JP2007516449A - Bioanalytical cartridge recording and protection mechanism - Google Patents

Abstract

  A reusable bioanalytical cartridge is provided that includes a built-in mechanism for recording various parameters and usage data. The recording mechanism includes a “smart key” which is a non-volatile rewritable memory associated with the cartridge to provide automatic recording dedicated to the cartridge. The key is physically connected to the cartridge with good high voltage insulation properties. When a cartridge is used with a device, the associated key is inserted into the I / O interface to communicate with the device. The device performs “authentication” of the cartridge and is consistent to determine whether the particular cartridge has the correct characteristics (eg, gel chemistry, serial number, patient ID) for the particular sample analysis You may comprise so that a check may be performed. In addition, the device may communicate / record information regarding cartridge usage (eg, usage history, test parameters, and possibly test results). Such information provides an update to information stored from previous use of the cartridge.

Description

  The present invention relates to a reusable specimen cartridge for use in a bioanalytical system, and more particularly to a bioanalytical cartridge including a recording mechanism and a protection mechanism for the contents thereof, and more particularly such a recording mechanism and contents. The present invention relates to a capillary electrophoresis cartridge having a protection mechanism.

  Bioanalysis, such as DNA analysis, is rapidly moving from pure scientific pursuit of accuracy to routine procedures with proven and improved reliability. Medical researchers, pharmacologists, and forensic investigators all use DNA analysis to engage in their tasks. At present, due to the complexity of the equipment for detecting and measuring DNA samples and the difficulty of sample preparation, existing DNA analysis procedures are often time consuming and expensive. Therefore, it is desirable to reduce size, number of parts and equipment costs to facilitate sample handling during the process, and it is generally desirable to have a simplified, low cost and sensitive detector. .

  One type of DNA analyzer separates DNA molecules by electrophoresis. Electrophoretic techniques can be used to isolate DNA fragments in genotyping applications, including human identification tests, expression analysis, pathogen detection, mutation detection and pharmacogenetics studies. The term electrophoresis refers to the movement of charged molecules under the influence of an electric field. Electrophoresis can be used to separate molecules with equivalent charge mass ratios and different masses. A DNA fragment is an example of such a molecule.

  There are many commercially available devices that apply electrophoresis to analyze DNA samples. One such is a capillary electrophoresis (CE) device. By applying electrophoresis to a quartz glass capillary column with a separation support (eg, buffer solution, gel matrix with a specific gel chemistry), the sample size requirements are very small, Separation speed and resolution can be increased several times compared to slab gel electrophoresis. In CE, DNA fragments are detected by illuminating the components separated from the phosphor-tagged sample through the capillary wall and detecting the fluorescence emission produced by the incident light or by using an absorption measurement method. There are many cases. For the type of fluorescence detection, the radiation intensity represents the concentration, amount and / or size of the components of the sample. In the past, laser induced fluorescence (LIF) detection methods have been developed in CE devices. Fluorescence detection is a detection method that is often selected in the field of genomics and proteomics because it has excellent sensitivity compared to other detection methods.

  The capillary column may be part of a removable cartridge that can be separated from the system for storage, transportation or reuse. Since different cartridges may be assembled with different contents, such as those with different gel chemistry, the contents of the cartridge should be identified. A visual indicator may be provided to identify the cartridge and its contents. For example, a label (for example, a barcode) or an individual information sheet may be attached to the cartridge. In addition, individual logs may be associated with individual cartridges to record cartridge usage in terms of cartridge reusability and lifetime of cartridge contents or prescribed usage. However, the label only has information at the time it is attached to the cartridge. The individual information sheets are likely to be mistakenly attached to different cartridges of different gel chemistries, for example, or are inconsistent. Information updates are usually done manually by the user by writing to the cartridge, re-labeling, or leaving an accurate record in the individual log. In the laboratory environment, when important bioanalyses (applications such as clinical diagnostics where FDA orders proper record keeping procedures, ie patient records / information records) are performed, manual updates to record and log information The procedure has the potential for error. Therefore, it is preferable to have a reusable capillary cartridge that includes a mechanism for automatically recording information associated with individual cartridges for use in a CE device.

  The cartridges are assembled with capillaries filled with a separating support of a nature that can deteriorate upon prolonged exposure in the environment. Taking into account that reusable cartridges may be stored between uses, the separation support exposed at the tip of the capillary will degrade, such as drying of the gel matrix, and clogging the capillary Is very likely to cause problems when the cartridge is reused. It is desirable to improve the life of the cartridge and its contents during storage.

  The present invention is a reusable and replaceable cartridge for use in a bioanalytical system, including a built-in mechanism for reliably recording various parameters and data, and means for protecting its contents from damage and drying. I will provide a. The present invention also provides a bioanalyzer equipped with an interface that supports the reusable cartridge recording mechanism.

  In one aspect of the invention, the reusable cartridge includes a recording mechanism that stores relevant data regarding the cartridge and its attributes, such as contents and usage. The cartridge is portable, recyclable, reusable and interchangeable with other cartridges having different types of channels (eg, separation media, channel size, inner wall coat, etc.). It defines a separation channel, which may be a capillary supported on the cartridge or a microcolumn defined on the cartridge. In one embodiment of the present invention, the recording mechanism is non-volatile rewritable such as a “smart key” (eg, having an EEPROM) associated with the cartridge to provide automatic recording provided for the cartridge Includes memory. The key may be physically connected to the cartridge (eg, attached to the cartridge body or with a string) or may be separate from the cartridge. When a cartridge is used in a device, its associated key is inserted into the device's data interface (eg, reader / writer) to communicate relevant information about the cartridge and its contents to the device. The apparatus may be configured to authenticate the cartridge and perform a consistency check to determine whether the particular cartridge has the correct characteristics for the analysis of the particular sample being performed. In addition, the device may communicate / record information regarding cartridge usage (eg, when and how the cartridge was used, usage history or number of runs, test parameters and possibly test results). Such information updates the information stored with previous use of the cartridge.

  In another aspect of the invention, a cartridge interface module that is part of a dedicated bioanalyzer is provided. In one embodiment of the invention, the cartridge interface module comprises a cartridge coupling interface and an input / output (I / O) port. The interface module is part of a portable bioanalytical system and is designed, for example, for single or multiple capillary cartridges used in CE analysis. In yet another embodiment, the bioanalyzer reads and writes data with respect to the cartridge recording device in relation to the operation of the device.

  In yet another aspect of the invention, the fragile capillary tip of the capillary cartridge is protected from damage. In one embodiment, a cartridge stand is provided in which the capillary cartridge is held in an upright or vertical position so that the capillary tip is immersed in a compatible material designed to keep the contents of the tip from drying. . In other embodiments, a package container and tip cushion / protector are provided to protect the cartridge and its contents from damage and drying during storage and shipping.

  This application claims priority from US Provisional Patent Application No. 60/532671 filed on Dec. 23, 2003. This provisional patent application is hereby incorporated by reference in its entirety as if fully set forth herein.

  No. 10/059993 (“multi-channel bioseparation cartridge”) filed Jan. 28, 2002, and US patent application No. 10/973828 filed Oct. 25, 2004. ("Integrated Bioanalysis and Sample Generation System"), U.S. Patent Application No. 10 / 31,8033 ("Photodetection Alignment Coupling Device"), filed December 13, 2002, on December 15, 2003. One of the filed international patent applications US 03/39971 (“light detection alignment coupling device”) and US patent application Ser. No. 10 / 823,382 (“multi-capillary electrophoresis cartridge”) filed April 12, 2004. Part continuation applications, all of which are applications of Biocal Technology, the assignee of the present invention.

The present invention also relates to US Pat. No. 6,828,567, filed by Biotech, the assignee of the present invention.
All other applications, patents, documents and references mentioned in the above application and the following disclosure are hereby incorporated by reference in their entirety as if fully set forth herein.

  For a full understanding of the nature and advantages of the present invention, reference should be made to the following detailed description, taken together with the accompanying drawings, as well as the preferred mode of use. In the drawings, like reference numerals designate the same or similar parts throughout the drawings.

  The invention is described below with reference to various embodiments in conjunction with reference figures. While the invention has been described in terms of the best mode for carrying out the objects of the invention, various modifications can be made in light of these teachings without departing from the spirit and scope of the invention. This will be apparent to those skilled in the art.

  The present invention provides a reusable capillary cartridge that includes a built-in mechanism for reliably recording various parameters and data for use in a bioanalytical system, and further means for protecting its contents from damage and drying. . The present invention also provides a bioanalyzer equipped with an interface that supports the reusable cartridge recording mechanism. In one aspect of the invention, a reusable cartridge includes a recording mechanism that stores relevant data regarding the cartridge, its contents, and usage. In another aspect of the invention, a cartridge interface module that is part of a dedicated bioanalyzer is provided. In yet another aspect of the invention, the fragile capillary tip of the capillary cartridge is protected from damage.

  For purposes of explaining the principles of the present invention without limiting it, the present invention will be described with reference to an embodiment directed to CE analysis. In an exemplary embodiment, the present invention provides a recording mechanism (data key) for a reusable CE cartridge supported by an integrated and automated multi-channel CE system.

  Biocal Technology, the assignee of the present invention, has developed a CE-based automation device (eg, model HDA-GT12 DNA analyzer system). An exemplary embodiment of an automated device is based on Biocal's CE device, which is used for real-time fluorescence analysis to form a highly sensitive and accurate pathogen detection (gene analysis) system. It incorporates a low-cost, high-sensitivity photodetection technology, an integrated reagent cartridge, and an interface that supports the recording key along with the microfluidic electrophoresis principle. The system is designed for high throughput, easy to use, portable, inexpensive, very robust and for field work and field applications.

  A cartridge developed by Biocal (eg, model GC-500 or GC-10K) is designed to be supported by the device, along with all the important cartridge members arranged and connected to the support elements in the device. Has been. The cartridge is held against a sample tray that is movable relative to a capillary separation channel within the cartridge. The recording data key can be inserted into the reader / writer of the apparatus.

Overview of CE System FIG. 1 is a schematic illustration of a capillary electrophoresis (CE) system 200 according to one embodiment of the present invention. CE system 200 generally has a capillary separation column 22 (eg, 200-500 μm OD) that defines a separation channel 36 (eg, 25-200 μm ID). The capillary column 22 may be made of quartz glass, glass, polyimide or other plastic / ceramic / glassy material. The inner wall of the separation column 22 (ie, the inner wall of the separation channel 36) may be coated with a material capable of accumulating static electricity to facilitate electrokinetic transfer and / or electrophoresis of sample components. Separation channel 36 is filled with a separation support, which may be a running buffer or, in the illustrated embodiment, a known “sieving” gel matrix. For radiation-induced fluorescence detection, the gel matrix includes known fluorescent probes such as ethidium bromide.

  One end of the capillary column 22 is immersed in a reservoir 28 for running buffer / gel 34. The other end of the capillary column 22 is connected to a sample cartridge 26. It should be understood that other detection configurations are implemented in a system similar to the CE system 200. The radiation detector 24 is arranged outside the transparent part of the capillary wall in the detection zone 30. The excitation fiber 16 extends from a radiation source 18 (eg, an LED or laser) and is directed to the detection zone 30 from outside the column wall. Electrodes 12 and 14 that are part of the cartridge assembly are connected to a buffer reservoir 26 and a gel reservoir 28 to complete the electrophoresis path.

Overview of CE separation and analysis During operation, biological samples (eg, DNA / RNA samples) prepared in the sample cartridge 26 can be obtained in a number of ways (eg, electrokinetic injection from a sample reservoir). Guided to the distal end of the capillary column 22 away from the detection zone 30. The sample binds the fluorescent probe to the gel matrix supported by the capillary column 22.

  When a DC voltage (eg 1-30 KV) is applied between the electrodes 12 and 14, the sample moves along the separation channel 36 under the applied voltage (eg negatively charged DNA As shown in FIG. 1, proceed through a sieving gel with an integrated die matrix / fluorescent probe towards the positive electrode) and separate into bands of sample components (DNA fragments). The extent of separation and the distance traveled along separation channel 36 depends on a number of factors, such as sample component mobility, sample component mass and size or length, and separation support. The driving force in the separation channel 36 for sample separation can be electrophoresis, pressure or electroosmotic flow (EOF) means.

  When the sample reaches the detection zone, excitation radiation is directed through the excitation fiber 16 in that detection zone. Sample components emit fluorescence with an intensity proportional to the concentration of the individual sample components (proportional to the amount of fluorescent tag substance). The detector 24 detects the intensity of the fluorescence emitted at a wavelength different from the wavelength of the incident radiation. The detected emitted light can be analyzed by known methods. For an automated system, a controller 32 (described below in connection with FIG. 5) on the electronic board 64 (FIG. 4) controls the operation of the CE system 200.

Capillary Cartridge with Data Recording Key FIG. 2 is a perspective view of a CE cartridge having a data recording key according to one embodiment of the present invention.
Multichannel capillary cartridge 200 is defined by capillaries 140 held in the cartridge body and includes 12 detection zones (represented schematically as 30 in FIG. 1). The data key 500 is associated with the cartridge 100 (eg, by a string or code 510 as shown). Details regarding the data key 500 will be described later. The cartridge 100 includes a 12-channel quartz glass capillary array that is disposable and / or portable and used as part of the replaceable cartridge assembly 100 for sample separation and detection. The cartridge 100 shown in FIG. 2 holds twelve capillaries 140 having a length of 12-18 cm. The cartridge 100 is integrated with a buffer reservoir port common to all capillaries 140, which is inert, interchangeable, or replaceable with non-reactive gases (eg, nitrogen, compressed air, CO _2, etc.). The interface mechanism 300 directly connects to a compressed gas source module 78 such as a compressed gas cartridge or a pressure pump. Appropriate pressure piping is provided including tubes, pressure valves and solenoid controls (as it is well known to those skilled in the art to configure such piping to provide the functionality, features and operation of the system 200 disclosed herein, Details of such piping are omitted). The pressure source 78 fills all 12 capillaries with the “sieving” gel contained in the reservoir 130 and provides the necessary gas pressure to remove the previous run gel from the capillary during the refill process. Depending on the viscosity of the gel, pressures up to 40 PSI may be applied to the capillary 140 through the gel-filled reservoir 130.

  The cartridge gel reservoir 130 is mounted on a common anode electrode (not shown, but equivalent to the anode 14 of FIG. 1) for all twelve capillaries, and when attached to the system 200, The interface mechanism 300 automatically connects to a high voltage supply 76 for electrophoresis (FIG. 2). A structure adjacent to the cartridge 100 may be provided with a fan or a Peltier cooler (not shown) for adjusting the temperature of the cartridge. In addition or alternatively, the cartridge may have vents (inflow and outflow) for air circulation (temperature-controlled air to be introduced into the cartridge from the device side). Depending on the heat generated during CE separation, the auxiliary cooling mechanism may not be provided and the cartridge may simply be exposed to ambient temperature.

In one embodiment, the cartridge 100 is received by an automated CE system 200 as shown in FIGS. The power supply 66 (FIG. 4) provides DC power to the CE system 200 for supply to the cartridge, as will be described below.
For further details of the cartridge, reference may be made to co-pending US patent application Ser. No. 10/059993, which is hereby incorporated by reference in its entirety.

Data Key According to an embodiment of the present invention, the capillary cartridge 100 includes a recording mechanism that includes an EEPROM serial memory key 500 that is attached to the capillary cartridge 100 with a string or cord. This serial memory key (for example, manufactured by Data Key Electronics) is a portable data key that allows data to be stored and carried. Each of these devices has a non-volatile, serial micro-wired EEPROM that can be read, erased and written through an I / O port 400 (FIG. 4) located in the CE device 200. The key 500 is packaged to include memory and appropriate conductive contacts or leads for interfacing with an external reader / writer at the I / O port 400 (discussed below in connection with FIG. 4). The data key 500 requires about +5 V and operates by directly connecting to the I / O port 400 of the CE device 200. It should be noted that other types of data keys including magnetic recording memory, optical recording memory, etc. may be used instead.

  The code 510 is used to physically attach the data key 500 to the capillary cartridge 100 so that the data in the data key 500 can be identified as that of the capillary cartridge 100. The code 510 also has sufficient slack to allow the data key 500 to be inserted into the electrically protected I / O port 400, which I / O port 400 is a memory during the high voltage electrophoresis process. It is physically isolated from the cartridge coupling interface 300 (described below) to prevent loss or memory corruption. In other embodiments, for a cartridge designed for use in a low voltage device environment, a data key may be physically attached to the cartridge by gluing, or formed integrally or as an integral part of the cartridge body. May be. In addition, although a string is shown in the exemplary embodiment, depending on the application, the data key is separated from the cartridge as long as the data key is associated with the cartridge in some way, such as physical marking, labeling, etc. May be.

  In one embodiment, the data key 500 is used to hold data regarding cartridge attributes, characteristics and / or configuration. Such data includes one or more of the following. Model number, serial number, patient / subject ID with cartridge specified, cartridge type (eg, capillary channel number, capillary channel size, gel chemistry type), date of manufacture, chemistry lot number Etc. Also, pre-programmed test protocols, design specification limitations, cartridge usage limitations or restrictions (eg, expiration date, maximum operating voltage, maximum number of runs, maximum usage time, scientific suitability, device suitability, application Method / sequence procedures / settings associated with the specification, test protocol, compatibility with other analysis parameters, user authority class, etc.), and when the cartridge is first used or specific / specification advance A programmed method / sequence procedure / function may include other data used to “initialize” the device or / and cartridge when called by the reader / device. A programmed test protocol is a sequence of programmed specifications / procedures that can be read by the instrument / software as the cartridge is connected for use / analysis (eg, method = removal + pre-release ( Solution wash) + DNA / sample release + in-buffer separation) with preprogrammed time and potential differences may be included to prevent end-user misuse and / or misuse of the cartridge. In addition, it extends the lifetime / resolution quality / consistency of the detected DNA fragments.

  In other embodiments, the data key 500 is used to hold usage data that is updated with each use. For example, the data may be updated for one or more of the following: That is, the number of executions of electrophoresis applied, execution type, execution ID, patient / subject ID, execution protocol, execution conditions and parameters, use date and time, individual execution time and cumulative execution time, applied execution voltage / Current, device system ID, user or patient ID, etc. By recording the usage details, the user (or the apparatus 200) can determine the remaining life of the cartridge by considering factors such as execution time and execution conditions. By storing the system ID, the use of the cartridge can be tracked. For example, if a cartridge recall problem occurs, it is possible to quickly identify the executions made with a particular cartridge on various devices, and the results of those executions can be used to determine the impact of the problem with that cartridge on the analysis results. Can be audited to judge. Alternatively, patient test data / results can be easily tracked by having a patient ID. If it is desirable to use a particular cartridge exclusively for a particular device, the data key may be “locked” to work only with the particular device on first use. A “lock” code associated with the device can be stored in the data key.

In yet other embodiments, the data key 500 may store all or some results of the performed execution.
The data key 500 can be read / written by the I / O port 510 of the apparatus 200 or a dedicated reader / writer (not shown).

Cartridge stand FIG. 6 shows a capillary cartridge with attached recording mechanism placed on a capillary cartridge parking stand 600. Stand 600 includes two supports 605 having a notch 607 spaced apart on base 606 to receive cartridge 100. In the embodiment shown in FIG. 6, the stand 600 is designed to support two cartridges 100.

  In one embodiment of the invention, the parking stand 600 is designed to keep the cartridge 100 in an upright (vertical) position, facilitating gel movement within the microchannel of the capillary 140. Capillary cartridge 100 is kept ready for use in a bioanalytical system by maintaining stable and reliable capillary operating conditions for gravity feeding of the gel in the microchannel. For example, the gel matrix is held full of coated capillaries 140 to maintain coating integrity.

  The parking stand 600 is designed to have a microwell liquid slot 610 at the bottom of the stand where the capillary tip and surrounding electrodes are inserted while the cartridge 100 is in the parking position. Well 610 may be filled with a Biocal wash solution (Product No. GCW-5000) or filled with other liquids such as mineral oil to protect the gel matrix from drying and keep the tip of the capillary much wet. May be. Alternatively, pastes, non-dry gels or concentrated oil type reagents may be used for well 610. The reagent in the well 610 of the parking stand 600 is designed to have chemical properties that are compatible with the gel solution held in the capillary cartridge 100.

Sealing of Capillary Tip FIG. 7 is a perspective view of a capillary cartridge 100 having a capillary tip covered with a protective cap 710 having a sealing material for protecting the tip from early drying. In one embodiment, the protective cap 710 has a capsule structure similar to a pharmaceutical soft gel capsule and has a thin sealed capsule with a sealant. The capsule may be formed of a plastic agent or a silicone agent. The sealed / closed capsule of cap 710 is filled with mineral oil or other gel compatible solution or paste. In order to use the cap 710, a small hole may be formed in the capsule with a hole punch such as a pin before inserting the tip of the capillary, or the tip of the capillary 140 to which the cap is attached is attached to the capsule. Small holes may be formed by directly drilling holes. The elasticity of the thin capsule captures the capillary tip.

In other embodiments, the protective cap 710 may have an open capsule filled or coated with a thick sealant such as a gel compatible paste or gel.
In a modified embodiment, not shown, the cap 710 may be integrated into a single large one-piece capsule seal cap having a separate capsule compartment corresponding to each capillary 140 in the cartridge 100, or the cartridge It may be integrated into a single elongated capsule that covers all or a group of capillaries within 100. Alternatively, the protective cap may be in the form of an elongated well (similar to the well 610 of FIG. 6) or trough filled with a compatible sealant. In still other embodiments, the base 606 of the stand 600 can include an opening sized to receive an elongated cap. In other words, in the modified embodiment of FIG. 6, a removable trough is defined, as schematically shown by the dotted line 620, which is received at a compatible opening in the base of the stand 600. The cartridge 100 may be removed or may be placed on the stand 600 together with a one-piece protective cap at an appropriate position at the tip of the capillary.

Cartridge Transport Package As shown in FIG. 8, the cartridge 100 having the protective cap shown in FIG. 7 is stored in a protective case 700 for storing and transporting the cartridge 100, thereby further preventing physical hazards. Protected. Case 700 may be formed of a molded rigid plastic or semi-rigid plastic such as ethylene, polyethylene, PVC, or the like. At least one of the two parts of the case 700 is molded into a shape that matches the outer shape of the cartridge 100, and the two parts are shaped and sized so that they can be closed together like a shell. Alternatively or additionally, the case 700 may include a data key 500, a small tool, a solution dispensing pipette, a DNA / calibration marker, a microtiter sample plate, a reagent well, a spare protective cap 710, and other replenishments that complement the use of the cartridge 100. A predetermined opening or well 702 may be included to hold and / or receive items such as items.

  In other embodiments not shown, the protective case 700 may include a well (not shown) filled with a gel compatible sealant so that the tip of the capillary 140 is placed when the cartridge 100 is placed in the case 700 without the cap 10. The part covers the protective sealant. This can be viewed as a cartridge 100 container having a cartridge holder similar to the parking stand 600 of FIG. Furthermore, the protective case may be formed using a known method so as to protect the capillary cartridge 100 and its recording device 500 from electrical damage caused by electrostatic discharge.

Multi-capillary cartridge-based CE system FIG. 4 is a schematic perspective view of the internal components of a CE system 200 (eg, a DNA analyzer). FIG. 3 is an external view of the system. The CE system 200 incorporates an interface mechanism 300 according to one embodiment of the present invention. The interface mechanism 300 supports the multi-channel cartridge 100 according to one embodiment of the present invention, facilitates handling of the multi-channel separation column, and easily optically couples its detection area to the detection optical system of the CE system 200. Make it possible.

  The fully automated DNA analysis system 200 has a base 74 that supports an XZ mechanism module 80 having a sample tray support frame 81. The X-Z mechanism 80 supports and moves the buffer plate 70 relative to the multi-capillary cartridge 100 supported by the interface mechanism 300, and is a sample holder (eg, 96 wells) held in the optional PCR sample preparation device 250. The microtiter plate 72) is supported and moved. In particular, the mechanism 80 includes an X mechanism 82 that moves the support frame 81 in the X direction with respect to the cartridge 100, and a Z mechanism 83 that moves the cartridge in the Z direction with respect to the support frame 81. The PCR sample preparation device 250 is controlled by the PCR thermoelectric controller 68 (FIG. 5). For further details regarding the PCR sample preparation device 250, reference may be made to US patent application Ser. No. 10/973828, which is hereby incorporated by reference in its entirety.

Cartridge interface mechanism The cartridge interface mechanism 300 includes an I / O port 400 for reading / writing the data key 500. The I / O port 400 may include any reader / writer that is compatible with the data key 500. The data key 500 is inserted into the I / O port 400 after the cartridge 100 is supported by the cartridge interface mechanism 300. The read / write operation of the I / O port 400 is controlled by the controller 32 (described below).

  Other structures and operations of the CE system 200 interface mechanism may be referred to US patent application Ser. No. 10 / 823,382, which is hereby incorporated by reference in its entirety. The cartridge interface achieves a quick and reliable interface connection with the disposable gel held in the capillary cartridge 100. These interface connections include gas pressurization connections, high voltage connections and precision optical connections. The interface also provides accurate and repeatable mechanical alignment of the cartridge to the correct position of the cartridge components with respect to the support member in the CE system 200, for example, a 96-well titer plate. Aligning the tip of the capillary with respect to the external sample or buffer reservoir. In addition, the interface provides separate electrical, optical and pneumatic connections for each separation channel, so that channel-to-channel isolation from both electrical and optical crosstalk and from high voltages. Provides insulation for the rest of the device.

Detection System US Pat. No. 6,828,567, which is hereby incorporated by reference in its entirety, is more specifically directed to a time division / time multiplexing detection scheme that can be employed in CE system 200.

Control of the automation system 200 The CE system 200 provides an integrated controller for operating the various components of the system. The operation of the CE system 200 including the interface mechanism 300 having the I / O port 400, the detection system, the power supply, the XY control system, etc. is linked with the external user control interface in order to coordinate the functions described here. Controlled by a controller 32 (for example, a PC 918).

  Referring again to FIG. 5, a block diagram of the controller 32 of the CE system 200 is shown according to one embodiment of the present invention. The controller 32 transmits a signal to each part of the CE system 200 according to a command from the CPU 910 and receives a detection signal received from the detector 24 (for example, PMT) coming from the LEDScan PCBA interface 914 that receives the signal from each part. A processor is provided as part of an A / D board (LED processor PCBA) 912 including a CPU 910 that converts the signal into a signal. The A / D (LED processor PCBA) interface 912 includes at least a high voltage source 76, an air compressor 78 (hidden in the illustration of the interface mechanism 300 in FIG. 2), a motor controller (XZ sample / buffer tray) 80. And an interface mechanism for connecting and controlling (using the interface mechanism 300) and interlocks (cartridge and transport doors) 61 and 62 (details of which are not shown in the interface mechanism 300 of FIG. 2). It is connected to 300 I / O ports 400 and various actuators. The A / D or LED processor PCBA 912 also includes a high voltage source 76 for sample injection and electrophoretic functions of the CE system 200, a circuit 914 (LEDScan substrate) that regulates the excitation radiation source (eg, LED) 921, and The detector module 24 of the CE system 200 is controlled. For details of adjusting the excitation radiation source, reference may be made to co-pending US patent application Ser. No. 10/060052, which is hereby incorporated by reference in its entirety.

  In addition, an A / D (LED processor PCBA) 912 may be coupled to an external personal computer 918, which can be used, for example, to control various features and functions of the automated multi-channel CE system 200. The biocalculator software is used to perform data processing as well, or to perform additional control functions on the CE system 200 (including an optional integrated PCR sample preparation device).

  The components of the controller 32 except for the PC 918 are packaged as an electronic board 64 (FIG. 4) and a cooling fan 63 on the board of the CE system 200, and are electrically connected to the PC 918 via a serial port (not shown). Or they may be part of a separate controller module external to the CE system 200. The CPU 910 and / or PC 918 is programmed to achieve various control functions and features of the CE system 200. In one embodiment, the PC 918 may be configured to provide a user control interface to the CE system 200 (eg, user initialization of the connection mechanism 300 interface sequence). It is within the scope of those skilled in the art to implement program code that provides the functions and features disclosed herein. In other embodiments, the controller 32 or its components may be incorporated as part of the PC 918.

-Operation of the CE system When the capillary cartridge 100 and the data key 500 are mounted on the apparatus, the cartridge ID and the pre-programmed available number of executions are read from the cartridge 100 into the CE system 200 via the I / O port 400. It is. The CE system 200 may employ an algorithm that determines whether the capillary cartridge 100 has a sufficient remaining number of executions to complete a process cycle before initiating a CE sequence. Otherwise, the CE system 200 may display an error message and stop the sequence. If it is determined that the capillary cartridge has a sufficient number of executions available, the CE sequence is started and the number of executions is recorded by the CE system. At the end of the analysis, the remaining number of executions is calculated and sent to the data key 500 for storage.

  The controller 32 of the device may be configured to “authenticate” the cartridge and perform a consistency check to determine if the particular cartridge 100 has the correct characteristics for the particular sample analysis being performed. . The device may also verify that the user is in a class of users authorized to use a particular cartridge. In addition, the device may communicate / record information regarding use of the cartridge 100 (eg, usage history, sequence / method procedure / parameter settings, patient ID, test parameters and possibly test results). Such information provides an update of information stored from previous use of the cartridge. Further, reading and writing may be controlled with respect to the data and information described above with respect to the data key 500. The device may authenticate that the test protocol that the user wants to apply to a particular cartridge is correct in order to determine whether there are any limitations, restrictions or constraints as previously indicated. You may go through the check.

  In the CE analysis operation, a sample handling tray transport mechanism 80 comprising 96 well plates (8 × 12) 72 and 70 is used to guide the amplified DNA sample (or analyte) to each capillary 140. The X-Z transport mechanism 80 indexes the row of sample carry wells 73 of the microtiter plate 72 below the row of tips of the capillary 140 and drops the tip into the well. By applying a voltage, electrokinetic injection moves a known amount of the DNA sample to the starting point of the separation column 140. After injection, the DNA sample from sample tray 72 may be replaced with a running buffer from tray 70. Alternatively, after injection, the transport mechanism 80 moves the row of 12 wells 73 of the titer plate 72 holding the buffer solution to a position below the cartridge that replaces the 12 wells holding the DNA sample. May be indexed.

  By applying a high voltage over the entire length of the capillary 140, separation of the DNA sample into DNA fragments is achieved. As the fragment approaches the end of the capillary 140 and enters the detection zone, excitation light energy (eg, from 12 LEDs carried by the optical fiber) is directed to the detection zone to illuminate the movement of the DNA fragment. The detection scheme may be a time division method as disclosed in co-pending US patent application Ser. No. 10/060052.

  In preparation for the next run with a different sample, the old gel from the previous run is released from the capillary by applying pressure to the reservoir to refill the capillary with fresh gel. Trays 70 and / or 72 carry cleaning solutions, collected soil and samples. The released gel is collected on one of the trays 70 and 72 by positioning the tip of the capillary in the row of wells on one of the trays collecting dirt. The tip of the capillary may be washed with such a solution by aligning the tip of the capillary and dropping into water or a wash solution in a suitable tray well. When the capillary is refilled and ready for the next run, the tip of the capillary is dropped into the sample by repositioning the tray 72. The process sequence described above may be programmed as one of the automated functions of the controller 32. The interface mechanism 300 provides a coupling between the support elements of the CE system 200 and the cartridge, such as the high voltage, gas pressure, LED radiation source and detection optics, as described above.

  After the analysis is completed, the cartridge 100 may be stored in the parking stand 600 or the protective case 700, or the capillary may be capped with a protective cap 710. At a later date or at a later date, the cartridge 100 may be removed and reused if needed for another analysis. If different performance conditions are expected, different cartridges with different attributes and characteristics may be used instead. The data key mechanism of the present invention automatically continues to record the use of different replaceable cartridges and does not require the user to continue such recording manually.

  Although the invention has been particularly described and illustrated with reference to preferred embodiments, workers skilled in the art will recognize that various changes can be made in form and detail without departing from the spirit, scope and teachings of the invention. Will do.

  Although some embodiments refer to a recording mechanism and I / O port consisting of a serial memory key and a card reader / writer, the present invention describes other types of erasures such as multimedia cards or compact flash cards. Possible memory may be used. In other embodiments, the recording mechanism may use a wireless transmitter / receiver, or may use optical means such as an optical disc and an optical disc reader / recorder. Such a recording mechanism may be activated when the CE device is not involved in the high voltage processing procedure to ensure the quality of the data link. In still other embodiments, the recording mechanism may comprise a smart label, an optical reader, and a printer. For example, the smart label includes a bar code and a series of symbols that can be read optically by the scanner of the CE system to extract the cartridge ID and number of completed runs. After a subsequent analysis cycle, the CE system thermal printer or inkjet printer can modify the smart label to reflect the current number of runs completed by the cartridge.

  Although some embodiments have been described as attaching the recording device to the cartridge with a cord, it is clear that the recording device can be attached to the cartridge by anchoring it with another type, such as a chain. Alternatively, the recording device can be connected to the cartridge via a fixed connection, such as a flange or fixed length extension arm, so that the cartridge and the recording device can be coupled to the cartridge coupling interface and I / O port in a single movement. it can.

  The automation system 200 may be configured to perform in addition to other types of different analyzes or CE separation analyses. For example, it can also be used in carbohydrate or immunoassays combined with microfluidic electrophoresis systems for protein or pathogen detection. Extracted proteins from the culture are used for immunoassays. Amplified signals are automatically applied to the multichannel cartridge for high resolution detection in a few minutes through the interaction of antigen and antibody conjugated to a fluorescent dye.

  Although some embodiments have referred to a communication process that includes read / write capabilities between the bioanalytical system and the recording device, it is clear that the communication process may include a read-only process. For example, the bioanalytical system can read the cartridge ID and send this information to a central remote database before starting the bioanalytical sequence. After the subsequent bioanalysis cycle is complete, the bioanalysis system can send the latest information to the central database instead of sending them to the recording device for storage.

  The interface mechanism may be adapted to accept capillary cartridges of other structural designs. One skilled in the art will also recognize that devices incorporating the essence of the present invention can be used for biomolecule analysis rather than DNA analysis. For example, by changing the separation gel or buffer, the device can be modified to analyze biomolecules such as proteins, carbohydrates and lipids.

  For purposes of illustration and without limitation, the detection scheme of the present invention has been described with capillary electrophoresis and radiation-induced fluorescence detection. The present invention can also be applied to detection of specimens separated based on biological separation phenomena other than electrophoresis, and not only detection based on UV and visible absorption, but also phosphorescence, luminescence, and chemiluminescence. It can also be applied to detection of luminescent radiation other than fluorescent radiation, including the following types of radiation emission.

Furthermore, although the separation channel in the described embodiment is defined by a cylindrical column or tube, the concept of the present invention is defined by a channel, eg, a micromachine in an etch or substrate (microfluidic type device or biochip). It is equally applicable to separation channels defined by defined microchannels (such as square, rectangular or essentially semi-circular cross sections).
The transport mechanism can also be configured to move the tray in a plane, and an additional transport mechanism can be provided to move the tray vertically to access the tray.

  Accordingly, the disclosed invention is to be considered merely as illustrative and limited in scope only as specified in the appended claims.

1 is a schematic illustration of a capillary electrophoresis system having a sample preparation device according to one embodiment of the present invention. FIG. 1 is a perspective view of a capillary cartridge having a recording device according to one embodiment of the present invention. FIG. FIG. 3 is an external perspective view of a biological analyzer using the capillary cartridge of FIG. 2 according to one embodiment of the present invention. FIG. 4 is an exploded perspective view of the bioanalyzer of FIG. 3 according to one embodiment of the present invention. 1 is a block diagram of a control system for a bioanalyzer according to one embodiment of the present invention. 1 is a perspective view of a capillary cartridge placed on a parking stand according to one embodiment of the present invention. FIG. 1 is a perspective view of a capillary cartridge in which a capillary tip is inserted into a protective cap according to one embodiment of the present invention. FIG. 1 is a perspective view of a capillary cartridge housed in a shipping case according to one embodiment of the present invention. FIG.

Claims (20)

A cartridge defining at least one channel for the passage of the sample for analysis;
A data key readable by an external reader, storing data relating to the attributes of the cartridge, and associated with the cartridge;
A bioanalytical cartridge system.   The cartridge system according to claim 1, wherein the data key is connected to the data key by a string.   The cartridge system according to claim 1, wherein the data key has a nonvolatile memory for storing data. The data key stores data relating to at least one attribute;
The attributes include model number, serial number, channel number, channel size, channel medium, designated patient or subject ID, date of manufacture, chemistry lot number, designated user restrictions, and design specifications. The cartridge system of claim 1, wherein the cartridge system is: limits, restrictions or constraints, expiration date, maximum working voltage, maximum number of runs, maximum working time, scientific suitability and device suitability. The data key further stores data relating to at least one of updatable data relating to use,
The updatable data includes cumulative execution count, execution type, execution condition and parameters, use date and time, cumulative execution time, execution protocol, individual execution time, execution ID, patient or subject ID, user ID, applied execution The cartridge system of claim 4, wherein the cartridge system ID is for the voltage and each run.   The cartridge is characterized by at least one of being portable, recyclable, reusable and interchangeable with other cartridges having different types of channels. The cartridge system described in 1.   The cartridge system according to claim 1, wherein the cartridge has a main body portion, and the channel has a capillary column supported by the main body portion.   The cartridge system according to claim 7, wherein the cartridge has a structure designed for capillary electrophoretic separation of a sample in the capillary column.   The cartridge system according to claim 1, further comprising a stand that removably supports the cartridge.   The cartridge has a main body, the channel is supported by the main body, has a capillary column containing a gel that terminates at one end, a stand has a sealing material, and the cartridge is removed from the stand with respect to the sealing material. The cartridge system of claim 1, wherein the cartridge system is supported and the end of the capillary extends to the sealing material.   The cartridge has a main body, the channel is supported by the main body and has a capillary column containing a gel that terminates at one end, the cartridge system further includes a thin capsule having a sealing material, and the end of the capillary The cartridge system of claim 1, wherein the cartridge is inserted into the capsule to seal the end. Base and
The cartridge system of claim 1;
A cartridge interface supported on the base connected to the cartridge system;
A controller operably coupled to the cartridge interface to control operation of the cartridge interface;
A bioanalytical system.   The bioanalytical system of claim 12, wherein the cartridge interface has a data interface for a data key.   The biological analysis system according to claim 13, wherein the data interface has an I / O port for reading data from the data key.   The biological analysis system according to claim 14, wherein the I / O port further writes data to the data key.   The bioanalytical system of claim 12, wherein the controller controls the cartridge interface to provide electrophoretic separation of a sample in the channel. The data key communicates with the cartridge interface via the data interface in association with data relating to at least one attribute;
The attributes include model number, serial number, channel number, channel size, channel medium, designated patient or subject ID, date of manufacture, chemistry lot number, designated user restrictions, and design specifications. 14. The bioanalytical system according to claim 13, wherein the bioanalytical system is: limits, restrictions or constraints, expiration date, maximum voltage used, maximum number of uses, maximum time used, scientific suitability and device suitability. The data key communicates with the cartridge interface via the data interface in association with at least one updatable data regarding usage;
The updatable data includes cumulative execution count, execution type, execution condition and parameters, use date and time, cumulative execution time, execution protocol, individual execution time, execution ID, patient or subject ID, user ID, applied execution The bioanalytical system of claim 13, wherein the system is a system ID for each run. A cartridge having a main body and a capillary column supported by the main body, terminated at one end, and containing a gel for passage of a sample for analysis;
A stand having a sealing material, removably supporting the cartridge with respect to the sealing material, and an end of the capillary extending over the sealing material;
A bioanalytical cartridge system. A cartridge having a main body and a capillary column supported by the main body, terminated at one end, and containing a gel for passage of a sample for analysis;
A thin capsule having a sealing material and inserted so that the end of the capillary seals the end;
A bioanalytical cartridge system.

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