TWI356167B - Signal detecting method for biochip - Google Patents

Signal detecting method for biochip Download PDF

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TWI356167B
TWI356167B TW96145957A TW96145957A TWI356167B TW I356167 B TWI356167 B TW I356167B TW 96145957 A TW96145957 A TW 96145957A TW 96145957 A TW96145957 A TW 96145957A TW I356167 B TWI356167 B TW I356167B
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matrix
signal
tested
detecting
biochip according
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TW96145957A
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TW200925603A (en
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Hsun Heng Tsai
Wei Hua Lu
Chyun Chau Fuh
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Univ Nat Pingtung Sci & Tech
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4 I 九、發明說明: 【發明所屬之技術領域】 本發明係關於一種生物晶片之#缺 A 號檢測方法,特別.是 晶片内不同 關於一種無需進行成份分離即可同時得到生物 成份信號之信號檢測方法。 【先前技術】 近年來由於生醫檢測技術不斷快速發展, 分析技術。在傳統上,該電泳分析 松測 速度較慢及效率低落的缺點, 由於必須使聽多樣品量’.故其具有檢 成本較高的缺點。 乂長及 :頌f職3電泳分析方法,如#射誘導 =Ced fl_S_e) ’在進行該分析時係利 =光染料樣品照射激發’使該帶f光染料樣品發4疒 接者,利用光偵測器偵測該帶營光染料樣品 完成螢光檢測。然而,雷射誘導t光法的 賴大型光學债測系統,如顯微鏡、 =均讀 系4統’且其檢測受到成份通過之形狀及心:::學 -般而言,大型光學偵測系統具有體 -、:甚大。 缺點。因此,雖然晶片已經達成微小化,作=^雜等 適用大型檢測系統的窘境。 彳—疋仍面臨其僅 然而’若欲將晶片電泳系統適#微小化 測機構整合在晶片上,其方可能達成進-步微小^須將檢 學檢測機構整合在晶片上, 化。將枣 可大_小科學檢測系 1356167 •、统的體積,且可獲得與大型檢測系統相近的檢測結果,作 料具有許錄制,例如絲檢_構必須另❹光源及 光感測益荨設備’雖然半導體製造技術可將該光源或光感 測器設備製作成-小型模組,但其仍然需要面臨系統整合 . _難的問題,且亦不可避免的面臨需要進行光搞合裎序 的問題。 再-習用生物晶片檢測方法储二分子探針分別附 著於-導電珠粒及固定在二電極之間隙中,並對該電極施 • 彳一電位差’藉由觀察該電極之電流增量;及該探針與一 待測目標物之間反應的專一性以作為偵測之基礎,藉此 行微量分子待測目標物之測定。 ㈣’上述制方法無論是光學或是電性進行檢 一測’仍具有不少缺點,其中,較大的缺點即是習用技術無 法在同-時間檢測多種成份’例如:若該待測目標物内^ 數種不同的成份時’該些習用方法必須將個別的成份經由 一成份分離的方法(如利用緩衝溶液稀釋)以將待測目標物 # ㊣行純化預處理’分離各個不同的成份後,再接著針^個 別成份逐-進行上述習用的檢測,因此其將造成檢測複雜 度之增加,進而造成檢測效,的低落及檢測精確度不足。 有鑑於此,本發明改良上述之缺點,藉由在生物晶片. - 找置數個制單元,崎對含有數種不同祕之待^液 - 體進行檢測,再藉由本發明之信號分析方法,將各成份之 信號分離,藉此同時得到不同成分之信號,而能確實提 檢測效率及檢測精確度。 —6 — 行鄉鮮,以㈣-估聰陣u,該估測 測液®2之一原始信號矩陣s,以便將 二參明較佳實施例之生物晶 〔S1〕步财,鱗測錢矩陣X如 待 ;車:與-混合矩陣一,該待测===4 I. Description of the Invention: [Technical Field] The present invention relates to a method for detecting a missing A number of a biochip, in particular, a signal in a wafer that simultaneously obtains a biological component signal without performing component separation. Detection method. [Prior Art] In recent years, due to the rapid development of biomedical detection technology, analysis technology. Traditionally, this electrophoresis analysis has the disadvantages of slower speed and low efficiency, and it has the disadvantage of having a high inspection cost because it has to make a large sample amount.乂长和:颂f job 3 electrophoresis analysis method, such as #射引化=Ced fl_S_e) 'When performing this analysis, the profit = light dye sample irradiation excitation' makes the f-light dye sample 4 splicer, using light The detector detects the sample of the camping light dye to complete the fluorescence detection. However, the laser-induced t-light method relies on large-scale optical debt measurement systems, such as microscopes, and the structure of the heart and the heart::: learning, in general, large optical detection systems Has a body -,: very large. Disadvantages. Therefore, although the wafer has been miniaturized, it is difficult to apply a large-scale detection system.彳 疋 疋 still faces it only. However, if the wafer electrophoresis system is to be integrated into the wafer, it may be possible to achieve further steps to integrate the inspection and inspection mechanism on the wafer. The jujube can be large _ small scientific testing department 1356167 •, the volume of the system, and the detection results similar to the large-scale detection system, the material has a record, such as silk inspection _ structure must be another light source and light sensory equipment Although the semiconductor manufacturing technology can make the light source or the light sensor device into a small module, it still needs to face the problem of system integration. _ difficult, and inevitably faces the problem of requiring light integration. Re-utilizing the biochip detection method, the two molecular probes are respectively attached to the -conductive beads and fixed in the gap between the two electrodes, and the potential difference is applied to the electrode by observing the current increment of the electrode; The specificity of the reaction between the probe and a target to be tested is used as a basis for detection, whereby the determination of the target molecule to be tested is performed. (4) 'The above-mentioned method, whether it is optical or electrical inspection, still has many shortcomings. Among them, the big disadvantage is that the conventional technology cannot detect multiple components at the same time. For example: if the target to be tested When several different components are used, 'these methods must separate the individual components by a component separation method (such as dilution with a buffer solution) to prepare the target to be tested for purification. Then, the individual components are subjected to the above-mentioned conventional detection, so that the detection complexity is increased, and the detection efficiency is lowered, and the detection accuracy is insufficient. In view of the above, the present invention improves the above-mentioned disadvantages, by detecting a plurality of units in a biochip, and detecting a liquid crystal containing a plurality of different secrets, and by the signal analysis method of the present invention, The signals of the components are separated, thereby simultaneously obtaining signals of different components, and the detection efficiency and the detection accuracy can be surely improved. —6 — 行乡鲜, to (4)- 聪聪阵u, the estimated original liquid matrix s of one of the measuring liquids®2, in order to take the biocrystals [S1] of the preferred embodiment of the two embodiments Matrix X is waiting; car: and - mixing matrix one, the test is to be ===

X = AS ⑴ ^〔 s 2〕步驟中,該置中處理即是將 各個獨立成份之信號處理獲得一平均值矩::虎^ 立成二均值矩陣m,使該待測信號矩陣X之沒 號矩“值為零;該白化處理技去除該待则In the step of X = AS (1) ^ [ s 2], the centering process is to obtain an average moment for the signal processing of each independent component:: tiger ^ establishes a two-mean matrix m, so that the signal matrix X of the signal to be tested is not numbered The moment "the value is zero; the whitening treatment removes the waiting

化了 Μ 成份之信號彼此_相關性,從W q獨立成份的提取過程6在〔S3〕步驟中,當上 成後,將待測信號矩陣x進行降階,;此' +間化_立祕分析料算的速度及複㈣。在 =’右該彳_#號矩衫料_方陣〔_麟 N仃維度〕,則可獲得一解 X,.; 右如寻,則㈣矩陣X非為 =’而疋Μ列維度大於N行維度,則f經過:, M列維度降為1^列維度後,再進行運算。 1 夕二二^2圖所*,本發日她佳實補之生物晶片 、:纏二方法之〔S4〕步驟係尋找—目標矩陣函數w 據w是_,魏斂之依據係根 T付之仏矩陣函數w Μ為該混合矩陣A之反矩陣 ^後Ά參照第2圖所示,本發雜佳實施例之, :片之信號檢測方法之〔S5〕步驟係將經由前處 待卿號轉X及™函數奶 車運#,以求得該估測矩陣u,The signal of the Μ component is _ correlation, and the extraction process from the W q independent component is in the [S3] step, and when it is formed, the signal matrix x to be measured is reduced, and this '+interval_ The speed of the analysis of the secret analysis and complex (four). In the = ' right 彳 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the row dimension, f passes:, and the M column dimension is reduced to 1^ column dimension, and then the operation is performed. 1 夕二二^2图*, on the date of her hair, the biochip, the method of the second method [S4] is searched for - the target matrix function w is based on w, and the basis of Wei is based on the root T The matrix function w Μ is the inverse matrix of the hybrid matrix A. Referring to FIG. 2, in the present embodiment, the [S5] step of the signal detection method of the slice will be processed via the front. No. X and TM function milk truck transport #, in order to obtain the estimation matrix u,

u = WX 4 (: 其中該估測矩陣u與該原始矩陣s具有下列關係 u%s (4) ’藉由本發明之上述步驟可針對該生物^之 體2進行有效率的檢測分析。 例夕巧參照第3至5圖所*,其揭林發明上述較佳實施 生物晶片之信號檢測方法之波形示意圖。如帛3⑻至 信圖所7F ’其絲*該待測賴2個賴立成份之原始 至4U Sl〜s3 ’該原'始信號sl〜s3為-未知的信號;如第4(a) (c)圖所示,其係表示該待測液體2 三個感測單元 個猫不同位置條件下〔如第1圖所示之位置〕所測得的三 立成份之信號xl〜x3。如第5(粗5⑷圖所示,藉由 述之獨立成份分析法可將 運算,以產生-組估測信號上成經由 與未知的原始信號sl〜s3進 、' "。號U1〜U3 信號ul的特徵相同於第 盾可知第5(a)圖的佑測 ul盥;圖的原始信號S3,即估測俨號 以的特徵相同於第3 :⑻圖的估挪信號 ,咖:第t⑷及第5(她 與原始信號Sl的波形與頻率相::::上:::信號U3 _各個估測信號ul〜u3與第3_飾==第5 si〜S3雖具有振幅不同的差異, ^4號 的處理,以使—估·Eul〜u3° 猎由正規化運算 的振幅一樣。 旧與對應的原始信號sI〜s3 ^ Tsjf此喊測單元3之數量選擇比該待刮⑼ =個成份數量為多時,或等於該待測液體2之=吸2 里,右在此條件下,糾上述之獨域份分 成份 該待騎體2 U個成份產生N個估·冬可對 ’藉此可針對該待·體2之财成份進行分^ ^ _ 假設該感測單元3之數量選擇少於該制 外, 份數量時,铁而,泣产以欠从 個成 主要的二:L 下,亦可針對該待測液體2 ,要的成W仃分析’可產生主要部分的估測信號 再者’若該待測液體2内具有干擾信號, 祕u = WX 4 (wherein the estimated matrix u has the following relationship u%s (4) with the original matrix s ' With the above steps of the present invention, an efficient detection analysis can be performed for the body 2 of the organism. Referring to Figures 3 to 5, it discloses a waveform diagram of the signal detecting method of the above-described preferred biochip. For example, 帛3(8) to 信图7F 'the wire* is to be measured by two ray components The original to 4U Sl~s3 'the original' initial signal sl~s3 is an -unknown signal; as shown in Fig. 4(a)(c), it indicates the liquid to be tested 2 three sensing units different cats The signal xl~x3 of the three components measured under the positional condition (as shown in Fig. 1). As shown in the fifth (thick 5 (4) diagram, the operation can be performed by the independent component analysis method to generate - The group estimated signal is passed through the unknown original signal sl~s3, ' ". The U1~U3 signal ul has the same characteristics as the first shield, and the original signal of the figure 5(a); S3, that is, the estimated nickname is the same as the estimated signal of the 3: (8) graph, coffee: t (4) and 5 (the waveform and frequency of her and the original signal Sl) ::::Up:::Signal U3_ Each estimated signal ul~u3 and 3__== 5th si~S3 Although there is a difference in amplitude, ^4 is processed to make -Eul~ U3° hunting is the same as the amplitude of the normalization operation. The old and corresponding original signals sI~s3 ^ Tsjf The number of the calling unit 3 is selected to be larger than the number of components to be scraped (9) = or equal to the liquid to be tested 2 = 吸 2, right under this condition, correct the above-mentioned unique domain component to the rider 2 U components to generate N estimates · winter can be 'to this for the body of the body 2 Subdivided ^ ^ _ Assume that the number of sensing units 3 is less than the number of parts, when the number of parts is iron, and that the product is owed to the main two: L, or for the liquid to be tested 2 The W仃 analysis 'can generate the main part of the estimated signal and then' if the liquid to be tested 2 has an interference signal, secret

發明之上述步驟進行檢測,以便分離出該干擾信Z 使該待測液體可進行更為精確的檢測。 另外,本發明之感測單元3並不限定僅作為量測電訊 號之用,事實上,該感測單元3可依據所欲量測的物理量 進行選擇’例如電訊號、磁訊號或光訊號等量測。 如上所述,相較於習用生物晶片檢測方法無法同時進 行數種成份之分析而具有檢測複雜度增加及檢測效率的低 落等缺點,本發明實施例之生物晶片之信號檢測方法,對 於待測液體2内含的數種混合成份所對應的錢同時進行 分析,其確實可提㈣麵分析、提冑制效率及降低檢 測成本 雖然本發明已利用上述較佳實施例揭示,熱其並非用 ^ 艮定本發明’任何熟f此技藝者在不脫離本i明之精神 和乾圍之内,相對上述實施例進行各種更動與修改仍 發明所賴之技術@此本發明之保護範圍當視 之申請專利範圍所界定者為準。 曰 【圖式簡單說明】 第1圖.本發明較佳實施例之生物晶片之信號檢測方法 應用於生物晶片之示意圖。 第2圖·本發明較佳實施例之生物晶片之信號檢測方法 之步驟流程圖。 /第3圖·本發明較佳實施例之生物晶片之信號檢測方法 之待測液體個_立成份之假設的原始信號S1〜S3波形示 意圖。The above steps of the invention are carried out to separate the interference signal Z so that the liquid to be tested can be more accurately detected. In addition, the sensing unit 3 of the present invention is not limited to use only as a measuring electrical signal. In fact, the sensing unit 3 can select according to the physical quantity to be measured, such as an electric signal, a magnetic signal or an optical signal. Measure. As described above, compared with the conventional biochip detection method, the analysis of several components cannot be performed at the same time, and the detection complexity is increased and the detection efficiency is low. The signal detection method of the biochip according to the embodiment of the present invention is for the liquid to be tested. 2 The money corresponding to several mixed components contained in the analysis is simultaneously analyzed, which can indeed provide (four) surface analysis, improve the efficiency of the extraction process and reduce the detection cost. Although the present invention has been disclosed by the above preferred embodiment, the heat is not used. The invention is not limited to the spirit and the scope of the present invention, and various modifications and modifications are made to the above-described embodiments. The scope of protection of the present invention is regarded as the scope of patent application. The definition is final. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram of a method for detecting a biochip according to a preferred embodiment of the present invention. Fig. 2 is a flow chart showing the steps of a signal detecting method for a biochip according to a preferred embodiment of the present invention. / Fig. 3 is a schematic diagram of the signal of the biochip according to the preferred embodiment of the present invention. The original signals S1 to S3 of the hypothetical liquid to be tested are shown.

第4圖:本發明較佳實施例之生物晶片之信號檢測方法 利用二個感測單元在不同位置條件下所測得的三個獨立成 份之#號xl〜x3波形示意圖。Fig. 4 is a diagram showing the signal detection method of the biochip according to the preferred embodiment of the present invention. The waveform diagram of the ##1 to x3 of the three independent components measured by the two sensing units under different positional conditions is used.

第5圖:本發明較佳實施例之生物晶片之信號檢測方法 產生的估測k號u 1〜u3波形示意圖。 【主要元件符號說明】 1 生物晶片 11 入液槽 12 出液槽 13 槽道 2 待測液體 3 感測單元 U 估測矩陣 X 待測信號矩陣 S 原始信號矩陣 W 目標函數矩陣 m 平均值矩陣 xl〜xN獨立成份信號 sl〜S3 原始信號 ul〜uN估測信號 —13 —Fig. 5 is a schematic view showing the waveform of the estimated k number u 1 to u3 generated by the signal detecting method of the biochip according to the preferred embodiment of the present invention. [Description of main component symbols] 1 Biochip 11 Inlet tank 12 Outlet tank 13 Channel 2 Liquid to be tested 3 Sensing unit U Estimation matrix X Signal matrix to be tested S Original signal matrix W Objective function matrix m Mean matrix xl ~xN independent component signal sl~S3 original signal ul~uN estimated signal—13 —

Claims (1)

、申請專利範圍: 卜-種生物晶片之信號檢·法 利用數個感測單元針對 3,驟· 體感洌,數種不同成份之一待測液 沒」以掏取出-待測信號矩陣; 將该待測信號矩陣進行前處管 待測信號矩障之平均值,:一:= ^去除該相信號轉的相關性; =則處理運异步驟之後將該待測信號矩陣進行降階 k擇目私函數矩陣,並將該目標函數矩陣運算至收 ;及 將、’二由剛處理運算及降階運算後的該待測信號矩陣及 收斂的目標函數矩陣進行矩陣運算,以得到一相同或近 似於原始信號矩陣之估測矩陣。 2、 依申請專利範圍第1項所述之生物晶片之信號檢測方法 ’其中該原始信號矩陣具有數個獨立的原始信號,各個 原始信號為該待測液體内不同成分之信號。 3、 依申請專利範圍第1或2項所述之生物晶片之信號檢測 方法’其中該待測信號矩陣具有數個待測的獨立成份之 "ί。说’且各個獨立成份之信被為非南斯分布。 4、 依申請專利範圍第1或2項所述之生物晶片之信號檢測 方法,其中該感測單元之數量比該待測液體之成份之數 量為多。 5、 依申請專利範圍第1或2項戶斤述之生物晶片之信號檢測 5=其切_單元之數量與該待職叙成份之數 6、=專利範圍第1或2項所述之生物晶狀信號檢測 Θ、/、巾該_單元之數量比該待職體之成份之數 置為少。 1明專利範圍第6項所述之生物晶片之信號檢測方法 ’其中該估測矩陣可分離出該數種不同成份之主要成分 之信號。 8'依申請專利範圍第1或2項所述之生物晶片之信號檢測 方法’其中該待測信號矩陣另包含一混合矩陣,該混合 矩陣與該原始信號矩陣進行矩陣運算以形成該待測信 號矩陣。 9、依申请專利範圍第$項所述之生物晶片之信號檢測方法 ’其中該目標矩陣函數與該混合矩陣互為反矩陣。 10、依申請專利範圍第丨或2項所述之生物晶片之信號檢測 方法,其中該生物晶片設有一入液槽,該感測單元設置 在接近該待測液體之入浪槽。Patent application scope: The signal detection method of the biological chip uses several sensing units for 3, sudden and somatosensory, and one of several different components to be tested is not taken out to extract the signal matrix to be tested; The matrix of the signal to be tested is subjected to an average value of the signal barrier of the signal to be tested in the front tube: one: = ^ removes the correlation of the signal transition of the phase; = the matrix of the signal to be tested is degraded after the step of processing the difference Selecting a private function matrix, and computing the objective function matrix to receive; and performing a matrix operation on the signal matrix to be tested and the convergence objective function matrix after the processing operation and the reduced order operation to obtain an identical Or approximate to the estimation matrix of the original signal matrix. 2. The method for detecting a biochip according to claim 1, wherein the original signal matrix has a plurality of independent original signals, and each of the original signals is a signal of a different component of the liquid to be tested. 3. A method for detecting a biochip according to claim 1 or 2 wherein the matrix of the signal to be tested has a plurality of independent components to be tested. The words of each individual component are distributed as non-Nuss. 4. The method of detecting a biochip according to claim 1 or 2, wherein the number of the sensing units is greater than the number of components of the liquid to be tested. 5. The signal detection of the biochip according to the first or second item of the patent application scope 5=the number of the unit_the number of the unit and the number of the component to be serviced, and the creatures mentioned in the first or second patent range The number of units of the crystalline signal detection Θ, /, towel is less than the number of components of the standby body. A method for detecting a biochip according to claim 6 wherein the estimation matrix separates signals of the main components of the plurality of different components. The method for detecting a biochip according to claim 1 or 2, wherein the signal matrix to be tested further comprises a mixing matrix, and the mixing matrix performs matrix operation on the original signal matrix to form the signal to be tested. matrix. 9. The method of detecting a biochip according to claim 10, wherein the target matrix function and the mixing matrix are inverse to each other. 10. The method for detecting a biochip according to the invention of claim 2 or 2, wherein the biochip is provided with a liquid inlet tank, and the sensing unit is disposed adjacent to the inlet tank of the liquid to be tested.
TW96145957A 2007-12-03 2007-12-03 Signal detecting method for biochip TWI356167B (en)

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