Patent Publication Number: US-2007122834-A1

Title: Biochip substrate holding method and biochip-reader

Description:
This application is a divisional of application Ser. No. 10/928,184, filed Aug. 30, 2004. 
    
    
     BACKGROUND OF THE INVENTION  
      1. Field of the Invention  
      The present invention relates to a biochip substrate holding method and a biochip-reader using the above mentioned method, and in more detail, to a holding method in which positions of biochip sites can be arranged in a good repeatability and a biochip-reader using the above mentioned method.  
      2. Description of the Prior Art  
      There are conventional biochip-readers which are configured to read fluorescence generated from a sample by irradiating exciting light such as laser light onto the sample in each biochip site (for example, refer to Patent Document 1).  
      These conventional biochip-readers include scanning types (scan type) that use a microlens array in which a plurality of microlenses is arranged and the irradiating beam is scanned after passing through the microlenses, or non-scanning types (scan-less type) that use no scanning, or those that do not use a microlens-array.  
      In all of these biochip-readers, a substrate used for biochips (hereinafter called the biochip substrate or simply the substrate) is normally fixed to a base using a sample holder adopted for microscopes or its equivalent.  FIG. 1  shows an example of the above sample holder mechanism. The sample holder is (as shown in  FIG. 1 ) equipped with glass slide support  2  and pivoting arm  4  which is mounted so as to enable it to pivot via coupling  3  on base  1  and is used to press end faces  5   a  and  5   b  of the two sides of rectangular glass slide (equivalent to the biochip substrate)  5 , adjacent to each other, to glass slide support  2  using the action of a spiral spring (not shown in the drawing) provided in coupling  3  (for example, refer to Patent Document 2).  
      [Patent Document  1 ]
          Gazette for Japanese Laid-open Patent Application No. 2003-028799        

      [Patent Document  2 ]
          Gazette for Japanese Laid-open Patent Application No. 10-39230        

      However, conventional sample holders have the following disadvantages: 
      (1) Because the positioning mechanism of sample holders is insufficient in biochip mounting and dismounting, positions of biochip sites deviate in directions of x, y, and/or z (the directions of x and y are those orthogonal to the optical axis and the direction of z is the direction of the optical axis itself). This necessitates position-locating after mounting.     (2) In the case of a scan-less type, positions of microlenses deviate from positions of sites and thus position-aligning becomes necessary.     (3) Even if the sample holder is not a scan-less type, deviation of positions must be corrected using pattern recognition or the like.     (4) Since, for biochip substrates, accuracy in their external dimensions is not very precise that their sides are not straight and the adjacent two sides are also not perpendicular to each other, positioning using glass slide support  2  of the above mentioned sample holder and pivoting arm  4  is not exact, and its repeatability is low, introducing no exact positioning.     (5) Since the biochip fixing scheme when samples are spotted to each site of a biochip is different from the biochip fixing scheme used in the sample holder, in the case of a scan-less type, deviations (in the directions of x, y, and θ) are generated between sites  6  and corresponding light beam irradiation positions  7 , as shown in  FIG. 2 ( a ). In addition, θ shows the angle formed in the surface of the biochip substrate  14 , which is orthogonal of the optical axis. Each site and corresponding light beam irradiation position must coincide with the other as shown in  FIG. 2 ( b ).    

     SUMMARY OF THE INVENTION  
      The objective of the present invention is to solve the above problems and so to offer a biochip substrate holding method which does not cause deviation of site positions during measurement, and thus does not require position-aligning by making holding mechanisms of biochip substrate equal both in arranging multiple samples on a biochip and in mounting a biochip to a biochip-reader, and to offer a biochip-reader using the above mentioned method. 
    
    
     BRIEF DESCRIPTION OF DRAWINGS  
      [ FIG. 1 ] 
       FIG. 1  is a configuration drawing indicating an example of conventional sample holders.  
      [ FIG. 2 ] 
       FIG. 2  is a drawing showing the relationship between site positions and corresponding light beam irradiation positions on a biochip substrate.  
      [ FIG. 3 ] 
       FIG. 3  is a configuration drawing indicating an embodiment of the substrate holding mechanism for achieving the biochip holding method concerning the present invention.  
      [ FIG. 4 ] 
       FIG. 4  gives two bird&#39;s-eye views of a biochip substrate holding mechanism of the present invention.  
      [ FIG. 5 ] 
       FIG. 5  is a drawing indicating another embodiment of a biochip substrate holding mechanism of the present invention.  
      [ FIG. 6 ] 
       FIG. 6  is a drawing indicating further another embodiment of a biochip substrate holding mechanism of the present invention. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS  
      The present invention will be described below in detail using drawings.  FIG. 3  is a configuration drawing indicating an embodiment of the substrate holding mechanism for achieving the biochip holding method concerning the present invention.  
      In  FIG. 3 , numeral  10  denotes a base, numerals  11 ,  12  and  13  denote stays attached to base  10 , numeral  14  a biochip substrate (hereafter simply called “substrate”) on which multiple samples are arranged in an array, numeral  15  denotes sites on substrate  14 , and numeral  16  a pressing means.  
      Stays  11  to  13  are fixed to base  10  so that the side faces of two adjacent sides of substrate  14  mounted onto base  1  touch these stays. These stays are formed with round columns or cylinders (for example, pins) and configure point contacts with side faces of substrate  14 .  
      Pressing means  16  applies a pressing force in an oblique direction towards the touching sides from the corner where two sides, not being the touching sides, cross each other, when substrate  14  is touched to the three stays.  
      In such a construction, if two adjacent sides of substrate  14  are pressed to stays  11  to  13 , substrate  14  is always mounted on the predetermined position of base  10  with good repeatability, without being affected by the bend of the sides or the angle between two sides because substrate  14  contacts with these three points only.  
      In this case, as shown in  FIG. 4 , the substrate is held using essentially the same three-point contact structure either in spotting of biochip samples ( FIG. 4 ( a )) or during measurements with the reader ( FIG. 4 ( b )). Employing the above structure eliminates the generation of deviation in site positions when measurement is made.  
      Further, the present invention is not restricted to the above embodiment but may be embodied in other specific forms, changes, and versions without departing from the true spirit thereof.  
      For example, it is also acceptable to apply the pressing force by pressing means  16  in two directions perpendicular to each side of two sides orthogonal to each other as shown in  FIG. 5 , not the oblique direction as described in the above embodiment.  
      Further, the external shape of stays  11  to  13  is not limited to a round type but may be polygonal, for example, triangular as shown in  FIG. 6 . However, their edges must be touching in point contacts with the biochips.  
      In addition, DNA, RNA, proteins, and bio-metabolites (low-molecular materials in living bodies other than protein) and the like are used as samples.  
      Further, spotting of samples to the sites of a biochip can be carried out using pin, ink-jet, electrostatic adsorption and the like by holding a substrate with the substrate holding mechanism of the present invention.  
      Furthermore, a substrate which is the object of holding may be a glass slide or a cartridge.  
      As apparent from the above description, the present invention has the following effects: 
      (1) Positional deviation during measurement using a reader can be minimized by making the biochip substrate holding mechanism of the reader agree with the holding mechanism when samples are spotted onto a biochip substrate.     (2) It is not necessary to perform adjustment of site position-aligning and pattern matching based on images required in conventional readers.     (3) Since the biochip substrate is supported at three points, good supporting reproducibility can be easily obtained without being affected by the linearity of substrate sides and orthogonality of two sides, or the like.     (4) Glass slides or synthetic-resin or cartridges can be used as biochip substrates.