TW555972B - The method and apparatus of optical heterodyne surface plasma wave measuring system - Google Patents

The method and apparatus of optical heterodyne surface plasma wave measuring system Download PDF

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TW555972B
TW555972B TW90112140A TW90112140A TW555972B TW 555972 B TW555972 B TW 555972B TW 90112140 A TW90112140 A TW 90112140A TW 90112140 A TW90112140 A TW 90112140A TW 555972 B TW555972 B TW 555972B
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wave
polarized
frequency
heterodyne interference
laser
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TW90112140A
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Chinese (zh)
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Cheng Jou
Wen-Jiuan Guo
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Cheng Jou
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Abstract

The present invention relates to a method and an apparatus of optical heterodyne surface plasma wave measuring system which uses a dual frequency linear polarized steady-frequency laser to generate two surface plasma waves simultaneously on the interface of a metal film, and measures the amplitude of the reflected heterodyne interference optical signal to measure in real-time the data such as interactions between the biological and chemical material molecules, reaction rate, reaction dynamics thereof etc. The invented method and device have a high detection sensitivity and a larger linear detection range.

Description

經濟部智慧財產局員工消費合作社印製 555972 A7 -- ---—— ___B7 五、發明制(/) - 一 傳統上經由一些免疫分析法(ELISA〇rRIA)檢測病原體細菌或病 毒至少需要三天,它必須經過清洗反應_清洗等步驟方可完成,如果 利用光纖生物感測1!,雖然可大大縮短檢驗的時間,然而還需要標該 螢光物質方可執行,而且在螢光制錄度上有其關,目前最新的 方法是利用表面電聚波共振方法(Surface Plasma SpR可 同時擁有快速檢驗而且不需使用螢光物標誌的優點。表面電漿波 (SurfacePlasmaWave)SPW是”在金屬表面同步震盪的電磁波”,而表 面電漿共振現象的發生原理是藉由稜鏡或其他不同的光學耦合 (optical coupling)架構使入射之P偏極化光(TM wave)在平行於金屬薄 膜界面的方向之傳播常數kx與表面電漿波的傳播常數ksp相同,而滿 足共振的條件:kx= kgsine = ksp,其中 kg= [ω/ς^ε())1/2 , ksp=[co/C](W2/(Sr^2))1/2,ω為入射雷射光頻率,而ε〇,^&分別為 稜鏡、金屬膜和被測試介質的介電常數,此時產生於金屬膜和附著在 金屬膜上之介電質的界面會產生表面電漿波並同時將入射光能量帶 走,因此造成反射光的強度下降,如第一圖。而藉由债測因為介電常 數的改變或折射率的改變所產生共振角度的平移或是固定雷射光人 射角而量測反射光強度的變化(如第二圖),而可求得如折射率改變等 物理量。以上兩種方法已廣泛地被採用於生物醫學或化學物質的快速 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) (請先閱讀背面之注意事項再填寫本買)Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 555972 A7-------- ___B7 V. Inventive System (/)-One traditionally requires some three days to detect pathogenic bacteria or viruses through some immunoassays (ELISA0rRIA) , It must be completed by washing reaction_cleaning and other steps. If fiber optic biosensor 1! Is used, although the inspection time can be greatly shortened, it is also necessary to mark the fluorescent substance before it can be performed. The point is that the latest method is to use the surface electric wave resonance method (Surface Plasma SpR can also have the advantages of fast inspection and no need to use fluorescent signs. Surface Plasma Wave SPW is "on the metal surface "Synchronous oscillating electromagnetic waves", and the principle of the surface plasma resonance phenomenon is that the incident P-polarized light (TM wave) is parallel to the interface of the metal thin film by chirped or other different optical coupling structures. The propagation constant kx in the direction is the same as the propagation constant ksp of the surface plasma wave, and the resonance condition is satisfied: kx = kgsine = ksp, where kg = [ω / ς ^ ε ()) 1/2, ksp = [co / C] (W2 / (Sr ^ 2)) 1/2, ω is the frequency of the incident laser light, and ε〇, ^ & are the dielectric constants of 稜鏡, the metal film, and the tested medium, respectively. At the time, the interface between the metal film and the dielectric substance attached to the metal film will generate surface plasma waves and take away the incident light energy at the same time, thus causing the intensity of the reflected light to decrease, as shown in the first figure. By measuring the change of the reflected light intensity (such as the second picture) by measuring the shift of the resonance angle due to the change of the dielectric constant or the change of the refractive index or the fixed angle of the laser light (as shown in the second figure), it can be obtained as Refractive index and other physical quantities. The above two methods have been widely used for rapid biomedical or chemical substances. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling in this purchase)

555972 A7 ________B7 五、發明説明(>) 檢驗中,然而該種方法不論利用反射光強度的變化或共振角發生位置 之、炎化來彳貞測物理|,在靈敏度上都有一定的限制。本發明則提供一 種新的外差干涉表面電漿波感測裝置及方法,採用雙頻率相互垂直 (orthogonal)線偏極化雷射,例如Zeeman雷射在金屬膜等界面上產生 兩個表面電漿波,利用量測產生表面電漿波之p偏極化反射波(^波 +P2波)的外差干涉信號的振幅大小變化,取代傳統上以量測共振角的 位置或單一反射P波的強度變化等方法(如第三圖),本發明裝置及方 法偵測靈敏度可大幅提高並可即時量測被測試分子間的交互作用,例 如結合(association),解離(diSS0Ciati0n)速率和濃度(c〇ncentmti〇n)等功 月b ’同時亦可發展成為化學及生物感知器(sens〇r)或其他應用。 第四圖表面電漿波稜鏡光學組件中玻璃基板(glass based plate)(53)表面蒸鍍金(au)或銀(Ag)等金屬薄膜,厚度約sonm,其中 光折射率匹配溶液(indexmatchingoil)(52)的目的在結合稜鏡(5〇與玻 璃基板(53)使其折射率相同,金屬膜及其表面上鍍一層化學薄膜(54) 並和具有相同特性之分子結合產生交互作用。在反應器(58)中而形成 分子結合體(57)。表面電漿波因受到金屬薄膜表面所附著分子結合體 例如抗原抗體之結合體(57)而造成光折射率的變化,而使得反射的& 波和P2波所產生的外差干涉信號的振幅改變,再利用鎖相放大器或 相關之振幅解調裝置可即時量測振幅大小以達到即時偵測相關的物 本紙張尺度適用中國國家標準(CNS) A4規格(210x297公釐) (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 丨裝·--^----訂 "--Γ.---線------ I 1· 555972 A7 B7555972 A7 ________B7 V. Description of the invention (>) In the test, however, whether this method uses the change of the reflected light intensity or the inflammation at the position of the resonance angle to determine the physical measurement, there are certain limitations in sensitivity. The invention provides a new heterodyne interference surface plasma wave sensing device and method, which adopts dual-frequency orthogonal polarized lasers. For example, Zeeman laser generates two surface currents on the interface of a metal film. Plasma waves, the amplitude of the heterodyne interference signal of the p-polarized reflected wave (^ wave + P2 wave) generated by the measurement of the surface plasma wave is measured to replace the traditionally measured position of the resonance angle or a single reflected P wave (Such as the third picture), the detection sensitivity of the device and method of the present invention can be greatly improved, and the interaction between the tested molecules can be measured in real time, such as association, diSS0Ciati0n rate and concentration ( c〇ncentmti〇n) and other work months b 'can also develop into chemical and biological sensors (sensor) or other applications. In the fourth figure, a metal film such as gold (au) or silver (Ag) is vapor-deposited on the surface of a glass based plate (53) in a plasma plasma wave optical component, and the thickness is about sonm, in which the index matching oil (index matching oil) The purpose of (52) is to combine rhenium (50) with the same refractive index as the glass substrate (53), to coat a metal film and its surface with a chemical film (54), and to interact with molecules with the same characteristics. A molecular conjugate (57) is formed in the reactor (58). The surface plasma wave is caused by the change in the refractive index of the light caused by the molecular conjugates such as the antigen-antibody conjugate (57) attached to the surface of the metal thin film, which makes the reflected & The amplitude of the heterodyne interference signal generated by the & P2 wave is changed, and then a lock-in amplifier or related amplitude demodulation device can be used to measure the amplitude in real time to achieve the real-time detection of related objects. (CNS) A4 size (210x297 mm) (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs --- line ------ I 1555555 A7 B7

R=(l/V2) Ape'V 五、發明説明(多/ 理量及其隨時間的變化 本發明提出-種創新的外差干涉表面電漿波感測裝置及方 法’所提出的光學架構如第五圖,採用的光源為一雙頻率相互垂直線 偏極化翻雷射,例如Zeeman ⑽,錄雷射輸減束為互相垂 直的線偏極光(P波和s波),其振幅和頻率分別為 (ΑΡ,ωρ)和(As,6;s)。其後放置一又/2玻片(2〇),可將雷射輸出的p波 和S波偏極化光旋轉角度,使得p波平行χ軸可表示成 APe1<yptU ],同時S波平行γ軸表示成[丨當ρ波及s波同 時入射至一;1/4玻片(30)後,P波和S波轉換成一個右旋(只波)及 一個左旋(L波)的圓偏極化光,它可表示成: and L=(l/V^") A产 經由P偏極化片(40),使得R波和L波的p波分量通過極化片(4〇), 而產生雙頻率的Pi波和P2波,並可分別寫成[丨]eiWpt和 (1Λ/?)ΑΑ ]e“t,再經分光片(50)將光束分成兩束,其中信號光東 入射至表面電漿波棱鏡光學組件(6〇),旋轉稜鏡光學組件使得雷射光 入射角度改變,當入射角等於表面電漿共振角度時,不同頻率且相互 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) I---------^----訂—[---線 (請先閲讀背面之注意事項再填寫本頁} 經濟部智慧財產局員工消費合作社印製 555972 A7 ____ B7_ 五、發明説明(厶) ----------^φ — (請先閲讀背面之注意事項再填寫本頁) 關連(correlate)^ 波和P2波同時分別在金屬薄膜界面上產生表面電 漿波,因而同時有兩個表面電漿波在金屬薄膜上傳播,而Pi波和P2 波的反射光被偵測器(70)接收後產生外差干涉信號,其差頻為 Δω=ωρ-ω8 。信號光外差干涉信號可表示成 Ι^(Δωί) = l/2(Ap,)2+l/2(As,)2+Ap,As’cos (Δωί + ΔΦ’) ------(1) 其中Δφ’=φΡι’-φρ2’。(Ap’,As’)及(φΡι,,φΡ2,)為反射信號光p1 波和 P2波之振幅及相位,在通過以Δω為中心頻率的帶通濾波器(80)過濾 後,濾出的交流信號可寫成R = (l / V2) Ape'V V. Description of the invention (multiple / physical quantities and their changes over time) The present invention proposes an innovative heterodyne interference surface plasma wave sensing device and method 'Proposed optical architecture As shown in the fifth figure, the light source used is a double-frequency mutually polarized line-turned polarized laser. For example, Zeeman ⑽, the laser transmission reduction beam is a line-polarized aurora (P wave and s wave) perpendicular to each other. The frequencies are (Ap, ωρ) and (As, 6; s). Then placing another / 2 slides (20), the p-wave and S-wave polarized light output by the laser can be rotated by the angle, so that The p-wave parallel x-axis can be expressed as APe1 < yptU], and the S-wave parallel γ-axis is expressed as [丨 when ρ wave and s wave are incident on one at the same time; after 1/4 slide (30), P wave and S wave are converted into A right-handed (only wave) and a left-handed (L wave) circularly polarized light, which can be expressed as: and L = (l / V ^ ") A product passes through the P polarizing plate (40), so that The p-wave components of the R wave and the L wave pass through the polarizing plate (4) to generate Pi waves and P2 waves of dual frequencies, which can be written as [丨] eiWpt and (1Λ /?) ΑΑ] e "t, then The beam is split into two beams by a beam splitter (50), where No. East light is incident on the surface plasma wave prism optical component (60). Rotating the chirped optical component changes the incident angle of the laser light. When the angle of incidence is equal to the surface plasma resonance angle, different frequencies and mutual dimensions of this paper are applicable to China. Standard (CNS) A4 Specification (210X297 mm) I --------- ^ ---- Order — [--- Line (Please read the precautions on the back before filling this page) Intellectual Property of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives 555972 A7 ____ B7_ V. Description of Invention (厶) ---------- ^ φ — (Please read the notes on the back before filling this page) Correlate ^ Bohe The P2 wave generates surface plasma waves at the metal film interface at the same time, so two surface plasma waves propagate on the metal film at the same time, and the reflected light of the Pi wave and P2 wave is received by the detector (70) to generate external waves. Differential interference signal, the difference frequency is Δω = ωρ-ω8. The signal optical heterodyne interference signal can be expressed as ^ (Δωί) = l / 2 (Ap,) 2 + l / 2 (As,) 2 + Ap, As 'cos (Δωί + ΔΦ') ------ (1) where Δφ '= φΡι'-φρ2'. (Ap ', As') and (φΡι, φΡ2,) are reflected signal light p The amplitude and phase of 1 wave and P2 wave are filtered by a band-pass filter (80) with Δω as the center frequency, and the filtered AC signal can be written as

Isig(Aiyt) = Ap’As’cos (Δωί + ΔΦ’) ______(2) 並將Isig(Aan)輸入到鎖相放大器(90)作處理。同理,分光鏡(50)所反射 出的參考光束由光偵測器(71)接收,所得到的參考光外差干涉信號為 Iref(AiL)t)= l/2Ap2+l/2As2 +Ap As cos (Δωΐ + ΔΦ) ------(3) 經濟部智慧財產局員工消費合作社印製 其中ΔΦ = ΦΡγΦΡ2。(φΡι,φρ2)分別為參考光束的Pl波和P2波之相 位。經帶通濾波器(81)過濾,所濾出的參考光交流信號可寫成 Iref(A6;t) = Ap As cos (Δωί + ΔΦ) ------(4) 也同樣送入鎖相放大器(90)。如此,鎖相放大器會根據參考光信號的 頻率Δω,偵測並放大信號光之訊號,而大幅提高了信雜比(SNR)及 靈敏度。最後由電腦(91)記讀及計算,可即時測得外差干涉信號之振 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) 555972 A7 五、發明説明(Γ ) 幅(AP’AS’)的大小及相位ΔΦ’隨時間變化量,而能即時反應出待測之 化學或生物分子與感應片之間的交互作用關係。 (請先閲讀背面之注意事項再填寫本頁) 第六圖已完成實驗中IgG抗體固定於感應片(BIAcore,CM5 chip)表面 的過程,第七圖則是固定在感應片表面的IgG抗體與待測樣品中之 anti-IgG(約l〇〇ng/ml)相互結合之即時反應數據。第七圖為不同濃度之 待測物所得訊號關係數據(25ng/ml or 0·2ηΜ)。由實驗結果可證實本發 月裝置及方法的债測靈敏度以及其較大的線性量測範圍較傳統方法 大幅提高至50倍。 線泰 經濟部智慧財產局員工消費合作社印製 本發明專利如使用振幅解調裝置例如Digital volt meter(DVM)來量取 外差干涉信號之振幅大小,則本發明專利外差干涉表面電漿波感測裝 置及方法可以轉換成為多通道感測系統(如第九圖),其中雙頻率線偏 極化雷射光(100)經極化組件(11〇)產生雙頻率ρι波和P2波雷射光 束,柱狀透鏡(120)將雷射光擴束且平行可同時入射至表面電漿波棱 鏡光學組件(130)中,再經由一維陣列光偵檢器(14〇)和帶通濾波裝置 (150) ’振幅解調裝置(160),個人電腦(17〇)而達到多通道檢測的功能。 綜上所述本發明之外差干涉表面電漿波感測裝置和方法確能藉 上揭之構造將以往以量測反射光強度的方法轉換成以雙頻率線偏極 化雷射光和外差干涉式並量測振幅信號大小,無論在偵測靈敏度以及 有效量測範圍均大幅提高,本發明係一開創性發明符合發明專利之新 555972 A7 ______B7 五、發明説明(厶) - 穎進步要件,惟上揭圖示及說明僅為了解本發明實施例而已,為非為 限定本發明之實施,凡熟_項醜人士依本發明特徵細因素所作 之其他等效變化或修飾皆應涵蓋在以下本等之申請專利範圍内。 本發明專利具有下列幾項優點: 1·外差干涉式表面電漿波感測裝置之光學架構簡單。 2·高靈敏度及較大的線性範圍: 因傳統上測量單一入射角度反射光強度的方法比測量共振角度 平移變化的方法靈敏度高,再加上本發明以量測外差干涉信號的 振幅而非強度信號更增加了偵測靈敏度,同時偵測之線性範圍也 較大。 3·因合併外差干涉及鎖相放大的技術,信雜比大幅提高。 4· 一般振幅的量測易受雷射強度不穩定的影響,本發明架構亦可同 時量測信號光束之外差干涉信號及參考光束之外差干涉信號的振幅 大小比值/=(AP’AS,/APAS),可大幅降低雷射光強度不穩定的影響, 提南靈敏度。 5·本發明不需標Ί志螢光物質,不但使檢驗過程快速而且簡單化,且因 是屬於即時性的偵測,可對分子間相互作用過程中的動態變化做即時 測量。 本紙張尺度適用中國國家標準(CNS ) Μ規格(210χ297公釐) -----------— (請先閲讀背面之注意事項再填寫本頁) 訂- 線 經濟部智慧財產局員工消費合作社印製 555972 A7 B7 五、發明説明(7 ) 6.本發明可發展成多通道外差干涉表面電漿波感測系統 ----------#—.----?τ---------00 (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) 555972 A9 B9 C9 D9 圖式’ 第一圖稜鏡表面電漿波產生說明圖 第二圖強度反射率R和入射角度0關係說明 第三圖稜鏡雙表面電漿波(Pi波+?2波)產生說明 第四圖表面電漿波稜鏡光學組件圖 第五圖新型外差干涉式表面電漿波感測裝置及方法圖 第六圖生物分子固定化過程(IgG濃度為38pg/ml) 第七圖anti-IgG與IgG分子作用情形 第八圖(a)各濃度對應飽和訊號的結果 (b)將(a)圖轉換成對數座標 第九圖多通道外差干涉表面電漿波感測系統 (請先閲讀背面之注意事項再行繪製) 經濟部智慧財產局g(工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 555972Isig (Aiyt) = Ap’As’cos (Δωί + ΔΦ ’) ______ (2) and input Isig (Aan) to the lock-in amplifier (90) for processing. Similarly, the reference beam reflected by the beam splitter (50) is received by the light detector (71), and the obtained reference light heterodyne interference signal is Iref (AiL) t) = l / 2Ap2 + l / 2As2 + Ap As cos (Δωΐ + ΔΦ) ------ (3) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs where ΔΦ = ΦΡγΦΡ2. (ΦPi, φρ2) are the phases of the Pl wave and the P2 wave of the reference beam, respectively. After being filtered by the band-pass filter (81), the filtered reference optical AC signal can be written as Iref (A6; t) = Ap As cos (Δωί + ΔΦ) ------ (4) is also sent to the phase lock Amplifier (90). In this way, the lock-in amplifier will detect and amplify the signal of the signal light according to the frequency Δω of the reference optical signal, thereby greatly improving the signal-to-noise ratio (SNR) and sensitivity. Finally, it is recorded and calculated by the computer (91), and the vibration of the heterodyne interference signal can be measured in real time. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 555972 A7 V. Description of the invention (Γ) Amplitude (AP) The magnitude and phase ΔΦ 'of the' AS ') change with time, and can instantly reflect the interaction between the chemical or biological molecule to be measured and the sensor sheet. (Please read the precautions on the back before filling out this page) Figure 6 has completed the process of IgG antibody immobilized on the surface of the sensor chip (BIAcore, CM5 chip) in the experiment, and Figure 7 is the IgG antibody and Instant response data of anti-IgG (about 100 ng / ml) bound to each other in the test sample. The seventh graph is the signal relationship data (25ng / ml or 0 · 2ηΜ) obtained from the analytes at different concentrations. From the experimental results, it can be confirmed that the debt measurement sensitivity and the large linear measurement range of the device and method of this month have been greatly improved by 50 times compared with the traditional method. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs. If an amplitude demodulation device such as Digital volt meter (DVM) is used to measure the amplitude of the heterodyne interference signal, the patented heterodyne interference surface plasma wave The sensing device and method can be converted into a multi-channel sensing system (as shown in the ninth figure), in which a dual-frequency line-polarized laser light (100) passes through a polarization component (11) to generate a dual-frequency ρ wave and a P2 wave laser The light beam, the lenticular lens (120) expands the laser light in parallel and can be incident simultaneously into the surface plasma wave prism optical component (130), and then passes through a one-dimensional array light detector (14) and a band-pass filter device ( 150) 'Amplitude demodulation device (160), personal computer (170) and multi-channel detection function. In summary, the heterodyne interference surface plasma wave sensing device and method of the present invention can indeed convert the conventional method for measuring the intensity of reflected light into a dual-frequency line polarized laser light and heterodyne through the structure of the above disclosure. Interferometric measurement of the amplitude signal greatly improves both the detection sensitivity and the effective measurement range. The invention is a groundbreaking invention that conforms to the new invention patent 555972 A7 ______B7 5. Description of the invention (厶)-Requirements for Ying progress, However, the above-mentioned illustrations and descriptions are only for understanding the embodiments of the present invention, and are not intended to limit the implementation of the present invention. Any other equivalent changes or modifications made by those skilled in the art based on the characteristics of the present invention should be covered in the following. Within the scope of the patent application. The invention patent has the following advantages: 1. The optical structure of the heterodyne interference surface plasma wave sensing device is simple. 2. High sensitivity and large linear range: Because the traditional method of measuring the intensity of reflected light at a single incident angle is more sensitive than the method of measuring the translational change of the resonance angle, plus the present invention measures the amplitude of the heterodyne interference signal instead of The intensity signal further increases the detection sensitivity, and at the same time, the detection linear range is larger. 3. Since the combined heterodyne technique involves phase-locked amplification, the signal-to-noise ratio is greatly improved. 4. The measurement of general amplitude is susceptible to the instability of the laser intensity. The structure of the present invention can also measure the amplitude ratio of the heterodyne interference signal of the signal beam and the heterodyne interference signal of the reference beam / = (AP'AS , / APAS), can greatly reduce the influence of laser light intensity instability, and improve the sensitivity of the South. 5. The present invention does not need to label fluorescent materials, which not only makes the test process fast and simple, but also because it is an instantaneous detection, it can make real-time measurement of the dynamic changes in the process of intermolecular interaction. This paper size applies the Chinese National Standard (CNS) M specification (210 x 297 mm) ------------- (Please read the notes on the back before filling this page) Order-Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the employee consumer cooperative 555972 A7 B7 V. Description of the invention (7) 6. The invention can be developed into a multi-channel heterodyne interference surface plasma wave sensing system ---------- # --.--- -? τ --------- 00 (Please read the notes on the back before filling out this page) Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is sized according to the Chinese National Standard (CNS) Α4 (210X297 (Mm) 555972 A9 B9 C9 D9 Schematic diagram 第一 First diagram 稜鏡 Surface plasma wave generation illustration diagram Second diagram Intensity reflectance R and incidence angle 0 Description Third diagram 稜鏡 Dual-surface plasma wave (Pi wave + (2 waves) Generation description The fourth figure is the surface plasma wave and the optical components. The fifth figure is the novel heterodyne interference surface plasma wave sensing device and method. The sixth figure is the biomolecule immobilization process (IgG concentration is 38pg / ml) Figure 7 Interaction between anti-IgG and IgG molecules Figure 8 (a) Result of saturation signal corresponding to each concentration (b) Turn (a) figure Logarithmic coordinates of the ninth figure Multi-channel heterodyne interference surface plasma wave sensing system (please read the precautions on the back before drawing) The Intellectual Property Bureau of the Ministry of Economyg CNS) A4 size (210X297 mm) 555972

ABCD 式 圖 第四圖符號元件說明: (51)棱鏡 (53)玻璃基板 (55)固定化分子 (57)結合分子 (52)折射率匹配溶液 (54)金屬薄膜 (56)待測分子 (58)反應器 經濟部智慧財產局a(工消費合作社印製 第五圖符號元件說明: (10)Zeeman線偏極化雷射光源 (20) λ/2 玻片 (30)又/4玻片 (40)極化片 (50)分光片 (60)稜鏡表面電漿波產生裝置 (70)(71)光偵檢器 (80)(81)帶通濾波器 (90) 鎖相放大器 (91) 個人電腦 本紙張尺度適用中國國家標準(CNS〉A4規格(210X297公釐〉 ---------峰丨:--------------^#1 (請先閲讀背面之注意事項再行繪製) 555972 A9 B9 C9 D9 圖式 第九圖符號元件說明: (100)雙頻率線偏極化雷射 (110)極化光學組件 (120)柱狀透鏡 (130)表面電漿波稜鏡光學組件 (140) 1-D陣列光偵檢器 (150)帶通率波裝置 (160)振幅解調裝置 (170)個人電腦 (請先閱讀背面之注意事項再行繪製) 經濟部智恶財產局員工消骨合作社印製 本纸張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)ABCD-style diagram The fourth figure symbol element description: (51) prism (53) glass substrate (55) immobilized molecule (57) binding molecule (52) refractive index matching solution (54) metal film (56) test molecule (58 ) The Intellectual Property Bureau of the Ministry of Economic Affairs a (The fifth figure printed by the Industrial and Consumer Cooperatives describes the symbol components: (10) Zeeman line polarized laser light source (20) λ / 2 glass (30) and / 4 glass ( 40) Polarizer (50) Beamsplitter (60) 稜鏡 Surface Plasma Wave Generator (70) (71) Light Detector (80) (81) Band Pass Filter (90) Phase-Locked Amplifier (91) The paper size of the personal computer applies the Chinese national standard (CNS> A4 specification (210X297mm) --------- Peak 丨: -------------- ^ # 1 (Please Read the precautions on the back before drawing) 555972 A9 B9 C9 D9 Figure 9th Symbol Symbol Description: (100) Dual-frequency line polarized laser (110) Polarized optical component (120) Cylindrical lens (130 ) Surface Plasma Wave 稜鏡 Optical Components (140) 1-D Array Light Detector (150) Band Passivity Wave Device (160) Amplitude Demodulation Device (170) Personal Computer (Please read the precautions on the back first (Drawing) Erasing and Cooperating with Employees of Intellectual Property Office, Ministry of Economic Affairs This paper printed scale applicable Chinese National Standard (CNS) A4 size (210X297 mm)

Claims (1)

551972^ ^ A8 B8 C8 D8 foil ^ίι( 申請專利範圍 經 部 智 慧 財 4. 局 消 費 合 作 社 印 製 1· 一種利用表面電漿波並結合外差干涉技術以量測化學或生物分 子交互作用的物理量之方法,該方法主要在界面產生表面電漿波時 測量兩相互同調關連(C〇rrelate)不同頻率之反射、Ρι偏振光和Ρ2 偏振光,所產生外差干涉信號的振幅變化來計算出待測的物理量, 該方法包括下列步驟: (1) 以一具有第一折射率的全反射裝置作為全反射用的基底,一 具有第二折射率且規範一定厚度的金屬薄膜,其緊靠於該全反射 裝置基底,同時在該金屬薄膜的另一面附著一化學或生物薄膜, 其中該第二折射率係低於該第一折射率; (2) 調整並校正入射雷射光的角度使得表面電漿波在該金屬薄膜 和該化學或生物薄膜界面上產生表面電漿波; (3) 採用雙頻率且相互垂直線偏極化(ρ偏振光和s偏振光雷射) 雷射,並經過一極化光元件組使得入射雷射光轉變成不同頻率且 相互同調關連之Pi偏振波和P2偏振波,卜和匕偏振雷射光經全反 射在金屬膜和化學薄臈界面上分別產生表面電漿波,其反射ρ/波 和&波產生外差干涉信號,其拍頻等於雙頻率之差頻; (4) 相同載波頻率之參考光束和信號光束之光干涉信號藉由帶通 遽波器過濾,並將外差干涉信號輸入到鎖相放大器或振幅解調裝 (請先閱讀背面之注意事項再填寫本頁) • 訂· • In tm 555972^ 4 部 智 慧 財 局 員 工 消 骨 合 作 社 印 製 A8 B8 C8 D8 六、申請專利範圍 置中’可即時量測外差干涉信號之振幅及相位變化 ;以及 (5)選擇適當入射角度(在表面電漿波產生之共振角附近)量取外 差干涉信紅振幅大小及其_相的變化量或她變化量。 2.根據申,月專利範圍第i項所述之方法,其中雙頻率相互關連卜波 和P2波線偏極化雷射光可由選擇自以下方法所組成的族群中而完 成: (1) 單頻率線偏極化雷射結合相位調制器,極化光之元件, Mach-Zehnder 干涉儀; (2) 單頻率線偏極化雷射結合固定驅動頻率之電光調變器; (3) 半導體雷射配合電流調制之電源供應器和極化光元件,組成 Mach-Zehnder 干涉儀; ⑷雙頻率同調相關之?1偏振光和Pa偏振光可利用單頻率線偏極化 半導體雷射配合極化保持單模光纖和積體光學元件,相位調制器 形成Mach-Zehnder干涉儀;以及 (5)雙頻率同調相關之R偏振光和pa偏振光亦可利用單頻率p波線 偏極雷射光配合相位調變裝置形成Michels〇n干涉儀。 3.根據申請專利範圍第1項所述之方法,其中雙頻率相互垂直線偏 極化雷射可由雙頻率相互垂直圓偏極化雷射光取代,裝置中極化光 兀件組為一 P偏振之極化片,可產生不同頻率之Ρι偏振光和朽偏振 (請先閱讀背面之注意事項再填寫本頁) 、1Τί tr // Lh I:— I - . · 555972551972 ^ ^ A8 B8 C8 D8 foil ^ ί ((Applicable patent scope, Ministry of Economics, Smart Property 4. Printed by Bureau of Consumer Cooperatives 1. A physical quantity using surface plasma waves combined with heterodyne interference technology to measure chemical or biomolecular interactions This method is mainly used to measure two coherent reflections (Correlate) at different frequencies when the plasma wave is generated at the interface. The two polarized light and P2 polarized light are measured. The method includes the following steps: (1) A total reflection device having a first refractive index is used as a substrate for total reflection, and a metal thin film having a second refractive index and having a certain thickness is close to the The substrate of the total reflection device, and at the same time a chemical or biological film is attached to the other side of the metal film, wherein the second refractive index is lower than the first refractive index; (2) adjusting and correcting the angle of the incident laser light so that the surface is plasma Waves generate surface plasmon waves at the interface between the metal film and the chemical or biological film; (3) Dual-frequency and mutually perpendicular linear polarization (ρ polarization) And s-polarized laser) The laser passes through a polarized light element group to make the incident laser light into Pi polarized wave and P2 polarized wave of different frequencies and coherently related to each other. The polarized laser light and the polarized laser light are totally reflected on the metal. Surface plasma waves are generated at the interface between the film and the chemical thin film, and the reflected ρ / wave and & wave generate heterodyne interference signals whose beat frequency is equal to the difference between the two frequencies; (4) Reference beams and signals of the same carrier frequency The optical interference signal of the beam is filtered by a bandpass chirp, and the heterodyne interference signal is input to a lock-in amplifier or amplitude demodulation device (please read the precautions on the back before filling this page) • Order · • In tm 555972 ^ A8 B8 C8 D8 printed by the bone-eliminating cooperative of the 4 employees of the Smart Finance Bureau VI. Patent application centered 'can measure the amplitude and phase change of heterodyne interference signal in real time; and (5) choose the appropriate incident angle (on the surface Near the resonance angle generated by the plasma wave), the amplitude of the heterodyne interference signal red and its phase change or her change are measured. 2. According to the method described in item i of the patent application, where the dual frequency Interrelated Bubo and P2 wave line polarized laser light can be achieved by selecting from the group consisting of: (1) single frequency line polarized laser combined with phase modulator, polarized light element, Mach-Zehnder Interferometer; (2) Single frequency line polarization laser combined with electro-optic modulator with fixed driving frequency; (3) Semiconductor laser with current modulation power supply and polarized light components to form Mach-Zehnder interferometer;之 Dual-frequency coherence correlation? 1 Polarized light and Pa-polarized light can use single-frequency linearly polarized semiconductor lasers with polarization to maintain single-mode fiber and integrated optical elements, and the phase modulator forms a Mach-Zehnder interferometer; and ( 5) Dual-frequency coherent R-polarized light and pa-polarized light can also be used to form a Michels On interferometer using a single-frequency p-wave polarized laser with a phase modulation device. 3. The method according to item 1 of the scope of the patent application, wherein the dual-frequency mutually perpendicular line-polarized laser can be replaced by the dual-frequency mutually perpendicular circularly-polarized laser light, and the polarized light element group in the device is a P-polarization Polarizing plate, which can produce Pl polarized light and decay polarized light of different frequencies (please read the precautions on the back before filling this page), 1Τ tr // Lh I: — I-. · 555972 ^申請專刹範圍 光0 經 A 部 智 % 財 4 消 合 作 钍 印 製 4.根射請專利第1項所述之方法,其中該全反《置可由光栅(咖㈣取代而產生表面電聚波,入射之雙頻率線偏極化雷射光 是先經過透光之被職薄膜再人射至金屬_而在其界面上產生表 面電漿波。 5·根射請專利細第丨項所述之方法,其中該物理量為待測物體 之折射率及其變化量。 6.根據申請專利範圍第i項所述之方法,其中該物理量為待測物體 分子間之結合(association)或解離(diss〇ciati〇n)反應速率及其 動力學。 7·根據_請專利範圍第丨_述之方法,可經由抗原抗體結合成為 生物感知器。 8·根據中請專鄕圍第丨項所述之方法,可經由化學侧成為化學 感知器。 9·根據申請專利範圍第1項所述之方法,可經由量取信號光束和參 考光束之外差干涉信號振幅大小的比值χ = («)/(〜〜)而提 高偵測靈敏度,以避免入射雷射光強度的不穩定。 10·根據申請專利範圍第1項所述之方法,其中外差干涉信號之振幅 大小可利用振幅解調裝置完成,可擴充成為多通道外差干涉表面電 (請先閲讀背面之注意事項再填寫本頁) -------參 .^---^ I t.--2i----------- 本纸張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) I m. -SB Α8 Β8 C8 D8 、申請專利範圍 漿波感測系統。 11.根據申請專利範圍帛1〇項所述之方法,其中多通道外差干涉信 號光束係由-維陣列光傭器所接收,並分別由振幅解調裝置即時 量測對應之外差干涉信號的振幅變化,該雙頻率線偏極化雷射光束 可利用柱形透鏡方式以達到多通道感測所需要的平行光束。 12·根據申請專利範圍第丨項所述之方法,更包含利用不同方法產生 雙頻率同調相關之Pl波和Ρ2波在金屬薄膜界面上產生表自電聚波和 其反射之!^波和Ρ2’波產生外差干涉信號及其振幅大小的測量方法。 13. 根據申請專利範圍帛10項所述之方法,其中多通道外差干涉信 號光束係由二維陣列光倾器所接收,並分別由振幅解調裝置即時 s測對應之外差干涉信號的振幅變化,該雙頻率線偏極化雷射光束 可利用雷射光透鏡組以賴多通道_所需要的平行光束。 14. 根腳請專利範圍第丨項所述之方法,其中該極化光元件組包括 λ/2玻片、λ/4玻片及極化片。 15. 根據申請專利細第丨項所述之方法,其中該雷射是日曼%獅η) 雷射。 16. 根據申請專利細第!項所述之方法,其中該全反射裝置係選擇 自稜鏡、光纖以及積體光學元件所組成的族群中。 17. -種·表面·波並齡外差干频_制化學或生物分 •----------1·1 (請先閲讀背面之注意事項再填寫本頁) 訂 經 A 部 智 慧 η ί 局 員 X 消 骨 合 作 社 印 製 本纸張尺度適用令國國各樣準(CNS ) Α4規格(210 X 297公慶) 5^ Application of special brake range light 0 Printed by the Ministry of Intellectual Property Co., Ltd. 4. Printing method according to item 1 of the patent, in which the total reflection can be replaced by a grating (cathode to generate surface electrocondensation). Waves, the incident dual-frequency line polarized laser light is first transmitted through a transparent film and then incident on the metal, and a surface plasma wave is generated at its interface. Method, wherein the physical quantity is the refractive index of the object to be measured and its change amount. 6. The method according to item i of the patent application scope, wherein the physical quantity is an association or diss 〇ciati〇n) The reaction rate and its kinetics. 7. According to the method described in the patent scope, it can be combined with an antigen-antibody to become a biosensor. 8. According to the method described in item 丨The method can become a chemical sensor through the chemical side. 9. According to the method described in the first item of the patent application range, the ratio of the amplitude of the signal beam and the reference beam heterodyne interference signal amplitude can be measured by χ = («) / ( ~~) while increasing detection sensitivity to avoid The intensity of the incident laser light is unstable. 10. According to the method described in the first item of the patent application range, wherein the amplitude of the heterodyne interference signal can be completed by using an amplitude demodulation device, which can be expanded into a multi-channel heterodyne interference surface electrical (please (Please read the precautions on the back before filling this page) ------- Ref. ^ --- ^ I t .-- 2i ----------- This paper size applies to Chinese national standards (CNS) A4 specification (210X297 mm) I m. -SB Α8 B8 C8 D8, patent-pending plasma wave sensing system. 11. According to the method described in item 10 of the patent scope, multi-channel heterodyne interference The signal beam is received by a -dimensional array optical servo, and the amplitude variation of the corresponding heterodyne interference signal is measured in real time by the amplitude demodulation device. The dual-frequency line-polarized laser beam can be formed using a cylindrical lens. Parallel beams required to achieve multi-channel sensing. 12. According to the method described in item 丨 of the patent application scope, it also includes the use of different methods to generate dual-frequency coherence-dependent Pl waves and P2 waves to generate self-electricity at the interface of the metal film. Condensed waves and their reflections! ^ Wave and P2 'wave The method of measuring the heterodyne interference signal and its amplitude. 13. According to the method described in 帛 10 of the scope of the patent application, the multi-channel heterodyne interference signal beam is received by the two-dimensional array optical tilter, and the amplitude is The demodulation device measures the amplitude variation of the corresponding heterodyne interference signal in real time. The dual-frequency line polarized laser beam can use the laser lens group to rely on the multi-channel_ parallel beams required. The method according to item 丨, wherein the polarized light element group comprises a λ / 2 glass plate, a λ / 4 glass plate and a polarizing plate. 15. The method according to item 丨 of the patent application, wherein the laser It is Riman% lion) laser. 16. According to the patent application details! The method according to the above item, wherein the total reflection device is selected from the group consisting of chirped fiber, optical fiber and integrated optical element. 17. -Species · Surface · Wave age heterodyne dry frequency _ Chemical or biological analysis • ---------- 1 · 1 (Please read the notes on the back before filling this page) Book A Ministry of Wisdom ί Bureaux X Bone Reduction Cooperative Co., Ltd. Printed on this paper. Applicable to national standards (CNS) Α4 specifications (210 X 297 public holidays) 5 經^部智慧財4局員工消費合作社印製 聲日修七 - V* - ί mxj\ 六、申請專利範圍 子交互侧的物理量之裝置,其主要在界面產生表面f驗時測量 兩相互同調關連(correlate)不同頻率之反射、h偏振光和p2偏振 光,所產生外差干涉信號的振幅變化來計算出待測的物理量,該裝 置包括: 一雷射光源,用於產生雷射光; 一極化光元件組,使得入射雷射光轉變成不同頻率且相互同調關 連之Pi偏振波和P2偏振波,Pi和P2偏振雷射光經全反射在金屬膜和 化學薄膜界面上分別產生表面電漿波,其反射Plf波和p2,波產生外差 干涉信號,其拍頻等於雙頻率之差頻; 一具有第一折射率的全反射裝置,一具有第二折射率且規範一定 厚度的金屬薄膜,其緊靠於該全反射裝置基底,以及一化學或生物薄 膜,其附著於該金屬薄膜的另一面;其中該第二折射率係低於該第一 折射率; 一角度調整裝置,用以調整並校正入射雷射光的角度,使得表面 電漿波在該金屬薄膜和該化學或生物薄膜界面上產生表面電激波; 一光偵檢器,分別用以將一參考光束及一信號光束轉換成外差干 涉信號; 一帶通濾波器,用於將參考光束的外差干涉信號及信號光束的外 差干涉信號過濾;以及 . 本纸法尺度適用令國國家榡準(CNS ) A4規格(2丨0X297公釐) 5炉5»卿曰谬工丨 ABl 1 補釗 g8s -** ::¾¾¾ 碎―‘丨丨】赞·T-r~~myrarrv, - -------- _ 丨· --------------- 六、申請專利範圍 一鎖相放大器或振幅調解裝置,可測量外差干涉信號之振幅及相 位變化。 18·根據申請專利範圍第17項所述之裝置,其中該極化光元件組包 括λ/2玻片、λ/4玻片及極化片。 19·根據申請專利範圍第17項所述之裝置,其中該雷射是曰曼 (Zeeman)雷射。 20.根據申請專利範圍第17項所述之裝置,其中該全反射裝置係選 擇自稜鏡、光纖以及積體光學元件所組成的族群中。 (請先閱讀背面之注意事項再填寫本頁) 經.4部智慧財4局員工消費合作社印製 本纸張尺度適用中國國家榡準(CNS ) A4说格(210X297公釐)Ministry of Wisdom 4th Bureau, Consumer Cooperatives, Printed Sounds, Day 7-V *-ί mxj \ 6. Applicants for a patent-scope sub-interaction-side physical quantity device, which mainly measures two coherent connections when the surface f test is generated on the interface (correlate) The reflection of different frequencies, h-polarized light and p2 polarized light, the amplitude variation of the heterodyne interference signal generated to calculate the physical quantity to be measured, the device includes: a laser light source for generating laser light; a pole The photochemical element group enables the incident laser light to be converted into Pi polarized waves and P2 polarized waves of different frequencies that are coherently related to each other. Pi and P2 polarized laser lights generate surface plasma waves at the interface of the metal film and the chemical thin film through total reflection, respectively. It reflects the Plf wave and p2, and the wave generates a heterodyne interference signal, whose beat frequency is equal to the difference between the two frequencies; a total reflection device with a first refractive index, a metal thin film with a second refractive index and a certain thickness, and Abutting on the substrate of the total reflection device, and a chemical or biological film, which is attached to the other side of the metal film; wherein the second refractive index is lower than the first refractive index An angle adjusting device is used to adjust and correct the angle of incident laser light, so that the surface plasma wave generates a surface electric shock wave at the interface between the metal thin film and the chemical or biological thin film; a light detector is used to separate a The reference beam and a signal beam are converted into a heterodyne interference signal; a band-pass filter is used to filter the heterodyne interference signal of the reference beam and the heterodyne interference signal of the signal beam; and (CNS) A4 specification (2 丨 0X297 mm) 5 furnaces 5 »Qing Yue absurdity 丨 ABl 1 Bu Zhao g8s-** :: ¾¾¾ Broken ― '丨 丨】 Zan · Tr ~~ myrarrv,----- ---- _ 丨 · --------------- 6. Scope of patent application: A lock-in amplifier or amplitude adjustment device can measure the amplitude and phase changes of heterodyne interference signals. 18. The device according to item 17 of the scope of the patent application, wherein the polarized light element group includes a λ / 2 glass plate, a λ / 4 glass plate, and a polarizing plate. 19. The device according to item 17 of the scope of patent application, wherein the laser is a Zeeman laser. 20. The device according to item 17 of the scope of patent application, wherein the total reflection device is selected from the group consisting of chirped fiber, optical fiber, and integrated optical element. (Please read the precautions on the back before filling out this page). Printed by the 4 Consumer Finance Cooperatives of 4 Bureau of Wisdom and Wealth. This paper size is applicable to China National Standards (CNS) A4 standard (210X297 mm).
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