TW504491B - Chip-type device for counting/classifying and analyzing the micro-fluid particle and manufacturing method thereof - Google Patents
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504491 五、發明說明^ ^----- 【發明之技術領域】 ^發明係提供一種晶片式微流體粒子計數/分類及分 t t =置及其製造方法,係以快速且低成本的製程整合光 及微流管道於晶片上’用於微粒子如:細胞、血球 等之計數/分類及分析。 【發明背景】 近年來,由於微機電製程技術之發展,使得許多原本 魔大之元件得以微小化,人類也逐漸可以藉由微小化之設 備’從事之前所無法進行之實驗,例如細胞之操控以及快 速蛋白質或DNA之分離…等。在眾多微機電研究領域中, 將元件應用於生醫檢測尤其受到重視。藉由微機電製程技 術所生產之微流體生醫檢測晶片,其具有高檢測效能、低 樣品消耗量、低耗能、體積小以及成本低等優點,尤其以 整合微流體系統及檢測機構於同一晶片上之設計,最具發 展潛力以及市場價值,因此,除了具有微型化之優勢外, 更免除了複雜及昂貴之檢測設備,使得單一晶片便具有完 整之檢測功能。504491 V. Description of the invention ^ ^ ----- [Technical Field of the Invention] ^ The invention provides a wafer-type microfluidic particle counting / sorting and classification method and its manufacturing method, which integrates light with a fast and low-cost process. And microfluidic channels on the wafer 'for counting / sorting and analyzing microparticles such as cells, blood cells, etc. [Background of the Invention] In recent years, due to the development of micro-electro-mechanical process technology, many of the original magic components have been miniaturized, and humans can gradually use the miniaturized equipment to perform experiments that were previously impossible, such as the manipulation of cells and Fast protein or DNA separation ... etc. In many fields of micro-electromechanical research, the application of components to biomedical testing is particularly valued. The microfluidic biomedical detection chip produced by the micro-electro-mechanical process technology has the advantages of high detection efficiency, low sample consumption, low energy consumption, small size, and low cost. Especially, it integrates the micro-fluid system and the detection mechanism in the same The design on the chip has the most development potential and market value. Therefore, in addition to the advantages of miniaturization, it also dispenses with complex and expensive testing equipment, so that a single chip has a complete testing function.
利用流體細胞計數器(f low cytometer)進行細胞之計 數(counting)以及分類(sorting)已廣泛被應用於生醫 檢測上,其結果亦為臨床診斷重要依據之一。傳統之細胞 計數器如圖一所示,係將樣本由中央管道注入,利用兩側 注入之邊鞘流(s h e a t h f 1 〇 w ),以流體聚焦 (hydrodynamic focusing)之原理,將中央樣品流縮減 至單一細胞之寬度’再令樣品流經電極或光學等檢測機構Counting and sorting of cells using a f cytometer has been widely used in biomedical testing, and the results are also one of the important basis for clinical diagnosis. The traditional cell counter is shown in Figure 1. The sample is injected through a central pipe, and the side sheath flow (sheathf 1 0w) injected from both sides is used to reduce the central sample flow to a single unit using the principle of hydrodynamic focusing. Cell width 'then let the sample flow through the electrode or optical detection mechanism
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進行計數。 將檢測機構整合於晶片中 但對於體積僅有數微米之 日日片發展之趨勢, 細胞流過之電極並不容易 人衣绝可以解析單一 有數十微米之高度,傳:半因導=管道垂直方向必須具 電鑄方式製造電極則有結構設計:困iU成;利用微 析度不佳等問題。 M及檢測空間解 電極法之典型設計為 但無論其是利用電容或是 米寬的流道中偵測細胞流 且此設計中,電極之佈置 甚為複雜。 休用 對平行電極板進行量測 兒阻量測方式,均不 q不易在數十Count. The detection mechanism is integrated in the chip, but for the development trend of solar tablets with a volume of only a few micrometers, the electrode through which the cells flow is not easy. The clothing can never resolve a single height of tens of micrometers. The direction must have an electroformed method to make the electrode. There are structural designs: trapped iUcheng; use of poor resolution and other issues. M and the detection space solution The typical design of the electrode method is, but whether it uses a capacitor or a meter-wide flow channel to detect cell flow, and in this design, the arrangement of the electrodes is very complicated. Not used to measure parallel electrode plates
動柃所造成之電性微小改變量 以及其絕緣等問題將使製程變 无学法亦 本進行螢光染色,或以一料I巨、、統光學檢測必須將樣 中,再利用細胞對光線< 5=之光纖將光線導人樣品流 測。然而,此二種方法均;欠=在外部對散射光進行量 得良好之計測結果,C': *光染色法之雖可獲 傷害細胞,使其失去原有=所、阿丄但染色程序複雜且可能 光物質標定細⑽,但光纖*: μ 2光纖法’雖不需以螢 題,且i。至2。微米内徑連接為-大問 )#鑪俨姝曰眚,並不碥 ^ )之早杈怨(Slngie de )先纖饧格吓貝,亚不適合商業化之量產。 【發明概述】 有鑑於微流體細胞計壑夕捕从从4 + 在敝# 士八昍夕日的/歎之傳統技術有其製程上的缺陷 和弊端,本發明之目的係拯征一絲a u二、/The slight changes in electrical properties caused by dynamics and its insulation will make the process unskilled and should be fluorescently stained. Or, using a single material, the optical detection must be in the sample, and then the cells are used to light. < 5 = The optical fiber guides light into the sample for flow measurement. However, both of these two methods; ow = good measurement results of scattered light externally, C ': * Although the light staining method can damage the cells, it loses the original = so, ah, but the staining procedure Complex and possible calibration of optical substances is fine, but the optical fiber *: μ 2 fiber method is not necessary to use a fluorescent question, and i. To 2. The micron inner diameter connection is-大 问) # 炉 俨 姝 说 眚 , 不 碥 ^) The early complaints (Slngie de) first dwarfed the shell, which is not suitable for commercial mass production. [Summary of the Invention] In view of the fact that the traditional technique of microfluidic cell counting from the 4+ to the 叹 # 叹 八 昍 日 日 / sigh has traditional process defects and disadvantages, the purpose of the present invention is to recover a trace of au, /
故仏種曰曰片式微流體粒子計數Particle counting
/刀類及分析裂置及其製造方法。 /分^壯發明之主要目的係提供一種晶片式微流體粒.子計數 一刀/、衣置,至少包含:一幫浦,係提供流體驅動之用; 供i係整合微管道及光纖結構於其上;一光源,係提 2,么則述光纖結構;一光偵測單元;及一訊號處理單 處理前述光偵測單元產生之訊號。 ^述’浦係為注射幫浦(S y r i n g e p u m p )。 道。、述从g道主要包含·樣品流微管道及邊鞘流微管 例如:雷射(如 綠光/ Knife and analysis of cracking and its manufacturing method. The main purpose of the Zhuang invention is to provide a wafer-type microfluidic particle. The knife counts one piece of clothing and at least includes: a pump for providing fluid drive; for the i-series to integrate microchannels and optical fiber structures on it A light source, which refers to 2, the optical fiber structure; a light detection unit; and a signal processing unit that processes the signals generated by the aforementioned light detection unit. ^ Said 'pu system is injection pump (Sy r i n g e p u m p). Road. The channel from G mainly includes the sample flow micropipes and side sheath flow micropipes. For example: laser (such as green light
前述光源可為各種發光單元 ^紅光雷射)或各式LED發光二極 器,2述光偵測單元係包含:一光偵測器及一訊號放大 二述之訊號放大器係將偵測到之光訊號放大之用。 器及號處理單元主要包含:一類比/數位訊號轉桷 井 電恥。珂述電腦係可控制前述幫浦之運作,並紀< 谓測單元之訊號且加以分析。 、、: 上$發明之另一目的,係提供一種整合光纖結構於晶片The aforementioned light source may be various light emitting units (red light laser) or various LED light emitting diodes. The two light detection units include: a light detector and a signal amplifier. The light signal is used for amplification. The processor and signal processing unit mainly include: an analog / digital signal converter. The Keshu computer system can control the operation of the aforementioned pumps, and analyze the signals of the < prediction unit >. ... Another purpose of the invention is to provide an integrated optical fiber structure on the chip
通道包含下列步驟:购片基材;钱刻光纖 、於則述基材上;結合兩片具有相同光纖通道之晶片美 tj充材料於前述光纖通道中;及形成光纖結構。土 丽述之方法進一步可包含:於蝕刻後之光纖通道表 ^先塗佈一層折射係數較基材低之物質,例如:低折射 奴、丈之有機物質,以增加基材與填充材料介面間之折射係 數差’以及可使通道内之表面平坦化。 ^、The channel includes the following steps: buying a substrate; engraving the optical fiber on the substrate; combining two wafers with the same fiber channel into the aforementioned fiber channel; and forming an optical fiber structure. The method of Turismo may further include: coating the fiber channel surface after the etching first with a substance having a lower refractive index than the substrate, such as low-refractive material and organic materials to increase the interface between the substrate and the filler The refractive index difference 'and the surface inside the channel can be flattened. ^,
第7頁 504491 五、 料 習 整 品製 樣 鞘 纖 相 片 此導 流 用 於 輯 用 發明說明(4) 前述之晶片 前述之填充 均可,例如: 透過本發明 知晶片上微管 合於晶片上, 分析之領域上 利用本發明 造方法,係可 本發明之第 品微管道,係 流微管道,係 結構,作為光 互對位之光纖 本發明之第 ,係可同時進 晶片至少包含 入之用;至少 體之用;至少 ; 及至少三對 藉由製成多 各微管道中不 運算以偵測在 雙重光束線進 基材例如:玻璃。 ^ =係指折射係數高於基材折射係數之材 同刀子材料、有機溶液···等。 光纖結構於晶片上,之方法,並配合 =^ 4造方法,同時將微管道與光纖結構 〜用於微流體中粒子之計數/分類或樣 上述之整 製造各種 合光纖結構及微管道於晶片上之 實施態樣之晶片。 一實施例之晶片,其至少包含:至少一個 作為樣品 作為導入 線傳輪之 結構。 一實施例 行至少兩 :至少雨 三個之邊 兩個之出 之光纖結 對光纖結 同之位置 該微管道 4亍♦輯運 導流之用;至少一組(兩個)邊 邊勒流流體之用;及至少一對光 用。前述一對光纖結構係指兩個 之晶片 種以上 個之樣 鞘流微 口微管 構,作 構以形 ’利用 中樣品 算,可 係為多流 之微流體 品流微管 管道,係 道,係作 為光線傳 成多條光 兩條光束 流中通過 同時進行 道平行檢測晶 中粒子之計數, 道’係作為樣品 作為導入邊鞘流 為樣品導出之 輸之用。 束線,分別交會 線進行n AND”邏 粒子之數目。利 多流道樣品流 504491Page 7 504491 V. Photographs of sample sheath fiber made of materials. This diversion is used to edit the description of the invention. (4) The aforementioned wafers and the aforementioned fillings can be used. In the field of analysis, the method of the present invention is used, which can be the first product of the present invention. At least; and at least three pairs of non-computing micro-channels to detect substrates such as glass entering in a double beam line. ^ = Refers to the material whose refractive index is higher than the refractive index of the base material, like knife materials, organic solutions, etc. The method of optical fiber structure on the wafer, combined with the method of manufacturing, and using micropipes and optical fiber structures at the same time ~ for the counting / sorting of particles in microfluids or the above-mentioned manufacturing of various optical fiber structures and micropipes on the wafer The implementation of the above-mentioned wafer. A wafer according to an embodiment includes at least one structure serving as a sample as a lead wire transfer wheel. An embodiment has at least two: at least three of the two sides of the fiber are connected to the fiber at the same position as the optical fiber. The micropipe 4 is used for transportation and diversion; at least one group (two) of the side is used to draw fluid. For use; and at least one pair of lights. The aforementioned pair of optical fiber structures refers to the sheath-flow microport microtubule structure of two wafer types or more, and the structure is calculated by using a sample. It can be a multi-flow microfluidic flow microtubule pipeline. It is used to count the particles in the crystal as two rays of light are transmitted into a plurality of light by parallel tracking. The channel is used as a sample to introduce the edge sheath flow for the export of the sample. Beam lines and intersection lines for n AND "number of logical particles. Lido flow channel sample flow 504491
例如 本發明之第三實施例之晶片,係可同時 細胞流)之平行檢測。 微粒子之計數、分翻菸、日r 土 ,a a 體r ^ 刀類及測速,此晶片至少包含:至少一個 樣品流微管道,係作炎 管道,係作為導二::¥入之用;至少兩組邊鞘流微 為v入邊鞘流流體之用;至少一個之出口彳吟管 逞,係作為樣品導出之用·、 u 線傳輸之用。 用,及至V兩對光義、、、。構,作為光 ?及隹:ΐ至ί兩組邊鞘流微管道’其中一組係作為樣品流 ’,另一組係將樣品流中不同粒子運送至不同之微 吕迢=,則述之之兩組邊鞠流微管道係以前後排列方式配 置於晶片上。 — 則述至少兩對之光纖結構係前後排列,作為粒 及流體測速之用。 β 本發明之第三實施例係藉由兩道平行光束線進行粒子 流,量測,藉由樣品流中粒子通過兩道光束線之時間差, 計算出粒子在流體中之流速,並透過電腦自動分析參數後 控制第二組邊鞘流之幫浦推力,以改變第二組邊鞘流體之 Μ速,並將樣品流中粒子依其大小或數量分別運送至不同 之出口微管道中,進行各種所需之生醫檢測。 本發明之第四實施例之晶片,係提供一種應用於榮光 偵測之分析晶片,至少包含··至少一樣品流微管道,係為 樣品導流之用;及至少一個光纖結構,係作為光線傳輸之 用。 前述之第四實施例之晶片之應用,其特徵係將光纖結For example, the wafer of the third embodiment of the present invention is capable of detecting cells in parallel at the same time. Counting of micro-particles, dividing smoke, soil, soil, aa body, knife, and speed measurement, this chip contains at least: at least one sample flow micro-pipe, which is used as an inflammation pipe, and is used as a guide 2 :: ¥ to enter; at least The two sets of side sheath flow are slightly used for v-to-side sheath flow fluid; at least one of the outlet moaning tubes is used for sample derivation and u-line transmission. Use, and to V two pairs of Guangyi ,,,. Structure, as light and 隹: ΐ to 两组 two sets of edge sheath flow microchannels 'one of which is used as a sample flow', and the other is to transport different particles in the sample flow to different micro The two sets of edge-flow microchannels are arranged on the wafer in a back-and-forth arrangement. — The at least two pairs of optical fiber structures are arranged one behind the other for velocity measurement of particles and fluids. β The third embodiment of the present invention uses two parallel beam lines to perform particle flow measurement. The flow velocity of the particles in the fluid is calculated from the time difference between the particles passing through the two beam lines in the sample stream, and automatically calculated by the computer. After analyzing the parameters, the pump thrust of the second group of sheath flow is controlled to change the M velocity of the second group of sheath flow, and the particles in the sample stream are transported to different outlet microchannels according to their size or quantity, and various Required biomedical tests. The wafer according to the fourth embodiment of the present invention provides an analysis wafer for glory detection, including at least one sample flow microchannel for sample flow; and at least one optical fiber structure for light For transmission. The application of the fourth embodiment of the chip described above is characterized in that the optical fiber is bonded
$ 9頁 五、發明說明(6) 構整合於a Η μ —"""" 中,利用;加之螢光;:f:::,樣品導入前述微管道 -透::述光纖結構將樣品之螢光::=:J:激發, 本發明係以光學法作為耵得出而破偵測。 球或各式微小粒子...等)Λ /边子(例如··細胞、血 光纖結構整合於晶片中、,解之機日構,主要係將 定義,因此可以輕易標2光刻顯影程序所 ,之水流對焦系統’完成一製程簡 以 光學對準之光纖檢測機構整合之微流體;3數 於光纖結構内外層之折射係數相差極大,因此可 以彳貝之一極體作為檢測光源,大幅降低檢測設備之費 =。此種微流體粒子計數器並可執行在眾多粒子中偵測特 定粒子之功能,進而分辨其大小,並配合後端之分類 (sort ing)機構,可快速檢測並收集特定粒子,乃生物醫學 晶片中非常重要之樣品前處理裝置。 【主要元件符號對照說明】 樣品流微管道 1 、 171 、 172 、 173 18 3 4 67 8 邊鞘流微管道 晶片基材 光纖結構 粒子 光情測單元 幫浦 <1$ 9Page V. Description of the invention (6) The structure is integrated in a & μ — " " " ",using; plus fluorescence ;: f :::, the sample is introduced into the aforementioned microchannel-through :: the optical fiber The structure excites the fluorescence of the sample :: =: J :. The present invention uses optical method to detect the fluorescence. Spheres or all kinds of tiny particles ... etc) Λ / edge (for example, · cells, blood fiber structure integrated in the chip, the solution of the structure of the structure, mainly defined, so you can easily mark 2 lithographic development program Therefore, the water flow focusing system 'completes a process and simply integrates the microfluidics of the optical alignment of the optical fiber detection mechanism; the refractive index between the inner and outer layers of the fiber structure is very different, so a polar body can be used as the detection light source, greatly Reduce the cost of detection equipment =. This kind of microfluidic particle counter can perform the function of detecting specific particles among many particles, and then distinguish their size, and cooperate with the sorting mechanism at the back end to quickly detect and collect specific Particles are very important sample pretreatment devices in biomedical wafers. [Comparison of main component symbols] Sample flow micropipes 1, 171, 172, 173 18 3 4 67 8 Edge sheath flow micropipe wafer substrate fiber structure particle light Sentiment unit pump < 1
第10頁 504491 五、發明說明(7) 9 --- 光源 10 --- 晶片 11 — 訊號處理单元 12 --- 類比/數位訊號轉換器 13 --- 電腦 14 --- 中間層 15 --- 樣品進樣孔 1 6、1 6 ’ 邊勒流孔洞 17--- 出口孔洞 19 --- 出口微管道 20 、20’ —-一 晶片 21 --- 螢光激發光源 30 —-一 晶片 31 --- 光阻層 32 --- 光罩 41--- 光纖通道 7 0--- 光價測器 71--- 訊號放大 100--- 晶片式微流體粒子計數/分類及分析之裝置 20 0 --- 流體集中機構 3 0 0 --- 光纖計數機構 a、b、c、d--- 光束線 【發明之詳細說明】 本發明係有關晶片式微流體粒子計數/分類及分析之Page 10 504491 V. Description of the invention (7) 9 --- Light source 10 --- Chip 11-Signal processing unit 12-Analog / digital signal converter 13 --- Computer 14 --- Intermediate layer 15- -Sample injection holes 1 6 and 1 6 'Edger flow holes 17 --- Outlet holes 19 --- Outlet microchannels 20, 20' --- One wafer 21 --- Fluorescence excitation light source 30 --- One wafer 31 --- Photoresist layer 32 --- Photomask 41 --- Fibre channel 7 0 --- Optical valence detector 71 --- Signal amplification 100 --- Chip-type microfluidic particle counting / sorting and analysis device 20 0 --- Fluid concentration mechanism 3 0 0 --- Optical fiber counting mechanism a, b, c, d --- Beamline [Detailed description of the invention] The present invention relates to the counting / classification and analysis of wafer-type microfluidic particles.
第11頁 丄 丄Page 11 丄 丄
五、發明說明(8)V. Description of the invention (8)
裝置1 0 0及其製造方法, 說明並配合圖式得到進」、諸多優點與特徵將從下述詳細 本發明之晶片式徼冷步的瞭解。 主要由兩大部分所組成概f粒子計數/分類及分析裝置100 集中機構2 0 0,如圖二第一部份係為樣品流進樣及流體 3 0 0,其操作原理如圖—:,第二部分係為光纖計數機構 ^ 一^斤示。 首先參考圖二(A) 集中機構示意圖”t~,隹係本發明之樣品流進樣及流體 個樣品流微管道卜係作體為二中Λ構200至少包含:至少一 (兩個)邊鞘流微管道2 ‘、】a: t入之用’及至少-組 ^ . ^ , ru ,其係为別位於前述樣品流微管 1 \係作為邊鞍流體導人之用。此流體集中機構 糸彳用=側邊鞘流將中央樣品流縮減至單一粒子(如:細 胞)之見度,如此,樣品流中之粒子便可依需排列流動前The device 100 and its manufacturing method are explained and improved in accordance with the drawings. Many advantages and features will be understood from the following detailed description of the wafer type cold step of the present invention. It mainly consists of two major parts: particle counting / sorting and analysis device 100. Concentration mechanism 200, as shown in Figure 2. The first part is sample flow injection and fluid 3 0, and its operation principle is shown in Figure ::, The second part is the optical fiber counting mechanism. First, referring to FIG. 2 (A), the schematic diagram of the centralized mechanism "t ~", which is the sample stream injection and fluid sample stream micropipes of the present invention. The structure is two in the Λ structure 200 and contains at least one (two) edges. Sheath flow microchannel 2 ',] a: t 入 的 用' and at least -groups ^. ^, Ru, which are located in the aforementioned sample flow microtubes 1 \ are used as saddle fluid guides. This fluid concentration The mechanism uses = side sheath flow to reduce the central sample flow to the visibility of a single particle (such as a cell), so that the particles in the sample flow can be aligned as needed before the flow
進。請進一步參看圖二(B)及圖二(C),其中圖二(B )係圖二(A )機構之影像圖,圖二(C )係利用圖二(B )之機構,以染料測試水流集中效果之影像圖。由圖二 (C )之測試結果顯示,染料經邊鞘流聚焦後寬度可縮減 至3 // m。將樣品流經邊鞘流聚焦後即可進入第二部分之光 纖計數機構3 0 0,此機構將透過圖三作詳細之介紹。 接下來參考圖三,圖彡(A ) 、( B )係分別顯示本發 明利用司乃耳定律(Snell,s law)將光纖結構整合於晶片 之結構之上視圖及侧視圖。本發明係採用價格低廉之晶片 基材3 (例如:玻璃),姐利用濕式蝕刻法在前述基材3上 餘刻出樣品流之微管道1以及光纖結構4之通道,利用折射Advance. Please refer to Fig. 2 (B) and Fig. 2 (C), where Fig. 2 (B) is an image diagram of the mechanism of Fig. 2 (A), and Fig. 2 (C) is a mechanism using the mechanism of Fig. 2 (B) for dye testing An image of the effect of water concentration. The test results in Figure 2 (C) show that the width of the dye can be reduced to 3 // m after focusing by the side sheath flow. After focusing the sample through the side sheath flow, it can enter the second part of the fiber counting mechanism 300, which will be described in detail through Figure 3. Next, referring to Fig. 3, Figs. 彡 (A) and (B) respectively show an upper view and a side view of the present invention using Snell's law to integrate an optical fiber structure into a wafer structure. The present invention uses a low-cost wafer substrate 3 (for example, glass), and the micro-pipe 1 and the channel of the optical fiber structure 4 of the sample stream are engraved on the aforementioned substrate 3 by wet etching, using refraction
504491 五、發明說明(9) 係數約為1. 5之玻璃作為晶片基材3之材料,並在通道中埴 入折射係數大於1.5之材料,如:折射係數為i 8之別_8負 型光阻,如此即可形成光纖結構4。當光線於前述填充材 料内行進時,由於外圍包覆折射係數較小之玻璃材質,若 光線之入射角大於臨界角,根據司乃耳定律(S 〇 e 11, s law),光線將全反射回高折射係數之介質中,=如 充材料為SU-8負型光阻且光線與介面間之掠角小於田5。、 時,光線將會被全反射至高折射係數之讥_8負光中。 利用光線在填充材料中行進時因全反射而不至旦 原理’設計適當的光纖路徑’並利用標準之: 光纖結構4之通道,再填充高折射 先/釭序衣以 士構4 ’ U入射光傳導至樣品流微管道泣 之::或=程度不同’導致出口端光強度改變,並,由 一外接之光偵測單元7收集出口端 夂亚猎由 測細胞之經過並計算其數目。 ° k ’便可即時偵 如前述,本發明之晶片式微 析裝置1〇〇,主要係結合前述樣品流進樣二數/:= 2 0 0及光纖計數機構3 〇 〇兩大部八、,’ ;IL體集中機構 運算單元所組成。圖四係顯示:發;:::?測及訊號 計數/分類及分析裝置1 〇 〇之示咅二 2 式微流體粒子 幫浦8,係提供流體驅動之用广回1衣置至少包含:一 4 ; 一光偵測單元7 ;及一吨 > 老扣仏先至月'』述光纖結構 '娆處理單元11,係處理前述光504491 V. Description of the invention (9) A glass with a coefficient of about 1.5 is used as the material of the wafer substrate 3, and a material with a refractive index greater than 1.5 is inserted in the channel, such as: a refractive index of i 8 is different from _8 negative Photoresist, so that the fiber structure 4 can be formed. When the light travels inside the aforementioned filling material, because the outer surface is coated with a glass material with a smaller refractive index, if the incident angle of the light is greater than the critical angle, according to Sone's Law (S oe 11, s law), the light will be totally reflected In the medium with a high refractive index, = if the filling material is a SU-8 negative photoresistor and the sweep angle between the light and the interface is smaller than Tian 5. When,, the light will be totally reflected into the high-refractive index 讥 _8 negative light. Use light to travel through the filling material due to total reflection instead of denier principle 'design appropriate fiber path' and use the standard: the optical fiber structure 4 channel, and then fill the high refractive first / 釭 order clothes with the structure 4 'U incidence The light transmission to the sample stream micropipes: The difference in light intensity at the exit end caused by: or = different degrees, and an external light detection unit 7 was collected by an external light detection unit 7 to measure the passage of cells and calculate its number. ° k 'can be detected immediately as described above, the wafer-type micro-analysis device 100 of the present invention is mainly based on the combination of the aforementioned sample flow sampling number /: = 2000 and the optical fiber counting mechanism 3000, '; IL body centralized mechanism operation unit. Figure 4 shows: Sending :::: Measurement and signal counting / sorting and analysis device 1 2 00 Type 2 microfluidic particle pump 8, which is used to provide fluid-driven wide-return 1 at least: 1 4; a light detection unit 7; and one ton > old buckle first to month '' 'described fiber structure' 娆 processing unit 11, which processes the aforementioned light
504491 五、發明說明(ίο) 偵測單元7產生之訊號 本發明之裝置100係透過前述幫浦8將樣品流及邊鞘流 ^別導入晶片1 〇上之樣品流微管道i及邊鞘流微管道2中, 藉由控制兩側邊鞘流體及樣品流之流速將樣品流聚焦至一 4特定之上度,例如:-個細胞之寬度,之後纖結構 光源9發射光線,前述光線從晶片"中之光 、截、、,口構4之入口端進入並通過樣品流,此時 泣 i:6另對一光二之二收或散射後造⑽^ 偵測光心产ϋ结構4之出口端輸出’並由光偵測單元7 u進”Ϊ: 化’並將前述光訊號傳至訊號處理單元 丄i進订分析以及計數之動作。 心干 d:8、係為注射幫浦(syringe pump)。 道3,…“逼主要包含:樣品流微管道2及邊鞘流微管 或= Π各種發光單元’例如:雷射(如:綠光 飞、、、工先辑射)或各式LED發光二極體。 前述光偵測單元7係包含:一光偵 大器Π。前述之訊號放大器71係 測、。。70及-訊號放 用,並可增加债測之靈敏度。谓測到之光訊號放大之 前述訊號處理單元n主要句合· 換器12及-電腦13。前述電腦=可;數封位訊號轉 ,品流及邊鞘流體之流速大小,並 訊號且加以分析。 项九價測早兀7之 本發明之晶片10上光纖結構4之製造方法將藉由圖五504491 V. Explanation of the invention (ίο) Signal generated by the detection unit 7 The device 100 of the present invention introduces the sample flow and the edge sheath flow through the aforementioned pump 8 ^ Do not introduce the sample flow micropipe i and the edge sheath flow on the wafer 10 In the micro-channel 2, the sample stream is focused to a specific degree above 4 by controlling the flow velocity of the fluid and the sample stream on both sides of the sheath, for example, the width of a cell, and then the fiber structure light source 9 emits light, and the light is emitted from the wafer. " In the light, cut, and the entrance end of the mouth structure 4 enters and passes through the sample stream, at this time, i: 6 is made after receiving or scattering one light two or two ^ Detect the light center production structure 4 The output side outputs' and enters the "light-emitting" by the light detection unit 7 u and transmits the aforementioned optical signal to the signal processing unit 订 i for ordering analysis and counting. Heart stem d: 8, is an injection pump ( Syringe pump). Channel 3, ... "Forcing mainly includes: sample flow microchannel 2 and edge sheath flow microtubules or = various light-emitting units' for example: laser (such as: green light flying, first, the first series) or Various LED light emitting diodes. The aforementioned light detection unit 7 includes: a light detector Π. The aforementioned signal amplifier 71 is tested. . The 70 and-signals are released and can increase the sensitivity of debt measurement. The aforesaid signal processing unit n, which is said to be amplifying the measured optical signal, is mainly composed of a converter 12 and a computer 13. The aforementioned computer = may; several bits of signal conversion, the flow rate of the product flow and the edge sheath fluid, and the signal and analysis. The method for manufacturing the optical fiber structure 4 on the wafer 10 of the present invention will be described with reference to FIG.
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及圖六作詳細之說明。 圖五係顯示本發明之光纖結構製造方法之方塊图 要至少包含下列步驟··提供晶片基材3 ;蝕刻光纖通θ道 於前述基材3上;接合兩片具有前述相同光纖通道41之義 材3 ;填充材料於前述光纖通道中;及形成光纖結構4。土 前述之方法進一步可包含:於蝕刻後之光纖通道表 面’先塗佈一層折射係數較基材3低之物質,例如:低折 射係數之有機物質,以增加基材3與填充材料介面間之折 射係射差,以及可使通道内之表面平坦化。 前述之晶片基材3係為玻璃或高分子材料,例如:壓 克力(PMMA)、聚碳酸酯(PC)或聚二甲矽氧烷(pDMs^ 前述之填充材料係指折射係數高於晶片基材3之折射 係數之材料均可,例如:高分子材料、有機溶液…等。 前述之填充材料係為SU-8光阻。 接著以圖六中之(A )至(G )各製程,詳細說明本發 明之光纖結構之製程如下:And Figure 6 for a detailed description. FIG. 5 is a block diagram showing the manufacturing method of the optical fiber structure of the present invention including at least the following steps: providing a wafer substrate 3; etching the optical fiber through the channel θ on the aforementioned substrate 3; joining two pieces having the same meaning as the aforementioned optical fiber channel 41 Material 3; a filling material in the aforementioned optical fiber channel; and forming an optical fiber structure 4. The foregoing method may further include: coating a layer of a substance having a lower refractive index than the substrate 3 on the surface of the optical fiber channel after the etching, such as a low refractive index organic substance, to increase the distance between the substrate 3 and the filling material interface. Refraction is a refractive error, and can flatten the surface in the channel. The aforementioned wafer substrate 3 is made of glass or polymer materials, for example: acrylic (PMMA), polycarbonate (PC) or polydimethylsiloxane (pDMs). The aforementioned filling material means that the refractive index is higher than the wafer The material of the refractive index of the base material 3 may be, for example, a polymer material, an organic solution, etc. The aforementioned filling material is a SU-8 photoresist. Then, in each of the processes (A) to (G) in FIG. 6, The manufacturing process of the optical fiber structure of the present invention is described in detail as follows:
本發明之製造方法主要係包含下列步驟:如圖六(A )所示,首先k供一晶片基材3,於其上塗佈一光阻層3 1 (例如:AZ462 0光阻),並利用一設計之光罩32進行光刻 (Lithography )之步驟;之後,如圖六(B )所示,進行 光阻顯影(PR developing )之步驟;接下來如圖六(c ) 所示’進行玻璃姓刻(G 1 ass e t ch i ng )之步驟,將晶片 基板3蝕刻預定大小之光纖通道41 (例如:寬7〇 “瓜、深2〇The manufacturing method of the present invention mainly includes the following steps: as shown in FIG. 6 (A), first, a wafer substrate 3 is provided, and a photoresist layer 3 1 (eg, AZ462 0 photoresist) is coated thereon, and Use a designed photomask 32 to perform the lithography (Lithography) step; then, as shown in Figure 6 (B), perform the PR developing step; then, as shown in Figure 6 (c), In the step of engraving the glass surname (G 1 ass et ch i ng), the wafer substrate 3 is etched into a fiber channel 41 of a predetermined size (for example, a width of 70 mm and a depth of 2 mm).
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五、發明說明(12) # m );之後,如圖六(β )所示,進行光阻剝除(pR stripping)步驟,將殘餘之光阻清除;接下來\如圖六 (E)所示,將兩片同樣經由前述圖六(a)至(D)之步 驟製成之具有相同光纖通道41之晶片基材3對位並接合; 為了使光纖通道4 1内之表面平坦化而增加光線傳輸效率、 減少因表面不平整造成之光散射效應,接下來可進行中間 層塗佈(Intermediate layer coating)之步驟,將折射V. Description of the invention (12) # m); After that, as shown in FIG. 6 (β), a photoresist stripping (pR stripping) step is performed to remove the remaining photoresist; next, as shown in FIG. 6 (E) As shown in the figure, two wafer substrates 3 having the same optical fiber channel 41, which are also prepared through the steps of FIGS. 6 (a) to (D) above, are aligned and joined; it is increased to flatten the surface inside the optical fiber channel 41 Light transmission efficiency, reducing the light scattering effect caused by uneven surface, then the intermediate layer coating step can be performed to refract
率較晶片基材3低之物質塗佈於光纖通道41之表面形成中 間層14,例如:有機系列之旋轉塗佈玻璃(spin 〇n glass, SOG ),如圖六(F )所示;最後,利用真空吸引 方式填充高折射係數之材料於前述光纖通道41中,形成本 發明之光纖結構4,如圖六(g )所示。 利用本發明上述之光纖結構之製造方法並結合習知之 ΐ片上微官迢之製造方法,係可製成整合光纖結構4及微 官逞之各種貫施態樣之晶片,將由下述各實施例加以詳細 介紹。 第一實施例 如圖七所示,係顯示本發明之第一實施例之晶片,其 包含·一個樣品流微管道丨,係作為樣品導流之用;一組 (兩個)邊鞘流微管道2,係作為導入邊鞘流流體之用;及 一對光纖結構4,作為光線傳輪之用。 將上述第一實施例之晶片配合圖四之裝置(如:幫浦 8光源9、光偵測單元7及訊號處理單元1 1 )即可進行微 流體中粒子之計數。首A,將樣品流及兩側之邊鞘流體分A substance having a lower rate than the wafer substrate 3 is coated on the surface of the optical fiber channel 41 to form an intermediate layer 14, such as: an organic series of spin-on glass (SOG), as shown in FIG. 6 (F); finally The high-refractive-index material is filled in the aforementioned optical fiber channel 41 by a vacuum suction method to form the optical fiber structure 4 of the present invention, as shown in FIG. 6 (g). By using the above-mentioned manufacturing method of the optical fiber structure of the present invention in combination with the conventional manufacturing method of the micro-guan on the cymbal, various wafers can be made that integrate the optical fiber structure 4 and the micro-guan. Describe in detail. The first embodiment is shown in FIG. 7, which shows a wafer according to the first embodiment of the present invention, which includes a sample flow microchannel, which is used for sample diversion; a set of (two) side sheath flow microchannels 2. It is used to introduce the fluid in the side sheath; and a pair of optical fiber structures 4 is used to transmit light. Counting the particles in the microfluid can be performed by combining the wafer of the first embodiment with the device of FIG. 4 (such as: pump 8 light source 9, light detection unit 7, and signal processing unit 1 1). First A, separate the sample stream and the sheath fluid on both sides
504491 五、發明說明(13) 別從晶片10之樣品進樣孔15及邊鞘流孔洞16導入,藉由電 送之樣品流及兩側邊鞘流之流速將樣品 焦至-個粒子之寬度,如:—個細胞之寬度,之後粒 子依序流經光纖結構4後從出口孔洞17導出。藉由一外接 光源9發射光線,前述光線從晶片1〇中之光纖結構4之入口 端進入並通過樣品流,此時,樣品流中之粒子6對光線之 吸收或散射後造成光強度變化,前述光線經由另一端之 纖結構4之出口端輸出,並由光偵測單元7偵測光線強度之 變化,並將前述光訊號傳至訊號處理單元丨丨進行分析二及 計數之動作。 弟二實施例 平行:本發1之第二實施例之晶片係為多流道 =晶片:係可同時進行至少兩種以上之微流體中粒 此曰日片包含.二個之樣品流微管道1 71、1 72及 ,為¥入邊鞘流流體之用;九個出口微揭 ::用出之用;及四對光纖結•(圖未顯示),作 藉由製程多對光纖結構形成多條光束線(例如 線a、b、c、d)分別交會於各微管道中不同之位 $束 ===光束線進行”卿邏輯運算則貞測微: :樣中通過粒子之數目。利用雙重光束 、逼 ;,7同時進行多流道樣品流(例如:細 運 測。例如、圖八所示’光束線_光束線b交;道 五、發明說明(14) T,之//二上—利用該兩組光束線a、b進行” AO"邏輯運 悄測到粒子通過時,則表示該樣品 飢〒有粒子流過,因此該樣品流之計數器 理,當光束線a與光束線〇同時 Q U數目。同 微管道1 72上之# 口 4』 子經過時,則表示 行多流道平行檢測之功能。 b頰推則可同時進 第三實施例 如圖九(A)所示,本發明之第二〜 係可同時執行微流體中微粒子之 二貫施例之晶片20 , 片20包含:一個樣品流微管道},作分類及測速,此晶 兩組邊鞘流微管道2、2,,係作 #、邛為樣品導入之用; 七個出口微管道19,係作為樣品‘、、'¥入邊鞘流流體之用; 構4 ’作為光線傳輸之用。 之用;及兩對光纖結 前述兩組邊鞘流微管道2、2,甘 流微管道2 )係作為樣品流聚隹用其中第一組(即邊鞘 微管道2’)係將樣品流中不同粒’另一組(即邊鞘流 ,19中;前述之兩組邊鞘流微管 达至不同之出口微管 式配置於晶片20上。 2’係以前後排列方 月丨J述至少兩對之光纖結構4 子計數及流體測速之用。 ’、相平行排列,作為粒 圖九(B )本發明之第三實 固此曰曰片2 0 ’相較於圖九(a )、,之另~晶片2 0之影像 二道Η。首先’將樣品流及兩側之=係具有三個出口微 之樣品進樣孔15及第一組邊、勒流體分別從晶片 概孔洞1 6導入,並將樣 504491 五、發明說明(15) ' ^--- 品流聚焦至一個粒子之寬度後流經井 光纖結構4產生之兩道平行光束線通過 =中:::: 間差,計算出粒子在流體中之流速,奸4 2 1 I守 .^ 亚透過電腦自動分析 參數後控制第二組邊鞠流(邊鞘流微管道2,)之封 力,以改變第二組邊鞘流體之流速,剎田1 / 丄 脸括σ、士丄 ^ t ^ 牙〗用水流切換之方式 n w μ 〜連迗至不同之樣品出 口锨官道1 9中,並從出口孔洞1 7送出样口、六士 々仏 印樣品流中之粒子進行 各種所需之生醫檢測。 第四實施例 如圖十所示’本發明之第四實施例之晶片3〇,係提供 :種應用於螢光债測之分析晶片30,包含:一樣品流微管 係為樣品導流之用,及一個光纖結構4,係 傳輸之用。 本發明第四實施例之晶片30,其特徵係將光纖結構4 ι合於晶片30上。將具有螢光標定之樣品導入前述微管道 中’利用外加之螢光激發光源2 1將樣品中之螢光染料激 發’並透過前述光纖結構4將樣品之螢光放射傳出了經由 光偵測單元7進行偵測。此一晶片之應用可整合毛細管電 泳分析,或細胞極化破壞後細胞内物質之分析及ΜΑ之檢 測。 匕以上所舉之本發明之實施例只要不脫離本發明之要 曰’可進行種種微流體管道及光纖結構數量及設計之變 更’其保護範圍由以下之申請專利範圍所界定。 【發明之功效】504491 V. Description of the invention (13) Do not introduce from the sample injection hole 15 and side sheath flow hole 16 of the wafer 10, and focus the sample to the width of one particle by the flow rate of the sample stream and the side sheath flow on both sides. For example: the width of a cell, after which the particles flow through the optical fiber structure 4 sequentially and exit from the exit hole 17. An external light source 9 emits light, which enters from the entrance end of the optical fiber structure 4 in the wafer 10 and passes through the sample stream. At this time, the particles 6 in the sample stream absorb or scatter the light and cause the light intensity to change. The aforementioned light is output through the exit end of the fiber structure 4 at the other end, and the light detection unit 7 detects the change in light intensity, and transmits the aforementioned optical signal to the signal processing unit 丨 丨 for analysis and counting operations. The second embodiment is parallel: the wafer of the second embodiment of the present invention is a multi-flow channel = wafer: it can perform at least two or more microfluid medium particles at the same time. 1 71, 1 72, and ¥ are used for the flow into the side sheath fluid; nine outlets are micro-exposed :: used for the purpose; and four pairs of optical fiber junctions • (not shown in the figure) are formed by the process of multiple pairs of optical fiber structures Multiple beam lines (such as lines a, b, c, and d) intersect at different positions in each micro-pipe. $ 束 === 光线 为 “Logical operation” is used to measure micro :: The number of particles in the sample. Use Double beam, forcing; 7 simultaneous multi-channel sample flow (for example: fine movement measurement. For example, 'beam line_beam line b intersection shown in Figure 8; Road five, description of the invention (14) T, of / / 2 Top—Using the two sets of beam lines a and b for "AO" logic to detect that the particles pass through, it means that the sample is hungry for particles to flow through. Therefore, the counter of the sample flow is calculated. When the beam line a and the beam line 〇Number of QUs at the same time. When the # # 4 4 on the same micro-pipe 1 72 passes, it indicates the parallel detection of multiple channels. B. The buccal push can enter the third embodiment at the same time. As shown in FIG. 9 (A), the second to second aspects of the present invention are wafers 20 that can simultaneously execute the two consecutive embodiments of microparticles in microfluidics. The wafer 20 includes: a sample stream Micro-pipes} for classification and speed measurement. The two sets of side-sheath flow micro-pipes 2, 2 are used for sample introduction. The seven outlet micro-pipes 19 are used as samples. The use of side sheath flow fluid; the structure 4 'for light transmission. The use; and two pairs of optical fiber junctions. The first group (ie, the sheath microtubule 2 ') is a sample of different particles in the sample stream. The other group (ie, sheath sheath flow, 19; the two sets of sheath sheath microtubules described above reach different outlet microtubule configurations. On the wafer 20. 2 'is arranged in front and back, and it is described in the optical fiber structure of at least two pairs of 4 counting and fluid velocity measurement.', Phase parallel arrangement, as the particle diagram 9 (B) the third embodiment of the present invention As a result, the film 20 is compared with the image of the wafer 20 in Figure 9 (a), and the image of the chip 20 is different. First, the sample is flowed And the two sides = the sample injection hole 15 with three outlet micros and the first set of edges and holes are introduced from the wafer hole 16 respectively, and sample 504491 V. Description of the invention (15) ^ --- Focused on the width of one particle, the two parallel beam lines generated by flowing through the well fiber structure 4 pass through the middle = :::: difference, calculate the flow velocity of the particle in the fluid, and 4 2 1 I. After automatically analyzing the parameters through the computer, the sealing force of the second group of side sheath flow (side sheath flow micropipe 2,) is controlled to change the flow velocity of the second group of side sheath fluid. Sakata 1 / 丄 面 丄 σ, 士 丄 ^ t ^ Teeth nw μ, the method of switching water flow ~ to the different sample outlets in the official road 19, and send out the sample hole from the exit hole 17 to the particles in the sample stream for various purposes. Biomedical testing. The fourth embodiment is shown in FIG. 10. The wafer 30 of the fourth embodiment of the present invention provides: an analysis wafer 30 for fluorescent debt measurement, including: a sample flow microtube system for sample flow , And an optical fiber structure 4, for transmission purposes. The wafer 30 according to the fourth embodiment of the present invention is characterized in that an optical fiber structure is bonded to the wafer 30. Introduce the sample with the fluorescent cursor into the aforementioned microchannel 'excitation of the fluorescent dye in the sample with the additional fluorescent excitation light source 2 1 and excite the fluorescent radiation of the sample through the optical fiber structure 4 through the light detection Unit 7 performs detection. The application of this chip can be integrated with capillary electrophoresis analysis, or analysis of intracellular material after cell polarization destruction and detection of MA. As long as the embodiments of the present invention mentioned above do not depart from the gist of the present invention, ‘the various microfluidic pipelines and optical fiber structures may be modified in number and design’, the scope of protection is defined by the scope of patent applications below. [Effect of the invention]
504491 五、發明說明(16) 本發明係提供一種晶片式微粒子計數/分類及分析裝 置及其製造方法,其優點如下:一、本發明係可快速、簡 單、可靠地製作一光纖整合微型粒子(例如:細胞、血球 )及生物檢測分析晶片。此製程不需使用任何昂貴之真空 鍍膜或電漿蝕刻設備,僅需標準光纖顯影程序以及化學濕 式蝕刻步驟,輔以高可靠度之熔接接合技術則完成本發明 之前述各種態樣之晶片。二、本發明係將光纖結構整合於 晶片中,因此操作時不需任何之光學對位機構,免除體積 龐大且昂貴之光學設備,並以廉價之光源(例如:發光二 極體或半導體雷射)作為檢測光源,配合微小化之光偵測 單元可將整個檢測裝置體積大幅縮小,並製作成可攜式檢 測設備。三、本發明之裝置可與電腦整合檢測系統,將量 測訊號即時以電腦處理,進行即時計數之功能及資料之分 析。綜上所述,本發明可被利用於生化分析、醫療偵測等 各種分析領域以增進人類社會之福祉。504491 V. Description of the invention (16) The present invention provides a wafer-type particle counting / sorting and analysis device and a manufacturing method thereof, which have the following advantages: 1. The present invention can quickly, simply, and reliably produce an optical fiber integrated micro-particle ( For example: cells, blood cells) and bioassay analysis wafers. This process does not require any expensive vacuum coating or plasma etching equipment. It only requires standard fiber development procedures and chemical wet etching steps, and is supplemented with high-reliability fusion bonding technology to complete the aforementioned various aspects of the wafer of the present invention. 2. The present invention integrates the optical fiber structure in the wafer, so no optical alignment mechanism is required for operation, eliminating bulky and expensive optical equipment, and using cheap light sources (such as light emitting diodes or semiconductor lasers) ) As a detection light source, with the miniaturized light detection unit, the volume of the entire detection device can be greatly reduced, and made into a portable detection device. 3. The device of the present invention can be integrated with a computer detection system, and the measurement signals are processed by the computer in real time to perform real-time counting functions and data analysis. In summary, the present invention can be used in various analytical fields such as biochemical analysis, medical detection, etc. to improve the well-being of human society.
第20頁 504491 圖式簡單說明 圖一係習知典型之細胞計數器原理之示意圖。 圖二(A )係本發明之樣品流進樣及流體集中機構示 意圖。 圖二(B )係圖二(A )之機構之影像圖。 圖二(C )係利用圖二(A )之機構測試水流集中效果 之影像圖。 圖三係本發明之晶片上之光纖結構示意圖。 圖四係本發明之晶片式微流體粒子計數裝置示意圖。 圖五係本發明之光纖結構製造方法之方塊圖。 圖六係本發明之光纖結構製造方法之流程圖。 圖七係本發明之第一實施例之用於微流體粒子計數之 晶片影像圖。 圖八係本發明之第二實施例之用於多流道平行檢測之 晶片不意圖。 圖九(A )係本發明之第三實施例之晶片式微流體粒 子計數/分類及測數之裝置示意圖。 圖九(B )係圖九(A )之晶片影像圖。 圖十係本發明之第四實施例之螢光分析晶片裝置之示 意圖。Page 504491 Brief description of the diagram Figure 1 is a schematic diagram of the principle of a typical cell counter. Figure 2 (A) is a schematic view of a sample stream sampling and fluid concentration mechanism of the present invention. Figure 2 (B) is an image of the mechanism of Figure 2 (A). Figure 2 (C) is an image of testing the effect of water flow concentration using the mechanism of Figure 2 (A). Figure 3 is a schematic diagram of the structure of an optical fiber on a wafer of the present invention. FIG. 4 is a schematic diagram of a wafer-type microfluidic particle counting device according to the present invention. FIG. 5 is a block diagram of the manufacturing method of the optical fiber structure of the present invention. FIG. 6 is a flowchart of the manufacturing method of the optical fiber structure of the present invention. Fig. 7 is an image diagram of a wafer for counting microfluidic particles according to the first embodiment of the present invention. Fig. 8 is a schematic diagram of a wafer for multi-channel parallel detection according to the second embodiment of the present invention. Figure 9 (A) is a schematic diagram of a wafer-type microfluidic particle counting / sorting and counting device according to a third embodiment of the present invention. Figure IX (B) is a wafer image of Figure IX (A). Fig. 10 is a schematic view of a fluorescence analysis wafer device according to a fourth embodiment of the present invention.
第21頁Page 21
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