504945504945
五、發明說明（ 發明背景 1) 發明之領域 (請先閱讀背面之注意事項再填寫本頁) 本發明係有關一種以有機電激發光（0EL)_為基礎的生 物曰曰片其包括一個生物晶片被設計成要用來進行一個預 疋的生物刀析(用於DNA、蛋白質或細胞，或藥物篩選、以 細胞為主的分析等等），以及-個QEL放射元件被製造作為 該生物晶片的基材並當作該生物晶片的一個光源或一個熱 源。 2) 相關技藝的福述 經濟部智慧財產局員工消費合作社印製 近年來，在各種不同的載體上分離生物分子之陣列的 方法，即所謂的生物晶片，已被發展出並應用於DNa合 成疋序、犬變研究、基因表現分析和基因的發現上。特 別地，已經做了許多的努力來製造上面被固著有呈預定之 陣列的蛋白質或DNA等生物分子之晶片。將該等分子圖樣 化於半導體基材上，偶合以特定之辨識，對於生物分子網 絡之真實化而言是必須的。一般而言，該等生物晶片是為 由直接地或經由一個連結基團或更近期地係藉由一個凝膠 層被結合於一個基材上之分子所構成的微矩陣（亦即微陣 列）。更甚者，可定址於一基材上的DNA陣列（FODOR，S. P. A·，READ，J. L·，PIRRUNG，M· C·，STRYER，L·，LU，A. T·， AND SOLAS，D. SCIENCE 251:767 (1991);以及SOUTHERN， Ε· Μ· TRENDS IN GENETICS 12:1 10 (1996)，此二者在此以 其整體被併入本案作為參考文獻）或是被固著在一個基材 上的蛋白質可被用來提供以一快速及可靠的方式用於下列 -4- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 504945 A7 B7 五、發明說明（2 ) 的工具：資料檢索、DNA雜交反應，以及諸如蛋白質、抗 體、脂質或碳水化合物之分子的結合親和力反應。 大部分的生物晶片被設計用來促進生物分子在一個基 材上之已知位置處的合成。例如，一個此種生物晶片使用 光和一系列的光刻光罩來活化位於一個諸如玻璃或塑膠之 基材上的特定位址，俾以選擇性地將核酸到結合至該處， 以及接而附接上額外之核酸，俾以在所欲的位置處形成已 知的寡核甘酸。這個使用光和光刻光罩來活化位於一個基 材上之特定位置處的方法係相似於被使用在微電半導體晶 片之生產上的方法。該等晶片的製造大體上借用了由電腦 微處理器工業所發展且被最佳化的光刻微製造技術，該等 技術容許使用光刻模板之大批晶片的經濟化生產。 現今大部分用於生物分析之可獲得的光學檢測系統係 呈昂貴及巨大的儀器（例如螢光顯微鏡）之形式。當技術朝 向微小化和高生產力的裝置來發展，檢測系統將需要朝向 一種可攜帶以及感應型的檢測來予以修改。雖然M.A. Burns 等人（SciMa，Oct. 1998，Vol. 282，pp. 484-487)曾發 表一種使用一個外源性放射藍光的二極體（LED)來作為微 晶片用之激發光源的整合型Naloliter DNA分析裝置，該一 放光系統可能不適合供用於具多個通道或陣列的生物晶 片，因為LED僅是作為一個點光源之用。 因此，存在有一個需要來發展新的生物晶片系統，該 系統可被更經濟地製造並藉由被普遍使用在實驗室中的一 般光學檢測儀器來作檢查。 本紙張尺度適用中國國家標準（CNSJA4規格（210 X 297公釐） ---------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 504945 A7 五、發明說明（3 ) 在 1987年，Kodak-USA (Applied Physics letter，v〇lume (請先閱讀背面之注意事項再填寫本頁) 51，ρρ· 914，1987)藉著施加低電壓於一種小分子上而成功 地發展出一種電激發光裝置；在1990年，劍橋大學（Nature， Volume 347, ΡΡ· 539, 1990)更發展出一種藉由使用聚合物作 為光放射層的電激發光裝置，而這裝置改善了電激發光裝 置的實用性。自那時起，眾多的根據電激發光裝置的學術 界和產業界研究被建立起來。 有機電激發光（OEL)裝置由於其在大面積、扁平面板 和高亮度全彩的顯示器（利用低驅動電壓以作為背光源或 直接作為激發型顯示器的激發源）上之可能的應用而在近 年來已變得普遍。雖然如此，在生物分析應用上以有機電 激發光作為激發源的使用至今仍未被提出。 發明之概要說明 經濟部智慧財產局員工消費合作社印製 因此，在本發明中，有機電激發光（〇EL)裝置被提議 要被製造作為生物晶片的一個光源或一個熱源。在所提議 的方法下，一個OEL-放射元件被製造作為該生物晶片的基 材’在該生物晶片之上諸如DNA、蛋白質和其他相關的小 分子等生物樣品被加工以達所欲之應用，該等應用包括但 不限於生物分子的分析，諸如電泳分離作用、聚合酶連鎖 反應（PCR)擴增作用和雜交作用等。 在一個第一具體例中，本發明提供一個以有機電激發 光（OEL)-為基礎的生物晶片，其包含： 一個板片元件，其併入有一個OEL層，以及 一個微晶片組件被安裝於該板片元件之一側上以供進 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 504945 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（4) 行一個選自於由下列所構成的群組中之預定的應用：基因 表現分析、蛋白質免疫分析、藥物筛選和以細胞為主的分 析，且該應用任擇地涉及到一種生物系統。 該〇E L層係當作該微晶片組件的一個光源與^一個熱源 當中之一者，或是引起由一種由電化學反應所產生的光電 流’該電化學反應係發生於該微晶片組件之應用中所涉及 的生物系統内。 較佳地，該板片元件和微晶片組件被一體成型地微製 造以形成一個單件式裝置。 較佳地，該板片元件被製造，藉此，該OEL層被形成 於一個可撓性基材之上。 在一個任擇的具體例中，該板片元件被製造成為一個 透明的OLED (TOLED)組件，該組件容許來自其每一側之 OEL放射，並且一個微晶片組件可以被安裝在該板片元件 之每一側之表面上。 較佳地，該以OEL-為基礎的生物晶片更包含被疊置於 該微晶片組件之上的構件，用以光譜地收集自該OEL層放 射並通過該微晶片組件之營光訊號或是透明光。該光譜收 集構件可被製造成為一個分離式組件，或是較佳地，被一 體成型地微造製於該微晶片組件之上。較佳地，該光譜收 集構件包含一種光感測器用以收集經過濾之被放射的螢光 訊號或透明光。較佳地，該光感測器是一個光電倍增管 (PMT)或是一個光二極體或是一個電荷耦合裝置（CCD)。較 佳地，該光感測器被連結至一部用於資料處理與顯示之電 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 504945 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（5 ) 腦。 較佳地，該以OEL-為基礎的生物晶片更包含位在該微 晶片組件與該光谱收集構件之間的構件，用以光譜地過濾 自該OEL層放射並通過該微晶片組件之螢光訊號或是透明 光。較佳地，該濾光構件可包含一個光學透鏡用以過濾自 該OEL層放射並通過該微晶片組件之螢光訊號或是透明 光。 根據光源的性質和要被檢測的分析物的特性，該以 OEL-為基礎的生物晶片之上述設計可應用於被該分析物 所吸收之光或螢光的偵測。 在又一個具體例中，本發明提供一個以有機電激發光 (OEL)-為基礎的生物晶片，其包括： (a) —個板片元件，其併入有一個〇E]L層，以及 (b) —個被安裝於該板片元件之一側上之複合層合 物’其包含下列部件依序地層疊在前一者之上·· (1) 第一過濾構件，用以過濾自該〇El層激發之螢 光訊號或透明光； (2) —個球面透鏡和一個針孔層，用以對焦經過濾 之被激發的螢光訊號或透明光； (3) —個微晶片組件，用以進行一個選自於由下列 所構成的群組中之預定的應用：基因表現分 析、蛋白質免疫分析、藥物篩選和以細胞為主 的分析，且該應用任擇地涉及到一種生物系統； (4) 第二過濾構件，其被疊置在該微晶片組件之 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 504945 經濟部智慧財產局員工消費合作社印製 A7 _B7__ 五、發明說明（6 ) 上，用以過濾自該微晶片組件放射之螢光訊號 或透明光；以及 (5) —個光感測器，用以收集經過濾之被放射的螢 光訊號或透明光； 該OEL層係當作該微晶片組件的一個光源或^一個熱 源，或是引起由一種由電化學反應所產生的光電流，該電 化學反應係發生於該微晶片組件之應用中所涉及的生物系 統内。 若此具體例之板片元件被製造成為一個透明的OLED 組件，一個具有同於該第一複合層合物之構造的第二複合 層合物可被安裝在該板片元件的另一側上。 較佳地，該光感測器是一個光電倍增管（PMT)或是一 個光二極體或是一個電荷耦合裝置（CCD)。較佳地，該光 感測器被連結至一部用於資料處理與顯示之電腦。 較佳地，該以OEL為基礎的生物晶片之上述構造組件 被一體成型地微製造。 圖式之簡要說明 本發明之上述以及其他目的與特徵可藉由參考如下之 描述、隨文檢附的申請專利範圍和伴隨之圖式而變得更為 明顯，其中： 第1圖顯示利用一個光學顯微鏡之第一具體例的偵測 操作； 第2A和2B圖顯示兩種螢光染劑的〇EL放射行為； 第^圖顯示被來自作為光源之〇EL層的〇EL放射所激 i I n n n n n II ·ϋ n ϋ I · n n ϋ I ϋ n ϋ 一：0, · ϋ ϋ n n ϋ ϋ ϋ I (請先閱讀背面之注意事項再填寫本頁)V. Description of the invention (Background of invention 1) Field of invention (Please read the notes on the back before filling this page) The present invention relates to a biological film based on organic electro-excitation light (0EL) _, which includes a biological The wafer is designed to be used for a pre-cleaved bioanalysis (for DNA, protein or cell, or drug screening, cell-based analysis, etc.), and a QEL radiation element is manufactured as the biochip And used as a light source or a heat source for the biochip. 2) Blessing of related skills Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs In recent years, a method of separating an array of biomolecules on various carriers, the so-called biochip, has been developed and applied to DNa synthesisNa Sequence, canine mutation research, gene expression analysis and gene discovery. In particular, many efforts have been made to manufacture wafers on which biomolecules such as proteins or DNA are fixed in a predetermined array. The patterning of these molecules on a semiconductor substrate, coupled with a specific identification, is necessary for the authenticity of a biomolecular network. Generally speaking, these biochips are micromatrixes (ie, microarrays) composed of molecules that are bound to a substrate directly or via a linking group or more recently via a gel layer. . Furthermore, a DNA array (FODOR, SP A ·, READ, J. L ·, PIRRUNG, M · C ·, STRYER, L ·, LU, A. T ·, AND SOLAS, AND SOLAS, which can be addressed on a substrate, D. SCIENCE 251: 767 (1991); and SOUTHERN, E.M. TRENDS IN GENETICS 12: 1 10 (1996), both of which are hereby incorporated in their entirety as references) or are anchored in Protein on a substrate can be used to provide a fast and reliable method for the following -4- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 504945 A7 B7 V. Description of the invention (2) Tools: data retrieval, DNA hybridization reactions, and binding affinity reactions of molecules such as proteins, antibodies, lipids, or carbohydrates. Most biochips are designed to facilitate the synthesis of biomolecules at known locations on a substrate. For example, one such biochip uses light and a series of photolithographic masks to activate specific locations on a substrate, such as glass or plastic, to selectively bind nucleic acids there, and then Additional nucleic acids are attached to form a known oligonucleotide at the desired location. This method of using light and lithographic masks to activate specific locations on a substrate is similar to the method used in the production of microelectronic semiconductor wafers. The fabrication of these wafers generally borrows lithographic microfabrication technology developed and optimized by the computer microprocessor industry, which allows the economical production of large batches of wafers using lithographic stencils. Most of the available optical detection systems for bioanalysis today are in the form of expensive and large instruments such as fluorescent microscopes. As technology moves toward miniaturization and high-productivity devices, inspection systems will need to be modified toward a portable and inductive inspection. Although MA Burns et al. (SciMa, Oct. 1998, Vol. 282, pp. 484-487) have published an integrated type that uses an exogenous blue light emitting diode (LED) as an excitation light source for microchips Naloliter DNA analysis device, this light-emitting system may not be suitable for use in biochips with multiple channels or arrays, because LEDs are only used as a point light source. Therefore, there is a need to develop a new biochip system that can be manufactured more economically and inspected by general optical inspection instruments commonly used in laboratories. This paper size applies to Chinese national standard (CNSJA4 specification (210 X 297 mm)) --------------------- Order --------- (Please Read the notes on the back before filling this page) 504945 A7 V. Description of the invention (3) In 1987, Kodak-USA (Applied Physics letter, v〇lume (Please read the notes on the back before filling this page) 51, ρρ · 914, 1987) successfully developed an electro-excitation light device by applying a low voltage to a small molecule; in 1990, Cambridge University (Nature, Volume 347, PP · 539, 1990) further developed a borrowing device An electro-optical device using a polymer as a light emitting layer has improved the practicality of the electro-optical device. Since then, numerous academic and industrial studies based on the electro-optical device have been established. Organic electroluminescent (OEL) devices have been used in recent years due to their possible applications in large-area, flat-panel, and high-brightness full-color displays (using low drive voltages as backlight sources or directly as excitation sources for excitation-type displays). Has become commonplace. Nonetheless, in bioanalytical applications The use of organic electrical excitation light as the excitation source has not been proposed so far. SUMMARY OF THE INVENTION Description of the Invention Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Manufactured as a light source or a heat source for a biochip. Under the proposed method, an OEL-radiating element is manufactured as the substrate for the biochip 'on top of the biochip such as DNA, proteins and other related small molecules And other biological samples are processed to achieve desired applications, such applications include, but are not limited to, analysis of biomolecules, such as electrophoretic separation, polymerase chain reaction (PCR) amplification, and hybridization. In a first specific example In the present invention, an organic electroluminescent (OEL) -based biochip is provided. The biochip includes: a plate element incorporating an OEL layer, and a microchip assembly mounted on the plate element. The paper size on one side applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 504945 Member of Intellectual Property Bureau, Ministry of Economic Affairs Printed by Consumer Cooperatives A7 B7 V. Description of the invention (4) A predetermined application selected from the group consisting of: gene expression analysis, protein immunoassay, drug screening and cell-based analysis, And the application optionally involves a biological system. The OEL layer is used as one of a light source and a heat source of the microchip assembly, or causes a photocurrent generated by an electrochemical reaction ' The electrochemical reaction occurs in a biological system involved in the application of the microchip assembly. Preferably, the plate element and microchip assembly are microfabricated integrally to form a one-piece device. Preferably, the plate element is manufactured, whereby the OEL layer is formed on a flexible substrate. In an optional specific example, the plate element is manufactured as a transparent OLED (TOLED) module that allows OEL emission from each side thereof, and a microchip module can be mounted on the plate element On each side of the surface. Preferably, the OEL-based biochip further includes a component stacked on the microchip module for spectrally collecting the optical signal emitted from the OEL layer and passing through the microchip module or Transparent light. The spectral collection member can be manufactured as a separate component, or preferably, micro-fabricated integrally on the microchip component. Preferably, the spectral collection member includes a light sensor for collecting the filtered emitted fluorescent signal or transparent light. Preferably, the light sensor is a photomultiplier tube (PMT) or a photodiode or a charge coupled device (CCD). Preferably, the light sensor is connected to an electronic paper size for data processing and display, which is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --------- ---- Equipment -------- Order --------- line (Please read the precautions on the back before filling this page) 504945 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention (5) Brain. Preferably, the OEL-based biochip further includes a component located between the microchip component and the spectral collection component for spectrally filtering the fluorescence emitted from the OEL layer and passing through the microchip component. Signal or transparent light. Preferably, the filter member may include an optical lens for filtering a fluorescent signal or transparent light emitted from the OEL layer and passing through the microchip device. Based on the nature of the light source and the characteristics of the analyte to be detected, the above design of the OEL-based biochip can be applied to the detection of light or fluorescence absorbed by the analyte. In yet another specific example, the present invention provides an organic electroluminescent (OEL) -based biochip, including: (a) a plate element that incorporates a 0E] L layer, and (b) A composite laminate 'installed on one side of the plate element', comprising the following components sequentially laminated on the former ... (1) a first filter member for filtering from The OEl layer excited fluorescent signal or transparent light; (2) a spherical lens and a pinhole layer to focus the filtered excited fluorescent signal or transparent light; (3) a microchip component For a predetermined application selected from the group consisting of: gene expression analysis, protein immunoassay, drug screening, and cell-based analysis, and the application optionally involves a biological system ; (4) the second filter member, which is stacked on the microchip assembly and the size of the paper is in accordance with China National Standard (CNS) A4 (210 X 297 mm) ----------- installation -------- Order --------- line (please read the notes on the back before filling this page) 504945 Ministry of Economic Affairs Printed by A7 _B7__ in the Consumer Cooperatives of the Property Bureau. 5. In the description of the invention (6), it is used to filter the fluorescent signal or transparent light emitted from the microchip component; and (5) a light sensor to collect The filtered emitted fluorescent signal or transparent light; the OEL layer is used as a light source or a heat source of the microchip assembly, or causes a photocurrent generated by an electrochemical reaction, the electrochemical reaction system Occurs within the biological system involved in the application of the microchip assembly. If the plate element of this specific example is manufactured as a transparent OLED component, a second composite laminate having the same structure as the first composite laminate may be installed on the other side of the plate element . Preferably, the light sensor is a photomultiplier tube (PMT) or a photodiode or a charge coupled device (CCD). Preferably, the light sensor is connected to a computer for data processing and display. Preferably, the aforementioned structural components of the OEL-based biochip are microfabricated integrally. BRIEF DESCRIPTION OF THE DRAWINGS The above and other objects and features of the present invention can be made more obvious by referring to the following description, the scope of patent application attached to the article, and accompanying drawings. Among them: Figure 1 shows the use of a Detection operation of the first specific example of an optical microscope; Figs. 2A and 2B show the oEL emission behavior of two fluorescent dyes; Fig. ^ Shows the excitation by oEL emission from the oEL layer as a light source. nnnnn II · ϋ n ϋ I · nn ϋ I ϋ n ϋ 1: 0, · ϋ ϋ nn ϋ ϋ ϋ I (Please read the precautions on the back before filling this page)
504945 A7 B7 五、發明說明（7 ) 發之螢光微球體（Fluorescent microspheres)的螢光放射現 象； 第4A和4B圖顯示使用第一具體例之螢光微球體的螢 光安定性； 第5圖顯示本發明之一個第二具體例；以及 第6圖顯示本發明之一個第三具體例。 立d牛標號對昭矣 2 微晶片組件 4 針孔層 6 光感測器 8 針孔層 (請先閱讀背面之注意事項再填寫本頁) 1 OEL放射元件 3 物鏡 5 放射過濾器 7 激發過濾器 9 球形透鏡 發明之詳細說明 經濟部智慧財產局員工消費合作社印製 使用OEL放射作為生物晶片應用之光源或是熱源在邏 輯上應是有益的，因為一個0EL放射元件的扁平形式與生 物晶片是可相提並論的，且更重要的是，一個〇EL放射元 件的製造過程可以容易地納入生物晶片的製造過程中。另 外，一個OEL放射元件具有一較大的可撓性，例如一種溶 許使用較便宜及可拋棄的聚合物材料之可軋製的基材。一 旦用於該以OEL為基礎之生物晶片之平台製造技術被發展 出，很多生物分析可有如一種可棄式檢驗套組被應用之。 當使用OEL放射作為一個光源時，發光區域被光刻地 製造在一個OEL放射元件之基材的劃定區域内。較佳地， 該OEL放射經由一個光學透鏡被導向被置放於上方之稽 -10- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 504945 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（8 ) 品，該光學透鏡被製造成有如一個位在該基材之表面的整 合單元以供對焦之用。接著該螢光訊號或透明光會藉由光 二極體被光譜地過濾並收集，該光二極體有如一個分離式 裝置被放置於該以OEL為基礎之生物晶片之上方或是有如 一個整合的部件被微製造在該以OEL為基礎之生物晶片之 上方。 當使用OEL放射作為一個熱源時，位於近紅外線區域 之OEL放射被利用來產生供生物化學反應（諸如PCR或酵 素水解反應）所需之熱能。 除了上述之外，該OEL放射亦可被使用來引發由發生 在一個生物系統中之一個特定電化學反應所產生的光電 流。例如，已經發展出各種不同形式的微生理測量計可適 用於藉由電流測量予以檢測之測量變量的4貞測（McConnel， H.M·，Owicki，J.C·，Parce，J.W·，Miller，D.L.，Baxter, G.T·， Wada, J.G. and Pitchford,S. (1992), Science, 257:1906-1912; Adami, M., Piras, L., Lanzi, M., Fanigliulo, A., Vakula, S. and Nicoini,C. (1994), Sens. Actuators (B) 18:178-1 82; Baxter,G.T., Bousse,. L.J., Dawes, T.D., Libby, J.M., Modlin, D.N., Owicki, J.C. and Parce, J.W. (1994), Clin, Chem., 40:1800-1804; Adami, M., Sartore, M. and Nicolini, C. (1995), Biosens. Bioelec., 10:155-167; Adami, M., Sartore, M. and Nicolini, C. (1995), Biosens. Bioelec.， 10:633-638; K.R. Rogers et al.，Anal. (1992)，Vol. 202，pp· 111-116 ;以及D. Hafeman a/·，We_ (1998) Vol. 240, pp.1 182-1 185) ° -11- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） II ϋ n «ϋ »^1 ϋ I — ϋ 1_1 I 0 ί ·ϋ meMt ϋ— ·ϋ ·ϋ I 1_1 mmmMmm n ϋ— n an I I (請先閱讀背面之注意事項再填寫本頁) 504945 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（9 ) 該微生理測量計被設計用於測量由於細胞性過程（諸 如磷酸化、擴散作用和離子泵作用）所造成之質子濃度之淨 變化。當依據本發明之以OEL為基礎之生物晶片被使用於 偵測發生在一個經固著之生物製品内上的一種特定生物化 學反應時’該OEL放射將不會干擾由該反應所引發的電訊 號。 根據本發明，提供一種以OEL為基礎之生物晶片，其 包含：一個OEL放射元件，其被製造成為該生物晶片之基 材且可作為該生物晶片的一個光源或一個熱源；以及一個 微晶片組件，其被疊置在該OEL放射元件上且被設計用來 進行一種預定的應用，諸如基因表現分析、蛋白質免疫分 析、藥物篩選和以細胞為主的分析等。 較佳地，該OEL放射元件和該微晶片組件被一體成型 地微製造以形成一個單件式裝置。 較佳地，該以OEL為基礎之生物晶片被微製造成具有 一尺寸範圍為長20 mm至10 cm、寬20 mm至10 cm以及高 0.5 mm至4 mm。例如，假若該以〇EL為基礎之生物晶片被 製造成一種微陣列晶片的形式，其可被微製造成具有數百 微米至數毫米之尺寸。至於一種微流體化晶片，該以〇EL 為基礎之生物晶片可被微製造成為具數公分之尺寸。在一 個較佳具體例中，該以OEL為基礎之生物晶片被微製造成 具一為 30 mm X 30 mm X 0.6 mm之尺寸。 該OEL放射元件可藉由一般使用於〇el顯示器組件之 製造的技術來製成。為達此目的，可用之參考文獻包括但 -12 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） --------------------訂---------^ (請先閱讀背面之注意事項再填寫本頁) 504945 A7 B7 五、發明說明（10) (請先閱讀背面之注意事項再填寫本頁) 並不限於C.W. Tang and S.A. Vanslyke，ΡΛγ. ie"., July 1987, 51 (12): 913-915; Chemistry (The Chinese Chem. Soc.f Taipei) Mar. 1996 54 (1), pp. 125-145; Andrei A. Shoustikov et al., IEEE Journal of Selected Topics in Quantum Electronics, Vol. 4, No. 1, January/ February, 1998, pp. 3-13; M. G. Mason et al., J. Appl. Physics, Vol. 86, No. 3, August 1999, pp. 1688-1692; Junji Kido and Yasuhiro Iizumi, AppL Phys. Lett., 9 November 1998, Vol. 73, No. 19, pp. 2721-2723; G. Gu and Stephen R. Forrest, IEEE Journal of Selected Topics in Quantum Electronics, Vol. 4? No. 1, January/ February, 1998, pp. 83-99 ；以及 L. S. Hung et al., Appl. Phys. Lett. January 1997, 70 (2)M52-154 〇 該OEL放射元件可被製成具一厚度在範圍0.35 mm至 0·75 mm之間，較佳為0.5 mm。 經濟部智慧財產局員工消費合作社印製 較佳地，該OEL放射元件被微製造在一種可撓性基材 (例如塑膠基材）上。較佳地，該OEL放射元件被製造成為 一個透明的OLED (TOLED)組件，該組件容許OEL自其頂 側和底側放射出來。在這些方面中，可用之參考文獻包括 但並不限於Ye He and Jerzy Kanichi，Jpp/·户Ze"·, 7 February 2000，76 (6): 661-663 ;以及Ρ· E. Burrows α/·，“A Bright, Transparent, Blue Organic Light Emitting Device，” Author Affiliation: Princeton University, Source: Annual Device Research Conference Digest，Jun 24-26 1996，IEEE pp· 146-147 o -13- 本紙張尺度適用中國國家標準（CNS)A4規格i210 X 297公釐） 504945 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（11) 該OEL放射元件可被製成為併入有一個由適合之有機 電激發光物質所構成的OEL層，藉此，該〇el層放射出一 個擇自於下列之OEL放射：一個較佳地位在5〇〇-55〇 nm的 範圍内之綠色發光波長放射、一個較佳地位在590-640 nm 的範圍内之紅色發光波長放射、一個較佳地位在43 5_485 nm的範圍内之藍色發光波長放射以及一種全彩放射。例 如，該OEL 放射元件可依據 C.W. Tang and S.A. Vanslyke， July，1987, Appl. Phys. Lett·，51: 913-915被製成，藉此，其 可提供一個具綠色發光波長範圍的OEL放射。 該微晶片組件可被固著有諸如DNA、RNA、蛋白質、 脂質、碳水化合物或激素之生物分子位於一個基材之上， 該基材為例如玻璃、矽石、石英、壓克力和聚合性材料[諸 如聚碳酸酯（PC)、聚四酞酸乙二醇酯（p〇iyethylene tetraphthalate glycol，PETG)或親水性聚（甲基丙烯酸曱 酯）(PMMA)]以及相似之物，且該微晶片組件在生物電子 學、DNA雜交反應分析、藥物分析等方面具有應用性。 依據本發明，該微晶片組件可被製造成呈一種陣列型 裝置或是一種微流體系統的形式。 描述生物性聚合物陣列和其製造方法之專利和已公開 之專利申請案包括：美國專利案第5,242,974、5,384,261、 5,405,783、5,412,087、5,424，186、5,429,807、5,436,327、 5,445,934、5,472,672、5,527,68卜 5,529,756、5,545,53 1、 5,554,5(H、5,556,752、5,561，071、5,599,895、5,624,71 1、 5,639,603與 5,658,734號；W0 93/17126、W0 95/11995、 -14- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------------訂---------^ i^w— (請先閱讀背面之注意事項再填寫本頁) 504945 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（12) WO 95/35505 ; EP 742 287 以及 EP 799 897。 描述在不同應用中使用陣列之方法之專利和已公開之 專利申請案包括：美國專利案第5，143,854、5,288,644、 5,324,633、5,432,049、5,470,710、5,492,806、5,503,980、 5.5 10,270、5,525,464、5,547,839、5,580,732 與 5,661，028 號；WO 95/21265、WO 96/3 1622、WO 97/10365、WO 97/273 17 ; EP 373 203 以及 EP 785 280 〇 其他提供微陣列技術之一回顧（包括陣列的形式和其 使用方法）的參考文獻包括：Lockhart et al·，Nature Biotechnology (December 1996) 14: 1675 o Clontech Catalogue， 97/98，（Clontech Laboratories，Inc· 1020 East Meadow Circle， Palo Alto Calif· 94303) p. 81描述經預製的北方墨點分析。 關於呈一種微流體系統形式的微晶片組件，可參考文 獻下列：Chen YH，Chen SH，Analysis of DNA fragments by microchip electrphoresis fabricated on PMMA substrates using wire-imprinting method, Electrophoresis，2000，Vol. 21，issue 1，pp· l65-l7〇，以及其中所引述之相關參考文獻。 該微晶片組件可被製造成具一厚度在範圍0.5 mm至 4.6 mm之間，較佳為0.5 mm。 該微晶片組件上所進行的分析可藉由一個被標識在存 在於該微晶片組件上之活性生物分子的染劑來偵測。 為確保彳貞測之敏感度，該染劑較佳地可藉由吸收該 OEL層所產生的OEL放射而被激發，藉此，當使用之時， 該染劑產生一個可偵測之放射波長，該放射波長之波峰與 15- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------裝--------訂·--------線 (請先閱讀背面之注意事項再填寫本頁) 504945 經濟部智慧財產局員工消費合作社印製 A7 B7___ 五、發明說明（13 ) 該染劑之激發波長的波峰和該OEL放射之波峰充分地分隔 開。 較佳地，該染劑之激發波長的波峰和放射波長的波峰 之間彼此相隔至少25 nm。較佳地，該染劑之激發波長的 波峰約在525土25 nm。 當該OEL層放射一個具有較佳地位在500-550 nm範圍 内之綠色發光波長的OEL放射時，可供用於本發明的合適 染劑包括但不限於：TransFluoSpheres®羧酸改值的微球體 (carboxylate-modified microspheres，購自於 Molecular Probes，Inc.)、7-胺基放線菌素D (7-aminoactinomycin D， 7-ADD)、尼羅紅（Nile Red)和波皮丁碘（Propidium Iodine)。此等染劑各個具有一個接近525 nm之放射波長波 峰。雖然此等染劑具有一個放射波長波峰不同於另一者所 具者，其等共享有一個共同的特徵，亦即其等之激發波長 波峰和放射波長波峰彼此相隔得夠遠。依據所選擇的染 劑，所獲得的訊號強度可變化之。 … 當該OEL層放射一個較佳地位在590-640 nm的範圍内 之紅色發光波長的OEL放射時，可供用於本發明的合適染 劑包括但不限於：萘螢光素（Naphthofluorescein)、5-和6-叛基萘榮光素（5- and 6-carboxynaphthofluoresceins)、號 ί白醯 亞胺基酯（succinimidyl ester)混合的異構物以及 transfluospheres螢光性微球體（fluorescent microspheres) 〇 當該OEL層放射一個較佳地位在435-485 nm的範圍内 之藍色發光波長的OEL放射時，可供用於本發明的合適染 -16- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------#裝--------訂---------線#_ (請先閱讀背面之注意事項再填寫本頁) 504945 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（I4) 劑包括但不限於：NBD、3-(4-羧基苯甲醯基）喳啉-2-羧醛 [3-(4-carboxybenzoyl)quinoine-2-carboxaldehyde，CBQCA]、 6-(N-(7-硝基苯並-2-噁-1，3-二唑-4-基）胺基）己酸 [6-(N-(7-nitrobenz-2-oxa-1 ?3-diazol-4-yl)amino)hexanoic acid)、萘-2,3-二竣酸（naphthalene-2,3-dicarboxaldehyde， NDA)、號ίό龜亞胺基6-(N-(7 -石肖基苯並-2- °惡-1，3 -二吐-4_ 基）胺基）己酸醋[3\1(：(^1^1111<1；716-(]^-(7-11^1*〇66112-2-〇父&-1，3-diazo-4-yl)amino)hexanote，NBD-X，SE)和漠化乙鍵單疊氮化 合物（ethidium monoazide bormide)。所有此等染劑可購自於 Molecules Probes，Inc.(參見“Handbook of Fluorescent Probes and Research Chemicals” edited by Richard P. Haugland，sixth edition，1996)。 較佳地，該以OEL-為基礎的生物晶片更包含被疊置於 該微晶片組件之上的構件，用以光譜地收集自該OEL層放 射並通過該微晶片組件之螢光訊號或透明光。 該光譜收集構件可被製造成為一個分離式組件或是被 一體成型地微製造於該微晶片組件之上。較佳地，該收集 構件包含一個光感測器用以收集經過濾之被放射的螢光訊 號或透明光。較佳地，該光感測器是一個光電倍增管（PMT) 或是一個光二極體或是一個電荷耦合裝置（CCD)。較佳 地，該光感測器被連結至一部用於資料處理與顯示之電腦。 較佳地’該以OEL-為基礎的生物晶片更包含位在該微 晶片組件和該收集構件之間的第一過濾構件，用以光譜地 過濾自該OEL層放射並通過該微晶片組件之螢光訊號或透 17- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 2_97公釐） -------------裝--------訂·--------線 (請先閱讀背面之注意事項再填寫本頁) A7504945 A7 B7 V. Description of the invention (7) Fluorescence emission phenomenon of Fluorescent microspheres; Figures 4A and 4B show the fluorescence stability of the fluorescent microspheres using the first specific example; The figure shows a second specific example of the present invention; and FIG. 6 shows a third specific example of the present invention. Li d Bull symbol pair Zhao 2 microchip module 4 pinhole layer 6 light sensor 8 pinhole layer (please read the precautions on the back before filling out this page) 1 OEL radiation element 3 objective lens 5 radiation filter 7 excitation filter Device 9 Detailed description of the invention of the spherical lens. It is logically beneficial to print the use of OEL radiation as a light source or heat source for biochip applications by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics, because the flat form of an 0EL radiation element and the biochip It is comparable, and more importantly, that the manufacturing process of an OEL radiation element can be easily incorporated into the manufacturing process of a biochip. In addition, an OEL radiating element has a greater flexibility, such as a rollable substrate that allows the use of cheaper and disposable polymer materials. Once platform manufacturing technology for this OEL-based biochip has been developed, many bioassays can be applied as a disposable inspection kit. When OEL radiation is used as a light source, the light-emitting area is lithographically manufactured in a defined area of the substrate of an OEL radiation element. Preferably, the OEL radiation is guided through an optical lens and placed on the upper surface. -10- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public love). The cooperative prints A7 B7 V. Description of the invention (8). The optical lens is manufactured as an integrated unit on the surface of the substrate for focusing. The fluorescent signal or transparent light is then spectrally filtered and collected by a photodiode, which is placed as a separate device on top of the OEL-based biochip or as an integrated component It is microfabricated on top of the OEL-based biochip. When OEL radiation is used as a heat source, OEL radiation located in the near-infrared region is used to generate the thermal energy required for biochemical reactions such as PCR or enzyme hydrolysis reactions. In addition to the above, the OEL emission can also be used to trigger a photocurrent generated by a specific electrochemical reaction occurring in a biological system. For example, various forms of microphysiometers have been developed that can be applied to the measurement of measured variables (McConnel, HM ·, Owicki, JC ·, Parce, JW ·, Miller, DL, Baxter) , GT ·, Wada, JG and Pitchford, S. (1992), Science, 257: 1906-1912; Adami, M., Piras, L., Lanzi, M., Fanigliulo, A., Vakula, S. and Nicoini , C. (1994), Sens. Actuators (B) 18: 178-1 82; Baxter, GT, Bousse ,. LJ, Dawes, TD, Libby, JM, Modlin, DN, Owicki, JC and Parce, JW (1994 ), Clin, Chem., 40: 1800-1804; Adami, M., Sartore, M. and Nicolini, C. (1995), Biosens. Bioelec., 10: 155-167; Adami, M., Sartore, M and Nicolini, C. (1995), Biosens. Bioelec., 10: 633-638; KR Rogers et al., Anal. (1992), Vol. 202, pp. 111-116; and D. Hafeman a / · , We_ (1998) Vol. 240, pp.1 182-1 185) ° -11- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) II ϋ n «ϋ» ^ 1 ϋ I — Ϋ 1_1 I 0 ί · ϋ meMt ϋ— · ϋ · ϋ I 1_1 mmmMmm n ϋ— n an II (please first Read the notes on the back and fill out this page) 504945 Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (9) This microphysiometer is designed to measure cell processes (such as phosphorylation, diffusion, etc.) Effect and ion pump effect). When an OEL-based biochip according to the present invention is used to detect a specific biochemical reaction occurring in a fixed biological product, 'the OEL radiation will not interfere with telecommunications caused by the reaction number. According to the present invention, there is provided an OEL-based biochip including: an OEL radiation element that is manufactured as a substrate of the biochip and can be used as a light source or a heat source of the biochip; and a microchip assembly It is stacked on the OEL radiation element and is designed to perform a predetermined application, such as gene expression analysis, protein immunoassay, drug screening, and cell-based analysis. Preferably, the OEL radiating element and the microchip assembly are integrally micro-manufactured to form a one-piece device. Preferably, the OEL-based biochip is microfabricated to have a size ranging from 20 mm to 10 cm in length, 20 mm to 10 cm in width, and 0.5 mm to 4 mm in height. For example, if the OEL-based biochip is manufactured in the form of a microarray wafer, it can be microfabricated to have a size of hundreds of microns to several millimeters. As for a microfluidic wafer, the oEL-based biochip can be microfabricated to a size of a few centimeters. In a preferred embodiment, the OEL-based biochip is microfabricated to a size of 30 mm X 30 mm X 0.6 mm. The OEL radiating element can be manufactured by a technique generally used for manufacturing an Oel display module. For this purpose, the available references include but -12-This paper size applies to China National Standard (CNS) A4 (210 X 297 public love) ----------------- --- Order --------- ^ (Please read the notes on the back before filling this page) 504945 A7 B7 V. Description of the invention (10) (Please read the notes on the back before filling this page) Not limited to CW Tang and SA Vanslyke, ΡΛγ. Ie "., July 1987, 51 (12): 913-915; Chemistry (The Chinese Chem. Soc.f Taipei) Mar. 1996 54 (1), pp. 125- 145; Andrei A. Shoustikov et al., IEEE Journal of Selected Topics in Quantum Electronics, Vol. 4, No. 1, January / February, 1998, pp. 3-13; MG Mason et al., J. Appl. Physics , Vol. 86, No. 3, August 1999, pp. 1688-1692; Junji Kido and Yasuhiro Iizumi, AppL Phys. Lett., 9 November 1998, Vol. 73, No. 19, pp. 2721-2723; G. Gu and Stephen R. Forrest, IEEE Journal of Selected Topics in Quantum Electronics, Vol. 4? No. 1, January / February, 1998, pp. 83-99; and LS Hung et al., Appl. Phys. Lett. January 1997, 70 (2) M52-154 〇 The OEL radiating element can be made to have a thickness ranging from 0.35 mm to 0.75 mm, preferably 0.5 mm. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Preferably, the OEL radiation element is microfabricated on a flexible substrate (such as a plastic substrate). Preferably, the OEL radiating element is manufactured as a transparent OLED (TOLED) component, which allows the OEL to emit from its top and bottom sides. In these respects, available references include, but are not limited to, Ye He and Jerzy Kanichi, Jpp / · House Ze " ·, 7 February 2000, 76 (6): 661-663; and P · E. Burrows α / · , "A Bright, Transparent, Blue Organic Light Emitting Device," Author Affiliation: Princeton University, Source: Annual Device Research Conference Digest, Jun 24-26 1996, IEEE pp · 146-147 o -13- This paper standard applies to China Standard (CNS) A4 specification i210 X 297 mm) 504945 Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (11) The OEL radiating element can be made to incorporate an organic electro-excitation An OEL layer composed of a light substance, whereby the Oel layer emits an OEL emission selected from the following: a green emission wavelength with a preferable position in the range of 500-550 nm, and a preferred one Red emission wavelength emission in the range of 590-640 nm, a blue emission wavelength emission in the preferred range of 43 5_485 nm, and a full-color emission. For example, the OEL radiating element can be made according to C.W. Tang and S.A. Vanslyke, July, 1987, Appl. Phys. Lett., 51: 913-915, whereby it can provide an OEL emission having a green emission wavelength range. The microchip assembly may be fixed with a biomolecule such as DNA, RNA, protein, lipid, carbohydrate or hormone on a substrate such as glass, silica, quartz, acrylic, and polymerizability Materials [such as polycarbonate (PC), polytetraphthalate glycol (PETG) or hydrophilic poly (methyl methacrylate) (PMMA)] and the like, and the micro The chip assembly has applicability in bioelectronics, DNA hybridization reaction analysis, and drug analysis. According to the present invention, the microchip assembly can be manufactured in the form of an array-type device or a microfluidic system. Patents and published patent applications describing biopolymer arrays and methods of making them include: U.S. Patent Nos. 5,242,974, 5,384,261, 5,405,783, 5,412,087, 5,424,186, 5,429,807, 5,436,327, 5,445,934, 5,472,672, 5,527,68, 5,529,756 , 5,545,53 1, 5,554,5 (H, 5,556,752, 5,561,071, 5,599,895, 5,624,71 1, 5,639,603, and 5,658,734; WO 93/17126, WO 95/11995, -14- This paper standard applies to Chinese national standards (CNS) A4 specification (210 X 297 mm) ------------------- Order --------- ^ i ^ w— (Please read first Note on the back, please fill out this page again) 504945 Printed by A7 B7, Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (12) WO 95/35505; EP 742 287 and EP 799 897. Describe the use of arrays in different applications. Method patents and published patent applications include: U.S. Patent Nos. 5,143,854, 5,288,644, 5,324,633, 5,432,049, 5,470,710, 5,492,806, 5,503,980, 5.5 10,270, 5,525,464, 5,547,839, 5,580,732 and 5,661,028; WO 95/21265; , WO 96/3 1622, WO 97/10 365, WO 97/273 17; EP 373 203 and EP 785 280 〇 Other references that provide a review of one of the microarray technologies (including the format of the array and its use) include: Lockhart et al., Nature Biotechnology (December 1996) 14: 1675 o Clontech Catalogue, 97/98, (Clontech Laboratories, Inc. 1020 East Meadow Circle, Palo Alto Calif 94303) p. 81 describes prefabricated northern dot analysis. About microchips in the form of a microfluidic system The components can be referenced in the following literatures: Chen YH, Chen SH, Analysis of DNA fragments by microchip electrphoresis fabricated on PMMA substrates using wire-imprinting method, Electrophoresis, 2000, Vol. 21, issue 1, pp · 165-l70, and among others Related references cited. The microchip assembly can be manufactured with a thickness ranging from 0.5 mm to 4.6 mm, preferably 0.5 mm. The analysis performed on the microchip assembly can be detected by a dye that is labeled with active biomolecules present on the microchip assembly. In order to ensure the sensitivity of the test, the dye is preferably excited by absorbing the OEL radiation generated by the OEL layer, so that when used, the dye generates a detectable emission wavelength The peak of the emission wavelength and 15- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------- installation -------- Order -------- line (please read the precautions on the back before filling this page) 504945 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7___ V. Description of the invention (13) Excitation wavelength of the dye The peaks of and are sufficiently separated from the peaks of the OEL emission. Preferably, the peak of the excitation wavelength and the peak of the emission wavelength of the dye are separated from each other by at least 25 nm. Preferably, the peak of the excitation wavelength of the dye is about 525 to 25 nm. When the OEL layer emits an OEL emission having a green emission wavelength in the range of 500-550 nm, suitable dyes for use in the present invention include, but are not limited to: TransFluoSpheres® carboxylic acid-modified microspheres ( carboxylate-modified microspheres, purchased from Molecular Probes, Inc.), 7-aminoactinomycin D (7-ADD), Nile Red, and Propidium Iodine . Each of these dyes has an emission wavelength peak near 525 nm. Although these dyes have one emission wavelength peak that is different from the other, they share a common feature, that is, their excitation wavelength peaks and emission wavelength peaks are sufficiently far apart from each other. Depending on the dye chosen, the strength of the signal obtained can vary. … When the OEL layer emits OEL radiation with a red emission wavelength in the range of 590-640 nm, suitable dyes for use in the present invention include, but are not limited to: Naphthofluorescein, 5 -Isomers mixed with 5- and 6-carboxynaphthofluoresceins, succinimidyl ester and transfluospheres fluorescent microspheres. When the OEL When the layer emits OEL radiation with a blue light emission wavelength in the range of 435-485 nm, it is suitable for the present invention. -16- This paper is in accordance with China National Standard (CNS) A4 (210 X 297 mm) ----------- # 装 -------- Order --------- Line # _ (Please read the notes on the back before filling this page ) 504945 A7 B7 printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (I4) Agents include but are not limited to: NBD, 3- (4-carboxybenzyl) pyridin-2-carboxaldehyde [3- (4-carboxybenzoyl) quinoine-2-carboxaldehyde, CBQCA], 6- (N- (7-nitrobenzo-2-oxo-1,3-diazol-4-yl) amino) hexanoic acid [ 6- (N- (7-nitrobenz-2-oxa-1? 3-diazol-4-yl) amino) hexanoic acid), naphthalene-2,3-dicarboxaldehyde (NDA) , No. Turmine imino 6- (N- (7-Shithosylbenzo-2- ° oxa-1,3-diureth-4_yl) amino) hexanoic acid vinegar [3 \ 1 (: (^ 1 ^ 1111 <1; 716-() ^-(7-11 ^ 1 * 〇66112-2-〇 Father & -1,3-diazo-4-yl) amino) hexanote, NBD-X, SE) and desertification Ethidium monoazide bormide. All these dyes are available from Molecules Probes, Inc. (see "Handbook of Fluorescent Probes and Research Chemicals" edited by Richard P. Haugland, sixth edition, 1996). Preferably, the OEL-based biochip further includes a component stacked on the microchip module for spectrally collecting fluorescent signals or transparent signals emitted from the OEL layer and passing through the microchip module. Light. The spectral collection member can be manufactured as a separate component or microfabricated integrally on the microchip component. Preferably, the collecting means includes a light sensor for collecting the filtered emitted fluorescent signal or transparent light. Preferably, the light sensor is a photomultiplier tube (PMT) or a photodiode or a charge coupled device (CCD). Preferably, the light sensor is connected to a computer for data processing and display. Preferably, the OEL-based biochip further includes a first filter member located between the microchip module and the collection member for spectrally filtering the radiation emitted from the OEL layer and passing through the microchip module. Fluorescent signal or transparent 17- This paper size applies to China National Standard (CNS) A4 specification (210 X 2_97 mm) ------------- Installation -------- Order · -------- Line (Please read the precautions on the back before filling this page) A7
504945 五、發明說明（IS) 明光。 較佳地，該第一過濾構件是一種放射過濾器。商業上 可獲得之放射過濾器包括那些可得自於〇pt〇sigma Corporation 者。 任擇地，該第一過濾構件可藉由一個選自於電鍍、濺 射E東和熱蒸發之傳統技術方法，在該微晶片組件之上 形成一個預定厚度（例如，在100人至1〇〇〇 A的範圍，較佳 為500 A)的過濾器塗層，而被置放於該微晶片組件之上。 為了增進過濾的效果，該第一過濾構件可包含一個針 孔層和一個被疊置於該針孔層之上的放射過濾器。 較佳地’該以0EL-為基礎的生物晶片更包含位在該 0EL元件和該微晶片組件之間的第二過濾構件，用以光譜 地過濾自該0EL層放射之螢光訊號或透明光。 較佳地’該第二過遽構件是一種激發過濾、器。商業上 可獲得之激發過濾器包括那些可得自於〇pt〇sigma Corporation者 〇 任擇地’該第一過遽構件可藉由一個選自於電鎪、賤 射、E束和熱蒸發之傳統技術方法，在該〇EL層之上形成一 個預定厚度（例如，在100 A至1000 A的範圍，較佳為500 A) 的過濾器塗層，而被形成於該0EL層之上。 為了增進該以0EL-為基礎的生物晶片之彳貞測敏感 度’一個球面透鏡和一個針孔層可被置放於該第二過遽構 件和該微晶片組件之間，用以對焦自該0EL層放射並通過 該第二過濾構件之螢光訊號或透明光。 -18- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) --------^---------線. 經濟部智慧財產局員工消費合作社印製 504945 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明（Μ 在本發明之一個任擇的具體例中，該以OEL為基礎的 生物晶片包含一個被建造成為一個透明0LED組件的0EL 放射兀件，於該透明0LED組件之各側可安裝一個複合層 合物，該複合層合物包含下列部件依序地層疊在前一者之 上·（ 1)第一過濾構件，用以過濾自該〇El層激發之螢光訊 號或透明光；（2) —個球面透鏡和一個針孔層，用以對焦經 過濾之被激發的螢光訊號或透明光；一個微晶片組件， 用以進行一個選自於由下列所構成的群組中之預定的應 用·基因表現分析、蛋白質免疫分析、藥物篩選和以細胞 為主的分析，且該應用任擇地涉及到一種生物系統；（4) 第二過濾構件，其被疊置在該微晶片組件之上，用以過濾 自該微晶片組件激發之螢光訊號或透明光；以及（5)一個光 感測器’用以收集經過濾之被放射的螢光訊號或透明光。 較佳地，該光感測器是一個光電倍增管（pMT)或是一 個光二極體或是一個電荷耦合裝置（CCD)，該光感測器可 被連結至一部用於資料處理與顯示之電腦。 用於實施本發明之較佳具艘例 下面的具體例被提供僅是為了舉例說明的目的，而非 意欲要限制本發明的範圍。 參照第1圖，一個依據本發明之第一具體例被提供在一 個光學顯微鏡（OLYMPUS BX40)的載物台上來供偵測之 用。該第一具體例係由一個0EL放射元件1和一個被疊置於 該0EL放射元件1之上的微晶片組件2所構成。 該 0EL放射元件 1 是依據C.W. Tang and S.A. Vanslyke， -19- 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） —1 ϋ ϋ I l n m ϋ n ϋ ϋ n I · n I n I ϋ an in 一〆口，I n I— n n I n I (請先閱讀背面之注意事項再填寫本頁) 504945 A7 B7_ 五、發明說明（Π) (請先閱讀背面之注意事項再填寫本頁)504945 5. Description of invention (IS) Bright light. Preferably, the first filtering member is a radiation filter. Commercially available radiation filters include those available from Optosigma Corporation. Alternatively, the first filter member may be formed on the microchip assembly by a conventional technique selected from electroplating, sputtering, and thermal evaporation to a predetermined thickness (for example, from 100 to 100). A filter coating in the range of 0 A, preferably 500 A), is placed on the microchip assembly. To enhance the filtering effect, the first filtering member may include a pinhole layer and a radiation filter stacked on the pinhole layer. Preferably, the 0EL-based biochip further includes a second filter member located between the OEL element and the microchip assembly, for spectrally filtering the fluorescent signal or transparent light emitted from the 0EL layer. . Preferably, the second passing member is an excitation filter. Commercially available excitation filters include those available from ptsigma Corporation. Optionally, the first pass member can be selected from a In a conventional technique, a filter coating having a predetermined thickness (for example, in a range of 100 A to 1000 A, preferably 500 A) is formed on the OEL layer, and is formed on the OEL layer. In order to improve the sensitivity of the 0EL-based biochip, a spherical lens and a pinhole layer can be placed between the second transition member and the microchip assembly for focusing on the The 0EL layer emits a fluorescent signal or transparent light that passes through the second filter member. -18- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) -------- ^ ------ --- line. Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 504945 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 5. Description of the invention The biochip contains a 0EL radiation element that is built into a transparent 0LED component. A composite laminate can be installed on each side of the transparent 0LED component. The composite laminate contains the following components sequentially stacked on the former. Above · (1) a first filter member for filtering the fluorescent signal or transparent light excited from the OEl layer; (2) a spherical lens and a pinhole layer for focusing the filtered excited Fluorescent signal or transparent light; a microchip module for performing a predetermined application selected from the group consisting of: • gene expression analysis, protein immunoassay, drug screening and cell-based analysis, And the app optionally involves A biological system; (4) a second filter member, which is stacked on the microchip assembly to filter a fluorescent signal or transparent light excited from the microchip assembly; and (5) a light sensor 'To collect filtered emitted fluorescent signal or transparent light. Preferably, the light sensor is a photomultiplier tube (pMT) or a photodiode or a charge-coupled device (CCD), The light sensor may be connected to a computer for data processing and display. Preferred Examples for Implementing the Invention The following specific examples are provided for illustrative purposes only and are not intended to be limiting The scope of the present invention. Referring to FIG. 1, a first specific example according to the present invention is provided on the stage of an optical microscope (OLYMPUS BX40) for detection. The first specific example is radiated by a 0EL Element 1 and a microchip assembly 2 stacked on top of the 0EL radiation element 1. The 0EL radiation element 1 is based on CW Tang and SA Vanslyke, -19- This paper standard applies Chinese National Standard (CNS) A4 Specifications (210 297 mm) —1 ϋ ϋ I lnm ϋ n ϋ ϋ n I · n I n I ϋ an in a mouth, I n I— nn I n I (Please read the notes on the back before filling this page) 504945 A7 B7_ V. Description of Invention (Π) (Please read the notes on the back before filling this page)
July，1987, Appl· Phys. Lett·，51: 913-915所建造，藉此，一 個可提供一個具一波峰為525 nm之OEL放射的OEL層被併 入於該0EL放射元件内。關於該0EL放射之波峰自550 nm 位移到525 nm，這可能是由於所使用之物質的純度以及由 之所形成的OEL層的厚度所致。 該微晶片組件 2 是依據 Chen YH，Chen SH， 2000, Vol. 21，issue 1，pp. 165-170而被建造在一種聚（甲基丙 丁烯酸曱酯）(PMMA)的基材之上。 該第一具體例被對比成呈一體積為3 5 0 mm X 450 mm x 600 mm，而該OEL放射元件1和該微晶片組件2被分別地 製作成具一厚度為0.6 mm和2.0 mm。 一個物鏡3、一個針孔層4、一個放射過濾器5和一個光 感測器6依序地被置放於該以〇eL-為基礎的生物晶片之 上。關於偵測，自該OEL放射元件1放射出的螢光訊號或透 明光通過該微晶片組件2、該物鏡3和該針孔層4和該放射過 濾器5而到達該光感測器6，該光感測器6可被連結至一部用 於資料處理與顯示之電腦（未示出）。 經濟部智慧財產局員工消費合作社印製 為確保依據本發明之以0EL-為基礎的生物晶片的债 測敏感度，較為適宜的是，一種被選定以供標識至存在於 該微晶片組件上的被反應之生物分子（特別是被固著在該 微晶片組件上以供與位於一樣品中之所欲的分析物相反應 的生物分子）上的染劑可藉由吸收來自該〇EL層的〇EL放 射而被激發，藉此，當使用之時，該染劑產生一個可偵測 的放射波長，該染劑之放射波長的波峰與該染劑之激發波 -20- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 504945 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（18) 長的波峰以及該OEL放射的波峰充分地分隔開。 為達此目的，兩種不同的染劑，即若丹明藍（Rh〇damine Blue，購自於Riedel-deHaSn)和螢光性微球體（Flu〇rescent Microsphere，即TransFluoSpheres®羧酸改值的微球體，購 自於Molecular Probes，Inc·)，就其等之激發和放射行為而 被試驗。如從第2B圖中所示結果可見的，螢光性微球體的 ^ 激發波長的波峰和放射波長的波峰相隔有多於2 5 nm之 遠。與若丹明藍相比較（第2 A圖），螢光性微球體的激發波 長和放射波長的曲線不會干擾來自該〇EL層的〇EL放射曲 線。 因此’螢光性微球體適合供用作為該微晶片組件用的 標§己物’且其被選擇作為進行下一步的實驗。其他具有相 似的激發和放射特徵的染劑包括但不限於·· 7 _胺基放線菌 素D、尼羅紅或波皮丁碘。 為了確保該OEL層可當作為螢光性微球體的一個光 ^ 源，由被用作為光源之該OEL層所激發之螢光性微球體的 螢光放射圖譜被研究之，而結果被顯示於第3圖中。該圖之 右側顯示在一為9V之操作電壓下被測試的螢光性微球體 的螢光放射圖譜，其中被顯示於該圖之右側的兩個箭頭意 指該染劑的移除。從第3圖可知，螢光性微球體的一個單純 螢光可藉由來自該OEL層的激發光而被產生之。 螢光性微球體的螢光安定性亦被測試，而結果被顯示 在第4A圖和第4B圖中。在第4A圖中，一個載有該染劑的玻 片被置放於位在該顯微鏡載物台上的〇EL層之上，並在一 -21- --------------- (請先閱讀背面之注意事項再填寫本頁) ί 言 Τ 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297_公釐） 504945 經濟部智慧財產局員工消費合作社印製 A7 _____；_B7_ 五、發明說明（19) 為9V之操作電壓下進行訊號偵測歷時1〇分鐘。接著該微晶 片組件被置於該玻片和該OEL層之間，再次進行訊號偵測 歷時10分鐘。結果被顯示在第4B圖中。 從上述之實驗，獲得之結論為該OEL層可作為該微晶 片組件的一個光源。 也有可能讓該OEL層當作為一個熱源，設若該〇EL光 被選定為坐落在近於紅外線區域，俾以產生供生物化學反 應（諸如PCR或酵素水解反應）所需之熱能。 為了增進彳貞測效率，該以OEL -為基礎的生物晶片可被 製成具有如第5圖中所顯示之結構，其中一個依據本發明之 第二具體例包含有一個OEL放射元件1、一個微晶片組件 2、一個針孔層4、一個放射過遽器5和一個光感測器6，它 們依序地被一體成型地微製造。 第6圖顯示一個依據本發明之第三具體例，其被製造成 依序地包含有一個OEL放射元件1、一個激發過濾器7、一 個針孔層8、一個球形透鏡9、一個微晶片組件2、一個針孔 層4、一個放射過遽器5和一個光感測器6 [諸如一個光電倍 增管（PMT)或是一個光二極體或是一個電荷耦合裝置 (CCD)]〇 較佳地，該光感測器被連結至一部用於資料處理與顯 示之電腦。 較佳地，上述之該第三具體例的結構組件被一體成型 地微製造以形成一個單件式裝置。 於本說明書中被引述之所有專利和文獻以其整體被併 -22- 电紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------·裳--------訂---------線#. (請先閱讀背面之注意事項再填寫本頁) 504945July, 1987, Appl. Phys. Lett., 51: 913-915, whereby an OEL layer that provides an OEL emission with a peak of 525 nm is incorporated into the 0EL radiating element. The shift of the peak of the 0EL emission from 550 nm to 525 nm may be due to the purity of the substance used and the thickness of the OEL layer formed by it. The microchip assembly 2 is built on a poly (methacrylic acid methyl ester) (PMMA) substrate according to Chen YH, Chen SH, 2000, Vol. 21, issue 1, pp. 165-170. . The first specific example is compared to a volume of 350 mm X 450 mm x 600 mm, and the OEL radiation element 1 and the microchip assembly 2 are fabricated to have a thickness of 0.6 mm and 2.0 mm, respectively. An objective lens 3, a pinhole layer 4, a radiation filter 5 and a light sensor 6 are sequentially placed on the oeL-based biochip. Regarding detection, a fluorescent signal or transparent light emitted from the OEL radiation element 1 passes through the microchip assembly 2, the objective lens 3, the pinhole layer 4 and the radiation filter 5 to reach the light sensor 6, The light sensor 6 can be connected to a computer (not shown) for data processing and display. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs to ensure the sensitivity of debt measurement of 0EL-based biochips in accordance with the present invention, it is more appropriate to select one for identification to the microchip components Reacted biomolecules (especially biomolecules that are fixed to the microchip assembly for reaction with a desired analyte in a sample) can absorb the dye from the OEL layer by 〇EL is excited by radiation, thereby, when used, the dye produces a detectable emission wavelength, the peak of the emission wavelength of the dye and the excitation wave of the dye -20- This paper applies to China National Standard (CNS) A4 specification (210 X 297 public love) 504945 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (18) The long wave peaks and the OEL emission peaks are sufficiently separated. To achieve this, two different dyes, Rhodamine Blue (from Riedel-deHaSn) and Fluorescent Microsphere (TransFluoSpheres® carboxylic acid-modified Microspheres, purchased from Molecular Probes, Inc.), were tested for their excitation and radiation behavior. As can be seen from the results shown in Figure 2B, the peaks of the excitation wavelength and the emission wavelength of the fluorescent microspheres are separated by more than 25 nm. Compared with rhodamine blue (Figure 2A), the curve of the excitation wavelength and the emission wavelength of the fluorescent microsphere does not interfere with the OEL emission curve from the OEL layer. Therefore, the 'fluorescent microspheres are suitable for use as the target of the microchip module' and are selected as the next experiment. Other dyes with similar excitation and radiation characteristics include, but are not limited to, 7-amino actinomycin D, Nile Red or Popidine iodine. In order to ensure that the OEL layer can be used as a light source of fluorescent microspheres, the fluorescence emission spectrum of the fluorescent microspheres excited by the OEL layer used as a light source is studied, and the results are displayed in Figure 3. The right side of the figure shows the fluorescence emission spectrum of the fluorescent microspheres tested at an operating voltage of 9V. The two arrows shown on the right side of the figure indicate the removal of the dye. It can be seen from Fig. 3 that a simple fluorescent light of the fluorescent microsphere can be generated by the excitation light from the OEL layer. The fluorescence stability of the fluorescent microspheres was also tested, and the results are shown in Figures 4A and 4B. In Figure 4A, a glass slide containing the dye is placed on the OEL layer on the microscope stage, and a -21 ----------- ----- (Please read the notes on the back before filling this page) ί Τ This paper size is applicable to China National Standard (CNS) A4 (210 χ 297_mm) 504945 Employee Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs Print A7 _____; _B7_ V. Description of the Invention (19) Signal detection under the operating voltage of 9V lasted 10 minutes. The microchip assembly was then placed between the glass slide and the OEL layer, and signal detection was performed again for 10 minutes. The results are shown in Figure 4B. From the above experiments, it was concluded that the OEL layer can be used as a light source for the microchip assembly. It is also possible to use the OEL layer as a heat source, provided that the OEL light is selected to be located in the near-infrared region to generate the thermal energy required for biochemical reactions such as PCR or enzyme hydrolysis reactions. In order to improve the measurement efficiency, the OEL-based biochip can be made to have a structure as shown in FIG. 5, one of which according to the second embodiment of the present invention includes an OEL radiation element 1, a The microchip assembly 2, a pinhole layer 4, a radiation filter 5 and a light sensor 6 are sequentially micro-manufactured in one piece. FIG. 6 shows a third specific example according to the present invention, which is manufactured to sequentially contain an OEL radiation element 1, an excitation filter 7, a pinhole layer 8, a spherical lens 9, and a microchip assembly 2. A pinhole layer 4, a radiation filter 5 and a light sensor 6 [such as a photomultiplier tube (PMT) or a photodiode or a charge coupled device (CCD)]. The light sensor is connected to a computer for data processing and display. Preferably, the structural component of the third specific example described above is integrally molded and microfabricated to form a one-piece device. All patents and documents cited in this specification have been incorporated as a whole. -22- Electrical paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----------- · Chang -------- Order --------- Line #. (Please read the precautions on the back before filling this page) 504945
人本案作為參考資料H所衝突時’本案詳細說明（包含 界定在内）將佔上風。 雖然本發明已參考上述特定的具體例被描述，明顯地 在不背離本發明之範圍和精神之下可作出很多的修改和變 化。因此意欲的是’本發明僅受如隨文檢附之申請專利範 圍所示者之限制。 -------------裝--------訂· (請先閱讀背面之注意事項再填寫本頁) 線 經濟部智慧財產局員工消費合作社印製 -23- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）When this case conflicts with reference H, the detailed explanation (including the definition) of this case will prevail. Although the invention has been described with reference to the specific examples described above, it will be apparent that many modifications and changes can be made without departing from the scope and spirit of the invention. Therefore, it is intended that the present invention is limited only by those indicated in the scope of patent applications attached to the text. ------------- Equipment -------- Order · (Please read the precautions on the back before filling out this page) Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-23 -This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)