Portable electrophoresis system with integrated thermal cycler

Abstract

A thermal control module for a bioseparation system comprises: a thermal platform thermally coupled to a thermoelectric module, the thermal platform including a base and at least one thermal block thermally conductively supported on the base, the thermal block configured to receive at least a container containing a sample, the thermal block comprising a body including a divided longitudinal block having two longitudinal sides defining a valley, each opposing wall of the sides having a sectorial concave profile that matches a convex conical tubular profile of a bottom surface of a well of a container tray; a heat sink; and a thermoelectric module thermally conductively coupled between the thermal platform base and the heat sink for heating / cooling the thermal platform according to a desired heating / cooling temperature profile.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 318,778, filed March 10, 2022. This application and all published documents discussed below are incorporated by reference in their entirety as if fully set forth herein. [Technical field]

[0002] The present invention relates to bioanalysis, in particular to a capillary electrophoresis device including sample processing, and more particularly to a capillary electrophoresis device including a thermal control module (e.g., heating, cooling, thermocycling) for sample processing (e.g., PCR: polymerase chain reaction). [Background technology]

[0003] Capillary electrophoresis (CE) separation is a microfluidic approach to gel electrophoresis (a microchannel device for simplifying gel electrophoresis separation), and its biggest advantage is that its application range is very wide. CE technology has been widely accepted by the biotechnology industry as a reliable high-resolution and high-sensitivity separation and detection means, especially in nucleic acid-based testing methods, and CE has been applied to, for example, protein analysis, carbohydrate analysis, and DNA-related analysis such as oligonucleotide analysis, DNA sequencing and dsDNA fragment analysis, as well as glycan profiling.

[0004] The commonly assigned US Pat. No. 6,399,633 discloses a reusable cartridge-based portable electrophoresis system that is easy to assemble and use with no moving parts and is configured to utilize a pen-shaped bioseparation cartridge with a built-in reagent (separation buffer) reservoir. The cartridge comprises a body defining an opening as a detection window for receiving external detection optics, at least one capillary column supported within the body and having a first end extending beyond the first end of the body, the detection window exposing a portion along the capillary column and the external optics aligned with the portion through the detection window, and a reservoir attached to a second end of the body and in fluid communication with the second end of the capillary column. The reservoir is configured to connect to a pneumatic pump or N2 tank that pressurizes the gel reservoir to purge the capillary and further fill the capillary with a buffer / gel as a separation support medium. A negatively charged sample can be loaded into the capillary column to perform CE separation for analysis. Once the sample separation run is finished, the spent sample (negatively charged separated DNA / RNA fragments) is captured in a gel-reservoir (large pool) in an embedded electrode (anode) away from the output of the capillary column. Another sample can then be loaded into the capillary column and analyzed in another run using the same cartridge.

[0005] In the context of DNA / RNA analysis based on CE separation, polymerase chain reaction (abbreviated as PCR) is a laboratory technique for rapidly generating (amplifying) hundreds to billions of copies of a specific segment of DNA, which can then be studied in greater detail at high resolution without the need to first provide large samples of DNA / RNA. PCR uses short synthetic DNA / RNA fragments called primers to select a segment of the genome to be amplified, and then involves multiple rounds of DNA / RNA synthesis to amplify that segment prior to conventional gel electrophoresis or capillary electrophoresis (CE) separation and detection analysis, thus providing high-resolution results based on an initial low sample volume (e.g., picoliters). The PCR process requires thermocycling of the sample DNA segment to prepare the sample for subsequent CE separation analysis.

[0006] It has been practiced for many years to employ a separate PCR process performed using a thermocycler that is not part of (i.e., external to) the CE separation and detection system / apparatus, and the prepared samples are then transferred to the CE system for separation analysis. U.S. Patent No. 5,399,433, assigned to the assignee of the present invention, discloses a CE apparatus that includes a temperature control mechanism, such as a Peltier heating / cooling module, connected to a table (e.g., underneath) that supports sample vials that are placed under a capillary cartridge. The heating / cooling module provides temperature control to facilitate PCR amplification and electrophoresis / detection in one apparatus. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Pat. No. 8,778,155 [Patent Document 2] U.S. Pat. No. 11,531,004 Summary of the Invention [Problem to be solved by the invention]

[0008] There is a need for improved CE systems that include improved thermocyclers within the systems. [Means for solving the problem]

[0009] We present a portable capillary gel electrophoresis system with integrated thermal cycler to perform polymerase chain reaction (PCR) for highly efficient and rapid biomolecular analysis applications in molecular diagnostics. The automated PCR-CE system is a newly developed product that significantly improves the pace at which DNA / RNA research and point-of-care are performed in laboratories, saves preparation time, and ensures accurate, consistent, and economical results.

[0010] In one aspect of the present invention, a high-performance capillary gel electrophoresis analyzer system is integrated with a built-in PCR device for molecular diagnostics (MDx) applications. The system uses integrated dual fiber optic fluorescence detection technology and a novel disposable pen-type gel cartridge design. The system can hold a total of eight samples that can be analyzed automatically within 1-2 hours. The fully automated CE-PCR system uses a fluorescence detector (high detection sensitivity) and can be used in laboratories for DNA / RNA amplification and end-point PCR analysis for rapid molecular diagnostic applications.

[0011] PCR reactors and capillary electrophoresis (CE) have been successfully combined to form an integrated DNA fragment analysis system. This construct combines the rapid thermal cycling capability of the mini-PCR device (open system; no lid / door provides access to sample collection by the gel cartridge of the CE system) with the fast DNA separation and fluorescence detection of the CE system. Direct electrophoretic injection from the PCR (open system) chamber through the gel cartridge is achieved for rapid analysis of biomolecules with this system. To demonstrate the functionality of this system, a fast CE separation was performed in less than 120 seconds immediately after 60 minutes of PCR amplification of saliva samples, providing rapid PCR-CE analysis in less than 90 minutes. A rapid assay for SARS-CoV-2 detection was performed in less than 90 minutes, demonstrating that even challenging amplification of diagnostically interesting targets can be performed with high detection sensitivity. Real-time monitoring of PCR target amplification in these integrated PCR-CE devices is also feasible due to the open system (no lid / door on the PCR module provides easy access to samples during or after the thermocycling process). The PCR-CE system establishes the feasibility of performing high-speed DNA analysis in an integrated PCR-CE system.

[0012] In one aspect of the present invention, a thermal control module for a bioseparation system is provided, comprising: a thermal platform thermally coupled to a thermoelectric module, the thermal platform including a base and at least one thermal block thermally conductively supported on the base, the thermal block configured to receive at least a vessel containing a sample, the thermal block comprising a body including a divided longitudinal block having two longitudinal sides defining a valley, each opposing wall of the sides having a sectorial concave profile that matches a convex conical tubular profile of a bottom surface of a well of a vessel tray; a heat sink; and a thermoelectric module thermally conductively coupled between the base of the thermal platform and the heat sink to heat / cool the thermal platform according to a desired heating / cooling temperature profile.

[0013] In one embodiment, the opposing walls are spaced apart by a tapered gap to define a valley to accommodate the joined midline sections of the wells, and the sector profile of the opposing walls, together with the gap between the opposing walls, substantially matches the profile of the exterior bottom surface of the wells of the container tray, allowing efficient thermal conduction between the thermal block and the walls of the wells, thereby efficiently heating / cooling the contents within the wells. In another embodiment, when viewed from the top of the thermal block toward the valley, the sector profile generally resembles a series of adjacent concave surfaces, each having a cross-sectional shape that is a concave curve or arc (e.g., a semicircle or portion thereof) along the opposing walls of the thermal block. In a further embodiment, the opposing walls of the thermal block define a row of cavities, and adjacent cavities are joined / connected to accommodate the midline sections adjacent the bottom of the container tray. In a further embodiment, the adjacent cavities resemble a row of adjacent conical spaces along a tapered gap (the gap narrows / tapers towards the bottom of the block) to receive the conical outer bottom surfaces of the wells in the container tray.

[0014] The thermal block receives the body of the container tray, with the bottom exterior walls of the wells contacting or closely adjacent opposing walls of the thermal block to facilitate thermal conduction between the sides of the thermal block and the wells.

[0015] In one embodiment, the thermal platform comprises two thermal blocks, each thermal block thermally conductively supported on a different section of the base of the thermal platform, and the thermoelectric module comprises separate heating / cooling sub-modules that heat / cool the different sections of the base of the thermal platform according to different heating / cooling temperature profiles, thereby heating / cooling the thermal blocks according to the different heating / cooling temperature profiles, the sub-modules under separate control to achieve the different heating / cooling temperature profiles of the corresponding thermal blocks, thereby subjecting the sample in the container to different temperature profiles.

[0016] In one embodiment, the thermal block and base are separate structures that are thermally coupled together or are an integral monolithic structure, with the thermoelectric module thermally sandwiched between an upper thermal platform and a lower heat sink.

[0017] In another embodiment, a thermal platform that is thermally supported on a thermal platform base includes a second thermal block that includes a body having a plurality of cavities for receiving container tubes.

[0018] In another aspect of the present invention, a bioseparation system includes: a chassis; a cartridge supporting a capillary column for capillary electrophoresis, the cartridge body being supported by the chassis; a thermal control module as described in any of claims 1 to 4, supporting a container containing at least a sample against an extended end of the capillary column, the thermal control module heating / cooling the thermal platform within the thermal control module according to a desired heating / cooling temperature profile; a separation mechanism for effecting biological separation in the capillary column after loading a sample subjected to heating / cooling from a container tray; and a controller for controlling the separation mechanism to perform the separation.

[0019] For a more complete understanding of the nature and advantages of the present invention, as well as the preferred mode of use, reference should be made to the following detailed description taken in conjunction with the accompanying drawings, in which like reference numerals designate like or similar parts throughout the drawings, and in which: [Brief description of the drawings]

[0020] [Figure 1A] FIG. 1 is a perspective external view of a PCR-CE system / apparatus incorporating a thermal (heating and cooling) control module of the present invention, according to one embodiment of the present invention. [Figure 1B] FIG. 1 is a cross-sectional view of a PCR-CE system / apparatus incorporating a thermal (heating and cooling) control module of the present invention, according to one embodiment of the present invention. [Figure 1C] FIG. 1 is a cross-sectional perspective view of a PCR-CE system / apparatus incorporating a thermal (heating and cooling) control module of the present invention, according to one embodiment of the present invention. [Figure 2A] FIG. 1 is a perspective view of a thermocycle module according to an embodiment of the present invention; [Figure 2B] FIG. 2 is a partial perspective view of a thermocycle module according to an embodiment of the present invention; [Figure 2C] 1 is a cross-sectional view of a thermocycle module according to one embodiment of the present invention; [Figure 3A]FIG. 1 is a perspective view of a thermal control module including a thermal platform having a thermal block for supporting a vessel for temperature control (i.e., heating and / or cooling operations), according to one embodiment of the present invention; [Figure 3A] FIG. 1 is a perspective view of a thermal control module including a thermal platform having a thermal block for supporting a vessel for temperature control (i.e., heating and / or cooling operations), according to one embodiment of the present invention; [Figure 3B] FIG. 1 is a perspective view of a thermal control module including a thermal platform having a thermal block for supporting a vessel for temperature control (i.e., heating and / or cooling operations), according to one embodiment of the present invention; [Figure 3C] FIG. 1 is a perspective view of a thermal control module including a thermal platform having a thermal block for supporting a vessel for temperature control (i.e., heating and / or cooling operations), according to one embodiment of the present invention; [Figure 3D] FIG. 1 is a top view of a thermal control module including a thermal platform having a thermal block for supporting a vessel for temperature control (i.e., heating and / or cooling operations), according to one embodiment of the present invention. [Figure 3E] FIG. 1 is a cross-sectional perspective view of a thermal control module including a thermal platform having a thermal block for supporting a vessel for temperature control (i.e., heating and / or cooling operations), according to one embodiment of the present invention; [Figure 3F] FIG. 1 is a cross-sectional perspective view of a thermal control module including a thermal platform having a thermal block for supporting a vessel for temperature control (i.e., heating and / or cooling operations), according to one embodiment of the present invention; [Figure 4A] FIG. 1 is a top perspective view of a container tray that can be received and supported within a thermal block for temperature control, according to one embodiment of the present invention; [Figure 4B] FIG. 1 is a bottom perspective view of a container tray that can be received and supported within a thermal block for temperature control, according to one embodiment of the present invention. [Figure 4C]FIG. 1 is a cross-sectional perspective view of a container tray that can be received and supported within a thermal block for temperature control, according to one embodiment of the present invention. [Figure 4D] FIG. 1 is a cross-sectional perspective view of a container tray that can be received and supported within a thermal block for temperature control, according to one embodiment of the present invention. [Figure 4E] FIG. 1 is a bottom view of a container tray that can be received and supported within a thermal block for temperature control, according to one embodiment of the present invention. [Figure 5A] FIG. 1 is a perspective view of a tray of containers supported on a thermal block; [Figure 5B] FIG. 1 is a perspective view of a tray of containers supported on a thermal block; [Figure 5C] FIG. 1 is a perspective view of a tray of containers supported on a thermal block; [Figure 6] FIG. 1 is a schematic diagram of a simplified PCR-CE workflow using the CE system of the present invention, according to one embodiment of the present invention. [Figure 7] FIG. 1 is a schematic diagram of a PCR-CE workflow for oral samples using the CE system of the present invention, according to one embodiment of the present invention. [Figure 8] Block diagram of the process of introducing a sample into the CE instrument, preparing the sample by heating, and proceeding through CE analysis to RT-PCR and end-point PCR. [Figure 9] Schematic diagram of an intra-oral sample collection procedure according to one embodiment of the present invention. [Figure 10] FIG. 1 is a schematic diagram of a sample preparation process for intra-oral samples, according to one embodiment of the present invention. [Figure 11A] FIG. 1 is a perspective view of a thermal platform according to another embodiment of the present invention; [Figure 11B] FIG. 1 is a cross-sectional perspective view of a preheat thermal block according to another embodiment of the present invention; [Figure 11C] FIG. 1 is a perspective view of a thermal platform supporting vessel tubes on a preheat thermal block and a vessel tray on a PCR thermal block, according to another embodiment of the invention. [Figure 12]1 is a perspective view of a thermal platform according to a further embodiment of the present invention; [Figure 13] FIG. 1 is a schematic diagram of a CE system incorporating a thermal control module of the present invention, according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The present invention will now be described in terms of various embodiments with reference to the drawings. Although the invention will be described in connection with the best mode for accomplishing the objects of the invention, those skilled in the art will recognize that modifications can be made in light of these teachings without departing from the spirit or scope of the invention.

[0022] Reference is made to biological analysis systems, including detection systems, disclosed in U.S. Patent Nos. 8,778,155, 8,784,626, and 11,531,004, and U.S. Patent Application Publication No. 20150338347, all of which are incorporated by reference herein as if fully set forth herein. These patents and patent applications are assigned to BiOptic, Inc., the assignee and assignee of the present invention. In particular, these patents disclose simplified, low-cost, highly efficient, sensitive, and high-throughput bioseparation systems (e.g., capillary electrophoresis (CE) systems). The bioseparation system includes an apparatus configured to work with a single-channel or multi-channel capillary cartridge and equipped with a detection arrangement, which includes an optical system for irradiating an incident radiation to a detection area along the separation channel and detecting an output radiation from a detection area along the separation channel to detect radiation (e.g., radiation-induced fluorescence) emitted by a sample analyte without the need for fine alignment of the optical system to the separation column. The apparatus is configured to automatically perform a bioseparation in a separation channel of the bioseparation cartridge. The CE system has a simpler optical detection mechanism to reduce costs, which complements the ease of operation, high efficiency, high sensitivity, and rapid analysis with high throughput. US Patent Publication No. 20150338347 further discloses fluorescence detection in two colors. The present invention adopts these systems and modifies them to include improvements to the system (i.e., the thermal controller of the present invention for PCR, for example) according to the disclosure below.

[0023] To illustrate the principles of the invention in a non-limiting manner, the invention will be described with reference to embodiments relating to capillary electrophoresis using a single capillary separation column, and further, the invention will be described in the context of, but not limited to, radiation-induced fluorescence detection (e.g., using a laser or LED light source).

[0024] System Overview Miniaturization and automation of analytical instruments offers many advantages over traditional labor-intensive techniques (i.e., manual slab gel electrophoresis), including improved accuracy and reproducibility of data, short analysis times, minimal sample consumption, increased automation, and integration of complex workflows.

[0025] The assignee of the present invention has designed a fully automated biological separation device / system 100, in particular a CE device incorporating a dual stage thermal module for sample preparation and PCR that provides fast amplification, as well as fast separation and direct end-point PCR check in fluorescent detection for clinical applications (hereafter referred to as PCR-CE device or system). Figures 1A-1C show a PCR-CE system / device 100 incorporating a thermal control module of the present invention, according to one embodiment of the present invention. Figure 13 is a schematic diagram of a PCR-CE system incorporating a thermal control module of the present invention, according to one embodiment of the present invention. The PCR-CE system 100 incorporates a detection configuration as shown diagrammatically in Figure 13. The PCR-CE system 100 typically comprises a capillary separation column 10 (e.g., OD (outer diameter) of 200-500 μm), which defines an internal separation channel 12 (e.g., ID (inner diameter) of 25-200 μm), which may be a capillary column 10 (only one separation channel / capillary column is shown for simplicity). The capillary column 10 may be made of fused silica, glass, polyimide, or other ceramic / glassy materials. The interior walls of the separation column 10 (i.e., the walls defining the separation channel 12) may be coated with a material that can be electrostatically charged to facilitate electrophoretic and / or electrokinetic migration of sample components. The separation channel 12 may be filled with a separation support medium, which may simply be an electrophoretic buffer or may be a sieving gel matrix (of linear or non-linear polymeric composition) as known in the art.

[0026] One end of the capillary column 10 is connected to a reservoir 14 of electrophoresis buffer. The other end of the capillary column 10 is connected to another reservoir 16, which may alternately contain a sample (to be injected into the separation channel 12) and an electrophoresis buffer (for carrying out the separation after sample injection). A power supply 18 provides high voltage to the reservoirs 14 and 16 via electrodes 20 and 22. According to the illustrated embodiment, the capillary column is supported in a cartridge C, as disclosed in U.S. Pat. No. 8,778,155, which is incorporated herein by reference and is discussed further below.

[0027] The mechanisms of electrophoresis and radiation-induced fluorescence, when considered alone, are outside the scope of the present invention. For completeness, a brief description of the operation of PCR-CE system 100 is sufficient. In operation, a prepared biological sample, labeled with at least one known fluorophore, is introduced to the distal end of the capillary column, away from the detection zone, by any of a number of methods (e.g., electrokinetic injection from a sample reservoir, or physical pressure injection using a syringe pump) that do not form part of the present invention. When a DC potential (e.g., 1-30 KV) is applied from power supply 18 to electrodes 20 and 22, the sample migrates in direction 24 along separation channel 12 under the applied potential (e.g., a negatively charged sample migrates toward positive electrode 22, as shown in FIG. 13) and is separated into bands of sample components. The extent of separation and the distance traveled along separation channel 12 depends on a number of factors, including the electrophoretic migration mobility of the sample components, the mass and size or length of the sample components, and the separation support medium. The driving force within the separation channel 12 to separate the samples can be electrophoretic force, pressure, or electroosmotic flow (EOF) means.

[0028] When the sample reaches the detection zone 32, excitation radiation is directed to the detection zone 32 in direction 35 via excitation radiation 34. The sample components fluoresce with an intensity proportional to the concentration of the respective sample component (proportional to the amount of fluorescent labeling material). A detector 42 detects the intensity of the fluorescence emitted via emission fiber 36 in direction 37 at one or more wavelengths different from the wavelength of the incident radiation. The detected fluorescence radiation can be analyzed by multicolor (e.g., two-color) detection schemes (described further below with reference to U.S. Patent Application Publication No. 20150338347, incorporated by reference).

[0029] For an automated system, a controller 26 having a processor (e.g., in the form of an external notebook or desktop computer, or a computing device built into the instrument) controls the operation of the various components of the PCR-CE system 100 to control the capillary electrophoretic separation and data collection, as well as other functions described below. The controller 26 provides a user interface and programming of the experiment / test settings and parameters. The controller includes the necessary application software routines, which may also include data reduction applications. The controller 26 may be an integral part of the instrument 100 (e.g., as part of the system board, with the application routines coded in an ASIC (Application Specific Integrated Circuit)), or the controller may be a separate unit that is connected / interfaced to the PCR-CE instrument 100. FIG. 13 shows an embodiment of the PCR-CE instrument 100 with the controller 26 removed; FIGS. 1A and 1B illustrate an embodiment of the PCR-CE instrument 100 with the controller 26 integrated. The controller 26 and / or the system board may be integrated into the front panel of the instrument housing. A sample door DS is provided on the front of the housing to allow user access for installing and removing sample and / or container trays R and / or reagent trays RT. Input / output ports may be provided on the housing, such as a slot SL for reading secure digital (SD) cards, a USB port DU, and additional ports for access by external computing devices (e.g., notebook computers or mobile devices via USB, Ethernet, Wifi, etc.). The front panel may also include a touch screen user interface panel that can be used as a control panel for setting up the operation of the PCR-CE apparatus 100.

[0030] In the embodiment shown in Fig. 13, the controller is provided outside the housing of the PCR-CE device 100 in the form of a desktop or notebook computer that is connected to the PCR-CE device 100 via a system board, for example via a USB interface. The external controller 26 may include mass storage devices, a display, a keyboard, etc., or some of these user interface components may be configured to be part of the PCR-CE device (e.g., a display and keyboard mounted on the front housing). Alternatively, the system board may be incorporated as part of the external controller 26 without departing from the scope and spirit of the present invention. The specific implementation of such control is within the knowledge of one of ordinary skill in the art from the disclosure herein.

[0031] As shown in Figures 1B and 1C and Figure 5C, the cartridge C is supported vertically with a capillary column 10 hanging from its end to access sample wells W in a container tray R supported on a thermal block B and reagents in wells BW in a reagent tray RT carried on a transport mechanism TM (e.g., a transport that moves the various trays in two axes XZ (horizontal and vertical) or XYZ (horizontal and vertical) directions by stepper motors). Further references in this regard can be found in the patent publications incorporated herein by reference. A cartridge door DC is provided on the upper side of the device housing to allow insertion and removal of the cartridge C. It should be noted that the sample wells W in the container tray R correspond to the reservoirs 16 shown in the schematic Figure 13.

[0032] A reagent tray RT is provided which contains buffer wells BW for, for example, buffers and is accessed by the cartridges C.

[0033] As an example, using the PCR-CE device 100, the entire assay for SARS-CoV-2 detection could be completed in 90 min with rapid small volume (1-20 μl) thermal cycling and integrated fast electrophoretic separation and detection. The detection limit of this system for multiplex amplification of genomic DNA is as low as 10-20 copies in the PCR-CE system. The preferred technology of disposable gel cartridges is a simple but very robust design approach for the manufacture of large volume types for easy-to-operate capillary gel electrophoresis (CGE) devices, which results in a remarkable background noise reduction and, consequently, an improved signal-to-noise (S / N) for high detection sensitivity of biomolecules (e.g., pathogens) at a very low cost per sample run.

[0034] Gel Cartridge C The reusable single channel pen-type gel cartridge C allows for easy plug-and-play use in a robust injection molded body with an integrated gel reservoir design incorporating a microfluidic glass capillary column 10 (e.g., 20-100 μm inner diameter (ID)) with an effective separation length of 11 cm. The shortened capillary length allows for lower operating voltages (1-15 KV) and the elimination of expensive cooling systems such as low-temperature circulating water baths. The design includes upper and lower electrodes (anode and cathode), exposed detection areas, and an embedded RFID chip / label to provide ID for the gel cartridge type and to track the number of electrophoresis runs per cartridge. Each cartridge contains a linear gel-matrix and can analyze 100-300 samples in as little as 2 minutes per sample run using as little as 1 pl directly from the PCR sample wells immediately after polymerase chain reaction. The pen-shaped cartridge design with narrow-bore capillaries facilitates sample injection from PCR sample wells directly accessible from the integrated thermal cycling module TC, which is an open system with no lid / door on the wells W of the container tray R supported on the thermal block B. The amplified PCR products are then directly injected into gel-filled capillaries containing fluorescent dyes (gel matrix) for electrophoretic analysis. The reusable / disposable gel cartridge is a simple yet very robust design approach for mass production of easy-to-operate CGE devices that result in a remarkable reduction in background noise, thereby improving S / N and resulting in high detection sensitivity of biomolecules at a very low cost per sample electrophoresis.

[0035] The pen-shaped gel cartridge is integrated with an upper / outlet buffer / gel reservoir, which is directly coupled to a modular pneumatic pump (outside the device). The pneumatic pump (or N2 gas tank) provides the air pressure required to fill the capillaries (microfluidic channels) with separation gel / buffer (dynamic coating of the capillaries). Depending on the viscosity of the separation gel / buffer, a pressure of up to 60 PSI is applied to the glass capillaries through the upper buffer / gel reservoir. Each cartridge reservoir is equipped with a built-in electrode (anode), which is automatically connected to the HV power supply for electrophoresis once installed in the device. The anode is embedded in the gel reservoir to capture the DNA fragments separated from the large pool of gel and prevent re-injection into the capillary column during the purge phase between runs. The test sample (covered with mineral oil) is introduced into the separation capillaries (microfluidic channels) by electrical injection directly from the PCR sample tray. A high voltage power supply (American Power Design) is used to deliver an electric field of 0-20 KV to the capillary for electrical injection and separation of biomolecules. An excitation LED with broadband optical energy (FWHM = 50 nm) and a viewing angle of 100 degrees is coupled to a large core excitation fiber (100-1000 μm) with a flat input end (polished or cleaved end). We use a line filter (FWHM = 2-50 nm bandpass line filter) in front of the LED before coupling the light to a 300 μm core with a 500 μm ball-end excite fiber to reduce background noise. The fluorescence emission signal generated by the separated analytes is then collected at the detection zone of the capillary using a ball-end fiber (larger core fiber with a 500 μm ball) and relayed to a detector module (using a PMT or SiPMT or CCD) incorporating an emission filter (bandpass filter) for monochromatic or dual-chromatic type detection.

[0036] PCR-CE Thermal Control Module / Thermocycler TC The PCR-CE system 100 has an integrated thermal control module TC. For PCR amplification of DNA / RNA samples, the dual thermal control module TC is in the form of a thermocycler that can heat samples, cool samples, and / or perform heating and cooling cycles of samples. Although the following discussion refers to a thermocycler TC, it should be understood that the thermocycling function is a specific control of the thermal control module TC that simply cycles the temperature, and that the temperature can also be controlled to increase and / or decrease without cycling the temperature.

[0037] 2A to 2C are respectively a perspective view, a partial perspective view, and a cross-sectional view of a thermocycle module according to one embodiment of the present invention.

[0038] The thermocycler TC includes a thermoelectric module E thermally sandwiched between a lower heat sink S and an upper thermal platform P. The thermoelectric module E can operate according to the Peltier effect, which creates a temperature difference by transferring heat between two electrical junctions when a voltage is applied across the junctions, as is well known in the art. The thermoelectric module E thus regulates / controls the temperature of the thermal platform P according to a desired heating / cooling temperature profile, which is dissipated in the heat sink S. A fan F is provided on the device housing to move air in and out of the housing to ventilate and regulate the heat of the heat sink S within the housing. In the illustrated embodiment (see also the enlarged view of FIG. 5A ), the thermoelectric module E has sub-modules E1 and E2 that are separately controllable for each half of the thermal platform P, as will be further described below in connection with the thermal platform P.

[0039] The thermal platform P has a base BP (made of metal, e.g., aluminum) that thermally conductively supports one or more thermal blocks B (made of metal, e.g., aluminum) for receiving and supporting one or more container trays R having wells W for temperature control (i.e., heating and / or cooling operations) according to one embodiment of the present invention. In the illustrated embodiment (see, e.g., FIG. 5A ), two identical thermal blocks B are supported on the base BP of the thermal platform P. Two container trays R are supported by the thermal blocks B, respectively. See FIGS. 11 and 12 for alternative embodiments of the thermal platforms P′ and P″. The thermal blocks B and the supporting base BP (and other thermal block features discussed below in connection with the alternative embodiments of FIGS. 11 and 12 ) may be separate structures thermally coupled to each other or may be one-piece monolithic structures (e.g., machined from a metal block).

[0040] The temperature of each of the thermal blocks B is separately controlled by the thermoelectric module E, more specifically by the submodules E1 and E2. As will be discussed more fully below, one thermal block (e.g., the left side of FIG. 5B) can be used for thermal treatment of samples (e.g., to prepare samples for PCR, as will be discussed more fully below), and the other thermal block B can be used for PCR thermocycling to obtain PCR products from the samples. The submodules E1 and E2 are separately controlled to achieve different temperature profiles in the corresponding thermal block B, thereby subjecting the samples in the two container trays R to different temperature profiles. The separate control of the submodules E1 and E2 may be performed by a dedicated controller and / or a controller 26 (integral or external). The thermal blocks B each include a temperature sensor (e.g., a thermocouple) for feedback of temperature conditions to control the temperature profiles of the corresponding submodules E1 and E2.

[0041] Figures 3A-3C are perspective views, Figure 3D is a top view, and Figures 3E and 3F are cross-sectional perspective views of thermal block B. Figure 4A is a top perspective view, Figure 4B is a bottom perspective view, Figures 4C and 4D are cross-sectional perspective views, and Figure 4E is a bottom view of a container tray R that can be received and supported by thermal block B for temperature control according to one embodiment of the present invention.

[0042] The vessel tray R is made of a plastic material (e.g., any injection moldable polymer with good physical strength, uniformity and smoothness of the wells W - e.g., polyurethane, PE, PTE, PTFE, urethane, etc.) that includes a plurality of wells W (e.g., 2-100 μl volume each) configured to hold fluid samples. In the illustrated embodiment, the vessel tray R includes a row of eight wells W. As clearly shown by the bottom views of FIGS. 4B and 4E, the longitudinal cross-sectional view of FIG. 4C taken along the plane of the longitudinal centerline of the center of the wells W, the cross-sectional view of FIG. 4D, and the bottom view of FIG. 4E, the outer bottom surfaces WB of adjacent wells W are joined at the midline section WM of the wells W.

[0043] As shown, to accommodate (i.e., receive and support) the wells W of the container tray R, the thermal block B comprises a body resembling a split longitudinal block having two longitudinal sides BS defining a valley, with opposing walls BF of the sides BS each having a sector-shaped concave profile that matches the external convex conical tubular shaped profile of the bottom surface WB of the wells W of the container tray R. The thermal block B receives the container tray R with the bottom outer wall WB of the wells W in contact with or closely adjacent to the inner wall BF of the thermal block B to facilitate thermal conduction between the thermal block and the wells W. The opposing walls BF are spaced apart by a tapered gap G to define a valley for accommodating the joined midline sections WM (compare the similar perspective views of FIG. 3F and FIG. 4D). In the illustrated embodiment, thermal block B is shown as being substantially symmetrical with respect to a longitudinal cross section through gap G along the center of well W (i.e., with respect to a cross section corresponding to the cross section shown in FIG. 4C ) and with respect to a cross section transverse to such longitudinal cross section (i.e., with respect to a cross section shown in FIG. 3F ). The sector-shaped profile of the opposing inner walls BF, together with the gap G between the opposing walls BF, substantially matches the shape of the outer bottom surface WB of well W in vessel tray R, allowing efficient thermal conduction between thermal block B and the walls of well W, thereby allowing efficient heating / cooling of contents (e.g., samples) within well W.

[0044] Looking into gap G from the top of thermal block B, the sector profile generally resembles a series of adjacent concave surfaces each having a cross-sectional shape of a concave curve or arc (e.g., a semicircle or portion thereof) along the interior sidewall BF of thermal block B. In the illustrated embodiment, the interior sidewall BF of thermal block B defines a row of cavities, with adjacent cavities joined / connected to accommodate a midline section WM adjacent the bottom of vessel tray R. The adjacent cavities resemble a row of adjacent conical spaces along tapered gap G (narrowing / tapering gap G toward the bottom of block B) for receiving the conical outer bottom surface WB of well W in vessel tray R.

[0045] To securely support the container tray R on the thermal block B, the container tray R is provided with a handle FH in the form of a flap depending from a longitudinal edge of the upper surface of the container tray R. Complementary cut-outs CO are provided in the outer walls of the sides BS of the thermal block B. Additionally, key slots KS are provided in the end walls of the longitudinal ends of the container tray R. Complementary end posts EP, each having a vertical key K, are provided on the outside of each end of the longitudinal gap G of the thermal block B.

[0046] 5A-5C, which are various perspective views of the container tray R supported on the thermal block B, when the container tray R is seated on the thermal block B, the wells W extend into the corresponding spaces defined by the sector walls BF, and the flap handles FH fit over the outer cutouts CO of the side surfaces BS of the thermal block B. In this position, the side walls BS of the thermal block B extend upward and are sandwiched between the outer bottom surfaces WB of the wells W and the corresponding flap handles FH. The flap handles FH resiliently grip the side walls BS of the thermal block B. Furthermore, the end walls EW of the container tray R fit over the longitudinal ends of the side surfaces BS of the thermal block B, and the keys K on the end posts EP of the thermal block B fit into corresponding key slots KS of the end walls EW of the container tray R.

[0047] In the illustrated embodiment of Figures 5A-5C, the PCR-CE device 100 has two thermal blocks B (compare with the embodiment of Figure 11, which includes one thermal block B and one preheated thermal block PB), each supporting a vessel tray R. See also Figure 6, which is a schematic diagram of a simplified PCR-CE workflow using the inventive PCR-CE system, according to one embodiment of the present invention. The thermocycler TC heats the samples (e.g., taken from a patient; 8 samples) in the wells W of the first vessel tray R (e.g., tray R on the left block B of Figure 5B) to 95 °C (by activating the thermoelectric module E) in the sample preparation stage (e.g., proteinase K treatment; this can also be done with the four vessel tubes T of Figure 11). The prepared samples can then be transferred to the wells W in the second vessel tray R (e.g., tray R on the right block B of Figure 5B) for PCR amplification processing. In the second container tray R, thermocycling (one-step RT-PCR or reverse transcription-polymerase chain reaction) is accomplished in, for example, 90 minutes (by actuating the thermoelectric module E to cycle between desired high and low temperatures) to amplify DNA / RNA fragments, followed by direct electrical injection, high-voltage separation, and fluorescence detection of the PCR products utilizing the pen-type gel cartridge of the PCR-CE system 100. The samples (i.e., PCR products) do not need to be removed from the wells W of this container tray R after the PCR process (open PCR module without lid / door) but are directly loaded into the capillary column 10 for the subsequent electrophoresis run. As shown in FIG. 5C, the cartridge C with the subordinate capillary column 10 then accesses the samples in the thermal block B after the PCR process and undergoes electrophoretic separation and analysis of the samples.

[0048] The thermal control and other processes described above may be programmed as one or more automated functions of the controller 26.

[0049] It should be noted that the PCR thermocycler module TC of the present invention is an open system that does not require a lid. The samples in the wells W of the container tray R are covered with a thin layer of mineral oil to prevent evaporation and heat loss. By using mineral oil, a separate mechanical door / lid over the PCR sample wells W is not required. In such an open system, CE can be performed with fewer PCR cycles, reducing the overall operation time (i.e., instead of performing 40 PCR cycles, 20 cycles can be performed in half the time of 90 minutes, and sample injection, separation, and detection can be completed using the high detection sensitivity CE approach enabled by the PCR-CE system 100 described herein).

[0050] In an alternative embodiment, when both thermal blocks B are used for PCR thermocycling, PCR products of up to 16 samples can be analyzed automatically using a three-axis transport mechanism TM.

[0051] Alternative Embodiments According to another embodiment of the invention, a preheating thermal block PB replaces one of the thermal blocks B in the previous embodiment. FIG. 11A is a perspective view of a thermal platform P', and FIG. 11B is a cross-sectional perspective view of a thermal block in the form of a preheating thermal block PB thermally conductively supported on a base DP of the thermal platform P'. A thermoelectric module E controls the temperature of the thermal block B'. ​​FIG. 11C is a perspective view of the thermal platform P' supporting container tubes T on the preheating thermal block PB, together with a container tray R on the thermal block B as in the previous embodiment, for PCR thermocycling. In this embodiment, the preheating process of the samples may be similar to the process described above (i.e., similar to the function of the thermal block B on the left side of FIG. 5B), but in this embodiment it is performed in larger container tubes T. This improves the convenience of the user to work with larger container tubes T (e.g., 200 μl volume). As shown in FIG. 11B, the preheat thermal block PB has a row of four conical cavities CV for receiving conical container tubes T in the form of vials with a conical bottom. The main function of the container tubes T is to be used to inactivate proteinase K. After inactivation, the user needs to transfer the samples from the container tubes T to the wells W of the container tray R in order to perform PCR-CE.

[0052] As in the previous embodiment of Figures 1-10, the respective temperatures of the pre-heated thermal block PB and the thermal block B are separately controlled by the thermoelectric module E, more specifically, by sub-modules E1 and E2 that are separately controlled to achieve different temperature profiles. In this embodiment, the temperature profile of the pre-heated thermal block PB is controlled by sub-module E1 for thermal treatment (e.g., heating and subsequent cooling) of the sample to prepare the sample for PCR, and the temperature profile of the thermal block B is controlled by sub-module E2 for PCR thermocycling (e.g., undergoing multiple temperature cycles) to obtain a PCR product from the sample. As in the previous embodiment, the pre-heated thermal block PB and the thermal block B each include a temperature sensor (e.g., a thermocouple) for feedback of the temperature state to control the temperature profile of the corresponding sub-modules E1 and E2.

[0053] Additionally, in this embodiment, the reagent tray RT' includes two additional smaller wells BW' for additional reagents that may be required for a particular CE protocol, such as alignment markers (AM) and size markers (SM).

[0054] In a further embodiment, the pre-heating thermal block PB is replaced with a different thermal block PB' having more cavities. FIG. 12 is a perspective view of another thermal platform P" according to a further embodiment of the present invention. In this embodiment, the thermal block PB' has two rows of four cavities (similar to the cavities CV in FIG. 11) for receiving similar conical container tubes T (or vials) for sample pre-heating and cooling processing. As shown in FIG. 12, the thermal platform P" includes a thermal block B similar to that in the previous embodiment.

[0055] As in the previous embodiment, the respective temperatures of preheat thermal block PB' and thermal block B are separately controlled by thermoelectric module E, and more specifically by submodules E1 and E2 which are separately controlled to achieve different temperature profiles.

[0056] Application Examples Most of the standard virus detection methods around the world use real-time PCR (qPCR). However, the operation and interpretation of real-time PCR test results require experts or well-trained technicians, and false positive results often occur. The assignee of the present invention has developed a total solution including a direct "RT-PCR" (using a pre-programmed chip for 8 sample runs) integrated with a portable PCR-CE system 100 to solve the problems associated with traditional real-time PCR systems. Furthermore, the PCR-CE detection platform in the PCR-CE system 100 utilizes suitable direct "RT-PCR" reagents, which eliminates the need for nucleic acid extraction and purification and provides a unique solution for rapid pathogen detection with reproducible results by non-technical operators. Moreover, the PCR-CE system 100 platform of the present invention has a much higher detection sensitivity and provides better detection capability for the early stage of infected patient screening (i.e., pathogen detection on site), thus solving the false positive problem associated with real-time PCR systems. Moreover, the platform of the present invention is suitable as a reconfirmation platform after real-time PCR, more efficiently increasing the reliability of disease diagnosis.

[0057] Such a system performs the test automatically by mixing the swab with our lysis buffer and transferring 2 microliters of the lysed sample directly onto the PCR-CE system 100 .

[0058] Example: PCR-CE system for detecting SARS-CoV-2 As an example, the compact detection platform in the PCR-CE system 100 can provide fast, accurate and cost-effective results, which is suitable for distributed testing applications for COVID-19.

[0059] Bioptics, Inc., the assignee of the present invention, has developed the Qexp-MDx Direct SARS-CoV-2 Detection Kit-B, which includes an assay and positive controls for a direct multiplex one-step reverse transcription PCR (RT-PCR) test for the qualitative detection of RNA from SARS-CoV-2 in oral specimens from individuals suspected by healthcare professionals of COVID-19. Results are for the identification of SARS-CoV-2 RNA, which is generally detectable in oral specimens during the acute phase of infection. A positive result indicates the presence of SARS-CoV-2 RNA. Clinical correlation with the patient's medical history and other diagnostic information is necessary to determine the patient's infection status. A positive result does not exclude bacterial infection or co-infection with other viruses. The detected material may not be the definite cause of disease. Laboratories within the United States, Europe, Asia and the region are required to report all positive results to the appropriate public health authorities. Additionally, a negative result does not exclude SARS-CoV-2 infection and should not be used as the sole basis for patient management decisions. Negative results must be combined with clinical observations, patient history, and epidemiological information.

[0060] The BiOptic Qexp-MDx Direct SARS-CoV-2 Detection Kit-B contains the following components: a. Direct Lysis Assay Sample lysis assay contains collection buffer, proteinase K, RNase inhibitor, and RNA lysis buffer. b. Direct SARS-CoV-2 Kit Assay Direct SARS-CoV-2 Multiplex One-Step RT-PCR Assay: The multiplex assay contains a primer set specific for the envelope region of the SARS-CoV-2 genome (E=129bp) and a primer set for an internal control specific for the human RNase P (170bp) gene. c. Direct SARS-CoV-2 Kit Positive Control: The main component of the positive control is a synthetic RNA containing the target region of SARS-CoV-2 and human RNase P.

[0061] RNA from buccal specimens can be released by using the required RNA lysis buffer. RNA from buccal sample lysates is reverse transcribed into cDNA and amplified by multiplex one-step RT-PCR on a PCR thermal cycler. In this process, primers anneal to specific genes of SARS-CoV-2 and human internal controls as follows: E (envelope) protein and human RNase P.

[0062] FIG. 7 is a schematic diagram of a PCR-CE workflow for oral samples using the automated system of the present invention, according to one embodiment of the present invention.

[0063] FIG. 8 is a block diagram of the complete process for introducing a sample into the PCR-CE device, preparing the sample by heating, and proceeding through CE analysis to RT-PCR and end-point PCR.

[0064] Direct oral sample lysis and proteinase K treatment Figure 9 is a schematic diagram of an intra-oral sample collection procedure according to one embodiment of the present invention. Figure 10 is a schematic diagram of a sample preparation process for an intra-oral sample according to one embodiment of the present invention.

[0065] Once the buccal sample lysate is prepared, 20 μL of the buccal mixture (RNA lysis buffer) is transferred to a clean vessel (e.g., well W in the left vessel tray R in the embodiment of FIG. 5B, or vessel tube T in FIG. 11C), then heated to 95° C. for 5 minutes to inactivate the proteinase K, and then cooled to 4° C. by the thermal control module TC. The PCR-CE instrument comprises an 8-sample capacity vessel tray R for the thermocycling (PCR) stage (see, e.g., FIG. 5B and FIG. 11C).

[0066] Exemplary Thermal Cycling Operation In the illustrated embodiment, the built-in thermocycler module TC (Peltier heater and cooler) in the PCR-CE device 100 is equipped with an 8-well sample tray (receptacle tray R in FIG. 5C or FIG. 11C) to perform the direct SARS-CoV-2 multiplex one-step RT-PCR step. Predefined PCR protocols can be preprogrammed or stored, for example, on a USB memory key or SD memory card, which are inserted into the USB port DU or SD card slot SL in the device housing to run the programmed test (FIG. 1A). The following table shows the PCR cycles preprogrammed, for example, on a USB memory key or SD memory card, for the operation of the thermocycler. In one embodiment, in the following table, the memory card can be preprogrammed to include, as an example, the number of cycles for each step specific to the application of the MDx. [Table 1]

[0067] The post-PCR samples are then analyzed by the PCR-CE system 100. Once the RT-PCR process is completed, the PCR products are automatically injected into a capillary gel cartridge and analyzed individually by the automated PCR-CE system (e.g., FIG. 5A). The results are then analyzed by the data analysis software, and a report is generated by displaying the size (retention time) of the target sequence or calling the peaks (RNase P and E genes). The test results can be displayed in electropherogram and gel image formats by the data analysis software.

[0068] In summary, the PCR-CE platform of the present invention utilizes direct "RT-PCR" reagents, which eliminates the need for nucleic acid extraction and provides a unique solution for rapid pathogen detection with highly sensitive and reproducible results by non-technical operators. Moreover, it solves the problem of false positives associated with traditional real-time PCR systems, as the platform has much higher sensitivity and provides better detection capabilities. Moreover, the platform of the present invention is suitable as a reconfirmation platform after real-time PCR, more efficiently increasing the reliability of disease diagnosis. Advantages include: Direct RT-PCR amplification. No RNA extraction and purification is required. Oral or nasal swabs are soaked in a lysis buffer that releases nucleic acids. The RNA in these lysates can then be used to set up a reverse transcriptase PCR amplification. b. Reverse transcriptase PCR amplification is performed on a PCR-CE system, eliminating the need for expensive real-time PCR equipment. c. The PCR products generated after all cycles are then analyzed by a fully automated capillary gel electrophoresis (CGE) platform (PCR-CE system 100) that utilizes reusable pen-type gel cartridges. Results for up to eight samples can be obtained quickly.

[0069] Although the present invention has been particularly illustrated and described with reference to preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail can be made therein without departing from the spirit, scope and teaching of the invention.

Claims

1. 1. A thermal control module for a bioseparation system, comprising: a thermal platform thermally coupled to the thermoelectric module; A heat sink; and a thermoelectric module thermally conductively coupled between the base of the thermal platform and the heat sink for heating / cooling the thermal platform according to a desired heating / cooling temperature profile; The thermal platform comprises: Base; and At least one thermal block thermally supported on the base. Including, The thermal block is configured to receive at least a vessel containing a sample, the thermal block comprising a body including a split longitudinal block having two longitudinal sides defining a valley, the opposing walls of the sides each having a sectorial concave profile that matches a convex conical tube-shaped profile of a bottom surface of a well of the vessel tray. A thermal control module comprising:

2. 2. The thermal control module of claim 1, wherein the opposing walls are spaced apart by a tapered gap to define the valley to accommodate the joined midline sections of the wells, and the sectorial profile of the opposing walls, together with the gap between the opposing walls, substantially matches the profile of the exterior bottom surfaces of the wells of the container tray, allowing efficient thermal conduction between the thermal block and the walls of the wells, thereby efficiently heating / cooling contents within the wells.

3. 3. A thermal control module as described in claim 1 or 2, characterized in that when viewed from the peak of the thermal block towards the valley, the sector profile generally resembles a series of adjacent concave surfaces each having a cross-sectional shape that is a concave curve or arc (e.g., a semicircle or portion thereof) along opposing walls of the thermal block.

4. 4. The thermal control module of claim 1, wherein opposing walls of the thermal block define a row of cavities, adjacent cavities joining / connecting to accommodate adjacent midline sections at the bottom of the container tray.

5. 5. The thermal control module of claim 4, wherein the adjacent cavities resemble a row of adjacent conical spaces along the tapered gap (the gap narrowing / tapering toward the bottom of the block) to receive the conical outer bottom surfaces of wells in the container tray.

6. A thermal control module as described in any one of claims 1 to 5, characterized in that the thermal block receives the main body of the container tray and the bottom outer wall of the well contacts or is closely adjacent to an opposing wall of the thermal block to promote thermal conduction between the side of the thermal block and the well.

7. 7. The thermal control module of claim 1, wherein the thermal platform comprises two thermal blocks, each thermal block being thermally conductively supported on a different section of the base of the thermal platform, and the thermoelectric module comprises separate heating / cooling sub-modules that heat / cool different sections of the base of the thermal platform according to different heating / cooling temperature profiles, thereby heating / cooling the thermal blocks according to the different heating / cooling temperature profiles, the sub-modules being under separate control to achieve different heating / cooling temperature profiles of corresponding thermal blocks, thereby subjecting the sample in the container to different temperature profiles.

8. The container comprises: the exterior bottom surfaces of adjacent wells joined at midline sections of said wells; a flap handle in the form of a flap depending from an edge of an upper surface of the container tray; and a key slot in an end wall at a longitudinal end of the container tray; Including, The thermal block further comprises: A notch provided in the outer wall of the side of the thermal block; and end posts each having a vertical key disposed outside each end of the gap in the thermal block; Including, The notches receive flap handles of the container tray to resiliently grip the side walls of the thermal block, and keys on the end posts engage corresponding key slots in the end walls of the container tray.

8. The thermal control module according to claim 1, wherein the thermal control module is a thermal control module having a first insulating layer and a second insulating layer.

9. The thermal control module of any one of claims 1 to 8, wherein the thermal block and base are separate structures or an integral monolithic structure that are thermally coupled together, and the thermoelectric module is thermally sandwiched between an upper thermal platform and a lower heat sink.

10. A thermal control module as claimed in any one of claims 1 to 9, characterized in that the thermal platform, thermally conductively supported on the thermal platform base, comprises a second thermal block having a body having a plurality of cavities for receiving container tubes.

11. The thermal control module of any one of claims 1 to 10, characterized in that the thermal block is configured to support multiple vessels with wells in the vessel tray or multiple vessel tubes for heating / cooling.

12. 1. A bioseparation system comprising: Chassis; a cartridge for supporting a capillary column for capillary electrophoresis, the cartridge body being supported by said chassis; A thermal control module according to any one of claims 1 to 11, supporting at least a vessel containing a sample against the extended end of the capillary column, the thermal control module heating / cooling the thermal platform within the thermal control module according to a desired heating / cooling temperature profile; a separation mechanism for effecting biological separation within the capillary column after loading of a sample subjected to heating / cooling from the container tray; and A controller for controlling the separation mechanism to perform separation A bioseparation system comprising:

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