US20030104465A1 - DNA chip and method for producing the same - Google Patents

Abstract

A DNA chip includes a large number of minute spots formed by dripping sample solutions onto a base plate. The base plate is provided with positional deviation-correcting means for displacing the spots and automatically correcting any positional deviation of each of the spots. The positional deviation-correcting means includes any one of at least one projection, at least one recess and electric field-generating means for providing charged states on the base plate centered at a correct position for each of the spots supplied on the base plate.

Description

BACKGROUND OF THE INVENTION
• 1. Field of the Invention[0001]
• The present invention relates to a DNA chip (DNA microarray) in which several thousands to not less than ten thousands kinds of different types of DNA fragments are aligned and fixed as minute spots at a high density on a base plate such as a microscopic slide glass, and a method for producing the same.[0002]
• 2. Description of the Related Art[0003]
• The method for analyzing the genetic structure has been remarkably progressed in recent years. A large number of genetic structures represented by those of human gene have been clarified. The analysis of the genetic structure as described above uses a DNA chip (DNA microarray) in which several thousands to not less than ten thousands kinds of different types of DNA fragments are aligned and fixed as minute spots on a base plate such as a microscopic slide glass.[0004]
• Those widely used as a method for forming the minute spots in the production of the DNA chip are based on a system such as the QUILL system, the pin & ring system, and the spring pin system in which a sample solution containing DNA fragments is supplied in a contact manner onto the base plate by using a so-called pin. Even when any one of the foregoing methods is adopted, it is important to suppress the dispersion of the volume and the shape of each of the minute spots to be low so that the distance between the respective minute spots is maintained to be constant.[0005]
• On the other hand, in order to realize a higher density, it is also greatly expected to develop a new method in which the shape control performance is satisfactory for the minute spot, and the productivity is excellent.[0006]
• When the large number of minute spots are formed on the base plate by supplying (including dripping) the sample solution, a dispenser is used, in which a large number of supply nozzles (for example, pins or spring pins) are arranged, for example, in a matrix form.[0007]
• Usually, the arrangement pitch of the supply nozzles is larger than the arrangement pitch of the minute spots to be formed on the base plate. Therefore, the sample solution is supplied while deviating the supply position for the dispenser.[0008]
• During this process, if any dispersion arises in the deviation width for the dispenser or in the arrangement pitch of the supply nozzles, it is feared that the dispersion is directly reflected on the arrangement state of the minute spots, and the adjoining spots are merged to one another to form one spot.[0009]
• On the other hand, a procedure has been also investigated, in which the spotting is performed by using the so-called ink-jet system which is practically used for printers. However, if a supply apparatus based on the ink-jet system is used, it is feared that the adjoining spots are merged to one another to form one spot, for example, due to the influence of the so-called traveling curvature in which the direction of the discharged droplets is bent, and the unnecessary discharged droplets called satellites.[0010]
SUMMARY OF THE INVENTION
• The present invention has been made taking the foregoing problems into consideration, an object of which is to provide a DNA chip which makes it possible to realize a state in which the arrangement state of a large number of minute spots to be formed on a base plate conforms to a prescribed arrangement pitch, even when any dispersion occurs in the deviation width of a dispenser or the arrangement pitch of supply nozzles, and even when any positional deviation of discharged droplets occurs due to the traveling curvature or the satellites when a supply apparatus based on the ink-jet system is used.[0011]
• Another object of the present invention is to provide a method for producing a DNA chip, which makes it possible to realize a state in which the arrangement state of a large number of minute spots to be formed on a base plate conforms to a prescribed arrangement pitch, even when any dispersion occurs in the deviation width of a dispenser or the arrangement pitch of supply nozzles, and even when any positional deviation of discharged droplets occurs due to the traveling curvature or the satellites when a supply apparatus based on the ink-jet system is used, making it possible to improve the quality of the DNA chip and improve the yield.[0012]
• According to the present invention, there is provided a DNA chip comprising a large number of minute spots formed by supplying sample solutions onto a base plate; wherein the base plate is provided with a positional deviation-correcting means for automatically correcting any positional deviation of the minute spot.[0013]
• Accordingly, when the sample solution is supplied onto the base plate, even if the supply position is deviated from a prescribed position, then the minute spot to be formed by supplying the sample solution is moved to the prescribed position by the aid of the positional deviation-correcting means. Thus, the positional deviation is corrected.[0014]
• As described above, according to the DNA chip concerning the present invention, it is possible to realize a state in which the arrangement state of the large number of minute spots to be formed on the base plate conforms to a prescribed arrangement pitch, even when any dispersion occurs in the deviation width of a dispenser or the arrangement pitch of supply nozzles, and even when any positional deviation of discharged droplets occurs due to the traveling curvature or the satellites when a supply apparatus based on the ink-jet system is used.[0015]
• According to another aspect of the present invention, there is provided a method for producing a DNA chip by supplying a large number of sample solutions onto a base plate; comprising the step of using, as the base plate, a base plate provided with a positional deviation-correcting means for automatically correcting any positional deviation of the minute spot to produce the DNA chip.[0016]
• Accordingly, it is possible to realize a state in which the arrangement state of the large number of minute spots to be formed on the base plate conforms to a prescribed arrangement pitch, even when any dispersion occurs in the deviation width of a dispenser or the arrangement pitch of supply nozzles, and even when any positional deviation of discharged droplets occurs due to the traveling curvature or the satellites when a supply apparatus based on the ink-jet system is used, making it possible to improve the quality of the DNA chip and improve the yield.[0017]
• It is preferable that the sample solution is supplied by using a supply apparatus based on the ink-jet system. In this case, it is preferable that the supply apparatus is a dispenser comprising a plurality of arranged micropipettes each including a pouring port for pouring the sample solution from the outside, a cavity for pouring and charging the sample solution thereinto, and a discharge port for discharging the sample solution, formed on at least one or more substrates, the micropipette further including a piezoelectric/electrostrictive element disposed on at least one wall surface of the substrate which forms the cavity so that the sample solution is movable in the cavity, and mutually different types of the sample solutions being discharged from the discharge ports of the respective micropipettes. Further, it is more preferable that the sample solution is moved in a laminar flow.[0018]
• When the ink-jet system is used, then the minute spot can be formed at a high speed, and it is possible to freely set the speed and the liquid amount of the discharged droplets. Therefore, the following advantages are obtained. That is, it is possible to correctly form the minute spot with the prescribed liquid amount and/or with the shape. The dispersion between the respective minute spots is decreased as compared with a system in which the operation is performed with a pin or a spring pin.[0019]
• Unlike the pin system, the minute spot is formed in a non-contact manner in the ink-jet system. Therefore, there is neither physical interference nor contact with respect to the positional deviation-correcting means. Thus, the ink-jet system can be preferably used.[0020]
• Concerning the degree of freedom of the design, for example, of the spot amount and the discharge speed, possessed by the ink-jet system, another advantage is obtained such that it is easy to effect the matching with the positional deviation-correcting means. That is, the following advantage is obtained. When the correction is to be made to a great extent due to a large positional deviation amount, the contact with the positional deviation-correcting means may be facilitated, for example, by increasing the discharge amount and the discharge speed to enlarge the spread of the spot on the base plate. Thus, it is possible to perform the correction of the positional deviation in a reliable manner.[0021]
• It is also preferable that the positional deviation-correcting means is a projection formed at a position at which the minute spot is to be formed on the base plate, or the positional deviation-correcting means is constructed by a hydrophilic zone formed at a position at which the minute spot is to be formed, and a water-repellent zone formed at the other portions on the base plate.[0022]
• It is also preferable that the positional deviation-correcting means is a recess formed at a position at which the minute spot is to be formed on the base plate, or the positional deviation-correcting means is constructed by providing different surface state for a portion at which the minute spot is to be formed and the other portions on the base plate.[0023]
• It is also preferable that the positional deviation-correcting means includes an electric field-generating means for providing a charged state of a portion at which the minute spot is to be formed, the charged state being opposite to that of the sample solution on the base plate.[0024]
• For example, the electric field-generating means is operated as follows. That is, when the-sample solution is negatively charged (minus charge), if the portion, at which the minute spot is to be formed, is allowed to have the charged state opposite to that of the sample solution, i.e., the positive charged state (state of plus charge), then the spotting can be reliably performed at the prescribed position, which is preferred. When the sample solution is in the state of plus charge, the portion, at which the minute spot is to be formed, may be in the state of minus charge.[0025]
• Further, when the ink-jet system is used as the system for supplying the sample solution, the minute spot can be formed in a non-contact manner. Therefore, the discharge direction of droplets is aligned with the direction of the electric field. Further, the correction is easily made for the dripping position by the aid of the electric field. Therefore, this system can be preferably used.[0026]
• When the sample solution is a solution containing the DNA fragment, the following procedure is preferred in order to obtain a more effective positional deviation-correcting effect by the electric field. That is, a functional group for adding the charge is added to the DNA fragment, or the DNA fragment is dispersed in a solution having charge.[0027]
• The above and other objects, features, and advantages of the present invention will become more apparent from the following description when taken in conjunction with the accompanying drawings in which a preferred embodiment of the present invention is shown by way of illustrative example.[0028]
BRIEF DESCRIPTION OF THE DRAWINGS
• FIG. 1 shows a perspective view illustrating a DNA chip according to an embodiment of the present invention (DNA chip produced by a production method according to the embodiment of the present invention);[0029]
• FIG. 2 shows a magnified sectional view illustrating an arrangement of the DNA chip according to the embodiment of the present invention;[0030]
• FIG. 3 shows a block diagram illustrating the steps of the method for producing the DNA chip according to the embodiment of the present invention;[0031]
• FIG. 4 shows a block diagram illustrating details of the step of preparing a sample;[0032]
• FIG. 5A shows a plan view illustrating an arrangement of a dispenser to be used for the method for producing the DNA chip according to a first embodiment;[0033]
• FIG. 5B shows a front view thereof;[0034]
• FIG. 5C shows a magnified plan view illustrating one micropipette for constructing the dispenser;[0035]
• FIG. 6 shows a longitudinal sectional view illustrating an arrangement of the micropipette;[0036]
• FIG. 7 shows a perspective view illustrating a shape of a flow passage including a cavity formed in a substrate of the micropipette;[0037]
• FIG. 8 shows an exploded perspective view illustrating the dispenser together with a cartridge;[0038]
• FIG. 9 illustrates a first method in which the DNA chip is produced by using the dispenser;[0039]
• FIG. 10 illustrates a second method in which the DNA chip is produced by using the dispenser;[0040]
• FIG. 11 shows a sectional view illustrating a positional deviation-correcting means according to a first modified embodiment;[0041]
• FIG. 12 shows a sectional view illustrating a positional deviation-correcting means according to a second modified embodiment;[0042]
• FIG. 13 shows a sectional view illustrating a positional deviation-correcting means according to a third modified embodiment;[0043]
• FIG. 14 shows a sectional view illustrating a positional deviation-correcting means according to a fourth modified embodiment;[0044]
• FIG. 15 shows a sectional view illustrating a positional deviation-correcting means according to a fifth modified embodiment;[0045]
• FIG. 16 shows a sectional view illustrating a positional deviation-correcting means according to a sixth modified embodiment;[0046]
• FIG. 17 shows a sectional view illustrating a positional deviation-correcting means according to a seventh modified embodiment;[0047]
• FIG. 18 shows a sectional view illustrating a positional deviation-correcting means according to an eighth modified embodiment;[0048]
• FIG. 19A illustrates the fact that an effect equivalent to that obtained in the first modified embodiment is obtained by using the positional deviation-correcting means according to the eighth modified embodiment; and[0049]
• FIG. 19B illustrates the fact that an effect equivalent to that obtained in the sixth modified embodiment is obtained by using the positional deviation-correcting means according to the eighth modified embodiment.[0050]
DESCRIPTION OF THE PREFERRED EMBODIMENTS
• Exemplary embodiments of the DNA chip and the method for producing the same according to the present invention will be explained below with reference to FIGS.[0051]1 to19B.
• As shown in FIG. 1, a[0052]DNA chip20 according to an embodiment of the present invention comprises a large number of arranged minute spots80 constructed by supplying (including dripping) a sample solution onto abase plate10. Especially, a positional deviation-correcting means for automatically correcting the positional deviation of theminute spot80 is provided on thebase plate10.
• Specifically, as shown in FIG. 2, a poly-L-[0053]lysine layer12 having a hydrophilic property is formed on the surface of thebase plate10. Projections14 are formed at respective central portions of positions on which the minute spots80 are to be formed respectively. The projections14 function as the positional deviation-correcting means.
• That is, as shown in FIG. 2, upon the formation of the[0054]minute spot80 by supplying the sample solution onto thebase plate10, when a part of theminute spot80 contacts with the projection (see two-dot chain line), then theminute spot80 is moved in accordance with the surface tension of theminute spot80, and the central position of theminute spot80 approximately coincides with the projection14.
• As described above, in the case of the[0055]DNA chip20 according to the embodiment of the present invention, even when theminute spot80 is dripped while being deviated-from the prescribed position, then theminute spot80 is moved by the projection14 formed on thebase plate10, and the positional deviation is corrected.
• When the[0056]DNA chip20 is produced by forming theminute spot80 by supplying the sample solution onto thebase plate10, for example, production steps as shown in FIG. 3 are carried out.
• That is, the[0057]DNA chip20 is produced by executing the pretreatment step S1 for forming the poly-L-lysine layer12 (see FIG. 2) on the surface of thebase plate10, the sample preparation step S2 for preparing the sample solution containing a DNA fragment, and the supply step S3 for supplying the obtained sample solution onto thebase plate10.
• As shown in FIG. 4, the sample preparation step S[0058]2 includes the amplification step S11 for PCR-amplifying the DNA fragment to prepare a PCR product, the powder formation step S12 for drying the obtained PCR product to give DNA powder, and the mixing step S13 for dissolving the obtained DNA powder in a buffer solution.
• The steps will be specifically explained. In the pretreatment step S[0059]1, at first, thebase plate10 is immersed in an alkaline solution, followed by being gently shaken for at least 2 hours at room temperature. The alkaline solution is a solution obtained, for example, by dissolving NaOH in distilled water and adding ethanol thereto, followed by being agitated until the solution is completely transparent.
• After that, the[0060]base plate10 is taken out, and it is transferred into distilled water, followed by being rinsed to remove the alkaline solution. Subsequently, thebase plate10 is immersed in a poly-L-lysine solution prepared by adding poly-L-lysine to distilled water, followed by being left to stand for 1 hour.
• After that, the[0061]base plate10 is taken out, and it is applied to a centrifugal machine to perform centrifugation so that any excessive poly-L-lysine solution is removed. Subsequently, thebase plate10 is dried at 40° C. for about 5 minutes to obtain thebase plate10 comprising the poly-L-lysine layer12 formed on the surface.
• Subsequently, in the sample preparation step S[0062]2, at first, 3 M sodium acetate and isopropanol are added to the PCR product amplified with a known PCR equipment (amplification step S11), followed by being left to stand for several hours. After that, the PCR product solution is centrifuged with a centrifugal machine to precipitate the DNA fragment.
• The precipitated DNA fragment is rinsed with ethanol, and it is centrifuged, followed by being dried to produce the DNA powder (powder formation step S[0063]12). A ×1 TE buffer is added to the obtained DNA powder, followed by being left to stand for several hours to completely dissolve the DNA powder (mixing step S13). Thus, the sample solution is prepared. At this stage, the concentration of the sample solution is 1 to 10 μg/μl. An immobilizing solution may be supplied thereafter from a sample-pouringport52 into acavity56.
• In the embodiment of the present invention, the obtained sample solution is supplied onto the[0064]base plate10 to produce the DNA chip20 (supply step S3). The immobilizing solution may be mixed with the sample solution obtained by carrying out the sample preparation step S2, or the sample solution may be diluted. In this procedure, an aqueous solution containing water and NaCl or an aqueous solution containing polymer can be used as a dilution solution.
• When the[0065]DNA chip20 is produced in this embodiment, for example, adispenser30 shown in FIGS. 5A to7 is effectively used.
• As shown in FIGS. 5A and 5B, the[0066]dispenser30 includes, for example,. tenmicropipettes34 which are arranged in five rows and two columns on the upper surface of afixation plate32 having a rectangular configuration. A group of themicropipettes34, which are aligned in the direction of the respective columns, are fixed on thefixation plate32 by the aid of a fixingjig36 respectively.
• As shown in FIGS. 5C and 6, the[0067]micropipette34 comprises a sample-pouringport52 which is formed at the upper surface of asubstrate50 having a substantially rectangular parallelepiped-shaped configuration, asample discharge port54 which is formed at the lower surface of thesubstrate50, acavity56 which is formed at the inside between the sample-pouringport52 and thesample discharge port54, and anactuator section58 which is used to vibrate thesubstrate50 or change the volume of thecavity56.
• Therefore, as shown in FIG. 6, through-[0068]holes40 are provided through thefixation plate32 at portions corresponding to thesample discharge ports54 of themicropipettes34 respectively. Accordingly, the sample solution, which is discharged from thesample discharge port54 of themicropipette34, is supplied through the through-hole40, for example, to thebase plate20 which is fixed under thefixation plate32.
• An introducing bore[0069]60 having a substantially L-shaped configuration with a wide opening width is formed over a region ranging from the sample-pouringport52 to the inside of thesubstrate50 in themicropipette34. Afirst communication hole62 having a small diameter is formed between the introducingbore60 and thecavity56. The sample solution, which is poured from the sample-pouringport52, is introduced into thecavity56 through the introducingbore60 and thefirst communication hole62.
• A[0070]second communication hole64, which communicates with thesample discharge port54 and which has a diameter larger than that of thefirst communication hole62, is formed at a position different from that of thefirst communication hole62, of thecavity56. In the embodiment of the present invention, thefirst communication hole62 is formed at the portion of the lower surface of thecavity56. The position of thefirst communication hole62 is deviated toward the sample-pouringport52. Thesecond communication hole64 is formed at the position of the lower surface of thecavity56 as well corresponding to thesample discharge port54.
• Further, in this embodiment, the portion of the[0071]substrate50, with which the upper surface of thecavity56 makes contact, is thin-walled to give a structure which tends to undergo the vibration with respect to the external stress so that the portion functions as a vibratingsection66. Theactuator section58 is formed on the upper surface of the vibratingsection66.
• The[0072]substrate50 is constructed by laminating a plurality of green sheets made of zirconia ceramics (firstthin plate layer50A,first spacer layer50B, secondthin plate layer50C,second spacer layer50D, and thirdthin plate layer50E), followed by sintering into one unit.
• That is, the[0073]substrate50 is constructed by laminating the thin-walled firstthin plate layer50A which is formed with a window for constructing the sample-pouringport52 and which constitutes a part of the vibratingsection66, the thick-walledfirst spacer layer50B which is formed with a part of the introducingbore60 and a plurality of windows for constructing thecavity56 respectively, the thin-walled secondthin plate layer50C which is formed with a part of the introducingbore60 and a plurality of windows for constructing a part of thesecond communication hole64 and thefirst communication hole62 respectively, the thick-walledsecond spacer layer50D which is formed with a plurality of windows for constructing a part of the introducingbore60 and a part of thesecond communication hole64 respectively, and the thin-walled thirdthin plate layer50E which is formed with a window for constructing thesample discharge port54, followed by sintering into one unit.
• The[0074]actuator section58 is constructed to have the vibratingsection66 described above as well as alower electrode70 which is directly formed on the vibratingsection66, apiezoelectric layer72 which is composed of, for example, a piezoelectric/electrostrictive layer or an anti-ferroelectric layer formed on thelower electrode70, and anupper electrode74 which is formed on the upper surface of thepiezoelectric layer72.
• As shown in FIG. 5C, the[0075]lower electrode70 and theupper electrode74 are electrically connected to an unillustrated driving circuit via a plurality ofpads76,78 which are formed on the upper surface of thesubstrate50 respectively.
• The[0076]micropipette34 constructed as described above is operated as follows. That is, when an electric field is generated between theupper electrode74 and thelower electrode70, then thepiezoelectric layer72 is deformed, and the vibratingsection66 is deformed in accordance therewith. Accordingly, the volume of the cavity (pressurizing chamber)56 contacting with the vibratingsection66 is decreased.
• When the volume of the[0077]cavity56 is decreased, the sample solution charged in thecavity56 is discharged at a predetermined speed from thesample discharge port54 which communicates with thecavity56. As shown in FIG. 1, it is possible to prepare theDNA chip20 in which the sample solutions discharged from themicropipettes34 are aligned and fixed as the minute spots80 on thebase plate10 such as a microscopic slide glass.
• In this embodiment, the arrangement pitch of the[0078]sample discharge ports54 of thedispenser30 is larger then the arrangement pitch of the minute spots80 to be-formed on thebase plate10. Therefore, the sample solution is supplied while deviating the supply position for thedispenser30.
• During this process, even when any dispersion arises in the deviation width for the[0079]dispenser30 or the arrangement pitch of thesample discharge ports54, then the minute spots80, which are formed by supplying the sample solutions, are moved to the prescribed positions respectively by the aid of the projections14 formed on thebase plate10, and the positional deviation is corrected. Accordingly, in this embodiment, the arrangement state of the large number of minute spots80 to be formed on thebase plate10 can be in the state which conforms to the prescribed arrangement pitch.
• Further, it is also preferable that the movement of the[0080]minute spot80 is facilitated by adding water to thebase plate10 so that theminute spot80 is moved toward the projection14. It is also possible to expect such an effect that the cross-sectional configuration of theminute spot80 gathered to the projection14 can be corrected to give a hemispherical configuration, which is-preferred.
• An apparatus structure based on the so-called ink-jet system may be adopted as the structure in which the volume of the[0081]cavity56 is decreased in accordance with the driving of the actuator section58 (see Japanese Laid-Open Patent Publication No. 6-40030).
• It is preferable that the cavity (pressurizing chamber)[0082]56 is formed to have such a flow passage dimension that the sample solution containing DNA fragments or the like is moved in a laminar flow.
• That is, the dimension of the[0083]cavity56 differs depending on the type of the sample, the size of liquid droplets to be prepared, and the density of formation. However, for example, when a sample, which is obtained by dispersing DNA fragments of base pairs of about 1 to 10,000 in a buffer solution (TE buffer) at a concentration of 1 μg/μl, is dripped at a pitch of several hundreds μm to give a liquid droplet diameter of several hundreds μmφ, then it is preferable that the cavity length (L) is 1 to 5 mm, the cavity width (W) is 0.1 to 1 mm, and the cavity depth (D) is 0.1 to 0.5 mm as shown in FIG. 7. It is preferable that the inner wall of thecavity56 is smooth without involving any projection to disturb the flow. It is more preferable that the material of thecavity56 is made of ceramics which has good affinity with respect to the sample solution.
• When the shape as described above is adopted, the[0084]cavity56 can be used as a part of the flow passage ranging from the sample-pouringport52 to thesample discharge port54. The sample can be introduced to thesample discharge port54 without disturbing the flow of the sample solution which is moved from the sample-pouringport52 via the introducingbore60 and thefirst communication hole62 to the inside of thecavity56.
• As shown in FIG. 5A, a plurality of[0085]pins38 for positioning and fixing themicropipettes34 are provided on the upper surface of thefixation plate32. When themicropipette34 is fixed on thefixation plate32, themicropipette34 is placed on thefixation plate32 while inserting thepins38 of thefixation plate32 into positioning holes90 (see FIG. 5C) provided at the both sides of thesubstrate50 of themicropipette34. Thus, a plurality ofmicropipettes34 are automatically aligned and positioned with a predetermined array arrangement.
• Each of the fixing[0086]jigs36 has aholder plate100 for pressing the plurality ofmicropipettes34 against thefixation plate32. Insertion holes for insertingscrews102 thereinto are formed through both end portions of theholder plate100. When thescrews102 are inserted into the insertion holes, and they are screwed into thefixation plate32, then the plurality ofmicropipettes34 can be pressed against thefixation plate32 by the aid of theholder plate100 at once. One unit is constructed by the plurality ofmicropipettes34 which are pressed by oneholder plate100. The example shown in FIG. 5A is illustrative of the case in which one unit is constructed by the fivemicropipettes34 which are arranged in the direction of the column.
• The[0087]holder plate100 is formed with introducing holes104 (see FIG. 5B) which are used to supply the sample solutions to the portions corresponding to the sample-pouringports52 of therespective micropipettes34 respectively when the plurality ofmicropipettes34 are pressed.Tubes106 for introducing the sample solution to the introducingholes104 respectively are held at upper end portions of the respective introducingholes104.
• Considering the realization of the efficient wiring operation, it is preferable that the width of the[0088]holder plate100 resides in such a dimension that thepads76,78 connected to therespective electrodes70,74 of theactuator section58 are faced upwardly when the plurality ofmicropipettes34 are pressed against thefixation plate32.
• As described above, the[0089]dispenser30 is constructed such that the plurality ofmicropipettes34 each having the sample-pouringport52 and thesample discharge port54 are provided in an upstanding manner with the respectivesample discharge ports54 directed downwardly.
• That is, the[0090]respective micropipettes34 are aligned and arranged such that the respective sample-pouringports52 are disposed on the upper side, thesample discharge ports54 are disposed on the lower side, and the respectivesample discharge ports54 are aligned two-dimensionally. Sample solutions of mutually different types are discharged from thesample discharge ports54 respectively.
• When the[0091]dispenser30 constructed as described above is used, several methods are available to supply the sample solutions of mutually different types corresponding to the respective sample-pouringports52. That is, as shown in FIG. 8, for example, a method is available, which is based on the used of acartridge112 arranged with a large number of recesses (storage sections)110 each having a substantially V-shaped cross section. For this method, for example, the following procedure is available. That is, the mutually different sample solutions are poured into therespective recesses110 of thecartridge112. Thecartridge112 is attached so that therespective recesses110 correspond to thetubes106 respectively. The bottoms of therespective recesses110 are opened with needles or the like. Accordingly, the sample solutions having been charged in therespective recesses110 are supplied via the-tubes106 to therespective micropipettes34.
• When the[0092]tubes106 are not used, for example, the following method is available. That is, thecartridge112 is attached so that therespective recesses110 correspond to the respective introducingholes104 of the fixingjig36. The bottoms of therespective recesses110 are opened with needles or the like. Accordingly, the sample solutions having been charged in therespective recesses110 are supplied via the introducingholes104 to therespective micropipettes34. Alternatively, needles or the like may be formed in the vicinity of the respective introducingholes104 of the fixingjig36 so that therespective recesses110 may be opened simultaneously with the attachment of thecartridge112 to the fixingjig36.
• Alternatively, it is also preferable to add a mechanism for feeding the gas or the like under the pressure after the opening to forcibly extrude the sample solutions. It is desirable to provide a mechanism for-washing the space ranging from the sample-pouring[0093]port52 to thesample discharge port54 formed at the inside of thesubstrate50 of each of themicropipettes34, for example, in order that several thousands to several tens thousands types or many kinds of DNA fragments are discharged as the minute spots80 with good purity without involving any contamination.
• In the example shown in FIG. 5A, the both ends of the[0094]holder plate100 are tightened to thefixation plate20 by the aid of thescrews102. However, theholder plate100 may be fixed in accordance with other methods based on the mechanical procedure by using screws and springs, as well as based on an adhesive or the like.
• As described above, the[0095]substrate50 for constructing themicropipette34 is formed of ceramics, for which it is possible to use, for example, fully stabilized zirconia, partially stabilized zirconia, alumina, magnesia, and silicon nitride.
• Among them, the fully stabilized/partially stabilized zirconia is used most preferably, because the mechanical strength is large even in the case of the thin plate, the toughness is high, and the reactivity with the[0096]piezoelectric layer72 and the electrode material is small.
• When the fully stabilized/partially stabilized zirconia is used as the material, for example, for the[0097]substrate50, it is preferable that the portion (vibrating section66), on which theactuator section58 is formed, contains an additive such as alumina and titania.
• Those usable as the piezoelectric ceramic for the[0098]piezoelectric layer72 for constructing theactuator section58 include, for example, lead zirconate, lead titanate, lead magnesium niobate, lead magnesium tantalate, lead nickel niobate, lead zinc niobate, lead manganese niobate, lead antimony stannate, lead manganese tungstate., lead cobalt niobate, and barium titanate, as well as composite ceramics containing components obtained by combining any of them. However, in the embodiment of the present invention, a material containing a major component composed of lead zirconate, lead titanate, and lead magnesium niobate is preferably used, because of the following reason.
• That is, such a material has a high electromechanical coupling constant and a high piezoelectric constant. Additionally, such a material has small reactivity with the substrate material during the sintering of the[0099]piezoelectric layer72, making it possible to stably form the product having a predetermined composition.
• Further, in the embodiment of the present invention, it is also preferable to use ceramics obtained by appropriately adding, to the piezoelectric ceramics described above, for example, oxides of lanthanum, calcium, strontium, molybdenum, tungsten, barium, niobium, zinc, nickel, manganese, cerium, cadmium, chromium, cobalt, antimony, iron, yttrium, tantalum, lithium, bismuth, and stannum, or a combination of any of them, or other compounds.[0100]
• For example, it is also preferable to use ceramics containing a major component composed of lead zirconate, lead titanate, and lead magnesium niobate, and further containing lanthanum-and/or strontium.[0101]
• On the other hand, it is preferable that the[0102]upper electrode74 and thelower electrode70 of theactuator section58 are made of metal which is solid at room temperature and which is conductive. For example, it is possible to use metal simple substance of, for example, aluminum, titanium, chromium, iron, cobalt, nickel, copper, zinc, niobium, molybdenum, ruthenium, palladium, rhodium, silver, stannum, tantalum, tungsten, iridium, platinum, gold, and lead, or alloy obtained by combining any of them. It is also preferable to use a cermet material obtained by dispersing, in the metal described- above, the same material as that of thepiezoelectric layer72 or thesubstrate50.
• Next, explanation will be made with reference to FIGS. 9 and 10 for several methods for producing the[0103]DNA chip20 by using thedispenser30.
• At first, a first method is shown in FIG. 9. That is, mutually different types of sample solutions are charged from the[0104]respective tubes106 via the introducingholes104 of the fixingjig36 into thecavities56 of therespective micropipettes34 respectively. Subsequently, therespective actuator sections58 are driven to discharge the sample solutions from thesample discharge ports54 of therespective micropipettes34. As for the method for charging the solution into thecavity56, the solution may be poured in accordance with the capillary force of the solution introduced from the sample-pouringport52. However, it is reliable to adopt a method in which the solution is charged by means of vacuum aspiration through thesample discharge port54.
• As for the voltage waveform to be applied to the[0105]respective electrodes70,74 of theactuator section58, when theactuator section58 is subjected to the ON operation to decrease the volume of thecavity56, a pulsed voltage is applied to therespective electrodes70,74. In this case, the deformation of the vibratingsection66 is increased by increasing the amplitude of the pulse, and the discharge amount of the sample solution is also increased in accordance therewith. When a plurality of pulses are applied for a certain period, a large number of sample solutions each having a small amount can be discharged by shortening the pulse cycle and decreasing the amplitude of each pulse.
• During this process, when the supply position is appropriately changed, the droplets of the supplied sample solution are combined (integrated) on the[0106]base plate10 to form the sample solution having one spot diameter. However, it is possible to realize a uniform spot diameter formed on thebase plate10 by controlling the number of supply operations, the supply position, and the amount of one time supply, depending on the type of the sample solution to be supplied.
• Next, explanation will be made for a second method based on the use of the[0107]dispenser30. The second method is shown in FIG. 10. That is, a substitution solution such as a buffer solution, an aqueous solution containing NaCl, and an aqueous solution containing polymer is charged into thecavity56 of each of themicropipettes34 from each of thetubes106 via the introducinghole104 of the fixingjig36 respectively. Subsequently, the sample is poured into thecavity56 from the sample-pouringport52 while effecting the laminar flow substitution to wait for the completion of the substitution thereafter. After that, theactuator section58 is driven to discharge and supply the sample solution onto thebase plate10.
• It is preferable that the completion of the laminar flow substitution of the sample in the[0108]cavity56 is recognized by sensing the change of the fluid characteristic in thecavity56.
• It is preferable that the substitution between the substitution solution and the sample solution in the[0109]cavity56 is performed in a form of the laminar flow. However, when the type of the sample is changed, or when the movement speed of the liquid is extremely fast, then it is not necessarily indispensable to use the laminar flow at portions of thecavity56 in the vicinity of thefirst communication hole62. In this case, the purge amount of the sample solution is increased due to the mixing of the sample and the substitution solution. However, it is possible to suppress the increase in the purge amount to be minimum by judging the completion of the substitution by sensing the change of the fluid characteristic in thecavity56.
• In the present invention, the change of the fluid characteristic in the[0110]cavity56 is recognized by applying a voltage in such a degree as to excite the vibration in theactuator section58, and detecting the change of the electric constant caused by the vibration. Such a procedure for sensing the change of the fluid characteristic is disclosed, for example, in Japanese Laid-Open Patent Publication No. 8-201265.
• Specifically, the electric connection from a power source for driving the discharge is separated from the[0111]actuator section58 at a predetermined interval by using a relay. Simultaneously, a means for measuring the resonance frequency is connected by using the relay. At this point of time, the impedance or the resonance characteristic such as the resonance frequency or the attenuation factor is electrically measured.
• Accordingly, it is possible to recognize, for example, whether or not the viscosity and the specific gravity of the liquid-are those of the objective sample (liquid containing the DNA fragment or the like). That is, as for each of the[0112]micropipettes34, themicropipette34 itself functions as a sensor. Therefore, it is also possible to simplify the structure of themicropipette34.
• The[0113]actuator section58 is driven under a driving condition corresponding to the amount of liquid droplets suitable for the required spot diameter, and the sample solution is repeatedly supplied. Accordingly, theDNA chip20 is produced. Usually, when oneminute spot80 is formed, one to several hundreds of droplet or droplets are discharged from themicropipette34.
• When the amount of the sample in the sample-pouring[0114]port52 is decreased, the discharge is continued by adding the buffer solution so that no bubble enters the inside of the flow passage. Accordingly, all of the sample solution can be used without allowing the sample solution to remain in themicropipette34. The completion of the substitution from the sample to the substitution solution (completion of the sample discharge) is confirmed by detecting the viscosity and the specific gravity of the liquid by using theactuator section58 in the same manner as described above.
• It is preferable to use the substitution solution and the sample solution such that the dissolved gas in the solution is previously removed by performing the degassing operation. When such a solution is used, if any bubble obstructs the flow passage at an intermediate portion to cause the defective charge upon the charge of the solution into the flow passage of the[0115]micropipette34, then the inconvenience can be avoided by dissolving the bubble in the solution. Further, no bubble is generated in the fluid during the discharge, and no defective discharge is caused as well.
• In the second method described above, the substitution solution such as a buffer solution, an aqueous solution containing NaCl, and an aqueous solution containing polymer is poured from the sample-pouring[0116]port52 into thecavity56 while discharging the sample solution, and the sample solution remaining in thecavity56 is completely discharged to make provision for the next pouring of the sample.
• When it is sensed whether or not the sample solution remains in the cavity[0117]56 (whether or not the discharge can be effected as the sample solution), the recognition can be also made by sensing the change of the fluid characteristic in thecavity56. In this case, a mechanism for detecting the completion of the substitution can be used to extremely decrease the purge amount of the sample which is not used and improve the efficiency of the use of the sample solution.
• It is also preferable that when the sample is charged from the sample-pouring[0118]port52 to thecavity56, the interior of thecavity56 is substituted with the sample from the sample-pouringport52 while driving theactuator section58. In this procedure, the interior of thecavity56 can be completely substituted in a reliable manner with the inexpensive substitution solution beforehand. As a result, it is possible to completely avoid the occurrence of any defective discharge, and it is possible to efficiently discharge the expensive sample.
• Further, the following procedure may be adopted. That is, the substitution solution such as a buffer solution, an aqueous solution containing NaCl, and an aqueous solution containing polymer is charged into the[0119]cavity56. The amount of the substitution solution existing in thecavity56 and in the sample-pouringport52 is adjusted to be a predetermined amount. Subsequently, a predetermined amount of the sample solution is poured from the sample-pouringport52, and then theactuator section58 is driven in an amount corresponding to a predetermined number of pulses to discharge the amount of the substitution solution existing in thecavity56 and in the sample-pouringport52.
• By doing so, the amount of the substitution solution existing in the[0120]cavity56 and in the sample-pouringport52 is correctly discharged, and it is possible to complete the charge of the sample solution without any loss.
• As described above, in the[0121]DNA chip20 according to the embodiment of the present invention, the projection14, which serves as the positional deviation-correcting means for automatically correcting the positional deviation of theminute spot80, is provided on thebase plate10. Therefore, when the sample solution is supplied onto thebase plate10, even if the supply position is deviated from the prescribed position, then theminute spot80 to be formed by supplying the sample solution is moved to the prescribed position by the aid of the projection14, and the positional deviation is corrected.
• As described above, in the[0122]DNA chip20 and the method for producing the same according to the embodiment of the present invention, even when any dispersion occurs in the deviation width of thedispenser30 or the arrangement pitch of thesample discharge ports54, the arrangement state of the large number of minute spots80 formed on thebase plate10 can be the state which conforms to the prescribed arrangement pitch. Thus, it is possible to improve the quality of theDNA chip20 and improve the yield.
• Next, explanation will be made with reference to FIGS.[0123]11 to19B for modified embodiments of the positional deviation-correcting means provided for thebase plate10.
• As shown in, FIG. 11, the first modified embodiment differs in that a hydrophilic zone Z[0124]1 is formed at a position of thebase plate10 at which theminute spot80 is to be formed, and a water-repellent zone Z2 is formed at the other portions. Specifically, this arrangement is achieved by forming a water-repellent film16 at the portions other than the position at which theminute spot80 is to be formed. Those usable as the water-repellent film include, for example, Si coat and fluororesin.
• In this arrangement, as shown in FIG. 11, upon the formation of the[0125]minute spot80 by supplying the sample solution onto thebase plate10, when a part of theminute spot80 contacts with the water-repellent film16 (see two-dot chain line), then theminute spot80 is moved in accordance with the surface tension of theminute spot80 and the water-repellent function of thefilm16, and the center of theminute spot80 can be positioned at the prescribed position. In this case, even when the part of theminute spot80 contacts with the water-repellent film16, no trace is formed after the movement-of the sample solution, because thefilm16 is water-repellent. The shape of the spot after the immobilization is the shape which is formed by only the hydrophilic portion. Thus, the dispersion of the shape is reduced.
• The second modified embodiment is shown in FIG. 12. In this modified embodiment, a[0126]tapered surface16a, which is inclined downwardly toward the hydrophilic zone Z1, is provided at only the surroundings of the hydrophilic zone Z1 of the water-repellent film16. In this case, as shown by a dashed line, even when theminute spot80 contacts with the water-repellent film16, theminute spot80 is moved to the position at which theminute spot80 is to be formed, in accordance with the water-repellent function of the water-repellent film16, the surface tension of theminute spot80, and the gravity effected by the inclination of the tapered surface. Thus, the center of theminute spot80 can be positioned at the prescribed position.
• As shown in FIG. 13, the third modified embodiment differs in that a[0127]recess18 is formed at the position at which theminute spot80 is to be formed on thebase plate10.
• Accordingly, as shown in FIG. 13, upon the formation of the[0128]minute spot80 by supplying the sample solution onto thebase plate10, when a part of theminute spot80 contacts with the shoulder of the recess18 (see two-dot chain line), then theminute spot80 is moved in accordance with the surface tension of theminute spot80, and theminute spot80 can be positioned in therecess18. In this arrangement, when the sample solution enters therecess18, then the film thickness of the sample is made uniform, and it is possible to reduce the dispersion of the thickness of the spot. As a result, an advantage is obtained such that it is possible to suppress the deterioration of the sensitivity and the dispersion of the sensitivity when the fluorescence emitted by the spot is detected.
• The fourth modified embodiment is shown in FIG. 14. In this modified embodiment, a plurality of[0129]projections150 are formed at the surroundings of the portion at which theminute spot80 is formed, or anannular projection152 is formed at the surroundings. In the case of theannular projection152, the portion, at which theminute spot80 is formed, is formed to have a crater-shaped configuration. In the case of the fourth modified embodiment, in addition to the effect obtained in the third modified embodiment described above, an effect is obtained such that theminute spot80 is easily concentrated at the predetermined position (position at which theminute spot80 is to be formed). Especially, the effect described above is further remarkable when the bottom portion of theprojection150,152 is formed to be a gentleinclined surface154.
• The[0130]projections150,152 as described above can be formed on thebase plate10 by performing the spotting while appropriately adjusting, for example, the jetting pressure and the distance between the jet nozzle and thebase plate10 in the ink-jet system which is practically used for printers.
• As shown in FIG. 15, the fifth modified embodiment differs in that the surface state is different between the portion at which the[0131]minute spot80 is to be formed and the other portions of thebase plate10.
• Accordingly, as shown in FIG. 15, upon the formation of the[0132]minute spot80 by supplying the sample solution onto thebase plate10, when a part of theminute spot80 contacts with the portion other than a rough surface22 (see two-dot chain line), then theminute spot80 is moved in accordance with the surface tension of theminute spot80, and the center of theminute spot80 can be positioned at the prescribed position. In this arrangement, in the same manner as in the first modified embodiment described above, even when the part of theminute spot80 contacts with the portion other than therough surface22, no trace is formed after the movement of the sample solution at the portion other than therough surface22. The shape of the spot after the immobilization is the shape which is formed by only therough surface22. Thus, the dispersion of the shape is reduced. Theminute spot80 is tightly fixed to thebase plate10 owing to the large contact area, because the contact surface is the rough surface. It is possible to reduce the flow out of the sample solution upon the immobilization after the spotting.
• As for the change of the surface state, including, for example, the formation of the tapered[0133]surface16a, the formation of therecess18, and the formation of therough surface22 in the second, third, and fifth modified embodiments described above, a large amount of base plates can be processed at once, for example, by means of the blast machining, the laser machining, and the cutting machining. Such procedures are preferred, because they can be carried out inexpensively.
• In the sixth modified embodiment, the positional deviation is corrected by applying a magnetic field. Specifically, for example, as shown in FIG. 16, a large number of[0134]electrode patterns130 based on a metal film are formed at portions corresponding to the positions at which the minute spots80 are to be formed, in the underlying layer of a poly-L-lysine layer12 on thebase plate10. Further, acommon electrode pattern132 based on a metal film, which is common to the pattern of therespective electrodes130, is formed in a layer disposed thereunder.
• For example, a[0135]power source134 is connected between thecommon electrode pattern132 and the ground. Therespective electrode patterns130 are charged, for example, to the plus side. In this state, when theminute spot80 is formed by supplying the sample solution on thebase plate10, theminute spot80 is moved onto theelectrode pattern130 in accordance with the attracting force of the electric field when a part of theminute spot80 contacts with the portion over the electrode pattern130 (see two-dot chain lines), because the sample solution, which constitutes theminute spot80, is charged on the minus side. Thus, the center of theminute spot80 is positioned at the prescribed position.
• When the intensity of the electric field is increased, the[0136]liquid droplet140, which is discharged from thesample discharge port54 of each of themicropipettes34, is corrected for its traveling direction in the air so that the traveling direction is directed toward the correspondingelectrode pattern130. Theminute spot80 based on theliquid droplet140 correctly falls onto the correspondingelectrode pattern130. In this case, theliquid droplet140 is not moved on the surface of thebase plate10. Therefore, an effect is obtained such that no trace is formed by the movement of the liquid droplet, and it is possible to obtain a stable (uniform) shape of the spot.
• As shown in FIG. 17, the seventh modified embodiment is based on substantially the same principle as that of the sixth modified embodiment described above (see FIG. 16). However,[0137]predetermined electrode patterns130,132 are provided on astage142 on which thebase plate10 is placed and fixed. In this arrangement, it is unnecessary to provide theelectrode patterns130,132 on thebase plate10. Therefore, an advantage is obtained such that this modified embodiment can be carried out inexpensively.
• The eighth modified embodiment is shown in FIG. 18. In this modified embodiment, for example, the[0138]base plate10 is made of glass,predetermined electrode patterns130,132 are formed in thebase plate10, and especially theelectrode pattern130 is exposed to the surface of thebase plate10. The voltage is supplied to theelectrode patterns130,132 by using anelectrode144 formed in astage142.
• In the eighth modified embodiment, the glass surface of the[0139]base plate10 is water-repellent, and theelectrode pattern130 exposed to the glass surface is hydrophilic. Therefore, the operation is effected in the same manner as in the first modified embodiment described above. That is, for example, as shown in FIG. 19A, upon the formation of theminute spot80 by supplying the sample solution onto thebase plate10, when a part of theminute spot80 contacts with the water-repellent glass surface (see a two-dot chain line), theminute spot80 is moved in accordance with the surface tension of theminute spot80 and the water-repellent function of the glass surface. Thus, the center of theminute spot80 can be positioned at the prescribed position. In this arrangement, even when the part of theminute spot80 contacts with the glass surface, no trace after the movement of the sample solution is formed, because the glass surface is water-repellent. The shape of the spot after the immobilization is determined by only the hydrophilic portion. Thus, the dispersion of the shape is reduced.
• When the intensity of the electric field is increased, as shown in FIG. 19B, the[0140]liquid droplet140, which is in the falling process, is corrected for its traveling direction in the air so that the traveling direction is directed toward the correspondingelectrode pattern130, in the same manner as in the sixth modified embodiment described above. The minute-spot80 based on theliquid droplet140 correctly falls onto the correspondingelectrode pattern130. In this case, theliquid droplet140 is not moved on the surface of thebase plate10. Therefore, an effect is obtained such that no trace is formed by the movement of the liquid droplet, and it is possible to obtain a stable (uniform) shape of the spot.
• As described above, both of the effects of the first modified embodiment and the sixth modified embodiment described above are simultaneously exhibited in the eighth modified embodiment which is more preferred. The material for the[0141]base plate10 is not limited to glass, which may be an insulating matter such as ceramics and plastic.
• As described above, even in the case of the use of the positional deviation-correcting means according to the first to eighth modified embodiments, the arrangement state of the large number of minute spots[0142]80 formed on thebase plate10 can be the state which conforms the prescribed arrangement pitch, even when any dispersion occurs in the deviation width of thedispenser30 and the arrangement pitch of thesample discharge ports54, in the same manner as in the embodiment according to the present invention described above. Thus, it is possible to improve the quality of theDNA chip20 and improve the yield.
• It is a matter of course that the DNA chip and the method for producing the same according to the present invention are not limited to the embodiments described above, which may be embodied in other various forms without deviating from the gist or essential characteristics of the present invention.[0143]

Claims (10)

1. A DNA chip comprising a plurality of sample spots supplied on a base plate, wherein:

said base plate is provided with positional deviation-correcting means for displacing said spots and automatically correcting any positional deviation of each of said plurality of spots after said spots are supplied on said base plate,

wherein said positional deviation-correcting means comprises at least one recess positioned on said base plate, said at least one recess being centered at a correct position for each of said plurality of spots supplied on said base plate.

2. A DNA chip comprising a plurality of sample spots supplied on a base plate, wherein:

said base is provided with positional deviation-correcting means for displacing said spots and automatically correcting any positional deviation of each of said plurality of spots after said spots are supplied on said base plate,

wherein said positional deviation-correcting means comprises electric field-generating means for providing at least one charged state positioned on said base plate, said at least one charged state being centered at a correct position for each of said plurality of spots supplied on said base plate, wherein said at least one charged state is opposite to at least one charged state of said plurality of spots supplied on said base plate.

3. A method for producing a DNA chip comprising a plurality of sample spots supplied on a base plate, comprising the steps of:

providing a base plate having positional deviation-correcting means for displacing said spots and automatically correcting any positional deviation of each of said plurality of spots after said spots are supplied on said base plate; and

supplying said plurality of spots onto said base plate,

wherein said positional deviation-correcting means comprises at least one recess positioned on said base plate, said at least one recess being centered at a correct position for each of said plurality of spots supplied on said base plate.

4. The method for producing said DNA chip according toclaim 3, wherein said step of supplying said plurality of spots on said base plate is performed in accordance with an ink-jet system using a supply apparatus.

5. The method for producing said DNA chip according toclaim 4, wherein said supply apparatus is a dispenser comprising a plurality of arranged micropipettes each including a pouring port for pouring said sample solution from the outside, a cavity for pouring and charging said sample solution thereinto, and a discharge port for discharging said sample solution supplied on said base plate, said micropipette further including a piezoelectric/electrostrictive element disposed on at least one wall surface of said substrate forming said cavity to operate as a means for moving said sample solution through said cavity, the method further comprises the step of discharging mutually different types of said sample solutions from said discharge ports of said respective micropipettes.

6. The method for producing said DNA chip according toclaim 5, wherein said sample solution moves in a laminar flow within said cavity in said dispenser comprising said plurality of arranged micropipettes.

7. A method for producing a DNA chip comprising a plurality of sample spots supplied on a base plate, comprising the steps of:

providing a base plate having positional deviation-correcting means for displacing said spots and automatically correcting any positional deviation of each of said plurality of spots after said spots are supplied on said base plate; and

supplying said plurality of spots onto said base plate,

wherein said positional deviation-correcting means comprises electric field-generating means for providing a charged state on at least a portion of said base plate, said electric field-generating means being centered at a correct position for each of said plurality of spots supplied on said base plate, and said charged state being opposite to a charged state of said plurality of spots supplied on said base plate.

8. The method for producing said DNA chip according toclaim 7, wherein said step of supplying said plurality of spots on said base plate is performed in accordance with an ink-jet system using a supply apparatus.

9. The method for producing said DNA chip according toclaim 8, wherein said supply apparatus is a dispenser comprising a plurality of arranged micropipettes each including a pouring port for pouring said sample solution from the outside, a cavity for pouring and charging said sample solution thereinto, and a discharge port for discharging said sample solution supplied on said base plate, said micropipette further including a piezoelectric/electrostrictive element disposed on at least one wall surface of said substrate forming said cavity to operate as a means for moving said sample solution through said cavity, the method further comprises the step of discharging mutually different types of said sample solutions from said discharge ports of said respective micropipettes.

10. The method for producing said DNA chip according toclaim 9, wherein said sample solution moves in a laminar flow within said cavity in said dispenser comprising said plurality of arranged micropipettes.

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