1261620 九、發明說明： 【發明所屬之技術領域】 本發明係有關一種生物檢測細胞晶片，尤指一種應用於檢測細胞特定 檢體定位之生物晶片。 【先前技術】 生物晶片是運用分子生物學、基因資訊、分析化學等原理進行設計， 以矽晶片、玻璃或高分子有機塑膠為載板，配合微機電或其他精密加工 技術，所製作成的高科技元件，具有反應迅速、結果精確及低成本的生物 分析檢驗能力。在歐美先進國家中常利用晶片功能，以加速生命科學研 究5縮短新藥開發之時程。 生物晶片的概念起源於1980年代，生物晶片依照其特性可分為基因晶 片（gene chlp )、程序晶片（process chip，lal>〇n ehip )及蛋白質晶片（ chip): /土因晶片（genechip):是在面積數平方公分的載板上，安置數千到 數萬支不同的基因段(稱為核酸探針)所製成的晶片。使用時將晶片置於受 測液體中，使晶片上的核酸探針與液體中的待測基因進行雜交 (Hybndization)，若是某段基因有雜交反應，則會顯現出不同勞光色，得 =由肉眼或是特殊加以辨視。其好處是經由—次制，就可提供 的基因序列相關訊息，免除以往一次只能檢測-個基因表現 兴其^日f，大幅節省時間及手續，對加速解讀基因訊息有很大的助 重要且最基本原理就是彻基騎具有雜交反應的特性， 來達到辨識基因的目的。 ^寸丨王 ^蛋白^ (Ρ輸inehip):以蛋白質為生雌針 片上’進行抗原·抗體免疫反應，㈣檢測蛋㈣。 晶片中彻光ί二3=將生化#驗移置在晶片上進行，因此在微流體 右，再道，#勒㈣销百《甚至幾微米左 環境,將，使液_計好的 進仃刀部ep咖ed)、混合(Mixed)、培養卜bation)、加熱 1261620 (Heated) ^ (Polymerase Chain Reaction)^1261620 IX. Description of the Invention: [Technical Field of the Invention] The present invention relates to a biodetection cell wafer, and more particularly to a biochip for detecting cell-specific sample localization. [Prior Art] Biochips are designed using molecular biology, genetic information, analytical chemistry, etc., using wafers, glass or polymer organic plastics as carrier plates, combined with microelectromechanical or other precision processing techniques. Scientific and technological components, with rapid response, accurate results and low cost bioanalytical testing capabilities. Wafer functions are often used in advanced countries in Europe and the United States to accelerate life science research 5 to shorten the time course for new drug development. The concept of biochips originated in the 1980s. According to their characteristics, biochips can be divided into gene chlp, process chip (lal> 〇n ehip) and protein chip: /genechip : It is a wafer made up of thousands to tens of thousands of different gene segments (called nucleic acid probes) on a square of a square centimeter. In use, the wafer is placed in the liquid to be tested, and the nucleic acid probe on the wafer is hybridized with the gene to be tested in the liquid. If a certain gene has a hybridization reaction, a different labor color is displayed, and It is discerned by the naked eye or by special. The advantage is that the gene sequence-related information can be provided through the secondary system, eliminating the need to detect only one gene expression in the past, which greatly saves time and procedures, and is of great help to accelerate the interpretation of gene information. And the most basic principle is that Cheki rides the characteristics of hybridization reaction to achieve the purpose of identifying genes. ^ inch 丨 king ^ protein ^ (Ρ ine hip): protein as a raw female needle on-chip 'antigen · antibody immune response, (d) detection of eggs (four). In the wafer, the light is 355, and the biochemical # inspection is placed on the wafer, so in the microfluid right, then the road, #勒(四)pin hundred "even a few micrometer left environment, will make the liquid _ good 仃Knife ep), mixed (mixed), culture b), heating 1261620 (Heated) ^ (Polymerase Chain Reaction)^
相同的反應。 ' ' X 於 為了能大量同步平行對檢測之細胞或基因進行分析，許多研究者I不 絞盡腦汁研究如何有效轉檢體定位於生物晶片上，最倾用的莫過續 點陣技術，_觸_關械手扣高密度_方式將生物探針固定a 生物晶片’再以抽取針將待檢體與生物探針接觸，進行檢測分析，铁而 此-方式每-_點均f配置—生物探針及抽取針，構件過於複雜，而且 使用抽取針吸取待檢體，容轉麟檢體及生物探針損壞。 另一種方式則為設有固定生物探針之反應區及配合樣本溶液注入、抽 離之微流H配置料有效隔雜本與外界之接觸 控制’而且不會損傷待檢體，但是礙於成本及技術 = 上僅能配置數個反應區，難以大量檢測，而且單—反應區内』 數龍’進行後續螢光檢測時，由於每—檢體之活 均不相同，會影響檢測精確度。 物知『生 【發明内容】 私之綠目的，在練決上述之缺失，戦敎的存在， 晶片上根據特定檢體大小開設有容置區，且於容ϊ區 行後i檢測。層，使得每一檢體被精確定位於單一容置區，可進 【實施方式】 3=詳細說明及技術内容，現就配合圖式說明如下： 及局=二二=、2·2_示』，係本發明之製造流程、外觀立體 久句文大斷面不意圖，如圖所 I ϋ 之步驟：絲檢體容置空間丨，係於之製造方法係包括以下 上，以晶_刻及陣列排列、=所切敗長、寬各為2公分晶片 測晶片10定義出向下漸縮狀之i體留二萬點）於微生物檢 口 11，前述之_技術可為㊣爛 :4空間上方係為一滴入 刻，乾侃__物理__行.L +祕刻係以化學反應進行钱 在檢體留置空間完成後，切割非檢體抽離口 2，根據特定檢體大小切 1261620 吾1j留置空間底部，使得留晋允p E|念立 、 κ 、， 置工間底斗形战—抽離口 12，藉由前述滴入口 11 及抽離口 12定義出一壁面向下漸縮之容置區13 ; 鈍化層3 π成4置區13後，為進—步精確控制容置區13大小， =述容置區13表面形成—鈍化層14，該鈍化層14係金屬鉻電做容置區 ;亥鈍化層14之作用有二：（一)可透過此一金屬鈍化層14修補前 =置區13尖銳之接觸角’並進一步精確控制抽離口 12之孔徑，㈡在 双側物進行螢光檢測時，背景最好不要產生光線反射，而影響掃描儀CCD ^ge-_Pled dev㈣或共焦鐳射掃描（eGnfbean_議The same reaction. ' ' X in order to be able to analyze a large number of parallel cells or genes for detection, many researchers I do not rack their brains to study how to effectively locate the body on the biochip, the most difficult to use dot matrix technology, _ Touch _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The biological probe and the extraction needle have too complicated components, and the extraction needle is used to absorb the sample to be tested, and the substrate and the biological probe are damaged. Another method is to provide a reaction zone with a fixed bioprobe and a microfluidic H material that is injected and withdrawn from the sample solution to effectively control the contact between the environment and the outside world, and does not damage the object to be tested, but it is costly. And technology = only a few reaction zones can be configured, it is difficult to detect a large number of samples, and when the subsequent fluorescence detection is performed in the single-reaction zone, the number of each sample is different, which will affect the detection accuracy. The material knows the "life" [invention content] The purpose of private green, in the determination of the above-mentioned lack, the existence of 戦敎, the wafer is opened according to the size of the specific sample, and is detected in the Rongsong area. Layer, so that each specimen is accurately positioned in a single accommodating area, can be advanced [Embodiment] 3 = detailed description and technical content, now with the following description of the diagram: and Bureau = two two =, 2 · 2 _ 』, the manufacturing process of the present invention, the appearance of the three-dimensional long sentence is not intended, as shown in Figure I ϋ steps: the silk sample housing space 丨, the manufacturing method is included in the following, with crystal Array arrangement, = cut length, width 2 cm each, wafer measurement wafer 10 defines a downwardly tapered shape of the body, leaving 20,000 points) in the microbial inspection port 11, the aforementioned technology can be positive: 4 space above The system is a drop into the engraving, dry __ physics __ line. L + secret engraving is carried out by chemical reaction. After the specimen indwelling space is completed, the non-sample excision port 2 is cut, and the size of the specific specimen is cut 1261620 I 1j retains the bottom of the space, so that the stay of the Jin Yun p E| 立立, κ, 置 底 底 形 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽 抽After the passivation layer 3 is π into the 4 region 13 , the size of the accommodating region 13 is precisely controlled for the step-by-step, The surface of the region 13 is formed as a passivation layer 14 which is a metal chromium electroplating region; the passivation layer 14 functions as two: (1) the metal passivation layer 14 can be repaired before the front region 13 is sharpened. Contact angle 'and further precise control of the aperture of the extraction port 12, (b) when the bilateral detection of fluorescence, the background is best not to produce light reflection, affecting the scanner CCD ^ge-_Pled dev (four) or confocal laser scanning (eGnfbean _
=理想狀況為黑色陣列⑽心牆），透過鉻之低反射性，減二 學檢測誤差； U 在^鈍化層後’為了戦鈍_4職生辟，而導致檢測 :,披復檢測層4，該檢測層15係沈積—生物相容性聚合物於純化層μ 2，該生物相容性聚合物係為聚對笨二甲烯（㈣。㈣挪⑽） 在德νί匕(150〇C)與裂解(650〇c)的過程後以沈積方式生成，聚對苯二甲 細之優點在於披覆性良好，可完全隔絕下方鈍化層14。 請參閱『第3、4圖所示』，係本發明之實施例示意圖，如圖所示： 測心〇可組裝於一基座2咖，該基獅包括供生物檢測晶 ^置之疋位區21及位於該定位區21下方且兩側分別連接於果浦（圖中 未不）之抽離通道22，使用時’將生物檢測晶片1〇安置於基座如之定位區 ’、=錄細之抽離觸2㈣連接至泵浦，此時即完成檢測系統配 置，進行貫驗時，將樣本溶液由滴人叫滴進前述生物檢測晶㈣，再啟 動泵浦將樣本溶液巾之雜f及水分藉由下方_口12及抽離通道_ 出，同時，由於栗浦提供-麼力差，使檢體可更加穩固定位於生物檢測晶 片二之谷置區13 (請參細）内’關縣浦’則每—檢體分別被定位於 各容置區13内，即可進行後續檢測。 、 由於本發明之容置區13制以定位特定尺寸之缝，因此抽離口 u 之孔輕必須針對檢體大小而設置’常見檢體之尺寸大小詳見附件]，最常 用以檢測人體疾病之檢體包括：肝細胞、紅血球及細菌，其大小介於 ⑽-1·(微米尺寸）’因此，如欲針對此種細胞進行檢測，則本創 1261620 作之柚離口mi徑大小必須小於100_，如要檢測更大（植物細胞')或更 小（病毒'蛋白質或DNA等奈米尺寸）之檢體，只需更改抽離口 12之孔 徑大小，即可將特定檢體定位於容置區13内，至於尺寸更小之雜質或水， 則會由容置區13下方抽離口 12被析離。 ' 惟以上所述者，僅為本發明之較佳實施例而已，當不能以之限定本發 明貫施之範圍，即大凡依本發明申請專利範圍所作之均等變化與修飾，皆 應仍屬本發明專利涵蓋之範圍内。 1261620 【圖式簡單說明】 第1圖，係本發明之製造流程示意圖 第2-1圖，係本發明之外觀立體示意圖 第2-2圖，第2-1圖之局部放大斷面示意圖 第3圖，係本發明之實施例示意圖 第4圖，係本發明之實施例斷面示意圖 附件一，係常見檢體之尺寸分佈圖 【主要元件符號說明】 定義檢體容置空間...............1= ideal condition is black array (10) core wall), through the low reflectivity of chrome, minus the detection error of U; U after the passivation layer 'for the blunt _4 occupation, resulting in detection:, the detection layer 4 The detection layer 15 is deposited as a biocompatible polymer in the purification layer μ 2 , and the biocompatible polymer is poly(p-diphenylene) ((4). (4) (10) in De νί匕 (150〇C It is formed by deposition after the process of cracking (650 〇c). The advantage of the polyethylene terephthalate is that the coating is good, and the lower passivation layer 14 can be completely isolated. Please refer to "Fig. 3, 4" for a schematic view of an embodiment of the present invention, as shown in the figure: The heart can be assembled on a pedestal 2, which includes a niche for biometric detection. The area 21 and the extraction channel 22 located below the positioning area 21 and connected to both sides of the fruit pump (not shown) are used, and the biodetection wafer 1 is placed on the pedestal such as the positioning area, The fine extraction contact 2 (four) is connected to the pump, and the detection system configuration is completed at this time. When the inspection is performed, the sample solution is dripped into the biodetection crystal (4), and then the pump is used to pump the sample solution. And the water is discharged by the lower _ port 12 and the detachment channel _, and at the same time, because of the poor force provided by Lipu, the sample can be more stably fixed in the bio-detection chip 2 of the valley area 13 (please refer to the details) Guanxianpu's each specimen is positioned in each housing area 13 for subsequent testing. Since the accommodating area 13 of the present invention is configured to position a slit of a specific size, the hole of the detaching port u must be set for the size of the sample, and the size of the common sample is detailed in the attachment, which is most commonly used to detect human diseases. The specimens include: hepatocytes, red blood cells and bacteria, and their size ranges from (10)-1·(micron size). Therefore, if the cells are to be tested for this type of cells, the size of the pomelo mi path must be smaller than that of the original 1261620. 100_, if you want to detect a larger (plant cell') or smaller (virus size of the protein or DNA, etc.), simply change the pore size of the extraction port 12 to position the specific sample. In the region 13, as for the smaller size impurities or water, the separator 12 is separated from the lower portion of the accommodating portion 13. The above is only the preferred embodiment of the present invention, and the scope of the present invention is not limited thereto, that is, the equal variation and modification of the patent application scope of the present invention should still belong to the present invention. Within the scope of the invention patent. 1261620 [Simplified Schematic Description] Fig. 1 is a schematic view of a manufacturing process of the present invention, and is a perspective view of a second embodiment of the present invention. Figure 4 is a schematic view of an embodiment of the present invention, which is a schematic sectional view of an embodiment of the present invention, which is a size distribution diagram of a common sample [Description of main component symbols] Defining a sample housing space. ..........1
切割非檢體抽離口...............2 包覆鈍化層..................3 彼覆檢測層..................4 生物檢測晶片.................10 滴入口....................11 抽離π....................12 容置區....................13 鈍4匕層....................14 檢測層....................15 .....................20Cutting non-sample body extraction port..................2 Coating passivation layer..................3 ..................4 Bio-detection wafers.................10 drop inlets........ ............11 抽。π....................12 容区.......... ..........13 blunt 4 layers..................14 detection layer............ ........15 .....................20
定位區....................21 抽离隹通道...................22Positioning area....................21 抽 隹 channel........................22