TWI668245B - Manufacturing method of thiophene polymer imprinted electrode film and use thereof - Google Patents
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Abstract
本發明有關於一種噻吩類聚合物之拓印電極薄膜的製備方法及用途，其製備步驟包含有取一電極基板；將噻吩衍生物(thiophene derivative)、過氯酸鋰(LiClO4)與十二烷基硫酸鈉(Sodium dodecyl sulfate,SDS)混合成一單體溶液；添加一模板分子至單體溶液中，並塗佈於電極基板；施加一恆定電壓於電極基板；以及利用一清洗溶液洗去模板分子，以獲得具有管狀奈米結構之一噻吩類聚合物之拓印電極薄膜；藉此，噻吩類聚合物之拓印電極薄膜係可用於檢測尿液之賀爾蒙濃度。 The invention relates to a preparation method and application of a thiophene polymer-based electrode film, wherein the preparation step comprises taking an electrode substrate; thiophene derivative, lithium perchlorate (LiClO 4 ) and twelve Sodium dodecyl sulfate (SDS) is mixed into a monomer solution; a template molecule is added to the monomer solution and coated on the electrode substrate; a constant voltage is applied to the electrode substrate; and the template is washed away with a cleaning solution. Molecules to obtain a rubbed electrode film having a thiophene polymer having a tubular nanostructure; whereby a rubbed electrode film of a thiophene polymer can be used to detect the hormone concentration of urine.
Description
本發明係有關於一種噻吩類聚合物之拓印電極薄膜的製備方法及用途，尤其係指一種透過電化學技術，將噻吩衍生物與模板分子製備成分子拓印高分子(molecular imprinting polymer,MIP)，以電極薄膜型態應用於高敏感性的感應裝置，可用來檢測尿液中的賀爾蒙含量。 The invention relates to a preparation method and a use of a rubbed electrode film of a thiophene polymer, in particular to a method for preparing a molecular imprinting polymer (MIP) by using an electrochemical technique to prepare a thiophene derivative and a template molecule. ), in the form of electrode film applied to high sensitivity sensing device, can be used to detect the hormone content in urine.
按，居家生物感測器為檢測生物代謝過程中特定生物分子的濃度，其檢測方式分為物理性與化學性，主要包括有放射性、光學、重量改變及電化學方式等，例如家用之血糖機，其利用葡萄糖酶作為感測媒介，通常會作成試紙，能夠與檢體血液中之血糖產生各種不同的反應，血糖機再根據試紙的變化，來判斷血液中的血糖水平；亦有採用電化學式之血糖試片的方式，為一種電化學生物感測電極，當檢體血液中的葡萄糖與試片反應後，產生的電子會被累積在電極表面，藉由血糖機提供一個外部之電壓後，可以偵測出累積在電極表面的電子數量，檢測出之電流值能夠計算出血液內葡萄糖的濃度。 According to the home biosensor, the concentration of specific biomolecules in the process of bio-metabolism is divided into physical and chemical methods, including radioactivity, optics, weight change and electrochemical methods, such as blood glucose meter for household use. It uses glucose enzyme as a sensing medium, and usually produces test paper, which can react with blood sugar in the blood of the sample. The blood glucose machine can judge the blood sugar level in the blood according to the change of the test paper. The blood glucose test piece is an electrochemical bio-sensing electrode. When the glucose in the blood of the sample reacts with the test piece, the generated electrons are accumulated on the surface of the electrode, and after the blood glucose machine provides an external voltage, The amount of electrons accumulated on the surface of the electrode can be detected, and the detected current value can calculate the concentration of glucose in the blood.
近年來，研究人員與學者將分子拓印技術(molecular imprinting technology,MIT)應用於生物感測器，由於利用分子拓印高分子(MIP)的生物感測器具有低成本和便攜性等優點，因此對於 家庭保健具備相當的吸引力，且分子拓印高分子(MIP)奈米顆粒具有較高的比表面積，適用於生物感測和生物分離，分子拓印高分子(MIP)薄膜在光學或電化學之感測器的表面上形成互補的空腔以辨識檢測出檢體之分子。例如中華民國專利公開號TW 201435344「一種可檢測尿液中生物指標分子的塗佈高分子拓印立體微結構感測器之製備方法」即是將生物指標分子拓印在高分子中，再塗佈在金基版上之陶瓷奈米結構的表面上，以獲得高分子拓印立體微結構感測器，可用來檢測尿液中的生物指標分子。 In recent years, researchers and scholars have applied molecular imprinting technology (MIT) to biosensors. Because of the low cost and portability of biosensors using molecular imprinting polymers (MIP), So for Home health care is quite attractive, and molecularly imprinted polymer (MIP) nanoparticles have a high specific surface area for biosensing and bioseparation. MIP films are optical or electrochemical. A complementary cavity is formed on the surface of the sensor to identify the molecules from which the sample is detected. For example, the Republic of China Patent Publication No. TW 201435344 "A method for preparing a coated polymer microscopic microstructure sensor capable of detecting biomarker molecules in urine" is to extrude a biomarker molecule into a polymer and recoat it. The surface of the ceramic nanostructure on the gold base plate is obtained to obtain a polymer-printed stereo microstructure sensor for detecting biomarker molecules in urine.
黃體素(progesterone)又稱為孕酮，係女性體內的主要孕激素，亦為一種賀爾蒙，由卵巢分泌，涉及女性月經週期，懷孕和胚胎過程，在懷孕過程中，黃體素濃度對於調解子宮頸，***和子宮的細胞變化係相當重要；透過檢測黃體素的濃度，即可監測女性的生育能力、黃體(corpus luteum)功能和子宮內膜之發育狀況，而黃體素一般會存在於血液及尿液中，因此，可藉由檢測血液或是尿液，而得知目前人體內之黃體素濃度。目前一般黃體素的檢查，皆須直接到診所或醫院，由醫護人員協助抽血後，透過免疫分析儀檢驗其黃體素濃度。 Progesterone, also known as progesterone, is the main progesterone in women. It is also a hormone, secreted by the ovaries, involving the female menstrual cycle, pregnancy and embryonic processes. During pregnancy, the concentration of lutein is used for mediation. Cellular changes in the cervix, vagina and uterus are important; by measuring the concentration of lutein, we can monitor women's fertility, corpus luteum function and endometrial development, while lutein is usually present in the blood. And in the urine, therefore, the concentration of lutein in the human body can be known by detecting blood or urine. At present, the examination of the general lutein should be carried directly to the clinic or hospital. After the blood pumping is assisted by the medical staff, the concentration of lutein is tested by an immunoassay analyzer.
然而，黃體素或其他賀爾蒙與人類之身體健康息息相關，若能在家中自行檢測出賀爾蒙濃度，將能提高其使用便利性。爰此，如何提供一種能夠以非侵入方式準確檢測出人體內賀爾蒙濃度之產品，即為本發明人所思及之方向。 However, lutein or other hormones are closely related to the health of human beings. If the hormone concentration can be detected at home, it will improve the convenience of use. Thus, how to provide a product capable of accurately detecting the concentration of hormones in the human body in a non-invasive manner is the direction that the inventors have thought.
例如，本案發明人先前提出的中華民國專利公告號TW I561821「分子拓印薄膜之製備方法及其分子拓印薄膜、分子感測電極之製備方法及其分子感測電極以及分子感測系統與其用途」，即揭示一種可用於製備成檢測尿液荷爾蒙分子感測系統的分子拓印薄膜，可達到高準確率與避免侵入性抽取檢體之目的；但，由於 高分子聚合條件若掌握不佳，或是高分子聚合時無有效包覆模板分子之官能基位置，則可能導致辨識性及穩定性不足，例如上述前案中黃體素、***(estradiol)或睪固酮(testosterone)等同時存在尿液中的賀爾蒙仍可能會產生相互干擾而影響檢測的準確性，需要在高濃度下才能降低其干擾性。 For example, the inventor of the present invention has previously proposed the Republic of China Patent Publication No. TW I561821 "Method for preparing molecular rubbing film and its molecular rubbing film, method for preparing molecular sensing electrode, molecular sensing electrode thereof, and molecular sensing system and use thereof Revealing a molecularly-printed film that can be used to prepare a urine molecule sensing system for high accuracy and avoiding invasive sampling; however, If the polymer polymerization conditions are poorly controlled, or if the functional group position of the template molecule is not effectively coated during the polymerization, the identification and stability may be insufficient. For example, the lutein and estradiol in the above case. Or hormones in the urine, such as testosterone, may still interfere with each other and affect the accuracy of the detection. It is necessary to reduce the interference at high concentrations.
今，發明人即是鑑於上述現有之檢測賀爾蒙之方式於實際實施使用時仍具有多處缺失，於是乃一本孜孜不倦之精神，並藉由其豐富專業知識及多年之實務經驗所輔佐，而加以改善，並據此研創出本發明。 Nowadays, the inventor is still in the spirit of tirelessness in view of the above-mentioned existing methods of detecting hormones in actual implementation, and is supported by his rich professional knowledge and years of practical experience. Improvements have been made, and the present invention has been developed based on this.
本發明主要目的為提供一種噻吩類聚合物之拓印電極薄膜的製備方法及用途，其透過電化學技術，使噻吩衍生物與賀爾蒙之模板分子聚合成分子拓印高分子(MIP)，並披覆於一般的電極上，以電極薄膜型態製備之生物感測器，可提供居家時用來檢測尿液中的黃體素、***、皮質醇或睪固酮之含量。 The main object of the present invention is to provide a preparation method and application of a thiophene-based polymer electrode film, which polymerizes a thiophene derivative and a hormone template molecule into a molecularly-imprinted polymer (MIP) through an electrochemical technique. It is coated on a common electrode and is a biosensor prepared by electrode film type, which can be used to detect the content of lutein, estradiol, cortisol or testosterone in urine at home.
為了達到上述實施目的，本發明一種噻吩類聚合物之拓印電極薄膜的製備方法，其製備步驟包含有步驟一：取一電極基板；步驟二：將噻吩衍生物(thiophene derivative)、過氯酸鋰(LiClO4)與十二烷基硫酸鈉(SDS)混合成一單體溶液，其中噻吩衍生物係選自噻吩(thiophene)、3,4-乙烯二氧噻吩(3,4-ethylenedioxythiophene,EDOT)、3,4-亞丙基二氧噻吩(3,4-propylenedioxythiophene)、3,4-二甲氧基噻吩(3,4-dimethoxythiophene)、羥甲基3,4-乙烯二氧噻吩(hydromethoxy EDOT,EDOT-OH)、3,4-(2,2-二乙基丙烯)二氧基噻吩(3,4-(2',2’-diethylpropylene)dioxythiophene)、3,4-(2,2-二甲基丙烯二氧基)噻吩(3,4-(2' 2’-dimethylproppylene)dioxythiophene)、3,4-乙烯二氧噻吩二羧酸(EDOT 2-carboxylic acid) 或2-(氯甲基)-2,3-二氫-噻吩并[3,4-b]-1,4-二噁英(2-chloromethyl-2,3-dihydrothieno[3,4-b]-1,4-dioxine)；步驟三：添加一模板分子至單體溶液中，並塗佈於電極基板；步驟四：施加一恆定電壓於電極基板；以及步驟五：利用一清洗溶液洗去模板分子，以獲得具有管狀奈米結構之一噻吩類聚合物之拓印電極薄膜。 In order to achieve the above-mentioned object, a preparation method of a thiophene-based polymer electrode film comprises the steps of: taking an electrode substrate; and step 2: thiophene derivative, perchloric acid Lithium (LiClO 4 ) is mixed with sodium dodecyl sulfate (SDS) to form a monomer solution, wherein the thiophene derivative is selected from the group consisting of thiophene and 3,4-ethylenedioxythiophene (EDOT). , 3,4-propylenedioxythiophene, 3,4-dimethoxythiophene, hydroxymethyl 3,4-ethylenedioxythiophene (hydromethoxy EDOT) , EDOT-OH), 3,4-(2,2-diethylpropylene)dioxythiophene, 3,4-(2,2- 3,4-(2'2'-dimethylproppylene) dioxythiophene, 3,4-ethylenedioxythiophene dicarboxylic acid (EDOT 2-carboxylic acid) or 2-(chloromethyl) -2,3-Dihydro-thieno[3,4-b]-1,4-dioxin (2-chloromethyl-2,3-dihydrothieno[3,4-b]-1,4-dioxine) Step 3: adding a template molecule to the monomer solution and coating on the electrode substrate; Step 4: applying a constant voltage to the electrode substrate; and step 5: washing the template molecule with a cleaning solution to obtain a rubbed electrode film having a thiophene polymer having a tubular nanostructure.
於本發明之一實施例中，電極基板係為鍍上氧化銦錫(ITO)或氟二氧化錫(FTO)之導電玻璃或塑膠基板。 In an embodiment of the invention, the electrode substrate is a conductive glass or plastic substrate plated with indium tin oxide (ITO) or fluorine tin dioxide (FTO).
於本發明之一實施例中，單體溶液係含有5~20mM之噻吩衍生物、50~250mM之過氯酸鋰與30~50mM之十二烷基硫酸鈉。 In one embodiment of the present invention, the monomer solution contains 5 to 20 mM of a thiophene derivative, 50 to 250 mM of lithium perchlorate, and 30 to 50 mM of sodium lauryl sulfate.
於本發明之一實施例中，模板分子為黃體素、***、皮質醇或睪固酮，濃度為0.001~1mg/mL。 In one embodiment of the invention, the template molecule is lutein, estradiol, cortisol or steroid, at a concentration of 0.001 to 1 mg/mL.
於本發明之一實施例中，恆定電壓為1.0~1.45V。 In an embodiment of the invention, the constant voltage is 1.0 to 1.45V.
於本發明之一實施例中，清洗溶液為乙醇、甲醇、丙酮、水、十二烷基硫酸鈉其中之一或上述任兩者之組合。 In one embodiment of the invention, the cleaning solution is one of ethanol, methanol, acetone, water, sodium lauryl sulfate, or a combination of the two.
本發明之另一目的為提供一種將噻吩類聚合物之拓印電極薄膜用於檢測尿液之黃體素、***、皮質醇或睪固酮濃度的用途，係將噻吩衍生物、過氯酸鋰(LiClO4)、十二烷基硫酸鈉(SDS)與模板分子於一電極基板上進行電聚合程序而獲得，且噻吩類聚合物之拓印電極薄膜係具有管狀奈米結構，其中噻吩衍生物係為噻吩(thiophene)、3,4-乙烯二氧噻吩(3,4-ethylenedioxythiophene,EDOT)、3,4-亞丙基二氧噻吩(3,4-propylenedioxythiophene)、3,4-二甲氧基噻吩(3,4-dimethoxythiophene)、羥甲基3,4-乙烯二氧噻吩(hydromethoxy EDOT,EDOT-OH)、3,4-(2,2-二乙基丙烯)二氧基噻吩(3,4-(2',2’-diethylpropylene)dioxythiophene)、3,4-(2,2-二甲基丙烯二氧基)噻吩(3,4-(2' 2’-dimethylproppylene)dioxythiophene)、3,4-乙烯二氧噻吩二羧酸(EDOT 2-carboxylic acid) 或2-(氯甲基)-2,3-二氫-噻吩并[3,4-b]-1,4-二噁英(2-chloromethyl-2,3-dihydrothieno[3,4-b]-1,4-dioxine)。 Another object of the present invention is to provide a use of a thiophene-based polymer electrode film for detecting the concentration of lutein, estradiol, cortisol or ketosterone in urine, which is a thiophene derivative or lithium perchlorate. (LiClO 4 ), sodium dodecyl sulfate (SDS) and template molecules are obtained by electropolymerization on an electrode substrate, and the rubbed electrode film of the thiophene polymer has a tubular nanostructure, wherein the thiophene derivative It is thiophene, 3,4-ethylenedioxythiophene (EDOT), 3,4-propylenedioxythiophene, 3,4-dimethoxy 3,4-dimethoxythiophene, hydroxymethyl 3,4-ethylenedioxythiophene (EDOT-OH), 3,4-(2,2-diethylpropene)dioxythiophene (3) , 4-(2',2'-diethylpropylene)dioxythiophene), 3,4-(2,2'-dimethylproppylene)dioxythiophene, 3 , 4-ethylenedioxythiophene dicarboxylic acid (EDOT 2-carboxylic acid) or 2-(chloromethyl)-2,3-dihydro-thieno[3,4-b]-1,4-dioxin (2-chloromethyl-2,3-dihydrothieno[3,4-b]-1,4-dioxine).
於本發明另一實施例中，噻吩類聚合物之拓印電極薄膜係將5~20mM之噻吩衍生物、50~250mM之過氯酸鋰(LiClO4)、30~50mM之十二烷基硫酸鈉(SDS)與模板分子於該電極基板上進行電聚合程序而獲得。 In another embodiment of the present invention, the thiophene-based polymer electrode film is a 5-20 mM thiophene derivative, 50-250 mM lithium perchlorate (LiClO 4 ), 30-50 mM dodecyl sulfate. Sodium (SDS) and template molecules are obtained by electropolymerization on the electrode substrate.
於本發明另一實施例中，模板分子為黃體素，其濃度為0.001~1mg/mL，電極基板係為鍍上氧化銦錫(ITO)或氟二氧化錫(FTO)之導電玻璃或塑膠基板。 In another embodiment of the present invention, the template molecule is a lutein, the concentration of which is 0.001 to 1 mg/mL, and the electrode substrate is a conductive glass or plastic substrate plated with indium tin oxide (ITO) or fluorine tin oxide (FTO). .
第一圖：本發明較佳實施例之拓印模板分子之示意圖。 First Figure: Schematic representation of a thumbprint template molecule in accordance with a preferred embodiment of the present invention.
第二圖：本發明較佳實施例之表面型態之電子顯微鏡比較圖。 Second Figure: Comparison of electron microscopy of the surface morphology of the preferred embodiment of the present invention.
第三圖：本發明較佳實施例之薄膜成長之電子顯微鏡圖。 Third Figure: Electron micrograph of film growth in accordance with a preferred embodiment of the present invention.
第四圖：本發明較佳實施例之薄膜成長時間與角度關係圖。 Fourth Figure: A graph showing the relationship between film growth time and angle in a preferred embodiment of the present invention.
第五圖：本發明較佳實施例之薄膜成長時間與電流密度關係圖。 Figure 5 is a graph showing the relationship between film growth time and current density in a preferred embodiment of the present invention.
第六圖：本發明較佳實施例之循環伏安量測結果圖。 Figure 6 is a graph showing cyclic voltammetry results of a preferred embodiment of the present invention.
第七圖：本發明較佳實施例之濃度影響電化學響應性(electrochemical response)曲線比較圖。 Figure 7 is a graph comparing the concentration of the electrochemical response curves of the preferred embodiment of the invention.
第八圖：本發明較佳實施例之其他激素干擾曲線圖。 Figure 8 is a graph showing other hormone interference profiles of a preferred embodiment of the invention.
本發明之目的及其結構功能上的優點，將依據以下圖面所示之結構，配合具體實施例予以說明，俾使審查委員能對本發明有更深入且具體之瞭解。 The object of the present invention and its structural and functional advantages will be explained in conjunction with the specific embodiments according to the structure shown in the following drawings, so that the reviewing committee can have a more in-depth and specific understanding of the present invention.
本發明一種噻吩類聚合物之拓印電極薄膜的製備方法，其製 備步驟包含有步驟一：取一鍍上氧化銦錫(ITO)或氟二氧化錫(FTO)之導電玻璃或塑膠基板的電極基板；步驟二：將10mM之噻吩衍生物、100mM的過氯酸鋰(LiClO4)與50mM的十二烷基硫酸鈉(SDS)混合成一單體溶液，其中噻吩衍生物可例如為噻吩(thiophene)、3,4-乙烯二氧噻吩(3,4-ethylenedioxythiophene,EDOT)、3,4-亞丙基二氧噻吩(3,4-propylenedioxythiophene)、3,4-二甲氧基噻吩(3,4-dimethoxythiophene)、羥甲基3,4-乙烯二氧噻吩(hydromethoxy EDOT,EDOT-OH)、3,4-(2,2-二乙基丙烯)二氧基噻吩(3,4-(2',2’-diethylpropylene)dioxythiophene)、3,4-(2,2-二甲基丙烯二氧基)噻吩(3,4-(2' 2’-dimethylproppylene)dioxythiophene)、3,4-乙烯二氧噻吩二羧酸(EDOT 2-carboxylic acid)或2-(氯甲基)-2,3-二氫-噻吩并[3,4-b]-1,4-二噁英(2-chloromethyl-2,3-dihydrothieno[3,4-b]-1,4-dioxine)；步驟三：添加一濃度為0.001~1mg/mL的黃體素、***、皮質醇或睪固酮模板分子至單體溶液中，並塗佈於電極基板；步驟四：施加一恆定電壓1.1V於電極基板；以及步驟五：利用一清洗溶液洗去模板分子，以獲得具有管狀奈米結構之一噻吩類聚合物之拓印電極薄膜，其中清洗溶液為乙醇、甲醇、丙酮、水、十二烷基硫酸鈉其中之一或上述任兩者之組合，可例如為10vol%之乙醇水溶液。 The invention provides a method for preparing a thiophene polymer-based electrode film, wherein the preparation step comprises the step 1: taking an electrode of a conductive glass or plastic substrate plated with indium tin oxide (ITO) or fluorine tin oxide (FTO). Substrate; Step 2: 10 mM thiophene derivative, 100 mM lithium perchlorate (LiClO 4 ) and 50 mM sodium dodecyl sulfate (SDS) are mixed into a monomer solution, wherein the thiophene derivative can be, for example, thiophene , 3,4-ethylenedioxythiophene (EDOT), 3,4-propylenedioxythiophene, 3,4-dimethoxythiophene (3, 4-dimethoxythiophene), hydroxymethyl 3,4-ethylenedioxythiophene (EDOT-OH), 3,4-(2,2-diethyl propylene)dioxythiophene (3,4-(2) ',2'-diethylpropylene)dioxythiophene), 3,4-(2,2'-dimethylproppylene)dioxythiophene, 3,4-ethylene EDOT 2-carboxylic acid or 2-(chloromethyl)-2,3-dihydro-thieno[3,4-b]-1,4-dioxin (2-chloromethyl-) 2,3-dihydrothieno[3,4-b]-1,4-dioxine); Step 3: Add a concentration of 0.001~ 1 mg/mL of lutein, estradiol, cortisol or sterol template molecule to the monomer solution and applied to the electrode substrate; step 4: applying a constant voltage of 1.1 V to the electrode substrate; and step 5: using a cleaning The template molecule is washed away to obtain a rubbed electrode film having a thiophene polymer having a tubular nanostructure, wherein the cleaning solution is one of ethanol, methanol, acetone, water, sodium lauryl sulfate or any of the above two The combination may be, for example, a 10 vol% aqueous solution of ethanol.
本發明亦提供將噻吩類聚合物之拓印電極薄膜用於檢測尿液之黃體素、***、皮質醇或睪固酮濃度的用途。 The invention also provides the use of a thiophene-based polymer electrode film for detecting the concentration of lutein, estradiol, cortisol or ketosterone in urine.
此外，藉由下述具體實施例，可進一步證明本發明可實際應用之範圍，但不意欲以任何形式限制本發明之範圍。 In addition, the scope of the invention may be further exemplified by the following specific examples, which are not intended to limit the scope of the invention.
請參閱第一圖，於此次實施中本發明係使用羥甲基3,4-乙烯二氧噻吩(EDOT-OH)單體、3,4-乙烯二氧噻吩(EDOT)單體兩者合成之EDOT-co-EDOT-OH共聚物作為單體；將EDOT、 EDOT-co-EDOT-OH、EDOT-OH三種高分子單體分別與過氯酸鋰(LiClO4)、十二烷基硫酸鈉(SDS)混合成單體溶液，並以黃體素作為模板分子添加至單體溶液中，塗佈於氧化銦錫(ITO)電極基板，再以Metrohm Autolab公司所推出之恆電位儀(型號PGSTAT101)，施加1.1V之恆定電壓於電極基板，經過此電聚合過程，單體溶液與黃體素會進行聚合，使EDOT、EDOT-co-EDOT-OH、EDOT-OH包覆黃體素之官能基的位置，形成結構穩定的網狀高分子，最後再以乙醇水溶液移除掉模板分子，以完成拓印，並分別獲得PEDOT、poly(EDOT-co-EDOT-OH)、poly(EDOT-OH)三種拓印電極薄膜。 Please refer to the first figure. In this implementation, the present invention is synthesized by using both methylol 3,4-ethylenedioxythiophene (EDOT-OH) monomer and 3,4-ethylenedioxythiophene (EDOT) monomer. EDOT-co-EDOT-OH copolymer as a monomer; three polymer monomers EDOT, EDOT-co-EDOT-OH, EDOT-OH and lithium perchlorate (LiClO 4 ), sodium lauryl sulfate (SDS) is mixed into a monomer solution, and added to the monomer solution with the lutein as a template molecule, coated on an indium tin oxide (ITO) electrode substrate, and then a potentiostat (Model PGSTAT101) introduced by Metrohm Autolab Applying a constant voltage of 1.1V to the electrode substrate. After this electropolymerization process, the monomer solution and the lutein will be polymerized to make the functional groups of the EDOT, EDOT-co-EDOT-OH, and EDOT-OH coating the lutein. Forming a structurally stable network polymer, and finally removing the template molecules with an aqueous ethanol solution to complete the rubbing, and obtaining PEDOT, poly(EDOT-co-EDOT-OH), and poly(EDOT-OH) respectively. Printed electrode film.
將PEDOT、poly(EDOT-co-EDOT-OH)、poly(EDOT-OH)三種拓印電極薄膜與未添加模板分子之純聚合的PEDOT、poly(EDOT-co-EDOT-OH)、poly(EDOT-OH)三種電極薄膜作表面的檢視，可參考第二圖，係藉由掃描式電子顯微鏡(SEM)去檢視六種薄膜的表面，圖中左側三張編號(a)、(c)、(e)為無拓印之電極薄膜，由上至下分別為PEDOT、poly(EDOT-co-EDOT-OH)、poly(EDOT-OH)，右側三張編號(b)、(d)、(f)為拓印電極薄膜，由上至下分別為PEDOT、poly(EDOT-co-EDOT-OH)、poly(EDOT-OH)；由圖中可知，無拓印之電極薄膜與拓印電極薄膜之外觀結構看起來相當類似，黃體素拓印並不會干擾薄膜的形成，然而其具有些微之差異，PEDOT拓印電極薄膜與PEDOT電極薄膜為纖維狀之奈米結構，且PEDOT拓印電極薄膜比無拓印之PEDOT電極薄膜具有更密集之結構，poly(EDOT-co-EDOT-OH)電極薄膜與poly(EDOT-co-EDOT-OH)拓印電極薄膜為管狀微米結構，但poly(EDOT-co-EDOT-OH)拓印電極薄膜在奈米管底部具有許多小凸起物，而本發明之poly(EDOT-OH)電極薄膜係比poly(EDOT-co-EDOT-OH)電極薄膜有更均勻且更小尺寸的管狀奈 米結構，poly(EDOT-OH)拓印電極薄膜又比無拓印之poly(EDOT-OH)電極薄膜擁有更多的管狀奈米結構。 PEDOT, poly(EDOT-co-EDOT-OH), poly(EDOT-OH) three kinds of rubbing electrode films and purely polymerized PEDOT, poly(EDOT-co-EDOT-OH), poly (EDOT) without template molecules added -OH) Three electrode films for surface inspection. Referring to the second figure, the surface of the six films is examined by scanning electron microscopy (SEM). The three numbers on the left side are (a), (c), ( e) is an electrode film without rubbing, from top to bottom, PEDOT, poly(EDOT-co-EDOT-OH), poly(EDOT-OH), three numbers on the right (b), (d), (f For the rubbed electrode film, PEDOT, poly(EDOT-co-EDOT-OH), and poly(EDOT-OH) are respectively from top to bottom; as can be seen from the figure, the electrode film without rubbing and the electrode film of rubbing are The appearance structure looks quite similar. The yellow voxel rubbing does not interfere with the formation of the film, but it has slight differences. The PEDOT rubbing electrode film and the PEDOT electrode film are fibrous nanostructures, and the PEDOT rubbing electrode film ratio The PEDOT electrode film without rubbing has a denser structure, and the poly(EDOT-co-EDOT-OH) electrode film and the poly(EDOT-co-EDOT-OH) rubbing electrode film have a tubular micro-structure, but poly(E The DOT-co-EDOT-OH) rubbed electrode film has many small protrusions at the bottom of the nanotube, and the poly(EDOT-OH) electrode film of the present invention is a poly(EDOT-co-EDOT-OH) electrode film. a more uniform and smaller size tubular nai The rice structure, poly(EDOT-OH) rubbed electrode film has more tubular nanostructures than the non-printed poly(EDOT-OH) electrode film.
感測測試時發現，添加黃體素會增加電流，並且將陽極峰移到較高的電位，因此PEDOT拓印電極薄膜係隨著黃體素濃度的增加(亦可能是隨著黃體素吸附增加)，使電化學響應隨之增加，而黃體素的吸附也將陰極峰移向更高的電位，代表黃體素的吸附也會降低PEDOT拓印電極薄膜的電化學活性。 During the sensing test, it was found that the addition of lutein increased the current and shifted the anode peak to a higher potential, so the PEDOT rubbing electrode film system increased with the concentration of lutein (may also increase with the adsorption of lutein). The electrochemical response is increased, and the adsorption of lutein also shifts the cathode peak to a higher potential, indicating that the adsorption of lutein also reduces the electrochemical activity of the PEDOT rubbing electrode film.
雖然EDOT和EDOT-OH單體具有相當高的化學相似性，但是EDOT-OH中的羥甲基可以提供較好的辨識性，而共聚物之EDOT-co-EDOT-OH的電化學響應性(electrochemical response)則劣於EDOT和EDOT-OH，因此，發明人選擇EDOT-OH作為電聚合之拓印電極薄膜的材料。 Although EDOT and EDOT-OH monomers have relatively high chemical similarities, the hydroxymethyl group in EDOT-OH provides better visibility, while the electrochemical responsiveness of the copolymer's EDOT-co-EDOT-OH ( Electrochemical response) is inferior to EDOT and EDOT-OH. Therefore, the inventors chose EDOT-OH as the material for the electropolymerized rubbed electrode film.
為了優化拓印電極薄膜在工作電極上的厚度或生長，本發明實施時試驗了三種電聚合時間，圖式第三圖係顯示poly(EDOT-OH)拓印電極薄膜的管狀奈米結構的長度的掃描式電子顯微鏡(SEM)圖像，左側編號(a)之圖像為電聚合時間5秒的成長情形，奈米結構之長度約為1-5μm,，右側編號(b)之圖像為電聚合時間20秒的成長情形，奈米結構之長度約為10-20μm；請再參閱第四圖與第五圖，由圖中可知，電聚合時間從5-20秒，poly(EDOT-OH)拓印電極薄膜的管狀奈米結構之接觸角度從40°成長至50°，而無拓印之poly(EDOT-OH)電極薄膜的管狀奈米結構之接觸角度則是從30°成長至47°，再檢視poly(EDOT-OH)拓印電極薄膜之電化學響應性，電聚合時間從5-20秒，其電流密度從約32μA/cm2成長到約200μA/cm2，顯然，本發明僅需要1分鐘以內的時間，就可以製造出所需的poly(EDOT-OH)拓印電極薄膜。 In order to optimize the thickness or growth of the rubbed electrode film on the working electrode, three electropolymerization times were tested in the practice of the present invention, and the third figure shows the length of the tubular nanostructure of the poly(EDOT-OH) rubbed electrode film. Scanning electron microscope (SEM) image, the image on the left side (a) is a growth condition of 5 seconds of electropolymerization time, the length of the nanostructure is about 1-5 μm, and the image of the right side number (b) is The electropolymerization time is 20 seconds. The length of the nanostructure is about 10-20μm. Please refer to the fourth and fifth diagrams. It can be seen from the figure that the electropolymerization time is from 5 to 20 seconds, poly(EDOT-OH). The contact angle of the tubular nanostructure of the rubbed electrode film is increased from 40° to 50°, and the contact angle of the tubular nanostructure of the unprinted poly(EDOT-OH) electrode film is increased from 30° to 47°. °, and then examine the electrochemical responsiveness of the poly(EDOT-OH) rubbed electrode film, the electropolymerization time is from 5 to 20 seconds, and the current density is increased from about 32 μA/cm 2 to about 200 μA/cm 2 , obviously, the present invention It takes only less than one minute to produce the desired poly(EDOT-OH) rubbed electrode film.
以1000pg/mL、100pg/mL、10pg/mL、1pg/mL、0.1pg/mL、 0.01pg/mL六種不同濃度的黃體素模板分子製備成poly(EDOT-OH)拓印電極薄膜，再加上一個無添加模板分子的無拓印之poly(EDOT-OH)電極薄膜，並透過循環伏安法(cyclic voltammetric,CV)量測，以進行電化學分析，係使用CH Instruments公司所推出之電化學分析儀(型號608E)，掃描速率設定為0.1V/s，其量測結果如第六圖所示，其氧化還原電對(redox couple)約在0.42V，隨著黃體素濃度的增加，電流密度也隨之增加，可知可選用較高濃度的黃體素模板分子，而在無添加模板分子的實施例中，則電化學響應性明顯較差；而第七圖為poly(EDOT-OH)拓印電極薄膜和無拓印之poly(EDOT-OH)電極薄膜之電化學響應性的校準曲線，由圖中可發現，poly(EDOT-OH)拓印電極薄膜之電流密度可到達無拓印之poly(EDOT-OH)電極薄膜的2-3倍。 1000pg/mL, 100pg/mL, 10pg/mL, 1pg/mL, 0.1pg/mL, 0.01pg/mL six different concentrations of lutein template molecules were prepared into poly(EDOT-OH) rubbing electrode film, plus a non-printing poly (EDOT-OH) electrode film without template molecules, and through Cyclic voltammetric (CV) measurement for electrochemical analysis using an electrochemical analyzer (model 608E) from CH Instruments, with a scan rate set to 0.1 V/s, and the measurement results are as follows. As shown in the sixth figure, the redox couple is about 0.42V. As the concentration of lutein increases, the current density increases. It can be seen that a higher concentration of lutein template molecules can be used. In the examples of adding template molecules, the electrochemical responsiveness is significantly poor; and the seventh figure is the electrochemical responsiveness of the poly(EDOT-OH) rubbing electrode film and the non-printing poly(EDOT-OH) electrode film. The calibration curve shows that the current density of the poly(EDOT-OH) rubbed electrode film can reach 2-3 times that of the non-printed poly(EDOT-OH) electrode film.
本發明之噻吩衍生物選用羥甲基3,4-乙烯二氧噻吩製成的poly(EDOT-OH)拓印電極薄膜其檢測黃體素濃度最小可以到0.1fg/ml，相較於以聚苯胺-苯胺酸(poly(aniline-cometanilic acid))製備而成之生物感測器，本發明係具有較佳的感測範圍；實際用於尿液感測時，由圖式第八圖，17 β***(17 β-estradiol)、睪固酮(testosterone)、尿素(urea)和肌酸酐(creatinine)對於poly(EDOT-OH)拓印電極薄膜檢測黃體素之干擾有限，即便濃度上升，也不會干擾poly(EDOT-OH)拓印電極薄膜的電流密度，因此本發明確實可用來檢測人體尿液中的黃體素濃度。 The thiophene derivative of the present invention is a poly(EDOT-OH) rubbed electrode film made of methylol 3,4-ethylenedioxythiophene, and the concentration of the progesterone can be as small as 0.1 fg/ml, compared with polyaniline. - Biosensor prepared from poly(aniline-cometanilic acid), the present invention has a better sensing range; when used in urine sensing, the eighth figure, 17 β Estradiol (17 β-estradiol), testosterone, urea (urea) and creatinine have limited interference with the detection of lutein in poly(EDOT-OH) rubbed electrode films, even if the concentration rises, it will not Interfering with the current density of the poly(EDOT-OH) rubbing electrode film, the present invention can indeed be used to detect the concentration of lutein in human urine.
再者，發明人以Abbott Core Laboratory公司推出的免疫分析儀(型號ARCHITECT ci 8200)與以本發明poly(EDOT-OH)拓印電極薄膜製成之生物感測器對兩個尿液樣本進行檢測；將1ml的尿液樣本放置離心管中，並儲存於4℃的環境中，經由ARCHITECT ci 8200檢測後，測出之黃體素濃度分別為0.7±0.0pg/ml與3.4±0.2 pg/ml；以本發明製成之生物感測器進行檢測前，係先將尿液樣本以緩衝液稀釋1000倍，緩衝液為125mM之氯化鉀(KCl)、5mM之亞鐵氰化鉀(K4[Fe(CN)6])與5mM之鐵氰化鉀(K3[Fe(CN)6])混合之溶液，於生物感測器中反應約5-90分鐘，其所檢測出之黃體素濃度分別為76.0±2.0μA/cm2與100.0±1.0μA/cm2，換算後即為0.7±0.22pg/ml與4.0±0.3pg/ml，代表本案之準確率約為88.8%，且發明人亦發現，若稀釋更高的倍數(例如1000倍稀釋)，其檢測出的濃度準確率更高。 Furthermore, the inventors tested two urine samples using an immunoassay analyzer (model ARCHITECT ci 8200) from Abbott Core Laboratory and a biosensor made of the poly(EDOT-OH) rubbing electrode film of the present invention. 1 ml of urine sample was placed in a centrifuge tube and stored in an environment of 4 ° C. After detection by ARCHITECT ci 8200, the measured concentrations of lutein were 0.7 ± 0.0 pg / ml and 3.4 ± 0.2 pg / ml, respectively; Before the biosensor made by the present invention is tested, the urine sample is diluted 1000 times with a buffer, and the buffer is 125 mM potassium chloride (KCl) and 5 mM potassium ferrocyanide (K 4 [ a solution of Fe(CN) 6 ]) mixed with 5 mM potassium ferricyanide (K 3 [Fe(CN) 6 ]), reacted in a biosensor for about 5-90 minutes, and the concentration of lutein detected were 76.0 ± 2.0μA / cm 2 and 100.0 ± 1.0μA / cm 2, was converted after 0.7 ± 0.22pg / ml and 4.0 ± 0.3pg / ml, representative of the accuracy of the case is approximately 88.8%, and the inventors have also It was found that if a higher multiple was diluted (for example, a 1000-fold dilution), the detected concentration accuracy was higher.
由上述之實施說明可知，本發明與現有技術相較之下，本發明具有以下優點： It can be seen from the above description that the present invention has the following advantages compared with the prior art:
1.本發明選用噻吩衍生物單體作為檢測黃體素之反應物，其管狀奈米結構具有較高的感測面積，由電子顯微鏡之圖像中，可看見聚羥甲基3,4-乙烯二氧噻吩(poly(EDOT-OH))之拓印電極薄膜表面具有皺褶，可知其接觸面積相當大，因此應用在生物感測器時，具有敏銳且良好的電化學響應性(electrochemical response)。 1. The present invention uses a thiophene derivative monomer as a reactant for detecting lutein, and its tubular nanostructure has a high sensing area. From the image of an electron microscope, polyhydroxymethyl 3,4-ethylene is visible. Dithithiophene (poly(EDOT-OH)) has a wrinkle on the surface of the electrode film, which shows that the contact area is quite large, so it has a sharp and good electrochemical response when applied to a biosensor. .
2.本發明噻吩衍生物係能與多種官能團作結合，且與多種模板分子具有高親和力的鍵結位點，因此相較於傳統之聚合物，係具有較高的電化學響應性，且又易於製備，係適合作為生物感測電極。 2. The thiophene derivative of the present invention is capable of binding with a plurality of functional groups and has a high affinity bonding site with a plurality of template molecules, and thus has higher electrochemical responsiveness than conventional polymers, and It is easy to prepare and is suitable as a biosensing electrode.
3.本發明以噻吩類聚合物之拓印電極薄膜製成的生物感測器，確實能夠用於準確地檢測人體尿液中的黃體素濃度，尤其將檢體的濃度稀釋更高的倍數，即可獲得更精確的檢測結果，因此，其具有低成本和便攜性的優點。 3. The biosensor made of the rubbed electrode film of the thiophene polymer of the present invention can be used for accurately detecting the concentration of lutein in human urine, especially diluting the concentration of the sample by a higher multiple. More accurate detection results are obtained, so that it has the advantages of low cost and portability.
綜上所述，本發明之噻吩之拓印電極薄膜的製備方法及用途，的確能藉由上述所揭露之實施例，達到所預期之使用功效，且本發明亦未曾公開於申請前，誠已完全符合專利法之規定與要求。 爰依法提出發明專利之申請，懇請惠予審查，並賜准專利，則實感德便。 In summary, the preparation method and use of the thiophene electrode film of the present invention can achieve the intended use efficiency by the above disclosed embodiments, and the present invention has not been disclosed before the application. Full compliance with the requirements and requirements of the Patent Law. 爰Issuing an application for a patent for invention in accordance with the law, and asking for a review, and granting a patent, is truly sensible.
惟，上述所揭之圖示及說明，僅為本發明之較佳實施例，非為限定本發明之保護範圍；大凡熟悉該項技藝之人士，其所依本發明之特徵範疇，所作之其它等效變化或修飾，皆應視為不脫離本發明之設計範疇。 The illustrations and descriptions of the present invention are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention; those skilled in the art, which are characterized by the scope of the present invention, Equivalent variations or modifications are considered to be within the scope of the design of the invention.
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| TW201727232A (en) * | 2016-01-22 | 2017-08-01 | Nat Univ Of Kaohsiung | Preparation method of molecularly imprinted film and its molecularly imprinted film, preparation method of molecular sensing electrode and its molecular sensing electrode and molecular sensing system and purpose thereof obtaining a molecular imprinted film with high specificity and high accuracy by selecting a particular conductive polymer and its doping mole ratio in a specific range |
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| US7122106B2 (en) * | 2002-05-23 | 2006-10-17 | Battelle Memorial Institute | Electrosynthesis of nanofibers and nano-composite films |
| TW201727232A (en) * | 2016-01-22 | 2017-08-01 | Nat Univ Of Kaohsiung | Preparation method of molecularly imprinted film and its molecularly imprinted film, preparation method of molecular sensing electrode and its molecular sensing electrode and molecular sensing system and purpose thereof obtaining a molecular imprinted film with high specificity and high accuracy by selecting a particular conductive polymer and its doping mole ratio in a specific range |
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