1316873 九、發明說明： 【發明所屬之技術領域】 本發明係有關於一種生物晶片製造裝置，特別是有關 於一種可大量生產具高密度陣列試劑之生物晶片的製造裝 置。 【先前技術】 參 在化學、醫藥、生化、材料的領域，經常需要平行進 行大量的篩選檢測或化學、生化反應，例如組合化學 (combinatorial chemistry)必須使用多種單體合成多樣的化 學品以供新藥篩選或新材料開發；例如，基因晶片 (biochip、DNA chip、cDNA chip)或蛋白質晶片（protein chip) 在平面上佈置成千上萬的探針（probe)用以分析檢驗；例 如，在高速篩選(high throughput screening)中，必須將不同 的試劑加到多孔盤(micro plate)中，進行生化檢測。在這也 • 應用中’有一個共通點就是將多樣性的試劑，傳輪到特定 方式排列的位置，以進行後續的反應或分析。 美國專利第5445934號中所揭露的佈點系統，係利用 光線照射改變材料之表面特性，進而抓取其中—★式气 者將不需藥劑的之區域去除。重覆上述步驟，〜 一試劑。了疋義出另 美國專利弟5658802號所揭露的佈點系统 個儲液槽’此複數個儲液槽接至一噴出哭，、包括複數 、时母一嘴出器有 0949-A21691TWF(N2)；P51950043TW；kai 1316873 一喷嘴，可對準放置於支架上的基材，並進行佈點。 美國專利第5807522號之佈點系統，包括一試劑分配 器，具有一適合的毛細管柱，可容納一定量之試劑，並進 . 行佈點。 習知的佈點裝置速度慢且使用不方便，相對成本高， 並不適於大量生產。 由以上可知，業界亟需一種生物晶片製造裝置，其可 _ 大量生產具有高密度陣列試劑之生物晶片。 【發明内容】 本發明的目的為提供一種生物晶片製造裝置，其可大 量生產具有高密度陣列試劑之生物晶片。 為達上述目的，本發明提供一種生物晶片製造裝置， 包括，至少一滴嘴；至少一儲液槽，用以儲存一試劑；以 及至少一導管，其中該導管之一端與該滴嘴陣列板連接， ® 另一端與該儲液槽連接，其中該儲液槽與該滴嘴可作相對 之上下移動。 為達上述目的，本發明另提供一種生物晶片製造裝 置，包括；至少一滴嘴陣列板；至少一儲液槽，用以儲存 一試劑；至少一導管，其中該導管之一端與該滴嘴陣列板 連接，另一端與該儲液槽連接；一壓力控制器，與該儲液 槽連接，用以控制儲液槽内之壓力。 為達上述目的，本發明更提供一種製備滴嘴陣列板的 0949-A21691 TWF(N2)；P51950043TW；kai 6 ,1316873 笛包括提供—基板，形成—総層在該基板上，以一 央阻i罩對ΐ光阻層進行第—次曝光，以—第二光罩對該 阻‘進仃第二次曝光’顯影該光阻層形成-圖案化光 ^^具有複數個柱狀光阻凸塊，以陣列方式排列，沉積 :屬或一合金’以填入該些柱狀光阻凸塊以外的區域， 脫:金屬結構’去除該圖案化光阻，以及將該金屬結構 果’形n轉顺’其具有複數侧立的滴嘴 陣列方式間隔排列。 明顧讓本發明之上述和其他目的、特徵、和優點能更 重下文特舉較佳實施例，並配合所附圖示，作祥 細說明如下： 作。手 【實施方式】 此苓照第1圖，本發明之生物晶片製造裝置100包括滴 陣列板110 ’儲液槽13〇與導管15〇，其中導管之— _端與滴嘴陣列板110連接，另一端與儲液槽連接。 滴嘴陣列板no包括複數個滴嘴⑴，以陣列 列’每一滴嘴in包括入口部113及出口部115，每 剤可經由-滴嘴接觸基材，完成佈點。滴嘴陣列板㈣可 以電鑄或機械加工的方式製作，其材質可為金屬（如鎳、 鈷、金）、陶瓷或高分子材質。 、 儲液槽130包括儲液盤131，儲液盤131中設置 數個館液腔133，每—個儲液腔内錯存一既定試劑，且 同的儲液腔館存不同的試劑。儲液槽130可以電鑄或機械 0949-A21691 TWF(N2) ； P51950043TW；kai 7 1316873 加工的方式製作，其材質可為金屬（如鎳、鈷、金）、陶瓷 或高分子材質。 導管150，用以連接滴嘴陣列板110與儲液槽130，其 中導管150的一端與入口部113連接，另一端與儲液盤131 連接。儲液槽130的直徑可相同或不同於導管150,且儲 液腔131中的試劑可經由導管150傳送至滴嘴陣列板 110，進行佈點。第2a至2g圖顯示本發明滴嘴陣列板之製 作流程。參照第2a圖，首先，在基板201上形成光阻層 202。基板201可為一矽基板，或包括矽、鍺、銅或上述之 組合。參照第2b-2c圖，以光罩203對光阻層202進行第 一次曝光，接著，以另一光罩204對光阻層202進行第二 次曝光。接著，經過顯影形成圖案化光阻結構205，此圖 案化光阻結構205具有複數個柱狀光阻凸塊，且以陣列方 式排列，如第2d圖所示。參照第2e圖，進行沉積，例如， 利用電鍍的原理，將金屬或合金，如鎳、鈷、金等，電鑄 在光阻結構205上，並填入柱狀光阻凸塊以外的區域，形 成金屬結構206，此外，也可以機械加工的方式，在光阻 結構205上形成金屬結構206。參照第2f-2g圖，去除光阻 層202，並使金屬結構206從基板201上脫模，即可獲得 滴嘴陣列板200，其具有複數個獨立的滴嘴，並以陣列的 方式間隔排列。滴嘴陣列板200包括入口部207及出口部 208，出口部208的外徑約在50〜500/xm之間，較佳約在 300μπι。第2h圖顯示，滴嘴陣列板200的立體結構，包括 複數個入口部207及出口部208。 0949-A21691TWF(N2)；P51950043TW；kai 8 1316873 、—荃照第3圖’本發明之儲液槽13〇包括鍺液盤i3i及 後數個儲液腔133，每一儲液腔133内儲存一既定的試劑 液盤131以導管150連接至入口部113。試劑可經 -由導管輪送至滴嘴陣列板110。 . 在製作生物晶片時，首先，將基材170覆蓋在滴嘴陣 列板110上，然後提高儲液槽130的高度使儲液槽13〇高 於滴嘴陣列板110，產生一高度差N ,較佳為5公分。高 φ 度差N可使試劑180從儲液槽13〇流至出口部115，並接 觸基材170。在一實施例中，基材170覆蓋於滴嘴陣列板 110上，提高儲液槽13〇的高度，使試劑18〇往基材17〇 的方向流動’因滴嘴111與基材170間之間隙非常小，故 毛細力很大’而試劑不會從出口部115滲漏。參照第4圖， 在試劑接觸基材170後，降低儲液槽130的高度，使儲液 槽130低於滴嘴陣列板11〇 一高度差γ。 請參照第5圖，其顯示一個製作完成的生物晶片，每 _ 一出口部都可使一既定的試劑佈點在基材的一既定位置 上，且滴嘴彼此間有一適當的間距，使不同的試劑在基材 上的位置彼此不重疊。第6圖顯示利用本發明所完成的晶 片之一實施例。基材上的試劑直徑約在100 μπι。 第7圖顯示本發明另一實施例，在此實施例中，不是 利用調整儲液槽130的高度來使試劑180流動，而是利用 一壓力控制器190。儲液槽130連接壓力控制器190，壓力 控制器190可控制導管150内的壓力’用以控制試劑於滴 嘴之位置。當基材170覆蓋至滴嘴陣列板110上時，增加 0949-Α21691 TWF( Ν2) ； P51950043TW；kai 9 1316873 導管Γ50内的壓力使試劑從出口部113冒出，待試劑接觸 至基材170後，降低導管150内的壓力，取下基材即可獲 得佈點完成的生物晶片。 本發明之生物晶片製造裝置，具有佈點快速、使用方 便，成本低，且適合大量生產高密度陣列試劑之生物晶片。 雖然本發明已以較佳實施例揭露如上，然其並非用以 限定本發明，任何熟習此技藝者，在不脫離本發明之精神 和範圍内，當可作些許之更動與潤飾，因此本發明之保護 範圍當視後附之申請專利範圍所界定者為準。 0949-A21691 TWF(N2)；P51950043TW：kai 10 1316873 【圖式簡早說明】 第1圖顯示本發明之生物晶片製造裝置。 第2a-2h圖顯示滴嘴陣列板之製備流程圖。 第3圖顯示提高儲液槽高度進行佈點。 第4圖顯示完成佈點，降低儲液槽高度。 第5圖顯示生物晶片佈點示意圖。 第6圖顯示佈點試劑的大小。 第7圖顯示本發明另一實施例之生物晶片製造裝置。 【主要元件符號說明】 100〜生物晶片製造裝置； 110〜滴嘴陣列板； 111〜滴嘴； 13 0〜儲液槽； 131〜儲液盤； 133〜儲液腔； 150〜導管； 170〜基材； 180〜試劑； 190〜壓力控制器； 113、207〜入口部； 115、208〜出口部； 201〜基板； 202〜光阻層； 0949-A21691 TWF(N2)；P51950043TW；kai 11 1316873 203、204〜光罩層； 205〜光阻結構； 206〜金屬結構； 200〜滴嘴陣列板； N、Y〜高度差。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a biochip manufacturing apparatus, and more particularly to a manufacturing apparatus capable of mass producing a biochip having a high density array of reagents. [Prior Art] In the fields of chemistry, medicine, biochemistry, and materials, it is often necessary to perform a large number of screening tests or chemical and biochemical reactions in parallel. For example, combinatorial chemistry must use a variety of monomers to synthesize various chemicals for new drugs. Screening or new material development; for example, a biochip, DNA chip, cDNA chip or protein chip is arranged on the plane with thousands of probes for analytical testing; for example, at high speed screening In high throughput screening, different reagents must be added to a microplate for biochemical detection. There is also a common point in this application. The common reagents are to transfer the reagents in a specific way to the subsequent reaction or analysis. The dispensing system disclosed in U.S. Patent No. 5,445,934 uses light illumination to change the surface characteristics of the material, thereby picking up the area where the drug is not removed. Repeat the above steps, ~ a reagent. In addition, the United States Patent No. 5,565,082 discloses a liquid storage system for the dispensing system. The plurality of liquid storage tanks are connected to a spray to cry, including the plural, and the time of the mother has a 0949-A21691TWF (N2); P51950043TW; kai 1316873 A nozzle that aligns the substrate placed on the holder and performs a dot placement. U.S. Patent No. 5,807,522, a dispensing system comprising a reagent dispenser having a suitable capillary column for holding a quantity of reagents and feeding points. The conventional dispensing device is slow in speed and inconvenient to use, and relatively high in cost, and is not suitable for mass production. From the above, there is a need in the industry for a biochip manufacturing apparatus which can mass produce biochips having high density array reagents. SUMMARY OF THE INVENTION An object of the present invention is to provide a biochip manufacturing apparatus which can mass-produce a biochip having a high density array of reagents. To achieve the above object, the present invention provides a biochip manufacturing apparatus comprising: at least one drip nozzle; at least one liquid storage tank for storing a reagent; and at least one catheter, wherein one end of the catheter is connected to the dripper array plate, The other end is connected to the reservoir, wherein the reservoir and the nozzle can be moved up and down. In order to achieve the above object, the present invention further provides a biochip manufacturing apparatus, comprising: at least one nozzle array plate; at least one liquid storage tank for storing a reagent; at least one catheter, wherein one end of the catheter and the nozzle array plate The other end is connected to the liquid storage tank; a pressure controller is connected to the liquid storage tank to control the pressure in the liquid storage tank. In order to achieve the above object, the present invention further provides a 0949-A21691 TWF (N2); P51950043TW; kai 6 , 1316873 flute comprising a nozzle array plate, comprising: providing a substrate, forming a germanium layer on the substrate, to a central resistance The cover performs a first exposure on the photoresist layer, and the second photomask performs the second exposure on the resist. The photoresist layer is formed. The patterned light has a plurality of columnar photoresist bumps. Arranging in an array manner, depositing: a genus or an alloy to fill a region other than the columnar photoresist bumps, removing the metal structure to remove the patterned photoresist, and turning the metal structure into a shape It is arranged in a manner that it has a plurality of side-dropping nozzle arrays. The above and other objects, features and advantages of the present invention will become more apparent from [Embodiment] Referring to Figure 1, the biochip manufacturing apparatus 100 of the present invention comprises a droplet array plate 110' reservoir 13' and a conduit 15A, wherein the end of the catheter is connected to the nozzle array plate 110, The other end is connected to the reservoir. The nozzle array plate no includes a plurality of drip nozzles (1) in an array. Each drop nozzle in includes an inlet portion 113 and an outlet portion 115, each of which can contact the substrate via a drip nozzle to complete the dispensing. The nozzle array plate (4) can be made by electroforming or machining, and the material can be metal (such as nickel, cobalt, gold), ceramic or polymer material. The liquid storage tank 130 includes a liquid storage tray 131. The liquid storage tray 131 is provided with a plurality of liquid chambers 133, and each of the liquid storage chambers is staggered with a predetermined reagent, and the same liquid storage chamber stores different reagents. The liquid storage tank 130 can be fabricated by electroforming or mechanical 0949-A21691 TWF (N2); P51950043TW; kai 7 1316873, and the material can be metal (such as nickel, cobalt, gold), ceramic or polymer material. The conduit 150 is configured to connect the dripper array plate 110 and the reservoir 130, wherein one end of the conduit 150 is connected to the inlet portion 113 and the other end is connected to the liquid storage tray 131. The reservoir 130 may have the same or different diameter than the conduit 150, and the reagents in the reservoir 131 may be delivered to the dripper array plate 110 via conduit 150 for dispensing. Figures 2a through 2g show the flow of the nozzle array plate of the present invention. Referring to Fig. 2a, first, a photoresist layer 202 is formed on a substrate 201. The substrate 201 can be a tantalum substrate or include tantalum, niobium, copper or a combination thereof. Referring to Figures 2b-2c, the photoresist layer 202 is first exposed with a mask 203, and then the photoresist layer 202 is exposed a second time with another mask 204. Next, a patterned photoresist structure 205 is formed through development, and the patterned photoresist structure 205 has a plurality of columnar photoresist bumps arranged in an array as shown in Fig. 2d. Referring to FIG. 2e, deposition is performed. For example, a metal or an alloy such as nickel, cobalt, gold, or the like is electroformed on the photoresist structure 205 by using the principle of electroplating, and filled in a region other than the columnar photoresist bump. The metal structure 206 is formed, and in addition, the metal structure 206 may be formed on the photoresist structure 205 by mechanical processing. Referring to FIG. 2f-2g, the photoresist layer 202 is removed, and the metal structure 206 is released from the substrate 201, thereby obtaining a nozzle array plate 200 having a plurality of independent drip nozzles and arranged in an array manner. . The nozzle array plate 200 includes an inlet portion 207 and an outlet portion 208. The outlet portion 208 has an outer diameter of between about 50 and 500/xm, preferably about 300 μm. Figure 2h shows the three-dimensional structure of the nozzle array plate 200, including a plurality of inlet portions 207 and outlet portions 208. 0949-A21691TWF(N2); P51950043TW; kai 8 1316873, - see Fig. 3 'The liquid storage tank 13 of the present invention includes a liquid pan i3i and a plurality of liquid storage chambers 133, which are stored in each liquid storage chamber 133 A predetermined reagent liquid tray 131 is connected to the inlet portion 113 by a conduit 150. The reagent can be delivered to the dripper array plate 110 via a catheter. When fabricating the bio-wafer, first, the substrate 170 is covered on the dripper array plate 110, and then the height of the liquid storage tank 130 is raised so that the liquid storage tank 13 is higher than the dripper array plate 110, resulting in a height difference N. It is preferably 5 cm. The high φ degree difference N allows the reagent 180 to flow from the reservoir 13 to the outlet portion 115 and contact the substrate 170. In one embodiment, the substrate 170 covers the dripper array plate 110, and the height of the liquid storage tank 13 is increased to cause the reagent 18 to flow in the direction of the substrate 17 ' 'between the drip nozzle 111 and the substrate 170. The gap is very small, so the capillary force is large 'and the reagent does not leak from the outlet portion 115. Referring to Fig. 4, after the reagent contacts the substrate 170, the height of the reservoir 130 is lowered, so that the reservoir 130 is lower than the nozzle array plate 11 by a height difference γ. Please refer to FIG. 5, which shows a finished bio-wafer. Each of the outlets can have a predetermined reagent spotted at a predetermined position on the substrate, and the drip nozzles have an appropriate spacing from each other to make a different The positions of the reagents on the substrate do not overlap each other. Figure 6 shows an embodiment of a wafer completed using the present invention. The reagent on the substrate has a diameter of approximately 100 μm. Fig. 7 shows another embodiment of the present invention. In this embodiment, instead of adjusting the height of the reservoir 130 to allow the reagent 180 to flow, a pressure controller 190 is utilized. The reservoir 130 is coupled to a pressure controller 190 which controls the pressure within the conduit 150 to control the position of the reagent at the nozzle. When the substrate 170 is overlaid onto the nozzle array plate 110, the pressure in the conduit 50 is increased by the pressure of 0949-Α21691 TWF(Ν2); P51950043TW; kai 9 1316873, and the reagent is ejected from the outlet portion 113 after the reagent contacts the substrate 170. The pressure in the catheter 150 is lowered, and the substrate is removed to obtain a finished biochip. The biochip manufacturing apparatus of the present invention has a biochip which is fast in layout, convenient to use, low in cost, and suitable for mass production of high density array reagents. While the present invention has been described in its preferred embodiments, the present invention is not intended to limit the invention, and the present invention may be modified and modified without departing from the spirit and scope of the invention. The scope of protection is subject to the definition of the scope of the patent application. 0949-A21691 TWF(N2); P51950043TW: kai 10 1316873 [Description of the drawings] Fig. 1 shows a biochip manufacturing apparatus of the present invention. Figures 2a-2h show a flow chart for the preparation of a nozzle array plate. Figure 3 shows the height of the reservoir to make the placement. Figure 4 shows the completion of the placement and lowering the height of the reservoir. Figure 5 shows a schematic diagram of the biowafer layout. Figure 6 shows the size of the dispensing reagent. Fig. 7 shows a biochip manufacturing apparatus according to another embodiment of the present invention. [Main component symbol description] 100~ biochip manufacturing device; 110~ drip nozzle array plate; 111~ drip nozzle; 13 0~ liquid storage tank; 131~ liquid storage tray; 133~ liquid storage chamber; 150~ conduit; Substrate; 180~reagent; 190~pressure controller; 113, 207~ inlet portion; 115, 208~ outlet portion; 201~ substrate; 202~ photoresist layer; 0949-A21691 TWF(N2); P51950043TW; 203, 204~ photomask layer; 205~ photoresist structure; 206~ metal structure; 200~ nozzle nozzle array board; N, Y~ height difference.
0949-A21691TWF(N2)；P51950043TW；kai0949-A21691TWF(N2); P51950043TW; kai