1245893 玖、發明說明： 【發明所屬之技術領域】 本發明係關於一種雙極化檢測之表面電漿共振生化感 測器，特別是指一種可使用TM和TE兩種極化光來進行檢 測，使單一元件可以檢測兩種生化物質，提高單一晶片檢測 生化物質數目之雙極化檢測之表面電漿共振生化感測器。 【先前技術】 1983年，B.Liedberg和C.Nylander等人將表面電漿共振（Surface Plasmon Resonance )原理應用於氣體成分檢測後，以表面電漿 共振為基礎之分析元件已被廣泛地應用在各類領域上，其優 點包含有： 1. 靈敏度（sensitivity)高。 2. 不需對檢測物作標定（label-free)。 3. 可做即時（real-time)快速的分析。 4. 免於外在環境之電磁場干擾。 5. 可整合於同一晶片上（on one chip)以達到大量平行篩檢 的目的。 應用表面電漿共振原理所製作的感測器，其結構包含 有：衰逝全反射（attenuated total reflection，ATR)、光波導（optical waveguide)、光纖（fiber)、光柵搞合器（grating coupler)等結構； 利用衰逝全反射的感測器，其結構主要組成包含有稜鏡層、 金屬層、空氣層，另依結構的不同還可分為Kretschmann組態 和Otto組態兩種，而較新的結構為waveguide-prism coupler的結 構，其結構在金屬層和空氣層間多了一層氧化層，其與傳統 上只有TM極化光能造成表面電漿共振的情形並不一樣，其 1245893 反射光強度不管是TM極化光或是TE極化光在某一角度範圍 内都會造成衰減，雖然ΤΜ極化光和ΤΕ極化光具有同樣衰減 的效果，但是在原理上並不相同。ΤΜ極化光在光強度上的吸 收’乃是由於表面電漿共振所造成，但是ΤΕ極化光之吸收， 則是由於當滿足某一範圍入射角時，ΤΕ極化光可在氧化層中 傳播’並且來回地反射於氧化層和金屬層之間的介面，光強 度也因此而衰減，值得注意的是，ΤΕ極化光之最大吸收所對 應之入射角’並不會因感測層之折射率變化而改變，除非當 整個感測器結構參數有所改變時（不包括感測層之折射率改 變）才會產生變化，因此輸入的ΤΕ極化光只能當作一參考 訊號。此一結構的最大優點在於只要ΤΕ極化光之最大吸收 所對應之入射角沒有偏移，則代表整個結構並沒有不同，而 此時造成ΤΜ極化光之共振角產生偏移的因素，就只有感測 層之折射率改變，如此一來，就可提升感測器中感測層之折 射率改變時，所量測到共振角產生偏移之可信度。 目刖使用光波導結構的各式感測器，其波導結構為條形 波導（strip waveguide)，只有顶極化光具有與表面垂直的電場 分量，可用於激發同樣具有與表面垂直之電場分量的表面電 漿波，因此可應用於化學或生化感測上。而TE極化光僅有 平行於介面之電場分量，無法激發出表面電漿波，所以無法 應用表面電漿共振原理，製作生化感測器。 由此可見，上述習用物品仍有諸多缺失，實非一良善之 設計者，而亟待加以改良。 本案發明人鑑於上述習用物品所衍生的各項缺點，乃亟 思加以改良創新，並經多年苦心孤詣潛心研究後，終於成功 1245893 研發完成本件雙極化檢測之表面電漿共振生化感測器。 【發明内容】 本發明之目的即在於提供一種隨著使用的檢測層不同， 可用於進行各種化學與生物物質檢測之雙極化檢測之表面 電漿共振生化感測器。 本發明之次一目的係在於提供一種單一晶片上可檢測 之生化物質數目加倍，可大幅提昇晶片檢測效能之雙極化檢 測之表面電漿共振生化感測器。 可達成上述發明目的之雙極化檢測之表面電漿共振生 化感測器，其結構係為—”分岔波導，輸出端波導製作成 脊形結構’其ϋ波導作為檢測用波導，另—輸出波導為 參考用波導，其輸w強度可用於正規化檢利波導之輸出 光強度值，防止因檢測光源強度變化，所造成表面電漿共振 波長之判讀誤差。其於量測時，可將任意極化方向光入射於 生化感測器上，在輸出端放置一極化器以作為分析器，藉由 選擇ΤΕ或ΤΜ極化光，即可決定所量測的信號是來自於哪一 極化光，所檢測的是哪一種生化物質，因此可於單一生化感 測器上量測兩種生化物質。應用此一新設計，可使得單一晶 片上量測的生化物質數目加倍，將可有效提升晶片之效能， 降低檢測成本。 【實施方式】 請參閱圖一所示，為本發明雙極化檢測之表面電漿共振 生化感測器之結構示意圖’其結構係為—γ形分岔波導，輸 出端波導製作成脊形結構’其—為檢測用波導，在表面覆^ 有金膜’並在其表面上自組裝人血清球蛋白，用以檢測乙型 1245893 阻斷劑，其係為一種治療心臟病之藥物；另一輸出波導為參 考用波導，其輸出光強度可用於正規化檢測用波導之輸出光 強度值，防止因檢測光源強度變化，所造成表面電漿共振波 長之判項誤差；其應用上係可將兩種生化物質的檢測層分別 覆蓋於脊形波導的上方與側面，當量測時，可將任意極化方 向光入射於生化感測器上，在輸出端放置一極化器以作為分 析器，藉由選擇TE或TM極化光，即可決定所量測的信號是 來自於哪一極化光，所檢測的是哪一種生化物質，因此可於 單一生化感測器上量測兩種生化物質，使其得以於單一晶片 上量測的生化物質數目加倍，將可有效提升晶片之效能，降 低檢測成本。除此之外，隨著使用的檢測層不同，在應用上 可以進行以下檢測，如藥物濃度檢測、藥物與血清球蛋白之 親和性檢測、化學成分檢測、環境污染物檢測。 請參閱圖二所示，為傳統表面電漿共振生化感測器之tm 與ΤΕ極化光之傳輸頻譜，由於產生表面電t共振之緣故， TM極化光的輸出光功率在波長49437nm上會有明顯的減少， 但對於TE極化光而纟，由於無法產生表面電聚共振，因此 在頻譜上並沒有出現輸出光功率明顯減少的情況。 凊參閱圖三所不，為傳統表面電漿共振生化感測器之tm 極化光的表面電漿共振波長隨乙型阻斷劑濃度之 形，當乙型阻斷劑濃度較低時，表面電漿共振波長會隨濃度 變化呈現線性增加之情形，其增加率為〇〇64nm/ppm，當濃度 增加超過200PPm時，表面電漿共振波長的增加量會減I，呈 現飽和之情形。這是由於此時大多數的人血清球蛋白已與乙 型阻斷劑產生連結，加入更多之乙型阻斷劑，並無法使已連 1245893 結之血清球蛋白與其產生作用，因此表面電漿共振波長增加 會有飽和的現象。 明參閱圖四所示，為本發明雙極化檢測之表面電漿共振 生化感測器的TM極化光之表面電漿共振波長隨乙型阻斷劑 濃度變化之情形，其中該插圖為其表面電漿共振傳輸頻譜， 所量測之乙型阻斷劑濃度範圍為〇?1)111至5〇〇ppm。當乙型阻斷 劑濃度增加時，表面電漿共振波長會有增加之情形，其線性 增加率為0.08nm/ppm，且最大吸收之光功率值有明顯的降低， 攻是由於當人血清球蛋白與乙型阻斷劑結合形成錯合物 時，彼覆在金膜表面之介質其介電常數會增加，而使表面電 漿共振波長產生明顯的紅位移；除此之外，由於波導中光場 之衰逝場增加，即延伸出披覆層之光場量增加，光傳輸損耗 臭大，使得光波導輸出之光強度下降，有利於辨識表面電漿 共振波長之位置。 請參閱圖五所示，為本發明雙極化檢測之表面電漿共振 生化感測器的TE極化光之表面電漿共振波長隨乙型阻斷劑 濃度變化之情形，其插圖為表面電漿共振傳輸頻譜，所量測 之乙型阻斷劑濃度範圍同為〇ppm至5〇〇ppm，其結果和圖二明 顯不同。此時由於TE極化光可與表面電漿波產生耦合，在 其傳輸頻譜上產生明顯光功率變化之情形，表面電漿共振波 長隨乙型阻斷劑濃度變化之趨勢和TM極化光相同，其線性 增加率為〇.27nm/ppm，因此亦可應用於生化物質的檢測上。 本發明所提供之雙極化檢測之表面電漿共振生化感測 為與其他習用物品相互比較時，更具有下列之優點·· 1·本發明之結構設計，係可使其得以在單一晶片上量測的 1245893 片之效能，降低檢測成 生化物質數目加倍’將可有效提升晶 本0 不同，使其得以進行各種 2·本發明係可隨著使用的檢測層 化學與生化物質之檢測。 上列詳細說明係針對本發明之一可行實施例之具體說 明’惟該實施例並非用以限制本發明之專利範圍，凡未脫離 本發明技藝精神所為之等效實施或變更，均應包含於本宰之 專利範圍中。 4 所述本案不但在技術思想上確屬創新，並能較習 用：.口增進上述多項功效，應已充分符合新穎性及進步性之 法疋發明專利要件，爰依法提出申請，懇言青貴局核准本件 發明專利申請案，以勵發明，至感德便。 【圖式簡單說明】 π參閱以下有關本發明一較佳實施例之詳細說明及其附 圖將可進一步瞭解本發明之技術内容及其目的功效；有關 該實施例之附圖為： 圖一為本發明雙極化檢測之表面電漿共振生化感測器之 結構示意圖； 圖二為傳統表面電漿共振生化感測器之ΤΜ與ΤΕ極化光 之傳輪頻譜； “圖一為傳統表面電漿共振生化感測器中，ΤΜ極化光的表 電漿共振波長隨乙型阻斷劑濃度變化之情形； ΤΜ圖四為本發明雙極化檢測之表面電漿共振生化感測器之 極化光之表面電漿共振波長隨乙型阻斷劑濃度變化之情 形；以及 1245893 圖五為本發明雙極化檢測之表面電漿共振生化感測器 之TE極化光之表面電漿共振波長隨乙型阻斷劑濃度變化之 情形。1245893 发明 Description of the invention: [Technical field to which the invention belongs] The present invention relates to a dual-polarization surface plasmon resonance biochemical sensor, and particularly to a type that can use TM and TE polarized light for detection. A surface plasma resonance biochemical sensor for dual polarization detection that enables a single component to detect two types of biochemicals and increase the number of biochemicals detected on a single wafer. [Previous technology] In 1983, B. Liedberg and C. Nylander et al. Applied the principle of surface plasma resonance (Surface Plasmon Resonance) to the detection of gas components, and the analysis elements based on surface plasma resonance have been widely used in In various fields, its advantages include: 1. High sensitivity. 2. No label-free is required for the test object. 3. Can do real-time fast analysis. 4. Free from electromagnetic interference from external environment. 5. Can be integrated on the same chip (on one chip) to achieve the purpose of a large number of parallel screening. The sensor manufactured by applying the principle of surface plasmon resonance has a structure including: attenuated total reflection (ATR), optical waveguide, optical fiber, grating coupler And other structures; sensors that use evanescent total reflection, the structure of which mainly consists of a rhenium layer, a metal layer, and an air layer. In addition, it can be divided into Kretschmann configuration and Otto configuration depending on the structure. The new structure is the structure of a waveguide-prism coupler. Its structure has an additional oxide layer between the metal layer and the air layer, which is different from the traditional situation where only TM polarized light can cause surface plasmon resonance, and its 1245993 reflected light Whether the intensity is TM polarized light or TE polarized light will cause attenuation within a certain range of angles. Although TM polarized light and TE polarized light have the same attenuation effect, they are not the same in principle. The absorption of TM polarized light in light intensity is caused by surface plasmon resonance, but the absorption of TE polarized light is because TE polarized light can be in the oxide layer when a certain range of incident angles are satisfied. It propagates and reflects back and forth on the interface between the oxide layer and the metal layer, and the light intensity is also attenuated. It is worth noting that the incident angle corresponding to the maximum absorption of TE polarized light is not affected by the sensing layer. The refractive index changes and changes occur only when the structure parameters of the entire sensor are changed (excluding the refractive index change of the sensing layer), so the input TE polarized light can only be used as a reference signal. The biggest advantage of this structure is that as long as the incident angle corresponding to the maximum absorption of TE polarized light is not shifted, it means that the entire structure is not different, and the factor that causes the resonance angle of TM polarized light to shift at this time, Only the refractive index of the sensing layer is changed. In this way, the reliability of the measured resonance angle shift when the refractive index of the sensing layer in the sensor is changed can be improved. Various types of sensors using optical waveguide structures. The waveguide structure is a strip waveguide. Only top-polarized light has an electric field component that is perpendicular to the surface. It can be used to excite the same electric field component that is also perpendicular to the surface. Surface plasma waves can therefore be used for chemical or biochemical sensing. However, TE polarized light has only an electric field component parallel to the interface and cannot excite surface plasma waves. Therefore, the principle of surface plasma resonance cannot be used to make a biochemical sensor. It can be seen that there are still many shortcomings in the above-mentioned conventional articles, and they are not a good designer. They need to be improved. In view of the various shortcomings derived from the above-mentioned conventional articles, the inventor of this case has been eager to improve and innovate. After years of painstaking and meticulous research, he finally succeeded in developing and completing the surface plasma resonance biochemical sensor for dual polarization detection. SUMMARY OF THE INVENTION The object of the present invention is to provide a surface plasma resonance biochemical sensor that can be used for dual polarization detection of various chemical and biological substances detection with different detection layers. A second object of the present invention is to provide a surface plasma resonance biochemical sensor for dual polarization detection that doubles the number of biochemical substances detectable on a single wafer and can greatly improve the detection performance of the wafer. The surface plasma resonance biochemical sensor for dual polarization detection that can achieve the purpose of the invention mentioned above, its structure is-"bifurcated waveguide, the output end waveguide is made into a ridge structure ', its chirped waveguide is used as a detection waveguide, and the other-output The waveguide is a reference waveguide, and its output intensity can be used to normalize the output light intensity value of the detection waveguide to prevent the interpretation error of the surface plasma resonance wavelength caused by the change in the intensity of the detection light source. The polarization direction light is incident on the biochemical sensor, and a polarizer is placed at the output end as an analyzer. By selecting TE or TM polarized light, you can determine which polarization the measured signal comes from. Light, which kind of biochemical substance is detected, so two biochemical substances can be measured on a single biochemical sensor. With this new design, the number of biochemical substances measured on a single wafer can be doubled, which can effectively improve [Effectiveness of the chip, reducing the cost of inspection.] [Embodiment] Please refer to FIG. 1, which is a schematic diagram of the structure of a surface plasma resonance biochemical sensor for dual polarization detection according to the present invention. It is a γ-shaped bifurcated waveguide. The output waveguide is made into a ridge structure. 'It's a detection waveguide with a gold film on the surface' and self-assembled human serum globulin on the surface to detect type B. 1245893 blocking agent, which is a medicine for treating heart disease; the other output waveguide is a reference waveguide, and its output light intensity can be used to normalize the output light intensity value of the detection waveguide to prevent the detection light source intensity from changing, Discrimination error of the surface plasma resonance wavelength; its application is to cover the top and side of the ridge waveguide with the detection layers of two biochemical substances respectively. When measuring, the light can be incident on the biochemical sensor in any polarization direction. On the detector, a polarizer is placed at the output as an analyzer. By selecting TE or TM polarized light, you can determine which polarized light the measured signal is from and which one is detected. Biochemical substances, so two types of biochemical substances can be measured on a single biochemical sensor, so that the number of biochemical substances measured on a single wafer can be doubled, which will effectively improve the performance of the chip and reduce the detection cost. In addition, depending on the detection layer used, the following tests can be performed on the application, such as drug concentration detection, drug and serum globulin affinity testing, chemical composition testing, and environmental pollutant testing. See Figure 2 It shows that the transmission spectrum of tm and TE polarized light of traditional surface plasma resonance biochemical sensor, due to the generation of surface electric t resonance, the output optical power of TM polarized light will be significantly reduced at a wavelength of 49437nm. However, for TE polarized light, there is no apparent decrease in the output optical power in the frequency spectrum because the surface electrocondensation resonance cannot be generated. 凊 Refer to Figure 3, which is one of the traditional surface plasma resonance biochemical sensors. The surface plasmon resonance wavelength of tm polarized light is shaped by the concentration of type B blocker. When the concentration of type B blocker is low, the surface plasmon resonance wavelength will increase linearly with the concentration. The increase rate is 〇64nm / ppm, when the concentration increases more than 200PPm, the increase in the surface plasma resonance wavelength will decrease by 1 and will appear saturated. This is because at this time, most human serum globulins have been linked with type B blocking agents. Adding more types of type B blocking agents will not be able to interact with the serum globulin that has been connected to 1245893, so the surface electricity Saturation occurs as the resonance wavelength of the slurry increases. Referring to FIG. 4, the surface plasma resonance wavelength of TM polarized light of the dual-polarization detection surface plasma resonance biochemical sensor according to the present invention varies with the concentration of the type B blocking agent. The illustration is The surface plasmon resonance transmission spectrum, the measured range of the type B blocking agent concentration is from 0.01 to 500 ppm. When the concentration of Type B blocking agent is increased, the surface plasma resonance wavelength may increase. The linear increase rate is 0.08nm / ppm, and the maximum absorbed light power value is significantly reduced. When a protein and a B-type blocking agent are combined to form a complex, the dielectric constant of the medium coated on the surface of the gold film will increase, which will cause a significant red shift in the surface plasmon resonance wavelength. The increase of the evanescent field of the light field, that is, the amount of light field extending out of the cladding layer increases, and the optical transmission loss is large, which makes the light intensity output by the optical waveguide decrease, which is helpful for identifying the position of the surface plasma resonance wavelength. Please refer to FIG. 5. The surface plasma resonance wavelength of TE polarized light of the dual-polarization detection surface plasma resonance biochemical sensor according to the present invention varies with the concentration of the type B blocking agent. The plasma resonance transmission spectrum, the measured range of B-blocker concentration is 0ppm to 5000ppm, the results are obviously different from Figure 2. At this time, because TE polarized light can be coupled with the surface plasma wave, a significant optical power change occurs in its transmission spectrum. The tendency of the surface plasma resonance wavelength to change with the concentration of the type B blocker is the same as TM polarized light. , Its linear increase rate is 0.27nm / ppm, so it can also be applied to the detection of biochemical substances. The dual-polarization surface plasmon resonance biochemical sensing provided by the present invention has the following advantages when compared with other conventional items. 1. The structural design of the present invention can enable it to be on a single chip The effectiveness of the measured 1245893 tablets and reducing the number of biochemicals detected will double the number of crystals, which will enable them to perform a variety of tests. 2. The present invention allows the detection of chemical and biochemical substances with the detection layer used. The above detailed description is a specific description of one of the feasible embodiments of the present invention, but this embodiment is not intended to limit the scope of the patent of the present invention. Any equivalent implementation or change that does not depart from the technical spirit of the present invention should be included in Ben Jae's patent scope. 4 The case mentioned above is not only innovative in terms of technical ideas, but also can be used more conventionally........... The Bureau approves this patent application for invention to encourage invention and it is a matter of virtue. [Brief description of the drawings] π Please refer to the following detailed description of a preferred embodiment of the present invention and the accompanying drawings to further understand the technical content of the present invention and its effects. The drawings related to this embodiment are as follows: The schematic diagram of the structure of the surface plasma resonance biochemical sensor for dual polarization detection according to the present invention; FIG. 2 is the transmission spectrum of the TM and TE polarized light of the traditional surface plasma resonance biochemical sensor; In the plasma resonance biochemical sensor, the surface plasma resonance wavelength of the TM polarized light varies with the concentration of the B-blocker; FIG. 4 shows the pole of the surface plasma resonance biochemical sensor of the dual polarization detection of the present invention. The surface plasma resonance wavelength of chemical light changes with the concentration of type B blocker; and 1245893 Figure 5 is the surface plasma resonance wavelength of TE polarized light of the surface plasma resonance biochemical sensor of the dual polarization detection of the present invention Changes with B-blocker concentration.
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