JP2011122858A - Chemical analysis chip - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a chemical analysis chip demonstrating highly accurate test results by controlling the pulsation of a sample solution. <P>SOLUTION: The chemical analysis chip 300 is equipped with: a pumping means 330 for transporting the sample solution; a flow channel 340 for flowing the sample solution; and a testing means 350 for testing the sample solution. The pumping means 330 has: a structure provided with a thin film piezoelectric element and a supporting member for supporting the piezoelectric element; and a pump chamber having first and second substrates between which the structure is inserted, and being surrounded by the second substrate and the structure. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a chemical analysis chip.

  Currently, chemical inspection systems using chemical reactions are used in various fields such as medical diagnosis, drug discovery, DNA analysis, environmental inspection, and food quality inspection. Of these, testing systems such as medical on-site diagnostics, drug discovery experiments, and DNA analysis are particularly inexpensive and require a shorter time to determine the results in order to shorten the testing time. It has been.

  Here, since the chemical reaction rate in the chemical inspection system is constant in each reaction, the reaction time is shortened by reducing the amount of the inspection solution to a few tens to several hundreds nL, and the time until the result becomes clear. Is shortened. As a technique for shortening the reaction time, the use of a fine chemical analysis chip has been studied.

  Conventionally, as a chemical analysis chip (microchemical chip), for example, those described in Patent Documents 1 and 2 are known. Patent Document 1 discloses a microchemical chip in which a pump unit is provided in a flow path from a fluid storage unit to a discharge unit, and a plurality of minute sample liquids (test liquids) are merged. Patent Document 2 discloses a technique in which a plurality of micropumps are used to stir a mixture solution by reciprocating it in a meandering mixing channel, thereby increasing the extraction efficiency of a substance for analysis in the mixture solution. Yes.

JP 2007-10676 A JP 2008-209281 A

  However, the present inventors have made a detailed examination of these conventional chemical analysis chips, and in such conventional chemical analysis chips, the inspection section (analysis section) for inspecting the sample liquid has a pulsation of the sample liquid. It has been found that the test results do not show highly accurate test results, such as it is difficult to detect trace components under the influence of the above.

  The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a chemical analysis chip capable of suppressing the pulsation of a sample solution and showing a highly accurate test result.

  As a result of intensive studies to achieve the above object, the present inventors have suppressed the pulsation of the sample liquid by improving the piezoelectric material used for the actuator of the pump from that provided in the conventional chemical analysis chip. As a result, the present invention has been completed. That is, the present invention is a chemical analysis chip comprising pump means for transferring a sample liquid, a flow path for circulating the sample liquid, and inspection means for inspecting the sample liquid, the pump means comprising a thin film piezoelectric element and A chemical analysis chip including a structure including a support member for supporting the piezoelectric element, and first and second substrates sandwiching the structure, and having a pump chamber surrounded by the second substrate and the structure It is. Here, the “thin film piezoelectric element” in the present invention means a thin film piezoelectric element formed by a so-called gas phase method.

  Patent Documents 1 and 2 show a pump that is provided in a chemical analysis chip and that is driven using a piezoelectric material for an actuator. The piezoelectric material is formed by a thick film forming method or a piezoelectric element plate, and both are thick. The inventors of the present invention have found that the inspection part is affected by the pulsation of the sample liquid in the conventional chemical analysis chip due to the thick film thickness of the piezoelectric material. That is, since a piezoelectric material with a large film thickness has a low resonance frequency, a pump using the piezoelectric material as an actuator increases the pulsation of the sample liquid to be transferred. As a result, the inspection unit is strongly influenced by the pulsation of the sample liquid, and it is difficult to obtain a highly accurate inspection result.

  On the other hand, in the chemical analysis chip of the present invention, a thin film piezoelectric element is provided as an actuator for driving the pump means. Since the thin film piezoelectric element has a high resonance frequency, the pulsation of the sample liquid can be suppressed, and as a result, a highly accurate test result can be shown. Further, in the thin film piezoelectric element provided in the chemical analysis chip of the present invention, the displacement in the in-plane direction (d31 direction) is more dominant than the displacement in the thickness direction (d33 direction). Curved in the thickness direction, thereby enabling the volume and pressure in the pump chamber to be increased or decreased. As a result, compared to a thick film piezoelectric element that increases or decreases the volume and pressure in the pump chamber due to displacement in the thickness direction, the applied voltage can be more efficiently converted into the transfer amount of the sample liquid.

  In addition, as the amount of the sample solution to be handled becomes extremely small, it is difficult to manufacture the chemical analysis chip so that the pump means has a certain quality, especially when the chips are manufactured in large quantities. However, in the present invention, the piezoelectric element is formed into a thin film, that is, formed by a vapor phase method, so that deterioration of the quality of the pump means due to poor bonding or misalignment of the piezoelectric element can be prevented.

  In the chemical analysis chip of the present invention, it is preferable that the structure includes two or more piezoelectric elements arranged along the flow direction of the sample liquid. In such a chemical analysis chip, the pump means applies voltage sequentially from the piezoelectric element arranged on the sample solution suction side (upstream side) to the piezoelectric element arranged on the discharge side (downstream side). The sample liquid can be transferred by operating the plurality of piezoelectric elements in a swinging manner as a whole. Therefore, it is not necessary to provide a valve for controlling the liquid supply upstream and downstream of the pump means, the chip structure can be simplified, the chip can be further downsized and thinned, and a large number of inexpensive ones can be obtained. Can be manufactured. In addition, since the pump means also serves as a valve, the number of members can be reduced, and there is no need for a flow path to connect each member. Therefore, the pump means and the valve are provided separately. As a result, the distance between the members is shortened and the responsiveness is improved, and the pressure control of the effective sample liquid is facilitated within the chip. The pump means displaces the upstream piezoelectric element to push out (discharge) the sample liquid, and also displaces the downstream piezoelectric element to inhale the sample liquid, thereby transferring the sample liquid. In this way, by appropriately combining the discharge and suction of the sample liquid, the pump means exhibits a higher efficiency and can realize a larger transfer amount of the sample liquid even when a smaller voltage is applied. Therefore, the inspection time can be further shortened. Furthermore, the pump means can reversely feed the sample solution by changing the order of voltage application from the downstream side to the upstream side. Still further, the pump means can swing, vibrate, pressurize, etc. the sample liquid by adjusting the order of voltage application to each piezoelectric element. This facilitates efficient mixing of sample liquids and chemical reactions, enabling multi-functional inspections, and inadequate mixing due to laminar flow when handling very small amounts of sample liquids. Can also be eliminated.

  In the chemical analysis chip of the present invention, it is preferable that the structure surrounding the pump chamber and the second substrate are in direct contact when the pump means is not operating. Such a pump means has a capacity of the pump chamber substantially zero when not operating. This pump means has a larger capacity (ΔV) when sucking the sample liquid, compared with a pump having a predetermined capacity and a space in the pump chamber even when not operating. The sample liquid transfer efficiency is further increased.

  The chemical analysis chip of the present invention preferably further comprises a storage means for storing the sample solution. As a result, the chemical analysis chip can be handled in a state where the sample liquid is injected. For example, the chemical analysis chip and the sample liquid can be installed or removed from the inspection apparatus at a time. To do.

  The chemical analysis chip of the present invention includes first and second storage means for storing a sample liquid, and first and second pumps for transferring the sample liquid from the first and second storage means by suction and discharge, respectively. Means, a flow path for combining the sample liquids discharged from the first and second pump means, and statically mixing the combined sample liquids, an inspection means for inspecting the sample liquid that has passed through the flow paths, A chemical analysis chip comprising: a third pump means for transferring the sample liquid after being inspected by the inspection means by suction and discharge; and a third storage means for storing the sample liquid discharged from the third pump means. Each of the first, second, and third pump means includes a structure including a thin film piezoelectric element and a support member that supports the piezoelectric element, and first and second substrates sandwiching the structure. Contained and surrounded by the second substrate and the structure And pump chamber, it is preferable that is chemical analysis chip having a first and a second opening communicating with the pump chamber.

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the chemical analysis chip which can suppress the pulsation of a sample liquid and can show a highly accurate test result.

It is a top view showing typically a chemical analysis chip concerning an example of the present invention. It is sectional drawing which shows typically the cross section which appears by cut | disconnecting the II-II line | wire shown in FIG. It is process drawing which shows typically operation | movement of the pump means which concerns on an example of this invention. It is a mimetic diagram showing an inspection system concerning an example of the present invention. It is a top view which shows typically the drive method of the pump means which concerns on an example of this invention. It is a top view which shows typically the drive method of the pump means which concerns on an example of this invention. It is a top view which shows typically the chemical analysis chip concerning another example of this invention. It is a top view which shows typically the chemical analysis chip concerning another example of this invention.

  Hereinafter, a form for carrying out the present invention (hereinafter simply referred to as “the present embodiment”) will be described in detail with reference to the drawings as necessary. In the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted. Further, the positional relationship such as up, down, left and right is based on the positional relationship shown in the drawings unless otherwise specified. Further, the dimensional ratios in the drawings are not limited to the illustrated ratios.

  FIG. 1 is a plan view schematically showing the chemical analysis chip of the first embodiment (however, a second substrate 114 described later is seen through), and FIG. It is sectional drawing which shows typically the cross section which appears by cut | disconnecting by the -II line. The chemical analysis chip 100 of the present embodiment includes a first substrate 110, a structure 112, and a second substrate 114, which are stacked in this order. Each of these members includes first and second storage means 120A and 120B for storing a sample liquid before inspection (hereinafter referred to as “pre-inspection sample liquid”), and first and first reservoirs for transferring the pre-inspection sample liquid. 2 pump means 130A and 130B, a flow path 140 through which the pre-inspection sample liquid flows, an inspection means 150 for inspecting the pre-inspection sample liquid, and an inspected sample liquid (hereinafter referred to as “post-inspection sample liquid”). The third pump means 130C for transporting the liquid and the third storage means 120C for storing the sample liquid after the inspection are configured.

  The sample liquid is a liquid containing a sample to be inspected, and may be a liquid in which the sample is dissolved or dispersed in a solvent, and may further include a carrier liquid for transporting the sample. . When the carrier liquid is used, when the sample is liquid, the amount of the sample used can be reduced.

  Examples of the sample include nucleic acids, proteins, saccharides, cells, and complexes thereof. Examples of the nucleic acids include DNA, cDNA, RNA, and antisense RNA, or a fragment thereof or an amplified product thereof, a chemically synthesized DNA and a chemically synthesized RNA, or an amplified product thereof. Examples of proteins include antigens, antibodies, lectins, adhesins, receptors for physiologically active substances, and peptides. In addition, examples of the carrier liquid include water, alcohols such as methanol and ethanol, and aqueous solutions such as phosphoric acid, acetic acid, and hydrochloric acid.

  The first substrate 110 is not particularly limited as long as it can form a probe 156 (described later) disposed on the surface of the structure 112 and the inspection unit 150 on the surface thereof, and does not impede their functions. It may be a substrate used for forming a thin film. Examples of the first substrate include a silicon substrate, a glass substrate, and a ceramic substrate. The thickness of the first substrate is the thickest portion, for example, 0.2 mm to 2.0 mm. The first substrate 110 is preferably a silicon substrate from the viewpoint of a combination with a piezoelectric material and a film forming method, which will be described later, and a highly oriented piezoelectric body.

  The first substrate 110 corresponds to the storage means in order to form the first, second and third storage means 120A, 120B and 120C (abbreviated as “120A-C”, the same applies hereinafter). The part is provided with a recess having an opening on the upper side. Further, the first substrate 110 is provided with a recess having an opening on the lower side so that the thickness in the lower part of the first, second and third pump means 130A-C is reduced. . Thereby, the 1st, 2nd and 3rd pump means 130A-C operate | moves more effectively, and can transfer a sample liquid more efficiently.

  The structure 112 is bonded to the first substrate 110 at a portion in contact with the first substrate 110, and the first, second, and third piezoelectric elements 160A to 160C and the piezoelectric elements 160A to 160C are joined. And a support member 170 that is directly joined to and supported by the support member 170. The support member 170 is, for example, a film having a thickness of 10 to 30 μm at the thickest portion. The material of the support member 170 is an insulating material and needs to be appropriately curved and follow without being damaged by the displacement of the first, second, and third piezoelectric elements 160A to 160C. Therefore, a material having flexibility is preferable. When a material having flexibility is used as the material of the support member 170, the displacement of the first, second, and third piezoelectric elements 160A to 160C can be well transmitted to the pump chamber described later. The efficiency (sample liquid transfer efficiency, operating efficiency) of the second and third pump means 130A to 130C is increased. Specifically, the material of the support member 170 is preferably a resin material, more preferably a material that adheres well to a piezoelectric body and an upper electrode described later, and examples thereof include silicone resin, polyimide, and parylene. In the support member 170, the first, second and third storage means 120 </ b> A to 120 </ b> C and the inspection means 150 are formed, and a through hole is provided in the thickness direction thereof. Further, the support member 170 embeds the first, second and third piezoelectric elements 160A to 160C from below.

  The second substrate 114 is bonded to the structure body 112 at a portion in contact with the structure body 112. As the 2nd board | substrate 114, a glass substrate and a ceramic substrate are mentioned, for example, The thickness is 0.2 mm-2.0 mm in the thickest part, for example. In the second substrate 114, in order to form the first, second, and third storage means 120A to 120C, a recess having an opening on the lower side is provided in a portion corresponding to the storage means. Further, on the second substrate 114, the sample liquid is supplied from the first and second storage means 120A to 120B to the first, second and third pump means 130A to 130C, the flow path 140, the inspection means 150 and the first. A groove and a recess having an opening on the lower side are provided in a part corresponding to the third storage unit 120C through the third pump unit 130C.

  The first and second storage means 120A-B store the pre-test sample solution, respectively, except that they communicate with the flow paths 122A-B, respectively, and the first substrate 110, the structure 112, and the first. Two substrates 114 are surrounded. The shapes of the storage means 120A to 120B shown in the figure are both substantially cylindrical, but the shapes may be the same or different from each other, as long as the pre-test sample liquid can be stored. It is not limited.

  The first and second storage means 120A-B communicate with the first and second pump means 130A-B via the flow paths 122A-B, respectively. The flow paths 122A-B communicate with the second substrate 114 and the structure 112 except that the flow paths 122A-B communicate with the first and second storage means 120A-B and the first and second pump means 130A-B, respectively. Surrounded and formed.

  FIG. 3 is a process diagram (shown in section) schematically showing the operation of the first pump means 130A, and (A) shows the state before the operation. The first pump means 130A includes a part of the structure 112 including the first piezoelectric element 160A of a thin film and a part of the support member 170 that supports the piezoelectric element 160A, and the part of the structure 112. The pump chamber 132A includes a part of the first and second substrates 110 and 114 sandwiched therebetween and is surrounded by the part of the second substrate 114 and the part of the structure 112. The piezoelectric element 160A includes a lower electrode 162, a thin film piezoelectric body 164, and three upper electrodes 166a, 166b and 166c (abbreviated as “166a to c”) arranged along the flow direction of the sample liquid before inspection. The same applies hereinafter.), And the lower electrode 162 and the upper electrodes 166a to 166c sandwich the piezoelectric body 164 from above and below.

  The piezoelectric element 160A is, for example, a thin film having a thickness of 0.5 μm to 10.0 μm, and the upper electrodes 166a to 166c each have a substantially circular main surface, and the lower electrode 162 and the piezoelectric body 164 have three upper portions. It has a larger planar dimension than the electrodes 166a-c. The piezoelectric element 160 </ b> A is embedded and bonded to the support member 170 from below, and the lower surface is bonded to the first substrate 110. The three upper electrodes 166a to 166c in the piezoelectric element 160A are not in direct contact with each other, and the lower surface of the support member 170 is joined to the upper surface of the piezoelectric body 164 between them.

  A wiring (not shown) is taken out from the lower electrode 162 provided in the piezoelectric element 160A, and a wiring (not shown) is taken out from each of the three upper electrodes 166a to 166c. These taken-out wirings extend to a terminal (not shown) and are connected to a power source (not shown) through the terminal.

  Here, an operation method of the first pump means 130A will be described with reference to FIG. In the piezoelectric element 160A, an upper electrode 166a is provided on the lower electrode 162 and the piezoelectric body 164, and a portion that operates by applying a voltage between them is an upper portion on the piezoelectric operation section 168a, the lower electrode 162, and the piezoelectric body 164. A portion that includes the electrode 166b and operates by applying a voltage between them, a portion that includes the piezoelectric operation unit 168b, the lower electrode 162, and the upper electrode 166c on the piezoelectric body 164, and that operates by applying a voltage between them. Is represented as a piezoelectric operating portion 168c. First, in step (A), the pump means 130A is in a stopped state. Next, in step (B), a voltage is applied between the lower electrode 162 and the upper electrode 166a located on the most upstream side with respect to the flow direction of the sample liquid before inspection. At this time, a voltage is applied so that the portion of the piezoelectric body 164 that contacts the upper electrode 166a contracts in the in-plane direction (d31 direction). Then, while the portion of the piezoelectric body 164 is displaced (shrinks in the in-plane direction), the lower electrode 162 and the first substrate 110 are not displaced in the in-plane direction. Curved downward with one substrate 110. As a result, the capacity of the pump chamber 132A increases and the pump chamber 132A has a negative pressure. Therefore, the pump means 130A causes the pre-test sample liquid stored in the first storage means 120A to pass through the flow path 122A. It sucks into the pump chamber 132A.

  Next, in step (C), a voltage is applied between the lower electrode 162 and the upper electrode 166b in a state where the application of the voltage between the lower electrode 162 and the upper electrode 166a is maintained. Then, the portion of the piezoelectric body 164 that contacts the upper electrode 166b is displaced (shrinks in the in-plane direction), while the lower electrode 162 and the first substrate 110 are not displaced in the in-plane direction. Along with the displacement of the portion, the piezoelectric operating portion 168 b is bent downward along with the support member 170 and the first substrate 110. As a result, the capacity of the pump chamber 132A further increases and the pump chamber 132A has a negative pressure. Therefore, the pump means 130A further sucks the pre-inspection sample liquid into the pump chamber 132A from the flow path 122A.

  Subsequently, in the step (D), the application of the voltage between the lower electrode 162 and the upper electrode 166a is stopped, and the application of the voltage between the lower electrode 162 and the upper electrode 166b is maintained, A voltage is applied between the electrode 162 and the upper electrode 166c located on the most downstream side with respect to the flow direction of the sample liquid before inspection. Then, since the contraction in the in-plane direction of the portion that contacts the upper electrode 166a of the piezoelectric body 164 is eliminated, the piezoelectric operation unit 168a returns to the stopped state. Further, the portion of the piezoelectric body 164 that contacts the upper electrode 166c is displaced (shrinks in the in-plane direction), while the lower electrode 162 and the first substrate 110 are not displaced in the in-plane direction. Along with the displacement of the portion, the piezoelectric operation portion 168 c is bent downward along with the support member 170 and the first substrate 110. As a result, the capacity of the portion of the pump chamber 132A corresponding to the piezoelectric operation portion 168a is reduced and the portion is pressurized, and the capacity of the portion of the pump chamber 132A corresponding to the piezoelectric operation portion 168c is increased. Since the portion has a negative pressure, the pump unit 130A pushes out the pre-inspection sample liquid at the portion of the pump chamber 132A corresponding to the piezoelectric operation portion 168a, while pre-inspecting the portion of the pump chamber 132A corresponding to the piezoelectric operation portion 168c. The sample liquid is inhaled and the pre-inspection sample liquid is transferred further downstream.

  Next, in step (E), the application of voltage between the lower electrode 162 and the upper electrode 166b is stopped. Then, since the contraction in the in-plane direction of the portion of the piezoelectric body 164 that contacts the upper electrode 166b is eliminated, the piezoelectric operation unit 168b returns to the stopped state. As a result, the capacity of the portion of the pump chamber 132A corresponding to the piezoelectric operating portion 168b is reduced and the portion is pressurized, so that the pump means 130A is inspected at the portion of the pump chamber 132A corresponding to the piezoelectric operating portion 168b. The previous sample solution is pushed out and transferred to the flow path 140 downstream of the pump means 130A.

  Then, returning to the step (A), the application of voltage between the lower electrode 162 and the upper electrode 166c is stopped. Then, since the contraction in the in-plane direction of the portion that contacts the upper electrode 166c of the piezoelectric body 164 is eliminated, the piezoelectric operation unit 168c returns to the stopped state. As a result, the capacity of the portion of the pump chamber 132A corresponding to the piezoelectric operating portion 168c is reduced and the portion is pressurized, so that the pump means 130A is inspected at the portion of the pump chamber 132A corresponding to the piezoelectric operating portion 168c. The pre-sample liquid is pushed out, and the pre-inspection sample liquid is further transferred to the flow path 140 downstream of the pump unit 130A.

  By repeating the above steps, the piezoelectric element 160A in the pump unit 130A of the present embodiment is swung (moved) as a whole to move the sample solution before the inspection through the pump unit 130A. can do. In this case, for example, the step (B) may be started together with the start of the step (E). As a result, the amount of fluid transferred per unit time by the piezoelectric pump 130A can be further increased.

  The second pump unit 130B includes a second piezoelectric element 160B, and the pre-inspection sample liquid stored in the second storage unit 120B is pumped into the pump chamber (not shown) via the flow path 122B. ) And then discharged from the pump chamber can be transferred to the flow path 140. In the present embodiment, since the second pump unit 130B has the same structure and operation as the first pump unit 130A, detailed description thereof is omitted here.

  The flow path 140 is formed by being surrounded by the structure body 112 and the second substrate 114 except that the flow path 140 communicates with the first and second pump means 130A-B and the inspection means 150. The flow path 140 includes a flow path section 140A communicating from the first pump means 130A, a flow path section 140B communicating from the second pump means 130B, and a flow path after the flow path sections 140A and 140B merge. 140C. The channel part 140C meanders in a planar shape as shown in the figure. The flow path 140 circulates the pre-inspection sample liquid transferred from the first and second pump means 130A-B to the inspection means 150, and mixes or reacts the pre-inspection sample liquid as necessary. Is. That is, the flow path 140 is configured to pass the pre-inspection sample liquid from the first pump means 130A and the pre-inspection sample liquid from the second pump means 130B of a type different from the pre-inspection sample liquid to the flow path section 140C. Then, the sample liquids before inspection are statically stirred by the meandering shape. As a result, the mixing or reaction of these pre-test sample solutions can be rapidly advanced, and can be used for, for example, DNA chemical synthesis, amplification, and test analysis.

  The inspection means 150 is for retaining the pre-inspection sample solution in the portion and performing the analysis and inspection. The inspection means 150 is formed so as to be surrounded by the first and second substrates 110 and 114 and the structure body 112 except that the inspection means 150 communicates with the flow path 140 and the third pump means 130C. The inspection means preferably secures a predetermined volume or more so that the pre-inspection sample solution can be retained for a predetermined time in order to perform more accurate and accurate analysis and inspection. Further, it is preferable that the inspection means 150 is provided with a sensor 156 that enables detection of DNA by binding to DNA.

  The third pump means 130C includes a third piezoelectric element 160C, and sucks the sample liquid after inspection from the inspection means 150 into the pump chamber (not shown) via the flow path 152, Furthermore, it can transfer to the flow path 154 by discharging from the pump chamber. In the present embodiment, the third pump unit 130C has the same structure and operation as the first pump unit 130A, and thus a detailed description thereof is omitted here. The flow path 152 is formed so as to be surrounded by the second substrate 114 and the structure 112 except that it is in communication with the inspection means 150 and the third pump means 130C.

  The third storage unit 120C stores the post-inspection sample liquid transferred from the third pump unit 130C, except that the third storage unit 120C communicates with the flow path 154. It is formed so as to be surrounded by the second substrate 114. The shape of the third storage means 120C shown in the figure is substantially cylindrical, but is not particularly limited as long as it can store the sample liquid after the test. The flow path 154 is formed so as to be surrounded by the second substrate 114 and the structure body 112 except that it communicates with the third pump means 130C and the third storage means 120C.

  Then, the manufacturing method of the chemical analysis chip | tip 100 of this embodiment is demonstrated. First, a first substrate 110 that also serves as a film formation substrate is prepared, and a lower main surface of the first substrate 110 is processed by etching or the like, so that first, second, and third pump means 130A to 130A to 130A. A depression having an opening on the lower side is formed in the lower part of C so that the thickness in the lower part is reduced. Next, first, second, and third piezoelectric elements 160 </ b> A to 160 </ b> C are formed at predetermined positions on the first substrate 110. The piezoelectric element 160A will be described as an example. First, a thin film lower electrode 162 and a thin film piezoelectric body 164 are stacked in this order on the first substrate 110. More specifically, first, the lower electrode 162 is formed on the surface of the first substrate 110 by a vapor phase method such as a sputtering method, a CVD method, or an evaporation method, and the lower electrode 162 is formed on the first substrate 110. Join. The material of the lower electrode 162 is not particularly limited as long as it can be used as the electrode material of the piezoelectric element, and examples thereof include platinum, gold, copper, and alloys containing these. The thickness of the lower electrode 162 is, for example, 0.05 μm to 1.0 μm.

  Next, a thin film piezoelectric body 164 is formed on the surface of the lower electrode 162. A method for forming the piezoelectric body 164 is not particularly limited as long as it is a vapor phase method, and examples thereof include a sputtering method, a CVD method, and a vapor deposition method. The material of the piezoelectric body 164 is not particularly limited as long as it is a piezoelectric material capable of forming a thin film, and examples thereof include PZT and barium titanate. Among these, PZT (lead zirconate titanate) is preferable from the viewpoint of showing excellent piezoelectric characteristics and being easily available. The thickness of the piezoelectric body 164 is, for example, 0.5 μm to 5.0 μm.

  Subsequently, a layer to be a thin film upper electrode 166a-c is formed on the surface of the piezoelectric body 164 by a vapor phase method such as a sputtering method, a CVD method, or an evaporation method. Next, the layer to be the upper electrodes 166a to 166c is patterned into a desired shape. The patterning method is not particularly limited. For example, after forming a mask resist on the surface of the layer to be the upper electrodes 166a to 166c as an etch mask, the portion of the layer not covered with the mask resist is removed by etching. Thereafter, the mask resist may be removed. As another patterning method, a lift-off method for resist patterning, film formation, and removal of unnecessary portions may be used. Thereby, thin film upper electrodes 166a to 166c are formed, and a thin film piezoelectric element 160A is obtained in a region where the lower electrode 162, the piezoelectric body 164, and the upper electrodes 166a to 166c are stacked. The material of the upper electrodes 166a to 166c is not particularly limited as long as it can be used as the electrode material of the piezoelectric element, and examples thereof include platinum, gold, copper, and alloys containing these. The thickness of the upper electrodes 166a to 166c may be, for example, 0.05 μm to 1.0 μm.

  The second and third piezoelectric elements 160B to 160C are also formed in the same manner as the first piezoelectric element 160A.

  Next, a support member 170 is formed on the exposed surfaces of the first substrate 110, the piezoelectric elements 160A to 160C, and the piezoelectric body 164. As described above, the material of the support member 170 is specifically preferably a resin material. When the material of the support member 170 is a resin material, first, a resin composition (for example, a mixture of a resin and / or a monomer and a solvent) that is a raw material of the resin material is used as the first substrate 110 and the piezoelectric element 160A. ~ C and the exposed surface of the piezoelectric body 164 are applied. Next, the applied resin composition is solidified by drying or the like and cured by heating or light irradiation. Thereafter, the resin material in portions corresponding to the first, second, and third storage units 120A to 120C and the inspection unit 150 is removed. In this way, the structure body 112 including the first, second, and third piezoelectric elements 160A to 160C and the support member 170 that supports the piezoelectric elements 160A to 160C is obtained. Thereafter, the wiring is connected to the lower electrode 162 and the upper electrodes 166a to 166c.

  Next, a desired portion of the upper main surface of the first substrate 110 is etched. Specifically, the portions corresponding to the first, second and third storage means 120A to 120C are etched from the upper main surface to form depressions for providing them. The etching method is not particularly limited. For example, after a mask resist having a predetermined shape is formed on the surface of the first substrate 110 as an etch mask, the portion of the first substrate 110 that is not covered with the mask resist by etching. Then, the mask resist may be removed. Other etching methods include resist patterning, film formation, and lift-off methods for removing unnecessary portions. The etching is preferably dry etching, and examples thereof include reactive gas etching, reactive ion etching, reactive ion beam etching, ion beam etching, and reactive laser beam etching. Thus, a composite including the first substrate and the structure body 112 is obtained.

  On the other hand, a second substrate 114 is prepared, and a lower main surface of the second substrate 114 is patterned by wet etching or the like to form grooves and depressions having a predetermined shape. The shape and position of the grooves and recesses are the first, second and third storage means 120A-C, the flow paths 122A-B, 140, 152 and 154, the pump chamber 132A in the first pump means 130A, the first. The pump chambers in the second and third pump units and the inspection unit 150 are formed.

  Next, the composite and the second substrate 114 after patterning are aligned and joined. The joining may be performed using an adhesive resin. The type of the adhesive resin is not particularly limited as long as it can join the composite and the second substrate 114, and examples thereof include polyimide, modified polyimide, parylene, and silicone resin. Thus, the chemical analysis chip 100 of this embodiment is obtained.

  Next, an inspection system using the chemical analysis chip 100 of this embodiment will be described. FIG. 4 is a schematic diagram showing the inspection system of the present embodiment. The inspection system 200 of this embodiment drives and controls the detection device 210 for analyzing the sample liquid in the inspection means 150 of the chemical analysis chip 100 and the first to third pump means 130A to 130C of the chemical analysis chip 100. Power supply and control device 220, and wiring 230 that connects each electrode of the first to third pump means 130 </ b> A to 130 </ b> C and the power supply and control device 220.

  The detection device 210 is not particularly limited as long as it can detect information to be analyzed in the sample solution. For example, when the information to be analyzed is DNA analysis, the detection device 210 is a general fluorescent dye. A method of monitoring and analyzing the sign may be used. Examples of the other detection apparatus 210 include a sensing method for detecting an enzyme action having a radioactive dye, a luminescent dye, a magnetic marker, or the like.

  The power supply and control device 220 includes, for example, a drive circuit and a microcomputer, and drives the first, second, and third pump units 130A to 130C by executing a predetermined control program and the like. The drive circuit may include a signal generation unit and a signal amplification unit. In the drive circuit, a voltage signal generated in a signal generation unit such as a signal generation circuit or signal generation software is amplified to a predetermined voltage by a signal amplification unit such as a piezo driver, and wired to each of the lower electrode and the upper electrode described above. 230. The timing for supplying the voltage signal to each lower electrode and upper electrode is controlled by a predetermined control program by the microcomputer.

  Next, an inspection method for inspecting the chemical analysis chip 100 of the present embodiment using the inspection system 200 will be described. First, a sample solution is supplied to each of the first and second storage means 120A-B of the chemical analysis chip 100. Next, the chemical analysis chip 100 is installed at a predetermined position of the inspection system 200. Next, a predetermined voltage is applied to each electrode of the first and second pump means 130A-B via the wiring 230 from the power supply and control device 220, and driving of each pump means 130A-B is started. Thereby, the sample liquid before a test | inspection stored by the 1st and 2nd storage means 120A-B is supplied to the flow path 140 via each pump means 130A-B. In the flow path 140, the pre-inspection sample liquids from the first and second storage means 120A-B merge and are further sufficiently mixed by the meandering flow path 140. Subsequently, by driving the first and second pump units 130 </ b> A to 130 </ b> B, the pre-inspection sample liquid mixed in the flow path 140 is supplied to the inspection unit 150. After the pre-inspection sample solution is sufficiently supplied to the inspection means 150, the application of voltage to the first and second pump means 130A-B is stopped, and the drive of these pump means 130A-B is stopped. Next, the sample liquid is analyzed by the detection device 210. After a predetermined time until the analysis is completed, a predetermined voltage is applied to each electrode of the third pump unit 130C from the power source and control device 220 via the wiring 230, and the driving of the pump unit 130C is started. To do. As a result, the post-inspection sample liquid is collected by the third storage unit 120C via the pump unit 130C. When all of the sample liquid after the inspection is collected and stored in the third storage unit 120C, the application of voltage to the third pump unit 130C is stopped, and the driving of the pump unit 130C is stopped.

  In the chemical analysis chip 100 of the present embodiment described above, a thin film piezoelectric element (for example, the piezoelectric element 160A) is provided as an actuator for driving the first, second and third pump means 130A to 130C. Since the thin-film piezoelectric element has a high resonance frequency, it can suppress the pulsation of the sample liquid by being driven at high speed, and can show a highly accurate analysis / inspection result. In addition, the thin film piezoelectric element provided in each of the pump means 130A to 130C of the chemical analysis chip 100 has a displacement in the in-plane direction (d31 direction) dominant over the displacement in the thickness direction (d33 direction). With the displacement in the inward direction, it curves downward in the thickness direction, thereby enabling the volume and pressure in the pump chamber (for example, the pump chamber 132A) to be increased or decreased. This realizes the advantage that the applied voltage can be more efficiently converted into the transfer amount of the sample solution compared to the thick film piezoelectric element that increases or decreases the volume and pressure in the pump chamber by displacement in the thickness direction. To do.

  In addition, as the amount of the sample solution to be handled becomes extremely small, it is difficult to manufacture the chemical analysis chip so that the pump means has a certain quality, especially when the chips are manufactured in large quantities. However, in the present embodiment, the piezoelectric element is formed into a thin film, that is, formed by a vapor phase method, so that deterioration of the quality of the pump means due to bonding failure or positional deviation of the piezoelectric element can be prevented.

  Furthermore, the chemical analysis chip 100 of the present embodiment can apply a voltage in order from the piezoelectric element arranged on the sample solution suction side (upstream side) to the piezoelectric element arranged on the discharge side (downstream side). Each possible pump means 130A-C is provided. In these pump means 130A to 130C, the sample liquid can be transferred by operating the plurality of piezoelectric elements in a swinging manner as a whole. Therefore, it is not necessary to provide a valve (valve) for controlling the transfer amount of the sample liquid upstream and downstream of the pump means 130A to 130C, the structure of the chip 100 can be simplified, and the chip 100 can be further reduced in size and Thinning is possible, and inexpensive products can be manufactured in large quantities. In addition, since the pump means 130A-C also serve as a valve, the number of members can be reduced, and the number of flow paths connecting the members can be reduced, so that the pump means and the valve are provided separately. As compared with the above, the distance between the respective members is shortened and the responsiveness is improved, and the pressure control of the effective sample solution in the chip is facilitated. In each pump means 130A to 130C, the upstream piezoelectric element is displaced to push out (discharge) the sample liquid, and the downstream piezoelectric element is displaced to inhale the sample liquid, thereby transferring the sample liquid. To do. As described above, by appropriately combining the discharge and suction of the sample liquid, the pump units 130A to 130A-C exhibit a greater efficiency, and realize a larger transfer amount of the sample liquid even when a smaller voltage is applied. Therefore, the analysis / inspection time can be further shortened.

  Moreover, the chemical analysis chip 100 of this embodiment can handle the chemical analysis chip 100 in a state in which the sample liquid is injected by including the storage units 120A to 120C that store the sample liquid. For example, the chemical analysis chip 100 and the sample solution can be set and removed from the 200 at a time.

  As mentioned above, although the form for implementing this invention was demonstrated, this invention is not limited to the said this embodiment. The present invention can be variously modified without departing from the gist thereof. For example, the structures of the first, second, and third pump means 130A to 130C in the first embodiment may be different from each other.

  In the above-described embodiment, the pump means provided in the chemical analysis chip of the present invention drives the sample liquid upstream by sequentially driving the piezoelectric body portion from the upstream side to the downstream side along the flow direction of the sample liquid. However, the driving method of the pump means is not limited to this. 5 and 6 are plan views schematically showing the driving method of the pump means according to the present invention. The pump means shown in the figure is one in which three piezoelectric operating portions corresponding to three upper electrodes arranged along the sample liquid flow direction can operate independently, as in the present embodiment. FIG. 5 shows a case where one such pump means is operated, and FIG. 6 shows a case where two such pump means are arranged in parallel.

  FIG. 5A shows that the pump means transfers the sample liquid from the upstream side to the downstream side by driving the piezoelectric operation unit in order from the upstream side to the downstream side as in the present embodiment. In (B), the piezoelectric operation unit is driven in order from the downstream side to the upstream side, so that the pump means transfers the sample liquid from the downstream side to the upstream side. Such a driving method is useful, for example, when the sample liquid transferred to the downstream side is desired to flow backward to the upstream side. (C) First, the piezoelectric operation unit is driven in order from the upstream side to the downstream side, and then the most downstream piezoelectric operation unit is driven, and then the piezoelectric operation unit is immediately driven in order from the downstream side to the upstream side. This is a driving method in which the piezoelectric operating unit is driven again from the upstream side to the downstream side immediately after the piezoelectric part is driven, and this is repeated. Thereby, it becomes possible to mix and stir the sample liquid efficiently in the pump means. Further, (D) is a driving method for randomly driving each piezoelectric operation unit. This also makes it possible to efficiently mix and stir the sample liquid in the pump means.

  FIG. 6A shows a case where a branched flow path is provided upstream of two pump means arranged in parallel. In this case, the two pump means are simultaneously driven, and the piezoelectric operation unit is driven in order from the upstream side to the downstream side. At this time, by changing the voltage applied to the two pump means and the driving sequence of the piezoelectric operation unit, the transfer amount (transfer ratio) of the sample liquid by each pump means can be arbitrarily changed. Moreover, (B) is a case where the downstream flow path of the two pump means arranged in parallel joins, and the storage means is provided and terminates there. In this case, when the two pump units are driven simultaneously and the piezoelectric operation unit is driven in order from the upstream side to the downstream side, the sample liquid transferred by these pump units stays in the storage unit, and two pumps By continuing to drive the means, the pressure of the sample liquid in the storage means increases. This makes it possible to shorten or control the time of chemical reaction by using it together with temperature control, etc. Therefore, such pressurization method is suitable for hydrogenation reaction, polymerization reaction, carbonyl in chemical / chemical product development. It can be used for the experiment of the addition pressure synthesis of the fluorination reaction. (C) is a case where the downstream flow path of the two pump means arranged in parallel merges, and the downstream flow path after the merge further includes the pump means having only one piezoelectric operation unit. In this case, when the three pump means are simultaneously driven and the piezoelectric operation units are sequentially driven from the upstream side to the downstream side for the pump means arranged in parallel, the sample liquids transferred by these pump means merge downstream. . The sample liquid after the merge is further supplied to a pump means having only one piezoelectric operation unit. If the pump means having only one piezoelectric operation part is not provided with a valve upstream and downstream thereof, it is dominant to vibrate the sample liquid up and down rather than transfer the sample liquid by driving. Therefore, this enables efficient mixing and stirring of the sample liquid.

  Thus, the pump means in the chemical analysis chip of the present invention can perform various operations depending on its arrangement and driving method. In particular, in the conventional chemical analysis chip, when trying to reduce the size thereof, the Reynolds number of the sample liquid becomes extremely low due to insufficient capacity of the pump. However, according to the chemical analysis chip of the present invention, as is apparent from the above, the sample liquid is vibrated to generate turbulent flow, thereby enabling efficient mixing and stirring of the sample liquid. Therefore, it can be an effective means for rapid and sufficient mixing and reaction of the sample solution, and the functionality as a chemical analysis chip is enhanced.

  Moreover, the chemical analysis chip of the present invention may have a configuration as shown in FIG. FIG. 7 is a plan view schematically showing the chemical analysis chip of the second embodiment (however, the second substrate is seen through). The chemical analysis chip 300 of this embodiment includes a first storage unit 320A for storing a pre-inspection sample liquid, a flow path 340 for circulating the pre-inspection sample liquid, an inspection unit 350 for inspecting the pre-inspection sample liquid, A flow path 342 for flowing the sample liquid after inspection upstream of the pump means 330, a pump means 330 for transferring the sample liquid after inspection, a flow path 344 for flowing the sample liquid after inspection downstream of the pump means 330, and after the inspection Second storage means 320B for storing the sample liquid. The first storage means 320A and the inspection means 350 communicate with each other via a flow path 340, and the inspection means 350 and the pump means 330 communicate with each other via a flow path 342. The two storage means 320 </ b> B communicate with each other via a flow path 344.

  In the chemical analysis chip 300, the first storage unit 320A, the inspection unit 350, the pump unit 330, and the second storage unit 320B are respectively the first storage unit 120A, the inspection unit 150, and the second storage unit 320B. This is the same as the third pump means 130C and the third storage means 120C. Further, the flow path 340 through which the pre-inspection sample liquid according to this embodiment is not meandering and is linear. Since the chemical analysis chip 300 of this embodiment has a simple configuration as compared with the first embodiment, the flow paths are not joined or meandering, and therefore, two or more kinds thereof. This is useful when it is not necessary to mix or react the sample solution. In the chemical analysis chip 300 of this embodiment, all the sample liquids in the system are transferred by driving the pump means 330.

  Furthermore, the chemical analysis chip of the present invention may have a configuration as shown in FIG. FIG. 8 is a plan view schematically showing the chemical analysis chip of the third embodiment (however, the second substrate is seen through). The chemical analysis chip 400 of this embodiment includes first and second storage means 420A and 420B for storing a sample liquid, first and second pump means 430A and 430B for transferring the sample liquid, and the sample liquid. A flow path 440 that circulates, a first inspection unit 450A that inspects the sample solution, a third pump unit 430C that transfers the sample solution, and a third storage unit 420C that stores the sample solution are provided. Furthermore, the chemical analysis chip 400 mixes the sample liquid transferred from the first pump means 430A with the sample liquid transferred from the second pump means 430B and inspects the second inspection means 450B, and a flow path. And heating means 460 incorporating sensors such as a heater and a temperature sensor in 440. The first storage means 420A and the first pump means 430A communicate with each other via the flow path 422A, and the second storage means 420B and the second pump means 430B communicate with each other via the flow path 422B. The first pump means 430A and the second inspection means 450B communicate with each other via the flow path 424A, and the second pump means 430B and the second inspection means 450B communicate with the flow path 424B. It communicates through. The second inspection means 450B and the first inspection means 450A communicate with each other via a flow path 440, and the first inspection means 450A and the third pump means 430C pass through a flow path 426. The third pump unit 430C and the third storage unit 420C communicate with each other via a flow path 428.

  In the chemical analysis chip 400, the first, second, and third storage units 420A to 420C, 1, the second and third pump units 430A to 430C, the flow path 440, and the first inspection unit 450A are respectively This is the same as the first, second and third storage means 120A to 120C, the first, second and third pump means 130A to 130C, the flow path 140 and the inspection means 150 in the first embodiment. .

  The second inspection means 450B is for performing analysis and inspection of the sample liquid. In the first inspection means 450A, the sample liquid after sufficient mixing and reaction is analyzed through the flow path 440, whereas in the second inspection means 450B, the sample liquid before passing through the flow path 440 is analyzed. Sample solution prior to thorough mixing and reaction is analyzed. Therefore, by comparing the analysis results in the first and second inspection means 450A to 450B, changes before and after mixing in the channel 440, comparison before and after the reaction, changes with time, and the like can be examined. Similarly to the first inspection unit 450A, the second inspection unit 450B is also connected to the flow paths 422A and B and the flow path 440, except for the first and second substrates and the structure (not shown above). ) And surrounded. The second inspection means 450B preferably secures a predetermined volume or more so that the sample liquid can stay for a predetermined time in order to perform a more accurate and accurate analysis and inspection. The second inspection means 450B is preferably provided with a probe (not shown) that can detect the DNA by binding to the DNA. The heating means 460 is for heating the sample liquid mixed and stirred in the flow path 440 to a predetermined temperature and promoting the reaction there. When the heating means 460 incorporates a sensor such as a temperature sensor together with the heater, it becomes easy to control to a desired temperature, and the reaction can be easily controlled.

  Further, for example, in the first embodiment, the support member 170 is disposed on the upper side (the pump chamber side) of the piezoelectric element 160A, but the support member is disposed on the lower side (the side opposite to the pump chamber) of the piezoelectric element. It may be arranged and may be omitted. However, in those cases, the piezoelectric element is in direct contact with the fluid, and the piezoelectric element is likely to be deteriorated. Therefore, the support member is preferably disposed on the pump chamber side of the piezoelectric element. Further, in the present embodiment, the piezoelectric element 160A includes one lower electrode 162, one piezoelectric body 164, and three upper electrodes 166a to 166c, but the number of upper electrodes is naturally five. It is not limited to one, and a plurality of piezoelectric bodies and a plurality of upper electrodes may be sequentially stacked on one lower electrode 162, and a piezoelectric element may be provided on each of the plurality of lower electrodes. The body and the upper electrode may be stacked in order. Furthermore, in any one or more of the first, second, and third pump units 130A to 130C of the present embodiment, the structure 112 and the second substrate 114 may be in direct contact without bonding. . Such a pump means has a capacity of the pump chamber substantially zero when not operating. This pump means has a larger capacity (ΔV) when sucking the sample liquid, compared with a pump having a predetermined capacity and a space in the pump chamber even when not operating. The sample liquid transfer efficiency is further increased.

  Further, in another embodiment, any one or more of the first, second and third pumping means 130A to 130C includes a single lower electrode, a single piezoelectric body and a single upper electrode. It may have only one piezoelectric element provided. In that case, in order for the pump means to efficiently transfer the sample liquid, it is preferable to provide valves that can be opened and closed separately in the upstream channel and the downstream channel. Moreover, the planar shape of each storage means, inspection means, and upper electrode may not be substantially circular, and may be, for example, an egg cross-sectional shape, an ellipse, or a rectangle. Furthermore, in the first embodiment, the first substrate 110 has a lower portion in the lower part of the first, second, and third pumping means 130A to 130C so that the thickness thereof is reduced. The first substrate forms a through-hole in that portion, and the lower surfaces of the first, second and third pumping means 130A-C are exposed. Also good.

  Further, in the first embodiment, the second substrate 114 may be provided with a protruding portion protruding downward so as to partition the pump chamber 132A for each of the piezoelectric operating portions 168a to 168c. The lower surfaces of these protrusions partition the pump chamber 132A by directly contacting the upper surface of the support member 170 when the pump means 130A is not operating. That is, the pump chamber 132A may have a partial pump chamber for each of the piezoelectric operating units 168a to 168c.

  Furthermore, the chemical analysis chip of the present invention may not include a storage means. In this case, for example, by connecting the external storage means and the chemical analysis chip of the present invention so that they can communicate with each other, it can be used in the same manner as the chemical analysis chip of the present embodiment.

  Since the chemical analysis chip of the present invention can suppress the pulsation of the sample solution and show highly accurate test results, it can be used in various fields such as medical diagnosis, drug discovery, DNA analysis, environmental testing, food quality testing, etc. There is a possibility, and among these, there is a possibility that it can be used for inspection systems such as medical on-site diagnosis, drug discovery experiment, and DNA analysis.

  DESCRIPTION OF SYMBOLS 100, 300, 400 ... Chemical-analysis chip | tip, 110 ... 1st board | substrate, 112 ... Structure, 114 ... 2nd board | substrate, 120A-C, 320A-B, 420A-C ... Storage means, 140, 340, 440 ... Flow path, 130A-C, 330, 430A-C ... pump means, 132A ... pump chamber, 150, 350, 450A-B ... inspection means, 160A-C ... piezoelectric element, 162 ... lower electrode, 164 ... piezoelectric body, 166a -C ... Upper electrode, 170 ... Supporting member.

Claims (5)

A chemical analysis chip comprising: pump means for transferring the sample liquid; a flow path for circulating the sample liquid; and inspection means for inspecting the sample liquid,
The pump means includes a structure including a thin film piezoelectric element and a support member that supports the piezoelectric element, and first and second substrates sandwiching the structure, and the second substrate and the A chemical analysis chip having a pump chamber surrounded by a structure.   The chemical analysis chip according to claim 1, wherein the structure includes two or more piezoelectric elements arranged along a flow direction of the sample solution.   The chemical analysis chip according to claim 1 or 2, wherein the structure surrounding the pump chamber and the second substrate are in direct contact with each other when the pump means is not operating.   The chemical analysis chip according to claim 1, further comprising storage means for storing the sample solution. First and second storage means for storing sample liquid, first and second pump means for transferring the sample liquid from the first and second storage means by suction and discharge, respectively, and the first And a flow path for merging the sample liquid discharged from the second pump means and statically mixing the merged sample liquid, an inspection means for inspecting the sample liquid that has passed through the flow path, and Third pump means for transferring the sample liquid after being inspected by the inspection means by suction and discharge; and third storage means for storing the sample liquid discharged from the third pump means. A chemical analysis chip,
Each of the first, second, and third pump means includes a structure including a thin film piezoelectric element and a support member that supports the piezoelectric element, and first and second substrates that sandwich the structure. And a pump chamber surrounded by the second substrate and the structure.

Images