Abstract:
A method and apparatus for a slide loading/unloading system is described. A slide storage cassette is provided to store slides in which the slides are stored with an end protruding from the slide storage cassette. A slide feeder is described having grippers, which grip the end of a slide and transport the slide to a sample holder. The sample holder receives and retains the transported slide.

Description:
FIELD OF THE INVENTION 
     The present invention relates to an apparatus and method for use in a slide loading/unloading system and in particular, to a microarray loading/unloading system. 
     BACKGROUND 
     Deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and proteins are complex molecules that are integral to every living organism. DNA contains information required to define a structure and process of a cell. RNA transfers that information by becoming a template for protein synthesis and enabling protein synthesis process. Proteins initiate and control all functions within a cell. Because of the fundamental nature of these molecules to biology, researchers have developed methods of experimenting and characterizing their structure. One method that is commonly used is called “hybridization”. 
     Hybridization takes advantage of the complimentary nature of RNA and DNA to characterize their sequence. Typically, a reference strand of DNA (the “target”) is bound to a substrate. One or more types of DNA under test (the “probes”) are labeled with either radioactive or fluorescence tags. The probes are then mixed with the target. Probe molecules with a sequence similar that of to the target will bind or hybridize to the target molecules. Dissimilar probe molecules will not bind and be washed away in a subsequent rinsing process. By measuring the quantity of bound probe molecules, a researcher can determine the likeness between the probe and target. This method is used to measure a variety of biological characteristics including gene expression, genotype, and gene sequence. 
     Hybridization experiments are normally conducted in large quantities in order to be generally useful. There are approximately 100,000 genes in the human genome, several thousand of which are considered in a typical study. Technologies to allow for massive parallel hybridization experiments have been developed. 
     One such technology is the microarray. A microarray is a substrate, typically a one-by-three inch glass slide, that is “spotted” with an array of reference target genes, typically in the form of DNA. Several thousand to several tens of thousands of genes (or partial genes) in the order of 100-114 microns in diameter are generally spotted onto a typical microarray. This allows a researcher to compare the probe DNA to many targets simultaneously. The result is the ability to characterize the gene profile of a tissue or cell type under a specified condition. 
     Spotting is accomplished by using an instrument called an “arrayer”. A typical arrayer is a robot that can spot 40 to 100 microarrays in an automated fashion. Arrayers are usually kept in an environment in which humidity is controlled, since it affects the rate of evaporation of the solution to be spotted. This is particularly important where there is significant evaporation before the solution is transferred to the substrate. Cleanliness will directly affect the quality of any microarray because the information gleaned from the microarray is the image captured at the surface of the substrate. Any artifact, such as dust or fingerprints, will degrade the fidelity of the microarray. Thus, microarrays are manually loaded into and removed from the arrayer which may affect the quality of the spotted microarray. 
     The next step of the microarray process is to introduce the probe DNA. The DNA is mixed in a buffer solution to enable its transfer. A small amount of probe solution is placed on the surface of the microarray. A thin piece of glass is then used to sandwich the probe with the microarray causing the probe to spread across the region that contains the target. The probes are typically labeled with fluorescence tags. The fluors convert incident light, referred to as “excitation light”, into fluoresced light, referred to as “emitted light”. However, the fluors are generally susceptible to damage caused by ambient light and thus, such light should be avoided. Excitation caused by ambient light degrades the efficiency of fluors prior to scanning with an imager. This damage is called photobleaching. 
     Next, the target and probe are hybridized. This is accomplished by putting the microarray into a humid, thermally controlled environment where it is “baked”. During this stage, the target and probe molecules with similar structures bind. After hybridization, the thin piece of glass is removed and the microarray is rinsed to wash away the non-binding probe DNA. At this point, the microarray is susceptible to damage from dirt, heat and light. Image degradation caused by contamination from handling continues to be a problem. Heat can cause the probe and target to become disassociated. Further, the fluorescent labels on the probe DNA are susceptible to photobleaching. 
     Finally, the microarray is imaged. The substrate is loaded into an microarray imager which excites the fluors and senses the emitted light. The resulting image is analyzed to determine the density of probe DNA that hybridized to each target DNA spot. This information is used to characterize the state and structure of the probe DNA. Any dirt or marks will contribute to fluorescence which is not related to DNA density. As a result, these artifacts will reduce the accuracy of the calculations. 
     After the process is complete, the microarrays are often saved for later inspection. They need to be properly stored if they are to be useful in later imaging. 
     If the procedure above is performed manually, the procedure will be costly and time consuming. A researcher or technician is required to handle each microarray at every step in the process. The imaging process is particularly labor intensive. Each slide is inserted by hand for single slide imaging while the user waits to load the next slide. The problem becomes acute for high volume users. Research facilities that process several hundred microarrays a day will need to hire several technicians just to keep up with the imaging. 
     There is a further problem with tracking microarrays. In a typical lab there are many avenues of research being pursued simultaneously by separate research groups. Since the microarrays are identical to the naked eye, they are difficult to sort manually. Even if they are labeled for tracking, the large number of microarrays being used will result in some confusion and errors during the process. 
     As described above, microarrays are prone to damage each time that they are handled. Everything ranging from dust to fingerprints cause image artifacts that pollute the final result. Statistically, when a large number of microarrays are processed, the amount of degradation will be proportional to the amount of handling of each slide. 
     Microarrays are susceptible to damage if they are not stored properly. Everything from dust to light can affect the data that is gleaned from the microarray. 
     There are automated microarray scanning systems available currently. These systems, however require the substrate to be placed in a metal “sub-frame” or “clip” prior to loading it into the storage mechanism. Both the substrate and frame are then located into the scanning field and subsequently scanned. This approach is forgiving of dimensional variability in substrates. Further, it provides for metal-on-metal wear surfaces, which provide for a more tolerant system design. However, as throughput demands increase, the sub-frame approach becomes limiting. 
     Typically, high-throughput microarray applications process batches of microarrays numbering from 10 to 100, and this is increasing. Sub-frames are less attractive to the user because of the added manual labor placing each microarray into a sub-frame. Additionally, the user needs to gather sufficient sub-frames to process a batch of microarrays. Sub-frames also increase the amount of space required by each microarray in a storage mechanism and may make a system built to handle 100 or more microarrays unmanageable to use. 
     Downstream microarray quantitation processes require that microarray be accurately placed in a scanning field repeatedly. Sub-frames have been shown to be inadequate in this respect. 
     SUMMARY 
     In accordance with the invention, a slide storage cassette stores a plurality of slides, with an end of each slide protruding from the cassette. A slide feeder having grippers grips the end of a slide and transports the slide to a sample holder. The sample holder receives and retains the transported slide wherein one or more functions are performed on the slide. The slides are held in the cassette without the frames, thereby eliminating the problems associated with frames. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The invention description below refers to the accompanying drawings, of which: 
     FIG. 1 is an overview of an exemplary microarray slide loading/unloading system in accordance with an embodiment of the invention; 
     FIG. 2 is a slide storage cassette and an elevator in accordance with an embodiment of the invention; 
     FIG. 3 is a top view of a slide feeder in accordance with an embodiment of the invention; 
     FIG. 4 is a bottom view of the slide feeder shown in FIG. 3; 
     FIG. 5 is a hidden-line detail of the top view of the slide feeder shown in FIG. 3; and 
     FIG. 6 is a sample holder in accordance with an embodiment of the invention. 
    
    
     DETAILED DESCRIPTION 
     While the invention has been conceived with the loading and unloading of microarray slides in mind, the invention may be adapted for use in other areas. For example, one area of such usage may be microscopic slides. In the passages to follow, specific embodiments of the invention will be described. The specific embodiments are given to aid in the understanding of the invention and thus, should not be construed as limitations to the invention. 
     As shown in FIG. 1, a microarray slide loading/unloading system  100  in accordance with an embodiment of the invention comprises a slide storage cassette  114  containing slides  115 , a slide feeder  116 , a sample holder  118  and an elevator  120 . 
     The slides  115  are inserted into the cassette  114  with one end protruding towards the slide feeder  116 . The elevator  120  moves the cassette  114  up and down until a selected slide is aligned with the slider feeder  116 . Once the selected slide  115  is aligned, the slide feeder  116  grips the protruding end and transports the slide  115  to the sample holder  118 . As will be further described, the slide feeder  116  is configured to compensate for the width discrepancies of the slide  115 . The sample holder  118  receives and retains the slide  115 . Within the sample holder  118 , there are precision reference surfaces that precisely positions the slide  115 . The slide  115  is subjected to one or more functions in accordance with a designed instrumentation. For example, the instrument may be a microarray scanner, a microarray spotter, a microarray hybridizer, a microarray washer, a microarray probe processing instrument and so forth. 
     Once the desired functions have been performed on the retained slide  115 , a reverse operation similar to that described above is performed. The slide feeder  116  grips an end of the retained slide  115  from the sample holder  118  and transports the slide  115  back to the cassette  114 . Once the slide is received by the cassette  114 , the elevator  120  is activated to align another slide with the slide feeder  116  to repeat the process. 
     The cassette  114  is detachable from the elevator  120 . A latch  124  located at the elevator  120  latches the cassette  114  to the elevator. 
     FIG. 2 is a more detailed view of the slide storage cassette  114  and the elevator  120  shown in FIG.  1 . The cassette  114  comprises a body  202  having a chamber  204  that has a plurality of horizontal grooves  206 . The opposing grooves  206  form individual compartments to retain the slides  115 . Specifically, the grooves  206  support and contact the slides  115  along the longitudinal peripheries of the sides. The contact avoids the sample area of the slide  115 . The spacing between the grooves is selected to allow individual slides  115  to be captured laterally by the slide feeder  116 . 
     Within each compartment, there is spring (not shown) to retain the slide by friction. Each spring prevents the individual slides from falling out of the cassette  114 . However, the spring retention force should be applied as not to cause the slide feeder  116  to have trouble extracting the individual slides. 
     It is desirable to structure the cassette  114  such that both ends of the slide  115  protrude from the cassette  116 . The protruding end of the slide  115  away from the slide feeder  116  provides easy manual access without risk of finger contamination to the sample portion of the slide  115 . 
     The elevator  120  comprises a motor  232 , a leadscrew  234 , and a carriage  236  mounted on a base  238 . The cassette  116  attaches to the carriage  236 . Although not shown in the drawing, the elevator base  238  houses a toothed timing belt and pulleys that connect the motor shaft to the leadscrew. 
     When actuated, the motor  232  rotates the leadscrew  234  which engages a leadscrew nut  235  in the carriage  236  and causes the cassette  114  to move up and down moving with the carriage  236 . An arm  242 , attached to the base  238 , supports a linear bearing  242  which guides the motion of the carriage  236 . The motor  232  is preferably a stepper motor. 
     It is desirable to calibrate the motor  232  to position the slides at the correct position for lateral grip by the slide feeder  116 . This may be performed by an interrupt sensor  246  located on is the carriage  236  and sensor flag  248  located on the arm  242 . As the sensor flag  248  passes through the sensor  246 , a signal is sent to a motor controller (not shown) that energized the motor. The interruption point is the calibrating point by which all subsequent carriage positions are controlled as relative positions 
     FIG.  3  and FIG. 4 are a top view and a bottom view of the slide feeder  116 , respectively. The slide feeder  116  comprises a feeder base  302  having on its top surface two movable belt feed assemblies  304 ,  306 . Between the two assemblies  304 ,  306 , there is a guide track  342  that guides the slide  115 . It is preferable that the guide track  342  be generally resistant to the abrasion caused by the motion of the slide  115 . For example, it may be made of chrome-plated steel or hard stainless steel. Each assembly  304 ,  306  is powered by a motor  329 ,  339 . A solenoid  346  is mounted at the base  302  and, when actuated, it causes the two assemblies  304 ,  306 , supported on linear bearings  362 , to close towards the guide track  342  and engage the slide  115 . 
     The slide feeder  116  further comprises a interrupt sensor  352  and a sensor flag  354  attached to the base  302  and one of the assemblies  304 ,  306 , respectively, to detect a closed or open position of assemblies  304 ,  306 . 
     As shown in FIG. 5 each belt feed assembly  304 ,  306  comprises a belt  322 ,  332  held in place by three pulleys  324 ,  326 ,  328 ,  334 ,  336 ,  338 . The belts  322 ,  332  are toothed elastomer belts that grip an end of the slide  115  and retain the slide as it travels through the slide feeder  116 . The tooth  117  of the belts are bendable and the belts adapt to the width of the slide  115 . Each motor  329 ,  339 , when actuated, uses one of the pulleys  328 ,  338  to rotate the belts  322 ,  332 . 
     The solenoid  346  is located approximately at midpoint of the feeder base  302 . The solenoid has two pins  364 ,  366  which are located at opposing points with respect to the center of the solenoid. Each pin  364 ,  366  corresponds to a cam surface (not shown) located in an assembly  304 ,  306 . When the solenoid  346  is actuated, the solenoid rotates and thus brings the pins  364 ,  366  into engagement with their corresponding cam surfaces and draw the two assemblies  304 ,  306  toward the guide track  342 . Conversely, when the solenoid  346  is de-actuated, spring forces separate the movable belt feed assemblies  304 ,  306  from the guide track  346 . 
     In the closed state, the belts  322 ,  332  grip the slide  115  and draw the slide  115  into the guide track  342 . Continued movement of the belts propels the slide  115  to the sample holder  118  (FIG.  1 ). Idler pulleys  356  are positioned behind each belt  322 ,  332  to support the back side of the belt. This allows the belts  322 ,  332  to apply a constant and steady traction force to the slide  115  as it is propelled through the guide track  342  regardless of the position of the slide  115  along the guide track. 
     As shown in FIG. 6, the sample holder  118  comprises retainer brackets  606 ,  608  mounted on a base  602 . The base  602  also supports a spring loaded platform  604 . The brackets  606 ,  608  adapted to position each slide along a longitudinal edge. Specifically, the bracket  606  is spring loaded toward the bracket  608 , which is fixed in position. The platform  604  has a ramped portion adapted to receive the slides  115  emerging from the slide feeder  116 . 
     Accordingly, as a slide enters the sample holder, it passes between the platform  604  and the horizontal surfaces  606   a  and  608   a  of the brackets and continues to move until it reaches a precision stop  609 . The platform  604  positions the slide against the surfaces  606   a  and  608   a,  and the spring loaded bracket  606  position the slide laterally against a precision surface (not shown) in the bracket  608 . When the slide reaches the stop  609 , the motors stall, thereby preventing damage to the slide or the belts. A position sensor (not shown) can provide a signal to stop the belt movement after the slide is fully positioned. 
     Once the functions to be performed on the slide  115  are completed, a reverse operation of the loading operation is performed. The solenoid  346  is actuated and the belts  322 ,  332  rotate in a reverse direction to propel the slide  115  towards the cassette  114  and insert into a compartment of the cassette. Once the slide  115  is thus inserted, the solenoid  346  is de-actuated to release the grip on the slide  115 . The elevator  120  then operates to align another slide with the slide feeder  116  to repeat the process. 
     The belts  322 ,  332  may be made of carbon impregnated urethane or other elastomer to allow for the dissipation of static charges. Conductive paths to dissipate charges from pulleys, the guide track and the slides themselves can be implemented with static-dissipation brushes and the use of electrically conductive materials.