Abstract:
A biochip production apparatus, which forms an array of biopolymers on a substrate, has a substrate moving unit which moves the substrate up, down, left and right, and a plurality of solution supply units which are disposed to be fixed, in which solutions containing biopolymers are stored, which deposit the solutions on the substrate. When the solution supply units deposit the solutions on a predetermined position of the substrate, the substrate moving unit moves the substrate to a predetermined position.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
       [0001]     This application is based upon and claims the benefit of priority from the prior Japanese Patent Applications No. 2004-263218, filed on Sep. 10, 2004, the entire contents of which are incorporated herein by reference.  
       BACKGROUND OF THE INVENTION  
       [0002]     1. Field of the Invention  
         [0003]     The present invention relates to a biochip production apparatus for producing a biochip.  
         [0004]     2. Description of the Related Art  
         [0005]     A biochip in which biopolymers such as DNA, protein, etc. are fixed at high density has appeared. For example, this type biochip is formed so that tens to tens of thousands of heterogenous biopolymers are arranged on a substrate.  
         [0006]     JP-A-2002-243736 is referred to as a related art of a method of producing a biochip by arranging biopolymers on a substrate.  
         [0007]      FIG. 8  is a partly schematic view of a dispensing device for achieving the biochip producing method described in JP-A-2002-243736. The dispensing device  1  includes a reagent dispenser  2  having an elongate open capillary channel  4 . The capillary channel  4  is made from a pair of long and narrow members  2   a  and  2   b.  The members  2   a  and  2   b  approach each other so that the capillary channel  4  is tapered off to a tip of a lower end of the channel  4 , that is, to a tip region  3  of the channel  4 . A certain amount of a reagent solution  5  is held in the tip region  3 .  
         [0008]     The reagent dispenser  2  is connected to a connection member  8  so that the reagent dispenser  2  can also move up and down in accordance with the up/down motion of a solenoid piston  7  of a solenoid  6 . The solenoid  6  is connected to an arm  9  so that the dispensing device  1  as a whole can be moved up, down, left and right to a predetermined position suitably by the arm  9 .  
         [0009]     As shown in  FIG. 9 , the dispensing device  1  is attached to a dispensing device cage. While the dispensing device  1  comes near to or goes away from a dispensing position, the tip of the dispensing device  1  softly touches a surface of a support  210  so that the solution at the tip of the reagent dispenser  2  can be dispensed. Detailed description will be made below.  
         [0010]     The dispensing device  1  is moved in an X-axis (horizontal) direction by a worm screw  80 . The worm screw  80  is driven to rotate by a stepper motor  82  controlled by a control unit  77 . The stepper motor  82  is attached to a sleeve  86  at one end of the worm screw  80 . The other end of the worm screw  80  is rotatably supported by a sleeve  84 .  
         [0011]     One sleeve  86  is fitted onto a fixed rod  88  mounted between a pair of frame bars  90  and  92  while the other sleeve  84  is fitted onto a worm screw  94  rotatably mounted between a pair of frame bars  96  and  98 . The worm screw  94  is driven to rotate by a stepper motor  99  controlled by the control unit  77 . The rotations of the worm screws  80  and  94  are controlled in this manner so that the worm screw  80  as a whole is moved in a Y-axis (vertical) direction.  
         [0012]     According to this configuration, the position of the dispensing device  1  can be decided as an arbitrary position in the X-axis and Y-axis directions so that the solution in the dispensing device  1  can be spotted on a surface of a support (e.g. biochip)  210 .  
         [0013]     The above method however has the following problem.  
         [0014]     Although reduction in weight of the reagent dispenser  2  is preferably required for improving the speed of the operation for spotting, a solution reservoir for reserving the reagent solution needs to be provided separately so that the reagent dispenser  2  can go to the solution reservoir as a supply base if reduction in weight of the reagent dispenser  2  is attained. In this case, both operation and structure are complicated so that a long time is taken, and that the reagent dispenser  2  is apt to be dried. There is therefore a problem that an inhomogeneous site is generated because the amount of the spot is not uniform.  
       SUMMARY OF THE INVENTION  
       [0015]     An object of the invention is to provide a biochip production apparatus in which solutions can be supplied directly to spotting pins (hereinafter referred to as “pins” simply) to attain improvement in speed, simplification in structure and uniformity in amount of a spot on each site simultaneously.  
         [0016]     The invention provides a biochip production apparatus for forming an array of biopolymers on a substrate, having: a substrate moving-unit which moves the substrate up, down, left and right; and a plurality of solution supply units which are disposed to be fixed, in which solutions containing biopolymers are stored, which deposit the solutions on the substrate.  
         [0017]     In the biochip production apparatus, when the solution supply units deposit the solutions on a predetermined position of the substrate, the substrate moving unit moves the substrate to a predetermined position.  
         [0018]     According to this configuration, when the substrate is moved without moving the solution supply units, the array of biopolymers can be formed on the substrate. It is easy to improve the moving speed of the substrate. According to the biochip production apparatus, the speed of the operation for spotting can be therefore improved easily. Both structure and operation for solution supply are easy and simple. In addition, a proper quantity of solution can be deposited easily on the substrate at the time of spotting. As a result, a homogeneous site can be formed easily.  
         [0019]     In the biochip production apparatus, the substrate moving unit has a stage, on which the substrate is disposed, which enables to move up, down, left and right.  
         [0020]     In the biochip production apparatus, each of the solution supply units stores solutions containing biopolymers different in kind, respectively.  
         [0021]     In the biochip production apparatus, the substrate is located in an upper or lower side of each solution supply unit.  
         [0022]     In the biochip production apparatus, each of the solution supply units has a syringe or a needle which enables to supply the solutions with using capillarity.  
         [0023]     In the biochip production apparatus, each of the solution supply units deposits the solutions on the substrate at a point or at multi-points.  
         [0024]     In the biochip production apparatus, a pitch of the multi-points on the substrate is not larger than  1  mm.  
         [0025]     In the biochip production apparatus, the solution supply units deposit the solutions on the substrate by a mechanical contact method, an ink jet method, or an electrostatic adsorption method.  
         [0026]     The invention also provides a biochip production apparatus, wherein solutions on a substrate deposited by another biochip production apparatus, which is mentioned above, are transferred onto another substrate to form an array of biopolymers.  
         [0027]     The following advantages can be obtained in accordance with the biochip production apparatus.  
         [0028]     (1) When only the substrate is moved to a predetermined position while each solution supplier is fixed, the solution in the solution supplier can be spotted on a surface of the substrate. On this occasion, the biochip production apparatus can perform the operation for spotting particularly at a higher speed than the biochip production apparatus as the prior art.  
         [0029]     (2) Because there is no moving mechanism in the solution supply unit, the biochip production apparatus is simpler in structure than the biochip production apparatus as the prior art.  
         [0030]     (3) Because each solution supplier is formed so that an adequate quantity of solution can be always supplied to the substrate, a uniform amount of solution can be spotted so that a homogeneous site can be formed easily. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0031]      FIG. 1  is a configuration diagram of important part showing a biochip production apparatus as an embodiment of the invention;  
         [0032]      FIG. 2  is a view showing an example of spotting due to the biochip production apparatus depicted in  FIG. 1 ;  
         [0033]      FIG. 3  is a configuration diagram of important part showing another embodiment of the invention;  
         [0034]      FIG. 4  is a configuration diagram of important part showing a solution supplier as another embodiment of the invention;  
         [0035]      FIGS. 5A and 5B  are configuration diagrams of important part showing a further embodiment of the invention;  
         [0036]      FIGS. 6A and 6B  are configuration diagrams of important part showing a further embodiment of the invention;  
         [0037]      FIG. 7  is a configuration diagram of important part showing a further embodiment of the invention;  
         [0038]      FIG. 8  is a configuration diagram showing an example of a dispensing device for achieving a background-art biochip producing method; and  
         [0039]      FIG. 9  is a view showing the configuration of a portion in which the dispensing device depicted in  FIG. 8  is mounted. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0040]     Embodiments of the invention will be described below in detail with reference to the drawings.  FIG. 1  is a configuration diagram of important part showing a biochip production apparatus as an embodiment of the invention. As shown in  FIG. 1 , the biochip production apparatus of the embodiment has solution suppliers  10 ,  20  and  30 , a stage  100 ; and a substrate  110 .  
         [0041]     The solution supplier  10  has a solution supply portion  11  and a pin  12 . The solution supply portion  11  is formed so that a biopolymer-containing solution can be reserved in the solution supply portion  11  and can be supplied to the pin  12 . The pin  12  is shaped like a needle and has a structure in which a base portion of the pin  12  is connected to the solution supply portion  11  so that the solution in the solution supply portion  11  is led to a tip portion of the pin  12 .  
         [0042]     Each of the other solution suppliers  20  and  30  has the same configuration as that of the solution supplier  10 . These solution suppliers are connected and fixed by a support member not shown so that the solution suppliers are arranged at regular intervals.  
         [0043]     The stage  100  is shaped like a plate and formed so that the stage  100  as a whole can be moved up, down, left and right by a known moving mechanism. The substrate  110  is detachable attached onto the stage  100 .  
         [0044]     According to this configuration, when only the stage  100  is moved up, down, left and right suitably while the solution supplier  10  is fixed, solutions led to the tip portions of the pins  12 ,  22  and  32  (represented by the pin  12 ) can be spotted on desired positions of the substrate  110 , respectively.  
         [0045]     Assume now that the solution supplier  10  is filled with a kind A of solution (hereinafter referred to as “solution A”), the solution supplier  20  is filled with a kind B of solution (hereinafter referred to as “solution B”) and the solution supplier  30  is filled with a kind C of solution (hereinafter referred to as “solution C”) as shown in  FIG. 1 .  
         [0046]     (1) The stage  100  is moved to a predetermined position so that a place of the substrate  110  on which the solution A will be deposited comes just under the pin  12 . Then, the stage  100  is moved up so that the solution A is spotted on the surface of the substrate  110  in the condition that the substrate  110  abuts on the tip portion of the pin  12 . Incidentally, the moving speed of the stage  100  can be changed so suitably that the stage  100  can come near to or go away from the pin  12  rapidly particularly at the time of spotting.  
         [0047]     After spotting, the stage  100  is moved down to a predetermined position so that the substrate  110  can be sufficiently far from the pin  12 .  
         [0048]     (2) Then, the stage  100  is moved to a predetermined position in the same manner as described above, so that the solution B is spotted on the predetermined position of the substrate  110 .  
         [0049]     (3) Then, the stage  100  is moved to a predetermined position by the same operation as described above, so that the solution C is spotted on the predetermined position of the substrate  110 .  
         [0050]     In this manner, an array of biopolymers formed from the solutions A, B and C deposited on one substrate  110  can be provided as shown in  FIG. 2 .  
         [0051]     As described above, in accordance with the embodiment, both structure and operation are simpler and speedier than those in the background-art biochip production apparatus in which the reagent dispenser is moved up, down, left and right for spotting. Moreover, an array of biopolymers excellent in uniformity of spotting (homogeneity of the site) can be formed.  
         [0052]     Particularly a biochip substrate for clinical examination has about 100 sites whereas a biochip substrate for research has tens of thousands of sites. Accordingly, the biochip production by the biochip production apparatus according to the invention is very useful practically.  
         [0053]     The invention is not limited to the above embodiment and may include various changes and modifications without departing from the spirit of the invention.  
         [0054]     For example, the number of solution suppliers is not limited to three described in the above embodiment but may be changed if necessary.  
         [0055]     Although the embodiment has been described on the case where one substrate  110  is put on the stage  100  by way of example, the invention may be applied to the case where a plurality of substrates  110  are arranged simultaneously on the stage  110  like a belt conveyer and the stage  110  is moved suitable in order to perform spotting. The latter is a method very suitable for mass production.  
         [0056]     The substrate  110  and the solution suppliers  10 ,  20  and  30  may be turned upside down as shown in  FIG. 3  with respect to the embodiment. For example, a syringe may be used as each of the solution suppliers  10 ,  20  and  30 . Otherwise, a needle  12 , having a capillary  12   2  formed therein as shown in  FIG. 4  may be used so that a lower end portion of the needle  12   1  is immersed in a solution in a vessel  11 , and that the solution is sucked up to an upper end of the needle by the capillary  12   2 .  
         [0057]     As shown in  FIG. 5A , a plurality of pins  12   a,    12   b,    12   c  and  12   d  may be provided in each of the solution suppliers so that a plurality of spottings may be performed simultaneously on the substrate  110 .  FIG. 5B  is a view showing a result of the spottings. In  FIG. 5B , the symbol ◯ designates a spot of the solution A due to the solution supplier  10   a,  the symbol Δ designates a spot of the solution B due to the solution supplier  20   a,  and the symbol □ designates a spot of the solution C due to the solution supplier  30   a.  As is obvious from  FIG. 5B , the operation for spotting becomes easy when the interval (pitch) of the pins is widened.  
         [0058]      FIGS. 6A and 6B  are views showing another method for depositing solutions. In  FIGS. 6A and 6B , the reference numeral  40  denotes a multi-pin implanted body in which a plurality of pins  41  are implanted; and the reference numeral  50  denotes a solution supply portion having a plurality of solution reservoir portions  51  provided at intervals of the same pitch as the implanting pitch of the pins  41 . The multi-pin implanted body  40  is formed so that the multi-pin implanted body  40  can move up, down, left and right relative to the solution supply portion  50  and the substrate  110 .  
         [0059]     In this configuration, solutions are injected in the solution reservoir portions  51  in advance, for example, by a method shown in  FIG. 1 . As shown in  FIG. 6A , the multi-pin implanted body  40  is moved down so that the tip portions of the all pins  41  are immersed in the solution reservoir portions  51  respectively. In this manner, the solutions are deposited on the pins  41  respectively. Then, the multi-pin implanted body  40  is moved up and moved laterally to just above the substrate  110 . Then, the multi-pin implanted body  40  is moved down so that the tips of the pins  41  abut on the fixed substrate  110 . In this manner, the solutions are deposited on a surface of the substrate  110 . After the solutions are deposited on the substrate  110 , the multi-pin implanted body  40  is moved up.  
         [0060]     In this case, for example, even a narrow pitch P of about 1 mm can be achieved easily by use of the method shown in  FIG. 1 .  
         [0061]      FIG. 7  is a view showing a further method for depositing solutions. A plurality of chevron protrusions  61  are provided in a solution supplier  60 . As shown in  FIG. 7 , solution reservoir portions  62  are formed in the protrusions  61  respectively. The solution reservoir portions  62  are formed so that solutions in the solution reservoir portions  62  are sucked up to tips of the protrusions  61  respectively by means using capillarity or the like.  
         [0062]     The heights of the protrusions  61  are equalized so that all the tips of the protrusions  61  abut on a lower surface of the substrate  110  when the solution supply portion  60  is moved up. In this manner, the solutions can be spotted simultaneously on a plurality of places on the substrate  110 .  
         [0063]     As the method of depositing solutions, an ink jet method or electrostatic adsorption method deposition method may be used instead of the aforementioned mechanical contact method deposition method.  
         [0064]     The solutions of biopolymers spotted on the substrate in the aforementioned manner may be transferred onto another substrate to produce an array of biopolymers newly.