Abstract:
A docking mechanism provided for analytical apparatus, such as an acoustic bio-sensor apparatus. The mechanism is operable releasably to receive a cartridge ( 58 ) for use in analysing a sample comprising a fluid and having a flow cell ( 104, 106; 304, 306 ) for the sample and an electrically operated sensor ( 92 ) for performing the analysis. The docking mechanism has a clamping mechanism ( 12, 8, 10 ) for urging fluid connector means such as ferules ( 50, 52 ) against the cartridge to provide a fluid connection between the flow cell inlet and a sample delivery means. The docking mechanism also has an electrical connector ( 74, 76, 78 ) for engaging the sensor to connect the latter to electrical circuitry for operating the sensor, the electrical connector being moveable towards and away from the sensor relative to the clamping mechanism, so that, in use, the electrical connector exerts on the sensor a force which is sufficient to maintain the necessary electrical connection, whilst not being so great as to have a substantial detrimental effect on the accuracy of the sensor. There is also shown analytical apparatus which includes such a docking mechanism.

Description:
FIELD OF THE INVENTION 
       [0001]    This invention relates to a docking mechanism for releasably receiving a cartridge for use in analysing a sample comprising fluid, and to analysing apparatus which includes such a docking mechanism and cartridge. 
       BACKGROUND TO THE INVENTION 
       [0002]    The invention is particularly, but not exclusively, applicable to apparatus, for example a quartz crystal microbalance system, which uses an electrical-mechanical transducer as a sensor. In such a system, an electrical signal causes the transducer to vibrate. 
         [0003]    The crystal typically has an active surface on which a receptor group is immobilised. That group has a chemical affinity or reactivity towards a substance to be detected or analysed. The substance to be analysed is normally present in a fluid which is bought into contact with the active surface of the crystal. Physical, chemical and biochemical interactions between the receptor group on the active surface and the substance cause a change in the mass attached to the surface (and in other physical properties of the active surface) and these affect the vibrational characteristics, in particular the resonant frequency, of the crystal. Analysis of these effects can be used to obtain qualitative and/or quantitative data on the substance, and its interaction with the receptor. 
         [0004]    This type of analysing apparatus is used in situations, for example to analyse chemical and biochemical interactions, in which it may be desirable to interchange the sensor with another sensor which may be identical to the first sensor or may carry a different receptor group. To that end, it is known to provide the sensor and a flow cell, for bringing the sample into contact with the sensor, in a cartridge which co-operates with a docking mechanism in the analysing apparatus in order to releasably connect inlet and outlet openings for the flow cell to a sample delivery/removal system. The docking mechanism also connects the electrodes on the sensor to diving/measuring circuitry for oscillating the sensor and measuring the frequency of oscillation and/or other characteristics of the oscillation (for example the magnitude of the damping force being experienced by the sensor). 
         [0005]    U.S. Pat. No. 6,196,059 shows an example of such apparatus. The cartridge comprises an injection moulded body which has an annular rib that surrounds a surface that is to fort the base of the flow cell and that includes inlet and outlet openings which communicate with an inlet and outlet of the cartridge through small tubes. The sensor is adhered to the rib which spaces the sensor from the other surface so that the sensor, the surface and the rib between them define the flow cell. The cartridge is received in a docking mechanism that comprises a lid pivotally mounted on a base. The base includes fluid conduits for connecting the inlet and outlet ribs of the cartridge to a sample delivery/removal system, whilst the lid of the mechanism includes an electrical connector for connecting the electrodes of the sensor to the drive/measurement circuitry. Although the connector is described as being spring loaded, it appears to exert enough force on the cartridge to require that the connector engages contacts which are laterally spaced from the sensor so that the electrical connector does not exert a force directly on the sensor. As a result, the cartridge is of a relatively complicated construction having two spaced apart contacts for the electrical connector and wires connecting those contacts to the electrodes on the sensor. 
       SUMMARY OF THE INVENTION 
       [0006]    According to a first aspect of the invention, there is provided a docking mechanism for releasably receiving a cartridge for use in analysing a sample comprising a fluid, the cartridge having a flow cell for the sample and an electrically operated sensor for performing said analysis, the docking mechanism comprising a clamping mechanism for urging fluid connector means against the cartridge to provide a fluid connection between the flow cell inlet and sample delivery means; the docking mechanism also comprising an electrical connector for engaging the sensor to connect the latter to electrical circuitry for operating the sensor, the electrical connector being movable, towards and away from the sensor, relative to the clamping mechanism, so that, in use, the electrical connector exerts on the sensor a force which is sufficient to maintain the necessary electrical connection, whilst not being so great as to have a substantial affect on the accuracy of the sensor. 
         [0007]    Thus the invention enables the fluid connector to be urged against the cartridge with sufficient force to create a seal with the cartridge, without causing the electrical connector to exert too great a force on the sensor. 
         [0008]    Preferably, the clamping mechanism comprises a carrier member and a co-operating surface, at least one of which is movable towards and away from the other, releasably to compress a cartridge therebetween. 
         [0009]    In one embodiment of the invention, the carrier member is attached to a fixed reference surface, and the co-operating surface is movable. In another embodiment, the co-operating surface constitutes the fixed reference surface which locates the cartridge in position in the mechanism, so that the movable member is the carrier member. 
         [0010]    Preferably, the carrier member carries the fluid connector means. 
         [0011]    Preferably, the fluid connector means comprises a connector so sized and shaped as to make mating engagement with a complimentary connector on a cartridge. 
         [0012]    In this case, the fluid connector means of the docking mechanism may conveniently be the male connector. 
         [0013]    This enables the cartridge to have a recessed female connector, and thus to be of a relatively compact construction. 
         [0014]    Preferably, the male fluid connector comprises a tube which is, in use, inserted into a bore in a cartridge received in the docking mechanism. The tube is preferably a ferrule. 
         [0015]    The fluid connector on the carrier member may to advantage be one of two such connectors for respective connection to an inlet and an outlet of a flow cell of a cartridge. 
         [0016]    The docking mechanism may to advantage include actuation means for automatically closing and opening the clamping mechanism, respectively to clamp and release the cartridge. 
         [0017]    Preferably, the actuation means also acts on the electrical connector automatically to move the connector into and out of engagement with the sensor. 
         [0018]    The carrier member and electrical connector may conveniently be arranged in an opposed relationship so that a cartridge received in the docking mechanism is interposed between the carrier member and the electrical connector. 
         [0019]    Thus the fluid and electrical connections for the sensor are made from opposite sides of the cartridge, so that the cartridge can be of a relatively compact and simple construction. 
         [0020]    In this case, the actuation means preferably comprises a drive assembly which acts between the electrical connector and the carrier member to alter the separation therebetween. 
         [0021]    Where the co-operating surface is interposed between the carrier member and electrical connector, the drive assembly is preferably fixed in position relative to the co-operating surface. 
         [0022]    This allows a single drive assembly to be used to bring both the electrical and fluid connectors into and out of engagement with the cartridge, and for the fluid connector to be urged against the cartridge with a greater force than the electrical connectors. 
         [0023]    The drive assembly conveniently comprises a hydraulic or pneumatic gas cylinder. Alternatively, the drive assembly includes a motor for driving the electrical connector and carrier member. 
         [0024]    The actuation means is preferably operable to close the clamping mechanism before bringing the electrical connector into engagement with a sensor. 
         [0025]    The clamping mechanism preferably includes a clamping mechanism biasing means for urging the clamping mechanism into a closed position. 
         [0026]    Preferably the docking mechanism includes electrical connector biasing means, weaker than said clamping mechanism biasing means, for urging the electrical connector into engagement with the sensor of a cartridge in the docking mechanism. 
         [0027]    Where the clamping mechanism includes said drive assembly, the clamping mechanism and electrical connector biasing means may form part of the actuating mechanism. 
         [0028]    With this arrangement, the drive assembly is operable only to separate the carrier member and electrical connector from the cartridge, the force with which those components engage the cartridge being determined by the clamping mechanism biasing mean and electrical connector biasing means. 
         [0029]    Thus the drive assembly operates to release a cartridge from the docking mechanism. When a fresh cartridge is inserted, the drive assembly is then deactivated so that it ceases to counteract the effect of the two biasing means. As a result, the clamping mechanism biasing means first urges the carrier member towards the cartridge whilst acting on the electrical connector at least through the driver assembly to prevent the latter from moving towards the cartridge until the cartridge has been engaged by the carrier member. Once this happens, the electrical connector biasing means moves the electrical connector into contact with the sensor. 
         [0030]    Preferably, the electrical connector is mounted on a further carrier member movable relative to cartridge in the docking mechanism to bring the electrical connector into and out of engagement with the sensor. 
         [0031]    Preferably, the electrical connector biasing means acts on said further carrier member. 
         [0032]    The electrical connector may to advantage be one of two such connectors, each for connecting a respective electrode of the sensor to the circuitry. 
         [0033]    Preferably, the or each electrical connector comprises a spring loaded pin. 
         [0034]    Preferably, the co-operating surface is so arranged as to engage the cartridge to retain the latter in position in the docking station. 
         [0035]    To that end, the co-operating surface may comprise a formation, for example a rib or groove, which is fixed relative to the docking mechanism and which receives an edge portion of a cartridge. 
         [0036]    Said formation may conveniently form part of, or be attached to, a frame of the docking mechanism. 
         [0037]    Preferably, the further carrier member comprises a printed circuit board which may to advantage include interface circuitry for matching the sensor to the circuitry for operating the latter. 
         [0038]    For example, the printed board may carry switching and/or impedance matching circuitry. 
         [0039]    With this arrangement, analytical apparatus equipped with this sort of docking station may be relatively easy modified, by interchanging the printed circuit board with another printed circuit board having interface circuitry of differing characteristics, to be compatible with different types of sensor. 
         [0040]    If the docking mechanism is operable to receive the plurality of cartridges simultaneously, the PCB may additionally include switching circuitry to enable each cartridge in turn to be connected to the circuitry for operating the sensors. 
         [0041]    According to a second aspect of the invention, there is provided a docking mechanism for releasably receiving a cartridge for use in analysing a sample comprising a fluid, the cartridge having a sensor for performing said analysis, the docking mechanism comprising opposed first and second carrier members movable in use towards and away from the position to be occupied by a cartridge in the mechanism, and co-operating means for locating the cartridge between the carrier members, the first carrier member carrying a fluid connector for making a fluid connection between the cartridge and a sample delivery means, the second carrier member carrying an electrical connector for connecting the sensor to circuitry for operating the latter, wherein the co-operating surface prevents movement of a cartridge, received by the docking mechanism, in the directions of movement of the carrier members. 
         [0042]    Thus the force applied to the cartridge by the first carrier member clamps the cartridge against the locations without transmitting any substantial amount of force to the second carrier member or electrical connector. 
         [0043]    Preferably, the location means comprises a co-operating surface, such as a rib or groove against which the periphery a cartridge in the docking mechanism is seated. 
         [0044]    The invention also lies in analysing apparatus for analysing samples comprises a fluid, the apparatus comprising a cartridge having an electrically operated sensor for analysing the sample, a docking mechanism and hereinabove described, for releasably receiving the cartridge, sample delivery means for delivering the sample, via the docking mechanism to the cartridge and electrical circuitry for operating the sensor. 
         [0045]    Preferably, the cartridge contains a flow cell for bringing the sample into contact with the sensor. 
         [0046]    Preferably, the sensor comprises an electrical-mechanical transducer, for example a piezoelectric, piezomagnetic or acoustic transducer. One example of such a sensor is a quartz crystal microbalance. Other suitable transducers include surface acoustic wave devices, Love wave devices etc. 
         [0047]    The transducers may be provided either in single cartridges, cartridges containing multiple transducers, or as multiple cartridges, either in linear (e.g. 1×4) or array configuration (e.g. 4×4), or combinations of these two arrangements. 
         [0048]    The cartridge may be provided with further apertures through which during the electronic clamping action earthed pins pass. These earthed pins are earthed by contact with an earth rail on the circuit board, and on completion of the clamping action contact an earthed bar of the structure. The function of these earthed bars is to form a “Faraday cage” around the drive pins and electrodes of the sensor. By suitable election of the separation of these earth pins, a means of suppressing the emission of RF signals from the transducer and drive pins can be engaged automatically on closing the clamping action. 
         [0049]    Additionally or alternatively, these pins may locate the cartridge in position in the mechanism. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0050]    The invention will now be described, by way of example only, with reference to the accompanying drawings, in which: 
           [0051]      FIG. 1  is an isometric view of a first embodiment of a docking mechanism, in accordance with the invention, for an analyser, also in accordance with the invention, the mechanism being shown with one cartridge inserted therein, and with its clamping mechanism in its open condition; 
           [0052]      FIG. 2  is a similar view of the docking station, but showing two cartridges inserted therein and with the clamping mechanism in its closed condition; 
           [0053]      FIG. 3  is simplified sectional front view of the docking station at the stage of operation shown in  FIG. 4 ; 
           [0054]      FIG. 4-6  are sectional side views of part of the docking mechanism of  FIGS. 1 and 2  at successive stages during the operation of the mechanism; 
           [0055]      FIGS. 7 and 8  are front sectional views of certain parts of the apparatus of  FIG. 3  at the stages of operation shown in  FIGS. 5 and 6  respectively; 
           [0056]      FIG. 9  is a detailed front sectional view of part of the docking mechanism, showing in particular an electrical connector; 
           [0057]      FIG. 10  is an exploded perspective view of a cartridge of the apparatus; 
           [0058]      FIG. 11  is a sectional side view of the cartridge shown in  FIG. 10 ; 
           [0059]      FIG. 12  is a sectional end view of the cartridge, taken along the line XII-XII of  FIG. 11 ; and 
           [0060]      FIG. 13  is an isometric view, corresponding to  FIG. 1 , of a second embodiment of docking mechanism in accordance with the invention; 
           [0061]      FIG. 14  is a more detailed view of part of the apparatus shown in  FIG. 13 ; 
           [0062]      FIG. 15  is an isometric view of a third embodiment of docking mechanism in accordance with the invention; 
           [0063]      FIG. 16  is an isometric view, from a higher angle, of the third embodiment with four cartridges inserted therein; 
           [0064]      FIG. 17  is a view of the underside of the quartz crystal wafer (and the electrode thereon) used in the cartridge of  FIGS. 10 and 11 ; 
           [0065]      FIG. 18  is a plan view of the crystal (showing the other electrodes); 
           [0066]      FIG. 19  is a view of the underside of the crystal with an adhesive membrane thereon; 
           [0067]      FIGS. 20-22  are views corresponding to  FIGS. 17 to 19  respectively, of a modified version of crystal, membrane and electrodes; 
           [0068]      FIG. 23  compares, graphically, the resistance and Q-Factor of the modified version with the version of sensor shown in  FIGS. 10 and 17  to  19 ; 
           [0069]      FIG. 24  is a block diagram of analysing apparatus also in accordance with the invention. 
       
    
    
     DETAILED DESCRIPTION 
       [0070]    With reference to  FIG. 1 , a docking mechanism comprises a base plate  1  from which a front plate  2  rises vertically. At the top of the front plate  2  there is provided a vertical generally U-shaped slot  4  at the base of which a cartridge location bar  6  is provided. The bar  6  extends horizontally across the bottom of the slot  4 , and is secured to the plate by means of bolts or rivets at either side of the slot  4 . The top of the bar  6  is provided with a pair of parallel horizontal channels  8  and  10 . These channels ( 8  and  10 ) have opposed side slots in which cartridges containing the flow cells and sensors for use in the analysis are located. Thus the bar  6  co-operates with the base plate  2  and front plate  4  to fix the vertical position of the cartridges during the use of the docking station. 
         [0071]    Situated immediately behind the front plate  2  is a carrier member  12  which has two U-sectioned end portions  14  and  16 , each of which includes a set of four apertures into each of which a respective bolt extends. Five of those bolts are visible in  FIG. 1 , and are denoted by reference numerals  18 - 22 . The bolts extend vertically upwards from the base of actuators  36  and  38  such as hydraulic or pneumatic cylinders, to the underside of the carrier member  12 . In between the two end portions  14  and  16 , there is a plate (which will be described in more detail in relation to  FIGS. 3-8 ), which bears fluidic connections for connecting flow cells in the cartridges to a sample delivery/removal system (also described below). 
         [0072]    The carrier member  12  is also slideably mounted on two support and guide posts, one of which is shown at  26 , which extend vertically upwards from the plate  1  to an upper plate  30  to support the latter in position in the mechanism. Each of the support posts includes a carrier member biasing means in the form of a respective compression spring such as the spring  32 . The other post is shown at  40  in  FIG. 4 . 
         [0073]    The frame of the machine comprises base plate  1 , the front plate  2  and the upper plate  30 . A further carrier member in the form of plate  34  is situated immediately beneath the plate  30  and includes apertures through which the support and guide posts extend so that the upper carrier plate can move vertically relative to the machine frame. The carrier member  12  includes apertures  35  and  37  through which the push rods of the actuating cylinders extend (see  FIG. 3 ). The tops of these rods act against the underside of the plate  34 . The upper plate  30  is attached to the instrument frame and provides a reference surface. All plates, carriers the machine frame and the like are constructed of aluminium unless otherwise specified. 
         [0074]    The push rods of the cylinders are denoted by reference numerals  39  and  41 , and constructed of stainless steel. As can be seen from  FIG. 3 , the support and guide post  26  and corresponding vertical support post  40  (the associated compression spring for which is shown at  42 ) flank plate portion  44  of the lower carrier member  12 . That portion is provided in its upper face with a U-shaped channel  46  which accommodates a microfluidic manifold  48  forming part of the fluid supply/removal system. The manifold is a microfluidic system for storing, switching and delivering fluids to the cartridge, and is of a general type known from existing instrumentation, and the rest of the system is shown at  45 . For example the manifold may comprise a first channel for retaining and supplying samples to the cartridge (under control of an inlet valve) and a further channel for receiving used samples from the cartridge. The manifold  48  communicates with inlet ferrule connectors  50  and  52 . Each of these connectors is aligned with a respective female connector, ( 54  and  56 ) in a cartridge  58  (held in channel  8 ), so as to enable fluid to be supplied to each of two flow cells in the cartridge  58 . The manifold also includes two outlet ferrule connectors (not shown) aligned, in use with outlet connectors (not shown) on the cartridge. 
         [0075]    For one or more examples of how ferrules may be used to connect microfluidic systems, reference is made to WO2004/022233 (Epigem). 
         [0076]    The cartridge  58 , when received in the docking mechanism, is located by a channel in the bar  6  and by means of a cartridge mounting block  60 . The cartridge mounting block  60  includes passages  62  and  64  through each of which a respective one of the posts  26  and  40  extends. Unlike the plates  34  and  44 , however, the block  60  is fixed to these posts and is thus supported in a fixed vertical position relative to the base plate  1 . The block  60  includes a slot  66  in its lower surface which is of a substantially T-shaped cross section corresponding to the cross sectional shape of the cartridge  58  so that the cartridge  58  may be slid into and out of the slot  66 . The upper surface of the block  60  includes three vertical bores,  68 ,  70  and  72  which extend from the top of the block to the slot  66  and which accommodate corresponding electrical connectors in the form of vertical spring loaded gold plated contact pins  74 ,  76  and  78  which extend vertically down from a printed circuit board  80  carried on the underside of the upper carrier plate  34 . In the present example the contact pins  74 ,  76  and  78  are coda pins, although other types of spring loaded gold plated contact pins may be used. 
         [0077]    With reference to  FIG. 4 , the plate  44  also carries a set of earthed, electrically conductive vertical location pins, three of which are denoted by numerals  47 ,  49  and  51 , the view of the fourth being blocked by pin  51  (but the corresponding pin is shown at  53  in  FIG. 14 ). In use, the pins  47  and  49  extend through apertures in the cartridge while the remaining two pins engage opposite sides of the cartridge. These four pins further locate the cartridge in the docking mechanism, and also form a Faraday cage around the flow cell in the cartridge. To that end each pin engages a respective opposed downwardly directed pin which is mounted on the circuit board, and connected to the earth rail of the latter, so that the pins form an earthed cage. 
         [0078]    The upper pins are not visible in the sectional side views (and have been omitted from  FIGS. 3 ,  7  and  8 ) for the sake of clarity. However, in the embodiment shown in  FIGS. 13 and 14 , one of the pins is shown at  51   a . Another upper earth pin  53   a  and opposed pin  53  are also shown in  FIG. 14 . The pin  53  engages the opposite side of the cartridge from the pin  51 . 
         [0079]    It will be appreciated that the springs  32  and  42  constitute the clamping mechanism biasing means. 
         [0080]    The plate  34 , and hence the PCB  80  and coda pins, is biased in the downward direction by a pair of compression springs  82  and  84  which function as electrical connector biasing means for the apparatus. Each of the springs  82  and  84  is located on a respective one of two vertical spring location rods  86  and  87  mounted on the plate  34 . 
         [0081]    The PCB  80  carries impedance matching and switching circuitry which enables drive/measurement circuitry to operate the sensor in the cartridge  58 . In this particular example, the drive/measurement circuitry comprises an oscillator circuit with automatic gain control means such as is described in the present Applicant&#39;s UK Patent No. GB 0413134.8 or that in WO00/25118. 
         [0082]    The docking mechanism can accept two cartridges side by side. The apparatus thus has two recesses in the cassette mounting block, each for a respective cartridge, two pairs of ferrules on the microfluidic manifold and two sets of three electrical connectors extending from the overhead PCB. These elements are identical to each other, and only one set of the elements has therefore been described. The corresponding reference numerals followed by an apostrophe are used to denote the elements in the other set. For the sake of simplicity only one set of the elements is shown in  FIGS. 7 and 8 . 
         [0083]    Referring back to  FIG. 3  the three electrical connectors  74 ,  76  and  78  (of said one set of elements) take the form of coda pins, one of which, the pin  74 , is shown in more detail in  FIG. 9 . The coda pin is in the form of an assembly in which a central elongate connecting pin  86  is slideably mounted in a plastics sleeve  88  of, for example, PTFE, PolyAcetal, or Nylon. A downward biasing force is exerted on the pin  86  by a compression spring  90  secured at one end of the inner periphery of the sleeve  88  and at the other to the pin  86 . Sleeve  88  helps to locate the pin  86  prior to the latter making connection with a transducer  92  forming part of a cartridge in the docking mechanism. As can also be seen from  FIG. 9 , the cartridge mounting block  60  carries a dead stop  94  (another similar stop being provided on the other side of the block  60 ) for limiting the extent of allowable downward movement of the board  80 . 
         [0084]    As is indicated above, the transducer  92  forms part of a cartridge, which is shown in more detail in  FIG. 10 . The transducer comprises a quartz crystal plate. The plate is coated on one surface with gold in a pattern that defines a pair of drive electrodes  96  and  98 , each of which is in registry with a respective one of two separate flow cells. The underside of the plate is also coated with gold to form a common earth electrode ( 105  in  FIG. 17 ) on the ceiling of the flow cell. The top surface of the plate carries a further gold coating which has two keyhole shapes openings in which the drive electrodes (and their connection strips  99  and  101 ) are situated, and are spaced from coating  97 . The coating  97  extends around the edge  103  of the crystal to provide a contact for enabling a coda pin engaging the top surface of the plate to connect to the earth electrode underneath. The common earth electrode on the underside of the crystal carries a binding layer (not shown) for binding with a target substance. 
         [0085]    The underside of the transducer  92  is adhered to the top surface of an adhesive membrane  100  the underside of which is adhered to a plastics plate  102  the upper surface of which constitutes a support surface for the transducer  92 . 
         [0086]    The membrane  100  is a three layered structure comprising a carrier layer of 12 microns thickness sandwiched between upper and lower adhesive layers, each of approximately 36.5 microns thickness. An example of suitable material for the membrane is the double sided adhesive tape sold under the trademark FASTOUCH. Adhesive membranes of various thicknesses, greater or less than 85 microns are available, which can be used to control the height of the flow cell. The membrane  100  has two apertures  104  and  106 . 
         [0087]    The shape of the apertures, and hence each flow cell is arranged to provide a suitable profile to ensure laminar flow conditions over the surface, for example the diamond shape illustrated, but other shapes may be designed by those skilled in the art of fluidic design. Each of the apertures  104  and  106  is in registry with a respective electrode  96  and  98 , and thus with an active area of the quartz crystal, i.e. an area of the common earth electrode in registry with one of the electrodes  96  and  98 . The membrane  100  spaces the transducer  92  from the upper surface of the plate  102  so that there is a small gap between each of two said active areas of the quartz crystal and the upper surface of the plate  102 , each gap being bounded by the edge of a respective one of the two apertures  104  and  106 . Each gap constitutes a respective flow cell which communicates with a respective pair of inlet/outlet passages  109 - 112  in the plate  102 . Passages  109  and  111  are inlet passages, whilst passages  110  and  112  are outlet passages. Each passage leads onto a female connector, such as the connectors  114  and  116  which is generally cylindrical and has a tapered end portion, each of the connectors being arranged to receive a respective ferrule of the fluid delivery/removal system. Either or both of the flow cells may be used for the sample to be analysed. Alternatively one may receive the sample, the other a reference solution. 
         [0088]    As can be seen from  FIG. 10 , the inlet and outlet for each flow cell are located at opposite end regions of the latter. Consequently, a sample introduced into the inlet of the flow cell will flow along the length of the flow cell to the outlet, during which period the sample will interact with the active surface of the crystal and the effect of that interaction will be measured. 
         [0089]    As can be seen from  FIG. 10 , the flow cells are situated towards one end of plate  102 , towards the other end of which there is provided a patch  118  of the same material as the membrane  100 . The purpose of this patch is to help to adhere a top plate  120  (of a plastics material) to the bottom plate  102 . The top plate  120  includes a recess  122  which, in the assembled cartridge, accommodates the sensor  92  so that the latter makes no contact with the plate  120 . The membrane  100 , however, does extend beyond the boundaries of the recess  122  so as to adhere the two plates  102  and  120  together at their forward ends. 
         [0090]    As well as securing the transducer  92  in position and defining each flow cell, the membrane  100  provides a suitable seal, by virtue of the adhesive layers, for preventing fluid escaping from the flow cells. 
         [0091]    The upper plate  120  includes through bores  124 ,  125  and  126  through which, in use, the coda pins extend to make contact with the electrodes  96  and  98  and the common earth contact of the transducer  92 . Notches H in the upper plate serve to provide an initial location of the cartridge in the docking station as will be described below. 
         [0092]    The two plates  102  and  120  also include large diameter through bores  127 - 130 , the bore  127  in the plate  120  being in line with the bore  130  in plate  102 , the bore  128  with the bore  129  so that there are two large bore through passages in the cartridge housing (defined by the plates  102  and  120 ). These passages, in use, accept electrically conductive lateral location pins (e.g  47 ,  49 ) of the docking mechanism for assisting in the correct location of the cartridge. The lateral location pins when extended into and past the cartridge engage opposed earth pins on the circuit board  80 , and thus also to act as a Farraday cage around the drive Coda pins and electrodes of the sensor. The spacing between the pins is chosen, based on the frequency of the drive signal to the sensor, to achieve that end. 
         [0093]    Before a cartridge is inserted into the docking mechanism, the hydraulic/pneumatic cylinders  36  and  38  are extended to urge the upper carrier plate  34  and lower carrier member  12  away from each other against action of the springs  32 ,  42 ,  82  and  84 . This moves ferrules  50  and  52  and the coda pins  74 ,  76  and  78  clear of the slot  66  in the cartridge mounting block  60  so that a cartridge can be inserted into the latter. This thus puts the docking mechanism into a condition into which a cartridge can be received or removed.  FIGS. 1 ,  3  and  4  illustrate the docking mechanism when in that condition. 
         [0094]    The cartridge  58  is then slid into one of the channels  8 ,  10  of the cassette location bar  6 , and is moved into the slot  66  until the inboard end of the cartridge  58  abuts the end of the slot. It will be appreciated that the docking mechanism for the cartridge shown in  FIG. 10  will have a sufficient number of electrical and fluidic connectors to provide electrical/fluid connection to both flow cells in the cartridge. 
         [0095]    After a cartridge has been inserted into the docking mechanism, the pressure in the fluid (hydraulic or pneumatic) being used to extend the cylinder  36  and  38  is released so that both cylinders no longer exert any substantial separating force between the carrier member  12  and plate  34 . As a result, the movement of the plate  34  and member  12  is determined by the action of the springs  32 ,  42 ,  82  and  84 . Since the springs  82  and  82  are considerably weaker than springs  32  and  42 , the springs  32  and  42  act on the plate  34  (through the plate  44 , and the shafts  39  and  41  of cylinders  36  and  38 ) to retain the plate  34  in its retracted position. However, at the same time as the cylinders  36  and  38  retract, the springs  32  and  42  also move the carrier member  12  upwards towards the cartridge mounting block  60 . This movement continues (whilst the plate  34  remains stationary) until the ferrules on the fluidic manifold  48  engage the female fluid connectors in the bottom plate of the cartridge. The springs  32  and  42  urge the ferrules into the female connectors with sufficient force to cause the ferrules to form liquid tight seal. 
         [0096]    This condition is illustrated in the docking mechanism shown in  FIG. 4  and in the simplified schematic arrangement of  FIG. 7 . The plate  44  engages the block  60  so that further upward movement of the plate  44  is prevented. At this stage, the springs  32  and  42  can no longer act on the plate  32  through the cylinders  36  and  38  so that the plate  34 , and hence the PCB  80  and the coda pins  74 ,  76  and  78 , moves down towards the cartridge under the action of springs  86 ,  87 . As a result, each coda pin extends into a respective aperture of the cartridge upper plate to engage a drive electrode or, as the case may be, the earth contact on the transducer. The plate  34  continues to move down until the downward movement of the corner plate  34  is prevented by contact with the base of a transverse slot  59  in the mounting block  60 . The height of this slot is selected to ensure that the good contact is made by the spring loaded coda pins on the sensor, and acts as the dead stop  94  shown in  FIG. 9 . This condition of the mechanism is shown in  FIGS. 2 ,  6  and  8 . 
         [0097]    Since the cartridge is located separately from the plate  44  and  34 , the relatively large force exerted by the plate  44  on the cartridge (to obtain a fluid seal), does not result in any large reaction force between the coda pins and the transducer. Thus the invention enables an effective and reliable fluid seal to be provided without exerting large forces on the transducer. 
         [0098]    The embodiment of docking mechanism shown in  FIG. 13  is similar in many respects to the embodiment shown in  FIGS. 1-9 . Therefore, in  FIG. 13 , components corresponding to those shown in  FIG. 1-9  are denoted by the same reference numerals as are used in those figures. In  FIGS. 13 and 14  the block  60  has been omitted to enable the electronic contacts to be shown. The mechanism has two pneumatic/hydraulic actuator cylinders corresponding to cylinders  36  and  38 , but the cylinder  36  has been omitted from  FIG. 13  to enable the post  26  and spring  32  to be seen. In addition the mounting plate  34  whilst present in this embodiment, has been omitted from  FIG. 14  for the sake of clarity. 
         [0099]    In the first embodiment, the carrier member  12  comprises a sub-assembly of two U-shaped end portions  14  and  16  to which a central plate portion  44  is bolted. In the  FIG. 13  embodiment, however, the sub-assembly has been replaced by a single flat plate referenced  12 / 44   a , the end regions of which are denoted by reference numerals  14  and  16  (but are not U-shaped). Each actuator cylinder has a body which is attached to the underside of the plate  12 / 44   a  by means of four vertical bolts, one of which is shown at  20  in  FIG. 13 . 
         [0100]    In the embodiment shown in  FIGS. 13 and 14  the carrier member (i.e. the mounting plate  34 ) is mounted on slidable bushes B 1  and B 2  which run on rods  26  and  40 . Screw heads S 1  and S 2  are recessed into apertures in plate  34  and hold the spring in its compressed state, against plate  30 . Various rods R 1 - 5  are used to precision align the carrier plate  34  with respect to block  60  Stub pin P is one of several similar (others not shown) to precision attach the PCB  80  to plate  34 , i.e. to define a fixed vertical distance between plate  34  and the PCB  80 . 
         [0101]    To assist location of the cartridge a screw  150  comprising an internally spring loaded ball bearing  150   a  is aligned to locate with notches H in the side of the cartridge and provide positive feedback to the user that the cartridge is properly located. 
         [0102]    Screw connectors N 1  and N 2  attach plate L to the block  60 . Plate L is fixed with respect to the frame. This plate provides a continuation of the T shaped channels  8  and  10  from bar  6  into the docking station (i.e. mechanism). Upper plate  30  comprises two parts, a lower part  30   a  and an upper part  30   b , which face each other along a longitudinal phase. In  FIG. 14  the part  30   a  has been removed. In this embodiment a peltier cooling device E is located on top of  30   b  and in good thermal contact with it. This assist in dissipating heat generated on the PCB  80 . Screw connections M 1  and M 2  connect  30   a  and  30   b  and allow the plate  30   b  in turn to be attached to an exterior frame plate. Stub pin T and a corresponding one on the other side of the  30   b  precision space the plate  30   b  from an external cover to allow for the thickness of the cooling device E. 
         [0103]    Other parts visible in  FIGS. 13 and 14  include electrical connectors C to the PCB  80 . 
         [0104]    The embodiment of docking mechanism shown in  FIGS. 15 and 16  is operable to receive four cartridges of the type described above, and is thus for use with an eight channel analyser (two channels per cartridge). 
         [0105]    This embodiment of docking mechanism has numerous features which correspond to features of the other two embodiments of docking mechanism, and are therefore denoted by the same reference numerals as have been used in relation to the other embodiments. Thus, for example, the third embodiment has two hydraulic or pneumatic actuating cylinders  36  and  38  which act between a lower plate  44  carrying ferrules and fluid supply manifold and a upper plate  34  which carries the PCB  80 . In this case, however, the bases of the actuating cylinders  36  and  38  are attached to the plate  44 . 
         [0106]    The cylinders  36  and  38  flank a reference plate  151  attached to a frame of the machine that includes the base plate  1  and the upper plate  30  ( FIG. 16 ). The underside of the reference plate  150  carries five vertical, parallel plastics strips  151 - 155 . The opposing sides of adjacent strips carry grooves for accepting cartridges so that the apparatus accept four cartridges, each retained in the grooves between a respective neighbouring pair of the strips. The plate  151  also includes four slots  156 - 159  through which a respective group of three electrodes extend so as to be able to contact the terminals on a crystal in a cartridge under the plate  151 . One group of the electrodes is denoted by the reference numerals  74 ,  76  and  78 , the other electrodes are identical, and all of the electrodes are identical to those used in the other embodiment described above. In the embodiment shown in  FIGS. 15 and 16 , the circuit board  80  by which the immediate connection to the crystal is made is entirely passive. The active components for driving and sensing the crystals have been removed to the second upper circuit board  161  positioned above the board  80 . The upper board carries four sets of three electrical connectors, generally referenced  160 ,  162 ,  164  and  166  which provide connections between the electrical connectors on the lower board  80  and a separate analyser (not shown) for providing the power to drive the crystals in the cartridges and analysing the resultant signals. Thus  176  and  176   b  are the active drive connections to the board  80  and  176   a  is the earth connection to the board. 
         [0107]    The upper board also carries earth connectors  168 ,  170 ,  172  and  174  for providing earth connections for the earth pins, e.g.  47 . The lower passive board  80  is mounted to the upper active board by metal connecting pins, K1-3. These are also earthed on both the upper and lower boards, and together with the earth connectors  168 , etc form a Faraday cage around the driving connectors between the two boards. The Faraday cage around the cartridges is formed by the earth pins and cartridge locating pins, as with the other embodiments. 
         [0108]    The assembly  44  comprises a mounting section  45  for housing the microfluidic manifold, made of Acetal plastic. The manifold is located in an aluminium insert A to provide rigidity and thermal control under the cover plate D. The manifold connects the macro fluid delivery system to the eight pairs of ferrule connectors (not shown). and hence to the four flow cells of the cartridges in the docking mechanism. 
         [0109]    Each of the support posts  26  and  40  is of a stepped construction, and only this aspect of the support post  40  will be described. That post has an enlarged diameter lower portion  180  separated from a further, upper enlarged diameter portion  182  by a reduced diameter portion  184 . The compression spring  42  acts between the base plate  1  and the underside of the plate  44 , which is slideably mounted on the reduced diameter portion  184 , so that the spring exerts an upward biasing force on the plate  44 . The upper surface of the reference plate  151  is attached to the enlarged diameter portion  182  and thus to the frame of the machine. 
         [0110]    The top of the post  40  has a further reduced diameter portion  186  which extends through an aperture  188  in the plate  34 . That aperture contains a radially inwardly directed flange (not visible) which is of an inner diameter slightly larger than that of the portion  186  and which provides a shoulder for a spring (corresponding to spring  84 ) which acts between the shoulder and the underside of the top plate  30  to exert a downward biasing force on the plate  34 . For the sake of clarity all of the springs have been omitted from  FIG. 15 , although the springs  32  and  42  are shown in  FIG. 16  (from which the base plate  1  and columns  26  and  40  have been omitted). 
         [0111]    The operation of the docking mechanism is similar to that of the other embodiments described above. More specifically, the cartridges are inserted into the spaces between the strips  151 - 155 , while the actuators  36  and  38  are in an extended condition, as shown in  FIG. 15 . The four cartridges are shown at  188 ,  190 ,  192  and  194  in  FIG. 16 , and are orientated with the openings for the electrical contact pins uppermost and the female fluidic connectors on their underside. The cartridges are located by sliding into opposed recesses (one of which is denoted C′ in  FIG. 15 ) located on the sides of strips  151 - 155 . Part way down these recesses are located spring loaded ball bearings which locate in the notches H in the side of the cartridge as it is pushed into the recess, and so positively locates the cartridge. The actuators are then retracted, causing the springs  32  and  42  (which are stronger than the springs acting on the plate  34 ) to move the plate  44  up against the underside of the cartridges so that, initially, the fluidic connections are established. As the actuators  36  and  38  continue to retract, the springs acting between the plates  34  and  30  urge the plate  34  downwards so that the Coda pins engage the electrical contacts on the quartz crystals in the cartridges and so that the earthed upper pins engage the corresponding, aligned earthed lower pins (e.g.  49  and  47 ) to create a respective Farraday cage around each cartridge. 
         [0112]    The embodiment of sensor (shown in  FIGS. 17-19 ) has a dual channel sensing plate  92  of quartz which carries an active gold layer on either side. The biochemically active side of the sensor coated with a continuous coating of gold and is connected to earth. the electrically driven side has a pattern in which the active areas ( 96  and  98 ) are circular, with contiguous rectangular areas  99  and  101  extending to the edge of the quartz plate. These rectangular areas provide four electrical contacts between the active electrodes and the Coda pins in the docking mechanism. The electrically active side (i.e. the side carrying the circular electrodes) is also provided with a “guard” earth electrode  97  which forms a respective ring around each driven circular area and serves to dampen any electrical cross-talk between the two or more resonators. 
         [0113]    In use, the electrical drive applied to the circular electrodes (through the rectangular areas) causes the quartz plate to resonate. This resonance occurs where the electrically driven electrode opposes the ground plate electrode. Conventionally, this causes a transfer shear mechanical mode to be set up under the circular areas of the driven electrodes. 
         [0114]    Applicants have discovered, however, that the presence of the drive signal in the rectangular areas can cause the plate under these areas also to oscillate where the ground plain also opposes the rectangular areas. More particularly, with reference to  FIG. 19  (which shows the overlay between the adhesive membrane and the electrodes), the region of each rectangular electrode between the edge of the earth electrode  105  and the edge of the flow cell (e.g. the shaded area S in  FIG. 19 ) can give rise to oscillations which can either be reflected off the edge of the crystal  92  or place stresses on the crystal (by virtue of the restraining effect of the adhesive membrane). These effects can vary over time, be hard to predict and therefore are detrimental to the accuracy of the instrument. 
         [0115]    The effects are at least mitigated by the spacing of the bottom portion of the electrode  105  (as viewed in  FIG. 17-19 ) from the bottom of the crystal  92  so that there is at least an area G at the edge of the crystal where the rectangular portions do not overlap the earth electrode and therefore do not cause the unwanted vibrations. 
         [0116]    An improved version of the sensor (forming part of the cartridge) shown in  FIGS. 20-22  will now be described. 
         [0117]    The improved resonator design shown in  FIGS. 20-22  has many features in common with or corresponding to those of the design shown in  FIG. 7-19 , and these are denoted by the reference numerals used in  FIG. 7-19  raised by 200. 
         [0118]    In this case, further portions of the earth electrode  205  have been removed where these overlap with the rectangular areas  299  and  301  of the driven electrodes. This change means that there are little or no areas of opposing driven and earth electrodes where the membrane  300  touches the crystal plate  292 . Thus the area of crystal under the rectangular portions and in contact with the adhesive membrane does not significantly oscillate when the sensor is driven. As a result, the resistance of the quartz plate at resonance is not affected by damping caused by the presence of the membrane contacting this area, and a lower resistance and higher Q factor are achieved. 
         [0119]    These improvements illustrated in the graph of  FIG. 23 , in which the left-hand column of each graph shows the resistance or, as the case may be, Q factor of the first embodiment sensor, whilst the right hand column of each graph shows a corresponding measurement for the improved version. 
         [0120]    As can be seen from  FIG. 22 , the lower edges  350  and  352  of the electrode  205 , i.e. the edges which extend across the rectangular portions  301  and  299 , are inclined in the same sense as the corresponding adjacent edge  354  and  356  of the aperture in the membrane, and hence the flow cell. Thus, the edges of the electrode substantially conform to the adjacent edge of the flow cell, thereby further reducing the overlap mentioned above. 
         [0121]    The result of the improvements discussed above is that the sensor, when used in contact with a liquid, has reduced noise and improved unit to unit variance. Additionally, it has been found that the elastic properties of some adhesives may change with time, and that this can give rise to slow changes in the damping of the resonator if substantial portions of the crystal under the membrane are vibrated. This is also undesirable as it leads to baseline drift. With the improved design, the changes in the elastic or mechanical properties of the adhesive or the membrane have a much reduced effect. This can contribute to improved baseline stability and drift which is important in certain types of biochemical assay. 
         [0122]    The improvements are optimised when the edge of the membrane does not overlap the edge of the modified electrode boundary at all. However, improvements over the earlier design are also achieved where there is a significant reduction of overlap. It is desirable not to extend a flow cell boundary too far outside the electrode boundary because this exposes uncoated quartz to the analyte fluid. This may result in non-specific absorption of coatings and the like to the quartz which is undesirable. 
         [0123]    It can also be seen from  FIGS. 21 and 22  that the outboard ends  358  and  360  of the rectangular portions are of an enlarged width. This improves the tolerance of the analytical apparatus to changes in alignment between the Coda pins and the electrodes. 
         [0124]    The analytical apparatus shown in block diagram form in  FIG. 24  comprises a docking station, referenced  403 , of the type shown in  FIGS. 14 and 15  connected to a fluid supply system  45  (also shown in those figures). The operation of the fluid supply system  45  is controlled by a controller  400  which is also connected to the docking mechanism  403 , and controls the operation of the actuating cylinders  36  and  38 , selectively to open and close the mechanism. In  FIG. 24 , the mechanism has received four cartridges,  404 ,  406  and  408  and  410 , which are clamped in position in the docking mechanism. The controller  400  also controls the circuitry on the board  80 , so as to drive the sensors in the cartridges, and receives the signals resulting from the oscillation of the sensors, which are then analysed in the controller  400 .