Abstract:
A sample processing/injection device for liquid chromatography comprises a septum at one end of the device, a processing chamber and injection needle disposed on a second end of the device. A fluid sample is transferred into the device by a transfer needle penetrating the septum of the device. The sample device may be positioned to a receiving component such as an injection valve of an instrument by movement of the transfer needle. The sample is injected into the receiving component through the injection needle of the sample processing/injection device through motive pressure supplied by the transfer needle. The sample processing/injection device reduces sampling steps and improves automation by performing sample processing and injection with a single device.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to sample processing and, more particularly, to a method and apparatus for automated sample handing, processing and testing utilizing a sample processing/injection device. 
       BACKGROUND OF THE INVENTION 
       [0002]    The growth in medical and pharmaceutical research as well as diagnostic analysis and testing has created a need for equipment and procedures for low cost, high-speed sample collection and processing. Automated equipment is available for filling and retrieval of samples from sample wells, vials, bottles and other containers. 
         [0003]    Microplates comprising a plurality of sample wells provide a convenient means to handle and store samples. Automated equipment positions microplates for sample filling, retrieving, and analysis. Despite improvements in sample handling equipment, many applications require manual labor when performing evolutions such as; preparing sample containers or vials, relocating sample containers, and passing sample fluids through process elements such as absorbents, adsorbents, filters, solid phase extraction mediums, or additive compound materials. Manual processing steps are usually required when sample numbers are insufficient to justify design and building custom automated equipment. 
         [0004]    Often the wells of microplates are used as the sample containers. In other applications, vials or sample bottles are inserted into the wells of microplates to contain the samples or testing fluids. 
         [0005]    Certain types of testing such as chromatography, combinatorial chemistry, or high-throughput screening utilize processing of a sample by a processing element such as solid phase extraction medium, a filter, or an adsorbent disk. The compounds of interest are recovered by passing solvents through the processing element. This process requires multiple steps that are difficult to automate, especially if the sample numbers are not sufficiently large to justify specialized equipment, containers and processes. 
         [0006]    Sample processing devices such as those disclosed in U.S. Pat. No. 6,959,615, hereby incorporated as reference, provide a means to withdraw, discharge, process and elute samples from sample vessels including wells of microplates. While this is a significant improvement in reducing the number of steps and devices required for sample collection, processing and testing, intermediate sample vessels are still required between sample collection and sample injection into the final test instrument. Additionally, sample-to-sample exposure is a significant threat to sample integrity and quality of the resulting analytical data. 
         [0007]    There exists a need for improved sample collection, processing and testing devices to further reduce processing steps, improve speed and productivity of sample testing evolutions, and perform serial processing on existing automated devices to improve data quality. 
       OBJECTS AND SUMMARY OF THE INVENTION 
       [0008]    Therefore, an object of the present invention is to provide a sample processing/injection device that can be used to collect, process and inject fluid samples. 
         [0009]    Another object of the present invention is to provide a sample processing/injection device that can be repositioned by movement of a transfer needle penetrating a septum of the device. 
         [0010]    Another object of the present invention is to provide a sample processing/injection device having an injection needle sealable with an injection port of sampling instrument injection valve. 
         [0011]    Another object of the present invention is to provide a sample processing/injection device with an injection needle attachable by quick removable connectors such as luer slip and luer lock fittings. 
         [0012]    Another object of the present invention is to provide a sample processing/injection device that can be placed in standard multi-well trays. 
         [0013]    Still another object of the present invention is to provide a sample processing/injection device that is simple and low in cost. 
         [0014]    The sample processing/injection device of the present invention is an elongated tubular structure having a sealing septum on one end and an injection needle on the opposite end. The septum seals a conical needle guide and a reduced diameter through chamber having a close or tight fit with a transfer needle of a manual or automated sampling apparatus. The reduced diameter through chamber opens to a larger diameter processing chamber containing one or more processing elements such as frits, filters or solid phase extraction elements. The processing chamber is in fluid connection with the injection needle. In the preferred embodiments, an in-line fluid communication channel exists between the sealed septum end, reduced diameter through chamber, processing chamber, and injection needle. 
         [0015]    In another embodiment, the sample device has a sealing septum on one end and a connector on the opposite end. The connector allows mechanical attachment and fluid communication of the device with an injection needle. In the preferred embodiments, the connector is a quick-connect tapered connector such as a luer slip or a luer-lock connector. The taper portion of the connector may act as a drip tube for sample intake or discharge from the sample processing/injection device. 
         [0016]    The close or tight fit of the through chamber with a transfer needle and a through chamber length of at least 5 times the diameter of the through chamber provides both engagement of the transfer needle and sample device and automatic alignment of the device with the transfer needle. The good alignment provided by the fit allows precision movement and placement of the device utilizing only the transfer needle, simplifying instrument design and construction and speeding automated sampling. For example, the device may be transferred to the injection port of a testing machine and the injection needle sealed with the injection port by positioning of the transfer needle alone. 
         [0017]    The combination of a luer slip or luer lock connector allows use of a small diameter injection needle compatible with low volume testing injection ports and a larger diameter drip tube portion for fast sample transfer with the injection needle removed. The design also allows use of the connector as a drip tube for fast elution, intake or discharge of sample or wash fluids into our out of the sample device. 
         [0018]    The sample processing/injection device with both a drip tube and an injection needle connectable with a quick-connect/disconnect connector allows a number of sampling operations especially suitable for automation. These operations and procedures include: intake or discharging sample or wash fluids quickly into or out of the sample device using the drip tube integral with the connector, or withdrawing or injecting a sample or wash fluid via an injection needle attached by the connector; moving and precise positioning the device with or without an injection needle by movement of a transfer needle inserted into the septum and reduced-diameter through chamber of the sample device; attaching or removing the injection needle to/from the device by movement of the transfer needle inserted into the septum and reduced-diameter through chamber of the sample device and injection of sample fluid into a sample valve by an injection needle attached to the sample device, the positioning and injection needle penetration accomplished by movement of the transfer needle inserted into the septum and reduced-diameter through chamber of the sample device. 
         [0019]    These and many other operations are made possible by transfer needle engagement and alignment features of the device and the combination drip tube and injection needle connector of the present invention. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0020]    These and other features, aspects and advantages of the present invention will become better understood with regard to the following description, appended claims and accompanying drawings where: 
           [0021]      FIG. 1  is cross section elevation drawing of a prior art sample processing device; 
           [0022]      FIG. 2  is cross section elevation drawing of a sample processing/injection device having an injection needle fixed to a removable bottom end cap; 
           [0023]      FIG. 2A  is a detail cross section drawing of the sealing portion of the injection needle of  FIG. 2 ; 
           [0024]      FIG. 3  is cross section elevation drawing of another embodiment of a sample processing/injection device having an injection needle attached to a bottom end cap of the device by a tapered connector such as a luer slip connector; 
           [0025]      FIG. 4  is cross section elevation drawing of another embodiment of a sample processing/injection device having an injection needle attached to a bottom end cap of the device by a luer lock connector; 
           [0026]      FIGS. 5A-5I  are schematic drawings of process steps showing use of the sample processing/injection device through engagement of a transfer needle with the device to engage the injection needle of the device, to move the device, to transfer sample to a receiving component and to remove the device from the transfer needle portion. 
       
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0027]      FIG. 1  is a cross section drawing of a prior art sample processing device  100  for retrieving, processing and discharging samples. The device utilizes a penetrable septum  103 , a conical needle guide  105 , a reduced diameter through chamber  107 , a processing chamber  109  and a drip tube  111 . A top cap, such as a crimp cap  113  secures septum  103  to a body portion  115  of the device. Cap aperture  113 A provides access of a needle (not shown) into the device. Sample processing elements such as filters or frits  117 A,  117 B provide sample addition, subtraction, filtering, or other processing functions as known in the art. Bottom cap  119  provides a means to insert, remove or replace processing elements  117 A,  117 B in the device. Drip tube  111  provides sample collection from, or discharge into, a sample vessel or container. 
         [0028]      FIG. 2  is a cross section drawing of an improved sample processing/injection device capable of direct sample injection by use of a needle such as injection needle  201  attached to bottom cap  219  of processing/injection device  200 . The construction and functions of septum  103 , needle guide  105 , reduced diameter through chamber  107 , sample processing chamber  109 , cap  113 , body  115  and sample processing elements  117 A,  117 B is similar to that of  FIG. 1 . In the preferred embodiments, the device is made of a polymeric material such as polyethylene, polypropylene, or polytetrafluoroethylene. 
         [0029]    In the preferred embodiments, injection needle  201  is a metal needle having a length, diameter and end treatment suitable for sample collection from a well, or penetration into a septum such as septum  103  of another vessel or processing device. Needle  201  may have a formed seat surface  202  such as a beveled seat surface  203  of  FIG. 2A  for seating in other sample receiving apparatus such as sample injection valves of a liquid chromatography instrument as described later. In still other embodiments, needle  201  may be angled for improved septum penetration, or it may have a side opening for other applications. 
         [0030]    In the preferred embodiments, needle  201  comprises a blunt end as shown in  FIG. 2  and is sized for processing small sample volumes. In one preferred embodiment, needle  201  diameter is selected to form a close fit tolerance with reduced diameter through chamber  107  to allow series connection of the devices. In another embodiment, needle  201  diameter is selected to form a tight or slight interference fit with reduced diameter through chamber  107  to allow positioning of one device by another device. 
         [0031]    Needle  201  may be attached to bottom cap  219  of device  200  by press fit, co-molding, or use of mechanical engagement elements such as threads or mechanical joints. In still other embodiments, welding, bonding or adhesives may be used. 
         [0032]    In the preferred embodiments, bottom cap  219  is removable from body  115  of the device to allow for insertion, removal or changing of processing elements  117 A,  117 B, and to allow changing of needle  201 . Cap  219  may form an interference, press fit with body  115 , forming a liquid seal at seal portion  204 . In other embodiments, bottom cap  219  may utilize snap fittings or other mechanical fittings known in the art. In still other embodiments, bottom cap  210  is permanently attached to body  115 . 
         [0033]      FIG. 3  is a cross section drawing of another embodiment  300  of the sample processing/injection device of  FIG. 2  having a removable needle portion  303  attached to bottom cap  319  of the device. In the preferred embodiments, needle portion  303  comprises a female interference taper fitting or luer slip fitting  305  which form an interference fit with a complementary male luer slip fitting  307 . In the preferred embodiments, male luer fitting  307  also functions as a high capacity drip tube on bottom cap  309 . 
         [0034]    Injection needle  301  is similar to needle  201  of  FIG. 2  and is attached to body  311  of needle portion  303  by press fit, snap fit, threaded connection or other means known in the art. In the preferred embodiments, the diameter of bottom cap opening  308  is greater than the opening of injection needle  301  to allow fast sample transfer time with needle  301  removed. Other components of device  300  are similar to those of  FIG. 2 . 
         [0035]      FIG. 4  is a cross section drawing of another embodiment  400  of the sample processing/injection device of  FIG. 2 . Device  400  differs from that of the embodiment of  FIG. 3  in that needle portion  403  incorporates locking threads  415  that engage complementary locking threads such as luer lock threads  417  of bottom cap  419  to securely retain needle portion  403  to bottom cap  419 . Other components of device  400  are similar to those of the earlier embodiments. In still other embodiments, other connector means such as snap fittings or compression fittings may be used to attach the injection needle to the bottom cap or body of the device. 
         [0036]      FIGS. 5A-5L  show a preferred embodiment of a method of utilizing the sample processing/injection device to reduce processing steps and improve productivity during sample processing and testing. 
         [0037]      FIG. 5A  is a schematic diagram of two sample processing/injection devices  300 A,  300 B disposed in wells of a standard multi-well sample tray  501  and accessed by a needle such as transfer needle  503  of an automated processing instrument  502 . In the preferred embodiments, reduced diameter through chamber  107  is selected to form a close fit or slight interference fit with transfer needle  503  and the reduced diameter through chamber comprises a length of at least 5 times the diameter of the chamber to provide alignment of transfer needle  503  and device  300 A. A tight or slight interference fit also provides sufficient grip between needle  503  and the device to allow handling and precise movement and positioning of the device with needle  503 . In the preferred embodiments, a close tolerance fit is less than 0.005 on the diameter. In the preferred embodiments, a slight interference fit is less than 0.005 on the diameter. 
         [0038]    Needle guide  105  provides guidance for needle  503  during insertion of the needle as shown by arrow  505 . Needle stop  507  provides control of insertion depth as shown in the needle-inserted position shown in phantom lines. 
         [0039]      FIG. 5B  is a schematic diagram of device  300 A withdrawn vertically in direction  505 A from well  501 A by the interference fit of needle  503  and chamber  107 . In the preferred embodiments, the length of chamber  107  is chosen to be at least 5 and preferably at least 10 diameters of chamber  107  in order to provide axial alignment for precision placing of device  300 A. 
         [0040]      FIG. 5C  is a schematic diagram of device  300 A withdrawn from well  501 A and being displaced horizontally in direction  505 B to another processing location by needle  503  of the automated processing instrument. 
         [0041]      FIG. 5D  is a schematic diagram of device  300 A positioned vertically above needle portion  303 A in well  521 A of tray  521 . Device  300 A is positioned vertically downward in the direction of arrow  505  by needle  503  of the automated processing instrument. As needle  503  positions device  300 A downward, male luer slip fitting  307  of bottom cap  319  engages to form an interference fit with female luer slip fitting  305  of needle portion  303 A as shown in  FIG. 5E . Needle stop  507  of needle  503  provides the interference fit insertion force and ledge  522  of well  521  provides a reaction structure to accomplish the secure attachment of needle portion  303 A to device  300 A. 
         [0042]      FIG. 5E  is a schematic diagram of device  300 A with needle portion  303 A attached positioned vertically upwards in the direction of arrow  505 A by needle  503  of the processing instrument. 
         [0043]      FIG. 5F  is a schematic diagram of device  300 A with needle portion  303 A attached positioned horizontally in the direction of arrow  505 B by needle  503  of the processing instrument. 
         [0044]      FIG. 5G  is a schematic diagram of device  300 A positioned vertically above a sample injection port such as injection port  541  of sample injection valve  543  and being positioned vertically downward in the direction of arrow  505  by needle  503  of the automated processing instrument. As needle  503  positions device  300 A downward, valve-seating surface  302  of needle  301 A engages injection valve seat  545  as shown in  FIG. 5H . Needle stop  507  of needle  503  provides the injection valve seating insertion force against seat  545  to accomplish the necessary sealing of device  300 A to injection valve  543 . The accomplishment of this step allows injection of sample volume directly from sample processing/injection device  300 A into injection valve  543  for instrument processing. 
         [0045]      FIG. 5  I is schematic diagram of device  300 A with needle portion  303 A attached positioned vertically upwards in the direction of arrow  505 A and horizontally in the direction of arrow  505 B by needle  503  of the processing instrument. 
         [0046]      FIG. 5J  is a schematic diagram of device  300 A positioned vertically above a sample device receiving component such as multi well tray  561  and being positioned vertically downward in the direction of arrow  505  by needle  503  of the automated processing instrument. As needle  503  positions device  300 A downward against device support surface  563  of tray  561  a device retaining element  565  is inserted by the processing instrument as shown in  FIG. 5K . Upon withdrawal of needle  503  in the direction of arrow  505 A, retaining element  565  retains device  300 A in well  561 A. The interference fit of needle  503  in reduced diameter through chamber  107  is overcome by the upwards motion of needle  503  and provides automated separation of device  303 A and needle  503  as shown in  FIG. 5L . 
         [0047]    Although the process steps of  FIGS. 5A-5L  are shown for the embodiment of  FIG. 3 , similar process steps can be used for other device embodiments. For example, the fixed needle  201  attachment of  FIG. 2  would eliminate the necessity of steps  5 D and  5 E. The embodiment of  FIG. 4  would require an additional step of rotation of needle portion  403  in order to secure or unlock needle portion  403  from bottom cap  419 . In still other embodiments, the female taper portion of the connectors of embodiments  300  and  400  allow sample intake and elution directly from the device, similar to drip tube  111  of  FIG. 1 . In still other embodiments, sample is withdrawn or discharged by needle  503  during any of the process sequences shown in  FIGS. 5A-5L . 
         [0048]    Although the description above contains many specifications, these should not be construed as limiting the scope of the invention but merely providing illustrations of some of the presently preferred embodiments of this invention. Thus the scope of the invention should be determined by the appended claims and their legal equivalents, rather than by the examples given.