge portion 1702 may be configured to support a first end of the fixed magnet assembly 1710, and the second bridge portion 1706 may be configured to support an opposite second end of the fixed magnet assembly 1710, thereby forming a bridge.

[0263] In some embodiments, bridge 1700 may have a mirror-symmetrical first bridge portion 1702 and a second bridge portion 1706. The first bridge portion 1702 and the second bridge portion 1706 may be configured to engage with slots on opposite sides of a cover 1720 in a receiving rack of an automated diagnostic or preparation device, thereby causing bridge 1700 to span cover 1720, as... Figure 17B As shown.

[0264] This can be done Figure 17C and Figure 17D To see it better in the middle, Figure 17C and Figure 17DA first bridge portion 1702 is shown mounted on one end of the cover 1720. A second bridge portion 1706 is not shown, but it will be located on the opposite end of the cover 1720. The opposite ends of the retaining magnet assembly 1710 can be respectively mounted on the first bridge portion 1702 and the second bridge portion 1706, which hold the retaining magnet assembly 1710 above the cover 1720 and position it in place to precisely apply magnetic force to the magnetic particles remaining in the corresponding tube of the pedestal already placed in the receiving rack.

[0265] In some embodiments, the first bridge portion 1702 and the second bridge portion 1706 may have notches that allow the first bridge portion 1702 and the second bridge portion 1706 to fit cleanly onto the ends of the cover 1720 without obstructing any components of a diagnostic or preparation device that may be located beneath the cover 1720. For example, Figure 17C and Figure 17D A first bridge portion 1702 is shown with a notch 1704, the shape and size of which are configured to receive a component (e.g., a printed circuit board) of a diagnostic or preparation device.

[0266] Many variations and modifications can be made to the above embodiments, and the elements of these embodiments should be understood as elements of other acceptable examples. All such modifications and variations are intended to be included within the scope of this disclosure. The foregoing description details certain embodiments. However, it should be understood that the system and method can be practiced in many ways, no matter how detailed the foregoing appears in the text. As mentioned above, it should be noted that the use of specific terms in describing certain features or aspects of the system and method does not mean that the term is redefined herein to be limited to any specific characteristic associated with that term that includes the features or aspects of the system and method.

[0267] Unless otherwise expressly stated, or otherwise understood in the context in which they are used, conditional language, such as “can,” “able,” “may,” or “may,” and other equivalent expressions, is generally intended to express that certain embodiments include certain features, elements, and / or steps, but other embodiments do not include said features, elements, and / or steps. Therefore, such conditional language is not generally intended to imply that one or more embodiments require such features, elements, and / or steps in any way, or that one or more embodiments must include logic for determining whether to include such features, elements, and / or steps, or to perform such features, elements, and / or steps in any particular embodiment, regardless of user input or prompting.

[0268] When used in conjunction with the term "real-time," the term "substantially" forms phrases that will be easily understood by a person skilled in the art. For example, it is easy to understand that such language would include speeds with no or almost no perceptible delay or waiting, or delays so short as to not disturb, irritate, or annoy the user.

[0269] Unless otherwise explicitly stated, conjunctions such as “at least one of X, Y, and Z” or “at least one of X, Y, or Z” should generally be used in context to express that an item, term, etc., can be X, Y, or Z, or a combination thereof. For example, the term “or” is used in its inclusive meaning (rather than its exclusive meaning) so that, for example, when used to connect lists of elements, the term “or” indicates one, some, or all of the elements in the list. Therefore, such conjunctions are generally not intended to imply that some embodiments require at least one X, at least one Y, and at least one Z to be present.

[0270] The term “a” as used herein should be interpreted inclusively rather than exclusively. For example, unless otherwise specified, the term “a” should not be construed as meaning “exactly one” or “one and only one”; rather, the term “a” is used, whether in the claims or elsewhere in the specification, to mean “one or more” or “at least one”, and is unrelated to the use of quantifiers such as “at least one,” “one or more,” or “multiple” elsewhere in the claims or specification.

[0271] As used herein, the term "comprising" should be interpreted in an inclusive rather than exclusive sense. For example, a general-purpose computer that includes one or more processors should not be construed as excluding other computer components and may include components such as memory, input / output devices, and / or network interfaces.

[0272] While the detailed description above has shown, described, and pointed out novel features applicable to various embodiments, it should be understood that various omissions, substitutions, and changes may be made to the form and details of the illustrated apparatus or process without departing from the spirit of this disclosure. It will be appreciated that some embodiments of the invention described herein may be implemented in forms that do not provide all the features and advantages set forth herein, as certain features can be used or implemented separately from other features. The scope of certain aspects of the invention disclosed herein is indicated by the appended claims rather than the foregoing description. All changes falling within the equivalent meaning and scope of the claims should be included within their scope.

Claims

1. A system for analyzing nucleic acids, the system comprising: a receiving rack configured to receive a plurality of lysis tubes aligned along a lysis axis and a plurality of mixing tubes aligned along a mixing axis substantially parallel to the lysis axis, the receiving rack comprising: one or more first magnets aligned along a first magnet axis substantially parallel to the lysis axis and the mixing axis, the one or more first magnets configured to move between a first position distal to the plurality of lysis tubes and a second position proximate to the plurality of lysis tubes when the plurality of lysis tubes are received in the receiving rack, the one or more first magnets configured to exert a first magnetic force to contents of the plurality of lysis tubes when the plurality of lysis tubes are received in the receiving rack and the one or more first magnets are in the second position, and a plurality of second magnets enclosed within a plurality of housings, the plurality of second magnets aligned along a second magnet axis substantially parallel to the first magnet axis, each housing of the plurality of housings enclosing two magnets of the plurality of second magnets, the plurality of second magnets configured to remain stationary when the plurality of mixing tubes are received in the receiving rack, the plurality of second magnets configured to exert a second magnetic force to contents of the plurality of mixing tubes when the plurality of mixing tubes are received in the receiving rack, the first magnet axis spatially separated from the second magnet axis by a distance such that the plurality of second magnets do not exert the second magnetic force to contents of the plurality of lysis tubes when the plurality of lysis tubes are received in the receiving rack.

2. The system of claim 1, wherein the plurality of second magnets are included in a stationary magnet assembly, the stationary magnet assembly comprising: a mounting plate; a support plate having a height relative to the mounting plate; and a first plurality of fasteners mechanically coupling the support plate to the mounting plate, wherein the first plurality of fasteners make the height of the support plate relative to the mounting plate adjustable by a user.

3. The system of claim 2, wherein each fastener of the first plurality of fasteners comprises a jack screw. the first magnetic force is exerted to contents of each lysis tube of the plurality of lysis tubes in a direction substantially perpendicular to the lysis axis and the second magnetic force is exerted to contents of each mixing tube of the plurality of mixing tubes in a direction substantially parallel to the mixing axis when the plurality of lysis tubes and the plurality of mixing tubes are received in the receiving rack.

4. The system of claim 1, wherein, the first magnetic force is exerted to contents of each lysis tube of the plurality of lysis tubes in a direction substantially perpendicular to the lysis axis and the second magnetic force is exerted to contents of each mixing tube of the plurality of mixing tubes in a direction substantially perpendicular to the mixing axis when the plurality of lysis tubes and the plurality of mixing tubes are received in the receiving rack.

5. The system of claim 1, wherein, ​ 6. The system of claim 1, wherein the receiving rack is further configured to receive a processing apparatus comprising the plurality of lysis tubes and the plurality of mixing tubes, a lysis tube of the plurality of lysis tubes and a mixing tube of the plurality of mixing tubes aligned along each of a plurality of parallel processing axes, wherein the first magnet axis and the second magnet axis are substantially perpendicular to the plurality of processing axes when the processing apparatus is received in the receiving rack.

7. The system of claim 1, wherein the one or more first magnets do not exert the first magnetic force on contents of the plurality of mixing tubes when the plurality of mixing tubes are received in the receiving rack.

8. The system of claim 1, wherein, a first magnet of the two magnets in each housing is configured to exert the second magnetic force on contents of a first mixing tube at a first position of the first mixing tube, and wherein a second magnet of the two magnets in each housing is configured to exert the second magnetic force on contents of a second mixing tube adjacent to the first mixing tube, the second magnet of the two magnets configured to exert the second magnetic force at a second position of the second mixing tube, the second position of the second mixing tube being about 180° or less than 180° from the first position of the second mixing tube.

9. The system of claim 1, wherein, a ratio of the mixing tubes to the housings is two to one when the plurality of mixing tubes are received in the receiving rack.

10. The system of claim 9, comprising a plurality of first magnets aligned along the first magnet axis, and wherein, a ratio of the lysis tubes to the first magnets is one to one when the plurality of lysis tubes are received in the receiving rack.

11. The system of claim 1, wherein each housing comprises two faces, each face at a different angle relative to the second magnet axis, and wherein, each of the two second magnets is positioned adjacent to an interior wall of one angled face.

12. The system of claim 1, comprising an integrated structure comprising the plurality of housings.

13. The system of claim 1, wherein the plurality of housings are separated by a plurality of connectors.

14. The system of claim 1, wherein the receiving rack further comprises a support plate between the plurality of second magnets and a lid of the receiving rack.

15. The system of claim 14, wherein the support plate comprises a plurality of notches, each of the notches configured to receive a bottom of a mixing tube when the plurality of mixing tubes are received in the receiving rack.

16. The system of claim 14, wherein, the plurality of housings are movable relative to the support plate when the plurality of mixing tubes are not received in the receiving rack.

17. The system of claim 1, further comprising the plurality of lysis tubes and the plurality of mixing tubes received in the receiving rack.

18. The system of claim 1, wherein, when the plurality of lysis tubes and the plurality of mixing tubes are received in the receiving rack: a lysis tube of the plurality of lysis tubes and a mixing tube of the plurality of mixing tubes are aligned along each of a plurality of parallel processing axes, the first magnetic force is exerted along a respective processing axis of each lysis tube of the plurality of lysis tubes, and the second magnetic force is exerted at a point offset from the respective processing axis of each mixing tube of the plurality of mixing tubes.

19. A system for analyzing nucleic acids, the system comprising: a receiving rack configured to receive an apparatus, the apparatus comprising lysing tubes and mixing tubes aligned along each of a plurality of parallel processing axes, the receiving rack comprising: one or more first magnets aligned along a first magnet axis substantially perpendicular to the plurality of processing axes, the one or more first magnets configured to move between a first position distanced from the plurality of lysing tubes and a second position proximate to the plurality of lysing tubes when the apparatus is received in the receiving rack, the one or more first magnets configured to exert a first magnetic force on contents of the plurality of lysing tubes when the apparatus is received in the receiving rack and the one or more first magnets are in the second position, and a plurality of second magnets enclosed within a plurality of housings, the plurality of second magnets aligned along a second magnet axis substantially perpendicular to the plurality of processing axes, each housing of the plurality of housings enclosing two magnets of the plurality of second magnets, the plurality of second magnets configured to remain stationary when the plurality of mixing tubes are received in the receiving rack, the plurality of second magnets configured to exert a second magnetic force on contents of the plurality of mixing tubes when the apparatus is received in the receiving rack, the first magnet axis spatially separated from the second magnet axis by a distance such that the plurality of second magnets do not exert the second magnetic force on contents of the plurality of lysing tubes when the plurality of lysing tubes are received in the receiving rack.

20. The system of claim 19, wherein the plurality of second magnets are included in a stationary magnet assembly, the stationary magnet assembly comprising: a mounting plate; a support plate having a height relative to the mounting plate; and a first plurality of fasteners mechanically coupling the support plate to the mounting plate, wherein the first plurality of fasteners make the height of the support plate relative to the mounting plate adjustable by a user.

21. The system of claim 20, wherein each fastener of the first plurality of fasteners comprises a jack screw. the first magnetic force is exerted along a respective processing axis of each lysing tube of the plurality of lysing tubes and the second magnetic force is exerted at a point offset from a respective processing axis of each mixing tube of the plurality of mixing tubes when the apparatus is received in the receiving rack.

22. The system of claim 19, wherein, the first magnetic force is exerted along a respective processing axis of each lysing tube of the plurality of lysing tubes and the second magnetic force is exerted along a respective processing axis of each mixing tube of the plurality of mixing tubes when the apparatus is received in the receiving rack.

23. The system of claim 19, wherein, 24. The system of claim 19, wherein the one or more first magnets do not exert the first magnetic force on contents of the plurality of mixing tubes when the apparatus is received in the receiving rack. ​ 25. The system of claim 19, wherein, a first magnet of the two magnets in each housing is configured to apply the second magnetic force to contents of a first mixing tube at a first position of the first mixing tube when the apparatus is received in the receiving rack, and wherein a second magnet of the two magnets in each housing is configured to apply the second magnetic force to contents of a second mixing tube adjacent to the first mixing tube, the second magnet of the two magnets configured to apply the second magnetic force at a second position of the second mixing tube that is about 180° or less than 180° from a first position of the second mixing tube.

26. The system of claim 19, wherein, a ratio of the mixing tubes to the housings is two to one when the apparatus is received in the receiving rack.

27. The system of claim 26, comprising a plurality of first magnets aligned along the first magnet axis, and wherein, a ratio of the lysis tubes to the first magnets is one to one when the apparatus is received in the receiving rack.

28. The system of claim 19, wherein each housing comprises two faces, each face angled relative to an adjacent processing axis, and wherein each magnet of the two second magnets is positioned adjacent to an interior wall of one angled face.

29. The system of claim 19, comprising an integrated structure comprising the plurality of housings.

30. The system of claim 19, further comprising the apparatus received in the receiving rack.

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